Exercise responses with transcutaneous spinal cord stimulation (using electrodes placed on the skin surface) following spinal cord injury

INTERVENTION: The project is formed of acute (Aim 1) and longitudinal (Aim 2) components. Aim 1 lasts 3 weeks with a total time commitment of approx. 11.5 hours, split across 5 assessment visits. Aim 2 lasts 9 weeks plus a 6‐week follow‐up period with a total time commitment of approx. 34 hours. This consists of 16 exercise sessions (2 sessions per week for 8 weeks) and 6 assessment visits. Aim 1 (the acute component) adopts a single‐blind randomised‐crossover trial design. Following the provision of informed consent, participants will undergo a transcutaneous spinal cord stimulation (TSCS) mapping session to identify the specific stimulation parameters that robustly modulate cardiovascular outcomes (called CV‐TSCS). A sham stimulation that does not modulate cardiovascular outcomes will be used as a control (called SHAM‐TSCS). Essentially, TSCS will involve electrical stimulation delivered to the spinal cord through the skin and tissue using cathode electrodes to deliver the stimulation and anode electrodes to ground the circuit. Possible adjustable parameters include waveform (biphasic or monophasic), pulse width, amplitude and location of cathodes along the spinal column (T7 ‐ L2). Across two assessment visits, participants will partake in a series of tests designed to challenge the autonomic nervous system (ANS). Throughout the mapping session and during the ANS test battery, beat‐to‐beat heart rate, blood pressure and cerebrovascular blood velocity will be monitored, along with skin temperature near the electrodes. Following this, participants will perform a graded cardiopulmonary exercise test (CPET) on an arm‐crank ergometer to volitional exhaustion to identify their peak oxygen uptake (V?O2peak). On separate days they will then perform three s CONDITION: Chronic (>1 year) motor‐complete (AIS A‐B) spinal cord injury between C5‐T6 ; Nervous System Diseases PRIMARY OUTCOME: ; Aim 1:; Time to fatigue assessed as the duration of exercise performed during an aerobic arm‐crank exercise trial at a range of workloads corresponding to light, moderate and vigorous‐intensity exercise, both with and without CV‐TSCS.; ; Aim 2:; Cardiorespiratory fitness assessed as the peak oxygen uptake (V?O2peak) achieved during a graded cardiopulmonary exercise test performed on an arm‐crank ergometer until volitional exhaustion. Expired gases will be collected using a calibrated, metabolic cart (Vyntus CPX, Jaeger, Germany). Cardiorespiratory fitness will be assessed pre‐intervention, mid‐intervention (Week 4) and post‐intervention (Week 8).; SECONDARY OUTCOME: ; Aim 1:; 1. Blood pressure instability (self‐report). Measured via the Autonomic Dysfunction Following SCI Questionnaire. Assessed at baseline.; 2. Beat‐to‐beat heart rate, blood pressure and cerebrovascular blood velocity responses to a battery of autonomic nervous system stress tests. Measured via electrocardiogram, non‐invasive finger plethysmography and Transcranial Doppler ultrasound, respectively. Assessed with and without CV‐TSCS at baseline.; 3. Gas exchange variables (oxygen uptake, respiratory exchange ratio, end tidal CO2). Measured via a calibrated, metabolic cart (Vyntus CPX, Jaeger, Germany). Assessed during the cardiopulmonary exercise test at baseline, familiarisation session and exercise trials with CV‐TSCS and SHAM‐TSCS.; 4. Oxygen pulse. Measured using heart rate (Polar Electro, Kempele, Finland) and oxygen uptake (Vyntus CPX, Jaeger, Germany) and used as a reasonable surrogate for stroke volume. Assessed during the cardiopulmonary exercise test at baseline, familiarisation session and exercise trials with CV‐TSCS and SHAM‐TSCS.; 5. Beat‐to‐beat cerebrovascular blood velocity in the left and right middle cerebral artery. Measured via Transcranial Doppler ultrasound. Assessed during the familiarisation session and exercise trials with CV‐TSCS and SHAM‐TSCS.; 6. Haemodynamics and oxygenation of lower extremity skeletal muscle tissue. Measured using near‐infrared spectroscopy (NIRS‐500, Hamamatsu Photonics, Japan). Assessed during the familiarisation session and exercise trials with CV‐TSCS and SHAM‐TSCS.; 7. Ratings of perceived exertion, exercise enjoyment and affective valence. Measured via the Borg scale (6 to 20), the Stanley, Williams & Cumming scale (1 to 7), and the Hardy & Rejeski scale (‐5 to +5). Assessed during the familiarisation session and exercise trials with CV‐TSCS and SHAM‐TSCS.; 8. Blood biomarkers including metabolic (e.g., glucose, lactate), cytokines (e.g., interleukin‐6), catecholamines (e.g., adrenaline, noradrenaline) and brain‐derived neurotrophic factor. Blood samples taken immediately before and after the exercise trials with CV‐TSCS and SHAM‐TSCS.; 9. Immune cell dynamics. Measured via automated haematology followed by phenotyping using flow cytometry. Blood samples taken immediately before, immediately after, and 90 minutes following the exercise trials with CV‐TSCS and SHAM‐TSCS.; 10. Adverse events. Recorded throughout.; ; Aim 2:; 1. Beat‐to‐beat heart rate, blood pressure and cerebrovascular blood velocity responses to a battery of autonomic nervous system stress tests. Measured via electrocardiogram, non‐invasive finger plethysmography and Transcranial Doppler ultrasound, respectively. Assessed with and without CV‐TSCS at baseline (as part of Aim 1) and post‐intervention.; 2. Blood pressure instability over a 24‐hour period. Measured via periodic (day time: every 15 minutes; night‐time: every 60 minutes) brachial blood pressure measurements using an ambulatory blood pressure monitor (IEM Mobil‐O‐Graph). Assessed pre‐intervention and post‐intervention.; 3. Heart rate variability (HRV). The non‐stationary balance between sympathetic and parasympathetic branches of the cardiac autonomic nervous system will be measured using ECG in accordance with best practice recommendations. Assessed pre‐intervention and post‐intervention.; 4. Central arterial stiffness. Arterial pulse waveforms will be acquired at two locations (carotid and femoral arteries) simultaneously to determine pulse transit time and carotid‐to‐femoral pulse wave velocity (cfPWV); measured using the Vicorder (Smart Medical, UK) system with standard vascular cuffs. Assessed pre‐intervention and post‐intervention.; 5. Cardiac structure and function. Transthoracic echocardiography (TTE) will be performed using a Vivid iq ultrasound system (General Electric Medical, Norway) in accordance with recommendations of the American Society for Echocardiography. Assessed pre‐intervention and post‐intervention.; 6. Cardiovascular disease risk blood biomarkers including: triglycerides, total cholesterol, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, glucose, insulin and C‐reactive protein. Assessed pre‐intervention and post‐intervention.; 7. Characterising daily energy expenditure. Participants will wear an individually calibrated multisensor device for 4 days. The ActiheartTM, which incorporates tri‐axial accelerometry and physiological signals, will be used to predict physical activity energy expenditure and minutes per week of activity within certain intensity thresholds (sedentary, light, moderate, and vigorous). Assessed pre‐intervention and post‐intervention.; 8. Cognitive function. A shortened neuropsychological test battery will be utilised that includes the Digit Span and Symbol Digit Modality Test (SDMT) to give a global indication of cognitive function. Assessed pre‐intervention and post‐intervention.; 9. Seated balance. Measured via the Function in Sitting Test in SCI (FIST‐SCI). Assessed pre‐intervention and post‐intervention.; 10. Corticospinal excitability of the respiratory muscles and muscles below the injury. Assessed using surface electromyography and transcranial magnetic stimulation. Assessed pre‐intervention and post‐intervention.; 11. Respiratory function. Functional vital capacity, forced expiratory volume in 1 second, ratio (FEV1/FVC), and peak expiratory flow will be measured via standard spirometry testing procedures in accordance with the American Thoracic Society and European Respiratory Society. Assessed with and without CV‐TSCS pre‐intervention and post‐intervention.; 12. Health‐related quality of life. Physical and emotional quality of life will be measured via the SF‐36 walk/wheel questionnaire. Bowel function will be measured via the Neurogenic Bowel Dysfunction Score. Bladder function will be measured via the Neurogenic Bladder Symptom Score. Sex INCLUSION CRITERIA: For individuals with spinal cord injury: 1. Male or female of at least 16 years of age. 2. Chronic SCI (non‐progressive, with motor‐complete paralysis) between the C5 – T6 spinal segments and =1‐year post injury. 3. Documented presence of cardiovascular dysfunction including presence of persistent low resting BP and/or symptoms of autonomic dysreflexia and/or orthostatic hypotension. This will be assessed using the The Autonomic Dysfunction Following SCI questionnaire. 4. American Spinal Injury Association Impairment Scale A or B (motor‐complete SCI). 5. Willing and able to comply with all clinic visits and study‐related procedures. 6. Able to understand and complete study‐related questionnaires (i.e., English language speaking only). 7. No painful musculoskeletal dysfunction, unhealed fracture, pressure sore, or active infection that may interfere with testing activities. 8. Can move their arms/hands v