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. This work is supported by the National Natural Science Foundation of China awarded to GW (Grant No. 62271415, 61876156), LW (Grant No. 32360212, 31900764).

CB is supported by an Applied Biomedical (TBM) grant of the Agency for Innovation through Science and Technology (IWT), part of the Research Foundation - Flanders (FWO) PrevenD Project 2.0 (T000720N), the BRAINN HORIZON-WIDERA-2021-ACCESS-03 – Twinning project (Grant No. 101079001), BeNeFIT No 10390082210018, a WEAVE senior - FWO project (G0AA926N), and SOA FRA 2024 0023. SDS is funded by a FWO-Flanders PhD fellowship (Grant Number: 3F001120). Key Laboratory of Cognition and Personality, Faculty of Psychology, Southwest University, Chongqing, China Ghent Experimental Psychiatry (GHEP) lab, Faculty of Medicine and Health Sciences, Department of Head and Skin, Ghent University, Ghent, Belgium Guo-Rong Wu, Linde De Wandel, Debby Klooster, Chanyu Wang, Paula Horczak, Stefanie De Smet, Qinyuan Chen, Jonathan Remue, Gilbert Lemmens & Chris Baeken Department of Psychiatry, the First Affiliated Hospital of Chongqing Medical University, key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Psychiatric Center of Chongqing Medical University the First Affiliated Hospital Chongqing, Chongqing, China Department of Radiology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium Peter Van Schuerbeek, Hubert Raeymaekers & Johan De Mey Eindhoven University of Technology, Department of Electrical Engineering, Eindhoven, The Netherlands Department of Psychiatry, NEUR Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis UZBrussel, Laarbeeklaan 101, 1090, Brussels, Belgium The authors declare no competing interests.

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