Multi-modal assessment of GABA function in psychosis

精神病中 GABA 功能的多模式评估

• 批准号: 10196982
• 负责人: Stephan F Taylor
• 金额: $ 65.25万
• 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/10196982
• 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; 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; 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 大量证据表明 GABA 能功能障碍存在于精神病谱系中，其中包括 精神分裂症和双相情感障碍。 GABA 能药物治疗精神病谱系患者，通常用于治疗焦虑、 紧张症患者对增强 GABA 的苯二氮卓类药物的反应表明，两者之间存在更深层次的联系 GABA 和精神病。尸检工作强烈表明这些患者体内存在 GABA 能中间神经元，但是 这些发现、临床表型和治疗之间的联系尚不清楚。据此，这 该提案将采用跨诊断方法来详细阐述 GABA 和 这种精神病中常见的负面情感状态（NA，例如焦虑、压力敏感性） 光谱。使用多模态神经影像策略，磁共振波谱 (MRS) 可以 结合药物功能磁共振成像 (phfMRI) 挑战范式测量血氧水平依赖性 （粗体）变化。对精神病谱系中 GABA 水平的 MRS 研究得出了不一致的结果， 该提案将通过提出两个过程来解决这个问题：1）早期精神病患者中 GABA 升高 嘴内侧额叶皮层 (rMFC)，以及 2) GABA 减少与更多 NA 相关。调查人员 将寻求初步数据，表明 NA 可能与 rMFC 中的低 GABA 水平有关，并且何时 控制 NA 后，早期精神病患者的 rMFC 中 GABA 较高。在目标 1 中，本研究将利用 GABA MRS 用于评估精神病谱系患者的 GABA 水平，比较早期发作患者（50% 不服用抗精神病药物）的健康对照者，以及精神分裂症、情感分裂和双相情感障碍患者。 通过探测内侧额叶皮层中的三个不同的体素，研究人员将显示特定的区域 并证明抗精神病药物与 GABA 水平降低有关。 在目标 2 中，使用苯二氮卓类药物的 phfMRI 挑战范例将用于测量动态 GABA 功能。在已发表的作品中，研究人员表现出异常的 BOLD 反应（增加而不是 精神分裂症患者背内侧前额叶皮层 (dmPFC) 的信号减弱。这个大胆的回应 GABAergic 操作与患者和对照组的 NA 相关，与 跨诊断维度。该项目将把这些发现扩展到整个精神病谱系。作为 GABA 功能的调节在兴奋/抑制 (E/I) 平衡中起着关键作用，phfMRI 探针 作为 E/I 平衡的代理衡量标准，它将用于检验这种动态的假设 测量值与 MRS 测量的 NA 和 GABA 浓度相关。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，从而进行后续研究 研究疾病阶段在 GABA 活性和 E/I 平衡中的作用。由于 NA 是一种强大的、跨诊断的 功能结果的预测因子，这项工作的影响将建立潜在的治疗杠杆点 将 GABA 能治疗与 NA 作为精神病谱系的临床结果联系起来。