Excitation-inhibition imbalance, posteromedial cortical dysconnectivity, and thought disorder in first-episode psychosis

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PROJECT SUMMARY/ABSTRACT This is an application for a K23 award for Dr. Michael Murphy, a psychiatrist and systems neuroscientist at McLean Hospital and Harvard Medical School. The training objectives for this award are for the candidate to (1) develop expertise in magnetic resonance spectroscopy (MRS) including integrating MRS with electroencephalography data, (2) develop expertise in symptom assessment using psychometric scales and deep-phenotyping, and (3) prepare the candidate for an independent research career. Dr. Murphy has proposed a rigorous didactic curriculum as well as a skilled mentoring team including Dr. Dost Ongur, Chief of the McLean Hospital Psychotic Disorders Division, as primary mentor. Psychotic disorders (PDs) are severe psychiatric illnesses with poorly understood pathophysiologies. Our understanding of these illnesses is limited both by a problematic syndrome- based nosology and the technical limitations inherent in our neuroimaging and genetic techniques. These disorders consist of multiple symptoms each of which may be driven by a distinct neural pathology and which may change on its own timescale. Therefore, research that focuses on specific symptoms rather than syndromes may be better able to ameliorate the limitations of current technology. Schizophrenia has been proposed to be a dysconnection syndrome and given this hypothesis the symptoms of schizophrenia may be caused by particular patterns of dysconnectivity. Thought disorder (TD) is a commonly encountered symptom in psychotic disorders and is associated with poor prognosis. I propose to test the hypothesis that TD arises from dysfunction within the thalamus and posteromedial cortex (PMC) as well as dysconnectivity within cortico-thalamo-cortico loops involving the PMC. The proposed dysconnectivity may partially decouple networks that maintain conscious awareness from those that regulate attention. Inappropriate PMC connectivity will be tested with directional functional connectivity which can distinguish between aberrant inputs to and outputs from the PMC, a distinction that would be obscured in directionless measures. Functioning of neural circuits within the thalamus and PMC will be assessed using MRS to assess levels of glutamate and GABA. The proposed project will test a novel hypothesis linking neurochemistry, directed functional connectivity, and psychiatric symptomology. This project will potentially provide a treatment biomarker which could be used to assess non-human models of psychotic disorders and test treatment options.