The purpose of this review is to highlight the potential role of exercise in promoting neuroplasticity and repair in Parkinson’s disease (PD). Exercise interventions in individuals with PD incorporate goal-based motor skill training in order to engage cognitive circuitry important in motor learning. Using this exercise approach, physical therapy facilitates learning through instruction and feedback (reinforcement), and encouragement to perform beyond self-perceived capability. Individuals with PD become more cognitively engaged with the practice and learning of movements and skills that were previously automatic and unconscious. Studies that have incorporated both goal-based training and aerobic exercise have supported the potential for improving both cognitive and automatic components of motor control. Utilizing animal models, basic research is beginning to reveal exercise-induced effects on neuroplasticity. Since neuroplasticity occurs at the level of circuits and synaptic connections, we examine the effects of exercise from this perspective.

Objectives-To obtain preliminary data on the effects of high-intensity exercise on functional performance in people with Parkinson's disease (PD) relative to exercise at low and no intensity; and to determine whether improved performance is accompanied by alterations in corticomotor excitability as measured through transcranial magnetic stimulation (TMS).Design-Cohort (prospective), randomized controlled trial. Setting-University-based clinical and research facilities.Participants-Thirty people with PD, 3 years or more since diagnosis, with Hoehn and Yahr stage 1 or 2.Interventions-Subjects were randomized to high-intensity exercise using body weight-supported treadmill training, low-intensity exercise, or a zero-intensity education group. Subjects completed 24 exercise sessions over 8 weeks and had 5 education classes over 8 weeks. Main Outcome Measures-UnifiedParkinson's Disease Rating Scales (UPDRS), biomechanic analysis of self-selected, fast walking, and sit-to-stand tasks; corticomotor excitability was assessed with cortical silent period durations (CSP) in response to single-pulse TMS.Results-A small improvement in total and motor UPDRS was observed in all groups. Highintensity group subjects demonstrated postexercise increases in gait speed, step and stride length, and hip and ankle joint excursion during self-selected and fast gait and improved weight distribution No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. SuppliersPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptArch Phys Med Rehabil. Author manuscript; available in PMC 2010 November 22. Published in final edited form as:Arch Phys Med Rehabil. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript during sit-to-stand. Improvements in gait and sit-to-stand measures were not consistently observed in low-and zero-intensity groups. Importantly, the high-intensity group demonstrated lengthening in CSP.Conclusions-The findings suggest the dose-dependent benefits of exercise and that highintensity exercise can normalize corticomotor excitability in early PD. KeywordsBasal ganglia; Central nervous system; Neuronal plasticity; Rehabilitation; Walking Both basic research and clinical studies suggest that high intensity (ie, high repetition, velocity, complexity) is a characteristic of exercise that may be important in promoting activitydependent neuroplasticity of the injured brain, includin...

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Studies have suggested that there are beneficial effects of exercise in patients with Parkinson's disease, but the underlying molecular mechanisms responsible for these effects are poorly understood. Studies in rodent models provide a means to examine the effects of exercise on dopaminergic neurotransmission. Using intensive treadmill exercise, we determined changes in striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse. C57BL/6J mice were divided into four groups: (1) saline, (2) saline plus exercise, (3) MPTP, and (4) MPTP plus exercise. Exercise was started 5 d after MPTP lesioning and continued for 28 d. Treadmill running improved motor velocity in both exercise groups. All exercised animals also showed increased latency to fall (improved balance) using the accelerating rotarod compared with nonexercised mice. Using HPLC, we found no difference in striatal dopamine tissue levels between MPTP plus exercise compared with MPTP mice. There was an increase detected in saline plus exercise mice. Analyses using fast-scan cyclic voltammetry showed increased stimulus-evoked release and a decrease in decay of dopamine in the dorsal striatum of MPTP plus exercise mice only. Immunohistochemical staining analysis of striatal tyrosine hydroxylase and dopamine transporter proteins showed decreased expression in MPTP plus exercise mice compared with MPTP mice. There were no differences in mRNA transcript expression in midbrain dopaminergic neurons between these two groups. However, there was diminished transcript expression in saline plus exercise compared with saline mice. Our findings suggest that the benefits of treadmill exercise on motor performance may be accompanied by changes in dopaminergic neurotransmission that are different in the injured (MPTP-lesioned) compared with the noninjured (saline) nigrostriatal system.

Physical activity has been shown to be neuroprotective in lesions affecting the basal ganglia. Using a treadmill exercise paradigm, we investigated the effect of exercise on neurorestoration. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model provides a means to investigate the effect of exercise on neurorestoration because 30-40% of nigrostriatal dopaminergic neurons survive MPTP lesioning and may provide a template for neurorestoration to occur. MPTP-lesioned C57 BL/6J mice were administered MPTP (four injections of 20 mg/kg free-base, 2 hr apart) or saline and divided into the following groups: (1). saline; (2). saline + exercise; (3). MPTP; and (4) MPTP + exercise. Mice in exercise groups were run on a motorized treadmill for 30 days starting 4 days after MPTP lesioning (a period after which MPTP-induced cell death is complete). Initially, MPTP-lesioned + exercise mice ran at slower speeds for a shorter amount of time compared to saline + exercise mice. Both velocity and endurance improved in the MPTP + exercise group to near normal levels over the 30-day exercise period. The expression of proteins and genes involved in basal ganglia function including the dopamine transporter (DAT), tyrosine hydroxylase (TH), and the dopamine D1 and D2 receptors, as well as alterations on glutamate immunolabeling were determined. Exercise resulted in a significant downregulation of striatal DAT in the MPTP + exercise compared to MPTP nonexercised mice and to a lesser extent in the saline + exercised mice compared to their no-exercise counterparts. There was no significant difference in TH protein levels between MPTP and MPTP + exercise groups at the end of the study. The expression of striatal dopamine D1 and D2 receptor mRNA transcript was suppressed in the saline + exercise group; however, dopamine D2 transcript expression was increased in the MPTP + exercise mice. Immunoelectron microscopy indicated that treadmill exercise reversed the lesioned-induced increase in nerve terminal glutamate immunolabeling seen after MPTP administration. Our data demonstrates that exercise promotes behavioral recovery in the injured brain by modulating genes and proteins important to basal ganglia function.

Mutations in ␣-synuclein cause a form of familial Parkinson's disease (PD), and wild-type ␣-synuclein is a major component of the intraneuronal inclusions called Lewy bodies, a pathological hallmark of PD. These observations suggest a pathogenic role for ␣-synuclein in PD. Thus far, however, little is known about the importance of ␣-synuclein in the nigral dopaminergic pathway in either normal or pathological situations. Herein, we studied this question by assessing the expression of synuclein-1, the rodent homologue of human ␣-synuclein, in both normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In normal mice, detectable levels of synuclein mRNA and protein were seen in all brain regions studied and especially in ventral midbrain. In the latter, there was a dense synuclein-positive nerve fiber network, which predominated over the substantia nigra, and only few scattered synuclein-positive neurons. After a regimen of MPTP that kills dopaminergic neurons by apoptosis, synuclein mRNA and protein levels were increased significantly in midbrain extracts; the time course of these changes paralleled that of MPTP-induced dopaminergic neurodegeneration. In these MPTP-injected mice, there was also a dramatic increase in the number of synuclein-immunoreactive neurons exclusively in the substantia nigra pars compacta; all synuclein-positive neurons were tyrosine hydroxylasepositive, but none coexpressed apoptotic features. These data indicate that synuclein is highly expressed in the nigrostriatal pathway of normal mice and that it is up-regulated following MPTP-induced injury. Parkinson's disease (PD) is a common disabling neurodegenerative disorder that can present as both a familial and a nonfamilial (i.e., sporadic) condition (Fahn, 1988). Its cardinal clinical features include tremor, stiffness, and slowness of movement, all of which are attributed to the dramatic loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Fahn, 1988). Although the actual cause of PD remains unknown, a breakthrough on this question emerged from studies on the small brain-specific protein ␣-synuclein. The first clue linking ␣-synuclein to PD comes from the observation that point mutations in the ␣-synuclein gene cause an autosomal dominant parkinsonian syndrome almost indistinguishable from the prominent sporadic form of PD (Polymeropoulos et al., 1997;Kruger et al., 1998). The two missense mutations identified thus far result in a single amino acid substitution in ␣-synuclein protein, that is, an alanine being replaced by a hydrophobic residue threonine, at position 53, and proline, at position 30. Since the discovery of these mutations, data have been accumulated suggesting that both mutations may alter ␣-synuclein's normal intracellular distribution, enhance ␣-synuclein's propensity to interact with other intracellular proteins, and increase ␣-synuclein disposition to aggregate and consequently to form intraneuronal inclusions (Conway et al., 1998;El-Agnaf et al., 1998;Engelend...

We have previously demonstrated changes in dopaminergic neurotransmission after intensive exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD), including an increase in the dopamine D2 receptor (DA-D2R), using noninvasive PET imaging with the radioligand [18F]fallypride. The purpose of this feasibility and translational study was to examine whether intensive exercise leads to similar alterations in DA-D2R expression using PET imaging with [18F]fallypride in individuals with early-stage PD. In this pilot study, four patients with early-stage PD were randomized to receive intensive exercise (treadmill training sessions three times/week for 8 weeks) or no exercise. Two healthy age-matched individuals participated in treadmill training. Alterations in the DA-D2R binding potential (BP) as a marker for receptor expression were determined using PET imaging with [18F]fallypride. Turning performance in the patients with PD as a measure of postural control and the Unified Parkinson's Disease Rating Scale scores pre-exercise and postexercise were determined. Our data showed an exercise-induced increase in [18F]fallypride BP as well as improved postural control in patients with PD who exercised. Changes in DA-D2R BP were not observed in patients with PD who did not exercise. These results suggest that exercise can lead to neuroplasticity in dopaminergic signaling and contribute to improved function that may be task specific (postural control) in early-stage PD.