Longer Temporal Interference Stimulation Induces Detectable Intrinsic Activity Alterations in Human Nucleus Accumbens

The nucleus accumbens (NAc) possesses critical neurobiological and pathophysiological significance as a hub within the mesolimbic reward circuitry. Recent advances in non-invasive neuromodulation have demonstrated that temporal interference (TI) stimulation can achieve focal deep brain targeting in humans with favorable safety profiles. Therefore, TI stimulation on the NAc holds substantial promise for treating neuropsychiatric disorders. While stimulation duration represents an understudied parameter that may critically influence clinical outcomes, its impact on TI-induced NAc neuromodulation remains entirely unexplored. To address this knowledge gap, we employed a randomized, within-subject, counterbalanced crossover design in 24 healthy volunteers (HVs). Participants underwent both 20-minute or 40-minute 130 Hz TI stimulation targeting the NAc. Resting-state functional MRI (fMRI) data were acquired pre- and post-stimulation. Regional homogeneity (ReHo) and seed-based functional connectivity analyses were utilized to quantify intrinsic brain activity and connectivity. Paired t-tests revealed that 40-minute TI stimulation significantly attenuated NAc ReHo (P = 0.04), an effect not observed for 20 minutes of stimulation. Exploratory analyses revealed that the 40-minute stimulation also reduced ReHo of the orbitofrontal cortex (OFC) and attenuated NAc-OFC functional connectivity (Ps < 0.005). Critically, the 20-minute TI elicited no significant alterations. These findings demonstrate a duration-dependent response, where a longer (40-minute) TI protocol produced detectable functional alterations in the NAc and NAc-OFC pathway. Our study provides the first neuroimaging evidence that stimulation duration is a key parameter influencing TI-induced neuromodulatory effects, thereby providing crucial guidance for parameter selection in future clinical applications.