Evidence for Subcortical Plasticity after Paired Stimulation from a Wearable Device

Abstract

Existing non-invasive stimulation protocols can generate plasticity in the motor cortex and its corticospinal projections; techniques for inducing plasticity in sub-cortical circuits and alternative descending pathways such as the reticulospinal tract are less well developed. One possible approach developed by this laboratory pairs electrical muscle stimulation with auditory clicks, using a wearable device to deliver stimuli during normal daily activities. In this study, we applied a variety of electrophysiological assessments to male and female healthy human volunteers during a morning and evening laboratory visit. In the intervening time (~6 hours), subjects wore the stimulation device, receiving three different protocols, in which clicks and stimulation of the biceps muscle were paired at either low or high rate, or delivered at random. Paired stimulation: 1) increased the extent of reaction time shortening by a loud sound (the StartReact effect); 2) decreased the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; 3) enhanced muscle responses elicited by a TMS coil oriented to induce anterior-posterior (AP) current, but not posterioranterior (PA) current in the brain. These measurements have all been suggested to be sensitive to sub-cortical, possibly reticulospinal, activity. Changes were similar for either of the two paired stimulus rates tested, but absent after unpaired (control) stimulation. Taken together, these results suggest that pairing clicks and muscle stimulation for long periods does indeed induce plasticity in sub-cortical systems such as the reticulospinal tract. Significance StatementSub-cortical systems such as the reticulospinal tract are important motor pathways, which can make a significant contribution to functional recovery after cortical damage such as stroke. Here, we measure changes produced after a novel non-invasive stimulation protocol, 3 which uses a wearable device to stimulate for extended periods. We observed changes in electrophysiological measurements consistent with the induction of sub-cortical plasticity. This protocol may prove an important tool for enhancing motor rehabilitation, in situations where insufficient cortical tissue survives to be a plausible substrate for recovery of function.

Understanding them to understand ourselves: The importance of NHP research for translational neuroscience

“… Foysal et al (2016) exploited this effect by developing a wearable device for human use, which paired clicks with electrical stimulus to a muscle. Consistent stimulus pairing over hours with this device seemed to induce long-term changes consistent with spike-timing dependent plasticity in reticulospinal cells, a pathway supported by more recent work ( Germann and Baker, 2021 ). A clinical trial of this device in stroke patients showed a long-lasting benefit on hand function ( Choudhury et al, 2020 ).…”

Startling stimuli increase maximal motor unit discharge rate and rate of force development in humans

“…Although the strength of the reticulospinal inputs has been suggested to vary across muscle groups ( 77 , 78 ), subsequent studies have shown a wide distribution of reticulospinal inputs ( 18 , 79 ). Indeed, the StartReact effect has been observed in a variety of muscle groups ( 26 , 32 , 52 , 58 , 80 ). Therefore, we would expect the effect observed in the present study to be replicated across several muscles and muscle groups, though the magnitude of the effect might vary depending on the muscle.…”

“…Both healthy individuals after an intervention targeting the reticular formation (58), and patient populations with extensive cortical damage (59)(60)(61) have shown an enhanced StartReact response. Nevertheless, the contribution of cortical influences to startling stimuli cannot be fully excluded (62), and similarly, the performance of a rapid, high-force task likely has a cortical component.…”

Reticulospinal drive increases maximal motoneuron output in humans

“…Both healthy individuals after an intervention targeting the reticular formation (Germann and Baker, 2021), and patient populations with extensive cortical damage (Honeycutt and Perreault, 2012; Nonnekes et al, 2014; Choudhury et al, 2019) have shown an enhanced StartReact response. Nevertheless, the contribution of cortical influences to startling stimuli cannot be fully excluded (Marinovic and Tresilian, 2016), and similarly, the performance of a rapid, high-force task likely has a cortical component.…”