Multiscale reorganization of brain and behavior under large-scale electrical perturbation

Abstract Large-scale electrical perturbation of the human brain provides a unique model for understanding how multiscale biological constraints shape behaviorally relevant reorganization. Here, we integrate longitudinal neuroimaging coordinates from 148 experiments (≈2,300 subjects) with normative connectomics, chemoarchitecture, intrinsic electrophysiology, and transcriptomics to identify cross-scale principles governing human brain reconfiguration under strong perturbation. Convergent hubs of structural and functional plasticity embed within default-mode and salience systems and show complementary coupling to visual networks, linking perturbation-induced change to large-scale circuits supporting affective regulation, memory, interoception, and psychosis-relevant processes. These macroscopic patterns align with intrinsic cortical dynamics and chemoarchitectural gradients dominated by 5-HT1A receptors, with additional contributions from D2, μ-opioid and GABAA systems, and are enriched for astrocytic and microglial gene expression, implicating glial plasticity in systems-level reorganization. Finally, in a separate intervention dataset, regularized statistical-learning models demonstrate that this multiscale signature tracks behaviorally relevant symptom change specifically under strong electrical perturbation. Together, these results outline general organizing principles linking molecular, cellular and network-level constraints to human behavioral adaptation, providing a computational framework for understanding how large-scale perturbations reshape brain systems across levels of biological organization. Competing Interest Statement J.D. received support from the German Research Foundation (DFG; project number 549186835). D.B. is shareholder and scientific advisor of MindState Design Labs (USA) and Biossil (Canada); the contribution to this manuscript is unrelated to this affiliation. T.B.P. received support from the German Research Foundation (DFG; project number 519094028). Within the past three years, T.B.P. received honoraria for speaking engagements from Laboratorios Farmacéuticos Rovi; this activity was unrelated to the present work. The remaining authors declare no competing interests.