Cognitive state dependent enhancement of cognitive control with transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), yet variability of therapeutic responses remains high. A key contributor to this variability may be state-dependent effects of brain stimulation, where activity in underlying circuits can shape the propagation of TMS-evoked activity. Thus, pushing target circuits into a desired state by engaging cognition may sensitise those circuits to TMS-evoked plasticity. We tested whether TMS effects on cognitive control, a transdiagnostic construct implicated across psychiatric disorders and a putative mediator of TMS efficacy, are state-dependent. Participants (N = 25) completed a context-dependent behavioural assay of cognitive control before and after we delivered rTMS to the prefrontal cortex (PFC). During rTMS, participants performed either the cognitive control task (active-state TMS), or performed a context-independent perceptual task (control-state TMS). We assessed changes in downstream behavioural metrics of circuit function, as well as neural indices of cognitive control measured from electroencephalography (EEG). rTMS enhanced cognitive control performance only when PFC-anchored control circuits were actively engaged during stimulation. Similarly, only active-state TMS modulated theta band oscillatory activity, which is thought to be a marker of cognitive control engagement. Moreover, modulation of those EEG indices by TMS predicted gains in behavioural performance in the cognitive control task. These findings demonstrate that TMS effects on cognitive control are state-dependent, in which endogenous engagement of PFC-anchored networks can shape the magnitude and functional relevance of TMS-induced plasticity. Considering cognitive states during TMS may therefore offer a framework to enhance and/or accelerate TMS therapeutic effects.