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Project 5 — Alterations of cortical connectivity and cognition in schizophrenia
Cognitive dysfunction is the main contributor to social and occupational problems in schizophrenia. This project will link knowledge about cellular pathology to cortical pathophysiology in medication naïve subjects in a first-episode of psychosis, providing the foundation for the development of pathophysiologically-informed biomarkers for new therapeutic approaches.

Investigators
Beatriz Luna, PhD
Professor, Psychiatry


Dean Salisbury, MD
Associate Professor, Psychiatry


Avniel S. Ghuman, PhD
Assistant Professor, Neurological Surgery, Neurobiology and Psychiatry


Gretchen L. Haas, PhD
Associate Professor, Psychiatry


Debra Montrose, MSW, PhD
Program Coordinator


Figure of images showing cross-frequency coupling in healthy controls vs. schizophrenia subjects.

Abstract
Impairments in attention and working memory are core disturbances in schizophrenia. The Central Hypothesis posits that these arise due to molecular (Project 1) and morphological (Project 2) abnormalities 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 abnormalities give rise to cortical network and cognitive disturbances in medication naïve, 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 communication 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 multimodal imaging approach taking advantage of the high temporal resolution of concurrent MEG and EEG (M/EEG) together with the high spatial resolution of fMRI. M/EEG will evaluate the synchrony of frequency band-specific neural activity 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 functional 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 reflected 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 abnormalities, thereby identifying physiological biomarkers for future novel therapeutic approaches.

Project:   1    2    3    4    5    Statistics Core
 
Silvio O. Conte Center for Translational Mental Health Research
Funded by the National Institute of Mental Health (MH103204)

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