DMN-Targeted TMS Reduces Neural Cue-Reactivity in Individuals with Schizophrenia who Use Nicotine

Background: Nicotine dependence is a major contributor to early mortality in individuals with schizophrenia, yet effective treatments remain limited. Drug cue-reactivity is a key contributor to nicotine use. Although transcranial magnetic stimulation (TMS) can reduce nicotine use and cue-reactivity, conventional left dorsolateral parietal (DLPFC)-targeted TMS is less effective in those with schizophrenia, highlighting the need for alternative, circuit-based targets. Because default node network (DMN) function is implicated in schizophrenia, cue-reactivity, and nicotine use, we investigated whether DMN-targeted TMS modulates cue-elicited brain activity in nicotine-using individuals with schizophrenia. Study Design: 63 nicotine-using individuals (schizophrenia: n=31, non-psychosis control: n=32) participated in a randomized, crossover study comparing DMN-targeted and DLPFC-targeted TMS with pre/post-TMS neuroimaging and craving assessment. A nicotine cue-reactivity task was used concurrently with neuroimaging. Mixed-effect models were used to determine effects of TMS target and diagnosis, and model relationship between baseline craving and cue-reactivity change. Study Results: At baseline, we found a Cue Reactive Network composed of regions overlapping with the DMN, including clusters in the posterior cingulate cortex, medial prefrontal cortex, and bilateral lateral occipital cortex (voxel-wise p<0.005, cluster p<0.05). Baseline cue-reactivity in schizophrenia did not differ from controls. DMN-targeted TMS decreased cue-reactivity in schizophrenia across Cue Reactive Network (estimate=-0.180, p=0.009). DLPFC-targeted TMS did not impact cue-reactivity. We did not observe an effect of either TMS target in controls. Higher baseline unprovoked craving predicted larger decrease in cue-reactivity across the Cue Reactive Network (estimate=-0.034, p=0.004). Conclusion: DMN-targeted TMS is a promising intervention that modulates nicotine cue-elicited brain activity in schizophrenia.