The Effects of Spinal Cord Stimulation on Autonomic Function in People With Spinal Cord Injury
Trial Snapshot
- Phase
- Not Applicable
- Sponsor
- University of Calgary
- Enrollment
- 46
- Locations
- 4
- Primary Endpoint
- Heart Rate Changes, the unit is beat per minute (bpm)
Study Overview
Brief Summary
Despite being studied less than half as frequently, autonomic dysfunction is a greater priority than walking again in spinal cord injury. One autonomic condition after spinal cord injury is orthostatic hypotension, where blood pressure dramatically declines when patients assume the upright posture. Orthostatic hypotension is associated with all-cause mortality and cardiovascular incidents as well as fatigue and cognitive dysfunction, and it almost certainly contributes to an elevated risk of heart disease and stroke in people with spinal cord injury. In addition, autonomic dysfunction leads to bladder, bowel, sexual dysfunctions, which are major contributors to reduced quality and quantity of life. Unfortunately, the available options for treating this condition, are primarily limited to pharmacological options, which are not effective and are associated with various side effects. It has been recently demonstrated that spinal cord stimulation can modulate autonomic circuits and improve autonomic function in people living with spinal cord injury. Neuroanatomically, the thoracolumbar sympathetic pathways are the primary spinal cord segments involved in blood pressure control. Recently, a pilot study has been published demonstrating that transcutaneous spinal cord stimulation of thoracolumbar afferents can improve cardiovascular function. However, some studies have shown that lumbosacral transcutaneous spinal cord stimulation can also elicit positive cardiovascular effects. Therefore, there is no consensus on the optimal strategy in order to deliver transcutaneous spinal cord stimulation to improve the function of the autonomic system, and it may be that lumbosacral (i.e. the stimulation site being used most commonly for restoring leg function is sufficient). Another key knowledge gap in terms of transcutaneous spinal cord stimulation is whether or not the current is directly or indirectly activating these spinal circuits. Last but not least, the effects of epidural spinal cord stimulation on the function of cardiovascular, bladder, bowel and sexual system in spinal cord injury have been investigated in no study yet.
AIMS AND HYPOTHESES:
Aim 1. To examine the effects of short-term (one session) transcutaneous spinal cord stimulation on the frequency and severity of episodes of orthostatic hypotension/autonomic dysfunction, and bladder, bowel, and sexual functions. These effects will be compared at two sites of stimulation.
Hypothesis 1.1: Short-term transcutaneous mid-thoracic cord stimulation will mitigate the severity and frequency of orthostatic hypotension/autonomic dysfunction.
Hypothesis 1.2: Lumbosacral transcutaneous spinal cord stimulation will improve bladder, bowel, and sexual functions.
Aim 2. To examine the effects of long-term (one month) transcutaneous spinal cord stimulation on the severity and frequency of orthostatic hypotension/autonomic dysfunction.
Hypothesis 2.1: Long-term stimulation of the mid-thoracic cord will result in sustained improvements in mitigated severity and frequency of orthostatic hypotension/autonomic dysfunction that is not dependent on active stimulation.
Hypothesis 2.2: Long-term lumbosacral transcutaneous spinal cord stimulation will result in sustained improvements in bowel, bladder, and sexual function that is not dependent on active stimulation.
Aim 3: To examine the effects of short-term (one session) epidural spinal cord stimulation on the severity and frequency of orthostatic hypotension/autonomic dysfunction, and bladder, bowel, and sexual functions.
Hypothesis 3.1: Epidural spinal cord stimulation will mitigate the severity and frequency of orthostatic hypotension/autonomic dysfunction and improve bladder, bowel, and sexual function.
Hypothesis 3.3: There is no significant difference between immediate effects of lumbosacral transcutaneous spinal cord stimulation and epidural spinal cord stimulation on bladder, bowel, and sexual function.
For aim 1, 14 participants with spinal cord injury and no implanted electrodes on the spinal cord will be recruited. Participants will randomly receive one-hour stimulation under each of the two stimulation conditions in a crossover manner: Mid-thoracic and Lumbosacral. For aim 2, 28 individuals with spinal cord injury and no implanted electrode will be pseudo-randomized (1:1) to one of two stimulation sites. Participants will receive one-hour stimulation, five sessions per week for four weeks. Cardiovascular and neurological outcomes will be measured before the first stimulation session and after the last stimulation session. For aim 3, 4 participants with spinal cord injury with implanted electrodes on the spinal cord will be recruited to study the immediate effects of invasive epidural spinal cord stimulation.
All outcomes will be measured in two positions: a) Supine, b) ~ 70° upright tilt-test. Additionally, bowel, bladder, and sexual functions in project 2 will be assessed weekly.
Detailed Description
STUDY DESIGN AND DURATION Project 1 and 2: This multi-site open-label exploratory clinical trial (phase IIb) on examination of the effects of non-invasive transcutaneous spinal cord stimulation will take place at the University of Calgary and, UBC, Canada. In a pseudo-randomized controlled 2×2 between-subject factorial design.
Project 3: This is a multi-site open-label case study exploring the effects of invasive epidural spinal cord stimulation on a small number of individuals with spinal cord injury who underwent epidural implantation in Canada or abroad.
Duration of study participation for each participant Eligible participants will be enrolled into the study. Four visits (1 screening session and 3 assessment + stimulation sessions) for project 1 and 21 visits during a month (1 "screening" session, 5 "assessment+ stimulation", and 15 "stimulation only" sessions) for Project 2 will be conducted. Eligible participants who are involved in Project 3 will make two separated visits to our laboratory: one screening session and one "assessment + stimulation" session.
Briefly, the study involves the following:
Project 1, 2, and 3, Visit 1: Screening Phase After providing informed consent, participants will be assigned a unique study number and will be then be assessed for study eligibility. Baseline assessments at this phase include a tilt-up test (to confirm orthostatic hypotension), administration of the Montreal Cognitive Assessment Scale, a take-home bladder and bowel diary (to monitor bladder incontinence and frequency of bowel movements), as well as a take-home Bristol Stool Scale (to monitor constipation). Prior to leaving the site, participants will then be equipped with a 24-hour ambulatory blood pressure monitor in order to establish a baseline parameter of severity and frequency of spontaneous episodes of autonomic dysfunction and orthostatic hypotension.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age limit for Project 1 and Project 2 is 18-65 years, and age limit for Project 3 is 22-65 years (Based on FDA approval, participants below 22 are not allowed undergo to implantation surgery).
- •The volunteer should have >1-year injury, at least 6 months from any spinal surgery
- •Underwent electrode implantation surgery before
- •Documented presence of cardiovascular dysfunction including the presence of persistent resting blood pressure and/or symptoms of AD/OH.
- •Greater than or equal to antigravity strength in deltoids and biceps bilaterally.
- •Participants must have documented 3 days of bladder and bowel history prior to their baseline visit.
- •Willing 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 issue (spasticity management).
- •Women of childbearing potential must not be intending to become pregnant, currently pregnant, or lactating.
- •Sexually active males with female partners of childbearing potential must agree to effective contraception during th eperiod of the tril nad for at least 28 days after completion of treatment.
- •Must provide informed consent.
Exclusion Criteria
- •Presence of severe acute medical issue that in the investigator's judgement would adversely affect the participant's participation in the study.
- •Recent treatment with OnabotulinumtoxinA into the detrusor muscle (within 9 months of the baseline visit).
- •Ventilator dependent
- •Clinically significant depression or ongoing drug abuse
- •Use of any medication or treatment that in the opinion of the investigator indicates that it is not the best interest of participant to participate in this study
- •Indwelling baclofen pump
- •Any implanted metal in the trunk or spinal cord under the sites of application of electrodes (between anode and cathode) for those who are allocated to receive NTSCS.
- •Severe anemia (Hgb<8 g/dl) or hypovolemia.
- •Participant is a member of the investigational team or his /her immediate family.
Outcomes
Primary Outcomes
Heart Rate Changes, the unit is beat per minute (bpm)
Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).
We will monitor beat-to-beat changes in heart rate by electrocardiography. This outcome will be measured in two different positions: supine and 70 degrees upright position.
Episodic Blood Pressure Changes, the unit of measurement is mmHg
Time Frame: In project 1 and 3: before stimulation and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).
We will monitor beat-to-beat changes of blood pressure by a Finometer. This outcome will be measured in two different positions: supine and 70 degrees upright position.
Cerebral Blood Flow Changes, the unite of measurement is mililitter/(100 gram tissue minute)
Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).
We will monitor beat-to-beat changes in blood flow by a Finometer. This outcome will be measured in two different positions: supine and 70 degrees upright position.
Continues Blood Pressure Changes, the unit of measurement is mmHg
Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).
We will monitor 24 hours of blood pressure changes by 24-hour Ambulatory Blood Pressure Monitoring.
Secondary Outcomes
- Cerebrovascular Structure Changes(Project 2 only: before the first stimulation session and after the last stimulation session (one month after the first stimulation session).)
- Incontinence Quality of Life (I-QoL) Questionnaire(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- Sympathetic Skin Responses (SSR) Changes, the unit of measurement is mV(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- Urodynamic Study Changes(Project 2 only: before the first stimulation session and one week, two weeks, three weeks, and four weeks after the first stimulation session.)
- Electromyography (EMG) Changes(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- Orthostatic Tilt Test Changes(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- Neurocognitive Changes(Project 2 only: before the first stimulation session and one month after the first stimulation session.)
- Montreal Cognitive Assessment Scale (MoCA)(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- American Spinal Injury Association Impairment Scale (AIS) Changes(In project 1 and 3: before and after one hour spinal cord stimulation. Project 2: before the first stimulation session and after the last stimulation session (one month after the first stimulation session).)
- Bristol Stool Scale and Neurogenic Bowel Dysfunction (NBD) Score changes(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- Autonomic Dysreflexia Health-Related Quality of Life (AD-HR QoL) Questionnaire(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- Catecholamine Levels in Serum, the unit of this measurement is pmol/L(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
- Sexual Behaviour Changes(In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session).)
Investigators
Aaron Phillips
Assistant Professor, Physiology & Pharmacology, Cardiac Sciences and Clinical Neurosciences
University of Calgary