Aerobic exercise increases hippocampal volume and
improves memory in multiple sclerosis: Preliminary
V. M. Leavitt1,2, C. Cirnigliaro3, A. Cohen1, A. Farag3, M. Brooks3, J. M. Wecht3,
G. R. Wylie1,2, N. D. Chiaravalloti1,2, J. DeLuca1,2, and J. F. Sumowski1,2
1Kessler Foundation Research Center, West Orange, NJ, USA
2Rutgers – New Jersey Medical School, Newark, NJ, USA
3James J. Peters VA Medical Center, Bronx, NY, USA
4Kessler Institute of Rehabilitation, West Orange, NJ, USA
Multiple sclerosis leads to prominent hippocampal atrophy, which is linked to memory deficits. Indeed, 50% of
multiple sclerosis patients suffer memory impairment, with negative consequences for quality of life. There are
currently no effective memory treatments for multiple sclerosis either pharmacological or behavioral. Aerobic
exercise improves memory and promotes hippocampal neurogenesis in nonhuman animals. Here, we investigate
the benefits of aerobic exercise in memory-impaired multiple sclerosis patients. Pilot data were collected from two
ambulatory, memory-impaired multiple sclerosis participants randomized to non-aerobic (stretching) and aerobic
(stationary cycling) conditions. The following baseline/follow-up measurements were taken: high-resolution MRI
(neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Intervention was 30-minute
sessions 3 times per week for 3 months. Aerobic exercise resulted in 16.5% increase in hippocampal volume and
53.7% increase in memory, as well as increased hippocampal resting-state functional connectivity. Improvements
were specific, with no comparable changes in overall cerebral gray matter (+2.4%), non-hippocampal deep gray
matter structures (thalamus, caudate: −4.0%), or in non-memory cognitive functioning (executive functions, pro-
cessing speed, working memory: changes ranged from −11% to +4%). Non-aerobic exercise resulted in relatively
no change in hippocampal volume (2.8%) or memory (0.0%), and no changes in hippocampal functional connec-
tivity. This is the first evidence for aerobic exercise to increase hippocampal volume and connectivity and improve
memory in multiple sclerosis. Aerobic exercise represents a cost-effective, widely available, natural, and self-admin-
istered treatment with no adverse side effects that may be the first effective memory treatment for multiple sclerosis
Keywords: Multiple sclerosis; Aerobic; Memory; Functional connectivity; Hippocampus.
Aerobic exercise stimulates hippocampal neuroge-
nesis and improves memory in nonhuman animals
(van Praag, Christie, Sejnowski, & Gage, 1999).
To date, only two randomized controlled trials
(RCTs) have investigated the impact of aerobic
exercise on hippocampal volume in human sam-
ples characterized by memory decline (healthy
elders (Erickson, Voss, & Prakash, 2011) and
Address correspondence to Victoria M. Leavitt, Neuropsychology and Neuroscience Laboratory, Kessler Foundation Research
Center, 300 Executive Drive, Suite 70, West Orange, NJ 07052, USA. (E-mail: email@example.com).
Gruber, 2010)). While both studies linked aerobic
exercise to increased hippocampal volume, only
one investigated episodic memory, showing a
concomitant improvement in memory (Pajonk
et al., 2010). Here, we present preliminary evidence
for aerobic exercise as a treatment to increase
hippocampal volume and improve memory in
a memory-impaired neurologic sample: multi-
ple sclerosis (MS). Approximately 50% of MS
c ? 2013 Taylor & Francis
2 LEAVITT ET AL.
patients suffer memory impairment (Thornton
& Raz, 1997), even early in the disease course,
with negative consequences for quality of life.
Memory impairment in MS has been linked to
prominent hippocampal atrophy (Sicotte, Kern, &
Giesser, 2008), with about 10% hippocampal vol-
ume reduction in relapsing-remitting MS (RRMS)
patients within 5 years of diagnosis (Sicotte et al.,
2008). There are currently no effective memory
treatments for MS, either pharmacological or
behavioral (das Nair, Ferguson, Stark, & Lincoln,
2012). Promising findings for aerobic exercise as an
effective method to increase hippocampal volume
and improve memory in nonhuman animals and
two RCTs in non-neurologic populations motivated
the current investigation in MS patients. Of note,
this is the first study to investigate benefits on
three levels: neuroanatomical (hippocampal vol-
ume), neurophysiological (hippocampal functional
connectivity), and behavioral (memory).
In this pilot study, two ambulatory, memory-
impaired female RRMS patients were randomized
to one of two exercise training conditions, non-
aerobic (Patient 1: age 33, 15 months since MS
diagnosis) and aerobic exercise (Patient 2: age 44,
14 months since MS diagnosis). Both subjects were
memory-impaired as determined by the selected
reminding test (Patient 1: z = –1.64, 5‰, Patient
2: z = –3.07, <1‰).
resolution MRI was collected for each participant
on a 3T Siemens scanner (Erlangen, Germany).
Structural volumes for hippocampus, caudate,
thalamus, and overall cerebral gray matter were
calculated using Freesurfer software (http://surfer.
nmr.mgh.harvard.edu). Functional MR images
were acquired during rest. Seed-based functional
connectivity was derived using AFNI software
(Cow, 1996). Correlations were calculated between
a 3-mm-radius seed centered in left hippocampus
(LHIPP) and every brain voxel. Cognitive impair-
ment in MS patients is characterized primarily by
memory impairment and cognitive inefficiency.
Memory was assessed with verbal and nonverbal
tasks (California Verbal Learning Test-second
edition (CVLT-II), Brief Visual Memory Test-
assessed with tests of processing speed (Symbol
Digit Modality Test (SDMT), Paced Auditory
and follow-up measurements.
Serial Addition Test (PASAT), executive function
(Stroop), and working memory (Digit Span).
Patients underwent VO2 peak testing to measure
Treatment. Intervention was 30-minute sessions,
3 times per week for 12 weeks, consistent with
methods of a prior study conducted in schizophre-
nia patients (Pajonk et al., 2010). The aerobic con-
dition consisted of stationery cycling using an indi-
vidualized program of graduated resistance devel-
oped by an exercise physiologist (CC) informed by
baseline aerobic fitness testing. The non-aerobic
condition consisted of a program of stretching
specifically developed for MS patients.
Aerobic exercise resulted in a 16.5% increase
in hippocampal volume (baseline = 5958 mm3,
follow-up = 6942 mm3), a 55.9% increase in
verbal memory (CVLT Total Learning base-
line = 31, follow-up = 48; CVLT Long Delay
Free Recall baseline = 7, follow-up = 11),
(BVMT Total Learning baseline = 18, follow-
up = 23; BVMT Delayed Recall baseline = 4,
follow-up = 7). Additionally, a large increase in
hippocampal resting-state functional connectivity
was shown (see Figure 1, bottom panel). VO2 peak
increased by 10% (baseline = 20.2 ml/kg/min,
exercise resulted inrelatively
hippocampal volume (+2.8%), no change in
verbal and nonverbal memory (0.0%), no changes
in hippocampal resting-state functional connec-
tivity (see Figure 1, top panel), and no increase
in VO2 peak. Furthermore, and consistent with our
a priori hypotheses, effects of aerobic exercise were
specific to the hippocampus and memory, as there
were no comparable changes in overall cerebral
gray matter (+2.4%) or in non-hippocampal deep
gray matter structures (thalamus, caudate: –4.0%),
nor were there any changes in non-memory cog-
nitive functioning (executive functions, processing
speed, working memory: change ranged from
−11% to +4%).
These are the first data supporting the benefits
of aerobic exercise to increase hippocampal vol-
ume, improve memory, and increase hippocampal
functional connectivity in MS. These improvements
AEROBIC EXERCISE INCREASES HIPPOCAMPAL VOLUME IN MS3 Download full-text
Figure 1. Displayed are r-maps for each participant revealing
cortical regions showing functional connectivity to the LHIPP
seed at baseline and follow-up in each participant. [To view this
figure in color, please visit the online version of this Journal.]
were shown after only 12-weeks of aerobic exer-
cise training. Although based on only two cases,
the strength of this interventional case report is
bolstered by the specificity of our findings. That
is, the positive effects of exercise on hippocampal
volume/functional connectivity and memory, were
specific to the aerobic exercise condition. The
results for the aerobicpatient alsoshowed
specificity to our stated hypotheses: increased
hippocampal volume/functional connectivity and
memory, but not non-hippocampal volume or non-
memory cognition. Furthermore, an increase in
hippocampal volume of this magnitude (+16.5%)
over 3 months in the absence of an outside influ-
ence is unlikely to occur by chance alone. There is
currently no effective approved treatment for mem-
ory impairment in MS. Aerobic exercise represents
an inexpensive, widely available, natural, and self-
administered treatment with no adverse side effects
that may be the first effective memory treatment
for MS patients. Future large-scale RCTs to test
aerobic exercise as a treatment for memory decline
in MS are clearly warranted, particularly to high-
light the specific benefit of aerobic exercise for
memory function that is supported by these pilot
data, and not cognitive function more generally
(e.g., executive functioning, processing speed).
Original manuscript received 4 March 2013
Revised manuscript received 22 July 2013
Revised manuscript accepted 28 August 2013
First published online 27 September 2013
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