Temporal Interference Methods for Addiction Treatment

Substance use disorders (SUDs) are difficult to treat effectively, with high relapse rates despite behavioral and pharmacological interventions. Previous clinical and case studies have shown that direct stimulation of deep brain regions-including the nucleus accumbens (NAcc) and anterior insula (AI)-can produce rapid, sustained reductions in addictive behaviors. Deep brain stimulation (DBS) of the NAcc has resulted in remission of opioid and alcohol use, while disruption of the AI has led to spontaneous loss of cigarette addiction. Although highly effective, DBS is invasive, expensive, and inaccessible to most patients. This randomized controlled clinical trial will evaluate whether temporal interference non-invasive deep brain stimulation (TI-NDBS) to the NAcc or AI can modulate deep brain activity and reduce nicotine craving and use in individuals who vape nicotine. TI uses two high-frequency electrical currents that intersect to create a low-frequency envelope capable of stimulating deep brain structures while sparing the overlying cortex. Pilot studies conducted by the investigators have shown that TI can safely and effectively activate the NAcc, as confirmed by increased BOLD signal during fMRI. In this study, 120 to 150 nicotine-dependent adults will be randomized to receive TI to the NAcc, TI to the AI, or sham stimulation. All participants will abstain from nicotine for at least 8 hours prior to the session, then undergo 60 minutes of stimulation while using a custom vape device that measures vapor inhalation in real time. Craving will be self-reported every 10 minutes. The primary outcome is a reduction in craving or nicotine use during the stimulation session. Secondary outcomes include changes in craving and use over the following week, assessed via ecological momentary assessment (EMA) three times daily using a smartphone app. Participants will also complete pre- and post-session assessments of cognitive function, emotional state, and stimulation experience. TI stimulation will be delivered with gradual current ramping to reduce discomfort, and previous pilot data support its tolerability. Findings from this study will provide early evidence of the safety and efficacy of TI-NDBS as a novel, low-cost, and scalable treatment for nicotine dependence, with potential applications in other addiction and psychiatric disorders involving deep brain circuitry.