Multi-modal assessment of GABA function in psychosis

摘要 相当多的证据表明，GABA能功能障碍与精神病有关，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，通常是为了焦虑， 紧张症患者对GABA增强型苯二氮卓类药物的反应表明， GABA和精神病。尸检结果表明这些患者体内存在GABA能中间神经元，但 这些发现、临床表型和治疗方法之间的联系还远不清楚。因此，这 提案将采用跨诊断方法来阐述GABA和 负性情绪状态(NA，如焦虑、压力敏感)在整个精神病中很常见 频谱。使用多模式神经成像策略，磁共振波谱(MRS)与BE 结合药物功能磁共振成像(PhfMRI)挑战范式测量依赖的血氧水平 (大胆的)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， 本提案将通过以下两个过程来解决这一问题：1)早期精神病患者体内GABA水平升高 嘴内侧额叶皮质(RMFC)，以及2)GABA减少与更多的NA有关。调查人员 将寻求初步数据显示，NA可能与rMFC中的低GABA水平有关，以及何时 对照NA，早期精神病患者rMFC中的GABA较高。在目标1中，本研究将利用 GABA MRS评估精神病谱系患者的GABA水平，与早期发作患者(50%)进行比较 不服用抗精神病药物)与健康对照，以及精神分裂症、分裂情感障碍和躁郁症患者。 通过探测内侧额叶皮质中的三个不同的体素，研究人员将显示特定的区域 对rMFC的影响，并表明抗精神病药物与GABA水平降低有关。 在目标2中，将使用含有苯二氮卓类药物的phfMRI挑战范式来测量动态GABA 功能。在已发表的研究中，调查人员表现出异常大胆的反应(更确切地说 精神分裂症患者的背内侧前额叶皮质(DmPFC)。这一大胆的回应 在患者和对照组中，GABA能操纵与NA相关，符合 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功能的调节在兴奋性/抑制性(E/I)平衡中起着关键作用，phfMRI探针 作为E/I平衡的代理度量，它将被用来检验这种动态的假设 测量与用MRS测量的NA和GABA浓度相关预期影响：成功 研究目标的实现将澄清精神病谱系中的GABA能功能障碍，从而导致后续研究 病程对GABA活性及E/I平衡影响的研究因为NA是一种强大的、跨诊断的 功能结果的预测，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联系起来，作为精神病谱系的临床结果。

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.