Defining and Engaging a Novel rTMS Target for Nicotine Craving in Psychotic Disorders

Tobacco use is the top preventable cause of early mortality in schizophrenia, but the underlying pathophysiology remains unknown. In schizophrenia, small studies have linked default mode network (DMN) organization to tobacco use and showed that nicotine normalizes DMN disorganization. We sought to 1) validate the relationship between DMN organization and tobacco use using a large psychosis-spectrum sample (Bipolar-Schizophrenia Network on Intermediate Phenotypes 2, B-SNIP2); and 2) test if targeting this network with single and multiple sessions of repetitive transcranial magnetic stimulation (rTMS) affects craving. In B-SNIP2, we tested associations between DMN connectivity and tobacco use. In the Single Session DMN-targeted rTMS study, individuals received single rTMS sessions (intermittent theta burst stimulation, iTBS; continuous theta burst stimulation, cTBS; sham) with pre-/post-neuroimaging and craving assessment. In the Accelerated, Multi-Session DMN-targeted cTBS study, individuals received 5 sessions of cTBS with pre-/post-neuroimaging and craving assessment. In B-SNIP2 (n=596), current smokers had lower DMN connectivity than former (p=.017) and never smokers (p=.021). These differences were also observed in the psychosis group (current vs. former p=.044; current vs. never p=.011). In the Single Session DMN-targeted rTMS study (n=10), there was a nonsignificant treatment*time interaction (p=.059) where iTBS increased craving (p _adj =.015) compared to cTBS and sham. In the Accelerated, Multi-Session DMN-targeted cTBS study (n=12), DMN-targeted cTBS reduced craving after each session (p<.001) and reduced DMN connectivity (p=.052). We identified a mechanism of nicotine use in psychosis and demonstrated that engaging this target reduces craving, suggesting a novel target for nicotine interventions in psychosis.