A large proportion of spinal cord injuries (SCI) are incomplete. Even in clinically complete injuries, silent non-functional connections can be present. Therapeutic approaches that can strengthen transmission in weak neural connections to improve motor performance are needed. Our aim was to determine whether long-term delivery of paired associative stimulation (PAS, a combination of transcranial magnetic stimulation [TMS] with peripheral nerve stimulation [PNS]) can enhance motor output in the hands of patients with chronic traumatic tetraplegia, and to compare this technique with long-term PNS. Five patients (4 males; age 38–68, mean 48) with no contraindications to TMS received 4 weeks (16 sessions) of stimulation. PAS was given to one hand and PNS combined with sham TMS to the other hand. Patients were blinded to the treatment. Hands were selected randomly. The patients were evaluated by a physiotherapist blinded to the treatment. The follow-up period was 1 month. Patients were evaluated with Daniels and Worthingham's Muscle Testing (0–5 scale) before the first stimulation session, after the last stimulation session, and 1 month after the last stimulation session. One month after the last stimulation session, the improvement in the PAS-treated hand was 1.02 ± 0.17 points (p < 0.0001, n = 100 muscles from 5 patients). The improvement was significantly higher in PAS-treated than in PNS-treated hands (176 ± 29%, p = 0.046, n = 5 patients). Long-term PAS might be an effective tool for improving motor performance in incomplete chronic SCI patients. Further studies on PAS in larger patient cohorts, with longer stimulation duration and at earlier stages after the injury, are warranted.

HighlightsPAS improved hand function in 5 patients with incomplete non-traumatic tetraplegia.The effect persisted for at least 6 months after the end of the 6-week stimulation.There were no adverse effects.

Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS), is emerging as a promising tool for alleviation of motor deficits in neurological disorders. The effectiveness and feasibility of PAS protocols are essential for their use in clinical practice. Plasticity induction by conventional PAS can be variable and unstable. Protocols effective in challenging clinical conditions are needed. We have shown previously that PAS employing 50 Hz PNS enhances motor performance in chronic spinal cord injury patients and induces robust motor-evoked potential (MEP) potentiation in healthy subjects. Here we investigated whether the effectiveness of PAS can be further enhanced. Potentiation of MEPs up to 60 minutes after PAS with PNS frequencies of 25, 50, and 100 Hz was tested in healthy subjects. PAS with 100 Hz PNS was more effective than 50 ( P = 0.009) and 25 Hz ( P = 0.016) protocols. Moreover, when administered for 3 days, PAS with 100 Hz led to significant MEP potentiation on the 3 rd day ( P = 0.043) even when the TMS target was selected suboptimally (modelling cases where finding an optimal site for TMS is problematic due to a neurological disease). PAS with 100 Hz PNS is thus effective and feasible for clinical applications.

Paired associative stimulation (PAS) combines transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) to induce plastic changes in the corticospinal tract. PAS employing single 0.2-Hz TMS pulses synchronized with the first pulse of 50-100 Hz PNS trains potentiates motor-evoked potentials (MEPs) in a stable manner in healthy participants and enhances voluntary motor output in spinal cord injury (SCI) patients. We further investigated the impact of settings of this PAS variant on MEP potentiation in healthy subjects. In experiment 1, we compared 0.2-Hz vs 0.4-Hz PAS. In experiment 2, PNS frequencies of 100 Hz, 200 Hz, and 400 Hz were compared. In experiment 3, we added a second TMS pulse. When compared with 0.4-Hz PAS, 0.2-Hz PAS was significantly more effective after 30 minutes (p = 0.05) and 60 minutes (p = 0.014). MEP potentiation by PAS with 100-Hz and 200-Hz PNS did not differ. PAS with 400-Hz PNS was less effective than 100-Hz (p = 0.023) and 200-Hz (p = 0.013) PNS. Adding an extra TMS pulse rendered PAS strongly inhibitory. These negative findings demonstrate that the 0.2-Hz PAS with 100-Hz PNS previously used in clinical studies is optimal and the modifications employed here do not enhance its efficacy.

Paired associative stimulation (PAS) is a stimulation technique combining transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) that can induce plastic changes in the human motor system. A PAS protocol consisting of a high-intensity single TMS pulse given at 100% of stimulator output (SO) and high-frequency 100-Hz PNS train, or “the high-PAS” was designed to promote corticomotoneuronal synapses. Such PAS, applied as a long-term intervention, has demonstrated therapeutic efficacy in spinal cord injury (SCI) patients. Adding a second TMS pulse, however, rendered this protocol inhibitory. The current study sought for more effective PAS parameters. Here, we added a third TMS pulse, i.e., a 20-Hz rTMS (three pulses at 96% SO) combined with high-frequency PNS (six pulses at 100 Hz). We examined the ability of the proposed stimulation paradigm to induce the potentiation of motor-evoked potentials (MEPs) in five human subjects and described the safety and tolerability of the new protocol in these subjects. In this study, rTMS alone was used as a control. In addition, we compared the efficacy of the new protocol in five subjects with two PAS protocols consisting of PNS trains of six pulses at 100 Hz combined with (a) single 100% SO TMS pulses (high-PAS) and (b) a 20-Hz rTMS at a lower intensity (three pulses at 120% RMT). The MEPs were measured immediately after, and 30 and 60 min after the stimulation. Although at 0 and 30 min there was no significant difference in the induced MEP potentiation between the new PAS protocol and the rTMS control, the MEP potentiation remained significantly higher at 60 min after the new PAS than after rTMS alone. At 60 min, the new protocol was also more effective than the two other PAS protocols. The new protocol caused strong involuntary twitches in three subjects and, therefore, its further characterization is needed before introducing it for clinical research. Additionally, its mechanism plausibly differs from PAS with high-frequency PNS that has been used in SCI patients.

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