UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have indicated that GABAergic disinhibition contributes to cognitive deficits mediated by NMDA receptor hypofunction in schizophrenia model of rats. However, the underlying mechanism of GABAergic disinhibition in schizophrenia remains elusive. In this study, we found that the maintenance of long term potentiation (LTP) was impaired in the hippocampus of rats with MK-801-induced cognitive impairments. The impairment of LTP maintenance was significantly reversed by picrotoxinin, a specific GABA(A) receptor-chloride channel blocker and furosemide, a K+-Cl- cotransporter 2 (KCC2) blocker, respectively. Furthermore, immunoblotting results indicated KCC2 expression in hippocampal CA1 of MK-801-treated rats was lower than that of normal rats before LTP induction. Additionally, LTP-accompanied downregulation of KCC2 was prevented in MK-801-treated rats during LTP induction. Our results suggested that KCC2 expression in hippocampal CA1 of MK-801-treated rats was not further decreased by LTP induction because of its low expression caused by MK-801 treatment. Accordingly, GABAergic inhibition was not further decreased during LTP induction due to the depressed basal GABAergic tone in MK-801-treated rats, Therefore, GABAergic disinhibition in MK-801-treated rats restricts the further downregulation of KCC2 during LTP induction and contributes to the stable GABAergic inhibition and the impaired LTP expression. Our results thus reveal the mechanism that GABAergic disinhibition contributes to cognitive deficits.
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PMID:Contribution of K+-Cl- cotransporter 2 in MK-801-induced impairment of long term potentiation. 1942 48

N-methyl-D-aspartate receptors (NMDARs) play a pivotal role in excitatory neurotransmission, synaptic plasticity and brain development. Clinical and experimental evidence suggests a dysregulation of NMDAR function and glutamatergic pathways in the pathophysiology of schizophrenia. We evaluated electrophysiological and behavioral properties of NMDAR deficiency utilizing mice that express only 5-10% of the normal level of NMDAR NR1 subunit. Auditory and visual event related potentials yielded significantly increased amplitudes for the P20 and N40 components in NMDAR deficient (NR1(neo)-/-) mice suggesting decreased inhibitory tone. Compared to wild types, NR1(neo)-/- mice spent less time in social interactions and showed reduced nest building. NR1(neo)-/- mice displayed a preference for open arms of a zero maze and central zone of an open field, possibly reflecting decreased anxiety-related behavioral inhibition. However, locomotor activity did not differ between groups in either home cage environment or during behavioral testing. NR1(neo)-/- mice displayed hyperactivity only when placed in a large unfamiliar environment, suggesting that neither increased anxiety nor non-specific motor activation accounts for differential behavioral patterns. Data suggest that NMDAR NR1 deficiency causes disinhibition in sensory processing as well as reduced behavioral inhibition and impaired social interactions. The behavioral signature in NR1(neo)-/- mice supports the impact of impaired NMDAR function in a mouse model with possible relevance to negative symptoms in schizophrenia.
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PMID:Assessment of NMDA receptor NR1 subunit hypofunction in mice as a model for schizophrenia. 1956 16

Common clinical wisdom suggests that people who engage in self-injury are impulsive. However, virtually all prior work in this area has relied on individuals' self-report of impulsiveness, despite evidence that people are limited in their ability to accurately report on cognitive processes that occur outside awareness. To address this knowledge gap, we used performance-based measures of several dimensions of impulsiveness to assess whether people engaging in non-suicidal self-injury (NSSI) demonstrate greater impulsiveness than non-injurers. In Study 1, we compared adolescent self-injurers (n=64) to age-, sex-, and race/ethnicity-matched, non-injurious controls (n=30) on self-reported impulsiveness (Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and LifetimeVersion) and on performance-based measures of two dimensions of impulsiveness: behavioral disinhibition (Conners' Continuous Performance Test) and risky decision-making (Iowa Gambling Task). In Study 2, we compared adult female self-injurers (n=20) with age- and race/ethnicity-matched, non-injurious controls (n=20) on self-reported impulsiveness (Barratt Impulsiveness Scale-11), and performance-based measures of behavioral disinhibition, risky decision-making, and two measures of delay discounting. In both studies, self-injurers reported greater impulsiveness; however, performance-based measures of impulsiveness failed to detect any between-group differences. We propose several potential explanations for the discrepancies observed between self-report and performance-based measures of impulsiveness and discuss directions for future research on impulsiveness and self-injury.
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PMID:Are self-injurers impulsive?: Results from two behavioral laboratory studies. 1975 6

Schizophrenia is characterized by cortical circuit abnormalities, which might be reflected in gamma-frequency (30-100 Hz) oscillations in the electroencephalogram. Here we used a computational model of cortical circuitry to examine the effects that neural circuit abnormalities might have on gamma generation and network excitability. The model network consisted of 1000 leaky integrate-and-fire neurons with realistic connectivity patterns and proportions of neuron types [pyramidal cells (PCs), regular-spiking inhibitory interneurons, and fast-spiking interneurons (FSIs)]. The network produced a gamma oscillation when driven by noise input. We simulated reductions in: (1) recurrent excitatory inputs to PCs; (2) both excitatory and inhibitory inputs to PCs; (3) all possible connections between cells; (4) reduced inhibitory output from FSIs; and (5) reduced NMDA input to FSIs. Reducing all types of synaptic connectivity sharply reduced gamma power and phase synchrony. Network excitability was reduced when recurrent excitatory connections were deleted, but the network showed disinhibition effects when inhibitory connections were deleted. Reducing FSI output impaired gamma generation to a lesser degree than reducing synaptic connectivity, and increased network excitability. Reducing FSI NMDA input also increased network excitability, but increased gamma power. The results of this study suggest that a multimodal approach, combining non-invasive neurophysiological and structural measures, might be able to distinguish between different neural circuit abnormalities in schizophrenia patients. Computational modeling may help to bridge the gaps between post-mortem studies, animal models, and experimental data in humans, and facilitate the development of new therapies for schizophrenia and neuropsychiatric disorders in general.
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PMID:The functional consequences of cortical circuit abnormalities on gamma oscillations in schizophrenia: insights from computational modeling. 1987 8

Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.
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PMID:Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. 2003 77

Frontal hypoactivation has consistently been demonstrated in schizophrenia patients. We hypothesized that this well-known deficit is asymmetrical, ie, centered over left frontal locations and, in-line with Crow's theory, associated with both loss of linguistic asymmetry and correlated with positive symptoms. Electroencephalography delta band was used as a quantitative index of cortical inhibition in 17 paranoid schizophrenia patients with prevailing positive symptoms and 17 matched control subjects. Delta amplitude was measured by 38 electrodes, while participants performed 3 linguistic tasks, visuoperceptual, rhyming, and semantic judgment. Compared with control subjects, patients did not show overall delta band differences, revealing no detrimental effects of pharmacological treatment. In healthy participants, analysis of 4 quadrants/regions of interest revealed higher delta amplitude in right vs left anterior sites, indicating significant left anterior disinhibition during linguistic processing. Instead, patients showed bilateral delta band distribution and, compared with control subjects, significant greater delta amplitude (ie, brain inhibition) in linguistic left anterior centers. Patients' left hypofrontality was functionally related to their lack of hemispheric specialization for language and was positively correlated with higher levels of delusions (P1) and conceptual disorganization (P2) Positive and Negative Syndrome Scale subscales. Results suggest, in schizophrenia patients, a functional deficit of Broca's area, a region playing a fundamental hierarchical role between and within hemispheres by integrating many basic processes in linguistic and conceptual organization. The significant correlation between lack of anterior asymmetry and increased positive symptoms is in-line with Crow's hypothesis postulating the etiological role of disrupted linguistic frontal asymmetry on the onset of the key symptoms of schizophrenia.
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PMID:Delta EEG band as a marker of left hypofrontality for language in schizophrenia patients. 1993 13

Recently a new category of treatment-responsive encephalitis has been proposed associated with antibodies against neuronal cell membrane antigens, including VGKC, NMDA receptor (NMDAR) and AMPA receptor. Anti-NMDAR encephalitis is caused by the antibodies, which bind to extracellular conformal epitope in the NR1/NR2 heteromers of the NMDAR. The antibodies are usually detected in CSF/serum of young women with ovarian teratoma (OT), who typically developed schizophrenia-like psychiatric symptoms. Most patients developed seizures, followed by unresponsive/catatonic state, central hypoventilation, and bizarre orofacial-limb dyskinesias. Based on symptomatology and current NMDAR hypofunction hypothesis in schizophrenia, we speculated that the antibodies might cause inhibition of NMDAR in presynaptic GABAergic interneurons, causing a reduction of release of GABA. This results in disinhibition of postsynaptic glutamatergic transmission, excessive release of glutamate in the prefrontal/subcortical structures, and glutamate/dopamine dysregulation. Recent studies demonstrated that the antibodies cause reversible reduction in the numbers of cell-surface NMDAR and NMDAR clusters in postsynaptic dendrites, suggesting antibodies-mediated decreased function of NMDAR. Early tumor resection with immunotherapy is recommended in OT-positive cases but not in OT-negative cases. However, exploratory laparotomy may increase the chance to identify microscopic teratoma and improve the outcome if patients who were refractory to immunotherapy had anti-NMDAR antibodies and ovarian cyst.
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PMID:[Unique clinical features and pathophysiology of anti-NMDA receptor encephalitis]. 2003 Feb 7

Injection of NMDAR antagonist into the thalamus can produce delta frequency EEG oscillations in the thalamocortical system. It is surprising that an antagonist of an excitatory neurotransmitter should trigger such activity, and the mechanism is unknown. One hypothesis is that the antagonist blocks excitation of GABAergic cells, thus producing disinhibition. To test this hypothesis, we investigated the effect of NMDAR antagonist (APV) on cells of the nucleus reticularis (nRT) in rat brain slices, a thalamic nucleus that can serve as a pacemaker for thalamocortical delta oscillations and that is composed entirely of GABAergic neurons. We found, unexpectedly, that nRT cells are hyperpolarized by APV. This occurs because these cells have an unusual form of NMDAR (probably NR2C) that contributes inward current at resting potential in response to ambient glutamate. The hyperpolarization produced by APV is sufficient to deinactivate T-type calcium channels, and these trigger rhythmic bursting at delta frequency. The APV-induced delta frequency bursting is abolished by dopamine D2 receptor antagonist, indicating that dopamine and NMDAR antagonist work synergistically to stimulate delta frequency bursting. Our results have significant implications concerning the electrophysiological basis of schizophrenia and bring together the NMDAR hypofunction, dopamine, and GABA theories of the disease. Our results suggest that NMDAR hypofunction and dopamine work synergistically on the GABAergic cells of the nRT to generate the delta frequency EEG oscillations, a thalamocortical dysrhythmia (TCD) in the awake state that is an established abnormality in schizophrenia.
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PMID:Inhibition of NMDARs in the Nucleus Reticularis of the Thalamus Produces Delta Frequency Bursting. 2005 28

Violence is an important social problem. Violence in the community has important social relevance for the political, criminal justice, and health care systems. Studies of homicide offenders have suggested a high prevalence of neurologic dysfunction due to organic brain damage such as traumatic brain injury, epilepsy and dementia have been observed to exhibit excessive violence. Moreover, violence in the mentally ill can be viewed as an important medical and mental health problem with significant implications for forensic psychiatry and the community. Although numerous previous studies showed that rate of violent behavior in the community is not much higher in patients with serious mental disorders (schizophrenia) than in healthy controls, that rate is substantially higher in patients with psychiatric comorbidity and substance abuse. A high proportion of patients in forensic psychiatric facilities are diagnosed with comorbidity, most often with schizophrenia, paranoid psychosis, organic brain syndrome, various personality disorders and comorbid substance abuse. These patients represent a high risk group for violence within forensic psychiatric facilities, and repetitive violent behavior in the community. Understanding the neurobiological basis of aggressive behavior clearly has important social and clinical implications. By introduction of neuroimaging studies (MRI, fMRI, PET, SPECT) as a useful tool in forensic psychiatry, the neurobiological aspect of violence is better understood. Previous studies have shown that individuals with frontotemporal brain dysfunction are frequently displaying antisocial behavior (disinhibition, impulsivity, lack of empathy) that justify the diagnosis of "acquired sociopathy/psychopathy". A correlation between the potential for impulsive aggression mediated by limbic brain structures, and the control of the aggression by frontotemporal brain regions has been shown. The individuals with such brain dysfunction have an increased risk of violent behavior and scored high on the Webster's and Hare's violence risk assessment scale. This article reviews the relationship between psychiatric comorbidity, violence risk assessment and neuroimaging in forensic psychiatry and showing the useful directions for future research, screening and prevention of violent behavior among mentally ill criminal offenders.
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PMID:Relationship between comorbidity and violence risk assessment in forensic psychiatry - the implication of neuroimaging studies. 2056 56

The negative symptoms of schizophrenia have been considered to be a psychiatric form of the frontal lobe syndrome. However, no studies have compared these two disorders at the clinical level. In this study, 12 negative symptom schizophrenic patients and 11 patients with behavioural variant frontotemporal dementia (bv-FTD) were rated for negative symptoms and for occurrence of frontal lobe behaviours in everyday life. They were also rated for speech disorder and were given a series of executive tests. Both patient groups showed positive ratings on negative symptoms and frontal lobe behaviours in daily life; however, the schizophrenic patients had higher negative symptom scores and the bv-FTD patients had higher carer ratings on frontal behaviours in daily life. Both groups were impaired on the executive tests, but the bv-FTD patients showed significantly greater impairment on verbal fluency and a test requiring inhibition of prepotent responses. A minority of the bv-FTD patients unexpectedly showed speech abnormalities typically associated with schizophrenia. The findings indicate that the negative syndrome in schizophrenia and the frontal lobe syndrome resemble each other clinically in important respects. Some of the differences may be attributable to the additional presence of disinhibition in the frontal lobe syndrome.
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PMID:Negative schizophrenic symptoms and the frontal lobe syndrome: one and the same? 2071 84

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