Deficits of the Early Visual System in Schizophrenia, a Combined Psychophysical, Computational, and Neuroimaging Approach

摘要 精神分裂症是一种慢性病程的致残性精神障碍，影响着世界上300多万人。 国家和全球数千万人。目前对精神分裂症的治疗方法不多。 有效改善这些患者的生活质量，部分原因是不清楚的神经机制 无序。精神分裂症除了其核心临床症状外，还与视觉感知障碍有关。 视觉系统是大脑中研究最广泛的系统之一。因此，它提供了 有机会借鉴和结合基础神经科学的不同技术，研究两者之间的关系 在精神分裂症的神经功能障碍和知觉缺陷之间，这是本提案的目的 K23导师以病人为本的研究事业发展奖。这项提案详细介绍了一项全面的 申请人是一名计算神经学家和精神病学家，需要接受为期四年的培训 在人类视觉神经科学和功能神经成像方面的其他正式培训和指导。为了测试他的 假设，申请者将首先对精神分裂症患者进行一系列视觉心理物理研究。 和正常对照受试者，跟踪和定位连续三个视觉阶段的视觉缺陷 精神分裂症的加工，即对比度检测、方向检测和深度知觉。这个 需要检验的假设是，赤字在所有三个阶段都是普遍存在的。第二，他将开发计算机 上述视觉处理阶段的基本神经结构的生物物理模型的模拟， 包括外侧膝状核(LGN)、初级和次级视觉皮质(V1和V2， )。然后他将调整模型的参数，以复制每个受试者在 上述阶段，以便为每个科目开发个性化的计算模型。 随后，他将比较生物物理模型的兴奋性和抑制性成分。 精神分裂症和对照受试者，以检验这一假设，即同时减少兴奋和 抑制是精神分裂症患者视觉缺陷的原因。第三，进一步检验这样一种假设，即 缺陷是由于潜在神经基质内的活动不足和连接障碍，他将获得 精神分裂症和正常对照组的LGN、V1和V2的高分辨率(7特斯拉)fMRI扫描。他会的 将受试者在视觉加工的三个阶段的知觉表现与活动联系起来 大脑底层区域的水平和内在功能连接。这项研究的结果将产生一个 对电路水平的功能障碍如何导致明显的行为缺陷的机械理解 精神分裂症。这种机械性的理解将为识别新的治疗靶点铺平道路 治疗精神分裂症，以及开发新的治疗剂。它还可能导致识别 目的用生物标志物评价治疗反应，促进本病的早期发现。

SUMMARY Schizophrenia is a disabling psychiatric disorder with a chronic course, affecting over three million people in the country and several tens of millions worldwide. The available treatments for schizophrenia are only modestly effective in improving the quality of life of these patients, partly due to the unclear neural mechanism of the disorder. Schizophrenia is associated with deficits in visual perception, in addition to its core clinical symptoms. The visual system is among the most extensively studied systems in the brain. Therefore, it provides the opportunity to borrow and combine different techniques from basic neuroscience, to investigate the relationship between neural dysfunction and the perceptual deficits in schizophrenia, which is the aim of this proposal for a K23 Mentored Patient-Oriented Research Career Development Award. This proposal details a comprehensive four-year training program for the applicant, who is a computational neuroscientist and a psychiatrist, to acquire additional formal training and mentorship in human visual neuroscience and functional neuroimaging. To test his hypotheses, the applicant will first carry out a series of visual psychophysical studies on schizophrenia patients and normal control subjects, to track and localize the visual deficits in three consecutive stages of visual processing in schizophrenia, namely contrast detection, orientation detection, and depth perception. The hypothesis to be tested is that the deficits are pervasive at all three stages. Second, he will develop computer simulations of biophysical models for the underlying neural structures of the above visual processing stages, including the lateral geniculate nucleus (LGN), the primary, and the secondary visual cortices (V1 and V2, respectively). He will then tune the parameters of the models to replicate the performance of each subject in the above-mentioned stages, such that a personalized computational model will be developed for each subject. Subsequently, he will compare the excitatory and inhibitory components of the biophysical models across schizophrenia and control subjects, to test the hypothesis that a simultaneous reduction in both excitation and inhibition accounts for the visual deficits in schizophrenia. Third, to further test the hypothesis that the perceptual deficits are due to the hypoactivity and dysconnectivity within the underlying neural substrates, he will obtain high resolution (7 Tesla) fMRI scans of LGN, V1, and V2 in schizophrenia and normal control subjects. He will correlate the perceptual performance of the subjects in the three stages of visual processing with the activity level and intrinsic functional connectivity of the underlying brain areas. The results of this research will yield a mechanistic understanding of how dysfunctions at the circuit level can lead to distinct behavioral deficits in schizophrenia. Such a mechanistic understanding will pave the way for identification of new therapeutic targets for schizophrenia, and development of novel therapeutic agents. It could also potentially lead to identification of objective biomarkers to assess response to treatment, and to facilitate early detection of this disease.