Disinhibition across Secondary Motor Cortical Regions during Motor Sequence Learning: A TMS-EEG Study

Secondary motor cortical regions, such as the supplementary motor area (SMA), are involved in planning and learning motor sequences; however, the neurophysiological mechanisms across these secondary cortical networks remain poorly understood. In the primary motor cortex, changes in excitatory and inhibitory neurotransmission (E:I balance) accompany motor sequence learning. In particular, there is an early reduction in inhibition (i.e., disinhibition). Here, we investigated whether disinhibition occurs across secondary motor cortical regions during motor sequence learning using combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG). Twenty-nine healthy adults (14 female) practiced a sequential motor task with TMS applied to the SMA during sequence planning. TMS-evoked potentials (TEPs) were measured with EEG before, during, and after practice. The N45 TEP peak was our primary measure of disinhibition, while we analyzed the slope of aperiodic EEG activity as an additional E:I balance measure. We observed a reduction in N45 amplitudes across an electrode cluster encompassing the SMA and nearby cortical regions as participants began learning new motor sequences, compared with a baseline rest phase (p < 0.01). Smaller N45 amplitudes during early learning were associated with improvements in reaction times across learning (p < 0.05). Intriguingly, aperiodic exponents increased as learning progressed and were associated with greater improvements in skill (p < 0.05). Overall, our results show that inhibition is modulated across SMA and secondary motor cortex during the planning phase of motor sequence learning and thus provide novel insight on the neurophysiological mechanisms within higher-order motor cortex that accompany new sequence learning.