Closing the loop between brain and electrical stimulation: A proof-of-concept randomized trial of real-time fMRI-guided tACS optimization

Closed-loop transcranial alternating current stimulation (tACS) combined with real-time functional MRI (tACS–fMRI) enables adaptive optimization of noninvasive brain stimulation based on ongoing neural dynamics. We implemented one of the first randomized, double-arm, closed-loop tACS–fMRI protocols to iteratively adjust stimulation frequency and phase alignment between the right dorsolateral prefrontal cortex (F4) and right inferior parietal cortex (P4) to modulate frontoparietal functional connectivity (FFC) during a 2-back working memory task. Twenty healthy adults were randomized to an up-regulation group (n = 10), receiving parameters optimized to maintain or enhance FFC, or a down-regulation group (n = 10), receiving parameters optimized to reduce FFC using a simplex-based adaptive algorithm across two training runs. Individualized optimized parameters were applied during a subsequent test run, with resting-state fMRI acquired before and after stimulation. During the test phase, connectivity trajectories diverged across groups: FFC was preserved in the up-regulation group but declined in the down-regulation group (signed-rank p = 0.019), with a significant between-group difference confirmed by permutation testing (20,000 iterations; p = 0.043). Behavioral effects were primarily observed in the accuracy learning dynamics. Although overall mean performance was comparable, the up-regulation group demonstrated a more positive accuracy trajectory, greater within-test accuracy gain (p = 0.036), and steeper trial-wise improvement (p = 0.035). Reaction time decreased across runs in both groups, consistent with practice effects, with no significant group differences in gain; however, the test-run RT slope showed a trend toward a steeper reduction in reaction time in the up-regulation group relative to the down-regulation group (p = 0.065). Resting-state analyses revealed significant time-by-group interaction clusters in seed-based connectivity (voxel-wise p < 0.001; cluster-level FDR p < 0.05), with connectivity increases observed in the up-regulation group relative to the down-regulation group, indicating persistent network modulation following stimulation. These findings demonstrate the feasibility of closed-loop tACS–fMRI for individualized network-targeted neuromodulation and suggest that real-time connectivity optimization selectively stabilizes task-relevant connectivity and enhances accuracy learning while producing sustained effects on intrinsic brain networks.