GABA Modulation and Negative Affect in Psychosis

描述(申请人提供)：精神分裂症患者的GABA调节和负性情绪经常表现为临床上显著的负性情绪。除了抑郁症和焦虑症的共病(高达60 O/O)外，患者还表现出高水平的特质负性情感。焦虑和对压力的敏感出现在疾病的前驱期和整个病程中，与疾病的阳性症状一起变化，但也解释了与阳性和缺陷症状无关的表型差异和功能结果。负面影响的药物治疗，特别是焦虑，经常用苯二氮类药物(BDZ)增强GABA能功能。BDZ还可以防止复发早期的精神病发作，这表明GABA能功能与精神病的发生之间存在联系。GABA能增强的临床应用耐人寻味，因为尸检证据表明精神分裂症患者抑制性皮质间神经元的GABA能功能降低。虽然GABA-A受体分布广泛，但与精神病相关的亚型可能有更具地区性的分布模式。利用BDZ提供的治疗杠杆，这份R21提案将专注于BDZ如何调节处理情感信息的大规模网络。利用情感评估网络进行验证的任务将集中在内侧额叶皮质(MFC)，这是一种与精神分裂症有关的结构。新的数据显示，精神分裂症/分裂情感(SCZ)患者在处理负面情绪刺激时MFC过度活跃。这项提议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，以及那些普遍存在的焦虑回路。20名SCZ患者、20名健康对照(HC)和20名社交恐惧症(SP)患者将以随机交叉设计进行研究，分别静脉注射劳拉西潘和安慰剂。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)。比较目标1中的SCZ与HS和SP，我们预测在评估期间和BDZ之后MFC中的特定效应：BDZ将对SCZ的MFC活动产生更大的抑制作用，这是由于评估负面刺激而引起的。在目标2中，我们将寻找参与情感评估的区域，如被BDZ减弱的前岛区，以及两组焦虑患者共同的区域，即SCZ和SP&GT；HC的减少。AIM 3将探索BDZ引起的网络水平变化，特别关注丘脑皮质与MFC的连接。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。一旦发现，特定的神经回路可能被神经调节干预措施靶向，这些干预措施可以增强抑制功能，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：精神分裂症和分裂情感障碍的治疗经常使用药物，如苯二氮类药物(BDZ)，以治疗经常伴随精神病的负面情绪，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，因为在尸检工作中已经发现了GABA系统的功能障碍。该项目将使用功能神经成像来识别BDZ在精神分裂症患者处理负面情绪材料时改变的网络，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.