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.
Status | Not yet recruiting |
Enrollment | 46 |
Est. completion date | March 1, 2022 |
Est. primary completion date | December 1, 2021 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 65 Years |
Eligibility |
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. |
Country | Name | City | State |
---|---|---|---|
Canada | University of Calgary | Calgary | Alberta |
Canada | University of British Columbia | Vancouver | British Columbia |
Lead Sponsor | Collaborator |
---|---|
University of Calgary | International Collaboration on Repair Discoveries |
Canada,
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* Note: There are 55 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Episodic Blood Pressure Changes, the unit of measurement is mmHg | 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. | 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). | |
Primary | Cerebral Blood Flow Changes, the unite of measurement is mililitter/(100 gram tissue minute) | 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. | 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). | |
Primary | Heart Rate Changes, the unit is beat per minute (bpm) | 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. | 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). | |
Primary | Continues Blood Pressure Changes, the unit of measurement is mmHg | We will monitor 24 hours of blood pressure changes by 24-hour Ambulatory Blood Pressure Monitoring. | 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). | |
Secondary | Sympathetic Skin Responses (SSR) Changes, the unit of measurement is mV | The Sympathetic Skin Responses will be elicited by stimulation of median and posterior tibial nerve, and recorded bilaterally and simultaneously from both hands and feet to assess the extent of disruption to spinal autonomic pathways. Ten electrical stimuli (duration 0.2 ms; intensity 8-10 mA) will be applied to the left median nerve and left posterior tibial nerve, in random order and with variable and long-time delays to minimize habituation. | 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). | |
Secondary | Urodynamic Study Changes | Urodynamic study evaluation typically consists of cystometry with water at 37°C and a filling rate of <30 mL per minute through a 6F double lumen catheter with the participant in the supine position. Abdominal pressure will be measured with a 10F intrarectal balloon catheter. Pelvic floor electromyography will be recorded during cystometry with a bipolar wire electrode in the urethral sphincter. Filling will be stopped when the participants have reported a sensation of fullness, at the moment of urine leakage. The bladder outlet obstruction index (BOOI), will be obtained by formulaic calculations: (BOOI = PdetQmax - 2Qmax). Cystometrogram parameters including first sensation, maximum cystometric capacity (MCC), and the presence of detrusor overactivity with or without incontinence will be annotated. Valsalva leak point pressures will be assessed at a minimum volume of 200 mL. Detrusor compliance was calculated using the formula Compliance= Volume at MCC/Pdet at MCC. | Project 2 only: before the first stimulation session and one week, two weeks, three weeks, and four weeks after the first stimulation session. | |
Secondary | Electromyography (EMG) Changes | The Electromyography activity of the skeletal muscles will be also recorded from left and right side to confirm that skeletal muscle contractions are not occurring and therefore the pressure responses are not attributed to the skeletal muscle pump of the venous vasculature. Bipolar surface electrodes will be placed bilaterally on large skeletal muscles such as the vastus lateralis (VL), rectus femoris (RF), and medial hamstrings (MH), tibialis anterior (TA), soleus (SOL), and medial gastrocnemius (MG) muscles. EMG has previously been utilized by our team, as approved by the UBC Clinical Research Ethics Board (H12-02945). Measured EMG potentials range between less than 50 µV and up to 30 mV, depending on the muscle under observation. Typical repetition rate of muscle motor unit firing is about 7-20 Hz, depending on the size of the muscle. | 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). | |
Secondary | American Spinal Injury Association Impairment Scale (AIS) Changes | Neurological evaluations of participants with spinal cord injury will be performed using the AIS unless available in the participant chart at the discretion of the investigator. Total duration to do the test is ~ 30 minutes at baseline and ~15 minutes for post-intervention measurements. The level and severity of damage to the motor and sensory pathways will be determined using the standard AIS examination. | 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). | |
Secondary | Orthostatic Tilt Test Changes | Upon arrival to the laboratory, participants will be asked to empty their bladder to minimize the influence of reflex sympathetic activation on peripheral vascular tone (total duration: 25 min). In the supine position, participants will be instrumented with a single- lead ECG. Beat-to-beat systolic (SBP), diastolic (DBP), and mean (MAP) blood pressures will be recorded continuously from the right hand (Finometer; Finapres Medical Systems BV, Arnhem, Netherlands), while discrete blood pressures will be taken every minute from the brachial artery (mmHg). Following instrumentation, baseline recordings will be made during a 10-minute supine rest period. Data acquisition will be performed as detailed above. Participants will then be passively moved to approximately 70° upright stand position by the investigators using the tilt table. This position will be maintained for 15 minutes, during which recordings of heart rate and blood pressure will be continued. | 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). | |
Secondary | Cerebrovascular Structure Changes | For each participant, brachial blood pressure will be measured. The followings will be sampled at 1,000 Hz using an analog-to-digital converter interfaced with data acquisition software on a laptop computer: non-invasive beat-by-beat blood pressure measurement via finger photo plethysmography, electrocardiogram, velocity in the left middle cerebral artery (MCAV) and/or right posterior cerebral artery. These arteries will be insonated using a 2 MHz probe mounted on the temporal bone and a fitted head strap. As described in depth elsewhere, the P1 segment of the posterior cerebral artery and middle cerebral artery (MCA) velocities will be insonated. Arteries will be confirmed using ipsilateral common carotid artery compression, ensuring an increase in posterior cerebral artery velocity and decrease in the middle cerebral artery velocity. | Project 2 only: before the first stimulation session and after the last stimulation session (one month after the first stimulation session). | |
Secondary | Neurocognitive Changes | Participants will remain fitted in the same equipment as used for the cerebrovascular assessment. A visual task will be employed to activate the occipital lobe (while measuring posterior cerebral artery blood flow velocity (cm/sec)). Total duration: 15 minutes. | Project 2 only: before the first stimulation session and one month after the first stimulation session. | |
Secondary | Autonomic Dysreflexia Health-Related Quality of Life (AD-HR QoL) Questionnaire | The AD HR-QoL Questionnaire is derived from the original version of the autonomic dysreflexia sub-section of the Autonomic Dysfunction Following Spinal Cord Injury (ADFSCI) questionnaire which was much more comprehensive in order to assess autonomic dysreflexia frequency and severity on a daily basis and specifically when the bladder is full. The ADFSCI questionnaire was created for use in clinical practice and research to assess blood pressure instability and was designed using the Delphi technique by an expert panel experienced in spinal cord injury treatment. The ADFSCI questionnaire is a 24-item self-reported questionnaire. The questionnaire consists of demographics, medications, frequency/severity of symptoms during autonomic dysreflexia and hypotensive events. | 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). | |
Secondary | Incontinence Quality of Life (I-QoL) Questionnaire | The I-QoL Questionnaire is a self-administered, previously validated and reliable disease-specific questionnaire that measures bladder-related QoL in individuals with neurogenic bladder. The questionnaire is formatted as a 22-items divided into 3 sub-scales: 1) avoidance and limiting behaviour (8 items); 2) psycho-social impact (9 items); and 3) social embarrassment (5 items). Scoring is based on a five-point response scale with values ranging from one (extremely) to five (not at all). Scores are then tallied and transformed into a scale score ranging from 0-100 points with higher scores indicating a greater QoL. | 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). | |
Secondary | Montreal Cognitive Assessment Scale (MoCA) | We will use the MoCA, a standardized cognitive evaluation test. We have utilized this evaluation in our previous studies with spinal cord injury individuals and cognitive deficits related to blood pressure fluctuations. MoCA is a well-accepted general screening tool for individuals with mild cognitive dysfunction. The test assesses eight domains of cognitive functioning, including attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations and orientation. Total scores below 26 (out of a maximum 30) are considered abnormal and suggest presence of cognitive dysfunctions. | 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). | |
Secondary | Bristol Stool Scale and Neurogenic Bowel Dysfunction (NBD) Score changes | The Bristol Stool Scale is a tool designed to classify faeces into seven categories. The NBD score is a measure of both constipation and fecal incontinence and was developed for and validated in the spinal cord injury population. The NBD score is a 10-item symptom-based score for NBD in individuals with spinal cord injury. The maximum total NBD score is 47 points. The interpretation of the total NBD score is very minor NBD (0-6), minor NBD (7-9), moderate NBD (10-13), and severe NBD (=14). | 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). | |
Secondary | Catecholamine Levels in Serum, the unit of this measurement is pmol/L | Standard hematology and chemistry laboratory blood tests will be collected by a local laboratory three times in each session: before, during, and immediately after tilt up test. The normal range for epinephrine is 0 to 140 pg/mL (764.3 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). | |
Secondary | Sexual Behaviour Changes | Sexual behaviour changes will be measured by two questionnaires: one for women and one for men. The Questionnaires are • Female Sexual Distress Scale (FSDS) and Female Sexual Function Index (FSFI), females only and International Index of Erectile Function (IIEF)-15, males only. | 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). |
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