Multi-modal assessment of GABA function in psychosis

精神病中 GABA 功能的多模式评估

• 批准号: 10001023
• 负责人: Stephan F Taylor
• 金额: $ 68.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10001023
• 关键词: Accounting; Achievement; Address; Affect; Affective; Agreement; Antipsychotic Agents; Anxiety; Autopsy; Benzodiazepines; Bipolar Disorder; Bipolar I; Clinical; Data; Development; 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 structure; Outcome; Parvalbumins; Patients; Pharmaceutical Preparations; Pharmacology; Placebos; Play; Prefrontal Cortex; Process; Proteins; Proxy; Psychopathology; Psychotic Disorders; 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; dysphoria; frontal lobe; functional outcomes; gamma-Aminobutyric Acid; in vivo; multimodality; negative affect; neuroimaging; response; synthetic enzyme

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.

抽象的 大量证据暗示了精神病谱中的GABA能功能障碍，其中包括 精神分裂症和躁郁症。 GABA能药物治疗精神病患者，通常是为了焦虑， Catatonic患者对增强GABA增强苯二氮卓类的反应表明， GABA和精神病。验尸工作强烈暗示这些患者的GABA能中间神经元，但 这些发现，临床表型和治疗剂之间的联系远非明确。因此，这个 提案将采用经诊断的方法，以详细的加巴与加巴之间的联系 在这种精神病中常见的负面情感状态（例如焦虑，压力敏感性） 光谱。使用多模式神经影像学策略，磁共振光谱（MRS） 结合Pharmaco-FMRI（PHFMRI）挑战范式，测量血液氧合水平依赖性 （粗体）更改。 MRS对精神病谱系中GABA水平的研究产生了不一致的发现， 该提案将通过提出两个过程来解决：1）早期精神病患者的GABA升高 内侧额叶皮层（RMFC）和2）降低了与更多Na相关的GABA。调查人员 将寻求初步数据，以表明NA可能与RMFC中的GABA水平低相关，以及 控制NA，早期的精神病患者在RMFC中具有更高的GABA。在AIM 1中，这项研究将使用 GABA MRS评估精神病患者的GABA水平，比较早期发作患者（50％ 不服用具有健康对照的抗精神病药，以及精神分裂症，精神分裂症和双极患者。 通过探测内侧皮层中的三个不同的体素，研究人员将显示特定的区域性 RMFC中的影响并证明抗精神病药与GABA水平降低有关。 在AIM 2中，将使用苯二氮卓的PHFMRI挑战范式来测量动态GABA 功能。在已发表的工作中，调查人员证明了异常的大胆反应（增加了 比信号减少）在背额前额叶皮层（DMPFC）中的精神分裂症中。这种大胆的回应 在患者和对照组中，与NA相关的GABA能操纵与A 转诊维度。该项目将把这些发现扩展到整个精神病范围内。作为 GABA功能的调节在兴奋/抑制（E/I）平衡中起关键作用 用作E/I平衡的代理度量，将用于测试这种动态的假设 测量与MRS测量的Na和GABA浓度有关。预期影响：成功 研究目标的实现将阐明精神病谱系中的GABA能功能障碍，从而导致随访 研究疾病阶段在GABA活性和E/I平衡中的作用。由于NA是一个强大的经诊断 功能结果的预测指标，这项工作的影响将建立潜在的治疗杠杆点 将GABA能处理与NA联系在一起，作为精神病谱系中的临床结果。