Neuroimaging studies of mechanism, modulation, and plasticity of cognitive impairment in first-episode schizophrenia

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ABSTRACT Cognitive impairment is a core, treatment-resistant symptom of schizophrenia that has strong influence on functional outcome. In particular, deficits in working memory, an important component of higher order cognition, have been well documented in schizophrenia. Nevertheless, mechanisms underlying these deficits are poorly understood. Recent advances in functional MRI connectivity methods provide an opportunity to better understand working memory dysfunction at the network level. Understanding cognitive impairment especially in its early phase could accelerate the development of new personalized treatments. Indeed, functional connectivity MRI is increasingly utilized to precisely select targets for Transcranial Magnetic Stimulation (TMS). In the proposed series of neuroimaging studies and analyses, our goals are to (1) identify circuit-level mechanisms that underlie working memory impairment in first-episode patients with schizophrenia, (2) modulate and measure activity in target networks that are disrupted in these patients, and (3) determine if TMS responsiveness predicts longitudinal outcomes. These goals are directly in line with NIMH’s strategic research objectives in that (1) they define the mechanism of a complex behavior and (2) they include a follow-up assessment over a 1-year period, and thus chart progression of an illness in its early phase. To achieve these goals, we designed imaging and brain stimulation experiments that will allow us to study rest-task dynamics between working memory- related brain networks. Aim 1 will combine functional connectivity and graph theory to characterize the segregation-integration dynamics of task-related networks such as frontoparietal control network and default mode network; and determine the degree to which first-episode patients differ from healthy controls in these network measures. It will also link these differences to behavioral performance. Aim 2 will utilize TMS to modulate activity in networks that underlie disrupted cognition in first-episode patients with schizophrenia. Importantly, we will individualize the target region for each patient using a combination of resting and task-based connectivity. We will then compare pre- and post-TMS behavioral and connectivity measures and determine how the degree of TMS-induced change in connectivity predicts improvement in behavior. Finally, Aim 3 will determine the degree to which TMS-induced plasticity is associated with functional outcome measured longitudinally over one year in patients. The PI’s main training goals are (1) to acquire expertise on theoretical and practical aspects of TMS, (2) to develop expertise on clinical and cognitive aspects of schizophrenia, and (3) extend his skills in connectivity methods via graph theoretical approaches and apply these techniques on fMRI data.