Recovery of volitional motor control and overground walking in participants

with chronic clinically motor complete spinal cord injury: RESTORES trial – A

preliminary study

Kai Rui Wan1,2*, Ng Zhi Yan Valerie3, Seng Kwee Wee3,4, Fatimah Misbaah1,2, Wenli

Lui3, Min Wee Phua3, So Qi Yue Rosa5, Tomasz Karol Maszczyk6, Brian Premchand5,

Seyed Ehsan Saffari7, Rui Xin Justin Ker1,2, Wai Hoe Ng1,2

Affiliations
1
Department of Neurosurgery, National Neuroscience Institute, Tan Tock Seng

Hospital
2
Department of Neurosurgery, National Neuroscience Institute, Singapore General

Hospital
3
Department of Rehabilitation Medicine, Tan Tock Seng Hospital
4
Singapore Institute of Technology
5
Institute for Infocomm Research, Agency for Science, Technology and Research
6
Institute of High Performance Computing, Agency for Science, Technology and

Research
7
Centre for Quantitative Medicine, Duke-NUS Medical School, National University of

Singapore

* Corresponding author

Keywords: Spinal cord injury; Spinal cord stimulation; Neuro-rehabilitation; Neuro-

robotics; Neuromodulation; Clinical trial

Correspondence details of the included authors

Kai Rui Wan (Corresponding author)

Wan.kai.rui@singhealth.com.sg

11 Jalan Tan Tock Seng Singapore 308433

Ng Zhi Yan Valerie

Valerie_ng@ttsh.com.sg

7 Jalan Tan Tock Seng Singapore 308440

Seng Kwee Wee

Seng_kwee_wee@ttsh.com.sg

7 Jalan Tan Tock Seng Singapore 308440

Fatimah Misbaah

Fatimah_misbaah_abdul_rahim@nni.com.sg

11 Jalan Tan Tock Seng Singapore 308433

Wenli Lui

wen_li_lui@ttsh.com.sg

7 Jalan Tan Tock Seng Singapore 308440

Min Wee Phua

Min_wee_phua@ttsh.com.sg
7 Jalan Tan Tock Seng Singapore 308440

So Qi Yue Rosa

rosa-so@i2r.a-star.edu.sg

1 Fusionopolis Way, #21-01 Connexis, Singapore 138632

Tomasz Karol Maszczyk

maszczyk_tomasz_karol@ihpc.a-star.edu.sg

1 Fusionopolis Way, #16-16 Connexis, Singapore 138632

Brian Premchand

brian_premchand@i2r.a-star.edu.sg

1 Fusionopolis Way, #21-01 Connexis, Singapore 138632

Ehsan Syed

Ehsan.saffari@duke-nus.edu.sg

8 College Rd, Singapore 169857

Rui Xin Justin Ker

justin.ker.r.x@singhealth.com.sg

11 Jalan Tan Tock Seng Singapore 308433

Wai Hoe Ng

ng.wai.hoe@singhealth.com.sg

11 Jalan Tan Tock Seng Singapore 308433

ABSTRACT

Spinal cord injury (SCI) is damage to any part of the spinal cord resulting in

paralysis, bowel and/or bladder incontinence, loss of sensation and other bodily

functions. Current treatments for chronic SCI are focused on managing symptoms

and preventing further damage to the spinal cord with limited neuro-restorative

interventions. Recent research and independent clinical trials of spinal cord

stimulation (SCS) or intensive neuro-rehabilitation including neuro-robotics in

participants with SCI have suggested potential malleability of the neuronal networks

for neurological recovery. We hypothesize that epidural electrical stimulation (EES)

delivered via SCS in conjunction with mental imagery practice and robotic neuro-

rehabilitation can synergistically improve volitional motor function below the level of

injury in participants with chronic clinically motor-complete SCI.

In our pilot clinical RESTORES trial (RESToration Of Rehabilitative function with

Epidural spinal Stimulation) we investigate the feasibility of this combined multi-

modal approach in restoring volitional motor control and achieving independent

overground locomotion in participants with chronic motor complete thoracic SCI.

Secondary aims are to assess the safety of this combination therapy including the

off-label SCS usage as well as improving functional outcome measures. To our

knowledge, this is the first clinical trial that investigates the combined impact of this

multi-modal EES and rehabilitation strategy in participants with chronic motor

complete SCI.

Two participants with chronic motor-complete thoracic SCI were recruited for this

pilot trial. Both participants have successfully regained volitional motor control below

their level of SCI injury and achieved independent overground walking within a
month of post-operative stimulation and rehabilitation. There were no adverse events

noted in our trial and there was an improvement in postoperative truncal stability

score.

Results from this pilot study demonstrates the feasibility of combining EES, mental

imagery practice and robotic rehabilitation in improving volitional motor control below

level of SCI injury and restoring independent overground walking for participants with

chronic motor-complete SCI. Our team believes that this provides very exciting

promise in a field currently devoid of disease-modifying therapies.

INTRODUCTION

Spinal cord injury (SCI) is a devastating condition that occurs at an approximate

incidence of 250,000 to 750,000 globally each year, with a bimodal age distribution.

(1–3) SCI interrupts efferent and afferent pathways between the brain, brainstem and

spinal cord, leading to loss of essential neurological function. (4,5) This translates to

significant and often catastrophic permanent dysfunction and disability to the

individuals’ physical and mental health. (1,4,6) The subsequent downstream

secondary conditions result in reduced quality of life, caregiver burden and high

socioeconomic costs. (2,4,7)

The severity of SCI is graded with the American Spinal Injury Association

(AIS) scale. Patients with Grade A injuries have no motor or sensory function

(including sacral roots) distal to the level of injury. Patients with Grade B have

sensory function, but no motor function below the level of injury. Both Grade A and B

injuries are considered clinically motor-complete SCI. The level of SCI also
determines which systems are affected, which consequently impacts on potential

rehabilitation as well as final functional status of the patient. (4) Unfortunately,

majority of subjects (94.4%) who have a neurologically complete (AIS A) injury at 1

year remained complete at 5 years postinjury. (8–10) Despite intense research in this

field, there are limited neuro-restorative interventions for complete SCI and current

management goals generally focus on adaptive devices and prevention and/or

management of SCI related medical complications.

Epidural electrical stimulation (EES) via spinal cord stimulator (SCS),

originally approved by the US Food and Drug Administration (FDA) in 2004 for the

management of chronic pain, has been recently heralded for its pivotal role in

exploiting neuronal activity and pathways in chronic SCI. (11–15) Recent pilot trials

(16–21) have demonstrated the potential of EES in restoring neurological function

including improving volitional motor movement below the level of injury and even

achieving independent control of walking. (7,22) EES consists of surgically

implanting a small array of electrodes onto the dorsal aspect of spinal epidural space

to stimulate afferent sensory pathways in specific patterns. This is postulated to

increase baseline levels of spinal excitability and drive voluntary and autonomically

controlled motor responses. (4) SCS systems consist of flexible spatial configuration

of electrodes to adjust the temporospatial pattern of electrical current delivered. The

broad number of permutations in settings provide a unique challenge to find optimal

stimulation parameters for each patient. Its limitations also include the costs of

implant and at present poorly defined selection criteria of patients who may benefit

from this therapy.

 Mental imagery coupled with activity-based training have been shown to

improve motor performance. (10,17,23) Mental imagery is the process of creating

and rehearsing vivid realistic images in the mind’s eye. (24,25) Research has shown

that activation sequences in the motor cortex during mental imagination of a

movement are similar to those occurring during performance of that movement and

activating similar neural circuits, thus contributing to neural plasticity to facilitate

motor recovery. (24–26) This cognitive technique also encourages individuals to

mentally practice different movement strategies such as adjusting limb positions,

coordinating muscle contractions and maintaining balance. This rehearsal can act as

cognitive priming to improve the individual’s understanding of movement mechanics;

leading to smoother and more coordinated movements when they are eventually

able to attempt them physically. (23) However, there are possible significant inter-

individual motor imagery abilities which can subsequently influence the performance

of motor tasks. (26)

Wearable robotics, also known as robotic exoskeletons (RE), have emerged

as promising tools in the field of neurorehabilitation. (27–29) These devices

supplement traditional physical therapy with their ability to provide quantifiable

external support and real-time sensorimotor feedback in patients with motor

impairments. (30,31) These neuro-rehabilitative assistive technologies are both

practical and resource-effective due to its ability to deliver patient-specific and

precise high dose training regime (32) coupled with a reduced physical reliance on

therapists. (33) RE can be programmed by the therapists to provide varying levels of

assistance during each task-specific training, thus enhancing assistance induced

plasticity.(28) Despite its initial promise, there is still limited success reported in the
usage of the exoskeletons; possibly attributing to patients with SCI being unable to

respond with active body control and sensing of movements to such bionic

innovations. (32) In addition, RE have high initial upfront costs and require

specialized therapist training for its use, thus limiting its widespread availability.

In our pilot clinical RESTORES trial (RESToration Of Rehabilitative function with

Epidural spinal Stimulation) we investigate the feasibility of this combined multi-

modal approach in restoring volitional motor control below the level of injury and

independent overground locomotion in participants with chronic motor complete

thoracic SCI. Secondary aims are to assess the safety of this combination therapy

including the off-label SCS usage as well as the potential of improving functional

outcome measures. To our knowledge, this is the first clinical trial that investigates

the combined impact of this multi-modal surgical and rehabilitation strategy in

participants with motor complete SCI.

PARTICIPANTS AND METHODS

Study design and participants

This study was performed in accordance with local Institutional Review Board

approval. Consent and authorization to present identifiable information for research

purposes was given by the study participants. The study protocol is registered with

Clinical-trials.gov (NCT05644171; Registered 13 November 2022.

https://clinicaltrials.gov/ct2/show/NCT05644171)
 Participants with chronic (greater than one year) clinically motor complete

(AIS classification A or B) SCI were recruited into the trial if they fulfilled all of the

following: they were 21 years old and older; their spinal injury between the levels of

Thoracic 1 (T1) to Lumbar 1 (L1); their segmental reflexes remain functional below

the level of lesion; they were able to perform the perioperative rehabilitation program

as judged by the research team. Written informed consent was obtained from the

participant prior to entry into the study in accordance with local EC/IRB regulations.

Potential participants will be excluded from the trial if they fulfil any of the

following criteria: Significant medical co-morbidities that would significantly increase

the risk of the operation; severe dysautonomia with systolic blood pressure

fluctuation less than 50 or more than 200mmHg on tilt table testing; painful

musculoskeletal dysfunction, contractures, unhealed fractures, pressure sores,

severe spasticity, and osteoporosis; significant psychological issues or ongoing drug

abuse; pregnancy and lactating participants; progressive spinal cord disease and

any disease, in the opinion of the Investigator, which could jeopardize the safety of

the participant.

Details of included participants

Two male participants with chronic thoracic AIS A SCI were recruited into this

study. Participant 1 (P1) is a 47-year-old male ex-jockey with Thoracic 4 (T4) AIS A

SCI after a horse-riding accident in 2017. He suffered a Thoracic 6 (T6) burst

fracture with multiple thoracic vertebral fractures spanning from Thoracic 3 (T3) to
Thoracic 7 (T7). He underwent Thoracic 1 to 9 (T1-9) spine fixation and

decompressive laminectomy of Thoracic 3 to 7 (T3-7).

Participant 2 (P2) is a 26-year-old male with Thoracic 1 (T1) AIS A SCI after a

motorcycle accident in 2018. He suffered a Thoracic 3 (T3) and Thoracic 4 (T4) tri-

column chance fracture with subluxation and multi-ligamentous tears. He underwent

a Thoracic 3-4 (T3-4) laminectomy and reduction, a Cervical 7 (C7) to Thoracic 2

(T2) instrumentation as well as a Thoracic 5 (T5) to Thoracic 7 (T7) instrumentation.

Two clinicians independently performed a physical exam following the

International Standards for Neurological Classification of SCI and classified both

patients as AIS A (no motor and sensation present below the level of lesion)

Further details of our participants are tabulated in Table 1.

Surgical procedure

All antiplatelet or anticoagulant agents are withheld up to 14 days prior to

surgery and resumed 1 to 3 days after. Perioperative platelet count <100 000 or

prolonged prothrombin or partial thromboplastin time are corrected prior to surgery.

Both participants receive prophylactic antibiotics perioperatively.

Both participants underwent surgical implantation of a 3 column, 16 contact

spinal cord stimulator (SpecifySureScanTM 5-6-5 Medtronic) paddle leads under

general anaesthesia. The electrode array was placed on the dorsal epidural surface

of the spinal cord. Intraoperative stimulation (2Hz, 450 microseconds, 0-10mA)

[Supplementary Figure 1] was performed to confirm the location of the paddle at the

midline and to ensure adequate coverage of the intended muscles (Rectus femoris,

vastus lateralis, medial hamstring, tibialis anterior, medial gastrocnemius, soleus)

using surrogate electrophysiological monitoring. The paddle is then anchored in

place with surgical adhesives and using standard surgical techniques, the lead would

be tunnelled out subcutaneously to the right iliac fossa where a small subcutaneous

pocket is created. The lead wires would then be connected to the implantable pulse

generator (Medtronic Intellis AdaptiveStim). The stimulation system’s in vivo

impedance is tested to ensure electrical continuity of the device system. The incision

wounds are then irrigated and sutured closed in anatomical layers. The stimulator

was only turned on one month after the surgery, at the commencement of the post-

operative rehabilitation phase.

Prehabilitation

Prehabilitation programmes have been shown to reduce medical

expenditures, and improve patients' postoperative pain, disability, self-efficacy,

psychological behaviours, and satisfaction with surgical outcomes. (34) The

prehabilitation phase commenced one month prior to the planned surgical date and

the participants received twice weekly prehabilitation for a period of 4 weeks, with

the aim of conditioning them physically and mentally for the subsequent daily post-

operative rehabilitation therapy. In each week of the prehabilitation phase, each

participant received one conventional physiotherapy session and one RE session,

each lasting 1 hour.

 Conventional physiotherapy consisting of stretching and strengthening

exercises for the trunk, upper and lower limbs. Supported standing exercises using a

movable standing frame - THERA-Trainer Balo (Medica Medizintechnik GmbH,

Germany) was used for verticalization tolerance. (Figure 1) In addition, the THERA-

Trainer was coupled with virtual reality games for our participants to actively practise

weight shifting in all directions and improve truncal control. Electric arm and leg

cycling with the MOTOMED viva2 (RECK-Technik GmbH & Co. KG, Germany) was

also used to help maintain the range of motion. Overground gait training with manual

physical assistance was also performed.

In addition, both participants received overground gait training using a

wearable RE, EksoGT (Ekso Bionics, Richmond, California, USA) once weekly for

one hour. Robot-assisted gait therapy is a promising rehabilitation therapy that

provides individualised, highly repetitive and intensive gait training. (35) The EksoGT

has motors at the hips and knees, a spring-loaded footplate to aid foot clearance as

well as a backpack support for the trunk. The device’s software enables

customisation of gait parameters (level of assistance from the robot, step height,

step length and swing speed) in order to promote active participation that is

reasonably challenging. The participants practised dynamic weight shifts whilst

walking with the EksoGT; hence improving their trunk control, balance as well as

facilitating motor learning and control. This is key as the participants would need to

perform dynamic weight shifting for overground walking with assistive aids post

operatively.
 Participants are encouraged to perform mental imagery training at home. Two

main types of imagery techniques are taught: external or visual, in which they

imagine seeing themselves from the viewpoint of an external observer; and internal

or kinaesthetic, in which subjects imagine the sensations of motion in their own

bodies.(24) Participants are encouraged to practice either/both techniques in

accordance to their preference. They are encouraged to mentally rehearse individual

muscle movements (hip flexion/extension, knee flexion/extension, ankle

dorsiflexion/plantar flexion) unilaterally in turn as well as combined movements (sit-

to-stand movements and overground locomotion). The intensity of their home-based

mental imagery practice was left to the individual participant.

During their conventional and RE training rehabilitation sessions, participants

are encouraged to evoke visualization of the intended movements prior to attempting

the intended movements.

Post-operative Rehabilitation

The participants commenced on their postoperative rehabilitation phase one

month after the surgery to allow for the surgical wounds to heal. This comprised of

daily sessions with each session lasting an hour. The participants received 3-4 times

of conventional physiotherapy and 1-2 times Ekso RE therapy with overground gait

training based on their tolerance per week. Rehabilitation sessions were coupled

with neurostimulation and participant-evoked visualisation of the intended

movements prior to actual attempts to enhance neuroplasticity. Both participants

were encouraged to continue their mental imagery exercises and attempts at

volitional movements at home, as described below. Bipolar surface EMG (sEMG)

(Medtronic NIM Eclipse) recordings are performed weekly with and without

stimulation to guide the coverage of intended stimulation and recruitment of muscles

with intent. Further information regarding our sEMG set up are as follows.

sEMG Recording set up

All recordings were conducted with the participants placed supine on a

comfortable examination table with their lower limbs exposed. This configuration

allowed flexion/extension movements of the lower limb to unfold smoothly and

minimized friction between the heel and supporting surface. To monitor activity of

volitional movement with intent and using stimulation, silver-silver chloride surface

electrodes (NIM electrodes, Medtronic) were used. The bipolar surface electrodes

were placed centrally over the bilateral muscle bellies of rectus femoris, vastus

lateralis, medial hamstring, tibialis anterior, medial gastrocnemius, soleus. Baseline

sEMG recording of at least 30 seconds would be obtained for reference.

Subsequently, the participants are given audio cues from the research team to

mentally visualize the intended movements prior to attempts at performing motor

actions for the following: Hip flexion and extension, knee flexion and extension, ankle

dorsiflexion and plantarflexion. Each action was repeated for at least three trials,

whilst ensuring that the signals return to baseline before the next attempt at

movement. This was performed unilaterally in turn. The above protocol would then

be repeated with the stimulation turned on post-operatively. Baseline sEMG

recording when the stimulator is turned on will also be obtained for at least 30

seconds for reference. Each set of sEMG signals for each motor action with and
without stimulation was recorded for minimum of 20 seconds and labelled in

accordance to the intended movement as well as timing of the audio cues. All

recordings were performed on Medtronic NIM-Eclipse® machine with a notch filter of

60 Hz and butterworth low pass filter of 30 Hz and high pass filter of 1500 Hz. The

sEMG recordings were downloaded and analyzed retrospectively in an offline

fashion.

Programming parameters

The stimulator was switched on after approximately a month post-surgery to

allow the surgical wounds to heal and coincide with the post-operative rehabilitation

program. With the participants in a supine position, sEMG was used to identify the

intended muscle groups activated by stimulating each epidural anode and cathode.

The initial stimulation paradigm was similar to the intraoperative testing (2Hz, 350

microseconds, 0-10 mA). [Supplementary Figure 1] This program was used for

participants to practice individual motor action (Hip flexion and extension, knee

flexion and extension, ankle dorsiflexion and plantarflexion) with mental rehearsal

prior to the actual movement attempt as well as with stimulation. The electrode

arrays were operated as bipolar electrodes and impedances were generally about

1000 microhms. The stimulus pulses were biphasic and actively charge balanced.

The contacts were systematically chosen to evoke posterior roots muscle responses

(PRMRRs) (36) and target the intended main muscle of each action. The required

amplitude was adjusted till the participants could consistently achieve each intended

action at least 5 consecutive times.

Once both participants were deemed to have sufficient volitional control of individual

motor actions by the research team, they were progressed to sit-to-stand and
overground walking exercises with similar self-evoked mental rehearsal priming prior

to motor attempts. The stimulation protocol was subsequently adjusted in

accordance to sEMG electrophysiological and clinical response to target appropriate

muscle groups for a rhythmical pattern for stepping gait pattern with an interleaving

program (21) (50Hz, 100-400 microseconds, 5-20mA). [Supplementary Figure 2] The

stimulation protocol during RE therapy would follow the last parameter setting during

traditional physical therapy. All post-operative rehabilitation activities were coupled

throughout the session with EES.

Both participants were also discharged with low-dose constant stimulation (50% of

the maximum stimulation applied during the daily hourly rehabilitation regime) for

their theoretical adjustments to their stimulation programs and encourage further

neuroplasticity as both participants were encouraged to continue mental imagery

exercises and attempt practice of volitional motor tasks at home. The participants

were able to switch off their stimulator if required although this was not done by

either of the participants during the period of this trial. Adaptive stimulation was not

used during this trial.

Functional outcome measure scales

Standardized rating scales are required for the functional assessment of

patients with SCI. The following functional scales were used in this trial: AIS motor

scale, Spinal cord independence measure (SCIM), Walking index of spinal cord

injury II (WISCI II), Trunk assessment for spinal cord injury (TASS). These outcome

measures were performed at 3 time points during this trial: i) at the end of the one

month pre-rehabilitation phase; ii) one month after the surgery prior to the start of the
postoperative rehabilitation with stimulation and iii) after one month of post-operative

rehabilitation with stimulation.

AIS motor scale is a widely used scale for functional assessment of SCI. It

expresses the degree of disability and neurological level of injury with motor

functions of motor and upper limbs represented by their respective motor scores.

(37)

SCIM is a validated disability scale with high interrater reliability developed

specifically for patients with SCI to assess performance in activities of daily living and

mobility. It is a more sensitive measure than the traditionally used functional

independence measure (FIM) in detecting meaningful functional changes in patients

with SCI. It covers three principal areas of function: self-care (subscore (0-20),

respiration and sphincter management (0-40) and mobility (0-40). Each area is

scored according to its proportional weight in these patients' general activity. The

final score ranges from 0 to 100. (38)

WISCI II is a functional capacity scale designed to measure improvements in

persons with spinal cord injury by evaluating the degree of impairment and

assistance required to walk 10 meters.(39) The assessment is ranked along a

dimension of impairment, from the level of most severe impairment (0) to least

severe impairment (20) based on the use of devices, braces and physical assistance

of one or more persons. It has been demonstrated to have good intra and inter-rater

reliability. (40)
 Effective control of posture is of utmost importance for standing and walking,

as well as for providing support for voluntary movements. TASS is a validated 9-item

scale to assess truncal balance in patients with SCI with high intra and inter-rater

stability. (41)

RESULTS

Study participants and stimulator implantation

Both participants have severe SCI with less than 1 mm of residual cord at the

level of the lesion and extensive myelomalacia as revealed by MRI and shown in

Figure 2. Prior to implantation, both individuals were unable to stand or walk

independently or voluntarily move their legs despite one month of preoperative

rehabilitative sessions. Both participants had a total of 8 preoperative rehabilitation

sessions and 20 post operative rehabilitation sessions at the time of reporting. [Table

1]

Epidural spinal cord stimulator placement in both participants was guided by

intraoperative monitoring. The final placement of the SCS was over spinal levels of

Thoracic 11 to Lumbar 1 in Participant 1 and Thoracic 12 to Lumbar 1 at Participant

2. [Figure 2] Final SCS placement corresponded with intraoperative

neurophysiological EMG responses in muscles corresponding to bilateral L1,2,3,4,5

and S1 equal activation at 2Hz, 0-10mA, 350 microseconds pulse width.

Feasibility of achieving volitional movements and overground independent

locomotion with multi-modality paradigm

Both participants complied with all the planned 8 preoperative and 20 post-operative

rehabilitation schedules. [Table 1] There were no improvement in volitional motor

control below the level of injury for both participants after a month of preoperative

rehabilitation.

However, both participants exhibited voluntary control over their lower extremity

movements through self-induced mental imagery just before attempting the

movements upon the activation of EES.

Participant 1 was able to continuously dorsiflex and plantarflex his ankle as

well as flex and extend his knees at the end of Week 1. This progressed quickly to

bilateral hip flexion and abduction in Week 2. These motor actions were achieved in

a supine position. He was then able to take his first step and perform overground

walking with a rollator frame in Week 3 with assistance by the therapists. By the end

of Week 4, Participant 1 was able to perform independent overground walking with a

rollator frame. [Figure 3; Supplementary video 1]

Participant 2 was able to flex and extend his hip and knee with good volitional

control at the end of Week 1 in a supine followed by seated position. This progressed

quickly to being able to flex his thigh with good control in a standing position at the

end of Week 2. He could perform independent sit to stand movements at Week 3. By

the end of Week 4 of the post operative rehabilitation, Participant 2 was able to
subsequently perform overground walking with a rollator frame with good gait stance

and swing through of lower limbs in reciprocal pattern. [Figure 4; Supplementary

video 2]

sEMG outcomes

sEMG of both participants at their preoperative baseline and at Week 4 (with

and without stimulation) are presented in Figure 5. For each of these recordings, the

participants were instructed to extend their left knee. The sEMG of the following left

sided muscles are presented during this activity: Psoas major, Rectus femoris,

Vastus Lateralis, Tibialis anterior, Gluteus Maximus and Biceps Femoris,

Gastrocnemius and Soleus. Vertical scale (µV) and horizontal scale (s) are the same

across Figures 5A-C and Figures 5E-G. Because electrical noise was variable on

different recording days, voltage values for each day were z-normalised, such that

the standard deviation of the left rectus femoris EMG during the no-stimulation

baseline recording of that day was equal to 1.

Both participants had an increase in their z-normalized sEMG activity at Week

4 with and without stimulation, compared to their preoperative baseline. This is

demonstrated for Participant 1 in Figures 5B and C respectively and for Participant 2

in Figures 5F and G respectively.

Relative spectral power for sEMG recordings from P1 and P2 at 4 weeks post

operatively are presented at Figure 5D and H respectively with left sided

movements. Baseline spectral power is taken as surface EMG with no stimulation

and no movement of the same muscle on the same day. Spectral power was
significantly higher with the stimulation turned on (p<0.0005, one-tailed Wilcoxon

signed-rank test) for both participants.

Functional Outcomes

The clinical functional outcomes of the participants are as tabulated in Table

2.

Participant 1, as expected, scored zero for all his motor scores in his AIS

scoring at the end of the pre-habilitation phase as well as prior to the start of the

post-operative rehabilitation. This improved significantly during the post-1-month

post-operative rehabilitation assessment. He achieved a score of 1 for bilateral L2, 2

on the Left L3, 1 on bilateral L4 as well as 1 for bilateral L4. His WISCI II score

improved from 0 to 1 at the post-1-month rehabilitation assessment. In addition, his

TASS scored improved from 2 to 6 at the same time points. This change of 4 points

in meets the minimal clinical important difference of TASS as defined by Sato et al.

(37) There was no change in his SCIM score.

Participant 2, similarly, had scored zero for all his motor scores in his AIS

scoring with no change at the end of one month postoperatively. P2 had a one-point

improvement of his TASS score from 7 to 8. There was no change in his SCIM or

WISCI II scores.

RE outcomes
The RE provides the distance walked per session as well as the percentage of

support provided by the robot per limb during each session. For the latter, the lower

the percentage support, the higher the amount of effort required by the Participants

to produce the required motion.

Both participants each had a total of 4 RE sessions preoperatively and 4 RE

sessions postoperatively. With the combined rehabilitation and EES program, both

participants managed to reduce reliance on bilateral lower limbs and increased

ambulatory distance post-operatively on the RE. [Table 2, Supplementary figure 3]

At the end of a month of pre-operative rehabilitation, Participant 1 walked an average

of 282 metres (m) per session with 77% assistance on the right lower limb and 75%

assistance on the left lower limb from the RE. After a month of the trial’s post-

operative rehabilitation, Participant 1 improved to an average of 432 m per session

with 62.6% assistance on the right lower limb and 65% assistance on the left lower

limb. Participant 2 walked an average of 330 m at the end of his preoperative

rehabilitation which improved to 358 m after a month of his postoperative

rehabilitation. His lower limb assistance was 79% on the right and 80% on the left

after a month of preoperative rehabilitation. This assistance decreased to 75% on

the right and 76% on the left after a month of postoperative rehabilitation.

Adverse events

None of our participants experienced any significant adverse events during

our trial. Our first participant suffered mild skin erythema during the first few RE

sessions related to the strap. This issue was resolved after ensuring that our
participants only wore loose soft clothing without intervening straps or buttons that

might abrade their skin. There were otherwise no reports of increased neuropathic

pain, unusual sensations, autonomic dysfunction, increased spasticity, hardware

complications or intolerance to stimulation.

DISCUSSION

SCI is a devastating disease, which exerts a disproportionate medical,

social and economic toll on those injured and the society. The severity of SCI can

range from incomplete injuries with mild motor and sensory deficits to complete

injuries resulting in total paralysis and loss of sensation below level of injury. In

injuries to the peripheral nervous system, the conduction blockage due to cell death,

demyelination and/or axonal damage may be circumvented with collateral

regeneration of spared and injured axons, synaptic remodelling, and sometimes

functional reconnection of axons to the end organ resulting in functional recovery.

However, this occurs in a lesser extent in SCI and (4) sufficient neuroplasticity

recovery for functional sensory and/or motor volitional activity in SCI remains elusive.

(4,7,10) The current standard of care for SCI includes early surgical intervention,

rehabilitation and symptomatic management of complications such as spasticity and

neuropathic pain. (30,42–44) Despite many exciting pre-clinical studies underway,

there are at present limited neuro-restorative interventions to definitively improve

neurological outcomes or mitigate the effects of secondary neural injury. (32,45,46)

Electrical modulation of neurologic tissues to augment neurological function

has been of great scientific interest for centuries. (47) SCS as mentioned earlier, has
been used successfully for the management of chronic pain, and there has been

growing interest in its potential use for motor recovery in SCI. Although the

mechanisms by which electrical stimulation augments function of the spinal cord is

unclear (9), animal and human clinical trials have suggested that the effects of

epidural electrical stimulation may be attributed to the presence of functionally silent

fibers and engaging local lumbosacral circuitry to allow greater influence of

supraspinal activity. (10,46)

In order to ensure sensorimotor re-education of the spinal circuitry and central

pattern generators consistent with walking, EES should be supported with intensive

locomotor training. Activity-dependent training in conjunction with EES is known to

bolster connections between neurons caudal to injury site by enhancing efficacy of

existing synapses as well as by inducing growth-promoting factors that enhance

axonal sprouting and result in formation of new synapses. (48) RE are assistive

technologies designed to offer customisable overground weight-bearing gait while

allowing various levels of lower extremity movements based on the level of swing

assistance/resistance provided by the device. (6,28) The delivery of participant-

specific and precise high-dose training regimen with its demonstrated safety and

tolerability confers a possible superior advantage to other intensity-matched manual

training strategies. (6,29,30,33) Summary statistics of each robotic session is also a

useful objective feedback to impact patient performance and confidence as well as

guide the therapy’s progress. In addition, the significantly reduced therapist burden

(29) also allows for more cost-effective care. (28,30) Both participants had an

increase in average distance walked and reduced reliance on the RE assistance per

limb post-operatively with the combined EES and rehabilitation program.

 Nevertheless, it should also be emphasized our team recognises mental

imagery practice as a crucial part of our treatment paradigm. Mental imagery is

defined as not just a reproduction of data arising from the senses, perception or

memory; but that it also actively contributes to the (re)construction of a reality that is

different from that of the perceived reality. This imaginative function has proven its

capacity in re-organizing functional cerebral processes and activation of plasticity in

both brain and spinal injury patients. A review by Carrasco (24) suggested that

mental imagery training when combined with other therapies is able to improve

spatio-temporal gait parameters. In addition, it is a safe, low-cost technique that can

be practiced independently by patients during non-rehabilitation sessions to reflect

real-world practical usage of this cognitive therapy. Both participants were

encouraged to perform motor imagery exercises at home, although neither the

duration nor intensity were stipulated and standardized by the research team. They

were also primed to evoke the self-induced mental imagery just prior to attempting

the volitional motor activity or overground walking during their rehabilitation sessions.

The research team also did not control the specifics of the imagery as the intent was

for participants to develop their own set of intuitive cognitive techniques that would

best help them visualize and rehearse the intended movement.

In our pilot Phase I clinical trial conducted at the National Neuroscience

Institute (NNI), we have demonstrated the feasibility of this multi-modal therapy

combining EES, cognitive mental imagery exercises as well as assistive RE in

participants with chronic clinically motor-complete thoracic SCI. For both participants

in our trial, there was no improvement in their volitional control of muscles below
their level of injury nor improvement in functional scales after the month of pre-

operative rehabilitation phase utilizing both RE as well as mental imagery practice

and self-evoked mental rehearsals prior to attempt at movements. However, both

participants managed to achieve consistent volitional control of muscles below their

level of injuries as well as independent overground walking within a month

postoperatively utilizing the above combined treatment paradigm with the stimulation

turned on. To our knowledge, this is the most efficient motor recovery for overground

walking in patients with chronic SCI using any of the above therapies reported in the

literature(16,18,49) and our team attributes to the synergistic effects of the therapies.

In addition to locomotor improvement, there was improvement in their trunk control

from this combinatory approach. SCI affects ascending and descending pathways of

the spinal cord which consequently results in an alteration of the postural control

system. Trunk function in individuals with SCI is known to be associated with sitting

balance, walking ability, and activities of daily living. (50) Participant 1 demonstrated

a 4-point change in TASS, which meets the minimal clinical important difference,

after 4 weeks of intensive rehabilitation. Participant 1 also reports improved lateral

trunk flexion for better pressure relief of ischial tuberosity. This is critical for patients

with SCI as pressure ulcers occur from prolonged unrelieved pressure and are a

costly medical complication leading to morbidity, reduced quality of life and possible

mortality. (51) Participant 2 demonstrated a 1-point change in TASS at the end of the

same time point. The improvement in trunk control in both these two participants

likely contributed to their remarkable motor progress and locomotor ability. (41) We

hypothesize that the more modest improvement of the TASS score in Participant 2

may be due to his higher level of thoracic injury of AIS T1 compared to Participant 1

at AIS T4. The two participants in this study will continue to receive daily
rehabilitation paired with stimulation for another 6 months as part of this trial. We

acknowledge that whilst it may be possible that the motor and functional

improvements by both participants could be due to natural history alone, however,

given their stability of their scores prior to enrolment into this study and lack of

improvement after the pre-rehabilitation phase, our team attributes their subsequent

improvements to the combined multi-modal therapy regime.

This study has limitations in that it only involves 2 participants in this pilot trial. Both

participants are also relatively young (less than 50 years of age) and therefore this

may compromise the generalisation of our results, particularly as the full potential of

mental imagery have been shown to decrease with age.(26) The intensity and

duration of the home based practice of mental imagery and attempt at volitional

movements, with the stimulator switched on at 50% of the maximum stimulation

applied during the daily hourly rehabilitation regime, were also not standardized nor

recorded for both participants. In addition, due to the absence of longer term follow-

up, we could not report on this aspect as yet.

The future of Neurosurgery and Neuro-rehabilitation is to extend beyond current

mechanical tools and allow biological manipulation with increased understanding and

exploitation of the nervous system’s internal circuitry. Our team believes that this

multi-modal approach in modulating the malleability of the spinal circuitry for

meaningful neurological recovery will potentiate a paradigm shift in the management

and rehabilitative efforts for patients who suffer from SCI. We recognize that there is

also a need for larger randomized controlled trials to further evaluate the

effectiveness of this multimodal treatment paradigm for motor recovery in SCI.

 Future research should also focus on optimizing EES protocols and developing

closed loop and/or phasic epidural stimulation (17) paradigms to promote functional

recovery in SCI.

CONCLUSION

EES holds tremendous promise in the care and possible cure of SCI and we

hope our findings encourage the implementation of the synergistic potential using

EES neuromodulation and advanced robotic neurorehabilitation with mental imagery

practice as an accepted rehabilitative treatment strategy for patients with SCI.

DECLARATIONS

Ethics approval

This research has been approved ethics approval from the Singhealth centralized

institutional review board (CIRB 2022/2496)

Consent for publication

Not relevant

Availability of data and materials

Data and material from this pilot trial will be made publicly.

Competing interests

The listed authors have no financial and non-financial competing interests to declare.

Funding

This research is supported by the National Medical Research Council of Singapore

(NIG grant MOH-001083-00) The funder of the study had no role in study design,

data collection, data analysis, data interpretation, or writing of the report. The authors

had full access to all the data in the study and had overall responsibility for the

decision to submit for publication. No funding was received from the drug

manufacturer or distributor.

Author’s contributions
KRW provided all oversight for this study. KRW, NWH, JKRX, SKW, NZYV and WLL

designed the study. KRW, NWH, JKRX performed the critical surgical procedures of

the study. SKW, MWP, KRW, NZYV and WLL provided perioperative rehabilitation.

KRW, FM, SQYR, BP, TKM, ES analyzed the sEMG data. All authors provided

critical feedback and approved the final manuscript.

Acknowledgements

The authors would like to thank our participants for their valuable contribution to this

study. We would also like to gratefully acknowledge Medtronic for their generous

support in this trial. We would also like to thank Dr Deidre DeSilva, Dr David Low

Chyi Yeu, Dr Robin Pillay, Dr Ling Jimin and Dr Derrick Chan for their valuable

insights and contributions to our work.

Transparency, Rigor and Reproducibility statement

This transparency, rigor, and reproducibility statement aims to provide an overview of

the principles and practices followed in conducting and reporting this research study.

It outlines the steps taken to ensure transparency in the research process, the rigor

of the study design and methodology, and the measures in place to facilitate

reproducibility of the study's findings.

Study design and methodology

Research Objectives: The research study clearly states its objectives, research

questions, and hypotheses, thus providing a roadmap for the investigation and

analysis.

Study design: The study pilot design is described in detail including the rationale for

selecting this specific design and its suitability for addressing the research objectives

Data collection: The methods used for data collection has been clearly documented.

This includes details of the intraoperative set up, surface EMG recording set up and

programming parameters.

Variables and measures: This study defines the variables of interest and provides a

clear description of the measures and indicators used to assess them

Transparency

Data availability: The transparency of this research study includes making the data

or a representative sample of the data , available to interested parties whenever

possible and within ethical and legal constraints. This enables other parties to

examine and verify the study's findings, conduct further analyses, or explore

alternative interpretations.
Methodological details: Sufficient information is provided to enable readers to

understand and potentially replicate the research study. This includes detailed

descriptions of procedures, protocols, algorithms, and any necessary contextual

information to support the replication of the study.

Limitations and assumptions: The study acknowledges and discusses its limitations,

including any assumptions made or potential sources of bias that may affect the

validity or generalizability of the findings. This promotes transparency by providing a

clear understanding of the study's boundaries and potential implications.

Rigor:

Ethics and compliance: The research study adheres to applicable ethical guidelines,

institutional review board (IRB) approvals, and relevant regulations governing the

treatment of human subjects and sensitive data. Ethical considerations and informed

consent procedures are addressed appropriately and transparently.

Sample Size and Power: The study provides a rationale for the selected sample size,

taking into account statistical power calculations or considerations of feasibility.

Validity and Reliability: The research study employs rigorous methods to enhance

internal and external validity. Steps taken to ensure the reliability of measurements,

minimize confounding variables, control for biases, or address potential threats to

validity are clearly outlined.

Reproducibility

Detailed Documentation: The research study is accompanied by comprehensive

documentation, including a detailed methodology section, and any supplementary

materials necessary for reproducing the study. This facilitates the replication of the

study and enables others to verify the reported findings.

Data Sharing: Whenever possible and within ethical and legal boundaries, the

research study encourages data sharing with appropriate safeguards to protect

privacy and confidentiality. This promotes the opportunity for others to validate the

study's findings or conduct secondary analyses using the provided data.

Peer Review and Collaboration: The research study actively engages in the peer

review process by submitting the study to reputable journals or conferences.

Constructive feedback from reviewers will help strengthen the study's rigor and

ensures the adherence to scientific standards.

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