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Top 10 Research Questions Related to Physical Activity and Multiple Sclerosis a

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Robert W. Motl , Yvonne C. Learmonth , Lara A. Pilutti , Eduard Gappmaier & Susan Coote a

University of Illinois at Urbana-Champaign

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University of Utah

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University of Limerick Published online: 15 Apr 2015.

Click for updates To cite this article: Robert W. Motl, Yvonne C. Learmonth, Lara A. Pilutti, Eduard Gappmaier & Susan Coote (2015): Top 10 Research Questions Related to Physical Activity and Multiple Sclerosis, Research Quarterly for Exercise and Sport, DOI: 10.1080/02701367.2015.1023099 To link to this article: http://dx.doi.org/10.1080/02701367.2015.1023099

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Research Quarterly for Exercise and Sport, 00, 1–13, 2015 Copyright q SHAPE America ISSN 0270-1367 print/ISSN 2168-3824 online DOI: 10.1080/02701367.2015.1023099

SPECIAL TOPICS: Top 10 Research Questions

Top 10 Research Questions Related to Physical Activity and Multiple Sclerosis Robert W. Motl, Yvonne C. Learmonth, and Lara A. Pilutti Downloaded by [West Virginia University] at 19:49 16 April 2015

University of Illinois at Urbana-Champaign

Eduard Gappmaier University of Utah

Susan Coote University of Limerick

An estimated 2.5 million people worldwide are living with multiple sclerosis (MS), and this disease may be increasing in prevalence. MS is a disease of the central nervous system that is associated with heterogeneous symptoms and functional consequences, and the current firstline disease-modifying therapies often become ineffective later in the disease. There is increasing evidence for the benefits of physical activity (PA) in people with MS, but this population is generally physically inactive and sedentary. We proposed 10 research questions to guide future research on PA and MS: (1) Is PA an MS disease-modifying behavior? (2) What are the benefits of PA among people with MS? (3) What is the optimal PA prescription for people with MS? (4) What are the safety issues with PA in people with MS? (5) What characteristics of people with MS modify the benefits of PA? (6) What variables explain participation in PA among people with MS? (7) What are effective behavioral interventions for PA change in people with MS? (8) How do we translate PA research into clinical MS practice? (9) What is the role of sedentary behavior in people with MS? And (10) what is the optimal measurement of PA in people with MS? These questions are critical for informing our understanding of the short- and long-term consequences of PA in MS as well as for identifying approaches for promoting and sustaining PA in MS. Addressing these questions may greatly improve the lives of people with this chronic disease. Keywords: exercise, neurology, rehabilitation, sedentary behavior

Multiple sclerosis (MS) is a nontraumatic, chronic, disabling disease of the brain, brain stem, spinal cord, and optic nerves. An estimated 2.5 million people worldwide are living with MS, and there are nearly 400,000 cases of MS in the United States (National Multiple Sclerosis Society [NMSS], 2005). Some recent epidemiological studies have suggested a possible trend of increasing prevalence and Correspondence should be addressed to Robert W. Motl, Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 233 Freer Hall, Urbana, IL 61801. E-mail: [email protected]

incidence of MS worldwide (Benito-Leon, 2011). This disease most frequently occurs among young and middleaged adult women of European descent (NMSS, 2005; Page, Kurtzke, Murphy, & Norman, 1993), and is seemingly caused by an environmental trigger in genetically susceptible people. MS often begins with intermittent but recurring periods of multifocal inflammation in the central nervous system (CNS; Bjartmar & Trapp, 2001; Hemmer, Nessler, Zhou, Kieseier, & Hartung, 2006; Trapp & Nave, 2008), and this description is characteristic of relapsing-remitting MS (RRMS; Lublin & Reingold, 1996). The inflammatory

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processes result in demyelination and transection of axons (i.e., lesions) that manifest as conduction delay and conduction block of action potentials in the CNS (Bjartmar & Trapp, 2001; Hemmer et al., 2006; Trapp & Nave, 2008). Further neurodegenerative processes are associated with a lack of neurotrophic support that result in axo-neuronal loss during the latter stages of MS (Bjartmar & Trapp, 2001; Hemmer et al., 2006; Trapp & Nave, 2008), and this pathology is characteristic of primary and secondary progressive MS (Lublin & Reingold, 1996). The axoneuronal damage within the CNS accumulates over time and results in neurological disability, walking and cognitive dysfunction, and a multitude of symptoms (Bjartmar & Trapp, 2001; Samkoff & Goodman, 2011). Symptoms of MS include fatigue, numbness or tingling, weakness, dizziness and vertigo, pain, bowel and bladder problems, sexual problems, vision problems, spasticity, depression and other emotional problems, and other secondary and tertiary manifestations based on a trickle-down effect (NMSS, 2005). MS and its consequences further result in compromised quality of life (QOL) and reduced community participation (Benito-Leon, Morales, Rivera-Navarro, & Mitchell, 2003). Disease-modifying drugs represent the first line of treatment by targeting the immuno-pathophysiological processes of MS (Katrych, Simone, Azad, & Mousa, 2009). These drugs typically target subsets of immune cells presumably involved in the pathophysiology of MS. The early use of disease-modifying drugs (e.g., interferons) has decreased the number of lesions seen through magnetic resonance imaging (MRI), as well as the rates of relapses (i.e., periods of disease activity) and disease progression (Filippini et al., 2003). There is increasing recognition that disease-modifying drugs are only modestly effective in slowing the eventual progression of neurological disability in MS (Confavreux & Vukusic, 2006; Confavreux, Vukusic, & Adeline, 2003). Accordingly, the long-term course of MS is still characterized by the progression of neurological disability, despite ongoing treatment with disease-modifying drugs (Confavreux & Vukusic, 2006; Confavreux et al., 2003). This might be explained by disease-modifying drugs having minimal effects on nonimmunological pathophysiological causes and consequences of MS (Motl, 2010). This further highlights the importance of identifying other approaches for managing the long-term consequences of MS. There has been a long history of interest in physical activity (PA) as a behavioral approach for managing the consequences of MS (Murray, 2005). This interest is based on the recognition that rehabilitation (e.g., exercise training) is the only effective approach for restoring function in MS (Kraft, 1999). Other researchers have speculated that PA is the single most effective nonpharmacological approach for managing symptoms of MS (Dalgas & Stenager, 2014), although some researchers disagree with

such a statement based on an insufficient quantity of research and poor quality of research (Coote, 2014). Such interest, nevertheless, reflects the importance of identifying approaches that can assist in managing the lifelong symptomatic and functional consequences of MS (Motl & Pilutti, 2012). There is even some speculation that PA might exert a disease-modifying effect in MS (Dalgas & Stenager, 2012). More than 50 clinical trials have examined the benefits of PA in people with MS (Motl, 2014a); these studies have typically focused on exercise training, although there is emerging evidence for the benefits of lifestyle PA in MS (Motl, 2014b). There have been many prominent literature reviews (Andreasen, Stenager, & Dalgas, 2011; LatimerCheung, Pilutti, et al., 2013; Motl & Pilutti, 2012) and metaanalytic reviews (Asano & Finlayson, 2014; Ensari, Motl, & Pilutti, 2014; Motl & Gosney, 2008; Paltamaa, Sjogren, Peurela, & Heinonen, 2012; Pilutti, Greenlee, Motl, Nickrent, & Petruzzello, 2013; Snook & Motl, 2009) of those clinical trials that allow for a focal summary of the benefits of PA in people with MS who are largely ambulatory (i.e., mild or moderate MS severity), but there is insufficient evidence regarding the benefits in nonambulatory people with MS (Toomey & Coote, 2012). The reviews indicate that PA is associated with improvements in health-related fitness (Latimer-Cheung, Pilutti, et al., 2013), balance (Paltamaa et al., 2012), symptoms of fatigue (Pilutti et al., 2013) and depression (Ensari et al., 2014), walking function (Snook & Motl, 2009), and QOL (Motl & Gosney, 2008). Researchers have examined the effects of PA on other outcomes such as peripheral immune cells, peripheral neurotrophic factors, cognition, and participation, but the evidence in those areas is minimal and inconclusive (Motl, 2014a; Motl & Pilutti, 2012). Researchers have generated a large body of evidence regarding PA and MS, but there is still considerable work that should be done. The current article provides our top 10 research questions regarding PA and MS. We derived the top 10 questions by first having all five authors create a list of the top 12 questions individually. All five authors have extensive experience and publication history in the areas of PA, exercise, and rehabilitation of people with MS. The five lists were then distilled based on commonality into 15 questions by the first author (RWM). The resulting list of questions was then reviewed by coauthors (YCL and LAP) and discussion ensued until consensus was reached on the top 10 questions. Admittedly, there are questions in the top 10 list that some researchers will not view as critical, and there are questions that were not included in the top 10 that other researchers will see as important oversights. We believe that our small group has considerable breadth and longevity of experience in the area of PA and MS and that we generated questions that will be viewed as critical by most researchers, clinicians, and people living with MS; interestingly, many of our top 10 questions run parallel with

PA AND MS RESEARCH TABLE 1 Top 10 Research Questions Regarding Physical Activity and Multiple Sclerosis 1. 2. 3. 4. 5. 6. 7.

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8. 9. 10.

Is physical activity an MS disease-modifying behavior? What are the benefits of physical activity among people with MS? What is the optimal physical activity prescription for people with MS? What are the safety issues with physical activity in people with MS? What characteristics of people with MS modify the benefits of physical activity? What variables explain participation in physical activity among people with MS? What are effective behavioral interventions for physical activity change in people with MS? How do we translate physical activity research into clinical MS practice? What is the role of sedentary behavior in people with MS? What is the optimal measurement of physical activity in people with MS? Note. MS ¼ multiple sclerosis.

those developed for PA and cancer survivorship (Courneya, Rogers, Campbell, Vallance, & Friedenreich, this issue). Our top 10 questions are listed in Table 1, and the ranking does not reflect the relative importance of the questions. We have organized the questions by topics such that the first 5 reflect consequences of PA, the next 3 reflect processes for promoting PA, and the last 2 reflect other issues of sedentary behavior and measurement of PA. The remainder of the article provides a brief background and rationale for the top 10 questions but does not provide a systematic literature review per question.

TOP 10 RESEARCH QUESTIONS 1. Is Physical Activity an MS Disease-Modifying Behavior? There is both excitement and skepticism regarding PA as a disease-modifying behavior in MS (Dalgas & Stenager, 2012; L. J. White & Castellano, 2008a, 2008b). Such a proposition would indicate that PA could mediate the basic pathophysiological processes of MS. On the one hand, evidence for disease-modifying effects of PA opens the door for selection of a behavior rather than a pharmacological agent for managing MS pathophysiology and disease progression; this might further allow for consideration of PA as an adjuvant for pharmacological approaches for disease modification. Such a possibility could represent a pivotal change in the way clinicians and patients manage MS. On the other hand, the lack of evidence for a diseasemodifying effect of PA does not undermine the importance of this behavior for managing the consequences of MS. There further is an important mechanistic inquiry embedded

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in the study of PA as a disease-modifying behavior (i.e., does PA have effects on consequences of MS through pathophysiology or through other pathways?). The skepticism, in part, is based on the equivocal effects of PA on immune cells collected from peripheral samples of blood in humans with MS (Motl & Pilutti, 2012). The immune cells collected from peripheral samples may have questionable validity for inferring on the milieu of the CNS. If correct, the study of PA as a disease-modifying behavior should seemingly focus on MS pathophysiological outcomes from tissues in the CNS. This is necessary as MS pathophysiology involves immune-mediated processes that originate in the periphery lymph nodes but occur in the CNS itself. There further is skepticism because of the longstanding belief that PA can exacerbate the disease processes and result in relapses (i.e., acute periods of MS disease activity). Accordingly, research examining the diseasemodifying effects of PA should focus on animal models of MS or relapse rates in human clinical trials. There are multiple animal models of MS that could be included in studies of PA and MS pathophysiology (Klaren, Motl, Woods, & Miller, 2014), including experimental autoimmune encephalomyelitis (EAE), virally induced models such as Theiler’s murine encephalomyelitis infection, and toxin-induced models of demyelination (Denic et al., 2011). The different animal models allow for understanding mechanisms and targets of therapeutic interventions in MS (Denic et al., 2011). To date, EAE is the most extensively studied murine model of MS because many of the pathologies observed in the CNS of mice resemble those observed in the CNS of people with MS (McCarthy, Richards, & Miller, 2012). The EAE model further has been extremely useful for studying disease pathogenesis and potential therapeutic interventions (Robinson, Harp, Noronha, & Miller, 2014). Indeed, variations of the EAE model that produce different patterns of clinical MS presentation are often used in preclinical research for identifying the benefits and dissecting the mechanisms of new therapeutic interventions for subsequent translation into human clinical trials of MS (McCarthy et al., 2012). This model would seemingly be beneficial for dissecting the possible disease-modifying benefits of PA in MS. The application of the EAE model in the context of PA has recently been summarized (Klaren, Motl, et al., 2014). That review included five published studies of PA and EAE. The studies were quite varied. Some studies focused on exercise as a physiological stressor that might worsen disease development, whereas others focused on PA as a therapeutic intervention for reducing disease activity and its expression. The studies further included different models of EAE induction and types of exercise training (i.e., design heterogeneity). There was no research that examined the effect of PA initiated after disease induction and the occurrence of a first relapse. Such an approach is critical for

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studying the effect of PA on pathophysiology once the disease is established and expressed, thereby maximizing translation for PA in humans. We recommend that researchers carefully design experiments involving PA and animal models to maximize translation for understanding disease-modifying effects in humans with MS. Another approach for supporting PA as a diseasemodifying behavior would involve focusing on relapse occurrence and rates in human clinical trials. To that end, one article recently provided a systematic review of relapses in randomized controlled trials (RCTs) of exercise training in MS (Pilutti, Platta, Motl, & Latimer-Cheung, 2014). The researchers searched electronic databases for RCTs of exercise training in MS, calculated the rates of relapse in exercise and control conditions, and estimated the relative risk for relapse for exercise versus control conditions expressed as the ratio of the two rates between conditions. Twenty-six studies were reviewed for reporting of relapses, and those studies included 1,295 participants with MS. The rates of relapse averaged across the studies were 6.3% and 4.6% for control and exercise, respectively. The ratio of rates yielded a relative risk for relapse for exercise training compared with controls of 0.73. Such evidence is promising as it suggests a possible disease-modifying effect of PA in MS, but it is highly speculative regarding a definitive conclusion given that many studies did not report relapses and the period of monitoring (3–6 months) was brief and might not reflect the annualized rate of relapses. The studies further included relatively small samples and were not designed or powered for detecting an effect of PA on relapses. 2. What Are the Benefits of Physical Activity Among People With MS? We noted in the introduction section of this article that there are many benefits of PA in MS. Such benefits include improvements in cardiorespiratory fitness, muscle strength, walking, postural control, fatigue, depression, and QOL (Motl, 2014a; Motl & Pilutti, 2012). The research supporting those benefits in MS is promising but suffers from a number of limitations. Some limitations are poor description of samples and inclusion of samples without evidence of elevated symptomatology (e.g., severe fatigue or major depressive disorder) or dysfunction (e.g., walking impairment); consideration of a limited range of MS symptoms and other outcomes; not focusing on comparative effectiveness trials; not including adequate follow-up; and not examining PA effects on brain health (i.e., neuroprotection and neurorepair). To date, studies of PA and fatigue, depression, walking mobility, and QOL have not focused on recruiting samples with elevated symptoms, walking dysfunction, or compromised QOL; the studies have enrolled participants regardless of the presence of a condition or symptom. This creates two, if not more, problems. We first do not know the true magnitude of the effect of PA on outcomes in

people with MS, as the existing research likely suffers from floor and ceiling effects. This is important as there might be larger effects of PA on depressive symptoms in samples with major depressive disorder compared with samples that have no depressive symptomatology (Ensari et al., 2014). We secondly do not know if PA can actually combat clinically relevant problems in MS. For example, people with MS who have severe fatigue might not benefit from PA participation, and some researchers have suggested that PA could worsen fatigue in such people (Krupp, 2004). Another point of importance is that the existing research has typically focused on a relatively narrow set of MS consequences, yet MS is associated with a heterogeneous array of symptoms and outcomes that are poorly managed. Researchers might consider the effects of PA on cognition, sleep, pain, visual dysfunction, bladder and bowel dysfunction, and sexual problems; these are common, lifealtering, and poorly managed consequences in MS (cf. cognitive dysfunction per Benedict & Zivadinov, 2011). We further note that there have been few examinations of PA and its effects on comorbid disease conditions in MS, and this is important as comorbidity might worsen the disease and its consequences. Comparative effectiveness research is designed to inform clinical care and practice by providing evidence on the effectiveness, benefits, and harms of different treatment options. For example, one recent systematic review and meta-analysis quantified the effects of self-management, exercise training, and pharmacological approaches for managing fatigue in people with MS (Asano & Finlayson, 2014). The researchers reported that self-management programs and exercise training, but not pharmacological agents, were similarly effective for reducing fatigue in MS. This suggests that two of the treatments are comparable, but we require direct head-to-head comparison of independent and possibly additive effects of these approaches in the same clinical trial. Such an approach would be comparable with research comparing exercise training and antidepressant medications alone and combined for managing major depressive disorder in older adults (Blumenthal et al., 1999). We believe that such research will be critical for identifying the optimal approaches for managing consequences of MS that can be selected by patients and providers. Another outcome of interest is the effect of PA on brain health (i.e., neuroprotection and neural repair). Indeed, MS is a disease that influences both white- and gray-matter structures in the CNS, and research with older adults consistently has indicated that PA can reverse age-related atrophy of CNS tissues (Erickson, Leckie, & Weinstein, 2014). Recent research has supported similar effects in schizophrenia and other conditions such as Parkinson and Alzheimer disease (cf. Pajonk et al., 2010). This would support the natural extension of examining PA effects on brain health using MRI and other imaging modalities in clinical trials of MS, as the existing research in MS is cross-

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PA AND MS RESEARCH

sectional and only supports associations between cardiorespiratory fitness as a proxy of PA and structural MRI outcomes (Prakash, Snook, Motl, & Kramer, 2010). Such research will be important for identifying PA as a behavioral approach for preventing or reversing the atrophy of CNS tissue in MS. We lastly need research that establishes if the improvements associated with PA in MS are clinically meaningful. For example, one meta-analysis reported an overall effect size for PA and QOL of , 0.25 standard deviation (SD) in MS (Motl & Gosney, 2008). This magnitude of change does not meet the established criterion of 0.5 SD that researchers have established as a clinically meaningful change in QOL (Norman, Sloan, & Wyrwich, 2003). This might suggest that the effect of PA on QOL is statistically significant, but not clinically meaningful, in MS. Researchers have not applied other relevant thresholds for judging the clinical relevance of PA benefits in MS (e.g., Learmonth, Dlugonski, Pilutti, Sandroff, & Motl, 2013). If PA effects are not surpassing a threshold of clinical relevance, this has direct implications for designing more impactful PA interventions in MS. 3. What Is the Optimal Physical Activity Prescription for People With MS? The issue of a PA prescription for people with MS has received recent attention based on a systematic literature review (Latimer-Cheung, Pilutti, et al., 2013) that guided the generation of MS-specific PA guidelines (LatimerCheung, Martin Ginis, et al., 2013). The researchers applied international standards for guideline development (i.e., Appraisal of Guideline Research and Evaluation II instrument) and created evidence-based PA guidelines for people with MS (Latimer-Cheung, Martin Ginis, et al., 2013). The evidence for the guidelines was based on a systematic review of PA and its effects on health-related fitness, fatigue, mobility, and health-related QOL among those with MS (Latimer-Cheung, Pilutti, et al., 2013). The researchers consisted of a multidisciplinary consensus panel, and the members deliberated about the scientific evidence and subsequently generated the PA guidelines. The guidelines and materials were then refined after a review by stakeholders and experts. The resulting guidelines indicated that adults with MS who have mild or moderate disability should undertake 30 or more minutes of moderateintensity aerobic activity two times per week and strengthtraining exercises for major muscle groups two times per week (Latimer-Cheung, Martin Ginis, et al., 2013). This is an excellent first step, but there are numerous next steps and research questions regarding PA prescription. For example, researchers should confirm that the PA guidelines are actually appropriate for improving outcomes in MS. There further is a need for research that directly compares PA prescriptions in MS. The main components of

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PA prescription include frequency, intensity, time, and type. Researchers could manipulate these characteristics and examine the resulting effects on consequences of MS. For example, is there an optimal duration or type of PA that maximizes reductions in fatigue? Should participants engage in several shorter bouts of PA compared with one longer bout for maximizing symptomatic outcomes? Are the American College of Sports Medicine (ACSM, 2014) recommendations for the general population of adults applicable for those with MS, or should people with MS be following different guidelines such as those developed for older adults? Of note, researchers might compare the benefits of lifestyle PA with exercise training for managing consequences of MS (Motl, 2014b). There is a need for systematically examining the mode of PA in people with MS. We are aware of some researchers who have compared the effects of arm and leg ergometry and seated rowing as types of aerobic exercise on fitness and cognition in people with progressive MS (Briken et al., 2014), and other researchers have compared aerobic exercise and yoga for managing cognitive dysfunction and other outcomes in people with MS (Oken et al., 2004). Some researchers have examined the outcomes associated with modes of PA such as aquatic exercise (Kooshiar et al., 2014), Tai Chi (Azimzadeh, Hosseini, Nourozi, & Davidson, 2014), and sport climbing (Velikonja, Curic, Ozura, & Jazbec, 2010) in MS. There is little known about aerobic and resistance exercise training alone or in combination for promoting benefits in people with MS. The intensity of PA, particularly aerobic exercise, is an important element of PA programming in MS. This is based on the linear association between aerobic exercise intensity and core body temperature changes and the observation of thermal intolerance in MS. For example, one study examined core body temperature changes associated with moderate-intensity aerobic exercise in six patients with MS and reported that an increase of , 18 C in core temperature coincided with reduced walking performance (A. T. White, Wilson, Davis, & Petajan, 2000). Researchers should directly examine if different intensities of light, moderate, and vigorous aerobic exercise yield comparable outcomes for symptoms but with different degrees of thermal load. Researchers might further consider high-intensity interval training and its benefits compared to standard continuous aerobic exercise. There are data to support the benefits of high-intensity interval training for improving fitness and other health outcomes in older adults and patients with other chronic health conditions such as obesity, diabetes, and coronary artery disease (Gillen & Gibala, 2014). Importantly, there is much to be learned from examining different intensities and modalities of resistance exercise training in MS. For example, is there a threshold or optimal intensity of resistance exercise for promoting strength adaptations in MS, and does this depend on the integrity of the neuromuscular system? There is a need for examining different modalities of resistance exercise that involve

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concentric versus eccentric contractions (Hayes, Gappmaier, & LaStayo, 2011) or even functional electric stimulation (i.e., electrically assisted resistance training). For example, one group of researchers examined the effect of progressive resistance training augmented with neuromuscular electrical stimulation on strength, balance, health-related QOL, and fatigue impact in those with advanced MS (Coote, Hughes, Rainsford, Minogue, & Donnelly, 2015).

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4. What Are the Safety Issues With Physical Activity in People With MS? There has been a long-standing concern regarding the safety of PA in people with MS. Indeed, people with MS were often advised against exercise based on the notion of potential disease exacerbation and symptom worsening (Pilutti, Platta, et al., 2014; Tallner et al., 2012). This notion is surprising considering the long history of recommendations for PA participation in MS (Murray, 2005), but some degree of uncertainty regarding safety still persists. One article recently provided a systematic review of adverse events (AEs) reported in RCTs of exercise training in MS (Pilutti, Platta, et al., 2014). The rates of other AEs across 26 studies with 1,295 participants with MS were 1.2% and 2.0% for control and exercise, respectively. There were only 13 AEs reported among all of the exercise training conditions. The most common AEs associated with exercise training were back and joint pain (i.e., musculoskeletal injuries) followed by acute illnesses, and the musculoskeletal injuries typically occurred with resistance training. The ratio of rates yielded a relative risk for AEs for exercise training versus control of 1.67. Overall, the risk for AEs with exercise was comparable with that reported in healthy populations (ACSM, 2014). This evidence should reduce concerns regarding the safety of PA in MS, and it further supports recent statements that exercise is a safe intervention without reported side effects and serious AEs (Dalgas & Stenager, 2014). Nevertheless, the study and reporting of AEs associated with PA can be improved and extended. The improvement requires that researchers systematically track and report side effects and AEs in PA intervention and control conditions of RCTs; there is no uniform reporting in the existing research (Pilutti, Platta, et al., 2014). This will be important for understanding the true extent of side effects and AEs and for informing participants and clinicians of risks associated with PA in MS. There further is a need for research on the risks of PA during a relapse itself. Does PA worsen the relapse or perhaps improve the relapse and its symptomatic manifestations? Another area of research includes examinations of PA in conjunction with medications and the effect on AEs. For example, does PA worsen side effects of medications, thereby increasing the likelihood of AEs? Or does PA lessen the side effects of medications in MS?

5. What Characteristics of People With MS Modify the Benefits of Physical Activity? To date, the majority of research on the outcomes of PA has included samples with either a relapsing-remitting clinical course of MS or mild-to-moderate disability status (i.e., minimal walking dysfunction; Motl, 2014a). This reflects the largest percentage of people living with MS. Accordingly, the current evidence is applicable for the majority of people currently living with MS. Nevertheless, there is very little knowledge about the benefits of PA among those with progressive clinical courses of MS and severe disability, and subsequently, there have been recent calls for such inquiry (Toomey & Coote, 2012). There is a need for focal research on people with progressive courses of MS and severe disability. These two clinical characteristics of MS seemingly are unresponsive to current disease-modifying therapies that work among those with RRMS and less severe disability (Confavreux & Vukusic, 2006; Confavreux et al., 2003), and this presumably reflects differences in pathophysiological processes of the disease. Those patients with progressive clinical courses and severe disability have entered into a second stage of MS. The rate of progression in this “second stage of MS” is usually considered irreversible as it is invariant with respect to baseline characteristics, course, signs, and symptoms assessed at the onset of disease (Confavreux & Vukusic, 2006; Confavreux et al., 2003). Therefore, there are two reasons for examining PA in people with progressive courses of MS and severe disability. The first reason is that people with these clinical characteristics are unresponsive to current disease-modifying therapies and require alternative types of approaches (i.e., rehabilitation) for delaying and possibly reversing the effects of MS. The second reason is that the study of PA across different clinical characteristics might shed light on the possible pathophysiological mechanisms of PA benefits in MS. Other patient characteristics that might moderate PA benefits in MS are disease-modifying and symptomatic pharmacotherapies. Indeed, one of the most obvious future directions involves examining the independent, interactive, and additive effects of PA and pharmaceutical approaches for managing consequences of MS (Motl, 2013). We envision that these approaches might work through different mechanisms of action, thereby resulting in possible additive effects on outcomes. For example, PA could result in a positive adaptation of brain structure and function (Prakash et al., 2010; L. J. White & Castellano, 2008a, 2008b) or physiological conditioning (Motl, 2010, 2014a), whereas pharmaceuticals such as 4-Aminopyridine (i.e., dalfampridine) seemingly work through an increase in action potential duration and amplitude, an improvement of conduction in demyelinated nerves, and neurotransmitter release at synaptic endings (Motl, 2013). We further suspect that pharmaceutical approaches might allow for people with

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PA AND MS RESEARCH

MS to engage in significantly greater amounts of PA that would yield even larger adaptations and benefits. The study of older adults with MS represents an opportunity for examining PA benefits in people undergoing the intersection between aging and a chronic disease. Of note, the older-adult population is expected to double by 2050 (Administration for Community Living, 2014), and advancing age is accompanied by poor health, declines in functional performance (Centers for Disease Control and Prevention, 2014), and increased disability (Freedman, Martin, & Schoeni, 2002). This can be accelerated by the onset and/or progression of chronic disabling diseases such as MS (Wo´jcicki et al., 2014). Importantly, 45% of people living with MS are 55 years of age and older (Minden, Frankel, Hadden, Srinath, & Perloff, 2004) and exhibit MSrelated impairments that are reflective of the aging process (e.g., compromised strength, balance, mobility, coordination, and QOL; Stern, Sorkin, Milton, & Sperber, 2010). Those impairments are hastened by physical inactivity in MS (Motl, 2010) but can be managed through participation in PA. To date, research examining PA as an intervention for these outcomes in older adults with MS is minimal (Stern et al., 2010) but should be a focus of future endeavors (Wo´jcicki et al., 2014), particularly considering the combined health burden of aging and MS. 6. What Variables Explain Participation in Physical Actvity Among People With MS? To date, there is established evidence for the benefits of PA participation among those with MS, yet only a small percentage of people with MS are meeting public healthrecommended levels of PA necessary for accruing health benefits (Klaren, Motl, Dlugonski, Sandroff, & Pilutti, 2013; Motl, McAuley, Sandroff, & Hubbard, 2015). We further note that PA levels are approximately 1 SD lower in patients with MS than in controls without MS or any other chronic disease (Motl, McAuley, & Snook, 2005), and there is a linear decline in PA levels over time in people with RRMS (Motl, McAuley, & Sandroff, 2013). This underscores the importance of identifying variables that might explain variation in PA levels among those with MS. Such inquiry might focus on examining general categories of PA determinants in MS or the veracity of theoretical models for explaining variation in PA. Such research is necessary for informing the development of PA behavioral interventions in MS. There are established categories of PA determinants (Trost, Owen, Bauman, Sallis, & Brown, 2002) that could be examined in people with MS. These categories include demographic (e.g., sex), clinical (e.g., MS type or disability status), behavioral (e.g., diet or self-monitoring), psychological (e.g., self-efficacy or enjoyment), social (e.g., family or friend support), environmental (e.g., environmental access or safety), and PA (e.g., mode or intensity) characteristics. Researchers might examine variables from these categories

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for explaining variance in PA in MS. For example, demographic and clinical variables such as biological sex or disease status would inform decisions on those who should be the target of PA interventions. Behavioral, psychological, and social variables are often malleable and might inform decisions on variables that can be targeted by interventions for changing PA. Environmental variables might inform public policy decisions regarding the built environment for promoting PA in MS. To date, there have been limited efforts in this area, but this can be ameliorated with targeted qualitative and quantitative inquiry. Researchers further should adopt and test theoretical models for explaining PA patterns in MS. This is important as a well-defined, elaborated theoretical model identifies (a) the important variables that predict behavior and (b) mechanisms or targets for changing those variables. We further note that the generality of theory in MS and other populations allows for bringing existing behavioral interventions to those with MS, whereas specificity of theory in MS indicates the need for disease-targeted behavioral interventions. To date, the majority of research has focused on social-cognitive theory (SCT; Bandura, 1997, 2004), although a few studies have considered the health action process approach (Schwarzer, 1992), theory of unpleasant symptoms (Lenz, Pugh, Milligan, Audrey, & Suppe, 1997), and transtheoretical model (TTM; Prochaska & DiClemente, 1983). Researchers might consider other theories such as theory of planned behavior or even adopt the recent proposed integrated behavior-change model for PA (Hagger & Chatzisarantis, 2014). This recent model integrates variables and causal pathways from socialcognitive, motivational, dual-phase, and dual-systems theories as well as other theories that have been effective for predicting PA in populations with disabling conditions (e.g., International Classification of Functioning framework in spinal cord injury; Ginis et al., 2012). The focal study of theory is essential for designing and informing the most effective behavioral interventions for increasing PA in MS. 7. What Are Effective Behavioral Interventions for Physical Activity Change in People With MS? The promotion and maintenance of PA can be facilitated through behavioral interventions that prompt sedentary and physically inactive people to both reduce sedentary pursuits and engage in physical activities that achieve or surpass public health guidelines (Motl, 2014b). Such PA interventions should be based on established theoretical models and teach people the skills, techniques, resources, and strategies for modifying and self-regulating sedentary and PA behaviors. The interventions can be implemented on a large scale, through cost-effective modes of delivery, and in diverse sets of people, including those with neurological diseases. Such behavioral interventions likely increase the end result of beneficial consequences.

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To date, one group of researchers has conducted a series of Phase I and II clinical trials with relatively small samples for examining the efficacy of an Internet-delivered behavioral intervention based on SCT for increasing PA among ambulatory people with MS (Motl, Dlugonski, Wo´jcicki, McAuley, & Mohr, 2011; Pilutti, Dlugonski, Sandroff, Klaren, & Motl, 2014). The advantages of behavioral interventions delivered via the Internet are the provision of advice, information, and treatment at any time and location with minimal barriers of traditional face-to-face treatment. This has the potential for extending the reach of an intervention as well as maximizing time efficiency and ease/ convenience of accessibility. People with MS further appear to be an ideal target of a behavioral intervention delivered through the Internet. One survey indicated that 93% of people with MS used the Internet compared with 75% of the general population (NMSS, 2007), and another survey indicated that nearly 90% of people with MS were interested in online information about maintaining a healthy lifestyle (Wardell, Hum, Laizner, & Lapierre, 2009). Collectively, such data support the efficacy of behavioral interventions delivered through the Internet for increasing and sustaining PA in people with MS and possibly improving meaningful outcomes. There are undoubtedly other approaches for designing and delivering behavioral interventions in MS. For example, some researchers have delivered PA interventions based on TTM (Plow, Bethoux, McDaniel, McGlynn, & Marcus, 2014) and SCT (Suh, Motl, Olsen, & Joshi, in press) using newsletters for people with MS, and both approaches have yielded increases in PA. Other researchers are delivering PA interventions based on SCT using DVD technology for people with MS (Wo´jcicki et al., 2014), and this application is based on the success of the same intervention delivered to older adults (McAuley et al., 2013). There are a multitude of approaches and theories for designing PA behavioral interventions in MS, and this will be an important avenue for future research that moves PA from supervised settings into the real world. The focus on behavior interventions is particularly important as such approaches could promote long-term maintenance of PA and beneficial outcomes. That is, there is little known about the long-term promotion and benefits of PA in MS, but this is critical considering that MS is so far an incurable, ultimately progressive disease that has many longterm consequences (Samkoff & Goodman, 2011). To date, we are aware of very few studies that have considered the longterm, lasting effects of behavioral interventions on PA itself, and this is the necessary focus for ensuring the long-term maintenance of symptomatic and functional benefits in MS. 8. How Do We Translate Physical Activity Research Into Clinical MS Practice? There is consistent evidence for the efficacy of PA interventions in people with MS when examined in the context of supervised laboratory settings with trained

research staff (i.e., center-based interventions with supervision). This evidence has yielded PA guidelines that are applicable for the majority of people with MS. There have been, to date, few effectiveness trials for people with MS. The existing effectiveness trials have demonstrated positive benefits (Garrett et al., 2013) but have encountered significant attrition. This highlights the challenges of implementing PA programs in community and clinical settings. There is some agreement that dissemination could be accomplished through the education of health care providers about (a) the benefits of PA, (b) behavioral approaches for maximizing compliance, and (c) guidelines for PA and its benefits in MS (Vollmer et al., 2012). To that end, one approach for maximizing translation likely resides within the interaction between patients with MS and health care providers. Indeed, patients want to know more about exercise and PA, and they consider the health care provider within coordinated MS care as a critical source for such information. This was evident in a survey-based study of 930 Americans with MS indicating that 30% to 50% of patients wanted more information about PA in the context of health care services (Vickrey et al., 2000). Qualitative research has highlighted that people with MS report wanting PA to be facilitated through ongoing health care support (Hale, Smith, Mulligan, & Treharne, 2012). Another qualitative study indicated that although health professionals were viewed as the most important and credible messengers of PA information by patients with MS, most physicians provided inadequate information (Sweet, Perrier, Podzyhun, & Latimer-Cheung, 2013). Additional qualitative research has indicated that many people with advanced MS had received no or insufficient advice on PA and exercise as a therapeutic strategy from any health professional (Learmonth, Rice, Rice, Ostler, & Motl, in press). Researchers should explore two overarching yet interrelated questions using a basic qualitative research approach in MS. The first overarching question is, “What do patients want and need from providers regarding advice, support, and resources for participating in exercise and PA?” The second overarching question is, “What resources do providers require for meeting the patient’s wants and needs for advice, support, and resources regarding exercise and PA participation?” These overarching questions would provide rich data that could inform a conceptual model and consequent tool kit for guiding the promotion of PA through patient – provider interactions during coordinated care of MS. This approach represents an avenue for moving PA promotion into clinical practices of MS care and for bridging the transition between rehabilitation and PA in the community. 9. What Is the Role of Sedentary Behavior in People With MS? There has been an ever-increasing interest in sedentary behavior (i.e., behavior involving sitting or lying that does

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not increase energy expenditure during the waking hours) as it is pervasive among adults (Bauman et al., 2011). For example, adults in countries around the world accumulate 3 hr to 8 hr of sitting per day (Healy, Matthews, Dunstan, Winkler, & Owen, 2011), and sitting time has been detrimentally associated with disease risk factors such as insulin resistance, dyslipidemia, and obesity (Healy et al., 2011), as well as increased risks for morbidity and mortality (Patel et al., 2010), independent of PA. Accordingly, researchers have begun focusing on sedentary behavior, particularly breaking up daily sitting, as an important target of behavioral interventions for reducing health risks (Peddie et al., 2013). To date, the majority of research on sedentary behavior has focused on the general population without a chronic disease condition, and there is minimal research on sedentary behavior in adults with progressive diseases that result in mobility disability (Manns, Dunstan, Owen, & Healy, 2012) such as MS. The clinical expression of MS and associated mobility disability might increase the rate of sedentary behavior in people with MS and further exacerbate the disease and its progression, based on increased rates of comorbid health conditions. We located a few studies that have examined sedentary behavior in MS. One study quantified sedentary time as the percentage of the day spent inactive using a step activity monitor worn during the waking hours of the day in 21 people with MS (Cavanaugh, Gappmaier, Dibble, & Gappmaier, 2011). The data indicated that, on average, 80% of the waking hours of the day were spent inactive, and if we adopt a minimal wear time of 10 hr per day, this translates into an estimated 8 hr of sedentary time per day in people with MS. Another study examined the association between sitting time and disability status, walking performance, and cognitive function in 82 people with MS (Hubbard & Motl, 2015). The researchers reported that those with higher levels of sitting time had worse disability and walking performance but not worse cognitive function. We are aware of one study that has reported on the initial efficacy of a behavioral intervention for reducing sitting time in people with MS (Klaren, Hubbard, & Motl, 2014). Collectively, there is much that can be accomplished through research on sedentary behavior in MS. This includes measurement, descriptive epidemiology, predictors, consequences, and behavioral interventions. For example, there is virtually nothing known about the measurement of sedentary behavior—either volume or structure—in MS. Another questions is, can we apply cut points for quantifying time spent in sedentary behavior from the adult population in people with MS? Regarding the descriptive epidemiology, we know very little about the types, structure, and volume of sedentary behavior in MS and how this compares to the general population or varies as a function of demographic and clinical characteristics of those with MS. We further need research that examines

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predictors of sedentary behavior that can inform the design of behavioral interventions targeting a reduction in sedentary behavior (i.e., sitting less and moving more). We lastly need research establishing the consequences of sedentary behavior in MS and research comparing the consequences associated with sedentary, light, and moderate PA behaviors in MS. 10. What Is the Optimal Measurement of Physical Activity in People With MS? There has been major advancement in the measurement of PA among those with MS during the past decade (Motl & Sandroff, 2010), yet many questions remain to be answered. This advancement was based on concerns that symptoms and manifestations of MS might influence the psychometric properties of common PA measures and thereby undermine the validity of score interpretation. For example, cognitive impairment in memory is common in MS and might influence recall with self-report questionnaires and compliance with wearing accelerometers. Another common manifestation of MS is walking dysfunction, and this can influence the accuracy of common motion sensors as well as the calibration of output from motion sensors based on energy expenditure as walking dysfunction impacts the energetic cost of movement in MS. One last concern is that we are unaware of the application of PA measures in people with MS who rely upon wheeled mobility devices (e.g., scooters or wheelchairs). Those concerns have been partially addressed during the past decade. Researchers have validated the scores from self-report measures (e.g., Godin Leisure-Time Exercise Questionnaire [GLTEQ]) using a multimethod, multiindicator approach for construct validity (Gosney, Scott, Snook, & Motl, 2007). Researchers have further calibrated the output from waist-worn accelerometers (i.e., counts/ min) for measuring time spent in moderate-to-vigorous physical activity (MVPA) during ambulatory PA based on cut points in people with MS (Sandroff, Motl, & Suh, 2012) and across the MS disability spectrum (Sandroff, Riskin, Agiovlasitis, & Motl, 2014). This research has been carried over to those who rely upon wheelchairs for daily mobility whereby we generated cut points from wrist-worn accelerometers for quantifying time spent in MVPA during wheelchair use (Learmonth, Kinnett-Hopkins, Rice, Dysterheft, & Motl, in press). We still do not have an ideal or optimal measurement system in place that is universally accepted and invariant/ equivalent in measurement across patients with MS. Such a system is necessary for standardization across studies and clinical practices that occur worldwide and would permit meaningful comparisons of values—for example, across the disability spectrum. There further is limited understanding of the “right” motion sensor for measuring PA in MS. Researchers have compared the accuracy of the ActiGraph

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and StepWatch devices for measuring steps during slow, moderate, and fast walking across the disability spectrum in MS (Sandroff, Motl, et al., 2014), but there are many other devices that might provide comparable accuracy (e.g., ActiBelt; Motl et al., 2012). We further do not know if there is a preferable device placement on the body for maximizing compliance with wear instructions by participants and yielding accurate data. There is a need for additional research on self-report measures in MS. To date, researchers have primarily focused on the GLTEQ and abbreviated International PA Questionnaire in MS, but there are other innumerable selfreport measures that might serve as better assessments of PA in MS. On a related note, we need data on the measurement equivalence of self-report PA measures across clinical characteristics of MS (e.g., levels of disability or degrees of symptoms such as fatigue). This would permit meaningful comparisons of scores regarding PA levels. We further need research on the ideal metric for quantifying PA in MS. For example, is there clinical and public health relevance for the recommendation of 10,000 steps/day in MS? Should we focus on volume (i.e., total minutes) or the structure (i.e., number of 10-min bouts) of MVPA accumulated during the course of the day? Is the metric of metabolic equivalents (METs) a meaningful metric for outcomes in MS, and does it vary across disability levels considering differences in energetic costs of movement? Do we need to assign different MET values for physical activities based on disability status? The measurement of PA has advanced considerably during the past decade, but there is considerable room for improvement and this will be essential for addressing all of the other top 10 questions regarding PA in MS.

CONCLUSION There are a large number of people living with MS in the United States and worldwide, and this number is seemingly increasing in prevalence. This disease is associated with a variety of symptoms and functional consequences, and the current first-line disease-modifying therapies have limited efficacy, particularly later in the disease course. There is increasing evidence for the benefits of PA in MS, but this population is largely physically inactive and sedentary. We proposed 10 research questions regarding PA and MS that should guide future inquiry. These questions are critical for informing our understanding of the short-term and longterm consequences of PA in MS and for developing approaches for promoting and sustaining PA in MS. The research that addresses these questions may greatly improve the lives of people living with this chronic, unpredictable, and incurable disease.

ORCID Lara A. Pilutti

http://orcid.org/0000-0002-3074-4903 REFERENCES

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