Noninvasive Spinal Cord Stimulation for Recovery of Autonomic Function After Spinal Cord Injury

Study Overview
=================
Brief Summary
-----------------
This study is a pilot clinical trial to explore the efficacy of transcutaneous spinal cord stimulation (TCSCS) (proof-of-concept) in mitigating crucial autonomic dysfunctions that impact the health-related quality of life of individuals with spinal cord injury (SCI).

Detailed Description
-----------------
This is a pilot clinical trial to explore the efficacy of TCSCS (proof-of-concept) in mitigating crucial autonomic dysfunctions that impact the health-related quality of life of individuals with SCI. A total of 30 eligible participants will be recruited and attend forty-two visits. All experiments will be performed at ICORD (Primary site) and the Brenda and David McLean Integrated Spine Clinic (SCI clinic), with the exception of anorectal manometry testing conducted at the Gastroenterology Clinic, St Paul's Hospital (GI clinic). Following completion of screening and signing informed consent forms, participants will undergo spatiotemporal mapping of spinal cord segments known to be involved in blood pressure, lower urinary tract and bowel control (visit 2). Following mapping, all individuals will undergo baseline functional assessments during 5 visits (visits 3-7), over a period of 4 weeks. To minimize the order effect, the functional assessments will be performed in a randomized order. Following baseline assessments, using a randomized counter-balanced approach, individuals will be allocated in two distinct pathways; the participants in Groups 1 and 2 will receive 8 weeks of TCSCS (3 times/week) at either mid/low thoracic or lumbosacral spinal cord levels respectively (visits 8- 31). Following long-term TCSCS, participants will undergo functional assessments during 5 visits (visits 32- 36) over a period of 4 weeks. In order to evaluate the persistent effects of TCSCS, all assessments will be repeated 8 weeks after cessation of the therapy.

Official Title
-----------------
Noninvasive Spinal Cord Stimulation for Recovery of Autonomic Function After Spinal Cord Injury: Moving From Mechanisms to Clinical Practice

Conditions
-----------------
Spinal Cord Injuries, Autonomic Dysfunction

Intervention / Treatment
-----------------
* Device: TESCoN device - Thoracic stimulation
* Device: TESCoN device - Lumbosacral stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. >1-year post injury, at least 6 months from any spinal surgery. American Spinal Injury Association Impairment Scale (AIS) A, B. Stable management of spinal cord related clinical issues (i.e., spasticity management). Documented impaired lower urinary tract, bowel or sexual function. No painful musculoskeletal dysfunction, unhealed fracture, pressure sore, or active infection that may interfere with testing. For women of childbearing potential, not intending to become pregnant, currently pregnant, or lactating. The following conditions apply: 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. Use adequate contraception, or practice complete abstinence from sexual activities, during the period of the trial and for at least 28 days after completion of treatment. If using combined hormonal contraceptives, a stable regimen during the period of the trial and for at least 28 days after completion of treatment. For sexually active males with female partners of childbearing potential, use adequate contraception, or practice complete abstinence from sexual activities, during the period of the trial and for at least 28 days after completion of treatment. Must provide informed consent. 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). Exclusion Criteria: Ventilator dependent. Signs of lower motor neuron damage (i.e. concomitant conus medullaris/cauda equina injury). Severe anemia (Hgb<8 g/dl) or hypovolemia as measured by hematocrit via blood test in the last six months. History of cardiovascular, respiratory, bladder, or renal disease unrelated to SCI or presence of hydronephrosis or presence of obstructive renal stones. History of seizures/epilepsy or recurring headaches. History of gastrointestinal atresia or stenosis. Clinically significant, unmanaged, depression (PHQ-9 above 15) or ongoing drug abuse. Intrathecal baclofen pump. Oral baclofen dose > 60mg. Individuals that have received intradetrusor or intrasphincter onabotulinumtoxinA injections within 9 months of baseline. Any implanted metal (other than dental implants) in the skull or presence of pacemakers, stimulators, or medication pumps in the trunk. Past electrode implantation surgery. Member of the investigational team or his/her immediate family. Presence of severe acute medical issue and use of any specific medication or treatment that, in the investigator's judgement, would adversely affect the participant's participation in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Using a randomized counter-balanced approach, individuals will be allocated in two distinct pathways; the participants in Groups 1 (thoracic stimulation) and Group 2 (lumbosacral stimulation) will receive 8 weeks of TCSCS (3 times/week) at either mid/low thoracic or lumbosacral spinal cord levels respectively.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Thoracic stimulation<br>Participants will receive 8 weeks TCSCS at the mid/low thoracic spinal cord levels. | Device: TESCoN device - Thoracic stimulation<br>* TCSCS will be delivered using a non-invasive central nervous system stimulator (TESCoN, SpineX Inc., CA, USA). The stimulation site will be over the thoracic spinal cord (T7-T12, Group 1).<br>|
| Experimental: Group 2- Lumbosacral stimulation<br>Participants will receive 8 weeks TCSCS at the lumbosacral spinal cord levels. | Device: TESCoN device - Lumbosacral stimulation<br>* TCSCS will be delivered using a non-invasive central nervous system stimulator (TESCoN, SpineX Inc., CA, USA). The stimulation site will be over the lumbosacral spinal cord (L1 - L3, Group 2).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Targeted TCSCS map modulate resting blood pressure (BP) | Using continuous beat-by beat BP monitoring via finger photoplethysmography during TCSCS, the researchers will identify the location and stimulation parameters to increase and decrease resting BP. Stimulation site will be either on the thoracic spinal cord (T7-T12) or the lumbosacral spinal cord (L1 - L3). Stimulation will be applied at various frequencies ranging between 1Hz and 90Hz. The outcome is an individualized TCSCS map (i.e. location and stimulation parameters) with change in systolic BP at rest during TCSCS. | Week 1-2 (once) | 
| Targeted TCSCS map to activate to activate skeletal muscles and pelvic floor muscles | Using surface electromyography (EMG), the researchers will identify the motor threshold for skeletal muscles known to be involved in lower urinary tract, bowel and sexual control by delivering TCSCS at various spinal cord segments (T7 to conus medullaris). The outcome is an individualized TCSCS map (i.e. location and stimulation parameters) with pertinent motor thresholds for TCSCS-driven surface EMG. | Week 1-2 (once) | 
| Immediate change in BP during the head up tilt test (HUTT) | During HUTT, participants will be passively moved to approximately 60° upright stand position by the investigators using the tilt table. Using TCSCS to activate spinal sympathetic circuitry and mitigate low resting BP and orthostatic hypotension (OH) and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of short-term TCSCS in reproducibly improving OH triggered by HUTT. | Week 3 - 6 (once) | 
| Change in BP during the head up tilt test (HUTT) from baseline to after completion of 8 weeks of TCSCS | Using TCSCS and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of long-term TCSCS in improving OH triggered by HUTT. | Week 15-18 (once) | 
| Change in BP during the head up tilt test (HUTT) from baseline to 8 weeks after cessation of TCSCS | Using TCSCS and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of long-term TCSCS in improving OH triggered by HUTT after cessation of therapy. | Week 27-30 (once) | 
| Immediate change in BP during digital anorectal stimulation (DARS) | DARS is a routine procedure to initiate a bowel routine, with the participant laying on their right side and DARS will be delivered via an index finger inserted into the rectum, applying gentle pressure for 30-60s. Utilizing TCSCS to inhibit nociceptive afferent and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of short-term TCSCS in reproducibly improving autonomic dysreflexia (AD) triggered by DARS. | Week 3 - 6 (once) | 
| Change in BP during digital anorectal stimulation (DARS) from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of long-term TCSCS in improving AD triggered by DARS. | Week 15-18 (once) | 
| Change in BP during digital anorectal stimulation (DARS) from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of TCSCS in improving AD triggered by DARS after cessation of therapy. | Week 27-30 (once) | 
| Immediate change in rectal pressure measured by anorectal manometry (ARM) | ARM is well-established methodology that provides a direct assessment of anal sphincter pressure and anorectal coordination during simulated defecation. The test is performed by inserting a catheter, that contains a probe embedded with pressure sensors, through the anus and into the rectum. Researchers will test the safety and efficacy of short-term TCSCS in reproducibly changing average max resting and squeeze pressure (mmHg). | Week 3 - 6 (once) | 
| Immediate change in high pressure anal canal zone measured by ARM | Researchers will test the safety and efficacy of short-term TCSCS in reproducibly changing length of high pressure anal canal zone (cm). | Week 3 - 6 (once) | 
| Immediate change in recto-anal inhibitory reflex measured by ARM | Researchers will test the safety and efficacy of short-term TCSCS in reproducibly changing recto-anal inhibitory reflex. | Week 3 - 6 (once) | 
| Immediate change in rectal sensation measured by ARM | Researchers will test the safety and efficacy of short-term TCSCS in reproducibly changing rectal sensation (mL). | Week 3 - 6 (once) | 
| Change in rectal pressure measured by ARM from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of long-term TCSCS in changing average max resting and squeeze pressure (mmHg). | Week 15-18 (once) | 
| Change in high pressure anal canal zone measured by ARM from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of long-term TCSCS in changing length of high pressure anal canal zone (cm). | Week 15-18 (once) | 
| Change in rectal sensation measured by ARM from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of long-term TCSCS in changing rectal sensation (mL). | Week 15-18 (once) | 
| Change in recto-anal inhibitory reflex measured by ARM from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of long-term TCSCS in changing recto-anal inhibitory reflex. | Week 15-18 (once) | 
| Change in rectal pressure measured by anorectal manometry (ARM) from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of TCSCS in changing average max resting and squeeze pressure (mmHg). | Week 27-30 (once) | 
| Change in high pressure anal canal zone measured by anorectal manometry (ARM) from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of TCSCS in changing length of high pressure anal canal zone (cm). | Week 27-30 (once) | 
| Change in recto-anal inhibitory reflex measured by anorectal manometry (ARM) from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of TCSCS in changing recto-anal inhibitory reflex. | Week 27-30 (once) | 
| Change in rectal sensation measured by anorectal manometry (ARM) from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and ARM, researchers will test the safety and efficacy of TCSCS in changing rectal sensation (mL). | Week 27-30 (once) | 
| Immediate change in intravesical pressure at first sensation measured by urodynamic investigation (UDI) | Standard clinical procedures for UDI, including cystometry with water at 21°C and a filling rate of < 30 mL per minute through a 6F double lumen catheter with the participants in the supine position, provides a direct assessment of voiding and storage function. Abdominal pressure will be measured with a 10F intrarectal balloon catheter. Filling will be stopped when the participants report a sensation of fullness. Researchers will test the safety and efficacy of short-term TCSCS in reproducibly changing intravesical pressure at first sensation (mmHg). | Week 3 - 6 (once) | 
| Immediate change in intravesical pressure at leakage point measured by UDI | Filling will be stopped at the moment of urine leakage. Researchers will test the safety and efficacy of short-term TCSCS in reproducibly changing intravesical pressure at leakage point (mmHg). | Week 3 - 6 (once) | 
| Immediate change in intravesical pressure at maximal volume measured by UDI | Filling will be stopped at the moment of discomfort/per the request of patient. Researchers will test the safety and efficacy of short-term TCSCS in reproducibly changing intravesical pressure at maximal volume (mmHg). | Week 3 - 6 (once) | 
| Change in intravesical pressure at first sensation measured by UDI from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and UDI, researchers will test the safety and efficacy of long-term TCSCS in changing intravesical pressure at first sensation (mmHg). | Week 15-18 (once) | 
| Change in intravesical pressure at leakage point measured by UDI from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and UDI, researchers will test the safety and efficacy of long-term TCSCS in changing intravesical pressure at leakage point (mmHg). | Week 15-18 (once) | 
| Change in intravesical pressure at maximal volume measured by UDI from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and UDI, researchers will test the safety and efficacy of long-term TCSCS in changing intravesical pressure at maximal volume (mmHg). | Week 15-18 (once) | 
| Change in intravesical pressure at first sensation measured by UDI from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and UDI, researchers will test the safety and efficacy of TCSCS in changing intravesical pressure at first sensation (mmHg). | Week 27-30 (once) | 
| Change in intravesical pressure at leakage point measured by UDI from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and UDI, researchers will test the safety and efficacy of TCSCS in changing intravesical pressure at leakage point (mmHg). | Week 27-30 (once) | 
| Change in intravesical pressure at maximal volume measured by UDI from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS and UDI, researchers will test the safety and efficacy of TCSCS in changing intravesical pressure at maximal volume (mmHg). | Week 27-30 (once) | 
| Immediate change in BP during penile or clitoral vibrostimulation | Genital vibration will be applied by an experienced physician using one or more handheld vibrators placed about the glans penis or the clitoral area with an amplitude of 1.0-3.5 mm and a frequency of 70-100 Hz. Utilizing TCSCS to inhibit nociceptive afferent and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of short-term TCS in reproducibly improving AD triggered by vibrostimulation. | Week 3 - 6 (once) | 
| Change in BP during penile or clitoral vibrostimulation from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of long-term TCSCS in improving AD triggered by vibrostimulation. | Week 15-18 (once) | 
| Change in BP during penile or clitoral vibrostimulation from baseline to 8 weeks after cessation of TCSCS | Utilizing TCSCS to inhibit nociceptive afferent and continuous beat-by beat BP monitoring via finger photoplethysmography, researchers will test the safety and efficacy of TCSCS in improving AD triggered by vibrostimulation. | Week 27-30 (once) | 
| Baseline assessment of colonic motility using the wireless motility capsule | The wireless motility capsule will be ingested and pass naturally through the GI tract, and data will be sent wirelessly to the data receiver. Researchers will use the collected data to assess baseline transit times. | Week 3 - 6 (once) | 
| Change in colonic motility using the wireless motility capsule from baseline to after completion of 8 weeks of TCSCS | Utilizing TCSCS and the wireless motility capsule, researchers will test the safety and efficacy of long-term TCSCS in improving transit times. | Week 15-18 (once) | 
| Change in colonic motility using the wireless motility capsule from baseline to 8 weeks after TCSCS cessation. | Utilizing TCSCS and the wireless motility capsule, researchers will test the safety and efficacy of TCSCS in improving transit times after cessation of therapy. | Week 27-30 (once) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immediate change in cerebral blood flow (CBF) measured by trans-cranial doppler (TCD) during HUTT | TCD is a non-invasive ultrasound technique used to measure real-time CBF velocity. Researchers will test the safety and efficacy of short-term TCSCS in reproducibly improving CBF during HUTT. | Week 3 - 6 (once) | 
| Change in CBF measured by TCD during HUTT from baseline to after completion of 8 weeks of TCSCS | Researchers will test the safety and efficacy of long-term TCSCS in improving CBF during HUTT. | Week 15-18 (once) | 
| Change in CBF measured by TCD during HUTT from baseline to 8 weeks after TCSCS cessation | Researchers will test the safety and efficacy of TCSCS in improving CBF during HUTT after cessation of therapy. | Week 27-30 (once) | 
| Immediate change in performance on the verbal fluency test (VFT) during HUTT | Phonetic/letter fluency, specifically total number of words, will be measured using the verbal fluency test (VFT). Researchers will test the safety and efficacy of short-term TCSCS in reproducibly improving cognitive function during HUTT. | Week 3 - 6 (once) | 
| Change in performance on the VFT from baseline to after completion of 8 weeks of TCSCS | Researchers will test the safety and efficacy of long-term TCSCS in improving phonetic/letter fluency using the VFT. | Week 15-18 (once) | 
| Change in performance on the VFT from baseline to 8 weeks after TCSCS cessation | Researchers will test the safety and efficacy of TCSCS in improving phonetic/letter fluency after cessation of therapy. | Week 27-30 (once) | 
| Immediate change in performance on the Stroop Color and Word (SCW) test during HUTT | Ability to inhibit cognitive interference, specifically completion time, will be measured using the Stroop Color and Word (SCW) test. Researchers will test the safety and efficacy of short-term TCSCS in reproducibly improving completion time of the SCW. | Week 3 - 6 (once) | 
| Change in performance on SCW from baseline to after completion of 8 weeks of TCSCS | Researchers will test the safety and efficacy of short-term TCSCS in reproducibly improving completion time of the SCW. | Week 15-18 (once) | 
| Change in performance on SCW from baseline to 8 weeks after TCSCS cessation | Researchers will test the safety and efficacy of short-term TCSCS in reproducibly improving completion time of the SCW after cessation of therapy. | Week 27-30 (once) |