Network-targeted TMS modulates nicotine craving and default mode network connectivity in psychotic disorders

Objective 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 transcranial magnetic stimulation (TMS) would affect craving. Methods In B-SNIP2 (n = 596), we tested associations between DMN connectivity and tobacco use. In the Single Session DMN-targeted TMS study, 10 individuals received single TMS 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, 12 individuals received 5 cTBS sessions with pre-/post-neuroimaging and craving assessment. Results 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 TMS study (n = 10), there was a treatment∗time interaction (p = .020) where iTBS increased craving (p adj = 0.018) compared to cTBS. 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 = .047). Conclusions We identified a potential mechanism of nicotine use in psychosis and demonstrated that engaging this target reduces craving, suggesting a novel target for nicotine interventions in psychosis.