Neurophysiological and MRI Studies of Schizophrenia

精神分裂症的神经生理学和 MRI 研究

• 批准号: 9337244
• 负责人: MARGARET A NIZNIKIEWICZ
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337244
• 关键词: Affect; Age; Animals; Anterior; Antipsychotic Agents; Auditory; Auditory Physiology; Award; Bilateral; Biological Markers; Brain region; Categories; Cell Nucleus; Clinical; Communication; Communities; Cues; Data; Decision Making; Effectiveness; Electroencephalography; Employee Strikes; Event-Related Potentials; Failure; Functional disorder; Funding; Glutamates; Guidelines; Impairment; Lead; Left; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Molecular; Monitor; National Institute of Mental Health; Neurons; Neurosciences; P300 Event-Related Potentials; Parvalbumins; Pathology; Pathway interactions; Patients; Peer Review; Pharmacology; Phase; Physiological; Physiology; Play; Population; Prevalence; Productivity; Protons; Publications; Recruitment Activity; Research; Research Domain Criteria; Role; Scalp structure; Schizophrenia; Schizotypal Personality Disorder; Sequence Analysis; Superior temporal gyrus; Symptoms; Targeted Research; Work; associated symptom; base; cingulate cortex; gamma-Aminobutyric Acid; gray matter; hippocampal pyramidal neuron; indexing; information processing; interest; neural circuit; neurochemistry; neurophysiology; neurotransmission; novel; presynaptic; public health relevance; receptor; response; social

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.

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毁灭性影响都太明显了，随之而来的深入研究却众所周知。该申请是自1998年以来获得资助的VA功绩奖的竞争续签，自上次提交以来，其35个同行评审的出版物表明生产率很高。在一项针对40名VA SZ患者和40名社区聘请的40名社区选择，非患者，从未与神经性化的型精神分裂症（SPSD）相比，HES的48例HESM（HESC）相比，该应用程序在包含3T质子磁共振光谱（MRS）的3T质子磁共振光谱（MRS）方面开辟了新的道路。允许与SZ和SPD主题组相匹配。 该提案遵循RDOC概念化在检查神经回路的神经回路，包括在SZ和SPD的DSM类别中，在上颞回（STG）中，含有白蛋白和谷氨酸性金字塔神经元的皮质GABA神经元之间的相互作用。使用RDOC指南，我们根据其组成分子和神经元以及更高级别的其与生理学和症状的关系在更基本的水平上检查了这一神经回路（在简介部分的表中示出了）。因此，我们的MRS研究提供了有关该神经回路的分子基础的关键信息，以GABA和谷氨酸能代谢产物的度量。与HC相比，SZ和SPD的GABA能神经传递的总体假设具有增加的谷氨酸能和GABA能神经传递的降低，导致神经生理学和临床异常。我们的PD表明，与SZ相比，SPD的谷氨酸能较小，尤其是较小的GABA能异常。 从神经回路到更高水平的生理学，广泛的基本神经科学工作表明，该神经回路负责 产生伽马频带振荡（GBO，在头皮录制的脑电图中约40 Hz）。 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，我们根据我们的初步数据（PD）假设，GBO的强度提供了衡量GABA能和谷氨酸能MRS值的功能相关性的度量。听觉稳态反应（ASSR）提供了GBO强度的可靠实验指数。 SZ和SPD均表现出对40 Hz的反应受损。由于GBO在跨大脑区域的信息处理和转移中发挥了作用，因此我们概念化它们的异常情况会导致感知的腐败，并导致垂直感知整合（包括社会提示）的失败，并导致正面和负面症状成分。我们对新型MRS感兴趣区域的主要关注，STG（尤其是在左侧）取决于其在产生ASSR GBO中的作用以及我们广泛的初步数据，显示了STG灰质降低以及相关的异常事件与事件相关潜力（ERP）发生在SZ（优点奖励）和SPD（NIMH Achards）中。 此外，我们评估了由前扣带回皮层（ACC）和STG相互作用组成的神经回路，该神经是由来自每个核向另一个核的锥体神经元投射而成的。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。在生理层面，ACC在决策（ODDBALL P300）和显着网络（News P300）中具有已知作用。因此，我们预测和初步数据证实，STG和ACC MRS谷氨酸能和Gabaergic代谢物在SZ和SPD中调节了Oddball和News P300。我们根据我们的初步数据进一步预测ERP-MENMPTOM关联。