Long-term paired associative stimulation can restore voluntary control over paralyzed muscles in incomplete chronic spinal cord injury patients

Abstract

Emerging therapeutic strategies for spinal cord injury aim at sparing or restoring at least part of the corticospinal tract at the acute stage. Hence, approaches that strengthen the weak connections that are spared or restored are crucial. Transient plastic changes in the human corticospinal tract can be induced through paired associative stimulation, a noninvasive technique in which transcranial magnetic brain stimulation is synchronized with electrical peripheral nerve stimulation. A single paired associative stimulation session can induce transient plasticity in spinal cord injury patients. It is not known whether paired associative stimulation can strengthen neuronal connections persistently and have therapeutic effects that are clinically relevant. We recruited two patients with motor-incomplete chronic (one para-and one tetraplegic) spinal cord injuries. The patients received paired associative stimulation for 20-24 weeks. The paraplegic patient, previously paralyzed below the knee level, regained plantarflexion and dorsiflexion of the ankles of both legs. The tetraplegic patient regained grasping ability. The newly acquired voluntary movements could be performed by the patients in the absence of stimulation and for at least 1 month after the last stimulation session. In this unblinded proof-of-principle demonstration in two subjects, long-term paired associative stimulation induced persistent and clinically relevant strengthening of neural connections and restored voluntary movement in previously paralyzed muscles. Further study is needed to confirm whether long-term paired associative stimulation can be used in rehabilitation after spinal cord injury by itself and, possibly, in combination with other therapeutic strategies.

Paired Associative Stimulation with High-Frequency Peripheral Component Leads to Enhancement of Corticospinal Transmission at Wide Range of Interstimulus Intervals

“…Our aim was to develop and test tools for patient rehabilitation, and the observed increase of efficacy of the motor activation by the PAS is promising in this respect. The results support the usefulness of the stimulation parameters selected for our proof of concept—study of PAS used in rehabilitation of two patients with spinal cord injuries (Shulga et al, 2016 ).…”

“…For PNS, we used high-frequency peripheral pulses at minimal intensity required to elicit F-response to ensure the activation of the motor neurons. We have previously reported the use of otherwise identical protocol in one healthy subject at intensity higher than minimal intensity for F-response (15 mA); this has led to MEP potentiation observable at 1 h, but not immediately after PAS (Shulga et al, 2016 ). Lowering the intensity in the same subject to 11 mA (subject 1 in this study) has led to observable MEP potentiation immediately after the protocol.…”

“…We conducted all experiments in the presence of motor imagery, since we used this method on our spinal cord injury patients (Shulga et al, 2016 ). Control experiment without motor imagery revealed that it is not required for MEP amplitude potentiation in healthy subjects at 0 ms ISI.…”

“…The potential of single-session spinal PAS as rehabilitation for spinal cord injury patients, and of multiple-session cortical PAS for stroke patients has been reported (Uy et al, 2003 ; Bunday and Perez, 2012 ). We have recently published a case report of two incomplete spinal cord injury patients showing the positive long-term effect of multiple-session spinal PAS consisting of single high-intensity TMS pulses combined with 50 Hz PNS trains (Shulga et al, 2016 ). Here we characterize single-session PAS with these parameters in healthy subjects.…”

Paired associative stimulation after spinal cord injury: who should undergo?

“…9 Applied together, PNS and TMS are called paired associative stimulation (PAS) and are believed to strengthen excitatory synapses and inducing neural plasticity. 10 Depending on intervals between these two stimuli, PAS may induce long term inhibition or potentiation (LTP) underlaying neuro plasticity that correlates with an increase in muscle voluntary force. 11 Previous research suggested that spike timing-dependent plasticity of residual corticospinal-motoneuronal synapses after SCI could be a promising therapeutic target.…”