Hybrid HIIT-FES Cycling Program on Individuals With Spinal Cord Injury to Improve Health

Specific Aims: Obesity and cardiometabolic disorders are epidemic among people with spinal cord injury (SCI). A recent study conducted on a large cohort of individuals with chronic SCI revealed that 90% of them were obese, and 60% suffered from metabolic syndrome, which includes dyslipidemia, hyperglycemia, and hypertension along with obesity. This health disparity is even worse for those living with SCI in Mississippi, a perennial national leader in the prevalence of obesity and cardiometabolic disease. These data indicate that individuals with SCI are on an accelerated trajectory toward cardiometabolic disease and early mortality. This accelerated trajectory is multi-factorial, but substantial evidence suggests low physical activity is a significant contributing factor. Paralysis combined with a sedentary lifestyle leads to individuals with SCI experiencing significant changes in body composition with evidence of increased fat mass and a reduction in lean mass. The investigators recently reported that the ratio of fat to lean mass was a strong predictor of systemic inflammation and cardiometabolic disorders in individuals with SCI. Since medical advancements are increasing survival and longevity after SCI, it is critical to develop programs and establish best-practice interventions aimed at decreasing obesity and cardiometabolic disease risk in the SCI population.

Although arm exercises have some benefits, they do not engage the large muscle groups of the legs, which limits muscle participation. However, leg cycling with functional electrical stimulation (FES) has been found to be a safe and effective way to exercise paralyzed leg muscles. This can lead to muscle hypertrophy and an improved lean mass to fat mass ratio. To prevent cardiometabolic diseases, it is important to recruit adequate muscle mass at high enough intensity levels to induce central and peripheral physiological training adaptations. Combining the paralyzed leg muscles through FES with voluntary arm muscle activity (hybrid exercise) will increase overall muscle involvement and exercise intensity, potentially improving cardiometabolic health.

The investigators have developed a novel hybrid high-intensity interval training (HIIT) protocol that combines FES lower extremity cycling and voluntary arm cycling in a HIIT protocol for individuals with SCI. This hybrid HIIT-FES cycling program is designed to incorporate greater muscle mass into the activity. HIIT training programs have been shown to provide equal or more significant benefits with less time commitment in the general population. Our proof-of-principle studies in persons with SCI confirmed that HIIT-FES leg cycling three times per week for eight weeks can increase leg lean mass (5-9%) and improve cardiovascular health markers. However, some participants could not cycle against greater than the default resistance until after 12 sessions, even with the maximum electrical stimulation. For this reason, our intervention protocol will be in two phases, with phase one consisting of peripheral remodeling intermittent muscular exercise (PRIME) two times per week for four weeks. This resistance training part of the program prepares the participants for phase two, which is the hybrid HIIT-FES cycling program twice weekly for eight weeks. Exercise sessions will last 30 to 40 minutes, depending on the participants' tolerance. We will recruit twelve adults, 21-70 years of age, with chronic SCI ranging in neurological level between C4-T12 and maintaining the ability to perform arm cycling (incomplete injuries C4-T1). Participants will be randomly divided into the hybrid HIIT-FES group (n=6) or the control group (n=6) (active range of motion exercise with arms and passive with the legs). Research AIM: The purpose of this study is to determine the effectiveness of four-weeks of PRIME resistance training followed by eight weeks of hybrid HIIT-FES cycling on adults with SCI. The goal is to provide new insights into developing exercise programs for individuals with SCI. The investigators specific hypothesis is that a twice-weekly PRIME plus hybrid HIIT-FES cycling program will lead to significant improvements in aerobic fitness, lean mass to fat mass ratio, blood lipid and glucose levels, inflammation markers, muscle oxygenation, and physical transfers and wheelchair propulsion. This study aligns with the mission of the Mississippi IDeA Network of Biomedical Research Excellence by providing valuable information about the battle against obesity and cardiometabolic disease in a highly vulnerable and at-risk population. The findings from this pilot study are expected to serve as preliminary data for further, in-depth research.

Research Strategy Significance: Approximately 18,000 accidents lead to spinal cord injury (SCI) in the U.S. annually. Life span after SCI was previously short, but thanks to medical advances, SCI has been converted to a long-term chronic disability. Consequently, increased longevity in this population has been accompanied by many adverse health conditions, with obesity and cardiometabolic diseases being at the forefront of health disparities. Obesity prevalence among individuals with SCI is about 90%. Additionally, because greater obesity is related to greater disability and chronic diseases, the risk of cardiometabolic diseases, including heart disease and type II diabetes, is elevated to more than twice that of the able-bodied population. One reason for high obesity after SCI is the loss of muscle mass. Shortly after the injury, those with SCI experience rapid and significant skeletal muscle atrophy below the level of injury, resulting in skeletal muscle cross-sectional areas of 45-80% less than that of able-bodied individuals. Therefore, after SCI, the loss of metabolically active muscle mass results in a 26% reduction in basal metabolic rate and resting energy expenditure. This is important because basal metabolic rate accounts for ~65% of the total daily energy expenditure and plays a major role in the positive energy balance that results in obesity after SCI. In addition to decreased muscle mass individuals with SCI are typically among the most sedentary. This adds to the creation of an unhealthy energy balance as well as deconditioning of major organ systems such as the cardiovascular and musculoskeletal systems.

Given these circumstances, it is important to develop exercise programs capable of increasing energy expenditure via increased physical activity, reversing the loss of muscle mass and improving the cardiometabolic health in people with SCI. The benefits of physical activity for reducing obesity and cardiometabolic disease have been well documented. In particular, high-intensity interval training (HIIT) has been shown to decrease cardiovascular and metabolic risk among able-bodied individuals in a shorter period of time than standard non-interval exercise programs. For example, compared interval walking, continuous walking in able-bodied adults with type II diabetes over a six month period. The continuous walking group walked for 60 minutes five days per week at a moderate intensity while the interval training group alternated between three minutes of high intensity walking and three minutes of low intensity walking five days per week. The walking intensities were determined by oxygen uptake (VO2peak) testing and energy expenditure, with moderate intensity being set at 55% and high intensity at 70% of VO2peak. Although, the mileage was the same for both groups, the interval training group lost 4.3 ± 1.2 kg total body weight and 3.1 ± 0.7 kg body fat mass, whereas no changes in body composition were found in the continuous walking group or the non-walking control group. In a similar study, using leg cycling three times per week for 12 weeks in both the continuous and interval groups and determined intensity levels based on heart rate. The interval training group performed three "all out" cycling sessions of 20 seconds each separated by two minutes low intensity cycling, while the continuous group cycled steady at 70% of maximal heart rate for 45 minutes. Both groups improved similarly in insulin sensitivity, cardiorespiratory fitness, and skeletal muscle mitochondrial content, however, the interval training group achieved these benefits with a five-fold lower exercise volume and training time commitment.

A major consequence of SCI is that paralysis makes voluntary exercise with the legs impossible. To circumvent this problem, functional electrical stimulation (FES) has been shown to be a safe and effective way to exercise paralyzed leg muscles in clinical and home settings. High-cadence moderate-resistance FES cycling can increase muscle mass and improve fasting blood glucose values and low-cadence higher-resistance FES cycling can lead to hypertrophy of the paralyzed leg muscles. However, to prevent cardiometabolic diseases, it's important to recruit enough muscle mass at adequate intensity levels to induce physiological training adaptations, which cause central and peripheral vascular changes9. As a result of developing our new protocol, which incorporates both voluntary arm cycling exercise and FES leg cycling into a hybrid high-intensity interval training (HIIT) FES cycling program, the investigators postulate that it may provide equal or greater benefits with less exercise time commitment, by analogy to HIIT programs used by able-bodied individuals. The protocol provides twice weekly total body cycling exercise alternating between high intensity exercise 80-85 percent of the participants maximal heart rate or a perceived rate of exercise intensity at 7-8 on the 10 point Borg rating of perceived exertion scale for two minutes interspersed with two minutes at a low intensity of 50-60% of their heart rate maximum or a 2-3 level on the 10 point Borg rating of exertion scale. The cycling speed will remain between 35-50 revolutions per minute according to the patients tolerance and comfort and the cycling resistance will be varied from higher and lower resistance also according to the patients tolerance with higher levels of resistance during the high intensity exercise intervals. During low intensity intervals the electrical stimulation will be decreased to 50% of the level used at the high intensity level (maximum of 150mA). In a study using our HIIT-FES leg cycling protocol three times per week for eight weeks, five individuals with SCI increased legs lean mass by 6.9% and a three participant proof of principle study the participants increased in leg lean mass of 5-9%, improved vascular endothelial health (mean increase of 58% in arterial flow mediated dilation), and decreased HbA1c blood levels (2-4%).

While HIIT exercise programs have been highly successful in the able-bodied population it is important to recognize that individuals with SCI have paralysis and extreme muscular deconditioning due to prolonged lack of function. In a recent research study using HIIT-FES leg cycling alone, the investigators found that two of the five participants could not cycle against a resistance greater than the lowest default resistance allowed by the FES cycle until after 12 and 14 training sessions respectively. To overcome this initial deficit for individuals with paralysis, we will provide a pre hybrid cycling muscle strengthening program consisting of neuromuscular electrical stimulation exercise (NMES) resistance training for the legs and voluntary resistance exercises for the arms to prepare participants for the more rigorous hybrid HIIT-FES cycling protocol. It builds on established evidence of advantages of increased resistance exercise for sedentary older adults before undergoing an aerobic exercise program. In that study, the able-bodied deconditioned older adults that underwent the initial resistance training outperformed those that underwent aerobic exercise only. Consequently, our expanded central hypothesis is that a combined program of peripheral remodeling intermittent muscular exercise (PRIME) twice weekly for four weeks followed by a hybrid HIIT-FES cycling program twice weekly for eight weeks will be effective in combating obesity and enhancing cardiometabolic health for those with SCI. To our knowledge this will be the first study of the effects of a hybrid HIIT-FES cycling program after undergoing a PRIME preparatory strengthening program in individuals with SCI. The hypothesis to be tested is whether the combination of PRIME resistance training followed by the hybrid HITT-FES cycling twice a week can bring about improvements in body composition such as a decrease in percent body fat and an increase in total body and legs lean mass. Additionally, it aims to improve blood lipid, glucose, and systemic inflammation markers, central vascular fitness (exercise VO2peak), peripheral vascular health (muscle oxygenation), and physical functioning (wheelchair propulsion and body transfer abilities). Overall, participants will undergo 24 training sessions over twelve weeks (eight PRIME resistance training sessions and sixteen hybrid HITT-FES cycling sessions).

Given the study aim and target population, this proposal is well aligned with the mission of the Mississippi IDeA Network of Biomedical Research Excellence call for biomedical research studies. The results of this pilot study will provide valuable information concerning the battle against obesity and cardiometabolic disease risk in the high at-risk SCI population. Evidence gathered from this pilot study is intended to lead to grant applications for furthermore in-depth study.

Innovation Our proposed pilot study provides multiple important innovations: 1) The use of the novel and promising combination of hybrid FES cycling (voluntary arms and electrically evoked legs exercise) and HIIT for the SCI population. 2) The first testing of potential benefits of the PRIME program which has been successful with older deconditioned adults as a preliminary muscle strengthening program in preparation for the more intense hybrid HIIT-FES cycling protocol. 3) Enrollment of a medically underserved and disadvantaged population with limited options for battling obesity and maintaining cardiometabolic health. 4) Lastly, our protocol will reduce the volume of exercise to just 30-40 minutes two days per week. This is less than half of the typically recommended volume of exercise for improved health across all populations (150 minutes per week) (USDHHS). HIIT exercise programs in the able-bodied population have been reported to provide similar health benefits with reduced exercise volume. The investigators will test this in the SCI population. Being able to receive significant health benefits while performing a reduced volume of exercise is especially important for individuals with SCI due to the physical limitations created by muscle paralysis and limited physical activity options due to environmental barriers.

FES cycling has been traditionally prescribed at a moderate-to-high cadence (i.e., 30-50 rpm) and has been shown to improve cardio-metabolic health in people with SCI7,. Low cadence cycling (10 rpm) has been shown to provide greater muscle hypertrophy in the legs than high cadence (50 rpm) cycling, demonstrating the importance of greater cycling resistance. Interval training, especially varying intensity levels from high to low, has demonstrated greater or equal cardiometabolic benefits with less exercise volume and shorter time frames than traditional continuous exercise in able-bodied individuals. The major innovation of this study is that it builds on established evidence of advantages of increased resistance exercise for those with SCI and high-intensity interval exercise programs in the able-bodied population. The investigators believe that the novel hybrid HIIT-FES cycling program is uniquely suited for the special needs of those with SCI and other paralytic conditions, which have been disadvantaged due to having limited options for physical activity. Also, because initial investigations have shown that the deconditioned state of paralyzed muscles limited the increase of resistance during the higher intensity intervals, the investigators are implementing the PRIME protocol which has been shown to remodel the deconditioned muscle of older deconditioned adults allowing greater optimization of a cycling program.

Finally, the investigators will be the first to introduce and document the preliminary efficacy of a novel program combining hybrid HIIT-FES cycling exercise and the PRIME pre-conditioning protocol. In the initial proof-of-principle trials using the novel HIIT-FES legs only cycling protocol without the PRIME program, improvements were demonstrated in body composition and cardiometabolic health markers, prompting the hypothesize that combining HIIT with hybrid FES cycling and the PRIME preparatory program will produce the same or even greater changes in body composition, central and peripheral vascular health and other markers of cardiometabolic health with reduced exercise volume.

Approach-Experimental Strategies:

This highly qualified multi-disciplinary research team has experience in performing and teaching all components of this research study. The research team will consist of William Carey University faculty from the Physical Therapy Program, College of Osteopathic Medicine, and the School of Nursing. The research study mentor and consultant are faculty members from the University of Southern Mississippi School of Nursing and Health Professions. Students involved with the research study will be from the Physical Therapy Program and the Undergraduate Nursing Program at William Carey University and the Undergraduate Kinesiotherapy Program at the University of Southern Mississippi. The PI Dr. David Dolbow has a track record of conducting research in individuals with SCI and expertise in the application of FES protocols. Dr. Dolbow has a certification in neurologic clinical practice and teaches full-time in the Physical Therapy Program at William Carey University and as an adjunct instructor in the Kinesiotherapy Program at the University of Southern Mississippi. Co-investigator Dr. Chris Boyd is an exercise physiologist with extensive expertise in graded exercise testing and exercise performance and teaches in the Physical Therapy Program at William Carey University. Co-investigator Dr. Emily Scott has extensive experience as a nurse and is the Associate Dean of the School of Undergraduate Nursing at William Carey University. Study consultant Dr. Melissa Zeigler has expertise in cardiovascular conditioning and rehabilitation and is the Program Coordinator of the Undergraduate Kinesiotherapy Program at the University of Southern Mississippi. The study mentor Dr. Jennifer Lemacks is the Associate Dean of Research in the School of Nursing and Health Professions at the University of Southern Mississippi. She has extensive research experience in the field of health professions.

Human Subject Involvement and Characteristics: The research protocols were approved by William Carey University Institutional Review Board (IRB), and an informed consent will be reviewed, signed, and obtained from each participant prior to data collection. The investigators will recruit men and women with C4-T12 SCI (n=12) American Spinal Injury Association Impairment Scale A, B, and C as per International Standards for Neurological Classification of SCI; ≥1 years post-SCI; age 21-70 years. Participants will be recruited through (1) querying the William Carey University Physical Therapy research database (>40 entries for traumatic SCI); (2) advertisement through local centers including "Living Independently for Everyone" [L.I.F.E.] (see letter of support). Exclusion criteria include pressure wounds on buttocks or feet; unhealed bone fractures or history of fragility fractures; uncontrolled cardiovascular or metabolic disease; severe osteoporosis (T score below -4); uncontrolled autonomic dysreflexia; and orthopedic or other problems that preclude leg and arm cycling. Participants in the PRIME + FES group will participate in the PRIME program for preliminary muscle strengthening twice weekly for four weeks then hybrid HIIT-FES cycling twice weekly for eight weeks. Participants in the range of motion (ROM) group will receive passive ROM to the legs and active ROM with the arms also twice per week for 12 weeks.

Involvement of Undergraduate and Other Students: Students from the undergraduate nursing program at William Carey University, the undergraduate kinesiotherapy program at the University of Southern Mississippi, the physical therapy program and college of osteopathic medicine at William Carey University will participate in all research activities under the supervision of faculty from the physical therapy program, nursing program and college of osteopathic medicine at William Carey University. Activities will include recruitment of participants, completing of research documents, consent form, medical history form, outcome questionnaires, measurement of vital signs, pre and post testing blood droplet testing, transfers, wheelchair propulsion, VO2 peak arm crank testing, weights and height measures regarding, application of electrodes, skin checks, NMES resistance training, hybrid FES-HIIT cycling, standard of care passive and active ROM exercises, and DXA scans.

Research AIM: To determine the impact of a combined program of PRIME muscle strengthening and hybrid HIIT-FES cycling in adults with SCI.

Rationale and Preliminary Study Results: Obesity and cardiometabolic diseases impact those with SCI perhaps above all other segments of the population1. Compounding the problem is the fact that paralysis greatly decreases the amount of voluntary muscle available for participation in physical activities. FES cycling has been shown to produce increased lean mass via muscle hypertrophy and improve in blood glucose levels; however, to date hybrid HIIT-FES cycling has not been explored in the SCI population even though HIIT has been shown to provide greater or equal benefits with less exercise volume and time commitment in the able-bodied population. Realizing the importance of developing alternative exercise programs for those with SCI, the investigators developed a hybrid HIIT-FES cycling protocol and add the PRIME four week muscle strengthening program to prepare paralyzed and deconditioned muscles for the hybrid HIIT-FES cycling program. Upon finding positive benefits (increased legs lean mass, enhanced cardiovascular health markers and decreased HbA1c blood levels) in a preliminary study using HIIT-FES cycling three times per week for eight weeks the investigators hypothesized that participants who complete hybrid HIIT-FES cycling following the PRIME muscle strengthening program will decrease body fat percentage, decrease fat mass, increase total and legs lean mass, increase aerobic fitness and peripheral muscle oxygenation, improve blood lipid levels, and improve blood glucose and HbA1c levels, decrease systemic inflammation markers, and enhance physical functioning with wheelchair propulsion and transfers to a greater extent than those that completed ROM exercises. Furthermore, we expect these results after 30-40 minutes of exercise twice per week which is about half of exercise volume recommended for health improvements across all populations. The investigators anticipant that these results will provide a new direction for exercise programs that battle obesity, decrease the risk of cardiometabolic conditions, and provide a basis for developing evidence-based practice information. The investigators believe this two group pre- post-test design pilot study is a prudent approach for determining the efficacy of the hybrid HIIT-FES cycling program with the following research phase being a larger randomized control trail comparing the benefits for individuals with SCI to able-bodied individuals.

Planned Experimental Protocols: The hypothesis for our research aim is that combining the PRIME muscle strengthening program and the hybrid HIIT-FES cycling will reduce obesity, enhance cardiometabolic health markers, improve central and peripheral vascular health, and improve physical function in persons with chronic SCI more than the standard of care ROM exercises. This will be tested using a two-group pre- post-test study design. For the initial study testing participants will report to the exercise research laboratory in the Health Sciences building at William Carey University. Prior to enrolling in the study potential participants must provide a medical clearance form signed by their physician stating that the participant is safe to use FES cycling. Potential participants must then review and sign an informed consent. The participant will then fill out a medical history form and have vital signs measured including blood pressure, heart rate, and oxygen saturation rate. The participants will then complete health-related questionnaires for shoulder pain, bladder control, and memory. Participants will be weighed using a Scale-Tronix Wheelchair Scale (Welch Allyn, Skaneatelest Falls, NY). The weight of the wheelchair alone subtracted from the combined weight of the participant and wheelchair will provide the weight of the participant. Participants will transfer from their wheelchair to a treatment mat. Participants in this study will likely require little or no assistance but we do have sliding boards and an electrically powered lift (Invacare, Reliant 450) if needed to ensure safe transfers. All research staff members have had ample experience using the lift during past studies and during physical therapy and nursing duties and training will be provided to all the students. Once on the mat in a supine position, a tape measure will be used to measure height. The left leg will be extended, and ankle dorsiflexed to enable an accurate measurement from the bottom of the foot to the top of the head. Following the measures of weight and height, participants will undergo a finger stick on the left hand to retrieve a droplet of blood for determination of blood lipid, glucose, hemoglobin A1c (HbA1c), and c-reactive protein levels. The participant will be asked to perform a ten meter wheelchair propulsion test starting from a still position. The time and number of wheel propulsions will be recorded over the ten-meter distance. Then a graded exercise test using the hybrid FES cycle will be performed to determine VO2peak, peak power output. During the first and last FES cycling session and first and last passive ROM session muscle oxygenation levels of the quadriceps muscles will be measured with near infra-red spectroscopy. Participants will then report to the Health Professions Building at the University of Southern Mississippi for a DXA scan. Trained technicians will complete the scan with research staff present to assist as needed. Participants will transfer from their wheelchair to the DXA scanner. Manual assistance, a sliding board or an electrically controlled lift are available if needed although most participants in this study should be able to transfer independently because their arms and upper body are functional.

The DXA scan will be performed with the participant in a supine position. The legs will be slightly internally rotated as recommended by the International Society for Clinical Densitometry with Velcro straps to secure the legs to prevent an untimely spasm from causing an extremity to involuntarily flex and bump the scanner. All metal such as belt buckles, rings and earrings will be removed prior to scanning. The scanning will determine body composition, including total body and regional lean and fat mass, percent body fat and total body bone mineral density. Contraindications to DXA scanning include pregnancy, presence of a pacemaker, or any condition that precludes the proper positioning of the patient to be able to obtain accurate values. After the initial testing the participants will be randomly divided into either the PRIME + FES group or the standard of care ROM group. The PRIME + FES group will complete PRIME muscle strengthening sessions twice weekly for four weeks and then hybrid HIIT-FES cycling twice weekly.