MACHINE: Motor and Autonomic Concomitant Health Improvements With Neuromodulation and Exoskeleton Training: A RCT in Individuals With SCI
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Sham Comparator: ABT+SHAM The SHAM is low-intensity, ineffective stimulation verified by the absence of lower extremity skeletal muscle activation and delivered at the same anatomical location as TCSCS. |
Device: SHAM (low-intensity) Transcutaneous Spinal Cord Stimulation
Ineffective stimulation will be verified by the absence of lower extremity skeletal muscle activation, determined by electromyography, and administered at the same anatomical location as therapeutic TCSCS.
Device: Activity-Based Therapy
Using the Lokomat exoskeleton by Hocoma, all participants (both arms) will train 3 times per week for 12 weeks with a target to reach 20 minutes of balance training and 30 minutes of gait training in each session.
For balance training, participants will be asked to attempt to stand to the best of their ability without relying on the Lokomat's structural support. Sensors built into the Lokomat will capture pressure the participant is applying to the joints and provide visual feedback for how much they are relying on the device for support. Will be done in 5-minute bouts with 1-minute rest inbetween.
For gait training, the Lokomat will provide participants with the complete walking assistance, but level of body weight support and speed of walking will be adjusted to allow the person to bear as much weight as possible while maintaining proper stance limb kinematics.
Other Names:
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| Experimental: ABT+TCSCS Therapeutic TCSCS will be delivered during ABT using an isolated bipolar constant current stimulator. Continuous TCSCS applied over the T11-T12 spinous processes at 5-40 Hz has been shown to induce stepping movements in participants with their legs in a gravity-independent position. |
Device: Transcutaneous Spinal Cord Stimulation
Therapeutic TCSCS will be delivered during ABT using an isolated bipolar constant current stimulator (Keypoint 4, Natus Medical Incorporated, USA). A biphasic rectangular waveform with 0.3 to 1.0-ms pulses, a carrier frequency of 10 kHz, administered at 5 to 40 Hz with a current ranging from 30 to 200 mA will be used.
Device: Activity-Based Therapy
Using the Lokomat exoskeleton by Hocoma, all participants (both arms) will train 3 times per week for 12 weeks with a target to reach 20 minutes of balance training and 30 minutes of gait training in each session.
For balance training, participants will be asked to attempt to stand to the best of their ability without relying on the Lokomat's structural support. Sensors built into the Lokomat will capture pressure the participant is applying to the joints and provide visual feedback for how much they are relying on the device for support. Will be done in 5-minute bouts with 1-minute rest inbetween.
For gait training, the Lokomat will provide participants with the complete walking assistance, but level of body weight support and speed of walking will be adjusted to allow the person to bear as much weight as possible while maintaining proper stance limb kinematics.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Change in corticospinal excitability [Weeks 2 and 14]
Corticospinal excitability is measured by recording motor evoked potentials to plot a slope that will provide an index score.
- Change in attempted voluntary contraction [Weeks 2 and 14]
Attempted voluntary contraction will be completed in the following muscles: rectus abdominis, pelvic floor muscles, vastus lateralis, biceps femoris, tibialis anterior, and soleus. The mean electromyography amplitude from each muscle during rest and an attempted contraction will be calculated.
- Change in seated and standing balance control [Weeks 2 and 14]
Balance control will be measured using force plate sensors embedded within the Lokomat while seated and standing.
Secondary Outcome Measures
- Change in blood pressure variability [Weeks 2 and 14]
Blood pressure variability will be measured using a 24 hour ambulatory blood pressure monitor which records the blood pressure every 15 minutes during the daytime period, and then every hour during the night-time period.
- Change in cardiac outcomes [Weeks 2 and 14]
Cardiac outcomes will be measured using echocardiogram. The echocardiogram images will be collected using parasternal long and short axis, apical 4, 2 and 3 chamber, and subcostal views.
- Change in dysautonomia [Weeks 2 and 14]
Dysautonomia will be measured using a 60-degree head-up tilt table test where the participant's blood pressure will be measured at supine rest for 10 minutes, and then at approximately 60° upright stand position for 15 minutes.
- Change in autonomic dysreflexia based on the autonomic dysreflexia following spinal cord injury questionnaire [Weeks 2 and 14]
Autonomic dysreflexia following spinal cord injury questionnaire assesses self-reported frequency and severity of autonomic related symptoms. The participant will complete 18 items from the third and fourth part of the questionnaire only, which evaluates autonomic dysfunction and hypotension.
- Change in bladder function based on the neurogenic bladder symptom score [Weeks 2 and 14]
Neurogenic bladder symptom score comprises 23 questions covering 3 domains, including incontinence, storage & voiding, and specific consequences, as well as one question on QoL.
- Change in bladder function based on the incontinence - quality of life questionnaire [Weeks 2 and 14]
Incontinence - Quality of life questionnaire comprises 10 questions covering 3 domains, including avoidance and limiting behaviour, psychosocial impacts, and social embarrassment, which will be summarised as a total score.
- Change in bowel function based on the neurogenic bowel dysfunction score [Weeks 2 and 14]
Neurogenic bowel dysfunction score comprises 10 questions focusing on defecation (i.e., frequency, duration, and clinical symptoms), constipation (i.e., use of aiding medication and digital stimulation), fecal incontinence (i.e., frequency, aiding medication, and flatus; and peri-anal skin problems.
- Change in sexual function based on the international index of erectile function questionnaire [Weeks 2 and 14]
International index of erectile function questionnaire comprises of 15 questions covering five domains, including erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction. Only males will complete the international index of erectile function questionnaire.
- Change in sexual function based on the female sexual function index [Weeks 2 and 14]
Female sexual function index comprises of 19 questions covering six domains, including desire, arousal, lubrication, orgasm, satisfaction, and pain. Only females will complete the female sexual function index.
- Change in quality of life based on the short form (SF-36) health survey [Weeks 2 and 14]
Short form (SF-36) health survey consists of 8 domains pertaining to the participants' experiences in the last 4 weeks. Each of the 8 summed scores is linearly transformed onto a scale from 0 (negative health) to 100 (positive health) to provide a score for each subscale.
- Change in quality of life based on fatigue severity scale [Weeks 2 and 14]
Fatigue severity scale is a 9-item questionnaire, which captures how fatigue interferes with certain activities of daily living and is accompanied by a global fatigue visual analogue scale.
- Change in quality of life based on spinal cord injury: spasticity evaluation tool [Weeks 2 and 14]
Spinal cord injury: spasticity evaluation tool is a thorough subjective assessment tool that asks the participant a total of 35 questions regarding both the problematic and useful effects of spasticity on daily life in the past 7 days.
Eligibility Criteria
Criteria
A participant must meet all of the following criteria in order to be eligible for inclusion:
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Resident of British Columbia, Canada with active provincial medical services plan
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Male or female, 18-60 years of age
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Chronic traumatic SCI (non-progressive, with complete motor paralysis) at or above the T6 spinal segment
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At least 1-year post injury, at least 6 months from any spinal surgery
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American Spinal Injury Association Impairment Scale (AIS) A, B
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Able to tolerate an upright posture for 30 minutes (with or without breaks)
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Willing and able to comply with all clinic visits and study-related procedures
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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)
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No painful musculoskeletal dysfunction, unhealed fracture, pressure sore, or active infection that may interfere with testing activities
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Stable management of spinal cord related clinical issues (i.e., spasticity management)
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Women of childbearing potential must not be intending to become pregnant, currently pregnant, or lactating. The following conditions apply:
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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
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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
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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
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Must provide informed consent
A participant who meets any of the following criteria will be ineligible to participate:
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Ventilator dependent
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Clinically significant, unmanaged, depression (PHQ-9 above 15) or ongoing drug abuse
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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
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Intrathecal baclofen pump
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Cardiovascular, respiratory, bladder, or renal disease unrelated to SCI or presence of hydronephrosis or presence of obstructive renal stones
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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
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Any implanted metal (other than dental implants) in the skull or presence of pacemakers, stimulators, or medication pumps in the trunk
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History of osteoporosis, low bone mineral density, or fragility fractures in the lower limbs
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History of seizures/epilepsy or recurring headaches
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Poor range of motion,severe spasticity, or contractures in the legs that prevents use of the Lokomat
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Weight greater than 136 kg, height less than 1.58m, or height greater than 1.88m (limits of the Lokomat)
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Severe anemia (Hgb<8 g/dl) or hypovolemia as measured by hematocrit via blood test in the last six months
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Participant is a member of the investigational team or his /her immediate family
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Participant has undergone electrode implantation surgery
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Blusson Spinal Cord Centre | Vancouver | British Columbia | Canada | V5Z 1M9 |
Sponsors and Collaborators
- University of British Columbia
- Praxis Spinal Cord Institute
Investigators
- Principal Investigator: Andrei Krassioukov, MD,PhD,FRCPC, University of British Columbia
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H20-01307