Targeting cortico-striatal-amygdalar networks via theta-band frontoparietal synchronization in opioid use disorder: a randomized tACS-fMRI Trial.

Ghazaleh Soleimani; Rayus Kuplicki; Martin P Paulus; Hamed Ekhtiari

doi:10.1038/s41380-026-03694-1

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Targeting cortico-striatal-amygdalar networks via theta-band frontoparietal synchronization in opioid use disorder: a randomized tACS-fMRI Trial.

Ghazaleh Soleimani·Rayus Kuplicki·Martin P Paulus·Hamed Ekhtiari

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Abstract

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. Sixty male participants with OUD were randomized to receive 20 min 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. (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). 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.

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Humans Male Magnetic Resonance Imaging Amygdala Adult Theta Rhythm Opioid-Related Disorders Parietal Lobe Transcranial Direct Current Stimulation Frontal Lobe Cues Neural Pathways Corpus Striatum Craving Nerve Net Brain Journal Article Randomized Controlled Trial

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Ghazaleh Soleimani, Rayus Kuplicki, Martin P Paulus, Hamed Ekhtiari. 2026-06-26. Targeting cortico-striatal-amygdalar networks via theta-band frontoparietal synchronization in opioid use disorder: a randomized tACS-fMRI Trial.. https://doi.org/10.1038/s41380-026-03694-1

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Journal Article; Randomized Controlled Trial resource Adult subject Amygdala subject Brain subject Craving subject Cues subject Humans subject Journal Article subject Magnetic Resonance Imaging subject Male subject Nerve Net subject Neural Pathways subject Opioid-Related Disorders subject Parietal Lobe subject Randomized controlled trials study

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