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.

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.