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Clinical Trial
. 2018 Sep 15;35(18):2145-2158.
doi: 10.1089/neu.2017.5461.

Non-Invasive Activation of Cervical Spinal Networks after Severe Paralysis

Parag Gad  1 , Sujin Lee  2 , Nicholas Terrafranca  3 , Hui Zhong  1 , Amanda Turner  1 , Yury Gerasimenko  1   4   5 , V Reggie Edgerton  1   6   7   8   9   10
Affiliations
Clinical Trial

Non-Invasive Activation of Cervical Spinal Networks after Severe Paralysis

Parag Gad et al. J Neurotrauma. .

Abstract

Paralysis of the upper extremities following cervical spinal cord injury (SCI) significantly impairs one's ability to live independently. While regaining hand function or grasping ability is considered one of the most desired functions in tetraplegics, limited therapeutic development in this direction has been demonstrated to date in humans with a high severe cervical injury. The underlying hypothesis is that after severe cervical SCI, nonfunctional sensory-motor networks within the cervical spinal cord can be transcutaneously neuromodulated to physiological states that enable and amplify voluntary control of the hand. Improved voluntary hand function occurred within a single session in every subject tested. After eight sessions of non-invasive transcutaneous stimulation, combined with training over 4 weeks, maximum voluntary hand grip forces increased by ∼325% (in the presence of stimulation) and ∼225% (when grip strength was tested without simultaneous stimulation) in chronic cervical SCI subjects (American Spinal Injury Association Impairment Scale [AIS] B, n = 3; AIS C, n = 5) 1-21 years post-injury). Maximum grip strength improved in both the left and right hands and the magnitude of increase was independent of hand dominance. We refer to the neuromodulatory method used as transcutaneous enabling motor control to emphasize that the stimulation parameters used are designed to avoid directly inducing muscular contractions, but to enable task performance according to the subject's voluntary intent. In some subjects, there were improvements in autonomic function, lower extremity motor function, and sensation below the level of the lesion. Although a neuromodulation-training effect was observed in every subject tested, further controlled and blinded studies are needed to determine the responsiveness of a larger and broader population of subjects varying in the type, severity, and years post-injury. It appears rather convincing, however, that a "central pattern generation" phenomenon as generally perceived in the lumbosacral networks in controlling stepping neuromodulator is not a critical element of spinal neuromodulation to regain function among spinal networks.

Keywords: cervical spinal cord injury; non-invasive spinal cord stimulation; tetraplegia; upper extremity rehabilitation.

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Conflict of interest statement

V.R.E, Y.P.G, N.T., and PG, researchers on the study team, hold shareholder interest in NeuroRecovery Technologies and hold certain inventorship rights on intellectual property licensed by the Regents of the University of California to NeuroRecovery Technologies and its subsidiaries.

Figures

<b>Fig. 1.</b>
Fig. 1.
(A) A series of spinally evoked responses (mean of five responses at each intensity) from proximal and distal muscles from one subject 491863 at rest with increasing intensities of stimulation at pre-intervention. In (B), the thick black line represents the average control response when stimulated at 110 mA, while the red trace was generated during a maximal voluntary effort to generate a grip force. (C) Mean ± standard deviation (n = 5 response) spinally evoked middle responses (latency ∼15 msec) in (B). (D) Area under the curve of the rectified long latency electromyography (latency 30 msec-100 msec) in B.
<b>Fig. 2.</b>
Fig. 2.
(A) Representative electromyography (EMG) and force during a maximum voluntary contraction (MVC) during the first treatment session in an American Spinal Injury Association Impairment Scale C subject without stimulation; then with one site stimulation at different locations; and then with two-site simultaneous stimulation. (B) Representative EMG and force during a MVC in the same subject as in (A) before (pre-intervention) and after (post-intervention) and with and without stimulation. (C) mean ± standard error (SE) integrated EMG (mV.s) and mean ± SE EMG amplitude (n = 6 subjects) during the MVC at pre- and post-intervention with and without two-site stimulation shown in (A). biceps, biceps brachia; extensors, extensor digitorium; flexors, flexor digitorium.
<b>Fig. 3.</b>
Fig. 3.
(A) Six individual subjects' maximum voluntary contraction (MVC) force for left and right hands at the start and end of intervention with (red) and without (black) stimulation. (B) Normalized mean ± standard error (n = 6 subjects) at Day 1 (pre-intervention) and Day 8 (post-intervention) during transcutaneous enabling motor control (tEmc) ON and tEmc Off. *tEmc On significantly different from tEmc off. †Day 8 significantly different from Day 1.
<b>Fig. 4.</b>
Fig. 4.
(A) A Six individual subjects' maximum voluntary contraction (MVC) force for left and right hands during the eight treatment sessions without stimulation. (B) Normalized mean ± standard error (n = 8 subjects, Day 1–4, n = 6, Day 5–8) forces generated without transcutaneous enabling motor control for the stronger hand. *Significantly different from Day 1. The dotted line represents a 4th order curve fitted to the data.
<b>Fig. 5.</b>
Fig. 5.
(A) An example of mean (n = 5 responses) evoked potential at pre-intervention (black) and post-intervention (green). (B) An example of mean evoked potential recruitment curve for proximal and distal muscles recorded at pre-intervention (black) and post-intervention (green). (C) Normalized change in maximum evoked responses (n = 6 subjects, both hands) shown in (C). *Significantly different from 0 at p < 0.05.
<b>Fig. 6.</b>
Fig. 6.
Representative electromyography and force during maximum voluntary contraction with and without transcutaneous enabling motor control in an American Spinal Injury Association Impairment Scale B subject (739144) on the first treatment session.
<b>Fig. 7.</b>
Fig. 7.
Representative electromyography and force during rhythmic submaximal voluntary efforts in an American Spinal Injury Association Impairment Scale B subject (739144) before (pre-intervention) and after (post-intervention) without transcutaneous enabling motor control.
<b>Fig. 8.</b>
Fig. 8.
Cumulative maximal voluntary contraction (MVC) force and numerical motor score for the left and right hands (all right dominant at pre-injury) for six individuals over the course of the eight treatment sessions. Note the blue and orange lines are plotted based on the first and second days of intervention; thus, those data points that fall above the line represent greater response compared with the responses seen in the first to the second intervention.
<b>Fig. 9.</b>
Fig. 9.
(A) Individual maximum voluntary contraction (MVC) forces at the Day 1 (hollow) and Day 8 (solid) of intervention relative to the start and end upper extremity (UE) motor scores for left and right hands. Note no change in motor score of subject 511282 but with one of greater improvement in grip force. Right hand of subject 739144 did not change in UE motor score and had minimal increase in grip force. Also note subject 491863's left hand did not improve even though the subject had a strong intial MVC and UE motor score. (B) Increased MVC force relative to initial UE motor scores for the subjects shown in (A). The 12 dots represent the left and right hands of six individuals listed in (A), r2 (linear) = 0.259, r2 (exponential) = 0.452. (C) Increased MVC force relative to initial grip force for the subjects shown in (A). 491863's left data point (non-responder) is not included in (C). Black line represents an exponential curve fitted to the data points. Note the marginal increase in grip force at lower initial motor scores and lower initial grip forces, compared with higher increased grip strength at higher initial motor scores and higher initial grip forces.
<b>Fig. 10.</b>
Fig. 10.
(A) Subject characteristics (n = 6) including motor and sensory scores before (yellow) and after the intervention (orange). Level of spinal cord injury neurological level based on International Standards for Neurological Classification of Spinal Cord Injury examination. (B) Examples of dermatomes for motor and sensory scores before and after the intervention for two subjects. Note: Subject 511282 had suffered an injury to the C7 vertebrae qualifying the subject for the study; however, based on the American Spinal Injury Association Impairment Scale (AIS) examination (motor and sensory scores) the subject level of injury was classified as a C8 AIS C.
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