Brain-state dependence of neuromodulation: psychosocial stress aligns prefrontal perfusion dynamics during online tDCS

Transcranial direct current stimulation (tDCS) shows broad therapeutic promise, yet high inter-individual variability limits its clinical efficacy. Here, we investigated whether pre-stimulation brain state reduces inter-individual variability in neural responses to online tDCS. Across two sham-controlled cohorts of healthy volunteers, we quantified cerebral blood flow (CBF)-based inter-subject correlation (ISC) during 20 minutes of active or sham tDCS (anodal left dorsolateral prefrontal cortex, right supraorbital return). In our hypothesis-driven ROI analyses, following psychosocial stress induction (Study 1, N = 42; NCT07406503), active tDCS significantly synchronized perfusion trajectories (elevated ISC) within prefrontal and corresponding electric-field regions, while reducing synchrony in the pregenual anterior cingulate cortex. Crucially, this stress-dependent synchronization was absent during resting-state stimulation without prior stress exposure (Study 2, N = 43; NCT07406464). Exploratory whole-brain voxel-wise ISC and neurotransmitter-map association analyses further suggested that stress-state ISC modulations were preferentially aligned with normative cortical distributions of dopaminergic, noradrenergic, serotonergic, and GABAergic receptors, whereas such associations were not observed in the cohort without experimental stress induction. Although imaging modality differences (ASL vs. BOLD-fMRI) preclude attributing these divergences solely to stress, our findings demonstrate that psychosocial context shapes tDCS-induced neural synchrony, with exploratory evidence linking these effects to cortical neurotransmitter landscapes, providing a critical biological framework for state-sensitive and personalized psychiatric neuromodulation.