Impairments in attenfion and working memory are core disturbances in schizophrenia. The Central Hypothesis posits that these arise due to molecular (Project 1) and morphological (Project 2) abnormalifies in the layer 3 pyramidal cells that that interconnect the dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC). The goal of Project 5 is use information from the normal properties of PPC-DLPFC circuitry in monkeys (Projects 3 and 4) to determine how these cellular abnormalifies give rise to cortical network and cognitive disturbances in medication naive, first-episode psychosis. We will use tasks that rely to different degrees on 'bottom-up'or 'top-down'processing to determine how activity within and communicafion between DLPFC and PPC are impaired, whether such disturbances are reflected equally or differentially in 'bottom-up'and 'top-down'processing, and if cortical oscillations provide signatures for such local and distributed circuit disturbances. We will employ a mulfimodal imaging approach taking advantage of the high temporal resolufion of concurrent MEG and EEG (M/EEG) together with the high spafial resolution of fMRI. M/EEG will evaluate the synchrony of frequency band-specific neural acfivity in local and distributed circuits, including cross-frequency coordination, through integrated spectral and connectivity approaches. fMRI will evaluate, with precise and definitive anatomic localization, activity of local and distributed circuits using regional BOLD and funcfional connectivity approaches. Abnormalities in cortical layer 3 pyramidal cell function are predicted to have a direct impact on both local and distributed circuit processing. These abnormalities are refiected in impaired functional connectivity and cortical synchrony within and between DLPFC and PPC. Our findings will provide novel insights into the local and distributed circuit pathophysiology underlying executive control disturbances in schizophrenia, providing a systems-level link to cellular abnormalifies, thereby identifying physiological biomarkers for future novel therapeutic approaches.

Public Health Relevance

Cognifive dysfuncfion is the main contributor to social and occupafional problems in schizophrenia. This project will link knowledge about cellular pathology to cortical pathophysiology in medication naive subjects in a first-episode of psychosis, providing the foundation for the development of pathophysiologically-informed biomarkers for new therapeutic approaches.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-L (01))
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University of Pittsburgh
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Moyer, Caitlin E; Shelton, Micah A; Sweet, Robert A (2015) Dendritic spine alterations in schizophrenia. Neurosci Lett 601:46-53
Hu, Wei; MacDonald, Matthew L; Elswick, Daniel E et al. (2015) The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci 1338:38-57