Empirical validation of a cerebellar-cortical hallucination circuit

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Project Summary / Abstract Projects like the BRAIN initiative hold the potential for a fundamentally new approach to therapeutics for severe mental illness. Neuromodulation technologies promise to allow selective intervention in which pathophysiology is specifically targeted for correction. These initiatives are critically dependent on the correct identification of circuit dysfunction that causes psychiatric symptoms. NIMH has prioritized this as a strategic objective: Identify and characterize the neural circuit mechanisms contributing to human behavior and their disruption in mental illnesses. Neuroimaging studies have generated promising leads while almost never demonstrating that these findings represent targets that can be engaged for therapeutic benefit. We thus lack a key perquisite for translation into the clinic: For imaging biomarkers to make the leap to translational use, they would need to accurately identify the circuits that give rise to symptoms. In this project we seek to understand how brain circuit dysfunction causes auditory hallucinations in schizophrenia. Published, technically challenging imaging studies provide a critical clue: These “symptom capture” experiments that collect MRI imaging during hallucinations have identified a disparate pattern of activations across multiple subcortical and cortical brain regions. Our hypothesis is that these brain regions are part of a single circuit than spans cerebellar, thalamic, and cortical brain regions. In our preliminary data we are able to identify the cerebellar node of this circuit, and then, in an independent cohort of participants with schizophrenia, we used neuromodulation to manipulate this circuit. We observe that non-invasive neuromodulation can manipulate connectivity across this entire circuit. Restoration of connectivity in this circuit is reflected in reduction of hallucination severity. In this proposal we seek to confirm and extend this result. We will use non-invasive neuromodulation to specifically target this circuit and observe change induced on the hallucination circuit in a sham-controlled study. If successful, this project will establish a circuit-level understanding of how pathophysiology is causally linked to hallucinations. This kind of mechanistic understanding of schizophrenia symptoms would be unprecedented and would identify biological target for engagement to reduce these symptoms.