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Exercise as a Countermeasure to Declining Central Nervous System Function in Multiple Sclerosis

  • Robert W. Motl
    Correspondence
    Address correspondence to: Robert W. Motl, University of Alabama at Birmingham, Department of Physical Therapy, SHP 336, 1720 2nd Ave S, Birmingham, AL 35294.
    Affiliations
    Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, Alabama
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  • Brian M. Sandroff
    Correspondence
    Address correspondence to: Brian M. Sandroff, University of Alabama at Birmingham, Department of Physical Therapy, SHP 336 (RWM); SHP 389 (BMS), 1720 2nd Ave S, Birmingham, AL 35294.
    Affiliations
    Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, Alabama
    Search for articles by this author

      Abstract

      Purpose

      The decline of central nervous system (CNS) function is a hallmark characteristic of multiple sclerosis (MS) that can manifest as cognitive impairment. We believe that exercise represents a potential behavioral approach for counteracting the declines in CNS structure and associated function among persons with MS (ie, exercise as a countermeasure of CNS decline). This theory is important because disease-modifying drugs represent a first-line approach for modifying the immune system and its effects on the CNS, but these drugs do not generally demonstrate robust improvements in cognitive performance.

      Methods

      To the best of our knowledge, this article presents the first argument positioning exercise as a countermeasure for CNS decline in MS.

      Finding

      The reviewed research indicates a proliferating body of evidence describing physical fitness, physical activity, and exercise effects on cognitive performance and neuroimaging outcomes (ie, CNS functioning) in MS, with the consistent and strong association between cognitive performance and neuroimaging outcomes in this population as a backdrop.

      Implications

      We further present a framework and future research directions for better positioning exercise as a possible neuroprotective behavior against declining CNS function in MS.

      Key words

      Introduction

      Multiple sclerosis (MS) is a common neurologic disease that is initially characterized by acute, inflammatory processes and focal demyelination and transection of axons in the central nervous system (CNS), particularly in the cerebral white matter.
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      The disease eventually becomes neurodegenerative and results in irreversible damage of white matter and gray matter in the CNS.
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      This CNS damage presents as brain atrophy on magnetic resonance imaging (MRI) and typically manifests as declines in physical and cognitive performance. Cognitive performance has been identified as a particularly relevant and obvious neuro-performance marker of CNS functioning in persons with MS.
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      The consideration of cognitive performance as a marker of CNS functioning is, in part, based on its consistent and strong association with brain neuroimaging outcomes,
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      as well as its origins in the CNS and minimal non-CNS (ie, peripheral body system) influences on measurement compared with physical performance outcomes. Cognitive performance can be readily measured by using neuropsychological and computerized testing wherein the outcome reflects performance primarily based on CNS function. Collectively, this makes the combination of cognitive performance and MRI a pair of complementary outcomes for understanding influences on CNS decline in MS.
      We believe that exercise represents a potential behavioral approach for counteracting the declines in CNS structure and function among persons with MS (ie, exercise as a countermeasure of CNS decline). This theory is important because disease-modifying drugs represent a first-line approach for modifying the immune system and its effects on the CNS, but these drugs do not generally result in robust improvements in cognitive performance.
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      Cognitive rehabilitation has been inconsistently associated with improvements in cognitive performance (ie, some studies report clinically meaningful results, whereas others report null results),
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      and there are few investigations of co-occurring effects on the CNS structure using MRI in MS.
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      Cognitive rehabilitation in multiple sclerosis: the role of plasticity.
      The proposal that exercise represents a promising approach for influencing both brain structure and cognitive function in MS is based largely on the wealth of evidence in gerontology
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      A review of the effects of physical activity and exercise on cognitive and brain functions in older adults.
      and emerging evidence in neurologic disease and conditions,
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      as proposed in a Topical Review.
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      • Benedict R.H.B.
      Cognitive dysfunction and multiple sclerosis: developing a rationale for considering the efficacy of exercise training.
      The argument for exercise as a countermeasure for CNS decline in MS complements previous reviews on exercise as a disease-modifying therapy
      • Motl R.W.
      • Pilutti L.A.
      Is physical exercise a multiple sclerosis disease modifying treatment?.
      and an approach for symptomatic/function rehabilitation
      • Motl R.W.
      • Sandroff B.M.
      Benefits of exercise training in multiple sclerosis.
      in this population.
      To our knowledge, the present article offers the first argument for exercise as a countermeasure for CNS decline in MS. To do so, the initial focus is on evidence describing dysfunction of cognitive performance and its neural correlates based on neuropsychological and neuroimaging outcomes as markers of declining CNS function in MS. We then review research on physical fitness, physical activity, and exercise effects on cognitive performance and neuroimaging outcomes (ie, CNS functioning) in MS; this represents the collective body of evidence supporting exercise as a possible countermeasure for CNS decline in MS. The last section of this article provides future research directions for better positioning exercise as a possibly neuroprotective behavior against declining CNS function in MS.

      Markers of Declining CNS Function in MS

      Between 45% and 70% of persons with MS experience some degree of impairment in cognitive performance based on results of objective neuropsychological testing.
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      The prevalence of impairment in cognitive performance varies based on the clinical course of MS,
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      whereby those with progressive presentations of MS exhibit more widespread and severe cognitive impairment than those with relapsing-remitting MS (RRMS).
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      Cognitive impairment in multiple sclerosis.
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      Cognitive impairment in different MS subtypes and clinically isolated syndromes.
      Studies have reported cognitive impairment in ~35% of patients with RRMS based on scores at least 1 SD below the normative value on 2 separate neuropsychological tests and ~60% when considering both relapsing and progressive presentations of MS.
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      Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS).
      Cognitive impairment is observed at the earliest stages of the disease, even before a definite MS diagnosis, and often occurs independently of physical disability.
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      Multiple sclerosis-related cognitive changes: a review of cross-sectional and longitudinal studies.
      Of note, although such cognitive impairments do occur early in the disease process, performance on neuropsychological tests worsens as the disease progresses.
      • Chiaravalloti N.D.
      • DeLuca J.
      Cognitive impairment in multiple sclerosis.
      Regardless of clinical disease course, MS-related cognitive dysfunction (ie, poor neuropsychological test performance), typically presents as slowed cognitive processing speed and impairments in learning and memory, as well as executive dysfunction.
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      Neuropsychological aspects of multiple sclerosis: a quantitative review.
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      Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis.
      This pattern of MS-related cognitive dysfunction has been consistently and strongly linked with structural and functional neuroimaging outcomes.
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      • et al.
      Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis.
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      • et al.
      The contribution of MRI in assessing cognitive impairment in multiple sclerosis.
      Regarding structural imaging, persons with MS who are cognitively impaired generally have greater numbers of lesions and overall lesion volume than cognitively preserved persons with MS.
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      Executive function in multiple sclerosis: the role of frontal lobe pathology.
      Several studies have reported that whole-brain white matter atrophy is associated with worse cognitive processing speed and working memory, whereas whole-brain gray matter atrophy seemingly reflects worse verbal memory, euphoria, and disinhibition.
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      Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis.
      Others have examined atrophy of specific brain regions and relationships with specific cognitive functions. The 2 most prominent regions of interest are the thalamus and hippocampus. For example, thalamic atrophy has been associated with cognitive impairment (particularly slowed cognitive processing speed, as well as learning and memory, verbal fluency, and spatial perception) and decline in both cross-sectional and longitudinal research in MS samples.
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      Thalamic atrophy and cognition in multiple sclerosis.
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      Neocortical atrophy, third ventricular width, and cognitive dysfunction in multiple sclerosis.
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      Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis.
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      Localized atrophy of the thalamus and slowed cognitive processing speed in MS patients.
      Hippocampal lesions and atrophy have been associated with MS-related memory impairment.
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      Extensive hippocampal demyelination in multiple sclerosis.
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      Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy.
      Other data indicate that persons with MS have worse white matter integrity (ie, fractional anisotropy) and greater diffusivity (ie, mean diffusivity, radial diffusivity) compared with healthy control subjects.
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      Cognitive dysfunction in patients with mildly disabling relapsing-remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging.
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      • Uitdehaag B.M.J.
      • et al.
      Cognitive impairment in MS: impact of white matter integrity, gray matter volume, and lesions.
      By comparison, cognitively impaired persons with MS have worse white matter integrity and less diffusivity compared with cognitively preserved persons with MS. Focal white matter damage is considered a stronger predictor of cognitive impairment in patients with MS than global lesion burden and white matter integrity.
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      Diffusion tensor MRI tractography and cognitive impairment in multiple sclerosis.
      Collectively, this information suggests that CNS decline in MS can be characterized by cognitive performance and neuroimaging outcomes.

      Exercise and the CNS in MS

      Exercise training and participation in physical activity are generally accepted as favorable approaches for managing declines in CNS structure and function in older adults from the general population. Such a statement reflects nearly 40 years of research examining physical fitness, physical activity, and exercise training effects on cognition and brain structure and function in older adults from the general population.
      • Voss M.W.
      • Nagamatsu L.S.
      • Liu-Ambrose T.
      • Kramer A.F.
      Exercise, brain, and cognition across the life span.
      To date, several meta-analyses have supported that exercise training is associated with improvements in cognitive performance in healthy
      • Colcombe S.
      • Kramer A.F.
      Fitness effects on the cognitive function of older adults: a meta-analytic study.
      and cognitively impaired
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      • Ottenbacher K.J.
      The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis.
      older adults. Exercise-related cognitive improvements further have coincided with improved brain structure and function in older adults.
      • Bherer L.
      • Erickson K.I.
      • Liu-Ambrose T.
      A review of the effects of physical activity and exercise on cognitive and brain functions in older adults.
      For example, 1 seminal randomized controlled trial (RCT) reported that 12 months of aerobic exercise training resulted in significantly improved spatial memory performance and hippocampal volume compared with a stretching control group in 120 older adults.
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      • Voss M.W.
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      • Basak C.
      • Szabo A.
      • Chaddock L.
      • et al.
      Exercise training increases size of hippocampus and improves memory.
      That study provided critical data on aerobic exercise as a countermeasure to CNS decline in older adults, considering that the aerobic exercise intervention group demonstrated increases in hippocampal volume that corresponded with a reversal of 1 to 2 years of age-related hippocampal atrophy. Additional data are emerging on exercise-related improvements in cognitive performance and associated neuroimaging markers in persons with neurologic disorders (eg, schizophrenia, dementia, Alzheimer’s disease, chronic fatigue syndrome).
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      • et al.
      Hippocampal plasticity in response to exercise in schizophrenia.
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      • et al.
      Does physical activity influence semantic memory activation in amnestic mild cognitive impairment?.
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      • et al.
      Interactive effects of physical activity and APOE-ε4 on white matter tract diffusivity in healthy elders.
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      Randomised controlled trial of graded exercise in chronic fatigue syndrome.
      Collectively, those data set the stage for considering exercise as a countermeasure of CNS decline (ie, based on cognitive performance outcomes and brain MRI) in MS.
      By comparison, the examination of physical fitness, physical activity, and exercise training as countermeasures to declining CNS function in MS is in its infancy but has grown considerably over the past decade. This growth is interesting as there is a wealth of evidence supporting the general benefits of exercise training in persons with MS, as the majority of exercise research in this population has reported small-to-moderate improvements in physical fitness, walking mobility, balance, fatigue, depressive symptoms, and quality of life.
      • Motl R.W.
      • Sandroff B.M.
      Benefits of exercise training in multiple sclerosis.
      • Motl R.W.
      • Sandroff B.M.
      • Kwakkel G.
      • Dalgas U.
      • Feinstein A.
      • Heesen C.
      • et al.
      Exercise in patients with multiple sclerosis.
      One recent review highlighted the importance of examining physical activity as a possible disease-modifying and neuroprotective behavior in future MS research.
      • Motl R.W.
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      • Coote S.
      • et al.
      Top 10 research questions related to physical activity and multiple sclerosis.
      To that end, the provision of data regarding the effects of exercise on neuropsychological and brain neuroimaging outcomes would strengthen the position of exercise as a potentially neuroprotective/disease-modifying behavior in MS. Such a selective focus on cognitive performance and neuroimaging outcomes would provide a much more proximal index of CNS functioning than other general MS-related end points (ie, mobility, fatigue).
      There has been 1 comprehensive systematic review examining the effects of exercise, physical activity, and physical fitness on cognitive performance (ie, neuropsychological testing) outcomes in persons with MS.
      • Sandroff B.M.
      • Motl R.W.
      • Scudder M.R.
      • DeLuca J.
      Systematic, evidence-based review of exercise, physical activity, and physical fitness effects on cognition in persons with multiple sclerosis.
      Overall, this systematic review noted that despite a paucity of highly developed RCTs, recent preliminary evidence reports beneficial effects of physical fitness, physical activity, and exercise training on cognitive performance in this population. This burgeoning body of early-phase, developmental research might provide foundational support for physical fitness, physical activity, and exercise training as putative countermeasures for declines in CNS function in MS based on performance on neuropsychological tests and neuroimaging outcomes.

      Physical Fitness

      One starting point for examining the effects of exercise as a countermeasure for declines in CNS function in persons with MS involves the evaluation of cross-sectional associations between measures of physical fitness (ie, characteristics reflecting the capacity to perform physical work) and cognitive performance. This approach is in parallel with that from the gerontology literature whereby cross-sectional examinations of physical fitness informed the development of longitudinal, exercise training studies on cognitive and neuroimaging outcomes,
      • Colcombe S.J.
      • Kramer A.F.
      • Erickson K.I.
      • Scalf P.
      • McAuley E.
      • Cohen N.J.
      • et al.
      Cardiovascular fitness, cortical plasticity, and aging.
      as physical fitness is often considered a cross-sectional surrogate for exercise training.
      One early study examined the relationships among multiple domains of physical fitness (eg, cardiorespiratory fitness, lower extremity muscular strength, balance) and cognitive processing speed in 31 persons with MS and 31 age and sex matched control subjects.
      • Sandroff B.M.
      • Motl R.W.
      Fitness and cognitive processing speed in persons with multiple sclerosis: a cross-sectional investigation.
      Participants underwent maximal exercise tests of cardiorespiratory fitness for measurement of peak oxygen consumption (VO2peak), muscular strength for measurement of lower limb muscular strength asymmetry (ie, relative difference in strength of a particular muscle group between strong and weak limbs), and static posturography for measurement of balance. Participants further underwent neuropsychological tests of cognitive processing speed (ie, Paced Auditory Serial Addition Test [PASAT], Symbol Digit Modalities Test [SDMT]). There were significant differences in measures of fitness and cognitive processing speed between persons with MS and matched control subjects (ie, d > 0.46; P < 0.04). Among those with MS, cardiorespiratory fitness (ie, higher VO2peak; better cardiorespiratory fitness; r = 0.44; P < 0.01), lower limb muscular strength (ie, lower knee extensor peak torque asymmetry; more efficient lower-limb muscular fitness; r = −0.39; P < 0.01), and balance (ie, less postural sway; better balance; r = −0.52; P < 0.01) were significantly associated with cognitive processing speed. Those 3 domains of fitness accounted for group differences (between persons with MS and control subjects) in cognitive processing speed and explained a statistically significant amount of variance in cognitive processing speed (R2 = 0.39) in the MS subsample. This pattern of results parallels other research
      • Sandroff B.M.
      • Pilutti L.A.
      • Benedict R.H.B.
      • Motl R.W.
      Association between physical fitness and cognitive function in multiple sclerosis: does disability status matter?.
      • Sandroff B.M.
      • Hillman C.H.
      • Motl R.W.
      Aerobic fitness is associated with inhibitory control in persons with multiple sclerosis.
      • Sandroff B.M.
      • Motl R.W.
      • DeLuca J.
      The influence of cognitive impairment on the fitness-cognition relationship in multiple sclerosis.
      and generally supports that physical fitness, as a cross-sectional surrogate of exercise training, is associated with cognitive performance based on neuropsychological and computerized testing in MS.
      The focus on physical fitness and cognitive performance has been complemented by recent research on neuroimaging outcomes as a biological substrate for the effects of exercise on CNS functioning in MS. One recent study examined the association between objectively measured cardiorespiratory fitness (ie, VO2peak as a presumed surrogate for aerobic exercise training) and volumes of the thalamus, hippocampus, and basal ganglia in 35 persons with MS.
      • Motl R.W.
      • Pilutti L.A.
      • Hubbard E.A.
      • Wtter N.C.
      • Sosnoff J.J.
      • Sutton B.P.
      • et al.
      Cardiorespiratory fitness and its association with thalamic, hippocampal, and basal ganglia volumes in multiple sclerosis.
      After controlling for age, sex, disability, and disease duration, VO2peak was moderately and significantly associated with caudate (pr = 0.47; P < 0.01), putamen (pr = 0.44; P < 0.05), pallidum (pr = 0.40; P < 0.05), and hippocampal (pr = 0.42; P < 0.01) volume, whereby better cardiorespiratory fitness was associated with larger volumes of subcortical deep gray matter structures. Interestingly, after controlling for covariates, VO2peak was not significantly associated with thalamic volume (pr = 0.31; P = 0.09). The nonsignificant association between cardiorespiratory fitness and thalamic volume is not consistent with previous cross-sectional data on the significant association between VO2peak and cognitive processing speed in MS.
      • Sandroff B.M.
      • Motl R.W.
      Fitness and cognitive processing speed in persons with multiple sclerosis: a cross-sectional investigation.
      • Sandroff B.M.
      • Pilutti L.A.
      • Benedict R.H.B.
      • Motl R.W.
      Association between physical fitness and cognitive function in multiple sclerosis: does disability status matter?.
      • Sandroff B.M.
      • Hillman C.H.
      • Motl R.W.
      Aerobic fitness is associated with inhibitory control in persons with multiple sclerosis.
      • Sandroff B.M.
      • Motl R.W.
      • DeLuca J.
      The influence of cognitive impairment on the fitness-cognition relationship in multiple sclerosis.
      However, the association between VO2peak and cognitive processing speed is seemingly selective for persons with MS with mild ambulatory disability.
      • Sandroff B.M.
      • Pilutti L.A.
      • Benedict R.H.B.
      • Motl R.W.
      Association between physical fitness and cognitive function in multiple sclerosis: does disability status matter?.
      It is possible that increased cardiorespiratory fitness via aerobic exercise training might result in improved cognitive processing speed and increased thalamic volume in only these persons. Nevertheless, the significant associations between cardiorespiratory fitness and volumes of other subcortical deep gray matter structures
      • Motl R.W.
      • Pilutti L.A.
      • Hubbard E.A.
      • Wtter N.C.
      • Sosnoff J.J.
      • Sutton B.P.
      • et al.
      Cardiorespiratory fitness and its association with thalamic, hippocampal, and basal ganglia volumes in multiple sclerosis.
      parallel another study that reported statistically significant associations among higher cardiorespiratory fitness, greater gray matter volume, and white matter fractional anisotropy in regions that are important for cognitive processing speed in persons with RRMS.
      • Prakash R.S.
      • Snook E.M.
      • Motl R.W.
      • Kramer A.F.
      Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis.
      Such data provide further support for exercise as a possible countermeasure for decline in CNS functioning, given the significant associations between measures of physical fitness and cognitive performance
      • Sandroff B.M.
      • Motl R.W.
      Fitness and cognitive processing speed in persons with multiple sclerosis: a cross-sectional investigation.
      and brain structure.
      • Motl R.W.
      • Pilutti L.A.
      • Hubbard E.A.
      • Wtter N.C.
      • Sosnoff J.J.
      • Sutton B.P.
      • et al.
      Cardiorespiratory fitness and its association with thalamic, hippocampal, and basal ganglia volumes in multiple sclerosis.

      Physical Activity

      Other research has examined the associations between free-living physical activity behavior and cognitive processing speed in persons with MS. The cross-sectional focus on physical activity behavior is advantageous because this construct reflects actual behavior, as opposed to a characteristic (ie, cardiorespiratory fitness) when advancing the research toward causation (ie, subsequent evaluations of actual physical activity/exercise behavioral interventions). The examination of free-living physical activity is further advantageous considering that physical fitness reflects other factors beyond exercise behavior (eg, genetics), and this approach may provide an overestimate of the effects of exercise on CNS functioning.
      • Bouchard C.
      • Shephard R.J.
      Physical activity, fitness, and health: international proceedings and consensus statement.
      Consequently, 1 study involved a cross-sectional examination of the association between objectively measured, free-living physical activity and cognitive processing speed in a large sample of 212 persons with MS.
      • Sandroff B.M.
      • Dlugonski D.
      • Pilutti L.A.
      • Pula J.H.
      • Benedict R.H.B.
      • Motl R.W.
      Physical activity is associated with cognitive processing speed in persons with multiple sclerosis.
      Participants wore an ActiGraph accelerometer (ActiGraph, LLC, Pensacola, Florida) for 7 days for measurement of average steps per day. After controlling for age, sex, and education, free-living physical activity was significantly associated with a composite measure of cognitive processing speed (ie, mean z scores for PASAT and SDMT performance) (pr = 0.26; P < 0.01). This association was attenuated but remained statistically significant after further controlling for ambulatory status (pr = 0.13; P = 0.03). Importantly, similar associations between physical activity and cognitive performance have been observed in other samples of persons with MS.
      • Motl R.W.
      • Gappmaier E.
      • Nelson K.
      • Benedict R.H.B.
      Physical activity and cognitive function in multiple sclerosis.
      • Sandroff B.M.
      • Pilutti L.A.
      • Dlugonski D.
      • Motl R.W.
      Physical activity and information processing speed in persons with multiple sclerosis: a prospective study.
      Other recent research has examined the association between physical activity behavior and CNS structures with the use of neuroimaging. The inclusion of neuroimaging outcomes provides more direct evidence of exercise as a possible countermeasure regarding the deleterious effects of MS on the CNS. One recent study examined the associations between free-living, moderate-to-vigorous physical activity (MVPA) behavior (measured objectively with ActiGraph accelerometers) and volume of subcortical deep gray matter brain structures (ie, hippocampus, thalamus, basal ganglia) in 39 persons with MS.
      • Klaren R.E.
      • Hubbard E.A.
      • Motl R.W.
      • Pilutti L.A.
      • Wetter N.C.
      • Sutton B.P.
      Objectively measured physical activity is associated with brain volumetric measurements in multiple sclerosis.
      That cross-sectional study indicated that after controlling for covariates, MVPA was significantly associated with normalized whole-brain gray matter (pr = 0.37; P < 0.05), normalized whole-brain white matter (pr = 0.43; P < 0.01), and hippocampal (pr = 0.50; P < 0.01), thalamic (pr = 0.38; P < 0.05), caudate (pr = 0.54; P < 0.01), putamen (pr = 0.37; P < 0.05), and pallidum (pr = 0.50; P < 0.01) volumes, whereby engaging in more MVPA was associated with greater volumes. Interestingly, there were no significant associations between measures of light physical activity or sedentary behavior and any brain volumetric measure.

      Exercise Training

      The cross-sectional research on physical fitness and physical activity as correlates of behavioral and neuroimaging outcomes of CNS functioning provides an initial foundation for exercise training as a possible countermeasure to CNS decline in persons with MS. Indeed, there have been several longitudinal studies of the effects of physical activity and exercise training on cognitive performance
      • Sandroff B.M.
      • Klaren R.E.
      • Pilutti L.A.
      • Dlugonski D.
      • Benedict R.H.B.
      • Motl R.W.
      Randomized controlled trial of physical activity, cognition, and walking in multiple sclerosis.
      • Briken S.
      • Gold S.M.
      • Patra S.
      • Vettorazzi E.
      • Harbs D.
      • Tallner A.
      • et al.
      Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.
      and exercise training on cognitive performance and brain structure and function
      • Leavitt V.M.
      • Cirnigliaro C.
      • Cohen A.
      • Farag A.
      • Brooks M.
      • Wecht J.M.
      • et al.
      Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings.
      • Sandroff B.M.
      • Johnson C.L.
      • Motl R.W.
      Exercise training effects on memory and hippocampal viscoelasticity in multiple sclerosis: a novel application of magnetic resonance elastography.
      in this population. One published RCT examined the effects of a 6-month Internet-delivered physical activity intervention compared with a waitlist control condition on cognitive performance in persons with MS.
      • Sandroff B.M.
      • Klaren R.E.
      • Pilutti L.A.
      • Dlugonski D.
      • Benedict R.H.B.
      • Motl R.W.
      Randomized controlled trial of physical activity, cognition, and walking in multiple sclerosis.
      The intervention condition involved visiting a study Website that was based on social cognitive theory; wearing a pedometer, completing a logbook, and using computerized software for guiding goal setting and attainment; and participating in one-on-one video chat sessions with a behavior-change coach. There were statistically significant improvements in cognitive processing speed (ie, SDMT performance) for persons with mild, but not moderate, MS ambulatory disability who underwent the intervention compared with persons who were randomized to the waitlist control condition (ηp2 = 0.08; P = 0.02). Among persons in the intervention condition, changes in objectively measured physical activity were associated with changes in SDMT scores in persons with mild, but not moderate, MS ambulatory disability. Of note, this study did not include neuroimaging outcomes that would reflect the effects of increased physical activity behavior on brain structure or function. However, it does provide evidence in support of subsequent, rigorous examinations of exercise training effects on the CNS (including both behavioral and neuroimaging approaches) in MS, given that exercise is a focused subset of physical activity.
      The strongest evidence supporting exercise as a possible countermeasure for declines in CNS functioning in MS derives from exercise training interventions that include both neuropsychological and neuroimaging outcomes and that evaluate exercise-related changes in behavior and possible neural mechanisms of such changes. There have been 2 published preliminary studies that describe changes in both cognitive performance and brain structure and function with supervised exercise training in persons with MS. The first study on exercise training
      • Leavitt V.M.
      • Cirnigliaro C.
      • Cohen A.
      • Farag A.
      • Brooks M.
      • Wecht J.M.
      • et al.
      Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings.
      involved a case study design that collected data on hippocampal volume and resting-state functional connectivity and cognitive functioning from 2 ambulatory, memory-impaired persons with MS who were randomly assigned to 12 weeks of aerobic exercise training (stationary cycling) or stretching and toning. Both conditions took place 3 times per week for 30 minutes per session. The intensity of stationary cycling gradually progressed over the 12-week intervention. Aerobic exercise training resulted in a 16.5% increase in hippocampal volume, a 55.9% increase in verbal memory (ie, California Verbal Learning Test–II [CVLT-II] performance), and a 53.7% increase in nonverbal memory (ie, Brief Visuospatial Memory Test–Revised) performance, as well as increased hippocampal resting-state functional connectivity. There were no changes in processing speed (ie, PASAT, SDMT), executive function (ie, Stroop Test), or working memory (ie, Digit Span), overall cerebral gray matter, or non-hippocampal deep gray matter structures. There were no changes in neuropsychological or neuroimaging outcomes for the participant who underwent stretching and toning.
      The second study adopted a single-blind RCT design and examined the effect of an aerobic exercise training intervention on learning and memory and hippocampal viscoelasticity using magnetic resonance elastography in persons with MS.
      • Sandroff B.M.
      • Johnson C.L.
      • Motl R.W.
      Exercise training effects on memory and hippocampal viscoelasticity in multiple sclerosis: a novel application of magnetic resonance elastography.
      There are no data on changes in hippocampal viscoelasticity and disease progression in MS; however, reduced hippocampal viscoelasticity is associated with worse memory performance and lower aerobic fitness in the general population.
      • Schwarb H.
      • Johnson C.L.
      • Daugherty A.M.
      • Himman C.H.
      • Kramer A.F.
      • Cohen N.J.
      • et al.
      Aerobic fitness, hippocampal viscoelasticity, and relational memory performance.
      Eight fully ambulatory female subjects with MS were randomly assigned into exercise training intervention or waitlist control conditions. The intervention condition involved 12 weeks of supervised, progressive treadmill walking exercise training and was developed from a systematic line of research on acute bouts of exercise and cognitive functioning in MS.
      • Sandroff B.M.
      Exercise and cognition in multiple sclerosis: the importance of acute exercise for developing better interventions.
      All participants underwent a neuropsychological measure of learning and memory (ie, CVLT-II) and further underwent magnetic resonance elastography scans for measurement of shear stiffness (μ) and damping ratio (ξ) of the hippocampus before and after the 12-week period. Overall, there were small-to-moderate intervention effects on CVLT-II performance (d = 0.34) and large, beneficial intervention effects on hippocampal μ (ie, increased shear stiffness; d = 0.94) and hippocampal ξ (ie, reduced damping ratio; d = −1.20) as metrics of viscoelasticity. The change in CVLT-II scores was strongly associated with changes in μ (r = 0.93; P < 0.01) and ξ (r = −0.96; P < 0.01) of the hippocampus.
      Further preliminary data from our research group describe exercise-related increases in resting state functional connectivity (ie, strengthened correlations in spontaneous brain activation between remote brain regions during rest) between the thalamus and prefrontal cortex in persons with MS. The thalamocortical resting state functional connectivity was associated with improvements in both cardiorespiratory fitness and cognitive processing speed. This research is ongoing, and we have reported on the fitness and cognitive processing speed data elsewhere.
      • Sandroff B.M.
      • Balto J.M.
      • Klaren R.E.
      • Sommer S.K.
      • DeLuca J.
      • Motl R.W.
      Systematically-developed pilot randomized controlled trial of exercise and cognition in persons with multiple sclerosis.
      The positive associations among changes in thalamocortical resting-state functional connectivity, cardiorespiratory fitness, and cognitive processing speed support the possibility of exercise-related adaptive neuroplastic changes in persons with MS.

      Summary and Future Directions

      There is an emerging body of evidence that exercise training represents an exciting approach for slowing, preventing, or even reversing the decline in CNS structure and function that occurs with MS. This is based on cross-sectional evidence of associations between physical fitness and physical activity with cognitive performance and brain structure, and recent evidence of exercise training effects on cognitive performance, including small trials of exercise, cognition, and brain structure.
      Although this is an exciting time, and the evidence is paralleling that of the extensive body of research in gerontology, there are many avenues for future research that would consolidate the idea of exercise as a countermeasure of CNS decline in MS. To that end, we have developed a framework for the systematic examination of exercise effects on CNS functioning and decline in persons with MS; this framework is depicted in the Figure and described in the Table. We envision the starting point for future research involving larger scale, appropriately powered RCTs that examine the effect of exercise training on cognitive performance and brain volumetrics and connectivity using MRI in MS, and further adopting mediator analyses for examining the proposition that changes in brain volumetrics and connectivity, or perhaps cerebral blood flow perfusion, account for exercise training effects on cognitive performance. This is particularly relevant for cognitively impaired persons with MS.
      • Sandroff B.M.
      • Motl R.W.
      • DeLuca J.
      The influence of cognitive impairment on the fitness-cognition relationship in multiple sclerosis.
      FigureAU: (1) Please review the figure graphic carefully to make sure it is clear and in focus. Revise text labels and legend as needed. (2) Add a comment to the legend explaining the use of the numbers?
      FigureFramework for examining exercise as a countermeasure for declines in central nervous system (CNS) functioning in persons with multiple sclerosis. fMRI = functional magnetic resonance imaging; fNIRS = functional near-infrared spectroscopy; MRI = magnetic resonance imaging; OCT = optical coherence tomography. Note. The numbers correspond with the research categories presented in the .
      TableDescription of a possible framework for examining exercise as a countermeasure for declines in central nervous system (CNS) functioning in persons with multiple sclerosis (MS).
      Number
      Numbers correspond with those presented in the Figure.
      Research CategoryDescriptionExample of Future Research Directions
      1Efficacy/effectiveness researchEffects of exercise training on CNS functioningFurther development of systematic, adequately powered RCTs examining the effects of exercise on cognitive performance in cognitively impaired persons with MS
      2Mechanistic researchNeuroimaging outcomes as mediators of exercise effects on CNS functioningInclusion of MRI/fMRI measures of brain structure and function in RCTs of exercise on cognition in MS as possible mediators of the effects of exercise on cognitive performance
      3Mechanistic researchEffects of exercise training on other markers of CNS structure/functionExamination of exercise effects on integrity of the anterior visual pathway using OCT and/or examination of CNS function (ie, cortical activation) during exercise using fNIRS in persons with MS
      4Mechanistic researchConsideration of possible intermediaries explaining effects of exercise on brain structure and functionInclusion of blood measures for examining the role of neurotrophic factors and immune markers on the effects of exercise on CNS structure and function, and/or adoption of a task-dependent neuroplasticity model for explaining exercise-related changes in CNS structure/function in MS
      5Prospective, longitudinal researchExercise training as a neuroprotective behaviorExamination of the durability/long-term effects of exercise on CNS functioning over time, and/or examination of exercise training/physical activity as a possible source of cognitive or physiological reserve for reducing the impact of cognitive decline in MS
      6Comparative effectiveness researchEffects of exercise plus other therapies on CNS functioningExamination of the comparative and combined effects of exercise training, cognitive rehabilitation, and/or pharmacotherapy on CNS functioning in persons with MS
      fMRI = functional magnetic resonance imaging; fNIRS = functional near-infrared spectroscopy; MRI = magnetic resonance imaging; OCT = optical coherence tomography; RCT = randomized controlled trial.
      low asterisk Numbers correspond with those presented in the Figure.
      We further believe that future exercise training trials might include other markers of CNS decline such as visual functioning and visual pathways. This belief is based, in part, on data indicating that physical activity levels are associated with integrity of the anterior visual pathways assayed by using optical coherence tomography.
      • Sandroff B.M.
      • Motl R.W.
      • Kam J.P.
      • Pula J.H.
      Accelerometer measured physical activity and the integrity of the anterior visual pathway in multiple sclerosis.
      Another avenue for future research involves focusing on the possible intermediaries such as neural metabolites (eg, N-acetyl aspartate, glutamine, gamma-aminobutyric acid) using nonconventional MRI techniques (ie, magnetic resonance spectroscopy)
      • Llufriu S.
      • Kornak J.
      • Ratiney H.
      • Oh J.
      • Brenneman D.
      • Cree B.
      • et al.
      Magnetic resonance spectroscopy markers of disease progression in multiple sclerosis.
      • Cawley N.
      • Solanky B.S.
      • Muhlert N.
      • Tur C.
      • Edden R.A.
      • Wheeler-Kingshott C.A.
      • et al.
      Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis.
      or circulating neurotrophic factors (eg, brain-derived neurotrophic factor, insulin-like growth factor-1) for explaining the effects of exercise on brain structure and function, cognitive performance, and other mental processes in MS.
      • Klaren R.E.
      • Motl R.W.
      • Woods J.A.
      • Miller S.D.
      Effects of exercise in experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis).
      We lastly see the importance of research on exercise training early in the disease for boosting physiological and cognitive reserve and examining such effects on the long-term degradation of CNS functioning over time in MS.
      • Sandroff B.M.
      • Schwartz C.E.
      • DeLuca J.
      Measurement and maintenance of reserve in multiple sclerosis.
      Collectively, there are many opportunities for examining exercise training as a countermeasure for CNS decline in MS based on the current state of knowledge in this disease. We suspect that exercise might become a partner with other approaches in the first-line therapy of managing the declines in CNS function that occur with MS.

      Conflicts Of Interest

      The authors have indicated that they have no conflicts of interest regarding the content of this article.

      Acknowledgments

      This article was not funded by an external grant, and neither author has financial support for the drafting of this paper. Both authors contributed equally to the manuscript.

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