Browse
Submit Data
Databases
API
Help

Dataset Information

35 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Global disruption in excitation-inhibition balance can cause localized network dysfunction and Schizophrenia-like context-integration deficits.

ABSTRACT: Poor context integration, the process of incorporating both previous and current information in decision making, is a cognitive symptom of schizophrenia. The maintenance of the contextual information has been shown to be sensitive to changes in excitation-inhibition (EI) balance. Many regions of the brain are sensitive to EI imbalances, however, so it is unknown how systemic manipulations affect the specific regions that are important to context integration. We constructed a multi-structure, biophysically-realistic agent that could perform context-integration as is assessed by the dot pattern expectancy task. The agent included a perceptual network, a memory network, and a decision making system and was capable of successfully performing the dot pattern expectancy task. Systemic manipulation of the agent's EI balance produced localized dysfunction of the memory structure, which resulted in schizophrenia-like deficits at context integration. When the agent's pyramidal cells were less excitatory, the agent fixated upon the cue and initiated responding later than the default agent, which were like the deficits one would predict that individuals on the autistic spectrum would make. This modelling suggests that it may be possible to parse between different types of context integration deficits by adding distractors to context integration tasks and by closely examining a participant's reaction times.

SUBMITTER: Calvin OL

PROVIDER: S-EPMC8184155 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Neocortical excitation/inhibition balance in information processing and social dysfunction.

Project description:Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80?Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.

| S-EPMC4155501 | biostudies-literature

Dysfunctional Neural Processes Underlying Context Processing Deficits in Schizophrenia.

Project description:BackgroundPeople with schizophrenia (PSZ) have profound deficits in context processing, an executive process that guides adaptive behaviors according to goals and stored contextual information. Although various neural processes are involved in context processing and are affected in PSZ, the core underlying neural dysfunction is unclear.MethodsTo determine the relative importance of neural dysfunctions within prefrontal cognitive control, sensory activity, and motor activity to context processing deficits in PSZ, we examined event-related potentials (ERPs) in 60 PSZ and 51 healthy control subjects during an optimal context processing task. We also analyzed the Ex-Gaussian reaction time distribution to examine abnormalities in motor control variability in PSZ.ResultsCompared with healthy control subjects, PSZ had lower response accuracy and greater variability in their normal reaction times during high context processing demands. Latencies of normal and slow responses were generally increased in PSZ. High context processing-related reductions in frontal ERPs were indicative of specific deficits in proactive and reactive cognitive controls in PSZ, while ERPs associated with visual and motor processes were reduced regardless of context processing demands, indicating generalized visuomotor deficits. In contrast to previous studies, we found that diminished frontal responses reflective of proactive control of the contextual cue, rather than visual responses of cue encoding, predicted response accuracy deficits in PSZ. In addition, probe-related ERP components of motor preparation, prefrontal reactive control, and frontomotor interaction predicted Ex-Gaussian indices of reaction time instability in PSZ.ConclusionsPrefrontal proactive and reactive control deficits associated with failures in using mental representation likely underlie context processing deficits in PSZ.

| S-EPMC6612435 | biostudies-literature

Deficits in context-dependent adaptive coding of reward in schizophrenia.

Project description:Theoretical principles of information processing and empirical findings suggest that to efficiently represent all possible rewards in the natural environment, reward-sensitive neurons have to adapt their coding range dynamically to the current reward context. Adaptation ensures that the reward system is most sensitive for the most likely rewards, enabling the system to efficiently represent a potentially infinite range of reward information. A deficit in neural adaptation would prevent precise representation of rewards and could have detrimental effects for an organism's ability to optimally engage with its environment. In schizophrenia, reward processing is known to be impaired and has been linked to different symptom dimensions. However, despite the fundamental significance of coding reward adaptively, no study has elucidated whether adaptive reward processing is impaired in schizophrenia. We therefore studied patients with schizophrenia (n=27) and healthy controls (n=25), using functional magnetic resonance imaging in combination with a variant of the monetary incentive delay task. Compared with healthy controls, patients with schizophrenia showed less efficient neural adaptation to the current reward context, which leads to imprecise neural representation of reward. Importantly, the deficit correlated with total symptom severity. Our results suggest that some of the deficits in reward processing in schizophrenia might be due to inefficient neural adaptation to the current reward context. Furthermore, because adaptive coding is a ubiquitous feature of the brain, we believe that our findings provide an avenue in defining a general impairment in neural information processing underlying this debilitating disorder.

| S-EPMC4945098 | biostudies-literature

Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition.

Project description:Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation increases excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it has the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Contrary to CYFIP1 upregulation, its loss in vivo, upon conditional knockout in neocortical principal cells, increases expression of postsynaptic GABAA receptor β2/3-subunits and neuroligin 3, enhancing synaptic inhibition. Thus, CYFIP1 dosage can bi-directionally impact inhibitory synaptic structure and function, potentially leading to altered E/I balance and circuit dysfunction in CYFIP1-associated neurological disorders.

| S-EPMC6381785 | biostudies-literature

Persistence, diagnostic specificity and genetic liability for context-processing deficits in schizophrenia.

Project description:Context-processing deficits have been shown in schizophrenia during first-episode, medication-naïve status, that persist after short-term antipsychotic treatment and also in first-degree relatives of individuals with schizophrenia. To confirm longer term persistence of deficits, we examined schizophrenia patients (n=63) during first-episode, medication-naïve status through to one-year follow-up, compared to healthy control (n=83) and non-schizophrenia psychosis comparison (n=47) groups, as well as unaffected first-degree relatives of individuals with schizophrenia (n=31). Context-processing ability was assessed by performance on the AX-CPT (Continuous Performance Test) at baseline, 8 weeks, 6 months, and 1 year (relatives only at baseline). Reaction time, error rates and signal detection indices (d'-context) of context processing were analyzed. Linear discriminant analyses (LDA) on early timepoints (baseline, 8 weeks) were conducted to predict confirmatory diagnosis (schizophrenia vs. psychosis control) at 6 months. Schizophrenia patients showed evidence of impaired context-processing relative to both the healthy and psychosis comparator groups at baseline and continued through to 1 year. While context-processing impairments persisted in schizophrenia patients through one year, the impairments in psychosis controls, which were more modest at baseline, remitted at follow-up. First-degree relatives showed deficits that were intermediate between the schizophrenia and healthy control groups. LDA showed 67% classification rates for distinguishing schizophrenia from non-schizophrenia psychosis. The persistence, diagnostic specificity and association with genetic liability give support for context processing impairments serving as a cognitive endophenotype for schizophrenia and evaluation of context processing could contribute to diagnostic assessments.

| S-EPMC3650125 | biostudies-literature

Temporal perception deficits in schizophrenia: integration is the problem, not deployment of attentions.

Project description:Patients with schizophrenia are known to have impairments in sensory processing. In order to understand the specific temporal perception deficits of schizophrenia, we investigated and determined to what extent impairments in temporal integration can be dissociated from attention deployment using Attentional Blink (AB). Our findings showed that there was no evident deficit in the deployment of attention in patients with schizophrenia. However, patients showed an increased temporal integration deficit within a hundred-millisecond timescale. The degree of such integration dysfunction was correlated with the clinical manifestations of schizophrenia. There was no difference between individuals with/without schizotypal personality disorder in temporal integration. Differently from previous studies using the AB, we did not find a significant impairment in deployment of attention in schizophrenia. Instead, we used both theoretical and empirical approaches to show that previous findings (using the suppression ratio to correct for the baseline difference) produced a systematic exaggeration of the attention deficits. Instead, we modulated the perceptual difficulty of the task to bring the baseline levels of target detection between the groups into closer alignment. We found that the integration dysfunction rather than deployment of attention is clinically relevant, and thus should be an additional focus of research in schizophrenia.

| S-EPMC4419531 | biostudies-literature

Pre-excitation induced left ventricular dysfunction: A less known cause of cardiomyopathy in children.

Project description:A 7-year-old boy was diagnosed to have dilated cardiomyopathy with severe left ventricular (LV) dysfunction at 1 year of age. Although well compensated, his LV function remained impaired over the follow-up years. His electrocardiogram (ECG) was initially misinterpreted as left bundle branch block. However, on follow-up, it was recognized as a pre-excited ECG. The accessory pathway causing pre-excitation was implicated as the cause of LV dysfunction and dysynchrony as the mechanism. Radiofrequency ablation was done. His LV function and dimensions improved significantly over 6 months follow up.

| S-EPMC3634255 | biostudies-literature

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders.

Project description:Recent theoretical accounts have proposed excitation and inhibition (E/I) imbalance as a possible mechanistic, network-level hypothesis underlying neural and behavioral dysfunction across neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and schizophrenia (SCZ). These two disorders share some overlap in their clinical presentation as well as convergence in their underlying genes and neurobiology. However, there are also clear points of dissociation in terms of phenotypes and putatively affected neural circuitry. We highlight emerging work from the clinical neuroscience literature examining neural correlates of E/I imbalance across children and adults with ASD and adults with both chronic and early-course SCZ. We discuss findings from diverse neuroimaging studies across distinct modalities, conducted with electroencephalography, magnetoencephalography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging, including effects observed both during task and at rest. Throughout this review, we discuss points of convergence and divergence in the ASD and SCZ literature, with a focus on disruptions in neural E/I balance. We also consider these findings in relation to predictions generated by theoretical neuroscience, particularly computational models predicting E/I imbalance across disorders. Finally, we discuss how human noninvasive neuroimaging can benefit from pharmacological challenge studies to reveal mechanisms in ASD and SCZ. Collectively, we attempt to shed light on shared and divergent neuroimaging effects across disorders with the goal of informing future research examining the mechanisms underlying the E/I imbalance hypothesis across neurodevelopmental disorders. We posit that such translational efforts are vital to facilitate development of neurobiologically informed treatment strategies across neuropsychiatric conditions.

| S-EPMC5436134 | biostudies-literature

Sensory integration deficits support a dimensional view of psychosis and are not limited to schizophrenia.

Project description:Visual dysfunction is commonplace in schizophrenia and occurs alongside cognitive, psychotic and affective symptoms of the disorder. Psychophysical evidence suggests that this dysfunction results from impairments in the integration of low-level neural signals into complex cortical representations, which may also be associated with symptom formation. Despite the symptoms of schizophrenia occurring in a range of disorders, the integration deficit has not been tested in broader patient populations. Moreover, it remains unclear whether such deficits generalize across other sensory modalities. The present study assessed patients with a range of psychotic and nonpsychotic disorders and healthy controls on visual contrast detection, visual motion integration, auditory tone detection and auditory tone integration. The sample comprised a total of 249 participants (schizophrenia spectrum disorder n=98; bipolar affective disorder n=35; major depression n=31; other psychiatric conditions n=31; and healthy controls n=54), of whom 178 completed one or more visual task and 71 completed auditory tasks. Compared with healthy controls and nonpsychotic patients, psychotic patients trans-diagnostically were impaired on both visual and auditory integration, but unimpaired in simple visual or auditory detection. Impairment in visual motion integration was correlated with the severity of positive symptoms, and could not be accounted for by a reduction in processing speed, inattention or medication effects. Our results demonstrate that impaired sensory integration is not specific to schizophrenia, as has previously been assumed. Instead, sensory deficits are closely related to the presence of positive symptoms independent of diagnosis. The finding that equivalent integrative sensory processing is impaired in audition is consistent with hypotheses that propose a generalized deficit of neural integration in psychotic disorders.

| S-EPMC5534945 | biostudies-literature

Excitatory dysfunction drives network and calcium handling deficits in 16p11.2 duplication schizophrenia iPSC-derived neurons

Project description:Background - Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human iPSC-derived neurons (iNs) has emerged as a promising strategy. Copy number variations (CNV) confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing risk 14.5 fold. Methods - To dissect the contribution of excitatory (iENs) versus GABAergic (iGNs) neurons to SCZ pathophysiology, we induced iNs from CRISPR-Cas9 engineered isogenic and SCZ patient-derived iPSCs, and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. Results - In iEN/iGN cocultures, we found reduced neuronal network firing rate and synchrony at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for excitatory neurons. Transcriptomic analysis of isogenic 16p11.2 duplication (DUP) iENs revealed pathway dysregulation related to neuroarchitecture and calcium ion binding. Consistent with this, isogenic DUP iENs showed reduced dendrite length and calcium imaging revealed deficits in calcium handling. Analysis of iENs from 16p11.2 duplication-carrying SCZ patients (SCZ) revealed overlapping deficits in network synchrony, dendrite arborization and calcium handling. Conclusions - Our results indicate 16p11.2 duplication-dependent alterations to SCZ neurodevelopment. Calcium ion binding was the only altered transcriptomic gene set shared between isogenic and patient-derived iENs, suggesting a central role of calcium signaling in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers and supports network synchrony and calcium handling as outcomes directly linked to this genetic mutation.

2022-10-13 | GSE215183 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data