Targeted medial prefrontal cortex stimulation prevents incubation of cocaine craving and restores functional connectivity

Lu, H.; Hoffman, S.; Duan, Y.; Ma, Z.; Nguyen, H.; Carney, A. F.; Scott, T.; Varlas, O.; Haque, M. M.; Stein, E. A.; Xi, Z.-X.; Shaham, Y.; Yang, Y.

doi:10.64898/2026.04.21.719530

bioRxiv · 10.64898/2026.04.21.719530

Targeted medial prefrontal cortex stimulation prevents incubation of cocaine craving and restores functional connectivity

Lu, H.·Hoffman, S.·Duan, Y.·Ma, Z.·Nguyen, H.·Carney, A. F.·Scott, T.·Varlas, O.·Haque, M. M.·Stein, E. A.·Xi, Z.-X.·Shaham, Y.·Yang, Y.

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Abstract

BackgroundRelapse remains a central obstacle in the treatment of cocaine use disorder (CUD), for which no medications have received approval from the U.S. Food and Drug Administration. Transcranial magnetic stimulation (TMS) has shown promise as a potential therapeutic intervention. However, current clinical trials often rely on a "trial-and-error" approach in target selection and experimental design. We previously developed a novel TMS platform and high-density theta burst stimulation (hdTBS) technology, enabling precise, focal stimulation of the rat medial prefrontal cortex (mPFC), including the prelimbic and anterior cingulate cortices. MethodsWe applied hdTBS intervention to a well-established rat model of cocaine relapse and craving after cessation of extended access intravenous drug self-administration and assessed brain response using resting-state functional magnetic resonance imaging (fMRI). ResultsAs expected, we observed robust time-dependent increases in cocaine seeking (incubation of cocaine craving) in control rats receiving sham stimulation over 3 weeks of abstinence accompanied by a reduction in prefrontal functional connectivity. In contrast, daily sessions of hdTBS for 7 days delivered on abstinence days 14-20 prevented the emergence of the incubation effect and restored prefrontal network functional connectivity. ConclusionsThis study provides strong preclinical evidence demonstrating that precise circuit modulation of medial prefrontal subregions causally reverses both behavioral and network-level adaptations associated with relapse vulnerability. Given the clinical accessibility and established safety profile of TMS, this work provides a mechanistically grounded framework for target selection and supports the translation of focal TMS of the mPFC for relapse prevention in CUD patient. One Sentence SummaryFocal transcranial magnetic stimulation (TMS) of the mPFC using the hdTBS procedure prevents incubation of cocaine craving and restores functional connectivity.

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Lu, H., Hoffman, S., Duan, Y., Ma, Z., Nguyen, H., Carney, A. F., Scott, T., Varlas, O., Haque, M. M., Stein, E. A., Xi, Z.-X., Shaham, Y., Yang, Y.. 2026-04-24. Targeted medial prefrontal cortex stimulation prevents incubation of cocaine craving and restores functional connectivity. https://doi.org/10.64898/2026.04.21.719530

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