GABA Modulation and Negative Affect in Psychosis

描述（由申请人提供）：精神分裂症患者的GABA调节与负性影响常表现为临床显著的负性影响。除了共病性抑郁和焦虑症（高达60 /O）外，患者还表现出高水平的特质性负面情绪。焦虑和对压力的敏感出现在前驱期和整个病程中，与疾病的阳性症状共同变化，但也独立于阳性和缺陷症状来解释表型差异和功能结果。药物治疗的负面影响，特别是焦虑，往往增加gaba能功能与苯二氮卓类药物（BDZ）。BDZ还可以预防早期复发的精神病发作，这表明gaba能功能与精神病的发生之间存在联系。鉴于精神分裂症患者死后发现抑制性皮质间神经元gaba能功能降低，增强gaba能的临床应用很有趣。虽然GABA-A受体广泛存在，但与精神病相关的亚型可能具有更多的区域特异性分布模式。利用BDZ提供的治疗作用，本R21提案将关注BDZ如何调节处理情感信息的大规模网络。利用情感评估网络的有效任务将集中在内侧额叶皮层（MFC）上，这是一种与精神分裂症有关的结构。新出现的数据显示，在处理负面情绪刺激的精神分裂症/分裂情感（SCZ）患者中，MFC过度活跃。本研究的探索性实验旨在功能性地识别慢性精神病的特定回路，以及焦虑的一般回路。20例SCZ患者，20例健康对照（HC）和20例社交恐惧症患者（SP）将采用静脉注射劳拉西泮和安慰剂的盲法交叉设计进行研究。他们将在功能磁共振成像过程中执行两项评估任务（对情绪图片进行评级和判断个人对情绪面孔的偏好）。将SCZ与Aim 1中的HS和SP进行比较，我们预测了BDZ在评价期间和之后对MFC的具体影响：BDZ对SCZ的负面刺激会引起MFC活性的更大衰减。在目标2中，我们将寻找与情感评估有关的区域，如被BDZ减弱的前岛，以及两组焦虑患者共有的区域，即SCZ和SP > HC的减少。目的3将探讨BDZ引起的网络水平变化，特别关注丘脑皮质与MFC的连通性。识别BDZ调节SCZ评估过程的大规模神经回路可能为定位与精神病相关的GABA系统提供重要线索。一旦确定，特定的神经回路可能被靶向神经调节干预，可以增强抑制功能，如经颅磁刺激，为治疗这种毁灭性的脑部疾病提供新的途径。公共卫生相关性：精神分裂症和分裂情感性障碍的治疗经常使用药物，如苯二氮卓类药物（BDZ），来治疗通常伴随精神病的负面影响，如焦虑。BDZ对GABA系统的调节可能与精神分裂症的病理生理有关，因为GABA系统的功能障碍已经在死后的工作中被确定。该项目将使用功能性神经成像来识别精神分裂症患者处理负面情绪材料时BDZ所改变的网络，这些知识可能会导致设计更好的治疗干预措施，以治疗这种毁灭性的疾病。

DESCRIPTION (provided by applicant): GABA modulation and negative affect in psychosis Schizophrenia frequently presents with clinically significant negative affect. In addition to co-morbid depression and anxiety disorders (up to 60 O/O), patients show high levels of trait negative affectivity. Anxiety and sensitivity to stress appear in the prodromal period and throughout the course of the illness, co-varying with positive symptoms of the illness, but also accounting for phenotypic variance and functional outcome independently of positive and deficit symptoms. Pharmacotherapy of negative affects, particularly anxiety, often augments GABAergic function with benzodiazepines (BDZ). BDZ's can also prevent a psychotic episode in the early stages of relapse, suggesting a link between GABAergic function and the genesis of psychosis. The clinical use of GABAergic augmentation is intriguing in light of post-mortem evidence of reduced GABAergic function of inhibitory cortical inter-neurons in schizophrenia. While GABA-A receptors are widespread, subtypes relevant for psychosis may have a more regionally-specific pattern of distribution. Exploiting the therapeutic leverage provided by a BDZ, this R21 proposal will focus on how BDZs modulate large-scale networks that process affective information. Validated tasks that tap affective appraisal networks will focus on the medial frontal cortex (MFC), a structure implicated in schizophrenia. Emerging data have shown excessive activity in the MFC of schizophrenic/schizoaffective(SCZ) patients processing negative emotional stimuli. The exploratory experiment in this proposal is designed to functionally identify circuits specific to chronic psychosis, as well as those general to anxiety. Twenty SCZ patients, 20 healthy controls (HC) and 20 patients with social phobia (SP) will be studied in a blinded cross-over design with intravenous lorazepam and placebo. They will perform two appraisal tasks (rating emotional pictures and judging personal preference for emotional faces) during functional magnetic resonance imaging. Comparing SCZ to HS and SP in Aim 1, we predict specific effects in the MFC during appraisal and after BDZ: greater attenuation of MFC activity, elicited by appraising negative stimuli, will be induced by BDZ for SCZ. In Aim 2, we will search for regions involved in affective appraisal, such as the anterior insula, attenuated by BDZ, and common to both groups with anxiety, i. e. decreases in SCZ & SP > HC. Aim 3 will explore network level changes induced by BDZ, specifically focusing on thalamocortical connectivity with the MFC. Identifying large- scale neurocircuits where a BDZ modulates the appraisal processes in SCZ may provide important clues to localize the GABA systems that are relevant to psychosis. Once identified, specific neurocircuits may be targeted with neuromodulatory interventions that can enhance inhibitory function, such as transcranial magnetic stimulation, providing new avenues for the treatment of this devastating brain disorder. PUBLIC HEALTH RELEVANCE: Treatment of schizophrenia and schizoaffective disorder frequently uses medications, such as benzodiazepines(BDZ), to treat negative affects, such as anxiety, that often accompany psychosis. Modulation of the GABA system by BDZ is potentially relevant to the pathophysiologyof schizophrenia, since dysfunction of the GABA system has been identified in post-mortem work. This project will use functional neuroimaging to identify networks changed by BDZ while schizophrenia patients process negative emotional material, knowledge that may lead to the design of better treatment interventions for this devastating illness.