Randomized controlled trial of physical activity, cognition, and walking in multiple sclerosis

ORIGINAL COMMUNICATION

Randomized controlled trial of physical activity, cognition,and walking in multiple sclerosis

Brian M. Sandroff • Rachel E. Klaren •

Lara A. Pilutti • Deirdre Dlugonski •

Ralph H. B. Benedict • Robert W. Motl

Received: 23 October 2013 / Revised: 22 November 2013 / Accepted: 24 November 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract The present study adopted a randomized con-

trolled trial design and examined the effect of a physical

activity behavioral intervention on cognitive and walking

performance among persons with MS who have mild or

moderate disability status. A total of 82 MS patients were

randomly allocated into intervention or wait-list control

conditions. The intervention condition received a theory-

based program for increasing physical activity behavior

that was delivered via the Internet, and one-on-one video

chat sessions with a behavior-change coach. Participants

completed self-report measures of physical activity and

disability status, and underwent the oral Symbol Digit

Modalities Test (SDMT) and 6-minute walk (6MW) test

before and after the 6-month period. Analysis using mixed-

model ANOVA indicated a significant time 9 condi-

tion 9 disability group interaction on SDMT scores

(p = 0.02, partial-g2 = 0.08), such that persons with mild

disability in the intervention condition demonstrated a

clinically meaningful improvement in SDMT scores (*6

point change). There was a further significant

time 9 condition interaction on 6MW distance (p = 0.02,

partial-g2 = 0.07), such that those in the intervention

condition demonstrated an increase in 6MW distance rel-

ative to those in the control group. The current study

supports physical activity as a promising tool for managing

cognitive impairment and impaired walking performance

in persons with MS, and suggests that physical activity

might have specific effects on cognition and non-specific

effects on walking performance in this population.

Keywords Multiple sclerosis � Cognition � Physical

activity � Walking

Introduction

Slowed cognitive processing speed (CPS) is common,

debilitating, and difficult to manage in persons with mul-

tiple sclerosis (MS) [1]. Researchers have recently advo-

cated for physical activity as a behavioral approach for

managing slowed CPS in MS [2]. This is based, in part, on

cross-sectional evidence of an association between ambu-

latory-based physical activity and measures of CPS in MS

[3, 4], and evidence of physical activity intervention effects

on cognitive outcomes in older adults [5]. There is further

evidence of coupling between walking performance and

CPS in MS [6, 7], perhaps based on co-occurring damage

in eloquent neural tracts sub-serving both domains of

function. Physical activity has improved walking perfor-

mance outcomes in clinical trials of MS [8]. Collectively,

this suggests the possibility of physical activity benefits for

CPS in MS.

The present study involved secondary outcomes from a

randomized controlled trial (RCT) and examined the effi-

cacy of a physical activity behavioral intervention for

improving CPS and walking performance among persons

with MS. The primary goal of the RCT involved examining

disability status as a moderator of an established behavioral

intervention [9–12] for increasing physical activity over a

6-month period among persons with MS. The current paper

B. M. Sandroff � R. E. Klaren � L. A. Pilutti � D. Dlugonski �R. W. Motl (&)

Department of Kinesiology and Community Health, University

of Illinois at Urbana-Champaign, 233 Freer Hall, 906 South

Goodwin Ave., Urbana, IL 61801, USA

e-mail: [email protected]

R. H. B. Benedict

Department of Neurology, SUNY Buffalo School of Medicine,

Buffalo, NY, USA

123

J Neurol

DOI 10.1007/s00415-013-7204-8

examined the efficacy of this physical activity behavioral

intervention for improving CPS and walking performance

in persons with MS. Importantly, we included a measure of

physical activity only as a manipulation check for the

intervention, and CPS and walking performance represent

the foci of this paper. We included the measure of walking

performance as a confirmation of previous beneficial

effects of physical activity in MS [8] and, in particular, as a

control for possible null intervention effects on CPS. We

hypothesized that the behavioral intervention would result

in increases in physical activity, and improved CPS and

walking performance. We hypothesized that the effect for

CPS would be larger in those with mild neurological dis-

ability than in those with moderate disability, and that

walking performance would improve following the inter-

vention, regardless of disability. Such hypotheses were

based on preliminary evidence that the magnitude of the

association between physical activity and CPS was stronger

in persons with mild MS disability compared with persons

with moderate MS disability [13], and that the association

of physical activity and 6-minute walk (6MW) perfor-

mance did not differ based on disability status in persons

with MS [14].

Methods

Participants

Prospective participants were contacted by a flyer that was

distributed amongst patients in the North American

Research Committee on Multiple Sclerosis (NARCOMS)

registry and a database from previous studies conducted in

our laboratory over the past 5 years. There were 511 par-

ticipants who initially expressed interest and who were

contacted via phone by the project coordinator for study

description and screening of inclusion/exclusion criteria.

The inclusion criteria involved: (a) definite diagnosis of

MS based on physician verification; (b) relapse-free for the

past 30 days; (c) ability to walk with or without an assistive

device; (d) age between 18 and 64 years; (e) willingness

and ability to complete in-person cognitive and functional

assessments; (f) physical inactivity defined as \60 min of

physical activity per week; (g) low risk for contraindica-

tions of physical activity indicated by no more than a single

‘‘yes’’ response on the Physical Activity Readiness Ques-

tionnaire (PAR-Q; [15]); and (h) physician’s approval for

participation. Those not meeting such criteria were exclu-

ded. The final sample included 82 participants who were

randomly assigned to intervention (n = 41) or waitlist

control (n = 41) conditions. The sample size was deter-

mined based on a power analysis for detecting a differential

pattern of change in physical activity as a function of

disability status. Participant flow through recruitment and

enrollment is included in the Consolidated Standards of

Reporting Trials (CONSORT) diagram (Fig. 1).

Measures

CPS

The oral version of the Symbol Digit Modalities Test

(SDMT) [16, 17] was administered in accordance with our

previous research [18]. Participants were presented with a

page showing symbols paired with single-digit numbers in

a key. The task was to voice the correct numbers for

unpaired symbols as rapidly as possible for 90 s. Responses

were recorded by the examiner. The outcome measure was

the number of correct responses provided in 90 s [19].

Walking performance

The 6MW was administered as a measure of endurance

walking performance in MS [20]. Participants were

instructed to walk as fast and as far as possible in a single

corridor with 180� turns for 6 min. One researcher fol-

lowed *1 m behind the participant with a measuring

wheel (Stanley MW50, New Briton, CT) and recorded the

total distance traveled (m). We recognize that following

behind the participant with a distance-measuring wheel

might bias 6MW performance, but this protocol is common

and well-established in research involving ambulatory

outcomes in persons with MS [14, 21], and ensures the

most accurate measurement of distance walked during the

test.

Physical activity

Physical activity was measured using the abbreviated

International Physical Activity Questionnaire (IPAQ) [22]

that has been well-validated in MS research [23–27]. The

abbreviated IPAQ is a self-report inventory that measures

the frequency of vigorous, moderate, and walking physical

activity during a 7-day period. The respective frequencies

for vigorous, moderate, and walking were multiplied by 8,

4, and 3.3 metabolic equivalents (METs), respectively.

This results in a measure of overall physical activity with

scores that range between 0 and 117, with higher scores

indicating more physical activity.

Disability status

The patient-determined disease steps (PDDS) scale [28]

was included as a self-report measure of disability status.

The PDDS was developed as an inexpensive surrogate for

the Expanded Disability Status Scale (EDSS) and contains

J Neurol

123

a single item for measuring self-reported neurological

impairment on an ordinal scale, ranging from 0 (normal)

through 8 (bedridden). This scale has been validated in MS

[29, 30], and scores of 0–2 and 3–6 have been adopted for

classifying mild and moderate disability status, respec-

tively [31], consistent with benchmarks of disability based

on the onset of gait impairment [30, 32].

Intervention condition

The physical activity intervention is safe [9] and tolerable

[10] for persons with MS, and has been well-tested and

refined in previous research [9–12]. Over a 6-month period,

patients visited a study website, wore a Yamax SW-401

Digiwalker pedometer, completed a log book and used

Goal Tracker software, and participated in one-on-one

video coaching sessions. The website provided content

based on social cognitive theory (SCT) [33] for increasing

ambulatory physical activity. For example, the website

content, in part, focused on teaching behavioral strategies

of self-monitoring and goal-setting by providing informa-

tion, instructions, and examples for using the Yamax SW-

401 Digiwalker pedometer, a log book for recording daily

steps, and Goal Tracker software for setting goals and

monitoring progress toward goal attainment. Additional

content on the website focused on outcome expectations,

Assessed for eligibility (n=230)

Excluded (n=97)Too physically active (n=57)

Not willing/able to travel (n=23)Recent relapse (n=5)

Non-ambulatory (n=3)Heart condition (n=3)

Did not meet age criteria (n=3)Not interested in participation (n=2)

No internet access (n=1)

Drop out before baseline (n=12) Health concerns (n=3)

Not willing/able to travel (n=2)Injury (n=2)

No longer willing to participate (n=2)Unable to schedule (n=1)

Relapse (n=1)No reason provided (n=1)

Completed baseline testing & randomized (n=82)

Completed follow up testing (n=37)

Allocated to intervention (n=41) Allocated to control (n=41)

Received information about study participation (n=766)

Made contact with study personnel (n=511)

Lost to follow up (n=4)No longer willing to participate (n=2)

Injury (n=1)Death (n=1)

Lost to follow up (n=2)No longer willing to participate (n=1)

Pregnancy (n=1)

Completed follow up testing (n=39)

Fig. 1 CONSORT diagram for

Internet-delivered physical

activity intervention

J Neurol

123

self-efficacy, and facilitators/barriers for physical activity

consistent with SCT. The website materials were delivered

in a titrated manner over the 6-month period such that new

content became available seven times during the first

2-month period, four times during the second 2-month

period, and twice during the final 2 months of the

intervention.

The behavioral intervention further involved weekly,

one-on-one behavioral coaching sessions via SkypeTM. The

sessions were semi-scripted and based on principles of

supportive accountability (i.e., encouraging participants to

wear the pedometer daily and monitor behavioral change

and goal attainment throughout the 6-month intervention).

The coaching sessions each consisted of a review of goal-

setting and progress toward goal attainment, as well as

discussion of strategies and facilitators of behavioral

change based on SCT and current website content. During

the 6-month intervention, there were 15 scheduled Sky-

peTM coaching sessions, which decreased in frequency over

the intervention; seven sessions occurred in the first

2 months, six in the second 2 months, and only two in the

final 2 months.

Control condition

We utilized a wait-list control in this RCT. Participants in

this condition completed the study measures before and

after the 6-month period, and then received the intervention

as described above once the study reached completion.

Procedures

The study procedures were approved by a university

institutional review board, and all participants provided

signed informed consent and physician’s clearance before

enrollment into the study. Participants initially provided

demographic/clinical information, completed the SDMT,

PDDS, IPAQ, and lastly the 6MW during a 1-h testing

session in the laboratory. The order of assessments per

testing session was intentionally standardized to minimize

cognitive and physical fatigue. All testing was adminis-

tered by laboratory personnel who were not blinded to

condition (i.e., intervention or control), as the funding

permitted limited support for study personnel necessary for

blinding. We adopted a very focused, stratified randomi-

zation process, as participants were initially grouped based

on disability (i.e., mild and moderate), then within each

disability group, matched into pairs based on physical

activity data, and randomly assigned into intervention or

wait-list control conditions using a random numbers gen-

erator and allocation by a person who was uninvolved in

testing and intervention delivery [34]. All participants

received notification of group assignment and instructions

for participation through email and United States Postal

Service. The participants completed the same assessments

in the laboratory immediately following the 6-month

intervention period, and received $50 remuneration for

completing each testing session. The payment was not

linked with completion of the intervention.

Data analysis

All analyses were conducted using SPSS Statistics 21

(SPSS Inc., Chicago, IL, USA). Data are presented in text

and tables as mean (standard deviation), unless otherwise

noted. We initially compared the demographic and clinical

characteristics between the disability groups by conditions

using two-way ANOVA and chi-squared tests. Only par-

ticipants who completed follow-up testing were included in

subsequent analyses (i.e., completers analysis). The effect

of the behavioral intervention on CPS and 6MW was

examined using three-way mixed-model ANOVA with

condition (intervention or control) and disability status

(mild or moderate disability) as between-subjects factors

and time as a within-subjects factor. We chose this analysis

because the primary aim of the current study was to

examine the differential effects of the intervention on CPS

and walking performance in persons with mild and mod-

erate disability. We expressed the overall effect sizes from

the ANOVA as partial eta-squared, with values of 0.01,

0.06, and 0.14 interpreted as small, moderate, and large,

respectively. We further computed effect sizes for the

change over time per group as Cohen’s d [35], interpreted

as small, moderate, and large based on criteria of 0.2, 0.5,

and 0.8, respectively. Lastly, we conducted Spearman’s

rank-order correlations (q) for the associations among

changes in physical activity, CPS, and 6MW distance,

respectively, in the intervention condition.

Results

Participant characteristics: comparability

between disability and condition

We randomized 41 persons per condition, and 39 individ-

uals (95.1 %) completed follow-up testing in the control

group, whereas 37 persons (90.2 %) completed follow-up

testing in the intervention group (Fig. 1). A total of 76

persons with MS were included in the data analyses.

Demographic and clinical characteristics of the samples per

condition by disability group are reported in Table 1. We

conducted two-way ANOVAs for examining baseline dif-

ferences in age, body mass index (BMI), MS duration, and

PDDS; we also conducted chi-squared difference tests for

gender and MS type (relapsing vs. progressive MS).

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Table 2 summarizes the ANOVA results for baseline dif-

ferences in demographic and clinical characteristics of the

sample. Briefly, there were no significant condi-

tion 9 disability group interactions for any demographic/

clinical variables at baseline.

There were significant disability group main effects for

age (p = 0.02) and PDDS score (p \ 0.01); these were

expected, as those in the moderate disability subgroup were

older, and had worse self-reported disability than those in

the mild disability subgroup. There were no other disability

group main effects, or condition main effects for baseline

demographic/clinical variables. The chi-squared tests

indicated no baseline condition 9 disability group differ-

ences in gender (p = 0.79) and no condition main effect

for MS type (p = 0.58). There was a significant disability

group main effect for MS type (p \ 0.01); this further was

expected, such that those in the moderate disability group

had a higher proportion of persons with progressive MS

compared to the mild disability group. Collectively, these

analyses confirm no detectable baseline differences in

demographic/clinical variables across conditions by dis-

ability subgroups.

Compliance

Overall compliance (i.e., percent participation in available

features of the intervention) with the behavioral interven-

tion was 88.6 % (11.3 %). Compliance with website log-in,

uploading weekly step counts, and video chat sessions (i.e.,

specific features of the behavioral intervention) was 80.0 %

(21.7 %), 88.8 % (12.0 %), and 97.0 % (8.0 %),

respectively.

Physical activity

Briefly, there were no baseline differences in physical

activity based on non-significant condition and disability

group main effects, and a non-significant condi-

tion 9 disability interaction on IPAQ scores (Table 2).

Physical activity data per condition and disability group

for baseline and follow-up are reported in Tables 3 and 4,

and the summary of the ANOVA results for the effect of

the intervention on physical activity per disability

group are further reported in Table 5. Based on our a

priori hypothesis, we report a statistically significant

Table 1 Demographic characteristics of 76 persons with multiple sclerosis with varying levels of disability based on PDDS groups

Control (n = 39) Intervention (n = 37)

Variable PDDS 0–2 (n = 18) PDDS 3–6 (n = 21) PDDS 0–2 (n = 18) PDDS 3–6 (n = 19)

Age (years) 49.0 (10.0) 51.6 (6.7) 45.4 (10.1) 52.1 (6.4)

Gender (n, % female) 15/18 (83.3 %) 15/21 (71.4 %) 12/18 (66.7 %) 15/19 (78.9 %)

BMI (kg/m2) 29.2 (6.0) 26.5 (6.7) 26.6 (5.6) 30.1 (9.4)

MS type (n, % RRMS) 17/18 (94.4 %) 15/21 (71.4 %) 17/18 (94.4 %) 11/19 (57.9 %)

MS duration (years) 12.7 (9.7) 14.0 (9.0) 9.0 (7.2) 12.3 (6.3)

Data are presented as mean (SD) unless otherwise noted

PDDS patient-determined disease steps scale, BMI body mass index, RRMS relapsing-remitting multiple sclerosis

Table 2 Summary of mixed-model ANOVA results for examining baseline differences in demographic, clinical, and primary outcome measures

among 76 persons with mild and moderate multiple sclerosis disability

Variable Condition Disability Condition 9 disability

F p F p F p

Age 0.634 0.429 5.650 0.020* 1.093 0.299

BMI 0.093 0.761 0.072 0.789 3.573 0.063

MS duration 2.086 0.153 1.511 0.223 0.244 0.623

PDDS 1.460 0.231 209.719 \0.001* 0.009 0.926

IPAQ 1.530 0.220 0.538 0.466 0.572 0.452

6MW distance 0.080 0.778 37.908 \0.001* 0.150 0.700

SDMT 0.682 0.412 6.385 0.014* 0.162 0.688

BMI body mass index, PDDS patient-determined disease steps, IPAQ International Physical Activity Questionnaire, 6MW 6-minute walk, SDMT

Symbol Digit Modalities Test

* Statistical significance at p \ 0.05

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time 9 condition 9 disability group interaction on IPAQ

scores (F1,69 = 5.28, p = 0.03) that was moderate in

magnitude (partial-g2 = 0.07). Those with mild disability

in the intervention condition reported a large increase in

physical activity (d = 1.63), whereas those with moderate

disability in the intervention condition reported a small

increase in physical activity (d = 0.24). There was a

moderate decrease in self-reported physical activity

amongst those with mild disability in the control condition

(d = -0.52), and no change in those with moderate dis-

ability (d = 0.03). The moderate decrease in physical

activity among persons with mild disability in the control

condition was similar to a previously reported decrease in

self-reported physical activity over a 6-month period

among persons with MS [10]. Overall, this supports the

successful manipulation of physical activity within this

RCT.

CPS

Baseline SDMT scores did not differ across conditions

overall and per group based on a non-significant

Table 3 Physical activity, functional, and cognitive outcomes in 76 persons with multiple sclerosis

Variable Control (n = 39) Intervention (n = 37)

Baseline Follow-up Baseline Follow-up

IPAQ 22.83 (18.8) 19.31 (17.0) 17.44 (20.8) 29.66 (20.7)

6MW distance (m) 429.69 (160.8) 419.98 (158.0) 444.74 (157.7) 457.07 (164.9)

SDMT 53.83 (11.6) 55.56 (11.3) 56.58 (13.8) 60.46 (13.9)

All data presented as mean (SD)

IPAQ International Physical Activity Questionnaire, 6MW 6-minute walk, SDMT Symbol Digit Modalities Test

Table 4 Physical activity, functional, and cognitive outcomes in 76 persons with multiple sclerosis with varying disability based on PDDS

groups

Variable Control (n = 39) Intervention (n = 37)

PDDS 0–2 (n = 18) PDDS 3–6 (n = 21) PDDS 0–2 (n = 18) PDDS 3–6 (n = 19)

Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up

IPAQ 26.66 (14.5) 19.19 (13.3) 19.73 (21.6) 20.32 (19.6) 14.47 (14.1) 37.43 (24.1) 17.49 (23.4) 23.13 (14.7)

6MW distance

(m)

526.0 (54.3) 521.1 (59.8) 351.7 (176.7) 338.1 (169.9) 546.2 (99.7) 562.1 (107.4) 348.6 (142.6) 357.6 (148.3)

SDMT 57.25 (11.7) 58.38 (11.9) 51.10 (11.1) 52.15 (10.1) 60.83 (13.6) 66.44 (12.8) 54.56 (10.8) 53.31 (12.3)

All data presented as mean (SD)

PDDS patient-determined disease steps, IPAQ International Physical Activity Questionnaire, 6MW 6-minute walk, SDMT Symbol Digit

Modalities Test

Table 5 Summary of mixed-model ANOVAs for baseline and follow-up differences in physical activity, cognition, and walking performance

among 76 persons in the intervention and control conditions with mild and moderate disability

IPAQ SDMT 6MW

F p gp2 F p gp

2 F p gp2

Time 9 Condition 9 Disability 5.275 0.025 0.071* 5.682 0.020 0.079* 0.009 0.926 \0.001

Time 9 Condition 10.292 0.002 0.130* 0.590 0.445 0.009 5.369 0.023 0.070*

Time 9 Disability 0.703 0.405 0.010 5.936 0.018 0.083* 0.696 0.407 0.010

Condition 9 Disability 0.158 0.692 0.002 0.410 0.524 0.006 0.141 0.708 0.002

Time 3.863 0.053 0.053 5.271 0.025 0.074* 0.114 0.737 0.002

Condition 0.231 0.632 0.003 2.201 0.143 0.032 0.419 0.519 0.006

Disability 1.540 0.219 0.022 8.390 0.005 0.113* 40.147 \0.001 0.361*

IPAQ International Physical Activity Questionnaire, SDMT Symbol Digit Modalities Test, 6MW 6-minute walk, PDDS patient-determined

disease steps

* Statistical significance at p \ 0.05

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condition 9 disability interaction and condition main

effect. There was a significant disability group main effect

(p = 0.01) for baseline SDMT scores; this was expected,

as persons in the moderate disability group had worse

cognitive performance than those in the mild disability

group (Table 2). SDMT data per condition and disability

group for baseline and follow-up are reported in Tables 3

and 4, and the ANOVA results summarizing the effect of

the intervention on CPS are further reported in Table 5.

Based on our a priori hypothesis, we report a statistically

significant time 9 condition 9 disability group interaction

on SDMT scores (F1,66 = 5.68, p = 0.02) that was mod-

erate in magnitude (partial-g2 = 0.08). Those with mild

disability in the intervention group demonstrated a mod-

erate increase in SDMT scores (d = 0.41; *6 point

increase), whereas those with moderate disability in the

intervention condition demonstrated minimal change

(d = -0.12; *1 point decrease). There were minimal

changes in SDMT scores for those with mild

(d = 0.10; *1 point increase) or moderate (d = 0.10; *1

point increase) disability in the control condition. These

data are presented in Fig. 2.

6MW

Baseline 6MW distance did not differ across conditions

based on a non-significant condition 9 disability interaction

and condition main effect. However, there was a significant

disability group main effect (p \ 0.01) for baseline 6MW

distance; this was expected, as persons in the moderate dis-

ability group walked substantially shorter distances than

those in the mild disability group (Table 2). Data on 6MW

distance per condition and disability group for baseline and

follow-up are reported in Tables 3 and 4, and the ANOVA

results summarizing the effect of the intervention on walking

performance are further reported in Table 5. Our a priori

hypothesis was that walking performance would increase

among those in the intervention condition, regardless of

disability. Briefly, there was not a

time 9 condition 9 disability group interaction on 6MW

distance (F1,71 = 0.01, p = 0.93, partial-g2 \ 0.01). By

comparison, there was a significant time 9 condition inter-

action on 6MW distance (F1,71 = 5.37, p = 0.02) of mod-

erate magnitude (partial-g2 = 0.07). This is consistent with

our hypothesis, as those in the intervention group demon-

strated a small increase in 6MW distance (d = 0.08; *12 m

increase), whereas there was a small decrease in the control

group (d = -0.06; *10 m decrease).

Correlations among physical activity, CPS, and 6MW

Among persons in the intervention condition, changes in

IPAQ scores were significantly associated with changes in

SDMT scores in those with mild (q = 0.45, p = 0.04), but

not moderate (q = -0.12, p = 0.33) MS disability. IPAQ

scores were significantly associated with changes in 6MW

distance (q = 0.34, p = 0.02), regardless of disability. We

further were interested in examining the associations

among changes in objectively-measured physical activity,

CPS, and 6MW distance in those who completed the

intervention, using uploaded pedometer data from weeks 1

and 24 of the intervention. Briefly, changes in average

steps/day were associated with changes in SDMT scores in

those with mild (q = 0.52, p = 0.01), but not moderate

(q = 0.09, p = 0.36) MS disability. Further, changes in

average steps/day from the pedometer were associated with

changes in 6MW in persons in the intervention condition,

regardless of disability (q = 0.43, p \ 0.01).

Discussion

This RCT examined the efficacy of an Internet-delivered

physical activity intervention for improving CPS and

walking performance, as secondary outcomes, in 76 per-

sons with MS. Accordingly, CPS measured by SDMT

scores increased in the intervention condition for those

with mild disability, whereas there was minimal change for

those with moderate disability; those in the control condi-

tion had minimal change regardless of disability status. By

comparison, the intervention increased walking perfor-

mance measured by 6MW regardless of disability status,

whereas walking performance decreased in the control

condition. To our knowledge, this is the first RCT dem-

onstrating improvements in cognitive and walking out-

comes following a physical activity intervention in persons

with MS. These efficacy results support the consideration

of implementing this behavioral intervention in a substan-

tially larger sample of persons with MS with varying dis-

ability, using an RCT design, for supporting effectiveness

of physical activity for improving CPS and walking

performance.

45

50

55

60

65

70

Baseline Follow-up

SD

MT

Sco

re (

0-11

0)

Intervention-MildControl-MildIntervention-ModerateControl-Moderate

Fig. 2 SDMT scores based on condition and disability in 76 persons

with multiple sclerosis

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The most interesting finding of this study was the pro-

found improvement in SDMT scores (CPS) demonstrated

by persons in the intervention condition with mild dis-

ability. SDMT scores increased by nearly six points in

those with mild disability who received the intervention—a

value well above the minimal clinically important differ-

ence (MCID) (i.e., 3–4 point change) indicative of clinical

meaningfulness [36, 37]. Persons in the intervention con-

dition with moderate disability did not demonstrate

improvements in SDMT scores. By comparison, we are

unaware of any RCT of cognitive rehabilitation that has

reported clinically meaningful improvements in CPS [38].

This pattern of results is particularly striking, as those in

the intervention condition with mild disability had a mean

baseline SDMT score of *61—a value similar to that of

other samples of persons with primarily relapsing-remitting

MS [39] and normative controls [40]—and still experi-

enced clinically meaningful improvements in CPS. Such

differential improvements in SDMT scores based on dis-

ability level are consistent with recent cross-sectional

studies reporting associations of moderate magnitude

between physical activity and CPS [3, 4], and stronger

associations between physical activity and CPS in persons

with mild MS disability versus those with moderate MS

disability [13]. Overall, the current results support the

consideration of physical activity as a potential tool for

managing slowed CPS in persons with mild MS disability.

Another exciting result from the current study was that

the intervention was efficacious for improving walking

performance in persons with MS, regardless of disability

status. Overall, persons in the intervention condition

demonstrated small increases in 6MW distance following

the intervention, whereas persons in the control condition

demonstrated small decreases in 6MW distance. This

suggests that the physical activity intervention had a non-

specific effect on walking performance, such that the

intervention seemed to be equally efficacious for improv-

ing walking performance in persons with mild and mod-

erate disability. The lack of differential intervention effects

between disability groups on walking performance con-

firms a previous cross-sectional study that reported no

differences in the associations among physical activity and

measures of walking performance in persons with mild and

moderate MS disability, respectively [14]. The differential

patterns of change in SDMT and 6MW distance by dis-

ability group might be explained by mechanisms respon-

sible for improvements in physiological conditioning,

which might lead to improvements in ambulatory, but not

cognitive, performance among persons with advancing MS

disability (e.g., [41]). Further, the overall small effect for

6MW distance was expected, considering previous physi-

cal activity interventions have yielded small effects on

endurance walking performance in persons with MS (e.g.,

[42]). Though the current results for walking performance

were consistent with our hypothesis, one previous meta-

analysis indicated the possibility of greater effects of

exercise training on walking mobility outcomes for persons

with mild MS disability compared with moderate disabil-

ity, though those effect sizes were small in magnitude [8].

This suggests a need to directly compare the head-to-head

effects of a physical activity intervention with exercise

training on cognitive and walking performance outcomes

based on disability.

Lastly, we conducted bivariate correlations among

changes in physical activity, SDMT scores, and 6MW

distance for the intervention condition. Among those who

received the intervention, changes in physical activity were

positively associated with changes in SDMT scores in

persons with mild, but not moderate disability, such that

greater increases in physical activity were associated with

greater improvements in CPS. Additionally, changes in

physical activity were associated with changes in 6MW

distance, regardless of disability, such that greater increa-

ses in physical activity were associated with greater

improvements in walking performance. These apparent

dose–response relationships suggest that the magnitude of

change in physical activity might be directly relevant for

improvements in cognitive and walking outcomes in MS.

Further, we examined the associations among changes in

objectively-measured pedometer steps/day, CPS, and 6MW

distance among those in the intervention condition. These

correlations largely mirror those using the IPAQ, which

supports that actual physical activity change might be

responsible for the improvements in CPS and walking

performance following the intervention.

Strengths of this study include the RCT design, rela-

tively large sample size, replication of a previously suc-

cessful physical activity intervention based on SCT, and

inclusion of widely-accepted measures of CPS and walking

performance. The primary limitation of the current study

was that testing was carried out by laboratory personnel

who were not blinded to condition (i.e., intervention or

control), and this could have influenced cognitive and

walking performance outcome assessments. In spite of this

major limitation, we do note that effects of previous RCTs

of exercise and cognition in the gerontology literature have

not differed based on having blinded assessors and the

effects of the current intervention on CPS were different

based on disability status [43]. Another limitation of the

study includes the absence of an active control condition.

Although the differential effect of the intervention on CPS

in persons with mild and moderate disability and the cor-

relations among objectively-measured physical activity,

CPS, and 6MW distance seem to suggest otherwise, it is

still impossible to determine if these changes were due to

increased physical activity and were not time/attention

J Neurol

123

effects. Another potential limitation includes the use of the

IPAQ as a self-report measure of physical activity, as the

scores might change based on the demand characteristics of

the intervention. However, we report that among persons in

the intervention condition, changes in objectively-mea-

sured physical activity were differentially associated with

changes in SDMT scores based on disability status, and

that changes in steps/day were associated with changes in

6MW distance regardless of disability. This is consistent

with previous studies that have demonstrated improve-

ments in objectively-measured physical activity with the

Internet-delivered intervention [10–12], suggesting that the

change in physical activity is real rather than a demand

characteristic. An additional limitation of this study

includes the use of the PDDS as a self-report measure of

disability rather than an EDSS score generated by a neu-

rologist as an approach for generating disability groups.

Such groups might not purely reflect MS disability, as other

factors such as cognitive impairment could influence PDDS

scores, although the PDDS has been reported to be valid

based on a strong correlation with the physician-adminis-

tered EDSS [28, 29]. The final limitation involves includ-

ing the SDMT (CPS) as the only cognitive outcome

measure, and future research should test the effectiveness

of this intervention on other domains of cognition (e.g.,

executive control, learning and memory).

Conclusions

This RCT reports that: (a) SDMT scores increased in the

intervention condition as a function of disability, and this

change was clinically meaningful and moderate in mag-

nitude for individuals with mild disability; (b) 6MW

distance increased in the intervention condition, and this

did not occur as a function of disability; and (c) greater

increases in physical activity were associated with faster

CPS and better walking performance in the intervention

condition. Collectively, such exciting results largely

support the development of a similar RCT in a sub-

stantially larger sample of persons with MS, using blin-

ded assessors and perhaps an attention control condition,

to examine the effectiveness and generalizability of this

Internet-delivered physical activity intervention on cog-

nitive and walking outcomes in this population. The

current study provides the first direct support from an

RCT of physical activity as a promising tool for man-

aging slowed CPS and impaired walking performance in

persons with MS.

Acknowledgments This study was funded by a grant from the

National Multiple Sclerosis Society, Grant Number PP1695, awarded

to the last author.

Conflicts of interest The authors declare that they have no conflicts

of interest.

Ethical statement The study procedures were approved by a uni-

versity institutional review board with guiding Ethical Principles and

Guidelines for the Protection of Human Subjects for Research (i.e.,

Belmont Report) and in accordance with Department of Health and

Human Services policy and the Common Rule.

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