Motor and Autonomic Concomitant Health Improvements With Neuromodulation and Exoskeleton Training: A RCT in Individuals With SCI
Motor and Autonomic Concomitant Health Improvements With Neuromodulation and Exoskeleton Training: A RCT in Individuals With SCI
Spinal cord injury (SCI) disrupts many aspects of life, including the loss of volitional
 movement and involuntary control of bodily functions; both crucial functional recovery
 priorities for this population. Mobility impairments and secondary complications limit an
 individual's ability to exercise, a behavior known to have wide-ranging functional and health
 benefits. This trial will investigate whether activity-based therapy (ABT), using a robotic
 exoskeleton, can change the strength of signals from the brain that control volitional
 movement, leading to improvements in standing and seated balance as well as other important
 involuntary bodily (i.e. cardiovascular, urinary tract, bowel and sexual) functions. The
 investigators aim to determine whether these improvements can be augmented with the addition
 of non-invasive transcutaneous spinal cord stimulation (TCSCS). This therapy has been shown
 to re-awaken dormant spinal circuits. In this randomized controlled trial, TCSCS with ABT,
 using robotic-assisted gait training (three sessions/week for twelve weeks), will be compared
 to ABT+SHAM in individuals with chronic motor-complete spinal cord injury (SCI). Those in the
 ABT+SHAM group will be given the option to complete an ABT+TCSCS open-label follow-up. Before
 and after training, the following outcomes will be assessed by validated methods:
 corticospinal excitability, motor function, and seated and standing balance (Hypothesis 1 -
 Motor Function); severity and frequency of blood pressure instability, urinary tract, bowel,
 and sexual dysfunctions (Hypothesis 2 - Autonomic Functions); and general health (Hypothesis
 3 - Quality of Life). This collaborative project is between consumers with SCI and
 clinicians/scientists with expertise in SCI care (kinesiologists, physiotherapists,
 physiatrists, sexual health clinicians). Compared to ABT alone, the investigators anticipate
 that ABT+TCSCS will result in superior improvements in motor and autonomic functions in
 individuals with SCI.
Spinal cord injury (SCI) is a severe disorder resulting in not only in motor deficits (i.e.
 paralysis) but also a myriad of autonomic dysfunctions (i.e. urinary tract/bowel/sexual
 impairments and blood pressure instability). The restoration of motor as well as autonomic
 functions remains among the top priorities for individuals with SCI. Individuals with SCI
 develop cardiovascular (CV) disease at a younger age and at greater rates than individuals
 without injury. Both low levels of physical activity and profound blood pressure (BP)
 instability, commonly experienced by individuals with injuries at or above the sixth thoracic
 level, likely explains the heightened risk.

 Neurogenic lower urinary tract (LUT) dysfunction impacts over 90% of individuals with SCI.
 This dysfunction leads to vesico-ureteral-renal reflux, urinary tract infections, bladder
 stone formation, and impaired renal function - ultimately leading to significant disease
 burden and poorer health-related quality of life. Bowel function is also significantly
 compromised after SCI, presenting as constipation, impaired colonic motility and loss of
 volitional control resulting in episodes of fecal incontinence - predisposing an individual
 to increased risk of long-term complications. Over 60% report that bowel dysfunction
 adversely impacts quality of life. Lastly, severe impairments in sexual function following
 SCI include erectile dysfunction, ejaculatory disorders/ anejaculation in men and reduced
 vaginal lubrication in women, with both sexes experiencing orgasmic difficulties or
 anorgasmia as well as alterations in sexual drive and sexual satisfaction.

 Activity-based therapy (ABT) is a common and an effective means to improve walking function
 post-injury and can facilitate general health maintenance; this includes an enhancement of
 neural BP control, as well as bladder, bowel, and sexual functions. The more recent
 development of robotic-assisted gait training (e.g. Lokomat) in contrast to labor-intensive
 manually assisted therapeutic strategies also reduces the load on therapists and health care
 expenditures. The Lokomat is a computer-controlled rehabilitation system for walking that
 consists of a pair of robotic legs to which an participant's thighs and legs are strapped.
 This device provides full assistance for the legs to go through the motion of walking with
 hip and knee motors. An over-head harness system holds the participant's body-weight above
 the treadmill.

 Neuromodulation, potentially activating isolated spinal cord neuronal circuitry, has received
 significant recognition in recent years as a promising approach to target various
 neurological dysfunctions. The immense therapeutic potential of epidural spinal cord
 stimulation demonstrates mitigation of spasticity in individuals with motor-incomplete
 injuries. Moreover, this stimulation improved standing ability, ability to generate rhythmic,
 locomotor-like limb movements, and restored voluntary control of functional movements in
 individuals with motor-complete injuries. Our past exciting and ground-breaking pilot work
 highlights the capacity for TCSCS to modulate spinal circuits (An Autonomic Neuroprosthesis:
 Noninvasive Electrical Spinal Cord Stimulation Restores Autonomic Cardiovascular Function in
 Individuals with Spinal Cord Injury. J Neurotrauma. 2018;35(3):446- 451.
 doi:10.1089/neu.2017.5082). To administer TCSCS, small adhesive electrodes are placed on the
 skin around the spinal cord and hips. The electrodes are connected to a machine that
 generates a small electric current. After turning the machine on, the participant may feel a
 small electric current under the electrodes, though it should not elicit any pain.

 Despite literature supporting the benefits of TCSCS and ABT, the effects of pairing TCSCS
 with ABT is largely unknown. These therapies are adaptable, non-invasive, and relatively
 affordable, with the potential to simultaneously benefit both motor and autonomic functions.
 Randomized controlled trials are needed to better validate these interventions for clinical
 settings.

 Project Rationale:

 Motor paralysis and autonomic dysfunctions have been identified as a major priority for
 recovery by individuals with SCI. Addressing these dysfunctions may ultimately translate to
 improved health-related quality of life (HRQOL). The use of ABT with non-invasive and
 adaptable TCSCS has the potential to reduce CV disease risk factors and other autonomic
 dysfunctions in this at-risk population.
A participant must meet all of the following criteria in order to be eligible for
 inclusion:

 -  Resident of British Columbia, Canada with active provincial medical services plan

 -  Male or female, 18-60 years of age

 -  Chronic traumatic SCI (non-progressive, with complete motor paralysis) at or above the
 T6 spinal segment

 -  At least 1-year post injury, at least 6 months from any spinal surgery

 -  American Spinal Injury Association Impairment Scale (AIS) A, B

 -  Able to tolerate an upright posture for 30 minutes (with or without breaks)

 -  Willing and able to comply with all clinic visits and study-related procedures

 -  Able to understand and complete study-related questionnaires (must be able to
 understand and speak English or have access to an appropriate interpreter as judged by
 the investigator)

 -  No painful musculoskeletal dysfunction, unhealed fracture, pressure sore, or active
 infection that may interfere with testing activities

 -  Stable management of spinal cord related clinical issues (i.e., spasticity management)

 -  Women of childbearing potential must not be intending to become pregnant, currently
 pregnant, or lactating. The following conditions apply:

 1. Women of childbearing potential must have a confirmed negative pregnancy test
 prior to the baseline visit. During the trial, all women of childbearing
 potential will undergo urine pregnancy tests at their monthly clinic visits as
 outlined in the schedule of events

 2. Women of childbearing potential must agree to use adequate contraception during
 the period of the trial and for at least 28 days after completion of treatment.
 Effective contraception includes abstinence

 -  Sexually active males with female partners of childbearing potential must agree to use
 effective contraception during the period of the trial and for at least 28 days after
 completion of treatment

 -  Must provide informed consent

 A participant who meets any of the following criteria will be ineligible to participate:

 -  Ventilator dependent

 -  Clinically significant, unmanaged, depression (PHQ-9 above 15) or ongoing drug abuse

 -  Use of any medication or treatment that in the opinion of the investigator indicates
 that it is not in the best interest of the participant to participate in this study

 -  Intrathecal baclofen pump

 -  Cardiovascular, respiratory, bladder, or renal disease unrelated to SCI or presence of
 hydronephrosis or presence of obstructive renal stones

 -  Presence of severe acute medical issue that in the investigator's judgement would
 adversely affect the participant's participation in the study. Examples include, but
 are not limited to acute urinary tract infections, active heterotopic ossification,
 newly changed antidepressant medications [tricyclics], debilitating muscle pain,
 pressure sores, or unstable diabetes

 -  Any implanted metal (other than dental implants) in the skull or presence of
 pacemakers, stimulators, or medication pumps in the trunk

 -  History of osteoporosis, low bone mineral density, or fragility fractures in the lower
 limbs

 -  History of seizures/epilepsy or recurring headaches

 -  Poor range of motion,severe spasticity, or contractures in the legs that prevents use
 of the Lokomat

 -  Weight greater than 136 kg, height less than 1.58m, or height greater than 1.88m
 (limits of the Lokomat)

 -  Severe anemia (Hgb<8 g/dl) or hypovolemia as measured by hematocrit via blood test in
 the last six months

 -  Participant is a member of the investigational team or his /her immediate family

 -  Participant has undergone electrode implantation surgery