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Sample records for subcortical 5-ht2a receptor

  1. Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients

    DEFF Research Database (Denmark)

    Erritzoe, David; Rasmussen, Hans; Kristiansen, Klaus Nyegaard

    2008-01-01

    MRIs and PET images. The cerebellum was used as a reference region. The binding potential of specific tracer binding (BP(p)) was used as the outcome measure. No significant difference was seen in cortical receptor distribution between patients and controls. An increase in 5-HT(2A) receptor binding...

  2. Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome

    DEFF Research Database (Denmark)

    Haugbøl, Steven; Pinborg, Lars H.; Regeur, Lisbeth

    2007-01-01

    Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's syndrome, PET imagi...

  3. BDNF downregulates 5-HT(2A) receptor protein levels in hippocampal cultures

    DEFF Research Database (Denmark)

    Trajkovska, V; Santini, M A; Marcussen, Anders Bue

    2009-01-01

    Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT(2A)) have been related to depression pathology. Specific 5-HT(2A) receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT(2A) receptor level. Here we show a direct effect of BDNF...... on 5-HT(2A) receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT(2A) receptor levels were further corroborated in (BDNF +/-) mice...... with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT(2A), but not of 5-HT(1A), receptor protein levels. The BDNF-associated downregulation of 5-HT(2A) receptor levels was also observed in mature hippocampal organotypic cultures...

  4. Activation of glucocorticoid receptors increases 5-HT2A receptor levels

    DEFF Research Database (Denmark)

    Trajkovska, Viktorija; Kirkegaard, Lisbeth; Krey, Gesa

    2009-01-01

    an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased......Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker...... of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish...

  5. Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese Ay mice

    International Nuclear Information System (INIS)

    Nonogaki, Katsunori; Nozue, Kana; Oka, Yoshitomo

    2006-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A y mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A y mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A y mice, but did not increase plasma adiponectin levels

  6. Reduced 5-HT2A receptor binding in patients with mild cognitive impairment

    DEFF Research Database (Denmark)

    Hasselbalch, S G; Madsen, K; Svarer, C

    2008-01-01

    cerebral 5-HT(2A) receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT(2A) receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [(18)F......Previous studies of patients with Alzheimer's disease (AD) have described reduced brain serotonin 2A (5-HT(2A)) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms. We assessed...

  7. Ebselen has lithium-like effects on central 5-HT2A receptor function.

    Science.gov (United States)

    Antoniadou, I; Kouskou, M; Arsiwala, T; Singh, N; Vasudevan, S R; Fowler, T; Cadirci, E; Churchill, G C; Sharp, T

    2018-02-27

    Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in G q protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT 2A receptor, a G q protein coupled receptor implicated in lithium's actions. 5-HT 2A receptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT 2A receptor agonist administration. Ebselen and lithium were administered either acutely or chronically prior to assessment of 5-HT 2A receptor function. Given the SSRI augmenting action of lithium and 5-HT 2A antagonists, ebselen was also tested for this action by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT 2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690,330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen increased regional brain 5-HT synthesis and enhanced the increase in extracellular 5-HT induced by citalopram. The current data demonstrate lithium-mimetic effects of ebselen in different experimental models of 5-HT 2A receptor function, likely mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorder, including as an antidepressant augmenting agent. This article is protected by copyright. All rights reserved.

  8. 5HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice.

    Science.gov (United States)

    Amodeo, D A; Rivera, E; Cook, E H; Sweeney, J A; Ragozzino, M E

    2017-03-01

    Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT 2A receptor activity is altered in autism, while recent work indicates that systemic 5HT 2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT 2A receptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT 2A receptor blockade in the dorsomedial striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT 2A receptor antagonist, M100907 into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT 2A receptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. 5HT 2A receptor signaling in the orbitofrontal cortex may be critical for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  9. Current radiosynthesis strategies for 5-HT2A receptor PET tracers

    DEFF Research Database (Denmark)

    Herth, Matthias M; Knudsen, Gitte M

    2015-01-01

    Serotonin 2A receptors have been implicated in various psychophysiological functions and disorders such as depression, Alzheimer's disease, or schizophrenia. Therefore, neuroimaging of this specific receptor is of significant clinical interest, and it is not surprising that many attempts have been...... made to develop a suitable 5-HT2A R positron emission tomography-tracer. In this review, we give an overview on the precursor, reference compound synthesis, and the preparation of promising 5-HT2A R radiopharmaceuticals applied in positron emission tomography. We also highlight possible learning...

  10. Contribution of 5-HT2A receptors on diaphragmatic recovery after chronic cervical spinal cord injury.

    Science.gov (United States)

    Lee, Kun-Ze; Gonzalez-Rothi, Elisa J

    2017-10-01

    Unilateral C2 spinal cord hemisection (C2Hx) interrupts bulbospinal respiratory pathways innervating ipsilateral phrenic motoneurons, resulting in cessation of ipsilateral diaphragm motor output. Plasticity within the spinal neural circuitry controlling the diaphragm can induce partial recovery of phrenic bursting which correlates with the time-dependent return of spinal serotonin (5-HT) immunoreactivity in the vicinity of phrenic motoneurons. The 5-HT 2A receptor subtype is present on phrenic motoneurons and its expression is up-regulated after cervical spinal cord injury; however the functional role of these receptors following injury has not been clearly defined. The present study evaluated the functional role of 5-HT 2A receptors by testing the hypothesis that pharmacologic blockade would attenuate diaphragm activity in rats with chronic cervical spinal cord injury. Bilateral diaphragm electromyography (EMG) was performed in vagal-intact and spontaneously breathing rats before and after intravenous administration of the 5-HT 2A receptor antagonist Ketanserin (1mg/kg). Intravenous ketanserin significantly attenuated ipsilateral diaphragm EMG activity in C2Hx animals but had no impact on diaphragm output in uninjured animals. We conclude that 5-HT 2A receptor activation contributes to the recovery of ipsilateral phrenic motor output after chronic cervical spinal cord injury. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Decreased frontal serotonin 5-HT2a receptor binding index in deliberate self-harm patients

    International Nuclear Information System (INIS)

    Audenaert, K.; Laere, K. van; Dierckx, R.A.; Dumont, F.; Slegers, G.; Mertens, J.; Heeringen, C. van

    2001-01-01

    Studies of serotonin metabolites in body fluids in attempted suicide patients and of post-mortem brain tissue of suicide victims have demonstrated the involvement of the serotonergic neurotransmission system in the pathogenesis of suicidal behaviour. Recently developed neuroimaging techniques offer the unique possibility of investigating in vivo the functional characteristics of this system. In this study the 5-HT 2a receptor population of patients who had recently attempted suicide was studied by means of the highly specific radio-iodinated 5-HT 2a receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl] -5-iodo-2-methox ybenzamide or 123 I-5-I-R91150. Nine patients who had recently (1-7 days) attempted suicide and 12 age-matched healthy controls received an intravenous injection of 185 MBq 123 I-5-I-R91150 and were scanned with high-resolution brain single-photon emission tomography (SPET). Stereotactic realigned images were analysed semi-quantitatively using predefined volumes of interest. Serotonin binding capacity was expressed as the ratio of specific to non-specific activity. The cerebellum was used as a measure of non-specific activity. An age-dependent 5-HT 2a binding index was found, in agreement with previous literature. Deliberate self-harm patients had a significantly reduced mean frontal binding index after correction for age (P=0.002) when compared with controls. The reduction was more pronounced among deliberate self-injury patients (DSI) (P 2a serotonin receptor system in attempted suicide patients who are free of drugs influencing the serotonergic system shows in vivo evidence of a decreased frontal binding index of the 5-HT 2a receptor, indicating a decrease in the number and/or in the binding affinity of 5-HT 2a receptors. (orig.)

  12. The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined

    DEFF Research Database (Denmark)

    Pinborg, Lars H; Arfan, Haroon; Haugbol, Steven

    2007-01-01

    With the appropriate radiolabeled tracers, positron emission tomography (PET) enables in vivo human brain imaging of markers for neurotransmission, including neurotransmitter synthesis, receptors, and transporters. Whereas structural imaging studies have provided compelling evidence that the human...... brain anatomy is largely genetically determined, it is currently unknown to what degree neuromodulatory markers are subjected to genetic and environmental influence. Changes in serotonin 2A (5-HT(2A)) receptors have been reported to occur in various neuropsychiatric disorders and an association between...

  13. The 5-HT2A receptor antagonist M100907 produces antiparkinsonian effects and decreases striatal glutamate

    Directory of Open Access Journals (Sweden)

    Twum eAnsah

    2011-06-01

    Full Text Available 5-HT plays a regulatory role in voluntary movements of the basal ganglia and have a major impact on disorders of the basal ganglia such as Parkinson’s disease (PD. Clinical studies have suggested that 5-HT2 receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT2A receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT2A receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT2A receptors may represent a novel therapeutic target for the motor symptoms of Parkinson’s disease.

  14. Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET

    DEFF Research Database (Denmark)

    Ettrup, Anders; Palner, Mikael; Gillings, Nic

    2010-01-01

    PET brain imaging of the serotonin 2A (5-hydroxytryptamine 2A, or 5-HT(2A)) receptor has been widely used in clinical studies, and currently, several well-validated radiolabeled antagonist tracers are used for in vivo imaging of the cerebral 5-HT(2A) receptor. Access to 5-HT(2A) receptor agonist...... PET tracers would, however, enable imaging of the active, high-affinity state of receptors, which may provide a more meaningful assessment of membrane-bound receptors. In this study, we radiolabel the high-affinity 5-HT(2A) receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[(11)C-OCH(3......)]methoxybenzyl)ethanamine ((11)C-CIMBI-5) and investigate its potential as a PET tracer....

  15. 5-HT2A Serotonin Receptor Density in Adult Male Rats’ Hippocampus after Morphine-based Conditioned Place Preference

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    Rabie Mohammadi

    2016-07-01

    Conclusion: We concluded that the phenomenon of conditioned place preference induced by morphine can cause a significant increase in the number of serotonin 5-HT2A receptors in neurons of all areas of hippocampus.

  16. 4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists.

    Science.gov (United States)

    Fletcher, Stephen R; Burkamp, Frank; Blurton, Peter; Cheng, Susan K F; Clarkson, Robert; O'Connor, Desmond; Spinks, Daniel; Tudge, Matthew; van Niel, Monique B; Patel, Smita; Chapman, Kerry; Marwood, Rose; Shepheard, Sara; Bentley, Graham; Cook, Gina P; Bristow, Linda J; Castro, Jose L; Hutson, Peter H; MacLeod, Angus M

    2002-01-17

    On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.

  17. Novel spirotetracyclic zwitterionic dual H(1)/5-HT(2A) receptor antagonists for the treatment of sleep disorders.

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    Gianotti, Massimo; Botta, Maurizio; Brough, Stephen; Carletti, Renzo; Castiglioni, Emiliano; Corti, Corrado; Dal-Cin, Michele; Delle Fratte, Sonia; Korajac, Denana; Lovric, Marija; Merlo, Giancarlo; Mesic, Milan; Pavone, Francesca; Piccoli, Laura; Rast, Slavko; Roscic, Maja; Sava, Anna; Smehil, Mario; Stasi, Luigi; Togninelli, Andrea; Wigglesworth, Mark J

    2010-11-11

    Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.

  18. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF(2L/2LCk-cre)). A severe impairment...... specific for the serotonin 2A receptor (5-HT(2A)R) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT(2A)Rs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered...... was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT(2A) and 5-HT(1A) mRNA expression but normal 5-HT(2C) content in these brain regions in BDNF(2L/2LCk-cre) mice. We investigated whether the reduction in frontal 5-HT(2A...

  19. Intrahippocampal LSD accelerates learning and desensitizes the 5-HT(2A) receptor in the rabbit, Romano et al.

    Science.gov (United States)

    Romano, Anthony G; Quinn, Jennifer L; Li, Luchuan; Dave, Kuldip D; Schindler, Emmanuelle A; Aloyo, Vincent J; Harvey, John A

    2010-10-01

    Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT(2A) receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT(2A)-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning. This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT(2A)-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning. LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT(2A) receptor as measured by a decrease in DOI-elicited head bobs. Acute parenteral or intrahippocampal LSD elicited a 5-HT(2A) but not a 5-HT(2C)-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls. LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT(2A) receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT(2A) receptor within the hippocampus as a result of repeated administration of its agonist (LSD).

  20. Stimulation of 5-HT2A receptors recovers sensory responsiveness in acute spinal neonatal rats.

    Science.gov (United States)

    Swann, Hillary E; Kauer, Sierra D; Allmond, Jacob T; Brumley, Michele R

    2017-02-01

    Quipazine is a 5-HT 2A -receptor agonist that has been used to induce motor activity and promote recovery of function after spinal cord injury in neonatal and adult rodents. Sensory stimulation also activates sensory and motor circuits and promotes recovery after spinal cord injury. In rats, tail pinching is an effective and robust method of sacrocaudal sensory afferent stimulation that induces motor activity, including alternating stepping. In this study, responsiveness to a tail pinch following treatment with quipazine (or saline vehicle control) was examined in spinal cord transected (at midthoracic level) and intact neonatal rats. Rat pups were secured in the supine posture with limbs unrestricted. Quipazine or saline was administered intraperitoneally and after a 10-min period, a tail pinch was administered. A 1-min baseline period prior to tail-pinch administration and a 1-min response period postpinch was observed and hind-limb motor activity, including locomotor-like stepping behavior, was recorded and analyzed. Neonatal rats showed an immediate and robust response to sensory stimulation induced by the tail pinch. Quipazine recovered hind-limb movement and step frequency in spinal rats back to intact levels, suggesting a synergistic, additive effect of 5-HT-receptor and sensory stimulation in spinal rats. Although levels of activity in spinal rats were restored with quipazine, movement quality (high vs. low amplitude) was only partially restored. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  1. G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations

    DEFF Research Database (Denmark)

    Ísberg, Vignir; Balle, Thomas; Sander, Tommy

    2011-01-01

    molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability......A 5-HT(2A) receptor model was constructed by homology modeling based on the ß(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(aq) peptide in four subsequent steered...

  2. 5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Ferguson, Marcus C; Nayyar, Tultul; Deutch, Ariel Y; Ansah, Twum A

    2010-01-01

    Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease. Published by Elsevier Ltd.

  3. 5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease

    OpenAIRE

    Ferguson, Marcus C.; Nayyar, Tultul; Deutch, Ariel Y.; Ansah, Twum A.

    2010-01-01

    Clinical observations have suggested that ritanserin, a 5-HT2A/C receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT2A receptor antagonist M100907 and the selective 5-HT2C receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited...

  4. MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor

    Directory of Open Access Journals (Sweden)

    Drew J. Puxty

    2017-07-01

    Full Text Available Previous research has shown that a single dose of MDMA induce a dissociative state, by elevating feelings of depersonalization and derealization. Typically, it is assumed that action on the 5-HT2A receptor is the mechanism underlying these psychedelic experiences. In addition, other studies have shown associations between dissociative states and biological parameters (heart rate, cortisol, which are elevated by MDMA. In order to investigate the role of the 5-HT2 receptor in the MDMA-induced dissociative state and the association with biological parameters, a placebo-controlled within-subject study was conducted including a single oral dose of MDMA (75 mg, combined with placebo or a single oral dose of the 5-HT2 receptor blocker ketanserin (40 mg. Twenty healthy recreational MDMA users filled out a dissociative states scale (CADSS 90 min after treatments, which was preceded and followed by assessment of a number of biological parameters (cortisol levels, heart rate, MDMA blood concentrations. Findings showed that MDMA induced a dissociative state but this effect was not counteracted by pre-treatment with ketanserin. Heart rate was the only biological parameter that correlated with the MDMA-induced dissociative state, but an absence of correlation between these measures when participants were pretreated with ketanserin suggests an absence of directional effects of heart rate on dissociative state. It is suggested that the 5-HT2 receptor does not mediate the dissociative effects caused by a single dose of MDMA. Further research is needed to determine the exact neurobiology underlying this effect and whether these effects contribute to the therapeutic potential of MDMA.

  5. Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

    International Nuclear Information System (INIS)

    Herth, Matthias M.; Petersen, Ida Nymann; Hansen, Hanne Demant; Hansen, Martin; Ettrup, Anders; Jensen, Anders A.; Lehel, Szabolcs; Dyssegaard, Agnete; Gillings, Nic; Knudsen, Gitte M.

    2016-01-01

    Introduction: The serotonin 2A receptor (5-HT 2A R) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT 2A R PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT 2A R agonist PET tracer, [ 11 C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an 18 F-labeled 5-HT 2A R agonist PET-ligand. Methods and results: Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT 2A agonists. 18 F-labeling of the appropriate precursors was performed using [ 18 F]FETos, typically yielding 0.2–2.0 GBq and specific activities of 40–120 GBq/μmol. PET studies in Danish landrace pigs revealed that [ 18 F]1 displayed brain uptake in 5-HT 2A R rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT 2A R selective antagonist. [ 18 F]2 and [ 18 F]3 showed very low brain uptake. Conclusion: None of the investigated 18 F-labeled Cimbi-36 derivatives [ 18 F]1, [ 18 F]2 and [ 18 F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT 2A R. Although for [ 18 F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT 2A R antagonist.

  6. Acute social defeat does not alter cerebral 5-HT2A receptor binding in male Wistar rats

    DEFF Research Database (Denmark)

    Visser, Anniek K D; Meerlo, Peter; Ettrup, Anders

    2014-01-01

    suppressed growth, but did not affect anxiety-like behavior in an open field test. A positron emission tomography scan with the 5-HT2A R tracer [11C]MDL 100907 1 day and 3 weeks after defeat did not show significant changes in receptor binding. To verify these results, [3H]MDL 100907 binding assays were...

  7. The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

    Science.gov (United States)

    Lin, Olivia A.; Karim, Zubair A.; Vemana, Hari Priya; Espinosa, Enma V. P.; Khasawneh, Fadi T.

    2014-01-01

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their

  8. MDMA Increases Excitability in the Dentate Gyrus: Role of 5HT2A Receptor Induced PGE2 Signaling

    Science.gov (United States)

    Collins, Stuart A.; Huff, Courtney; Chiaia, Nicolas; Gudelsky, Gary A.; Yamamoto, Bryan K.

    2015-01-01

    MDMA is a widely abused psychostimulant which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA treated rats which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA treated rats. PMID:26670377

  9. The effect of citalopram hydrobromide on 5-HT2A receptors in the impulsive-aggressive dog, as measured with 123I-5-I-R91150 SPECT

    International Nuclear Information System (INIS)

    Peremans, K.; Hoybergs, Y.; Gielen, I.; Audenaert, K.; Vervaet, M.; Heeringen, C. van; Otte, A.; Goethals, I.; Dierckx, R.; Blankaert, P.

    2005-01-01

    Involvement of the serotonergic system in impulsive aggression has been demonstrated in both human and animal studies. The purpose of the present study was to investigate the effect of citalopram hydrobromide (a selective serotonin re-uptake inhibitor) on the 5-HT 2A receptor and brain perfusion in impulsive-aggressive dogs by means of single-photon emission computed tomography. The binding index of the radioligand 123 I-5-I-R91150 was measured before and after treatment with citalopram hydrobromide in nine impulsive-aggressive dogs. Regional perfusion was measured with 99m Tc-ethyl cysteinate dimer (ECD). Behaviour was assessed before treatment and again after 6 weeks of treatment. A correlation was found between decreased binding and behavioural improvement in eight out of nine dogs. The 5-HT 2A receptor binding index was significantly reduced after citalopram hydrobromide treatment in all cortical regions but not in the subcortical area. None of the dogs displayed alterations in perfusion on the post-treatment scans. This study supports previous findings regarding the involvement of the serotonergic system in impulsive aggression in dogs in general. More specifically, the effect of treatment on the 5-HT 2A receptor binding index could be demonstrated and the decreased binding index correlated with behavioural improvement. (orig.)

  10. Distribution of 5HT2A receptors in the human brain: Comparison of data in vivo and post mortem

    International Nuclear Information System (INIS)

    Forutan, F.; Estalji, S.; Beu, M.; Nikolaus, S.; Vosberg, H.; Mueller-Gaertner, H.W.; Larisch, R.; Hamacher, K.; Coenen, H.H.

    2002-01-01

    Aim: The study presented here firstly compars the distribution of the binding potential of the serotonin-5HT 2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated. Methods: Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT 2A ligand 18 F-altanserin. The binding potential was quantified in 12 regions using Logan's graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature. Results: The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p 18 F-altanserin and PET in healthy volunteers and the true autoradiographically determined distribution of 5HT 2A receptors in human brains. The in vivo method seems to be sensitive enough to detect changes in receptor density of more than 18%. (orig.)

  11. Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor

    Science.gov (United States)

    Walterscheid, Jeffrey P.; Nghiem, Dat X.; Kazimi, Nasser; Nutt, Leta K.; McConkey, David J.; Norval, Mary; Ullrich, Stephen E.

    2006-01-01

    Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor. PMID:17085585

  12. Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice.

    Science.gov (United States)

    Moreno, José L; Holloway, Terrell; Rayannavar, Vinayak; Sealfon, Stuart C; González-Maeso, Javier

    2013-03-01

    Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT(2A) receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT(2A) agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT(2A) receptor-dependent hallucinogenic effects of LSD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Chronic treatment with LY341495 decreases 5-HT2A receptor binding and hallucinogenic effects of LSD in mice

    Science.gov (United States)

    Moreno, José L.; Holloway, Terrell; Rayannavar, Vinayak; Sealfon, Stuart C.; González-Maeso, Javier

    2013-01-01

    Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT2A receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24 mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5 mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [3H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT2A agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT2A receptor-dependent hallucinogenic effects of LSD. PMID:23333599

  14. Central Serotonin-2A (5-HT2A Receptor Dysfunction in Depression and Epilepsy: The Missing Link?

    Directory of Open Access Journals (Sweden)

    Bruno Pierre Guiard

    2015-03-01

    Full Text Available 5-Hydroxytryptamine 2A receptors (5-HT2A-Rs are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses.

  15. Effects of Constant Flickering Light on Refractive Status, 5-HT and 5-HT2A Receptor in Guinea Pigs.

    Science.gov (United States)

    Li, Bing; Luo, Xiumei; Li, Tao; Zheng, Changyue; Ji, Shunmei; Ma, Yuanyuan; Zhang, Shuangshuang; Zhou, Xiaodong

    2016-01-01

    To investigate the effects of constant flickering light on refractive development, the role of serotonin (i.e.5-hydroxytryptamine, 5-HT)and 5-HT2A receptor in myopia induced by flickering light in guinea pigs. Forty-five guinea pigs were randomly divided into three groups: control, form deprivation myopia (FDM) and flickering light induced myopia (FLM) groups(n = 15 for each group). The right eyes of the FDM group were covered with semitransparent hemispherical plastic shells serving as eye diffusers. Guinea pigs in FLM group were raised with illumination of a duty cycle of 50% at a flash frequency of 0.5Hz. The refractive status, axial length (AL), corneal radius of curvature(CRC) were measured by streak retinoscope, A-scan ultrasonography and keratometer, respectively. Ultramicroscopy images were taken by electron microscopy. The concentrations of 5-HTin the retina, vitreous body and retinal pigment epithelium (RPE) were assessed by high performance liquid chromatography, the retinal 5-HT2A receptor expression was evaluated by immunohistofluorescence and western blot. The refraction of FDM and FLM eyes became myopic from some time point (the 4th week and the 6th week, respectively) in the course of the experiment, which was indicated by significantly decreased refraction and longer AL when compared with the controls (plight could cause progressive myopia in guinea pigs. 5-HT and 5-HT2A receptor increased both in form deprivation myopia and flickering light induced myopia, indicating that 5-HT possibly involved in myopic development via binding to5-HT2A receptor.

  16. Convergent [18]F-labeling and evaluation of N-benzyl-phenethylamines as 5-HT2A receptor PET ligands

    DEFF Research Database (Denmark)

    Petersen, Ida Nymann; Villadsen, Jonas; Hansen, Hanne Demant

    2016-01-01

    Positron emission tomography (PET) investigations of the 5-HT2A receptor (5-HT2AR) system can be used as a research tool in diseases such as depression, Alzheimer's disease and schizophrenia. We have previously developed a (11)C-labeled agonist PET ligand ([(11)C]Cimbi-36), and the aim of this st......Positron emission tomography (PET) investigations of the 5-HT2A receptor (5-HT2AR) system can be used as a research tool in diseases such as depression, Alzheimer's disease and schizophrenia. We have previously developed a (11)C-labeled agonist PET ligand ([(11)C]Cimbi-36), and the aim...... of this study was to identify a (18)F-labeled analogue of this PET-ligand. Thus, we developed a convergent radiochemical approach giving easy access to 5 different (18)F-labeled ligands structurally related to Cimbi-36 from a common (18)F-labeled intermediate. After intravenous injection, all ligands entered...... the pig brain. However, since within-scan intervention with ketanserin, a known orthosteric 5-HT2A receptor antagonist, did not result in significant blocking, the radioligands seem unsuitable for neuroimaging of the 5-HT2AR in vivo....

  17. Association of 5-HT2A receptor gene polymorphisms with gastrointestinal disorders in Egyptian children with autistic disorder.

    Science.gov (United States)

    Abdelrahman, Hadeel M; Sherief, Laila M; Alghobashy, Ashgan A; Abdel Salam, Sanaa M; Hashim, Haitham M; Abdel Fattah, Nelly R; Mohamed, Randa H

    2014-11-12

    Gastrointestinal disturbances (GID) are frequently reported in children with autism spectrum disorders (ASD). Recently, mounting evidence suggests that there may be a genetic link for autism with gastrointestinal disturbances. We aimed to investigate whether there were any association between the -1438A/G, 102T/C and His452Tyr polymorphisms of the serotonin 2A receptor gene (5-HT2A) in Egyptian children with ASD and GID. Eighty children with autistic disorder and 100 healthy control children were examined. -1438A/G, 102T/C and His452Tyr polymorphisms of 5-HT2A were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant increase of the G allele and the GG genotype of the -1438A/G polymorphism was observed in children with autism than control, but there were no significant differences in the frequencies either of the 102T/C genotype or His452Tyr genotype between the two groups. There was a significant increase of homozygote A allele of the -1438A/G and CC genotype of the 102T/C polymorphism in ASD children with GID. This study supports the possible involvement of the 5-HT2A receptor in the development of ASD and associated GID. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Cannabis Users Show Enhanced Expression of CB1-5HT2A Receptor Heteromers in Olfactory Neuroepithelium Cells.

    Science.gov (United States)

    Galindo, Liliana; Moreno, Estefanía; López-Armenta, Fernando; Guinart, Daniel; Cuenca-Royo, Aida; Izquierdo-Serra, Mercè; Xicota, Laura; Fernandez, Cristina; Menoyo, Esther; Fernández-Fernández, José M; Benítez-King, Gloria; Canela, Enric I; Casadó, Vicent; Pérez, Víctor; de la Torre, Rafael; Robledo, Patricia

    2018-01-02

    Cannabinoid CB1 receptors (CB 1 R) and serotonergic 2A receptors (5HT 2A R) form heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB 1 R-5HT 2A R heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na + currents in patch clamp recordings. Interestingly, CB 1 R-5HT 2A R heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB 1 R-5HT 2A R heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.

  19. 5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex

    Science.gov (United States)

    Morici, Juan Facundo; Miranda, Magdalena; Gallo, Francisco Tomás; Zanoni, Belén; Bekinschtein, Pedro

    2018-01-01

    Context-dependent memories may guide adaptive behavior relaying in previous experience while updating stored information through reconsolidation. Retrieval can be triggered by partial and shared cues. When the cue is presented, the most relevant memory should be updated. In a contextual version of the object recognition task, we examined the effect of medial PFC (mPFC) serotonin 2a receptor (5-HT2aR) blockade during retrieval in reconsolidation of competing objects memories. We found that mPFC 5-HT2aR controls retrieval and reconsolidation of object memories in the perirhinal cortex (PRH), but not in the dorsal hippocampus in rats. Also, reconsolidation of objects memories in PRH required a functional interaction between the ventral hippocampus and the mPFC. Our results indicate that in the presence of conflicting information at retrieval, mPFC 5-HT2aR may facilitate top-down context-guided control over PRH to control the behavioral response and object memory reconsolidation. PMID:29717980

  20. Gender and the use of hormonal contraception in women are not associated with cerebral cortical 5-HT 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, V G; Erritzoe, D; Madsen, J

    2009-01-01

    to frontolimbic 5-HT(2A) receptor binding and to be more pronounced in women, again, the effect of gender was not significant (P=0.42, n=127). Also, the use of hormonal contraception (n=14) within the group of pre-menopausal women (total n=29) was not associated with cortical 5-HT(2A) receptor binding (P=0.......31). In conclusion, neither gender, nor the use of hormonal contraception in premenopausal women was associated with cortical 5-HT(2A) receptor binding....... binding it is not clear if gender or use of hormonal contraception exhibits associations with 5-HT(2A) receptor binding. We found no significant effect of gender on cortical 5-HT(2A) receptor binding (P=0.15, n=132). When adjusting for the personality trait neuroticism, known to be positively correlated...

  1. Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

    DEFF Research Database (Denmark)

    Herth, Matthias M; Petersen, Ida Nymann; Hansen, Hanne Demant

    2016-01-01

    INTRODUCTION: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins...... to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/μmol. PET studies in Danish landrace pigs revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake...

  2. Longitudinal assessment of cerebral 5-HT2A receptors in healthy elderly volunteers: an [18F]-altanserin PET study

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Knudsen, Gitte M; Haugbøl, Steven

    2009-01-01

    patients with neuropsychiatric diseases on a longitudinal basis. METHODS: [(18)F]-Altanserin PET was used to quantify 5-HT(2A) receptors in 12 healthy elderly individuals at baseline and at 2 years in six volumes of interest. A bolus/infusion protocol was used to achieve the binding potential, BP(P...... of our measurements over 2 years with the stability of data from an earlier study with 2-week test-retest measurements. RESULTS: BP(P) was unaltered at follow-up without the use of PV correction and when applying two-tissue PV correction, test-retest reproducibility was 12-15% and reliability 0...

  3. 5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

    Directory of Open Access Journals (Sweden)

    Minal Jaggar

    2017-12-01

    Full Text Available Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC and hippocampus in 5-HT2A receptor knockout (5-HT2A−/− and wild-type mice of both sexes. While 5-HT2A−/− male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2A−/− female mice with a hyperlipidemic baseline phenotype. 5-HT2A−/− male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2, trophic factors (Bdnf, Igf1 and immediate early genes (IEGs (Arc, Fos, Fosb, Egr1-4 in the PFC and hippocampus were altered in 5-HT2A−/− mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic. Keywords: 5-HT2A−/− mice, Prefrontal cortex, Hippocampus, Gene expression, Sexual dimorphism, Despair

  4. A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans

    DEFF Research Database (Denmark)

    Erritzoe, David; Holst, Klaus; Frokjaer, Vibe G.

    2010-01-01

    Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT2A) receptor and the presynaptic serotonin transporter (SERT) are sensitive...... tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT2A receptor binding. An inverted U-shaped relationship between the 5-HT2A receptor and the SERT binding was identified. The observed regional intercorrelation...

  5. Trait aggression and trait impulsivity are not related to frontal cortex 5-HT2A receptor binding in healthy individuals

    DEFF Research Database (Denmark)

    da Cunha-Bang, Sophie; Stenbæk, Dea Siggaard; Holst, Klaus

    2013-01-01

    age 47.0±18.7, range 23-86) to determine if trait aggression and trait impulsivity were related to frontal cortex 5-HT2A receptor binding (5-HT2AR) as measured with [(18)F]-altanserin PET imaging. Trait aggression and trait impulsivity were assessed with the Buss-Perry Aggression Questionnaire (AQ...... and the AQ or BIS-11 total scores. Also, there was no significant interaction between gender and frontal cortex 5-HT2AR in predicting trait aggression and trait impulsivity. This is the first study to examine how 5-HT2AR relates to trait aggression and trait impulsivity in a large sample of healthy......Numerous studies indicate that the serotonergic (5-HT) transmitter system is involved in the regulation of impulsive aggression and there is from post-mortem, in vivo imaging and genetic studies evidence that the 5-HT2A receptor may be involved. We investigated 94 healthy individuals (60 men, mean...

  6. Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice

    Directory of Open Access Journals (Sweden)

    Katsunori Nonogaki

    2018-01-01

    Full Text Available A recent report suggested that brain-derived serotonin (5-HT is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1 receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph inhibitor p-chlorophenylalanine (PCPA for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high-affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors.

  7. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding....

  8. Polimorfismos dos genes do receptor de serotonina (5-HT2A e da catecol-O-metiltransferase (COMT: fatores desencadeantes da fibromialgia? Serotonin receptor (5-HT 2A and catechol-O-methyltransferase (COMT gene polymorphisms: Triggers of fibromyalgia?

    Directory of Open Access Journals (Sweden)

    Josie Budag Matsuda

    2010-04-01

    Full Text Available INTRODUÇÃO: A fibromialgia é uma síndrome reumática caracterizada por dor difusa e crônica associada a fadiga, insônia, ansiedade, depressão, perda de memória e tontura. Embora os mecanismos fisiológicos que controlam a fibromialgia não tenham sido estabelecidos, fatores neuroendócrinos, genéticos ou moleculares podem estar envolvidos. OBJETIVO: O objetivo do presente estudo foi caracterizar os polimorfismos dos genes do receptor de serotonina (5-HT2A e da catecolO-metiltransferase (COMT em pacientes brasileiros com fibromialgia, a fim de avaliar sua participação na etiologia da doença. MATERIAL E MÉTODOS: O DNA genômico extraído de 102 amostras de sangue (51 pacientes, 51 controles foi usado para a caracterização molecular dos polimorfismos dos genes 5-HT2A e COMT, por meio de PCR-RFLP. RESULTADOS: A análise molecular dos polimorfismos do gene 5-HT2A demonstrou frequências de 25,49% C/C, 49,02% T/C e 25,49% T/T, nos pacientes com fibromialgia, e 17,65% C/C, 62,74% T/C e 19,61% T/T, no grupo controle, não apresentando diferença significativa entre o grupo de pacientes e o grupo controle. Os polimorfismos do gene da COMT em pacientes com fibromialgia apresentaram uma frequência de 17,65% e 45,10% para os genótipos H/H e L/H, respectivamente. No grupo controle, as frequências foram de 29,42%, para H/H, e 60,78%, para L/H, sem diferença significativa entre ambos os grupos. Entretanto, houve diferença significativa na frequência do genótipo L/L em pacientes (37,25% e controles (9,8%, o que permitiu a diferenciação entre os dois grupos. CONCLUSÃO: A frequência do genótipo L/L foi maior nos pacientes com fibromialgia. Apesar de a fibromialgia envolver uma situação poligênica e fatores ambientais, o estudo molecular do SNP rs4680 do gene da COMT pode auxiliar a identificação de indivíduos suscetíveis.INTRODUCTION: Fibromyalgia is a rheumatic syndrome characterized by diffuse and chronic pain associated with

  9. Impulsive traits and 5-HT2A receptor promoter polymorphism in alcohol dependents: Possible association but no influence of personality disorders

    OpenAIRE

    Preuss, Ulrich W.; Koller, G.; Bondy, Brigitta; Bahlmann, Miriam; Soyka, Michael

    2001-01-01

    Objective: Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impu...

  10. Specific in vivo binding in the rat brain of [18F]RP 62203: A selective 5-HT2A receptor radioligand for positron emission tomography

    International Nuclear Information System (INIS)

    Besret, Laurent; Dauphin, Francois; Huard, Cecile; Lasne, Marie-Claire; Vivet, Richard; Mickala, Patrick; Barbelivien, Alexandra; Baron, Jean-Claude

    1996-01-01

    In vivo pharmacokinetic and brain binding characteristics of [ 18 F]RP 62203, a selective high-affinity serotonergic 5-HT 2A receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 ± 0.07% injected dose/g, % ID/g and 0.08 ± 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT 2A receptor. Furthermore, specific [ 18 F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT 2A receptors, but not with known concentration profiles of dopaminergic D 2 or adrenergic α 1 receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT 2A antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [ 18 F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT 2A brain receptors in vivo with positron emission tomography

  11. Decreased hippocampal 5-HT2A receptors in post mortem tissue from schizophrenic but not bipolar subjects

    International Nuclear Information System (INIS)

    Scarr, E.; Pavey, G.; Bradbury, R.; Copolov, D.L.; Dean, B.

    2001-01-01

    Full text: The hippocampus is important in cognition and sensory gating,both of which are thought to be impaired in schizophrenia. Since 5HT has also been implicated in cognition we investigated the hippocampal serotonergic system in subjects with either schizophrenia or bipolar mood disorder. Using autoradiography,we found significant (p 3 H] ketanserin binding in the CA3 (Mean ±SEM:29.6 ± 4.0 vs.46.6 ± 4.2 fmol/mgETE), the stratum radiatum (27.3 ± 2.7 vs.38.7 ± 3.9 fmol/mgETE) and pyramidal cell layer (35.6 ± 3.4 vs.51.4 ± 2.7 fmol/ mgETE) of CA1 as well as the outer (8.3 ± 1.5 vs.12.2 ± 1.4 fmol/mgETE) and pyramidal cell layer (16.4 ± 2.5 vs.32.1 ± 3.2 fmol/mgETE) of the subiculum in hippocampal tissue from schizophrenic subjects. No such differences were found in the dentate gyrus or CA2 region from schizophrenia subjects or in any hippocampal region from bipolar subjects. The lack of change in the bipolar cohort suggests that the decreased density of hippocampal 5-HT 2A receptors is disease specific and not a result of neuroleptic treatment, which both cohorts received. Copyright (2001) Australian Neuroscience Society

  12. Synergistic effect of 5-HT2A receptor gene and MAOA gene on the negative emotion of patients with depression.

    Science.gov (United States)

    Guo, Huirong; Ren, Yuming; Zhao, Ning; Wang, Yali; Li, Shuying; Cui, He; Zhang, Sijia; Zhang, Jianhua

    2014-07-01

    To analyse the synergistic effect of polymorphism of the tandem repeat sequence u-VNTR of 5-hydroxytryptamine 2A (5-HT2A) receptor gene and monoamine oxidase A (MAOA) gene on the negative emotion in frontal lobe of patients with depression through functional magnetic resonance imaging (fMRI) technique. Functional magnetic resonance imaging scanning was performed for 72 patients with depression and 70 gender, age-matched healthy people with physical examination under negative emotion recognition task. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was adopted to analyse genotype. The superior, middle and inferior gyrus of bilateral frontal lobe was regarded as the brain region of interest, and then the difference of activation intensity in frontal lobe subregion between control groups and patient groups with different genotypes, and the interaction between the two kinds of polymorphism were compared. The activation intensity in right frontal middle gyrus of patients with CC genotype increased obviously compared with TT and TC genotype patient groups and TT genotype control group (Peffect of the two genotypes on the activation abnormality of negative emotion recognition in right frontal middle gyrus (F = 6·18, P = 0·029). The negative activation in right frontal middle gyrus of patients with CC+H genotypes increased most obviously (Peffect on the activity abnormality when recognizing negative emotion in right frontal middle gyrus of patients with depression. © 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

  13. Synthesis, radiofluorination, and preliminary evaluation of the potential 5-HT2A receptor agonists [18 F]Cimbi-92 and [18 F]Cimbi-150

    DEFF Research Database (Denmark)

    Edgar, Fraser Graeme; Hansen, Hanne D; Leth-Petersen, Sebastian

    2017-01-01

    An agonist PET tracer is of key interest for the imaging of the 5-HT2A receptor, as exemplified by the previously reported success of [11 C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an 18 F-labelled ......An agonist PET tracer is of key interest for the imaging of the 5-HT2A receptor, as exemplified by the previously reported success of [11 C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an 18 F......-labelled agonist 5-HT2A receptor (5-HT2A R) tracer is highly sought after. Herein, we report a 2-step, 1-pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5-HT2A R. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled...

  14. Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT2A) receptors in older, healthy adults

    International Nuclear Information System (INIS)

    Chow, Tiffany W; Mamo, David C; Uchida, Hiroyuki; Graff-Guerrero, Ariel; Houle, Sylvain; Smith, Gwenn S; Pollock, Bruce G; Mulsant, Benoit H

    2009-01-01

    Position emission tomography (PET) imaging using [ 18 F]-setoperone to quantify cortical 5-HT 2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT 2A receptor (5HT 2A R) binding potential. The purpose of this study was to assess the test-retest variability of [ 18 F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT 2A R availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65–78 years) completed two [ 18 F]-setoperone PET scans on two separate occasions 5–16 weeks apart. The average difference in the binding potential (BP ND ) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions. We conclude that the test-retest variability of [ 18 F]-setoperone PET in elderly subjects is comparable to that of [ 18 F]-setoperone and other 5HT 2A R radiotracers in younger subject samples

  15. Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity

    Directory of Open Access Journals (Sweden)

    Darya V. Bazovkina

    2015-01-01

    Full Text Available In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors.

  16. Relationship of obstructive sleep apnea syndrome with the 5-HT2A receptor gene in Brazilian patients.

    Science.gov (United States)

    de Carvalho, Thiago Bittencourt Ottoni; Suman, Marcela; Molina, Fernando Drimel; Piatto, Vânia Belintani; Maniglia, José Victor

    2013-03-01

    Serotonin (5-HT) regulates a variety of visceral and physiological functions, including sleep. Polymorphisms in the 5-HT2A receptor gene can alter its transcription, affecting the number of receptors in the serotoninergic system, contributing to obstructive sleep apnea syndrome (OSAS). The aim of this study was to determine the prevalence of the 102T-C and -1438G-A polymorphisms in the 5-HTR2A gene in Brazilian patients with and without OSAS. A cross-sectional study performed at the Otorhinolaryngology and Sleep Disorder Out Clinics, São José do Rio Preto Medical School, FAMERP. One hundred patients were examined as index cases and 100 persons as controls, of both genders to both groups. DNA was extracted from peripheral blood leukocytes, and the sites that encompassed both polymorphisms were amplified by PCR-RFLP. There was a significant prevalence of the male gender in index cases compared with the control group gender (p < 0.0001). There was no significant genotypic difference in the 102T-C polymorphism between the case and control groups (p = 1.000). The AA genotype of the -1438G-A polymorphism was more prevalent in the patients with OSAS compared with the controls (OR, 2.3; CI 95% 1.20-4.38; p = 0.01). There was no difference in the prevalence of the 102T-C polymorphism between patients with OSAS and the control group. Serotoninergic system dysfunction appeared to be related to OSAS. The -1438G-A polymorphism and OSAS are related in this studied Brazilian population.

  17. Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites.

    Science.gov (United States)

    Buchborn, Tobias; Schröder, Helmut; Dieterich, Daniela C; Grecksch, Gisela; Höllt, Volker

    2015-03-15

    Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding.

    Science.gov (United States)

    Kanagarajadurai, Karuppiah; Malini, Manoharan; Bhattacharya, Aditi; Panicker, Mitradas M; Sowdhamini, Ramanathan

    2009-12-01

    The serotonergic system has been implicated in emotional and cognitive function. In particular, 5-HT(2A) (5-hydroxytrytamine receptor 2A) is attributed to a number of disorders like schizophrenia, depression, eating disorders and anxiety. 5-HT(2A), being a GPCR (G-protein coupled receptor), is important in the pharmaceutical industry as a proven target for these disorders. Despite their extensive clinical importance, the structural studies of this protein is lacking due to difficulties in determining its crystal structure. We have performed sequence analysis and molecular modeling of 5-HT(2A) that has revealed a set of conserved residues and motifs considered to play an important role in maintaining structural integrity and function of the receptor. The analysis also revealed a set of residues specific to the receptor which distinguishes them from other members of the subclass and their orthologs. Further, starting from the model structure of human 5-HT(2A) receptor, docking studies were attempted to envisage how it might interact with eight of its ligands (such as serotonin, dopamine, DOI, LSD, haloperidol, ketanserin, risperidone and clozapine). The binding studies of dopamine to 5-HT(2A) receptor can bring up better understanding in the etiology of a number of neurological disorders involving both these two receptors. Our sequence analysis and study of interactions of this receptor with other ligands reveal additional residue hotspots such as Asn 363 and Tyr 370. The function of these residues can be further analyzed by rational design of site-directed mutagenesis. Two distinct binding sites are identified which could play important roles in ligand binding and signaling.

  19. Long-term estrogen therapy and 5-HT(2A) receptor binding in postmenopausal women; a single photon emission tomography (SPET) study

    NARCIS (Netherlands)

    Compton, J.; Travis, M. J.; Norbury, R.; Erlandsson, K.; van Amelsvoort, T.; Daly, E.; Waddington, W.; Matthiasson, P.; Eersels, J. L. H.; Whitehead, M.; Kerwin, R. W.; Ell, P. J.; Murphy, D. G. M.

    2008-01-01

    Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT(2A) receptor in human

  20. A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables

    DEFF Research Database (Denmark)

    Adams, Karen H; Pinborg, Lars H; Svarer, Claus

    2004-01-01

    This study presents the results of an analysis of 5-hydroxytryptamine (5-HT)(2A) receptors in 52 healthy subjects. Thirty men and twenty-two women aged between 21 and 79 years were investigated with magnetic resonance imaging (MRI) and [(18)F]-altanserin positron emission tomography (PET). The di...

  1. An immunocapture/scintillation proximity analysis of G alpha q/11 activation by native serotonin (5-HT)2A receptors in rat cortex: blockade by clozapine and mirtazapine.

    Science.gov (United States)

    Mannoury La Cour, C; Chaput, C; Touzard, M; Millan, M J

    2009-02-01

    Though transduction mechanisms recruited by heterologously expressed 5-HT(2A) receptors have been extensively studied, their interaction with specific subtypes of G-protein remains to be directly evaluated in cerebral tissue. Herein, as shown by an immunocapture/scintillation proximity analysis, 5-HT, the prototypical 5-HT(2A) agonist, DOI, and Ro60,0175 all enhanced [(35)S]GTPgammaS binding to G alpha q/11 in rat cortex with pEC(50) values of 6.22, 7.24 and 6.35, respectively. No activation of G o or G s/olf was seen at equivalent concentrations of DOI. Stimulation of G alpha q/11 by 5-HT (30 microM) and DOI (30 microM) was abolished by the selective 5-HT(2A) vs. 5-HT(2C)/5-HT(2B) antagonists, ketanserin (pK(B) values of 9.11 and 8.88, respectively) and MDL100,907 (9.82 and 9.68). By contrast, 5-HT-induced [(35)S]GTPgammaS binding to G alpha q/11 was only weakly inhibited by the preferential 5-HT(2C) receptor antagonists, RS102,221 (6.94) and SB242,084 (7.39), and the preferential 5-HT(2B) receptor antagonist, LY266,097 (6.66). The antipsychotic, clozapine, which had marked affinity for 5-HT(2A) receptors, blocked the recruitment of G alpha q/11 by 5-HT and DOI with pK(B) values of 8.54 and 8.14, respectively. Its actions were mimicked by the "atypical" antidepressant and 5-HT(2A) receptor antagonist, mirtazapine, which likewise blocked 5-HT and DOI-induced G alpha q/11 protein activation with pK(B) values of 7.90 and 7.76, respectively. In conclusion, by use of an immunocapture/scintillation proximity strategy, this study shows that native 5-HT(2A) receptors in rat frontal cortex specifically recruit G alpha q/11 and that this action is blocked by clozapine and mirtazapine. Quantification of 5-HT(2A) receptor-mediated G alpha q/11 activation in frontal cortex should prove instructive in characterizing the actions of diverse classes of psychotropic agent. 2008 Wiley-Liss, Inc.

  2. 5-HT2A receptors in the feline brain: 123I-5-I-R91150 kinetics and the influence of ketamine measured with micro-SPECT.

    Science.gov (United States)

    Waelbers, Tim; Polis, Ingeborgh; Vermeire, Simon; Dobbeleir, André; Eersels, Jos; De Spiegeleer, Bart; Audenaert, Kurt; Slegers, Guido; Peremans, Kathelijne

    2013-08-01

    Subanesthetic doses of ketamine can be used as a rapid-acting antidepressant in patients with treatment-resistant depression. Therefore, the brain kinetics of (123)I-5-I-R91150 (4-amino-N-[1-[3-(4-fluorophenyl)propyl]-4-methylpiperidin-4-yl]-5-iodo-2-methoxybenzamide) and the influence of ketamine on the postsynaptic serotonin-2A receptor (5-hydroxytryptamine-2A, or 5-HT2A) status were investigated in cats using micro-SPECT. This study was conducted on 6 cats using the radioligand (123)I-5-I-R91150, a 5-HT2A receptor antagonist, as the imaging probe. Anesthesia was induced and maintained with a continuous-rate infusion of propofol (8.4 ± 1.2 mg kg(-1) followed by 0.22 mg kg(-1) min(-1)) 75 min after tracer administration, and acquisition of the first image began 15 min after induction of anesthesia. After this first acquisition, propofol (0.22 mg kg(-1) min(-1)) was combined with ketamine (5 mg kg(-1) followed by 0.023 mg kg(-1) min(-1)), and the second acquisition began 15 min later. Semiquantification, with the cerebellum as a reference region, was performed to calculate the 5-HT2A receptor binding indices (parameter for available receptor density) in the frontal and temporal cortices. The binding indices were analyzed with Wilcoxon signed ranks statistics. The addition of ketamine to the propofol continuous-rate infusion resulted in decreased binding indices in the right frontal cortex (1.25 ± 0.22 vs. 1.45 ± 0.16; P = 0.028), left frontal cortex (1.34 ± 0.15 vs. 1.49 ± 0.10; P = 0.028), right temporal cortex (1.30 ± 0.17 vs. 1.45 ± 0.09; P = 0.046), and left temporal cortex (1.41 ± 0.20 vs. 1.52 ± 0.20; P = 0.046). This study showed that cats can be used as an animal model for studying alterations of the 5-HT2A receptor status with (123)I-5-I-R91150 micro-SPECT. Furthermore, an interaction between ketamine and the 5-HT2A receptors resulting in decreased binding of (123)I-5-I-R91150 in the frontal and temporal cortices was demonstrated. Whether the

  3. Impulsive traits and 5-HT2A receptor promoter polymorphism in alcohol dependents: possible association but no influence of personality disorders.

    Science.gov (United States)

    Preuss, U W; Koller, G; Bondy, B; Bahlmann, M; Soyka, M

    2001-01-01

    Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impulsive aggression in alcohol dependents. Alcohol dependents were investigated because these personality disorders and impulsive behavior are very frequent in alcohol dependence anf of clinical relevance. One hundred and thirty-five patients of German descent meeting DSM-IV criteria of alcohol dependence were recruited. Blood samples were taken from alcohol dependents to determine 5-HT2A promoter polymorphisms using PCR (polymerase chain reaction) of lymphocyte DNA. Impulsive aggression was assessed using a German version of the Barratt Impulsiveness Scale which was translated and backtranslated. Alcohol dependents were subdivided into low- or high-impulsivity groups using a median split of the Barratt score. APD and borderline personality disorder (BPD) were assessed using the SCID-II interview. The low-impulsivity group was slightly older and showed a later age at alcoholism onset than the highly impulsive group. Alcohol dependents with high impulsive traits showed a significant association with 5-HT2A 1438 A alleles. After excluding alcohol dependents with APD or BPD from the analysis, this association remained significant. Furthermore, no association between APD, BPD and 5-HT2A alleles was noted. Inpatient alcohol dependents showed a significant association between 5-HT2A A alleles and impulsive traits, independent of the presence of APD or BPD. No association was noted between personality disorders and the polymorphism. This is the first report about an association of 5-HT2A promoter

  4. Maternal aggression in Wistar rats: effect of 5-HT2A/2C receptor agonist and antagonist microinjected into the dorsal periaqueductal gray matter and medial septum

    Directory of Open Access Journals (Sweden)

    Almeida R.M.M. de

    2005-01-01

    Full Text Available The objective of the present study was to assess the role of the 5-HT2A/2C receptor at two specific brain sites, i.e., the dorsal periaqueductal gray matter (DPAG and the medial septal (MS area, in maternal aggressive behavior after the microinjection of either a 5-HT2A/2C receptor agonist or antagonist. Female Wistar rats were microinjected on the 7th postpartum day with the selective agonist alpha-methyl-5-hydroxytryptamine maleate (5-HT2A/2C or the antagonist 5-HT2A/2C, ketanserin. The agonist was injected into the DPAG at 0.2 (N = 9, 0.5 (N = 10, and 1.0 µg/0.2 µl (N = 9, and the antagonist was injected at 1.0 µg/0.2 µl (N = 9. The agonist was injected into the medial septal area (MS at 0.2 (N = 9, 0.5 (N = 7, and 1.0 µg/0.2 µl (N = 6 and the antagonist was injected at 1.0 µg/0.2 µl (N = 5. For the control, saline was injected into the DPAG (N = 7 and the MS (N = 12. Both areas are related to aggressive behavior and contain a high density of 5-HT receptors. Non-aggressive behaviors such as horizontal locomotion (walking and social investigation and aggressive behaviors such as lateral threat (aggressive posture, attacks (frontal and lateral, and biting the intruder were analyzed when a male intruder was placed into the female resident's cage. For each brain area studied, the frequency of the behaviors was compared among the various treatments by analysis of variance. The results showed a decrease in maternal aggressive behavior (number of bites directed at the intruder after microinjection of the agonist at 0.2 and 1.0 µg/0.2 µl (1.6 ± 0.7 and 0.9 ± 0.3 into the DPAG compared to the saline group (5.5 ± 1.1. There was no dose-response relationship with the agonist. The present findings suggest that the 5-HT2A/2C receptor agonist has an inhibitory effect on maternal aggressive behavior when microinjected into the DPAG and no effect when microinjected into the MS. Ketanserin (1.0 µg/0.2 µl decreased locomotion when microinjected

  5. MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

    Science.gov (United States)

    Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K

    2015-08-15

    MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach

    DEFF Research Database (Denmark)

    Haugbøl, Steven; Pinborg, Lars H; Arfan, Haroon M

    2006-01-01

    PURPOSE: To determine the reproducibility of measurements of brain 5-HT2A receptors with an [18F]altanserin PET bolus/infusion approach. Further, to estimate the sample size needed to detect regional differences between two groups and, finally, to evaluate how partial volume correction affects...... reproducibility and the required sample size. METHODS: For assessment of the variability, six subjects were investigated with [18F]altanserin PET twice, at an interval of less than 2 weeks. The sample size required to detect a 20% difference was estimated from [18F]altanserin PET studies in 84 healthy subjects....... Regions of interest were automatically delineated on co-registered MR and PET images. RESULTS: In cortical brain regions with a high density of 5-HT2A receptors, the outcome parameter (binding potential, BP1) showed high reproducibility, with a median difference between the two group measurements of 6...

  7. Different distributions of the 5-HT reuptake complex and the postsynaptic 5-HT(2A) receptors in Brodmann areas and brain hemispheres.

    Science.gov (United States)

    Rosel, Pilar; Arranz, Belén; Urretavizcaya, Mikel; Oros, Miguel; San, Luis; Vallejo, Julio; Navarro, Miguel Angel

    2002-08-30

    The aim of the present study was to determine the distribution of the presynaptic 5-HT reuptake complex and the 5-HT(2A) receptors through Brodmann areas from two control subjects, together with the possible existence of laterality between both brain hemispheres. A left laterality was observed in the postsynaptic 5-HT(2A) binding sites, with significantly higher B(max) values in the left frontal and cingulate cortex. In frontal cortex, [3H]imipramine and [3H]paroxetine binding showed the highest B(max) values in areas 25, 10 and 11. In cingulate cortex, the highest [3H]imipramine and [3H]paroxetine B(max) values were noted in Brodmann area 33 followed by area 24, while postsynaptic 5-HT(2A) receptors were mainly distributed through Brodmann areas 23 and 29. In temporal cortex, the highest [3H]imipramine and [3H]paroxetine B(max) was noted in Brodmann areas 28 and 34, followed by areas 35 and 38. All Brodmann areas from parietal cortex (1, 2, 3, 4, 5, 6, 7, 39, 40 and 43) showed similar presynaptic and postsynaptic binding values. In occipital cortex no differences were observed with regard to the brain hemisphere or to the Brodmann area (17, 18 and 19). These results suggest the need to carefully define the brain hemisphere and the Brodmann areas studied, as well to avoid comparisons between studies including different Brodmann areas or brain hemispheres.

  8. Membrane cholesterol effect on the 5-HT2A receptor: Insights into the lipid-induced modulation of an antipsychotic drug target.

    Science.gov (United States)

    Ramírez-Anguita, Juan Manuel; Rodríguez-Espigares, Ismael; Guixà-González, Ramon; Bruno, Agostino; Torrens-Fontanals, Mariona; Varela-Rial, Alejandro; Selent, Jana

    2018-01-01

    The serotonin 5-hydroxytryptamine 2A (5-HT 2A ) receptor is a G-protein-coupled receptor (GPCR) relevant for the treatment of CNS disorders. In this regard, neuronal membrane composition in the brain plays a crucial role in the modulation of the receptor functioning. Since cholesterol is an essential component of neuronal membranes, we have studied its effect on the 5-HT 2A receptor dynamics through all-atom MD simulations. We find that the presence of cholesterol in the membrane increases receptor conformational variability in most receptor segments. Importantly, detailed structural analysis indicates that conformational variability goes along with the destabilization of hydrogen bonding networks not only within the receptor but also between receptor and lipids. In addition to increased conformational variability, we also find receptor segments with reduced variability. Our analysis suggests that this increased stabilization is the result of stabilizing effects of tightly bound cholesterol molecules to the receptor surface. Our finding contributes to a better understanding of membrane-induced alterations of receptor dynamics and points to cholesterol-induced stabilizing and destabilizing effects on the conformational variability of GPCRs. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

  9. Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach

    International Nuclear Information System (INIS)

    Haugboel, Steven; Pinborg, Lars H.; Arfan, Haroon M.; Froekjaer, Vibe M.; Svarer, Claus; Knudsen, Gitte M.; Madsen, Jacob; Dyrby, Tim B.

    2007-01-01

    To determine the reproducibility of measurements of brain 5-HT 2A receptors with an [ 18 F]altanserin PET bolus/infusion approach. Further, to estimate the sample size needed to detect regional differences between two groups and, finally, to evaluate how partial volume correction affects reproducibility and the required sample size. For assessment of the variability, six subjects were investigated with [ 18 F]altanserin PET twice, at an interval of less than 2 weeks. The sample size required to detect a 20% difference was estimated from [ 18 F]altanserin PET studies in 84 healthy subjects. Regions of interest were automatically delineated on co-registered MR and PET images. In cortical brain regions with a high density of 5-HT 2A receptors, the outcome parameter (binding potential, BP 1 ) showed high reproducibility, with a median difference between the two group measurements of 6% (range 5-12%), whereas in regions with a low receptor density, BP 1 reproducibility was lower, with a median difference of 17% (range 11-39%). Partial volume correction reduced the variability in the sample considerably. The sample size required to detect a 20% difference in brain regions with high receptor density is approximately 27, whereas for low receptor binding regions the required sample size is substantially higher. This study demonstrates that [ 18 F]altanserin PET with a bolus/infusion design has very low variability, particularly in larger brain regions with high 5-HT 2A receptor density. Moreover, partial volume correction considerably reduces the sample size required to detect regional changes between groups. (orig.)

  10. A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice.

    Directory of Open Access Journals (Sweden)

    Yvonne Couch

    Full Text Available It is well documented that serotonin (5-HT plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS, which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5 mg/kg i.p., at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS.

  11. Direct comparison of [18F]MH.MZ and [18F]altanserin for 5-HT2A receptor imaging with PET

    DEFF Research Database (Denmark)

    Hansen, Hanne Demant; Ettrup, Anders; Herth, Matthias Manfred

    2013-01-01

    ]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT(2A) receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]altanserin as expected......]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and HPLC analysis allowed for tissue-compartment kinetic modelling of PET data. In vitro autoradiography showed high binding...

  12. Yokukansan, a traditional Japanese herbal medicine, enhances the anxiolytic effect of fluvoxamine and reduces cortical 5-HT2A receptor expression in mice.

    Science.gov (United States)

    Ohno, Rintaro; Miyagishi, Hiroko; Tsuji, Minoru; Saito, Atsumi; Miyagawa, Kazuya; Kurokawa, Kazuhiro; Takeda, Hiroshi

    2018-04-24

    Yokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia. To evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice. The anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT 1A and 5-HT 2A receptor in the mouse brain regions were quantified by western blot analysis. A single administration of fluvoxamine (5-20 mg/kg, i.p.) before the test session dose-dependently and significantly suppressed freezing behavior in mice. In the combination study, a sub-effective dose of fluvoxamine (5 mg/kg, i.p.) significantly suppressed freezing behavior in mice that had been repeatedly pretreated with yokukansan (0.3 and 1 g/kg, p.o.) once a day for 6 days after the conditioning session. Western blot analysis revealed that the expression level of 5-HT 2A receptor was specifically decreased in the prefrontal cortex of mice that had been administered yokukansan and fluvoxamine. Furthermore, microinjection of the 5-HT 2A receptor antagonist ketanserin (5 nmol/mouse) into the prefrontal cortex significantly suppressed freezing behavior. The present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT 2A receptor-mediated signaling in the prefrontal cortex. Therefore, combination therapy with fluvoxamine and yokukansan may be beneficial for the treatment of

  13. Pharmacological evaluation of halogenated and non-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles as D(2) and 5-HT(2A) receptor ligands.

    Science.gov (United States)

    Tomić, Mirko; Vasković, Djurdjica; Tovilović, Gordana; Andrić, Deana; Penjišević, Jelena; Kostić-Rajačić, Sladjana

    2011-05-01

    Five groups of previously synthesized and initially screened non-substituted and 4-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles were estimated for their in-vitro binding affinities at the rat D(2) , 5-HT(2A) , and α(1) -adrenergic receptors. Among all these compounds, 2-methoxyphenyl and 2-chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4-halogenation of benzimidazoles reveal that substitution with bromine may greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5-HT(2A)/D(2) pK(i) binding ratios slightly above or less than 1, while only 4-chloro-6-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1H-benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non-cataleptic action in rats and prevents d-amphetamine-induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains

    DEFF Research Database (Denmark)

    Fomsgaard, Luna; Moreno, Jose L; de la Fuente Revenga, Mario

    2018-01-01

    The serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors regulate each other and are associated with schizophrenia. The Roman high- (RHA-I) and the Roman low- (RLA-I) avoidance rat strains present well-differentiated behavioral profiles, with the RHA-I strain emerging as a putativ...

  15. Synthesis and in vivo evaluation of [O-methyl-11C](2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy] ethyl-1-methylpyrrolidine as a 5-HT2A receptor PET ligand

    International Nuclear Information System (INIS)

    Kumar, J.S. Dileep; Prabhakaran, Jaya; Erlandsson, Kjell; Majo, Vattoly J.; Simpson, Norman R.; Pratap, Mali; Heertum, Ronald L. van; Mann, J. John; Parsey, Ramin V.

    2006-01-01

    The serotonin 2A (5-HT 2A ) receptor is implicated in the pathophysiology of schizophrenia and mood disorders, and in vivo studies of this receptor would be of value in studying the pathophysiology of these disorders and in measuring the relationship of clinical response to receptor occupancy for 5-HT 2A antagonists such as atypical antipsychotics. Therefore, (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)-phenyl]ethyl] phenoxy]ethyl-1-methylpyrrolidine (MPM) (13), a selective and high-affinity (K i =0.79 nM) 5HT 2A antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-hydroxy)phenyl]ethyl]phenoxy] ethyl-1-methylpyrrolidine (12) with [ 11 C]methyltriflate in order to determine the suitability of [ 11 C]MPM to quantify 5-HT 2A in living brain using PET. Desmethyl-MPM 12 and standard MPM were prepared, starting from 3-hydroxymethylphenol (2), in excellent yield. The yield obtained for radiolabeling was 40±5% (EOB), and the total synthesis time was 30 min at EOS. PET studies with [ 11 C]MPM in baboon showed a distribution in the brain consistent with the known distribution of 5-HT 2A receptors. The time-activity curves for the high-binding regions peaked at ∼45 min after injection. Blocking studies with M100907 demonstrated not only 38-57% blocking of tracer binding in brain regions known to have 5-HT 2A receptors but also 38% blocking in cerebellum, which has a low 5-HT 2A receptor concentration. Although [ 11 C]MPM exhibits appropriate kinetics in baboon for imaging 5-HT 2A receptors, its specific binding in cerebellum and higher proportion of nonspecific binding limit its usefulness for the in vivo quantification of 5-HT 2A receptors with PET

  16. 5-HT2A Receptor Binding in the Frontal Cortex of Parkinson's Disease Patients and Alpha-Synuclein Overexpressing Mice

    DEFF Research Database (Denmark)

    Rasmussen, Nadja Bredo; Olesen, Mikkel Vestergaard; Brudek, Tomasz

    2016-01-01

    The receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer’s disease and related to the disease pathology. Even though Parkinson’s disease (PD) is primarily a motor disorder, reports of impaired executive...

  17. Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

    DEFF Research Database (Denmark)

    Yang, Kai-Chun; Stepanov, Vladimir; Martinsson, Stefan

    2017-01-01

    Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the c...... sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain....

  18. Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Zhao-hui Xu

    Full Text Available Fragile X syndrome is a common inherited form of mental retardation caused by the lack of fragile X mental retardation protein (FMRP because of Fmr1 gene silencing. Serotonin (5-HT is significantly increased in the null mutants of Drosophila Fmr1, and elevated 5-HT brain levels result in cognitive and behavioral deficits in human patients. The serotonin type 2A receptor (5-HT2AR is highly expressed in the cerebral cortex; it acts on pyramidal cells and GABAergic interneurons to modulate cortical functions. 5-HT2AR and FMRP both regulate synaptic plasticity. Therefore, the lack of FMRP may affect serotoninergic activity. In this study, we determined the involvement of FMRP in the 5-HT modulation of synaptic potentiation with the use of primary cortical neuron culture and brain slice recording. Pharmacological inhibition of 5-HT2AR by R-96544 or ketanserin facilitated long-term potentiation (LTP in the anterior cingulate cortex (ACC of WT mice. The prefrontal LTP induction was dependent on the activation of NMDARs and elevation of postsynaptic Ca(2+ concentrations. By contrast, inhibition of 5-HT2AR could not restore the induction of LTP in the ACC of Fmr1 knock-out mice. Furthermore, 5-HT2AR inhibition induced AMPA receptor GluR1 subtype surface insertion in the cultured ACC neurons of Fmr1 WT mice, however, GluR1 surface insertion by inhibition of 5-HT2AR was impaired in the neurons of Fmr1KO mice. These findings suggested that FMRP was involved in serotonin receptor signaling and contributed in GluR1 surface expression induced by 5-HT2AR inactivation.

  19. Radiosynthesis of a new radiobrominated ligand for 5HT2A receptors, a potential tracer for PET

    International Nuclear Information System (INIS)

    Terriere, D.; Hermanne, A.; Sonck, M.; Mertens, J.; Leysen, J.E.

    1997-01-01

    4-Amino-N-[1-[3-(4-fluorophenoxy)propyl]propyl]-4-methyl-4-pipe ridinyl]-2-methoxybenzamide, a compound with high affinity for 5HT 2 -receptors, was radiobrominated in the 5-position of the methoxybenzamide group by electrophilic substitution. Hydrogen peroxide/acetic acid, peracetic acid and a mixture of both were tried as oxidants. Radiobromination with the hydrogen peroxide method gave a labelling yield of 80% in the 5-position and 20% in the 3-position without any side products. On the other hand the labelling methods based on the use of peracetic acid gave a more selective radiobromination in the 5-position, but with low yields and moreover generated radioactive and non-radioactive side products. N.C.A radiobromide of high radio-chemical purity was obtained by an ion-exchange procedure on the target material solution coupled to a purification step using methanol. (Author)

  20. Altered 5-HT2A Receptor Binding after Recovery from Bulimia-Type Anorexia Nervosa: Relationships to Harm Avoidance and Drive for Thinness

    Science.gov (United States)

    Bailer, Ursula F; Price, Julie C; Meltzer, Carolyn C; Mathis, Chester A; Frank, Guido K; Weissfeld, Lisa; McConaha, Claire W; Henry, Shannan E; Brooks-Achenbach, Sarah; Barbarich, Nicole C; Kaye, Walter H

    2015-01-01

    Several lines of evidence suggest that a disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN) and bulimia nervosa (BN). This study applied positron emission tomography (PET) to investigate the brain serotonin 2A (5-HT2A) receptor, which could contribute to disturbances of appetite and behavior in AN and BN. To avoid the confounding effects of malnutrition, we studied 10 women recovered from bulimia-type AN (REC AN–BN, >1 year normal weight, regular menstrual cycles, no binging, or purging) compared with 16 healthy control women (CW) using PET imaging and a specific 5-HT2A receptor antagonist, [18F]altanserin. REC AN–BN women had significantly reduced [18F]altanserin binding potential relative to CW in the left subgenual cingulate, the left parietal cortex, and the right occipital cortex. [18F]altanserin binding potential was positively related to harm avoidance and negatively related to novelty seeking in cingulate and temporal regions only in REC AN–BN subjects. In addition, REC AN–BN had negative relationships between [18F]altanserin binding potential and drive for thinness in several cortical regions. In conclusion, this study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from bulimia-type AN, particularly in subgenual cingulate regions. Altered 5-HT neurotransmission after recovery also supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of eating disorders. It is possible that subgenual cingulate findings are not specific for AN–BN, but may be related to the high incidence of lifetime major depressive disorder diagnosis in these subjects. PMID:15054474

  1. Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics.

    Science.gov (United States)

    Blasi, Giuseppe; Selvaggi, Pierluigi; Fazio, Leonardo; Antonucci, Linda Antonella; Taurisano, Paolo; Masellis, Rita; Romano, Raffaella; Mancini, Marina; Zhang, Fengyu; Caforio, Grazia; Popolizio, Teresa; Apud, Jose; Weinberger, Daniel R; Bertolino, Alessandro

    2015-06-01

    Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.

  2. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

    Directory of Open Access Journals (Sweden)

    Malgorzata S. Martin-Gronert

    2016-04-01

    Full Text Available Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC peptides within the arcuate nucleus of the hypothalamus (ARC. We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus of in utero growth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.

  3. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats.

    Science.gov (United States)

    Martin-Gronert, Malgorzata S; Stocker, Claire J; Wargent, Edward T; Cripps, Roselle L; Garfield, Alastair S; Jovanovic, Zorica; D'Agostino, Giuseppe; Yeo, Giles S H; Cawthorne, Michael A; Arch, Jonathan R S; Heisler, Lora K; Ozanne, Susan E

    2016-04-01

    Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. © 2016. Published by The Company of Biologists Ltd.

  4. Serotonin hyperinnervation and upregulated 5-HT2A receptor expression and motor-stimulating function in nigrostriatal dopamine-deficient Pitx3 mutant mice.

    Science.gov (United States)

    Li, Li; Qiu, Guozhen; Ding, Shengyuan; Zhou, Fu-Ming

    2013-01-23

    The striatum receives serotonin (5-hydroxytryptamine, 5-HT) innervation and expresses 5-HT2A receptors (5-HT2ARs) and other 5-HT receptors, raising the possibility that the striatal 5-HT system may undergo adaptive changes after chronic severe dopamine (DA) loss and contribute to the function and dysfunction of the striatum. Here we show that in transcription factor Pitx3 gene mutant mice with a selective, severe DA loss in the dorsal striatum mimicking the DA denervation in late Parkinson's disease (PD), both the 5-HT innervation and the 5-HT2AR mRNA expression were increased in the dorsal striatum. Functionally, while having no detectable motor effect in wild type mice, the 5-HT2R agonist 2,5-dimethoxy-4-iodoamphetamine increased both the baseline and l-dopa-induced normal ambulatory and dyskinetic movements in Pitx3 mutant mice, whereas the selective 5-HT2AR blocker volinanserin had the opposite effects. These results demonstrate that Pitx3 mutant mice are a convenient and valid mouse model to study the compensatory 5-HT upregulation following the loss of the nigrostriatal DA projection and that the upregulated 5-HT2AR function in the DA deficient dorsal striatum may enhance both normal and dyskinetic movements. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors.

    Science.gov (United States)

    Viñals, Xavier; Moreno, Estefanía; Lanfumey, Laurence; Cordomí, Arnau; Pastor, Antoni; de La Torre, Rafael; Gasperini, Paola; Navarro, Gemma; Howell, Lesley A; Pardo, Leonardo; Lluís, Carmen; Canela, Enric I; McCormick, Peter J; Maldonado, Rafael; Robledo, Patricia

    2015-07-01

    Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.

  6. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors.

    Directory of Open Access Journals (Sweden)

    Xavier Viñals

    2015-07-01

    Full Text Available Activation of cannabinoid CB1 receptors (CB1R by delta9-tetrahydrocannabinol (THC produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.

  7. Estimates of regional cerebral blood flow and 5-HT2A receptor density in impulsive, aggressive dogs with 99mTc-ECD and 123I-5-I-R91150

    International Nuclear Information System (INIS)

    Peremans, Kathelijne; Coopman, Frank; Verschooten, Francis; Bree, Henri van; Audenaert, Kurt; Heeringen, Kees van; Blanckaert, Peter; Slegers, Guido; Jacobs, Filip; Otte, Andreas; Dierckx, Rudi; Mertens, John

    2003-01-01

    Impulsive aggression in dogs has an important impact on human public health. Better insight into the pathophysiology of this phenomenon could lead to more adequate diagnosis and treatment. Indirect in vivo research on peripheral body fluids and post-mortem studies in impulsive animals and humans indicate a deficient serotonergic system in general and disturbances in the serotonin-2A (5-HT2A) receptor in particular. In this study, brain perfusion and the 5-HT2A receptors were examined in impulsive, aggressive dogs, in comparison with a group of normally behaving animals. In order to decide which dogs to include in this study, owners were asked to describe the general behaviour of the dogs, the circumstances in which aggression occurred and their conduct during aggressive acts. Finally, 19 dogs were retained for this study, showing, according to different behavioural specialists, disinhibited dominance aggression. Functional imaging studies were performed on all these dogs. Single-photon emission tomography (SPET) was used to measure regional brain perfusion using technetium-99m labelled ethyl cysteinate dimer (ECD). The 5-HT2A receptor binding properties were investigated using the selective radioligand iodine-123 labelled 5-I-R91150. A significant increase in uptake of the 5-HT2A radioligand was noted in all cortical areas. No significant alterations were found in regional cortical perfusion, indicating that the increased binding index was not a consequence of increased tracer delivery. This study supports a role for the serotonergic system in canine impulsive aggression. (orig.)

  8. Estimates of regional cerebral blood flow and 5-HT2A receptor density in impulsive, aggressive dogs with {sup 99m}Tc-ECD and {sup 123}I-5-I-R91150

    Energy Technology Data Exchange (ETDEWEB)

    Peremans, Kathelijne; Coopman, Frank; Verschooten, Francis; Bree, Henri van [Department of Medical Imaging, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke (Belgium); Audenaert, Kurt; Heeringen, Kees van [Department of Psychiatry and Medical Psychology, Faculty of Medicine, Ghent University Hospital (Belgium); Blanckaert, Peter; Slegers, Guido [Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University (Belgium); Jacobs, Filip; Otte, Andreas; Dierckx, Rudi [Division of Nuclear Medicine, Ghent University Hospital (Belgium); Mertens, John [VUB-Cyclotron, Brussels (Belgium)

    2003-11-01

    Impulsive aggression in dogs has an important impact on human public health. Better insight into the pathophysiology of this phenomenon could lead to more adequate diagnosis and treatment. Indirect in vivo research on peripheral body fluids and post-mortem studies in impulsive animals and humans indicate a deficient serotonergic system in general and disturbances in the serotonin-2A (5-HT2A) receptor in particular. In this study, brain perfusion and the 5-HT2A receptors were examined in impulsive, aggressive dogs, in comparison with a group of normally behaving animals. In order to decide which dogs to include in this study, owners were asked to describe the general behaviour of the dogs, the circumstances in which aggression occurred and their conduct during aggressive acts. Finally, 19 dogs were retained for this study, showing, according to different behavioural specialists, disinhibited dominance aggression. Functional imaging studies were performed on all these dogs. Single-photon emission tomography (SPET) was used to measure regional brain perfusion using technetium-99m labelled ethyl cysteinate dimer (ECD). The 5-HT2A receptor binding properties were investigated using the selective radioligand iodine-123 labelled 5-I-R91150. A significant increase in uptake of the 5-HT2A radioligand was noted in all cortical areas. No significant alterations were found in regional cortical perfusion, indicating that the increased binding index was not a consequence of increased tracer delivery. This study supports a role for the serotonergic system in canine impulsive aggression. (orig.)

  9. Characterization of [(11)C]Cimbi-36 as an agonist PET radioligand for the 5-HT(2A) and 5-HT(2C) receptors in the nonhuman primate brain

    DEFF Research Database (Denmark)

    Finnema, Sjoerd J; Stepanov, Vladimir; Ettrup, Anders

    2014-01-01

    a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [(11)C]Cimbi-36 receptor binding in the primate brain. On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET...... agonist radioligand suitable for examination of 5-HT2A receptors in the cortical regions and of 5-HT2C receptors in the choroid plexus of the primate brain....

  10. A PET [18F]altanserin study of 5-HT2A receptor binding in the human brain and responses to painful heat stimulation

    DEFF Research Database (Denmark)

    Kupers, Ronny Clement Florent; Frokjaer, Vibe G; Naert, Arne

    2009-01-01

    There is a large body of evidence that serotonin [5-hydroxytryptamine (5-HT)] plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) to study the relationship between baseline 5-HT(2A) binding in the brain and responses to noxious heat...... stimulation in a group of young healthy volunteers. Twenty-one healthy subjects underwent PET scanning with the 5-HT(2A) antagonist, [(18)F]altanserin. In addition, participants underwent a battery of pain tests using noxious heat stimulation to assess pain threshold, pain tolerance and response to short......-lasting phasic and long-lasting (7-minute) tonic painful stimulation. Significant positive correlations were found between tonic pain ratings and [(18)F]altanserin binding in orbitofrontal (r=0.66; p=0.005), medial inferior frontal (r=0.60; p=0.014), primary sensory-motor (r=0.61; p=0.012) and posterior...

  11. Study of polymorphic variants of the serotonin 2A receptor gene (5-HT2A) and its possible effects on smoking habits of a population from northeastern Brazil.

    Science.gov (United States)

    Ramos Neto, E S; Mágulas, J O; Sousa, J J S; Moura, A C M; Pinto, G R; Yoshioka, F K N; Canalle, R; Motta, F J N

    2014-10-20

    Previous studies have revealed a genetic component, including genetic polymorphisms in the serotonergic pathway, particularly in the serotonin receptor gene (5-HT2A). The aim of this study was to investigate associations of the T102C (rs6313) and A-1438G (rs6311) polymorphisms with tobacco use in a population from northeastern Brazil. We evaluated these polymorphisms in 135 nonsmokers and 135 smokers using polymerase chain reaction-restricted fragment length polymorphism. The distribution of allele and genotype frequencies and associations of polymorphisms with smoking were assessed with the chi-squared (χ(2)) test, the Fisher exact test, and odds ratio (OR) with a 95% confidence interval (CI). There were no differences in the distribution of genotype and allele frequencies between nonsmokers and smokers for A-1438G (P = 0.80) and T102C (P = 0.35). However, these polymorphisms were significantly associated with habit frequency (A/G: P = 0.02, OR = 6.87, 95%CI = 1.23-38.31, P = 0.04; A/G+G/G: P = 0.04, OR = 3.67, 95%CI = 1.06-12.75, P = 0.07), age of onset (C/C: P = 0.02, OR = 3.26, 95%CI = 1.17-9.07, P = 0.03, and nicotine dependence level (A/G: P = 0.02, OR = 3.28, 95%CI = 1.17-9.18, P = 0.04; A/G+G/G: P = 0.04, OR = 2.81, 95%CI = 1.13-6.99, P = 0.04; T/C: P = 0.03, OR = 3.12, 95%CI = 1.13-8.57, P = 0.04; T/C+C/C: P = 0.02, OR = 3.06, 95%CI = 1.22-7.70, P = 0.02). Therefore, these polymorphisms may not contribute significantly to smoking initiation, they do appear to be associated with habit maintenance.

  12. 123I-5-I-R91150, a new single-photon emission tomography ligand for 5-HT2A receptors: influence of age and gender in healthy subjects

    International Nuclear Information System (INIS)

    Baeken, C.; D'haenen, H.; Flamen, P.; Bossuyt, A.; Mertens, J.; Terriere, D.; Chavatte, K.; Boumon, R.

    1998-01-01

    5-HT 2A receptors have been implicated in the pathophysiology of mood disorders and in the therapeutic effect of the so-called atypical antipsychotics. Recently, a new radioiodinated ligand with high affinity and selectivity for serotonin 5-HT 2A receptors, 123 iodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl-4-methyl-4-piperidinyl] 5-iodo-2-methoxybenzamide ( 123 I-5-I-R91150), has been developed and has been shown to be suitable for single-photon emission tomography (SPET) imaging. In this study the influence of age and gender on the ligand binding was investigated in normal volunteers. One hundred and fifty MBq of 123 I-5-I-R91150 was administered to 26 normal volunteers (13 females and 13 males) with an age range of 23-60 years. SPET imaging was performed with a triple-headed gamma camera. For semi-quantitative analysis, ratios of ligand binding in different regions of interest to the binding in the cerebellum were calculated. Mean ratios of 1.7 were obtained. No gender difference was demonstrated. 5-HT 2A binding was shown to decline with age. Over an age range of 40 years a reduction in ligand binding of 42%±7% was found. These results are in agreement with in vitro and positron emission tomography findings of a decline in 5-HT 2A receptor binding with age. The findings confirm the suitability of 123 I-5-I-R91150 for SPET imaging of 5-HT 2A receptors, and highlight the necessity for age-matched controls in clinical studies. (orig.)

  13. Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

    Science.gov (United States)

    Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

    2015-01-01

    Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

  14. Blockade of serotonin 5-HT2A receptors potentiates dopamine D2 activation-induced disruption of pup retrieval on an elevated plus maze, but has no effect on D2 blockade-induced one.

    Science.gov (United States)

    Nie, Lina; Di, Tianqi; Li, Yu; Cheng, Peng; Li, Ming; Gao, Jun

    2018-06-23

    Appetitive aspect of rat maternal behavior, such as pup retrieval, is motivationally driven and sensitive to dopamine disturbances. Activation or blockade of dopamine D 2 receptors causes a similar disruption of pup retrieval, which may also reflect an increase in maternal anxiety and/or a disruption of executive function. Recent work indicates that serotonin 5-HT 2A receptors also play an important role in rat maternal behavior. Given the well-known modulation of 5-HT 2A on the mesolimbic and mesocortical dopamine functions, the present study examined the extent to which blockade of 5-HT 2A receptors on dopamine D 2 -mediated maternal effects using a pup retrieval on the elevated plus maze (EPM) test. Sprague-Dawley postpartum female rats were acutely injected with quinpirole (a D 2 agonist, 0.10 and 0.25 mg/kg, sc), or haloperidol (a D 2 antagonist, 0.1 or 0.2 mg/kg, sc), in combination of MDL100907 (a 5-HT 2A receptor antagonist, 1.0 mg/kg, sc, 30 min before quinpirole or haloperidol injection) or saline and tested at 30, 90 and 240 min after quinpirole or haloperidol injection on postpartum days 3 and 7. Quinpirole and haloperidol decreased the number of pup retrieved (an index of maternal motivation) and sequential retrieval score (an index of executive function), prolonged the pup retrieval latencies, reduced the percentage of time spent on the open arms (an index of maternal anxiety), and decreased the distance travelled on the maze in a dose-dependent and time-dependent fashion. MDL100907 treatment by itself had no effect on pup retrieval, but it exacerbated the quinpirole-induced disruption of pup retrieval, but had no effect on the haloperidol-induced one. These findings suggest a complex interactive effect between 5-HT 2A and D 2 receptors on one or several maternal processes (maternal motivation, anxiety and executive function), and support the idea that one molecular mechanism by which 5-HT 2A receptors mediate maternal behavior is through

  15. Changes in the 5-HT2A receptor system in the pre-mammillary hypothalamus of the ewe are related to regulation of LH pulsatile secretion by an endogenous circannual rhythm

    Directory of Open Access Journals (Sweden)

    Karsch Fred J

    2003-01-01

    Full Text Available Abstract Background We wanted to determine if changes in the expression of serotonin 2A receptor (5HT2A receptor gene in the premammillary hypothalamus are associated with changes in reproductive neuroendocrine status. Thus, we compared 2 groups of ovariectomized-estradiol-treated ewes that expressed high vs low LH pulsatility in two different paradigms (2 groups per paradigm: (a refractoriness (low LH secretion or not (high LH secretion to short days in pineal-intact Ile-de-France ewes (RSD and (b endogenous circannual rhythm (ECR in free-running pinealectomized Suffolk ewes in the active or inactive stage of their reproductive rhythm. Results In RSD ewes, density of 5HT2A receptor mRNA (by in situ hybridization was significantly higher in the high LH group (25.3 ± 1.4 vs 21.4 ± 1.5 grains/neuron, P 3H-Ketanserin binding (a specific radioligand of the median part of the premammillary hypothalamus tended to be higher in the high group (29.1 ± 4.0 vs 24.6 ± 4.2 fmol/mg tissu-equivalent; P A receptor mRNA and 3H-Ketanserin binding were both significantly higher in the high LH group (20.8 ± 1.6 vs 17.0 ± 1.5 grains/neuron, P Conclusions We conclude that these higher 5HT2A receptor gene expression and binding activity of 5HT2A receptor in the premammillary hypothalamus are associated with stimulation of LH pulsatility expressed before the development of refractoriness to short days and prior to the decline of reproductive neuroendocrine activity during expression of the endogenous circannual rhythm.

  16. The Effect of Traumatic Stress on Multiple Aminergic Systems in the Basolateral Amygdala and Hypothalamus: Specific Impairment of Serotonin 5-HT2a Receptor Signaling and its Pathophysiological Role in an Animal Model of Post Traumatic Stress Disorder

    Science.gov (United States)

    2007-02-27

    discomfort, such as pain (Tanimoto et al., 2003;Bernard et al., 1992), psychological stressors (LeDoux, 2003;LeDoux, 2000), and the disturbance of plasma...Barbarich NC, Kaye WH (2004) Altered 5-HT(2A) receptor binding after recovery from bulimia -type anorexia nervosa: relationships to harm avoidance and...Serotonin alterations in anorexia and bulimia nervosa: New insights from imaging studies. Physiology & Behavior 85:73-81. Kaye WH, Frank GK, Meltzer CC

  17. 5-HT2A receptor SPECT imaging with [123I]R91150 under P-gp inhibition with tariquidar: More is better?

    International Nuclear Information System (INIS)

    Tsartsalis, Stergios; Tournier, Benjamin B.; Huynh-Gatz, Trinh; Dumas, Noé; Ginovart, Nathalie; Moulin-Sallanon, Marcelle; Millet, Philippe

    2016-01-01

    Introduction: Pharmacological P-glycoprotein (P-gp) inhibition with tariquidar (TQD) is considered a promising strategy for the augmentation of radiotracer brain uptake. However, a region-dependent effect may compromise the robustness of quantitative studies. For this reason, we studied the effect of a TQD pretreatment on 5-HT2A imaging with [ 123 I]R91150 and compared results with those obtained in Mdr1a knock-out (KO) rats. Methods: Ex vivo autoradiography was performed in TQD (15 mg/kg) pretreated wild-type (WT-TQD), Mdr1a knock-out (KO) and untreated WT rats for Specific Binding Ratio (SBR) estimation. In vivo dynamic SPECT imaging with serial arterial blood sampling was performed in the former two groups of rats and kinetic analysis was performed with a one tissue-compartment (1TC) model and the Specific Uptake Ratio (SUR). Results were analyzed statistically using repeated measures ANOVA. Results: SBR values differed between WT-TQD, Mdr1a KO and WT rats in a region-dependent manner (p < 0.0001). In vivo brain uptake of radiotracer did not differ between groups. Similarly, kinetic analysis provided distribution volume (V T ) values that did not differ significantly between groups. SUR binding potential (BP ND ) values from both groups highly correlated with corresponding V T (r = 0.970, p < 0.0001 and r = 0.962, p < 0.0001, respectively). However, SUR measured over averaged images between 100 and 120 min, using cerebellum as reference region, demonstrated values that were, by average, 2.99 ± 0.53 times higher in the WT-TQD group, with the difference between groups being region-dependent (p < 0.001). In addition, coefficient of variation of the SUR BP ND values across brain regions was significantly higher in the WT-TQD rats (41.25% ± 9.63% versus 11.13% ± 5.59%, p < 0.0001). Conclusion: P-gp inhibition with TQD leads to region-dependent effect in the rat brain, with probably sub-optimal effect in cerebellum. This warrants attention when it is used as a

  18. Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice

    DEFF Research Database (Denmark)

    Fantegrossi, William E; Gray, Bradley W; Bailey, Jessica M

    2015-01-01

    RATIONALE: 2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]methyl)phenol (25CN-NBOH) is structurally similar to N-benzyl substituted phenethylamine hallucinogens currently emerging as drugs of abuse. 25CN-NBOH exhibits dramatic selectivity for 5-HT2A receptors in vitro, but has not been behaviorally...... an intermediate degree of generalization (55 %) for the DOI training dose, and these interoceptive effects were attenuated by M100907. Finally, 25CN-NBOH did not generalize to M100907 at any dose, but ketanserin fully substituted in these animals. CONCLUSIONS: 25CN-NBOH was behaviorally active, but less effective...

  19. Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study.

    Science.gov (United States)

    Preller, Katrin H; Schilbach, Leonhard; Pokorny, Thomas; Flemming, Jan; Seifritz, Erich; Vollenweider, Franz X

    2018-04-04

    Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100 μg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 μg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HT 2A R) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT 2A R stimulation. The current results demonstrate that activity in areas of the "social brain" can be modulated via the 5-HT 2A R thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders. SIGNIFICANCE STATEMENT Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment

  20. Changes in global brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

    OpenAIRE

    Anticevic, Alan; Vollenweider, Franz; Murray, John; Krystal, John; Repovs, Grega; Staempfli, Philipp; Adkinson, Brendan; Schleifer, Charles; Ji, Jie; Burt, Joshua; Preller, Katrin

    2017-01-01

    Lysergic acid diethylamide (LSD) is a psychedelic drug with predominantly agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, the specific receptor contributions to its neurobiological effects remain largely unknown. To address this knowledge gap, we conducted a double-blind, randomized, counterbalanced, cross-over study during which 24 healthy participants received either i) placebo+placebo, ii) placebo+LSD (100 microgr...

  1. The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

    Directory of Open Access Journals (Sweden)

    Fabrice Trovero

    Full Text Available Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg and cyproheptadine (1 mg/kg (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France and cyproheptadine (1 mg/kg could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

  2. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI

    DEFF Research Database (Denmark)

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D

    2014-01-01

    Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly...... correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction......RNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating...

  3. Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice

    DEFF Research Database (Denmark)

    Holm, Peter; Ettrup, Anders; Klein, Anders B

    2010-01-01

    -HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C...

  4. Relationship between Job Stress and 5-HT2A Receptor Polymorphisms on Self-Reported Sleep Quality in Physicians in Urumqi (Xinjiang, China): A Cross-Sectional Study.

    Science.gov (United States)

    Gao, Xiaoyan; Ge, Hua; Jiang, Yu; Lian, Yulong; Zhang, Chen; Liu, Jiwen

    2018-05-21

    The serotonin receptor (5-HTR) plays a key role in sleep quality regulation. Job-related stress is an important factor that influences sleep quality. However, few reports on the interaction between 5-HTR2A polymorphisms and job stress, and how they may impact upon sleep quality are available. Therefore this study investigated the effects of job stress, 5-HTR2A polymorphisms, and their interaction on sleep quality, in physicians. Using a two-stage stratified sampling method, 918 participants were initially invited to participate in the study. After screening for study inclusion and exclusion criteria, 504 subjects were eventually included in the study. Job stress and sleep quality were assessed using the Job Stress Survey (JSS) and Pittsburgh Sleep Quality Index (PSQI), respectively. The 5-HTR2A receptor gene polymorphisms T102C and -1438G/A of were determined using polymerase chain reaction-restriction fragment length polymorphism. Job stress was significantly associated with sleep quality. High levels of job stress were linked to a higher risk of poor sleep quality compared to low or moderate levels [odds ratio (OR) = 2.909, 95% confidence interval (CI): 1.697⁻4.986]. High levels of stress may reduce subjects’ sleep quality, leading to an increase the likelihood of sleep disturbances and subsequent daytime dysfunction. The 5-HTR2A receptor gene polymorphism T102C was not significantly associated with sleep quality in this study, however, the -1438G/A polymorphism was significantly associated with sleep quality. The GG genotype of the -1438G/A polymorphism was linked to poorer sleep quality. When compared with subjects with low job-related stress levels×AG/AA genotype (OR = 2.106, 95% CI: 1.278⁻3.471), physicians with high job-related stress levels×GG genotype had a higher risk of experiencing poor sleep quality (OR = 13.400, 95% CI: 3.143⁻57.137). The findings of our study indicate that job stress and 5-HTR2A receptor gene polymorphisms are associated

  5. Relationship between Occupational Stress, 5-HT2A Receptor Polymorphisms and Mental Health in Petroleum Workers in the Xinjiang Arid Desert: A Cross-Sectional Study.

    Science.gov (United States)

    Jiang, Ting; Ge, Hua; Sun, Jian; Li, Rong; Han, Rui; Liu, Jiwen

    2017-04-10

    At present, there is growing interest in research examining the relationship between occupational stress and mental health. Owing to the socioeconomic impact of occupational stress and the unique environment of petroleum workers in Xinjiang, a cross-sectional study was carried out between April and December 2015 to investigate the relationship between occupational stress, 5-hydroxytryptamine receptor (5-HTR2A) genotype, and mental health. A total of 1485 workers were selected. The Symptom Checklist 90 was used to assess nine classes of psychological symptoms. Work-related stressors were evaluated using the Occupational Stress Inventory-Revised Edition. Levels of 5-HTR2A (the Tl02C and A-1438G single nucleotide polymorphism in the 5-HTR2A gene) were measured by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The findings of the present study revealed a high prevalence rate of mental health problems (40.29%) in petroleum workers stationed in the arid desert, and suggested a strong correlation between occupational stress and mental health. The TC and CC genotype of Tl02C were found to be protective factors against mental health problems (odds ratio (OR) = 0.455, 95% confidence interval (CI): = 0.269-0.771, odds ratio (OR) = 0.340, 95% confidence interval (CI): 0.162-0.716). AG and GG genotype of A-1438G [odds ratio (OR) 1 = 2.729, 95% confidence interval (CI): 1.433-5.195; odds ratio (OR) 2 = 2.480, 95% confidence interval (CI): 1.221-5.037] were revealed as risk factors. These data provide evidence that occupational stress and 5-HTR2A gene polymorphism contributes to the incidence of mental health problems.

  6. Relationship between Occupational Stress, 5-HT2A Receptor Polymorphisms and Mental Health in Petroleum Workers in the Xinjiang Arid Desert: A Cross-Sectional Study

    Directory of Open Access Journals (Sweden)

    Ting Jiang

    2017-04-01

    Full Text Available At present, there is growing interest in research examining the relationship between occupational stress and mental health. Owing to the socioeconomic impact of occupational stress and the unique environment of petroleum workers in Xinjiang, a cross-sectional study was carried out between April and December 2015 to investigate the relationship between occupational stress, 5-hydroxytryptamine receptor (5-HTR2A genotype, and mental health. A total of 1485 workers were selected. The Symptom Checklist 90 was used to assess nine classes of psychological symptoms. Work-related stressors were evaluated using the Occupational Stress Inventory-Revised Edition. Levels of 5-HTR2A (the Tl02C and A-1438G single nucleotide polymorphism in the 5-HTR2A gene were measured by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP. The findings of the present study revealed a high prevalence rate of mental health problems (40.29% in petroleum workers stationed in the arid desert, and suggested a strong correlation between occupational stress and mental health. The TC and CC genotype of Tl02C were found to be protective factors against mental health problems (odds ratio (OR = 0.455, 95% confidence interval (CI: = 0.269–0.771, odds ratio (OR = 0.340, 95% confidence interval (CI: 0.162–0.716. AG and GG genotype of A-1438G [odds ratio (OR 1 = 2.729, 95% confidence interval (CI: 1.433–5.195; odds ratio (OR 2 = 2.480, 95% confidence interval (CI: 1.221–5.037] were revealed as risk factors. These data provide evidence that occupational stress and 5-HTR2A gene polymorphism contributes to the incidence of mental health problems.

  7. Effect of 5-HT2A receptor polymorphisms and occupational stress on self-reported sleep quality: a cross-sectional study in Xinjiang, China.

    Science.gov (United States)

    Jiang, Yu; Cui, Changyong; Ge, Hua; Guan, Suzhen; Lian, Yulong; Liu, Jiwen

    2016-04-01

    Occupational stress and the serotonin receptor (5-HTR) play a key role in the regulation of sleep quality. Previous studies on the relationship between work-related stress, 5-HTR2A polymorphism, and sleep complaints found that 5-HTR2A modulates the response of the hypothalamic-pituitary-adrenal axis to stress and the maintenance of circadian rhythm. However, the effect of 5-HTR2A polymorphism and occupational stress on sleep quality has not been reported. The present study investigated the effects of 5-HTR2A genotypes, occupational stress, and gene-environment interactions on the sleep quality. Using a three-stage stratified sampling method, 1181 participants were recruited. Then, according to the study exclusion criteria, 810 subjects remained eligible. Finally, because some of subjects did not agree to being involved in this study, 700 workers were included. Of 700 workers finally included in the study, 251 had poor sleep quality based on the Pittsburgh Sleep Quality Index. The 5-HTR2A genotypes were determined with the SNaPshot single nucleotide polymorphism assay. Occupational stress was assessed with the Occupational Stress Inventory-Revised questionnaire. 5-HTR2A genotype was significantly associated with sleep quality. The CT genotype of rs1923884 was detected at a higher frequency among individuals with low sleep efficiency; the AA genotype of rs2070040 was associated with long sleep duration and more daytime dysfunction; and the CC genotype of rs6313 was linked to long sleep latency and duration and poor sleep quality. A high level of occupational stress was linked to higher risk of poor sleep quality than low or moderate levels (odds ratio [OR] = 12.55, 95% confidence interval [CI]: 7.02-22.43). A crossover analysis demonstrated an occupational stress × 5-HTR2A interaction. Compared to participants with low occupational stress and a CT/TT genotype, those with high occupational stress and a CC genotype had a higher risk of poor sleep quality (OR

  8. Detailed characterization of the in vitro pharmacological and pharmacokinetic properties of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH), a highly selective and brain-penetrant 5-HT2A receptor agonist

    DEFF Research Database (Denmark)

    Jensen, Anders A; McCorvy, John D; Petersen, Sebastian Leth

    2017-01-01

    ]ketanserin/[3H]mesulergine, [3H]LSD and [3H]Cimbi-36 binding assays (Ki 2C/Ki 2A ratio range 52-81, Ki 2B/Ki 2A ratio 37). Moreover, in inositol phosphate and intracellular Ca2+ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT2A/5-HT2C selectivities and 54-fold 5-HT2A/5-HT2B selectivity as measured...

  9. Changes of Serotonin (5-HT), 5-HT2A Receptor, and 5-HT Transporter in the Sprague-Dawley Rats of Depression,Myocardial Infarction and Myocardial Infarction Co-exist with Depression

    Institute of Scientific and Technical Information of China (English)

    Mei-Yan Liu; Yah-Ping Ren; Wan-Lin Wei; Guo-Xiang Tian; Guo Li

    2015-01-01

    Background:To evaluate whether serotonin (5-HT),5-HT2A receptor (5-HT2AR),and 5-HT transporter (serotonin transporter [SERT]) are associated with different disease states of depression,myocardial infarction (MI) and MI co-exist with depression in Sprague-Dawley rats.Methods:After established the animal model of four groups include control,depression,MI and MI with depression,we measured 5-HT,5-HT2AR and SERT from serum and platelet lysate.Results:The serum concentration of 5-HT in depression rats decreased significantly compared with the control group (303.25 ± 9.99 vs.352.98 ± 13.73;P =0.000),while that in MI group increased (381.78 ± 14.17 vs.352.98 ± 13.73;P =0.000).However,the depression + MI group had no change compared with control group (360.62 ± 11.40 vs.352.98 ± 13.73;P =0.036).The changes of the platelet concentration of 5-HT in the depression,MI,and depression + MI group were different from that of serum.The levels of 5-HT in above three groups were lower than that in the control group (380.40 ± 17.90,387.75 ± 22.28,246.40 ± 18.99 vs.500.29 ± 20.91;P =0.000).The platelet lysate concentration of 5-HT2AR increased in depression group,MI group,and depression + MI group compared with the control group (370.75 ± 14.75,393.47 ± 15.73,446.66 ± 18.86 vs.273.66 ± 16.90;P =0.000).The serum and platelet concentration of SERT in the depression group,MI group and depression + MI group were all increased compared with the control group (527.51 ± 28.32,602.02 ± 23.32,734.76 ± 29.59 vs.490.56 ± 16.90;P =0.047,P =0.000,P =0.000 in each and 906.38 ± 51.84,897.33 ± 60.34,1030.17 ± 58.73 vs.708.62 ± 51.15;P =0.000 in each).Conclusions:The concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression.Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.

  10. Association of the 5-HT2A receptor gene promoter polymorphism-1438G/A with anorexia nervosa and psychopathological traits in the Chinese Han population: A preliminary study.

    Science.gov (United States)

    Kang, Qing; Chen, Jue; Yu, Shunying; Yuan, Aihua; Zhang, Yanxia; Zhang, Ran; Jiang, Wenhui; Zhang, Chen; Zhang, Haiyin; Zhang, Mingdao; Xiao, Zeping

    2017-09-01

    The aim of the study was to explore the possible role of the 5-HT 2A -1438G/A polymorphism in the susceptibility to anorexia nervosa (AN) in the Chinese Han population. The -1438G/A polymorphism of 249 female AN patients, 228 matched healthy controls, and 198 trios was genotyped using SNaP shot assay. Psychopathological traits of eating-disordered behaviors in AN subjects were examined using the Chinese version of the Eating Disorder Examination Questionnaire. Neither the case-control analysis nor the transmission disequilibrium test revealed significant associations between the -1438G/A polymorphism and AN (P > .05). However, AA homozygote patients with AN had lower weight and shape concern scores of the EDE-Q6.0 than those of GA heterozygotes (P < .05). Our findings suggested that female AN patients with 5-HT 2A -1438AA genotype may be characterized by less severe eating-disordered psychopathological traits in the Chinese Han population. © 2017 John Wiley & Sons Australia, Ltd.

  11. Radiosynthesis, evaluation and preclinical studies of a new 5HT2A radioligand

    International Nuclear Information System (INIS)

    Mertens, J.; Terriere, D.; Baeken, C.; D'Haenan, H.; Flamen, P.; Bossuyt, A.; Leysen, J.

    1998-01-01

    123 I-5-I-R91150, a radioiodinated analogue of R91150 (a ligand (antagonist) of Janssen Research Foundation), showing high affinity and selectivity for 5HT 2A receptors, was developed as a potential in vivo 5HT 2A receptor tracer for SPECT. The applied radiochemistry, whereby the radioiodine was substituted on the 5 - position of the benzamide ring, allowed to obtain the tracer with high specific activity and high purity. In vitro and in vivo rat studies revealed that the new tracer bound reversibly with the required high affinity (Kd=0.1 nM) and high selectivity (a factor ranging from 10000 to at least 50 vis a vis other receptors) to 5HT 2A receptors. In young normal subjects the major part of the 123 I-5-I-R91150 radioactivity in the brain is present in cortical areas. Cortical area to cerebellum activity ratio reaches an equilibrium value of about 1.8 around 90 min. till 4 hours p.i.. This binding was specific and reversible. The cortical activity reflects a distribution in the brain similar to that of the mapping of 5HT 2A receptors from post mortem studies. These findings suggested that 123 I-5-I-R91150 allows imaging and quantitative estimation with SPECT and could be used for further clinical studies. The radiobromine analogue was synthetised as a potential PET tracer. (author)

  12. Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior

    DEFF Research Database (Denmark)

    Butini, Stefania; Gemma, Sandra; Campiani, Giuseppe

    2009-01-01

    with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c...

  13. Blockade of MK-801-induced heat shock protein 72/73 in rat brain by antipsychotic and monoaminergic agents targeting D2, 5-HT1A, 5-HT2A and α1-adrenergic receptors.

    Science.gov (United States)

    Romón, Tamara; Planas, Anna M; Adell, Albert

    2014-02-01

    Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can produce positive and negative symptomatology as well as impairment of cognitive function that closely resemble those present in schizophrenia. In rats, these drugs induce a behavioral syndrome (characterized by hyperlocomotion and stereotypies), an enhanced glutamatergic transmission in the medial prefrontal cortex, and damage to retrosplenial cortical neurons in adult rats, which was measured as the induction of the stress protein 72/73 kDa heat shock protein (Hsp72/73). In the present work, we have examined the existence of possible differences among different antipsychotic drugs in their capacity to block immunolabeling of Hsp72/73 in the retrosplenial cortex of the rat induced by the potent NMDA receptor antagonist, MK- 801. In addition, the effects of selective monoaminergic agents were also studied to delineate the particular receptors responsible for the actions of antipsychotic drugs. Pretreatment with clozapine, chlorpromazine, olanzapine, ziprasidone--and to a lesser extent haloperidol-reduced the formation of Hsp72/73 protein in the rat retrosplenial cortex after the administration of MK-801. In addition, antagonism at dopamine D2 (raclopride), 5-HT2 (M100907) and α1- adrenoceptors (prazosin) as well as agonism at 5-HT1A receptors (BAY x 3702) also diminished the MK-801-induced number of cells labeled with Hsp72/73. Each of these effects may contribute to antipsychotic action. The results suggest that the efficacy of atypical antipsychotic drugs in the clinic may result from a combined effect on 5-HT2, 5-HT1A and α1-adrenergic receptors added to the classical dopamine D2 receptor antagonism.

  14. Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers

    DEFF Research Database (Denmark)

    Ettrup, Anders; Hansen, Martin; Santini, Martin A

    2011-01-01

    Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer....... In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig...

  15. Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

    DEFF Research Database (Denmark)

    Ettrup, Anders; Hansen, Martin; Santini, Martin A

    2011-01-01

    Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer....... In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig...

  16. The 5-HT2A/1A agonist psilocybin disrupts modal object completion associated with visual hallucinations.

    Science.gov (United States)

    Kometer, Michael; Cahn, B Rael; Andel, David; Carter, Olivia L; Vollenweider, Franz X

    2011-03-01

    Recent findings suggest that the serotonergic system and particularly the 5-HT2A/1A receptors are implicated in visual processing and possibly the pathophysiology of visual disturbances including hallucinations in schizophrenia and Parkinson's disease. To investigate the role of 5-HT2A/1A receptors in visual processing the effect of the hallucinogenic 5-HT2A/1A agonist psilocybin (125 and 250 μg/kg vs. placebo) on the spatiotemporal dynamics of modal object completion was assessed in normal volunteers (n = 17) using visual evoked potential recordings in conjunction with topographic-mapping and source analysis. These effects were then considered in relation to the subjective intensity of psilocybin-induced visual hallucinations quantified by psychometric measurement. Psilocybin dose-dependently decreased the N170 and, in contrast, slightly enhanced the P1 component selectively over occipital electrode sites. The decrease of the N170 was most apparent during the processing of incomplete object figures. Moreover, during the time period of the N170, the overall reduction of the activation in the right extrastriate and posterior parietal areas correlated positively with the intensity of visual hallucinations. These results suggest a central role of the 5-HT2A/1A-receptors in the modulation of visual processing. Specifically, a reduced N170 component was identified as potentially reflecting a key process of 5-HT2A/1A receptor-mediated visual hallucinations and aberrant modal object completion potential. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  17. Obesitas dan hubungannya dengan polimorfisme gena promoter 5-HT2A, tekanan darah, profil lipid, kadar glukosa, dan malondialdehid

    Directory of Open Access Journals (Sweden)

    Pramudji Hastuti

    2011-10-01

    Full Text Available Background: Obesity among adults has risen significantly in the world-cutting across all ages, racial and ethnic groups and gender. The 5-HT 2A receptor is crucially involved in regulation of body weight and the appetite. Disturbances in the distribution and or gene regulation of the postsynaptic 5-HT2A receptor are implicated in the pathophysiology of conditions such as obesity, coronary heart disease, high blood pressure, diabetes, stroke dan some cancers. Objective: To test the association between obesity with polymorphism of promoter -1438G→A 5-HT2A receptors gene, blood pressure, lipid profiles, levels of blood glucose and malondialdehyde (MDA. Method: This cross-sectional study included thirty six unrelated obese young people (BMI ≥ 30 recruited from populations in Yogyakarta and 36 controls with age matched with BMI ≤ 25. Statistical differences between blood pressure, lipid profiles, glucose and MDA levels were assessed by t-test and genotypes by Chi square test. Results: There were no significant difference in blood pressure lipid profile, level of glucose and MDA in obese group compared with control (p>0,05. Allele A and G frequency in obese group 25% and 75% respectively, and controls 22.2% and 77.8% respectively, and no significant difference in all two groups, but G allele had higher risk to obese than A allele. Conclusion: These data indicated G allele was mild risk factor for obesity.

  18. Abeta(1-42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT(2A) levels

    DEFF Research Database (Denmark)

    Christensen, R; Marcussen, Anders Bue; Wörtwein, Gitta

    2008-01-01

    was used to monitor Abeta(1-42) induced memory impairment. Memory impairment was seen 22 days after injection of Abeta(1-42) in the experimental group and until termination of the experiments. In the Abeta(1-42) injected animals we saw an abolished increase in serum BDNF levels that was accompanied...... by significant lower BDNF levels in frontal cortex and by an 8.5% reduction in hippocampal 5-HT(2A) receptor levels. A tendency towards lowered cortical 5-HT(2A) was also observed. These results indicate that the Abeta(1-42) associated memory deficit is associated with an impaired BDNF regulation, which...

  19. Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L

    2016-08-01

    Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods. Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights

  20. Correlating the Metabolic Stability of Psychedelic 5-HT2A Agonists with Anecdotal Reports of Human Oral Bioavailability

    DEFF Research Database (Denmark)

    Leth-Petersen, Sebastian; Bundgaard, Christoffer; Hansen, Martin

    2014-01-01

    2,5-Dimethoxyphenethylamines and their N-benzylated derivatives are potent 5-HT2A agonists with psychedelic effects in humans. The N-benzylated derivatives are among the most selective 5-HT2A agonists currently available and their usage as biochemical and brain imaging tools is increasing, yet ve...

  1. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.

    Science.gov (United States)

    Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Narvaez, Manuel; Oflijan, Julia; Agnati, Luigi F; Fuxe, Kjell

    2014-01-03

    Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Behavioral Effects of Systemic, Infralimbic and Prelimbic Injections of a Serotonin 5-HT2A Antagonist in Carioca High- and Low-Conditioned Freezing Rats

    Directory of Open Access Journals (Sweden)

    Laura A. León

    2017-07-01

    Full Text Available The role of serotonin (5-hydroxytryptamine [5-HT] and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]. The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM. In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL and prelimbic (PL cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices.Highlights-CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more “anxious” phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF or increased (CLF anxiety-like behavior.-PL injections either decreased (CHF anxiety

  3. Design, Synthesis, and Pharmacological Characterization of N- and O-Substituted 5,6,7,8-Tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol Analogues: Novel 5-HT2A/5-HT2C Receptor Agonists with Pro-Cognitive Properties

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Plath, Niels; Pedersen, Martin Holst Friborg

    2013-01-01

    to be selective for the two receptors. Administration of 3d substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT2C antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most...

  4. Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

    Science.gov (United States)

    Xu, Xiangqing; Wei, Yaqin; Guo, Qiang; Zhao, Song; Liu, Zhiqiang; Xiao, Ting; Liu, Yani; Qiu, Yinli; Hou, Yuanyuan; Zhang, Guisen; Wang, KeWei

    2018-06-01

    Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin ( K i = 4.81 nM) and norepinephrine (NE) ( K i = 6.72 nM) transporters and moderate 5-HT 2A antagonist activity (IC 50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT 2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  5. 18F-labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging

    DEFF Research Database (Denmark)

    Debus, Fabian; Herth, Matthias Manfred; Piel, Markus

    2010-01-01

    ]tracers with a purity >96% and a typical specific activity of 25-35 GBq/mumol. Autoradiographic images of (R)-[(18)F]MH.MZ (5) and [(18)F]DD-1 (4) showed excellent visualization and selectivity of the 5-HT2A receptor for (R)-[(18)F]MH.MZ and less specific binding for [(18)F]DD-1. The binding potential (BP) of (R)-[(18......, equal levels of specific activities were used. High uptake could be demonstrated in cortex regions. CONCLUSION: Labeling of both novel tracers was carried out in high RCY. Autoradiography revealed (R)-[(18)F]MH.MZ as a very selective and affine 5-HT2A tracer (K(i)=0.72 nM), whereas [(18)F]DD-1 showed...... no reasonable distribution pattern on autoradiographic sections. Moreover, results from microPET scans of (R)-[(18)F]MH.MZ hint on improved molecular imaging characteristics compared with those of [(18)F]MH.MZ. Therefore, (R)-[(18)F]MH.MZ appears to be a highly potent and selective serotonergic PET ligand...

  6. The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval.

    Science.gov (United States)

    Vollenweider, Franz X; Csomor, Philipp A; Knappe, Bernhard; Geyer, Mark A; Quednow, Boris B

    2007-09-01

    Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT(2A) receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT(2A) receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 microg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120-2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

  7. [Other Possible Clinical Applications of Drugs with 5HT2A effect in Liaison Psychiatry: Cases Report].

    Science.gov (United States)

    Corredor, Catalina Ayala; Castillo, Carolina Solís

    2012-03-01

    In liaison psychiatry it is possible to get an integral view of patient's treatment and needs, paying special attention to pharmacological interactions and contraindications. Some particular cases motivated the description, report and review about other possible applications of 5HT2A and 5HT3 antagonist, particularly Mirtazapine and Olanzapine, in hyperalgesia syndrome, tinnitus and Progressive Multifocal Leukoencephalopathy by JC virus. Cases report. We describe 3 cases of patients in which Mirtazapine and Olanzapine were necessary not only to control psychiatric symptoms (affective / behavioral symptoms and insomnia) but to act as adjuvant therapy in axis III diseases. The use of any drug in psychiatry must take in to account the context of the patient, the presence of comorbidity, contraindications and pharmacological interactions so as to grant a positive outcome also promoting the multidisciplinary work between specialists. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  8. Pharmacokinetics and brain distribution in non human primate of R(-)[123I]DOI, A 5HT2A/2C serotonin agonist

    International Nuclear Information System (INIS)

    Zea-Ponce, Yolanda; Kegeles, Lawrence S.; Guo, Ningning; Raskin, Leonid; Bakthavachalam, Venkatesalu; Laruelle, Marc

    2002-01-01

    Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[ 123 I]iodophenyl)-2-aminopropane [R(-)[ 123 I]DOI], an in vitro potent and selective 5-HT 2A/2C serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT 2 receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [ 123 I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[ 123 I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f 1 ), was 31±0.9% (n=3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[ 123 I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin

  9. Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys.

    Science.gov (United States)

    Banks, Matthew L; Negus, S Stevens

    2017-04-01

    Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT 2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.032-0.1 mg/kg/h, intravenous) or the 5-HT 2A inverse agonist/antagonist pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent 'choice' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT 2C receptor activation nor 5-HT 2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT 2C agonists and 5-HT 2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.

  10. (11)C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand

    DEFF Research Database (Denmark)

    Andersen, Valdemar L; Hansen, Hanne D; Herth, Matthias M

    2015-01-01

    ]Pimavanserin was obtained by N-methylation of an appropriate precursor using [(11)C]MeOTf in acetone at 60°C giving radiochemical yields in the range of 1-1.7GBq (n=4). In Danish Landrace pigs the radio ligand readily entered the brain and displayed binding in the cortex in accordance with the distribution of 5-HT2ARs...

  11. Management of skin cancer by agonists of 5-HT1A and antagonists of 5-HT2A receptors

    OpenAIRE

    Menezes, Ana Catarina da Silva Fernandes Saraiva de

    2015-01-01

    Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2015 A pele é o maior órgão humano e apresenta funções importantes quer a nível neuroendócrino, quer imunológico. A presença de um análogo do eixo hipotalâmico-hipofisário-adrenal na pele permite reagir a fatores externos de stress e modular as funções da mesma, tais como a melanogénese. A serotonina (5-hidroxitriptamina, 5-HT) é um neuromodelador importante que atua como fator de crescimento no can...

  12. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF(2L/2LCk-cre)). A severe impairmen...

  13. Effects of autoshaping procedures on 3H-8-OH-DPAT-labeled 5-HT1a binding and 125I-LSD-labeled 5-HT2a binding in rat brain.

    Science.gov (United States)

    Tomie, Arthur; Di Poce, Jason; Aguado, Allison; Janes, Amy; Benjamin, Daniel; Pohorecky, Larissa

    2003-06-13

    Effects of experience with Pavlovian autoshaping procedures on lever-press autoshaping conditioned response (CR) performance and 3H-8-OH-DPAT-labeled binding of 5-HT(1a) receptors as well as 125I-LSD-labeled binding of 5-HT(2a) receptors were evaluated in four groups of male Long-Evans hooded rats. Two groups of rats (Group Paired High CR and Group Paired Low CR) received Pavlovian autoshaping procedures wherein the presentation of a lever (conditioned stimulus, CS) was followed by the response-independent presentation of food (unconditioned stimulus, US). Rats in Group Paired High CR (n=12) showed more rapid CR acquisition and higher asymptotic levels of lever-press autoshaping CR performance relative to rats in Group Low CR (n=12). Group Omission (n=9) received autoshaping with an omission contingency, such that performing the lever-press autoshaping CR resulted in the cancellation the food US, while Group Random (n=9) received presentations of lever CS and food US randomly with respect to one another. Though Groups Omission and Random did not differ in lever-press autoshaping CR performance, Group Omission showed significantly lower levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in post-synaptic areas (frontal cortex, septum, caudate putamen), as well as significantly higher plasma corticosterone levels than Group Random. In addition, Group Random showed higher levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in pre-synaptic somatodendritic autoreceptors on dorsal raphe nucleus relative to each of the other three groups. Autoradiographic analysis of 125I-LSD-labeled 5-HT(2a) receptor binding revealed no significant differences between Groups Paired High CR and Paired Low CR or between Groups Omission and Random in any brain regions.

  14. Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5-HT2A Antagonist

    Directory of Open Access Journals (Sweden)

    Mahantesh Namdev Jadhav

    2013-01-01

    Full Text Available Schizophrenia is a mental disorder manifested largely by disintegration of thought processes and emotional responsiveness. Given the therapeutic and toxic limitations of clinically available drugs, it is clear that there is still a need for the development of new generation antipsychotic agents with an improved clinical profile. Development of novel hybrid atypical tricyclic antipsychotic pharmacophore was achieved using direct (by measuring docking score of designed molecules on modelled 5- receptor and indirect (current, clinically available therapeutic agents’ data drug design approaches.

  15. Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia

    DEFF Research Database (Denmark)

    Santini, Martin A; Ratner, Cecilia Friis; Aznar, Susana

    2013-01-01

    Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia...

  16. Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure.

    Science.gov (United States)

    Hervig, Mona El-Sayed; Jensen, Nadja Cecilie Hvid; Rasmussen, Nadja Bredo; Rydbirk, Rasmus; Olesen, Mikkel Vestergaard; Hay-Schmidt, Anders; Pakkenberg, Bente; Aznar, Susana

    2017-05-30

    The medial prefrontal cortex (PFC) plays a major role in executive function by exerting a top-down control onto subcortical areas. Novelty-induced frontal cortex activation is 5-HT 2A receptor (5-HT 2A R) dependent. Here, we further investigated how blockade of 5-HT 2A Rs in mice exposed to a novel open-field arena affects medial PFC activation and basolateral amygdala (BLA) reactivity. We used c-Fos immunoreactivity (IR) as a marker of neuronal activation and stereological quantification for obtaining the total number of c-Fos-IR neurons as a measure of regional activation. We further examined the impact of 5-HT 2A R blockade on the striatal-projecting BLA neurons. Systemic administration of ketanserin (0.5mg/kg) prior to novel open-field exposure resulted in reduced total numbers of c-Fos-IR cells in dorsomedial PFC areas and the BLA. Moreover, there was a positive correlation between the relative time spent in the centre of the open-field and BLA c-Fos-IR in the ketanserin-treated animals. Unilateral medial PFC lesions blocked this effect, ascertaining an involvement of this frontal cortex area. On the other hand, medial PFC lesioning exacerbated the more anxiogenic-like behaviour of the ketanserin-treated animals, upholding its involvement in modulating averseness. Ketanserin did not affect the number of activated striatal-projecting BLA neurons (measured by number of Cholera Toxin b (CTb) retrograde labelled neurons also being c-Fos-IR) following CTb injection in the ventral striatum. These results support a role of 5-HT 2A R activation in modulating mPFC and BLA activation during exposure to a novel environment, which may be interrelated. Conversely, 5-HT 2A R blockade does not seem to affect the amygdala-striatal projection. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB.

    Science.gov (United States)

    Ribasés, M; Ramos-Quiroga, J A; Hervás, A; Bosch, R; Bielsa, A; Gastaminza, X; Artigas, J; Rodriguez-Ben, S; Estivill, X; Casas, M; Cormand, B; Bayés, M

    2009-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.

  18. Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice

    DEFF Research Database (Denmark)

    Jørgensen, Christinna Vangsgaard; Jacobsen, Jacob P; Caron, Marc G

    2013-01-01

    Transgenic mice with a knock-in (KI) of a tryptophan hydroxylase 2 (Tph2) R439H mutation, analogous to the Tph2 R441H single-nucleotide polymorphism originally identified in a late life depression cohort, have markedly reduced levels of 5-hydroxytryptamine (5-HT). These Tph2KI mice are therefore...

  19. Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala

    DEFF Research Database (Denmark)

    Hornboll, Bettina; Macoveanu, Julian; Rowe, James

    2013-01-01

    judging the gender of neutral, fearful and angry faces. Methods: 5-HT2A receptors were blocked with ketanserin to a variable degree across subjects by adjusting the time between ketanserin-infusion and onset of the fMRI protocol. Neocortical 5-HT2A receptor binding in terms of the binding potential (BPp...... blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of 5-HT2A receptor occupancy or neocortical 5-HT2A receptor BPp . The medial OFC also showed increased functional coupling with the left amygdala during processing of fearful faces depending...

  20. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered......: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  1. Laminar and Cellular Distribution of Monoamine Receptors in Rat Medial Prefrontal Cortex

    Directory of Open Access Journals (Sweden)

    Noemí Santana

    2017-09-01

    Full Text Available The prefrontal cortex (PFC is deeply involved in higher brain functions, many of which are altered in psychiatric conditions. The PFC exerts a top-down control of most cortical and subcortical areas through descending pathways and is densely innervated by axons emerging from the brainstem monoamine cell groups, namely, the dorsal and median raphe nuclei (DR and MnR, respectively, the ventral tegmental area and the locus coeruleus (LC. In turn, the activity of these cell groups is tightly controlled by afferent pathways arising from layer V PFC pyramidal neurons. The reciprocal connectivity between PFC and monoamine cell groups is of interest to study the pathophysiology and treatment of severe psychiatric disorders, such as major depression and schizophrenia, inasmuch as antidepressant and antipsychotic drugs target monoamine receptors/transporters expressed in these areas. Here we review previous reports examining the presence of monoamine receptors in pyramidal and GABAergic neurons of the PFC using double in situ hybridization. Additionally, we present new data on the quantitative layer distribution (layers I, II–III, V, and VI of monoamine receptor-expressing cells in the cingulate (Cg, prelimbic (PrL and infralimbic (IL subfields of the medial PFC (mPFC. The receptors examined include serotonin 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3, dopamine D1 and D2 receptors, and α1A-, α1B-, and α1D-adrenoceptors. With the exception of 5-HT3 receptors, selectively expressed by layers I–III GABA interneurons, the rest of monoamine receptors are widely expressed by pyramidal and GABAergic neurons in intermediate and deep layers of mPFC (5-HT2C receptors are also expressed in layer I. This complex distribution suggests that monoamines may modulate the communications between PFC and cortical/subcortical areas through the activation of receptors expressed by neurons in intermediate (e.g., 5-HT1A, 5-HT2A, α1D-adrenoceptors, dopamine D1 receptors and deep

  2. OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding.

    Science.gov (United States)

    Pittenger, Christopher; Adams, Thomas G; Gallezot, Jean-Dominique; Crowley, Michael J; Nabulsi, Nabeel; James Ropchan; Gao, Hong; Kichuk, Stephen A; Simpson, Ryan; Billingslea, Eileen; Hannestad, Jonas; Bloch, Michael; Mayes, Linda; Bhagwagar, Zubin; Carson, Richard E

    2016-05-15

    Obsessive-compulsive disorder (OCD) is characterized by impaired sensorimotor gating, as measured using prepulse inhibition (PPI). This effect may be related to abnormalities in the serotonin (5-HT) system. 5-HT1B agonists can impair PPI, produce OCD-like behaviors in animals, and exacerbate OCD symptoms in humans. We measured 5-HT1B receptor availability using (11)C-P943 positron emission tomography (PET) in unmedicated, non-depressed OCD patients (n=12) and matched healthy controls (HC; n=12). Usable PPI data were obtained from 20 of these subjects (10 from each group). There were no significant main effects of OCD diagnosis on 5-HT1B receptor availability ((11)C-P943 BPND); however, the relationship between PPI and (11)C-P943 BPND differed dramatically and significantly between groups. 5-HT1B receptor availability in the basal ganglia and thalamus correlated positively with PPI in controls; these correlations were lost or even reversed in the OCD group. In cortical regions there were no significant correlations with PPI in controls, but widespread positive correlations in OCD patients. Positive correlations between 5-HT1B receptor availability and PPI were consistent across diagnostic groups only in two structures, the orbitofrontal cortex and the amygdala. Differential associations of 5-HT1B receptor availability with PPI in patients suggest functionally important alterations in the serotonergic regulation of cortical/subcortical balance in OCD. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Anti-N-methyl-D-aspartate receptor encephalitis concomitant with multifocal subcortical white matter lesions on magnetic resonance imaging: a case report and review of the literature.

    Science.gov (United States)

    Wang, Rui-Jin; Chen, Bu-Dong; Qi, Dong

    2015-07-08

    Anti-N-methyl-D-aspartate receptor encephalitis is a severe autoimmune disorder characterized by severe psychiatric symptoms, seizures, decreased consciousness, autonomic dysregulation, and dyskinesias. Multifocal subcortical white matter lesions on fluid-attenuated inversion recovery and diffuse weighted images have rarely been reported in previous literature, and serial magnetic resonance imaging changes after plasma exchange have not been presented before. A previously healthy 24-year-old Chinese woman presented with acute psychiatric symptoms characterized by fear and agitation followed by decreased consciousness, dyskinesias, and seizures. Magnetic resonance imaging revealed hyperintense lesions on fluid-attenuated inversion recovery and diffuse weighted images in bilateral subcortical white matter. Cerebrospinal fluid analysis revealed a mild pleocytosis with lymphocytic predominance. Protein and glucose levels were normal. Aquaporin-4 antibodies in serum and cerebrospinal fluid were negative. Identification of anti-N-methyl-D-aspartate receptor antibodies in serum and cerebrospinal fluid confirmed the diagnosis of anti-N-methyl-D-aspartate receptor encephalitis. She was initially treated with combined intravenous immunoglobulin and methylprednisolone without improvement. Plasma exchange was then initiated with good response; the patient made a full recovery after several cycles of plasma exchange. Repeat magnetic resonance imaging performed 1 month after plasma exchange showed partial resolution of the hyperintense lesions in bilateral subcortical white matter, and follow-up magnetic resonance imaging 2 months after plasma exchange showed complete resolution. Anti-N-methyl-D-aspartate receptor encephalitis may be concomitant with multifocal subcortical white matter lesions. Such lesions may resolve after appropriate immunotherapy.

  4. Changes of Serotonin (5-HT, 5-HT2A Receptor, and 5-HT Transporter in the Sprague-Dawley Rats of Depression, Myocardial Infarction and Myocardial Infarction Co-exist with Depression

    Directory of Open Access Journals (Sweden)

    Mei-Yan Liu

    2015-01-01

    Conclusions: The concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression. Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.

  5. Estudio del receptor 5HT2A y de la vía Akt/GSK3 como mecanismos moleculares de la psicosis inducida por el consumo crónico de cannabis

    OpenAIRE

    Ibarra Lecue, Inés

    2015-01-01

    La esquizofrenia es una enfermedad mental de carácter crónico que afecta aproximadamente al 1% de la población , principalmente con edades comprendidas entre los 15 y 4 5 años . Se trata de una enfermedad de inicio en la adolescencia o comienzo de la madurez y cuyo potencial discapacitante persiste y se agrava a lo largo de la vida. La etiología de la esquizofrenia es multifactorial con evidencias de factores genéticos y ambientales. El carácter hereditario de la...

  6. Ontogeny of serotonin and serotonin2A receptors in rat auditory cortex.

    Science.gov (United States)

    Basura, Gregory J; Abbas, Atheir I; O'Donohue, Heather; Lauder, Jean M; Roth, Bryan L; Walker, Paul D; Manis, Paul B

    2008-10-01

    Maturation of the mammalian cerebral cortex is, in part, dependent upon multiple coordinated afferent neurotransmitter systems and receptor-mediated cellular linkages during early postnatal development. Given that serotonin (5-HT) is one such system, the present study was designed to specifically evaluate 5-HT tissue content as well as 5-HT(2A) receptor protein levels within the developing auditory cortex (AC). Using high performance liquid chromatography (HPLC), 5-HT and the metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was measured in isolated AC, which demonstrated a developmental dynamic, reaching young adult levels early during the second week of postnatal development. Radioligand binding of 5-HT(2A) receptors with the 5-HT(2A/2C) receptor agonist, (125)I-DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; in the presence of SB206553, a selective 5-HT(2C) receptor antagonist, also demonstrated a developmental trend, whereby receptor protein levels reached young adult levels at the end of the first postnatal week (P8), significantly increased at P10 and at P17, and decreased back to levels not significantly different from P8 thereafter. Immunocytochemical labeling of 5-HT(2A) receptors and confocal microscopy revealed that 5-HT(2A) receptors are largely localized on layer II/III pyramidal cell bodies and apical dendrites within AC. When considered together, the results of the present study suggest that 5-HT, likely through 5-HT(2A) receptors, may play an important role in early postnatal AC development.

  7. Frontal-subcortical circuits in obsessive-compulsive disorder: role of the dopamine D1 receptor

    International Nuclear Information System (INIS)

    Olver, J.S.; Reutens, D.C.; Maruff, P.; Burrows, G.D.; Norman, T.R.; Ellen, S.R.; Pantelis, C.; Tochon-Danguy, H.; Ackermann, U.; Stekelenberg, N.

    2000-01-01

    Full text: Obsessive-Compulsive Disorder (OCD) is an anxiety disorder which is increasingly being recognised as a neurobiological disorder. While serotonergic mechanisms have been proposed, the major competing theory in the pathophysiology of OCD involves the neurotransmitter dopamine. The Dopamine D1 receptor is implicated in OCD following the finding of specific spatial working memory abnormalities in a series of neuropsychological studies. Spatial working memory is known to depend on the integrity of D1 receptor function in the Dorso-lateral Prefrontal Cortex (DLPFC) of primates. This study aims to examine the role of dopamine in patients with OCD and in particular to test the hypothesis that there is an upregulation of dopamine D1 receptors in the DLPFC which correlates with spatial working memory deficits in OCD. Three OCD patients and three normal controls underwent Positron Emission Tomography (PET) following intravenous injection of the D1 antagonist PET ligand SCH23390. Reconstructed PET images were co registered with subject Magnetic Resonance Images (MRI) and regions of interest drawn manually. We will present the analysis of the Binding Potentials of SCH23390 in the regions of interest of the first three OCD patients and compare them with three normal control patients. In conclusion Dopamine-Serotonergic interactions are involved in the pathophysiology of OCD. Copyright (2000) The Australian and New Zealand Society of Nuclear Medicine Inc

  8. GABAergic and cortical and subcortical glutamatergic axon terminals contain CB1 cannabinoid receptors in the ventromedial nucleus of the hypothalamus.

    Directory of Open Access Journals (Sweden)

    Leire Reguero

    Full Text Available BACKGROUND: Type-1 cannabinoid receptors (CB(1R are enriched in the hypothalamus, particularly in the ventromedial hypothalamic nucleus (VMH that participates in homeostatic and behavioral functions including food intake. Although CB(1R activation modulates excitatory and inhibitory synaptic transmission in the brain, CB(1R contribution to the molecular architecture of the excitatory and inhibitory synaptic terminals in the VMH is not known. Therefore, the aim of this study was to investigate the precise subcellular distribution of CB(1R in the VMH to better understand the modulation exerted by the endocannabinoid system on the complex brain circuitries converging into this nucleus. METHODOLOGY/PRINCIPAL FINDINGS: Light and electron microscopy techniques were used to analyze CB(1R distribution in the VMH of CB(1R-WT, CB(1R-KO and conditional mutant mice bearing a selective deletion of CB(1R in cortical glutamatergic (Glu-CB(1R-KO or GABAergic neurons (GABA-CB(1R-KO. At light microscopy, CB(1R immunolabeling was observed in the VMH of CB(1R-WT and Glu-CB(1R-KO animals, being remarkably reduced in GABA-CB(1R-KO mice. In the electron microscope, CB(1R appeared in membranes of both glutamatergic and GABAergic terminals/preterminals. There was no significant difference in the percentage of CB(1R immunopositive profiles and CB(1R density in terminals making asymmetric or symmetric synapses in CB(1R-WT mice. Furthermore, the proportion of CB(1R immunopositive terminals/preterminals in CB(1R-WT and Glu-CB(1R-KO mice was reduced in GABA-CB(1R-KO mutants. CB(1R density was similar in all animal conditions. Finally, the percentage of CB(1R labeled boutons making asymmetric synapses slightly decreased in Glu-CB(1R-KO mutants relative to CB(1R-WT mice, indicating that CB(1R was distributed in cortical and subcortical excitatory synaptic terminals. CONCLUSIONS/SIGNIFICANCE: Our anatomical results support the idea that the VMH is a relevant hub candidate in

  9. Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use

    DEFF Research Database (Denmark)

    Erritzoe, D.; Frokjaer, V. G.; Haugbol, S.

    2009-01-01

    receptor (5-HT(2A)) in humans, we tested in 136 healthy human subjects if body mass index (BMI), degree of alcohol consumption and tobacco smoking was associated to the cerebral in vivo 5-HT(2A) receptor binding as measured with (18)F-altanserin PET. The subjects' BMI's ranged from 18.4 to 42.8 (25.......2+/-4.3) kg/m(2). Cerebral cortex 5-HT(2A) binding was significantly positively correlated to BMI, whereas no association between cortical 5-HT(2A) receptor binding and alcohol or tobacco use was detected. We suggest that our observation is driven by a lower central 5-HT level in overweight people, leading...

  10. Serotonin 2a Receptor and serotonin 1a receptor interact within the medial prefrontal cortex during recognition memory in mice

    Directory of Open Access Journals (Sweden)

    Juan Facundo Morici

    2015-12-01

    Full Text Available Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a -/- with wild type (htr2a+/+ littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex.

  11. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

    OpenAIRE

    Valle, Marta; Ana Elda, Maqueda; Rabella, Mireia; Rodríguez Pujadas, Aina; Antonijoan Arbós, Rosa Maria; Romero Lafuente, Sergio; Alonso López, Joan Francesc; Mañanas Villanueva, Miguel Ángel; Barker, Steven; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-01-01

    Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus ß-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimental...

  12. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations.

    Science.gov (United States)

    Kometer, Michael; Schmidt, André; Jäncke, Lutz; Vollenweider, Franz X

    2013-06-19

    Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. Although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-HT) receptors, recent evidence suggests that activation of 5-HT2A receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. To address this hypothesis, we assessed the effects of psilocybin (215 μg/kg vs placebo) on both α oscillations that regulate cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. To further disentangle the specific contributions of 5-HT2A receptors, subjects were additionally pretreated with the preferential 5-HT2A receptor antagonist ketanserin (50 mg vs placebo). We found that psilocybin strongly decreased prestimulus parieto-occipital α power values, thus precluding a subsequent stimulus-induced α power decrease. Furthermore, psilocybin strongly decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. All of these effects were blocked by pretreatment with the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. Specifically, activation of 5-HT2A receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of α oscillations. Furthermore, the observed reduction of N170 visual-evoked potentials may be a key mechanism underlying 5-HT2A receptor-mediated visual hallucinations. This change in N170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and Parkinson's disease.

  13. Serotonin 2A receptors contribute to the regulation of risk-averse decisions

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Rowe, James B; Hornboll, Bettina

    2013-01-01

    Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors...... in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5-HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were...

  14. Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music.

    Science.gov (United States)

    Barrett, Frederick S; Preller, Katrin H; Herdener, Marcus; Janata, Petr; Vollenweider, Franz X

    2017-09-28

    Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Distribution of serotonin 2A and 2C receptor mRNA expression in the cervical ventral horn and phrenic motoneurons following spinal cord hemisection.

    Science.gov (United States)

    Basura, G J; Zhou, S Y; Walker, P D; Goshgarian, H G

    2001-06-01

    Cervical spinal cord injury leads to a disruption of bulbospinal innervation from medullary respiratory centers to phrenic motoneurons. Animal models utilizing cervical hemisection result in inhibition of ipsilateral phrenic nerve activity, leading to paralysis of the hemidiaphragm. We have previously demonstrated a role for serotonin (5-HT) as one potential modulator of respiratory recovery following cervical hemisection, a mechanism that likely occurs via 5-HT2A and/or 5-HT2C receptors. The present study was designed to specifically examine if 5-HT2A and/or 5-HT2C receptors are colocalized with phrenic motoneurons in both intact and spinal-hemisected rats. Adult female rats (250-350 g; n = 6 per group) received a left cervical (C2) hemisection and were injected with the fluorescent retrograde neuronal tracer Fluorogold into the left hemidiaphragm. Twenty-four hours later, animals were killed and spinal cords processed for in situ hybridization and immunohistochemistry. Using (35)S-labeled cRNA probes, cervical spinal cords were probed for 5-HT2A and 5-HT2C receptor mRNA expression and double-labeled using an antibody to Fluorogold to detect phrenic motoneurons. Expression of both 5-HT2A and 5-HT2C receptor mRNA was detected in motoneurons of the cervical ventral horn. Despite positive expression of both 5-HT2A and 5-HT2C receptor mRNA-hybridization signal over phrenic motoneurons, only 5-HT2A silver grains achieved a signal-to-noise ratio representative of colocalization. 5-HT2A mRNA levels in identified phrenic motoneurons were not significantly altered following cervical hemisection compared to sham-operated controls. Selective colocalization of 5-HT2A receptor mRNA with phrenic motoneurons may have implications for recently observed 5-HT2A receptor-mediated regulation of respiratory activity and/or recovery in both intact and injury-compromised states. Copyright 2001 Academic Press.

  16. Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G.; Erritzoe, David; Juul, Anders

    2010-01-01

    the effect of plasma sex hormone levels on neocortical 5-HT2A receptor binding as imaged with [18F]altanserin PET. The effect of endogenous sex-hormone levels was evaluated by multiple linear regression analysis. Results: Mean neocortical 5-HT2A receptor binding was positively correlated with estradiol (p......Background: Sex-hormones influence brain function and are likely to play a role in the gender predisposition to mood and anxiety disorders. Acute fluctuations of sex-hormone levels including hormonal replacement therapy appear to affect serotonergic neurotransmission, but it is unknown if baseline...... levels affect serotonergic neurotransmission. This study was undertaken to examine if baseline levels of endogenous sex hormones are associated with cerebral serotonin 2A (5-HT2A) receptor binding in men. Methods: In a group of 72 healthy men (mean age 37.5 years ±17.4 SD, range 19.6–81.7) we studied...

  17. Tall Fescue Alkaloids Bind Serotonin Receptors in Cattle

    Science.gov (United States)

    The serotonin (5HT) receptor 5HT2A is involved in the tall fescue alkaloid-induced vascular contraction in the bovine periphery. This was determined by evaluating the contractile responses of lateral saphenous veins biopsied from cattle grazing different tall fescue/endophyte combinations. The contr...

  18. Serotonin 2A receptor regulation of striatal neuropeptide gene expression is selective for tachykinin, but not enkephalin neurons following dopamine depletion.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2001-08-15

    Serotonin (5-HT) 2A receptor-mediated regulation of striatal preprotachykinin (PPT) and preproenkephalin (PPE) mRNAs was studied in adult rodents that had been subjected to near-total dopamine (DA) depletion as neonates. Two months following bilateral 6-hydroxydopamine (6-OHDA) lesion, PPT mRNA levels decreased 59-73% across dorsal subregions of the rostral and caudal striatum while PPE transcripts increased 61-94%. Four hours after a single injection of the serotonin 2A/2C receptor agonist, (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1 mg/kg), PPT mRNA expression was significantly increased in DA-depleted rats across all dorsal subregions of the rostral and caudal striatum as compared to 6-OHDA-treated animals alone. In the intact rat, DOI did not influence PPT mRNA levels in the rostral striatum, but did raise expression in the caudal striatum where 5-HT2A receptors are prominent. DOI did not regulate PPE mRNA levels in any striatal sub-region of the intact or DA-depleted rat. Prior administration of the 5-HT2A/2C receptor antagonist, ritanserin (1 mg/kg) or the 5-HT2A receptor antagonist, ketanserin (1 mg/kg) completely blocked the DOI-induced increases in striatal PPT mRNA in both lesioned and intact animals. The ability of ketanserin to produce identical results as ritanserin suggests that 5-HT2A receptor-mediated regulation is selectively strengthened within tachykinin neurons of the rostral striatum which are suppressed by DA depletion. The selectivity suggests that 5-HT2A receptor upregulation following DA depletion is capable of regulating tachykinin biosynthesis without influencing enkephalin expression in striatal output neurons.

  19. Pharmacologic assessment of bovine ruminal and mesenteric vascular serotonin receptor populations

    Science.gov (United States)

    Prior work using a contractility bioassay determined that the serotonin (5-HT) receptor subtype 5-HT2A is present in bovine lateral saphenous veins and plays a role in ergot alkaloid-induced vascular contraction in steers grazing endophyte-infected (Epichloë coenophiala) tall fescue (Lolium arundina...

  20. Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure

    DEFF Research Database (Denmark)

    Hervig, Mona El-Sayed; Jensen, Nadja Cecilie Hvid; Rasmussen, Nadja Bredo

    2017-01-01

    The medial prefrontal cortex (PFC) plays a major role in executive function by exerting a top-down control onto subcortical areas. Novelty-induced frontal cortex activation is 5-HT2A receptor (5-HT2AR) dependent. Here, we further investigated how blockade of 5-HT2ARs in mice exposed to a novel open-field...... of 5-HT2AR blockade on the striatal-projecting BLA neurons. Systemic administration of ketanserin (0.5 mg/kg) prior to novel open-field exposure resulted in reduced total numbers of c-Fos-IR cells in dorsomedial PFC areas and the BLA. Moreover, there was a positive correlation between the relative time...... spent in the centre of the open-field and BLA c-Fos-IR in the ketanserin-treated animals. Unilateral medial PFC lesions blocked this effect, ascertaining an involvement of this frontal cortex area. On the other hand, medial PFC lesioning exacerbated the more anxiogenic-like behaviour of the ketanserin...

  1. LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

    Science.gov (United States)

    Kraehenmann, Rainer; Pokorny, Dan; Aicher, Helena; Preller, Katrin H.; Pokorny, Thomas; Bosch, Oliver G.; Seifritz, Erich; Vollenweider, Franz X.

    2017-01-01

    Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking – an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects. Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale. Results: LSD, compared with placebo, significantly increased primary index (p LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin. Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness. PMID:29167644

  2. LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

    Directory of Open Access Journals (Sweden)

    Rainer Kraehenmann

    2017-11-01

    Full Text Available Rationale: Stimulation of serotonin 2A (5-HT2A receptors by lysergic acid diethylamide (LSD and related compounds such as psilocybin has previously been shown to increase primary process thinking – an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects.Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally. The main outcome variable in this study was primary index (PI, a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC rating scale.Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected. The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected, and blissful state (p < 0.05, Bonferroni-corrected on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin.Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and

  3. [Association between 5-hydroxytryptamine 2A receptor gene polymorphisms and susceptibility to occupational stress in oilfield workers].

    Science.gov (United States)

    Jiang, Y; Palizhati, Abudoureyimu; Gao, X Y; Guan, S Z; Liu, J W

    2016-10-20

    Objective: To investigate the association between 5-hydroxytryptamine 2A (5-HT2A) receptor gene polymorphisms and occupational stress in oilfield workers. Methods: Cluster sampling was used to select 826 oilfield workers from January to August, 2013. The SNaPshot single nucleotide polymorphism (SNP) genotyping method was used to determine the genotypes of rs6313, rs1923884, and rs2070040 in 5-HT2A receptor gene, and the Occupational Stress Inventory-Revised Edition was used to analyze occupational stress in these workers. Results: There were no significant differences in occupational stress between groups with different individual characteristics ( P >0.05 ) . As for the comparison of occupational stress scores between workers with different genotypes of each SNP of 5-HT2A receptor gene, the workers with CC and CT genotypes of rs6313 had significantly higher role boundary scores than those with TT genotype ( P stress score than those with CT genotype ( P occupational role score than those with CC genotype ( P stress score than those with AA genotype ( P occupational stress ( OR =1.56, 95% CI 1.10~2.20) . Conclusion: CT genotype of rs1923884 in 5-HT2A receptor gene may be associated with the susceptibility to occupational stress in oilfield workers.

  4. Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation.

    Science.gov (United States)

    Basura, G J; Walker, P D

    1999-08-05

    Sixty days after bilateral dopamine (DA) depletion (>98%) with 6-hydroxydopamine (6-OHDA) in neonatal rats, serotonin (5-HT) content doubled and 5-HT(2A) receptor mRNA expression rose 54% within the rostral striatum. To determine if striatal 5-HT(2A) receptor mRNA upregulation is dependent on increased 5-HT levels following DA depletion, neonatal rats received dual injections of 6-OHDA and 5,7-dihydroxytryptamine (5,7-DHT) which suppressed 5-HT content by approximately 90%. In these 6-OHDA/5,7-DHT-treated rats, striatal 5-HT(2A) receptor mRNA expression was still elevated (87% above vehicle controls). Comparative analysis of 5-HT(2C) receptor mRNA expression yielded no significant changes in any experimental group. These results demonstrate that upregulated 5-HT(2A) receptor biosynthesis in the DA-depleted rat is not dependent on subsequent 5-HT hyperinnervation. Copyright 1999 Elsevier Science B.V.

  5. Antagonism of lateral saphenous vein serotonin receptors from steers grazing endophyte-free, wild-type, or novel endophyte-infected tall fescue

    Science.gov (United States)

    Pharmacologic profiling of 5-hydroxytryptamine (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline (ERV), 5HT, 5HT2A and 5HT7 agonists. To determine if 5HT...

  6. 5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder.

    Science.gov (United States)

    Papakosta, Vassiliki-Maria; Kalogerakou, Stamatina; Kontis, Dimitris; Anyfandi, Eleni; Theochari, Eirini; Boulougouris, Vasileios; Papadopoulos, Sokrates; Panagis, George; Tsaltas, Eleftheria

    2013-04-15

    The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

    Science.gov (United States)

    Dolder, Patrick C.; Grünblatt, Edna; Müller, Felix; Borgwardt, Stefan J.; Liechti, Matthias E.

    2017-01-01

    Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes. Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study. Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo. Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans. PMID:28701958

  8. The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11 C]-raclopride and [11 C]-(+)-PHNO PET.

    Science.gov (United States)

    Caravaggio, Fernando; Ku Chung, Jun; Plitman, Eric; Boileau, Isabelle; Gerretsen, Philip; Kim, Julia; Iwata, Yusuke; Patel, Raihaan; Chakravarty, M Mallar; Remington, Gary; Graff-Guerrero, Ariel

    2017-11-01

    Abnormalities in dopamine (DA) and brain morphology are observed in several neuropsychiatric disorders. However, it is not fully understood how these abnormalities may relate to one another. For such in vivo findings to be used as biomarkers for neuropsychiatric disease, it must be understood how variability in DA relates to brain structure under healthy conditions. We explored how the availability of striatal DA D 2/3 receptors (D 2/3 R) is related to the volume of subcortical brain structures in a sample of healthy humans. Differences in D 2/3 R availability measured with an antagonist radiotracer ([ 11 C]-raclopride) versus an agonist radiotracer ([ 11 C]-(+)-PHNO) were examined. Data from 62 subjects scanned with [ 11 C]-raclopride (mean age = 38.98 ± 14.45; 23 female) and 68 subjects scanned with [ 11 C]-(+)-PHNO (mean age = 38.54 ± 14.59; 25 female) were used. Subcortical volumes were extracted from T1-weighted images using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Partial correlations were used controlling for age, gender, and total brain volume. For [ 11 C]-(+)-PHNO, ventral caudate volumes were positively correlated with BP ND in the dorsal caudate and globus pallidus (GP). Ventral striatum (VS) volumes were positively correlated with BP ND in the VS. With [ 11 C]-raclopride, BP ND in the VS was negatively correlated with subiculum volume of the hippocampus. Moreover, BP ND in the GP was negatively correlated with the volume of the lateral posterior nucleus of the thalamus. Findings are purely exploratory and presented corrected and uncorrected for multiple comparisons. We hope they will help inform the interpretation of future PET studies where concurrent changes in D 2/3 R and brain morphology are observed. Hum Brain Mapp 38:5519-5534, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  9. Endogenous hallucinogens as ligands of the trace amine receptors: a possible role in sensory perception.

    Science.gov (United States)

    Wallach, J V

    2009-01-01

    While the endogenous hallucinogens, N,N-dimethyltryptamine, 5-hydroxy-N,N-dimethyl-tryptamine and 5-methoxy-N,N-dimethyltryptamine, have been acknowledged as naturally occurring components of the mammalian body for decades, their biological function remains as elusive now as it was at the time of their discovery. The recent discovery of the trace amine associated receptors and the activity of DMT and other hallucinogenic compounds at these receptor sites leads to the hypothesis that the endogenous hallucinogens act as neurotransmitters of a subclass of these trace amine receptors. Additionally, while activity at the serotonin 5-HT2A receptor has been proposed as being responsible for the hallucinogenic affects of administered hallucinogens, in their natural setting the 5-HT2A receptor may not interact with the endogenous hallucinogens at all. Additionally 5-HT2A agonist activity is unable to account for the visual altering effects of many of the administered hallucinogens; these effects may be mediated by one of the endogenous hallucinogen trace amine receptors rather than the serotonin 5-HT2A receptor. Therefore, activity at the trace amine receptors, in addition to serotonin receptors, may play a large role in the sensory altering effects of administered hallucinogens and the trace amine receptors along with their endogenous hallucinogen ligands may serve an endogenous role in mediating sensory perception in the mammalian central nervous system. Thus the theory proposed states that these compounds act as true endogenous hallucinogenic transmitters acting in regions of the central nervous system involved in sensory perception.

  10. The flinders sensitive line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17beta-estradiol.

    Science.gov (United States)

    Osterlund, M K; Overstreet, D H; Hurd, Y L

    1999-12-10

    The possible link between estrogen and serotonin (5-HT) in depression was investigated using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rats, in comparison to control Flinders Resistant Line rats. The mRNA levels of the estrogen receptor (ER) alpha and beta subtypes and the 5-HT(1A) and 5-HT(2A) receptors were analyzed in several limbic-related areas of ovariectomized FSL and FRL rats treated with 17beta-estradiol (0.15 microg/g) or vehicle. The FSL animals were shown to express significantly lower levels of the 5-HT(2A) receptor transcripts in the perirhinal cortex, piriform cortex, and medial anterodorsal amygdala and higher levels in the CA 2-3 region of the hippocampus. The only significant difference between the rat lines in ER mRNA expression was found in the medial posterodorsal amygdala, where the FSL rats showed lower ERalpha expression levels. Overall, estradiol treatment increased 5-HT(2A) and decreased 5-HT(1A) receptor mRNA levels in several of the examined regions of both lines. Thus, in many areas, estradiol was found to regulate the 5-HT receptor mRNA expression in the opposite direction to the alterations found in the FSL rats. These findings further support the implication of 5-HT receptors, in particular the 5-HT(2A) subtype, in the etiology of affective disorders. Moreover, the ability of estradiol to regulate the expression of the 5-HT(1A) and 5-HT(2A) receptor genes might account for the reported influence of gonadal hormones in mood and depression.

  11. Subcortical arteriosclerotic encephalopathy (Binswanger disease)

    International Nuclear Information System (INIS)

    Settanni, F.; Dumont, P.; Casella, C.L.; Pascuzzi, L.; Cecilio, S.; Caldas, J.G.

    1992-01-01

    Four patients with variable clinical and tomographic features were diagnosed as having subcortical arteriosclerotic encephalopathy (Binswanger disease). This diagnosis was done based on the presence of subacute progression of focal cerebral deficits, presence of hypertension, systemic vascular disease and dementia. The pathogenesis of subcortical arteriosclerotic encephalopathy is unknown; possible mechanism include diffuse ischemia and fluid transudation with subsequent gliosis related to subacute hypertensive encephalopathy. (author)

  12. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans.

    Science.gov (United States)

    Valle, Marta; Maqueda, Ana Elda; Rabella, Mireia; Rodríguez-Pujadas, Aina; Antonijoan, Rosa Maria; Romero, Sergio; Alonso, Joan Francesc; Mañanas, Miquel Àngel; Barker, Steven; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-07-01

    Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  13. Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior.

    Science.gov (United States)

    Gass, Natalia; Becker, Robert; Sack, Markus; Schwarz, Adam J; Reinwald, Jonathan; Cosa-Linan, Alejandro; Zheng, Lei; von Hohenberg, Christian Clemm; Inta, Dragos; Meyer-Lindenberg, Andreas; Weber-Fahr, Wolfgang; Gass, Peter; Sartorius, Alexander

    2018-04-01

    Evidence indicates that ketamine's rapid antidepressant efficacy likely results from its antagonism of NR2B-subunit-containing NMDA receptors (NMDAR). Since ketamine equally blocks NR2A- and NR2B-containing NMDAR, and has affinity to other receptors, NR2B-selective drugs might have improved therapeutic efficiency and side effect profile. We aimed to compare the effects of (S)-ketamine and two different types of NR2B-selective antagonists on functional brain networks in rats, in order to find common circuits, where their effects intersect, and that might explain their antidepressant action. The experimental design comprised four parallel groups of rats (N = 37), each receiving (S)-Ketamine, CP-101,606, Ro 25-6981 or saline. After compound injection, we acquired resting-state functional magnetic resonance imaging time series. We used graph theoretical approach to calculate brain network properties. Ketamine and CP-101,606 diminished the global clustering coefficient and small-worldness index. At the nodal level, all compounds induced increased connectivity of the regions mediating reward and cognitive aspects of emotional processing, such as ventromedial prefrontal cortex, septal nuclei, and nucleus accumbens. The dorsal hippocampus and regions involved in sensory processing and aversion, such as superior and inferior colliculi, exhibited an opposite effect. The effects common to ketamine and NR2B-selective compounds were localized to the same brain regions as those reported in depression, but in the opposite direction. The upregulation of the reward circuitry might partially underlie the antidepressant and anti-anhedonic effects of the antagonists and could potentially serve as a translational imaging phenotype for testing putative antidepressants, especially those targeting the NR2B receptor subtype.

  14. Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation.

    Science.gov (United States)

    Kraehenmann, Rainer; Pokorny, Dan; Vollenweider, Leonie; Preller, Katrin H; Pokorny, Thomas; Seifritz, Erich; Vollenweider, Franz X

    2017-07-01

    Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming. This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects. Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire. LSD, compared with placebo, significantly increased cognitive bizarreness (p < 0.001). The LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control (p < 0.05). Both LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin. LSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.

  15. Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

    Science.gov (United States)

    Córdova-Sintjago, Tania; Villa, Nancy; Fang, Lijuan; Booth, Raymond G.

    2014-02-01

    The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

  16. Serotonin₂A/C receptors mediate the aggressive phenotype of TLX gene knockout mice.

    Science.gov (United States)

    Juárez, Pablo; Valdovinos, Maria G; May, Michael E; Lloyd, Blair P; Couppis, Maria H; Kennedy, Craig H

    2013-11-01

    Deleting the tailless (TLX) gene in mice produces a highly aggressive phenotype yet to be characterized in terms of heterozygous animals or neurotransmitter mechanisms. We sought to establish pharmacological control over aggression and study the role of serotonin (5-HT)(2A/C) receptors in mediating changes in aggression. We analyzed aggression in mice heterozygous (+/-) or homozygous (-/-) for the TLX gene and wild-types (+/+) using a resident-intruder paradigm. No +/+ mice were aggressive, 36% of +/- TLX and 100% of -/- TLX mice showed aggression. Dose-effect functions were established for clozapine (0.1-1.5mg/kg, ip), ketanserin (0.3-1.25 mg/kg, ip), and (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI] (0.5-2.0 mg/kg, ip). Injecting clozapine decreased the frequency and duration of attacks for +/- TLX and -/- TLX mice. Clozapine did not decrease grooming in either +/- TLX or -/- TLX mice but may have increased locomotion for -/- TLX mice. Injecting ketanserin, a 5-HT(2A/C) receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting (±)DOI, a 5-HT(2A/C) receptor agonist, increased the frequency and duration of attacks, decreased the latency to attacks, and decreased locomotion in +/- and -/- TLX mice. Results of the current study suggest aggression displayed by TLX null and heterozygous mice involves 5-HT(2A/C) receptors. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Receptor binding profiles and behavioral pharmacology of ring-substituted N,N-diallyltryptamine analogs.

    Science.gov (United States)

    Klein, Landon M; Cozzi, Nicholas V; Daley, Paul F; Brandt, Simon D; Halberstadt, Adam L

    2018-02-27

    Substantial effort has been devoted toward understanding the psychopharmacological effects of tryptamine hallucinogens, which are thought to be mediated by activation of 5-HT 2A and 5-HT 1A receptors. Recently, several psychoactive tryptamines based on the N,N-diallyltryptamine (DALT) scaffold have been encountered as recreational drugs. Despite the apparent widespread use of DALT derivatives in humans, little is known about their pharmacological properties. We compared the binding affinities of DALT and its 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 5-methoxy-, 5-methoxy-2-methyl-, 5-fluoro-, 5-fluoro-2-methyl-, 5-bromo-, and 7-ethyl-derivatives at 45 receptor and transporter binding sites. Additionally, studies in C57BL/6 J mice examined whether these substances induce the head twitch response (HTR), a 5-HT 2A receptor-mediated response that is widely used as a behavioral proxy for hallucinogen effects in humans. Most of the test drugs bound to serotonin receptors, σ sites, α 2 -adrenoceptors, dopaminergic D 3 receptors, histaminergic H 1 receptors, and the serotonin transporter. DALT and several of the ring-substituted derivatives were active in the HTR assay with the following rank order of potency: 4-acetoxy-DALT > 5-fluoro-DALT > 5-methoxy-DALT > 4-hydroxy-DALT > DALT > 5-bromo-DALT. 2-Phenyl-DALT, 5-methoxy-2-methyl-DALT, 5-fluoro-2-methyl-DALT, and 7-ethyl-DALT did not induce the HTR. HTR potency was not correlated with either 5-HT 1A or 5-HT 2A receptor binding affinity, but a multiple regression analysis indicated that 5-HT 2A and 5-HT 1A receptors make positive and negative contributions, respectively, to HTR potency (R 2  = 0.8729). In addition to supporting the established role of 5-HT 2A receptors in the HTR, these findings are consistent with evidence that 5-HT 1A activation by tryptamine hallucinogens buffers their effects on HTR. Published by Elsevier Ltd.

  18. Mammal-like striatal functions in Anolis. I. Distribution of serotonin receptor subtypes, and absence of striosome and matrix organization.

    Science.gov (United States)

    Clark, E C; Baxter, L R

    2000-11-01

    Serotonin (5-HT) 5-HT(2A) and 5-HT(2C) receptors are thought to play important roles in the mammalian striatum. As basal ganglia functions in general are thought highly conserved among amniotes, we decided to use in situ autoradiographic methods to determine the occurrence and distribution of pharmacologically mammal-like 5-HT(2A) and 5-HT(2C) receptors in the lizard, Anolis carolinensis, with particular attention to the striatum. We also determined the distributions of 5-HT(1A), 5-HT(1B/D), 5 HT(3), and 5-HT(uptake) receptors for comparison. All 5-HT receptors examined showed pharmacological binding specificity, and forebrain binding density distributions that resembled those reported for mammals. Anolis 5 HT(2A/C) and 5-HT(1A) site distributions were similar in both in vivo and ex vivo binding experiments. 5-HT(2A & C) receptors occur in both high and low affinity states, the former having preferential affinity for (125)I-(+/-)-2,5-dimethoxy-4-iodo-amphetamine hydrochloride ((125)I-DOI). In mammals (125)I-DOI binding shows a patchy density distribution in the striatum, being more dense in striosomes than in surrounding matrix. There was no evidence of any such patchy density of (125)I-DOI binding in the anole striatum, however. As a further indication that anoles do not possess a striosome and matrix striatal organization, neither (3)H-naloxone binding nor histochemical staining for acetylcholinesterase activity (AChE) were patchy. AChE did show a band-like striatal distribution, however, similar to that seen in birds. Copyright 2001 S. Karger AG, Basel

  19. Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding

    DEFF Research Database (Denmark)

    Frøkjær, Vibe Gedsø; Vinberg, Maj; Erritzoe, David

    2010-01-01

    Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability...... stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission....... and is positively correlated to frontolimbic serotonin 2A (5-HT(2A)) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT(2A) receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co...

  20. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes.

    Science.gov (United States)

    Newman-Tancredi, Adrian; Cussac, Didier; Quentric, Yann; Touzard, Manuelle; Verrièle, Laurence; Carpentier, Nathalie; Millan, Mark J

    2002-11-01

    Although certain antiparkinson agents interact with serotonin (5-HT) receptors, little information is available concerning functional actions. Herein, we characterized efficacies of apomorphine, bromocriptine, cabergoline, lisuride, piribedil, pergolide, roxindole, and terguride at human (h)5-HT(1A), h5-HT(1B), and h5-HT(1D) receptors [guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding], and at h5-HT(2A), h5-HT(2B), and h5-HT(2C) receptors (depletion of membrane-bound [(3)H]phosphatydilinositol). All drugs stimulated h5-HT(1A) receptors with efficacies (compared with 5-HT, 100%) ranging from modest (apomorphine, 35%) to high (cabergoline, 93%). At h5-HT(1B) receptors, efficacies varied from mild (terguride, 37%) to marked (cabergoline, 102%) and potencies were modest (pEC(50) values of 5.8-7.6): h5-HT(1D) sites were activated with a similar range of efficacies and greater potency (7.1-8.5). Piribedil and apomorphine were inactive at h5-HT(1B) and h5-HT(1D) receptors. At h5-HT(2A) receptors, terguride, lisuride, bromocriptine, cabergoline, and pergolide displayed potent (7.6-8.8) agonist properties (49-103%), whereas apomorphine and roxindole were antagonists and piribedil was inactive. Only pergolide (113%/8.2) and cabergoline (123%/8.6) displayed pronounced agonist properties at h5-HT(2B) receptors. At 5-HT(2C) receptors, lisuride, bromocriptine, pergolide, and cabergoline were efficacious (75-96%) agonists, apomorphine and terguride were antagonists, and piribedil was inactive. MDL100,907 and SB242,084, selective antagonists at 5-HT(2A) and 5-HT(2C) receptors, respectively, abolished these actions of pergolide, cabergoline, and bromocriptine. In conclusion, antiparkinson agents display markedly different patterns of agonist and antagonist properties at multiple 5-HT receptor subtypes. Although all show modest (agonist) activity at 5-HT(1A) sites, their contrasting actions at 5-HT(2A) and 5-HT(2C) sites may be of particular significance to their

  1. Radiological diagnosis of periventricular and subcortical leukomalacia

    Energy Technology Data Exchange (ETDEWEB)

    Taboada, D.; Alonso, A.; Olague, R.; Mulas, F.; Andres, V.

    1980-08-01

    Nine newborn infants with histories of perinatal asphyxia are presented. The pneumoencephalographic findings which led to the diagnosis are typical and constant. They include marked subcortical atrophy with rounded, dilated, and undisplaced lateral ventricles. Cystography with 3 cc of air demonstrated multiple subcortical and paraventricular cavities, without communication with the ventricular system, but with the typical honeycomb appearance of paraventricular and subcortical leukomalacia described in postmortem findings. The CT findings are typical, and provide the location of the cavities as well as their density.

  2. Metabotropic glutamate receptor 2 and corticotrophin-releasing factor receptor-1 gene expression is differently regulated by BDNF in rat primary cortical neurons

    DEFF Research Database (Denmark)

    Jørgensen, Christinna V; Klein, Anders B; El-Sayed, Mona

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and plasticity. Incorporation of matured receptor proteins is an integral part of synapse formation. However, whether BDNF increases synthesis and integration of receptors in functional synapses directly is unclear. We...... are particularly interested in the regulation of the 5-hydroxytryptamine receptor 2A (5-HT2A R). This receptor form a functional complex with the metabotropic glutamate receptor 2 (mGluR2) and is recruited to the cell membrane by the corticotrophin-releasing factor receptor 1 (CRF-R1). The effect of BDNF on gene...... expression for all these receptors, as well as a number of immediate-early genes, was pharmacologically characterized in primary neurons from rat frontal cortex. BDNF increased CRF-R1 mRNA levels up to fivefold, whereas mGluR2 mRNA levels were proportionally downregulated. No effect on 5-HT2A R mRNA was seen...

  3. Subcortical functional reorganization due to early blindness.

    Science.gov (United States)

    Coullon, Gaelle S L; Jiang, Fang; Fine, Ione; Watkins, Kate E; Bridge, Holly

    2015-04-01

    Lack of visual input early in life results in occipital cortical responses to auditory and tactile stimuli. However, it remains unclear whether cross-modal plasticity also occurs in subcortical pathways. With the use of functional magnetic resonance imaging, auditory responses were compared across individuals with congenital anophthalmia (absence of eyes), those with early onset (in the first few years of life) blindness, and normally sighted individuals. We find that the superior colliculus, a "visual" subcortical structure, is recruited by the auditory system in congenital and early onset blindness. Additionally, auditory subcortical responses to monaural stimuli were altered as a result of blindness. Specifically, responses in the auditory thalamus were equally strong to contralateral and ipsilateral stimulation in both groups of blind subjects, whereas sighted controls showed stronger responses to contralateral stimulation. These findings suggest that early blindness results in substantial reorganization of subcortical auditory responses. Copyright © 2015 the American Physiological Society.

  4. Typical and Atypical Antipsychotic Drugs Increase Extracellular Histamine Levels in the Rat Medial Prefrontal Cortex: Contribution of Histamine H1 Receptor Blockade

    Directory of Open Access Journals (Sweden)

    Kjell A Svensson

    2012-05-01

    Full Text Available Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA efflux in the mPFC of the rat by means of in vivo microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine and perphenazine treatment. We found no effect of the selective 5-HT2A antagonist MDL100907, 5-HT2c antagonist SB242084 or the 5-HT6 antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H1 receptor antagonists pyrilamine, diphenhydramine and triprolidine, the H3 receptor antagonist ciproxifan and the mixed 5HT2A/H1 receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H1 receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H1 receptor affinity (risperidone, aripiprazole and haloperidol were also without effect on HA efflux. Perfusion of clozapine and pyrilamine into the TMN, but not the mPFC, increased local HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H1 receptors whereas 9 other receptors, including 5-HT2A, were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H1 receptors.

  5. Serotonin(2) receptors mediate respiratory recovery after cervical spinal cord hemisection in adult rats.

    Science.gov (United States)

    Zhou, S Y; Basura, G J; Goshgarian, H G

    2001-12-01

    The aim of the present study was to specifically investigate the involvement of serotonin [5-hydroxytryptamine (5-HT(2))] receptors in 5-HT-mediated respiratory recovery after cervical hemisection. Experiments were conducted on C(2) spinal cord-hemisected, anesthetized (chloral hydrate, 400 mg/kg ip), vagotomized, pancuronium- paralyzed, and artificially ventilated female Sprague-Dawley rats in which CO(2) levels were monitored and maintained. Twenty-four hours after spinal hemisection, the ipsilateral phrenic nerve displayed no respiratory-related activity indicative of a functionally complete hemisection. Intravenous administration of the 5-HT(2A/2C)-receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced respiratory-related activity in the phrenic nerve ipsilateral to hemisection under conditions in which CO(2) was maintained at constant levels and augmented the activity induced under conditions of hypercapnia. The effects of DOI were found to be dose dependent, and the recovery of activity could be maintained for up to 2 h after a single injection. DOI-induced recovery was attenuated by the 5-HT(2)-receptor antagonist ketanserin but not with the 5-HT(2C)-receptor antagonist RS-102221, suggesting that 5-HT(2A) and not necessarily 5-HT(2C) receptors may be involved in the induction of respiratory recovery after cervical spinal cord injury.

  6. Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex.

    Science.gov (United States)

    Gresch, Paul J; Smith, Randy L; Barrett, Robert J; Sanders-Bush, Elaine

    2005-09-01

    Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance

  7. Dysphagia Post Subcortical and Supratentorial Stroke.

    Science.gov (United States)

    Wan, Ping; Chen, Xuhui; Zhu, Lequn; Xu, Shuangjin; Huang, Li; Li, Xiangcui; Ye, Qing; Ding, Ruiying

    2016-01-01

    Studies have recognized that the damage in the subcortical and supratentorial regions may affect voluntary and involuntary aspects of the swallowing function. The current study attempted to explore the dysphagia characteristics in patients with subcortical and supratentorial stroke. Twelve post first or second subcortical and supratentorial stroke patients were included in the study. The location of the stroke was ascertained by computed tomography and magnetic resonance imaging. The characteristics of swallowing disorder were assessed by video fluoroscopic swallowing assessment/fiberoptic endoscopic evaluation of swallowing. The following main parameters were analyzed: oral transit time, pharyngeal delay time, presence of cricopharyngeal muscle achalasia (CMA), distance of laryngeal elevation, the amounts of vallecular residue and pyriform sinus residue (PSR), and the extent of pharyngeal contraction. Eighty-three percent of the 12 patients were found suffering from pharyngeal dysphagia, with 50% having 50%-100% PSRs, 50% having pharyngeal delay, and 41.6% cases demonstrating CMA. Simple regression analysis showed PSRs were most strongly associated with CMA. Pharyngeal delay in the study can be caused by infarcts of basal ganglia/thalamus, infarcts of sensory tract, infarcts of swallowing motor pathways in the centrum semiovale, or a combination of the three. Subcortical and supratentorial stroke may result in pharyngeal dysphagia such as PSR and pharyngeal delay. PSR was mainly caused by CMA. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  8. [Subcortical laminar heterotopia 'double cortex syndrome'].

    Science.gov (United States)

    Teplyshova, A M; Gaskin, V V; Kustov, G V; Gudkova, A A; Luzin, R V; Trifonov, I S; Lebedeva, A V

    2017-01-01

    This article presents a clinical case of a 29-year-old patient with 'Double cortex syndrome' with epilepsy, intellectual and mental disorders. Subcortical band heterotopia is a rare disorder of neuronal migration. Such patients typically present with epilepsy and variable degrees of mental retardation and behavioral and intellectual disturbances. The main diagnostic method is magnetic resonance imaging (MRI).

  9. Subcortical Brain Morphology in Schizophrenia : Descriptive analysis based on MRI findings of subcortical brain volumes

    OpenAIRE

    Gunleiksrud, Sindre

    2009-01-01

    The aim of this study was to investigate magnetic resonance images (MR) from patients with schizophrenia and healthy control subjects for difference in brain morphology with focus on subcortical brain volumes. Method: The study compared fourteen subcortical brain structure volumes of 96 patients diagnosed with schizophrenia (n=81) or schizoaffective disorder (n=15) with 106 healthy control subjects. Volume measures were obtained using voxel-based morphometry (FreeSurfer software suite) of ...

  10. Subcortical intelligence: caudate volume predicts IQ in healthy adults.

    Science.gov (United States)

    Grazioplene, Rachael G; G Ryman, Sephira; Gray, Jeremy R; Rustichini, Aldo; Jung, Rex E; DeYoung, Colin G

    2015-04-01

    This study examined the association between size of the caudate nuclei and intelligence. Based on the central role of the caudate in learning, as well as neuroimaging studies linking greater caudate volume to better attentional function, verbal ability, and dopamine receptor availability, we hypothesized the existence of a positive association between intelligence and caudate volume in three large independent samples of healthy adults (total N = 517). Regression of IQ onto bilateral caudate volume controlling for age, sex, and total brain volume indicated a significant positive correlation between caudate volume and intelligence, with a comparable magnitude of effect across each of the three samples. No other subcortical structures were independently associated with IQ, suggesting a specific biological link between caudate morphology and intelligence. © 2014 Wiley Periodicals, Inc.

  11. Pharmacokinetic-pharmacodynamic analysis of antipsychotics-induced extrapyramidal symptoms based on receptor occupancy theory incorporating endogenous dopamine release.

    Science.gov (United States)

    Matsui-Sakata, Akiko; Ohtani, Hisakazu; Sawada, Yasufumi

    2005-06-01

    We aimed to analyze the risks of extrapyramidal symptoms (EPS) induced by typical and atypical antipsychotic drugs using a common pharmacokinetic-pharmacodynamic (PK-PD) model based on the receptor occupancy. We collected the data for EPS induced by atypical antipsychotics, risperidone, olanzapine and quetiapine, and a typical antipsychotic, haloperidol from literature and analyzed the following five indices of EPS, the ratio of patients obliged to take anticholinergic medication, the occurrence rates of plural extrapyramidal symptoms (more than one of tremor, dystonia, hypokinesia, akathisia, extrapyramidal syndrome, etc.), parkinsonism, akathisia, and extrapyramidal syndrome. We tested two models, i.e., a model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition and a model not considering the endogenous dopamine release, and used them to examine the relationship between the D2 receptor occupancy of endogenous dopamine and the extent of drug-induced EPS. The model incorporating endogenous dopamine release better described the relationship between the mean D2 receptor occupancy of endogenous dopamine and the extent of EPS than the other model, as assessed by the final sum of squares of residuals (final SS) and Akaike's Information Criteria (AIC). Furthermore, the former model could appropriately predict the risks of EPS induced by two other atypical antipsychotics, clozapine and ziprasidone, which were not incorporated into the model development. The developed model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition may be useful for the prediction of antipsychotics-induced EPS.

  12. Implications of Subcortical structures in Aphasia.

    Directory of Open Access Journals (Sweden)

    Saleh Alamri

    2015-04-01

    Taken together, the results indicate that aphasia is a common outcome after a lesion to subcortical structures. Findings show that 110 out of 394 aphasic patients with lesion in the basal ganglia exhibited comprehension deficits, while 31 participants out of 288 with thalamic aphasia. Likewise, 129 aphasics of affected basal ganglia out of 394 had impaired naming, whereas 12 participants had impaired naming out of 288 individuals with thalamic aphasia. See figure 1. Figure 1: The percentage of language impairment in two sets of aphasic patients (the thalamus and the basal ganglia. Despite contradictory results and even cases of double dissociation (for an example of absence of language deficits in the event of thalamic lesions see Cappa et al., 1986, our literature review confirms the major role of subcortical structures in language processing.

  13. Dopamine, Noradrenaline and Serotonin Receptor Densities in the Striatum of Hemiparkinsonian Rats following Botulinum Neurotoxin-A Injection.

    Science.gov (United States)

    Mann, T; Zilles, K; Dikow, H; Hellfritsch, A; Cremer, M; Piel, M; Rösch, F; Hawlitschka, A; Schmitt, O; Wree, A

    2018-03-15

    Parkinson's disease (PD) is characterized by a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that causes a dopamine (DA) deficit in the caudate-putamen (CPu) accompanied by compensatory changes in other neurotransmitter systems. These changes result in severe motor and non-motor symptoms. To disclose the role of various receptor binding sites for DA, noradrenaline, and serotonin in the hemiparkinsonian (hemi-PD) rat model induced by unilateral 6-hydroxydopamine (6-OHDA) injection, the densities of D 1 , D 2 /D 3 , α 1 , α 2 , and 5HT 2A receptors were longitudinally visualized and measured in the CPu of hemi-PD rats by quantitative in vitro receptor autoradiography. We found a moderate increase in D 1 receptor density 3 weeks post lesion that decreased during longer survival times, a significant increase of D 2 /D 3 receptor density, and 50% reduction in 5HT 2A receptor density. α 1 receptor density remained unaltered in hemi-PD and α 2 receptors demonstrated a slight right-left difference increasing with post lesion survival. In a second step, the possible role of receptors on the known reduction of apomorphine-induced rotations in hemi-PD rats by intrastriatally injected Botulinum neurotoxin-A (BoNT-A) was analyzed by measuring the receptor densities after BoNT-A injection. The application of this neurotoxin reduced D 2 /D 3 receptor density, whereas the other receptors mainly remained unaltered. Our results provide novel data for an understanding of the postlesional plasticity of dopaminergic, noradrenergic and serotonergic receptors in the hemi-PD rat model. The results further suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing the interhemispheric imbalance in D 2 /D 3 receptor density. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. The brain 5-HT4 receptor binding is down-regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration

    DEFF Research Database (Denmark)

    Licht, Cecilie Löe; Marcussen, Anders Bue; Wegener, Gregers

    2009-01-01

    The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography....... In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4......) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate...

  15. Changes in serotoninergic receptors 1A and 2A in the piglet brainstem after intermittent hypercapnic hypoxia (IHH) and nicotine.

    Science.gov (United States)

    Say, Meichien; Machaalani, Rita; Waters, Karen A

    2007-06-04

    We studied the effects of intermittent hypercapnic hypoxia (IHH) and/or nicotine on the immunoreactivity of serotoninergic (5-HT) receptors 1A and 2A in the piglet brainstem. These exposures were developed to mimic two common risk factors for Sudden Infant Death Syndrome (SIDS); prone sleeping (IHH) and cigarette smoke exposure (nicotine). Immunoreactivity for 5-HT(1A)R and 5-HT(2A)R were studied in four nuclei of the caudal medulla. Three exposure groups were compared to controls (n=14): IHH (n=10), nicotine (n=14), and nicotine+IHH (n=14). In control piglets, the immunoreactivity of 5-HT(1A)R was highest in the hypoglossal nucleus (XII), followed by inferior olivary nucleus (ION), nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus (DMNV), whereas for 5-HT(2A)R, the immunoreactivity was highest in DMNV/NTS and then ION. Compared to controls, IHH reduced 5-HT(1A)R immunoreactivity in all studied nuclei (pIHH reduced 5-HT(1A)R in DMNV, ION and NTS (pIHH and/or nicotine can reduce 5-HT receptor immunoreactivity within functionally important nuclei of the piglet medulla. The findings support our hypothesis that 5-HT receptor abnormalities may be caused by postnatal exposures to clinically-relevant stimuli such as cigarette smoke exposure and/or prone sleeping.

  16. Drug Discovery Targeting Serotonin G Protein-Coupled Receptors in the Treatment of Neuropsychiatric Disorders

    Science.gov (United States)

    Felsing, Daniel E.

    Clinical data show that activation of 5-HT2C G protein-coupled receptors (GPCRs) can treat obesity (lorcaserin/BelviqRTM) and psychotic disorders (aripiprazole/Abilify.), including schizophrenia. 5-HT2C GPCRs are members of the 5-HT2 sub-family of 5-HT GPCRs, which include 5-HT2A, 5-HT2B, and 5-HT 2C GPCRs. 5-HT2C is structurally similar to 5-HT2A and 5-HT2B GPCRs, but activation of 5-HT2A and/or 5-HT 2B causes deleterious effects, including hallucinations and cardiac valvulopathy. Thus, there is a challenge to develop drugs that selectively activate only 5-HT2C. Prolonged activation of GPCRs by agonists reduces their function via a regulatory process called desensitization. This has clinical relevance, as 45% of drugs approved by the FDA target GPCRs, and agonist drugs (e.g., morphine) typically lose efficacy over time due to desensitization, which invites tolerance. Agonists that cause less desensitization may show extended clinical efficacy as well as a more acceptable clinical dose range. We hypothesized that structurally distinct agonists of the 5-HT2C receptor may cause varying degrees of desensitization by stabilizing unique 5-HT2C receptor conformations. Discovery of 5-HT2C agonists that exhibit minimal desensitization is therapeutically relevant for the pharmacotherapeutic treatment of chronic diseases such as obesity and psychotic disorders. The 5-HT7 receptor has recently been discovered as a druggable target, and selective activation of the 5-HT7 receptor has been shown to alleviate locomotor deficits in mouse models of Rett Syndrome. Additionally, buspirone has been shown to display therapeutically relevant affinity at 5-HT 1A and is currently in phase II clinical trials to treat stereotypy in children with autism. The 5-PAT chemical scaffold shows high affinity towards the 5-HT7 and 5-HT1A receptors. Modulations around the 5-phenyl moiety were able to improve selectivity in binding towards the 5-HT 7 receptor, whereas modulations of the alkyl chains

  17. Regulation of the fear network by mediators of stress: Norepinephrine alters the balance between Cortical and Subcortical afferent excitation of the Lateral Amygdala

    Directory of Open Access Journals (Sweden)

    Luke R Johnson

    2011-05-01

    Full Text Available Pavlovian auditory fear conditioning crucially involves the integration of information about and acoustic conditioned stimulus (CS and an aversive unconditioned stimulus (US in the lateral nucleus of the amygdala (LA. The auditory CS reaches the LA subcortically via a direct connection from the auditory thalamus and also from the auditory association cortex itself. How neural modulators, especially those activated during stress, such as norepinephrine (NE, regulate synaptic transmission and plasticity in this network is poorly understood. Here we show that NE inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased towards the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance towards the faster but more primitive subcortical input.

  18. Gait and Equilibrium in Subcortical Vascular Dementia

    Directory of Open Access Journals (Sweden)

    Rita Moretti

    2011-01-01

    Full Text Available Subcortical vascular dementia is a clinical entity, widespread, even challenging to diagnose and correctly treat. Patients with this diagnosis are old, frail, often with concomitant pathologies, and therefore, with many drugs in therapy. We tried to diagnose and follow up for three years more than 600 patients. Study subjects were men and women, not bedridden, aged 68–94 years, outpatients, recruited from June, 1st 2007 to June, 1st 2010. We examined them clinically, neurologically, with specific consideration on drug therapies. Our aim has been to define gait and imbalance problem, if eventually coexistent with the pathology of white matter and/or with the worsening of the deterioration. Drug intake interference has been detected and considered.

  19. Regulating prefrontal cortex activation: an emerging role for the 5-HT₂A serotonin receptor in the modulation of emotion-based actions?

    Science.gov (United States)

    Aznar, Susana; Klein, Anders B

    2013-12-01

    The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.

  20. Involvement of spinal serotonin receptors in the regulation of intraspinal acetylcholine release.

    Science.gov (United States)

    Kommalage, Mahinda; Höglund, A Urban

    2005-02-21

    Stimulation of spinal serotonin (5-HT) receptors results in analgesia and release of acetylcholine. We investigated the involvement of 5-HT1, 5-HT2, and 5-HT3 receptor subtypes in the regulation of spinal acetylcholine release. A spinal microdialysis probe was placed dorsally at about the C5 level in anaesthetized rats. The selective serotonin reuptake inhibitor citalopram was found to increase acetylcholine release when infused via the microdialysis probe. Several doses of the 5-HT receptor agonists 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT, 5-HT1A), 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (CP93129, 5-HT1B), alpha-methyl-5-hydroxytryptamine maleate (m5-HT, 5-HT2), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 5-HT2C), and 1-(m-chlorophenyl)-biguanide (5-HT3) were subsequently infused via the microdialysis probe. Only 8-OH-DPAT, CP93129, and m5-HT increased acetylcholine release dose dependently. The 5-HT1A receptor selective antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride and the 5-HT2A receptor selective antagonist ketanserin tartrate inhibited the 8-OH-DPAT and the m5-HT induced acetylcholine release. The results suggest that 5-HT1A and the 5-HT2A receptors are involved in the regulation of acetylcholine release in the spinal cord.

  1. Do serotonin(1-7) receptors modulate short and long-term memory?

    Science.gov (United States)

    Meneses, A

    2007-05-01

    Evidence from invertebrates to human studies indicates that serotonin (5-hydroxytryptamine; 5-HT) system modulates short- (STM) and long-term memory (LTM). This work is primarily focused on analyzing the contribution of 5-HT, cholinergic and glutamatergic receptors as well as protein synthesis to STM and LTM of an autoshaping learning task. It was observed that the inhibition of hippocampal protein synthesis or new mRNA did not produce a significant effect on autoshaping STM performance but it did impair LTM. Both non-contingent protein inhibition and 5-HT depletion showed no effects. It was basically the non-selective 5-HT receptor antagonist cyproheptadine, which facilitated STM. However, the blockade of glutamatergic and cholinergic transmission impaired STM. In contrast, the selective 5-HT(1B) receptor antagonist SB-224289 facilitated both STM and LTM. Selective receptor antagonists for the 5-HT(1A) (WAY100635), 5-HT(1D) (GR127935), 5-HT(2A) (MDL100907), 5-HT(2C/2B) (SB-200646), 5-HT(3) (ondansetron) or 5-HT(4) (GR125487), 5-HT(6) (Ro 04-6790, SB-399885 and SB-35713) or 5-HT(7) (SB-269970) did not impact STM. Nevertheless, WAY100635, MDL100907, SB-200646, GR125487, Ro 04-6790, SB-399885 or SB-357134 facilitated LTM. Notably, some of these changes shown to be independent of food-intake. Concomitantly, these data indicate that '5-HT tone via 5-HT(1B) receptors' might function in a serial manner from STM to LTM, whereas working in parallel using 5-HT(1A), 5-HT(2A), 5-HT(2B/2C), 5-HT(4), or 5-HT(6) receptors.

  2. β2-Adrenergic Receptor Activation Suppresses the Rat Phenethylamine Hallucinogen-Induced Head Twitch Response: Hallucinogen-Induced Excitatory Post-synaptic Potentials as a Potential Substrate

    Science.gov (United States)

    Marek, Gerard J.; Ramos, Brian P.

    2018-01-01

    5-Hydroxytryptamine2A (5-HT2A) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α1-adrenergic and orexin2) or suppress (metabotropic glutamate2 [mGlu2], adenosine A1, μ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the β2-adrenergic receptor. Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 μM). Epinephrine (0.3–10 μM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective β2-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective β2-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches. Clenbuterol (0.3–3 mg/kg, i.p.) suppressed DOI (1.25 mg/kg, i.p.)-induced head twitches. This clenbuterol effect appeared to be at least partially reversed by the selective β2-adrenergic receptor antagonist ICI-118,553 (0.01–1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg. Thus, β2-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While Gi/Go-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT2A receptor activation in the mPFC, the present work appears

  3. Serotonin 2A Receptors, Citalopram and Tryptophan-Depletion

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Hornboll, Bettina; Elliott, Rebecca

    2013-01-01

    in subjects with low 5-HT(2A) BP(P) but reduced the NoGo response in those with high 5-HT(2A) BP(P). These links between serotonergic function and response inhibition in healthy subjects may help to interpret serotonergic abnormalities underlying impulsivity in neuropsychiatric disorders...

  4. Impact of Vortioxetine on Synaptic Integration in Prefrontal-Subcortical Circuits: Comparisons with Escitalopram

    Directory of Open Access Journals (Sweden)

    Shreaya Chakroborty

    2017-10-01

    Full Text Available Prefrontal-subcortical circuits support executive functions which often become dysfunctional in psychiatric disorders. Vortioxetine is a multimodal antidepressant that is currently used in the clinic to treat major depressive disorder. Mechanisms of action of vortioxetine include serotonin (5-HT transporter blockade, 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, and 5-HT1D, 5-HT3, and 5-HT7 receptor antagonism. Vortioxetine facilitates 5-HT transmission in the medial prefrontal cortex (mPFC, however, the impact of this compound on related prefrontal-subcortical circuits is less clear. Thus, the current study examined the impact of systemic vortioxetine administration (0.8 mg/kg, i.v. on spontaneous spiking and spikes evoked by electrical stimulation of the mPFC in the anterior cingulate cortex (ACC, medial shell of the nucleus accumbens (msNAc, and lateral septal nucleus (LSN in urethane-anesthetized rats. We also examined whether vortioxetine modulated afferent drive in the msNAc from hippocampal fimbria (HF inputs. Similar studies were performed using the selective 5-HT reuptake inhibitor [selective serotonin reuptake inhibitors (SSRI] escitalopram (1.6 mg/kg, i.v. to enable comparisons between the multimodal actions of vortioxetine and SSRI-mediated effects. No significant differences in spontaneous activity were observed in the ACC, msNAc, and LSN across treatment groups. No significant impact of treatment on mPFC-evoked responses was observed in the ACC. In contrast, vortioxetine decreased mPFC-evoked activity recorded in the msNAc as compared to parallel studies in control and escitalopram treated groups. Thus, vortioxetine may reduce mPFC-msNAc afferent drive via a mechanism that, in addition to an SSRI-like effect, requires 5-HT receptor modulation. Recordings in the LSN revealed a significant increase in mPFC-evoked activity following escitalopram administration as compared to control and vortioxetine treated groups

  5. Affinity of Iresine herbstii and Brugmansia arborea extracts on different cerebral receptors.

    Science.gov (United States)

    Nencini, Cristina; Cavallo, Federica; Bruni, Giancarlo; Capasso, Anna; De Feo, Vincenzo; De Martino, Laura; Giorgi, Giorgio; Micheli, Lucia

    2006-05-24

    Iresine herbstii Hook. (Amaranthaceae) and Brugmansia arborea (L.) Lagerheim (Solanaceae) are used in the northern Peruvian Andes for magic-therapeutical purposes. The traditional healers use Iresine herbstii with the ritual aim to expel bad spirits from the body. Furthermore, Iresine herbstii was used in association with other plants, such as Trichocereus pachanoi Britt. et Rose, for divination, to diagnose diseases, and to take possession of another identity. Also, species of Brugmansia have been reported to be used during ritual practices for magical and curative purposes. Given the above evidence, the aim of the present study is to evaluate if the central effects of Iresine herbstii and Brugmansia arborea could be associated with interaction with SNC receptors. Two Iresine herbstii extracts (methanolic and aqueous) and one Brugmansia arborea aqueous extract were tested for in vitro affinity on 5-HT(1A), 5-HT(2A), 5-HT(2C), D1, D2, alpha(1), and alpha(2) receptors by radioligand binding assays. The biological materials for binding assay (cerebral cortex) were taken from male Sprague-Dawley rats. The extracts affinity for receptors is definite as inhibition percentage of radioligand/receptor binding and measured as the radioactivity of remaining complex radioligand/receptor. The data obtained for Iresine extracts have shown a low affinity for the 5-HT(1A) receptor and no affinity for 5-HT(2A) receptor. Otherwise the methanolic extract showed affinity for 5-HT(2C) receptor (IC(50): 34.78 microg/ml) and for D1 receptor (IC(50): 19.63 microg/ml), instead the Iresine aqueous extract displayed a lower affinity for D1 (48.3% at the maximum concentration tested) and a higher value of affinity for D2 receptors (IC(50): 32.08 microg/ml). The Brugmansia aqueous extract displayed affinity for D1 receptors (IC(50): 17.68 microg/ml), D2 receptors (IC(50): 15.95 microg/ml) and weak affinity for the serotoninergic receptors. None of the three extracts showed relevant affinity

  6. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    Depletion of central serotonin (5-HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT₄ receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  7. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    Depletion of central serotonin (5-HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT4 receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  8. [¹⁸F]Altanserin and small animal PET: impact of multidrug efflux transporters on ligand brain uptake and subsequent quantification of 5-HT₂A receptor densities in the rat brain.

    Science.gov (United States)

    Kroll, Tina; Elmenhorst, David; Matusch, Andreas; Celik, A Avdo; Wedekind, Franziska; Weisshaupt, Angela; Beer, Simone; Bauer, Andreas

    2014-01-01

    The selective 5-hydroxytryptamine type 2a receptor (5-HT(2A)R) radiotracer [(18)F]altanserin is a promising ligand for in vivo brain imaging in rodents. However, [(18)F]altanserin is a substrate of P-glycoprotein (P-gp) in rats. Its applicability might therefore be constrained by both a differential expression of P-gp under pathological conditions, e.g. epilepsy, and its relatively low cerebral uptake. The aim of the present study was therefore twofold: (i) to investigate whether inhibition of multidrug transporters (MDT) is suitable to enhance the cerebral uptake of [(18)F]altanserin in vivo and (ii) to test different pharmacokinetic, particularly reference tissue-based models for exact quantification of 5-HT(2A)R densities in the rat brain. Eighteen Sprague-Dawley rats, either treated with the MDT inhibitor cyclosporine A (CsA, 50 mg/kg, n=8) or vehicle (n=10) underwent 180-min PET scans with arterial blood sampling. Kinetic analyses of tissue time-activity curves (TACs) were performed to validate invasive and non-invasive pharmacokinetic models. CsA application lead to a two- to threefold increase of [(18)F]altanserin uptake in different brain regions and showed a trend toward higher binding potentials (BP(ND)) of the radioligand. MDT inhibition led to an increased cerebral uptake of [(18)F]altanserin but did not improve the reliability of BP(ND) as a non-invasive estimate of 5-HT(2A)R. This finding is most probable caused by the heterogeneous distribution of P-gp in the rat brain and its incomplete blockade in the reference region (cerebellum). Differential MDT expressions in experimental animal models or pathological conditions are therefore likely to influence the applicability of imaging protocols and have to be carefully evaluated. © 2013.

  9. Serotonin 2A and 2C receptor biosynthesis in the rodent striatum during postnatal development: mRNA expression and functional linkage to neuropeptide gene regulation.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2000-11-01

    The present study was designed to determine if there are region-specific differences in serotonin (5-HT) neurotransmission and 5-HT receptor expression that may limit the stimulatory effects of the 5-HT releaser p-chloroamphetamine (pCA) on striatal neuropeptide gene expression to the posterior striatum (P-STR) during postnatal maturation. Sprague-Dawley rat brains from postnatal days (PND) 1-35 were processed for 5-HT(2A) and 5-HT(2C) receptor mRNA expression by in situ hybridization and monoamine analysis by HPLC. Within the P-STR, 5-HT(2A) receptor mRNA expression reached young adult (PND 35) levels by PND 3, while levels in the A-STR were significantly less (range: 1.43 +/- 0.219-6. 36 +/- 0.478) than P-STR (5.36 +/- 0.854-12.11 +/- 1.08) at each respective age throughout the time course. 5-HT(2C) receptor mRNA expression reached young adult levels at PND 7 in the A-STR and by PND 3 in the P-STR. At each PND age 5-HT(2C) receptor mRNA levels within the P-STR were significantly less (6.23 +/- 1.02-12.32 +/- 0.427) than the A-STR (7.31 +/- 1.65-26.84 +/- 2.24). 5-HT content increased across the developmental time course within the P-STR (5.01 +/- 0.327-15.7 +/- 1.03 ng/mg protein) and A-STR (2.97 +/- 0. 223-11.2 +/- 0.701 ng/mg protein). Four hours following injection (i. p.) of pCA (10 mg/kg), preprotachykinin (PPT) mRNA levels increased 89% in the P-STR but not the anterior (A-STR) striatum of the 3-week-old rat, which were prevented by preinjection (30 min, i.p.) of the 5-HT(2) receptor antagonist ritanserin (1 mg/kg). Together, these data suggest that faster maturity of 5-HT(2A) receptor expression in the P-STR may be sufficient to convey the region-specific acute stimulatory effects of pCA on PPT mRNA transcription in the developing rodent striatum. These results provide further evidence that the influence of 5-HT on neuropeptide gene expression is far stronger in caudal vs. rostral striatal regions during postnatal development. Copyright 2000 Wiley

  10. Cellular complexity in subcortical white matter: a distributed control circuit?

    Science.gov (United States)

    Colombo, Jorge A

    2018-03-01

    The subcortical white matter (SWM) has been traditionally considered as a site for passive-neutral-information transfer through cerebral cortex association and projection fibers. Yet, the presence of subcortical neuronal and glial "interstitial" cells expressing immunolabelled neurotransmitters/neuromodulators and synaptic vesicular proteins, and recent immunohistochemical and electrophysiological observations on the rat visual cortex as well as interactive regulation of myelinating processes support the possibility that SWM nests subcortical, regionally variable, distributed neuronal-glial circuits, that could influence information transfer. Their hypothetical involvement in regulating the timing and signal transfer probability at the SWM axonal components ought to be considered and experimentally analysed. Thus, the "interstitial" neuronal cells-associated with local glial cells-traditionally considered to be vestigial and functionally inert under normal conditions, they may well turn to be critical in regulating information transfer at the SWM.

  11. 5-Hydroxytryptamine (serotonin 2A receptor gene polymorphism is associated with schizophrenia

    Directory of Open Access Journals (Sweden)

    Subash Padmajeya Sujitha

    2014-01-01

    Full Text Available Background & objectives: Schizophrenia, the debilitating neuropsychiatric disorder, is known to be heritable, involving complex genetic mechanisms. Several chromosomal regions associated with schizophrenia have been identified during the past; putative gene (s in question, to be called the global signature for the pathophysiology of the disease, however, seems to evade us. The results obtained from the several population-wise association-non association studies have been diverse. w0 e therefore, undertook the present study on Tamil speaking population in south India to examine the association between the single nucleotide polymorphisms (SNPs at the serotonin receptor gene (5HT2A and the occurrence of the disease. Methods: Blood samples collected from 266 cases and 272 controls were subjected to genotyping (PCR amplification of candidate SNPs, RFLP and sequencing. The data on the SNPs were subjected to statistical analysis for assessing the gene frequencies in both the cases and the controls. Results: The study revealed significant association between the genotypic frequencies of the serotonin receptor polymorphism and schizophrenia. SNP analysis revealed that the frequencies of GG (30%, rs6311 and CC genotypes (32%, rs6313, were higher in patients (P<0.05 than in controls. The study also showed presence of G and C alleles in patients. s0 ignificant levels of linkage disequilibrium (LD were found to exist between the genotype frequencies of rs6311 and rs6313. Interpretation & conclusions: This study indicated an association between the SNPs (rs6311 and rs6313 of the serotonin receptor 5HT2A and schizophrenia. HapMap analysis revealed that in its genotype distribution, the Tamil speaking population was different from several other populations across the world, signifying the importance of such ethnicity-based studies to improve our understanding of this complex disease.

  12. Genetic influences on schizophrenia and subcortical brain volumes

    DEFF Research Database (Denmark)

    Franke, Barbara; Stein, Jason L; Ripke, Stephan

    2016-01-01

    and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between...... genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk...

  13. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors

    DEFF Research Database (Denmark)

    Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian

    2013-01-01

    Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine...... about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure...... but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure...

  14. Subcortical aphasia and cerebral blood flow using SPECT

    International Nuclear Information System (INIS)

    Celsis, P.; Puel, M.; Demonet, J.P.; Bonafe, A.; Cardebat, D.; Viallard, G.; Pujol, T.; Marc-Vergnes, J.P.; Rascol, A.

    1985-01-01

    Possible cerebral blood flow (CBF) alteration in subcortical aphasia was investigated by single-photon emission tomography (SPECT). The results confirm the capsulo-striatal lesions and also point to the high rate of ipsilateral thalamic and cortical dysfunction. (author). 8 refs.; 1 fig.; 1 tab

  15. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, D.P.; Stein, J.L.; Renteria, M.E.; Arias-Vasquez, A.; Desrivières, S.; Jahanshad, N.; Toro, R.; Wittfeld, K.; Abramovic, L.; Andersson, M.; Aribisala, B.S.; Armstrong, N.J.; Bernard, M.; Bohlken, M.M.; Biks, M.P.; Bralten, J.; Brown, A.A.; Chakravarty, M.M.; Chen, Q.; Ching, C.R.K.; Cuellar-Partida, G.; den Braber, A.; Giddaluru, S.; Goldman, A.L.; Grimm, O.; Guadalupe, T.; Hass, J.; Woldehawariat, G.; Holmes, A.J.; Hoogman, M.; Janowitz, D.; Jia, T.; Kim, S.; Klein, M.; Kraemer, B.; Lee, P.H.; Olde Loohuis, L.M.; Luciano, M.; Macare, C.; Mather, K.A.; Mattheisen, M.; Milaneschi, Y.; Nho, K.; Papmeyer, M.; Ramasamy, A.; Risacher, S.L.; Roiz-Santiañez, R.; Rose, E.J.; Salami, A.; Sämann, P.G.; Schmaal, L.; Schork, A.J.; Shin, J.; Strike, L.T.; Teumer, A.; Donkelaar, M.M.J.; van Eijk, K.R.; Walters, R.K.; Westlye, L.T.; Welan, C.D.; Winkler, A.M.; Zwiers, M.P.; Alhusaini, S.; Athanasiu, L.; Ehrlich, S.; Hakobjan, M.M.H.; Hartberg, C.B.; Haukvik, U.K.; Heister, A.J.G.A.M.; Hoehn, D.; Kasperaviciute, D.; Liewald, D.C.M.; Lopez, L.M.; Makkinje, R.R.; Matarin, M.; Naber, M.A.M.; Reese McKay, D.; Needham, M.; Nugent, A.C.; Pütz, B.; Royle, N.A.; Shen, L.; Sprooten, E.; Trabzuni, D.; van der Marel, S.S.L.; van Hulzen, K.J.E.; Walton, E.; Wolf, C.; Almasy, L.; Ames, D.; Arepalli, S.; Assareh, A.A.; Bastin, M.E.; Brodaty, H.; Bulayeva, K.B.; Carless, M.A.; Cichon, S.; Corvin, A.; Curran, J.E.; Czisch, M.; de Zubicaray, G.I.; Dillman, A.; Duggirala, R.; Dyer, T.D.; Erk, S.; Fedko, I.O.; Ferrucci, L.; Foroud, T.M.; Fox, P.T.; Fukunaga, M.; Gibbs, J.R.; Göring, H.H.H.; Green, R.C.; Guelfi, S.; Hansell, N.K.; Hartman, C.A.; Hegenscheid, K.; Heinz, A.; Hernandez, D.G.; Heslenfeld, D.J.; Hoekstra, P.J.; Holsboer, F.; Homuth, G.; Hottenga, J.J.; Ikeda, M.; Jack, C.R., Jr.; Jenkinson, M.; Johnson, R.; Kanai, R.; Keil, M.; Kent, J.W. Jr.; Kochunov, P.; Kwok, J.B.; Lawrie, S.M.; Liu, X.; Longo, D.L.; McMahon, K.L.; Meisenzahl, E.; Melle, I.; Mohnke, S.; Montgomery, G.W.; Mostert, J.C.; Mühleisen, T.W.; Nalls, M.A.; Nichols, T.E.; Nilsson, L.G.; Nöthen, M.M.; Ohi, K.; Olvera, R.L.; Perez-Iglesias, R.; Pike, G.B.; Potkin, S.G.; Reinvang, I.; Reppermund, S.; Rietschel, M.; Romanczuk-Seiferth, N.; Rosen, G.D.; Rujescu, D.; Schnell, K.; Schofield, P.R.; Smith, C.; Steen, V.M.; Sussmann, J.E.; Thalamuthu, A.; Toga, A.W.; Traynor, B.J.; Troncoso, J.; Turner, J.A.; Valdés Hernández, M.C.; van t Ent, D.; van der Brug, M.; van der Wee, N.J.A.; van Tol, M.J.; Veltman, D.J.; Wassink, T.H.; Westmann, E.; Zielke, R.H.; Zonderman, A.B.; Ashbrook, D.G.; Hager, R.; Lu, L.; McMahon, F.J.; Morris, D.W.; Williams, R.W.; Brunner, H.G.; Buckner, R.L.; Buitelaar, J.K.; Cahn, W.; Calhoun, V.D.; Cavalleri, G.L.; Crespo-Facorro, B.; Dale, A.M.; Davies, G.E.; Delanty, N.; Depondt, C.; Djurovic, S.; Drevets, W.C.; Espeseth, T.; Gollub, R.L.; Ho, B.C.; Hoffmann, W.; Hosten, N.; Kahn, R.S.; Le Hellard, S.; Meyer-Lindenberg, A.; Müller-Myhsok, B.; Nauck, M.; Nyberg, L.; Pandolfo, M.; Penninx, B.W.J.H.; Roffman, J.L.; Sisodiya, SM; Smoller, J.W.; van Bokhoven, H.; van Haren, N.E.M.; Völzke, H.; Walter, H.; Weiner, M.W.; Wen, W.; White, T.; Agartz, I.; Andreassen, O.A.; Blangero, J.; Boomsma, D.I.; Brouwer, R.M.; Cannon, D.M.; Cookson, M.R.; de Geus, E.J.C.; Deary, I.J.; Donohoe, G.; Fernandez, G.; Fisher, S.E.; Francks, C.; Glahn, D.C.; Grabe, H.J.; Gruber, O.; Hardy, J.; Hashimoto, R.; Hulshoff Pol, H.E.; Jönsson, E.G.; Kloszewska, I.; Lovestone, S.; Mattay, V.S.; Mecocci, P.; McDonald, C.; McIntosh, A.M.; Ophoff, R.A.; Paus, T.; Pausova, Z.; Ryten, M.; Sachdev, P.S.; Saykin, A.J.; Simmons, A.; Singleton, A.; Soininen, H.; Wardlaw, J.M.; Weale, M.E.; Weinberger, D.R.; Adams, H.H.H.; Launer, L.J.; Seiler, S.; Schmidt, R.; Chauhan, G.; Satizabal, C.L.; Becker, J.T.; Yanek, L.; van der Lee, S.J.; Ebling, M.; Fischl, B.; Longstreth, Jr. W.T.; Greve, D.; Schmidt, H.; Nyquist, P.; Vinke, L.N.; van Duijn, C.M.; Xue, L.; Mazoyer, B.; Bis, J.C.; Gudnason, V.; Seshadri, S.; Arfan Ikram, M.; Martin, N.G.; Wright, M.J.; Schumann, G.; Franke, B.; Thompson, P.M.; Medland, S.E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common

  16. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    D.P. Hibar (Derrek); J.L. Stein; M.E. Rentería (Miguel); A. Arias-Vásquez (Alejandro); S. Desrivières (Sylvane); N. Jahanshad (Neda); R. Toro (Roberto); K. Wittfeld (Katharina); L. Abramovic (Lucija); M. Andersson (Micael); B. Aribisala (Benjamin); N.J. Armstrong (Nicola J.); M. Bernard (Manon); M.M. Bohlken (Marc M.); M.P.M. Boks (Marco); L.B.C. Bralten (Linda); A.A. Brown (Andrew); M.M. Chakravarty (M. Mallar); Q. Chen (Qiang); C.R.K. Ching (Christopher); G. Cuellar-Partida (Gabriel); A. den Braber (Anouk); S. Giddaluru (Sudheer); A.L. Goldman (Aaron L.); O. Grimm (Oliver); T. Guadalupe (Tulio); J. Hass (Johanna); G. Woldehawariat (Girma); A.J. Holmes (Avram); M. Hoogman (Martine); D. Janowitz (Deborah); T. Jia (Tianye); S. Kim (Shinseog); M. Klein (Marieke); B. Kraemer (Bernd); P.H. Lee (Phil H.); L.M. Olde Loohuis (Loes M.); M. Luciano (Michelle); C. MacAre (Christine); R. Mather; M. Mattheisen (Manuel); Y. Milaneschi (Yuri); K. Nho (Kwangsik); M. Papmeyer (Martina); A. Ramasamy (Adaikalavan); S.L. Risacher (Shannon); R. Roiz-Santiañez (Roberto); E.J. Rose (Emma); A. Salami (Alireza); P.G. Sämann (Philipp); L. Schmaal (Lianne); N.J. Schork (Nicholas); J. Shin (Jean); L.T. Strike (Lachlan); A. Teumer (Alexander); M.M.J. Van Donkelaar (Marjolein M. J.); K.R. van Eijk (Kristel); R.K. Walters (Raymond); L.T. Westlye (Lars); C.D. Whelan (Christopher); A.M. Winkler (Anderson); M.P. Zwiers (Marcel); S. Alhusaini (Saud); L. Athanasiu (Lavinia); S.M. Ehrlich (Stefan); M. Hakobjan (Marina); C.B. Hartberg (Cecilie B.); U.K. Haukvik (Unn); A.J.G.A.M. Heister (Angelien J. G. A. M.); D. Hoehn (David); D. Kasperaviciute (Dalia); D.C. Liewald (David C.); L.M. Lopez (Lorna); R.R.R. Makkinje (Remco R. R.); M. Matarin (Mar); M.A.M. Naber (Marlies A. M.); D. Reese McKay; M. Needham (Margaret); A.C. Nugent (Allison); B. Pütz (Benno); N.A. Royle (Natalie); L. Shen (Li); R. Sprooten (Roy); D. Trabzuni (Danyah); S.S.L. Van Der Marel (Saskia S. L.); K.J.E. Van Hulzen (Kimm J. E.); E. Walton (Esther); A. Björnsson (Asgeir); L. Almasy (Laura); D.J. Ames (David); S. Arepalli (Sampath); A.A. Assareh; M.E. Bastin (Mark); H. Brodaty (Henry); K. Bulayeva (Kazima); M.A. Carless (Melanie); S. Cichon (Sven); A. Corvin (Aiden); J.E. Curran (Joanne); M. Czisch (Michael); G.I. de Zubicaray (Greig); A. Dillman (Allissa); A. Duggirala (Aparna); M.D. Dyer (Matthew); S. Erk; I. Fedko (Iryna); L. Ferrucci (Luigi); T. Foroud (Tatiana); P.T. Fox (Peter); M. Fukunaga (Masaki); J. Raphael Gibbs; H.H.H. Göring (Harald H.); R.C. Green (Robert C.); S. Guelfi (Sebastian); N.K. Hansell (Narelle); C.A. Hartman (Catharina); K. Hegenscheid (Katrin); J. Heinz (Judith); D.G. Hernandez (Dena); D.J. Heslenfeld (Dirk); P.J. Hoekstra (Pieter); F. Holsboer; G. Homuth (Georg); J.J. Hottenga (Jouke Jan); M. Ikeda (Masashi); C.R. Jack Jr. (Clifford); S. Jenkinson (Sarah); R. Johnson (Robert); R. Kanai (Ryota); M. Keil (Maria); J.W. Kent (Jack W.); P. Kochunov (Peter); J.B. Kwok (John B.); S. Lawrie (Stephen); X. Liu (Xinmin); D.L. Longo (Dan L.); K.L. Mcmahon (Katie); E. Meisenzahl (Eva); I. Melle (Ingrid); S. Mohnke (Sebastian); G.W. Montgomery (Grant); J.C. Mostert (Jeanette C.); T.W. Mühleisen (Thomas); M.A. Nalls (Michael); T.E. Nichols (Thomas); L.G. Nilsson; M.M. Nöthen (Markus); K. Ohi (Kazutaka); R.L. Olvera (Rene); R. Perez-Iglesias (Rocio); G. Bruce Pike; S.G. Potkin (Steven); I. Reinvang (Ivar); S. Reppermund; M. Rietschel (Marcella); N. Seiferth (Nina); G.D. Rosen (Glenn D.); D. Rujescu (Dan); K. Schnell (Kerry); C.J. Schofield (Christopher); C. Smith (Colin); V.M. Steen (Vidar); J. Sussmann (Jessika); A. Thalamuthu (Anbupalam); A.W. Toga (Arthur W.); B. Traynor (Bryan); J.C. Troncoso (Juan); J. Turner (Jessica); M.C. Valdés Hernández (Maria); D. van 't Ent (Dennis); M.P. van der Brug (Marcel); N.J. van der Wee (Nic); M.J.D. van Tol (Marie-José); D.J. Veltman (Dick); A.M.J. Wassink (Annemarie); E. Westman (Eric); R.H. Zielke (Ronald H.); A.B. Zonderman (Alan B.); D.G. Ashbrook (David G.); R. Hager (Reinmar); L. Lu (Lu); F.J. Mcmahon (Francis J); D.W. Morris (Derek W); R.W. Williams (Robert W.); H.G. Brunner; M. Buckner; J.K. Buitelaar (Jan K.); W. Cahn (Wiepke); V.D. Calhoun Vince D. (V.); G. Cavalleri (Gianpiero); B. Crespo-Facorro (Benedicto); A.M. Dale (Anders); G.E. Davies (Gareth); N. Delanty; C. Depondt (Chantal); S. Djurovic (Srdjan); D.A. Drevets (Douglas); T. Espeseth (Thomas); R.L. Gollub (Randy); B.C. Ho (Beng ); W. Hoffmann (Wolfgang); N. Hosten (Norbert); R. Kahn (René); S. Le Hellard (Stephanie); A. Meyer-Lindenberg; B. Müller-Myhsok (B.); M. Nauck (Matthias); L. Nyberg (Lars); M. Pandolfo (Massimo); B.W.J.H. Penninx (Brenda); J.L. Roffman (Joshua); S.M. Sisodiya (Sanjay); J.W. Smoller; H. van Bokhoven (Hans); N.E.M. van Haren (Neeltje E.); H. Völzke (Henry); H.J. Walter (Henrik); M.W. Weiner (Michael); W. Wen (Wei); T.J.H. White (Tonya); I. Agartz (Ingrid); O.A. Andreassen (Ole); J. Blangero (John); D.I. Boomsma (Dorret); R.M. Brouwer (Rachel); D.M. Cannon (Dara); M.R. Cookson (Mark); E.J.C. de Geus (Eco); I.J. Deary (Ian J.); D.J. Donohoe (Dennis); G. Fernandez (Guillén); S.E. Fisher (Simon); C. Francks (Clyde); D.C. Glahn (David); H.J. Grabe (Hans Jörgen); O. Gruber (Oliver); J. Hardy (John); R. Hashimoto (Ryota); H.E. Hulshoff Pol (Hilleke); E.G. Jönsson (Erik); I. Kloszewska (Iwona); S. Lovestone (Simon); V.S. Mattay (Venkata S.); P. Mecocci (Patrizia); C. McDonald (Colm); A.M. McIntosh (Andrew); R.A. Ophoff (Roel); T. Paus (Tomas); Z. Pausova (Zdenka); M. Ryten (Mina); P.S. Sachdev (Perminder); A.J. Saykin (Andrew); A. Simmons (Andrew); A. Singleton (Andrew); H. Soininen (H.); J.M. Wardlaw (J.); M.E. Weale (Michael); D.R. Weinberger (Daniel); H.H.H. Adams (Hieab); L.J. Launer (Lenore); S. Seiler (Stephan); R. Schmidt (Reinhold); G. Chauhan (Ganesh); C.L. Satizabal (Claudia L.); J.T. Becker (James); L.R. Yanek (Lisa); S.J. van der Lee (Sven); M. Ebling (Maritza); B. Fischl (Bruce); W.T. Longstreth Jr; D. Greve (Douglas); R. Schmidt (Reinhold); P. Nyquist (Paul); L.N. Vinke (Louis N.); C.M. van Duijn (Cornelia); L. Xue (Luting); B. Mazoyer (Bernard); J.C. Bis (Joshua); V. Gudnason (Vilmundur); S. Seshadri (Sudha); M.A. Ikram (Arfan); N.G. Martin (Nicholas); M.J. Wright (Margaret); G. Schumann (Gunter); B. Franke (Barbara); P.M. Thompson (Paul); S.E. Medland (Sarah Elizabeth)

    2015-01-01

    textabstractThe highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate

  17. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivieres, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Loohuis, Loes M. Olde; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santianez, Roberto; Rose, Emma J.; Salami, Alireza; Saemann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Puetz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Goering, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzah, Eva; Melle, Ingrid; Mahnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Muehleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Noethen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdes Hernandez, Maria C.; van't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffman, Wolfgang; Hosten, Norbert; Kahn, Rene S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Mueller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Voelzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernandez, Guillen; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Pol, Hilleke E. Hulshoff; Joensson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To

  18. Neuropsychological Profile of Children with Subcortical Band Heterotopia

    Science.gov (United States)

    Spencer-Smith, Megan; Leventer, Richard; Jacobs, Rani; De Luca, Cinzia; Anderson, Vicki

    2009-01-01

    Aim: Subcortical band heterotopia (SBH) or "double cortex" is a malformation of cortical development resulting from impaired neuronal migration. So far, research has focused on the neurological, neuroimaging, and genetic correlates of SBH. More recently, clinical reports and small sample studies have documented neuropsychological dysfunction in…

  19. Phonemic Characteristics of Apraxia of Speech Resulting from Subcortical Hemorrhage

    Science.gov (United States)

    Peach, Richard K.; Tonkovich, John D.

    2004-01-01

    Reports describing subcortical apraxia of speech (AOS) have received little consideration in the development of recent speech processing models because the speech characteristics of patients with this diagnosis have not been described precisely. We describe a case of AOS with aphasia secondary to basal ganglia hemorrhage. Speech-language symptoms…

  20. Implication of 5-HT(2B) receptors in the serotonin syndrome.

    Science.gov (United States)

    Diaz, Silvina Laura; Maroteaux, Luc

    2011-09-01

    The serotonin (5-HT) syndrome occurs in humans after antidepressant overdose or combination of drugs inducing a massive increase in extracellular 5-HT. Several 5-HT receptors are known to participate in this syndrome in humans and animal models. The 5-HT(2B) receptor has been proposed as a positive modulator of serotonergic activity, but whether it is involved in 5-HT syndrome has not yet been studied. We analyzed here, a putative role of 5-HT(2B) receptors in this disorder by forced swimming test (FST) and behavioral assessment in the open field. In FST, genetic (5-HT(2B)(-/-) mice) or pharmacological (antagonist RS127445 at 0.5 mg/kg) ablation of 5-HT(2B) receptors facilitated selective 5-HT reuptake inhibitors (SSRI)-induced increase of immobility time as well as expression of other symptoms related to 5-HT syndrome like hind limb abduction and Straub tail. Increase in immobility was also developed in FST by both wild type (WT) and 5-HT(2B)(-/-) mice after the administration of 5-HT(1A), 5-HT(2A) or 5-HT(2C) receptor agonists, 8-OH-DPAT (5 mg/kg), DOI (1 mg/kg), or WAY161503 (5 mg/kg), respectively. In contrast, the 5-HT(2B) receptor agonist BW723C86 (3 mg/kg) or 5-HT(1B) receptor agonist CGS12066A (2 mg/kg) decreased immobility time in both genotypes. The 5-HT syndrome induced by fluoxetine at high doses was blocked in WT and 5-HT(2B)(-/-) mice by administration of 5-HT(1A) and 5-HT(2C) receptor antagonists (WAY100635 0.5 mg/kg and SB242084 0.5 mg/kg) but not by the 5-HT(2A) receptor antagonist MDL100907 (1 mg/kg). By behavioral assessment, we confirmed that 5-HT(2B)(-/-) mice were more prone to develop 5-HT syndrome symptoms after administration of high dose of SSRIs or the 5-HT precursor 5-Hydroxytryptophan, 5-HTP, even if increases in 5-HT plasma levels were similar in both genotypes. This evidence suggests that the presence of 5-HT(2B) receptors hinders acute 5-HT toxicity once high levels of 5-HT are attained. Therefore, differential agonism

  1. Repeated Exposure to the “Spice” Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats

    Directory of Open Access Journals (Sweden)

    Joshua S. Elmore

    2018-02-01

    Full Text Available Naphthalen-1-yl-(1-pentylindol-3-ylmethanone (JWH-018 is a synthetic compound found in psychoactive “spice” products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc, then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks, while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.

  2. Activation of 5-HT2 receptors enhances the release of acetylcholine in the prefrontal cortex and hippocampus of the rat.

    Science.gov (United States)

    Nair, Sunila G; Gudelsky, Gary A

    2004-09-15

    The role of 5-HT2 receptors in the regulation of acetylcholine (ACh) release was examined in the medial prefrontal cortex and dorsal hippocampus using in vivo microdialysis. The 5-HT(2A/2C) agonist +/-1-(2,5-dimethoxy-4-iodophenyl) -2- aminopropane hydrochloride (DOI) (1 and 2 mg/kg, i.p.) significantly increased the extracellular concentration of ACh in both brain regions, and this response was attenuated in rats treated with the 5-HT(2A/2B/2C) antagonist LY-53,857 (3 mg/kg, i.p.). Treatment with LY-53,857 alone did not significantly alter ACh release in either brain region The 5-HT(2C) agonist 6-chloro-2-(1-piperazinyl)-pyrazine) (MK-212) (5 mg/kg, i.p.) significantly enhanced the release of ACh in both the prefrontal cortex and hippocampus, whereas the 5-HT2 agonist mescaline (10 mg/kg, i.p.) produced a 2-fold increase in ACh release only in the prefrontal cortex. Intracortical, but not intrahippocampal, infusion of DOI (100 microM) significantly enhanced the release of ACh, and intracortical infusion of LY-53,857 (100 microM) significantly attenuated this response. These results suggest that the release of ACh in the prefrontal cortex and hippocampus is influenced by 5-HT2 receptor mechanisms. The increase in release of ACh induced by DOI in the prefrontal cortex, but not in the hippocampus, appears to be due to 5-HT2 receptor mechanisms localized within this brain region. Furthermore, it appears that the prefrontal cortex is more sensitive than the dorsal hippocampus to the stimulatory effect of 5-HT2 agonists on ACh release.

  3. Receptor⁻Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment.

    Science.gov (United States)

    Borroto-Escuela, Dasiel O; Narváez, Manuel; Ambrogini, Patrizia; Ferraro, Luca; Brito, Ismel; Romero-Fernandez, Wilber; Andrade-Talavera, Yuniesky; Flores-Burgess, Antonio; Millon, Carmelo; Gago, Belen; Narvaez, Jose Angel; Odagaki, Yuji; Palkovits, Miklos; Diaz-Cabiale, Zaida; Fuxe, Kjell

    2018-06-03

    Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A⁻FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A⁻FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A⁻5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1⁻15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1⁻GalR2⁻5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

  4. Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

    Directory of Open Access Journals (Sweden)

    Dasiel O. Borroto-Escuela

    2018-06-01

    Full Text Available Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL rats. Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15 was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

  5. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, Anders; Svarer, Claus; McMahon, Brenda

    2016-01-01

    INTRODUCTION: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C...... test-retest variability in [(11)C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [(18)F]altanserin. Regional differences in the brain distribution of [(11)C]Cimbi-36 and [(18)F]altanserin were assessed with a correlation of regional binding measures...... and with voxel-based analysis. RESULTS: Test-retest variability of [(11)C]Cimbi-36 non-displaceable binding potential (BPND) was consistently correlation between regional...

  6. Subcortical plasticity following perceptual learning in a pitch discrimination task

    OpenAIRE

    Carcagno, Samuele; Plack, Christopher J.

    2011-01-01

    Practice can lead to dramatic improvements in the discrimination of auditory stimuli. In this study, we investigated changes of the frequency-following response (FFR), a subcortical component of the auditory evoked potentials, after a period of pitch discrimination training. Twenty-seven adult listeners were trained for 10 h on a pitch discrimination task using one of three different complex tone stimuli. One had a static pitch contour, one had a rising pitch contour, and one had a falling pi...

  7. [A Case of Amusia Following Right Temporal Subcortical Hemorrhage].

    Science.gov (United States)

    Nagayoshi, Narumi; Arai, Takao; Tanno, Maiko; Watanabe, Motoi; Suzuki, Tadashi; Akasaki, Yasuharu; Murayama, Yuichi

    2017-07-01

    A woman in her 60s presented with amusia due to a localized subcortical hemorrhage of the right temporal lobe. No other symptoms of higher brain dysfunction or body paralysis were observed. One characteristic symptom in this case was rhythm impairment. Few cases of this impairment have been previously reported, and the responsible lesion and underlying mechanisms are still a matter of speculation. However, in this case, a relationship with the right temporal lobe was indicated.

  8. Mapping abnormal subcortical brain morphometry in an elderly HIV+ cohort.

    Science.gov (United States)

    Wade, Benjamin S C; Valcour, Victor G; Wendelken-Riegelhaupt, Lauren; Esmaeili-Firidouni, Pardis; Joshi, Shantanu H; Gutman, Boris A; Thompson, Paul M

    2015-01-01

    Over 50% of HIV + individuals exhibit neurocognitive impairment and subcortical atrophy, but the profile of brain abnormalities associated with HIV is still poorly understood. Using surface-based shape analyses, we mapped the 3D profile of subcortical morphometry in 63 elderly HIV + participants and 31 uninfected controls. The thalamus, caudate, putamen, pallidum, hippocampus, amygdala, brainstem, accumbens, callosum and ventricles were segmented from high-resolution MRIs. To investigate shape-based morphometry, we analyzed the Jacobian determinant (JD) and radial distances (RD) defined on each region's surfaces. We also investigated effects of nadir CD4 + T-cell counts, viral load, time since diagnosis (TSD) and cognition on subcortical morphology. Lastly, we explored whether HIV + participants were distinguishable from unaffected controls in a machine learning context. All shape and volume features were included in a random forest (RF) model. The model was validated with 2-fold cross-validation. Volumes of HIV + participants' bilateral thalamus, left pallidum, left putamen and callosum were significantly reduced while ventricular spaces were enlarged. Significant shape variation was associated with HIV status, TSD and the Wechsler adult intelligence scale. HIV + people had diffuse atrophy, particularly in the caudate, putamen, hippocampus and thalamus. Unexpectedly, extended TSD was associated with increased thickness of the anterior right pallidum. In the classification of HIV + participants vs. controls, our RF model attained an area under the curve of 72%.

  9. Mapping abnormal subcortical brain morphometry in an elderly HIV+ cohort

    Directory of Open Access Journals (Sweden)

    Benjamin S.C. Wade

    2015-01-01

    Full Text Available Over 50% of HIV+ individuals exhibit neurocognitive impairment and subcortical atrophy, but the profile of brain abnormalities associated with HIV is still poorly understood. Using surface-based shape analyses, we mapped the 3D profile of subcortical morphometry in 63 elderly HIV+ participants and 31 uninfected controls. The thalamus, caudate, putamen, pallidum, hippocampus, amygdala, brainstem, accumbens, callosum and ventricles were segmented from high-resolution MRIs. To investigate shape-based morphometry, we analyzed the Jacobian determinant (JD and radial distances (RD defined on each region's surfaces. We also investigated effects of nadir CD4+ T-cell counts, viral load, time since diagnosis (TSD and cognition on subcortical morphology. Lastly, we explored whether HIV+ participants were distinguishable from unaffected controls in a machine learning context. All shape and volume features were included in a random forest (RF model. The model was validated with 2-fold cross-validation. Volumes of HIV+ participants' bilateral thalamus, left pallidum, left putamen and callosum were significantly reduced while ventricular spaces were enlarged. Significant shape variation was associated with HIV status, TSD and the Wechsler adult intelligence scale. HIV+ people had diffuse atrophy, particularly in the caudate, putamen, hippocampus and thalamus. Unexpectedly, extended TSD was associated with increased thickness of the anterior right pallidum. In the classification of HIV+ participants vs. controls, our RF model attained an area under the curve of 72%.

  10. GABAA receptors, but not dopamine, serotonin or NMDA receptors, are increased in the frontal cortex from schizophrenic subjects

    International Nuclear Information System (INIS)

    Daen, B.; Hussain, T.; Scarr, E.; Tomaskovic, E.; Kitsoulis, S.; Pavey, G.; Hill, C.; Keks, N.; Opeskin, K.; Copolov, D.L.

    1998-01-01

    Full text: Having shown changed 5HT 2A receptor density in the frontal cortex (FC) from schizophrenic subjects (1) we now report on further studies of the molecular neuroanatomy of the FC in schizophrenia. We used in situ radioligand binding and autoradiography to measure the density of [ 3 H]8OH-DPAT (1 nM) binding (5HT 1A receptors) and [ 3 H]GR113808 (2.4nM) binding (5HT 4 receptors) in Brodmann's areas (BA) 8, 9 and 10 from 10 schizophrenic and 10 controls subjects. In addition, [ 3 H]muscimol (100 nM) binding (GABA A receptors), [ 3 H]TCP (20nM) binding (NMDA receptors), [ 3 H]SCH 23390 (3nM) binding (DA D 1 like receptors) and [ 3 H]YM-09151-2 (4nM) binding (DA D 2 -like receptors) was measured in BA 9 from 17 schizophrenic and 17 control subjects. Subjects were matched for age and sex and the post-mortem interval for tissue collection did not differ. There was a significant increase (18%) in the density of GABA A receptors in BA 9 from subjects with schizophrenia (p<0.05) with no change in NMDA, dopamine or serotonin receptors. These data support the hypothesis that there are selective changes in neurotransmitter receptors in the FC of subjects with schizophrenia. It is not yet clear if such changes contribute to the pathology of the illness. Copyright (1998) Australian Neuroscience Society

  11. Crystal Structure of an LSD-Bound Human Serotonin Receptor.

    Science.gov (United States)

    Wacker, Daniel; Wang, Sheng; McCorvy, John D; Betz, Robin M; Venkatakrishnan, A J; Levit, Anat; Lansu, Katherine; Schools, Zachary L; Che, Tao; Nichols, David E; Shoichet, Brian K; Dror, Ron O; Roth, Bryan L

    2017-01-26

    The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT 2B . The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT 2B R and 5-HT 2A R-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. A Biomarker to Differentiate between Primary and Cocaine-Induced Major Depression in Cocaine Use Disorder: The Role of Platelet IRAS/Nischarin (I1-Imidazoline Receptor

    Directory of Open Access Journals (Sweden)

    Benjamin Keller

    2017-12-01

    Full Text Available The association of cocaine use disorder (CUD and comorbid major depressive disorder (MDD; CUD/MDD is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD or cocaine-induced (CUD-induced MDD. Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology. Platelet biomarkers [5-HT2A receptor and imidazoline receptor antisera selected (IRAS/nischarin] were assessed by Western blot in subjects with CUD and primary MDD (n = 16 or CUD-induced MDD (n = 9; antidepressant free, AD−; antidepressant treated, AD+ and controls (n = 10 at basal level and/or after acute tryptophan depletion (ATD. Basal platelet 5-HT2A receptor (monomer was reduced in comorbid CUD/MDD subjects (all patients: 43% compared to healthy controls, and this down-regulation was independent of AD medication (decreases in AD−: 47%, and in AD+: 40%. No basal differences were found for IRAS/nischarin contents in AD+ and AD− comorbid CUD/MDD subjects. The comparison of IRAS/nischarin in the different subject groups during/after ATD showed opposite modulations (i.e., increases and decreases in response to low plasma tryptophan levels with significant differences discriminating between the subgroups of CUD with primary MDD and CUD-induced MDD. These specific alterations suggested that platelet IRAS/nischarin might be useful as a biomarker to discriminate between primary and CUD-induced MDD in this dual pathology.

  13. Lateral/Basolateral Amygdala Serotonin Type-2 Receptors Modulate Operant Self-administration of a Sweetened Ethanol Solution via Inhibition of Principal Neuron Activity

    Directory of Open Access Journals (Sweden)

    Brian eMccool

    2014-01-01

    Full Text Available The lateral/basolateral amygdala (BLA forms an integral part of the neural circuitry controlling innate anxiety and learned fear. More recently, BLA dependent modulation of self-administration behaviors suggests a much broader role in the regulation of reward evaluation. To test this, we employed a self-administration paradigm that procedurally segregates ‘seeking’ (exemplified as lever-press behaviors from consumption (drinking directed at a sweetened ethanol solution. Microinjection of the nonselective serotonin type-2 receptor agonist, alpha-methyl-5-hydroxytryptamine (-m5HT into the BLA reduced lever pressing behaviors in a dose-dependent fashion. This was associated with a significant reduction in the number of response-bouts expressed during non-reinforced sessions without altering the size of a bout or the rate of responding. Conversely, intra-BLA -m5HT only modestly effected consumption-related behaviors; the highest dose reduced the total time spent consuming a sweetened ethanol solution but did not inhibit the total number of licks, number of lick bouts, or amount of solution consumed during a session. In vitro neurophysiological characterization of BLA synaptic responses showed that -m5HT significantly reduced extracellular field potentials. This was blocked by the 5-HT2A/C antagonist ketanserin suggesting that 5-HT2-like receptors mediate the behavioral effect of -m5HT. During whole-cell patch current-clamp recordings, we subsequently found that -m5HT increased action potential threshold and hyperpolarized the resting membrane potential of BLA pyramidal neurons. Together, our findings show that the activation of BLA 5-HT2A/C receptors inhibits behaviors related to reward-seeking by suppressing BLA principal neuron activity. These data are consistent with the hypothesis that the BLA modulates reward-related behaviors and provides specific insight into BLA contributions during operant self-administration of a

  14. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  15. Fractal Dimension Analysis of Subcortical Gray Matter Structures in Schizophrenia.

    Directory of Open Access Journals (Sweden)

    Guihu Zhao

    Full Text Available A failure of adaptive inference-misinterpreting available sensory information for appropriate perception and action-is at the heart of clinical manifestations of schizophrenia, implicating key subcortical structures in the brain including the hippocampus. We used high-resolution, three-dimensional (3D fractal geometry analysis to study subtle and potentially biologically relevant structural alterations (in the geometry of protrusions, gyri and indentations, sulci in subcortical gray matter (GM in patients with schizophrenia relative to healthy individuals. In particular, we focus on utilizing Fractal Dimension (FD, a compact shape descriptor that can be computed using inputs with irregular (i.e., not necessarily smooth surfaces in order to quantify complexity (of geometrical properties and configurations of structures across spatial scales of subcortical GM in this disorder. Probabilistic (entropy-based information FD was computed based on the box-counting approach for each of the seven subcortical structures, bilaterally, as well as the brainstem from high-resolution magnetic resonance (MR images in chronic patients with schizophrenia (n = 19 and age-matched healthy controls (n = 19 (age ranges: patients, 22.7-54.3 and healthy controls, 24.9-51.6 years old. We found a significant reduction of FD in the left hippocampus (median: 2.1460, range: 2.07-2.18 vs. median: 2.1730, range: 2.15-2.23, p<0.001; Cohen's effect size, U3 = 0.8158 (95% Confidence Intervals, CIs: 0.6316, 1.0, the right hippocampus (median: 2.1430, range: 2.05-2.19 vs. median: 2.1760, range: 2.12-2.21, p = 0.004; U3 = 0.8421 (CIs: 0.5263, 1, as well as left thalamus (median: 2.4230, range: 2.40-2.44, p = 0.005; U3 = 0.7895 (CIs: 0.5789, 0.9473 in schizophrenia patients, relative to healthy individuals. Our findings provide in-vivo quantitative evidence for reduced surface complexity of hippocampus, with reduced FD indicating a less complex, less regular GM surface detected in

  16. The Reduction of Baseline Serotonin 2A Receptors in Mild Cognitive Impairment is Stable at Two-year Follow-up

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Knudsen, Gitte M; Madsen, Karine

    2011-01-01

    Alzheimer's disease (AD). In both patients and healthy subjects, no significant change in 5-HT2A receptor binding was found as compared to baseline values. In MCI patients, the average BPP in neocortex ranged from 1.49 to 2.45 at baseline and 1.38 to 2.29 at two-year follow-up; and in healthy subjects BPP...... ranged from 1.85 to 3.10 at baseline and 1.81 to 2.98 at two-year follow-up. The BPP of the patients that converted to AD during the follow-up period did not differ significantly from the patients that had not (yet) converted, neither at baseline, nor at follow-up. We conclude that the reduced levels...

  17. Expression and function of serotonin 2A and 2B receptors in the mammalian respiratory network.

    Directory of Open Access Journals (Sweden)

    Marcus Niebert

    Full Text Available Neurons of the respiratory network in the lower brainstem express a variety of serotonin receptors (5-HTRs that act primarily through adenylyl cyclase. However, there is one receptor family including 5-HT(2A, 5-HT(2B, and 5-HT(2C receptors that are directed towards protein kinase C (PKC. In contrast to 5-HT(2ARs, expression and function of 5-HT(2BRs within the respiratory network are still unclear. 5-HT(2BR utilizes a Gq-mediated signaling cascade involving calcium and leading to activation of phospholipase C and IP3/DAG pathways. Based on previous studies, this signal pathway appears to mediate excitatory actions on respiration. In the present study, we analyzed receptor expression in pontine and medullary regions of the respiratory network both at the transcriptional and translational level using quantitative RT-PCR and self-made as well as commercially available antibodies, respectively. In addition we measured effects of selective agonists and antagonists for 5-HT(2ARs and 5-HT(2BRs given intra-arterially on phrenic nerve discharges in juvenile rats using the perfused brainstem preparation. The drugs caused significant changes in discharge activity. Co-administration of both agonists revealed a dominance of the 5-HT(2BR. Given the nature of the signaling pathways, we investigated whether intracellular calcium may explain effects observed in the respiratory network. Taken together, the results of this study suggest a significant role of both receptors in respiratory network modulation.

  18. Common genetic variants influence human subcortical brain structures.

    Science.gov (United States)

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

    2015-04-09

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

  19. Common genetic variants influence human subcortical brain structures

    Science.gov (United States)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  20. Subcortical pathways: Towards a better understanding of auditory disorders.

    Science.gov (United States)

    Felix, Richard A; Gourévitch, Boris; Portfors, Christine V

    2018-05-01

    Hearing loss is a significant problem that affects at least 15% of the population. This percentage, however, is likely significantly higher because of a variety of auditory disorders that are not identifiable through traditional tests of peripheral hearing ability. In these disorders, individuals have difficulty understanding speech, particularly in noisy environments, even though the sounds are loud enough to hear. The underlying mechanisms leading to such deficits are not well understood. To enable the development of suitable treatments to alleviate or prevent such disorders, the affected processing pathways must be identified. Historically, mechanisms underlying speech processing have been thought to be a property of the auditory cortex and thus the study of auditory disorders has largely focused on cortical impairments and/or cognitive processes. As we review here, however, there is strong evidence to suggest that, in fact, deficits in subcortical pathways play a significant role in auditory disorders. In this review, we highlight the role of the auditory brainstem and midbrain in processing complex sounds and discuss how deficits in these regions may contribute to auditory dysfunction. We discuss current research with animal models of human hearing and then consider human studies that implicate impairments in subcortical processing that may contribute to auditory disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Subcortical regional morphology correlates with fluid and spatial intelligence.

    Science.gov (United States)

    Burgaleta, Miguel; MacDonald, Penny A; Martínez, Kenia; Román, Francisco J; Álvarez-Linera, Juan; Ramos González, Ana; Karama, Sherif; Colom, Roberto

    2014-05-01

    Neuroimaging studies have revealed associations between intelligence and brain morphology. However, researchers have focused primarily on the anatomical features of the cerebral cortex, whereas subcortical structures, such as the basal ganglia (BG), have often been neglected despite extensive functional evidence on their relation with higher-order cognition. Here we performed shape analyses to understand how individual differences in BG local morphology account for variability in cognitive performance. Structural MRI was acquired in 104 young adults (45 men, 59 women, mean age = 19.83, SD = 1.64), and the outer surface of striatal structures (caudate, nucleus accumbens, and putamen), globus pallidus, and thalamus was estimated for each subject and hemisphere. Further, nine cognitive tests were used to measure fluid (Gf), crystallized (Gc), and spatial intelligence (Gv). Latent scores for these factors were computed by means of confirmatory factor analysis and regressed vertex-wise against subcortical shape (local displacements of vertex position), controlling for age, sex, and adjusted for brain size. Significant results (FDR intelligence-related prefrontal areas. Copyright © 2013 Wiley Periodicals, Inc.

  2. 5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide.

    Science.gov (United States)

    Gresch, Paul J; Barrett, Robert J; Sanders-Bush, Elaine; Smith, Randy L

    2007-02-01

    d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, +/-1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 microg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 microg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)(2A) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 microg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 microg/microl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT(2A) receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.

  3. 21 CFR 882.5840 - Implanted intracerebral/subcortical stimulator for pain relief.

    Science.gov (United States)

    2010-04-01

    ... pain relief. 882.5840 Section 882.5840 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Devices § 882.5840 Implanted intracerebral/subcortical stimulator for pain relief. (a) Identification. An implanted intracerebral/subcortical stimulator for pain relief is a device that applies electrical current...

  4. Mapping Subcortical Brain Maturation during Adolescence: Evidence of Hemisphere-and Sex-Specific Longitudinal Changes

    Science.gov (United States)

    Dennison, Meg; Whittle, Sarah; Yücel, Murat; Vijayakumar, Nandita; Kline, Alexandria; Simmons, Julian; Allen, Nicholas B.

    2013-01-01

    Early to mid-adolescence is an important developmental period for subcortical brain maturation, but longitudinal studies of these neurodevelopmental changes are lacking. The present study acquired repeated magnetic resonance images from 60 adolescent subjects (28 female) at ages 12.5 and 16.5 years to map changes in subcortical structure volumes.…

  5. Development and heritability of subcortical brain volumes at age 9 and 12

    NARCIS (Netherlands)

    Swagerman, S.C.; Brouwer, R.; de Geus, E.J.C.; Hulshoff Pol, H.E.; Boomsma, D.I.

    2014-01-01

    Subcortical brain structures are involved in a variety of cognitive and emotional functions and follow different trajectories of increase and decrease in volume from childhood to adulthood. The heritability of development of subcortical brain volumes during adolescence has not been studied

  6. Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

    Science.gov (United States)

    Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

    2016-11-10

    On the basis of the structural similarity of our previous 5-HT 2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT 2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT 2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

  7. Disturbed oscillatory brain dynamics in subcortical ischemic vascular dementia

    Directory of Open Access Journals (Sweden)

    van Straaten Elisabeth CW

    2012-07-01

    Full Text Available Abstract Background White matter hyperintensities (WMH can lead to dementia but the underlying physiological mechanisms are unclear. We compared relative oscillatory power from electroencephalographic studies (EEGs of 17 patients with subcortical ischemic vascular dementia, based on extensive white matter hyperintensities (SIVD-WMH with 17 controls to investigate physiological changes underlying this diagnosis. Results Differences between the groups were large, with a decrease of relative power of fast activity in patients (alpha power 0.25 ± 0.12 versus 0.38 ± 0.13, p = 0.01; beta power 0.08 ± 0.04 versus 0.19 ± 0.07; p Conclusions This pattern of disturbance in oscillatory brain activity indicate loss of connections between neurons, providing a first step in the understanding of cognitive dysfunction in SIVD-WMH.

  8. Cortical and subcortical mechanisms of brain-machine interfaces.

    Science.gov (United States)

    Marchesotti, Silvia; Martuzzi, Roberto; Schurger, Aaron; Blefari, Maria Laura; Del Millán, José R; Bleuler, Hannes; Blanke, Olaf

    2017-06-01

    Technical advances in the field of Brain-Machine Interfaces (BMIs) enable users to control a variety of external devices such as robotic arms, wheelchairs, virtual entities and communication systems through the decoding of brain signals in real time. Most BMI systems sample activity from restricted brain regions, typically the motor and premotor cortex, with limited spatial resolution. Despite the growing number of applications, the cortical and subcortical systems involved in BMI control are currently unknown at the whole-brain level. Here, we provide a comprehensive and detailed report of the areas active during on-line BMI control. We recorded functional magnetic resonance imaging (fMRI) data while participants controlled an EEG-based BMI inside the scanner. We identified the regions activated during BMI control and how they overlap with those involved in motor imagery (without any BMI control). In addition, we investigated which regions reflect the subjective sense of controlling a BMI, the sense of agency for BMI-actions. Our data revealed an extended cortical-subcortical network involved in operating a motor-imagery BMI. This includes not only sensorimotor regions but also the posterior parietal cortex, the insula and the lateral occipital cortex. Interestingly, the basal ganglia and the anterior cingulate cortex were involved in the subjective sense of controlling the BMI. These results inform basic neuroscience by showing that the mechanisms of BMI control extend beyond sensorimotor cortices. This knowledge may be useful for the development of BMIs that offer a more natural and embodied feeling of control for the user. Hum Brain Mapp 38:2971-2989, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  9. Distinct subcortical volume alterations in pediatric and adult OCD

    Science.gov (United States)

    Boedhoe, Premika S.W.; Schmaal, Lianne; Abe, Yoshinari; Ameis, Stephanie H.; Arnold, Paul D.; Batistuzzo, Marcelo C.; Benedetti, Francesco; Beucke, Jan C.; Bollettini, Irene; Bose, Anushree; Brem, Silvia; Calvo, Anna; Cheng, Yuqi; Cho, Kang Ik K.; Dallaspezia, Sara; Denys, Damiaan; Fitzgerald, Kate D.; Fouche, Jean-Paul; Giménez, Mònica; Gruner, Patricia; Hanna, Gregory L.; Hibar, Derrek P.; Hoexter, Marcelo Q.; Huyser, Chaim; Ikari, Keisuke; Jahanshad, Neda; Kathmann, Norbert; Kaufmann, Christian; Koch, Kathrin; Kwon, Jun Soo; Lazaro, Luisa; Liu, Yanni; Lochner, Christine; Marsh, Rachel; Martínez-Zalacaín, Ignacio; Mataix-Cols, David; Menchón, José M.; Minuzzii, Luciano; Nakamae, Takashi; Nakao, Tomohiro; Narayanaswamy, Janardhanan C.; Piras, Fabrizio; Piras, Federica; Pittenger, Christopher; Reddy, Y.C. Janardhan; Sato, Joao R.; Simpson, H. Blair; Soreni, Noam; Soriano-Mas, Carles; Spalletta, Gianfranco; Stevens, Michael C.; Szeszko, Philip R.; Tolin, David F.; Venkatasubramanian, Ganesan; Walitza, Susanne; Wang, Zhen; van Wingen, Guido A.; Xu, Jian; Xu, Xiufeng; Yun, Je-Yeon; Zhao, Qing; Thompson, Paul M.; Stein, Dan J.; van den Heuvel, Odile A.

    2016-01-01

    Objective Structural brain imaging studies in Obsessive-Compulsive Disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in disease profile and developmental stage. Methods To address these limitations, we conducted a meta- and mega-analysis of data from OCD sites worldwide. T1 images from 1,830 OCD patients and 1,759 controls were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ in OCD patients and healthy controls. We additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. Results The meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohen’s d=−0.13; p=5.1x10−3, % difference −2.80) and larger pallidum volumes (d=0.16; p=1.6x10−3, % difference 3.16) compared to adult controls. Both effects were stronger in medicated patients compared to controls (d=−0.29; p=2.4x10−5, % difference −4.18 and d=0.29; p=1.2x10−5, % difference 4.38, respectively). Unmedicated pediatric patients had larger thalamic volumes (d=0.38, p=2.1x10−3) compared to pediatric controls. None of these findings were mediated by sample characteristics such as mean age or field strength. Overall the mega-analysis yielded similar results. Conclusion Our study indicates a different pattern of subcortical abnormalities in pediatric versus adult OCD patients. The pallidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. This highlights the potential importance of neurodevelopmental alterations in OCD, and suggests that further research on neuroplasticity in OCD may be useful. PMID:27609241

  10. Larger Gray Matter Volume in the Basal Ganglia of Heavy Cannabis Users Detected by Voxel-Based Morphometry and Subcortical Volumetric Analysis.

    Science.gov (United States)

    Moreno-Alcázar, Ana; Gonzalvo, Begoña; Canales-Rodríguez, Erick J; Blanco, Laura; Bachiller, Diana; Romaguera, Anna; Monté-Rubio, Gemma C; Roncero, Carlos; McKenna, Peter J; Pomarol-Clotet, Edith

    2018-01-01

    Background: Structural imaging studies of cannabis users have found evidence of both cortical and subcortical volume reductions, especially in cannabinoid receptor-rich regions such as the hippocampus and amygdala. However, the findings have not been consistent. In the present study, we examined a sample of adult heavy cannabis users without other substance abuse to determine whether long-term use is associated with brain structural changes, especially in the subcortical regions. Method: We compared the gray matter volume of 14 long-term, heavy cannabis users with non-using controls. To provide robust findings, we conducted two separate studies using two different MRI techniques. Each study used the same sample of cannabis users and a different control group, respectively. Both control groups were independent of each other. First, whole-brain voxel-based morphometry (VBM) was used to compare the cannabis users against 28 matched controls (HC1 group). Second, a volumetric analysis of subcortical regions was performed to assess differences between the cannabis users and a sample of 100 matched controls (HC2 group) obtained from a local database of healthy volunteers. Results: The VBM study revealed that, compared to the control group HC1, the cannabis users did not show cortical differences nor smaller volume in any subcortical structure but showed a cluster ( p users showed significantly larger volumes in the putamen ( p = 0.001) and pallidum ( p = 0.0015). Subtle trends, only significant at the uncorrected level, were also found in the caudate ( p = 0.05) and nucleus accumbens ( p = 0.047). Conclusions: This study does not support previous findings of hippocampal and/or amygdala structural changes in long-term, heavy cannabis users. It does, however, provide evidence of basal ganglia volume increases.

  11. Allosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine7 receptors.

    Science.gov (United States)

    Hedlund, P B; Carson, M J; Sutcliffe, J G; Thomas, E A

    1999-12-01

    Oleamide belongs to a family of amidated lipids with diverse biological activities, including sleep induction and signaling modulation of several 5-hydroxytryptamine (5-HT) receptor subtypes, including 5-HT1A, 5-HT2A/2C, and 5-HT7. The 5-HT7 receptor, predominantly localized in the hypothalamus, hippocampus, and frontal cortex, stimulates cyclic AMP formation and is thought to be involved in the regulation of sleep-wake cycles. Recently, it was proposed that oleamide acts at an allosteric site on the 5-HT7 receptor to regulate cyclic AMP formation. We have further investigated the interaction between oleamide and 5-HT7 receptors by performing radioligand binding assays with HeLa cells transfected with the 5-HT7 receptor. Methiothepin, clozapine, and 5-HT all displaced specific [3H]5-HT (100 nM) binding, with pK(D) values of 7.55, 7.85, and 8.39, respectively. Oleamide also displaced [3H]5-HT binding, but the maximum inhibition was only 40% of the binding. Taking allosteric (see below) cooperativity into account, a K(D) of 2.69 nM was calculated for oleamide. In saturation binding experiments, oleamide caused a 3-fold decrease in the affinity of [3H]5-HT for the 5-HT7 receptor, without affecting the number of binding sites. A Schild analysis showed that the induced shift in affinity of [3H]5-HT reached a plateau, unlike that of a competitive inhibitor, illustrating the allosteric nature of the interaction between oleamide and the 5-HT7 receptor. Oleic acid, the product of oleamide hydrolysis, had a similar effect on [3H]5-HT binding, whereas structural analogs of oleamide, trans-9,10-octadecenamide, cis-8,9-octadecenamide, and erucamide, did not alter [3H]5-HT binding significantly. The findings support the hypothesis that oleamide acts via an allosteric site on the 5-HT7 receptor regulating receptor affinity.

  12. Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster.

    Science.gov (United States)

    Blenau, Wolfgang; Daniel, Stöppler; Balfanz, Sabine; Thamm, Markus; Baumann, Arnd

    2017-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster , a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT 1A , Dm5-HT 1B , and Dm5-HT 7 couple to cAMP signaling cascades, the Dm5-HT 2A receptor leads to Ca 2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT 2B receptor. Knowledge about this receptor's pharmacological properties is very limited. This is quite surprising because Dm5-HT 2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT 2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT 2B 's pharmacology, we evaluated the receptor's response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT 2B signaling in vitro and in vivo .

  13. Intraoperative use of ultrasonography by small subcortical lesions

    International Nuclear Information System (INIS)

    Kondoff, Sl.; Gabrovski, St.; Krustev, E.; Poptodorov, G.; Gabrovski, N.; Uzunov, K.

    2004-01-01

    The aim of this study is to present the possibilities for use of intraoperative ultrasound (US) diagnostics as a method of image guided surgical navigation in neurosurgery. During an US scan of normal and pathologically changed tissues as well as volume taking lesion images are received in real time intraoperative display allowing dynamic control of the surgical radicalism and at the same time minimal invasiveness to the neural structures. Intraoperative ultrasound with real-time display characteristics finds a very wide application: subcortical and deeply localized tumour lesions, haematomas, large and giant aneurysms, arteriovenous (AV) malformations, spinal tumours and cysts. The real time dynamic scan is based on the B-mod. This method is founded on the US characteristic of reflecting in a different manner at the borderline of two mediums with different density as well as tissues with various physical and chemical characteristics. The reflection is partially absorbed depending on the acoustic impedance of the biologic field. We use a LOGIC200PRO unit with two probes I-type and T-type having a 'wedge of space' - 35 mm and working frequencies of 6 MHz and 7 MHz appropriate for visualizing lesions at a depth of 25 to 60 mm.The advantages of the Intraoperative US diagnostics are: non-invasiveness; real time display - i.e. presents the imminent intraoperative changes; it is a good alternative to other image-guided technologies; accessible price of the US unit

  14. Subcortical orientation biases explain orientation selectivity of visual cortical cells.

    Science.gov (United States)

    Vidyasagar, Trichur R; Jayakumar, Jaikishan; Lloyd, Errol; Levichkina, Ekaterina V

    2015-04-01

    The primary visual cortex of carnivores and primates shows an orderly progression of domains of neurons that are selective to a particular orientation of visual stimuli such as bars and gratings. We recorded from single-thalamic afferent fibers that terminate in these domains to address the issue whether the orientation sensitivity of these fibers could form the basis of the remarkable orientation selectivity exhibited by most cortical cells. We first performed optical imaging of intrinsic signals to obtain a map of orientation domains on the dorsal aspect of the anaesthetized cat's area 17. After confirming using electrophysiological recordings the orientation preferences of single neurons within one or two domains in each animal, we pharmacologically silenced the cortex to leave only the afferent terminals active. The inactivation of cortical neurons was achieved by the superfusion of either kainic acid or muscimol. Responses of single geniculate afferents were then recorded by the use of high impedance electrodes. We found that the orientation preferences of the afferents matched closely with those of the cells in the orientation domains that they terminated in (Pearson's r = 0.633, n = 22, P = 0.002). This suggests a possible subcortical origin for cortical orientation selectivity. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  15. Cortical and subcortical brain alterations in Juvenile Absence Epilepsy

    Directory of Open Access Journals (Sweden)

    Manuela Tondelli

    2016-01-01

    Full Text Available Despite the common assumption that genetic generalized epilepsies are characterized by a macroscopically normal brain on magnetic resonance imaging, subtle structural brain alterations have been detected by advanced neuroimaging techniques in Childhood Absence Epilepsy syndrome. We applied quantitative structural MRI analysis to a group of adolescents and adults with Juvenile Absence Epilepsy (JAE in order to investigate micro-structural brain changes using different brain measures. We examined grey matter volumes, cortical thickness, surface areas, and subcortical volumes in 24 patients with JAE compared to 24 healthy controls; whole-brain voxel-based morphometry (VBM and Freesurfer analyses were used. When compared to healthy controls, patients revealed both grey matter volume and surface area reduction in bilateral frontal regions, anterior cingulate, and right mesial-temporal lobe. Correlation analysis with disease duration showed that longer disease was correlated with reduced surface area in right pre- and post-central gyrus. A possible effect of valproate treatment on brain structures was excluded. Our results indicate that subtle structural brain changes are detectable in JAE and are mainly located in anterior nodes of regions known to be crucial for awareness, attention and memory.

  16. The influence of puberty on subcortical brain development.

    Science.gov (United States)

    Goddings, Anne-Lise; Mills, Kathryn L; Clasen, Liv S; Giedd, Jay N; Viner, Russell M; Blakemore, Sarah-Jayne

    2014-03-01

    Puberty is characterized by hormonal, physical and psychological transformation. The human brain undergoes significant changes between childhood and adulthood, but little is known about how puberty influences its structural development. Using a longitudinal sample of 711 magnetic resonance imaging scans from 275 individuals aged 7-20years, we examined how subcortical brain regions change in relation to puberty. Our regions of interest included the amygdala, hippocampus and corpus striatum including the nucleus accumbens (NA), caudate, putamen and globus pallidus (GP). Pubertal development was significantly related to structural volume in all six regions in both sexes. Pubertal development and age had both independent and interactive influences on volume for the amygdala, hippocampus and putamen in both sexes, and the caudate in females. There was an interactive puberty-by-age effect on volume for the NA and GP in both sexes, and the caudate in males. These findings suggest a significant role for puberty in structural brain development. © 2013. Published by Elsevier Inc. All rights reserved.

  17. Frontal and subcortical grey matter reductions in PTSD.

    Science.gov (United States)

    O'Doherty, Daniel C M; Tickell, Ashleigh; Ryder, Will; Chan, Charles; Hermens, Daniel F; Bennett, Maxwell R; Lagopoulos, Jim

    2017-08-30

    Post-traumatic stress disorder (PTSD) is characterised by a range of debilitating psychological, physical and cognitive symptoms. PTSD has been associated with grey matter atrophy in limbic and frontal cortical brain regions. However, previous studies have reported heterogeneous findings, with grey matter changes observed beyond limbic/frontal areas. Seventy-five adults were recruited from the community, 25 diagnosed with PTSD along with 25 healthy and 25 trauma exposed age and gender matched controls. Participants underwent clinical assessment and magnetic resonance imaging. The data-analyses method Voxel Based Morphometry (VBM) was used to estimate cortical grey matter volumes. When compared to both healthy and trauma exposed controls, PTSD subjects demonstrated decreased grey matter volumes within subcortical brain regions-including the hippocampus and amygdala-along with reductions in the anterior cingulate cortex, frontal medial cortex, middle frontal gyrus, superior frontal gyrus, paracingulate gyrus, and precuneus cortex. Significant negative correlations were found between total CAPS lifetime clinical scores/sub-scores and GM volume of both the PTSD and TC groups. GM volumes of the left rACC and right amygdala showed a significant negative correlation within PTSD diagnosed subjects. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  18. Occipital seizures and subcortical T2 hypointensity in the setting of hyperglycemia

    Directory of Open Access Journals (Sweden)

    Swapna L. Putta

    2014-01-01

    Conclusion: Hyperglycemia should be considered in the etiology of differential diagnosis of patients with visual abnormalities suspicious for seizures, especially when the MRI shows focal subcortical T2 hypointensity with or without leptomeningeal enhancement.

  19. Subcortical Band Heterotopia (SBH) in Rat Offspring Following Maternal Hypothyroxinemia: Structural and Functional Characteristics

    Science.gov (United States)

    Thyroid hormones (TH) play crucial roles in brain maturation, neuronal migration, and neocortical lamination. Subcortical band heterotopia (SBH) represent a class of neuronal migration errors in humans that are often associated with childhood epilepsy. We have previously reported...

  20. Subcortical and cortical correlates of pitch discrimination: Evidence for two levels of neuroplasticity in musicians

    DEFF Research Database (Denmark)

    Bianchi, Federica; Hjortkjær, Jens; Santurette, Sébastien

    2017-01-01

    superior temporal gyrus, Heschl's gyrus, insular cortex, inferior frontal gyrus, and in the inferior colliculus. Both subcortical and cortical neural responses predicted the individual pitch-discrimination performance. However, functional activity in the inferior colliculus correlated with differences...

  1. The Effects of Modified Constraint-Induced Movement Therapy in Acute Subcortical Cerebral Infarction

    OpenAIRE

    Yu, Changshen; Wang, Wanjun; Zhang, Yue; Wang, Yizhao; Hou, Weijia; Liu, Shoufeng; Gao, Chunlin; Wang, Chen; Mo, Lidong; Wu, Jialing

    2017-01-01

    Background: Constraint-induced movement therapy (CIMT) promotes upper extremity recovery post stroke, however, it is difficult to implement clinically due to its high resource demand and safety of the restraint. Therefore, we propose that modified CIMT (mCIMT) be used to treat individuals with acute subcortical infarction. Objective: To evaluate the therapeutic effects of mCIMT in patients with acute subcortical infarction, and investigate the possible mechanisms underlying the effect. ...

  2. Subcortical plasticity following perceptual learning in a pitch discrimination task.

    Science.gov (United States)

    Carcagno, Samuele; Plack, Christopher J

    2011-02-01

    Practice can lead to dramatic improvements in the discrimination of auditory stimuli. In this study, we investigated changes of the frequency-following response (FFR), a subcortical component of the auditory evoked potentials, after a period of pitch discrimination training. Twenty-seven adult listeners were trained for 10 h on a pitch discrimination task using one of three different complex tone stimuli. One had a static pitch contour, one had a rising pitch contour, and one had a falling pitch contour. Behavioral measures of pitch discrimination and FFRs for all the stimuli were measured before and after the training phase for these participants, as well as for an untrained control group (n = 12). Trained participants showed significant improvements in pitch discrimination compared to the control group for all three trained stimuli. These improvements were partly specific for stimuli with the same pitch modulation (dynamic vs. static) and with the same pitch trajectory (rising vs. falling) as the trained stimulus. Also, the robustness of FFR neural phase locking to the sound envelope increased significantly more in trained participants compared to the control group for the static and rising contour, but not for the falling contour. Changes in FFR strength were partly specific for stimuli with the same pitch modulation (dynamic vs. static) of the trained stimulus. Changes in FFR strength, however, were not specific for stimuli with the same pitch trajectory (rising vs. falling) as the trained stimulus. These findings indicate that even relatively low-level processes in the mature auditory system are subject to experience-related change.

  3. Double Cortex Syndrome (Subcortical Band Heterotopia): A Case Report.

    Science.gov (United States)

    Momen, Ali Akbar; Momen, Mehdi

    2015-01-01

    Objective Approximately 5-10% of preschool age children are considered developmentally disabled. Brain Magnetic Resonance Imaging (MRI) plays a key role in the diagnostic evaluation in these children. Many congenital or acquired brain anomalies are revealed with MRIs. Although the majority of these abnormalities are sporadic but patients with subcortical band heterotopia or double cortex syndrome have sex-linked inheritance. We are going to present the first case in Iran from Ahvaz city, which was presented with status epilepticus associated with developmental delay and finally diagnosed as double cortex syndrome, because band heterotopia cases especially for continuous or generalized form is rare. A 4.5-year-old developmentally delayed girl was admitted for generalized tonic clonic seizure attack of 1 hr, upward gaze, locked mouth, and urinary incontinence (status epilepticus) in the child neurology ward. She had a history of recurrent seizures that started as febrile seizures since she was 12 months of age and had frequent admissions for having recurrent seizure attacks. She was the only child of consanguineous parents with negative family history of any neurologic problems. She was a product of uneventful term pregnancy, vaginal delivery with a low Apgar score at birth who was admitted for six days in the neonatal ward for hypotonia and cyanosis. At 4.5 years of age, she had HC: 45cm (spike-wave discharges. A brain MRI showed corpus callosal dysplasia, generalized band heterotopia, and polymicrogyria. She was discharged home with oral valproate and regular outpatient follow-ups. In the diagnostic evaluation of developmentally delayed and epileptic children, a brain MRI is strongly recommended for accurate diagnosis of anomalies such as neuronal migration disorders (band heterotopia) and others, because appropriate therapeutic management, prognosis, prevention, and genetic counseling for prenatal diagnosis are dependent on definite diagnosis of the proband case.

  4. Larger Gray Matter Volume in the Basal Ganglia of Heavy Cannabis Users Detected by Voxel-Based Morphometry and Subcortical Volumetric Analysis

    Directory of Open Access Journals (Sweden)

    Ana Moreno-Alcázar

    2018-05-01

    Full Text Available Background: Structural imaging studies of cannabis users have found evidence of both cortical and subcortical volume reductions, especially in cannabinoid receptor-rich regions such as the hippocampus and amygdala. However, the findings have not been consistent. In the present study, we examined a sample of adult heavy cannabis users without other substance abuse to determine whether long-term use is associated with brain structural changes, especially in the subcortical regions.Method: We compared the gray matter volume of 14 long-term, heavy cannabis users with non-using controls. To provide robust findings, we conducted two separate studies using two different MRI techniques. Each study used the same sample of cannabis users and a different control group, respectively. Both control groups were independent of each other. First, whole-brain voxel-based morphometry (VBM was used to compare the cannabis users against 28 matched controls (HC1 group. Second, a volumetric analysis of subcortical regions was performed to assess differences between the cannabis users and a sample of 100 matched controls (HC2 group obtained from a local database of healthy volunteers.Results: The VBM study revealed that, compared to the control group HC1, the cannabis users did not show cortical differences nor smaller volume in any subcortical structure but showed a cluster (p < 0.001 of larger GM volume in the basal ganglia, involving the caudate, putamen, pallidum, and nucleus accumbens, bilaterally. The subcortical volumetric analysis revealed that, compared to the control group HC2, the cannabis users showed significantly larger volumes in the putamen (p = 0.001 and pallidum (p = 0.0015. Subtle trends, only significant at the uncorrected level, were also found in the caudate (p = 0.05 and nucleus accumbens (p = 0.047.Conclusions: This study does not support previous findings of hippocampal and/or amygdala structural changes in long-term, heavy cannabis users. It

  5. Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Wolfgang Blenau

    2017-05-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects and deuterostomes (e.g., mammals. In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor’s pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B’s pharmacology, we evaluated the receptor’s response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo.

  6. [Effects of fatigue and restraint stress on the expression of carnitine palmitoyltransferase-I and 5-hydroxytryptamine receptors in aorta of rats].

    Science.gov (United States)

    Wei, Cong; Han, Jian-ke; Wang, Hong-tao; Jia, Zhen-hua; Chang, Li-Ping; Wu, Yi-ling

    2011-04-05

    To investigate the effect of fatigue and restraint stress on the expressions of CPT (carnitine palmitoyltransferase)-I, PPAR (peroxisome proliferator-activated receptor) δ, 5-HT (hydroxytryptamine) 1D and 5-HT2A receptors in aorta of rats. A total of 45 healthy male Wistar rats were randomly divided into control group, excessive fatigue group and restraint stress group (n = 15 each). The general condition, morphological changes of aortic endothelium cell and the blood levels of ET-1 (endothelin) and NO (nitric oxide) were observed. The real-time reverse transcription PCR (polymerase chain reaction) and Western blot were used to detect the gene and protein expressions of CPT-I, PPAR δ, 5-HT1D and 5-HT2A receptors in aorta. Compared with control group, the structural damages of endothelial cell were induced by excessive fatigue and restraint stress. The plasma levels of ET-1 increased [(124 ± 18) ng/L vs (161 ± 18) ng/L, (154 ± 17) ng/L] (P fatigue rats, [(1.23 ± 0.21) vs (0.42 ± 0.05)], [(1.09 ± 0.10) vs (0.25 ± 0.07)] (P fatigue rats, [(1.32 ± 0.07) vs (0.83 ± 0.04)], [(1.41 ± 0.05) vs. (0.75 ± 0.06)]; the mRNA and protein expressions of 5-HT1D receptor decreased in excessive fatigue rats and restraint stress rats, [(1.10 ± 0.15) vs (0.46 ± 0.13), (0.45 ± 0.02)], [(1.19 ± 0.05) vs (0.71 ± 0.06), (0.70 ± 0.05)] (P fatigue rats and restraint stress rats, [(0.99 ± 0.08) vs (6.73 ± 0.46), (7.01 ± 1.56)], [(0.64 ± 0.03) vs (0.79 ± 0.05), (0.82 ± 0.03)] (P fatigue and restraint stress can injure the structure and function of endothelial cell. The changes in energy of abnormal carnitine metabolism and 5-HT receptors may play important roles.

  7. Different serotonin receptor types participate in 5-hydroxytryptophan-induced gonadotropins and prolactin release in the female infantile rat.

    Science.gov (United States)

    Lacau-Mengido, I M; Libertun, C; Becú-Villalobos, D

    1996-05-01

    Serotonin (5-HT) receptors can be classified into at least three, possibly up to seven, classes of receptors. They comprise the 5-HT1, 5-HT2, and 5-HT3 classes, the "uncloned' 5-HT4 receptor and the recombinant receptors 5-ht5, 5-ht6 and 5-ht7. We investigated the role of different serotonin receptor types in a neuroendocrine response to the activation of the serotonergic system. Female immature rats were chosen as an experimental model as it has been shown that during the 3rd week of life, and not at later developmental stages, 5-hydroxytryptophan (5-HTP, a serotonin precursor) induces gonadotropin release in females and not in males. Besides, at this age, serotonin releases prolactin in both sexes. 5-HTP (50 mg/kg) released prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as expected. Ketanserin (5-HT2A antagonist) and methysergide (5-HT2C antagonist) blocked 5-HTP-induced prolactin release, but did not block the LH or FSH responses. Ondansetron (5-HT3 receptor antagonist) did not modify prolactin response to 5-HTP, whereas it blocked 5-HTP-induced LH and FSH release. Propranolol (5-HT1 and beta-adrenergic antagonist) blocked prolactin, LH and FSH release induced by 5-HTP. The 5-HT2C agonist 1-(3-chlorophenyl)piperazine dihydrochloride released prolactin, without modifying LH or FSH release. Methyl-quipazine and phenylbiguanide (5-HT3 agonists) increased both LH and FSH levels, without altering prolactin secretion. The present experiments indicate that serotonin acting at the 5-HT3 receptor mediates LH and FSH release in infantile female rats, whereas 5-HT2C or 2A receptor types participate in the release of prolactin at this age. 5-HT1 receptor type may be involved in the release of the three hormones, though a beta-adrenergic component of the response cannot be discarded.

  8. An Allometric Analysis of Sex and Sex Chromosome Dosage Effects on Subcortical Anatomy in Humans

    Science.gov (United States)

    Clasen, Liv; Giedd, Jay N.; Blumenthal, Jonathan; Lerch, Jason P.; Chakravarty, M. Mallar; Raznahan, Armin

    2016-01-01

    Structural neuroimaging of humans with typical and atypical sex-chromosome complements has established the marked influence of both Yand X-/Y-chromosome dosage on total brain volume (TBV) and identified potential cortical substrates for the psychiatric phenotypes associated with sex-chromosome aneuploidy (SCA). Here, in a cohort of 354 humans with varying karyotypes (XX, XY, XXX, XXY, XYY, XXYY, XXXXY), we investigate sex and SCA effects on subcortical size and shape; focusing on the striatum, pallidum and thalamus. We find large effect-size differences in the volume and shape of all three structures as a function of sex and SCA. We correct for TBV effects with a novel allometric method harnessing normative scaling rules for subcortical size and shape in humans, which we derive here for the first time. We show that all three subcortical volumes scale sublinearly with TBV among healthy humans, mirroring known relationships between subcortical volume and TBV among species. Traditional TBV correction methods assume linear scaling and can therefore invert or exaggerate sex and SCA effects on subcortical anatomy. Allometric analysis restricts sex-differences to: (1) greater pallidal volume (PV) in males, and (2) relative caudate head expansion and ventral striatum contraction in females. Allometric analysis of SCA reveals that supernumerary X- and Y-chromosomes both cause disproportionate reductions in PV, and coordinated deformations of striatopallidal shape. Our study provides a novel understanding of sex and sex-chromosome dosage effects on subcortical organization, using an allometric approach that can be generalized to other basic and clinical structural neuroimaging settings. SIGNIFICANCE STATEMENT Sex and sex-chromosome dosage (SCD) are known to modulate human brain size and cortical anatomy, but very little is known regarding their impact on subcortical structures that work with the cortex to subserve a range of behaviors in health and disease. Moreover

  9. Gray matter volume changes in chronic subcortical stroke: A cross-sectional study

    Directory of Open Access Journals (Sweden)

    Qingqing Diao

    2017-01-01

    Full Text Available This study aimed to investigate the effects of lesion side and degree of motor recovery on gray matter volume (GMV difference relative to healthy controls in right-handed subcortical stroke. Structural MRI data were collected in 97 patients with chronic subcortical ischemic stroke and 79 healthy controls. Voxel-wise GMV analysis was used to investigate the effects of lesion side and degree of motor recovery on GMV difference in right-handed chronic subcortical stroke patients. Compared with healthy controls, right-lesion patients demonstrated GMV increase (P < 0.05, voxel-wise false discovery rate correction in the bilateral paracentral lobule (PCL and supplementary motor area (SMA and the right middle occipital gyrus (MOG; while left-lesion patients did not exhibit GMV difference under the same threshold. Patients with complete and partial motor recovery showed similar degree of GMV increase in right-lesion patients. However, the motor recovery was correlated with the GMV increase in the bilateral SMA in right-lesion patients. These findings suggest that there exists a lesion-side effect on GMV difference relative to healthy controls in right-handed patients with chronic subcortical stroke. The GMV increase in the SMA may facilitate motor recovery in subcortical stroke patients.

  10. A Case of Generalized Auditory Agnosia with Unilateral Subcortical Brain Lesion

    Science.gov (United States)

    Suh, Hyee; Kim, Soo Yeon; Kim, Sook Hee; Chang, Jae Hyeok; Shin, Yong Beom; Ko, Hyun-Yoon

    2012-01-01

    The mechanisms and functional anatomy underlying the early stages of speech perception are still not well understood. Auditory agnosia is a deficit of auditory object processing defined as a disability to recognize spoken languages and/or nonverbal environmental sounds and music despite adequate hearing while spontaneous speech, reading and writing are preserved. Usually, either the bilateral or unilateral temporal lobe, especially the transverse gyral lesions, are responsible for auditory agnosia. Subcortical lesions without cortical damage rarely causes auditory agnosia. We present a 73-year-old right-handed male with generalized auditory agnosia caused by a unilateral subcortical lesion. He was not able to repeat or dictate but to perform fluent and comprehensible speech. He could understand and read written words and phrases. His auditory brainstem evoked potential and audiometry were intact. This case suggested that the subcortical lesion involving unilateral acoustic radiation could cause generalized auditory agnosia. PMID:23342322

  11. Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene.

    Science.gov (United States)

    Pinard, J M; Motte, J; Chiron, C; Brian, R; Andermann, E; Dulac, O

    1994-01-01

    Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy. Images PMID:8057113

  12. A Rapid Subcortical Amygdala Route for Faces Irrespective of Spatial Frequency and Emotion.

    Science.gov (United States)

    McFadyen, Jessica; Mermillod, Martial; Mattingley, Jason B; Halász, Veronika; Garrido, Marta I

    2017-04-05

    There is significant controversy over the existence and function of a direct subcortical visual pathway to the amygdala. It is thought that this pathway rapidly transmits low spatial frequency information to the amygdala independently of the cortex, and yet the directionality of this function has never been determined. We used magnetoencephalography to measure neural activity while human participants discriminated the gender of neutral and fearful faces filtered for low or high spatial frequencies. We applied dynamic causal modeling to demonstrate that the most likely underlying neural network consisted of a pulvinar-amygdala connection that was uninfluenced by spatial frequency or emotion, and a cortical-amygdala connection that conveyed high spatial frequencies. Crucially, data-driven neural simulations revealed a clear temporal advantage of the subcortical connection over the cortical connection in influencing amygdala activity. Thus, our findings support the existence of a rapid subcortical pathway that is nonselective in terms of the spatial frequency or emotional content of faces. We propose that that the "coarseness" of the subcortical route may be better reframed as "generalized." SIGNIFICANCE STATEMENT The human amygdala coordinates how we respond to biologically relevant stimuli, such as threat or reward. It has been postulated that the amygdala first receives visual input via a rapid subcortical route that conveys "coarse" information, namely, low spatial frequencies. For the first time, the present paper provides direction-specific evidence from computational modeling that the subcortical route plays a generalized role in visual processing by rapidly transmitting raw, unfiltered information directly to the amygdala. This calls into question a widely held assumption across human and animal research that fear responses are produced faster by low spatial frequencies. Our proposed mechanism suggests organisms quickly generate fear responses to a wide range

  13. Serotonin and brain function: a tale of two receptors.

    Science.gov (United States)

    Carhart-Harris, R L; Nutt, D J

    2017-09-01

    Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

  14. Examining the subcortical infarcts in the era of acute multimodality CT imaging

    Directory of Open Access Journals (Sweden)

    Mindy Tan

    2016-12-01

    Full Text Available Background: Lacunar infarcts have been characterized as small subcortical infarcts, resulting from in situ microatheroma or lipohyalinosis in small vessels. Based on this hypothesis, such infarcts should not be associated with large areas of perfusion deficits extending beyond subcortical regions to involve cortical regions. By contrast, selected small subcortical infarcts, as defined by MR imaging in the subacute or chronic stage, may initially have large perfusion deficits or related large vessel occlusions. These infarcts with ‘lacunar’ phenotype may also be caused by disease in the parent vessel and may have very different stroke mechanisms from small vessel disease. Our aim was to describe differences in imaging characteristics between patients with small subcortical infarction with ‘lacunar phenotype’ from those with lacunar mechanism. Methods: Patients undergoing acute CT Perfusion/angiography (CTP/CTA within 6 hours of symptom onset and follow-up magnetic resonance imaging (MRI for ischaemic stroke were included (2009-2013. A lacunar infarct was defined as a single subcortical infarct (SSI ≤20 mm on follow-up MRI. Presence of perfusion deficits, vessel occlusion and infarct dimensions were compared between lacunar infarcts and other topographical infarct types. Results: Overall, 182 patients (mean age 66.4±15.3 years, 66% male were included. SSI occurred in 31 (17% patients. Of these, 12 (39% patients had a perfusion deficit compared with those with any cortical infarction (120/142, 67%, and the smallest SSI with a perfusion deficit had a diameter of <5mm. The majority of patients with SSI (8/12, 66.7% had a relevant vessel occlusion. A quarter of SSIs had a large-artery stroke mechanism evident on acute CTP/CTA. Lacunar mechanism was present in 3/8 patients with corona radiata, 5/10 lentiform nucleus, 5/6 posterior limb of internal capsule PLIC, 3/5 thalamic infarcts and 1/2 miscellaneous locations. There was a trend toward

  15. Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA.

    Science.gov (United States)

    Hasler, F; Studerus, E; Lindner, K; Ludewig, S; Vollenweider, F X

    2009-11-01

    Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system.

  16. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors.

    Science.gov (United States)

    Carter, Olivia L; Burr, David C; Pettigrew, John D; Wallis, Guy M; Hasler, Felix; Vollenweider, Franz X

    2005-10-01

    Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-HT1A receptor in the observed deficit. Based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

  17. Theophylline-induced respiratory recovery following cervical spinal cord hemisection is augmented by serotonin 2 receptor stimulation.

    Science.gov (United States)

    Basura, Gregory J; Nantwi, Kwaku D; Goshgarian, Harry G

    2002-11-22

    Cervical spinal cord hemisection leads to a disruption of bulbospinal innervation of phrenic motoneurons resulting in paralysis of the ipsilateral hemidiaphragm. We have previously demonstrated separate therapeutic roles for theophylline, and more recently serotonin (5-HT) as modulators to phrenic nerve motor recovery; mechanisms that likely occur via adenosine A1 and 5-HT2 receptors, respectively. The present study was designed to specifically determine if concurrent stimulation of 5-HT2 receptors may enhance motor recovery induced by theophylline alone. Adult female rats (250-350 g; n=7 per group) received a left cervical (C2) hemisection that resulted in paralysis of the ipsilateral hemidiaphragm. Twenty-four hours later rats were given systemic theophylline (15 mg/kg, i.v.), resulting in burst recovery in the ipsilateral phrenic nerve. Theophylline-induced recovery was enhanced with the 5-HT2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI; 1.0 mg/kg). DOI-evoked augmentation of theophylline-induced recovery was attenuated following subsequent injection of the 5-HT2 receptor antagonist, ketanserin (2.0 mg/kg). In a separate group, rats were pretreated with ketanserin, which did not prevent subsequent theophylline-induced respiratory recovery. However, pretreatment with ketanserin did prevent DOI-induced augmentation of the theophylline-evoked phrenic nerve burst recovery. Lastly, using immunocytochemistry and in situ hybridization, we showed for the first time a positive co-localization of adenosine A1 receptor mRNA and immunoreactivity with phrenic motoneurons of the cervical ventral horns. Taken together, the results of the present study suggest that theophylline may induce motor recovery likely at adenosine A1 receptors located at the level of the spinal cord, and the concurrent stimulation of converging 5-HT2 receptors may augment the response.

  18. Reduced prefrontal and increased subcortical brain functioning assessed using positron emission tomography in predatory and affective murderers.

    Science.gov (United States)

    Raine, A; Meloy, J R; Bihrle, S; Stoddard, J; LaCasse, L; Buchsbaum, M S

    1998-01-01

    There appear to be no brain imaging studies investigating which brain mechanisms subserve affective, impulsive violence versus planned, predatory violence. It was hypothesized that affectively violent offenders would have lower prefrontal activity, higher subcortical activity, and reduced prefrontal/subcortical ratios relative to controls, while predatory violent offenders would show relatively normal brain functioning. Glucose metabolism was assessed using positron emission tomography in 41 comparisons, 15 predatory murderers, and nine affective murderers in left and right hemisphere prefrontal (medial and lateral) and subcortical (amygdala, midbrain, hippocampus, and thalamus) regions. Affective murderers relative to comparisons had lower left and right prefrontal functioning, higher right hemisphere subcortical functioning, and lower right hemisphere prefrontal/subcortical ratios. In contrast, predatory murderers had prefrontal functioning that was more equivalent to comparisons, while also having excessively high right subcortical activity. Results support the hypothesis that emotional, unplanned impulsive murderers are less able to regulate and control aggressive impulses generated from subcortical structures due to deficient prefrontal regulation. It is hypothesized that excessive subcortical activity predisposes to aggressive behaviour, but that while predatory murderers have sufficiently good prefrontal functioning to regulate these aggressive impulses, the affective murderers lack such prefrontal control over emotion regulation.

  19. Large-scale cortico-subcortical functional networks in focal epilepsies: The role of the basal ganglia

    Directory of Open Access Journals (Sweden)

    Eva Výtvarová

    2017-01-01

    Significance: Focal epilepsies affect large-scale brain networks beyond the epileptogenic zones. Cortico-subcortical functional connectivity disturbance was displayed in LTLE, FLE, and POLE. Significant changes in the resting-state functional connectivity between cortical and subcortical structures suggest an important role of the BG and thalamus in focal epilepsies.

  20. Formulaic Language in Parkinson's Disease and Alzheimer's Disease: Complementary Effects of Subcortical and Cortical Dysfunction

    Science.gov (United States)

    Van Lancker Sidtis, Diana; Choi, JiHee; Alken, Amy; Sidtis, John J.

    2015-01-01

    Purpose: The production of formulaic expressions (conversational speech formulas, pause fillers, idioms, and other fixed expressions) is excessive in the left hemisphere and deficient in the right hemisphere and in subcortical stroke. Speakers with Alzheimer's disease (AD), having functional basal ganglia, reveal abnormally high proportions of…

  1. Subcortical structures in humans can be facilitated by transcranial direct current stimulation

    NARCIS (Netherlands)

    Nonnekes, Johan Hendrik; Arrogi, Anass; Munneke, Moniek; van Asseldonk, Edwin H.F.; Oude Nijhuis, Lars; Geurts, Alexander; Weerdesteyn, Vivian

    2014-01-01

    BACKGROUND: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that alters cortical excitability via application of a weak direct current. Interestingly, it was demonstrated in cats that tDCS can facilitate subcortical structures as well (Bolzonii et al., J

  2. Subcortical structures in humans can be facilitated by transcranial direct current stimulation

    NARCIS (Netherlands)

    Nonnekes, J.H.; Arrogi, A.; Munneke, M.A.M.; Asseldonk, E.H. van; Nijhuis, L.B.; Geurts, A.C.H.; Weerdesteyn, V.G.M.

    2014-01-01

    Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that alters cortical excitability. Interestingly, in recent animal studies facilitatory effects of tDCS have also been observed on subcortical structures. Here, we sought to provide evidence for the potential

  3. Subcortical Structures in Humans Can Be Facilitated by Transcranial Direct Current Stimulation

    NARCIS (Netherlands)

    Nonnekes, Johan Hendrik; Arrogi, A.; Munneke, M.A.M.; van Asseldonk, Edwin H.F.; Oude Nijhuis, L.B.; Geurts, A.C.; Weerdesteyn, V.

    2014-01-01

    Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that alters cortical excitability. Interestingly, in recent animal studies facilitatory effects of tDCS have also been observed on subcortical structures. Here, we sought to provide evidence for the potential

  4. Application of Intraoperative Ultrasonography for Guiding Microneurosurgical Resection of Small Subcortical Lesions

    International Nuclear Information System (INIS)

    Wang, Jia; Duan, Yun You; Liu, Xi; Wang, Yu; Gao, Guo Dong; Qin, Huai Zhou; Wang, Liang

    2011-01-01

    We wanted to evaluate the clinical value of intraoperative ultrasonography for real-time guidance when performing microneurosurgical resection of small subcortical lesions. Fifty-two patients with small subcortical lesions were involved in this study. The pathological diagnoses were cavernous hemangioma in 25 cases, cerebral glioma in eight cases, abscess in eight cases, small inflammatory lesion in five cases, brain parasite infection in four cases and the presence of an intracranial foreign body in two cases. An ultrasonic probe was sterilized and lightly placed on the surface of the brain during the operation. The location, extent, characteristics and adjacent tissue of the lesion were observed by high frequency ultrasonography during the operation. All the lesions were located in the cortex and their mean size was 1.3 ± 0.2 cm. Intraoperative ultrasonography accurately located all the small subcortical lesions, and so the neurosurgeon could provide appropriate treatment. Different lesion pathologies presented with different ultrasonic appearances. Cavernous hemangioma exhibited irregular shapes with distinct margins and it was mildly hyperechoic or hyperechoic. The majority of the cerebral gliomas displayed irregular shapes with indistinct margins, and they often showed cystic and solid mixed echoes. Postoperative imaging identified that the lesions had completely disappeared, and the original symptoms of all the patients were significantly alleviated. Intraoperative ultrasonography can help accurately locate small subcortical lesions and it is helpful for selecting the proper approach and guiding thorough resection of these lesions.

  5. Application of Intraoperative Ultrasonography for Guiding Microneurosurgical Resection of Small Subcortical Lesions

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jia; Duan, Yun You; Liu, Xi; Wang, Yu; Gao, Guo Dong; Qin, Huai Zhou; Wang, Liang [Tangdu Hospital of the Fourth Military Medicine University, Xi an (China)

    2011-10-15

    We wanted to evaluate the clinical value of intraoperative ultrasonography for real-time guidance when performing microneurosurgical resection of small subcortical lesions. Fifty-two patients with small subcortical lesions were involved in this study. The pathological diagnoses were cavernous hemangioma in 25 cases, cerebral glioma in eight cases, abscess in eight cases, small inflammatory lesion in five cases, brain parasite infection in four cases and the presence of an intracranial foreign body in two cases. An ultrasonic probe was sterilized and lightly placed on the surface of the brain during the operation. The location, extent, characteristics and adjacent tissue of the lesion were observed by high frequency ultrasonography during the operation. All the lesions were located in the cortex and their mean size was 1.3 {+-} 0.2 cm. Intraoperative ultrasonography accurately located all the small subcortical lesions, and so the neurosurgeon could provide appropriate treatment. Different lesion pathologies presented with different ultrasonic appearances. Cavernous hemangioma exhibited irregular shapes with distinct margins and it was mildly hyperechoic or hyperechoic. The majority of the cerebral gliomas displayed irregular shapes with indistinct margins, and they often showed cystic and solid mixed echoes. Postoperative imaging identified that the lesions had completely disappeared, and the original symptoms of all the patients were significantly alleviated. Intraoperative ultrasonography can help accurately locate small subcortical lesions and it is helpful for selecting the proper approach and guiding thorough resection of these lesions.

  6. CT findings and clinical analysis of subcortical hematomas in elderly patients

    International Nuclear Information System (INIS)

    Ueno, Yasushi; Tanaka, Akira; Yoshinaga, Shinya; Kimura, Masato

    1991-01-01

    Ten elderly patients (73-87 years, 78.4 years on the average) with subcortical hematomas were divided into two groups according to the shape of the hematoma on a CT scan: a lobulated group (6 patients) and a global group (4 patients). The lobulated group had a history of hypertension in one patient. The hematomas extended widely around the parietal lobe and were accompanied by perifocal edema, brain shifts and subarachnoid hemorrhages, deep consciousness disturbances, and poor prognosis of life and function. Amyloid depositions in the arteries around the hematomas were confirmed histologically in one patient. The global group had a history of hypertension in two patients. The hematomas were localized in the parietal, temporal, or occipital lobe without perifocal edema, brain shift and subarachnoid hemorrhages, and accompanied by mild consciousness disturbances. The life prognosis was good, but the functional prognosis was poor, with a subsequent development of dementia. A lobulated subcortical hematoma is thought to be due to amyloid angiopathy, while a global subcortical hematoma is thought to be due to hypertension. A surgical evacuation is seldom indicated for either type of subcortical hematoma in elderly patients. (author)

  7. Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects

    NARCIS (Netherlands)

    Duarri, A.; Teijido, O.; Lopez-Hernandez, T.; Scheper, G.C.; Barriere, H.; Boor, P.K.I.; Aguado, F.; Zorzano, A.; Palacin, M.; Martinez, A; Lukacs, G.L.; van der Knaap, M.S.; Nunes, V.; Estevez, R.

    2008-01-01

    Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy, most often caused by mutations in the MLC1 gene. MLC1 is an oligomeric plasma membrane (PM) protein of unknown function expressed mainly in glial cells and neurons. Most disease-causing missense

  8. Progressive subcortical calcifications secondary to venous hypertension in an intracranial dural arteriovenous fistula.

    Science.gov (United States)

    Pascoe, Heather M; Lui, Elaine H; Mitchell, Peter; Gaillard, Frank

    2017-05-01

    Intracranial dural arteriovenous fistulas (dAVF) are acquired lesions, with the most commonly reported findings on CT haemorrhage or focal oedema. We describe a case of progressive subcortical calcification on CT secondary to venous hypertension from a high grade dAVF. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Technical principles of direct bipolar electrostimulation for cortical and subcortical mapping in awake craniotomy.

    Science.gov (United States)

    Pallud, J; Mandonnet, E; Corns, R; Dezamis, E; Parraga, E; Zanello, M; Spena, G

    2017-06-01

    Intraoperative application of electrical current to the brain is a standard technique during brain surgery for inferring the function of the underlying brain. The purpose of intraoperative functional mapping is to reliably identify cortical areas and subcortical pathways involved in eloquent functions, especially motor, sensory, language and cognitive functions. The aim of this article is to review the rationale and the electrophysiological principles of the use of direct bipolar electrostimulation for cortical and subcortical mapping under awake conditions. Direct electrical stimulation is a window into the whole functional network that sustains a particular function. It is an accurate (spatial resolution of about 5mm) and a reproducible technique particularly adapted to clinical practice for brain resection in eloquent areas. If the procedure is rigorously applied, the sensitivity of direct electrical stimulation for the detection of cortical and subcortical eloquent areas is nearly 100%. The main disadvantage of this technique is its suboptimal specificity. Another limitation is the identification of eloquent areas during surgery, which, however, could have been functionally compensated postoperatively if removed surgically. Direct electrical stimulation is an easy, accurate, reliable and safe invasive technique for the intraoperative detection of both cortical and subcortical functional brain connectivity for clinical purpose. In our opinion, it is the optimal technique for minimizing the risk of neurological sequelae when resecting in eloquent brain areas. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. The developing human brain: age-related changes in cortical, subcortical, and cerebellar anatomy.

    Science.gov (United States)

    Sussman, Dafna; Leung, Rachel C; Chakravarty, M Mallar; Lerch, Jason P; Taylor, Margot J

    2016-04-01

    This study is the first to characterize normal development and sex differences across neuroanatomical structures in cortical, subcortical, and cerebellar brain regions in a single large cohort. One hundred and ninety-two magnetic resonance images were examined from 96 typically developing females and 96 age-matched typically developing males from 4 to 18 years of age. Image segmentation of the cortex was conducted with CIVET, while that of the cerebellum, hippocampi, thalamus, and basal ganglia were conducted using the MAGeT algorithm. Cortical thickness analysis revealed that most cortical regions decrease linearly, while surface area increases linearly with age. Volume relative to total cerebrum followed a quadratic trend with age, with only the left supramarginal gyrus showing sexual dimorphism. Hippocampal relative volume increased linearly, while the thalamus, caudate, and putamen decreased linearly, and the cerebellum did not change with age. The relative volumes of several subcortical subregions followed inverted U-shaped trends that peaked at ~12 years of age. Many subcortical structures were found to be larger in females than in males, independently of age, while others showed a sex-by-age interaction. This study provides a comprehensive assessment of cortical, subcortical, and cerebellar growth patterns during normal development, and draws attention to the role of sex on neuroanatomical maturation throughout childhood and adolescence.

  11. Is Intraoperative Diffusion tensor Imaging at 3.0T Comparable to Subcortical Corticospinal tract Mapping?

    Czech Academy of Sciences Publication Activity Database

    Ostrý, S.; Belšan, T.; Otáhal, Jakub; Beneš, V.; Netuka, D.

    2013-01-01

    Roč. 73, č. 5 (2013), s. 797-807 ISSN 0148-396X Institutional support: RVO:67985823 Keywords : corticospinal tract * intraoperative tractography * intraoperative image distortion * motor -evoked potentials * subcortical mapping Subject RIV: FH - Neurology Impact factor: 3.031, year: 2013

  12. Subcortical laminar heterotopia in two sisters and their mother : MRI, clinical findings and pathogenesis

    NARCIS (Netherlands)

    van der Valk, PHM; Snoeck, [No Value; Meiners, LC; des Portes, [No Value; Chelly, J; Pinard, JM; Ippel, PF; van Nieuwenhuizen, O

    MR imaging, clinical data and underlying pathogenesis of subcortical laminar heterotopia (SCLH), also known as band heterotopia, in two sisters and their mother are presented. On MR imaging a different degree of SCLH was found in all three affected family-members. The inversion recovery sequence was

  13. Assessment of cortical and sub-cortical function in neonates by electrophysiological monitoring

    NARCIS (Netherlands)

    Jennekens, W.

    2012-01-01

    The aim of this thesis was the assessment of cortical and sub-cortical function in neonates by electrophysiological monitoring, i.e. to evaluate the function of the neonatal cortex and brainstem through quantitative analysis of signals readily available in the NICU. These signals include

  14. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

    NARCIS (Netherlands)

    Guadalupe, Tulio; Mathias, Samuel R.; vanErp, Theo G.M.; Whelan, Christopher D.; Zwiers, Marcel P.; Abe, Yoshinari; Abramovic, Lucija; Agartz, Ingrid; Andreassen, Ole A.; Arias-Vásquez, Alejandro; Aribisala, Benjamin S.; Armstrong, Nicola J.; Arolt, Volker; Artiges, Eric; Ayesa-Arriola, Rosa; Baboyan, Vatche G.; Banaschewski, Tobias; Barker, Gareth; Bastin, Mark E.; Baune, Bernhard T.; Blangero, John; Bokde, Arun L.W.; Boedhoe, Premika S.W.; Bose, Anushree; Brem, Silvia; Brodaty, Henry; Bromberg, Uli; Brooks, Samantha; Büchel, Christian; Buitelaar, Jan; Calhoun, Vince D.; Cannon, Dara M.; Cattrell, Anna; Cheng, Yuqi; Conrod, Patricia J.; Conzelmann, Annette; Corvin, Aiden; Crespo-Facorro, Benedicto; Crivello, Fabrice; Dannlowski, Udo; de Zubicaray, Greig I.; de Zwarte, Sonja M.C.; Deary, Ian J.; Desrivières, Sylvane; Doan, Nhat Trung; Donohoe, Gary; Dørum, Erlend S.; Ehrlich, Stefan; Espeseth, Thomas; Fernández, Guillén; Flor, Herta; Fouche, Jean Paul; Frouin, Vincent; Fukunaga, Masaki; Gallinat, Jürgen; Garavan, Hugh; Gill, Michael; Suarez, Andrea Gonzalez; Gowland, Penny; Grabe, Hans J.; Grotegerd, Dominik; Gruber, Oliver; Hagenaars, Saskia; Hashimoto, Ryota; Hauser, Tobias U.; Heinz, Andreas; Hibar, Derrek P.; Hoekstra, Pieter J.; Hoogman, Martine; Howells, Fleur M.; Hu, Hao; Hulshoff Pol, Hilleke E.; Huyser, Chaim; Ittermann, Bernd; Jahanshad, Neda; Jönsson, Erik G.; Jurk, Sarah; Kahn, Rene S.; Kelly, Sinead; Kraemer, Bernd; Kugel, Harald; Kwon, Jun Soo; Lemaitre, Herve; Lesch, Klaus Peter; Lochner, Christine; Luciano, Michelle; Marquand, Andre F.; Martin, Nicholas G.; Martínez-Zalacaín, Ignacio; Martinot, Jean Luc; Mataix-Cols, David; Mather, Karen; McDonald, Colm; McMahon, Katie L.; Medland, Sarah E.; Menchón, José M.; Morris, Derek W.; Mothersill, Omar; Maniega, Susana Munoz; Mwangi, Benson; Nakamae, Takashi; Nakao, Tomohiro; Narayanaswaamy, Janardhanan C.; Nees, Frauke; Nordvik, Jan E.; Onnink, A. Marten H.; Opel, Nils; Ophoff, Roel; Paillère Martinot, Marie Laure; Papadopoulos Orfanos, Dimitri; Pauli, Paul; Paus, Tomáš; Poustka, Luise; Reddy, Janardhan Yc; Renteria, Miguel E.; Roiz-Santiáñez, Roberto; Roos, Annerine; Royle, Natalie A.; Sachdev, Perminder; Sánchez-Juan, Pascual; Schmaal, Lianne; Schumann, Gunter; Shumskaya, Elena; Smolka, Michael N.; Soares, Jair C.; Soriano-Mas, Carles; Stein, Dan J.; Strike, Lachlan T.; Toro, Roberto; Turner, Jessica A.; Tzourio-Mazoyer, Nathalie; Uhlmann, Anne; Hernández, Maria Valdés; van den Heuvel, Odile A.; van der Meer, Dennis; van Haren, Neeltje E.M.; Veltman, Dick J.; Venkatasubramanian, Ganesan; Vetter, Nora C.; Vuletic, Daniella; Walitza, Susanne; Walter, Henrik; Walton, Esther; Wang, Zhen; Wardlaw, Joanna; Wen, Wei; Westlye, Lars T.; Whelan, Robert; Wittfeld, Katharina; Wolfers, Thomas; Wright, Margaret J.; Xu, Jian; Xu, Xiufeng; Yun, Je Yeon; Zhao, Jing Jing; Franke, Barbara; Thompson, Paul M.; Glahn, David C.; Mazoyer, Bernard; Fisher, Simon E.; Francks, Clyde

    2017-01-01

    The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain

  15. Subcortical grey matter changes in untreated, early stage Parkinson's disease without dementia.

    Science.gov (United States)

    Lee, Hye Mi; Kwon, Kyum-Yil; Kim, Min-Jik; Jang, Ji-Wan; Suh, Sang-Il; Koh, Seong-Beom; Kim, Ji Hyun

    2014-06-01

    Previous MRI studies have investigated cortical or subcortical grey matter changes in patients with Parkinson's disease (PD), yielding inconsistent findings between the studies. We therefore sought to determine whether focal cortical or subcortical grey matter changes may be present from the early disease stage. We recruited 49 untreated, early stage PD patients without dementia and 53 control subjects. Voxel-based morphometry was used to evaluate cortical grey matter changes, and automated volumetry and shape analysis were used to assess volume changes and shape deformation of the subcortical grey matter structures, respectively. Voxel-based morphometry showed neither reductions nor increases in grey matter volume in patients compared to controls. Compared to controls, PD patients had significant reductions in adjusted volumes of putamen, nucleus accumbens, and hippocampus (corrected p grey matter and clinical variables representing disease duration and severity. Our results suggest that untreated, early stage PD without dementia is associated with volume reduction and shape deformation of subcortical grey matter, but not with cortical grey matter reduction. Our findings of structural changes in the posterolateral putamen and ventromedial putamen/nucleus accumbens could provide neuroanatomical basis for the involvement of motor and limbic striatum, further implicating motor and non-motor symptoms in PD, respectively. Early hippocampal involvement might be related to the risk for developing dementia in PD patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Disruptions in cortico-subcortical covariance networks associated with anxiety in new-onset childhood epilepsy

    Directory of Open Access Journals (Sweden)

    Camille Garcia-Ramos

    2016-01-01

    Full Text Available Anxiety disorders represent a prevalent psychiatric comorbidity in both adults and children with epilepsy for which the etiology remains controversial. Neurobiological contributions have been suggested, but only limited evidence suggests abnormal brain volumes particularly in children with epilepsy and anxiety. Since the brain develops in an organized fashion, covariance analyses between different brain regions can be investigated as a network and analyzed using graph theory methods. We examined 46 healthy children (HC and youth with recent onset idiopathic epilepsies with (n = 24 and without (n = 62 anxiety disorders. Graph theory (GT analyses based on the covariance between the volumes of 85 cortical/subcortical regions were investigated. Both groups with epilepsy demonstrated less inter-modular relationships in the synchronization of cortical/subcortical volumes compared to controls, with the epilepsy and anxiety group presenting the strongest modular organization. Frontal and occipital regions in non-anxious epilepsy, and areas throughout the brain in children with epilepsy and anxiety, showed the highest centrality compared to controls. Furthermore, most of the nodes correlating to amygdala volumes were subcortical structures, with the exception of the left insula and the right frontal pole, which presented high betweenness centrality (BC; therefore, their influence in the network is not necessarily local but potentially influencing other more distant regions. In conclusion, children with recent onset epilepsy and anxiety demonstrate large scale disruptions in cortical and subcortical brain regions. Network science may not only provide insight into the possible neurobiological correlates of important comorbidities of epilepsy, but also the ways that cortical and subcortical disruption occurs.

  17. Continuous physical examination during subcortical resection in awake craniotomy patients: Its usefulness and surgical outcome.

    Science.gov (United States)

    Bunyaratavej, Krishnapundha; Sangtongjaraskul, Sunisa; Lerdsirisopon, Surunchana; Tuchinda, Lawan

    2016-08-01

    To evaluate the value of physical examination as a monitoring tool during subcortical resection in awake craniotomy patients and surgical outcomes. Authors reviewed medical records of patients underwent awake craniotomy with continuous physical examination for pathology adjacent to the eloquent area. Between January 2006 and August 2015, there were 37 patients underwent awake craniotomy with continuous physical examination. Pathology was located in the left cerebral hemisphere in 28 patients (75.7%). Thirty patients (81.1%) had neuroepithelial tumors. Degree of resections were defined as total, subtotal, and partial in 16 (43.2%), 11 (29.7%) and 10 (27.0%) patients, respectively. Median follow up duration was 14 months. The reasons for termination of subcortical resection were divided into 3 groups as follows: 1) by anatomical landmark with the aid of neuronavigation in 20 patients (54%), 2) by reaching subcortical stimulation threshold in 8 patients (21.6%), and 3) by abnormal physical examination in 9 patients (24.3%). Among these 3 groups, there were statistically significant differences in the intraoperative (p=0.002) and early postoperative neurological deficit (p=0.005) with the lowest deficit in neuronavigation group. However, there were no differences in neurological outcome at later follow up (3-months p=0.103; 6-months p=0.285). There were no differences in the degree of resection among the groups. Continuous physical examination has shown to be of value as an additional layer of monitoring of subcortical white matter during resection and combining several methods may help increase the efficacy of mapping and monitoring of subcortical functions. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. [3H]-DOB(4-bromo-2,5-dimethoxyphenylisopropylamine) and [3H] ketanserin label two affinity states of the cloned human 5-hydroxytryptamine2 receptor

    International Nuclear Information System (INIS)

    Branchek, T.; Adham, N.; Macchi, M.; Kao, H.T.; Hartig, P.R.

    1990-01-01

    The binding properties of the 5-hydroxytryptamine2 (5-HT2) receptor have been the subject of much interest and debate in recent years. The hallucinogenic amphetamine derivative 4-bromo-2,5-dimethoxyphenylisopropylamine (DOB) has been shown to bind to a small number of binding sites with properties very similar to [3H]ketanserin-labeled 5-HT2 receptors, but with much higher agonist affinities. Some researchers have interpreted this as evidence for the existence of a new subtype of 5-HT2 receptor (termed 5-HT2A), whereas others have interpreted these data as indicative of agonist high affinity and agonist low affinity states for the 5-HT2 receptor. In this investigation, a cDNA clone encoding the serotonin 5-HT2 receptor was transiently transfected into monkey kidney Cos-7 cells and stably transfected into mouse fibroblast L-M(TK-) cells. In both systems, expression of this single serotonin receptor cDNA led to the appearance of both [3H]DOB and [3H]ketanserin binding sites with properties that matched their binding characteristics in mammalian brain homogenates. Addition of guanosine 5'-(beta, gamma-imido) triphosphate [Gpp(NH)p] to this system caused a rightward shift and steepening of agonist competition curves for [3H] ketanserin binding, converting a two-site binding curve to a single low affinity binding state. Gpp(NH)p addition also caused a 50% decrease in the number of high affinity [3H]DOB binding sites, with no change in the dissociation constant of the remaining high affinity states. These data on a single human 5-HT2 receptor cDNA expressed in two different transfection host cells indicate that [3H]DOB and [3H]ketanserin binding reside on the same gene product, apparently interacting with agonist and antagonist conformations of a single human 5-HT2 receptor protein

  19. Subcortical White Matter Changes with Normal Aging Detected by Multi-Shot High Resolution Diffusion Tensor Imaging.

    Directory of Open Access Journals (Sweden)

    Sheng Xie

    Full Text Available Subcortical white matter builds neural connections between cortical and subcortical regions and constitutes the basis of neural networks. It plays a very important role in normal brain function. Various studies have shown that white matter deteriorates with aging. However, due to the limited spatial resolution provided by traditional diffusion imaging techniques, microstructural information from subcortical white matter with normal aging has not been comprehensively assessed. This study aims to investigate the deterioration effect with aging in the subcortical white matter and provide a baseline standard for pathological disorder diagnosis. We apply our newly developed multi-shot high resolution diffusion tensor imaging, using self-feeding multiplexed sensitivity-encoding, to measure subcortical white matter changes in regions of interest of healthy persons with a wide age range. Results show significant fractional anisotropy decline and radial diffusivity increasing with age, especially in the anterior part of the brain. We also find that subcortical white matter has more prominent changes than white matter close to the central brain. The observed changes in the subcortical white matter may be indicative of a mild demyelination and a loss of myelinated axons, which may contribute to normal age-related functional decline.

  20. Alterations in serotonin receptor-induced contractility of bovine lateral saphenous vein in cattle grazing endophyte-infected tall fescue.

    Science.gov (United States)

    Klotz, J L; Brown, K R; Xue, Y; Matthews, J C; Boling, J A; Burris, W R; Bush, L P; Strickland, J R

    2012-02-01

    As part of a 2-yr study documenting the physiologic impact of grazing endophyte-infected tall fescue on growing cattle, 2 experiments were conducted to characterize and evaluate effects of grazing 2 levels of toxic endophyte-infected tall fescue pastures on vascular contractility and serotonin receptors. Experiment 1 examined vasoconstrictive activities of 5-hydroxytryptamine (5HT), α-methylserotonin (ME5HT; a 5HT(2) receptor agonist), d-lysergic acid (LSA), and ergovaline (ERV) on lateral saphenous veins collected from steers immediately removed from a high-endophyte-infected tall fescue pasture (HE) or a low-endophyte-infected mixed-grass (LE) pasture. Using the same pastures, Exp. 2 evaluated effects of grazing 2 levels of toxic endophyte-infected tall fescue on vasoconstrictive activities of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), BW 723C86 (BW7), CGS-12066A (CGS), and 5-carboxamidotryptamine hemiethanolate maleate (5CT), agonists for 5HT(2A),( 2B), 5HT(1B), and 5HT(7) receptors, respectively. One-half of the steers in Exp. 2 were slaughtered immediately after removal from pasture, and the other one-half were fed finishing diets for >91 d before slaughter. For Exp. 1, maximal contractile intensities were greater (P 91 d. Experiment 1 demonstrated that grazing of HE pastures for 89 to 105 d induces functional alterations in blood vessels, as evidenced by reduced contractile capacity and altered serotonergic receptor activity. Experiment 2 demonstrated that grazing HE pastures alters vascular responses, which may be mediated through altered serotonin receptor activities, and these alterations may be ameliorated by the removal of ergot alkaloid exposure as demonstrated by the absence of differences in finished steers.

  1. Test-retest paradigm of the forced swimming test in female mice is not valid for predicting antidepressant-like activity: participation of acetylcholine and sigma-1 receptors.

    Science.gov (United States)

    Su, Jing; Hato-Yamada, Noriko; Araki, Hiroaki; Yoshimura, Hiroyuki

    2013-01-01

    The forced swimming test (FST) in mice is widely used to predict the antidepressant activity of a drug, but information describing the immobility of female mice is limited. We investigated whether a prior swimming experience affects the immobility duration in a second FST in female mice and whether the test-retest paradigm is a valid screening tool for antidepressants. Female ICR mice were exposed to the FST using two experimental paradigms: a single FST and a double FST in which mice had experienced FST once 24 h prior to the second trail. The initial FST experience reliably prolonged immobility duration in the second FST. The antidepressants imipramine and paroxetine significantly reduced immobility duration in the single FST, but not in the double FST. Scopolamine and the sigma-1 (σ1) antagonist NE-100 administered before the second trial significantly prevented the prolongation of immobility. Neither a 5-HT1A nor a 5-HT2A receptor agonist affected immobility duration. We suggest that the test-retest paradigm in female mice is not adequate for predicting antidepressant-like activity of a drug; the prolongation of immobility in the double FST is modulated through acetylcholine and σ1 receptors.

  2. Effects of serotonin on expression of the LDL receptor family member LR11 and 7-ketocholesterol-induced apoptosis in human vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Nagayama, Daiji; Ishihara, Noriko [Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan); Bujo, Hideaki [Department of Clinical Laboratory Medicine, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan); Shirai, Kohji [Department of Vascular Function, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan); Tatsuno, Ichiro, E-mail: ichiro.tatsuno@med.toho-u.ac.jp [Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan)

    2014-04-18

    Highlights: • The dedifferentiation of VSMCs in arterial intima is involved in atherosclerosis. • 5-HT showed proliferative effect on VSMCs which was abolished by sarpogrelate. • 5-HT enhanced expression of LR11 mRNA in VSMCs which was abolished by sarpogrelate. • 5-HT suppressed 7KCHO-induced apoptosis of VSMCs via caspase-3/7-dependent pathway. • The mechanisms explain the 5-HT-induced remodeling of arterial structure. - Abstract: Serotonin (5-HT) is a known mitogen for vascular smooth muscle cells (VSMCs). The dedifferentiation and proliferation/apoptosis of VSMCs in the arterial intima represent one of the atherosclerotic changes. LR11, a member of low-density lipoprotein receptor family, may contribute to the proliferation of VSMCs in neointimal hyperplasia. We conducted an in vitro study to investigate whether 5-HT is involved in LR11 expression in human VSMCs and apoptosis of VSMCs induced by 7-ketocholesterol (7KCHO), an oxysterol that destabilizes plaque. 5-HT enhanced the proliferation of VSMCs, and this effect was abolished by sarpogrelate, a selective 5-HT2A receptor antagonist. Sarpogrelate also inhibited the 5-HT-enhanced LR11 mRNA expression in VSMCs. Furthermore, 5-HT suppressed the 7KCHO-induced apoptosis of VSMCs via caspase-3/7-dependent pathway. These findings provide new insights on the changes in the differentiation stage of VSMCs mediated by 5-HT.

  3. Role of medial prefrontal cortex serotonin 2A receptors in the control of retrieval of recognition memory in rats.

    Science.gov (United States)

    Bekinschtein, Pedro; Renner, Maria Constanza; Gonzalez, Maria Carolina; Weisstaub, Noelia

    2013-10-02

    Often, retrieval cues are not uniquely related to one specific memory, which could lead to memory interference. Controlling interference is particularly important during episodic memory retrieval or when remembering specific events in a spatiotemporal context. Despite a clear involvement of prefrontal cortex (PFC) in episodic memory in human studies, information regarding the mechanisms and neurotransmitter systems in PFC involved in memory is scarce. Although the serotoninergic system has been linked to PFC functionality and modulation, its role in memory processing is poorly understood. We hypothesized that the serotoninergic system in PFC, in particular the 5-HT2A receptor (5-HT2AR) could have a role in the control of memory retrieval. In this work we used different versions of the object recognition task in rats to study the role of the serotoninergic modulation in the medial PFC (mPFC) in memory retrieval. We found that blockade of 5-HT2AR in mPFC affects retrieval of an object in context memory in a spontaneous novelty preference task, while sparing single-item recognition memory. We also determined that 5-HT2ARs in mPFC are required for hippocampal-mPFC interaction during retrieval of this type of memory, suggesting that the mPFC controls the expression of memory traces stored in the hippocampus biasing retrieval to the most relevant one.

  4. Anatomy and behavioral function of serotonin receptors in Drosophila melanogaster larvae.

    Directory of Open Access Journals (Sweden)

    Annina Huser

    Full Text Available The biogenic amine serotonin (5-HT is an important neuroactive molecule in the central nervous system of the majority of animal phyla. 5-HT binds to specific G protein-coupled and ligand-gated ion receptors to regulate particular aspects of animal behavior. In Drosophila, as in many other insects this includes the regulation of locomotion and feeding. Due to its genetic amenability and neuronal simplicity the Drosophila larva has turned into a useful model for studying the anatomical and molecular basis of chemosensory behaviors. This is particularly true for the olfactory system, which is mostly described down to the synaptic level over the first three orders of neuronal information processing. Here we focus on the 5-HT receptor system of the Drosophila larva. In a bipartite approach consisting of anatomical and behavioral experiments we describe the distribution and the implications of individual 5-HT receptors on naïve and acquired chemosensory behaviors. Our data suggest that 5-HT1A, 5-HT1B, and 5-HT7 are dispensable for larval naïve olfactory and gustatory choice behaviors as well as for appetitive and aversive associative olfactory learning and memory. In contrast, we show that 5-HT/5-HT2A signaling throughout development, but not as an acute neuronal function, affects associative olfactory learning and memory using high salt concentration as a negative unconditioned stimulus. These findings describe for the first time an involvement of 5-HT signaling in learning and memory in Drosophila larvae. In the longer run these results may uncover developmental, 5-HT dependent principles related to reinforcement processing possibly shared with adult Drosophila and other insects.

  5. Artefactual subcortical hyperperfusion in PET studies normalized to global mean: lessons from Parkinson's disease

    DEFF Research Database (Denmark)

    Borghammer, Per; Cumming, Paul; Aanerud, Joel

    2008-01-01

    not be detected with present instrumentation and typically-used sample sizes. CONCLUSION: Imposing focal decreases on cortical CBF in conjunction with global mean normalization gives rise to spurious relative CBF increases in all of the regions reported to be hyperactive in PD. Since no PET study has reported......AIM: Recent studies of Parkinson's disease (PD) report subcortical increases of cerebral blood flow (CBF) or cerebral metabolic rate of glucose (CMRglc), after conventional normalization to the global mean. However, if the global mean CBF or CMRglc is decreased in the PD group, this normalization...... necessarily generates artificial relative increases in regions unaffected by the disease. This potential bias may explain the reported subcortical increases in PD. To test this hypothesis, we performed simulations with manipulation and subsequently analysis of sets of quantitative CBF maps by voxel...

  6. Subcortical frontal lesions on MRI in patients with motor neurone disease

    Energy Technology Data Exchange (ETDEWEB)

    Andreadou, E.; Sgouropoulos, P.; Varelas, P.; Papageorgiou, C. [Eginition Hospital, Athens (Greece); Gouliamos, A. [Department of Radiology, CT/MRI Unit, Areteion Hospital, University of Athens (Greece)

    1998-05-01

    MRI was performed in 32 patients with motor neurone disease (26 men and 6 women, aged 40-77 years) and in a control group of 21 subjects. Of the patients studied, 19 had definite and 11 probable amyotrophic lateral sclerosis (ALS) and two had progressive bulbar palsy. In 10 patients there were asymmetrical bilateral foci of increased signal intensity on proton-density and T{sub 2}-weighted images, confined to the white matter. Two patients had only cortical frontal atrophy and slightly increased ventricular size, whereas 20 had normal MRI. The focal lesions were not confined to corticospinal tracts, but were also observed in subcortical frontal areas. While the lesions along the corticospinal tracts correspond to pyramidal tract degeneration, the subcortical foci correlate with degeneration of the frontal bundles and indicate generalised involvement of the central nervous system. (orig.) With 3 figs., 2 tabs., 25 refs.

  7. Subcortical frontal lesions on MRI in patients with motor neurone disease

    International Nuclear Information System (INIS)

    Andreadou, E.; Sgouropoulos, P.; Varelas, P.; Papageorgiou, C.; Gouliamos, A.

    1998-01-01

    MRI was performed in 32 patients with motor neurone disease (26 men and 6 women, aged 40-77 years) and in a control group of 21 subjects. Of the patients studied, 19 had definite and 11 probable amyotrophic lateral sclerosis (ALS) and two had progressive bulbar palsy. In 10 patients there were asymmetrical bilateral foci of increased signal intensity on proton-density and T 2 -weighted images, confined to the white matter. Two patients had only cortical frontal atrophy and slightly increased ventricular size, whereas 20 had normal MRI. The focal lesions were not confined to corticospinal tracts, but were also observed in subcortical frontal areas. While the lesions along the corticospinal tracts correspond to pyramidal tract degeneration, the subcortical foci correlate with degeneration of the frontal bundles and indicate generalised involvement of the central nervous system. (orig.)

  8. Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions

    DEFF Research Database (Denmark)

    Hervig, Mona E; Thomsen, Morten S; Kalló, Imre

    2016-01-01

    and thalamus of rats. A single dose of PCP (10mg/kg, s.c.) significantly increased total number of c-Fos-IR in: (1) the prelimbic, infralimbic, anterior cingulate, ventrolateral orbital, motor, somatosensory and retrosplenial cortices as well as the nucleus accumbens (NAc), field CA1 of the hippocampus (CA1......) field of hippocampus and mediodorsal thalamus (MD); (2) PV-IR cells in the ventrolateral orbitofrontal and retrosplenial cortices and CA1 field of hippocampus; and (3) CB-IR cells in the motor cortex. Overall, our data indicate that PCP activates a wide range of cortical and subcortical brain regions...... and subcortical areas, but whether such induction occurs in specific populations of GABAergic interneuron subtypes still remains to be established. We performed an immunohistochemical analysis of the PCP-induced c-Fos-immunoreactivity (IR) in parvalbumin (PV) and calbindin (CB) interneuron subtypes in the cortex...

  9. PET studies of brain energy metabolism in a model of subcortical dementia: progressive supranuclear Palsy

    International Nuclear Information System (INIS)

    Blin, J.; Baron, J.C.; Cambon, H.

    1988-01-01

    In 41 patients with clinically determined Progressive Supranuclear Palsy, a model of degenerative subcortical dementia, alterations in regional brain energy metabolism with respect to control subjects have been investigated using positron computed tomography and correlated to clinical and neuropsychological scores. A generalized significant reduction in brain metabolism was found, which predominated in the prefrontal cortex in accordance with, and statistically correlated to, the frontal neuropsychological score

  10. Hearing it again and again: on-line subcortical plasticity in humans.

    Science.gov (United States)

    Skoe, Erika; Kraus, Nina

    2010-10-26

    Human brainstem activity is sensitive to local sound statistics, as reflected in an enhanced response in repetitive compared to pseudo-random stimulus conditions [1]. Here we probed the short-term time course of this enhancement using a paradigm that assessed how the local sound statistics (i.e., repetition within a five-note melody) interact with more global statistics (i.e., repetition of the melody). To test the hypothesis that subcortical repetition enhancement builds over time, we recorded auditory brainstem responses in young adults to a five-note melody containing a repeated note, and monitored how the response changed over the course of 1.5 hrs. By comparing response amplitudes over time, we found a robust time-dependent enhancement to the locally repeating note that was superimposed on a weaker enhancement of the globally repeating pattern. We provide the first demonstration of on-line subcortical plasticity in humans. This complements previous findings that experience-dependent subcortical plasticity can occur on a number of time scales, including life-long experiences with music and language, and short-term auditory training. Our results suggest that the incoming stimulus stream is constantly being monitored, even when the stimulus is physically invariant and attention is directed elsewhere, to augment the neural response to the most statistically salient features of the ongoing stimulus stream. These real-time transformations, which may subserve humans' strong disposition for grouping auditory objects, likely reflect a mix of local processes and corticofugal modulation arising from statistical regularities and the influences of expectation. Our results contribute to our understanding of the biological basis of statistical learning and initiate a new investigational approach relating to the time-course of subcortical plasticity. Although the reported time-dependent enhancements are believed to reflect universal neurophysiological processes, future

  11. Hearing it again and again: on-line subcortical plasticity in humans.

    Directory of Open Access Journals (Sweden)

    Erika Skoe

    2010-10-01

    Full Text Available Human brainstem activity is sensitive to local sound statistics, as reflected in an enhanced response in repetitive compared to pseudo-random stimulus conditions [1]. Here we probed the short-term time course of this enhancement using a paradigm that assessed how the local sound statistics (i.e., repetition within a five-note melody interact with more global statistics (i.e., repetition of the melody.To test the hypothesis that subcortical repetition enhancement builds over time, we recorded auditory brainstem responses in young adults to a five-note melody containing a repeated note, and monitored how the response changed over the course of 1.5 hrs. By comparing response amplitudes over time, we found a robust time-dependent enhancement to the locally repeating note that was superimposed on a weaker enhancement of the globally repeating pattern.We provide the first demonstration of on-line subcortical plasticity in humans. This complements previous findings that experience-dependent subcortical plasticity can occur on a number of time scales, including life-long experiences with music and language, and short-term auditory training. Our results suggest that the incoming stimulus stream is constantly being monitored, even when the stimulus is physically invariant and attention is directed elsewhere, to augment the neural response to the most statistically salient features of the ongoing stimulus stream. These real-time transformations, which may subserve humans' strong disposition for grouping auditory objects, likely reflect a mix of local processes and corticofugal modulation arising from statistical regularities and the influences of expectation. Our results contribute to our understanding of the biological basis of statistical learning and initiate a new investigational approach relating to the time-course of subcortical plasticity. Although the reported time-dependent enhancements are believed to reflect universal neurophysiological

  12. Early developmental gene enhancers affect subcortical volumes in the adult human brain.

    Science.gov (United States)

    Becker, Martin; Guadalupe, Tulio; Franke, Barbara; Hibar, Derrek P; Renteria, Miguel E; Stein, Jason L; Thompson, Paul M; Francks, Clyde; Vernes, Sonja C; Fisher, Simon E

    2016-05-01

    Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype-phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations. Hum Brain Mapp 37:1788-1800, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. The Effects of Modified Constraint-Induced Movement Therapy in Acute Subcortical Cerebral Infarction.

    Science.gov (United States)

    Yu, Changshen; Wang, Wanjun; Zhang, Yue; Wang, Yizhao; Hou, Weijia; Liu, Shoufeng; Gao, Chunlin; Wang, Chen; Mo, Lidong; Wu, Jialing

    2017-01-01

    Background : Constraint-induced movement therapy (CIMT) promotes upper extremity recovery post stroke, however, it is difficult to implement clinically due to its high resource demand and safety of the restraint. Therefore, we propose that modified CIMT (mCIMT) be used to treat individuals with acute subcortical infarction. Objective : To evaluate the therapeutic effects of mCIMT in patients with acute subcortical infarction, and investigate the possible mechanisms underlying the effect. Methods : The role of mCIMT was investigated in 26 individuals experiencing subcortical infarction in the preceding 14 days. Patients were randomly assigned to either mCIMT or standard therapy. mCIMT group was treated daily for 3 h over 10 consecutive working days, using a mitt on the unaffected arm for up to 30% of waking hours. The control group was treated with an equal dose of occupational therapy and physical therapy. During the 3-month follow-up, the motor functions of the affected limb were assessed by the Wolf Motor Function Test (WMFT) and Motor Activity Log (MAL). Altered cortical excitability was assessed via transcranial magnetic stimulation (TMS). Results : Treatment significantly improved the movement in the mCIMT group compared with the control group. The mean WMF score was significantly higher in the mCIMT group compared with the control group. Further, the appearance of motor-evoked potentials (MEPs) were significantly higher in the mCIMT group compared with the baseline data. A significant change in ipsilesional silent period (SP) occurred in the mCIMT group compared with the control group. However, we found no difference between two groups in motor function or electrophysiological parameters after 3 months of follow-up. Conclusions : mCIMT resulted in significant functional changes in timed movement immediately following treatment in patients with acute subcortical infarction. Further, early mCIMT improved ipsilesional cortical excitability. However, no long

  14. The Effects of Modified Constraint-Induced Movement Therapy in Acute Subcortical Cerebral Infarction

    Directory of Open Access Journals (Sweden)

    Changshen Yu

    2017-05-01

    Full Text Available Background: Constraint-induced movement therapy (CIMT promotes upper extremity recovery post stroke, however, it is difficult to implement clinically due to its high resource demand and safety of the restraint. Therefore, we propose that modified CIMT (mCIMT be used to treat individuals with acute subcortical infarction.Objective: To evaluate the therapeutic effects of mCIMT in patients with acute subcortical infarction, and investigate the possible mechanisms underlying the effect.Methods: The role of mCIMT was investigated in 26 individuals experiencing subcortical infarction in the preceding 14 days. Patients were randomly assigned to either mCIMT or standard therapy. mCIMT group was treated daily for 3 h over 10 consecutive working days, using a mitt on the unaffected arm for up to 30% of waking hours. The control group was treated with an equal dose of occupational therapy and physical therapy. During the 3-month follow-up, the motor functions of the affected limb were assessed by the Wolf Motor Function Test (WMFT and Motor Activity Log (MAL. Altered cortical excitability was assessed via transcranial magnetic stimulation (TMS.Results: Treatment significantly improved the movement in the mCIMT group compared with the control group. The mean WMF score was significantly higher in the mCIMT group compared with the control group. Further, the appearance of motor-evoked potentials (MEPs were significantly higher in the mCIMT group compared with the baseline data. A significant change in ipsilesional silent period (SP occurred in the mCIMT group compared with the control group. However, we found no difference between two groups in motor function or electrophysiological parameters after 3 months of follow-up.Conclusions: mCIMT resulted in significant functional changes in timed movement immediately following treatment in patients with acute subcortical infarction. Further, early mCIMT improved ipsilesional cortical excitability. However, no long

  15. Diffusion tractography of the subcortical auditory system in a postmortem human brain

    OpenAIRE

    Sitek, Kevin

    2017-01-01

    The subcortical auditory system is challenging to identify with standard human brain imaging techniques: MRI signal decreases toward the center of the brain as well as at higher resolution, both of which are necessary for imaging small brainstem auditory structures.Using high-resolution diffusion-weighted MRI, we asked:Can we identify auditory structures and connections in high-resolution ex vivo images?Which structures and connections can be mapped in vivo?

  16. Vitamin D, Homocysteine, and Folate in Subcortical Vascular Dementia and Alzheimer Dementia

    OpenAIRE

    Moretti, Rita; Caruso, Paola; Dal Ben, Matteo; Conti, Corrado; Gazzin, Silvia; Tiribelli, Claudio

    2017-01-01

    Dementia is a worldwide health problem which affects millions of patients; Alzheimer's disease (AD) and subcortical vascular dementia (sVAD) are the two most frequent forms of its presentation. As no definite therapeutic options have been discovered, different risk factors for cognitive impairment have been searched for potential therapies. This report focuses on the possible evidence that vitamin D deficiency and hyper-homocysteinemia can be considered as two important factors for the develo...

  17. Measurement and genetics of human subcortical and hippocampal asymmetries in large datasets.

    Science.gov (United States)

    Guadalupe, Tulio; Zwiers, Marcel P; Teumer, Alexander; Wittfeld, Katharina; Vasquez, Alejandro Arias; Hoogman, Martine; Hagoort, Peter; Fernandez, Guillen; Buitelaar, Jan; Hegenscheid, Katrin; Völzke, Henry; Franke, Barbara; Fisher, Simon E; Grabe, Hans J; Francks, Clyde

    2014-07-01

    Functional and anatomical asymmetries are prevalent features of the human brain, linked to gender, handedness, and cognition. However, little is known about the neurodevelopmental processes involved. In zebrafish, asymmetries arise in the diencephalon before extending within the central nervous system. We aimed to identify genes involved in the development of subtle, left-right volumetric asymmetries of human subcortical structures using large datasets. We first tested the feasibility of measuring left-right volume differences in such large-scale samples, as assessed by two automated methods of subcortical segmentation (FSL|FIRST and FreeSurfer), using data from 235 subjects who had undergone MRI twice. We tested the agreement between the first and second scan, and the agreement between the segmentation methods, for measures of bilateral volumes of six subcortical structures and the hippocampus, and their volumetric asymmetries. We also tested whether there were biases introduced by left-right differences in the regional atlases used by the methods, by analyzing left-right flipped images. While many bilateral volumes were measured well (scan-rescan r = 0.6-0.8), most asymmetries, with the exception of the caudate nucleus, showed lower repeatabilites. We meta-analyzed genome-wide association scan results for caudate nucleus asymmetry in a combined sample of 3,028 adult subjects but did not detect associations at genome-wide significance (P left-right patterning of the viscera. Our results provide important information for researchers who are currently aiming to carry out large-scale genome-wide studies of subcortical and hippocampal volumes, and their asymmetries. Copyright © 2013 Wiley Periodicals, Inc.

  18. Morphology of subcortical brain nuclei is associated with autonomic function in healthy humans.

    Science.gov (United States)

    Ruffle, James K; Coen, Steven J; Giampietro, Vincent; Williams, Steven C R; Apkarian, A Vania; Farmer, Adam D; Aziz, Qasim

    2018-01-01

    The autonomic nervous system (ANS) is a brain body interface which serves to maintain homeostasis by influencing a plethora of physiological processes, including metabolism, cardiorespiratory regulation and nociception. Accumulating evidence suggests that ANS function is disturbed in numerous prevalent clinical disorders, including irritable bowel syndrome and fibromyalgia. While the brain is a central hub for regulating autonomic function, the association between resting autonomic activity and subcortical morphology has not been comprehensively studied and thus was our aim. In 27 healthy subjects [14 male and 13 female; mean age 30 years (range 22-53 years)], we quantified resting ANS function using validated indices of cardiac sympathetic index (CSI) and parasympathetic cardiac vagal tone (CVT). High resolution structural magnetic resonance imaging scans were acquired, and differences in subcortical nuclei shape, that is, 'deformation', contingent on resting ANS activity were investigated. CSI positively correlated with outward deformation of the brainstem, right nucleus accumbens, right amygdala and bilateral pallidum (all thresholded to corrected P right amygdala and pallidum (all thresholded to corrected P Left and right putamen volume positively correlated with CVT (r = 0.62, P = 0.0047 and r = 0.59, P = 0.008, respectively), as did the brainstem (r = 0.46, P = 0.049). These data provide novel evidence that resting autonomic state is associated with differences in the shape and volume of subcortical nuclei. Thus, subcortical morphological brain differences in various disorders may partly be attributable to perturbation in autonomic function. Further work is warranted to investigate these findings in clinical populations. Hum Brain Mapp 39:381-392, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. The Association Between Specific Substances of Abuse and Subcortical Intracerebral Hemorrhage versus Ischemic Lacunar Infarction

    Directory of Open Access Journals (Sweden)

    Emma H Kaplan

    2014-09-01

    Full Text Available Background: Hypertension damages small vessels, resulting in both lacunar infarction and subcortical intracerebral hemorrhage (ICH. Substance abuse has also been linked to small vessel pathology. This study explores whether the use of specific substances (eg., cocaine, tobacco is associated with subcortical ICH over ischemia in hypertensive individuals.Methods: Patients with hypertension, admitted with lacunar infarcts (measuring 1 drink per day (women, >2 drinks per day (men. Logistic regression was performed with ICH as the dependent variable comparing those presenting with ICH to those presenting with ischemia.Results: Of the 580 patients included in analysis, 217 (37% presented with ICH. The average age was similar between the two groups (64.7 versus 66.3 years. Illicit/controlled drug use was associated with a significantly increased risk of ICH over stroke in unadjusted models (25% versus 15%, p=0.02, with the largest effect seen in users ≥65 years old (not statistically significant. Smoking was associated with ischemia over ICH in a dose-dependent manner: any history of smoking OR 1.84, CI 1.19-2.84; current use OR 2.23, CI 1.37-3.62; heavy use OR 2.48, CI 1.50-4.13. Alcohol use was not preferentially associated with either outcome (p=0.29.Conclusions: In hypertensive patients, tobacco use is associated with an increased risk of subcortical ischemia compared to ICH; while use of illicit/controlled substances appears to be predictive of hemorrhage.

  20. A high-resolution probabilistic in vivo atlas of human subcortical brain nuclei.

    Science.gov (United States)

    Pauli, Wolfgang M; Nili, Amanda N; Tyszka, J Michael

    2018-04-17

    Recent advances in magnetic resonance imaging methods, including data acquisition, pre-processing and analysis, have benefited research on the contributions of subcortical brain nuclei to human cognition and behavior. At the same time, these developments have led to an increasing need for a high-resolution probabilistic in vivo anatomical atlas of subcortical nuclei. In order to address this need, we constructed high spatial resolution, three-dimensional templates, using high-accuracy diffeomorphic registration of T 1 - and T 2 - weighted structural images from 168 typical adults between 22 and 35 years old. In these templates, many tissue boundaries are clearly visible, which would otherwise be impossible to delineate in data from individual studies. The resulting delineations of subcortical nuclei complement current histology-based atlases. We further created a companion library of software tools for atlas development, to offer an open and evolving resource for the creation of a crowd-sourced in vivo probabilistic anatomical atlas of the human brain.

  1. Low- and high-frequency subcortical SEP amplitude reduction during pure passive movement.

    Science.gov (United States)

    Insola, Angelo; Padua, Luca; Mazzone, Paolo; Valeriani, Massimiliano

    2015-12-01

    To investigate the effect of pure passive movement on both cortical and subcortical somatosensory evoked potentials (SEPs). Median nerve SEPs were recorded in 8 patients suffering from Parkinson's disease (PD) and two patients with essential tremor. PD patients underwent electrode implantation in the subthalamic (STN) nucleus (3 patients) and pedunculopontine (PPTg) nucleus (5 patients), while 2 patients with essential tremor were implanted in the ventral intermediate nucleus (VIM) of the thalamus. In anesthetized patients, SEPs were recorded at rest and during a passive movement of the thumb of the stimulated wrist from the intracranial electrode contacts and from the scalp. Also the high-frequency oscillations (HFOs) were analyzed. Amplitudes of both deep and scalp components were decreased during passive movement, but the reduction was higher at cortical than subcortical level. Also the HFOs were reduced by movement. The different amount of the movement-related decrease suggests that the cortical SEP gating is not only the result of a subcortical somatosensory volley attenuation, but a further mechanism acting at cortical level should be considered. Our results are important for understanding the physiological mechanism of the sensory-motor interaction during passive movement. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  2. Intra- and interhemispheric variations of diffusivity in subcortical white matter in normal human brain

    International Nuclear Information System (INIS)

    Yoshiura, Takashi; Noguchi, Tomoyuki; Hiwatashi, Akio; Togao, Osamu; Yamashita, Koji; Nagao, Eiki; Kamano, Hironori; Honda, Hiroshi

    2010-01-01

    Our purpose was to reveal potential regional variations in water molecular diffusivity within each cerebral hemisphere and across the right and left hemispheres. Diffusion-weighted images of 44 healthy right-handed adult male subjects were obtained using a diffusion tensor imaging sequence. Mean diffusivity (MD) values in subcortical white matter (WM) within 39 regions in each hemisphere were measured using an automated method. Intrahemispheric comparisons of MDs in subcortical WM were performed among six brain regions (frontal, parietal, occipital and temporal lobes and pre- and postcentral gyri). Interhemispheric comparisons of MDs were performed between the right and left counterparts of the 39 regions. In both hemispheres, diffusivity in the precentral gyrus was lower than those in other regions, while diffusivity in the parietal lobe was higher than others. MD asymmetry in which the left was lower than the right was found in the parietal lobe, middle occipital gyrus, and medial and orbital aspects of the frontal lobe. The converse asymmetry was revealed in the frontal operculum, supplementary motor cortex, temporal lobe, limbic cortices, precuneus and cuneus. Our results revealed significant intra- and interhemispheric regional variations in MD in subcortical WM, which may be related to different densities of axons and myelin sheaths. (orig.)

  3. Intra- and interhemispheric variations of diffusivity in subcortical white matter in normal human brain

    Energy Technology Data Exchange (ETDEWEB)

    Yoshiura, Takashi; Noguchi, Tomoyuki; Hiwatashi, Akio; Togao, Osamu; Yamashita, Koji; Nagao, Eiki; Kamano, Hironori; Honda, Hiroshi [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan)

    2010-01-15

    Our purpose was to reveal potential regional variations in water molecular diffusivity within each cerebral hemisphere and across the right and left hemispheres. Diffusion-weighted images of 44 healthy right-handed adult male subjects were obtained using a diffusion tensor imaging sequence. Mean diffusivity (MD) values in subcortical white matter (WM) within 39 regions in each hemisphere were measured using an automated method. Intrahemispheric comparisons of MDs in subcortical WM were performed among six brain regions (frontal, parietal, occipital and temporal lobes and pre- and postcentral gyri). Interhemispheric comparisons of MDs were performed between the right and left counterparts of the 39 regions. In both hemispheres, diffusivity in the precentral gyrus was lower than those in other regions, while diffusivity in the parietal lobe was higher than others. MD asymmetry in which the left was lower than the right was found in the parietal lobe, middle occipital gyrus, and medial and orbital aspects of the frontal lobe. The converse asymmetry was revealed in the frontal operculum, supplementary motor cortex, temporal lobe, limbic cortices, precuneus and cuneus. Our results revealed significant intra- and interhemispheric regional variations in MD in subcortical WM, which may be related to different densities of axons and myelin sheaths. (orig.)

  4. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex.

    Science.gov (United States)

    Guadalupe, Tulio; Mathias, Samuel R; vanErp, Theo G M; Whelan, Christopher D; Zwiers, Marcel P; Abe, Yoshinari; Abramovic, Lucija; Agartz, Ingrid; Andreassen, Ole A; Arias-Vásquez, Alejandro; Aribisala, Benjamin S; Armstrong, Nicola J; Arolt, Volker; Artiges, Eric; Ayesa-Arriola, Rosa; Baboyan, Vatche G; Banaschewski, Tobias; Barker, Gareth; Bastin, Mark E; Baune, Bernhard T; Blangero, John; Bokde, Arun L W; Boedhoe, Premika S W; Bose, Anushree; Brem, Silvia; Brodaty, Henry; Bromberg, Uli; Brooks, Samantha; Büchel, Christian; Buitelaar, Jan; Calhoun, Vince D; Cannon, Dara M; Cattrell, Anna; Cheng, Yuqi; Conrod, Patricia J; Conzelmann, Annette; Corvin, Aiden; Crespo-Facorro, Benedicto; Crivello, Fabrice; Dannlowski, Udo; de Zubicaray, Greig I; de Zwarte, Sonja M C; Deary, Ian J; Desrivières, Sylvane; Doan, Nhat Trung; Donohoe, Gary; Dørum, Erlend S; Ehrlich, Stefan; Espeseth, Thomas; Fernández, Guillén; Flor, Herta; Fouche, Jean-Paul; Frouin, Vincent; Fukunaga, Masaki; Gallinat, Jürgen; Garavan, Hugh; Gill, Michael; Suarez, Andrea Gonzalez; Gowland, Penny; Grabe, Hans J; Grotegerd, Dominik; Gruber, Oliver; Hagenaars, Saskia; Hashimoto, Ryota; Hauser, Tobias U; Heinz, Andreas; Hibar, Derrek P; Hoekstra, Pieter J; Hoogman, Martine; Howells, Fleur M; Hu, Hao; Hulshoff Pol, Hilleke E; Huyser, Chaim; Ittermann, Bernd; Jahanshad, Neda; Jönsson, Erik G; Jurk, Sarah; Kahn, Rene S; Kelly, Sinead; Kraemer, Bernd; Kugel, Harald; Kwon, Jun Soo; Lemaitre, Herve; Lesch, Klaus-Peter; Lochner, Christine; Luciano, Michelle; Marquand, Andre F; Martin, Nicholas G; Martínez-Zalacaín, Ignacio; Martinot, Jean-Luc; Mataix-Cols, David; Mather, Karen; McDonald, Colm; McMahon, Katie L; Medland, Sarah E; Menchón, José M; Morris, Derek W; Mothersill, Omar; Maniega, Susana Munoz; Mwangi, Benson; Nakamae, Takashi; Nakao, Tomohiro; Narayanaswaamy, Janardhanan C; Nees, Frauke; Nordvik, Jan E; Onnink, A Marten H; Opel, Nils; Ophoff, Roel; Paillère Martinot, Marie-Laure; Papadopoulos Orfanos, Dimitri; Pauli, Paul; Paus, Tomáš; Poustka, Luise; Reddy, Janardhan Yc; Renteria, Miguel E; Roiz-Santiáñez, Roberto; Roos, Annerine; Royle, Natalie A; Sachdev, Perminder; Sánchez-Juan, Pascual; Schmaal, Lianne; Schumann, Gunter; Shumskaya, Elena; Smolka, Michael N; Soares, Jair C; Soriano-Mas, Carles; Stein, Dan J; Strike, Lachlan T; Toro, Roberto; Turner, Jessica A; Tzourio-Mazoyer, Nathalie; Uhlmann, Anne; Hernández, Maria Valdés; van den Heuvel, Odile A; van der Meer, Dennis; van Haren, Neeltje E M; Veltman, Dick J; Venkatasubramanian, Ganesan; Vetter, Nora C; Vuletic, Daniella; Walitza, Susanne; Walter, Henrik; Walton, Esther; Wang, Zhen; Wardlaw, Joanna; Wen, Wei; Westlye, Lars T; Whelan, Robert; Wittfeld, Katharina; Wolfers, Thomas; Wright, Margaret J; Xu, Jian; Xu, Xiufeng; Yun, Je-Yeon; Zhao, JingJing; Franke, Barbara; Thompson, Paul M; Glahn, David C; Mazoyer, Bernard; Fisher, Simon E; Francks, Clyde

    2017-10-01

    The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

  5. Neural Correlates of Indicators of Sound Change in Cantonese: Evidence from Cortical and Subcortical Processes.

    Science.gov (United States)

    Maggu, Akshay R; Liu, Fang; Antoniou, Mark; Wong, Patrick C M

    2016-01-01

    Across time, languages undergo changes in phonetic, syntactic, and semantic dimensions. Social, cognitive, and cultural factors contribute to sound change, a phenomenon in which the phonetics of a language undergo changes over time. Individuals who misperceive and produce speech in a slightly divergent manner (called innovators ) contribute to variability in the society, eventually leading to sound change. However, the cause of variability in these individuals is still unknown. In this study, we examined whether such misperceptions are represented in neural processes of the auditory system. We investigated behavioral, subcortical (via FFR), and cortical (via P300) manifestations of sound change processing in Cantonese, a Chinese language in which several lexical tones are merging. Across the merging categories, we observed a similar gradation of speech perception abilities in both behavior and the brain (subcortical and cortical processes). Further, we also found that behavioral evidence of tone merging correlated with subjects' encoding at the subcortical and cortical levels. These findings indicate that tone-merger categories, that are indicators of sound change in Cantonese, are represented neurophysiologically with high fidelity. Using our results, we speculate that innovators encode speech in a slightly deviant neurophysiological manner, and thus produce speech divergently that eventually spreads across the community and contributes to sound change.

  6. Axial diffusivity changes in the motor pathway above stroke foci and functional recovery after subcortical infarction.

    Science.gov (United States)

    Liu, Gang; Peng, Kangqiang; Dang, Chao; Tan, Shuangquan; Chen, Hongbing; Xie, Chuanmiao; Xing, Shihui; Zeng, Jinsheng

    2018-01-01

    Secondary degeneration of the fiber tract of the motor pathway below infarct foci and functional recovery after stroke have been well demonstrated, but the role of the fiber tract above stroke foci remains unclear. This study aimed to investigate diffusion changes in motor fibers above the lesion and identify predictors of motor improvement within 12 weeks after subcortical infarction. Diffusion tensor imaging and the Fugl-Meyer (FM) scale were conducted 1, 4, and 12 weeks (W) after a subcortical infarct. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Region of interest analysis was used to assess diffusion changes in the motor pathway above and below a stroke lesion. Multivariable linear regression was employed to identify predictors of motor improvement within 12 weeks after stroke. Axial diffusivity (AD) in the underlying white matter of the ipsilesional primary motor area (PMA) and cerebral peduncle (CP) in both proportional and poor recovery groups was lower at W1 compared to the controls and values in the contralesional PMA and CP (all P motor improvement within 12 weeks after stroke in patients with proportional or poor recovery. Increases of AD in the motor pathway above stroke foci may be associated with motor recovery after subcortical infarction. Early measurement of diffusion metrics in the ipsilesional non-ischemic motor pathway has limited value in predicting future motor improvement patterns (proportional or poor recovery).

  7. Behavioral and subcortical signatures of musical expertise in Mandarin Chinese speakers.

    Directory of Open Access Journals (Sweden)

    Caitlin Dawson

    Full Text Available Both musical training and native language have been shown to have experience-based plastic effects on auditory processing. However, the combined effects within individuals are unclear. Recent research suggests that musical training and tone language speaking are not clearly additive in their effects on processing of auditory features and that there may be a disconnect between perceptual and neural signatures of auditory feature processing. The literature has only recently begun to investigate the effects of musical expertise on basic auditory processing for different linguistic groups. This work provides a profile of primary auditory feature discrimination for Mandarin speaking musicians and nonmusicians. The musicians showed enhanced perceptual discrimination for both frequency and duration as well as enhanced duration discrimination in a multifeature discrimination task, compared to nonmusicians. However, there were no differences between the groups in duration processing of nonspeech sounds at a subcortical level or in subcortical frequency representation of a nonnative tone contour, for fo or for the first or second formant region. The results indicate that musical expertise provides a cognitive, but not subcortical, advantage in a population of Mandarin speakers.

  8. Common late-onset subcortical cerebral hemorrhage following excessive alcohol consumption: a case report

    International Nuclear Information System (INIS)

    Incedayi, M.; Sivrioglu, A.; Velioglu, M.; Aribal, S.; Sonmez, G.; Basekim, C.

    2012-01-01

    Full text: 50 year old male patient who was suffering from cooperation disorder and bilaterally blindness was admitted to our emergency service. He was addicted to alcohol and had excessive alcohol consumption the day before. Cranial nonenhanced CT was normal. T2 weighed MR imaging performed at 1,5 T unit showed high signal intensity in bilateral putaminal foci. In this localization diffusion-weighed images (DWI) were hyperintense due to restricted diffusion and low ADC values. After two weeks, drowsiness and confusion were appeared suddenly. Cranial nonenhanced CT was showed extensive subcortical white matter and basal ganglia abnormalities consistent with edema and hemorrhagic changes. The patient was transferred to intensive care unit and died after one day. In methanol intoxication, cerebral and intraventricular hemorrhage, cerebellar necrosis, diffuse cerebral edema, bilateral subcortical white matter necrosis and edema were defined It should also be known that 2 or 3 weeks after ingestion of methyl alcohol, the deterioration of the patient's general situation is responsible for cerebral subcortical hemorrhage. We have also thought that patients' mortality and morbidity can be reduced with radiological imaging due to early diagnosis

  9. Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum.

    Science.gov (United States)

    Viney, Tim James; Salib, Minas; Joshi, Abhilasha; Unal, Gunes; Berry, Naomi; Somogyi, Peter

    2018-04-05

    Rhythmic theta frequency (~5-12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of 'upstream' and 'downstream' cortico-cortical circuits involved in mnemonic functions. © 2018, Viney et al.

  10. Relationship between extent of brain hypoperfused area and functional outcome in patients with a small subcortical infarction

    International Nuclear Information System (INIS)

    Isaka, Yoshinari; Imaizumi, Masatoshi; Ashida, Keiichi; Nakayama, Hirofumi; Iiji, Osamu; Itoi, Yoshihito; Furukawa, Toshiyuki

    1992-01-01

    We performed 123 I-IMP single photon emission computed tomography (SPECT) in 43 patients who had a small infarction ( 2 =29.3; p 123 I-IMP SPECT in patients with a small infarction may discriminate lacunar infarction from embolic or hemodynamic infarction, which was caused by vascular lesions of major cerebral arteries, in subcortical area. Our study suggests that functional outcome is better in lacunar infarction than embolic or hemodynamic infarction in subcortical area. (author)

  11. Bilingualism at the core of the brain. Structural differences between bilinguals and monolinguals revealed by subcortical shape analysis.

    Science.gov (United States)

    Burgaleta, Miguel; Sanjuán, Ana; Ventura-Campos, Noelia; Sebastian-Galles, Núria; Ávila, César

    2016-01-15

    Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control - two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface-based analysis in a sample of monolinguals and simultaneous bilinguals (N=88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors.

    Science.gov (United States)

    De Gregorio, Danilo; Posa, Luca; Ochoa-Sanchez, Rafael; McLaughlin, Ryan; Maione, Sabatino; Comai, Stefano; Gobbi, Gabriella

    2016-11-01

    d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT 1 and 5-HT 2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5-20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT 2A and D 2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30-120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D 2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT 1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR 1 ) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT 1A, D 2 and TAAR 1 receptors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats.

    Science.gov (United States)

    Yamada, Koji; Kobayashi, Minoru; Shiozaki, Shizuo; Ohta, Teruko; Mori, Akihisa; Jenner, Peter; Kanda, Tomoyuki

    2014-07-01

    Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson's disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests. We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model. Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A1/A2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A1 selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A1 specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT2A/2C receptor antagonist methysergide or the adrenergic α 2 antagonist yohimbine, nor the β-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline. Istradefylline exerts antidepressant-like effects via modulation of A2A receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms.

  14. Formulaic language in cortical and subcortical disease: Evidence of the dual process model.

    Directory of Open Access Journals (Sweden)

    Kelly Bridges

    2014-04-01

    Full Text Available Introduction: It is known that an intact cortical left hemisphere is crucial for language production. Recently, more credit is given to the right hemisphere and subcortical areas in the production of non-novel language, including formulaic language. John Hughlings Jackson (1874/1958, first described how propositional and non-propositional speech are differentially affected by neural impairment. Non-propositional language is often preserved following left hemisphere stroke even when aphasia is present (Code, 1982; Sidtis et al., 2009; Van Lancker Sidtis & Postman, 2006. With right hemisphere and subcortical stroke, formulaic language is reduced (Sidtis et al., 2009; Van Lancker Sidtis & Postman, 2006; Speedie et al., 1993. The dual process model of language competence states that propositional and non-propositional speech are processed differently in the brain, with novel speech controlled by the left hemisphere, and a right hemisphere/subcortical circuit modulating formulaic language (Van Lancker Sidtis, 2004; 2012. Two studies of formulaic language will be presented as further evidence of the dual process model: a study of formulaic language in Alzheimer’s disease, and a study of recited speech in Parkinson’s disease. Formulaic language includes overlearned words, phrases or longer linguistic units that are known to the native speaker, occur naturally in discourse, and are important for normal social interaction (Fillmore, 1979; Pawley & Syder, 1983; Van Lancker, 1988; Van Lancker Sidtis, 2004; Wray, 2002. Formulaic expressions include conversational speech formulas, idioms, proverbs, expletives, pause fillers, discourse elements, and sentence stems (stereotyped sentence-initials. Longer units of linguistic material, such as prayers, rhymes, and poems, termed recited speech, is another subtype of formulaic language that is learned in childhood and recited periodically throughout life. Cortical disease: Alzheimer’s disease and formulaic

  15. The Association between Specific Substances of Abuse and Subcortical Intracerebral Hemorrhage Versus Ischemic Lacunar Infarction.

    Science.gov (United States)

    Kaplan, Emma H; Gottesman, Rebecca F; Llinas, Rafael H; Marsh, Elisabeth B

    2014-01-01

    Hypertension damages small vessels, resulting in both lacunar infarction and subcortical intracerebral hemorrhage (ICH). Substance abuse has also been linked to small vessel pathology. This study explores whether the use of specific substances (e.g., cocaine, tobacco) is associated with subcortical ICH over ischemia in hypertensive individuals. Patients with hypertension, admitted with lacunar infarcts (measuring 1 drink per day (women), >2 drinks per day (men). Logistic regression was performed with ICH as the dependent variable comparing those presenting with ICH to those presenting with ischemia. Of the 580 patients included in analysis, 217 (37%) presented with ICH. The average age was similar between the two groups (64.7 versus 66.3 years). Illicit/controlled drug use was associated with a significantly increased risk of ICH over stroke in unadjusted models (25 versus 15%, p = 0.02), with the largest effect seen in users ≥65 years old (not statistically significant). Smoking was associated with ischemia over ICH in a dose-dependent manner: any history of smoking OR 1.84, CI 1.19-2.84; current use OR 2.23, CI 1.37-3.62; heavy use OR 2.48, CI 1.50-4.13. Alcohol use was not preferentially associated with either outcome (p = 0.29). In hypertensive patients, tobacco use is associated with an increased risk of subcortical ischemia compared to ICH, while use of illicit/controlled substances appears to be predictive of hemorrhage.

  16. Apraxia for differentiating Alzheimer’s disease from subcortical vascular dementia and mild cognitive impairment

    Directory of Open Access Journals (Sweden)

    Ozkan S

    2013-07-01

    Full Text Available Serhat Ozkan,1 Demet Ozbabalik Adapinar,1 Nese Tuncer Elmaci,2 Didem Arslantas31Department of Neurology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey; 2Department of Neurology, Marmara University Medical Faculty, Istanbul, Turkey; 3Department of Public Health, Eskisehir Osmangazi University Medical Faculty, Eskisehir, TurkeyAbstract: Although ideomotor limb apraxia is considered to be a typical sign of cortical pathologies such as Alzheimer’s disease (AD, it has been also reported in subcortical neurodegenerative diseases and vascular lesions. We aimed to investigate the difference between AD, subcortical vascular dementia (SVaD and mild cognitive impairment (MCI patients by means of ideomotor limb apraxia frequency and severity. Ninety-six AD, 72 SVaD, and 84 MCI patients were assessed with the mini-mental status examination (MMSE, clinical dementia rating (CDR and the apraxia screening test of TULIA (AST. Apraxia was significantly more frequent in the AD patients (32.3% than in both of the SVaD (16.7% and MCI (4.8% patients. The frequency of apraxia was also significantly higher in SVaD patients than in MCI patients. AD patients had significantly lower apraxia scores than both SVaD and MCI patients. In addition, a significant difference was found between SVaD and MCI patients in terms of apraxia scores. These results suggest that the widespread belief of the association between apraxia and cortical dementias is not exactly correct. The significant difference between both of the dementia groups and the MCI patients suggests that the absence of apraxia can be an indicator for MCI diagnosis.Keywords: apraxia, Alzheimer’s disease, subcortical vascular dementia, mild cognitive impairment

  17. Executive function and cerebral blood flow on dorsolateral prefrontal cortex in cases of subcortical infarction

    International Nuclear Information System (INIS)

    Hasegawa, Akira; Utsumi, Hiroya

    2006-01-01

    In order to clarify the extent of dysexecutive function of patients with subcortical infarctions, participants of this study underwent neuropsychological tests and single photon emission computerized tomography (SPECT). These participants were categorized into two groups; patients with basal ganglia lesions (BG group) (n=5) and those with white matter lesions (WM group) (n=12). Participants were administered executive function tests as a part of a comprehensive neuropsychological battery. Administered executive measures included the Wisconsin Card Sorting Test (WCST), the Ruff Figural Fluency Test (RFFT), the Controlled Oral Word Association Test (COWAT), and the Trait Making Test; Parts A and B. There were no group differences in their age, years of education and global cognitive performance. Student's t-tests were conducted to determine group differences in executive function. As a result, the number of total errors, the number of perseverative errors and the number of categories completed on the WCST were significantly worse for the BG group than for the WM group. These groups did not differ on other measures administered. In addition, all participants underwent SPECT, and their results were compared with the normal control data. Hypoperfusion was found on parts of the bilateral frontal, temporal, and parietal lobes for the BG and WM groups. These tendencies stood out in the right hemisphere of the BG group. The BG group exhibited decreased cerebral blood flow (CBF) on the area of right side dorsolateral prefrontal cortex (DLPFC) (e.g., Brodmann area 44). These analyses revealed that individuals with BG lesions showed significant executive declines that might be associated with decreased CBF in the subcortical-frontal system. It may support the idea that BG is connected with DLPFC via frontal-subcortical neuronal circuit. Patients with BG lesions may experience dysexecutive function due to the phenomenon of diaschisis from the disruption of this circuit. (author)

  18. Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity.

    Science.gov (United States)

    Alessandrini, Marco; Micarelli, Alessandro; Chiaravalloti, Agostino; Bruno, Ernesto; Danieli, Roberta; Pierantozzi, Mariangela; Genovesi, Giuseppe; Öberg, Johanna; Pagani, Marco; Schillaci, Orazio

    2016-03-01

    Multiple chemical sensitivity (MCS) patients usually react to odour compounds and the majority of neuroimaging studies assessed, especially at the cortical level, many olfactory-related correlates. The purpose of the present study was to depict sub-cortical metabolic changes during a neutral (NC) and pure (OC) olfactory stimulation by using a recently validated (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computer tomography procedure in 26 MCS and 11 healthy (HC) resting subjects undergoing a battery of clinical tests. Twelve subcortical volumes of interest were identified by the automated anatomical labeling library and normalized to thalamus FDG uptake. In both groups, when comparing OC to NC, the within-subjects ANOVA demonstrated a relative decreased metabolism in bilateral putamen and hippocampus and a relative increased metabolism in bilateral amygdala, olfactory cortex (OLF), caudate and pallidum. The between-groups ANOVA demonstrated in MCS a significant higher metabolism in bilateral OLF during NC. As in HC subjects negative correlations were found in OC between FDG uptake in bilateral amygdala and hippocampus and odor pleasantness scale, the latter positively correlated with MCS subjects' bilateral putamen FDG uptake in OC. Besides FDG uptake resemblances in both groups were found, for the first time a relative higher metabolism increase in OLF in MCS subjects at rest with respect to HC was found. When merging this aspect to the different subcortical FDG uptake correlations patterns in the two groups, the present study demonstrated to describe a peculiar metabolic index of behavioral and neurological aspects of MCS complaints.

  19. Adult plasticity in the subcortical auditory pathway of the maternal mouse.

    Directory of Open Access Journals (Sweden)

    Jason A Miranda

    Full Text Available Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.

  20. Adult plasticity in the subcortical auditory pathway of the maternal mouse.

    Science.gov (United States)

    Miranda, Jason A; Shepard, Kathryn N; McClintock, Shannon K; Liu, Robert C

    2014-01-01

    Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.

  1. Studies on the role of serotonin receptor subtypes in the effect of sibutramine in various feeding paradigms in rats

    Science.gov (United States)

    Grignaschi, G; Fanelli, E; Scagnol, I; Samanin, R

    1999-01-01

    The effect of the 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake inhibitor sibutramine was studied in food deprived, neuropeptide Y (NPY)- or muscimol-injected rats. Sibutramine dose-dependently reduced feeding caused by food-deprivation (ED50=5.1±0.8 mg kg−1) or by NPY injection into the paraventricular nucleus of the hypothalamus (ED50=6.0±0.5 mg kg−1). The increase in food intake caused by muscimol injected into the dorsal raphe was not modified by sibutramine (1–10 mg kg−1). The hypophagic effect of 5.1 mg kg−1 sibutramine in food-deprived rats was studied in rats pretreated with different serotonin receptor antagonists. Metergoline (non-selective, 0.3 and 1.0 mg kg−1), ritanserin (5-HT2A/2C, 0.5 and 1.0 mg kg−1) and GR127935 (5-HT1B/1D, 0.5 and 1.0 mg kg−1) did not modify the hypophagic effect of sibutramine, while SB206553 (5-HT2B/2C, 5 and 10 mg kg−1) slightly but significantly reduced it (Fint(2.53)=3.4; Psibutramine in NPY-injected rats was not modified by GR127935 (1.0 mg kg−1). The results suggest that, with the possible exception of a partial involvement of 5-HT2B/2C receptors in sibutramine's hypophagia in food-deprived rats, 5-HT1 and 5-HT2 receptor subtypes do not play an important role in the hypophagic effect of sibutramine, at least in the first 2 h after injection. PMID:10455265

  2. Serotonin-stimulated phosphoinositide turnover: mediation by the S2 binding site in rat cerebral cortex but not in subcortical regions

    International Nuclear Information System (INIS)

    Conn, P.J.; Sanders-Bush, E.

    1985-01-01

    In rat cerebral cortex, serotonin (5-HT) stimulates phosphoinositide turnover with an EC50 of 1 microM in the presence of pargyline. The EC50 is 16-fold higher in the absence of pargyline. Selective S2 antagonists inhibit 5-HT-stimulated phosphoinositide turnover. Schild analysis of the blockade by ketanserin of the 5-HT effect gives an estimated Kd of ketanserin for the phosphoinositide-linked receptor of 11.7 nM, which agrees with the Kd (3.5 nM) of [ 3 H]ketanserin for the S2 site. Furthermore, MK-212, 5-HT and 5-fluorotryptamine stimulate phosphoinositide turnover with potencies that resemble their potencies at the S2 but not the S1 binding site. Of 11 agonists tested, the tryptamine derivatives tend to be more efficacious than the piperazine derivatives. The selective S1 agonist 8-hydroxy-2-(di-N-propylamino)tetralin is inactive at stimulating phosphoinositide turnover. No significant relationship exists between the regional distributions of 5-HT-stimulated phosphoinositide turnover and S2 binding sites. Furthermore, the S2 antagonist ketanserin is less potent and less efficacious in hippocampus and limbic forebrain than in cerebral cortex. These data suggest that 5-HT-stimulated phosphoinositide turnover is linked to the S2 binding site in rat cerebral cortex. However, 5-HT increases phosphoinositide turnover in subcortical regions by mechanisms other than stimulation of the S2 receptor

  3. Marchiafava-Bignami disease: magnetic resonance imaging findings in corpus callosum and subcortical white matter

    Energy Technology Data Exchange (ETDEWEB)

    Kawarabuki, Kentaro E-mail: bukky@h2.dion.ne.jp; Sakakibara, Takehiko; Hirai, Makoto; Yoshioka, Yuji; Yamamoto, Yasumasa; Yamaki, Tarumi

    2003-11-01

    A case of Marchiafava-Bignami disease (MBD) is presented using magnetic resonance imaging (MRI). A patient with a long history of alcoholism developed a gait disturbance with involuntary movements at the lower extremities. MRI scans taken at the onset showed no particular abnormalities. He progressed to a coma 10 days later. MRI scans taken 20 days after the onset showed a focal lesion at the genu of the corpus callosum and he was diagnosed as having MBD. In addition, multiple lesions were observed in bilateral frontoparietal subcortical white matter. These lesions demonstrated similar intense MRI signals as the corpus callosum.

  4. Reliability and statistical power analysis of cortical and subcortical FreeSurfer metrics in a large sample of healthy elderly.

    Science.gov (United States)

    Liem, Franziskus; Mérillat, Susan; Bezzola, Ladina; Hirsiger, Sarah; Philipp, Michel; Madhyastha, Tara; Jäncke, Lutz

    2015-03-01

    FreeSurfer is a tool to quantify cortical and subcortical brain anatomy automatically and noninvasively. Previous studies have reported reliability and statistical power analyses in relatively small samples or only selected one aspect of brain anatomy. Here, we investigated reliability and statistical power of cortical thickness, surface area, volume, and the volume of subcortical structures in a large sample (N=189) of healthy elderly subjects (64+ years). Reliability (intraclass correlation coefficient) of cortical and subcortical parameters is generally high (cortical: ICCs>0.87, subcortical: ICCs>0.95). Surface-based smoothing increases reliability of cortical thickness maps, while it decreases reliability of cortical surface area and volume. Nevertheless, statistical power of all measures benefits from smoothing. When aiming to detect a 10% difference between groups, the number of subjects required to test effects with sufficient power over the entire cortex varies between cortical measures (cortical thickness: N=39, surface area: N=21, volume: N=81; 10mm smoothing, power=0.8, α=0.05). For subcortical regions this number is between 16 and 76 subjects, depending on the region. We also demonstrate the advantage of within-subject designs over between-subject designs. Furthermore, we publicly provide a tool that allows researchers to perform a priori power analysis and sensitivity analysis to help evaluate previously published studies and to design future studies with sufficient statistical power. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Early MR detection of cortical and subcortical hypoxic-ischemic encephalopathy in full-term-infants

    International Nuclear Information System (INIS)

    Christophe, C.; Clercx, A.; Blum, D.; Hasaerts, D.; Segebarth, C.; Perlmutter, N.

    1994-01-01

    Four observations illustrate the potential of MR imaging in the early depiction of multiple types of neuropathologic lesions which may coexist in the full-term newborn, upon severe hypoxic-ischemic encephalopathy (HIE). In particular, diffuse, postnatal involvement of cerebral cortex and subcortical white matter (WM) is demonstrated. Cortical hyperintensity on both proton-density- and T1-weighted images is probably related to cellular necrosis which is distributed diffusely or parasigattally. Hyperintense, frontal, subcortical WM edging on proton-density-weighted images results from the increase of water concentration, induced either by infract or by edema. Diffuse WM areas of low intensity on T1-weighted images and of high intensity on T2-weighted images are presumably related to cytotoxic and/or vasogenic edema, proportional to the underlying damaged tissues. On follow-up MR examinations, several months later, the importance of cortical atrophy and of the myelination delay appeared related to the importance of the lesions detected during the post-natal period. (orig.)

  6. Minimally Invasive Subcortical Parafascicular Transsulcal Access for Clot Evacuation (Mi SPACE for Intracerebral Hemorrhage

    Directory of Open Access Journals (Sweden)

    Benjamin Ritsma

    2014-01-01

    Full Text Available Background. Spontaneous intracerebral hemorrhage (ICH is common and causes significant mortality and morbidity. To date, optimal medical and surgical intervention remains uncertain. A lack of definitive benefit for operative management may be attributable to adverse surgical effect, collateral tissue injury. This is particularly relevant for ICH in dominant, eloquent cortex. Minimally invasive surgery (MIS offers the potential advantage of reduced collateral damage. MIS utilizing a parafascicular approach has demonstrated such benefit for intracranial tumor resection. Methods. We present a case of dominant hemisphere spontaneous ICH evacuated via the minimally invasive subcortical parafascicular transsulcal access clot evacuation (Mi SPACE model. We use this report to introduce Mi SPACE and to examine the application of this novel MIS paradigm. Case Presentation. The featured patient presented with a left temporal ICH and severe global aphasia. The hematoma was evacuated via the Mi SPACE approach. Postoperative reassessments showed significant improvement. At two months, bedside language testing was normal. MRI tractography confirmed limited collateral injury. Conclusions. This case illustrates successful application of the Mi SPACE model to ICH in dominant, eloquent cortex and subcortical regions. MRI tractography illustrates collateral tissue preservation. Safety and feasibility studies are required to further assess this promising new therapeutic paradigm.

  7. Modulation of Cortical-subcortical Networks in Parkinson’s Disease by Applied Field Effects

    Directory of Open Access Journals (Sweden)

    Christopher William Hess

    2013-09-01

    Full Text Available Studies suggest that endogenous field effects may play a role in neuronal oscillations and communication. Non-invasive transcranial electrical stimulation with low-intensity currents can also have direct effects on the underlying cortex as well as distant network effects. While Parkinson's disease (PD is amenable to invasive neuromodulation in the basal ganglia by deep brain stimulation, techniques of non-invasive neuromodulation like transcranial direct current stimulation (tDCS and transcranial alternating current stimulation (tACS are being investigated as possible therapies. tDCS and tACS have the potential to influence the abnormal cortical-subcortical network activity that occurs in PD through sub-threshold changes in cortical excitability or through entrainment or disruption of ongoing rhythmic cortical activity. This may allow for the targeting of specific features of the disease involving abnormal oscillatory activity, as well as the enhancement of potential cortical compensation for basal ganglia dysfunction and modulation of cortical plasticity in neurorehabilitation. However, little is currently known about how cortical stimulation will affect subcortical structures, the size of any effect, and the factors of stimulation that will influence these effects.

  8. Formulaic Language in Parkinson's Disease and Alzheimer's Disease: Complementary Effects of Subcortical and Cortical Dysfunction

    Science.gov (United States)

    Van Lancker Sidtis, Diana; Choi, JiHee; Alken, Amy

    2015-01-01

    Purpose The production of formulaic expressions (conversational speech formulas, pause fillers, idioms, and other fixed expressions) is excessive in the left hemisphere and deficient in the right hemisphere and in subcortical stroke. Speakers with Alzheimer's disease (AD), having functional basal ganglia, reveal abnormally high proportions of formulaic language. Persons with Parkinson's disease (PD), having dysfunctional basal ganglia, were predicted to show impoverished formulaic expressions in contrast to speakers with AD. This study compared participants with PD, participants with AD, and healthy control (HC) participants on protocols probing production and comprehension of formulaic expressions. Method Spontaneous speech samples were recorded from 16 individuals with PD, 12 individuals with AD, and 18 HC speakers. Structured tests were then administered as probes of comprehension. Results The PD group had lower proportions of formulaic expressions compared with the AD and HC groups. Comprehension testing yielded opposite contrasts: participants with PD showed significantly higher performance compared with participants with AD and did not differ from HC participants. Conclusions The finding that PD produced lower proportions of formulaic expressions compared with AD and HC supports the view that subcortical nuclei modulate the production of formulaic expressions. Contrasting results on formal testing of comprehension, whereby participants with AD performed significantly worse than participants with PD and HC participants, indicate differential effects on procedural and declarative knowledge associated with these neurological conditions. PMID:26183940

  9. Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

    Science.gov (United States)

    Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

    2015-01-01

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

  10. Recreational marijuana use impacts white matter integrity and subcortical (but not cortical) morphometry.

    Science.gov (United States)

    Orr, Joseph M; Paschall, Courtnie J; Banich, Marie T

    2016-01-01

    A recent shift in legal and social attitudes toward marijuana use has also spawned a surge of interest in understanding the effects of marijuana use on the brain. There is considerable evidence that an adolescent onset of marijuana use negatively impacts white matter coherence. On the other hand, a recent well-controlled study demonstrated no effects of marijuana use on the morphometry of subcortical or cortical structures when users and non-users were matched for alcohol use. Regardless, most studies have involved small, carefully selected samples, so the ability to generalize to larger populations is limited. In an attempt to address this issue, we examined the effects of marijuana use on white matter integrity and cortical and subcortical morphometry using data from the Human Connectome Project (HCP) consortium. The HCP data consists of ultra-high resolution neuroimaging data from a large community sample, including 466 adults reporting recreational marijuana use. Rather than just contrasting two groups of individuals who vary significantly in marijuana usage as typifies prior studies, we leveraged the large sample size provided by the HCP data to examine parametric effects of recreational marijuana use. Our results indicate that the earlier the age of onset of marijuana use, the lower was white matter coherence. Age of onset also also affected the shape of the accumbens, while the number of lifetime uses impacted the shape of the amygdala and hippocampus. Marijuana use had no effect on cortical volumes. These findings suggest subtle but significant effects of recreational marijuana use on brain structure.

  11. [Left lateral gaze paresis due to subcortical hematoma in the right precentral gyrus].

    Science.gov (United States)

    Sato, K; Takamori, M

    1998-03-01

    We report a case of transient left lateral gaze paresis due to a hemorrhagic lesion restricted in the right precentral gyrus. A 74-year-old female experienced a sudden clumsiness of the left upper extremity. A neurological examination revealed a left central facial paresis, distal dominant muscle weakness in the left upper limb and left lateral gaze paresis. There were no other focal neurological signs. Laboratory data were all normal. Brain CTs and MRIs demonstrated a subcortical hematoma in the right precentral gyrus. The neurological symptoms and signs disappeared over seven days. A recent physiological study suggested that the human frontal eye field (FEF) is located in the posterior part of the middle frontal gyrus (Brodmann's area 8) and the precentral gyrus around the precentral sulcus. More recent studies stressed the role of the precentral sulcus and the precentral gyrus. Our case supports those physiological findings. The hematoma affected both the FEF and its underlying white matter in our case. We assume the lateral gaze paresis is attributable to the disruption of the fibers from the FEF. It is likely that fibers for motor control of the face, upper extremity, and lateral gaze lie adjacently in the subcortical area.

  12. Intraoperative Subcortical Electrical Mapping of the Optic Tract in Awake Surgery Using a Virtual Reality Headset.

    Science.gov (United States)

    Mazerand, Edouard; Le Renard, Marc; Hue, Sophie; Lemée, Jean-Michel; Klinger, Evelyne; Menei, Philippe

    2017-01-01

    Brain mapping during awake craniotomy is a well-known technique to preserve neurological functions, especially the language. It is still challenging to map the optic radiations due to the difficulty to test the visual field intraoperatively. To assess the visual field during awake craniotomy, we developed the Functions' Explorer based on a virtual reality headset (FEX-VRH). The impaired visual field of 10 patients was tested with automated perimetry (the gold standard examination) and the FEX-VRH. The proof-of-concept test was done during the surgery performed on a patient who was blind in his right eye and presenting with a left parietotemporal glioblastoma. The FEX-VRH was used intraoperatively, simultaneously with direct subcortical electrostimulation, allowing identification and preservation of the optic radiations. The FEX-VRH detected 9 of the 10 visual field defects found by automated perimetry. The patient who underwent an awake craniotomy with intraoperative mapping of the optic tract using the FEX-VRH had no permanent postoperative visual field defect. Intraoperative visual field assessment with the FEX-VRH during direct subcortical electrostimulation is a promising approach to mapping the optical radiations and preventing a permanent visual field defect during awake surgery for epilepsy or tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Intraosseous migration of tendinous calcifications: cortical erosions, subcortical migration and extensive intramedullary diffusion, a SIMS series

    Energy Technology Data Exchange (ETDEWEB)

    Malghem, Jacques; Omoumi, Patrick; Lecouvet, Frederic; Berg, Bruno vande [Universite Catholique de Louvain, Departement de radiologie et d' imagerie medicale, Bruxelles (Belgium)

    2015-10-15

    Calcium hydroxyapatite crystal deposition is a common disorder, which sometimes causes acute pain as calcifications dissolve and migrate into adjacent soft tissue. Intraosseous calcium penetration has also been described. We illustrate the appearance of these lesions using a series of 35 cases compiled by members of the French Society of Musculoskeletal Imaging (Societe d'Imagerie Musculo-Squelettique, SIMS). The first group in our series (7 cases) involved calcification-related cortical erosions of the humeral and femoral diaphyses, in particular at the pectoralis major and gluteus maximus insertions. A second group (28 cases) involved the presence of calcium material in subcortical areas. The most common site was the greater tubercle of the humerus, accompanying a calcifying tendinopathy of the supraspinatus. In addition, an extensive intramedullary diffusion of calcium deposits was observed in four of these cases, associated with cortical erosion in one case and subcortical lesions in three cases. Cortical erosions and intraosseous migration of calcifications associated with calcific tendinitis may be confused with neoplasm or infection. It is important to recognize atypical presentations of hydroxyapatite deposition to avoid unnecessary investigation or surgery. (orig.)

  14. Subcortical encoding of speech cues in children with attention deficit hyperactivity disorder.

    Science.gov (United States)

    Jafari, Zahra; Malayeri, Saeed; Rostami, Reza

    2015-02-01

    There is little information about processing of nonspeech and speech stimuli at the subcortical level in individuals with attention deficit hyperactivity disorder (ADHD). The auditory brainstem response (ABR) provides information about the function of the auditory brainstem pathways. We aim to investigate the subcortical function in neural encoding of click and speech stimuli in children with ADHD. The subjects include 50 children with ADHD and 34 typically developing (TD) children between the ages of 8 and 12 years. Click ABR (cABR) and speech ABR (sABR) with 40 ms synthetic /da/ syllable stimulus were recorded. Latencies of cABR in waves of III and V and duration of V-Vn (P⩽0.027), and latencies of sABR in waves A, D, E, F and O and duration of V-A (P⩽0.034) were significantly longer in children with ADHD than in TD children. There were no apparent differences in components the sustained frequency following response (FFR). We conclude that children with ADHD have deficits in temporal neural encoding of both nonspeech and speech stimuli. There is a common dysfunction in the processing of click and speech stimuli at the brainstem level in children with suspected ADHD. Copyright © 2015. Published by Elsevier Ireland Ltd.

  15. Progressively Disrupted Brain Functional Connectivity Network in Subcortical Ischemic Vascular Cognitive Impairment Patients.

    Science.gov (United States)

    Sang, Linqiong; Chen, Lin; Wang, Li; Zhang, Jingna; Zhang, Ye; Li, Pengyue; Li, Chuanming; Qiu, Mingguo

    2018-01-01

    Cognitive impairment caused by subcortical ischemic vascular disease (SIVD) has been elucidated by many neuroimaging studies. However, little is known regarding the changes in brain functional connectivity networks in relation to the severity of cognitive impairment in SIVD. In the present study, 20 subcortical ischemic vascular cognitive impairment no dementia patients (SIVCIND) and 20 dementia patients (SIVaD) were enrolled; additionally, 19 normal controls were recruited. Each participant underwent a resting-state functional MRI scan. Whole-brain functional networks were analyzed with graph theory and network-based statistics (NBS) to study the functional organization of networks and find alterations in functional connectivity among brain regions. After adjustments for age, gender, and duration of formal education, there were significant group differences for two network functional organization indices, global efficiency and local efficiency, which decreased (NC > SIVCIND > SIVaD) as cognitive impairment worsened. Between-group differences in functional connectivity (NBS corrected, p  impairment worsened, with an increased number of decreased connections between brain regions. We also observed more reductions in nodal efficiency in the prefrontal and temporal cortices for SIVaD than for SIVCIND. These findings indicated a progressively disrupted pattern of the brain functional connectivity network with increased cognitive impairment and showed promise for the development of reliable biomarkers of network metric changes related to cognitive impairment caused by SIVD.

  16. Subcortical encoding of sound is enhanced in bilinguals and relates to executive function advantages

    Science.gov (United States)

    Krizman, Jennifer; Marian, Viorica; Shook, Anthony; Skoe, Erika; Kraus, Nina

    2012-01-01

    Bilingualism profoundly affects the brain, yielding functional and structural changes in cortical regions dedicated to language processing and executive function [Crinion J, et al. (2006) Science 312:1537–1540; Kim KHS, et al. (1997) Nature 388:171–174]. Comparatively, musical training, another type of sensory enrichment, translates to expertise in cognitive processing and refined biological processing of sound in both cortical and subcortical structures. Therefore, we asked whether bilingualism can also promote experience-dependent plasticity in subcortical auditory processing. We found that adolescent bilinguals, listening to the speech syllable [da], encoded the stimulus more robustly than age-matched monolinguals. Specifically, bilinguals showed enhanced encoding of the fundamental frequency, a feature known to underlie pitch perception and grouping of auditory objects. This enhancement was associated with executive function advantages. Thus, through experience-related tuning of attention, the bilingual auditory system becomes highly efficient in automatically processing sound. This study provides biological evidence for system-wide neural plasticity in auditory experts that facilitates a tight coupling of sensory and cognitive functions. PMID:22547804

  17. Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect: a current preclinical & clinical perspective.

    Science.gov (United States)

    Mahmood, Danish

    2016-10-01

    Histamine H 3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H 3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia. These medications works through diverse mechanisms which include agonism at metabotropic glutamate receptor (mGluR2/3), partial agonism at dopamine D 2 , D 3 and serotonin 5-HT 1A receptors, antagonism at D 2 , 5-HT 2A, 5-HT 2B and 5-HT 7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo-dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H 3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H 3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H 3 receptors as a target of antiobesity

  18. Similar serotonin-2A receptor binding in rats with different coping styles or levels of aggression

    DEFF Research Database (Denmark)

    Visser, Anniek Kd; Ettrup, Anders; Klein, Anders Bue

    2015-01-01

    is not an important molecular marker for coping style. Since neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5-HT2A R is co-varying with levels of aggression or active avoidance in WTG, RHA and RLA. This article is protected by copyright. All...

  19. NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

    Science.gov (United States)

    Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R

    2014-12-01

    N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.

  20. Facilitation of acetylcholine release in rat frontal cortex by indeloxazine hydrochloride: involvement of endogenous serotonin and 5-HT4 receptors.

    Science.gov (United States)

    Yamaguchi, T; Suzuki, M; Yamamoto, M

    1997-12-01

    Effects of indeloxazine hydrochloride, an inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake with a facilitatory effect on 5-HT release, on acetylcholine (ACh) output in frontal cortex of conscious rats were characterized using an in vivo microdialysis technique. Systemic administration of indeloxazine (3 and 10 mg/kg, i.p.) increased ACh and 5-HT output in a dose-dependent manner. Depletion of endogenous monoamines by reserpine and of 5-HT by p-chlorophenylalanine, but not that of catecholamines by alpha-methyl-p-tyrosine, significantly attenuated the facilitatory effect of indeloxazine on ACh release. When applied locally by reverse dialysis, indeloxazine (10 and 30 microM) and the selective 5-HT reuptake inhibitor citalopram (10 microM), but not the NE reuptake inhibitor maprotiline (30 microM), increased cortical ACh output. Indeloxazine (10 mg/kg)-induced increase in ACh release was significantly inhibited by local application of the 5-HT4 receptor antagonists RS23597 (50 microM) and GR113803 (1 microM), while the 5-HT1A antagonist WAY-100135 (100 microM), 5-HT1A/1B/beta-adrenoceptor antagonist (-)propranolol (150 microM), 5-HT2A/2C antagonist ritanserin (10 microM) and 5-HT3 antagonist ondansetron (10 microM) failed to significantly modify this effect. Neither depletion of monoamines nor treatment with serotonergic antagonists significantly changed the basal ACh level, indicating that endogenous monoamines do not tonically activate ACh release. These results suggest that indeloxazine-induced facilitation of ACh release in rat frontal cortex is mediated by endogenous 5-HT and involves at least in part cortical 5-HT4 receptors.

  1. Magnetisation transfer measurements of the subcortical grey and white matter in Parkinson's disease with and without dementia and in progressive supranuclear palsy

    International Nuclear Information System (INIS)

    Hanyu, H.; Asano, T.; Sakurai, H.; Takasaki, M.; Shindo, H.; Abe, K.

    2001-01-01

    We measured the magnetisation transfer ratio (MTR) in the subcortical grey and white matter of 11 patients with idiopathic Parkinson's disease (PD) without dementia, six with PD with dementia (PDD), six with progressive supranuclear palsy (PSP), and 12 elderly control subjects to assess regional differences in structural brain damage. There were no significant differences in MTR in any region between PD and controls. However, patients with PDD had significantly lower MTR in the subcortical white matter, including the frontal white matter and the genu of the corpus callosum than the controls, whereas PSP had significantly lower MTR in the subcortical grey matter, including the putamen, globus pallidus and thalamus, in addition to the subcortical white matter. This suggests that regional patterns of structural brain damage can be detected using the magnetisation transfer technique. Measurement of MTR in the subcortical grey and white matter may be useful in differential diagnosis. (orig.)

  2. Longitudinal cognitive decline in subcortical ischemic vascular disease--the LADIS Study

    DEFF Research Database (Denmark)

    Jokinen, Hanna; Kalska, Hely; Ylikoski, Raija

    2009-01-01

    BACKGROUND: Cross-sectional studies have indicated that subcortical ischemic vascular disease (SIVD), as defined according to imaging criteria, is associated with a specific clinical and cognitive profile. Much less is known about the long-term cognitive consequences of SIVD. The aim of the study...... was to investigate the longitudinal cognitive performance and incident dementia in subjects with and without SIVD in a sample of older adults with white matter lesions. METHODS: In the Leukoaraiosis and Disability (LADIS) study, 639 participants were examined with annual clinical and neuropsychological evaluations...... for 3 years. The subjects meeting the MRI criteria of SIVD at baseline were compared to the other subjects of the sample with linear mixed models. RESULTS: The overall level of cognitive performance over the follow-up period was inferior in multiple cognitive domains in SIVD subjects as compared...

  3. Voluntary activation of ankle muscles is accompanied by subcortical facilitation of their antagonists

    DEFF Research Database (Denmark)

    Geertsen, Svend S.; Zuur, Abraham Theodoor; Nielsen, Jens B.

    2010-01-01

    Flexion and extension movements are organized reciprocally, so that extensor motoneurones in the spinal cord are inhibited when flexor muscles are active and vice versa. During and just prior to dorsiflexion of the ankle, soleus motoneurones are thus inhibited as evidenced by a depression......) or soleus muscle of the left ankle. TMS was applied to the hotspot of TA and soleus muscles on separate days. Stimuli were delivered prior to and at the beginning of contraction. Soleus MEPs were significantly facilitated when TMS was applied 50 ms prior to onset of plantar flexion. Surprisingly, soleus...... was increased prior to plantar flexion, but not prior to dorsiflexion. These findings suggest that voluntary contraction at the ankle is accompanied by preceding facilitation of antagonists by a subcortical motor programme. This may help to ensure that the direction of movement may be changed quickly...

  4. Language experience differentiates prefrontal and subcortical activation of the cognitive control network in novel word learning.

    Science.gov (United States)

    Bradley, Kailyn A L; King, Kelly E; Hernandez, Arturo E

    2013-02-15

    The purpose of this study was to examine the cognitive control mechanisms in adult English speaking monolinguals compared to early sequential Spanish-English bilinguals during the initial stages of novel word learning. Functional magnetic resonance imaging during a lexico-semantic task after only 2h of exposure to novel German vocabulary flashcards showed that monolinguals activated a broader set of cortical control regions associated with higher-level cognitive processes, including the supplementary motor area (SMA), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC), as well as the caudate, implicated in cognitive control of language. However, bilinguals recruited a more localized subcortical network that included the putamen, associated more with motor control of language. These results suggest that experience managing multiple languages may differentiate the learning strategy and subsequent neural mechanisms of cognitive control used by bilinguals compared to monolinguals in the early stages of novel word learning. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Subcortical heterotopia appearing as huge midline mass in the newborn brain.

    Science.gov (United States)

    Fukumura, Shinobu; Watanabe, Toshihide; Kimura, Sachiko; Ochi, Satoko; Yoshifuji, Kazuhisa; Tsutsumi, Hiroyuki

    2016-02-01

    We report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment. After birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass.

  6. Advanced structural multimodal imaging of a patient with subcortical band heterotopia.

    Science.gov (United States)

    Kini, Lohith G; Nasrallah, Ilya M; Coto, Carlos; Ferraro, Lindsay C; Davis, Kathryn A

    2016-12-01

    Subcortical band heterotopia (SBH) is a disorder of neuronal migration most commonly due to mutations of the Doublecortin (DCX) gene. A range of phenotypes is seen, with most patients having some degree of epilepsy and intellectual disability. Advanced diffusion and structural magnetic resonance imaging (MRI) sequences may be useful in identifying heterotopias and dysplasias of different sizes in drug-resistant epilepsy. We describe a patient with SBH and drug-resistant epilepsy and investigate neurite density, neurite dispersion, and diffusion parameters as compared to a healthy control through the use of multiple advanced MRI modalities. Neurite density and dispersion in heterotopia was found to be more similar to white matter than gray matter. Neurite density and dispersion maps obtained using diffusion imaging may be able to better characterize different subtypes of heterotopia.

  7. The human auditory brainstem response to running speech reveals a subcortical mechanism for selective attention.

    Science.gov (United States)

    Forte, Antonio Elia; Etard, Octave; Reichenbach, Tobias

    2017-10-10

    Humans excel at selectively listening to a target speaker in background noise such as competing voices. While the encoding of speech in the auditory cortex is modulated by selective attention, it remains debated whether such modulation occurs already in subcortical auditory structures. Investigating the contribution of the human brainstem to attention has, in particular, been hindered by the tiny amplitude of the brainstem response. Its measurement normally requires a large number of repetitions of the same short sound stimuli, which may lead to a loss of attention and to neural adaptation. Here we develop a mathematical method to measure the auditory brainstem response to running speech, an acoustic stimulus that does not repeat and that has a high ecological validity. We employ this method to assess the brainstem's activity when a subject listens to one of two competing speakers, and show that the brainstem response is consistently modulated by attention.

  8. Theory of mind, empathy and emotion perception in cortical and subcortical neurodegenerative diseases.

    Science.gov (United States)

    Fortier, J; Besnard, J; Allain, P

    2018-04-01

    Although the impact of neurodegenerative diseases on everyday interactions is well known in the literature, their impact on social cognitive processes remains unclear. The concept of social cognition refers to a set of skills, all of which are essential for living in a community. It involves social knowledge, perception and processing of social cues, and representation of mental states. This report is a review of recent findings on the impact of cortical and subcortical neurodegenerative diseases on three social cognitive processes, namely, the theory of mind, empathy and processing emotions. The focus here is on a conceptual approach to each of these skills and their cerebral underpinnings. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  9. An unusual case of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy with occipital lobe involvement.

    Science.gov (United States)

    Trikamji, Bhavesh; Thomas, Mariam; Hathout, Gasser; Mishra, Shrikant

    2016-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant angiopathy caused by a mutation in the notch 3 gene on chromosome 19. Clinically, patients may be asymptomatic or can present with recurrent ischemic episodes and strokes leading to dementia, depression, pseudobulbar palsy, and hemi- or quadraplegia. Additional manifestations that have been described include migraine (mostly with aura), psychiatric disturbances, and epileptic seizures. Neuroimaging is essential to the diagnosis of CADASIL. On imaging CADASIL is characterized by symmetric involvement by confluent lesions located subcortically in the frontal and temporal lobes as well as in the insula, periventricularly, in the centrum semiovale, in the internal and external capsule, basal ganglia, and brain stem; with relative sparing of the fronto-orbital and the occipital subcortical regions. We describe a 49 year old male with CADASIL with absence of temporal lobe findings on MRI but predominant lesions within the periventricular white matter, occipital lobes with extension into the subcortical frontal lobes, corpus callosum and cerebellar white matter. Although CADASIL characteristically presents with anterior temporal lobe involvement, these findings may be absent and our case addresses the atypical imaging findings in CADASIL.

  10. An unusual case of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy with occipital lobe involvement

    Directory of Open Access Journals (Sweden)

    Bhavesh Trikamji

    2016-01-01

    Full Text Available Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL is an autosomal dominant angiopathy caused by a mutation in the notch 3 gene on chromosome 19. Clinically, patients may be asymptomatic or can present with recurrent ischemic episodes and strokes leading to dementia, depression, pseudobulbar palsy, and hemi- or quadraplegia. Additional manifestations that have been described include migraine (mostly with aura, psychiatric disturbances, and epileptic seizures. Neuroimaging is essential to the diagnosis of CADASIL. On imaging CADASIL is characterized by symmetric involvement by confluent lesions located subcortically in the frontal and temporal lobes as well as in the insula, periventricularly, in the centrum semiovale, in the internal and external capsule, basal ganglia, and brain stem; with relative sparing of the fronto-orbital and the occipital subcortical regions. We describe a 49 year old male with CADASIL with absence of temporal lobe findings on MRI but predominant lesions within the periventricular white matter, occipital lobes with extension into the subcortical frontal lobes, corpus callosum and cerebellar white matter. Although CADASIL characteristically presents with anterior temporal lobe involvement, these findings may be absent and our case addresses the atypical imaging findings in CADASIL.

  11. The effect of duration of illness and antipsychotics on subcortical volumes in schizophrenia: Analysis of 778 subjects

    Directory of Open Access Journals (Sweden)

    Naoki Hashimoto

    2018-01-01

    Discussion: A large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication.

  12. Serial recording of median nerve stimulated subcortical somatosensory evoked potentials (SEPs) in developing brain death.

    Science.gov (United States)

    Buchner, H; Ferbert, A; Hacke, W

    1988-01-01

    Subcortical somatosensory evoked potentials (SEPs) to median nerve stimulation were recorded serially in 35 patients during the evolution towards brain death and in brain death. Neuropathological alterations of the central nervous system down to the C1/C2 spinal cord segment in brain death are well known. SEP components supposed to be generated above this level should be lost in brain death, while components generated below should not be altered. Erb's point, scalp and neck potentials were recorded at C3/4, or over the spinous process C7, using an Fz reference. In 10 patients additional montages, including spinous process C2-Fz, a non-cephalic reference (Fz-contralateral shoulder) and a posterior to anterior neck montage (spinous process C7-jugulum) were used. The cephalic referenced N9 and N11 peaks remained unchanged until brain death. N9 and N11 decreased in parallel in amplitude and increased in latency after systemic effects like hypoxia or hypothermia occurred. The cephalic referenced 'N14' decreased in amplitude and increased in latency after the clinical brain death syndrome was observed, while N13 in the posterior to anterior neck montage remained unchanged. The alteration of 'N14' went parallel to the decrease of the P14 amplitude. The subcortical SEPs in the cephalic referenced lead are supposed to be a peak composed by a horizontally orientated dorsal horn generated N13 and a rostrally orientated P14 arising at the level of the foramen magnum. The deterioration of the non-cephalic referenced P14 and of its cephalic referenced reflection 'N14' seems to provide an additional objective criterion for the diagnosis of brain death.

  13. Sustained Cortical and Subcortical Measures of Auditory and Visual Plasticity following Short-Term Perceptual Learning.

    Science.gov (United States)

    Lau, Bonnie K; Ruggles, Dorea R; Katyal, Sucharit; Engel, Stephen A; Oxenham, Andrew J

    2017-01-01

    Short-term training can lead to improvements in behavioral discrimination of auditory and visual stimuli, as well as enhanced EEG responses to those stimuli. In the auditory domain, fluency with tonal languages and musical training has been associated with long-term cortical and subcortical plasticity, but less is known about the effects of shorter-term training. This study combined electroencephalography (EEG) and behavioral measures to investigate short-term learning and neural plasticity in both auditory and visual domains. Forty adult participants were divided into four groups. Three groups trained on one of three tasks, involving discrimination of auditory fundamental frequency (F0), auditory amplitude modulation rate (AM), or visual orientation (VIS). The fourth (control) group received no training. Pre- and post-training tests, as well as retention tests 30 days after training, involved behavioral discrimination thresholds, steady-state visually evoked potentials (SSVEP) to the flicker frequencies of visual stimuli, and auditory envelope-following responses simultaneously evoked and measured in response to rapid stimulus F0 (EFR), thought to reflect subcortical generators, and slow amplitude modulation (ASSR), thought to reflect cortical generators. Enhancement of the ASSR was observed in both auditory-trained groups, not specific to the AM-trained group, whereas enhancement of the SSVEP was found only in the visually-trained group. No evidence was found for changes in the EFR. The results suggest that some aspects of neural plasticity can develop rapidly and may generalize across tasks but not across modalities. Behaviorally, the pattern of learning was complex, with significant cross-task and cross-modal learning effects.

  14. Subcortical processing of speech regularities underlies reading and music aptitude in children

    Science.gov (United States)

    2011-01-01

    Background Neural sensitivity to acoustic regularities supports fundamental human behaviors such as hearing in noise and reading. Although the failure to encode acoustic regularities in ongoing speech has been associated with language and literacy deficits, how auditory expertise, such as the expertise that is associated with musical skill, relates to the brainstem processing of speech regularities is unknown. An association between musical skill and neural sensitivity to acoustic regularities would not be surprising given the importance of repetition and regularity in music. Here, we aimed to define relationships between the subcortical processing of speech regularities, music aptitude, and reading abilities in children with and without reading impairment. We hypothesized that, in combination with auditory cognitive abilities, neural sensitivity to regularities in ongoing speech provides a common biological mechanism underlying the development of music and reading abilities. Methods We assessed auditory working memory and attention, music aptitude, reading ability, and neural sensitivity to acoustic regularities in 42 school-aged children with a wide range of reading ability. Neural sensitivity to acoustic regularities was assessed by recording brainstem responses to the same speech sound presented in predictable and variable speech streams. Results Through correlation analyses and structural equation modeling, we reveal that music aptitude and literacy both relate to the extent of subcortical adaptation to regularities in ongoing speech as well as with auditory working memory and attention. Relationships between music and speech processing are specifically driven by performance on a musical rhythm task, underscoring the importance of rhythmic regularity for both language and music. Conclusions These data indicate common brain mechanisms underlying reading and music abilities that relate to how the nervous system responds to regularities in auditory input

  15. Subcortical processing of speech regularities underlies reading and music aptitude in children

    Directory of Open Access Journals (Sweden)

    Strait Dana L

    2011-10-01

    Full Text Available Abstract Background Neural sensitivity to acoustic regularities supports fundamental human behaviors such as hearing in noise and reading. Although the failure to encode acoustic regularities in ongoing speech has been associated with language and literacy deficits, how auditory expertise, such as the expertise that is associated with musical skill, relates to the brainstem processing of speech regularities is unknown. An association between musical skill and neural sensitivity to acoustic regularities would not be surprising given the importance of repetition and regularity in music. Here, we aimed to define relationships between the subcortical processing of speech regularities, music aptitude, and reading abilities in children with and without reading impairment. We hypothesized that, in combination with auditory cognitive abilities, neural sensitivity to regularities in ongoing speech provides a common biological mechanism underlying the development of music and reading abilities. Methods We assessed auditory working memory and attention, music aptitude, reading ability, and neural sensitivity to acoustic regularities in 42 school-aged children with a wide range of reading ability. Neural sensitivity to acoustic regularities was assessed by recording brainstem responses to the same speech sound presented in predictable and variable speech streams. Results Through correlation analyses and structural equation modeling, we reveal that music aptitude and literacy both relate to the extent of subcortical adaptation to regularities in ongoing speech as well as with auditory working memory and attention. Relationships between music and speech processing are specifically driven by performance on a musical rhythm task, underscoring the importance of rhythmic regularity for both language and music. Conclusions These data indicate common brain mechanisms underlying reading and music abilities that relate to how the nervous system responds to

  16. Recreational marijuana use impacts white matter integrity and subcortical (but not cortical morphometry

    Directory of Open Access Journals (Sweden)

    Joseph M. Orr

    2016-01-01

    Full Text Available A recent shift in legal and social attitudes toward marijuana use has also spawned a surge of interest in understanding the effects of marijuana use on the brain. There is considerable evidence that an adolescent onset of marijuana use negatively impacts white matter coherence. On the other hand, a recent well-controlled study demonstrated no effects of marijuana use on the morphometry of subcortical or cortical structures when users and non-users were matched for alcohol use. Regardless, most studies have involved small, carefully selected samples, so the ability to generalize to larger populations is limited. In an attempt to address this issue, we examined the effects of marijuana use on white matter integrity and cortical and subcortical morphometry using data from the Human Connectome Project (HCP consortium. The HCP data consists of ultra-high resolution neuroimaging data from a large community sample, including 466 adults reporting recreational marijuana use. Rather than just contrasting two groups of individuals who vary significantly in marijuana usage as typifies prior studies, we leveraged the large sample size provided by the HCP data to examine parametric effects of recreational marijuana use. Our results indicate that the earlier the age of onset of marijuana use, the lower was white matter coherence. Age of onset also also affected the shape of the accumbens, while the number of lifetime uses impacted the shape of the amygdala and hippocampus. Marijuana use had no effect on cortical volumes. These findings suggest subtle but significant effects of recreational marijuana use on brain structure.

  17. Childhood maltreatment and combat posttraumatic stress differentially predict fear-related fronto-subcortical connectivity.

    Science.gov (United States)

    Birn, Rasmus M; Patriat, Rémi; Phillips, Mary L; Germain, Anne; Herringa, Ryan J

    2014-10-01

    Adult posttraumatic stress disorder (PTSD) has been characterized by altered fear-network connectivity. Childhood trauma is a major risk factor for adult PTSD, yet its contribution to fear-network connectivity in PTSD remains unexplored. We examined, within a single model, the contribution of childhood maltreatment, combat exposure, and combat-related posttraumatic stress symptoms (PTSS) to resting-state connectivity (rs-FC) of the amygdala and hippocampus in military veterans. Medication-free male veterans (n = 27, average 26.6 years) with a range of PTSS completed resting-state fMRI. Measures including the Clinician-Administered PTSD Scale (CAPS), Childhood Trauma Questionnaire (CTQ), and Combat Exposure Scale (CES) were used to predict rs-FC using multilinear regression. Fear-network seeds included the amygdala and hippocampus. Amygdala: CTQ predicted lower connectivity to ventromedial prefrontal cortex (vmPFC), but greater anticorrelation with dorsal/lateral PFC. CAPS positively predicted connectivity to insula, and loss of anticorrelation with dorsomedial/dorsolateral (dm/dl)PFC. Hippocampus: CTQ predicted lower connectivity to vmPFC, but greater anticorrelation with dm/dlPFC. CES predicted greater anticorrelation, whereas CAPS predicted less anticorrelation with dmPFC. Childhood trauma, combat exposure, and PTSS differentially predict fear-network rs-FC. Childhood maltreatment may weaken ventral prefrontal-subcortical circuitry important in automatic fear regulation, but, in a compensatory manner, may also strengthen dorsal prefrontal-subcortical pathways involved in more effortful emotion regulation. PTSD symptoms, in turn, appear to emerge with the loss of connectivity in the latter pathway. These findings suggest potential mechanisms by which developmental trauma exposure leads to adult PTSD, and which brain mechanisms are associated with the emergence of PTSD symptoms. © 2014 Wiley Periodicals, Inc.

  18. Cognitively Engaging Activity is Associated with Greater Cortical and Subcortical Volumes

    Directory of Open Access Journals (Sweden)

    Talia R. Seider

    2016-05-01

    Full Text Available As the population ages and dementia becomes a growing healthcare concern, it is increasingly important to identify targets for intervention to delay or attenuate cognitive decline. Research has shown that the most successful interventions aim at altering lifestyle factors. Thus, this study examined how involvement in physical, cognitive, and social activity is related to brain structure in older adults. Sixty-five adults (mean age = 71.4 years, standard deviation = 8.9 received the Community Healthy Activities Model Program for Seniors (CHAMPS, a questionnaire that polls everyday activities in which older adults may be involved, and also underwent structural magnetic resonance imaging. Stepwise regression with backwards selection was used to predict weekly time spent in either social, cognitive, light physical, or heavy physical activity from the volume of one of the cortical or subcortical regions of interest (corrected by intracranial volume as well as age, education, and gender as control variables. Regressions revealed that more time spent in cognitive activity was associated with greater volumes of all brain regions studied: total cortex (β = .289, p = .014, frontal (β = .276, p = .019, parietal (β = .305, p = .009, temporal (β = .275, p = .020, and occipital (β = .256, p = .030 lobes, and thalamus (β = .310, p = .010, caudate (β = .233, p = .049, hippocampus (β = .286, p = .017, and amygdala (β = .336, p = .004. These effects remained even after accounting for the positive association between cognitive activity and education. No other activity variable was associated with brain volumes. Results indicate that time spent in cognitively engaging activity is associated with greater cortical and subcortical brain volume. Findings suggest that interventions aimed at increasing levels of cognitive activity may delay cognitive consequences of aging and decrease the risk of developing dementia.

  19. Subcortical processing of speech regularities underlies reading and music aptitude in children.

    Science.gov (United States)

    Strait, Dana L; Hornickel, Jane; Kraus, Nina

    2011-10-17

    Neural sensitivity to acoustic regularities supports fundamental human behaviors such as hearing in noise and reading. Although the failure to encode acoustic regularities in ongoing speech has been associated with language and literacy deficits, how auditory expertise, such as the expertise that is associated with musical skill, relates to the brainstem processing of speech regularities is unknown. An association between musical skill and neural sensitivity to acoustic regularities would not be surprising given the importance of repetition and regularity in music. Here, we aimed to define relationships between the subcortical processing of speech regularities, music aptitude, and reading abilities in children with and without reading impairment. We hypothesized that, in combination with auditory cognitive abilities, neural sensitivity to regularities in ongoing speech provides a common biological mechanism underlying the development of music and reading abilities. We assessed auditory working memory and attention, music aptitude, reading ability, and neural sensitivity to acoustic regularities in 42 school-aged children with a wide range of reading ability. Neural sensitivity to acoustic regularities was assessed by recording brainstem responses to the same speech sound presented in predictable and variable speech streams. Through correlation analyses and structural equation modeling, we reveal that music aptitude and literacy both relate to the extent of subcortical adaptation to regularities in ongoing speech as well as with auditory working memory and attention. Relationships between music and speech processing are specifically driven by performance on a musical rhythm task, underscoring the importance of rhythmic regularity for both language and music. These data indicate common brain mechanisms underlying reading and music abilities that relate to how the nervous system responds to regularities in auditory input. Definition of common biological underpinnings

  20. Cortical thickness and subcortical brain volumes in professional rugby league players

    Directory of Open Access Journals (Sweden)

    Magdalena Wojtowicz

    Full Text Available Purpose: The purpose of this study was to examine cortical thickness and subcortical volumes in professional rugby players with an extensive history of concussions compared to control subjects. Method: Participants included 24 active and former professional rugby league players [Age M(SD = 33.3(6.3; Range = 21–44] with an extensive history of concussion and 18 age- and education-matched controls with no history of neurotrauma or participation in contact sports. Participants underwent T1-weighted imaging and completed a neuropsychological battery, including two tests of memory. Whole brain cortical thickness analysis and structural volume analysis was performed using FreeSurfer version 6.0. Results: Professional rugby league players reported greater alcohol consumption (p < .001 and had significantly worse delayed recall of a visually complex design (p = .04. They did not differ from controls on other clinical outcome measures. There were no differences in cortical thickness between the groups. Professional players had smaller whole brain (p = .003, bilateral hippocampi (ps = .03, and left amygdala volumes (p = .01 compared to healthy controls. Within the players group, there were significant associations between greater alcohol use and smaller bilateral hippocampi and left amygdala volumes. There were no associations between structural volumes and history of concussions or memory performance. Conclusions: The literature examining cortical thickness in athletes with a history of multiple concussions is mixed. We did not observe differences in cortical thickness in professional rugby league players compared to controls. However, smaller subcortical volumes were found in players that were, in part, associated with greater alcohol consumption. Keywords: Volumetric MRI, Cortical thickness, Concussion, Brain morphometry, Athletes, Rugby

  1. 3D fully convolutional networks for subcortical segmentation in MRI: A large-scale study.

    Science.gov (United States)

    Dolz, Jose; Desrosiers, Christian; Ben Ayed, Ismail

    2018-04-15

    This study investigates a 3D and fully convolutional neural network (CNN) for subcortical brain structure segmentation in MRI. 3D CNN architectures have been generally avoided due to their computational and memory requirements during inference. We address the problem via small kernels, allowing deeper architectures. We further model both local and global context by embedding intermediate-layer outputs in the final prediction, which encourages consistency between features extracted at different scales and embeds fine-grained information directly in the segmentation process. Our model is efficiently trained end-to-end on a graphics processing unit (GPU), in a single stage, exploiting the dense inference capabilities of fully CNNs. We performed comprehensive experiments over two publicly available datasets. First, we demonstrate a state-of-the-art performance on the ISBR dataset. Then, we report a large-scale multi-site evaluation over 1112 unregistered subject datasets acquired from 17 different sites (ABIDE dataset), with ages ranging from 7 to 64 years, showing that our method is robust to various acquisition protocols, demographics and clinical factors. Our method yielded segmentations that are highly consistent with a standard atlas-based approach, while running in a fraction of the time needed by atlas-based methods and avoiding registration/normalization steps. This makes it convenient for massive multi-site neuroanatomical imaging studies. To the best of our knowledge, our work is the first to study subcortical structure segmentation on such large-scale and heterogeneous data. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  3. Peripheral and spinal 5-HT receptors participate in the pronociceptive and antinociceptive effects of fluoxetine in rats.

    Science.gov (United States)

    Cervantes-Durán, C; Rocha-González, H I; Granados-Soto, V

    2013-11-12

    The role of 5-HT receptors in fluoxetine-induced nociception and antinociception in rats was assessed. Formalin produced a typical pattern of flinching and licking/lifting behaviors. Local peripheral ipsilateral, but not contralateral, pre-treatment with fluoxetine (0.3-3 nmol/paw) increased in a dose-dependent fashion 0.5% formalin-induced nociception. In contrast, intrathecal pretreatment with fluoxetine (0.3-3 nmol/rat) prevented nociception induced by formalin. The peripheral pronociceptive effect of fluoxetine was prevented by the 5-HT2A (ketanserin, 3-10 pmol/paw), 5-HT2B (3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4(1H,3H)-quinazolinedione(+) tartrate, RS-127445, 3-10 pmol/paw), 5-HT2C (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido) phenyl-5-oxopentyl]1,3,8-triazaspiro[4.5] decane-2,4-dione hydrochloride, RS-102221, 3-10 pmol/paw), 5-HT3 (ondansetron, 3-10 nmol/paw), 5-HT4 ([1-[2-methylsulphonylamino ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate, GR-113808, 3-100 fmol/paw), 5-HT6 (4-iodo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzene-sulfonamide hydrochloride, SB-258585, 3-10 pmol/paw) and 5-HT7 ((R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl) pyrrolidine-1-sulfonyl) phenol hydrochloride, SB-269970, 0.3-1 nmol/paw), but not by the 5-HT1A (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate, WAY-100635, 0.3-1 nmol/paw), 5-HT1B/1D (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl-4-carboxamide hydrochloride hydrate, GR-127935, 0.3-1 nmol/paw), 5-HT1B (1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine hydrochloride, SB-224289, 0.3-1 nmol/paw), 5-HT1D (4-(3-chlorophenyl)-α-(diphenylmethyl)-1-piperazineethanol hydrochloride, BRL-15572, 0.3-1nmol/paw) nor 5-HT5A ((N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4

  4. Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised trial.

    Science.gov (United States)

    Kirton, Adam; Chen, Robert; Friefeld, Sharon; Gunraj, Carolyn; Pontigon, Anne-Marie; Deveber, Gabrielle

    2008-06-01

    Arterial ischaemic stroke (AIS) can cause disabling hemiparesis in children. We aimed to test whether contralesional, inhibitory repetitive transcranial magnetic stimulation (rTMS) could affect interhemispheric inhibition to improve hand function in chronic subcortical paediatric AIS. Patients were eligible for this parallel, randomised trial if they were in the SickKids Children's Stroke Program and had subcortical AIS more than 2 years previously, had transcallosal sparing, were more than 7 years of age, had hand motor impairment, had no seizures or dyskinesia, and were taking no drugs that alter cortical excitability. Patients were paired for age and weakness and were randomised within each pair to sham treatment or inhibitory, low-frequency rTMS over contralesional motor cortex (20 min, 1200 stimuli) once per day for 8 days. An occupational therapist did standardised tests of hand function at days 1 (baseline), 5, 10, and 17 (1 week post-treatment), and the primary outcomes were changes in grip strength and the Melbourne assessment of upper extremity function (MAUEF) between baseline and day 10. Patients, parents, and occupational therapists were blinded to treatment allocation. Analysis was per protocol. Ten patients with paediatric stroke were enrolled (median age 13.25 [IQR 10.08-16.78] years, mean time post-stroke 6.33 [SD 3.56] years): four with mild weakness, two with moderate weakness, and four with severe weakness. A repeated-measures ANOVA showed a significant interaction between time and the effect of treatment on grip strength (p=0.03). At day 10, grip strength was 2.28 (SD 1.01) kg greater than baseline in the rTMS group and 2.92 (1.20) kg less than baseline in the sham group (p=0.009). Benefits in mean grip strength persisted at day 17 (2.63 [0.56] kg greater than baseline with rTMS and 1.00 [0.70] kg less than baseline with sham treatment; p=0.01). Day 10 MAUEF score improved by more in the rTMS group than in the sham group (7.25 [3.8] vs 0.79 [1

  5. Cortical and Subcortical Coordination of Visual Spatial Attention Revealed by Simultaneous EEG-fMRI Recording.

    Science.gov (United States)

    Green, Jessica J; Boehler, Carsten N; Roberts, Kenneth C; Chen, Ling-Chia; Krebs, Ruth M; Song, Allen W; Woldorff, Marty G

    2017-08-16

    Visual spatial attention has been studied in humans with both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) individually. However, due to the intrinsic limitations of each of these methods used alone, our understanding of the systems-level mechanisms underlying attentional control remains limited. Here, we examined trial-to-trial covariations of concurrently recorded EEG and fMRI in a cued visual spatial attention task in humans, which allowed delineation of both the generators and modulators of the cue-triggered event-related oscillatory brain activity underlying attentional control function. The fMRI activity in visual cortical regions contralateral to the cued direction of attention covaried positively with occipital gamma-band EEG, consistent with activation of cortical regions representing attended locations in space. In contrast, fMRI activity in ipsilateral visual cortical regions covaried inversely with occipital alpha-band oscillations, consistent with attention-related suppression of the irrelevant hemispace. Moreover, the pulvinar nucleus of the thalamus covaried with both of these spatially specific, attention-related, oscillatory EEG modulations. Because the pulvinar's neuroanatomical geometry makes it unlikely to be a direct generator of the scalp-recorded EEG, these covariational patterns appear to reflect the pulvinar's role as a regulatory control structure, sending spatially specific signals to modulate visual cortex excitability proactively. Together, these combined EEG/fMRI results illuminate the dynamically interacting cortical and subcortical processes underlying spatial attention, providing important insight not realizable using either method alone. SIGNIFICANCE STATEMENT Noninvasive recordings of changes in the brain's blood flow using functional magnetic resonance imaging and electrical activity using electroencephalography in humans have individually shown that shifting attention to a location in space

  6. ADN-1184 a monoaminergic ligand with 5-HT(6/7) receptor antagonist activity: pharmacological profile and potential therapeutic utility.

    Science.gov (United States)

    Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

    2014-02-01

    Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. ADN-1184 exhibits substantial 5-HT6 /5-HT7 /5-HT2A /D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg(-1) i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg(-1) i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg(-1) ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg(-1) i.p.). ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. © 2013 The British Pharmacological Society.

  7. ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility

    Science.gov (United States)

    Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

    2014-01-01

    Background and Purpose Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. Experimental Approach We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. Key Results ADN-1184 exhibits substantial 5-HT6/5-HT7/5-HT2A/D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg−1 i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg−1 i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg−1 ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg−1 i.p.). Conclusions and Implications ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. PMID:24199650

  8. Pathological generosity: an atypical impulse control disorder after a left subcortical stroke.

    Science.gov (United States)

    Ferreira-Garcia, Rafael; Fontenelle, Leonardo F; Moll, Jorge; de Oliveira-Souza, Ricardo

    2014-01-01

    Changes in socio-emotional behavior and conduct, which are characteristic symptoms of frontal lobe damage, have less often been described in patients with focal subcortical injuries. We report on a case of pathological generosity secondary to a left lenticulocapsular stroke with hypoperfusion of several anatomically intact cortical areas. A 49-year-old man developed excessive and persistent generosity as he recovered from a left lenticulocapsular hematoma. His symptoms resembled an impulse control disorder. (99m)Tc-HMPAO SPECT demonstrated hypoperfusion mostly in the ipsilateral striatum, dorsolateral, and orbitofrontal cortex. This case study adds pathological generosity to the range of behavioral changes that may result from discrete unilateral lesions of the lenticular nucleus and nearby pathways. In our particular case, post-stroke pathological generosity was not ascribable to disinhibition, apathy, mania, or depression. Because pathological generosity may lead to significant distress and financial burden upon patients and their families, it may warrant further consideration as a potential type of impulse control disorder.

  9. Cortical Thickness, Surface Area and Subcortical Volume Differentially Contribute to Cognitive Heterogeneity in Parkinson's Disease.

    Science.gov (United States)

    Gerrits, Niels J H M; van Loenhoud, Anita C; van den Berg, Stan F; Berendse, Henk W; Foncke, Elisabeth M J; Klein, Martin; Stoffers, Diederick; van der Werf, Ysbrand D; van den Heuvel, Odile A

    2016-01-01

    Parkinson's disease (PD) is often associated with cognitive deficits, although their severity varies considerably between patients. Recently, we used voxel-based morphometry (VBM) to show that individual differences in gray matter (GM) volume relate to cognitive heterogeneity in PD. VBM does, however, not differentiate between cortical thickness (CTh) and surface area (SA), which might be independently affected in PD. We therefore re-analyzed our cohort using the surface-based method FreeSurfer, and investigated (i) CTh, SA, and (sub)cortical GM volume differences between 93 PD patients and 45 matched controls, and (ii) the relation between these structural measures and cognitive performance on six neuropsychological tasks within the PD group. We found cortical thinning in PD patients in the left pericalcarine gyrus, extending to cuneus, precuneus and lingual areas and left inferior parietal cortex, bilateral rostral middle frontal cortex, and right cuneus, and increased cortical surface area in the left pars triangularis. Within the PD group, we found negative correlations between (i) CTh of occipital areas and performance on a verbal memory task, (ii) SA and volume of the frontal cortex and visuospatial memory performance, and, (iii) volume of the right thalamus and scores on two verbal fluency tasks. Our primary findings illustrate that i) CTh and SA are differentially affected in PD, and ii) VBM and FreeSurfer yield non-overlapping results in an identical dataset. We argue that this discrepancy is due to technical differences and the subtlety of the PD-related structural changes.

  10. Psychopathic traits are associated with cortical and subcortical volume alterations in healthy individuals.

    Science.gov (United States)

    Vieira, Joana B; Ferreira-Santos, Fernando; Almeida, Pedro R; Barbosa, Fernando; Marques-Teixeira, João; Marsh, Abigail A

    2015-12-01

    Research suggests psychopathy is associated with structural brain alterations that may contribute to the affective and interpersonal deficits frequently observed in individuals with high psychopathic traits. However, the regional alterations related to different components of psychopathy are still unclear. We used voxel-based morphometry to characterize the structural correlates of psychopathy in a sample of 35 healthy adults assessed with the Triarchic Psychopathy Measure. Furthermore, we examined the regional grey matter alterations associated with the components described by the triarchic model. Our results showed that, after accounting for variation in total intracranial volume, age and IQ, overall psychopathy was negatively associated with grey matter volume in the left putamen and amygdala. Additional regression analysis with anatomical regions of interests revealed total triPM score was also associated with increased lateral orbitofrontal cortex (OFC) and caudate volume. Boldness was positively associated with volume in the right insula. Meanness was positively associated with lateral OFC and striatum volume, and negatively associated with amygdala volume. Finally, disinhibition was negatively associated with amygdala volume. Results highlight the contribution of both subcortical and cortical brain alterations for subclinical psychopathy and are discussed in light of prior research and theoretical accounts about the neurobiological bases of psychopathic traits. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  11. NEUROPSI battery subtest profile in subcortical vascular dementia and Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Maria Niures P.S. Matioli

    Full Text Available ABSTRACT Objective: To investigate the diagnostic value of subtests of the NEUROPSI battery for differentiating subcortical vascular dementia (SVaD from Alzheimer's disease (AD. Methods: Thirteen patients with mild SVaD, 15 patients with mild probable AD, and 30 healthy controls, matched for age, education and dementia severity (in the case of patients, were submitted to the Mini-Mental State Examination (MMSE and NEUROPSI battery. The performance of AD and SVaD groups on NEUROPSI subtests was compared. The statistical analyses were performed using Kruskal-Wallis, Chi-square and Mann-Whitney tests. The results were interpreted at the 5% significance level (p<0.05. Bonferroni's correction was applied to multiple comparisons (a=0.02. Results: SVaD and AD patients showed no statistical difference in MMSE scores (SVaD=20.8 and AD=21.0; p=1.0 or in NEUROPSI total score (SVaD=65.0 and AD=64.3; p=0.56, suggesting a similar severity of dementia. The AD group performed worse on memory recall (<0.01 and SVaD group was worse in verbal fluency subtests (p=0.02. Conclusion: NEUROPSI's memory and language subtests can be an auxiliary tool for differentiating SVaD from AD.

  12. Frequency and Predictors of Dysphagia in Patients With Recent Small Subcortical Infarcts.

    Science.gov (United States)

    Fandler, Simon; Gattringer, Thomas; Eppinger, Sebastian; Doppelhofer, Kathrin; Pinter, Daniela; Niederkorn, Kurt; Enzinger, Christian; Wardlaw, Joanna M; Fazekas, Franz

    2017-01-01

    Detailed data on the occurrence of swallowing dysfunction in patients with recent small subcortical infarcts (RSSI) in the context of cerebral small vessel disease are lacking. This prompted us to assess the frequency of and risk factors for dysphagia in RSSI patients. We identified all inpatients with magnetic resonance imaging-confirmed RSSI between January 2008 and February 2013. Demographic and clinical data were extracted from our stroke database, and magnetic resonance imaging scans were reviewed for morphological changes. Dysphagia was determined according to the Gugging Swallowing Screen. We identified 332 patients with RSSI (mean age, 67.7±11.9 years; 64.5% male). Overall, 83 patients (25%) had dysphagia, which was mild in 46 (55.4%), moderate in 26 (31.3%), and severe in 11 patients (13.3%). The rate of dysphagia in patients with supratentorial RSSI was 20%. Multivariate analysis identified a higher National Institutes of Health Stroke Scale score (PDysphagia is present in a quarter of patients with RSSI and has to be expected especially in those with higher stroke severity, pontine infarction, and severe white matter hyperintensities. © 2016 American Heart Association, Inc.

  13. Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism.

    Science.gov (United States)

    Kim, Yongsoo; Yang, Guangyu Robert; Pradhan, Kith; Venkataraju, Kannan Umadevi; Bota, Mihail; García Del Molino, Luis Carlos; Fitzgerald, Greg; Ram, Keerthi; He, Miao; Levine, Jesse Maurica; Mitra, Partha; Huang, Z Josh; Wang, Xiao-Jing; Osten, Pavel

    2017-10-05

    The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Disturbances in the positioning, proliferation, and apoptosis of neural progenitors contribute to subcortical band heterotopia formation

    Science.gov (United States)

    Fitzgerald, MP; Covio, M; Lee, KS

    2011-01-01

    Cortical malformations are commonly associated with intractable epilepsy and other developmental disorders. Our studies utilize the tish rat, a spontaneously occurring genetic model of subcortical band heterotopia (SBH) associated with epilepsy, to evaluate the developmental events underlying SBH formation in the neocortex. Our results demonstrate that Pax6+ and Tbr2+ progenitors are mislocalized in tish+/− and tish−/− neocortex throughout neurogenesis. In addition, mislocalized tish−/− progenitors possess a longer cell cycle than wildtype or normally-positioned tish−/− progenitors, owing to a lengthened G2+M+G1 time. This mislocalization is not associated with adherens junction breakdown or loss of radial glial polarity in the ventricular zone, as assessed by immunohistochemistry against phalloidin (to identify F-actin), aPKC-λ, and Par3. However, vimentin immunohistochemistry indicates that the radial glial scaffold is disrupted in the region of the tish−/− heterotopia. Moreover, lineage tracing experiments using in utero electroporation in tish−/− neocortex demonstrate that mislocalized progenitors do not retain contact with the ventricular surface and that ventricular/subventricular zone progenitors produce neurons that migrate into both the heterotopia and cortical plate. Taken together, these findings define a series of developmental errors contributing to SBH formation that differs fundamentally from a primary error in neuronal migration. PMID:21145942

  15. A Novel Missense Mutation of Doublecortin: Mutation Analysis of Korean Patients with Subcortical Band Heterotopia

    Science.gov (United States)

    Kim, Myeong-Kyu; Park, Man-Seok; Kim, Byeong-Chae; Cho, Ki-Hyun; Kim, Young-Seon; Kim, Jin-Hee; Heo, Tag; Kim, Eun-Young

    2005-01-01

    The neuronal migration disorders, X-linked lissencephaly syndrome (XLIS) and subcortical band heterotopia (SBH), also called "double cortex", have been linked to missense, nonsense, aberrant splicing, deletion, and insertion mutations in doublecortin (DCX) in families and sporadic cases. Most DCX mutations identified to date are located in two evolutionarily conserved domains. We performed mutation analysis of DCX in two Korean patients with SBH. The SBH patients had mild to moderate developmental delays, drug-resistant generalized seizures, and diffuse thick SBH upon brain MRI. Sequence analysis of the DCX coding region in Patient 1 revealed a c.386 C>T change in exon 3. The sequence variation results in a serine to leucine amino acid change at position 129 (S129L), which has not been found in other family members of Patient 1 or in a large panel of 120 control X-chromosomes. We report here a novel c.386 C>T mutation of DCX that is responsible for SBH. PMID:16100463

  16. MR volumetric measurement of medial temporal lobe in differentiating Alzheimer disease and subcortical ischemic vascular dementia

    International Nuclear Information System (INIS)

    Wang Liang; Li Kuncheng; Liu Shuliang

    2003-01-01

    Objective: To evaluate the value of measurement of medial temporal structure by MR imaging volumetry in the differential diagnosis for patients with Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD). Methods: Thirty-three probable patients of AD, 33 normal controls, and 17 patients suspected with SIVD had been scanned by MRI, and volumetric measurements of amygdala (AMY), hippocampal formations (HF), entorhinal cortices (EC), parahippocampal gyri (PHG), and temporal horn of lateral ventricle (TH) were done on a serial reconstructed MR images. Results: Both atrophy of HF and dilatation of TH were significant (P<0.05) in SIVD group compared with that in control group. All the measurements with the exception of TH were atrophied significantly (P<0.001) in AD group compared with that in SIVD group and could significantly discriminate the two group. Among these indexes, the left EC provided the best discrimination with the specificity of 82.4%, sensitivity of 87.9%, and accuracy of 86.0%, respectively, and the average accuracy of bilateral EC in discrimination was 85%. Conclusion: The MR imaging volumetric measurements of medial temporal structure could offer useful information in discriminating individuals with AD from that with SIVD. Meanwhile, it should be understood that the AD-type pathological changes could also be induced by cerebrovascular disease

  17. Neuropsychological Profiles Differentiate Alzheimer Disease from Subcortical Ischemic Vascular Dementia in an Autopsy-Defined Cohort.

    Science.gov (United States)

    Ramirez-Gomez, Liliana; Zheng, Ling; Reed, Bruce; Kramer, Joel; Mungas, Dan; Zarow, Chris; Vinters, Harry; Ringman, John M; Chui, Helena

    2017-01-01

    The aim of this study was to assess the ability of neuropsychological tests to differentiate autopsy-defined Alzheimer disease (AD) from subcortical ischemic vascular dementia (SIVD). From a sample of 175 cases followed longitudinally that underwent autopsy, we selected 23 normal controls (NC), 20 SIVD, 69 AD, and 10 mixed cases of dementia. Baseline neuropsychological tests, including Memory Assessment Scale word list learning test, control oral word association test, and animal fluency, were compared between the three autopsy-defined groups. The NC, SIVD, and AD groups did not differ by age or education. The SIVD and AD groups did not differ by the Global Clinical Dementia Rating Scale. Subjects with AD performed worse on delayed recall (p < 0.01). A receiver operating characteristics analysis comparing the SIVD and AD groups including age, education, difference between categorical (animals) versus phonemic fluency (letter F), and the first recall from the word learning test distinguished the two groups with a sensitivity of 85%, specificity of 67%, and positive likelihood ratio of 2.57 (AUC = 0.789, 95% CI 0.69-0.88, p < 0.0001). In neuropathologically defined subgroups, neuropsychological profiles have modest ability to distinguish patients with AD from those with SIVD. © 2017 S. Karger AG, Basel.

  18. Vitamin D, Homocysteine, and Folate in Subcortical Vascular Dementia and Alzheimer Dementia.

    Science.gov (United States)

    Moretti, Rita; Caruso, Paola; Dal Ben, Matteo; Conti, Corrado; Gazzin, Silvia; Tiribelli, Claudio

    2017-01-01

    Dementia is a worldwide health problem which affects millions of patients; Alzheimer's disease (AD) and subcortical vascular dementia (sVAD) are the two most frequent forms of its presentation. As no definite therapeutic options have been discovered, different risk factors for cognitive impairment have been searched for potential therapies. This report focuses on the possible evidence that vitamin D deficiency and hyper-homocysteinemia can be considered as two important factors for the development or the progression of neurodegenerative or vascular pathologies. To this end, we assessed: the difference in vascular risk factors and vitamin D-OH25 levels among groups of sVAD, AD, and healthy age-matched controls; the association of folate, B12, homocysteine, and vitamin D with sVAD/AD and whether a deficiency of vitamin D and an increment in homocysteine levels may be related to neurodegenerative or vessel damages. The commonly-considered vascular risk factors were collected in 543 patients and compared with those obtained from a healthy old volunteer population. ANOVA group comparison showed that vitamin D deficiency was present in demented cases, as well as low levels of folate and high levels of homocysteine, more pronounced in sVAD cases. The statistical models we employed, with regression models built, and adjustments for biochemical, demographic and neuropsychiatric scores, confirmed the association between the three measures (folate decrease, hyperhomocysteinemia and vitamin D decrease) and dementia, more pronounced in sVAD than in AD.

  19. Altered Spontaneous Brain Activity in Cortical and Subcortical Regions in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Jie Xiang

    2016-01-01

    Full Text Available Purpose. The present study aimed to explore the changes of amplitude of low-frequency fluctuations (ALFF at rest in patients with Parkinson’s disease (PD. Methods. Twenty-four PD patients and 22 healthy age-matched controls participated in the study. ALFF was measured on the whole brain of all participants. A two-sample t-test was then performed to detect the group differences with age, gender, education level, head motion, and gray matter volume as covariates. Results. It was showed that PD patients had significantly decreased ALFF in the left thalamus/caudate and right insula/inferior prefrontal gyrus, whereas they had increased ALFF in the right medial prefrontal cortex (BA 8/6 and dorsolateral prefrontal cortex (BA 9/10. Conclusions. Our results indicated that significant alterations of ALFF in the subcortical regions and prefrontal cortex have been detected in PD patients, independent of age, gender, education, head motion, and structural atrophy. The current findings further provide insights into the biological mechanism of the disease.

  20. Cortical and subcortical hyperfusion during migraine and cluster headache measured by Xe CT-CBF

    International Nuclear Information System (INIS)

    Kobari, M.; Meyer, J.S.; Ichijo, M.; Kawamura, J.; Baylor Univ., Houston, TX

    1990-01-01

    High-resolution, color-coded images of local cerebral blood flow (LCBF) were made utilizing stable xenon-enhanced computed tomography among patients with common migraine (n=18), classic migraine (n=12) and cluster headache (n=5). During spontaneously occurring headache in common and classic migraine patients, LCBF values for cerebral cortex and subcortical gray and white matter were diffusely increased by 20-40% with the exception of the occipital lobes. LCBF increases involved both hemispheres whether the head pain was unilateral or bilateral. No significant differences were noted in the degree or pattern of LCBF increases during headaches of common and classic migraineurs. Similar cerebral hyperperfusion of greater magnitude was observed during cluster headaches but was more prominent on the side of the head pain. Present observations do not support the hypothesis of spreading cortical depression as a cause of classic migraine. From a hemodynamic viewpoint, LCBF increases during headaches of common or classic migraine or cluster appear similar. Evidence is adduced that sympathetic hypofunction with denervation hypersensitivity of cerebral vessels plays a role in the cerebral hyperperfusion of migraine headaches. More pronounced unilateral autonomic derangements appear to account for the symptoms and cerebral hyperperfusion associated with cluster headaches. (orig.)

  1. Subcortical cerebral blood flow and metabolic changes elicited by cortical spreading depression in rat

    Energy Technology Data Exchange (ETDEWEB)

    Mraovitch, S.; Calando, Y.; Goadsby, P.J.; Seylaz, J. (Laboratoire de Recherches Cerebrovasculaire, Paris (France))

    1992-06-01

    Changes in cerebral cortical perfusion (CBF{sub LDF}), local cerebral blood flow (lCBF) and local cerebral glucose utilization (lCGU) elicited by unilateral cortical spreading depression (SD) were monitored and measured in separate groups of rats anesthetized with {alpha}-chloralose. CBF{sub LDF} was recorded with laser Doppler flowmetry, while lCBF and lCGU were measured by the quantitative autoradiographic ({sup 14}C)iodoantipyrine and ({sup 14}C)-2-deoxyglucose methods, respectively. SD elicited a wave of hyperemia after a latency of 2 to 3 min followed by an oligemic phase. Ninety minutes following the onset of SD cortical lCBF and lCGU were essentially the same as on the contralateral side and in sham-treated rats. However, alteration in the lCBF and lCGU in upper and lower brainstem persisted. The present results demonstrate that long-lasting cerebrovascular and metabolic alterations take place within the subcortical regions following SD. These regions provide an attractive site to integrate observations in man concerning spreading depression and the aura of migraine with the other features of the syndrome. 19 refs., 2 figs., 1 tab.

  2. Screening for New Biomarkers for Subcortical Vascular Dementia and Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Annika Öhrfelt

    2011-01-01

    Full Text Available Background: Novel biomarkers are important for identifying as well as differentiating subcortical vascular dementia (SVD and Alzheimer’s disease (AD at an early stage in the disease process. Methods: In two independent cohorts, a multiplex immunoassay was utilized to analyze 90 proteins in cerebrospinal fluid (CSF samples from dementia patients and patients at risk of developing dementia (mild cognitive impairment. Results: The levels of several CSF proteins were increased in SVD and its incipient state, and in moderate-to-severe AD compared with the control group. In contrast, some CSF proteins were altered in AD, but not in SVD. The levels of heart-type fatty acid binding protein (H-FABP were consistently increased in all groups with dementia but only in some of their incipient states. Conclusions: In summary, these results support the notion that SVD and AD are driven by different pathophysiological mechanisms reflected in the CSF protein profile and that H-FABP in CSF is a general marker of neurodegeneration.

  3. Training conquers multitasking costs by dividing task representations in the frontoparietal-subcortical system.

    Science.gov (United States)

    Garner, K G; Dux, Paul E

    2015-11-17

    Negotiating the information-rich sensory world often requires the concurrent management of multiple tasks. Despite this requirement, humans are thought to be poor at multitasking because of the processing limitations of frontoparietal and subcortical (FP-SC) brain regions. Although training is known to improve multitasking performance, it is unknown how the FP-SC system functionally changes to support improved multitasking. To address this question, we characterized the FP-SC changes that predict training outcomes using an individual differences approach. Participants (n = 100) performed single and multiple tasks in pre- and posttraining magnetic resonance imaging (fMRI) sessions interspersed by either a multitasking or an active-control training regimen. Multivoxel pattern analyses (MVPA) revealed that training induced multitasking improvements were predicted by divergence in the FP-SC blood oxygen level-dependent (BOLD) response patterns to the trained tasks. Importantly, this finding was only observed for participants who completed training on the component (single) tasks and their combination (multitask) and not for the control group. Therefore, the FP-SC system supports multitasking behavior by segregating constituent task representations.

  4. Disrupted topological organization of resting-state functional brain network in subcortical vascular mild cognitive impairment.

    Science.gov (United States)

    Yi, Li-Ye; Liang, Xia; Liu, Da-Ming; Sun, Bo; Ying, Sun; Yang, Dong-Bo; Li, Qing-Bin; Jiang, Chuan-Lu; Han, Ying

    2015-10-01

    Neuroimaging studies have demonstrated both structural and functional abnormalities in widespread brain regions in patients with subcortical vascular mild cognitive impairment (svMCI). However, whether and how these changes alter functional brain network organization remains largely unknown. We recruited 21 patients with svMCI and 26 healthy control (HC) subjects who underwent resting-state functional magnetic resonance imaging scans. Graph theory-based network analyses were used to investigate alterations in the topological organization of functional brain networks. Compared with the HC individuals, the patients with svMCI showed disrupted global network topology with significantly increased path length and modularity. Modular structure was also impaired in the svMCI patients with a notable rearrangement of the executive control module, where the parietal regions were split out and grouped as a separate module. The svMCI patients also revealed deficits in the intra- and/or intermodule connectivity of several brain regions. Specifically, the within-module degree was decreased in the middle cingulate gyrus while it was increased in the left anterior insula, medial prefrontal cortex and cuneus. Additionally, increased intermodule connectivity was observed in the inferior and superior parietal gyrus, which was associated with worse cognitive performance in the svMCI patients. Together, our results indicate that svMCI patients exhibit dysregulation of the topological organization of functional brain networks, which has important implications for understanding the pathophysiological mechanism of svMCI. © 2015 John Wiley & Sons Ltd.

  5. Effects of social adversity and HIV on subcortical shape and neurocognitive function.

    Science.gov (United States)

    Thames, April D; Kuhn, Taylor P; Mahmood, Zanjbeel; Bilder, Robert M; Williamson, Timothy J; Singer, Elyse J; Arentoft, Alyssa

    2018-02-01

    The purpose of the current study was to examine the independent and interactive effects of social adversity (SA) and HIV infection on subcortical shape alterations and cognitive functions. Participants included HIV+ (n = 70) and HIV- (n = 23) individuals who underwent MRI, neurocognitive and clinical assessment, in addition to completing questionnaires from which responses were used to create an SA score. Bilateral amygdalae and hippocampi were extracted from T1-weighted images. Parametric statistical analyses were used to compare the radial distance of the structure surface to a median curve to determine the presence of localized shape differences as a function of HIV, SA and their interaction. Next, multiple regression was used to examine the interactive association between HIV and SA with cognitive performance data. An HIV*SA interactive effect was found on the shape of the right amygdala and left hippocampus. Specifically, HIV-infected participants (but not HIV-uninfected controls) who evidenced higher levels of SA displayed an inward deformation of the surface consistent with reduced volume of these structures. We found interactive effects of HIV and SA on learning/memory performance. These results suggest that HIV+ individuals may be more vulnerable to neurological and cognitive changes in the hippocampus and amygdala as a function of SA than HIV- individuals, and that SA indicators of childhood SES and perceived racial discrimination are important components of adversity that are associated with cognitive performance.

  6. A translational study on looming-evoked defensive response and the underlying subcortical pathway in autism.

    Science.gov (United States)

    Hu, Yu; Chen, Zhuoming; Huang, Lu; Xi, Yue; Li, Bingxiao; Wang, Hong; Yan, Jiajian; Lee, Tatia M C; Tao, Qian; So, Kwok-Fai; Ren, Chaoran

    2017-11-07

    Rapidly approaching objects indicating threats can induce defensive response through activating a subcortical pathway comprising superior colliculus (SC), lateral posterior nucleus (LP), and basolateral amygdala (BLA). Abnormal defensive response has been reported in autism, and impaired synaptic connections could be the underlying mechanism. Whether the SC-LP-BLA pathway processes looming stimuli abnormally in autism is not clear. Here, we found that looming-evoked defensive response is impaired in a subgroup of the valproic acid (VPA) mouse model of autism. By combining the conventional neurotracer and transneuronal rabies virus tracing techniques, we demonstrated that synaptic connections in the SC-LP-BLA pathway were abnormal in VPA mice whose looming-evoked defensive responses were absent. Importantly, we further translated the finding to children with autism and observed that they did not present looming-evoked defensive response. Furthermore, the findings of the DTI with the probabilistic tractography showed that the structural connections of SC-pulvinar-amygdala in autism children were weak. The pulvinar is parallel to the LP in a mouse. Because looming-evoked defensive response is innate in humans and emerges much earlier than do social and language functions, the absence of defensive response could be an earlier sign of autism in children.

  7. Periventricular nodular and subcortical neuronal heterotopia in adult epileptic patients Heterotopía neuronal nodular y subcortical en pacientes adultos con epilepsia

    Directory of Open Access Journals (Sweden)

    Damián E. Consalvo

    2006-04-01

    Full Text Available Developmental malformations are brain abnormalities that occur during embryogenesis. Neuronal migration disorders, including heterotopic lesions, constitute one type of such abnormalities. The aim of the study was to compare the epileptic clinical patterns of patients with periventricular nodular heterotopia (PNH (G1 with those affected by subcortical heterotopia (SCH (G2 looking for differences between both groups which, eventually, might suggest the type of the underlying malformation. The variables studied in both groups were: type of the heterotopia depicted on MRI studies, sex, age, age at seizure onset, annual seizure frequency, localization of the ictal symptomatogenic zone, characteristics of the EEG, other associated anomalies on the magnetic resonance images (MRI besides the heterotopia, and response to treatment. The only difference found between both groups was the type of heterotopia as shown by MRI studies. The other assessed variables did not significantly (p>0.05 differ between groups. No differences in the clinical features characterizing epilepsy could be found in patients with PNH or SCH, being the images the only tool able to differentiate them.Las malformaciones de la corteza cerebral son un grupo de entidades que se producen durante las etapas del desarrollo embrionario y cuya manifestación clínica puede ser la epilepsia. Estas malformaciones pueden ser diagnosticadas in vivo a través de las imágenes por resonancia magnética (IRM. Un subtipo particular de éstas lo constituyen los trastornos en la migración neuronal, dentro de los cuales se ubican las heterotopías (HT. El objetivo del estudio fue comparar enfermos portadores de HT periventriculares (G1 con aquellos portadores de HT subcorticales (G2. Se analizaron las variables sexo, edad y edad de inicio de la epilepsia (EI en años, antecedentes familiares (AF o prenatales (AP, frecuencia anual de crisis (FAC y características semiológicas de las crisis

  8. Executive function assessment in patients with subcortical cerebral infarction using the Trail Making Test and Wisconsin Card Sorting Test

    International Nuclear Information System (INIS)

    Niiyama, Kazuhide; Hasegawa, Akira; Kato, Haruhisa; Umesato, Naoyuki; Utsumi, Hiroya

    2008-01-01

    To assess executive function in patients with subcortical cerebral infarctions, we implemented a Trail Making Test (TMT) and Wisconsin Card Sorting Test (WCST). We recruited 19 patients who had subcortical cerebral infarction on magnetic resonance images (MRI). The patients were classified into two categories depending on the degree of deep white matter hyperintensity (DWMH) on MRI. On comparing MRI and pathological findings, the punctate DWMH was not associated with infarction, but large confluent DWMH suggests subcortical ischemia. On this basis, the low grade DWMH group consisted of 12 patients with punctate foci, and seven patients with large confluent areas were classified in the high grade DWMH group. All patients were right-handed and without symptomatic hemiparesis. To exclude demented patients, cognitive function was examined. The vascular lesions were confirmed by brain magnetic resonance angiography and ultrasonography of the carotid arteries, and we excluded patients with severe stenotic or occlusive vascular lesions in cerebral or carotid arteries. On TMT, we analyzed the time required for Part A and Part B, and the difference in time required (required time difference). We also subtracted the time required for Part A form that required for Part B. To exclude the influence of potential hemiparesis, we also calculated the time required ratio expressed as follows; time required for Part B/time required for Part A. There was no significant increase in the time required for Part A, but we found significant increase in the time required for Part B, the required time difference and the required time ratio in the high grade DWMH group. There was no significant difference on WCST. On pathological examination in normal elderly subjects, punctate foci can be found, but not large confluent DWMH. In this study, we found that patients with severe DWMH may have impaired executive functions. These results might be induced by the pathological features of subcortical

  9. Association between exercise habits and subcortical gray matter volumes in healthy elderly people: A population-based study in Japan.

    Science.gov (United States)

    Yamamoto, Mikie; Wada-Isoe, Kenji; Yamashita, Fumio; Nakashita, Satoko; Kishi, Masafumi; Tanaka, Kenichiro; Yamawaki, Mika; Nakashima, Kenji

    2017-06-01

    The relationship between exercise and subcortical gray matter volume is not well understood in the elderly population, although reports indicate that exercise may prevent cortical gray matter atrophy. To elucidate this association in the elderly, we measured subcortical gray matter volume and correlated this with volumes to exercise habits in a community-based cohort study in Japan. Subjects without mild cognitive impairment or dementia (n = 280, 35% male, mean age 73.1 ± 5.9 years) were evaluated using the Mini-Mental State Examination (MMSE), an exercise habit questionnaire, and brain magnetic resonance imaging. Subcortical gray matter volume was compared between groups based on the presence/absence of exercise habits. The MMSE was re-administered 3 years after the baseline examination. Ninety-one subjects (32.5%) reported exercise habits (exercise group), and 189 subjects (67.5%) reported no exercise habits (non-exercise group). Volumetric analysis revealed that the volumes in the exercise group were greater in the left hippocampus (p = 0.042) and bilateral nucleus accumbens (left, p = 0.047; right, p = 0.007) compared to those of the non-exercise group. Among the 195 subjects who received a follow-up MMSE examination, the normalized intra-cranial volumes of the left nucleus accumbens (p = 0.004) and right amygdala (p = 0.014)showed significant association with a decline in the follow-up MMSE score. Subjects with exercise habits show larger subcortical gray matter volumes than subjects without exercise habits in community-dwelling elderly subjects in Japan. Specifically, the volume of the nucleus accumbens correlates with both exercise habits and cognitive preservation.

  10. Occipital lobe seizures and subcortical T2 and T2* hypointensity associated with nonketotic hyperglycemia: a case report.

    Science.gov (United States)

    Sasaki, Fuyuko; Kawajiri, Sumihiro; Nakajima, Sho; Yamaguchi, Ai; Tomizawa, Yuji; Noda, Kazuyuki; Hattori, Nobutaka; Okuma, Yasuyuki

    2016-08-12

    Nonketotic hyperglycemia often causes seizures. Recently, seizures associated with nonketotic hyperglycemia have been found to be associated with subcortical T2 hypointensity on magnetic resonance imaging, especially in the occipital lobes. However, the mechanism remains unclear, although iron accumulation is suggested. We present a case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the hypothesis that the mechanism of subcortical T2 hypointensity is iron accumulation using gradient-echo T2*-weighted magnetic resonance imaging. A 65-year-old Japanese man complained of intermittent pastel-colored flashing lights. On neurological examination, he also had lower right-side quadrant hemianopia. No other abnormal neurological findings were found. On laboratory analysis, his blood glucose level was 370 mg/dL, HbA1c was 11.4 %, and serum osmolarity was 326 mOsm/L. No ketones were detected in urine. A magnetic resonance imaging scan of his head showed subcortical T2 and T2* hypointensity in his left occipital lobe. Single-photon emission computed tomography with I123-N-isopropyl-iodoamphetamine revealed hyperperfusion in the left dominant occipital lobe. These magnetic resonance imaging abnormalities resolved during clinical recovery and treatment to control his blood sugar level. Therefore, a diagnosis of occipital lobe seizures associated with nonketotic hyperglycemia was made. To the best of our knowledge, this is the first case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the role of iron accumulation as a mechanism for subcortical T2 hypointensity using T2*-magnetic resonance imaging.

  11. Focal neuronal loss, reversible subcortical focal T2 hypointensity in seizures with a nonketotic hyperglycemic hyperosmolar state

    International Nuclear Information System (INIS)

    Raghavendra, S.; Ashalatha, R.; Thomas, Sanjeev V.; Kesavadas, C.

    2007-01-01

    Neuroimaging in seizures associated with nonketotic hyperglycemia (NKH) is considered normal. We report magnetic resonance imaging (MRI) abnormalities in four patients with NKH and seizures. We prospectively evaluated clinical and radiological abnormalities in four patients with NKH during the period March 2004 to December 2005. All patients presented with seizures, either simple or complex partial seizures or epilepsia partialis continua. Two of them had transient hemianopia. MRI showed subcortical T2 hypointensity in the occipital white matter and in or around the central sulcus (two patients each), T2 hyperintensity of the overlying cortex (two patients), focal overlying cortical enhancement (three patients) and bilateral striatal hyperintensity (one patient). Diffusion-weighted imaging (DWI) performed in three patients showed restricted diffusion. The ictal semiology and electroencephalographic (EEG) findings correlated with the MRI abnormalities. On clinical recovery, the subcortical T2 hypointensity and striatal hyperintensity reversed in all patients. The initial cortical change evolved to FLAIR hyperintensity suggestive of focal cortical gliosis. The radiological differential diagnosis considered initially included encephalitis, malignancy and hemorrhagic infarct rendering a diagnostic dilemma. We identified subcortical T2 hypointensity rather than hyperintensity as a characteristic feature of seizures associated with NKH. Only very few similar reports exist in literature. Reversible bilateral striatal T2 hyperintensity in NKH has not been reported to the best of our knowledge. (orig.)

  12. Assessing denoising strategies to increase signal to noise ratio in spinal cord and in brain cortical and subcortical regions

    Science.gov (United States)

    Maugeri, L.; Moraschi, M.; Summers, P.; Favilla, S.; Mascali, D.; Cedola, A.; Porro, C. A.; Giove, F.; Fratini, M.

    2018-02-01

    Functional Magnetic Resonance Imaging (fMRI) based on Blood Oxygenation Level Dependent (BOLD) contrast has become one of the most powerful tools in neuroscience research. On the other hand, fMRI approaches have seen limited use in the study of spinal cord and subcortical brain regions (such as the brainstem and portions of the diencephalon). Indeed obtaining good BOLD signal in these areas still represents a technical and scientific challenge, due to poor control of physiological noise and to a limited overall quality of the functional series. A solution can be found in the combination of optimized experimental procedures at acquisition stage, and well-adapted artifact mitigation procedures in the data processing. In this framework, we studied two different data processing strategies to reduce physiological noise in cortical and subcortical brain regions and in the spinal cord, based on the aCompCor and RETROICOR denoising tools respectively. The study, performed in healthy subjects, was carried out using an ad hoc isometric motor task. We observed an increased signal to noise ratio in the denoised functional time series in the spinal cord and in the subcortical brain region.

  13. Insular networks for emotional processing and social cognition: comparison of two case reports with either cortical or subcortical involvement.

    Science.gov (United States)

    Couto, Blas; Sedeño, Lucas; Sposato, Luciano A; Sigman, Mariano; Riccio, Patricia M; Salles, Alejo; Lopez, Vladimir; Schroeder, Johannes; Manes, Facundo; Ibanez, Agustin

    2013-05-01

    The processing of the emotion of disgust is attributed to the insular cortex (IC), which is also responsible for social emotions and higher-cognitive functions. We distinguish the role of the IC from its connections in regard to these functions through the assessment of emotions and social cognition in a double case report. These subjects were very rare cases that included a focal IC lesion and a subcortical focal stroke affecting the connections of the IC with frontotemporal areas. Both patients and a sample of 10 matched controls underwent neuropsychological and affective screening questionnaires, a battery of multimodal basic emotion recognition tests, an emotional inference disambiguation task using social contextual clues, an empathy task and a theory of mind task. The insular lesion (IL) patient showed no impairments in emotion recognition and social emotions and presented with a pattern of delayed reaction times (RTs) in a subset of both groups of tasks. The subcortical lesion (SL) patient was impaired in multimodal aversive emotion recognition, including disgust, and exhibited delayed RTs and a heterogeneous pattern of impairments in subtasks of empathy and in the contextual inference of emotions. Our results suggest that IC related networks, and not the IC itself, are related to negative emotional processing and social emotions. We discuss these results with respect to theoretical approaches of insular involvement in emotional and social processing and propose that IC connectivity with frontotemporal and subcortical regions might be relevant for contextual emotional processing and social cognition. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Focal neuronal loss, reversible subcortical focal T2 hypointensity in seizures with a nonketotic hyperglycemic hyperosmolar state

    Energy Technology Data Exchange (ETDEWEB)

    Raghavendra, S.; Ashalatha, R.; Thomas, Sanjeev V. [Sree Chitra Tirunal Institute for Medical Sciences and Technology, Department of Neurology, Trivandrum, Kerala (India); Kesavadas, C. [Sree Chitra Tirunal Institute for Medical Sciences and Technology, Department of Imaging Sciences and Interventional Radiology, Trivandrum (India)

    2007-04-15

    Neuroimaging in seizures associated with nonketotic hyperglycemia (NKH) is considered normal. We report magnetic resonance imaging (MRI) abnormalities in four patients with NKH and seizures. We prospectively evaluated clinical and radiological abnormalities in four patients with NKH during the period March 2004 to December 2005. All patients presented with seizures, either simple or complex partial seizures or epilepsia partialis continua. Two of them had transient hemianopia. MRI showed subcortical T2 hypointensity in the occipital white matter and in or around the central sulcus (two patients each), T2 hyperintensity of the overlying cortex (two patients), focal overlying cortical enhancement (three patients) and bilateral striatal hyperintensity (one patient). Diffusion-weighted imaging (DWI) performed in three patients showed restricted diffusion. The ictal semiology and electroencephalographic (EEG) findings correlated with the MRI abnormalities. On clinical recovery, the subcortical T2 hypointensity and striatal hyperintensity reversed in all patients. The initial cortical change evolved to FLAIR hyperintensity suggestive of focal cortical gliosis. The radiological differential diagnosis considered initially included encephalitis, malignancy and hemorrhagic infarct rendering a diagnostic dilemma. We identified subcortical T2 hypointensity rather than hyperintensity as a characteristic feature of seizures associated with NKH. Only very few similar reports exist in literature. Reversible bilateral striatal T2 hyperintensity in NKH has not been reported to the best of our knowledge. (orig.)

  15. [Successive subcortical hemorrhages in the superior parietal lobule and postcentral gyrus in a 23-year-old female].

    Science.gov (United States)

    Sato, K; Yoshikawa, H; Komai, K; Takamori, M

    1998-04-01

    We report a non-hypertensive 23-year-old female with successive hemorrhages in parietal subcortical regions. She had first experienced a transient pain in the left upper extremity one month before admission. She noticed dysesthesia in the same limb and weakness on her left hand, and, five days after, visited our hospital because of suddenly developed convulsion in the limb and loss of consciousness for a few minutes. Neurological examination revealed distal dominant flaccid paresis, positive pathological reflex and touch and position sense disturbances in the affected limb. Brain CT detected two high-density areas in the parietal lobe. Brain MRI demonstrated an acute phase subcortical hematoma in the left postcentral gyrus and a subacute phase one in the left superior parietal lobule. SPECT indicated hypoperfusion in the left frontal and parietal cortex. Cerebral angiography showed no abnormal findings. Her symptoms gradually improved, but left ulnar-type pseudoradicular sensory impairment remained on discharge. We considered the hemorrhage in this patient have arisen from rupture of cavernous hemangioma, because she was relatively young, the hematomas were oval in shape and successively developed in the left parietal lobe. Our patient suggests that a subcortical hemorrhage in the post-central gyrus causes flaccid paresis and pyramidal tract involvement.

  16. Parcellating an individual subject's cortical and subcortical brain structures using snowball sampling of resting-state correlations.

    Science.gov (United States)

    Wig, Gagan S; Laumann, Timothy O; Cohen, Alexander L; Power, Jonathan D; Nelson, Steven M; Glasser, Matthew F; Miezin, Francis M; Snyder, Abraham Z; Schlaggar, Bradley L; Petersen, Steven E

    2014-08-01

    We describe methods for parcellating an individual subject's cortical and subcortical brain structures using resting-state functional correlations (RSFCs). Inspired by approaches from social network analysis, we first describe the application of snowball sampling on RSFC data (RSFC-Snowballing) to identify the centers of cortical areas, subdivisions of subcortical nuclei, and the cerebellum. RSFC-Snowballing parcellation is then compared with parcellation derived from identifying locations where RSFC maps exhibit abrupt transitions (RSFC-Boundary Mapping). RSFC-Snowballing and RSFC-Boundary Mapping largely complement one another, but also provide unique parcellation information; together, the methods identify independent entities with distinct functional correlations across many cortical and subcortical locations in the brain. RSFC parcellation is relatively reliable within a subject scanned across multiple days, and while the locations of many area centers and boundaries appear to exhibit considerable overlap across subjects, there is also cross-subject variability-reinforcing the motivation to parcellate brains at the level of individuals. Finally, examination of a large meta-analysis of task-evoked functional magnetic resonance imaging data reveals that area centers defined by task-evoked activity exhibit correspondence with area centers defined by RSFC-Snowballing. This observation provides important evidence for the ability of RSFC to parcellate broad expanses of an individual's brain into functionally meaningful units. © The Author 2013. Published by Oxford University Press.

  17. Glutamate concentration in the medial prefrontal cortex predicts resting-state cortical-subcortical functional connectivity in humans.

    Directory of Open Access Journals (Sweden)

    Niall W Duncan

    Full Text Available Communication between cortical and subcortical regions is integral to a wide range of psychological processes and has been implicated in a number of psychiatric conditions. Studies in animals have provided insight into the biochemical and connectivity processes underlying such communication. However, to date no experiments that link these factors in humans in vivo have been carried out. To investigate the role of glutamate in individual differences in communication between the cortex--specifically the medial prefrontal cortex (mPFC--and subcortical regions in humans, a combination of resting-state fMRI, DTI and MRS was performed. The subcortical target regions were the nucleus accumbens (NAc, dorsomedial thalamus (DMT, and periaqueductal grey (PAG. It was found that functional connectivity between the mPFC and each of the NAc and DMT was positively correlated with mPFC glutamate concentrations, whilst functional connectivity between the mPFC and PAG was negatively correlated with glutamate concentration. The correlations involving mPFC glutamate and FC between the mPFC and each of the DMT and PAG were mirrored by correlations with structural connectivity, providing evidence that the glutamatergic relationship may, in part, be due to direct connectivity. These results are in agreement with existing results from animal studies and may have relevance for MDD and schizophrenia.

  18. Subcortical hyperintensity volumetrics in Alzheimer’s disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory

    OpenAIRE

    Ramirez, Joel; McNeely, Alicia A; Scott, Christopher JM; Stuss, Donald T; Black, Sandra E

    2014-01-01

    Introduction Subcortical hyperintensities (SHs) are radiological entities commonly observed on magnetic resonance imaging (MRI) of patients with Alzheimer’s disease (AD) and normal elderly controls. Although the presence of SH is believed to indicate some form of subcortical vasculopathy, pathological heterogeneity, methodological differences, and the contribution of brain atrophy associated with AD pathology have yielded inconsistent results in the literature. Methods Using the Lesion Explor...

  19. Awake Craniotomy in Arteriovenous Malformation Surgery: The Usefulness of Cortical and Subcortical Mapping of Language Function in Selected Patients.

    Science.gov (United States)

    Gamble, Alexander J; Schaffer, Sarah G; Nardi, Dominic J; Chalif, David J; Katz, Jeffery; Dehdashti, Amir R

    2015-11-01

    Awake craniotomy for removal of intra-axial lesions is a well-established procedure. Few studies, however, have investigated the usefulness of this approach for resection of arteriovenous malformations adjacent to eloquent language areas. We demonstrate our experience by using cortical stimulation mapping and report for the first time on the usefulness of subcortical stimulation with interrogation of language function during resection of arteriovenous malformations (AVMs) located near language zones. Patients undergoing awake craniotomy for AVMs located in language zones and at least 5 mm away from the closest functional magnetic resonance imaging activation were analyzed. During surgery, cortical bipolar stimulation at 50 Hz, with an intensity of 2 mA, increased to a maximum of 10 mA was performed in the region around the AVM before claiming it negative for language function. In positive language site, the area was restimulated 3 times to confirm the functional deficit. The AVM resection was started based on cortical mapping findings. Further subcortical stimulation performed in concert with speech interrogation by the neuropsychologist continued at key points throughout the resection as feasible. The usefulness of cortical and subcortical stimulation in addition to patient outcomes was analyzed. Between March 2009 and September 2014, 42 brain AVM resections were performed. Four patients with left-sided language zone AVMs underwent awake craniotomy. The AVM locations were fronto-opercular in 2 patients and posterior temporal in 2. The AVM Spetzler-Martin grades were II (2 patients) and III (2 patients). In 1 patient, complete speech arrest was noticed during mapping of the peri-malformation zone, which was not breached during resection. In a second patient who initially demonstrated negative cortical mapping, a speech deficit was noticed during resection and subcortical stimulation. This guided the approach to protect and avoid the sensitive zone. This patient

  20. Evidence for a role of 5-HT2C receptors in the motor aspects of performance, but not the efficacy of food reinforcers, in a progressive ratio schedule.

    Science.gov (United States)

    Bezzina, G; Body, S; Cheung, T H C; Hampson, C L; Bradshaw, C M; Glennon, J C; Szabadi, E

    2015-02-01

    5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathematical models can help to differentiate between these processes. The effects of the 5-HT2C receptor agonist Ro-600175 ((αS)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine) and the non-selective 5-HT receptor agonist 1-(m-chlorophenyl)piperazine (mCPP) on rats' performance on a progressive ratio schedule maintained by food pellet reinforcers were assessed using a model derived from Killeen's Behav Brain Sci 17:105-172, 1994 general theory of schedule-controlled behaviour, 'mathematical principles of reinforcement'. Rats were trained under the progressive ratio schedule, and running and overall response rates in successive ratios were analysed using the model. The effects of the agonists on estimates of the model's parameters, and the sensitivity of these effects to selective antagonists, were examined. Ro-600175 and mCPP reduced the breakpoint. Neither agonist significantly affected a (the parameter expressing incentive value), but both agonists increased δ (the parameter expressing minimum response time). The effects of both agonists could be attenuated by the selective 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carboxamide). The effect of mCPP was not altered by isamoltane, a selective 5-HT1B receptor antagonist, or MDL-100907 ((±)2,3-dimethoxyphenyl-1-(2-(4-piperidine)methanol)), a selective 5-HT2A receptor antagonist. The results are consistent with the hypothesis that the effect of the 5-HT2C receptor agonists on progressive ratio schedule performance is mediated by an impairment of motor capacity rather than by a reduction of the incentive value of the food reinforcer.

  1. Study of diffusion tensor imaging in subcortical ischemic vascular cognitive impairment

    Directory of Open Access Journals (Sweden)

    Hui-ying GUO

    2014-04-01

    Full Text Available Objective Using diffusion tensor imaging (DTI to explore the microstructure changes of white matter in subcortical ischemic vascular cognitive impairment (SIVCI and its correlation with cognitive function.  Methods Forty-nine patients with subcortical ischemic cerebrovascular diseases were collected. By using Clinical Dementia Rating Scale (CDR, they were classified into 10 cases of vascular dementia (VaD group, 20 cases of vascular cognitive impairment-no dementia (VCIND group and 19 cases of normal cognitive function (control group. Conventional MRI and DTI were performed in all cases. Based on the DTI data, voxel-based analysis was used to assess the whole brain region. Correlation analysis was applied to illustrate the relationship between DTI parameters and cognitive scale in VaD patients.  Results Compared with the control group, fractional anisotropy (FA values of patients in VaD group decreased in medial prefrontal cortex, anterior cingulate cortex, corpus callosum stem, bilateral parietal lobes, right temporal lobe and bilateral orbitofrontal lobes (P = 0.000, for all, and FA values of patients in VCIND group decreased in right inferior frontal gyrus, right hippocampus and bilateral precuneus (P = 0.000, for all. Compared with VCIND group, FA values of patients in VaD group decreased in medial prefrontal cortex, anterior cingulate, corpus callosum, bilateral parietal lobes and right temporal lobe (P = 0.000, for all. Compared with the control group, mean diffusivity (MD values in VaD group increased in medial prefrontal cortex, corpus callosum, bilateral parietal lobes, bilateral temporal lobes and anterior cingulate (P = 0.000, for all, while in VCIND group increased in bilateral precuneus and right hippocampus (P = 0.000, for all. Compared with VCIND group, MD values in VaD group increased in right medial prefrontal cortex, anterior cingulate cortex, corpus callosum stem, bilateral parietal lobes and bilateral temporal lobes (P = 0

  2. Frequency-dependent effects of background noise on subcortical response timing.

    Science.gov (United States)

    Tierney, A; Parbery-Clark, A; Skoe, E; Kraus, N

    2011-12-01

    The addition of background noise to an auditory signal delays brainstem response timing. This effect has been extensively documented using manual peak selection. Peak picking, however, is impractical for large-scale studies of spectrotemporally complex stimuli, and leaves open the question of whether noise-induced delays are frequency-dependent or occur across the frequency spectrum. Here we use an automated, objective method to examine phase shifts between auditory brainstem responses to a speech sound (/da/) presented with and without background noise. We predicted that shifts in neural response timing would also be reflected in frequency-specific phase shifts. Our results indicate that the addition of background noise causes phase shifts across the subcortical response spectrum (70-1000 Hz). However, this noise-induced delay is not uniform such that some frequency bands show greater shifts than others: low-frequency phase shifts (300-500 Hz) are largest during the response to the consonant-vowel formant transition (/d/), while high-frequency shifts (720-1000 Hz) predominate during the response to the steady-state vowel (/a/). Most importantly, phase shifts occurring in specific frequency bands correlate strongly with shifts in the latencies of the predominant peaks in the auditory brainstem response, while phase shifts in other frequency bands do not. This finding confirms the validity of phase shift detection as an objective measure of timing differences and reveals that this method detects noise-induced shifts in timing that may not be captured by traditional peak latency measurements. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

    Science.gov (United States)

    Richards, Jennifer S; Arias Vásquez, Alejandro; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Buitelaar, Jan K; Hartman, Catharina A

    2016-01-01

    Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

  4. Achieved Blood Pressure and Outcomes in the Secondary Prevention of Small Subcortical Strokes Trial.

    Science.gov (United States)

    Odden, Michelle C; McClure, Leslie A; Sawaya, B Peter; White, Carole L; Peralta, Carmen A; Field, Thalia S; Hart, Robert G; Benavente, Oscar R; Pergola, Pablo E

    2016-01-01

    Studies suggest a J-shaped association between blood pressure and cardiovascular events in the setting of intensive systolic blood pressure control; whether there is a similar association with stroke remains less well established. The Secondary Prevention of Small Subcortical Strokes was a randomized trial to evaluate higher (130-149 mm Hg) versus lower (blood pressure targets in participants with recent lacunar infarcts. We evaluated the association of mean achieved blood pressure, 6 months after randomization, and recurrent stroke, major vascular events, and all-cause mortality. After a mean follow up of 3.7 years, there was a J-shaped association between achieved blood pressure and outcomes; the lowest risk was at ≈124 and 67 mm Hg systolic and diastolic blood pressure, respectively. For example, above a systolic blood pressure of 124 mm Hg, 1 standard deviation higher (11.1 mm Hg) was associated with increased mortality (adjusted hazard ratio: 1.9; 95% confidence interval: 1.4, 2.7), whereas below this level, this relationship was inverted (0.29; 0.10, 0.79), Pblood pressure of 67 mm Hg, a 1 standard deviation higher (8.2 mm Hg) was associated with an increased risk of stroke (2.2; 1.4, 3.6), whereas below this level, the association was in the opposite direction (0.34; 0.13, 0.89), P=0.02 for interaction. The lowest risk of all events occurred at a nadir of ≈120 to 128 mm Hg systolic blood pressure and 65 to 70 mm Hg diastolic blood pressure. Future studies should evaluate the impact of excessive blood pressure reduction, especially in older populations with preexisting vascular disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306. © 2015 American Heart Association, Inc.

  5. Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

    Directory of Open Access Journals (Sweden)

    Jennifer S Richards

    Full Text Available Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD. Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE in interindividual variability of total gray matter (GM, caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312 and without ADHD (N = 437 from N = 402 families (age M = 17.00, SD = 3.60. GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

  6. Intracranial atherosclerosis is associated with progression of neurological deficit in subcortical stroke.

    Science.gov (United States)

    Hallevi, Hen; Chernyshev, Oleg Y; El Khoury, Ramy; Soileau, Michael J; Walker, Kyle C; Grotta, James C; Savitz, Sean I

    2012-01-01

    Progression of neurological deficit (PND) is a frequent complication of acute subcortical ischemic stroke (SCS). The role of intracranial atherosclerosis (IAS) in PND is controversial. Our goal was to evaluate IAS on admission, as predictor of PND in SCS patients. SCS patients were identified from our prosp