Network-Targeted Neuromodulation for Nicotine Dependence in Schizophrenia

PROJECT SUMMARY Tobacco use is the top preventable cause of early mortality in schizophrenia, leading to a 20-year decreased life expectancy compared to the general population. Current smoking cessation treatments are derived from people without psychosis and are significantly less effective for people with schizophrenia. We used a data-driven, agnostic approach to identify a schizophrenia-specific circuit of nicotine dependence (the Default Mode Network, DMN) then tested pharmacologic and neuromodulation interventions on this circuit. We observed craving was bidirectionally mediated by DMN connectivity: 1) nicotine administration (which reduces craving) decreased DMN connectivity in schizophrenia, while 2) a single session of intermittent theta burst stimulation (iTBS), which increases connectivity, applied to a DMN node acutely increased craving in schizophrenia. This provides evidence that 1) nicotine craving is mediated by this network and 2) this target can be engaged bidirectionally via multiple interventions. This K23 mentored patient-oriented career development award proposes to test if multiple repetitive transcranial magnetic stimulation (rTMS) sessions lead to enduring circuit change and reduce nicotine craving. Our central hypothesis is that the brain circuit most effective to reduce nicotine craving in schizophrenia is distinct from the pathway identified in a non-schizophrenia population. To test this hypothesis, we will compare 1) DMN-targeted continuous theta burst stimulation (cTBS) to 2) iTBS targeted to the left dorsolateral prefrontal cortex (L DLPFC), which reduces cigarette consumption and craving in smokers without psychosis. cTBS has been shown to decrease network connectivity. By applying cTBS to the DMN, we aim to decrease connectivity, thereby decreasing craving. We will determine if rTMS manipulates functional connectivity and craving and if craving change correlates with connectivity change for each rTMS target. To optimize rTMS response, we will also test if variability in rTMS response is explained by individual differences in network controllability. The applicant is a psychiatrist with fellowship-level training in neuroimaging and rTMS for substance use disorders in schizophrenia. Her long-term career goal is to build an independent research program using neuroimaging to identify brain networks linked to substance use in psychotic disorders then test neuroscience-based, network-targeted rTMS interventions in clinical trials for co-occurring substance use disorders in schizophrenia. To accomplish these goals, the applicant requires additional training in: 1) design and conduct of personalized network-targeted rTMS interventions, 2) individualized neuroimaging to optimize rTMS response, and 3) clinical trials and biostatistics. Training will include formal coursework, didactics, and on- site trainings, guided under a mentorship team of experts in network-targeted rTMS interventions in psychotic disorders, computational analysis of networks in psychotic disorders, and clinical trials design for rTMS and smoking cessation. Mentored training and completion of the proposed project will provide the applicant the skills and experience necessary to launch a successful independent research career.