Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans

Abstract

Previously, we reported that one individual who had a motor complete, but sensory incomplete spinal cord injury regained voluntary movement after 7 months of epidural stimulation and stand training. We presumed that the residual sensory pathways were critical in this recovery. However, we now report in three more individuals voluntary movement occurred with epidural stimulation immediately after implant even in two who were diagnosed with a motor and sensory complete lesion. We demonstrate that neuromodulating the spinal circuitry with epidural stimulation, enables completely paralysed individuals to process conceptual, auditory and visual input to regain relatively fine voluntary control of paralysed muscles. We show that neuromodulation of the sub-threshold motor state of excitability of the lumbosacral spinal networks was the key to recovery of intentional movement in four of four individuals diagnosed as having complete paralysis of the legs. We have uncovered a fundamentally new intervention strategy that can dramatically affect recovery of voluntary movement in individuals with complete paralysis even years after injury.

Keywords: epidural stimulation; human spinal cord injury; voluntary movement.

Figures

Figure 1

Transmagnetic stimulation motor evoked potentials of the soleus (SOL) and tibialis anterior (TA) for two subjects (Patients A45 and A53) performed during multiple stimulation intensities without active dorsiflexion (A and C) and during active dorsiflexion (B and D). No responses were seen for either subject at the recorded intensities.

Figure 2

Timeline of implantation and experimental sessions for all participants. All individuals underwent a screening phase with at least 80 sessions of locomotor training before implantation. Patient B07 was the first subject implanted and voluntary activity was not found until the end of stand with epidural stimulation (ES). He was tested with EMG at this time point, however, T1 represents the first experimental session with force and fine motor control testing. Patients A45, B13 and A53 were tested with the same protocol post implantation and before the beginning of stand training with epidural stimulation. All participants initiated a home training programme for voluntary activity after the initial finding of their ability to move with epidural stimulation. Clinical evaluations including transcranial magnetic stimulation, Functional Neurophysiological Assessment, somatosensory evoked potentials and ASIA (American Spinal Injury Association) exams were performed before and after the 80 sessions of locomotor training during the screening phase and at the conclusion of stand and step training with epidural stimulation. Blue arrows show time points where clinical evaluations took place. Patient A53 is currently undergoing step training with epidural stimulation. See Supplementary Tables 1 and 2 for further details.

Figure 3

Lower extremity EMG activity during voluntary movement occurred only with epidural stimulation in four individuals with motor complete spinal cord injury. EMG activity during attempts of ankle dorsiflexion (A) without stimulation and (B) with stimulation. Force was not collected for Patient B07. Electrode representation for each subject denotes the stimulation configuration used. Although stimulation was applied throughout the time shown in B, in all four subjects EMG bursts were synchronized with the intent to move. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency varied from 25 to 30 Hz. Muscles, surface EMG: intercostal sixth rib (IC), tibialis anterior (TA), soleus (SOL); fine wire EMG: iliopsoas (IL), extensor digitorum longus (EDL), extensor hallucis longus (EHL). Black bars represent flexion as determined by peak force generation and white bars represent passive extension (from peak force to return to resting position). Although the subjects were instructed to flex and extend, they were unable to actively extend before training. Grey highlighted indicates the active ‘flexion/extension’ period.

Figure 4

Force level and endurance of voluntary movements. (A) Left leg force and left iliopsoas, vastus lateralis and intercostals EMG activity generated during a low (20%), medium (60%) and high (100%) effort of hip/knee flexion with epidural stimulation from Patient A45. Grey shading indicates force duration. (B) Integrated leg force (left y-axis) and iliospsoas EMG activity (right y-axis) from Patients A45 (red), B07 (black) and A53 (blue) during hip/knee flexion with epidural stimulation. Solid symbols (with solid line) represent the integrated force for each attempt and open symbols (with dash line) represent the integrated EMG of the iliopsoas muscle for each attempt. (C) Left leg force and iliopsoas, vastus lateralis and intercostals EMG activity generated during a request to sustain voluntary flexion as long as possible from Patient A45. Shaded grey indicates duration of sustained force. (D) Integrated force (solid bar) and iliopsoas EMG (open bar) during sustained contraction from Patients A45, B07 and A53 as shown in C. Electrode representation denotes the stimulation configuration used by Patient A45. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency was 25 Hz. Muscles, surface EMG: intercostal sixth rib (IC), vastus lateralis (VL); fine wire EMG: iliopsoas (IL). Stimulation artefact recorded over paraspinal muscles at T12 [epidural stimulation (ES) = blue trace]. FRC = force measured through load cell and non-elastic wire.

Figure 5

Rate of voluntary movements controlled by three individuals with motor complete spinal cord injury. (A) Force and extensor hallucis longus (EHL) EMG activity during fast voluntary first toe flexion/extension against a compliant resistance from Patient B07 from a single attempt. (B) A 1-s sweep from A before initiation of force generation encompassed by the first dashed vertical box. Ten 10 ms traces of EHL are overlaid every 0.1 s (bottom panel). The red crosses represent the timing of the stimulation artefact. (C) A 1-s period (A) during one cycle of force generation encompassed by the second dashed vertical box. Traces of EHL are shown as an overlay of 31 responses marked relative to the stimulation stimulus (bottom panel). (D and F) Force (black line) and iliopsoas and vastus lateralis EMG activity during fast voluntary whole leg flexion/extension against a compliant resistance from Patients A45 and A53, respectively. The linear envelope of the EMG signals (purple line, filter: second-order Butterworth 500–100 Hz) is shown over the raw signal. (E and G) Plot of linear envelope of the vastus lateralis versus iliopsoas from D and F. Red over the linear envelopes represents the flexion phase while green represents the extension phase of one cycle of the movement. Electrode representation for each subject denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency varied from 25 to 30Hz. Muscles, surface EMG: vastus lateralis (VL); *fine wire EMG: iliopsoas (IL), extensor hallucis longus (EHL). Stimulation artefact recorded over paraspinal muscles at T12 [epidural stimulation (ES) = blue trace].

Figure 6

Voluntary movement with epidural stimulation performed in response to visual and auditory cues in four individuals with motor complete spinal cord injury. Averaged linear envelopes (filter: Winter Butterworth low-pass 2 Hz) of EMG activity and force (FORCE) generated from three trials. The left panel of each participant represents whole leg flexion/extension in response to a visual cue during optimal stimulation. Black line represents the mean signal and grey line indicates 1 SD (standard deviation) about the mean. The red line represents the oscilloscope signal which served as the visual cue. The right panel of each participant represents whole leg flexion in response three different volumes of an auditory cue during optimal stimulation. Black line represents the mean signal and grey line indicates one standard deviation about the mean. The red line represents the oscilloscope signal that matched the auditory volume cue. Stimulation parameters and voltages for the visual and auditory attempts were the same for each subject. Electrode representation for each subject denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency varied from 25 to 30 Hz. Muscles, surface EMG:intercostal sixth rib (IC), adductor magnus (AD); fine wire EMG: iliopsoas (IL).

Figure 7

Stimulation voltage to force relationship during voluntary movement with epidural stimulation in three individuals with motor complete spinal cord injury. (A) Relationship between stimulation strength (V) and peak force (N) during hip/knee flexion for three time points in Patients B07, A45, B13 and A53 (only two time points tested). Cubic line of best fit is shown. Electrode representation for each subject denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency varied from 25 to 30Hz. (B) Top: overlap of linear envelopes for IL (filter: Winter Butterworth low-pass 2 Hz) (green), force generation (red) and oscilloscope signal (dark blue) for first time point (T1 = red) performed at optimal voltage. Middle: overlap of linear envelopes (filter: Winter Butterworth low-pass 2 Hz) (green), force generation (black) and oscilloscope signal (dark blue) for post stand training (T2 = blue) performed at optimal voltage. Bottom: overlap of linear envelopes (filter: Winter Butterworth low-pass 2 Hz) (green), force generation (black) and oscilloscope signal (dark blue) for last time point (T3 = black) performed at optimal voltage. Attempts show improvements in accuracy of force generation during hip/knee flexion following a visual cue.

Figure 8

Modulation in EMG activity during volitional assistance during stepping with epidural stimulation by an individual with motor complete spinal cord. Coordination and amplitude of EMG was modified by the intent to step. (A) Left and right activity during continuous stepping (40% body weight support, 1.07 m/s) with epidural stimulation and manual assistance. Initial steps show EMG pattern while the subject (Patient A45) is not thinking about stepping. Section within the red dashed lines show the period of steps while the subject is consciously thinking about stepping and facilitating each step (with voluntary intent). (B) Plot of linear envelope of the EMG signals of the soleus (SOL) versus tibialis anterior (TA, top) and rectus femoris (RF) medial hamstrings (MH, bottom) (filter: second-order Butterworth 500–100 Hz). Black plots represent both the steps before and after the voluntary intent to assist; red plots represent all steps within the dashed lines during voluntary intent to assist from A. (C) Similar data from Patient A53 during continuous stepping (40% body weight support, 0.36 m/s) with epidural stimulation and manual assistance. Plot of linear envelope of the EMG signals of the soleus versus tibialis anterior (top) and rectus femoris versus medial hamstrings (bottom) (filter: second-order Butterworth 500–100 Hz). Black plots represent both the steps before and after the voluntary intent to assist, while red plots represent steps in which Patient A53 is consciously thinking about stepping and facilitating each step. Electrode representation denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency was 40 Hz for Patient A45 and 30 Hz for Patient A53. Note Patient A53 was using three interleaved configurations. Muscles: soleus (SOL), medial gastrocnemius (MG), tibialis anterior (TA), medial hamstrings (MH), vastus lateralis (VL), and rectus femoris (RF). EMG data are presented in mV. Hip, knee and ankle are sagittal joint angles (degrees). The break in kinematic data is the result of a brief interruption in the recording. Ground reaction forces (FSCAN) reflect stance and swing phase (N).