Analysis of the Effects of Exercise on Parkinson's Disease

Transcription

1 Analysis of the Effects of Exercise on Parkinson's Disease Item Type text; Electronic Thesis Authors Fallahi, Sara Publisher The University of Arizona. Rights Copyright is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 15/05/ :53:19 Link to Item

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4 Abstract Parkinson s disease is a neurodegenerative disorder characterized by dopaminergic loss in the basal ganglia of the brain. It leads to motor impairment and cognitive dysfunctions. Besides pharmacological and surgical treatments, exercise has been shown to help Parkinson s patients cope with symptoms. The purpose of my research is to determine whether certain forms of exercise are more effective in reducing the severity of symptoms. Aerobic exercises were compared with skill-based exercises with results indicating that combining both skill-based and aerobic exercises had an influence on the promotion of neuroplasticity, demonstrating that both forms of exercise should be implemented in programs. Specific techniques were then compared to each other to determine if specific exercises are more beneficial than simply doing physiotherapy exercises. Dancing demonstrated improvements in quality of life, balance, freezing gait, and stride width. Boxing improved balance, gait, bradykinesia, and quality of life. Tai chi aided patients in improving limb strength, agility, quality of life, and gait disturbances. These results indicate greater benefits when the exercises address multiple areas of the body. However, for any exercise to be the most beneficial for the patients, they must enjoy the exercise as this will aid in maintaining long-term adherence to the program.

5 Background Parkinson s disease (PD) is a neurodegenerative disorder that affects at least 1 million Americans (Trail, 2008). Both women and men are affected by this disorder, but men are times more likely to be affected. There is a greater prevalence of Parkinson s disease in America and Europe than in the Far East, however there does not seem to be a difference in the prevalence rates between various races (Trail, 2008). Symptoms Parkinson s disease results in various clinical manifestations including motor symptoms and cognitive impairments. The main motor symptoms include resting tremor, bradykinesia, rigidity, and postural instability (Trail, 2008). Resting tremor refers to the presence of a hand tremor while the hand is immobile or at rest, but that the tremor disappears during voluntary motion. Bradykinesia refers to slow movements. Freezing gait involves the sudden inability and hesitancy of leg movements, which happens most often during turns or when the patient is beginning a movement. Freezing gait is a concern because it leads to a greater risk of falling during the periods where the individual is unable to begin their movements again (Trail, 2008). This freezing happens most often when the individual is trying to go through a narrow doorway, trying to work through a crowded environment, or when their attention is focused on another task (King, 2009). The symptom of rigidity arises due to an increase in muscle tone (Trail, 2008). There is cocontraction of the antagonist and agonist muscle, which leads to resistance of changes in direction around a joint. Rigidity can result in a reduction of arm swing while walking. It can also lead to further symptoms such as a stooped posture and forward shifts in the individual s center of gravity. These contribute to the postural instability seen in PD (Trail,

6 2008). Another contributing factor to the postural instability is most likely bradykinesia. As the disease progresses, these symptoms can become more severe. Postural instability becomes more prevalent and is caused by a loss of postural reflexes, which makes it more difficult for the individual to adjust to different positions (Trail, 2008). Although some symptoms of PD respond to medicinal treatments, postural instability is one symptom that does not. Due to this lack of effectiveness, walking aids or physical therapy are needed to help with the postural instability. Furthermore, the patient may start to experience both resting tremors and action tremors and their movements may become less fluid and more labored (Trail, 2008). In the early stages of Parkinson s disease, cognitive impairments begin to be expressed as a slowing of executive functioning (which is involved in problem solving and planning) (Trail, 2008) and also cognitive slowing, which includes slowed thinking and memory in addition to difficulties with concentration ( Cognitive Impairment ). Moreover, it has been found that the patient will present with issues with long-term memory, language, and visuospatial functioning (the ability to perceive objects and their relationships to other objects) that is greater than that seen in individuals going through normal aging (Trail, 2008). In the later stages of Parkinson s disease dementia may also be present, specifically subcortical dementia. Subcortical dementia leads to the slowness of cognition and causes the memory issues that are associated with PD. However, 15-30% of PD individuals also have Alzheimer s disease, indicating that they also have cortical dementia (Trail, 2008). Parkinson s disease begins by affect[ing] the upper and/or lower limb asymmetrically (Trail, 2008). But as the disease progresses, it will affect most patients on

7 both sides of their body. During the early stages of Parkinson s disease, the symptoms are not very obvious and the main characteristic that is observed is stiffness and slowness (Trail, 2008). As the disease progresses, the resting tremor becomes apparent and at this point the patient will respond to levodopa medication (Trail, 2008) (See below for further explanation of pharmacological treatments). When the patient reaches the moderate stages of the disease, patients may need more medications or a greater dosage of their medication in order to maintain their motor functioning. This is true even if the patient is having a good response to the dopaminergic medication (Trail, 2008). This is because after years of being treated with medications, fluctuations in symptoms begin to occur, especially as the end of a dosage is reached. A greater dosage helps reduce these fluctuations. During more advanced stages of the disease the motor issues are no longer localized in the limbs but progresses to the trunk (Trail, 2008). Patients will have more trouble controlling their posture, leading to freezing gait and involuntarily accelerated steps. These issues in gait increase the risk of balance problems and falling (Trail, 2008). Other issues such as cognitive dysfunctions, sleep disturbances, and depression also become more prevalent as the disease progresses into the advanced stages. Etiology For most cases of Parkinson s disease (60-75%) the specific cause is unknown (Hughes, 1992), however there are some hypotheses as to why the neurodegeneration does occur (Trail, 2008). One class of possibilities includes effects of environmental factors, such as infectious agents, drugs, toxins, or endocrine disorders (Trail, 2008). These environmental factors may influence certain cellular mechanisms and thus lead to some of the pathology seen in Parkinson s disease. For example, some mechanisms that may induce

8 this pathology include oxidative stress, premature apoptosis, mitochondrial dysfunction, and glutamate toxicity (Trail, 2008). Genetics may also play a part in this disease, however it does not seem to be a typical cause. However, with individuals who have early-onset PD, studies suggest that the familial connection and genetics might have a bigger influence (Trail, 2008). Parkinson s disease is characterized by the depletion of pigmented neurons that produce dopamine in the substantia nigra component of the basal ganglia (Trail, 2008) (See Figure 1 below). The basal ganglia are structures located in the forebrain (Jaeger) that play a role in cognitive and motor functions (Knierim, 2007). Although the functions of the basal ganglia are not fully understood, they have been shown to play a role in activating emotional, cognitive, and executive functions in other regions of the brain s cortex (Knierim, 2007). The basal ganglia also play a component in certain learning processes (Knierim, 2007). And central to the movement symptoms of Parkinson s, the basal ganglia help the cortex with the initiation of voluntary movements and the transmission of motor commands throughout the motor pathway (Knierim, 2007).

9 Figure 1: Structure of the basal ganglia, including the substantia nigra. Source: Henkel, J Pathophysiology In order to process signals, the basal ganglia utilize two pathways referred to as the indirect pathway and the direct pathway, as seen in Figure 2. When the direct pathway is activated through the striatal neurons, it leads to excitation of the motor cortex (Knierim, 2007), particularly the frontal cortex (SGU Neuroscience Faculty, 2016). Activation of the indirect pathway leads to inhibition of the motor cortex. In other words, the direct pathway involves a positive feedback loop, whereas the indirect pathway involves a negative feedback loop (Knierim, 2007). Figure 2 below demonstrates this pathway. In order for the basal ganglia to function correctly, there has to be a balance between these two pathways. The striatal neurons in these two pathways contain two different dopamine receptors. The direct pathway contains the D1 dopamine receptor while the indirect pathway contains the D2 dopamine receptor. When dopamine binds to the D1 receptor it leads to cell depolarization. Dopamine binding to the D2 receptor causes cell hyperpolarization (Knierim, 2007). This allows for the simultaneous effect of inhibiting the indirect pathway while the direct pathway remains active (Knierim, 2007). In an individual with Parkinson s disease, the lack of dopamine leads to an imbalance in the functioning of the direct (D1) and indirect (D2) pathways. There is hyperexcitation of the indirect pathway, leading to increased inhibition of the motor cortex and a decreased cortical responsiveness (Farley). This then causes there to be a reduction in the motor output, which leads to the smaller and slower movements characterized by bradykinesia in Parkinson s patients (Farley). This can also be seen by Figure 2 shown below.

10 Figure 2: Schematic representation of the direct/indirect pathway classical model in the physiological condition and in Parkinson s disease. (a) In the physiological condition, DA arising from the SNpc is thought to activate D1-expressing striatal MSNs of the direct pathway (red lines) and to inhibit D2- expressing striatal neurons of the indirect pathway (blue lines). The output nuclei GPi and SNpr project to the thalamus, which in turn sends efferents that complete the cortico-basal ganglia-thalamo-cortical loop. (b) In Parkinson s disease, degeneration of nigral neurons reduces DA receptor stimulation in striatal MSNs. The imbalance between direct and indirect pathways results into abnormal activation of output nuclei and overinhibition of thalamic neurons projecting to the cortex. Source: Calabresi P, et al. 2014

11 Treatment Pharmacological Current treatments for Parkinson s disease primarily rely on pharmacological approaches. The most effective medication is Levodopa (Trail, 2008). Levodopa, which is the precursor to dopamine, works by entering the body and crossing the blood brain barrier. Dopamine cannot cross the blood brain barrier and thus Levodopa, which has this ability, is given instead. Once inside the cerebrospinal fluid and brain, dopa-decarboxylase (DDC) is able to convert levodopa into dopamine. However, dopa-decarboxylase is found in other areas of the body as well, leading to the possibility that the conversion of levodopa to dopamine will occur outside of the brain. Should this occur, the patient might experience side effects such as nausea, vomiting, or orthostatic hypotension (Trail, 2008). In order to avoid these side effects and increase the amount of levodopa that reaches the brain, the levodopa medication is often paired with a dopa-decarboxylase inhibitor to prevent the premature conversion of levodopa to dopamine. Fortunately, the DDC inhibitor cannot pass through the blood brain barrier, and thus it does not interfere with the actions of DDC in the brain (Trail, 2008). The dopa-decarboxylase inhibitor that is most commonly used is called carbidopa ( Prescription Medications ). Some brand names of levodopa and carbidopa combined medications include Sinemet, Parcopa, Rytary, and Duopa ( Prescription Medictations ). Levodopa can be effective in providing relief from the Parkinson s disease symptoms of rigidity and tremor; however it is not very effective in improving gait or balance difficulties (Trail, 2008). Typically, a dose of levodopa lasts about 8 hours due to the fact that the dopamine is stored in the nerve terminals. But as the patient s PD

12 progresses, there is a reduction in the amount of dopamine that can be stored in these terminals. For this reason, levodopa becomes less effective as the disease progresses and each dose does not last as long (Trail, 2008). It is unknown what the long-term effects of levodopa may be; however 50% of individuals who take this medication have been shown to develop dyskinesia, which are abnormalities in voluntary movements, after five years. This development of dyskinesia is thought to be related to hypersensitivity of the dopaminergic neurons (Trail, 2008). Besides this observation, levodopa does not seem to accelerate the progression of PD (Trail, 2008). Another form of pharmacological treatment is dopamine agonists. These can be used by themselves or in addition to levodopa. Often times a physician may choose to prescribe dopamine agonists as the first form of pharmacological treatment, adding levodopa treatment later. DA agonists have been shown to decrease the risk of developing dyskinesia, and when given early on before levodopa, seem to delay the onset of motor complications (Trail, 2008). For this reason, physicians may prescribe DA agonists to young Parkinson s patients and later transition into supplementation with levodopa. However, older patients may be prescribed levodopa right away because its effects are more predictable and it has fewer side effects. Dopamine agonists have stronger side effects than levodopa, including sleep attacks, vomiting, hypotension, edema, and hallucinations. When combined with levodopa, these side effects become especially prominent (Trail, 2008). Dopamine agonists function by acting like dopamine and binding to dopamine receptors, particularly dopamine D2 receptors (Trail, 2008). The two most common

13 agonists prescribed are pramipexole and ropinirole. Apomorphine is another form of DA agonist that works as a fast-acting drug. It is delivered by method of injection and its effects only last for minutes. For this reason, it is primarily used for patients whose regular medications wear off suddenly and leaves them immobile ( Prescription Medications ). An additional form of pharmacological treatment includes Catecholamine-O- Methyltransferase (COMT) inhibitors. These inhibitors are only used in addition to levodopa, and thus are adjunctive. Catecholamine-O-Methyltransferase is an enzyme that is found in glial cells of the brain that converts levodopa into the inactive metabolyte 3-Omethyldopa before it has the chance to cross the blood brain barrier. As more and more levodopa gets converted into 3-O-methyldopa, it begins to compete with the absorption of levodopa by the blood vessel walls and the gut. This leads to fluctuations in the amount of levodopa that is present and hinders the effectiveness of levodopa. Thus, COMT inhibitors are used to reduce the ability of COMT from interacting with levodopa. The two forms of this medication that are prescribed are entacapone and tolcapone; however, tocapone has the possibility of causing liver toxicity, and thus if taken, needs to be monitored (Trail, 2008). Monoamine Oxidase-B (MAO-B) inhibitors are another form of treatment. These are also used in combination with levodopa as a way to prevent MAO-B from degrading dopamine, but were found subsequently to also be a method of slowing down the progression of PD in patients. However, more recent research has found that these inhibitors may not actually have a neuroprotective effect. The only MAO-B inhibitors prescribed include selegiline and rasagiline, which are given to patients who are in the early stages of the disease (Trail, 2008).

14 Anticholinergics are used as a method of reducing Parkinsonian symptoms, particularly tremors; their effects on other symptoms are not as effective. This is due to the fact that the reduced dopamine availability in the substantia nigra causes the cholinergic neurotransmission to become more dominant, and this DA/Acetylcholine imbalance is thought to be one of the causes for parkinsonian tremor (Trail, 2008). They can be used either while the patient is early in the progression of Parkinson s disease and has not started taking levodopa yet, or it can be used in addition to levodopa treatment. However, if given in high does to elderly patients, this medication has many side effects including confusion, urinary retention, memory impairment, and blurred vision (Trail, 2008). Lastly, amantadine can be used for Parkinson s symptoms as well, even though it was originally used to treat influenza virus. It is mildly effective in early PD for the management of tremor, bradykinesia, and rigidity. It works by inhibiting the neurotransmission of glutamate and promoting the release of dopamine. The efficacy of amantadine diminishes after one or two years, but it can be effective in the late stages of Parkinson s disease to improve dyskinesia. Side effects of this medication include edema, dizziness, and livedo reticularis of the skin, which is a vein-relate skin discoloration (Trail, 2008). Surgical As Parkinson s disease progresses, an individual s symptoms may reach a point where pharmacological interventions no longer have an effect, leading to a significant decline in quality of life. In this case, surgical treatment may be considered. The goal of the surgery is to relieve the symptoms of PD while also reducing the side effects that may have

15 been caused by the medicine, such as dyskinesia caused by levodopa. The two main forms of surgery include electrical stimulation and brain stem cell transplantation (Trail, 2008). One type of electrical stimulation is deep brain stimulation (DBS) (See Figure 3). This procedure involves placing a battery-operated neurostimulator under the patient s skin over their chest or abdomen, very similar to an artificial pacemaker for heart dysfunction. An electrode, which is connected to the neurostimulator, is implanted in the brain, with the transmitting end of the electrode located within the brain region that is being targeted (Trail, 2008). Placing the electrode on the ventro-intermediate nucleus (Vim) of the thalamus aids in relieving tremor symptoms, but it is not effective for other symptoms. If the electrode is connected to either the subthalamic nucleus (STN) or the globus pallidus (GPi), many symptoms may be improved, including bradykinesia, tremor, rigidity, dyskinesia, and gait problems (Starr). Once in place and functioning, the neurostimulator sends electrical impulses that are transmitted through the wire to the electrode to the targeted region. Although the exact mechanism underlying the benefits of this type of treatment is not clear, the generally accepted concept is that these impulses interfere with and block the electrical signals that cause PD symptoms (Trail, 2008).

16 Figure 3: Image depicting Deep Brain Stimulation process. Source: Deep Brain Stimulation. WebMD. Accessed April 15, Exercise In addition to pharmacological and surgical treatments, exercise has also been studied as a mode of treatment for the symptoms associated with Parkinson s disease. Since patients experience motor impairments and have a fear of falling, they may want to adopt a sedentary lifestyle (Speelman, 2011). However this lifestyle contributes to a greater increase in motor and nonmotor impairments, such as increased risk for falls, cognitive decline, and postural instability. Furthermore, this can lead to greater complications including osteoporosis and cardiovascular disease. There is a higher than normal prevalence of osteoporosis among Parkinson s patients with 63% of women and 20% of men developing the disorder (Speelman, 2011). Since exercise has been shown to aid healthy individuals in improving their bone health, it is possible that exercise would

17 also improve the bone health in patients with Parkinson s disease. In addition, two-thirds of individuals with Parkinson s disease experience a sleep disorder. Non-controlled studies that required patients to participate in muscular strength and aerobic exercise indicated improvements in sleep (Speelman, 2011). Meta-analyses and systematic reviews have also demonstrated that exercise can improve physical functioning, health-related quality of life, leg strength, balance, posture, gait and physical condition (Speelman, 2011). Experiments with rodents have also demonstrated possible benefits of exercise. Rodents that were modified to express parkinsonian symptoms have been shown to restore the function of the basal ganglia (Speelman, 2011). The rodent experimental model for Parkinson s studies is often established by administering the neurotoxin 6- hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in order to induce the pathophysiology and behavioral impairments that are seen in Parkinson s disease. Such impairments include impaired cognition, impaired motor function, reduction in dopaminergic neurons in the midbrain, abnormal connectivity in the corticostriatum, and a decrease in striatal dopamine (Petzinger, 2015). Petzinger, et al. (2015) performed a study with rodents where the MPTP mice were exposed to intense treadmill exercise every day. This lead to an improvement in motor function and an elevation in dopamine transmission in the MPTP mice who exercised versus those that did not (Petzinger, 2015). The MPTP mice who exercised had a greater release of dopamine as well as an increase in the amount of extracellular dopamine. This was found to be due to a down regulation in the expression of dopamine transporters, leading to a reduction in the amount of dopamine cleared from the extracellular fluid in the dorsal striatum. These studies have also shown that the availability of dopamine plays a role in motor learning,

18 also known as rotarod training. If there is a sufficient amount of dopamine in the striatum then the process of motor learning will function properly. Petzinger et al. (2015) further found that when MPTP mice underwent intense treadmill training for 28 days, there was an increase in DA-D2R protein expression, with no change in DA-D1R expression. There were also increases in DA-D2R transcription in the medium spiny neurons of the dorsal striatum. This supports the role that exercise has on regulating gene expression (Petzinger, 2015). Another article written by Petzinger et al. (2013) also found that intense treadmill exercise reverse[d] the reduction of dopamine D2 receptors in the dorsal striatum (Petzinger, 2013). The DA-D2R protein has also been shown to be critical, with research done by Beeler et al. (2015) indicating that DA-D2R is also important in maintaining learned motor behaviors. This is because when DA-D2R is blocked pharmacologically but DA-D1R is untouched, there is a loss of a learned motor skill (Petzinger, 2015). Although it is still not fully known how exercise in human Parkinson s patients influences their expression of DA-D2R, clinical studies showed that those who were newly diagnosed with PD had an increase in dopamine-d2r expression when they participated in an exercise regimen. Overall these animal studies demonstrate a plausible underlying mechanism by which exercise can increase dopamine levels and also increase the expression of dopamine receptors. Thus it appears that exercise may lead to neuroplasticity and improvements in behavioral characteristics in patients with Parkinson s disease. However, in order to ensure that this relationship does exist, more studies need to be performed on humans (Petzinger, 2015). A further study performed by Petzinger, et al. (2013) using rodent models induced with MPTP or 6-OHDA was conducted to determine more specifically how exercise may

19 lead to neuroprotection (Petzinger, 2013). This study found that a key factor leading to neuroprotection is the increase in brain-derived growth factor (BDNF) or glial cell-derived neurotrophic factor (GDNF) that is due to exercise. BDNF and GDNF are neurotrophic factors helping with the development and survival of neurons ( Neurotrophic Factors ). Another factor that can lead to neuroprotection is the exercise-induced down regulation of the dopamine transporter (DAT) (Petzinger, 2013). DAT is involved in the reuptake of dopamine from the synapse and storage in the presynaptic neuron (Vaughan, 2013). When the dopamine transporter is down regulated, fewer transporters are expressed and this allows for dopamine to remain in the synapse for longer. Besides neuroprotection, neurorestoration is an important consequence of exercise. In contrast to neuroprotection, neurorestoration is defined as the brain s response to exercise when initiated well after the completion of toxin-induced cell death, whereas neuroprotection is considered to occur before there is complete cell death (Petzinger, 2013). The neurotransmission of glutamate has also been found to be important in learning, memory, and synaptic function. Glutamate mediates both long-term potentiation and long-term depression, which are dictated by specific receptor subtypes (Petzinger, 2015). Long-term potentiation refers to an increase in the transmission of a signal between neurons; long-term depression is a decrease in the transmission of a signal between neurons. Exercise has been found to have a direct effect on the expression of glutamate receptor subtypes, thus influencing neuroplasticity, and the localization of these receptors (Petzinger, 2015). Usually, a loss of dopamine leads to an abnormal increase in glutamatergic activity. However, in MPTP mice, exercise can reverse this hyperactivity.

20 Exercise changes the expression of glutamatergic receptor subunits, specifically the GluA2 subunit on the alpha-amino-3-hydroxy-5-methyl-1-isoxazolepropionic acid (AMPA) receptor (Petzinger, 2015). The GluA2 is a subunit of the AMPA receptor that is impermeable to calcium. The expression of GluA2 is also increased on the striatal medium spiny neurons (MSNs) because of exercise. Moreover, exercise reduces synaptic excitability and post-excitatory synaptic potentials and it decreases the amount of glutamate that is stored in the presynaptic neuron (Petzinger, 2015). By changing this glutamatergic hyperactivity, the function of the cortico-striatal circuit is restored (Petzinger, 2015). Normally, the cortico-striatal circuit is responsible for automatic (unconscious) and volitional (goal-directed) movements as well as cogntitive process, including executive function (Petzinger, 2015). Since exercise has the above effects on receptors and neurotransmitters, it demonstrates that exercise may be able to restore synapses that are found in the damaged striatum that are necessary for the proper functioning of motor behavior and learning (Petzinger, 2013). A loss in dopamine also leads to a reduction in the density of the dendritic spines of the glutamatergic synapse. This causes a disruption of connectivity in the motor circuit (Petzinger, 2015). Some studies have found that the location of this spine loss occurs on the DA-D2R-containing medium spiny neurons (MSNs) in the early stages of dopamine loss. However, other studies have found that both the DA-D2R and DA-D1R are affected with spine loss after there is has been depletion of dopamine for a long time. Mice that have been treated with MPTP have been subjected to intense treadmill exercise and have demonstrated a reversal in the loss of dendritic spines on striatal MSNs (Petzinger, 2015). Exercise also showed to increase the presynaptic and postsynaptic proteins synaptophysin

21 and PSD-95, respectively. The elevation in these proteins suggests that the synapses were restored under exercise; this allows for greater neurotransmission (Petzinger, 2013). In healthy animals, exercise has also been shown to increase the blood flow to the brain. This blood flow can change the vasculature of the CNS [Central Nervous System] through angiogenesis and altered blood-brain barrier permeability leading to neuroplasticity (Petzinger, 2013). Furthermore, healthy rodents have been shown to have an increase in vascular endothelial growth factor (VEGF) in the substatia nigra, striatum, and hippocampus. VEGF helps with angiogenesis and neuroprotection (Petzinger, 2013). One study was performed where rats were treated with 6-OHDA and then exercised. It was found that there were changes in blood flow to the underlying motor circuits that could possibly lead to changes in the connectivity of the brain and its circuits (Petzinger, 2013). The immune system is also affected by exercise. Although cytokine interleukin 6 (IL6) is related to functional impairment (including a reduction in walking speed) due to its pro-inflammatory effects in Parkinson s disease, exercise has been shown to change this to an anti-inflammatory role. During exercise, cytokine interleukin 6 promotes interleukin 1 and interleukin 10 antagonists but inhibits factors such as tumour necrosis factor alpha (TNFα) (Petzinger, 2013). In Parkinson s patients exercise also promotes the increase in cytokine interleukin 10, which is anti-inflammatory, and it also leads to enhanced motor function (Petzinger, 2013). Aerobic vs. Specific Exercise Although exercise has been shown to be helpful for individuals with Parkinson s disease, there is uncertainty whether general exercise affects the growth of tissue in the parts of the brain that are affected by Parkinson s disease, or whether this neurogenesis is

22 caused by specific forms of exercise (Petzinger, 2015). Research has been conducted to compare the effects of aerobic exercise versus specific, skilled, goal-based exercises. Aerobic exercise is defined as sustained vigorous activity that promotes cardiopulmonary function (Petzinger, 2013) whereas skilled exercise is goal-oriented movement where temporal and/or spatial accuracy is important for achieving pre-determined objectives (Petzinger, 2015). King and Horak (2009) suggest how Parkinson s patients who do aerobic exercise result in having better gait parameters, quality of life, and their levodopa medication is more effective (King, 2009). Most studies have found that the treadmill is useful in improving a Parkinson s patient s gait capacity (Petzinger, 2013). In order to retain the benefits that result from treadmill training, Petzinger et al. (2013) suggest cognitive engagement and repetition be included while the individual performs the treadmill exercise. Another exercise that involves aerobic exercise combined with cognitive engagement is the stationary tandem bicycle. Using this type of bicycle, the patients were forced to cycle at a rate that was 30% greater than their preferred rate. This ended up leading to improved connectivity between corticosubcortical regions that play a role in allowing an individual to perform a movement without conscious attention (Petzinger, 2013). Tanaka, et al. (2009) reported other benefits that aerobic training may have. Their data suggest such exercise can increase the volume of the brain and also activate neurotrophic factors which are important for neural learning and function due to their effects on glutamatergic neurons (Tananka, 2009). This may be particularly important for individuals with Parkinson s disease due to the impairment in glutamatergic neurons that is present in PD.

23 Aerobic exercise has also been shown to promote neuroplasticity and also lead to greater cognitive functioning. Colcombe et al. (2009) found that in older individuals who perform aerobic exercise, there is less of a loss of tissue density (Tanaka, 2009). Tanaka et al. (2009) did a study where Parkinson s patients underwent a program where they did aerobic exercises three times a week (one hour sessions each) for six months. They were tested with the Wisconsin Card Sorting Test to see if there were any changes in their executive function. It was determined that the aerobic exercise program did improve the patients functioning (Tanaka, 2009). However, compared to repetitive aerobic exercise, rats that performed task-specific exercises have been shown to have greater improvements in their motor skills and more changes in their synapses (King, 2009). Furthermore, exercises that are aimed at one specific movement impairment have been effective in improving the mobility of that area. For example, when an individual performs an exercise that focuses just on helping them take bigger steps, it has been useful in improving this function (King, 2009). In addition, goal-based exercise leads to improvements in simple motor actions as well, such as finger tapping. However this could be caused by the general effects that exercise has on shared motor circuitry (Petzinger, 2013). Comparing the two types of exercise revealed that rats that were exposed to aerobic exercise demonstrated an increase in their brain s capillary density but had no increase in the number of synapses, whereas those that performed goal-based exercises had an increase in the number of synapses in each of their neurons but had no increase in their capillary density (Petzinger, 2015). These differences demonstrate how skilled exercise and aerobic exercise can have different effects on neuroplasticity and the blood flow to the

24 brain. When 6-OHDA induced rats were placed in forced skilled aerobic exercises (thus combining both forms of exercise) or just forced aerobic exercises it was found that those doing skilled aerobic exercises had more of an increase in blood flow to their brain. Furthermore, skilled aerobic exercise (SAE) affected the circuits related to the frontalstriatum more than just doing aerobic exercise. SAE also demonstrated a greater restoration of motor function with the activation of the prelimbic cortex of the rats (Petzinger, 2015). This suggests that skilled aerobic exercise enhances the control that the prefrontal cortex has on motor function. This could be because skilled exercise requires more effort in preparation of the motor process and for motor control (Petzinger, 2015). Thus, skilled exercise might have effects on specific circuits in the brain, but aerobic exercise might have a global effect on the whole brain, including increasing cerebral blood flow and lowering the threshold for neuroplasticity to occur (Petzinger, 2015). However, although these two forms of exercise have different effects, they may have overlapping and synergistic influences on promoting neuroplasticity. For example, skilled exercise, which leads to an increase in neuronal activity, might lead to an increased need in oxygen consumption. The low tissue oxygenation, which is caused by the high metabolic demand, leads to the activation of hypoxia-inducible transcription factor 1 alpha (HIF-1alpha). Moderate to intensive aerobic exercise leads to transient cerebral hypoxia and HIF- 1alpha senses this. HIF-1alpha is important because it plays a role in neuroplasticity since it regulates the expression of many downstream target genes. These genes play essential roles in neurogenesis, synaptogenesis, and angiogenesis (Petzinger, 2015). Therefore, overall exercise activates a cascade that is necessary for neuroplasticity and repair (Petzinger, 2015) and data seem to support that exercise which includes both aerobic and

25 goal-based training might work well together to lead to neuroplasticity that can overcome the impaired circuitry of the basal ganglia that is characteristic of Parkinson s disease (Petzinger, 2013). Specific Forms of Exercise Exercise is very beneficial for individuals with Parkinson s disease, but it is often hard for patients to stick to exercise programs for a long time. For this reason, it is important to find exercises that they enjoy to help increase their adherence to the program (Volpe, 2013). At the present, research is being done on the effectiveness of exercises such as dancing, boxing, and tai chi for patients with PD. Dance Research has shown that interventions for Parkinson s disease are the most advantageous when they integrate cueing strategies, balance training, focuses attention and improves physical capacity (Shanahan, 2015). One form of exercise that seems to be effective for PD is dance, and particularly Irish set dancing. Irish set dancing involves gait movements and skilled movements while also having a component of dynamic balance activities. Furthermore, the music being played for the dancing can act as a cue that helps the patients generate their movements (Shanahan, 2015). A study performed by Shanahan, et al. (2015) had Parkinson s patients attend one dance class per week for 1.5 hours. The 8 week study paired each patient with an individual who did not have PD and were taught different sets that incorporated turning movements and gait aspects (Shanahan, 2015). A Parkinson s disease questionnaire-39 (PDQ-39) was implemented which showed that the quality of life of the participants improved significantly. The Unified Parkinson s disease rating scale-motor subscale 3 (UPDRS-3) test showed that there was also a trend toward

26 significance in the scores for motor impairment (Shanahan, 2015). In addition, a questionnaire was given to the participants at the end of the study, which indicated that the patients enjoyed the dance classes and they noticed improvements in several aspects of health and would like to continue if more classes were offered, (Shanahan, 2015). However, no significant changes were found in terms of balance for the participants. This could be due to the fact that to begin with, the participants did not have much impairment in their balance or because the sample size of the study was not big enough to determine a trend. Similarly, no improvements were found for functional endurance, but the participants did maintain the level that they were at previous to the training. It is possible that this was due to the fact that the participants were not offered enough dance classes; participants may need to dance more than once per week (Shanahan, 2015). Thus, this study demonstrates that Irish set dancing could have benefits for PD patients in the mild to moderate stages of the disease; however, studies need to be performed with bigger sample sizes in order to determine whether such dancing really does have a significant effect. Another study on Irish set dancing was performed by Daniele Volpe, et al (2013) in order to determine whether dancing was a more effective and enjoyable exercise compared to conventional therapeutic exercises over the long term (Volpe, 2013). Two groups of people were created, with some participants in the Irish set dancing group and others placed in a standard physiotherapy exercise group. The participants engaged in either of these two exercises once a week for 1.5 hours for a duration of 6 months (Volpe, 2013). The dance sets that were taught to some of the patients focused on improving symptoms of hypokinesia, balance impairment, and freezing gait whereas the standard physiotherapy group focused on exercises aimed at improving mobility postural control,

27 balance, and muscle strength (Volpe, 2013). The scores for the UPDRS-3 motor section were found to be better for the dancing group compared to the physiotherapy groups. Furthermore, the Berg Balance scale indicated that the dancing group had improved scores, however the scores were not statistically different from the physiotherapy group (Volpe, 2013). The freezing of gait (FOG) questionnaire found that there were statistically significant improvements for the Irish set dancing group and the PDQ-39 determined that both groups had similar outcomes in terms of their quality of life. Thus overall, both the dancing group and physiotherapy group showed improvements over the course of the study, but the Irish set dancing groups had greater gains (Volpe, 2013). These results indicate Irish set dancing may be an effective form of exercise for Parkinson s patients, but whether or not there are other genres of dance that may be more beneficial is yet to be determined (Volpe, 2013). Lastly, a study was done by Hashimoto, et al (2015) where participants were placed in a non-intervention group, a dance group, or a Parkinson s disease exercise group. The dance group consisted of movements that were derived from modern dance, jazz, aerobic dance, classical ballet, and tango. The movements performed in the PD exercise group involved extending the range of joint motion in upper and lower body, maintaining balance, shifting the center of gravity, walking on the spot, rising from and sitting down in a chair, and walking (Hashimoto, 2015). This group also involved physical therapy (Hashimoto, 2015). Both the intervention groups had similar levels of intensity in their exercises. After the program was completed, the results showed significant improvements in times reported for the Timed Up-and-Go (TUG) test, the scores for the Berg Balance Scale (BBS), and the number of steps taken in the dance group. The PD exercise group also had

28 improvements in their scores for the time it took them to complete the TUG test and their number of steps, however they showed no improvements in their BBS scores. Furthermore, the dance group demonstrated having a bigger stride width and greater stability than the other two groups. This suggests that dance is effective against the gait difficulties and poor balance characteristic of PD patients, and we would expect these improvements to have an effect on general symptoms in PD patients (Hashimoto, 2015). The dance group also showed improvements in the participants motivation and moods and was helpful in alleviating the depression that many Parkinson s patients experience (Hashimoto, 2015). Finally, the UPDRS test indicated that the dance group had significantly better scores than the other groups, with the PD exercise group having no improvements in UPDRS (Hashimoto, 2015). Therefore, overall the study demonstrated that the dance group was effective in showing improvements in mental symptoms, motor function, and cognitive function, in addition to being the only group to have improvement[s] in general symptoms, including mental symptoms (Hashimoto, 2015). Therefore, this study indicates that dance has many benefits in improving many aspects of Parkinson s disease symptoms and seems to be an effective treatment option. Boxing Boxing training involves whole-body movements. The lower body is engaged because of the foot-work that is required in various directions and the upper body is engaged because of the punching motions. These movements that are used in boxing seem to involve spinal flexibility, faster movements than normal, and stepping in many different directions, which could all be beneficial for patients with Parkinson s disease (Combs, 2011). Combs, et al. (2011) investigated the effects that long and short term boxing training

29 has on men with mild and moderate-severe Parkinson s disease, particularly its effects on gait, balance, mobility, quality of life, and disability. In this study, the participants completed sessions of boxing training for 12 weeks. Once this was done, the patients had the option to continue with the training or not. While the participants were involved in this study, they also continued with their regular exercise routines (Combs, 2011). At the end of the study, five out of the six patients had improvements in quality of life, balance, disability, and gait. Stephanie Combs and her colleagues stated that the reason for such improvements could be because boxing has a whole-body approach and the incorporation of a variety of activities that encompassed the whole body, as in other whole-body intervention programs that have shown promise, may have translated to the multiple areas of functional improvements shown by the patients in this case series (Combs, 2011). Furthermore, it was found that the patients who were in the mild stages of the disease began improving sooner than those who were in the moderate-severe stages. This trend was particularly prominent for the gait-related outcomes. This may be attributed to the fact that those in the earlier stages were able to complete more repetitions of the exercise during the circuit training. This indicates that individuals with more severe disease progression may need to engage in the training for a longer period of time in order to receive the same benefits (Combs, 2011). The study also found that even though attendance dropped after the 12 week training, all of the patients continued to have improvements in their balance, quality of life, and gait up until the 24 and 36 week assessments. This seems to indicate that the benefits of the training remained for a while even after the participants were no longer training. However, one limitation of the training is that only men were included, so based on this

30 study it is unknown how boxing would affect women (Combs, 2011). Lastly, Combs et al. (2011) emphasized that an exercise regimen should include activities that relate to the patient s personal interests while also meeting their fitness needs, because this is the best way to ensure that the patients will adhere long-term to the exercise program. Thus, overall this study showed that there were both long-term and short-term benefits to the boxing training, and so it is possible that community-based boxing training programs could be a substitute for physical therapy (Combs, 2011). The study s results seem to agree with the conclusions by King and Horak (2009), who state that boxing can be helpful with reducing symptoms of bradykinesia. They suggest that boxing can help patients learn how to control shifts in their weight and adjustments in their posture for the quick jabbing or hooking motions that are involved this exercise (King, 2009). Tai Chi Tai Chi has also been suggested as an exercise that may benefit patients with Parkinson s Disease. One study performed by Cheon, et al. (2013) aimed to determine the effects of Tai Chi on PD patients through measurements of quality of life (QoL) and functional fitness. The participants were placed into three groups including one where the patients performed Tai Chi, a second group where the participants performed combined exercises (which involved folk dancing, stepping, and elastic-band exercises), and third a control group which involved no exercise intervention (Cheon, 2013). Few men participated in the study, thus only the data for the 23 female patients were analyzed. The researchers found that in comparing the control group to both of the exercise groups, the participants who performed exercises had improvements in their physical functions; specifically, those who were in the Tai Chi group or in the combined exercise group showed

31 improvements in strength in their upper and lower limbs (Cheon, 2013). Agility also improved for both exercise intervention groups, but only significant improvements were found for the Tai Chi group. In measuring cardiovascular endurance, the combined exercise group was found to have better scores than the Tai Chi group. However, the Tai Chi group did show some improvements in endurance whereas the control showed no significant changes. In addressing quality of life, which was analyzed through the QoL scale, the participants performing Tai Chi demonstrated better scores in the emotional domain whereas the participants performing the combined exercises had better scores in the social domain. This could be due to the fact that Tai Chi is a slow, quiet exercise and thus helps the patients emotional levels. However, combined exercises may involve interactions among the patients, therefore leading to great socialization and a better social domain score (Cheon, 2013). The depression levels of the patients were also measured by Beck s Depression Inventory. The exercise groups seemed to have improvements in their depression, as shown by decreases in their depression inventory scores, however the scores were not significantly different between the groups. In comparison, the control group had significant increases in their scores, indicating that the patients depression had gotten worse (Cheon, 2013). The results of Cheon, et al. (2013) demonstrate that Tai Chi can be beneficial for improving gait disturbances due to its contribution in building muscle and improving agility. Although Tai Chi is beneficial for this, the combined exercise group also demonstrated increases in strength and agility among the patients. Thus, this indicates that any type of exercise is beneficial for improving the functional fitness of PD patients (Cheon, 2013). In addition, it was found that there was no significant improvement in parkinsonian symptoms among any of the three groups. Cheon and his colleagues attribute