GABA Modulation and Negative Affect in Psychosis

描述（由申请人提供）：精神病中的GABA调节和负面影响精神分裂症经常表现出临床显著的负面影响。除了共病的抑郁症和焦虑症（高达60 O/O），患者表现出高水平的特质消极情感。焦虑和对压力的敏感性出现在前驱期和整个病程中，与疾病的阳性症状共变，但也解释了独立于阳性和缺陷症状的表型方差和功能结果。药物治疗的负面影响，特别是焦虑，往往增强GABA能功能与苯二氮卓类（BDZ）。BDZ还可以在复发的早期阶段预防精神病发作，这表明GABA能功能与精神病的发生之间存在联系。根据精神分裂症患者抑制性皮层中间神经元的GABA能功能降低的死后证据，GABA能增强的临床应用是有趣的。虽然GABA-A受体分布广泛，但与精神病相关的亚型可能具有更具有区域特异性的分布模式。利用BDZ提供的治疗杠杆，这个R21建议将重点放在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验证任务将集中在内侧额叶皮层（MFC），这是一种与精神分裂症有关的结构。新出现的数据显示，精神分裂症/情感障碍（SCZ）患者处理负面情绪刺激的MFC活动过度。本研究中的探索性实验旨在从功能上识别慢性精神病特有的回路，以及焦虑的一般回路。20名SCZ患者、20名健康对照（HC）和20名社交恐惧症（SP）患者将采用盲法交叉设计，静脉注射劳拉西泮和安慰剂进行研究。他们将在功能性磁共振成像期间执行两项评估任务（对情感图片进行评级和判断个人对情感面孔的偏好）。比较SCZ的HS和SP的目的1，我们预测具体的影响，在MFC的评价和BDZ后：更大的衰减MFC的活动，引起的评价负面刺激，将诱导BDZ SCZ。在目标2中，我们将寻找与情感评价有关的区域，如前额叶，被BDZ减弱，并且是焦虑组的共同区域，即。e.降低SCZ和SP > HC。目标3将探索BDZ诱导的网络水平变化，特别关注丘脑皮质与MFC的连接。确定BDZ调节SCZ评价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，特定的神经回路可以通过神经调节干预来靶向，这些干预可以增强抑制功能，例如经颅磁刺激，为治疗这种毁灭性的大脑疾病提供了新的途径。公共卫生相关性：精神分裂症和情感障碍的治疗经常使用药物，如苯二氮卓类（BDZ），以治疗负面影响，如焦虑，往往伴随着精神病。BDZ对GABA系统的调节可能与精神分裂症的病理生理学有关，因为在死后工作中已经确定了GABA系统的功能障碍。该项目将使用功能性神经成像来识别BDZ改变的网络，而精神分裂症患者处理负面情绪材料，这些知识可能会导致为这种毁灭性疾病设计更好的治疗干预措施。

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.