Neurophysiology of Distributed Predictive Timing Systems in Early Psychosis

Project Summary/Abstract Schizophrenia is a debilitating disorder that affects over two million individuals in the United States alone1. Despite the burden placed on society and the individuals who suffer from this common and multifaceted disorder, we have a limited understanding of the neurobiological underpinnings of its broad range of symptoms. Dyscoordination of sensory and cognitive processes in schizophrenia may be a fundamental pathology that underlies many cognitive and behavioral impairments2,3 and cuts across the schizophrenia spectrum2,4,5. Impairments in perceptual processes that rely on the coordination of sensory, cognitive, and motor systems, such as time estimation6–10, sequence learning11,12, and rhythmic stimulus processing13, have been linked to dysfunction in cortico-striatal-thalamo-cortical (CSTC) and cerebello-thalamo-cortical (CTC) circuits, which are integral to the internal representation of temporal patterns14,15. Broad thalamocortical systems-level dysfunction in schizophrenia has garnered attention in the last decade16, with increasing evidence that CSTC excitability is decreased while CTC excitability is increased17. The identification of neuroanatomical and/or neurophysiological alterations in these circuits early in the disorder may inform future treatment interventions for schizophrenia. Based on published research and our extensive pilot data showing feasibility and scientific premise, we hypothesize hypoexcitability of CSTC systems and hyperexcitability of CTC systems within one year of the first episode of schizophrenia-spectrum psychosis (FESz). We posit that dyscoordination of timing and sequencing systems is reflected in alterations of beta-band neural activity and connectivity, evoked response amplitudes, and white matter structural abnormalities in CSTC and CTC systems, and that this dyscoordination is related to aberrant perceptual organization, negative symptoms, and cognitive dysfunction. Thus, we propose a series of multimodal experiments in FESz and healthy controls to investigate both structure and function of CSTC and CTC timing systems. We will utilize neurophysiological measures of auditory perception measured with electroencephalography and magnetoencephalography (EEG/MEG) to experimentally compare functional/task- related activity/connectivity, and we will use diffusion spectrum imaging (DSI) to examine structural connectivity. Elucidating the neural mechanisms underlying this pathophysiology is critical for understanding and potentially reducing these debilitating symptoms in schizophrenia. This study represents a great step toward that goal by delving deeply into the structure and function of CTC and CSTC timing systems in FESz.