Distinct cortical excitability and connectivity profiles within the human SMA complex

Understanding brain functions increasingly relies on a network-based perspective, emphasizing interactions across distributed regions. High-order cognitive functions, like language and executive processes, engage such networks rather than isolated cortical areas, yet mapping their dynamics in humans remains challenging. The supplementary motor area (SMA) complex serves as a crucial hub, functioning as an interface between cognitive and sensorimotor processing. Navigated transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) enables causal, time-resolved assessment of cortical excitability and connectivity with high temporal and spatial precision. Extending prior proof-of-concept work, this study aims to provide normative neurophysiological signatures of the SMA complex (pre-SMA and SMA).

Twenty-one healthy subjects underwent a TMS-EEG session where six stimulation targets over the SMA complex (three in pre-SMA, one in the border between pre-SMA and SMA, two in SMA) were recorded. Global cortical excitability via global mean field power (GMFP) was computed over three time-windows (10-50, 50-100, and 100-200 ms) and compared across targets. Normalized power in different frequency bands (α, β1, β2, γ) and natural frequency (NF) were also computed and compared across stimulation sites. Then, we calculated tractography-derived connectivity metrics to examine corticothalamic projections from each stimulation site. Apparent fiber density (AFD)-derived connection strength quantified intra-axonal fibre volume along pathways to the whole thalamus, whereas fibre bundle capacity (FBC) assessed the aggregate intra-axonal cross-sectional area at pathway endpoints, providing an estimate of information transmission capacity to each of the 23 thalamic nuclei.

Cortical excitability and oscillatory properties varied significantly across TMS targets. A gradient in cortical excitability was observed, where anterior and middle portions of pre-SMA exhibited significantly lower GMFP in the early post-stimulus phase (i.e., 10-50 ms) than SMA portions; interestingly, these differences were clearly dampened in a later time-window (50-100 ms) and disappeared after this period. Furthermore, higher α and lower β2 power were observed in anterior pre-SMA than posterior pre-SMA portions. No differences were observed in NF. Crucially, we also observed significant differences in whole- and single-nuclei thalamic structural connectivity.

These findings provide direct human in vivo evidence for distinct neurophysiological and structural connectivity profiles of the pre-SMA and SMA, possibly reflecting their different cytoarchitectonic, myeloarchitectonic and connectivity properties. Variations in cortical excitability, oscillatory dynamics, and FBC along the rostro-caudal axis may mirror functional specialization, with pre-SMA supporting cognitive control processes and SMA engaging motor-related thalamocortical networks. Together, the results demonstrate the sensitivity of TMS-EEG and diffusion-weighted connectomics to measure fine-grained neurophysiological differences of corticothalamic projections, which can lead to individualized neuromodulation targeting.