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%，但其在VA患者和世界人口中的破坏性影响非常明显，因此进行了深入的研究，但仍有许多未知之处。这项申请是自1998年以来资助的VA优异奖的竞争性更新，自上次提交以来，其35篇同行评审的出版物表明了高生产力。该应用开辟了一条新的道路，在一项对40名VA SZ患者和40名社区招募的、非患者且从未接受过神经安定药治疗的分裂型人格障碍受试者（SPD）进行的研究中，纳入了谷氨酸能和GABA能代谢物的3 T质子磁共振光谱（MRS），两者均与48名健康对照（HC）进行比较，HC过采样允许与SZ和SPD受试者组年龄匹配。 该建议遵循RDoC概念化，在DSM SZ和SPD类别中检查由含有小清蛋白的皮质GABA神经元和上级颞回（STG）中的海马锥体神经元之间的相互作用组成的神经回路。使用RDoC指南，我们在其组成分子和神经元方面的更基本水平上以及在更高水平上，其与生理学和症状的关系（在引言部分的表格中说明）中检查了该神经回路。因此，我们的MRS研究在GABA和谷氨酸能代谢物的测量中提供了关于这种神经回路的分子基础的关键信息。总体MRS假设是与HC相比，SZ和SPD中的谷氨酸能神经传递增加和GABA能神经传递减少，导致神经生理学和临床异常。我们的PD提示与SZ相比，SPD的多巴胺能异常更小，尤其是GABA能异常更小。 从神经回路到更高层次的生理学，广泛的基础神经科学工作表明，这种神经回路负责 产生伽马波段振荡（GBO，在头皮记录的EEG中约40 Hz）。GBO是进一步有利的，因为它们提供了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的强度是GABA能和谷氨酸能MRS值的功能相关性的量度。听觉稳态反应（ASSR）提供了一个可靠的实验指标GBO的强度，SZ和SPD显示受损的反应，40 Hz。由于GBO在信息处理和跨脑区域的传递中发挥作用，我们概念化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，从而导致积极和消极的症状成分。我们主要关注的是新的MRS感兴趣区域，STG（特别是左侧），这是由其在产生ASSR GBO中的作用决定的，我们广泛的初步数据显示，在SZ（优异奖）和SPD（NIMH奖）中均发生STG灰质减少和相关的异常事件相关电位（ERP）。 此外，我们评估的神经回路组成的前扣带皮层（ACC）和STG的相互作用，形成的锥体神经元从每个核的投影到其他。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（古怪P300）和显着网络（新颖P300）中具有已知的作用。因此，我们预测，并初步数据证实，STG和ACC MRS代谢产物和GABA能调节两个古怪的和新的P300在SZ和SPD。我们进一步预测，根据我们的初步数据，ERP症状协会。

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.