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: 10447941
• 负责人: Baktash Babadi
• 金额: $ 19.06万
• 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/10447941
• 关键词: Address; Affect; Area; Behavioral; Biological Markers; Biophysics; Brain; Chronic; Clinical; Clinical Research; Cognitive deficits; Complex; Computer Models; Computer Simulation; Country; Depth Perception; Detection; Development; Disease; Early Diagnosis; Functional Magnetic Resonance Imaging; Functional disorder; Human; Impairment; Individual; Lateral Geniculate Body; Lead; 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 impairment; Visual system structure; area striata; base; behavioral response; biomarker development; biophysical model; brain dysfunction; career; computational neuroscience; contrast enhanced; deep learning; experimental study; extrastriate visual cortex; functional MRI scan; improved; information processing; neural correlate; neuroimaging; neuromechanism; new therapeutic target; novel therapeutics; orientation columns; relating to nervous system; 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 精神分裂症是一种慢性病程的致残性精神疾病，影响着超过 300 万人。 国家和全世界数千万。精神分裂症的可用治疗方法很有限 有效改善这些患者的生活质量，部分原因是尚不清楚的神经机制 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 有机会借用和结合基础神经科学的不同技术来研究两者之间的关系 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 指导的以患者为中心的研究职业发展奖。该提案详细介绍了全面的 为计算神经科学家和精神病学家的申请人提供为期四年的培训计划，以获取 人类视觉神经科学和功能神经影像方面的额外正式培训和指导。来测试他的 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，跟踪和定位三个连续视觉阶段的视觉缺陷 精神分裂症的处理，即对比度检测、方向检测和深度感知。这 要检验的假设是赤字在所有三个阶段都普遍存在。第二，他要开发计算机 对上述视觉处理阶段的底层神经结构的生物物理模型的模拟， 包括外侧膝状核 (LGN)、初级和次级视觉皮层（V1 和 V2、 分别）。然后，他将调整模型的参数，以复制每个受试者在实验中的表现。 上述阶段，以便为每个主题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，以检验兴奋和兴奋同时减少的假设 抑制是精神分裂症视觉缺陷的原因。第三，进一步检验感知假设 缺陷是由于潜在神经基质内的活动减退和连接失调造成的，他将获得 精神分裂症和正常对照受试者 LGN、V1 和 V2 的高分辨率（7 特斯拉）fMRI 扫描。他会 将受试者在视觉处理的三个阶段中的感知表现与活动相关联 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 对电路层面的功能障碍如何导致明显的行为缺陷的机制理解 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，并开发新型治疗剂。它还可能导致识别 客观的生物标志物来评估治疗反应，并促进早期发现这种疾病。