A personalized map of where, when, and how to stimulate the brain to elicit controlled responses

Abstract

Brain stimulation has transformed the treatment of several neurological and psychiatric disorders and is now widely used to read out causal interactions in the human brain. However, its effects vary from one trial to the next, even when the stimulation parameters are kept identical. Identifying the sources of this variability and developing new strategies to reduce it are key to achieving more controllable interventions. Yet, exhaustive testing in real experiments is unfeasible, because each participant can only be probed at a handful of sites under conditions the experimenter cannot fully control. Here we use personalized brain models to map how stimulation responses vary across target sites and with the brains ongoing state. We show that stimulation responses are jointly determined by the targets position along the cortical unimodal-to-transmodal hierarchy and the brains global ongoing activity, with lower-activity states yielding larger responses. Accordingly, timing stimulation to low-activity periods reduces trial-to-trial variability in response magnitude. Even without state information, joint stimulation of specific region pairs reduces variability compared with stimulating either region alone. Together, these findings identify where, when, and how to stimulate the brain to achieve more reproducible responses, with concrete predictions for closed-loop and circuit-level stimulation protocols.