Noninvasive Reactivation of Motor Descending Control after Paralysis

Abstract

The present prognosis for the recovery of voluntary control of movement in patients diagnosed as motor complete is generally poor. Herein we introduce a novel and noninvasive stimulation strategy of painless transcutaneous electrical enabling motor control and a pharmacological enabling motor control strategy to neuromodulate the physiological state of the spinal cord. This neuromodulation enabled the spinal locomotor networks of individuals with motor complete paralysis for 2-6 years American Spinal Cord Injury Association Impairment Scale (AIS) to be re-engaged and trained. We showed that locomotor-like stepping could be induced without voluntary effort within a single test session using electrical stimulation and training. We also observed significant facilitation of voluntary influence on the stepping movements in the presence of stimulation over a 4-week period in each subject. Using these strategies we transformed brain-spinal neuronal networks from a dormant to a functional state sufficiently to enable recovery of voluntary movement in five out of five subjects. Pharmacological intervention combined with stimulation and training resulted in further improvement in voluntary motor control of stepping-like movements in all subjects. We also observed on-command selective activation of the gastrocnemius and soleus muscles when attempting to plantarflex. At the end of 18 weeks of weekly interventions the mean changes in the amplitude of voluntarily controlled movement without stimulation was as high as occurred when combined with electrical stimulation. Additionally, spinally evoked motor potentials were readily modulated in the presence of voluntary effort, providing electrophysiological evidence of the re-establishment of functional connectivity among neural networks between the brain and the spinal cord.

Keywords: motor complete paralysis; neuronal network; transcutaneous spinal cord stimulation; voluntary movements.

Figures

FIG. 1.

(A) Experimental time line. The experimental plan was divided into three segments. During the first 4 weeks (Pre-Train, t1 to Post-Train, t2; Train Stim) the subjects were trained with painless cutaneous enabling motor control at T11, Co1, and T11+Co1 plus conditioning (see Fig. 1B). From t2 to t3 (Maintenance) the same procedures were followed but without the conditioning oscillation with stimulation at both sites simultaneously. This 10-week Maintenance phase of the experimental protocol was designed to establish a stable functional baseline to more clearly differentiate the effects of painless cutaneous enabling motor control plus pharmacological enabling motor control from painless cutaneous enabling motor control alone. The final 4-week phase (Pre-Drug, t3 to Post-Drug, t4; Train Stim Drug) consisted of painless cutaneous enabling motor control plus conditioning as performed in the first phase with the addition of pharmacological enabling motor control. (B) Table summarizing the protocol of sequence of tasks performed during the study, while the subject was placed in a gravity-neutral position. EMG and limb kinematics were recorded when stimulated with the cathode electrode placed at T11, at Co1, or at both sites simultaneously (T11+Co1). At each stimulation site initiation (Initiate = response to stimulation alone) was first recorded followed by efforts to voluntarily oscillate (Voluntary) the limbs in a stepping-like fashion (rows 1–5). The lower limbs then were passively moved (Conditioning) in a stepping-like fashion for 3 min with and 3 min without stimulation (rows 6–15). After each of these conditioning procedures the subject was asked to oscillate the limbs without stimulation. ✓, tasks performed every session; ×, tasks not performed during the Maintenance phase that was designed to establish a new baseline prior to initiation of the drug treatment, that is, buspirone; S1–S5, Subjects 1–5. Color image is available online at www.liebertpub.com/neu

FIG. 2.

Facilitation of stepping-like movements during noninvasive T11 and/or Co1 transcutaneous stimulation. (A) Position of the legs of a paralyzed subject when in the gravity-neutral apparatus. (B) Mean ± SEM (n = 5 subjects) angular displacements of the hip and knee at the Pre-Train (t1) and Post-Drug (t4) phases. HM, TA, and MG raw EMG and angular displacement at the knee during leg movements in the presence of stimulation at T11, Co1, or T11+Co1 at the Pre-Train ((C), t1) and Post-Drug ((D), t4) phases are shown. Red arrows indicate the time the stimulation was initiated. *, significantly different from Pre-Train at p < 0.05. EMG, electromyogram; HM, medial hamstring; MG, medial gastrocnemius; SEM, standard error of mean; TA, tibialis anterior. Color image is available online at www.liebertpub.com/neu

FIG. 3.

Voluntary control of leg movements enabled by electrical and pharmacological stimulation and training. (A) VL, HM, TA, and soleus raw EMG and angular displacement at the knee during leg oscillations with a voluntary effort alone (Vol), stimulation at T11 (Stim), and Vol+Stim at the Pre-Train (t1), Post-Train (t2), and Post-Drug (t4) phases. (B) Mean ± SEM (n = 5 subjects) knee angular displacements at the Pre-Train (t1), Post-Train (t2), and Post-Drug (t4) phases under each experimental condition described in (A) with stimulation at T11, Co1, or T11+Co1. The red and black dashed horizontal lines indicate the mean voluntary effort at t1 and t2, respectively. The percentiles at t4 reflect differences between t4 and t1 (red) and t4 and t2 (black), respectively. *, significantly different from Vol; ‡, significantly different from Stim; ** (red), significantly different from Vol at t1; ‡‡ (red), significantly different from Vol+Stim at t1; **, significantly different from Vol at t2; ‡‡, significantly different from Vol+Stim at t2; all at p < 0.05. EMG, electromyogram; HM, medial hamstring; SEM, standard error of mean; TA, tibialis anterior; VL, vastus lateralis. Color image is available online at www.liebertpub.com/neu

FIG. 4.

Subject specific kinematics responses and NL-PCA. Mean angular displacements of the knee at the (A) Pre-Train, (B) Post-Train, and (C) Post-Drug phases for each subject during Vol and Vol+Stim. (D) NL-PCA to distill non-parametric multivariate kinematics cross-correlations into PC patterns. PC loading matrix depicts the relationship between variables and the extracted PC patterns. Positive loadings are red and inverse loadings are blue. Loading weights were used to calculate PC scores. (E) Three-way repeated measures ANOVA for testing the impact of Stim, Vol, and Vol+Stim on the improvement of the kinematics based on the PC1 score. (F) Interaction of Stim by Drug modulation on the improvement of the kinematics based on the PC1 score: significance was assessed by factorial three-way within subjects ANOVA followed by post hoc one-way ANOVA and Tukey's test. *, significantly different from Vol; ‡, significantly different from Stim; ‡‡ (red), significantly different from Pre-Train; ‡‡, significantly different from Post-Train; all at p < 0.05. ANOVA, analysis of variance; NL-PCA, non-linear principal component analysis; PC, principal component; S1–S5, Subjects 1–5.

FIG. 5.

Effects of proprioceptive conditioning on voluntary leg movements. (A) An example of raw EMG and hip and knee angular displacements from the first (start) and last (end) 30 sec of a single conditioning bout without and with stimulation at T11. (B) Scatterplots between filtered EMG activities of antagonistic muscle pairs (VL vs. HM, TA vs. MG, and TA vs. Soleus) for the first 5 sec from each segment shown in (A). (C) NL-PCA was used to distill non-parametric multivariate kinematics cross-correlations into PC patterns. PC loading matrix depicts the relationship between variables and the extracted PC patterns. (D) Three-way repeated measures ANOVA of the impact of Vol, Stim, and Vol+Stim using PC1 outcome as the end-point. (E) Interaction of Stim by Conditioning modulation. ‡, significantly different from Stim; ‡‡ (red), significantly different Pre-Cond; all at p < 0.05. ANOVA, analysis of variance; EMG, electromyogram; HM, medial hamstring; MG, medial gastrocnemius; NL-PCA, non-linear principal component analysis; PC, principal component; SEM, standard error of mean; TA, tibialis anterior; VL, vastus lateralis.

FIG. 6.

Voluntary performance (without spinal cord stimulation) at different phases of the study. (A) An example of VL and HM EMG activity and hip and knee displacements during voluntary leg oscillations without stimulation for Subject 1 during the Pre-Train (t1) and Post-Drug (t4) phases. (B) Pattern of reciprocity for EMG amplitudes of the HM and VL and kinematics coordination based on knee and hip movements. (C) Mean ± SEM knee displacement Pre-train (t1) and Post-train (t2), at the beginning (t2) and end (t3) of the maintenance phase, and the beginning (t3) and end (t4) of the drug phase. *, significantly different from t1-t3. (D) Clinical assessment according to AIS. AIS motor scores at t1, t2, and t4 for individual subjects (S1–S5) and the average for all subjects. EMG, electromyogram; EX, extension; DF, dorsiflexion; FL, flexion; HM, medial hamstring; PF, plantarflexion; S1–S5, Subject 1–Subject 5; SEM, standard error of mean; VL, vastus lateralis. Color image is available online at www.liebertpub.com/neu

FIG. 7.

Modulation of evoked potentials with and without voluntary effort. (A) Raw EMG from the TA and MG muscles under the influence of stimulation at T11, Co1, and T11+Co1 with and without voluntary effort to oscillate the legs (flexion-extension-flexion) when placed in a gravity-neutral position. (B) Evoked potentials generated within the shaded areas in (A) without (black traces) and with (red traces) voluntary effort. The sequence of traces is triggered from the stimulation pulse with the lowest trace being the first and the top trace being the last response. (C) Overlay of multiple responses (T11, 0–33 msec and Co1, 0–200 msec) during flexion and extension without (Stim) and with (Vol+Stim) voluntary effort. (D) Schematic summary of the variations in 20–35 msec TA (Flexor-F) and MG (Extensor-E) responses (see B) reflects how spinally evoked potentials can be gated by a voluntary effort. The dotted lines reflect minimal or no evoked potential and the thin and thick solid lines indicate modest and high amplitude evoked potentials, respectively. Generally, Co1 stimulation evoked more consistent responses in both muscles than T11 or T11+Co1 stimulation. EMG, electromyogram; MG, medial gastrocnemius; TA, tibialis anterior.

FIG. 8.

Spinally evoked motor potentials in one participant during transcutaneous electrical spinal stimulation delivered between the spinous processes of the T11 and T12 vertebrae. The average of three non-rectified responses in the HM, TA, and MG of the right leg at stimulation intensities from 50 to 150 mA (10 mA increments) at Pre-Train (A, t1) and Post-Drug (B, t4) phases of the study. Data are shown from the time window between 10 and 40 msec following the stimulus. Recruitment curves are shown for the HM, TA, and MG at stimulation intensities ranging from 50 to 150 mA at the Pre-Train (C, t1) and Post-Drug (D, t4) phases of the study. Note the increase in the response magnitudes at the higher intensities, especially at t4. (E) Schematic reflecting the increasing amplitudes of sEMP with an increasing intensity of stimulation and the generation of evoked motor potentials when the stimulation crosses motor threshold. Note the presence of motor units only after network excitability crosses the motor threshold. (F) Schematic representing the combination of various neuromodulation modalities including stimulation, pharmacology, proprioception, and descending input in the generation of the EMG bursting patterns and the corresponding force. EMG, electromyogram; HM, medial hamstring; MG, medial gastrocnemius; sEMP, spinally evoked motor potentials; TA, tibialis anterior. Color image is available online at www.liebertpub.com/neu

FIG. 9.

Electrophysiological assessment of brain–spinal network interactions. MG and soleus EMG recorded during plantarflexion with and without a maximum voluntary effort with stimulation at T11 at t1(A) and t4(B). (C,D) show schematic diagrams of hypothetical mechanisms underlying the observed results of short and long latency responses of motor pools (see Discussion for details).