Spinally targeted paired associative stimulation with high-frequency peripheral component induces spinal level plasticity in healthy subjects

A novel variant of paired-associative stimulation (PAS) consisting of high-frequency peripheral nerve stimulation (PNS) and high-intensity transcranial magnetic stimulation (TMS) above the motor cortex, called high-PAS, can lead to improved motor function in patients with incomplete spinal cord injury. In PAS, the interstimulus interval (ISI) between the PNS and TMS pulses plays a significant role in the location of the intended effect of the induced plastic changes. While conventional PAS protocols (single TMS pulse often applied with intensity close to resting motor threshold, and single PNS pulse) usually require precisely defined ISIs, high-PAS can induce plasticity at a wide range of ISIs and also in spite of small ISI errors, which is helpful in clinical settings where precise ISI determination can be challenging. However, this also makes the determination of high-PAS level of plasticity induction more challenging and calls for more research on the mechanism of action of high-PAS. We sought to determine if the TMS-induced orthodromic activation in upper motor neurons and PNS-induced antidromic activation in lower motor neurons arriving simultaneously to the intervening synapses at the spinal cord level can be shown to induce acute changes at the targeted location, unlike an otherwise identical but cortically targeted equivalent. Ten healthy subjects participated in two separate sessions, where high-PAS induced activation was set to target spinal (SPINAL) or cortical (CORTICAL) levels with ISI manipulation between otherwise identically applied TMS and PNS pulses. The outcomes were assessed with motor-evoked potentials (MEPs) and Hoffmann (H)-reflex before (PRE), immediately after, and 30 and 60 min after (POST, POST30, POST60) the intervention. MEPs were significantly enhanced in both interventions. In the SPINAL but not in the CORTICAL session, maximal H-reflex amplitudes significantly increased at two timepoints, indicating an increase in spinal excitability. The H/M ratio (maximal H-reflex normalized to maximal M-wave) also showed a significant increase from PRE to POST30 timepoint in the SPINAL session when compared with the CORTICAL equivalent. These results confirm that spinally targeted high-PAS with individualized ISIs indeed has an effect at the spinal level in the sensorimotor system. High-PAS is a novel PAS variant that has shown promising results in motor rehabilitation of individuals with SCI and these new findings contribute to the understanding of its mechanism of action. This provides further evidence for high-PAS as an option for clinical settings to target plasticity at different levels of the corticospinal tract.