Mechanisms influencing stimulus-response properties of the human corticospinal system

Background: Stimulus-response (S-R) properties of the corticospinal system in humans depend on the interactions that take place at different sites along the corticospinal pathway. The mechanisms influencing stimulus-response curves elicited by transcranial magnetic stimulation (TMS) and their operation site along the human neuraxis are poorly understood. In this study, we investigated the effects of CNS-active drugs with distinct mechanisms of action on S-R curves. Effects of each of these drugs on S-R curves would point to the involvement of specific mechanisms. Additionally, relative sensitivity of S-R curves compared with other measures of corticospinal excitability was studied. Methods: We studied the effects of lorazepam, which is a positive allosteric modulator of GABA_A receptors; lamotrigine, an inhibitor of voltage-gated Na⁺ and Ca²⁺ channels; and D-amphetamine, an indirect agonist of the dopaminergic-adrenergic system on S-R curves, motor thresholds (MT), and intracortical inhibition (ICI) and facilitation (ICF) with a double-pulse technique. Maximum peripheral M responses and F waves were investigated as measures of the total α-motoneuron pool and its excitability. Results: F and M waves were unaffected by either the drugs or placebo. S-R curves were significantly depressed by lorazepam and lamotrigine without changes in ICI and ICF. Both S-R curves and ICF were enhanced by D-amphetamine. MT increased only with lamotrigine. Conclusions: S-R curves were influenced by changes in the GABAergic and monoaminergic system and Na⁺ and Ca²⁺ channel properties. Our results indicate that, out of different parameters of motor system excitability, S-R curves were the most sensitive.