Characterizing Cognitive Impairment in Schizophrenia via Computational Modeling a

描述（由申请人提供）：精神病学领域在使用基本神经科学方法理解精神疾病方面取得了实质性进展，但细胞假设和临床现象之间的解释差距仍然很大。这种差距在我们对精神分裂症的理解上尤为明显，精神分裂症是一种破坏性疾病，其核心特征是认知障碍。精神分裂症患者表现为衰弱的认知缺陷，现有的治疗方法无法充分治疗。了解和恢复认知功能对改善患者的生活至关重要。缩小这一差距的一种方法是结合几种科学方法，在多个分析层次上调查临床现象。因此，本研究旨在将功能性神经成像与生物物理现实的神经功能计算模型结合起来，并在健康志愿者中使用安全和可逆的药理操作来测试模型预测。它进一步旨在将研究结果与精神分裂症患者观察到的缺陷进行直接比较。最终，目前的建议将架起解释的桥梁，以机械地理解精神分裂症的认知功能障碍。精神分裂症患者的一种严重受损的认知功能是工作记忆：暂时在头脑中保存和操作信息的能力。工作记忆的中断损害了患者追踪思想、想法和感觉的能力，甚至严重限制了基本的功能。尽管功能性神经影像学研究一再将工作记忆障碍与前额叶功能障碍联系起来，但突触机制仍然难以捉摸。一种主要的假说认为，由于n -甲基- d -天冬氨酸（NMDA）谷氨酸受体功能低下，皮质微回路的兴奋和抑制平衡被破坏。然而，为了验证这个与认知障碍有关的假设，并最终开发出减轻精神分裂症认知功能障碍的药物，我们需要超越神经成像的一步。我们需要在细胞机制的层面上理解工作记忆功能障碍，这是治疗方法发展的地方。本提案的具体目标是：i)扩展已建立的生物物理现实的工作记忆计算模型，以“模拟”假设的NMDA受体病理，并使用它对精神分裂症中观察到的缺陷进行行为和神经预测；ii)使用一种领先的精神分裂症安全药理学模型对这些预测进行实验测试，该模型扰乱了健康志愿者的精确机制，即氯胺酮对NMDA的短暂拮抗作用；Iii)将这些药理学结果与使用行为和功能神经影像学观察到的患者缺陷联系起来。提出的项目将缩小解释差距，并有助于发展精神分裂症认知功能障碍的多层次机制理解。最终，这项研究的成功将为合理指导的治疗提供营养，并改善患有这种毁灭性疾病的人的生活。

DESCRIPTION (provided by applicant): The field of psychiatry has made substantial progress towards understanding mental illness using basic neuroscience methods, but the explanatory gap between cellular hypotheses and clinical phenomena remains vast. This gap is particularly evident in our understanding of schizophrenia, a devastating disorder whose core feature is disrupted cognition. Schizophrenia patients present with debilitating cognitive deficits, not adequately treated by available therapies. Understanding and restoring cognitive function is critical to improving patients' lives. One way to close this gap is to investigate the clinical phenomena by combining several scientific methodologies, at multiple levels of analysis. Therefore, this proposal broadly aims to align functional neuroimaging with biophysically-realistic computational models of neural function and to test model predictions using safe and reversible pharmacological manipulations in healthy volunteers. It further aims to directly compare findings to deficits observed in schizophrenia patients. Ultimately, the current proposal will bridge levels of explanation to mechanistically understand cognitive dysfunction in schizophrenia. One severely compromised cognitive operation in schizophrenia is working memory: the ability to temporarily hold and manipulate information in mind. Disruptions in working memory compromise patients' ability to track thoughts, ideas, and feelings, severely limiting even basic functioning. Although functional neuroimaging studies repeatedly link working memory disturbances to prefrontal dysfunction, synaptic mechanisms remain elusive. One leading hypothesis proposes disruption in the balance of excitation and inhibition in cortical micro-circuitry caused by hypo-function of the N-methyl-D-aspartate (NMDA) glutamate receptor. However, to test this hypothesis in relation to disrupted cognition, and to ultimately develop medications that alleviate cognitive dysfunction in schizophrenia, we need to go a step beyond neuroimaging. We need an understanding of working memory dysfunction at the level of cellular mechanisms, which is where treatments are developed. The specific aims of this proposal are: i) to extend an established biophysically-realistic computational model of working memory to 'mimic' hypothesized NMDA receptor pathology and use it to make behavioral and neural predictions regarding deficits observed in schizophrenia; ii) experimentally test those predictions using a leading safe pharmacological model of schizophrenia that perturbs the precise mechanism in healthy volunteers, namely transient NMDA antagonism via ketamine; iii) to relate these pharmacological results to deficits observed in patients using behavior and functional neuroimaging. The proposed project will close the explanatory gap and help develop a multi-level mechanistic understanding of cognitive dysfunction in schizophrenia. Ultimately, the success of this research will fertilize rationally-guided treatments and improve the lives of people suffering from this devastating disorder.