Spinal Cord Injuries Clinical Trial
Official title:
The Effects of Spinal Cord Stimulation on Autonomic Function in People With Spinal Cord Injury
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.
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.
Project 1, Visits 2- 4 Participants that meet preliminary eligibility requirements will
undergo baseline measurements including sympathetic skin responses, cerebral blood flow
measurement, cardiovascular monitoring and blood tests (to measure catecholamine level in
serum before, during, immediately after tilt up test).
Participants will complete questionnaires, which will establish baseline parameters for
self-reported assessments of severity and frequency of autonomic dysfunction, bladder
incontinence, and neurogenic bowel Score.
In this randomized crossover study, participants will randomly receive one session of
mid-thoracic non-invasive transcutaneous spinal cord stimulation, lumbosacral non-invasive
transcutaneous spinal cord stimulation or field block anesthesia. Cardiovascular and
neurological outcomes will be measured immediately after stimulation. The stimulation
sessions will be separated by at least 72 hours to avoid any interference carry-over effects
at each stimulation site. non-invasive transcutaneous spinal cord stimulation is approved
under protocols: UBC-Protocol 06 24 14 ca; UCLA, CA - IRB# 14-000158-CR- 00002.
Project 2, Visit 1, Screening Phase After providing the informed consent form for this part
of the study (long-term application of Non-invasive Transcutaneous Spinal Cord Stimulation),
participants will undergo baseline assessment (explained above) to record severity and
frequency of spontaneous episodes of autonomic dysfunction and orthostatic hypotension.
participants will be asked to participate in stimulation sessions for four consecutive weeks,
with five one-hour sessions of stimulation per week.
Project 2, Visit 2: Baseline measurement and first stimulation session Participants will
return 72 hours after the screening phase (explained above). All neurological and
cardiovascular outcomes will be measured before applying the first stimulation session.
Outcomes will be measured in two positions: a) Supine, b) ~ 70° upright tilt-test, executed
in a random order. Participants will then be pseudo-randomized (1:1) to one of the
stimulation conditions: 1) Mid-thoracic or 2) Lumbosacral stimulation to receive 60-minute
stimulation. Total anticipated time is 3-4 hours including set-up and stimulation.
Project 2, Visits 3 to 20: Stimulation sessions Participants will return to the clinic 24
hours after the first stimulation. All stimulation parameters are identical. Total
anticipated time is 2 hours including set-up and one-hour of stimulation. No cardiovascular
or neurological outcome will be measured during visits 3 to 20. At the end of 6th, 11th,
16th, and 21st stimulation sessions, neurological bowel Score and the Montreal Cognitive
Assessment will be performed. Participants will be sent home with bladder, bowel, and sexual
function assessment questionnaires.
All visits will include one tilt-up test with no stimulation, and one with the specific
stimulation for that condition, executed in a random order.
Project 2, Visit 21: Last stimulation session and post-intervention outcome measurement In
the last visit, participants will receive the last stimulation session, and the
cardiovascular and neurological outcome will be measured before and immediately after
stimulation. Cardiovascular outcomes measured before and after last stimulation session in
two positions: a) Supine and b) ~ 70° upright tilt-test, executed in a random order.
Project 3, Visit 2 For invasive epidural spinal cord stimulation, only individuals who have
previously been implanted with an epidural stimulator will be invited to participate.
Participants will undergo one "assessment + stimulation" session.The the instructions which
are approved under protocols UBC-Protocol 06 24 14 ca; Louisville, KY - IRB Number: 14.0738;
Minnesota, MN - IRB Number: 4697-B, USA Veteran's Affairs: IRB Number: 16-4115 will be
followed. Outcomes will be measured before and immediately after stimulation. Total
anticipated time is 3-4 hours including set-up and all assessments which can be completed in
one day.
PROCEDURES AND ASSESSMENTS
Project 1, 2, and 3, Visit 1: Screening Phase
A screening assessment to determine study eligibility will be performed during this visit.
After the participant has provided informed consent, he/she will be assigned a unique study
number and the following information will be collected:
- Inclusion/Exclusion Criteria
- Medical History
- Demographic information
- Weight and height
- Concomitant Medication and Procedures
- Previous allergies and adverse events to medications
The following procedures will be conducted:
- Self-reported American Spinal Injury Association Impairment Scale
- Autonomic assessment of baseline blood pressure and heart rate and orthostatic
instability (i.e., Tilt up test)
- Pregnancy test by a Pregnancy Test Kit (Women of Child Bearing Potential)
- Administration of the Montreal Cognitive Assessment.
The following take home material will be provided:
- Bladder and Bowel Diary (to collect three days of information on incontinence and
frequency)
- Bristol Stool Scale (to collect 3 days of information on stool consistency) Project 1,
Visits 2 to 4, Project 2, Visits 2 & 21, and Project 3, Visit 2
The following information will be collected:
- Confirmation of Eligibility
- Completed Bladder and Bowel Diary provided at Visit 1
- Completed Bristol Stool Scale provided at Visit 1
The following questionnaires will be administered:
- Self-reported assessments of severity and frequency of autonomic dysfunction
- Adverse Events following electrical stimulation
- Bladder incontinence
- Neurogenic bowel Score
- Female Sexual Distress Scale and Female Sexual Function Index, females only
- International Index of Erectile Function-15, males only
The following procedures will be conducted:
- Blood tests to measure Catecholamine level in serum before, during, immediately after
tilt up test.
- 24-hour ambulatory blood pressure monitor
- Sympathetic skin responses Test
- Continuous beat-to-beat measurement of Systolic Blood Pressure, Diastolic Blood
Pressure, and Mean Blood Pressure from right finger
- Every minute blood pressure from left Brachial artery Project 2, Visits 6, 11, and 16
- Completed Bladder and Bowel Diary provided at Visit 5, 11, and 15
- Completed Bristol Stool Scale provided at Visit 5, 11, and 15
- Self-reported assessments of severity and frequency of autonomic dysfunction
- Bladder incontinence
- Neurogenic bowel Score
- Female Sexual Distress Scale and Female Sexual Function Index, females only
- International Index of Erectile Function-15, males only
- Adverse Events questionnaire following electrical stimulation For all visits other than
the screening phase, participants will be asked to abstain from drugs that directly
influence their blood pressure, (e.g., midodrine, fludrocortisone, nifedipine).
Patients will also be asked to arrive having not exercised vigorously for the past 24 hours
and to have abstained from caffeine, alcohol, cannabis, and withhold medications for the
previous 12 hours and to consume a light breakfast. Upon arrival to the laboratory,
participants were asked to empty their bladders to minimize the influence of reflex
sympathetic activation on peripheral vascular tone.
Non-invasive Transcutaneous Spinal Cord Stimulation The non-invasive transcutaneous spinal
cord stimulation will be performed within the scope of the previously approved ethics by UCLA
(45). A stimulator will be utilized for one hour of stimulation. Transcutaneous stimulation
will be applied using a self-adhesive cathode electrode with a diameter of 30 mm placed on
the skin between the TVII and TVIII spinous processes (approximately corresponding to the T8
spinal segment) at the midline over the vertebral column. For lumbosacral non-invasive
transcutaneous spinal cord stimulation, the cathode will be placed on the skin between the LI
and LII spinous processes (approximately corresponding to the L2/3 to S4/5) at the midline
over the vertebral column. Two self-adhesive anode electrodes with a size of 5 × 9 cm will be
symmetrically located on the skin over the iliac crests. Based on previous works it is expect
that stimulation will be delivered at 30 Hz as monophasic, 1-ms pulses, to provide afferent
input to the region of the spinal cord where sympathetic preganglionic neuron cell bodies are
located (24). The current will be increased from 10 mA until blood pressure is normalized.
Skin temperature will be monitored in the vicinity of the stimulating electrodes with skin
temperature probes.
In invasive epidural spinal cord stimulation, the use of use of stimulator is associated with
some risks, including lead migration causing changes in stimulation or reduced functional
benefit, lead breakage, over or under stimulation, battery failure, persistent pain at
stimulation site, unpleasant sensation or motor disturbance, spinal cord pressure at
stimulation site, In non-invasive transcutaneous spinal cord stimulation, again, no adverse
event is expected as only parameters and electrodes approved by Health Canada will be
utilized in this study. Also, skin temperature for potential irritation will be monitored
frequently. Stimulation could elicit autonomic dysfunction, however so far autonomic
dysfunction has not been directly observed in the published non-invasive transcutaneous
spinal cord stimulation studies. Furthermore, cessation in stimulation immediately reduces
blood pressure, and blood pressure closely will be measured during procedures. In case of
adverse events, the participant's primary physician would be notified as needed.
Subjects who choose to participate in this trial will be required to give a significant
commitment to this study without the guarantee of any benefit. The risks associated with this
study are warranted in humans because of the potential direct benefit of the study
participants and the spinal cord injury community.
Monitoring during experiment Participants will be continuously monitored for any signs of
risks or discomfort. As mentioned, cardiovascular signals such as blood pressure and heart
rate will be measured frequently. For non-invasive transcutaneous spinal cord stimulation,
skin temperature will be additionally measured. If adverse events occur the testing session
will be immediately discontinued. If any complications arise, the experiment will be
immediately stopped. In addition, the participant's primary care provider will be notified as
necessary if serious adverse events occur.
Data from an autonomic assessment of individuals included in ongoing clinical trials at
Foothills Medical Centre (Calgary) and Vancouver General Hospital (Vancouver) with invasive
epidural spinal cord stimulation or/and non-invasive transcutaneous spinal cord stimulation
after spinal cord injury will be analyzed at Phillips Lab at University of Calgary or within
ICORD (UBC). Furthermore, individuals who underwent implantation surgery, either at the
above-mentioned study centers or elsewhere, (i.e. as part of a clinical trial or as treatment
option), will be assessed and analyzed by Dr. Phillips Lab research team or at ICORD.
Finally, Dr. Phillips lab research team will examine individuals (healthy or following spinal
cord injury) using transcutaneous stimulation. No invasive procedure will be carried out. All
research protocols for the above-mentioned assessments have been previously approved by the
respective research ethics boards at the University of Louisville, UCLA, the University of
Minnesota, and UBC: UBC-Protocol 06 24 14 ca; Louisville, KY - IRB Number: 14.0738;
Minnesota, MN - IRB Number: 4697-B, USA Veteran's Affairs: IRB Number: 16-4115.
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