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.

Keywords: Diseases of the nervous system; Medical research.

Figures

Figure 1

Spinal MRI from patients A and B at the acute (a, c) and chronic (b, d) stages. (a) Patient A. Sagittal T2-weighted fast spin-echo (FSE) image of the lumbar spine achieved with 1.5-T MRI scanner. White star: L1 burst fracture and abnormal narrowing of the spinal canal due to fracture displacement. White arrow: conus medullaris ends at the level of L2 vertebra. The fractured L1 was stabilized with transpedicular fixation through Th12 and L2. The image was taken 1 week after the injury (unrelated to the research project). (b) Patient A. Sagittal T2-weighted FSE image of the lumbar spine, 3-T MRI scanner. Posttraumatic atrophy of the distal spinal cord is visualized (white star). White arrow: the end of conus medullaris (indicated with white arrow in (a)). The scan was taken before the first stimulation of the right leg. (c) Patient B. Sagittal T2-weighted FSE image of the cervical spine achieved with 1.5-T MRI scanner. There is T2 signal increase representing spinal cord contusion at the C2–C4 level (left-pointing white arrows). C4 and C5 processus spinosi are fractured (white stars). Soft-tissue edema as well as disruption of the C3/4 anterior longitudinal ligament and discus (right-pointing white arrow) are visualized. The image was taken 1 day after the injury (unrelated to the research project). (d) Patient B. Sagittal T2-weighted three-dimensional image of the cervical spine, 3-T MRI scanner. Posttraumatic atrophy of the spinal cord (black arrows) and trauma-induced syringomyelia (white arrow) at the C3/4 level are visualized. The scan was taken before the first stimulation.

Figure 2

Time course of the experiment. *During weeks 7 and 13, PAS was given only two times per week, **during weeks 5 and 12, stimulation was given two times per week.

Figure 3

PAS protocol and the sites of stimulation. (a) Schematic representation of stimulation protocol. PNS pulse width: 1 ms. (b) Cortical sites of TMS for patient A were paired with stimulation of the contralateral: yellow–peroneal nerve, red–tibial nerve. (c) Cortical sites of TMS for patient B were paired with stimulation of the contralateral: red–median nerve, yellow–ulnar nerve and blue–radial nerve. (d–h) Peripheral electrode location for stimulation of the: (d) tibial nerve (medial side of the ankle behind the medial malleolus) (e) peroneal nerve (frontal side of the ankle), (f) ulnar nerve (medial side of the wrist), (g) median nerve (middle of the wrist) and (h) radial nerve (lateral side of the arm).

Figure 4

EMG recordings from patient A. Vertical gray lines: event of the command to move the foot. (a) Right medial gastrocnemius (GC) muscle during plantarflexion (foot down). (b) Right TA muscle during dorsiflexion (foot up). (c) Left medial GC during plantarflexion. (d) Left TA during dorsiflexion. See also Supplementary Videos 1 and 2. See Figure 5 for control recordings.

Figure 5

Control recordings of the EMG traces shown in Figure 4. (a) EMG from right medial gastrocnemius (GC) during medial inversion of the hip. The recording was made at the same session as the one shown in Figure 4a (12-week trace). (b) EMG from left TA during contraction of quadriceps femoris muscle without attempt to dorsiflex the ankle. The recording was made in the same session as the one shown in Figure 4d (20-week trace).

Figure 6

Motor score of the right and left upper limbs of patient B before (pre-intervention) and 7 (mid-intervention) and 12 (post-intervention) weeks after the first stimulation. Follow-up: 1 month after the last stimulation session. Scores for median, ulnar, radial and other nerves are shown separately. See Supplementary Table for details. See also Supplementary Video 3.

Figure 7

Neurophysiological measurements from both patients. (a) MEP recordings from patient A (left leg) and patient B (right arm). Each trace is an average of 30 MEPs taken in a row at a 3.3-s ISI. BR, brachioradialis muscle (patient B); GC, gastrocnemius muscles; TA, TA muscle (patient A). Short latencies of MEPs from patient A are explained by the short height of the patient (163 cm); the latency for the vastus medialis muscle in the left leg was 24 ms. (b, c) MEP amplitudes during different weeks of stimulation. Follow-up: 1 month after the last stimulation session. The values are averages of 30 MEPs taken in a row. If no MEP was evoked by a stimulus, the amplitude was counted as 0. The values thus represent both amplitude and persistence of the MEPs. (b) MEPs in the paraplegic individual (left leg). (c) MEPs in the tetraplegic individual (right arm), ADM, abductor digiti minimi. Left APB: recordings during control PNS.