Archives of Physical Medicine and Rehabilitation journal homepage: www.archives-pmr.org Archives of Physical Medicine and Rehabilitation 2015;96:627-32

ORIGINAL RESEARCH

Pilot Study: Evaluation of the Effect of Functional Electrical Stimulation Cycling on Muscle Metabolism in Nonambulatory People With Multiple Sclerosis Mary Ann Reynolds, MS,a Kevin McCully, PhD,a Blake Burdett, BS,b Christine Manella, PT,b Laura Hawkins, BS,b Deborah Backus, PT, PhDb From the aDepartment of Kinesiology, University of Georgia, Athens, GA; and bShepherd Center, Atlanta, GA.

Abstract _ 2) using near-infrared spectroscopy (NIRS) after 4 weeks of training Objective: To investigate the changes in muscle oxygen consumption (mVO with functional electrical stimulation (FES) cycling in nonambulatory people with multiple sclerosis (MS). _ 2 after an FES cycling intervention. Design: Four-week before-after trial to assess changes in mVO Setting: Rehabilitation hospital. Participants: People (NZ8; 7 men, 1 women) from a volunteer/referred sample with moderate to severe MS (Expanded Disability Status Scale score>6.0). Intervention: Participants cycled 30 minutes per session, 3d/wk for 4 weeks or a total of 12 sessions. _ 2 of the right vastus lateralis muscle was measured with NIRS before and within 1 week after the intervention. Six Main Outcome Measures: mVO _ 2 was assessed by analyzing the slope of bouts of 15-second electrical stimulation increasing from 2 to 7Hz were used to activate the muscle. mVO the NIRS oxygen signal during a 10-second arterial occlusion after each electrical stimulation bout. _ 2 Results: Significant FES training by electrical stimulation frequency level interaction was observed (PZ.031), with an average increase in mVO of 47% across frequencies with a main effect of training (PZ.047). _ 2, suggesting that FES cycling is a potential therapy for improving muscle health in people Conclusions: FES cycling for 4 weeks improved mVO with MS who are nonambulatory. Archives of Physical Medicine and Rehabilitation 2015;96:627-32 ª 2015 by the American Congress of Rehabilitation Medicine

Multiple sclerosis (MS) is the most prevalent cause of neurologic disability in young adults. This inflammatory demyelinating disease of the central nervous system leads to impairments that can severely limit a person’s activity, participation in daily activities, and quality of life.1 Although there are a variety of medical therapies successful at reducing the number of relapses during MS and delaying disease progression, the question of how to address the remaining and evolving motor and sensory deficits in a safe manner remains unclear.2 Recent studies have shown that exercise, both aerobic and resistance, can induce marked

Presented to the National American College of Sports Medicine, May 29, 2014, Orlando, FL. Supported by the Eula C. and Andrew C. Carlos Multiple Sclerosis Rehabilitation and Wellness Program at the Shepherd Center. Disclosures: none.

improvements in variables (eg, muscle strength, fatigue, cardiorespiratory function, ambulation).3,4 These improvements suggest that not all functional impairments are a result of nonreversible tissue injury, but rather that a large proportion may be a result of low fitness caused by decreased activity as impairments become more severe. Although exercise may improve function through a host of avenues (eg, increased levels of neurotrophic factors, improved coordinated function),4,5 skeletal muscle function may also be improved and has been shown to have a significant impact on fatigue, ambulation, and overall function.3,6 One proposed physiological mechanism that could play a role in exercise-related changes in muscle function is skeletal muscle mitochondrial function. The mitochondrion is a dual-membrane organelle that is vital for maintaining proper cell function. Specific to muscle function, mitochondria are responsible for oxidative

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phosphorylation, which produces energy used in sustained physical activity.7 Exercise has been shown to increase mitochondrial density in healthy able-bodied participants, whereas inactivity results in the opposite effect.8,9 However, research is still needed to determine if mitochondrial function is a contributor to functional disability in people with MS. It is possible that inactivity resulting from the initial motor and sensory loss directly caused by MS could cause downregulation of mitochondria, which would decrease the ability to do sustained physical activity, resulting in further inactivity. People who are nonambulatory as a result of their MS are at an even greater risk of these secondary changes because they are generally dependent on their wheelchair for mobility. In fact, mitochondrial capacity is impaired in people with MS similar to or worse than its impairment in deconditioned able-bodied individuals.10 This impairment in muscle function may contribute to fatigue, which will further decrease participation in daily activities and ultimately quality of life.11-13 Traditionally, mitochondrial function has been studied using both invasive and noninvasive methods. The noninvasive criterion standard to assessing skeletal muscle mitochondrial function has been 31 phosphorous magnetic resonance spectroscopy (31P-MRS), which measures resynthesis of phosphocreatine after exercise.14 However, 31P-MRS has limitations in terms of cost and availability. Another approach that can measure skeletal muscle mitochondrial function noninvasively is near-infrared spectroscopy (NIRS).15 Our laboratory has designed a protocol that uses NIRS in combination with a rapid cuff inflation system, which blocks oxygen delivery and venous return, to measure kinetic changes in _ 2) after submaximal skeletal muscle oxygen consumption (mVO exercise. The advantage to using NIRS over 31P-MRS is that it is relatively inexpensive (w$10,000e$70,000 vs $2 million) and more accessible. NIRS has been shown to be reproducible,15 independent of exercise intensity,16 and able to identify changes caused by training status15 or disability.17 The evidence provides support that exercise is a necessary part of rehabilitation strategy to combat both primary motor and sensory loss and the secondary deconditioning that occurs because of decreased activity in people with MS. In those who are wheelchair dependent, there are few exercise options that are available. Functional electrical stimulation (FES) cycling is an intervention that allows people with severe lower-limb weakness or paralysis an avenue for exercise (eg, those with moderate to severe MS). Studies with FES cycling in people with spinal cord injury have demonstrated improvements in blood flow,18 exercise capacity,19 body composition,20 metabolism,21,22 muscle mass,23,24 and muscle strength.25-27 Impairments observed in people with spinal cord injury are similar to those seen in people with MS. Therefore, it is possible that people with MS will receive the same or similar benefits from FES cycling. The purpose of this article is to examine the effects of an FES cycling intervention on muscle function, specifically muscle metabolism using NIRS, in people with moderate to severe MS who are nonambulatory.

List of abbreviations: FES MS _ 2 mVO NIRS 31 P-MRS RPM

functional electrical stimulation multiple sclerosis muscle oxygen consumption near-infrared spectroscopy 31 phosphorous magnetic resonance spectroscopy revolutions per minute

Methods This was a prospective pre-post design to determine the muscle response, specifically muscle metabolism of the right vastus lateralis, to FES cycling in people with moderate to severe MS who were nonambulatory. Testing occurred before and within 1 week after a 4-week FES cycling training intervention. Testing consisted of NIRS measurements of muscle metabolism during a progressive work test in which measurements were made at progressively increasing frequencies of electrical stimulation.

Participants Participants with MS were recruited from a nonprofit rehabilitation hospital in the United States. The study was approved by the institutional review boards of all involved institutions. We certify that all applicable instructional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research. All participants provided written informed consent prior to data collection. Data were collected from December 2012 to August 2013. Participants were included if they were >18 years of age, unable to ambulate farther than household distances (200m), not using FES cycle or receiving weekly applications of electrical stimulation intervention in the lower limb, medically stable with approval from a physician to participate in exercise studies, and able to follow >3-step commands and comply with procedures and follow-up. Participants were excluded if they had experienced a diagnosed relapse in the last 6 months or if they were diagnosed with cardiovascular disease, uncontrolled hypertension, history of epileptic seizures, lower motor neuron disease, or peripheral neuropathy in the lower limbs. Other exclusion criteria included the inability to electrically stimulate leg muscles; presence of a pacemaker, implanted defibrillator, or other implanted electronic or metallic devices (exception being a baclofen pump); unstable long bone fractures of the lower limb or trunk; inability to tolerate sitting upright for at least 1 hour; and allergy to surface electrodes.

Muscle metabolism assessment Muscle metabolism was assessed using NIRS before and after the 4-week FES cycling training intervention. Resting metabolism and exercise metabolism during a progressive work test using electrical stimulation were measured. Participants were positioned supine on a padded therapy table. The NIRS probea was placed over the surface of the right vastus lateralis muscle and secured on the leg with biadhesive tape and 2 snapped straps. Two electrodes used on the right quadriceps during the FES cycling protocol were positioned over the vastus lateralis muscle and attached to the Theratouch 4.7 stimulator.b One electrode was placed proximal to the NIRS probe, and 1 electrode was placed distal to the NIRS probe. A blood pressure cuff attached to a Hokanson AG101 Rapid Cuff Inflatorc was wrapped around the upper thigh, as high as anatomically possible, proximal to the NIRS probe. The experimental setup is shown in figure 1. Adipose tissue thickness can influence quantification of NIRS measurements.28 To account for this, skinfold thickness was assessed by a trained rater at the beginning of each NIRS protocol. Metabolic rates were calculated from the slopes of the NIRS oxygenated hemoglobin signal using linear regression as previously published.29 The muscle metabolism assessment was performed as previously published by Erickson et al.29 Briefly, the assessment began with approximately 1 minute of rest to assess baseline muscle www.archives-pmr.org

Muscle metabolism in multiple sclerosis

Fig 1 Experimental setup. Two electrodes were used to activate the vastus lateralis. One electrode was placed distal to the NIRS device centered approximately 2.5cm above the knee, and another electrode was placed over the vastus lateralis proximal to the NIRS device. The blood pressure cuff was placed as high as anatomically possible on the thigh proximal to the NIRS device.

oxygenation. A series of cuff inflations (250e280mmHg) lasting 10 to 60 seconds were performed to determine the resting metabolic rate. At least 1 minute after the assessment of resting metabolism, the exercise muscle metabolic rate was measured using a progressive work test with increasing levels of electrical stimulation frequencies. Electrical stimulation intensity was selected individually based on the highest tolerable current to ensure the greatest possible muscle activation for each participant. Specifically, the progressive work test consisted of electrically stimulating the muscle for 15 seconds immediately followed by a 10-second arterial occlusion cuff to assess the metabolic rate with 1-minute rest before proceeding to the next frequency. Electrical stimulation frequencies were 2, 3, 5, 6, and 7Hz, in that order. NIRS data were collected at 10Hz. Both channels 1 and 2 of the oxygenated hemoglobin signal were analyzed offline using a correction approach to control for the redistribution of blood from high and low pressure arterioles during arterial occlusion with custom written routines in MATLAB version 7.13.0.564.30,d A physiological calibration consisting of a 6- to 8-minute arterial occlusion was performed after each test as previously described.29,30 Briefly, this was performed to normalize NIRS signals to 0% oxygen saturation in the muscle and 100% oxygen saturation during reactive hyperemia. This allowed us to express changes in the NIRS signal during each ischemic cuff as _ 2 values % hemoglobin-myoglobin/second (%/s). Maximal mVO _ 2 from the progressive work test were approximated from the mVO value obtained at the highest electrical stimulation frequency level (7Hz).

FES cycling intervention Participants trained at the rehabilitation hospital on a FES cyclee for 30 minutes, 3 times a week over 4 to 5 weeks for a total of 12 training sessions. After the initial screening and when informed consent was completed, participants underwent 1 session on the FES cycle to determine if their muscles would respond to FES with the RT300 FES cycle. If successful, they were enrolled into www.archives-pmr.org

629 the study and given a set of electrodes for the right and left hamstrings, quadriceps, and gluteus maximus to be used for the duration of the study. The goal of each session was to achieve a sustained pedal rate of 40 to 50 revolutions per minute (RPM) for 30 minutes. At the start of a training session, stimulation slowly increased until it reached an intensity that was tolerated by the participant and that adequately caused cycling at 50 RPM. This is referred to as active cycling. If the participant was unable to maintain at least a 40 RPM pedal rate, electrical stimulation was turned off and motor assist was activated to help pedal for the remainder of the training session. Once an individual was able to actively pedal for 30 minutes at 40 to 50 RPM for 3 sessions in a row without motor assist, resistance was increased in 0.14-Nm increments. Participants were questioned before the start of each FES cycle training session regarding the previous cycling session to determine if they had any significant pain or fatigue or limitations in function caused by the cycling.

Statistical analysis Data are presented as means  SDs. Statistical analyses were _ 2 comparisons were performed using SPSS version 22.0.f mVO made between pre- and post-FES cycling intervention using repeated-measure 2-way analysis of variance. Least significant difference pairwise comparison was used to evaluate the effect of training on the metabolic rate at the various electrical stimulation frequencies. Significance was accepted when P.05.

Results Fourteen participants (6 women, 8 men) completed the FES cycling intervention. There were no adverse events and specifically no reports of any increase in MS-related symptoms throughout the duration of the study. Half of these 14 participants were able to cycle for at least 30 minutes on the FES cycle at the beginning of the trial; they all significantly increased (P

Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.

To investigate the changes in muscle oxygen consumption (mV˙O2) using near-infrared spectroscopy (NIRS) after 4 weeks of training with functional elec...
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