Mechanisms of impaired subcortical auditory processing in schizophrenia

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Project Summary Schizophrenia is among the most severe and burdensome medical conditions worldwide, yet the pathophysiological basis for symptoms experienced by patients remain unknown. This F30 application presents a research and training program that will support the applicant on a path towards becoming an NIH- funded independent investigator and physician-scientist focused on understanding the neurobiology of schizophrenia and related psychotic disorders. The activities in this application build on the candidate’s prior training and are set in a resource-rich environment that will facilitate the development of expertise in: 1) principles of clinical imaging in schizophrenia, 2) methods in cognitive neuroscience and functional magnetic resonance imaging (fMRI), 3) model-based analysis of auditory processing using fMRI, 4), fundamentals of clinical medicine and translational research, and 5) the responsible and ethical conduct of research. This research proposal aims to determine the relationships between auditory verbal hallucinations (AVH) experienced by individuals with schizophrenia and previous findings of: 1) impaired thalamocortical connectivity in mouse models of 22q11 deletion syndrome (22q11DS), the strongest known genetic risk factor for psychosis; 2) reduced resting-state functional connectivity between MGN and AC in patients with schizophrenia; and 3) impaired computational processes in auditory cortex and MGN. The overarching goal of the research to be carried out in this application is to use resting-state, task-based, and model-based multiband fMRI to identify impairments that correlate with the presence and severity of AVH in: 1) connectivity between medical geniculate nucleus (MGN) and auditory cortex (AC), and 2) auditory learning and percept generation in medial geniculate nucleus. I aim to study the following groups of individuals: unmedicated patients with SCZ and schizoaffective disorder (n=30) and matched healthy controls (varying degrees of subclinical perceptual disturbances; n=30). Using a thalamic localizer fMRI task, voxels comprising the medial geniculate nucleus will be identified in each subject. Subsequently, resting-state functional connectivity (RSFC) between MGN and AC will be determined using task-free fMRI. Using a model-based auditory discrimination fMRI task, neurocomputational underpinnings of auditory learning and percept generation will be measured. Neurobiological impairments detected via fMRI will be correlated with clinical measures of AVH severity. Such evidence would have important implications for our understanding of the brain bases of auditory verbal hallucinations and the pathogenesis of schizophrenia and would help generate new targets for treatment of this devastating illness.