State-dependent dual-site prefrontal TMS bidirectionally modulates working-memory accuracy

Working memory (WM) is a core cognitive function that is both mechanistically tractable and clinically relevant, making it a prime target for noninvasive neuromodulation. However, transcranial magnetic stimulation (TMS) studies targeting the dorsolateral prefrontal cortex (DLPFC) have yielded variable WM outcomes, possibly because single-site protocols fail to engage the distributed network dynamics that support WM and because effects depend on momentary brain states. Here, we tested whether dual-site sequential TMS, excitatory intermittent theta-burst stimulation (iTBS) over left DLPFC combined with inhibitory continuous theta-burst stimulation (cTBS) over medial prefrontal cortex (mPFC), produces state-dependent modulation of WM performance compared with single-site DLPFC stimulation alone. Thirty-seven healthy adults completed a within-subjects protocol with intermixed 0-back and 2-back WM conditions. Self-reported fatigue before each task run served as a coarse indicator of the participant’s cognitive state. Bayesian linear mixed models revealed a clear state-dependent pattern: in the high-load 2-back condition, dual-site stimulation improved accuracy when participants reported low fatigue but impaired accuracy when they reported high fatigue. No reliable effects were found for the 0-back condition or for reaction time. These findings demonstrate that dual-site prefrontal TMS can bidirectionally modulate WM accuracy relative to single-site stimulation depending on the participant’s cognitive state, highlighting the importance of state-aware and network-sensitive stimulation approaches for cognitive enhancement.