Research participant

One of the four research participants with chronic motor complete SCI who were recruited to investigate the effects of activity-based training with scES on the recovery of lower limb motor function18 was enrolled to perform additional activity-based training with scES at home and in the laboratory following the completion of the initial study. Research participant B13, a 32-year old male, was implanted with a spinal cord epidural stimulation unit 4.2 years after SCI caused by a motorcycle accident. Prior to stimulator implant, this individual was unable to stand or walk independently or voluntarily move his legs despite standard-of-care rehabilitation and locomotor training received during the initial 21 months following the injury. Additional intensive locomotor training (80 sessions) performed prior to the stimulator implant did not result in functional improvements for standing, stepping or voluntary movement. Two clinicians independently performed a physical exam following the International Standards for Neurological Classification of Spinal Cord Injury20,21 prior to stimulator implant, and classified the individual as AIS B (pinprick and light-touch present below the lesion), with a neurological level of injury at C7. In addition, as reported in a previous publication19, no functional motor connectivity between the supraspinal and spinal centers below the level of injury was detected in this research participant. The individual signed an informed consent for electrode implantation, stimulation, activity-based training and physiological monitoring studies approved by the University of Louisville and the University of California, Los Angeles Institutional Review Boards. All research activities were performed in accordance with the guidelines and regulations of these Institutional Review Boards. The research participant and the other persons appearing in the Supplemental Videos included in this paper also gave written informed consent and granted full permission for their image to be used in publication online.

Surgical implantation of electrode array and stimulator

The lumbosacral enlargement was electrically stimulated during activity-based training using an epidural spinal cord stimulation unit (Restore ADVANCED, Medtronics) and a 16-electrode array (5-6-5 Specify, Medtronic) that was implanted at the T11-L1 vertebral level over the spinal cord segments L1-S116. The electrode lead was tunneled to a subcutaneous abdominal pouch where the pulse generator was implanted. Representative scES parameters utilized during activity-based training are reported in Supplemental Table S1.

Experimental Procedures

The data reported in the present study were collected without scES at different time points, over a period of 4.1 years (Fig. 1). In particular, a series of experiments in the supine position were aimed at evaluating volitional motor control during attempts to perform unilateral (right) hip flexion and knee extension22,23. During hip flexion at experimental time points t1 to t5, a non-elastic cable was secured to the ankle and attached to a fixed frame; this cable allowed a maximum hip flexion of 30 degrees.

Figure 1 Experimental protocol timeline. Panel (A) Standard of care and outpatient rehabilitation (locomotor training, LT) within the initial 21 months since injury. Panel (B) Experimental sessions (t a to t8) and activity-based interventions performed prior to and after scES implant (see text for details). Full size image

Another series of experiments were devoted to the assessment of lower limb muscle activation pattern generated during full weight-bearing standing and the amount of external assistance required for the individual to maintain upright position. Standing was performed overground using a custom designed standing apparatus comprised of horizontal bars anterior and lateral to the individual. These bars were used for upper extremity support and balance assistance. The participant initiated the sit to stand transition by positioning his feet shoulder width apart and shifting his weight forward to begin loading the legs. The participant used the horizontal bars of the standing apparatus during the transition phase to balance and to partially pull himself into a standing position. Trainers positioned at the pelvis and knees manually assisted as needed during the sit to stand transition. If the knees or hips flexed beyond the normal standing posture, external assistance at the knees distal to the patella was provided to promote knee extension, and at the hips below the iliac crest to promote hip extension and anterior tilt. Facilitation was provided either manually by a trainer or by elastic cords, which were attached between the two vertical bars of the standing apparatus.

Data acquisition

EMG, kinematics and ground reaction forces data were recorded at 2000 Hz using a custom-written acquisition software (National Instruments, Austin, TX). EMG activity of right (R) and left (L) gluteus maximus (GL), medial hamstring (MH), rectus femoris (RF), vastus lateralis (VL), tibialis anterior (TA), medial gastrocnemius (MG), soleus (SOL), sternocleidomastoid (SCM) and intercostal (sixth intercostal space; IC) muscles were recorded with bipolar surface electrodes with fixed inter- electrode distance16. Bilateral EMG from the iliopsoas (IL) was recorded with fine-wire electrodes. Lower limb joint angles were acquired using a high-speed optical motion capture system (Motion Analysis, Santa Rosa, CA). Ground reaction forces were collected using a high-resolution pressure sensing mat (HR mat system, TEKSCAN, Boston, MA) or two force platforms (Kistler Holding AG, Winterthur, Switzerland).

Data analysis

Data analysis of volitional attempts was performed on a 3-second time window, the onset of which coincided with the activation of the primary agonist muscle (iliopsoas for hip flexion attempts; vastus lateralis for knee extension attempts). If the primary agonist muscle was not active throughout the whole attempt, the time window onset corresponded to the beginning of the volitional attempt as estimated by the activation of intercostal or sternocleidomastoid muscles.

The amplitude of EMG activity during volitional attempts and standing was quantified by root mean square (RMS) and normalized (divided) by background (resting) RMS EMG amplitude that was recorded prior to the volitional attempts or during sitting, respectively. Hence, a normalized EMG amplitude value equal to 1 indicates that the EMG amplitude detected during the examined motor task (volitional movement attempt or standing) was equal to the background (resting) EMG amplitude. Joint probability density distributions (JPD) was calculated as reported by Hutchison and colleagues24 to obtain quantitative information about the coordination pattern between representative agonist and antagonist muscles during volitional movement attempts. Each data point in the JPD represents the amplitude relationship of the EMG signals from the two muscles at a given time point. Ten percent of the full scale value was then set as a threshold in order to define the four areas (A, B, C and D) represented in Fig. 2. The number of data points located in each of the four areas was finally expressed as a percentage of the total data points, representing the amount of isolated activation (area B and C) as well as the amount of co-contraction with low or high activation (area A and D, respectively) that occurred during a given attempt.

Figure 2 Quantitative joint probability density distributions analysis. The scatterplot obtained by the joint probability density distributions analysis (Hutchison et al.24), which describes the amplitude and temporal interrelationships of the EMG signals from two muscles (Ma and Mb), was divided into four areas (A,B,C and D) that were determined by setting a threshold equal to 10% of the of the EMG amplitude full scale values. Full size image

Activity-based training

Locomotor training without scES in the laboratory

Prior to epidural stimulator implant (t a to t b, Fig. 1), the research participant underwent 80 sessions of locomotor training with body weight support (1 hour per session, five sessions per week), which included stand and step training (with stepping comprising the majority of time25). This training was intented to achieve any positive adaptations induced by activity-based rehabilitation before the beginning of training with scES.

Stand training with Stand-scES in the laboratory

After the stimulator implant, participant B13 underwent 80 sessions of full weight-bearing stand training (t1 to t2, Fig. 1). Stand training lasted 1 hour per session (5 sessions per week) and was always performed with Stand-scES using the custom designed standing frame described above. The individual was encouraged to stand for as long as possible throughout the training session, with the goal to stand for 60 minutes with the least amount of assistance. Seated resting periods occurred when requested by the individual. If, during standing, the participant’s knees or hips flexed beyond the normal standing posture, external assistance to facilitate hip and knee extension was provided either manually by a trainer or by elastic cords, which were attached between the two vertical bars of the standing frame.

Step training with Step-scES in the laboratory

Following the completion of stand training with Stand-scES, participant B13 performed 80 sessions of step training with body weight support (Innoventor, St. Louis, MO) on a treadmill (t2 to t3, Fig. 1). Step training (1 hour, 5 sessions per week) was always performed with Step-scES. The research participant stepped at body weight load and speed adapted to achieve appropriate stepping kinematics25. Stepping bout duration was dependent on participant’s endurance and stepping behavior. Following a stepping bout, participant B13 was encouraged to remain standing; body weight support and length of standing break varied. All trainers were careful to provide manual assistance only when needed following standard locomotor training principles26.

Voluntary movement training with Vol-scES

Voluntary lower extremity movement was practiced on a daily basis (about 1 hour per session, 5 sessions per week) in a home-based setting and once a week in the laboratory for 9.5 months (t1 to t3, Fig. 1). Unilateral leg flexion, ankle dorsiflexion and toe extension exercises were performed with task-specific scES configurations.

Stand training with Stand-scES at home

Following the completion of all laboratory sessions, the participant continued stand training with Stand-scES in the home base setting for 12 months (t3 to t5, Fig. 1). A custom built standing frame similar to the laboratory frame was provided to the research participant for standing. Elastic cords positioned on the standing frame provided assistance for hip and knee extension when needed. All stand training was performed with Stand-scES. On average, the research participant performed stand training at home for about 30 minutes per day. However, detailed information about the stand training distribution is not available.

Stand training and step training with scES in the laboratory

After 12 months of home-based training, the research participant returned to the laboratory for training (t5 to t6, Fig. 1). Stand training with Stand-scES and step training with Step-scES occurred daily (5 days per week, 1 hour per session) in an alternating fashion. Morning sessions were alternated between standing and stepping; the participant was then given a three-hour break before returning for the afternoon session, which was focused on the motor task not trained in the morning.

Stand training with Stand-scES at home

After the conclusion of the 3-month stand and step training in the laboratory, the research participant continued with home-based stand training with Stand-scES for the following 14 months (t6 to t7, Fig. 1). The home-based training setting was the same as that described for the first period of stand training at home (see above). The average duration of stand training was about 30 minutes per day.

Step training (in the laboratory) and stand training (at home) with scES

After 14 months of home-based stand training, the participant returned to the laboratory for additional step training with Step-scES (t7 to t8, Fig. 1). During this period, he also performed stand training with Stand-scES at home on a daily basis (5 days per week).

Data Availability

All relevant data are within the paper and its Supporting Information files.