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

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.