ALTHOUGH EVIDENCE of motor benefits of physical. Active-Assisted Cycling Improves Tremor and Bradykinesia in. Parkinson s disease ORIGINAL ARTICLE

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1 ORIGINAL ARTICLE Active-Assisted Cycling Improves Tremor and Bradykinesia in Parkinson s Disease Angela L. Ridgel, PhD, Corey A. Peacock, MS, Emily J. Fickes, PhD, Chul-Ho Kim, PhD 2049 ABSTRACT. Ridgel AL, Peacock CA, Fickes EJ, Kim C-H. Active-assisted cycling improves tremor and bradykinesia in Parkinson s disease. Arch Phys Med Rehabil 2012;93: Objectives: To develop a rapid cadence cycling intervention (active-assisted cycling [AAC]) using a motorized bike and to examine physiological perimeters during these sessions in individuals with Parkinson s disease (PD). A secondary goal was to examine whether a single session of AAC at a high cadence would promote improvements in tremor and bradykinesia similar to the on medication state. Design: Before-after pilot trial with cross-over. Setting: University research laboratory. Participants: Individuals with idiopathic PD (N 10, age 45 74y) in Hoehn and Yahr stages 1 to 3. Intervention: Forty minutes of AAC. Main Outcome Measures: Heart rate, pedaling power, and rating of perceived exertion were recorded before, during, and after a bout of AAC. Functional assessments included tremor score during resting, postural, and kinetic tremor. Results: This AAC paradigm was well tolerated by individuals with PD without excessive fatigue, and most participants showed improvements in tremor and bradykinesia immediately after a single bout of cycling. Conclusions: This paradigm could be used to examine changes in motor function in individuals with PD after bouts of high-intensity exercise. Key Words: Cycling; Exercise; Movement disorders; Rehabilitation; Tremor by the American Congress of Rehabilitation Medicine ALTHOUGH EVIDENCE of motor benefits of physical therapy or exercise in individuals with Parkinson s disease (PD) has been widely published, 1 the optimal type or intensity of activity has not been determined. Furthermore, the variability in PD symptom severity among individuals has made it difficult to identify a one-type-fits-all approach to motor rehabilitation. In the field of rehabilitation, there has been a recent interest in exercise intensity or speed as an important factor in activity-dependent motor improvement. Studies in rodent models of PD have documented that animals that are forced to exercise at high intensity, on a motorized treadmill, show dopamine sparing and improved motor function after a toxic insult (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). 2-4 Human studies have shown that body weight supported treadmill training (BWSTT), 5,6 intensive treadmill walking, 7 and forced cycling exercise 8 all improved motor function, as measured with the Unified Parkinson s Disease Rating Scale (UPDRS) in individuals with PD. However, most high-speed exercise modes require either a rehabilitation clinic with a harness system or an able-bodied cycling partner, neither of which is conducive to an at-home or community-based setting. The primary goal of this study was to investigate a high-speed active-assisted cycling (AAC) paradigm using a commercially available motorized cycle trainer and examine physiological perimeters during these sessions in individuals with PD. Development of this rehabilitation paradigm was based on our earlier work with a tandem bicycle (ie, forced exercise) that was used to assist individuals in reaching higher pedaling rates than they could pedal on their own. 8 In this forced exercise study, individuals with PD successfully completed 24 sessions of high cadence cycling (ie, 85 revolutions per minute [rpm]) on a stationary tandem bicycle with an able-bodied trainer. Although the cycling cadence was high during these sessions, the trainer produced 75% of the total work so the participants with PD were able to maintain moderate heart rate intensities (ie, 60% 80% of the target heart rate) without excessive fatigue. Despite these positive benefits, it is not feasible to use a tandem cycling paradigm in the home or large-scale clinical studies because of the requirements of a trainer. Therefore, the development of alternative high-intensity exercise interventions, such as AAC, is warranted. We hypothesize that AAC can provide an alternative to forced tandem cycling, without excessive fatigue, for individuals with PD. This will be tested by examining physiological parameters (ie, heart rate, rating of perceived exertion [RPE]) during single bouts of AAC. A secondary goal of this study was to determine whether AAC promotes improvement in tremor as seen in forced cycling (ie, tandem). 8 Ridgel et al 8 documented a 38% improvement in tremor and a 28% improvement in bradykinesia after 8 weeks of forced exercise on a tandem bicycle. Therefore, we hypothesize that AAC will promote improvements in tremor and bradykinesia in individuals with PD. This will be tested by examining the amplitude and frequency of movement during tremor and bradykinesia tasks while on medication (ON) and before and after AAC in the off medication (OFF) state. From the Department of Exercise Physiology, School of Health Sciences, Kent State University, Kent, OH. Presented to the Society for Neuroscience, November 13-17, 2010, San Diego, CA. Supported by Kent State University Research Council. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Angela L. Ridgel, PhD, Dept of Exercise Physiology, School of Health Sciences, Kent State University, 350 Midway Dr, 163F MACC Annex, Kent, OH 44242, aridgel@kent.edu. In-press corrected proof published online on Jul 6, 2012, at /12/ $36.00/0 AAC BWSTT CI PD RPE rpm UPDRS V O2 max List of Abbreviations active-assisted cycling body weight supported treadmill training confidence interval Parkinson s disease rating of perceived exertion revolutions per minute Unified Parkinson s Disease Rating Scale maximum oxygen consumption

2 2050 ACTIVE-ASSISTED CYCLING FOR PARKINSON S DISEASE, Ridgel Table 1: Research Subject Demographics Sex Age (y) H&Y Duration of PD (y) LEDD Resting HR (beats/min) V O2 max (estimated) Male Female Female Male ND 22.4 Male Female Female Male Female Female Mean SD Abbreviations: Estimated V O2 max, cardiovascular fitness (L kg 1 min 1 ); H&Y, Hoehn and Yahr score; HR, heart rate; LEDD, levodopa equivalent daily dose; ND, no data. METHODS Participants A total of 10 individuals with idiopathic PD (4 men and 6 women, mean age SD, y) (table 1) were recruited from community support groups. The inclusion criteria were a diagnosis of idiopathic PD and Hoehn and Yahr stages 1 to 3. 9 Individuals were excluded if they had contraindications to exercise such as musculoskeletal injuries, cardiovascular disease, stroke, or dementia. Written informed consent was obtained from all subjects according to the guidelines of the Kent State University Institutional Review Board prior to the start of the study. All eligible participants were asked to visit the laboratory on 2 occasions. During the first visit, they were pretested for cardiovascular fitness and motor function while ON anti-parkinson s medication. During the second visit, all participants participated in a single active-assisted exercise session while OFF anti-parkinson s medications after overnight withholding (10 12h). Participants were asked to maintain their pre-enrollment activity level and current medication dosage when not in the laboratory. Protocol The YMCA submaximal cycle ergometer test was used to estimate cardiovascular fitness (ie, estimated maximum oxygen consumption or V O2 max). 10,11 Participants pedaled a cycling ergometer at 50 revolutions per minute (rpm) for two or three 3-minute stages. Each stage progressed by 25 watts after an initial warm-up. Heart rate was recorded every 30 seconds. Average heart rate during the last 30 seconds of each minute was plotted against the workload for each stage to calculate V O2 max. During AAC (Motomed Viva 2 movement therapy trainer a ), the motor speed was set at 75rpm and participants were asked to pedal 80 to 85rpm for the 30-minute main set. Participants were instructed to overpower the motor to maintain the cadence and were given visual feedback from the trainer monitor. This AAC paradigm was developed to mimic the forced (tandem) exercise study. If the individuals were unable to maintain 80 to 85rpm, the motor would take over and would move the legs at 75rpm. The 30-minute AAC set was preceded and concluded by a 5-minute warm up/cool down at 40 to 50rpm. Heart rate, RPE, and pedal power (watts) were monitored by a laboratory assistant who also provided support and encouragement during the entire session. Tremor assessments were carried out immediately before and within 10 minutes of each session. Tremor and Bradykinesia Assessment Kinesia b was used to evaluate tremor and bradykinesia of the more affected upper limb as described previously. 12 The system includes a finger sensor unit that integrates 3 orthogonal accelerometers and 3 orthogonal gyroscopes to record 3-dimensional motions. The sensor was worn on the most-affected hand. Participants watched three, 20-second computer videos that guided them through a resting tremor task, in which the hand was resting by the side, a postural tremor task, in which both arms were stretched out in front at 90 o, and a kinetic tremor task, in which individuals were instructed to repeatedly flex and extend the elbow, touching the nose with each flexion movement. The bradykinesia tasks included a finger tap (UPDRS Motor III item 23), hand grasp (UPDRS Motor III item 24), and hand pronation-supination (UPDRS Motor III item 25). The Kinesia software b provided unbiased scoring of rest, postural, and kinetic tremor tasks on a continuous scale ranging from 0 to 4, which has been shown to be highly correlated to UPDRS clinical scores. 13 These scores, calculated by the software (see Giuffrida et al 13 for details on the analysis), were summed for a comprehensive analysis of tremor. Further analysis, using Matlab, c of raw movement files allowed for calculation of the speed (ie, root mean squared angular velocity) and amplitude (ie, root mean squared excursion angle) during the bradykinesia tasks. 14,15 In short, raw movement files were first band pass filtered (2nd-order Butterworth, Hz). Log peak power of the angular velocity signal was used to quantify speed, and log peak power of the integrated angular velocity signal from the index finger was used as a measure of movement amplitude. Frequency and amplitude variables were averaged across the bradykinesia tasks to provide a global measure of bradykinesia and to minimize intrasubject variability. Statistical Analysis Repeated-measures analysis of variance was used to determine whether there was a main effect of time (ON, OFF Pre-AAC, OFF Post-AAC) in the outcome measures. When appropriate, a paired samples t test was used to examine differences between ON/OFF Pre-AAC, OFF Pre-AAC/OFF Post-AAC, and ON/OFF Post-AAC. All data were analyzed with SPSS d Statistical significance was set at P.05.

3 ACTIVE-ASSISTED CYCLING FOR PARKINSON S DISEASE, Ridgel 2051 RESULTS All 10 participants were able to successfully complete the 40-minute AAC session. This group had low baseline cardiovascular fitness ( L kg 1 min 1, 30 40th percentile in this age group 16 ), a disease duration of years, and Hoehn and Yahr stage score of (see table 1). Average heart rate during the main set was 98 4 beats per minute, which equates to 21 4 beats per minute over resting heart rate levels. These heart rate levels represent 60% to 70% of agepredicted maximum heart rate of most participants. RPE was (somewhat hard) and was within the aerobic zone (ie, 65% 70% maximal effort). Average power output was watts, and cycling distance was kilometers. To monitor fatigue after the AAC session, participants were asked to state their RPE during the easy warm up and cool down. RPE during the cool down ( ) was slightly elevated from warm-up levels (7.0.23), suggesting that participants recovered quickly and did not have excessive fatigue after the completion of the 30-minute AAC session. Our secondary goal was to examine whether tremor scores and bradykinesia task perimeters, as measured with Kinesia, would be sensitive to detecting differences in ON versus OFF Pre-AAC, OFF Pre-AAC versus OFF Post-AAC, and ON versus OFF Post-AAC states and to determine whether a single bout of AAC decreased tremor. Raw motion sensor data, as angular velocity in the x-dimension, from the Kinesia device illustrates the increase in resting tremor amplitude from the ON medicated state (fig 1A) to the OFF Pre-AAC state (fig 1B). It is clear that there is an increase in the magnitude of the tremor in this individual in the OFF medication state. Furthermore, figure 1C shows that the resting tremor was reduced in amplitude and showed a slight decrease in frequency (from 6Hz to 4Hz) after a single bout of AAC (OFF Post-AAC). Although this example is from a single individual (who had the greatest baseline resting tremor), other participants showed similar improvements in tremor after AAC (fig 2). Figure 2A shows individual results from 9 participants. Data from 1 subject is missing because of computer error. Although there was a large amount of variability in baseline tremor as well as tremor changes across individuals, 7 participants (78%) exhibited improvements in their summed tremor score in the OFF Post- AAC state. When data were averaged across all participants (see fig 2B), there was a significant increase (t , P.03, 95% confidence interval [CI] [ 1.47 to.08]) in summed tremor scores from the ON state ( ) to the OFF Pre-AAC state ( ). Although there was no significant difference in tremor scores between the pre- and post- AAC levels, 40 minutes of AAC resulted in a decrease in tremor score ( ) to a level that was not significantly different from that measured in the ON medication state (t 8.22, P.83, 95% CI [ 0.71 to 0.86]). The speed and amplitude scores were averaged across the 3 bradykinesia tasks for 9 individuals. Data from 1 subject are missing because of computer error. Movement speed showed a significant main effect of time (F 35.31, P.001). As can be seen in figure 3, there was an improvement in movement speed from OFF Pre-AAC to OFF Post-AAC (t , P.001, 95% CI [ ]) and a worsening in movement speed from the ON state to the OFF Pre-AAC state (t , P.001, 95% CI [ to 87.68]). There were no significant differences in movement speed between the ON state and the OFF Post-AAC state (t , P.313, 95% CI [ ]). In addition, movement amplitude during the bradykinesia tasks showed no significant main effect of time (F.368, P.69). A B C Fig 1. Time domain accelerometer signals recorded on the x-axis using the Kinesia during the resting tremor task from a subject with a significant resting tremor while OFF medication (tremor score 2.3 out of 4). (A) ON medication (tremor score 3.4 out of 4). (B) OFF medication pre-aac (tremor score 1.0 out of 4). (C) OFF medication post-aac. The magnitude of tremor in this individual increased in the OFF pre-aac medication state but decreased in the post-aac state. Each graph shows a 5-second recording.

4 2052 ACTIVE-ASSISTED CYCLING FOR PARKINSON S DISEASE, Ridgel A B Fig 2. Combined tremor scores as measured with Kinesia. (A) Individual subject scores while ON medication, OFF medication pre- AAC, and OFF medication post-aac; 78% of the participants showed improvements in tremor in the OFF post-aac condition. (B) Average tremor scores of 9 participants with PD. There was a significant increase in tremor score between the ON and OFF pre- AAC medication states. OFF post-aac tremor scores were similar to ON medication scores. Error bars indicate standard error of the mean. *P<.05. DISCUSSION Theoretical Implications These findings show that AAC can be tolerated by individuals with PD while OFF medication and that a single bout of AAC can improve tremor and bradykinesia in the upper extremity similar to the ON medication state. This study is also unique in that it used a quantitative measure of tremor and bradykinesia (ie, Kinesia) instead of a subjective clinical measure of motor symptoms (ie, UPDRS Motor III score). Use of a validated and automated system of tremor and bradykinesia assessment has several advantages including the ability to quantify speed, amplitude, and quality of movement. 13,14 This research fills a gap in the literature by documenting similar improvements in tremor between a cycling intervention and medication for individuals with PD that does not require a trainer or harness system. Many studies have documented the motor benefits of exercise and physical activity in PD, but few have focused on high-speed or high-intensity exercise. 5-7,17 High-speed walking (BWSTT), using partial body weight support and a treadmill, has been shown to increase overground walking speeds and stride length in healthy elderly 18 and in individuals with PD. 5-7,17 This overspeed method (ie, body weight unloading) allows for walk training at very fast speeds without an increase in energy cost or fatigue over self-selected speeds. 19 When high-speed BWSTT and low-intensity physical therapy were compared in groups of participants with PD, the high-intensity group showed greater improvements in stride length and walking speed. 17 Furthermore, Fisher et al 17 also suggested that high-speed treadmill training may facilitate activity-dependent neuroplasticity in association with improved motor performance, as measured with transcranial magnetic stimulation and the UPDRS Motor III score. This finding is intriguing because it suggests that high-intensity exercise can normalize corticomotor excitability in individuals with PD. In addition, recent studies using functional magnetic resonance imaging have described significant correlations between motor function improvements, as measured with the UPDRS Motor III scale, and blood-oxygenlevel-dependent magnetic resonance imaging response after acute bouts of forced cycling while OFF Parkinson s medication and in the ON medication state. 20 Specifically, these positive correlations were present in the putamen, thalamus, globus pallidus, supplementary motor cortex, and primary motor cortex, suggesting that PD medications and acute bouts of forced exercise use similar pathways to alter disease symptoms. AAC also resulted in immediate reduction in tremor and improvements in bradykinesia in the hands, suggesting that there is a global central nervous system effect of this intervention, similar to that described after forced exercise. 8,20 Although not yet measured in humans, it has been suggested that high-intensity and forced exercise could trigger endogenous release of neurotrophic factors or dopamine. 20,21 Studies in humans are also supported by the 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine animal model literature, which has documented improved motor function during gait and balance Movement Speed * * ON OFF Pre-AAC OFF Post-AAC Fig 3. Bradykinesia variables as measured with Kinesia. Average movement speed of 9 participants with PD. There was a significant decrease in movement speed between the ON and OFF pre-aac medication states. OFF post-aac movement speed was similar to ON medication scores. *P<.001.

5 ACTIVE-ASSISTED CYCLING FOR PARKINSON S DISEASE, Ridgel 2053 tasks after intensive treadmill exercise. 2-4,22 1-Methyl-4-phenyl- 1,2,3,6-tetrahydropyridine, a neurotoxin that targets dopaminergic neurons, was used to produce PD-like symptoms in the rodent and then a period of high-speed treadmill training was compared with nonexercised animals as well as saline-injected controls. 3 Interestingly, after a period of high-intensity treadmill exercise, animals showed increased running velocity, improved forelimb placement, and improved latency to fall (ie, balance), which was correlated with altered dopamine transmission and dopamine sparing. 2,3 These findings have important implications for the examination of exercise-induced neuroplasticity and neuroprotection after brain disease or injury. Rehabilitation Implications The use of high-intensity exercise as a rehabilitation method in PD poses an interesting conundrum. Moderate-intensity exercise reduces the risk of cardiovascular disease, 23 lessens daily fatigue, 24 and can increase the efficacy of levodopa in individuals with PD. 25 Conversely, high-intensity exercise could increase the risk of a cardiovascular event 26 and excessive fatigue and may not be well tolerated by individuals with PD. AAC is valuable because it allows for an increase in the rate of leg pedaling without excessively high heart rate or fatigue. In conjunction with standard treatments, this type of intervention may allow for a decrease in medication dose and improvements in ON-OFF fluctuations. Although forced cycling and BWSTT have been shown to have positive benefits in PD, these methods require either a very fit cycling partner or an expensive harness and safety system. The AAC paradigm described here, using the Motomed Viva 2 movement trainer, allows for controlled and safe cycling in a small space. Furthermore, this movement trainer can be used with a wheelchair or a standard chair that provides a stable and comfortable sitting posture. This study builds upon our previous work that showed that although tremor and bradykinesia (ie, speed of movement) are improved after a single session of passive cycling, there is no difference between low-cadence (ie, 60rpm) and high-cadence (ie, 80rpm) pedaling. 12 Passive cycling and AAC are dissimilar in that AAC requires individuals to overpower the motor by pushing on the pedals and doing work. Therefore, it is likely that AAC activates joint receptors, muscle spindles, and golgi tendon organs in the legs while passive cycling activates joint receptors and muscle spindles only. Afferent input from these proprioceptors could affect corticomotor excitability and motor function Individuals with PD show an abnormal pattern of oscillatory cortical activity, due to disrupted basal ganglia circuits, which is believed to contribute to the defective pattern of movement. 30 Levodopa has been shown to restore normal rhythmic activity in the motor output in PD. 31 Therefore, it is possible that AAC promotes patterned high-frequency input to the sensoriomotor cortex from peripheral afferents. Overall, these findings provide evidence for exercise-induced neuroplasticity and contribute important insights that will be helpful for the development of rehabilitation interventions in PD. Study Limitations There are a few limitations in this study. First, there were a small number of participants with a wide variety of PD symptom severity. This variability resulted in a large SD in our data set and contributed to reduced improvement between the pre- and post-aac levels. However, it is also possible that there was a delayed effect of AAC that was not detected immediately after the exercise bout. Anecdotal interviews of the participants suggested that many of them felt better later in the day after a bout of AAC. Future studies will monitor motor function during the hours and days following AAC to determine the time course of motor improvements. Second, it is possible that daily fluctuations in motor symptoms and timing of medications contributed to the variations seen among individuals. However, these differences were minimized within each individual by having them come to the laboratory at the same time every week. Third, subject-to-subject differences could be because individuals exercised at different times. For example, subject 1 exercised and was tested at 8:30 AM while subject 2 came into the laboratory at 10:30 AM. This difference could have an effect on the severity of PD symptoms among individuals. Last, if the participants were unable to overpower the motor, the motor would take over and would reduce the workload of the individual. However, we encouraged individuals to keep the goal cadence and we monitored their heart rate during the entire session. In light of the fact that there was little variability in the heart rate values of the individuals across trials, we do not believe this was a confounding variable in our analysis. CONCLUSIONS The goal of this study was to develop and test the benefits of an AAC paradigm in individuals with PD. We showed that single sessions of AAC were well tolerated and resulted in immediate reductions in tremor and bradykinesia in most individuals. This paradigm could be valuable for large-scale rehabilitation studies in this population because it does not require expensive harness systems, individual personal trainers, or large therapy spaces. Studies are currently underway that will examine the benefits of multiple sessions of AAC on motor and cognitive function. Acknowledgments: We thank the Reck Company (Betzenweiler, Germany) for providing the modified Motomed Viva 2 and technical support, and Jacob Barkley, PhD (Kent State University) and Thomas Mera, MS (Great Lakes Neurotechnologies) for providing assistance with data analysis. References 1. Keus SH, Munneke M, Nijkrake MJ, Kwakkel G, Bloem BR. Physical therapy in Parkinson s disease: evolution and future challenges. Mov Disord 2009;24: Tillerson JL, Caudle WM, Reveron ME, Miller GW. Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson s disease. Neuroscience 2003;119: Petzinger GM, Walsh JP, Akopian G, et al. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. 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