Waveform matters: enhanced cortical plasticity with monophasic intermittent theta-burst stimulation

• Monophasic intermittent theta-burst stimulation increased corticospinal excitability. • Monophasic intermittent theta-burst stimulation yielded a greater proportion of facilitators compared to biphasic stimulation. • Monophasic and biphasic intermittent theta-burst stimulation did not change intracortical facilitation and inhibition. Activity-dependent plasticity, mediated by mechanisms such as long-term potentiation (LTP), underlies learning and memory. Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation (rTMS), can induce LTP-like effects in humans. Traditionally, iTBS has been delivered using biphasic pulses. With advances in hardware, iTBS can be delivered using monophasic-like pulses via controllable pulse parameter rTMS. Emerging evidence suggests that iTBS administered with such monophasic pulses may produce more robust effects on cortical excitability compared to conventional biphasic stimulation. This study investigated the effects of monophasic versus biphasic iTBS on corticospinal excitability with the hypothesis that monophasic stimulation would produce greater facilitation of motor evoked potentials (MEPs). In a double-blinded, placebo-controlled, within-subjects design, 40 participants (equal males and females) received monophasic, biphasic, and sham iTBS in pseudo-randomized order. TMS measures (MEPs, intracortical facilitation (ICF), short-interval intracortical inhibition (SICI)) were recorded before and 10 min following iTBS stimulation. No sex differences were observed. Monophasic iTBS significantly enhanced MEP amplitude. Biphasic iTBS did not significantly alter MEPs. SICI and ICF remained unchanged by iTBS. Responder analysis showed a higher frequency of facilitatory responses following monophasic iTBS and inhibitory responses following biphasic iTBS. Monophasic iTBS enhances corticospinal excitability. These findings support the use of monophasic iTBS to optimize neuromodulatory interventions and improve outcomes in brain stimulation therapies.