Combined endogenous and exogenous disinhibition of intracortical circuits augments plasticity induction in the human motor cortex

Background: Motor imagery (MI) engages cortical areas in the human brain similar to motor practice. Corticospinal excitability (CSE) is facilitated during but not after MI practice. We hypothesized that lasting CSE changes could be achieved by associatively pairing this endogenous modulation with exogenous stimulation of the same intracortical circuits. Methods: We combined MI with a disinhibition protocol (DIS) targeting intracortical circuits by paired-pulse repetitive transcranial magnetic stimulation in one main and three subsequent experiments. The follow-up experiments were applied to increase effects, e.g., by individualizing inter-stimulus intervals, adding neuromuscular stimulation and expanding the intervention period. CSE was captured during (online) and after (offline) the interventions via input-output changes and cortical maps of motor evoked potentials. A total of 35 healthy subjects (mean age 26.1 +/- 2.6 years, 20 females) participated in this study. Results: A short intervention (48 stimuli within similar to 90s) increased CSE. This plasticity developed rapidly, was associative (with MIon, but not MIoff or REST) and persisted beyond the intervention period. Followup experiments revealed the relevance of individualizing inter-stimulus intervals and of consistent interburst periods for online and offline effects, respectively. Expanding this combined MI/DIS intervention to 480 stimuli amplified the sustainability of CSE changes. When concurrent neuromuscular electrical stimulation was applied, the plasticity induction was cancelled. Conclusions: This novel associative stimulation protocol augmented plasticity induction in the human motor cortex within a remarkably short period of time and in the absence of active movements. The combination of endogenous and exogenous disinhibition of intracortical circuits may provide a therapeutic backdoor when active movements are no longer possible, e.g., for hand paralysis after stroke. (C) 2019 Elsevier Inc. All rights reserved.