Antipsychotic Influence on Altered MTL Neuronal Activity in Schizophrenia

描述（由申请人提供）：精神分裂症（SZ）中描述了内侧颞叶（MTL）功能的改变。MTL显示基底血流灌注升高，SZ的任务刺激激活减少，尤其是在MTL前部。检查SZ患者的MTL变化将具有挑战性，因为抗精神病药物(APD) -用于治疗几乎所有患有这种疾病的人-减弱了这些行为和功能改变；因此，这里提出的研究必然涉及未治疗（SZ-off）和治疗（SZ-on）的精神分裂症志愿者。现在是表征精神分裂症MTL功能的最佳时机，因为可以使用复杂的研究工具来确定大脑区域神经元活动，认知神经科学的丰富进展，以及SZ研究的重点是认知。这是一个有利的时机来研究与精神分裂症中海马功能障碍相关的机制，考虑到开发认知治疗的多种努力，治疗可能会影响MTL。如本提案所述，检查SZ的MTL异常将需要评估灌注和任务刺激活动，因为两者都出现改变，可能相互作用，可能在两个SZ症状域，精神病和认知中有不同的反映。目前的成像方法允许对MTL进行标准和高分辨率的检查，因此我们将采用标准分辨率的全脑方法来测试在SZ的陈述性记忆任务中，中枢神经系统的哪些区域与MTL一起发生了改变，以及采用高分辨率（高分辨率）的集中方法来测试海马体的哪些子区在SZ发生了改变，并将这些变化与疾病的症状联系起来。在这两种情况下，我们将检测APD治疗对灌注和激活的影响。探索APD对精神分裂症患者MTL记忆功能的影响的最终目标之一是发现一种更直接，可能更有效的药理学方法来纠正疾病中MTL相关症状的改变。这一建议表明，并不是MTL是SZ中唯一与病理相关的区域，而是它在精神病理的整体表达中起着关键作用，并且是一个很好的模型区域，在这个模型区域中可以检查新的症状形式。我们在这个应用程序中提出的是检查SZ的记忆表现和MTL功能，以确定精神分裂症患者MTL神经元活动变化的性质、程度和情况。该项目代表了两个实验室之间的密切合作，一个专注于精神分裂症研究（UTSW的Tamminga），另一个专注于人类记忆机制（斯坦福大学的Wagner），共同试图将基本的认知神经科学转化为对SZ症状域的理解。虽然这一建议只包括在深圳的实验，但它是基于两个站点之间的广泛合作，包括围绕概念和范例、共享方法和分析方法的互动。公共卫生相关性：精神分裂症是一种没有已知病理生理学或病因的疾病。然而，定义症状学领域，即精神病和认知功能障碍，已经允许制定一个新的模型的疾病。这一理论包括了分子神经科学和功能神经科学的最新发现，并表明一个原发病变（与认知功能障碍相关）在下游组织靶中建立了一个改变的元可塑性过程，然后与精神病有关。我们建议使用基础活动和关系记忆探针测量体内脑成像来测试该模型的元素，将神经活动的改变与疾病的特征联系起来。

DESCRIPTION (provided by applicant): Alterations in the function of the medial temporal lobe (MTL) have been described in schizophrenia (SZ). The MTL shows elevated basal perfusion and decreases in task-stimulated activations in SZ, especially in the anterior MTL. The examination of these MTL changes in SZ will be challenging because antipsychotic drugs (APD) - used to treat almost all people with the illness - attenuate these behavioral and functional alterations; therefore, the studies here proposed will necessarily involve untreated (SZ-off) as well as treated (SZ-on) volunteers with schizophrenia. Now is an optimal time to characterize these MTL functions in schizophrenia because of the sophisticated research tools available to determine regional neuronal activity in brain, the rich advances in cognitive neuroscience, and the focus of SZ research on cognition. It is a propitious time to examine mechanisms associated with hippocampal dysfunction in schizophrenia given the multiple efforts to develop treatments for cognition, treatments that may affect the MTL. Examination of the MTL abnormalities in SZ as described in this proposal will require assessment of both perfusion and task-stimulated activity, since both appear altered, may interact with each other and may be differentially reflected in two of the SZ symptom domains, psychosis and cognition. Current imaging methods allow for a standard- and a high-resolution examination of MTL, so we will pursue both the standard-resolution whole brain approach to test which CNS areas overall are altered during declarative memory tasks in SZ along with the MTL, as well as the high- resolution (high-res), focused method to test which subfields of hippocampus are altered in SZ and to associate these changes with symptoms of the illness. Under both conditions, we will examine the effect of APD treatment on perfusion and activation. One of the ultimate goals in exploring the effects of APD on MTL memory function in schizophrenia is the promise of discovering a more direct, possibly more efficient, pharmacological approach for correcting altered MTL-associated symptoms in the illness. This proposal suggests, not that the MTL is the only region associated with pathology in SZ, but rather that it is a critical player in the overall expression of psychopathology and a good model region in which to examine a new formulation for symptoms. What we propose in this application is to examine memory performance and MTL function in SZ to determine the nature, extent, and circumstances of the changes in MTL neuronal activity in schizophrenia. This project represents a close collaboration between two laboratories, one focused on schizophrenia studies (Tamminga at UTSW) and the other on human memory mechanisms (Wagner at Stanford), together attempting to translate basic cognitive neuroscience to the understanding of symptom domains in SZ. Although this proposal includes only the experiments in SZ, it is based on extensive collaboration between the two sites, involving interactions around concepts and paradigms, shared methodology, and analytic approaches. PUBLIC HEALTH RELEVANCE: Schizophrenia is an illness without known pathophysiology or etiology. However, defining domains of symptomatology, namely, psychosis and cognitive dysfunction, has allowed the formulation of a new model for the illness. This formulation includes recent discoveries from molecular and functional neuroscience and suggests that one primary lesion (associated with the cognitive dysfunction) sets up an altered metaplasticity process in downstream tissue targets, which is then associated with psychosis. We propose to test the elements of this model with in vivo brain imaging using measures of basal activity and relational memory probes, correlating alterations in neural activity with characteristics of the illness.