PMC6786383_01
a Stimulation setup for long-term PAS therapy, b, c stimulation sites, and d basic principle of PAS. The upper motor neurons in the left primary motor cortex were stimulated with the TMS coil placed over the subject's head (marked with blue squares). The electric field and a stimulated hotspot in the brain were visualized online using a 3D MRI-based model (b) that ensures accuracy and repeatability of stimulation. c High-frequency electrical stimulation was delivered to a peripheral nerve of the contralateral hand (marked with green squares). d The interstimulus interval was adjusted for collision of multiple descending volleys propagating along the upper motor neurons within the corticospinal tract (dark blue line) and ascending volleys travelling along the lower motor neurons within the peripheral nerve (yellow line) at the level of their synaptic contacts (red circle) in the cervical segment of the spinal cord (shown in enlarged form in d)
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Fig1
The nTMS system enables accurate, reproducible stimulation of selected cortical sites, the "hotspots" (Fig. 1a), where MEPs are most readily elicited from the selected muscles. The hotspots were defined for abductor pollicis brevis (APB), abductor digiti minimi (ADM), and brachioradialis (BR) muscles in both hands as in our previous studies. PNS was delivered using a Dantec Keypoint electroneuromyography device (Natus Medical Inc., Pleasanton, CA, USA) and surface electrodes (Fig. 1b). For PAS (Fig. 1), nTMS (single-pulse, 0.2 Hz, 100% MSO) of the selected hotspots was synchronized with the first pulse of the PNS train given to the corresponding contralateral nerve. One session consisted of PAS of 3-6 hotspot-nerve pairs given in pseudo-random order of 1.5-3 h duration in total (20 min per nerve plus time for preparations, Fig. 1). The total and partial MMT scores were improved in both hands (Fig. 3 and Supplementary Table 2 parts 1, 2).
Time course of the intervention
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Fig2
PAS and 1-2-week breaks without stimulations (Fig. 2). PAS to a hotspot-nerve pair was stopped when strength and range of motion of all muscles innervated by this nerve reached an MMT score of 4-5. The total and partial MMT scores were improved in both hands (Fig. 3 and Supplementary Table 2 parts 1, 2).
Manual muscle test (MMT) score measured before intervention, and at the end of follow up in the left (a) and right (b) hand (full MMT data is shown in Supplementary Table 2 parts 1, 2). Y-axis depicts the MMT score (the highest possible MMT score for all muscles evaluated is 75). Solid black line and spheres indicate the sum of MMT score calculated for all evaluated muscles. Solid grey line and squares indicate the sum of MMT score for the muscles innervated by median nerve, ulnar nerve values are indicated by dotted line and triangles, and radial nerve values by dashed line and diamonds (see Supplementary Table 2 parts 1, 2)
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Fig3
The total and partial MMT scores were improved in both hands (Fig. 3 and Supplementary Table 2 parts 1, 2).
Changes in hand strength between pre-intervention and the end of the follow-up period. a The sum of tip, key, and palmar pinch tests results in the right (red) and left (blue) hand. b Grip tests in both hands (red, right hand; blue, left hand). Y-axis represents weight in kg. See Supplementary Table 4 for full pinch tests results
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Fig4
Grip strength increased in the right hand by 4.5 kg and in the left hand by 3.3 kg (Fig. 4).
Spinal cord independence measure (SCIM) scores (Y-axis) before intervention and at the end of follow up. Black bars indicate self-care, bars with diagonal lines indicate mobility (room and toilet), white bars indicate mobility (indoors and outdoors) subscales, and black line depicts change in total SCIM scores. See Supplementary Table 6 for details
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Fig5
His SCIM self-care score increased from 3 to 13 and SCIM indoor mobility from 6 to 10 (Fig. 5).
Representative motor-evoked potentials (MEPs) elicited by magnetic stimulation of the motor cortex hotspots used for PAS therapy. Responses from the right (a) and left brachioradialis (b), right (c) and left abductor digiti minimi (d), and right (e) and left abductor pollicis brevis (f) muscles recorded before the intervention and at the end of follow up. Each image consists of 1-10 superimposed MEPs. X-axis indicates time in ms (zero value corresponds to TMS onset; note the stimulus artefact). Y-axis indicates MEP amplitude in microV. Amplitude scales differ between responses from different muscles
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Fig6
The PAS potentiated MEPs in five out of six targeted muscles (Fig. 6). Although the changes were variable, the total amplitude increase was systematic when the first and last MEP recordings were compared (Fig. 6).