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MINERVA
MEDICACOPYRIGHT®EUR J PHYS REHABIL MED 2009;45:215-29Exercise and neuroplasticity in persons
living with ParkinsonÕs diseaseM. A. HIRSCH
1, B. G. FARLEY
2For many years, exercise was not a recommended reha-bilitation strategy for persons with a diagnosis of idio-
pathic ParkinsonÕs disease (PD). Since it was believed that
exercise had no measurable effect on PD, or might wors-
en the underlying pathology, it was to be avoided. A
rich vein of bench and translational research now sug-

gest non-pharmacological approaches, such as exercise
or physiotherapy, have a far greater effect on the cardinal

features of PD than previously believed. In particular,
recent studies utilizing animal models of PD have begun
to explore the molecular mechanisms of exercise-

induced changes in the pathophysiology of PD. Yet,
many clinicians and communities remain unaware of the
scientific literature underlying exercise-induced brain

repair or reorganization (neuroplasticity) and accom-
panying behavioral recovery in animal models of PD.
The authors will summarize some noteworthy prelim-
inary studies suggesting that continuous, deficit target-

ed, intensive training may confer neuroprotection and

thereby, slow, stop or reverse the progression of the
disease or promote neurorestoration through adapta-

tion of compromised signaling pathways. While much

work remains and these preliminary results await repli-
cation in larger prospective human trials, we believe a
major challenge in the field of non-pharmacological,
rehabilitative intervention for PD will be the extent to
which healthcare providers are able to translate the sci-
ence of exercise and PD to the level of the community. KEYWORDS
:Parkinson disease - Neuronal plasticity -Rehabilitation - Exercise.Acknowledgements.ÑThe authors would like to thank Andrew C.Dennison, MD, for helpful comments on the manuscript.Corresponding author: M. A. Hirsch, PhD, Carolinas Rehabilitation,Department of Physical Medicine and Rehabilitation, 1100 Blythe Blvd
Charlotte, North Carolina, 28203.
E-mail: [email protected] 45 - No. 2EUROPEAN JOURNAL OF PHYSICAL AND REHABILITATION MEDICINE
2151Carolinas RehabilitationDepartment of Physical Medicine and RehabilitationCharlotte, North Carolina, USA2University of Arizona, College of MedicineDepartment of Physiology, Tucson, AZ, USALack of activity destroys the good conditionof every human being, while movementand methodical physical exercise save it and preserve it.Plato (cited in H. Dawes, p. 867)
1ParkinsonÕs disease (PD) is marked by progressiveloss of motor function with loss of nigrostriataldopaminergic (DA) neurons. This paper aims to sum-

marize some of the most exciting basic and clinical sci-
ence studies suggesting exercise may promote brain
repair and reorganization (neuroplasticity) in people

with PD; and that this exercise-induced neuroplas-
ticity is accompanied by behavioral recovery.
Altogether, these data suggest a need for exercise

interventions that are intensive, available at diagnosis,
that promote continuous exercise (normal use), and

that avoid inactivity. It is hoped that clinicians, man-
aged care organizations and other healthcare providers

will begin to translate this information to the clinical

setting and to the level of the community, where it may
benefit the needs of individuals with early PD.

Historically, physiotherapy had been seen as an
ÒadjunctiveÓ (i.e., helpful) treatment to the pharma-
cological management of persons diagnosed with

PD.2Physical therapists, sport and recreation spe-cialists, fitness professionals and other educators often
participate in the rehabilitation of persons with PD


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MINERVA
MEDICACOPYRIGHT®HIRSCHEXERCISE AND NEUROPLASTICITY IN PERSONS LIVING WITH PARKINSONÕS DISEASE
by developing, administering and assessing the effects
of training programs to improve function. Yet, the

mainstream approach to the management of the signs
and symptoms of individuals living with PD remains
the use of pharmacological agents such as levodopa,

introduced in the late 1960s, dopamine agonists and,
in the later stages of the disease process, neurosurgi-

cal interventions such as deep brain stimulation (DBS).
While the pharmacological treatment of PD is essen-

tial, a growing body of bench and clinical research
suggests that adding nonpharmacological approach-

es to symptomatic management of the disease through
exercise and physical therapy enhances function
beyond that of medications or surgery alone.
3-5Theauthors hope this historical overview may help bring
about a paradigm shift that removes barriers to the
implementation of evidenced-based PD-specific exer-
cise approaches across disease severity, starting at
diagnosis.In a recent feature edition on rehabilitation and PD6Susan Calne, a leader in the field of allied healthfor PD, recounted an experience she had while mod-
erating a PD conference session at the first Parkinson
Foundation of Canada Educational Meeting in 1982:
ÒÉa patient asked the panel of internationally dis-

tinguished physicians whether exercise and physio-

therapy were useful for PD. One panelist (a giant in the

world of PD treatment at the time) told the patient

that it was a waste of timeÉ
Ó.6At the time the panelistgave his opinion, there were few randomized con-
trolled trials in medicine, and even fewer peer
reviewed controlled trials on the effect of exercise or

physiotherapy for PD. In 1994 the American Academy of Neurology cameto a different conclusion, recommending physiother-

apy and exercise as an adjunctive (i.e., helpful) strat-egy in early and advancing PD.7Koller et al.7urged
healthcare professionals to strongly encourage their
patients to exercise: ÒThe optimal approach to the
management of early PD includes daily exercise, one

of the most beneficial things a patient can do for him-
self. It can consist of stretching, walking, swimming,

or any activity the patient enjoys and will do regular-

ly. More formal cardiovascular programs are also

beneficialÉÓ.7 For patients with early PD, the guide-lines recommended Òstrengthening with light
weightsÓ.8 In patients with advancing PD the guidelinesstate Ò
Éexercise is also helpful. Although vigorous
exercise is not necessary, just doing a few pushups,

sit-ups, or isometric exercise is
not(emphasis added)enough. Patients must be encouraged to walk as muchas several miles a day, if possible, or swim regularly
Ó.7Surprisingly, neither of the treatment guidelines pro-vided citations specific to studies demonstrating treat-
ment efficacy of exercise or physiotherapy and the

2001 treatment guidelines 9failed to mention exer-cise altogether.
Despite best efforts by clinicians to encourage
patients to exercise, the attitude that physical therapy
or exercise had little or no effect on PD, prevailed

during the 1980s and 1990s among researchers and
clinicians. Dr. Katherine Deane from the Cochrane

collaboration was one of the first researchers to sys-
tematically summarize the literature on exercise and
physical therapy for PD. In a series of highly cited
papers conducted in the 1980s and 1990s, Deane et al.concluded that there is Òinsufficient evidence for the
effect of physiotherapy versus no physiotherapy
Ó, andÒno conclusive evidenceÓ that physiotherapy is bene-ficial for people with PD, despite individual studies
demonstrating measurable treatment effects.
10-12Theauthors cautioned about drawing firm conclusions

about the effect of PT for PD based on methodolog-

ical flaws in the quality of trials which may lead to bias.
Most clinical trials cited by Deane et al.were charac-terized by methodological flaws in research design
and execution, heterogeneity in patient selection with-
in and across studies, failure to use randomization or
control groups, lack of detail in describing the ingre-
dients of physiotherapy treatment, use of divergent

outcome measures, failure to blind assessors, failure
or inappropriate use of statistical tests, lack of follow-
up testing and other factors. Since the Cochrane reviews, the quality and num-
ber of published peer reviewed randomized trials on
exercise and/or physiotherapy has steadily increased.
Many systematic reviews and at least 3 meta-analytic
studies (Table I) have reported positive effects of

physiotherapy and exercise on the motor 13-31andnon-motor 32signs and symptoms of PD. Recently,the Quality Standards Subcommittee of the American
Academy of Neurology, and a joint task force of the

European Federation of Neurological Societies and
the Movement Disorders Society, European Section
reviewed the literature on the effects of exercise

and/or physiotherapy on improvement in motor symp-
toms, function, or disability of PD. Both panels inde-
pendently recommended the use of exercise and
physiotherapy in PD,20, 33citing studies publishedthrough January 2006 with certain caveats concerning
216EUROPEAN JOURNAL OF PHYSICAL AND REHABILITATION MEDICINEJune 2009



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MEDICACOPYRIGHT®EXERCISE AND NEUROPLASTICITY IN PERSONS LIVING WITH PARKINSONÕS DISEASEHIRSCH
to which the behavioral characteristics and patholo-gy mimic the human condition. For example, while
the 6-OHDA model serves primarily as a model of
striatal dopamine dysfunction, the MPTP model man-
ifests alterations in other catcholaminergic neurons

and neurotransmitter systems, more like the human
condition. In both models, despite the cell death;partial or complete behavioral recovery occurs. Thissuggests these animals possess robust molecular
mechanisms for plasticity in response to injury Ð
which can be useful for studying the effect of exer-

cise that may enhance recovery.83, 91The degree andtime course of recovery is dose-dependent and varies
across age, species and mode of toxin injections.
Thus, it is important that recovery in exercised ani-
mals is always compared to recovery in exercised

control groups to differentiate how exercise enhances

the spontaneous recovery that occurs in controls. Exercise as neuroprotection
Could there be a sensitive period after PD symp-toms first surface during which intense exercise

could reduce, halt, or reverse the neurodegenera-
tive process? Early studies on forced-use exercise

paradigms using animal models of PD were con-
ducted by Tim Schallert
et al.at the University ofTexas at Austin. In the first of a series of studies,
88Long-Evans male rats were randomized into four
lesioned groups after receiving unilateral 6-OHDA
lesion: (N=54; lesioned plus no cast; lesioned plus

cast on postoperative days 1-7 [early casts]; lesioned
plus casts on postoperative days 7-13 [late casts];
lesioned plus casts on postoperative days 3-9 [inter-
mediate casts]), or three sham-treated groups (N=16;Vol. 45 - No. 2EUROPEAN JOURNAL OF PHYSICAL AND REHABILITATION MEDICINE
221180120100806040200DADOPACHVA
140160******c 1-7Shamc 3-9c 7-13No castFigure 2.ÑAnimals receiving early casts (days 1-7) and sham animals
do not show significant differences in DA, DOPAC or HVA levels.

Animals receiving casts on days 3-9 show intermediate DA levels,
although still not significantly different from sham. Animals with late
casts (days 7-13) and animals not receiving casts show significantly

lower (*) DA levels when compared with sham-treated animals.

Figure reprinted with permission from Tillerson.
88 10080604020-2001421283540
Day post-lesion0Forced non-use (c 1-17)
ShamMild lesion/no cast10080604020-2001421283540
Day post-lesion0*10080604020-2001421283540
Day post-lesion0**c 1-7Figure 3.ÑBehavioral asymmetries after forced nonuse in animals with mild lesions. A) Animals given mild unilateral lesions did
not display
significant limb use asymmetry; when animals were forced to not use the impaired forelimb for the first 7 days after lesioning,
they demon-
strated limb use asymmetry that persisted across testing days; B) animals given mild unilateral lesions did not display significant forelimb aki-nesia; When animals were forced to not use the impaired forelimb for the first 7 days after lesioning, they demonstrated foreli
mb akinesiathat persisted across testing days; C) animals given mild unilateral lesions did suffer placing deficits; when animals were for
ced to not use
the impaired forelimb for the first 7 days after lesioning, they demonstrated significant placing deficits that persisted across testing days (*P<0.01compared with lesion only). Figure reprinted with permission from Tillerson
et al.89


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MEDICACOPYRIGHT®HIRSCHEXERCISE AND NEUROPLASTICITY IN PERSONS LIVING WITH PARKINSONÕS DISEASE
222EUROPEAN JOURNAL OF PHYSICAL AND REHABILITATION MEDICINEJune 2009
1201008060400No castNon-use
d 1-7Sham20Mild lesion1201008060400No castNon-use
d 1-7Sham20Mild lesionDATVMAT
THDADOPAC
HVA
DATTHVMAT2
CtrlLesLesLes
CtrlCtrl
ShamMild lesion
non-use***+*+**+*+*+Figure 4.ÑEffect of forced nonuse of the impaired forelimb after mild 6-OHDA lesion. A) A 5 µg infusion of 6-OHDA resulted in o
nlya mild loss of DA and HVA in striatal tissue when values were compared with the intact hemisphere; In contrast, forced nonuse of theimpaired forelimb for the first 7 days after lesioning resulted in significantly greater loss of DA and its metabolites when compared withboth sham animals and animals lesioned but not casted; *P<0.05 compared with sham;
+P<0.01 compared with lesion /no cast; B)
immunoreactivity of DAT, VMAT2, and TH was not reduced after mild lesioning (calculated as percentage remaining in lesion hemi-

sphere); In contrast, forced nonuse of the impaired forelimb for the first 7 days after lesioning resulted in significant decli
nes in DAT,
VMAT2, and TH immunoreactivity; *P<0.01 compared with sham; +P<0.02 compared with lesion/no cast; C) representative blots of VMAT2,DAT, and TH for sham, mild lesion, and mild lesion and nonuse groups. Ctrl:Control; Les:lesion. Figure reprinted with permissionfrom Tillerson
et al.89251050152013579111315171921232527293020100SalineDay 30MPTSaline +exercise
MPT +exercise
CABTime (days)
652613039521357911131517192123252729MPTP + Exercise
Saline + Exercise
MPTP + ExerciseSaline + Exercise
Time (days)
Figure 5.ÑExercise-induced changes in behavior. A) Change in run-
ning duration over the 30-day running period for the saline + exer-

cise group (gray bars) and MPTP + exercise group (black bars). The

bars represent the performance of all 10 mice/group running at the

same time. The increase over days of running reflects that all 10

mice met the criteria for increasing running duration. No statistical

analysis was carried out because each bar represents all 10 mice/group
as a single data point. B) Change in running velocity (in m/min)

over the 30-day running period for the saline + exercise group (tri-

angles) and MPTP + exercise group (circles). Symbols represent the

performance of all 10 mice in each running group; increase over

days of running reflects that all 10 mice met the criteria for increas-

ing running. C) Compares running velocity between the four groups
(saline, white bar; MPTP, light gray bar; saline plus exercise, black bar;
and MPTP + exercise, dark gray bar) at the conclusion of the running

program on day XXX. The bars represent performance of all 10
mice/group from the four groups running at the same time. Figure
reprinted with permission from Fisher
et al.83


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