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.

总结 精神分裂症是一种具有慢性病程的致残性精神疾病，影响着世界上超过300万人。 世界上有几千万人和几个国家。精神分裂症的现有治疗方法 有效地改善这些患者的生活质量，部分原因是神经机制尚不清楚， disorder.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 有机会借用和联合收割机不同的技术，从基础神经科学，调查的关系， 精神分裂症的神经功能障碍和知觉缺陷之间的关系，这是本提案的目的， K23指导以患者为导向的研究职业发展奖。该提案详细介绍了一个全面的 四年的培训计划，为申请人，谁是计算神经科学家和精神病学家，获得 在人类视觉神经科学和功能神经成像方面的额外正式培训和指导。上试了试 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学研究 和正常对照受试者，跟踪和定位视觉缺陷的三个连续阶段的视觉 在精神分裂症中的处理，即对比检测，方向检测和深度感知。的 有待检验的假设是，缺陷在所有三个阶段都普遍存在。其次，他将开发计算机 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， 包括外侧膝状体核（LGN）、初级和次级视觉皮质（V1和V2， 分别）。然后，他将调整模型的参数，以复制模型中每个受试者的表现 上述阶段，以便为每个受试者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和抑制成分， 精神分裂症和对照组，以检验这一假设，即同时减少兴奋和 抑制是精神分裂症中视觉缺陷的原因。第三，进一步检验知觉的假设， 缺陷是由于潜在的神经基质内的活动减退和连接障碍，他将获得 精神分裂症患者和正常对照组LGN、V1和V2的高分辨率（7特斯拉）fMRI扫描。他将 将受试者在视觉处理的三个阶段的知觉表现与活动相关联， 底层大脑区域的水平和内在功能连接。这项研究的结果将产生一个 机械地理解电路水平的功能障碍如何导致不同的行为缺陷， 精神分裂症这种机制的理解将为识别新的治疗靶点铺平道路 用于精神分裂症，以及开发新的治疗剂。它还可能导致识别 客观的生物标志物，以评估对治疗的反应，并促进这种疾病的早期检测。