Neurophysiological and MRI Studies of Schizophrenia

描述(由申请人提供)： 尽管精神分裂症(SZ)的患病率为1%，但它在VA患者和世界人口中的破坏性影响非常明显，以及随之而来的密集研究，许多人还不清楚。这项申请是对退伍军人事务部荣誉奖的竞争性更新，该奖项自1998年以来一直得到资助，自上次提交以来，其35篇同行评议的出版物表明生产率很高。这项应用开辟了一条新的途径，将谷氨酸和GABA能代谢物的3T质子磁共振波谱(MRS)纳入40名VA SZ患者和40名社区招募、非患者和从未服用抗精神病药物的分裂型人格障碍(SPD)受试者的研究中，两者都与48名健康对照组(HC)相比，HC过度抽样允许年龄匹配SZ和SPD受试者组。这一建议遵循了RDoC的概念，研究了包含小白蛋白的皮质GABA神经元和跨越SZ和SPD的DSM类别的颞上回(STG)中的谷氨酸能锥体神经元之间的相互作用的神经回路。使用RDoC指南，我们从其组成分子和神经元的角度，在更基本的水平上检查这种神经电路，并在更高的水平上，检查它与生理和症状的关系(如引言部分的表格所示)。因此，我们的MRS研究提供了关于这一神经回路在测量GABA和谷氨酸能代谢物方面的分子基础的关键信息。最重要的MRS假说是，与HC相比，SZ和SPD的谷氨酸能神经传递增加，GABA能神经传递减少，导致神经生理和临床异常。我们的PD提示与SZ相比，SPD的谷氨酸能，尤其是GABA能的异常较小。从神经回路到更高层次的生理学，广泛的基础神经科学研究表明，这一神经回路负责 产生伽玛频带振荡(GBO，在头皮记录的脑电中约为40赫兹)。GBO更具优势，因为它们提供了与神经传递相关的突触前(囊泡)和受体成分的功能读数。因此，我们假设，基于我们的初步数据(PD)，GBO的强度提供了GABA能和谷氨酸能MRS值的功能相关性的衡量标准。听觉稳态反应(ASSR)为GBO强度提供了可靠的实验指标；SZ和SPD在40赫兹时均表现出反应减退。由于GBO在信息加工和跨脑区域传递中起作用，我们概念化地认为，它们的异常导致知觉的腐败和真实知觉整合(包括社会线索)的失败，进而导致积极和消极的症状成分。我们主要关注新颖的MRS感兴趣区域STG(尤其是左侧)是因为它在产生ASSR GBO中所起的作用，以及我们广泛的初步数据显示STG灰质减少和相关的异常事件相关电位(ERPs)出现在SZ(奖励)和SPD(NIMH奖励)中。此外，我们评估了由前扣带回(ACC)和STG相互作用组成的神经回路，该回路由锥体神经元从两个核团投射到另一个核团形成。在分子水平上，我们研究了GABA和谷氨酸在电路调制中的作用。在生理水平上，ACC在决策(Odball P300)和突显网络(新颖P300)中扮演着已知的角色。因此，我们预测，初步数据证实，STG和ACC MRS谷氨酸和GABA能代谢产物调节SZ和SPD中奇怪的和新的P300。基于我们的初步数据，我们进一步预测了事件相关电位与症状的关系。

DESCRIPTION (provided by applicant): Despite schizophrenia's (SZ) 1% prevalence, its all too evident devastating effects in the VA patient and world population, and the consequent intensive research, much is not known. This application is a competing renewal of a VA Merit Award which has been funded since 1998, and whose 35 peer-reviewed publications since the last submission indicate high productivity. This application strikes a new path in the inclusion of 3T proton magnetic resonance spectroscopy (MRS) of glutamatergic and GABAergic metabolites in a study of 40 VA SZ patients and of 40 community-recruited, non-patient, and never neuroleptic-medicated schizotypal personality disorder subjects (SPD), both compared with 48 healthy controls (HC), with HC oversampling allowing age-matching to SZ and SPD subject groups. This proposal follows the RDoC conceptualization in examining the neural circuit consisting of interactions between cortical GABA neurons containing parvalbumin and glutamatergic pyramidal neurons in the superior temporal gyrus (STG) across DSM categories of SZ and SPD. Using RDoC guidelines, we examine this neural circuit at both more basic levels in terms of its constituent molecules and neurons, and at higher levels, its relationship to physiology and to symptoms (illustrated in the Table in the Introduction Section). Accordingly, our MRS study provides key information on the molecular basis of this Neural Circuit in measures of GABA and glutamatergic metabolites. The overarching MRS hypothesis is of increased glutamatergic and decreased GABAergic neurotransmission in both SZ and SPD, compared with HC, resulting in neurophysiological and clinical abnormalities. Our PD suggest smaller glutamatergic and especially smaller GABAergic abnormalities in SPD compared with SZ. Going from the neural circuit to the higher level of physiology, extensive basic neuroscience work indicates that this neural circuit is responsible for generating Gamma Band Oscillations (GBO, about 40 Hz in scalp-recorded EEG). GBO are further advantageous since they provide a functional readout of both neurotransmission-relevant presynaptic (vesicular) and receptor components. Thus, we hypothesize, based on our preliminary data (PD), that the strength of the GBO furnishes a measure of the functional relevance of the GABAergic and Glutamatergic MRS values. The auditory steady state response (ASSR) provides a reliable experimental index of GBO strength; both SZ and SPD show an impaired response to 40 Hz. Since GBO play a role in information processing and transfer across brain regions, we conceptualize that their abnormalities lead to corruption of percepts and to the failure of veridical perceptual integration (including that of social cues) and in turn, lead to both positive and negative symptom components. Our main focus on the novel MRS region of interest, the STG, (especially on the left) is dictated by its role in generating ASSR GBO and our extensive preliminary data showing STG gray matter reduction and associated abnormal event- related potentials (ERPs) occurring in both SZ (Merit awards) and SPD (NIMH awards). Additionally, we evaluate the neural circuit consisting of anterior cingulate cortex (ACC) and STG interaction, formed by projections of pyramidal neurons from each nucleus to the other. At the molecular level we investigate the role of GABA and glutamate in circuit modulation. At the physiological level, ACC has a known role in decision making (oddball P300) and in the salience network (novel P300). We thus predict, and preliminary data confirm, that STG and ACC MRS glutamatergic and GABAergic metabolites modulate both oddball and novel P300 in both SZ and SPD. We further predict, based on our preliminary data, ERP-symptom associations.