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

精神分裂症早期视觉系统的缺陷，综合心理物理学、计算和神经影像学方法

• 批准号: 10697353
• 负责人: Baktash Babadi
• 金额: $ 19.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697353
• 关键词: Address; Affect; Area; Behavioral; Biological Markers; Biophysics; Brain; Chronic; Clinical; Clinical Research; Cognitive deficits; Compensation; Complex; Computer Models; Computer Simulation; Country; Depth Perception; Detection; Development; Disease; Disparity; Early Diagnosis; Functional Magnetic Resonance Imaging; Functional disorder; Human; Impairment; Individual; Lateral Geniculate Body; Link; Measures; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Mentorship; Modeling; Molecular Abnormality; Nature; Neural Network Simulation; Neuronal Dysfunction; Neurosciences; Patients; Performance; Persons; Process; Psychiatrist; Psychiatry; Psychophysics; Quality of life; Reporting; Research; Resolution; Retina; Schizophrenia; Series; Signal Transduction; Stimulus; Structure; Symptoms; Synapses; System; Techniques; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Training; Training Programs; Visual; Visual Cortex; Visual Perception; Visual Psychophysics; Visual System; Visual impairment; area striata; behavioral response; biophysical model; brain dysfunction; career; computational neuroscience; contrast enhanced; deep learning; experimental study; extrastriate visual cortex; functional MRI scan; improved; information processing; neural; neural correlate; neuroimaging; neuromechanism; new therapeutic target; novel therapeutics; orientation columns; response; response biomarker; treatment response; visual information; visual neuroscience; visual processing; visual stimulus

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.

概括 精神分裂症是一种残疾的精神病患者，患有慢性病程，影响了超过300万人 国家和全球数千万。精神分裂症的可用疗法仅适度 有效地改善了这些患者的生活质量，部分原因是 紊乱。精神分裂症除了其核心临床症状外，还与视觉感知缺陷有关。 视觉系统是大脑中研究最广泛的系统之一。因此，它提供了 从基本神经科学中借用和结合不同技术的机会，调查关系 在神经功能障碍和精神分裂症的感知缺陷之间，这是该提案的目的 K23指导了面向患者的研究职业发展奖。该建议详细介绍了一个全面的 申请人的四年培训计划是一名计算神经科学家和精神科医生，以获取 人类视觉神经科学和功能性神经影像学方面的其他正式培训和指导。测试他 假设，申请人将首先对精神分裂症患者进行一系列视觉心理物理研究 和正常的控制对象，以跟踪和定位在连续三个阶段的视觉缺陷 精神分裂症的处理，即对比度检测，方向检测和深度感知。这 要测试的假设是，在所有三个阶段，缺陷都是普遍的。其次，他将开发电脑 上述视觉处理阶段的基础神经结构的生物物理模型的模拟， 包括侧向基核（LGN），一级和次级视觉皮层（V1和V2， 分别）。然后，他将调整模型的参数，以复制每个主题的性能 上述阶段，以便为每个主题开发一个个性化的计算模型。 随后，他将比较跨生物物理模型的兴奋性和抑制性成分 精神分裂症和对照对象，以检验以下假设 抑制作用解释了精神分裂症的视觉缺陷。第三，进一步检验了感知的假设 缺陷是由于潜在神经基质内的低连接性和异常连接性，他将获得 精神分裂症和正常对照受试者中LGN，V1和V2的高分辨率（7 Tesla）fMRI扫描。他会的 将视觉处理三个阶段中受试者的感知表现与活动相关联 基础大脑区域的水平和内在功能连通性。这项研究的结果将产生 机械理解对电路水平的功能障碍如何导致不同的行为缺陷 精神分裂症。这种机械理解将为识别新的治疗靶标铺平道路 精神分裂症和新型治疗剂的发展。它也可能导致确定 客观的生物标志物评估对治疗的反应并促进这种疾病的早期发现。