The Neural Mechanisms of Motor Dysfunction in Clinical High-Risk Youth.

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Project Summary Motor abnormalities are a core feature of schizophrenia that are present across all phases of the illness from the premorbid stage (i.e., pre-illness) to chronic psychosis. Consistent with a dopamine (DA) etiological conceptualization of psychosis, aberrant motor function across the different phases of the disorder is both associated with abnormal structural and functional dopamine mediated motor circuitry and predicts conversion. However, to date, the majority of research examining motor dysfunction in psychosis has focused on overt motor performance (e.g., video coded movement abnormalities) in patients with schizophrenia. Because of this, little is known about the timing of neural processes underlying abnormal motor behavior in schizophrenia, and there has been no work conducted in youth in the clinical high-risk (CHR) period of the disorder (the stage immediately preceding the first episode of psychosis). Given that both motor planning and motor execution arise from underlying dopamine (DA) mediated motor circuitry implicated in the pathogenesis of the illness, understanding how these mechanisms are impaired before the onset of the disorder (i.e., in CHR populations) stands to inform our understanding of the etiology of psychosis, as well as provide a putative vulnerability marker sensitive to progression. The current proposal will address these questions using a longitudinal investigation of neural abnormalities in motor planning and execution (Aim 1) in CHR youth and healthy controls. The individual processing stages underlying motor planning and execution will be measured using a combination of the lateralized readiness potential ERP component and behavioral reaction time (RT) variability (i.e., standard deviations of RT). The neural measures in Aim 1 will be validated against behavioral motor measures (i.e., dyskinesias) known to reflect abnormal DA mediated motor circuitry (Aim 2). To track clinical progression and risk, associations between the measures from Aim 1 and symptom severity, symptom progression, and psychosis risk will be examined (Aim 3). Training Plan: An extensive training plan has been developed to enable the Applicant to effectively complete the project. Through coursework, colloquia/conference attendance, workshops, and weekly meetings with the sponsors, the Applicant will develop theoretical expertise in motor pathology in psychosis, as well as specialized skills in the ERP technique and longitudinal research design. This training plan was designed to facilitate the Applicant’s career aspirations as a research scientist with the sound theoretical foundation and methodological expertise necessary to conduct his own independent program of research. Training Environment: The project will take place at Northwestern University, an ideal training environment given the accessibility to cutting- edge resources, equipment, and coursework at the site. Further, both the Sponsor and Co-Sponsor are located at the institution and are experts in the theory and methods needed to meet the Applicant’s training aims.