This K23 application proposes a training and mentored research plan that will provide the applicant with new skills related to cognitive neuroscience and functional neuroimaging that will support the development of an independent research career investigating the cognitive and neural mechanisms underlying clinical and functional outcome in individuals at ultra-high-risk (UHR) for psychosis. The proposed training plan incorporates rigorous training in fMRI methodology, and relevant coursework in statistical analysis, programming, and the responsible conduct of human research. The academic and professional environment at UC Davis provides rich resources for the implementation of this proposal, including consistent access to an experienced mentorship team, a distinguished research and clinical faculty, two on-site magnetic resonance imaging (MRI) scanners and support staff dedicated to research purposes. In addition to this outstanding research training environment, the applicant will have ongoing access to established clinical populations for subject recruitment, and a strong departmental commitment to the development of the applicant's research career. The proposed mentored research study seeks to elucidate cognitive markers of risk for clinical and functional deterioration in individuals at ultra-high-risk for psychosis using fMRI. This investigation will extend previous findings established in individuals with schizophrenia by exploring prefrontally-mediated cognitive control and the integrity of underlying neurobiological circuitry in UHR individuals and healthy matched controls. Cognitive control, which is subserved by a distributed network of brain regions, coordinates thoughts and actions in order to generate goal-directed behavior. Cognitive control impairments have been consistently demonstrated in individuals with schizophrenia and, more recently, linked to clinical and functional impairment. While impairments on behavioral measures of cognition have been observed in UHR populations, the neural mechanisms underlying such impairments have not been established. Further, the link between such cognitive impairments and deterioration in clinical and psychosocial domains has not been systematically explored. This investigation utilizes an event-related functional magnetic resonance imaging (fMRI) paradigm to examine the role of the dorsolateral prefrontal cortex (DLPFC), which serves as an integral part of the distributed cognitive control network, during a task requiring high levels of cognitive control. It is hypothesized that UHR individuals will demonstrate reduced cognitive control with concurrent reductions in DLPFC activation when compared to normal controls. Furthermore, it is predicted that connectivity between the DLPFC and the distributed neural network that supports cognitive control will also be reduced in the UHR group. Finally, relationships between cortical activation and measures of clinical symptomatology and psychosocial functioning will be examined in order to determine if dysfunction in the DLPFC circuit underlying cognitive control contributes to clinical and functional outcome in these at-risk individuals. In concordance with the goals of the current NIMH Strategic Plan, results of this investigation will provide novel information on the role of prefrontal connectivity during the period preceding psychosis onset, offering insight into potential neurobiological markers as well as the possible developmental trajectory of illness progression for those individuals who are at highest risk for developing psychosis. Further, this study will broaden our understanding of the impact of prefrontal functioning on clinical and psychosocial functioning for at-risk adolescents, enhancing early identification algorithms and contributing to the development of more effective early intervention efforts.
The identification of putative markers of risk for psychosis is an essential step toward enhancing early detection and intervention efforts. This research proposes to use an fMRI paradigm to investigate cognitive control processes in the prefrontal cortex to identify markers of risk for clinical and functional deterioration in youth at ultra-high risk for psychosis.
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