Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease, and characterized by both motor and non-motor symptoms. Motor symptoms manifest as rigidity, resting tremor, bradykinesia, and postural instability while non-motor symptoms include cognitive impairments, autonomic dysfunction, sleep disorders, and fatigue etc. [1] [2] . Fatigue is one of the most common and disabling non-motor symptoms experienced by patients with PD. The prevalence of fatigue in PD ranges from 33% - 81% and approximately one third of patients report fatigue as being the most disabling symptom experienced [3] .

Fatigue can be divided into two categories: peripheral fatigue and central fatigue. Peripheral fatigue is defined as a reduction in muscle strength due to repeated contractions commonly associated with physical activity. Central fatigue, related to the central nervous system, refers to the subjective experience of mental and physical exhaustion or weakness without the presence of any physical impairment [3] . Fatigue may hinder patient’s adherence to and compliance with therapeutic programs as observed in persons experiencing fatigue due to multiple sclerosis [4] [5] . Thus, it is critical for clinicians to be aware of this important topic. Fatigue was voted as the leading symptom in need of research by patients with PD [6] . Treatment of PD-fatigue is among the unmet needs in clinical management of Parkinson’s disease [7] .

Although fatigue in PD is a common and disabling symptom that severely impacts quality of life, the underlying pathophysiology and mechanisms remain elusive and require more research. This contributes to the limitation in treatment approaches. Options for treatment of fatigue are sparse, and include medication such as antidepressants, dopaminergic and psychostimulant drugs, and non-pharmacological treatment programs (e.g., transcranial direct current stimulation, and exercise intervention). However, further investigation is required to support the use of either therapy option [3] .

Ample research has been conducted to show the effect of exercise on the motor symptoms associated with PD and has shown benefits to muscular strength, endurance, gait, mobility, posture, and balance [8] . Yet, research on the effect of exercise on non-motor symptoms of PD, specifically fatigue, remains limited and demands more attention. The purpose of this systematic review was to evaluate the effects of exercise on fatigue in people with PD.

This study systematically reviewed 12 trials consisting of various exercise interventions and their effects on fatigue in patients with PD. To our best knowledge, this is one of the first systematic reviews to examine the efficacy of exercise and physical therapy on PD-fatigue. The findings of this study showed that various forms of exercises can be effective in managing fatigue experienced by patients with PD compared to usual and conventional care.

In four trials showing insignificant between-group differences, three studies included active comparators rather than usual care [15] [16] [19] . In addition, the sample size was relatively small in those trials [15] [16] [19] [20] . The combined factors might explain the findings obtained from those studies.

In recent years, an aggregation of research revealed that exercise induced changes in protein concentration of the brain-derived neurotrophic factor (BDNF) [23] . BDNF plays a role in neuroplasticity and neurogenesis which improve and maintain cognitive function, memory, mood, and have positive effects on overall mental health [24] [25] . Ample evidence has indicated that physical exercise training increases BDNF blood levels in patients with PD [26] [27] . One of the studies included in this review also measured plasma BDNF and found significant increases in both intervention and control groups [16] . Exercise increases serum BDNF levels that were accompanied by reduced motor severity and improved motor symptoms in patients with PD [28] . Improved motor function is expected to increase physical activity level in this patient population. This might have contributed to reducing fatigue as research showed significant association of increase physical activity with reduced fatigue [29] . And exercise has been observed to increase dopamine D2 receptor expression, brain activation and functional connectivity and enhanced neuroplasticity in patients with PD [30] [31] .

PD related fatigue may be associated with striatal and limbic serotonergic dysfunction. Pavese et al. [32] compared patients having fatigue with those without fatigue and found significantly reduced levels of serotonin transporter binding within the basal ganglia and limbic structures. Similar findings were also reported in animal studies that showed increased releases and synthesis of serotonin caused by increased firing rates of serotonin neurons after increasing motor activity in rats [33] . Tryptophan levels (i.e., a precursor for serotonin) have been observed to rise during exercise on rats [34] . A higher amount of this precursor can lead to a subsequential rise in serotonin synthesis during and after exercise. Based on these studies, it is plausible to infer that exercise may be an effective strategy to increase levels of serotonin in the basal ganglia and limbic structures of the brain and help to relieve symptoms of fatigue experienced in patients with PD.

Besides exercise intervention, non-pharmacologic treatments of symptoms in Parkinson’s disease also include non-invasive brain stimulation such as transcranial direct current stimulation (tDCS). Research has shown that tDCS can modulate functional connectivity of the cortico-striatal and thalamo-cortical circuits in the human brain and enhance neuroplasticity in patients with neurological disorders such as PD [35] - [38] . Both motor and cognitive function improved in people with PD following applications of tDCS to the motor cortex while brain stimulation was administered a stand-alone and an adjunctive therapy [36] . Kaski et al. [39] found that tDCS with concurrent physical training increased gait velocity and improved balance, with a stronger effect than physical training alone. Future research is warranted to explore efficacy of combining tDCS with physical therapy in management in PD-fatigue.

This systematic review is subject to a few limitations. The sample size is relatively small. The participants included only individuals in the early stages of PD, and were excluded if they exhibited motor fluctuations, dyskinesias, or cognitive decline that are common signs and symptoms associated with progression of the disease process, thereby limiting generalizability beyond the investigated patient group. Future studies using larger sample sizes and examining individuals at advanced stages of PD are needed to investigate the impact of exercise on all stages of the disease process. Another limitation was a lack of follow-up with participants post-intervention in many of the included studies. Of the studies that did include a follow up period, duration was short and could not adequately assess the retaining effects. The long-term effects of the impact of exercise on PD-fatigue requires further research.

All interventions, except for dance, showed improvement in fatigue, suggesting that exercise is effective for managing PD-fatigue. More research is needed to determine the optimal frequency, duration and intensity of exercise needed to produce substantial and long-term effects in treatment of fatigue for patients with PD.