权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Multi-modal assessment of GABA function in psychosis

精神病中 GABA 功能的多模式评估

基本信息

批准号：
10643979
负责人：
Stephan F Taylor
金额：
$ 64.29万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10643979
关键词：
Accounting Achievement Address Affect Affective Agreement Antipsychotic Agents Anxiety Autopsy Benzodiazepines Bipolar Disorder Bipolar I Clinical Data Development Diagnostic Dimensions Dose Double-Blind Method Equilibrium Follow-Up Studies Foundations Functional Magnetic Resonance Imaging Functional disorder GABA Agents Human Interneurons Link Literature Location Lorazepam Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Measures Medial Nature Nervous System Outcome Parvalbumins Patients Pharmaceutical Preparations Placebos Play Prefrontal Cortex Process Proteins Proxy Psychopathology Psychoses Publishing Recording of previous events Regulation Research Personnel Role Scanning Schizoaffective Disorders Schizophrenia Signal Transduction Stimulus Stress Syndrome System Testing Therapeutic Work bipolar patients blood oxygen level dependent blood oxygenation level dependent response clinical phenotype clinically significant diagnostic strategy dysphoria early psychosis frontal lobe functional outcomes gamma-Aminobutyric Acid in vivo multimodal neuroimaging multimodality negative affect pharmacologic response synthetic enzyme

项目摘要

Abstract Considerable evidence implicates GABAergic dysfunction in the psychosis spectrum, which includes schizophrenia and bipolar disorder. GABAergic agents treat psychosis spectrum patients, often for anxiety, and the response of catatonic patients to GABA-enhancing benzodiazepines suggests a deeper link between GABA and psychosis. Post-mortem work strongly implicates GABAergic interneurons in these patients, but the links between these findings, clinical phenotype and therapeutics are far from clear. Accordingly, this proposal will undertake a transdiagnostic approach to elaborate linkages between GABA and the negative affective states (NA, e.g. anxiety, stress sensitivity) that are common across this psychosis spectrum. Using a multimodal neuroimaging strategy, magnetic resonance spectroscopy (MRS) with be combined with a pharmaco-fMRI (phfMRI) challenge paradigm measuring blood oxygenation level dependent (BOLD) changes. MRS studies of GABA levels in the psychosis spectrum have yielded inconsistent findings, which this proposal will address by positing two processes: 1) Elevated GABA in early psychosis patients in the rostral medial frontal cortex (rMFC), and 2) Reduced GABA associated with more NA. The investigators will pursue preliminary data showing that NA may be linked to low GABA levels in the rMFC, and when controlling for NA, early psychosis patients have higher GABA in the rMFC. In Aim 1, this study will utilize GABA MRS to assess GABA levels in psychosis spectrum patients, comparing early episode patients (50% not taking antipsychotics) with healthy controls, as well as schizophrenia, schizoaffective and bipolar patients. By probing three distinct voxels in the medial frontal cortex, the investigators will show specific regional effects in the rMFC and demonstrate that antipsychotic medication is associated with reduced GABA levels. In Aim 2, the phfMRI challenge paradigm with a benzodiazepine will be used to measure dynamic GABA function. In published work, the investigators have demonstrated abnormal BOLD response (increased rather than decreased signal) in schizophrenia in the dorsomedial prefrontal cortex (dmPFC). This BOLD response to a GABAergic manipulation is correlated with NA in both patients and controls, consistent with a transdiagnostic dimension. The project will extend these findings across the psychosis spectrum. As the regulation of GABA function plays a critical role in the excitatory/inhibitory (E/I) balance, the phfMRI probe serves as a proxy measure of E/I balance, and it will be used to test the hypothesis that this dynamic measure is associated with NA and GABA concentration measured with MRS. Expected Impact: Successful achievement of study aims will clarify GABAergic dysfunction in the psychosis spectrum, leading to follow-up studies on the role of illness stage in GABA activity and the E/I balance. As NA is a strong, transdiagnostic predictor of functional outcome, the impact of this work will establish potential therapeutic leverage points linking GABAergic treatments with NA as a clinical outcome in the psychosis spectrum.

摘要