Stimulation priming and psychological state shape functional connectivity following prefrontal theta-burst stimulation

Intermittent theta-burst stimulation (iTBS) is increasingly used to neuromodulate prefrontal brain regions, such as the dorsolateral prefrontal cortex (DLPFC), allowing to effectively change local excitability in research settings and to optimize therapeutic outcomes. However, response variability remains high, and its clinical efficacy is modest. Priming with theta-burst stimulation (TBS), in which a preconditioning TBS protocol precedes a test iTBS protocol, has been proposed to enhance stimulation efficacy and reduce inter-individual variability, particularly when combining protocols that are expected to induce different changes in cortical excitability. Yet, its underlying neurobiological effects remain unclear. In this within-subjects study, we investigated the effects of TBS priming on resting-state functional connectivity in 47 healthy subjects. Each participant completed four counterbalanced sessions, 1 week apart, receiving either a control condition with sham priming and sham test stimulation, an iTBS-alone condition (without priming), a priming condition where iTBS preceded iTBS, or a priming condition where continuous TBS (cTBS) preceded iTBS. Resting-state scans were acquired before and after each stimulation condition, alongside assessments of self-reported mood and perseverative thinking. Contrary to our expectations, priming prefrontal iTBS with cTBS resulted in reduced connectivity changes in both regions near the stimulation site and more distal temporal areas, and priming with iTBS significantly reduced connectivity changes in prefrontal regions, both relative to iTBS alone. Changes in perseverative thinking further moderated stimulation effects, with greater increases associated with stronger decreases in left prefrontal connectivity following cTBS-iTBS priming. These findings highlight the complex effects of prefrontal TBS priming and its interaction with psychological states, underscoring the importance of accounting for state dependency in neuromodulation research.