Background Theta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcranial alternating current (tACS) is a technology to potentially engage this network. In this pre-registered, triple-blind, sham-controlled trial (NCT03907644), we tested this intervention targeting the right frontoparietal network in people with opioid use disorder (OUD) to measure network engagement and behavioral outcomes.

Method Sixty male participants with OUD were randomized to receive 20 minutes of active or sham 6 Hz tACS (HD electrodes over F4 and P4). Structural, resting-state, task-based fMRI drug cue reactivity, and repeated cue-induced craving assessments were collected immediately before and after stimulation. Pre-registered outcome measures were analyzed using time×group interaction models to examine (1) modulation of drug cue–related brain activity, (2) changes in craving, (3) alterations in functional connectivity, and (4) relationship between electric field, neural responses, and craving behavior.

Results (1) A significant Time × Group interaction revealed decreased post-stimulation opioid cue–related activity in the active group relative to sham, involving key nodes in reward processing (ventral striatum, amygdala and ventral tegmental area) (FWE corrected α=0.05) (2) subjective craving did not differ significantly between groups (3) Group by time generalized psychophysiological interaction analyses showed increased right frontoparietal network engagement (β=2.63, p=0.0308) following stimulation, and increased top-down inhibitory regulation of frontoparietal network on right ventral striatum (β=1.99, p=0.037) and left medial amygdala (β=1.97, p=0.039) (4) Electric field strength in the right frontal/parietal node predicted frontoparietal network engagement in the active group (r=0.43, p=0.02).

Conclusion Together, these findings demonstrate that theta-band frontoparietal tACS can modulate activity and task-dependent coupling within cortical–subcortical circuits in OUD, supporting network-targeted neuromodulation as a potential intervention for addiction.

Significance Statement Addiction is linked to imbalances in cortico-subcortical brain circuits that control reward processing and craving. This study tested whether a non-invasive brain stimulation method— theta-band transcranial alternating current stimulation (tACS)—can rebalance these circuits in people with opioid use disorder. Using advanced brain imaging, we found that tACS strengthened communication within frontoparietal brain regions involved in self-control while reducing their connections with reward and emotion centers. These brain changes were linked to reduced craving responses to drug cues. Our results demonstrate that dual-site, network-targeted tACS modulates neural activity and task-dependent engagement of brain circuits during drug cue reactivity in addiction, supporting its potential as a novel therapeutic approach.

The authors have declared no competing interest.

NCT03907644

This trial was supported by the NARSAD Young Investigator Award from the Brain and Behavior Research Foundation to Hamed Ekhtiari. Ghazaleh Soleimani was also supported by a fellowship from the University of Minnesota MnDRIVE (Minnesota Discovery, Research and Innovation Economy) initiative. The authors report that neither they nor their institutions received payment or services from a third party for any aspect of the submitted work beyond the funding sources listed above. Rayus Kuplicki and Martin P. Paulus report no other relevant biomedical financial interests or potential conflicts of interest.

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Institutional Review Board of Western Institutional Review Board, Puyallup, Washington, United States gave ethical approval for this work.

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Structural and functional MRI data generated in this study are available from the corresponding author upon reasonable request. All experimental code and questionnaires are publicly available at: https://github.com/SoleimaniGhazaleh/Frontoparietal-tACS-OUD/tree/main