KEY POINTS: • Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. • Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of TMS applied to primary motor cortex (M1) at different coil orientations. • We found an association between late I-wave recruitment (reflected by AP-LM latency, i.e. the excess latency of motor evoked potentials (MEPs) generated by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation) and changes in cortical excitability following iTBS, confirming previous studies. •AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. •Plasticity in the motor network may in part derive from a modulation of excitability and recruitment of late I-wave generating cortical pathways. ABSTRACT: Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor evoked potentials (MEPs) elicited by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation, referred to as "AP-LM latency" difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. We investigated in 20 healthy subjects whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced the AP-LM latency, and that this correlated significantly with changes in cortical excitability observed following iTBS: subjects with the largest reductions in AP-LM latencies had the largest increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel rTMS protocols
