Distinct impacts of sodium channel blockers on the strength–duration properties of human motor cortex neurons

Objective: This study was undertaken to determine how voltage-gated sodium channel (VGSC) blockers modulate cortical excitability in vivo. VGSCs are critical for regulating axonal excitability, yet the effects of sodium channel-blocking medications on human cortical neurons remain poorly characterized. We aimed to address this gap using transcranial magnetic stimulation (TMS)-derived strength–duration measures as a noninvasive index of VGSC function. Methods: Thirteen healthy adults received single doses of either carbamazepine, lacosamide, or placebo in a crossover design. TMS was used to assess changes in resting motor threshold and strength–duration properties, including rheobase and the strength–duration time constant, as indices of VGSC function. Results: Both medications elevated resting motor thresholds compared to placebo, indicating reduced excitability; however, their impacts varied according to TMS pulse width. Carbamazepine raised thresholds proportionally across all pulse widths, whereas lacosamide disproportionately influenced thresholds. Crucially, lacosamide reduced the strength–duration time constant and increased rheobase, whereas carbamazepine had minimal effects on both measures. Significance: These results reveal subtle and unexpected differences in cortical neuron behavior following VGSC-blocking medication administration. Lacosamide's response aligns with the proposed mechanism of sodium conductance blockade, whereas carbamazepine's effects suggest distinct VGSC interactions or potential off-target effects. Our findings advance the understanding of VGSC-blocking medication interactions in the human cortex and underscore the importance of employing specific TMS measures to gain deeper insights into medication mechanisms of action in vivo. Such measures could serve as valuable adjuncts in medication development and patient monitoring.