The Therapeutic Potential of Exercise to Improve Mood, Cognition, and Sleep in Parkinson’s Disease

Abstract

In addition to the classic motor symptoms, Parkinson’s disease (PD) is associated with a variety of non-motor symptoms that significantly reduce quality of life, even in the early stages of the disease. There is an urgent need to develop evidence-based treatments for these symptoms, which include mood disturbances, cognitive dysfunction, and sleep disruption. We focus here on exercise interventions, which have been used to improve mood, cognition, and sleep in healthy older adults and clinical populations, but to date have primarily targeted motor symptoms in PD. We synthesize the existing literature on the benefits of aerobic exercise and strength training on mood, sleep, and cognition as demonstrated in healthy older adults and adults with PD, and suggest that these types of exercise offer a feasible and promising adjunct treatment for mood, cognition, and sleep difficulties in PD. Across stages of the disease, exercise interventions represent a treatment strategy with the unique ability to improve a range of non-motor symptoms while also alleviating the classic motor symptoms of the disease. Future research in PD should include non-motor outcomes in exercise trials with the goal of developing evidence-based exercise interventions as a safe, broad-spectrum treatment approach to improve mood, cognition, and sleep for individuals with PD.

Although traditionally conceptualized as a motor disorder, Parkinson’s disease (PD) is also associated with a variety of non-motor symptoms. These symptoms – including disturbances of mood, cognition, and sleep – substantially reduce quality of life, often to a greater extent than the motor symptoms.^1–4 Also of note, traditional dopaminergic treatments for PD may exacerbate or contribute, at least in part, to mood, cognitive, and especially sleep symptoms in this population.⁵ In this article, we present the evidence supporting aerobic exercise and strength training as promising broad-spectrum interventions for these specific non-motor symptoms in PD, beyond the well-established benefits for core motor symptoms. To date, most exercise programs in PD have focused on improving physical function, including gait, mobility, and balance, and on targeting disease-specific physical impairments, such as bradykinesia, rigidity, and strength.^6–8 In general, exercise, including aerobic and resistance training, improves physical function and motor symptoms in PD.^9–19 Given these benefits to core symptoms, exercise has a potential to be one of those rare adjunct interventions to treat principal non-motor symptoms of PD without worsening the primary motor disorder.

In this manuscript, we review the efficacy of aerobic and strengthening exercise interventions in PD relative to more conventional treatments of mood, cognition, and sleep. The following electronic databases were searched: PubMed (1990 to July 6th 2015), Google Scholar (1990 to July 6th 2015), and Cochrane Library (1990 to July 6th 2015); citation tracking was also used to identify relevant references. Specifically, we included studies if they met the following criteria: 1) at least one target population was adults with PD; 2) aerobic exercise and/or resistance exercise was used in at least one of the exercise conditions; 3) at least one outcome measure was included to examine mood (depression or anxiety), cognition, or sleep; 4) the paper was available in English as of July 6, 2015. To inform these findings, we also discuss the relevant literature on aerobic and resistance exercise in healthy older adults, as well as neurologic populations. Although many forms of exercise may be beneficial, we limited our review to studies that included aerobic and/or strengthening exercise, as the evidence in these areas is more developed in healthy older adults and in persons with PD from both a clinical and mechanistic perspective. Also of note, additional non-motor symptoms manifest in PD, including fatigue and autonomic, gastrointestinal, and sensory symptoms,²⁰ but the literature investigating the effects of exercise on these symptoms remains very limited; accordingly, the present article focuses on the potential benefits of exercise interventions on mood, cognition and sleep only.

Treatment of Mood Symptoms in PD

Mood disturbance (here referring to depression and anxiety) develops in many individuals with PD, even in the early stages of the disease,²¹ contributing to poorer quality of life^1,2,22 and caregiver burden.²³ Major depression is estimated to occur in 20–40% of individuals with PD,^24,25 and clinically significant anxiety in approximately 40%^26–28 (prevalence of psychiatric symptoms in PD reviewed in ²²). Depression in PD is associated with poorer emotional well-being, communication, and activities of daily living,^29,30 as well as increased disability, falls, and caregiver distress, with some research indicating that depression may predict 10-year mortality.^31–33 Despite these high prevalence rates and associated distress and disability, clinical management of many non-motor symptoms, including depression and anxiety, remains inadequate.³⁴

Anxiety is common but less studied and treated in PD than depression.^34–37 In addition to generalized anxiety disorder, panic disorder, and simple and social phobias, individuals with PD also report recurrent situational anxiety related to their motor symptoms, including fear of falling or fear of crowded places due to freezing of gait.^27,28 Anxiety is associated with reduced quality of life in PD,^38–40 even after controlling for the effects of motor symptoms,^3,41 and to a greater extent than depression.²

The high prevalence, early manifestation, and negative impact of anxiety and depression in PD dictate the need to manage and improve these symptoms, which are under-treated and understudied.^42–46 To date, antidepressants have generally yielded non-significant and variable effects for both depression^46,47 and anxiety⁴⁶ in PD. Some controlled studies suggest that certain selective serotonin reuptake inhibitors, dual reuptake inhibitors, and dopamine agonists may improve depression in PD, albeit with some risk of treatment-related side effects (e.g. fatigue, dry mouth, orthostatic hypotension, dyskinesia).^48–50 Benzodiazepines are not recommended for the treatment of anxiety in PD due to potential side effects, including autonomic, cognitive, sleep, and psychomotor impairments.^22,51,52 There is emerging evidence for psychosocial alternatives to pharmacologic treatment of mood, with limited but promising data from cognitive behavioral therapy (CBT).^46,53–60

The Potential of Exercise Interventions for Mood

Exercise interventions have demonstrated robust efficacy in the treatment of mood symptoms in the general population and in older adults, but few exercise trials in PD have included mood as an outcome measure. A meta-analysis of 11 randomized control trials (RCTs) with adults with major depression reported a large combined effect size for exercise, usually aerobic or resistance training, relative to non-active control conditions.⁶¹ More recent meta-analyses confirm a significant acute effect of exercise on depression relative to non-exercising control groups,⁶² with benefits generally following programs of at least moderate aerobic activity delivered several times a week, often in a group setting, with session durations of 20 to 45 minutes.⁶¹ Although promising, these meta-analyses are not without limitations, such as restricted power due to the small number of included trials, as well as the selection bias of individuals who volunteer to participate in exercise research.^61,62 Despite this, the benefits of exercise are conferred across a wide range of settings and symptom severities. For example, Mota-Pereira and colleagues⁶³ found that aerobic exercise (30–45 minute sessions, 5 days/week) offered significant improvement or remission of depression in outpatients who had failed two previous trials of antidepressant medication (see also ⁶⁴). Aerobic exercise also has efficacy in combination with antidepressants or CBT.^65,66 Even in healthy adults without clinical depression, exercise interventions, including resistance exercise, have improved depressive symptoms.⁶⁷ In sum, exercise has been shown to reduce depression in the general population, suggesting that it may also benefit those with PD and depression, either as a stand-alone or adjunctive intervention to improve mood.

Besides its antidepressant effects, exercise is also anxiolytic.^68,69 Strong effects on self-reported anxiety were documented in a meta-analysis of primarily non-clinical samples⁷⁰ with further evidence from clinical trials for panic disorder, generalized anxiety disorder, and social anxiety.⁶⁸ These clinical trials have focused largely on aerobic exercise (usually completed 2–5 times per week, for 5–12 weeks), often in small samples, with unstandardized or unsupervised exercise sessions and/or lacking a non-exercising control group; nevertheless, the results are encouraging and suggest that aerobic exercise, in particular, may effectively treat anxiety disorders, either as a stand-alone intervention or as an adjunct treatment in combination with pharmacotherapy or CBT.^68,71 More controlled studies are needed to determine the optimal exercise dose and modality required to achieve lasting anxiolytic effects.

Exercise has also been shown to improve mood in healthy older adults (e.g. ⁷²). For example, physical exercise, usually aerobic or resistance training completed 3 times per week for 20–60 minutes for 6–19 weeks, yielded positive short-term outcomes for depressive symptoms;^73,74 and compared to a non-exercising control group, aerobic (but not resistance) exercise was associated with reduced depressive symptoms, regardless of baseline level of depression.⁷⁵ Comparing an aerobic exercise program to pharmacological treatment, exercise (three 45-minute sessions/week) was equally effective at reducing depressive symptoms after 16 weeks of treatment, although the study did not control for the social interaction aspect of the exercise group.⁷⁶

There is promising evidence that exercise may improve depression among adults with neurologic disorders,⁷⁷ but there remains limited research on the effects of aerobic and resistance exercise on mood in PD specifically. In a large RCT with 231 adults with PD, six months of strengthening exercises (40–60 minutes, 3 times/week) yielded improved positive affect relative to a usual-care control group.¹⁸ In a second controlled trial, individuals with PD were randomized to either an early- or late-start group exercise program (combined cardiovascular and strength training, completed for 60 minutes, 3 days/week, for 24–48 weeks).⁷⁸ Participants in the early-start group reported significantly fewer depressive symptoms after 48 weeks, relative to the delayed start group, although there was no control for the potential effects of weekly social interaction on mood. In a comparative trial of three types of exercise (high-intensity treadmill training, lower-intensity treadmill training, and stretching/resistance training), no changes in depression were observed for any group after 3 months of exercise (30–50 minutes, 3 times per week), although participants reported only mild levels of depressive symptoms at baseline.⁷⁹ In a smaller study, aerobic exercise, completed twice per week for 12 weeks, improved mood, while maintaining functional ability, among 13 adults with early PD relative to non-exercising PD participants.⁸⁰ In a sample of 11 early- to mid-stage participants with PD, 5 participants (mean age=64.0) completed a 4-week general exercise program (60-minute sessions of combined aerobic and resistance training, 4 times/week), and 6 participants (mean age=62.8) completed an exercise-based behavioral treatment focused on increasing amplitude of movement.⁸¹ Although there were no between group differences, the combined group showed improvement in depression and fatigue at all post-intervention assessments (weeks 4, 12, 24), suggesting benefits of both exercise approaches. In an uncontrolled trial, 49 individuals with PD (mean age=65.5) reported reduced depressive symptoms after six months of aerobic walking (3 times/week for 45 minutes per session), although depressive symptoms were very low among this sample.⁸² In general, the PD exercise studies that have included mood outcomes have included participants with minimal depressive symptoms, limiting their generalizability. Even so, these studies provide strong rationale for the targeted use of exercise to improve mood in PD.

Cognitive Impairment in PD

Like mood symptoms, cognitive impairments are common and heterogeneous in PD,^83–87 even in the early stages of the disease, with widespread implications for quality of life and functional abilities such as driving.^1,88–93 Cognitive disruptions can also co-occur with other non-motor symptoms, tending to be worse in PD with depression, for example.^94,95 Up to 57% of individuals with PD experience some cognitive impairment within the first 3–5 years after diagnosis,⁹⁶ including deficits in executive functioning, visuospatial function, and attention/working memory.^97–99 Measures of attention and executive function (“frontal” tests) are often the most sensitive to cognitive compromise.¹⁰⁰ Executive dysfunction often emerges early in the disease course and is thought to be associated with dopaminergic dysfunction in fronto-striatal regions, whereas memory impairment and visuoconstructional difficulties, along with cognitive decline and dementia, may be driven by cortical Lewy body pathology and cholinergic deficiency.^{87,88,96,101,102,103} With cognitive impairment beginning in the early stages of PD,⁸⁸ there is a corresponding need for early cognitive-enhancement strategies.

The Potential of Exercise Interventions for Cognitive Enhancement

There is reliable evidence for significant benefits conferred upon cognition by exercise programs.^104,105 A meta-analysis of RCTs (29 studies, 2049 participants) has indicated that healthy older adults reliably achieve modest improvements in attention and processing speed, executive function, and memory following aerobic training.¹⁰⁵ The exercise trials ranged in duration from 6 weeks to 18 months, with modal length of 2.5 to 4 months, but with relatively minimal range of exercise intensity or frequency across trials (most often 3 times per week at 70% peak oxygen uptake (VO₂)). Exercise typically comprised brisk walking and/or jogging relative to wait-list control or other comparison conditions (stretching and toning, health education, or relaxation). Greater benefits to attention and processing speed arose from trials that combined aerobic exercise with strength training, relative to aerobic only interventions. Likewise, aerobic training has been reported to improve cognition in healthy older adults, especially for executive-control processes¹⁰⁶ – a finding particularly pertinent to the goal of improving executive dysfunction in PD.^97,100 There remains need for additional research to examine how aerobic exercise may affect various cognitive domains when maintained for extended periods of time (e.g. several years instead of months).¹⁰⁵

Exercise may also improve general cognitive functioning and balance in older-adult neurological populations, including those with mild cognitive impairment, as well as Alzheimer’s disease (AD) and other dementia-causing disorders.^107,108 This research is relevant to PD, given that cognitive impairment, including dementia, often emerges over the course of the disease^109–111 and that an AD-like pattern of brain atrophy in PD may predict cognitive decline.¹¹² There is preliminary evidence that aerobic exercise may be associated with greater memory improvements among adults with mild cognitive impairment relative to cognitively intact adults.¹⁰⁵ In a large sample of adults (≥ 50 years) with subjective memory impairment, a six-month exercise program (at least three 50-minute sessions of moderate-intensity aerobic exercise per week) yielded modest improvements on brief cognitive tests of memory, language, and praxis (Alzheimer Disease Assessment Scale – ADAS-Cog) over an 18-month follow-up period; participants in the exercise group also improved on word list delayed recall.¹¹³ It is important to note that the primary outcome measure in this study was a non-specific measure of overall cognitive function, rather than an index of a specific cognitive domain. Relative to a non-active control group, elderly individuals with AD (mean age=78.3) demonstrated improved balance and executive functioning (Clock Drawing Test and Frontal Assessment Battery) following dual-task exercise that paired motor and cognitive tasks (60-minute sessions completed 3 times/week for 4 months).¹¹⁴ Aerobic training has also been reported to improve visual learning, working memory, and processing speed in psychiatric populations, including depression.¹¹⁵ In sum, exercise has demonstrated cognitive benefits in healthy older adults and in adults with conditions that may be observed in PD (e.g. depression and dementia), supporting the potential cognition-enhancing role of exercise for PD.

There is initial evidence that these expectations will be realized in PD.^116,117 Aerobic exercise may particularly impact executive function in PD,¹¹⁸ consistent with the findings in healthy older adults.¹⁰⁶ Twelve weeks of combined aerobic plus anabolic exercise, conducted twice weekly, resulted in selective improvement in frontal-based executive function (spatial working memory and verbal fluency, relative to spatial and pattern recognition memory) in 15 individuals with PD compared to 13 non-exercising PD control participants (all in mild to moderate disease stages and approximately 60 years old).¹¹⁹ Likewise, in relatively large studies of a long duration, 6 months of moderate-intensity aerobic exercise, conducted three times per week for 45–60 minutes, led to improved executive functioning for individuals with mild to moderate PD (mean age of approximately 65 in both studies), though only one of these studies used a non-exercising PD control group.^82,120 Across these studies, moderate-intensity aerobic exercise, conducted 2–3 times per week, produced promising effects on executive function in the mild to moderate stages of PD, consistent with studies in healthy older adults.¹⁰⁶ In small preliminary case studies, 8 weeks of aerobic exercise, completed 3 times per week for 20–40 minutes, yielded improvements in executive function, verbal fluency, and working memory for three individuals with PD – one with high cognitive performance at baseline (age 66), and two with cognitive impairments (ages 61 and 72).^121,122 Further research is warranted to examine the underlying mechanisms driving these selective improvements, which may relate to increased cerebral perfusion, release of growth factors, or angiogenesis following aerobic exercise, as suggested by Tabak and colleagues.¹²¹ Among healthy older adults, aerobic training, relative to non-aerobic, may even mitigate volume loss in prefrontal regions,¹²³ which are associated with a variety of executive control processes. Of note, both prefrontal atrophy and executive dysfunction occur in PD, even in the early stages of the disease.^97,124

At the same time, recent evidence suggests that resistance exercise may also benefit cognition in PD. After 24 months of twice weekly progressive resistance exercise (60–90 minutes per session), adults with PD improved their performance on measures of working memory, inhibition, and attention (Digit Span, Stroop, Brief Test of Attention).¹²⁵ The comparison group completed stretching, balance, and non-progressive strengthening exercises (of the same duration and frequency) and improved on Digit Span and Stroop after 24 months.¹²⁵ There were no between-group differences on any of the cognitive measures at 12 or 24 months, and the authors noted that their sample was relatively young, highly educated, and in mild-to moderate disease stages, thereby limiting the generalizability of their findings.¹²⁵ Even so, these results provide clear rationale for future research to examine the targeted use of resistance exercise to improve cognition in PD. Taken together, emerging research suggests that aerobic and resistance exercise may improve cognition in PD; however, there remains a need for larger, well-controlled studies on the cognitive effects of exercise interventions among adults with PD.

Sleep Disruption in PD

In the general population, the prevalence of insomnia symptoms ranges from 25% to 48% and insomnia diagnoses from 4.4% to 9.5%.^126–129 Sleep disruptions are common among older adults¹³⁰ and are particularly problematic and multifactorial in PD,^40,131,132 with reference to this problem dating back to James Parkinson’s observations in his original essay.¹³³ Fragmented sleep has been reported,^134–139 attributed in part to nighttime motor symptoms,^140,141 with reports of sleep benefits upon control of these symptoms.^142,143 Individuals with PD may present with REM sleep behavior disorder, excessive daytime sleepiness, sleep onset and sleep maintenance insomnia, as well as sleep disordered breathing, restless leg syndrome, and nocturia.^132,144 Furthermore, sleep disturbances in PD are linked to mood and cognitive dysfunction,^145–147 likely related to neurodegenerative changes. The underlying disease pathology in PD is now thought to begin in the brainstem,¹⁴⁸ where damage to specific nuclei (e.g., locus ceruleus, pedunculopontine nucleus) and neurotransmitters (e.g., norepinephrine, serotonin, dopamine, GABA, acetylcholine) likely affects sleep-wake and REM sleep modulation in PD years prior to the manifestation of motor symptoms.^{132,140,144,149} Given the magnitude of the impact of sleep disruption on quality of life in PD,^1,150 there is need to address general, age-related, and disease-specific sleep disruptions in those with PD.

The Potential of Exercise Interventions for Sleep Disruption

Meta-analytic review of 25 studies indicates that regular exercise programs help adults achieve moderate-to-large sleep quality benefits, as per the self-reported Pittsburgh Sleep Quality Index (PSQI),¹⁵¹ which includes subscales of daytime sleepiness as well as sleep disturbance, duration, efficiency, latency, and medication use.¹⁵² The moderate-to-large effects of regular exercise were observed for all PSQI subscales except sleep medication use. Across aerobic, anaerobic, and mixed studies, regular exercise had small effects on total sleep time and sleep efficiency and a small-to-moderate effect on sleep onset latency, predominantly assessed using objective measures (e.g. electroencephalogram or polysomnography).¹⁵² These benefits appear to be uniform across younger and older samples except for weaker effects on sleep-onset latency in older adults, consistent with its general worsening with age.¹²⁷ Even individual sessions of exercise, evaluated across 41 studies (predominantly aerobic training), conferred benefit on objective measures of sleep, though with small effect sizes that varied in reliability.¹⁵² Moderate-intensity aerobic exercise (30- to 40-minute sessions, completed four times per week, for 16 weeks) yielded improvements in self-reported sleep quality (global PSQI score) among healthy older adults (ages 50–76) with sleep complaints, relative to wait-list control participants.¹⁵³

There is some indication that the benefits of exercise for sleep extend to individuals with PD, including improved sleep, quality of life, and daily functioning.^154,155 In an RCT (with stratified randomization), 17 PD participants in mild to moderate stages (mean age=67.8) who completed six months of multimodal exercise (three 60-minute sessions per week of muscular resistance, balance/motor coordination, and aerobic fitness) reported enhanced sleep and functional abilities on standardized questionnaires compared to 17 PD control participants who did not exercise.¹⁵⁵ The sleep questionnaire (Mini-Sleep Questionnaire) included items related to both insomnia and daytime sleepiness. Only the total score was used for data analysis, so it is not possible to determine if exercise more strongly affected insomnia or daytime sleepiness. Likewise, after 36 group sessions of combined aerobic conditioning and muscular strengthening (75 minutes each, 3 times per week, for 3 months), twenty mild- to moderate- stage PD participants (mean age=61.5) reported significant improvements in quality of life, particularly within the domains of emotional reactions, social interactions, and physical ability, as well as reporting a trend toward improved sleep on a self-report questionnaire.¹⁵⁴ A significant limitation of both PD studies was the lack of objective sleep measures. Further research is needed to elucidate potential effects of exercise on daytime and nighttime sleep disturbances, including larger, well-controlled trials that include subjective and objective sleep outcome measures.

Potential Mechanisms of Action of Exercise on Mood, Cognition, and Sleep

Dopaminergic dysfunction in the hypothalamus and limbic regions may be associated with disturbances of mood, cognition, and sleep in PD.^156–159 It is plausible then that exercise may improve these non-motor symptoms at least partially via dopaminergic mechanisms. More specifically, exercise may modulate dopaminergic and glutamatergic neurotransmission, and thereby attenuate basal ganglia hyperexcitability in PD.^160,161 Among exercising rats (n=10) relative to sedentary counterparts (n=9), aerobic exercise (6 weeks of wheel running) has been associated with increased dopamine synthesis and reduced inhibition of dopamine neurons in the substantia nigra pars compacta.¹⁶² Preliminary evidence in humans suggests that aerobic exercise (three 60-minute treadmill sessions/week for 8 weeks) may lead to increased dopaminergic signaling (per imaging with positron emission tomography) and improved postural control in the early stages of PD.¹⁶³ Although non-motor outcomes were not included in this pilot study, the reported improvements in postural control are potentially relevant for non-motor symptoms given that common neural substrates may modulate balance control and anxiety (e.g. parabrachial nucleus network and associated connections to limbic regions).^156,164,165

Besides its dopaminergic effects, regular exercise also has a wide variety of effects on non-dopaminergic neurotransmitter systems, including serotonergic, noradrenergic, and GABA-ergic systems, which is relevant for depression, anxiety, and sleep.^166,167 In rats that swam (n=18) 5 days a week for 10 weeks (typically 30 minutes per day), exercise was associated with increased hippocampal levels of serotonin and norepinephrine¹⁶⁸ – two neurotransmitters that have been implicated in modulation of anxiety, depression, and sleep.^{156,169–171} In regard to the potential for improved cognition,¹⁷² animal work indicates that serotonin is necessary in order to achieve exercise-induced neurogenesis in the hippocampus (n=30 per group).¹⁷³ In human research, aerobic exercise (three 30-minute cycling sessions per week, for 7 weeks) has been associated with reduced depression and reduced blood serotonin, relative to a stretching-control group.¹⁷⁴ This effect is similar to effects of selective serotonin reuptake inhibitors, although the sample consisted of healthy undergraduate students who were not pre-screened for anxiety or depression, which limits its generalizability. These findings suggest that aerobic exercise may increase levels of serotonin and norepinephrine in the brain, which may positively affect mood, cognition, and sleep. For example, cognitive dysfunction and sleep disturbances (e.g. insomnia, vivid dreaming, and sleep-disordered breathing) in PD are generally unresponsive to dopamine therapy,¹⁷⁵ suggesting that these symptoms may develop, at least in part, through non-dopaminergic mechanisms. Likewise, anxiety in PD is associated with dysfunction in a variety of neurotransmitter systems, including noradrenergic and serotonergic, which may precede dopaminergic depletion.¹⁵⁶ Aerobic exercise, then, could act upon these non-dopaminergic systems to improve non-motor symptoms, particularly in the early stages of PD.

The mechanisms by which exercise may affect non-motor symptoms, especially cognition, in PD may be similar to structural and functional brain changes and proliferation of growth factors seen in exercising healthy adults. Higher aerobic fitness in healthy older adults (mean age=66.6) has been associated with greater gray matter volume in dorsolateral prefrontal cortex and improved executive function (Stroop test of inhibition) and spatial working memory.¹⁷⁶ The association with prefrontal volume is relevant to PD as affected individuals may show prefrontal and hippocampal atrophy even in early stages of the disease.¹²⁴ Imaging with positron emission tomography has also revealed that prefrontal dysfunction in PD (hypometabolism) contributes to difficulties with set-shifting.¹⁷⁷ Following a one-year walking intervention (three 40-minute sessions per week), aerobic fitness in older adults was associated with white matter changes in frontal and temporal regions, as well as improved short-term memory relative to an active control group (flexibility, toning, and balance).¹⁷⁸ Also following one year of aerobic exercise, increased functional connectivity in the temporal lobe among healthy older adults (mean age=66.4) was associated with increased levels of growth factors, including brain-derived neurotrophic factor (BDNF), as well as insulin-like growth factor type 1, and vascular endothelial growth factor.¹⁷⁹ Consistent with these findings, regular aerobic exercise in healthy older adults is thought to promote neuroplasticity and facilitate learning and memory through the release of neurotrophins, including BDNF, glia-derived neurotrophin (GDNF), nerve growth factor (NGF), and galanin.^106,180 In PD, aerobic exercise may increase the production of growth factors and promote gray and white matter changes, especially in prefrontal regions, both of which may contribute to improved cognitive function.

Animal and cellular studies further highlight the important effects of BDNF on neurogenesis, dendritic growth, and long-term potentiation.^181–184 Meta-analytic review of 29 human studies (1111 participants) indicates that single sessions of exercise induce BDNF activity and that there is a significant increase in this activity with regular exercise.¹⁸⁵ These effects appear reliable enough that Szuhany and colleagues¹⁸⁵ suggested that exercise can be considered as an intervention to induce BDNF for subsequent therapeutic benefit, although they note that future research is needed to examine the effects of exercise type (e.g. aerobic versus resistance training) on BDNF. Rodent and human studies indicate that BDNF may mediate both the mood and cognitive effects of exercise,^186–189 with a particular effect on executive function in older adults,¹⁹⁰ which is known to be compromised in PD.⁹⁷

These mechanisms may relate to potential cognitive benefits of exercise in PD, given the known executive dysfunction and reduced BDNF expression in this population. Postmortem human studies and rodent studies indicate significantly reduced expression of BDNF in the substantia nigra in PD,^191–194 and surviving dopaminergic neurons in the substantia nigra express reduced BDNF compared to control cases.¹⁹² In a 6-hydroxydopamine (6-OHDA) rat model of PD, exercise (4 weeks of treadmill running, 30 minutes/day, 5 days/week) has been found to increase levels of BDNF in the striatum.¹⁹⁵ In a recent human study of early-stage PD, 28 days of intensive aerobic exercise increased BDNF levels, improved motor symptoms (balance and gait),¹⁹⁶ and potentially slowed motor symptom progression after a two-year follow-up.¹⁹⁷ Indeed, drawing largely from animal studies, Fumagalli and colleagues¹⁹⁸ posited that BDNF may function as a neuroprotective molecule and also a neuromodulator in PD, such that it is associated with the loss of dopaminergic neurons when inhibited, and with improved cognition when expressed. Exercise may improve hippocampal function via BDNF expression,¹⁹⁹ and in non-PD rats (n=7 per group), BDNF expression has been associated with exercise-induced enhancement on learning and recall on the Morris water maze after one week of voluntary wheel running.¹⁸⁹ Though there are limitations related to translating results in animal models of PD to humans with PD,²⁰⁰ animal work as well as emerging human research suggest that aerobic exercise may lead to improvements in cognition that may be mediated, at least in part, by increased production of BDNF.²⁰¹ In sum, the potential effects of exercise-induced BDNF on cognition in PD are particularly promising.

These findings suggest that exercise has potential neuroprotective and neurorestorative effects in PD, which may be associated with subsequent improvements in overall brain health, mood, and especially cognition,¹¹⁸ though the majority of this evidence in PD comes from animal studies and small pilot studies. Other mechanisms may be active for the effects of exercise on sleep, and potentially include body temperature elevation (to promote slow wave sleep), increased cytokine levels, heart rate variability (and associated improvements in vagal modulation and parasympathetic control), as well as increased BDNF activity and associated changes in mood.^152,202,203 As sleep disruption is a core symptom of depression, and aerobic exercise improves depression, it is plausible that exercise may benefit sleep as a function of improved mood, or vice versa.^202,204 It may also be important to consider the potential effects of aerobic exercise on cholinergic function, as demonstrated in non-PD animal studies.²⁰⁵ It is unknown whether these positive effects translate to persons with PD, but it warrants examination, given the association between cholinergic dysfunction and disturbances of sleep, mood, and cognition in PD.^132,149 Ultimately, sleep benefits from exercise may result from some of the same or alternative mechanisms as those that positively affect mood and cognition.

It is also important to consider potential mechanisms specific to resistance exercise in PD. Progressive resistance training in PD has yielded improvements in strength and motor symptoms, as well as cognition.^19,125 Future research should more closely examine the effects of resistance training on non-motor symptoms in PD, especially cognition, which may relate to reduced levels of homocysteine and/or increased levels of insulin-like growth factor I.²⁰⁶ At the same time, resistance training may facilitate motor improvements via increased neural drive and central neural changes, such as cross-education and reduced agonist-antagonist coactivation.²⁰⁷ These mechanisms may be relevant for PD given the reduced muscle activation observed in the disorder, which largely contributes to bradykinesia and muscle weakness.²⁰⁶ Drawing from functional neuroimaging studies, resistance training may also promote functional neuroplasticity in the cortex and basal ganglia, although all of these potential mechanisms require further study in PD.²⁰⁶ For a review of potential mechanisms of resistance exercise in PD, please see ²⁰⁶.

Exercise Dose and Adherence in PD

Public health guidelines recommend a minimum of 150 minutes of moderate-intensity aerobic exercise plus 2–3 sessions of strengthening exercises per week for adults aged 18–65,²⁰⁸ but it is unknown whether this recommendation is also appropriate for individuals with PD. Optimal dosing of exercise in PD has not been determined. Current research efforts are beginning to examine this question, including an ongoing multi-site, randomized, controlled study designed to compare moderate-intensity to high-intensity aerobic training in PD.²⁰⁹ Intensive rehabilitation strategies (three daily exercise sessions, 60 minutes each, 5 days per week, for 4 weeks) that include aerobic exercise (heart rate reserve ≤60%; maximum speed of treadmill scrolling=3.5 km/hour) revealed increased BDNF levels and improved motor symptoms in the early stages of PD, suggesting the benefits of higher intensity exercise¹⁹⁶ as well as potential benefits in cognition via BDNF. Other exercise trials in PD, however, reveal equivalent benefits related to physical function for both low (50 minutes at 40%-50% of heart rate reserve) and high (30 minutes at 70%-80% of heart rate reserve) intensity of aerobic exercise conducted 3 times a week for 3 months.⁷⁹ In studies examining the benefits of strength training, high-intensity resistance programs have been shown to be safe and efficacious and associated with greater improvements in quality of life relative to active control groups.^8,210,211 A progressive resistance training program (at least 5% increase in resistance as participants were able) was found to be more effective in improving motor symptoms than a strengthening program that was not progressive (no systematic increase in load), suggesting greater benefits of a high dosing,⁸ although both programs produced improvements in cognition after 24 months.¹²⁵ The only other non-motor outcome included in these studies was quality of life, which may capture secondary effects on mood, but otherwise, the effects of exercise intensity on mood and sleep in PD remain largely unknown and warrant further study.²¹²

Generally speaking, adherence to exercise programs among adults with PD is relatively high (often >80%) in the context of research where there is typically a great deal of emphasis on promoting adherence.²¹³ Likewise, across exercise trials in PD, retention rates are largely above 80%, with studies typically conducted in clinic and lasting 8 weeks on average, though some studies have reported similar retention rates for trials of a longer duration (up to two years).^8,79,213 Persons with PD tolerate exercise programs quite well with relatively low dropout rates (~10–20%) and minimal adverse effects.^{8,18,78,79,82,213,214} The majority of adverse events tend to consist of relatively mild musculoskeletal issues that resolve relatively quickly and do not require medical attention or restrict activities.^18,82,214 This minimal-risk profile compares favorably to medications for non-motor symptoms in PD,²¹⁵ and provides further support for the use of exercise to simultaneously improve multiple motor and non-motor symptoms. At the same time, it should be noted that the largely supervised, in-clinic nature of current exercise studies in PD may limit generalizability of these findings to motivated research participants who have access to a highly structured research setting. Further research is warranted to better examine the longevity of effects and to effectively tailor the content, dose, and delivery of exercise programs to individuals at various stages of PD.

Treatment Stage and Exercise Intervention

Exercise has been shown to be beneficial to individuals with PD across Hoehn & Yahr stages I-IV, with most trials focusing on stages II and III.^{6,12,216–218} At the same time, the potential neuroprotective and neurorestorative effects of exercise¹¹⁸ underscore its importance early in the course of the disease.²¹⁹ Non-motor symptoms of PD, including disturbances in sleep and mood, can emerge years before the motor symptoms.^136,220,221 In particular, individuals in the early stages may present with depression or anxiety that may be more distressing or interfering than the motor symptoms.²²² Accordingly, exercise programs are particularly well suited to early implementation in PD with the potential for diffuse non-motor benefits (e.g. mood, sleep, cognition) and few side effects or adverse events. By implementing exercise interventions to improve depression, for example, in the early stages of PD, we can hope to also affect associated comorbidities, such as anxiety, memory difficulties, and sleep disruption²²³ and subsequently improve daily functioning and quality of life (e.g. ²²⁴). Of note, sufficient dopamine replenishment, most often with carbidopa/levodopa, may be necessary to facilitate adherence and motivation for regular exercise and to avoid the formation of sedentary habits among individuals with PD.^201,225 The majority of exercise trials in PD have been conducted with participants on appropriate dosages of dopaminergic medication, and the combined effect of dopaminergic medication plus exercise in PD has yielded greater physical benefits relative to medication or exercise alone.²²⁶ These findings highlight the importance of dopamine replenishment to enhance motor functioning and allow adults with PD to exercise at sufficient doses and intensities. In sum, for as long as individuals with PD are able to safely engage in physical activity, exercise should be seriously considered as an intervention strategy with the potential for widespread benefits for both non-motor and motor symptoms.

Conclusion

The conceptualization of PD has shifted from that of a pure motor disorder, with a burgeoning research effort in the domain of non-motor symptoms.^4,36 There is as yet limited research on the management of mood, cognitive, and sleep symptoms in PD,³⁴ with these symptoms often being comorbid.²²⁷ As we expand our understanding of the etiology and manifestation of the non-motor symptoms, a shift in attention to identifying and prescribing effective treatment is warranted. If these symptoms do share underlying pathologies, it is possible that a single treatment may yield multi-faceted symptom improvement.

Aerobic and resistance exercise, in particular, offer especially promising treatment strategies for alleviating a spectrum of PD symptoms, including motor function, mood, cognition, and sleep. It is important to emphasize that exercise programs have generally been well tolerated in PD with few adverse events,^{12,216,228,229} attenuating concerns about the ability of individuals with PD to successfully complete prescribed exercise due to motor limitations.

In conclusion, exercise presents a particularly feasible treatment approach in PD with minimal side effects and the potential to yield broad-spectrum benefits related to mood, cognition, and sleep, particularly if implemented in the early stages of the disease. The known benefits of exercise in healthy older adults may very well translate to this population, driven by potentially overlapping mechanisms. As with the majority of PD studies, exercise research in PD has focused primarily on the motor symptoms and largely failed to consider its potential to improve non-motor symptoms. Future studies should include a variety of non-motor outcome measures to systematically examine the effects of exercise on these symptoms. With greater research and clinical attention devoted to the potential utility of exercise interventions in PD, we may meet the goal of simultaneously treating motor and non-motor symptoms, and ultimately optimize quality of life for persons living with this disorder.

Table 1.

Exercise interventions for mood in PD.

Authors	Study Design	Mean Age	Intervention	Sample Size	Exercise Frequency/ Duration/ Setting	Control Group	Mood Outcome Measures	Main Results	Limitations
Canning et al., 201518	RCT	71.0	40-60 minutes of strengthening	231	3X/wk for 6 months (in clinic + at home)	Usual-care	PANAS	Improved affect in exercise group compared to usual care	No attention control; Mood measures included as secondary outcomes
Park et al., 201478	RCT (delayed- start)	59.9	60 minutes of combined aerobic and resistance	31	3X/wk for 48 weeks (in clinic)	Delayed- start at 24 weeks	BDI	Greater reduction in depression in early-start group compared to late-start group at 48 weeks	Greater social interaction in early- start group relative to late-start group
Shulman et al., 201379	RCT	65.8	3 exercise groups: 1) 30 minutes of high-intensity treadmill exercise; 2) 50 minutes of low-intensity treadmill exercise; 3) stretching and resistance training	67	3X/wk for 3 months (in clinic)	Stretching and resistance exercise (comparative trial)	BDI	No change in depression within any group	No non-exercising comparison condition
Bridgewater & Sharpe, 199680	Pilot RCT	67.3 (EX); 66.5 (CON)	20-30 minutes of aerobic exercise (+ warm-up calisthenics and cool- down stretching)	26	2X/wk for 3 months (in clinic)	Usual care + attendance at “interest talks” once every 3 wks	LPDQ	Improved mood in exercise group	Small sample size; Less social interaction in control group
Dashtipour et al., 201581	Prospective, double- blinded randomized trial	63.4	60 minutes of combined aerobic and resistance	11	4X/wk for 4 weeks (in clinic)	Exercise based behavioral treatment (LSVT BIG)	BAI, BDI	Reduced depression in combined group	Small sample size; Combined data analysis across both groups
Uc et al., 201482	Uncontrolled phase I/II trial	65.5	45 minutes of aerobic walking	49	3X/wk for 6 months (at home)	None	GDS	Reduced depression across all completers	Lack of a control group

BAI=Beck Anxiety Inventory. BDI=Beck Depression Inventory. CON=control group. EX=exercise group. GDS=Geriatric Depression Scale; LPDQ=Levine-Pilowsky Depression Questionnaire. LSVT BIG=Lee Silverman Voice Therapy. PANAS=Positive affect subscale of the Positive and Negative Affect Schedule. PD=Parkinson’s disease. RCT=randomized controlled trial.

Table 2.

Exercise interventions for cognition in PD.

Authors	Study Design	Mean Age	Intervention	Sample Size	Exercise Frequency/ Duration/ Setting	Control Group	Cognitive Outcome Measures	Main Results	Limitations
Cruise et al., 2011119	Controlled trial	59.5 (EX); 60.6 (CON)	60 minutes of progressive aerobic and anabolic exercise	28	2X/wk for 3 months (in clinic)	Usual lifestyle	COWAT, MMSE, PRM and SRM, SOC, SWM	EX group improved on specific measures of executive function (SWM, COWAT)	No attention control; No random allocation to groups
Uc et al., 201482	Uncontrolled phase I/II trial	65.5	45 minutes of aerobic walking	49	3X/wk for 6 months (at home)	None	Complex Figure Copy and Recall, COWAT, Eriksen flanker task, JLO, MoCA, RAVLT, Stroop, TMT B-A, WCST	Improved performance on flanker task after exercise program	Lack of a control group
Tanaka et al., 2009120	Quasi- experimental design	65.4	60 minutes of multimodal exercise (aerobics, flexibility, muscular resistance, motor coordination, balance)	20	3X/wk for 6 months (in clinic)	Usual lifestyle	Symbol Search, WCST	Improved executive function (WCST categories completed and perseverative errors) in the exercise group	Small sample size; Non- randomized control group; No attention control
Tabak et al., 2013121	Case series	61, 72	60 minutes of aerobic exercise	2	3X/wk for 2 months (in clinic)	None	CTT, MoCA, PDCRS	Both participants improved on all measures of executive function after exercise	Case series design; Selection bias; No attention control
Nocera et al., 2010122	Case study	66	20 minutes of aerobic exercise	1	3X/week for 2 months (in clinic)	None	COWAT, Digit Span Forward and Backward, MMSE, Picture Description, Stroop	Improved performance on Stroop, COWAT (especially animal fluency), Digit Span Backward, and Picture Description after exercise program	Case study design; Limited generalizability
David et al., 2015125	RCT	59.0 (EX); 58.6 (CON)	60-90 minutes of progressive resistance exercise (PRET)	51	2X/wk for 24 months (in clinic)	Stretching, balance, and non- progressive strengthening (mFC)	BTA, Digit Span, Stroop	At 24 months: PRET improved on BTA, Digit Span, and Stroop; and mFC improved on Digit Span and Stroop; No between- group differences at 12 or 24 months	No non- exercising comparison condition; Limited Generalizability (due to high education and younger age of participants)

BTA=Brief Test of Attention. CON=control group. COWAT=Controlled Oral Word Association Test. CTT=Color Trails Test 1 and 2. EX=exercise group. JLO=Judgment of Line Orientation Test. mFC=modified Fitness Counts. MMSE=Mini-Mental Status Examination. MOCA=Montreal Cognitive Assessment. PD=Parkinson’s disease. PDCRS=Parkinson’s Disease Cognitive Rating Scale. PRET=Progressive Resistance Exercise Training. PRM and SRM=Pattern and Spatial Recognition Memory (computerized versions) from the Cambridge Neuropsychological Test Automated Battery. RAVLT=Rey Auditory Verbal Learning Test. SOC=Stockings of Cambridge. SWM=Spatial Working Memory. TMT=Trail Making Test. WCST=Wisconsin Card Sorting Test.

Table 3.

Exercise interventions for sleep in PD.

Authors	Study design	Mean Age	Intervention	Sample Size	Exercise Frequency/Duration/ Setting	Control Group	Sleep Outcome Measures	Main Results	Limitations
Nascimento et al., 2014155	RCT with stratified randomization	66.3 (PD, CON) 67.8 (PD, EX)	60 minutes of muscular resistance, balance/motor coordination, and aerobic fitness	34	3X/week for 6 months (in clinic)	Usual care	MSQ	Improvements in sleep disturbance (insomnia + daytime sleepiness) in exercise group	No objective measures of sleep; No attention control
Rodrigues de Paula et al., 2006154	Uncontrolled trial	61.5	75 minutes of combined aerobic conditioning and muscular strengthening	20	3X/week for 3 months (in clinic)	None	NHP-S	Trend for improved sleep after exercise program	Lack of a control group; Small sample size; Non- specific and subjective measure of sleep

CON=control group. EX=exercise group. MSQ=Mini-Sleep Questionnaire (MSQ). NHP-S=Nottingham Health Profile (sleep domain). PD=Parkinson’s disease.