PD Exercise


Parkinson’s disease is a progressive neurological disease characterized by degeneration of the dopamine producing cells in the basal ganglia (specifically the substantia nigra) causing a subsequent decrease in dopamine. Exercise in this population is important to help maintain muscle strength as well as improve overall functional mobility, flexibility and balance. While it will not “cure” the disease, studies in both humans and animals have shown that exercise may be protective for the dopamine cells as well as other pathophysiological components, thus having beneficial effects at the cellular level as well. Exercise should be considered a standard treatment for all patients and its role in improving the overall quality of life for patients with PD cannot be denied.

Resistance Exercise

Exploration of the effects of PD on muscle strength is crucial when determining appropriate treatment for these individuals, because strength deficits can lead to functional decline and reduced ability to perform activities of daily living (ADL’s). [1] When compared to age matched, neurologically normal adults, those with PD engage in less physical activity, [2] have greater muscular weakness, [3] and have lower bone mineral density. [5] This decline in muscle strength has also been recognized as a secondary cause of one of the primary motor symptoms of PD, bradykinesia, due to mounting evidence that those with PD are weaker in multiple muscle groups than neurologically normal adults. [7] Specific PD-related changes in muscle activation and motor control have also been identified. This finding is supported by two studies showing that those with PD demonstrate increased latencies with muscle force production and relaxation, providing an objective measure to the pathophysiology of bradykinesia. [8] [7] Muscular weakness is also a primary cause of postural instability, [9] which contributes to not only to impaired function, but also to decreased safety and increased risk for falls. It has been suggested that the ability to achieve maximal strength [10] and the latency of force production [11] in the lower extremities is significant to quickly maintain the body’s center of mass over the base of support in order to prevent a loss of balance.

Central Effects

The particular mechanisms for the changes in motor control in PD have been suggested by functional anatomists to be the result of decreased activation of motor cortices through irregular drive from the basal ganglia to the thalamus, which leads to a delay in facilitation of intended movement. [28] In addition, decreased cortical activation results in decreased activation of motoneuron pools, which negatively affects both recruitment and discharge rate. [12] All of these PD-related changes may contribute to a reduction in neural drive, muscular weakness, and ultimately decreased functional capacity. [13] Physical activitiy in general has been shown to both decrease mortality rate in those with PD [14] and demonstrate a small protective effect for PD risk. [69] This may occur in those with PD specifically due to promotion of dopamine synthesis as a result of increased serum calcium levels, as demonstrated in animal models. [16] In neurologically normal older adults, resistance exercise has consistently been shown to increase muscle mass, strength, and function. [17] Although future studies will be required to determine the exact mechanisms by which resistance exercise may have therapeutic value for those with PD, maximal force production increases on a neurological level have been demonstrated in healthy older adults after short-term strength training. [18] This neural adaptation is hypothesized based on the lack of concurrent muscle hypertrophy in these subjects despite maximal force production gains. [18] It has been suggested that these results, in addition to lower recruitment thresholds measured after strength training intervention, may be the result of changes at the level of the central nervous system. [19] As mentioned previously, these studies were on neurologically normal subjects, so it is not certain that these results are achievable in those with PD. There have, however, been multiple clinical trials of the efficacy of physical exercise as an adjunct to pharmacological therapy in the management of PD.

Overview of Evidence

Dibble et al [20] examined the effects of a 12 week high intensity eccentric resistance exercise program on muscle force production, clinical measures of bradykinesia, and quality of life (QOL). The experimental group performed high intensity quadriceps contractions on an eccentric ergometer for 3 days a week, which an active control group participated in an evidence based exercise program for PD. After 12 weeks, muscle force, measures of bradykinesia, and QOL were improved to a greater degree in the exercise group versus the control, supporting the inclusion of high-intensity resistance training in exercise interventions for PD. This was similar to another study by Dibble et al [21] that also utilized eccentric training of the quadriceps, but was different in that it also measured changes in quadriceps muscle volume and included mobility outcome measures of 6 minute walk test and stair ascent/descent time. Once again, the experimental group demonstrated significantly greater improvement over controls in muscle structure and stair descent and 6 minute walk times.
Evidence has also been shown that those with PD can make strength improvements with traditional resistance exercises as well. In an 8 week study by Schilling et al [22] the training group performed 3 sets of 5-8 repetitions of leg press, leg curl, and calf press 2 times a week. Outcome measures included leg press strength relative to body mass, Timed Up and Go (TUG), Six-Minute Walk, and Activities-specific Balance Confidence. Results showed a significant group-by-time effect for maximum leg press strength relative to body mass, once again supporting the inclusion of high-load weight training in an exercise program for persons with PD with the goal of increasing muscular strength.


In light of the evidence stated above, resistance training has been shown to generally be successful in increasing muscular strength in those with PD, but clinicians and investigators developing exercise programs must be aware of the limiting effects of fatigue in this population when it comes to exercise. The etiology of fatigue in PD is still poorly understood, but may possibly be associated with mitochondrial dysfunction. [23] It is still uncertain whether this relationship is also true for skeletal muscle function. [24] There currently exists no established model for resistive exercise in those with PD, however there are also no studies which report that resistive exercise worsens symptoms associated with PD, [25] making it reasonable to incorporate progressive resistance exercise recommendations for healthy older adults into exercise programs for those with PD which provide adequate stimulus for neural and muscular adaptation while also managing fatigue. [23]
The American College of Sports Medicine (ACSM) recommends for healthy older adults to engage in a resistance exercise program that includes both concentric and eccentric muscle actions carried out in single- or multi-joint exercises, with multijoint and larger muscle group exercises performed prior to single-joint and smaller muscle group exercises. [26] This program should be performed 2-3 times per week, in 8-12 repetition sets. The program can be progressed by increasing training frequency to 4-5 days per week.

Summary of Resistance Exercise in Human Clinical Trials

Parameters Exercise Protocol Outcomes Results
Effects of resistance exercise in reduction of clinical measures of bradykinesia and self-reported quality of life[20] 12 weeks (experimental group performed high intensity quadriceps contractions on eccentric ergometer 3 nonconsecutive days per week; control group participated in an evidence-based exercise program for PD Clinical measures of bradykinesia (speed of gait, Timed Up and Go (TUG), quadriceps muscle force, Parkinson’s disease questionnaire (PDQ-39) Time by group interaction effects significant for gait speed, TUG, and composite PDQ-39 score. Compared to active control group, experimental group improved to a greater degree in measures of muscle force, bradykinesia, and PDQ-39 scores
Effects of eccentric resistance training on muscle size, muscle force production, and measures of mobility[21] 12 weeks (eccentric group performed high intensity quadriceps contractions on eccentric ergometer 3 nonconsecutive days per week; control group participated in standard exercise program for PD Quadriceps muscle hypertrophy, muscle strength, and measures of mobility (6-minute walk test, timed stair ascent/descent) Both groups saw improvement in muscle volume, force, and functional mobility measures. Eccentric group had significantly greater scores when compared to standard care group for muscle hypertrophy, stair descent time, and 6-minute walk test
Effects of moderate-volume, high-load lower-body resistance training on strength and functional mobility [22] 8 weeks (training group engaged in 3 sets of 5-8 repetitions of leg press, leg curl, and calf press two times a week. Control group members continued with standard care. Leg press strength relative to body mass, Timed Up and Go (TUG), 6 minute walk test, Activities-specific Balance Confidence (ABC) scale Group-by-time effect was significant for maximum leg press strength relative to body mass. Only the training group significantly increased their maximum relative strength
Effects of balance training alone, or balance training combined with high-intensity resistance exercise in persons with idiopathic PD[68] 10 weeks (combined group participated in both high-intensity resistance training for knee flexor/extensor, ankle plantarflexor muscle groups, as well as balance training with altered visual/somatosensory conditions) 3 times per week on nonconsecutive days Sensory Orientation Test (SOT), muscle strength were measured before, immediately following training, and 4 weeks post-intervention SOT performance, muscle strength improved for both groups with effects persisting at 4 weeks. Improvement in both outcomes was greater for the combined group

Endurance Exercise

Animal Models

While the effects of endurance exercise on mouse models of PD have been reported in multiple high quality studies, the results are varied. In part, this is the consequence of methodological heterogeneity including inconsistent chronicity of disease and exercise intensity and duration. This heterogeneity, however, has allowed for some insight as to the parameters of endurance exercise and stages of PD that allow for the greatest benefit on cellular, systemic, and functional outcomes.

Long Term, Moderate Intensity Exercise and Moderate Neurologic Deficits

A recent study by Lau and colleagues [29] used a chronic MPTP mouse model of PD with moderate neurologic deficits to examine the effects of endurance training on neurophysiologic, cellular, and behavioral outcomes. This chronic model is created by systemically injecting the mouse with MPTP over the course of five weeks to allow for behavioral and cellular effects similar to PD to last for up to six months. A group of chronic parkinsonian mice performed 18 weeks of treadmill running (one week before, five weeks during, and 12 weeks after MPTP injection) five times per week for 40 minutes per day at a moderate intensity of 15 meters per minute. The researchers reported that the exercisers demonstrated cardiorespiratory and metabolic adaptations similar to endurance trained humans.[29] These mice were compared to a sedentary group of chronic parkinsonian mice and a control group treated only with probenecid, a drug used to reduce neuronal and urinary elimination of MPTP in the chronic parkinsonian models.[29][30]

The researchers examined the consequences of endurance exercise on a wide variety of neurophysiologic and cellular components. First, it was found that the sedentary mice had significantly less tyrosine hydroxylase (TH) cells in the substantia nigra pars compacta (SNpc) than the control mice. Tyrosine hydroxylase is an enzyme that converts L-tyrosine to DOPA, the precursor for dopamine. Following 18 weeks of exercise, chronic parkinsonian mice demonstrated significantly more TH cells and protein content in the SNpc versus sedentary mice.[29] Similar results were demonstrated when striatal TH, dopamine, and dopamine uptake transporter (DAT) were measured.[29] Within the striatal mitochondria, sedentary mice demonstrated significantly increased carbonylated proteins and decreased SOD, an antioxidant enzyme, versus control mice. Carbonylated proteins are those that are marked for proteolysis by proteasomes. These mice also contained significantly less striatal state III and IV respiration and striatal mitochondrial ATP versus control mice. Conversely, the striatal mitochondria of exercised mice had significantly less carbonylated proteins, increased SOD, increased state III and IV respiration, and increased ATP versus sedentary mice.[29] Striatal and SN BDNF and GDNF content were the final cellular outcomes that were studied and they demonstrated interesting results. In sedentary mice, BDNF was significantly increased in the striatum versus SN while GDNF concentrations were similar in both structures. Furthermore, there was no difference in BDNF or GDNF content versus controls. In the exercised mice, however, BDNF was significantly increased in the SN versus the striatum. In addition, GDNF concentrations in the striatum were significantly higher than those in the sedentary mice.[29]

For comparison, the authors also discussed data from a study that utilized the exact same methods with the exception that exercised mice were only trained for 10 weeks.[29] The authorship of this study was not made clear and it appears that the study is not yet published. However, the results may help illustrate the difference between short and long term duration endurance exercise. While the number of TH cells in the SNpc and striatum of sedentary versus control mice were similar to the results reported by Lau and colleagues, exercised mice did not demonstrate levels that were significantly different from either control or sedentary mice. Similarly, striatal dopamine levels were not increased in the exercised mice versus the sedentary mice and remained significantly lower than the control mice.[29]

Functionally, the authors were interested in studying the effects of exercise on balance and coordination. The mice completed a course consisting of four gradually narrowing sections of a balance beam and researchers recorded the average number of limb slips time required to complete the course. Sedentary mice demonstrated significantly greater number of slips and time to complete the course versus the control mice whereas exercised mice had significantly fewer number of slips versus sedentary and control mice and required less time to complete the course versus sedentary mice.[29]

Several conclusions can be drawn from this article. First, 18 weeks of moderate intensity endurance exercise can attenuate the negative neurophysiologic and cellular changes associated with PD in chronic mouse models of PD with moderate neurologic deficits. It is important to note that only 10 weeks of exercise did not allow for some of these same effects. Furthermore, while striatal and SN BDNF and GDNF concentrations were not altered by disease in these mice, they were altered by exercise. Thus, these neurotrophic factors are enhanced and provide neuroprotection in exercised animals only. In addition, the changes are specific to the type of trophic factor and region of the basal ganglia.[29]

An additional study by Ahmad and colleagues[31] utilized the identical chronic parkinsonian mouse model as previously discussed. [29] The same methods for endurance exercise training and creating sedentary and control groups were also employed with the exception that some mice were exercised for 10 weeks and some were exercised for 18 weeks. The researchers were specifically interested in examining the effects of endurance training on content and morphology of TH cells in the ventral tegmental area (VTA) of these mice. [31] The VTA is adjacent to the SN and contains dopamine neurons whose projections comprise the mesolimbic and mesocortical systems. Damage to neurons of the VTA has been demonstrated in animal models of PD and may result in some of the non-motor behavioral impairments seen in PD involving cognition, motivation, emotion, and stress. [31] As expected, the number of TH positive cells in the VTA was significantly decreased in the sedentary group versus the control. Mice that underwent 10 weeks of exercise demonstrated significantly more TH positive cells than sedentary mice. Eight additional weeks of exercise resulted in further increases in TH positive cells reaching levels equivalent to those of controls. The remaining VTA dopamine neurons of sedentary mice demonstrated decreased immunoactivity, a thin distribution, decreased cell volume, and abnormal axonal and dendritic projections versus controls. Conversely, mice that exercised for 18 weeks demonstrated dopamine VTA neurons with immunoactivity and morphology similar to controls.[31]

This study provides additional support to Lau and colleagues in that long term endurance exercise in chronic parkinsonian mice with moderate neurologic changes is more beneficial at preventing degeneration of dopamine producing neurons than short term programs.[29] [31] Furthermore, it demonstrates that sparing of dopamine neurons with exercise extends outside of the SN and striatum into adjacent areas, specifically the VTA, and may allow for the attenuation of non-motor behavioral impairments.[31]

Long Term, Moderate Intensity Exercise and Severe Neurologic Deficits

A similar study by Pothakos and colleagues[30] examined the results of 18 weeks of moderate intensity endurance exercise in the chronic MPTP mouse model of PD with the exception that neuropathological changes were severe and mimicked a more advanced stage of the disease. Methods for endurance exercise training and creating sedentary and control groups were the same as those described by Lau and colleagues.[29][30] This study reported fewer neurophysiologic and cellular changes but found similar results in sedentary mice with significantly less TH cells in the SN versus control mice. Interestingly, exercised mice did not show attenuation of this loss.[30]

The authors used four tasks to study the effects of endurance training on functional outcomes. First, it was demonstrated that step length and consistency during gait was significantly reduced in sedentary versus control mice. Exercised mice demonstrated significantly increased step length and consistency versus sedentary mice.[30] Mice were trained and tested in two versions of a Morris water maze, one guided by a visual cue on the escape platform and one guided by spatial cues outside of the maze. In theory, the visually cued maze utilized habitual learning and engaged striatal networks while the spatially cued maze required cognitive learning and engaged primarily the hippocampus. Both the sedentary and exercised mice demonstrated increased latency in completing the visually cued maze versus the control mice while no between group differences were noted in the spatially cued maze.[30] To test balance, the mice also completed a beam task while researchers counted limb slips. To test coordination, mice completed a grid task during which they had to negotiate a metal grid while researchers counted full limb slips. During both the beam and grid tasks, sedentary mice demonstrated a significantly increased number of limb slips versus the control. Exercised mice demonstrated significantly fewer limb slips versus sedentary mice on the beam task while no between group differences were noted on the grid task.[30] Finally, the total distance traveled in an open field over the course of three hours was measured for each group. The sedentary mice traveled significantly less than the control group while the exercise group traveled significantly more than the sedentary group.[30]

The results from this article alone and compared to those reported by Lau and colleagues warrants the discussion of several key findings. First, the attenuation of neurophysiologic changes with endurance exercise in the chronic mouse model with only moderate neurologic deficits was not demonstrated in this study of animals with severe neurologic deficits.[29][30] Despite this, functional improvements in gait pattern, balance, and spontaneous activity were demonstrated in mice trained with long term, moderate intensity endurance exercise.[30] Unfortunately, a thorough review of the literature did not reveal any studies examining the effects of endurance exercise on mitochondrial or neurotrophic changes in models with severe neurologic changes. Thus, conclusions regarding the effects of endurance exercise on these factors and their relationship to functional changes can not be drawn. However, this study demonstrates that animals with neurophysiologic and behavioral changes associated with more advanced stages of PD experience attenuation of functional losses that is not mediated by striatal or SN dopamine changes.[30]

Short Term, Moderate to High Intensity Exercise and Severe Neurologic Deficits

Al-Jarrah and colleagues[65] utilized the chronic MPTP mouse model of PD similar to those described above to study the effects of endurance exercise on functional outcomes, autonomic function, cardiorespiratory fitness, muscle metabolic capacity, and neurophysiologic changes in mice with severe neurologic degeneration.[65] Methods for developing the chronic parkinsonian model, endurance exercise training, and creating sedentary and control groups were the same as those described by Lau and Pathakos except that the animals only exercised for four weeks and ran at a slightly higher intensity of 18 meters per minute. [29][30][65] Similar to results reported by Pothakos and colleagues, exercised mice did not demonstrate significant attenuation of the decreased striatal and SN TH, dopamine, and DOPAC in the sedentary group versus the control group. DOPAC, or 3,4-Dihydroxyphenylacetic acid, is a metabolite of dopamine.[30][65]

Consistency of movement pattern as measured by approximate entropy (ApEn) during 15 minutes of horizontal cage movement and locomotor activity as measured by distance traveled in an open cage environment for 30 minutes after amphetamine injection were the functional outcomes employed in this study. Amphetamine was injected as it indirectly stimulates the release of endogenous dopamine within the basal ganglia. Both consistency of movement and locomotor activity were significantly decreased in sedentary mice versus control mice. Exercised mice did not demonstrate any significant changes in these outcomes versus the sedentary group.[65] ECG recordings were used to assess autonomic responses including heart rate (HR) and R-wave amplitude. HR was significantly decreased from baseline in the exercised group while R-wave amplitude significantly increased from baseline in the sedentary group. Cardiac left ventricle mass was also measured in all mice and was significantly higher in exercised mice versus control mice.[65] Oxygen consumption (VO2) and body heat were two of the measures of cardiorespiratory fitness that demonstrated significant interactions. VO2 was significantly increased at rest in the sedentary versus control mice and significantly decreased at six and fifteen minutes into a maximal aerobic exercise test in exercised versus sedentary mice. Similarly, body heat was significantly decreased in exercised versus sedentary mice at six and fifteen minutes into the maximal exercise test.[65] Lastly, citrate synthase activity in various muscle groups was used as a measure of muscle metabolic capacity. Exercised mice demonstrated a significant increase in activity of this enzyme in gastrocnemius and soleus muscles, but not cardiac muscle, versus sedentary and control mice.[65]

From this study, it can be concluded that four weeks of moderate to high intensity endurance exercise in chronic MPTP mouse models of PD with severe neurologic deficits results in autonomic, cardiac, metabolic, and aerobic benefits.[65] As the motor changes that occur in PD may result in these individuals developing a sedentary lifestyle and negative changes to these systems, it can be proposed that endurance exercise is beneficial. Furthermore, restoration of neurophysiologic changes was not demonstrated in these animals. The exact reason for this observation can not be determined from this study; however, it is likely that both the short duration of the exercise program and severity of neurologic degeneration played a role. In addition, the increased intensity of exercise is a parameter that can not be overlooked as a potential contribution to these results and warrants further investigation.[65]


After reviewing the literature on the effects of endurance exercise on chronic MPTP mouse models of PD, it can be concluded that long term, moderate intensity endurance exercise in animals with moderate neurologic damage is the most beneficial for protecting against the negative neurophysiologic and cellular changes within the SN, striatum, and VTA; enhancing SN and striatal neurotrophic factors; and preventing impairments in balance and coordination. [29][31] Short term endurance exercise is still beneficial, however, as it allows for functional improvements in gait pattern, balance, and spontaneous activity. [30] Although not neuroprotective, endurance exercise in animals with severe neurologic deficits results in autonomic, cardiac, metabolic, and aerobic benefits. [65]

Summary of Endurance Exercise in Chronic MPTP Mouse Models

Parameters Exercise Protocol Outcomes Results
Effects of long term, moderate intensity exercise on SN, striatum, and motor behaviors in mice with moderate neurologic deficits[29] 18 weeks (1 wk. before, 5 wks. during, and 12 wks. after MPTP injection) of treadmill (TM) running 5 days/week for 40 min./day at 15 m/min. (moderate intensity) Number of SNpc TH positive cells; striatal TH, dopamine, and DAT content; balance/coordination; striatal mitochondrial indicators (ATP content, SOD activity, carbonylated protein content, state III and IV respiration activity); striatal and SN BDNF and GDNF content Exercised versus sedentary mice: attenuation of negative striatal (TH, dopamine, DAT, and mitochondrial) changes, attenuation of negative SN TH changes, increased SN BDNF, increased striatal GDNF, and attenuation of balance and coordination deterioration; 18 versus 10 weeks of exercise: attenuation of striatal and SNpc TH positive cells and striatal dopamine losses did not occur in similar study with only 10 weeks of exercise
Effects of short and long term, moderate intensity exercise on VTA dopamine neurons in mice with moderate neurologic deficits[31] 10 or 18 weeks (1 wk. before, 5 wks. during, and 4-12 wks. after MPTP injection) TM running 5 days/week for 40 min./day at 15 m/min. (moderate intensity) Number of VTA TH positive cells, morphology of VTA dopamine neurons Exercised versus sedentary mice: attenuation of VTA TH cell loss after 10 weeks of exercise; Exercised versus sedentary and control mice: normalization of VTA TH cells after 18 weeks of exercise to control values, attenuation and normalization of negative morphological dopamine cell changes
Effects of long term, moderate intensity exercise on SN dopamine neurons, learning, and motor behaviors in mice with severe neurologic deficits[30] 18 weeks (1 wk. before, 5 wks. during, and 12 wks. after MPTP injection) of TM running 5 days/week for 40 min./day at 15 m/min. (moderate intensity) Number of SN TH positive cells, gait pattern, habitual and cognitive learning, balance, coordination, and spontaneous locomotor activity No attenuation of SN TH cell loss in exercised mice; Exercised versus sedentary mice: attenuation of negative gait changes, no changes in learning, attenuation of balance losses, no changes in coordination, attenuation of decreases in spontaneous locomotion to exceed spontaneous locomotion of control mice
Effects of short term, moderate to high intensity exercise on autonomic function, cardiorespiratory fitness, muscle metabolic capacity, neurophysiologic changes and motor behaviors in mice with severe neurologic degeneration [65] 4 weeks of TM running 5 days/week for 40 min./day at 18 m/min. (moderate- high intensity) Striatal and SN TH, dopamine, and DOPAC content; cardiac responses (HR, R wave amplitude, LV mass), VO2, body heat, muscular citrate synthase activity, consistency of locomotion, spontaneous locomotor activity No attenuation of striatal and SN TH, dopamine, and DOPAC losses in exercised mice; No attenuation of decreases in locomotor consistency or spontaneous locomotor activity in exercised mice; Exercised versus sedentary: decreased resting HR, increased LV mass to exceed that of controls, decreased VO2 and body heat during submaximal exercise, increased citrate synthase activity in gastrocnemius and soleus muscles to exceed that of controls

Human Models

A thorough review of the literature revealed an absence of studies examining the effects of endurance exercise on cellular mechanisms in humans with PD. In fact, there is little evidence altogether on endurance exercise in individuals with PD. However, reports of several case studies and a small RCT support the use of endurance training to improve movement economy, disease symptoms, aerobic capacity, movement initiation, and functional movement in patients with PD .[66][67]

In a recent report of three case studies, patients with mild to moderate PD exercised for 16 months utilizing treadmills, bicycles, rowing ergometers, and ellipticals.[66] The first four months of the program were supervised during which the patients exercised an average of 122.8, 111.2, and 129.7 minutes per week and averaged 67%, 73%, and 80% of their maximal heart rates. Months five through 16 consisted of a home program during which the patients exercised 21.4, 92.5, and 140.5 minutes per week and were encouraged to average a heart rate between 70% and 85% of their maximal heart rates.[66] After the first four months of supervised exercise, all three patients demonstrated improvements in economy of walking as measured through oxygen consumption during 4 different walking speeds. These gains were maintained after the remaining 12 months of unsupervised exercise. In addition, two patients demonstrated improvements in Unified Parkinsons Disease Rating Scale (UPDRS) total score, Continuous-Scale Physical Functional Performance Test (CS-PFP), Functional Reach Test (FRT), and Functional Axial Rotation (FAR) Test that were maintained at the end of the16 months.[66] These results demonstrate that endurance exercise is capable of improving economy of walking, symptoms of PD, and functional movement in patients with mild to moderate PD.[66]

A slightly older study studied the effects of endurance exercise in eight patients with PD in Hoehn and Yahr stage II.[67] Four patients were randomly assigned to perform endurance exercise training three days per week for 16 weeks while the other four patients acted as disease-matched controls. In addition, 6 healthy, age-matched controls were utilized. The patients in the exercise group performed equal durations of bicycling and treadmill walking each session at 60% to 70% of their heart rate reserves. The total duration of exercise was progressed from 20 minutes to 40 minutes.[67] The exercised PD group demonstrated significant improvements in peak VO2 while the control PD group demonstrated a slight decline in this measure. In addition, the exercised PD group demonstrated significantly improved upper extremity movement initiation response times that were not significantly different from those of healthy controls. Conversely, response times of the PD control group were significantly higher than the healthy controls.[67] This study demonstrates not only that endurance exercise improves aerobic capacity in patients with PD but that it can potentially attenuate the declines in movement initiation commonly seen in this population.[67] Further studies investigating the effects at the neurophysiologic and cellular levels would strengthen these findings.

Treadmill Training

Animal Models

Treadmill Training


A recent study investigated whether locomotor training in a 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease could ameliorate neurochemical changes in the striatum [36]. The study also investigated whether this locomotor training could also result in amelioration of locomotor deficits due to the aforementioned neurochemical changes [36]. The rats utilized in this study were lesioned and then randomly assigned to one of three groups. These groups included the following: early treadmill training, late treadmill training, and zero treadmill training or exercise [36]. The rats in the early group participated in training for 30 days, and the training regimen started 24 hours following injection with 6-OHDA [36]. The rats in the early group exercised for a total of 20 minutes, 2 times per day on the treadmill. The late group participated in the same protocol, but started the treadmill training 7 days after injection [36]. For both trained groups, there was no significant difference found as to whether training was early or late when catecholamine levels were assessed at 8 weeks post-injection; however, compared to the untrained rats, there was a significant difference in levels of dopamine, but not norepinephrine [36]. Therefore, the authors concluded that treadmill training was able to attenuate striatal dopamine loss compared to an untrained control [36].

In this 6-OHDA study, the difference between the three groups of rats was also assessed via response to apomorphine injection and further assessment of striatal dopamine levels post-mortem [36]. However, the same training did not ameliorate locomotor deficits as it did with neurochemical deficits [36]. Some locomotor deficits assessed included the following: forelimb preference during exploration, forelimb placement during ladder crossing, and ground reaction forces generated during overground locomotion [36]. Interestingly, on several of the aforementioned locomotor tests, trained rats displayed more severe deficits when compared to the untrained, regardless of whether training was early or late. For example, the trained rats had developed forelimb akinesia in adduction earlier than untrained rats, and the trained rats also moved across the ladder at slower speeds and with smaller stride lengths compared to untrained [36]. The trained animals had less severe deficits on only one locomotor test when compared to untrained; and early training reduced forelimb akinesia when stepping in extension [36]. In general, late training had similar but smaller effects compared to early training.

In summary, early and late treadmill training have been found to attenuate neurochemical changes in the striatal DA neurons of rats; however, locomotor deficits remain, and in some instances are more pronounced [36].

A more recent study also had findings consistent with the above results from Poulton et al [36]. This study also investigated the relationship between treadmill exercise in 6-OHDA injected rats and suppression of DA neuron loss in the striatum [37]. The rats in this study ran on a treadmill for 30 minutes/day for 14 consecutive days following injection with 6-OHDA [37]. A DA agonist, apomorphine, was injected following the 14 days of exercise [37]. The results indicated that the treadmill trained rats had a significantly fewer number of rotations when compared to the lesioned sedentary rats [37]. Tyrosine hydroxylase expression was also analyzed following the exercise period, which revealed enhanced survival of DA neurons in the midbrain as well as their projection fibers in rats following treadmill exercise, suggesting a protective effect to running exercise [37].

An additional study involving treadmill training in mice examined changes in the expression of the dopamine D2 receptor (DA-D2R) within basal ganglia medium spiny neurons [38]. The mice in this study were exposed to MPTP to demonstrate PD-like pathology, and were then subjected to intense treadmill training [38]. The protocol for treadmill training started for the MPTP 5 days after lesioning. Mice from two different exercise groups were trained to run on a 100-cm motorized treadmill at incremental speeds [38]. This training lasted for a total of 6 weeks (5 days/week) to reach a total duration of 60 minutes/day, and a speed of 18-20 meters/min [38]. The results suggested that high intensity treadmill exercise led to an increase in DA-D2R expression in the striatum, and that it was most pronounced in MPTP mice as compared to control mice, which were treated with a saline solution instead of MPTP [38]. However, overall dopamine levels remained low in the MPTP model [38]. The MPTP mice had a more pronounced response to the high intensity exercise, which suggests potential of the injured brain to undergo neuroplasticity[38] . Overall, the results indicated that exercise in the form of intensive treadmill running can facilitate neuroplasticity, and the increased expression of striatal DA-D2R is the primary mechanism for this plasticity [38].

Running speed

This particular study examined the action of striatal dopamine (DA) in response to exercise using treadmill running using rats [39]. DA found outside the cell, as well as its pre-cursors and metabolites, which include dihydroxyphenylacetic acid (DO-PAC) and homovanillic acid (HVA) were measured [39]. In addition to these metabolites, tyrosine hydroxylase (TH) activity within the striatum as well as monoamine oxidase (MAO) activity was also measured [39]. DA turnover increased in response to running on the treadmill, and the increase found in the metabolites DO-PAC and HVA were highly related to the speed of running; however, the increase also seen in DA was not related to the speed of running [39]. Interestingly, an apparent threshold for the increase in DA, DO-PAC, and HVA was noted following running; which was found to be between 300 and 660 cm/min on the treadmill [39]. With a higher speed of treadmill running, tyrosine hydroxylase activity within the striatum was elevated up to 135% compared to baseline values after only 7 days of training at that speed [39]. Additionally, in response to increased training speed, MAO-B activity increased up to 160% of its baseline values after 7 days of training. However, it decreased both immediately after running and 2 hours after running, and then increased again 6 hours after running [39]. MAO-A had a similar fluctuating activity as MAO-B in the treadmill training mice [39]. Overall, the results of this study suggested that physical exercise and the synthesis/metabolism of DA are closely related, and that exercise may also contribute to the fluctuation in DA levels outside the cell, maintaining an optimal range in response to a specific exercise intensity [39].

Voluntary Running

This study sought to determine whether DA neurons in the substantia nigra are spared in rats that voluntarily participate in running exercise. [40] In this study design, two groups of rats were placed in cages with running wheels 7 days before injection of 6-OHDA into the medial forebrain. [40] After injection, the rats were then returned to their cages and remained there for 14 days. [40] Wheel revolutions during free running were recorded each day in the experimental groups, then following the intervention period the rats were injected with apomorphine ( a DA receptor agonist), and then the wheel revolutions were recorded again from the experimental rats. [40] The rats that exercised in the running wheels and who received the DA receptor agonist did not rotate contralaterally, and this suggests that the DA neurons had been spared well enough from the 6-OHDA to prevent any resultant increase in the expression of post-synaptic striatal DA receptors. [40] Contralateral rotations induced by the DA agonist, apomorphine, are normally only observed in animals that have a significant decrease in dopamine innervation of the striatum on one side.[40] This activity is widely used as a marker of over 90% depletion of DA in the striatum when a unilateral 6-OHDA lesion of dopamine neurons is produced for study purposes. [40] Overall, these results suggest that rats with free access to a running wheel for 7 days prior to 6-OHDA injection, who also have access again for 14 days after the lesion, showed neuroprotection for the DA neurons. [40]


A study by Gerecke et al investigated whether running exercise in MPTP mice can protect against neurotoxicity, and specifically the duration of exercise necessary for significant neuroprotection. [42] At baseline, the number of DA neurons in the SNpc were measured and compared. Mice in the experimental group ran independently on a wheel for a period of either1, 2or 3 months prior to injection with saline or MPTP, while the control mice were kept in different housing without a running wheel. [42] Following this period, the mice were treated with either saline or MPTP. [42] All exercise was performed prior to injection, and upon comparison, there was no significant protection in the group who exercised 1 month prior to injection. [42] However, mice that ran for 2 months prior to injection of MPTP had significantly decreased DA neuron loss as compared to the mice that ran for 1 month prior. [42] Furthermore, in the group who ran for 3 months prior to injection, there were fewer DA neurons lost and were not statistically different from the saline control group. [42] Overall, these results indicate that 3 months of voluntary running at a self-selected speed and intensity was able to protect against SNpc DA neuron degeneration.


This study examined the effect of stress on 6-OHDA rats and whether high stress, in conjunction with running exercises, will decrease the neuroprotective effect of exercise on DA neurons. [43] The rats were lesioned with 6-OHDA unilaterally in the medial forebrain. [43] Three different groups of rats were utilized; one group was the “stressed-runners” group, who had their running wheels immobilized for 1 hour/day, food restriction, and an altered light/dark cycle. [43] There was also a control group of lesioned rats who did not run as well as a group of unstressed runners. As described above in previous reports, apomorphine (a DA agonist) was injected and the number of rotations was measured in all three groups. [43] Tyrosine hydroxylase concentrations were measured to determine the amount of surviving DA neurons within the midbrain. [43] Based on rotational behavior, the non-runners had significantly more rotations than the runners, suggesting increased DA depletion in the sedentary rats, and thereby supporting the theory that exercise is neuroprotective.[43] However, the stressed-runners also had significantly more rotations than the non-stressed runners, suggesting that the added stress to these animals effectively cancelled out some of the neuroprotective effects of running exercise. [43]


Based on the results of the aforementioned studies with both 6-OHDA and MPTP lesioned animals, running exercise appears to have a protective effect on DA neurons in models of PD.[36], [37], [38] Additionally, prior running exercise was also found to protect DA neurons from degeneration, while increased stress that was chronic in duration was found to negate the protective effects of running. [43], [42] Therefore, for clinical application based on these animal models, running aerobic exercise should be beneficial to sparing DA neurons; however, stress levels need to be well managed, and those who were active prior to the onset of PD are likely to have more DA neurons spared.

Summary of Animal Models for Treadmill Training/Running Exercise

Parameters Exercise Protocol Outcomes Results
Early versus late effect of Treadmill Training. [36] 6-OHDA lesioned mice, separated into 3 groups: early TT, late TT, and no exercise. 30 days of training, starting either 24 hrs following lesion or 7 days following lesion. Total of 20 minutes, 2x/day on treadmill Rotations following apomorphine injection. Striatal DA levels. Locomotor deficits. Trained animals had less severe deficits on only one locomotor test compared to untrained. Early training reduced forlimb akinesia. In summary, early and late TT attenuated changes in striatal DA rats, while locomotor deficits remained.
Treadmill training to suppress DA loss in striatum. [37] Rats with 6-OHDA lesion; treadmill training for 30 minutes/day, 14 consecutive days. Rotations following apomorphine injection. Tyrosine hydroxylase expression. TT increased survival of DA neurons in the midbrain and their projection fibers. Indicates protective effect to running.
Changes in DA D2 receptor expression in response to TT. [38] MPTP rats; running initiated 5 days after lesioning. 5x/day for 6 weeks to reach duration of 60 min/day. D2 receptor expression. High intensity TT led to increased receptor expression in striatum, although overall DA levels remained low. Running can facilitate neuroplasticity via increased receptor expression.
Running speed in TT. [39] High intensity running speed on treadmill. DA metabolites and precursors: dihydroxyphenylacetic acid, homovanillic acid, tyrosine hydroxylase, and monoamine oxidase. DA turnover increased in response to running, highly related to speed of running as measure via metabolites. Increase in DA directly not related to speed.
Voluntary running to spare DA neurons. [40] 6-OHDA injected mice; apomorphine injection following training. Rats were placed in cages with running wheels versus control with no running cages Wheel revolutions during free running were recorded in each experimental group. Contralateral rotations induced with apomorphine. Rats with free access to a running wheel for 7 days prior to injection and with access 14 days after exhibited increased neuroprotection for DA neurons.
Duration of running for neuroprotection of DA neurons. [42] Mice in experimental groups ran indep on a wheel for either 1, 2, or 3 months prior to injection with saline or MPTP. Number of neurons in the SNpc. Mice that ran for 2 months prior had decreased DA neuron loss compared to 1 month; the group who ran for 3 months had less DA loss and were not statistically significant from the saline control groups.
Effects of stress on neuroprotective effect of running exercise. [43] Rats lesioned 6-OHDA; separated into stressed runners, non-stressed runners, and sedentary. Rats in stressed group: food restriction, altered light/dark cycle, running wheels immobilized 1 hr/day. Number of rotations following apomorphine injection; tyrosine hydroxylase concentrations to determine amount of surviving DA neurons in midbrain. Added stress shown to cancel out some of the neuroprotective effects of running exercise. Stressed runners had significantly more rotations then the non-stressed runners.

Human Models

Studies involving the intracellular effects of treadmill training in humans with Parkinson’s disease are currently lacking; however, there is significant literature regarding the positive effects of treadmill training on motor symptoms of PD.

One study assessing the benefits of treadmill training for patients with PD via a review of the literature found that there were long-term benefits, in the form of gait speed, stride length and disease severity rating. [41] There was also notable long-term carryover, and the results implied that treadmill training has the capacity to induce advantageous neural plastic changes; however, research in this area is currently lacking. [40]
Another study found that a treadmill training program using speed-dependent protocol has the capability to improve mobility, reduce postural instability as well as fear of falling in patients with Parkinson’s disease. [44] Additionally, Pohl et al found that both speed-dependent treadmill training (STT) and limited progressive treadmill training (LTT) improved clinically and functionally important gait parameters when compared to controls and conventional gait training. [45] These parameters included the following: overground walking speed and stride length at self-adapted speeds. [45] Additionally, there was a larger decrease in double limb support time following STT when compared to control subjects. However, overall there was no notable advantage found of STT over LTT. [45]

Neuroplasticity in PD

In the past few years, there has been increasing evidence to support exercise-induced neuroplasticity in patients that is furthermore, associated with behavioral recovery. [68] [68],[69] However, it should be acknowledged that there is limited research specifically on the neurobiology of exercise in various neurodegenerative diseases, including PD. [68] Much of the information about neuroplasticity in PD and that underlying the basis for LSVT principles (discussed below), are inferred from findings of studies showing exercise-induced neuroplasticity in other neurologic populations including stroke, spinal cord injury, etc. [68]

Many animal and human studies have shown that forced use of the impaired limb in subjects/patients with stroke (i.e. constraint induced therapy) results in improved motor recovery and functional organization in both the intact and damaged cortical areas, supporting the presence of activity-dependent plasticity. [68],[72],[73] In the two common animal models of PD (MPTP and 6-OHDA), studies have all found “partial to complete behavioral recovery”, evidence that in these animals there are mechanisms for neuroplasticity. [68] In a study looking at the impact of forced-use exercise in 6-OHDA lesioned rats, the investigators found that in those that were lesioned but not casted, there were “chronic behavioral deficits and no neurochemical protection against the loss of striatal dopamine”. [68], [74] Similarly, those who were lesioned but casted 7-13 days post-injury “showed strong akinetic tendencies”. [68],[74] In contrast, those who were lesioned and casted early (forced use of the impaired limb), showed behavioral and neurochemical benefits, suggestive that exercise may slow or prevent the onset of PD in healthy individuals and furthermore may slow the disease progression in those in the early stages of PD. [68],[74] Many other studies have also looked at neuroplasticity or neuroprotection in treadmill training (see Treadmill section), enriched environments, and other types of exercise training and have had similar findings. [68] One study specifically looking at the effect of an enriched environment with physical activity [in 6-OHDA lesioned rats] showed that the lesioned animals in the enriched environment (experimental condition) had close to two times more newborn cells in the substantia nigra than the lesioned controls. [75] The enriched environment also lead to improvement in rotational behavior in the lesioned animals after 7 weeks as compared to lesioned controls in typical environments. [75] Numerous studies have also found that exercise may lead to development of GDNF producing cells in the substantia nigra and thus be neuroprotective (See Neuroprotective Effects section). [68],[75]

Many studies have found an association between regular moderate to intense physical activity and a reduction in an individuals risk for developing PD as well as a delay in the onset/appearance of symptoms characteristic to PD. [68],[69] This being said, studies have found that after an individual is diagnosed with PD, they tend to decrease their physical activity levels. [68],[70],[71]. Furthermore, stress as well as no activity (forced non-use of the impaired limb) in animal models of PD have been found to reverse the positive and protective effects that exercise can have. [68],[76],[43] One study with 6-OHDA lesions animals found that forced non-use of the impaired limb immediately post-lesioning resulted in “significant limb use asymmetry, exacerbated loss of striatal dopamine (and metabolites) and loss of dopamine terminals”. [68],[76] Thus, the physical inactivity of many with PD may be “prodegenerative” and lead to greater extent of functional loss and disease progression than is typical. [68]

All of this evidence and information taken together supports the notion that exercise-induced neuroplasticity can occur in individuals with PD. As discussed below, the principles of LSVT-BIG are founded on this very rationale.

Lee Silverman Voice Treatment (LSVT®)-BIG


One new intervention approach for individuals with Parkinson’s disease is LSVT®-BIG. This approach is based on the foundation that exercise has shown to have effects at the molecular level that include inhibition of cell death, increased synaptic efficiency and improved behavioral recovery in PD animal models. [6],[55] Additionally, studies have shown and continue to demonstrate the role of exercise in neuroplasticity in animal models of PD as well as other neurological injuries. [6],[33] LSVT® BIG is an “intensive amplitude-specific exercise-based therapeutic approach that adheres to the principles of neuroplasticity”.[33] This approach consists of multiple repetitions (at least 12) of 12 “daily maximal whole-body bigness tasks”.[33] It is implemented in-person for 1 hour/day, 4 sessions/week for 4 weeks. [33] The therapists consistently encourage and cue the patient to perform at a self-perceived exertion level of 8 or more (on a 1-10 scale). [33] Over the 4 weeks, the treatment progressively increases in difficulty and complexity. [33] To encourage carryover and transfer to real-world tasks, the throughout patients are required to utilize and apply their “bigness effort” to their daily tasks or activities. [33] This treatment approach aims normalize the sensorimotor mismatch in PD.[33] Those with PD often exhibit bradykinesia or hypokinesia. However, while their movement is “smaller” than normals, it does not appear to be to the PD patient. In reality, their movement appears to be unchanged since the onset of the disease. Thus, LSVT® BIG teaches patients to move BIG, and while these movements would seem extremely exaggerated to someone without PD, the exaggerated movements lead to normal amplitude movements, intrinsically regulated by PD patients. [33] A couple studies have specifically evaluated the effectiveness of this intervention in patients with PD.


One study included 18 subjects (Hoehn and Yahr stages I-III) who received the LSVT®-BIG protocol (same intensity and duration as discussed above).[34] The sessions included a high number of repetitions of “standardized whole-body maximal amplitude drills including sustained BIG stretches and repetitive BIG multidirectional movements” and were encouraged throughout to focus on the “feel” of the “bigness”.[34] The sessions finished with application of the “bigness” to functional tasks and various ADLs that are part of and/or important to the patient’s everyday life.[34] Directions were either given to subjects to walk and reach as they typically would (preferred group) or to walk and reach as fast as they possibly were able to. [34] The results showed that training focused on increased amplitude of movement (LSVT®-BIG) in those with PD improves bradykinesia and “normalizes” movement amplitude. [34] Post-intervention, the subjects in the preferred speed group improved gait speed by means of increasing stride length but not cadence (12% improvement compared to 4% in the control group) as well as the speed of reaching (measured by wrist velocity) for 3 different target distances. [34] This increase was significant only for the 2 farthest points, with an average 14% increase at these 2 points compared to a 5% average increase in the control group. [34] Those in the “fast group” only significantly improved reaching speed for the furthest distance and while they did tend to take bigger steps (increased stride length), there was no corresponding increase found in velocity or cadence.[34] The subjects who were less impaired, as determined by corresponding Hoehn and Yahr stage, overall made more improvement that those who were more impaired with regard to both reaching and gait tasks.[34] Moreover, the authors suggest that “bigger”, not “faster”, may be more effective in improving/”normalizing” performance not only in gait and reaching but other functional tasks as well. [34]

Another study has demonstrated effectiveness of the LSVT®-BIG protocol. However, to date only an abstract has been published, limiting details of the study available for discussion purposes here. [33],[35] LSVT®-BIG resulted in significant improvements in trunk rotation that remained increased above baseline 3 months post-treatment. [33],[35] Furthermore, the patients’ gait speed and stride length improved and both gait components were maintained when asked to simultaneously perform another task (i.e. walk and recite days of the week). [33],[35] The subjects did better than an age-matched elderly control group on the dual tasks. [33],[35] Significant clinical improvements were demonstrated for the PD patients on the Activities Balance Confidence (ABC)-scale and the PD-Questionnaire (PDQ-39) that assesses overall quality of life. [33],[35]

Exercise Effects on Immune System/Inflammation

Because the role of inflammation and immune system dysfunction in Parkinson’s is so fundamental to the disease pathophysiology, some studies have evaluated the effects of exercise on inflammatory markers and thus, the disease process as a whole. One study examined the effects of cyclic exercise on plasma anti-inflammatory signal molecules including both interleukin-10 (IL-10) and adrenocorticotropin (ACTH). [4] The study included subjects that had been diagnosed with PD for approximately 8 years and were moderately to severely ill.[4] The plasma levels of pro- and anti-inflammatory cytokines and signaling molecules were measured at baseline (group 1), and at weeks 4, 8 and 12 of the intervention (groups 2, 3, and 4 respectively).[4] The intervention consisted of a prescribed 12-week long cyclic exercise protocol, performed 3 times/week and outlined below in Figure 1.[4]

Figure 1. Overview of the Cycle Protocol. [4]

Overall, the results found that in the tested population, a cyclic exercise protocol induces the formation of anti-inflammatory signaling molecules associated with immune, vascular and neural down regulation while pro-inflammatory cytokines did not change in response to the intervention.[4] The levels of these anti-inflammatory molecules were significantly elevated in the plasma of PD patients for months following the beginning of the cyclic exercise program.[4] Furthermore, ACTH and IL-10 levels were significantly increased 1 month after the initial of the intervention.[4] ACTH plasma levels were 76+/- 5, 81+/-5, 133 +/-23, and 139 +/- 17 pg/ml for groups 1-4 respectively.[4] IL-10 concentrations were 1.6 +/- 0.9, 3.6 +/-2.6, 51 +/- 7, and 74 +/- 9 pg/ml for groups 1-4 respectively.[4] On the contrary, pro-inflammatory markers including interleukin 1 (IL-1) and tumor necrotic factor alpha (TNFα) found in the PD brain and MPTP-induced mice were not found in any of the plasma samples in these patients.[4] Cortisol concentration in the plasma was 23 +/-2, 18 +/- 2, 15 +/-2 and 22+/-2 ug/dl for groups 1-4 respectively.[4] These levels were not found to be significantly different at any time, thus implicating that stress was not a factor with these individuals.[4]

Neuroprotective Effects of Exercise

Current evidence suggests that exercise can have neuroprotective effects on many neurologic diseases including Parkinson's disease. [29] Recent studies have looked at the effects of exercise on mitochondria in the subtantia nigra and nuerotrophic factors found in the substantia nigra including brain-derived and glial cell line-derived neurotrophic factors (BDNF and GDNF). A study by Lau et al used a MPTP chronic mouse model of parkinsons which closely replicated the early stages of PD. The exercise protocol was initiated 1 week prior to the administration of the MPTP and lasted for a total of 18 weeks. [29] The excersise protocol had the mice running on a treadmill 5 days a week. The mice ran 40 minute per day at speeds up the 15m/min. This study looked at mitochondrial respiration in the substantia nigra, mitochondrial ATP, and nuerotrophic factors BDNF and GDNF. Both mitochondrial dysfunction and decreases in BDNF and GDNF in the SN have been highly associated with PD. [29] Mitochondrial respiration was measured directly from the rate of oxygen consumption in the SN mitochondria. [29] Results showed an increase in both mitochondrial respiration and amount of mitochondrial ATP in the exercise group compared to the control. BDNF and GDNF were both measured directly from the SN and the striatum. In the exercise group BNDF was significantly increased in the SN but not the striatum and GDNF was significantly increased in the striatum and not the SN. [29] Overall, this study shows that an 18 week exercise program has the potential to be protective of mitochondria dysfunction associated with Parkinson's disease. [29] Also, exercise may selectively promote increases in BDNF and GDNF in different areas of the brain. In this study exercise was initiated one week before the MPTP was given.

Another study by Wu et al also looked at the effects of exercise on BDNF in the SN and striatum. In this study 8 week old mice ran on a treadmill 5 days a week for 4 weeks. In the first week the mice ran at 10 m/min for 20-60 min increasing the time by 10 min per day. [55] During the other three weeks they ran at 10 m/min for 60 min. Following the four weeks of running the mice were injected with LPS (an inflammatory model of Parkinson's). [55] Groups consisted of an exercise and LPS, LPS only, and exercise and LPS and K252A(a BDNF antagonist). Results showed that the exercise group had significantly increased levels of BDNF in both the striatum and SN compared to the control group. Furthermore in the exercise, LPS, and K252A group the levels of BDNF remained low showing more comparisons to the LPS only group. This shows that exercise protects against the loss of BDNF by increasing the signaling pathway TKRB. [55] This pathway is responsible for growth while the p75 pathway of BDNF causes apotosis. [56]

In both studies by Lau and Wu exercise was initiated before PD model was given. It is unclear if the positive affects achieved in both studies would have occurred if exercise was started later. This is something that needs to be studied further. Overall, both studies showed that moderate intensity exercise has a neuroprotective effect against PD in mice. Furthermore, the study by Wu showed not only that BDNF is increased with exercise but proved that this occurs because of an increase in the TKRB receptor/pathway.[55] Many additional studies have also confirmed the idea that exercise has the potential to increase neurtrophic factors BDNF and GDNF and protect against mitochondrial dysfunction in the SN therefore providing a neuroprotective effect in PD. [55] This area of study is promising but more research needs to be done specifically in human models.

Exercise Effects on Cognition

Individuals with PD commonly have cognitive impairments. These include mild impairments early in the disease process and severe impairments and dementia in the late stages.[52] 6-OHDA and MPTP rat models show beneficial effects from exercise protocols that were initiated before or during exposure to the neurotoxin. The effects of voluntary, low-intensity exercise were decreased striatal dopamine loss, decrease in dopamine transporter activity (DAT), and increased motor coordination. [40],[54] Low to moderate physical activity prior to exposure to reserpine (Reserpine interferes with dopamine storage causing a decrease in the nerve terminals) decreases the negative effect on short-term memory in rats.[53] This may illustrate that exercise can prevent behavioral problems from developing in PD.[53] Utilizing a combination of strength and cardiovascular training, researchers have been able to show a selective benefit on executive function tasks of the frontal lobe in humans.[52]

Drugs and Changes with Exercise


Status of pharmacotherapy is known to have a significant effect on muscular strength and maximal force production in individuals with PD, as strength is greatly reduced during OFF periods of medication. [64] Strength measurement has thus been proposed by Pedersen and Oberg [64] as a means of evaluation of pharmacological treatment after it was found that following withdrawal of medication, drops in strength were associated with changes in disability levels. Further studies are necessary in order to more explicitly determine the role medication status plays in the weakness seen in those with PD as compared to neurologically normal adults. [3]

Exercise Capacity and Strength

Levodopa may contribute to reduced exercise capacity by decreasing cortisol release.[61] This has been found at rest and during endurance exercise.[61] Exercise (15 minutes of cycling) does not affect the pharmacokinetics and pharmacodynamics of a levodopa fast-acting morning dose.[62]. Grip strength has been found to be increased during rest only and not during endurance exercise.[61] This functional decrease may cause some of the decrease in exercise capacity.[61]

Cardiovascular Responses

In one study by DiFrancisco-Donoghue et al., individuals with PD demonstrated markedly lower blood pressure, heart rate and norepinephrine responses following an exercise stress test regardless of being in the ON or OFF period of their medications.[57] PD subjects actually had a similar increase in norepinephrine as the healthy control group, but still did not have a normal cardiovascular response.[57] The authors suggest that this may be due to PD subjects having lower levels of norepinephrine prior to exercising.[57] They believe that this abnormal autonomic response to exercise is due to the disease and not to medications being in their ON or OFF period.[57]

A study on entacapone, a COMT inhibitor, showed no effects on the hemodynamic responses to submaximal exercise in healthy individuals.[58] The authors found that the effects of a single dose were short-lived and reversible.[58] They conclude that entacapone, does not affect cardiovascular responses to exercise.[58]


Plasma Homocysteine (Hcy), an amino acid, is elevated in individuals with PD.[59] Additionally, it is higher in individuals with PD that are taking levodopa by 30-80%.[59] Hcy may contribute to neurodegeneration and could be a risk factor for increasing the rate of motor and mental decline in PD. [59] Nascimento et. al. found that Hcy levels were significantly higher in individuals with PD that did not exercise when compared to exercising PD subjects and healthy subjects, although other factors may have contributed over the 6 month study such as nutrition or levodopa dose. Exercise consisted of moderate intensity aerobic exercise for 60 minutes, 3 times a week, over 6 months. Stretching, resistance, balance, and coordination activities were also incorporated. [59] It was found that exercising individuals were on lower doses of levodopa. This may have contributed to the higher levels of Hcy in non-exercisers.

Glutathione and Oxidative Stress

Glutathione (GSH) is an antioxidant produced in the body.[60] It works against oxidative stress by oxidation of GSH to glutathione disulfide (GSSG). [60] A balance is ideally maintained between GSH and GSSG levels.[60] However, with strenuous exercise, the oxidative stress and creation of additional GSSG through free radicals causes an imbalance.[60] GSH and the ratio of GSH to GSSG are considered biomarkers for oxidative stress.[60] Levodopa has been connected to decreased levels of GSH at rest.[60]

Resting GSH levels decrease with aging and in some disorders. [60] PD has the lowest levels of any neurological disorder.[60] GSH and the GSH:GSSG ratio has been found to be significantly higher in resting and exercise controls than in either ON or OFF periods of medication in individuals with PD at peak exercise during a maximal exercise test (Bruce protocol) and during rest.[60] The GSSG was significantly lower in ON and OFF med PD individuals than in the controls at peak exercise.[60] The actual response of GSH and GSSG levels was similar to the control group.[60] These results indicate that individuals with PD, although responding to acute exercise stress, do not have the ability to respond fully to negate the effects of acute stress.[60]

General Exercise Recommendations

Long-term, moderate intensity exercise during the peak "on" state [63] in earlier stages of PD is ideal and may potentially have the greatest benefits at both a functional and cellular level. Resistance training in general should be performed 2-3 times per week for an average of 8-12 repetition sets and progressed according to patient tolerance. Endurance training in general should be performed 5 days per week for anywhere from 30 to 60 minutes per session.

Mode Intensity Duration Frequency Time Disease Stage Cell Biology Rationale
Resistance Training High intensity, moderate volume 8-12 repetition maximum, with 3 minute rest intervals 2-3 days/week See Duration Any disease stage Significant gains in force production in healthy older adults without concurrent muscle hypertrophy suggest adaptation at level of central nervous system. These same gains may offset the reduced neural drive due to decrease cortical activation that results in weakness in those with PD.
Endurance Exercise/Treadmill Training Moderate 40 minutes 5 days/week Long term (>18 weeks) Early to middle disease stages Attenuation of negative striatal (tyrosine hydroxylase, dopamine, dopamine uptake transporter, and mitochondrial function) changes, attenuation of negative SN tyrosine hydroxylase changes, increased SN BDNF, and increased striatal GDNF in MPTP mouse models. Regular exercise may also decrease homocysteine levels (a neurodenerative amino acid) in human subjects
LSVT®-BIG Moderate to intense; multiple repetitions (at least 12) of 12 tasks/activities; self-perceived exertion level of at least 8 on a 10 pt scale 1 hour/day 4 sessions/week 4 weeks Primarily early to middle; can be used at any disease stage but the earlier, the better Evidence for neuroplasticity at the cellular level in PD; exercise has been shown to improve behavioral recovery in animal models of PD (MPTP and 6-OHDA); encourage normalization of sensorimotor mismatch characteristic to PD


  • Exercise should not be initialized for a patient for at least 1 hour after taking medication, especially levadopa, to ensure that medication absorption and effectiveness are not significantly affected [46].
  • When implementing an exercise or rehabilitation program with these patients, it is imperative that exercise periods are short in duration and sufficient periods of rest are given throughout [47].
  • Extra safety measures should be taken when implementing dual tasks (i.e. walking while reciting days of the week) as part of an intervention program [51]. The innate automaticity of daily movement and tasks is significantly decreased in these patients, requiring an increased focus and attention to tasks [51].
  • Consideration should be given to the patient’s on/off periods [51].
  • The earlier physical therapy/rehabilitation is implemented, the more effective and beneficial it will be!
  • Cueing of all types (i.e. tactile, visual, auditory, rhythmic, etc.) can be very beneficial for the patient and improve motor learning and the importance in PD is well-documented and supported in the literature [51],[48],[49],[50]. See Figure 2 [51].

Figure 2. Various types of cueing with examples of each for use in treatment of patients with PD. [51]


Human Studies

There is limited research on cellular mechanisms as they relate to exercise training in humans with PD. Evidence for neuroplasticity in PD is beginning to emerge and forms the basis for many interventions including treadmill training, forced use, and LSVT-BIG. Treadmill training was found to have long-term benefits in gait kinematics and balance in those with PD with long-term carryover and may have neuroplastic implications. Endurance training can improve efficiency of movement, symptoms of PD, aerobic endurance, movement initiation and functional outcomes in patients with mild to moderate PD. Regarding resistance training, there are not currently any accepted guidelines on the types of resistance training (i.e. concentric vs. eccentric) or intensity (i.e. moderate vs. high). However, an overview of the evidence suggests that an incorporation of a resistance training component as recommended by the ACSM's guidelines for healthy, older adults is beneficial to making functional improvements in strength and outcome measures. Levadopa has been found to decrease cortisol levels which may be related to decreased exercise capacity. Cardiovascular responses, although abnormal in individuals with PD, do not appear to be altered during exercise regardless of the "on" or "off" state of medication. Furthermore, being "on" or "off" had no effect on glutathione levels regardless of being in an exercise or resting state.

Animal Studies

Moderate intensity exercise, in general, has been found to be neuro-protective in relation to brain-derived neurotrophic factor, glial cell-lined neurotrophic factors and mitochondria in the substantia nigra. In addition, moderate intensity, long-term endurance exercise results in sparing of dopamine in the substantia nigra and upregulation of D2 receptors. Nonetheless, short-term endurance exercise has been found to be beneficial in making improvements in balance and gait. Also, endurance exercise in animals with severe neurological deficits in the later stages of the disease showed autonomic, cardiac, metabolic and aerobic benefits. Low-intensity exercise prior to and during exposure to the neurotoxin resulted in improvements in short-term memory. Moderate endurance exercise at least 2 months prior to injection improved dopamine sparing and better functional outcomes overall. Moreover, cyclic exercise has been found to improve anti-inflammatory markers and decrease pro-inflammatory markers. In regards to resistance training, there are not currently any studies specifically looking at this type of exercise training in animal models.

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