Exercise and Learning and Memory in Multiple Sclerosis

The proposed study involves a single-blind, Phase I randomized controlled trial (RCT) on the
effects of supervised treadmill walking exercise training on learning and memory, hippocampal
structure/function, and cardiorespiratory fitness outcomes in fully-ambulatory (i.e., EDSS ≤
4.0) persons with multiple sclerosis (MS) who have impairment in learning new information.
This study will compare the effects of 3 months of supervised, progressive (both intensity
and duration) chronic treadmill walking exercise (designed based on pilot work [Sandroff et
al., 2015; 2016a; 2016b] and American College of Sports Medicine (ACSM) guidelines) with
those of an active control condition (i.e., stretching-and-toning activities) on learning and
memory, hippocampal volume and resting-state functional connectivity, and cardiorespiratory
fitness. Learning and memory represents the primary outcome, whereas hippocampal volume and
resting-state functional connectivity and cardiorespiratory fitness represent the secondary
outcomes. Such an investigation will provide the first Class I evidence for the effects of
treadmill walking exercise training on those outcomes in MS.

During baseline, participants will first complete a battery of neuropsychological tests,
followed by an incremental exercise test to exhaustion on a motor-driven treadmill to measure
cardiorespiratory fitness, and will undergo a MRI scan. Those outcomes will be measured by
assessors who are blinded to condition. Participants will undertake several
neuropsychological tests addressing various aspects of learning and memory. These tests
include the California Verbal Learning Test-2 [Delis et al., 2000] and Selective Reminding
Task [Buschke & Fuld, 1974] as measures of verbal learning and memory, and the Brief
Visuospatial Memory Test-Revised [Benedict, 1997] and 10/36 Spatial Recall Test [Rao et al.,
1984] as measures of visuospatial learning and memory. Cognitive processing speed will be
measured using the Symbol Digit Modalities Test [Smith, 1982], verbal fluency will be
measured using the Controlled Oral Word Association Test [Benton, 1994], and executive
control (i.e., inhibitory control) will be measured using a modified flanker task [Eriksen &
Eriksen, 1974]. Cardiorespiratory fitness will be measured as peak oxygen consumption
(VO2peak), using an incremental exercise test to exhaustion on a motor-driven treadmill and
an open-circuit spirometry system (ParvoMedics True One 2400, Sandy, UT) for analyzing
expired gases using a modified Balke protocol. This protocol is commonly used for measuring
cardiorespiratory fitness in older adults [e.g. Colcombe et al., 2004] and persons with
chronic stroke [e.g., Macko et al., 1997] and further is consistent with the ACSM guidelines
for exercise testing of MS patients [ACSM, 2013]. Lastly, participants will undergo
structural and resting-state functional connectivity magnetic resonance images of the
hippocampus. The MR instrument that will be used is an FDA-approved Siemens 3 T clinical
imager. Following baseline testing, participants will be randomly assigned to either the
exercise training or active control condition using concealment. Participants further will
blinded to condition (i.e., unaware that the treadmill walking exercise training condition
represents the experimental condition and the stretching-and-toning condition represents the
active control condition).

The exercise training will include 3-months of supervised, progressive light, moderate, and
vigorous intensity treadmill walking exercise, and will be based on ACSM guidelines for
exercise prescription [ACSM, 2013]. We selected treadmill walking exercise as the aerobic
exercise modality based on pilot work that suggests that treadmill walking might exert larger
beneficial effects on cognition compared with stationary cycling [Sandroff et al., 2015], and
that such benefits occur for light, moderate, and vigorous intensity treadmill walking
exercise [Sandroff et al., 2016]. The exercise training itself will take place 3 times per
week over 3 months, led by trained exercise leaders, and will initially consist of 15 minutes
of light-to-moderate intensity treadmill walking exercise and eventually progress to 40
minutes of vigorous intensity exercise by month 3. The stretching-and-toning activities will
be included as a minimal exercise, active control condition. The control condition will be
delivered using the same frequency and duration of the treadmill walking exercise condition.
The stretching-and-toning activities will be based on a manual provided by the National
Multiple Sclerosis Society, and stretching-and-toning activities will be progressively
included over the course of the 3-month study period. Participants will further be asked to
not undertake additional exercise (i.e., not join a gym and begin exercising) over the
duration of the study. The cognitive, cardiorespiratory fitness, and MRI outcomes will be
assessed again following the 3-month study period by assessors who are blinded to condition.

The data will be analyzed using mixed-factor ANOVA with time (pre- and post-) as a
within-subjects factor and condition (exercise or control) as a between-subjects factor on
learning and memory, hippocampal, and cardiorespiratory fitness outcomes (see Specific
Aims/Hypotheses 1 and 2 in the Primary Study Objectives and Study Hypothesis sections).
Effect sizes will be expressed as partial eta-squared (ηp2) and Cohen's d [Cohen, 1988].
Spearman's rho rank-order correlations (ρ) will be performed for the associations among
changes in cardiorespiratory fitness, hippocampal structure/function, and learning and memory
for those who underwent the treadmill walking exercise training condition (See Specific
Aims/Hypotheses 3 and 4 in the Secondary Study Objectives and Study Hypothesis sections). The
effect sizes from the interaction terms from the ANOVAs and correlations will serve as effect
sizes for the subsequent power analyses required for a subsequent Phase II RCT.

Inclusion/Exclusion Criteria:

- All participants will:

- Be between the ages of 18-54 (Males 18-44; Females 18-54)

- Have a clinically definite MS diagnosis based on established criteria

- Be fully-ambulatory based on Expanded Disability Status Scale (EDSS) scores between
0-4.0

- Demonstrate impairment in learning new information based on open-trial Selective
Reminding Task scores at least 1.5 SD's below the normative score for healthy controls
(i.e., 5th percentile)

- Be relapse-free and will not have acutely taken corticosteroids for at least 30 days
(i.e., relative neurologic stability)

- Not have a history of major depressive disorder, schizophrenia, bipolar disorder I or
II, or substance-abuse disorders.

- Not be taking medications that can affect cognition (e.g., antipsychotics,
benzodiazepines).

- Be right-handed

- Have corrected vision better than 20/80

- Not have known/diagnosed cardiovascular, metabolic, or renal disease. Individuals with
known/diagnosed cardiovascular, metabolic, or renal disease who are asymptomatic will
be included only with a physician's approval.

- Demonstrate scores on the Mini-Mental State Examination (MMSE) of 21 or higher (no
decisional impairment)

- Be on a stable disease-modifying therapy regimen (i.e., at least 6 months prior to
study enrollment).

- Have a low risk for contraindications for MRI based on not having metal (e.g., non-MRI
compatible aneurysm clips, metal shards in the body or eyes, or recently placed
surgical hardware) or electronic devices (e.g., pacemaker, cochlear implant) within
the body.

- Not be pregnant

- Not be engaging in ≥ 150 min of moderate-to-vigorous physical activity (i.e., not
meeting public health guidelines for physical activity) per week

- Not be actively engaging in cognitive rehabilitation, or participating in regular
brain fitness activities

- Demonstrate systolic blood pressure values of < 200 mmHg or diastolic blood pressure
values < 110 mmHg at rest