This is an application for a NIMH Mentored Patient-Oriented Research Career Development Award (K-23) entitled, fMRI and TMS of Working Memory in Schizophrenia. Working memory (WM) deficits are a persistent, disabling and treatment-resistant feature of schizophrenia that are associated with dorsolateral prefrontal cortex (DLPFC) dysfunction. However, the responsible neural circuitry and the exact contribution of the DLPFC are unknown. The candidate aims to elucidate the neural basis and nature of WM deficits in schizophrenia. This work will clarify the function of the DLPFC and other components of WM neural circiutry and contribute to the development of more focused interventions to improve WM and the behaviors that rely on it. The DLPFC is a large and functionally heterogeneous area. Event- related functional magnetic resonance imaging (fMRI) on a 3.0 Tesla system and high resolution cortical flat mapping will be used to identify DLPFC subregions associated with each temporally separated behavioral subcomponent of WM performance in normal and schizophrenia subjects. Using a stereotactic mapping system, transcranial magnetic stimulation (TMS) will be applied to these DLPFC subregions, identified in each subject with fMRI, to produce reversible functional disruption with millisecond accuracy during WM performance. This will establish whether a region is necessary for WM, and the timing of its contribution. Together, these complementary methods yield more precise information about the location, timing and contribution of regional brain activity to WM than was previously available. The two WM paradigms employed in these paired fMRI/TMS studies will test the hypothesis that schizophrenia subjects fail to automate WM performance as reflected in aberrant recruitment of frontostriatal neural circuitry, a failure to show the normal lateralization of DLPFC function in response to task demands, and an increased sensitivity of DLPFC function to WM load. The training program supplements the candidate s strengths in experimental psycholpathology and neuropsychology and capitalizes on the rich, diverse neuroscience community in the Boston area. It provides didactic instruction and expert mentorship in advanced statistics, event-related fMRI, cortical flat mapping, TMS and models of brain function relevant to schizophrenia. The integrated training and research program will allow the candidate to master complex and sophisticated tools and to establish herself as an independent investigator of the neurobiology of cognitive deficits and symptoms in schizophrenia.
