Cerebellar Modulation of Cognition in Psychosis

PROJECT SUMMARY/ABSTRACT Psychotic disorders including schizophrenia, bipolar disorder, and related illnesses are severe, debilitating, and often fatal. Cognitive impairments in psychosis are among the leading predictors of disability and poor quality of life; despite this, there are no first line interventions to target these symptoms. Neuroimaging correlates of cognitive impairment in psychosis have been identified using fMRI techniques; however, these studies are mostly correlational in nature, limiting application of these findings to intervention. In order to develop targeted cognitive interventions, there is an urgent need to 1) identify neural circuits that are causally linked to cognitive function, and 2) demonstrate that circuits are modifiable and that circuit-level change is associated with cognitive change. This project is a renewal of a R01 funded multi-year, multi-PI plan to identify the circuit basis of medication refractory symptoms of psychotic disorders. With NIMH support we found that cerebellar-cortical functional connectivity is linked to both psychotic symptoms (hallucinations) and negative symptoms of schizophrenia. Functional connectivity can be engaged and manipulated non-invasively using neuromodulation techniques such as transcranial magnetic stimulation (TMS). The combination of TMS and longitudinal imaging can help establish causal links between circuits and cognition. In the current project we have identified distinct cortical-cerebellar circuits linked to cognitive deficits in psychosis and its prodrome. We replicated this finding and have pilot data that this circuit can be successfully engaged using rTMS. Thus, the goals of this project are 1) to test whether neural circuit dysfunction is dynamically and causally associated with cognitive impairments in people with psychotic disorders, and 2) to test whether TMS drives dynamic change in both neural circuitry and cognitive performance. We hypothesize that the relationship between circuit connectivity and cognition reflects dynamic states intra-individually and over time. Additionally, we hypothesize that the connectivity state of this circuit is modifiable by TMS and that circuit manipulation will result in cognitive change. The PIs have expertise in cognition and imaging in psychosis and the fMRI-guided TMS protocols proposed here, including successful engagement of cerebellar-cortical targets, as well as access to the equipment and resources necessary to carry out the study. If our hypotheses are supported, we will have identified an actionable target that can be immediately deployed in intervention trials to test the potential for fMRI-guided TMS to drive enduring change in cognitive circuitry and performance in psychosis.