Relationship between physical exercise and the most varied forms of dyskinesia

- Aim: Dyskinesia is a hyperkinetic abnormal involuntary movement (AIM), like chorea, dystonia, athe-tosis, and ballism. AIM can occur in Levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), tardive dyskinesia (TD) schizophrenia, and paroxysmal dyskinesias (PxDs). This review describes the effects of physical activity and exercise adaptation (e.g., rehabilitation) in the most varied forms of dyskinesias in an attempt to provide a comprehensive understanding of the role of physical exercise on this disorder. Methods: English-language articles available in the database PubMed electronics were examined. The following indexes were adopted with different combinations: LID and exercise; TD and exercise PED and exercise. Manual searches were performed in the references of the articles related to the chosen topic. Results. The relationship between many types of dyskinesia and exercise is poorly explored. The practice of physical activity showed antidyskinetic effects in Parkinson's LID, with well-described the biological mechanisms. Conclusion: Acute exercise does not modify the abnormal respiratory patterns in TD, and it reveals a normal response to progressive training and inspiratory time. Sustained walking or running may induce a type of paroxysmal dyskinesia in the healthy subjects, which was explored by us in this review. and paroxysmal dyskinesia.


Introduction
Dyskinesia refers to various unintentional, involuntary, rhythmic, and uncontrollable movements that can diminish or impair voluntary movements. These movements include spasms, twists, chorea, dystonia, or general restlessness in the upper body as well as trunk or lower extremities 1,2 . Muscle incoordination can also occur internally, particularly with the respiratory muscles, and it may often understudy 3,4 . Besides, this motor disorder can affect each one in different forms, considering time, frequency, and severity. For example, it can significantly interfere with the daily life activities (ADLs) of the patients, or it may be light and almost invisible. In general, the movements are similar to a dance, known as chorea; however, sometimes they are occasionally known as dystonia, which causes sustained spasms and involuntary muscle contractions. Dystonia is slower, painful, and contorted, forcing the body into unnatural postures. Choreic movements and dystonias often overlap and can co-occur 5 .
Dyskinesia may occur in Parkinson's disease (PD) and may result from the disease process itself more as a consequence of the side effect of levodopa medication used to treat the disease symptoms 1,6,7 . This abnormal involuntary movement (AIM) after L-DOPA treatment is known as a L-DOPA-induced dyskinesia (LID). The LID occurs when the plasma levels of the drugs decrease in the morning (dyskinesia of drugs "off") or during the day when the medication is working (dyskinesia of drugs) 8,9 . The most common types of dyskinesia in PD include chorea, ballism, dystonia, and myoclonus. Several individuals would rather be on dyskinesia than off without dyskinesia. The dyskinesia peak occurs when dopamine (AD), reaches the maximum plasma level "dyskinesia with maximum dose." In contrast, dyskinesia can also happen when levodopa begins to end its effect. It is known as dysphasic dyskinesia. Different parts of the body may be affected, the most common areas being limbs and trunk 8 . Dyskinesia can also occur in psychotic patients due to the use of medications (antipsychotics or other drugs). Psychotic patients show hyperkinetic dyskinesia like "grimaces" and "irregular movements of the tongue and lips". In this case, tardive dyskinesia (TD) is a syndrome that includes a variety of movement disorders.
Moreover, certain established risk factors are responsible for developing TD. Age seems consistently associated with the development, persistence, and pro-gression of TD. Women appear to be at an increased risk for TD 10 . Spontaneous dyskinesia in medication-control patients with schizophrenia, and rarely, in the general population, have been reported 11,12 . The defining characteristics of TD include its delayed onset, hence the name "tardive," signifying a delay of weeks to months until further symptoms appear, and may lead to dyskinetic AIM. Depending on the severity, TD can have an adverse functional impact in patients' lives that can be debilitating, stigmatizing, and associated with increased mortality.
Paroxysmal dyskinesias (PxDs) are considered a hyperkinetic movement disorder defined by their episodic nature 13 . Patients PxDs present with repeated episodes of this order (dystonia, chorea, or both) that have a sudden onset, and after a duration that ranges from seconds to days. PxDs may be primary or secondary, are often associated with genetic causes at the primary stage. PxDs triggered by sudden body movements, as well as paroxysmal exercise-induced dyskinesia (PED) that is triggered by continuous physical effort. PED is by attacks of dystonia and chorea triggered by prolonged physical exercise, typically lasting for 5-30 min 14 . The attack often starts in the body part involved in the physical activity. Paroxysmal nonkinesigenic dyskinesia (PNKD) is often provoked by consumption of coffee, alcohol, or by stress 15,16 . Several PxDs can be comorbid with other neurological disorders that are suggestive of an underlying channelopathy, such as epilepsy and migraine 17,18 .
Physical exercise can modify these different types of dyskinesias in various ways. In this review, we identified varied dyskinesias and their relationship with physical activity in clinical studies and experimental models.
Despite strong evidence about the benefits of physical exercise in LID, we could not find the same evidence in other types of dyskinesias such as TD and PxDs. After prolonged drug treatment, TD patients have weight gain, risk of falling, and respiratory dyskinesia while physical exercise mitigates these problems, unless respiratory dyskinesia.
Interestingly, unlike LID, physical exercise in patients with PED can activate dyskinesia. Besides, we attempted to review the evidence reported in clinical studies and experimental models to provide a comprehensive understanding of the role of physical exercise.

Material and methods
It is a narrative review, the National Library of Medicine (PubMed) electronic database used as a search tool. For the search, we used different terms: L-DOPA induced dyskinesia, tardive dyskinesia, and paroxysmal dyskinesia, all of these terms with exercise, physical activity, or rehabilitation. Additional manual searches were performed from the references found. The language for the search was English, with the availability between 1977 until 2018. The exclusion criteria were review papers, clinical and experimental papers that did not have relevant content, and articles that did not address physical activity and motor activity.

Selection results
In total, there were one hundred and sixty-two articles ( Figure 1), of which exclusively 25 were original articles that focused on the relationship between exercise or physical activity and many forms of dyskinesias. The clinical and experimental details of these 25 original articles, it is described in Tables 1, 2, and 3.

L-DOPA-induced dyskinesia and exercise
The treatment of PD is a complex issue due to the progression of the disease and a set of motor and nonmotor signs combined with late side effects after therapeutic interventions. Although there are still no approved treatments to reduce disease progression, surgical alternatives and other approaches, such as physical exercise and physical therapy, are available. As it is well known DA does not cross the barrier hematoencephalic while L-DOPA (L-3,4 dihydroxyphenylalanine) does; thus, it is the primary pharmacological treatment. The L-DOPA restablishes the dopaminergic neurotransmission and decreases the motor symptoms [19][20][21] . The clinical use of L-DOPA in PD began during the 1960s; it is still the most effective therapy to attenuate PD cardinal motor symptoms 22 . Motor dysfunctions are the main target of pharmacological treatment, with L-DOPA being the most effective drug 23 . The main side effect of L-DOPA treatment is the development of dyskinesia and motor fluctuations. Thus, the objective of current physical exercise researchers is to prolong the antiparkinsonian effects of L-DOPA to improve the patient's quality of life.
The other therapeutic strategy includes cell transplant and deep brain stimulation (DBS) 24 . More recently, the continuous administration of levodopa-carbidopa intestinal gel (LCIG), reduces the variability of dopamine plasmatic and improves motor complications associated with chronic oral levodopa treatment 25 . Previous studies have demonstrated that LCIG therapy reduced "Off" time and dyskinesia as well as improved the patient's ability to perform ADLs and their nonmotor symptoms 26 , improving the quality of life of de patients.
Actually, besides all drugs that exist for the treatment of PD, the L-DOPA remains the most effective treatment for motor symptoms of PD. Yet, the effects of physical exercise on L-DOPA treatment still poor understood. For example, in animal models, running training for three weeks increases the synthesis and release of DA in DP in the C57BL/6 mice model of PD treated with a low dose of L-DOPA (5 mg/kg) 27,28 . Besides, physical exercise may increase the mRNA levels of the receptor dopaminergic neurons of the D2 type in the striatum after treadmill exercise for 30 days in mice treated with MPTP 29 . Mice treated with MPTP and trained for six weeks in the treadmill revealed an increase in the expression of striatal D2 receptors showing the exercise-induced adaptations to dopaminergic neurotransmission 30 .
Physical exercise in PD patients, as in the rehabilitation strategy, shows an antidyskinetic effect. A summary of the studies is shown in Table 1. The results of a clinical trial showed a decreased dyskinesia in PD patients after intensive rehabilitation treatment (2 x day) for four weeks, five days a week 31 . This intensive rehabilitation protocol (which comprised gait training exercises, treadmill, 2× per day) resulted in a substantial reduction in dyskinesia. However, another group of the patients who did less intense rehabilitation (once a day), had more modest decreases in LID score ( Figure 2). This same research group and in a 6-month follow-up study demonstrated that this intensive rehabilitation protocol maintains the improvement in dyskinesia score, as well as the UPDRS scale, and can reduce the dose of L-DOPA for six months after treatment 32 .
Aguiar et al 33 published the first research showing the antidiskinetic effects of physical exercise in animal models (C57BL/6 mice)l on LID. In this study, the C57BL/6 mice received a unilateral lesion with 6-OHDA (12 μg). After that, they received L-DOPA (25 mg/kg) plus Benserazide (12.5 mg/kg) daily, i.p.. Simultaneously, these animals performed exercises in a running wheel (voluntary activity) for 14 days. After the protocol training, there was no modification of the lesion caused by 6-OHDA ( Figure 3 A-B). However, physical exercise decreased the axial and limb dyskinesia without orofacial  Finally, exercise can increase the glial cell-derived neurotrophic factor (GDNF), related to dyskinesia control. Treadmill protocol for four weeks (30 minutes) showed an antidyskinetic effect in the Swiss mice model. An increase in striatal GDNF levels provides a new mechanistic view ( Figure 4). The GDNF emerges as a particularly promising candidate since it exerts an essential role in the development and maintenance of spinal motor neurons and midbrain dopaminergic neurons. Moreover, GDNF downregulation is associated with PD pathophysiology. Additionally, Cohen 34 demonstrated that limb exercise could prevent behavioral deficits and neurochemicals induced by the administration of 6-OHDA; they related this beneficial effect of the physical exercise to increased levels of the GDNF in the striatal area. Evidence from both in vivo and in vitro studies indicates the protective and regenerative potential of GDNF on dopaminergic neurons 35 .
Interestingly, intrastriatal pretreatment (6-OHDA injury) with GDNF (100 μg) in rats prevents the degeneration of dopaminergic neurons 36 . Besides, intracerebroventricular GDNF in the 6-OHDA animal model restores striatal TH levels and improves motor symptoms 37 . Additionally, intrastriatal GDNF injection (5 μg) reduced LID in MPTP-treated monkeys 38 . Collectively, these results indicate that the increased striatal GDNF of dyskinetic animals might represent a critical attenuating effect mechanism of treadmill exercise in LID 39 . Thus, convergent evidence from clinical and experimental studies suggest that physical exercise might act as a modifying agent and could have antidyskinetic effects.

Tardive dyskinesia and exercise
The continuous use of antipsychotic drugs can cause tardive dyskinesia (TD), initially observed in the 1950s. These patients showed movements that were acute and short-lived in some cases and chronic in others 40 . The term "tardive dyskinesia" was introduced by Faurbye in 1964 41 , highlighting the delayed onset of the condition 42,43 . These movements also occur after the antipsychotic discontinuation or its dosage reduction. The pathophysiology of TD include upregulation of D2 and D3 receptors, deregulated DA influence on the substantia nigra, striatal neurodegeneration, changes in synaptic plasticity due to surges of γ-aminobutyric acid in the striatal neurons responsible for motor coordination, oxidative trauma, and changes in 5-HT2 receptor signaling [44][45][46][47] . The D2 receptor blockade causes an increase in D2 receptor synthesis (upregulation), creating a receptor supersensitivity.
The pattern ("topography") of dyskinesia is essential for differentiating the functional impact of this disease. Truncal TD, for example, affects gait and posture and exerts its detrimental effect quite broadly by interfering with their ADLs that require standing or moving, such as grooming, dressing, toileting, bathing, ambulating, and transport. In contrast, orofacial TD would not have a significant impact on these tasks but would perhaps affect speech, which is required for effective interpersonal interactions or getting and keeping a job 48 . Orofacial dyskinesia is more frequently type founded in animal models induced by reserpine.
It is important to emphasize that people with persistent mental illness have reduced physical activity and may interfere with their ADLs 49 . Several forms of TD were described, including tardive stereotypy, tardive dystonia, and tardive akathisia 50 . Occasionally, chorea (unlike LID), myoclonus, and tremor can also be a part of the TD spectrum 51 . Although several patients might not be aware of their TD, it can cause complications, including respiratory distress, dysphagia, dysarthria, falling, and suicide 51,52 .
These patients have gait speed problems like cadence, step length, posture, arm swing, gait initiation, turning, and gait efficiency. The loss of lower extremity power/strength or lack of endurance may further worsen the performance of gait-related everyday activities [52][53][54] . The gait can help with motor performance under a cognitive load, using dual-task gait assessments (e.g., walking while performing an attention-demanding task) 55,56 . They are also at high risk of major fall-related injuries such as fractures and head injuries that increase the mortality risk. Dual-task interventions improve attention and executive function as well as memory in older adults without dementia. Verghese et al. 57 conducted a pilot study in 24 older adults randomly assigned, 10 participants who completed the cognitive remediation presented improvement in the gait velocity during normal walking and walking while talking (dual-task).
Few studies refer to the effects of exercise in patients with TD; a summary of these articles is in Table 2. A 25year-old woman with severe TD due to neuroleptics had improved movement while skateboarding after deep brain stimulation (DBS). The participant received pale DBS, and gait and inline skates, the data were assessed before and after DBS; her twin sister was the control counterpart. The authors conclude that the possible explanation for her improvement include the balance stability required by inline skating provides external cues that are less prominent during gait. Since TD has a variable response to treatments, the proposal of current research that minimizes TD and that could advance the treatment and rehabilitation in this disabling disorder 58 .
One of the complications related to TD is the limitations of physical capacity. Several studies reported a modest but significant weight loss or improved cardiovascular fitness among patients with schizophrenia. Patients with schizophrenia are two-to three-times more likely to have a higher mortality rate and a reduced lifespan expectancy, approximately 13-30 years [59][60][61] . The treatment with antipsychotics, particularly the second generation, largely contributes to metabolic complications. Studies implemented interventions such as physical activity, dietary modification, or psychoeducation that targeted metabolic physical health and physical fitness. Some programs that implemented walking as the primary intervention presented significant changes in the tested parameters, mainly improvement in cardiovascular fitness and weight loss [62][63][64] .
Patients with TD can also develop respiratory dysrhythmias (RDs). These include irregular respiratory rate and rhythm in association with involuntary grunts and gasping sounds 3 . The cycle ergometer exercise test in the patient's symptom-limited maximal workload. The modified V2 and arterial oxygen saturation were monitored continuously with a portable oximeter. In this study, they compared patients with healthy control subjects. Exertional dyspnea is a common presenting symptom of patients with RDs. The authors suggest that RDs are not the cause of premature termination of exercise in patients with TD. Both volume and breathing frequency increased in a regular curvilinear pattern, and no patient demonstrated significant arterial oxygen desaturation during exercise 3 .
In animal models of TD, moderate physical exercise plays an essential role in improving the motor and cognitive impairments associated with monoaminergic depletion. The exercise training in the reserpine model (5.0 mg/kg, s.c.) for four weeks in the running wheel or treadmill attenuated the motor problems 65 . In the reserpine animal model, swimming activity, for eleven weeks, provoked an increase in orofacial dyskinesia 66 . However, swimming protocol for five times per week (increased 15 min per day until swam 90 min/day), for eight weeks showed prevention in orofacial dyskinesia 67 .

Paroxysmal dyskinesias and exercise
In 1740, Mount and Reback introduced the term "familial paroxysmal choreoathetosis. They described a 23-year-old man with an autosomal dominant disorder manifested by attacks choreoathetosis involving arms and legs 68 . The attacks occurred twice or three times a day for 5 min to several hours precipitated by alcohol, coffee, tea, fatigue, and smoking. Numerous reports of the patients with episodic dyskinesia have followed, and several classifications have been proposed to categorize this movement disorder 69 . In 1977, Lance reviewed 100 cases and added 12 patients with "familial paroxysmal dystonic choreoathetosis" 69   clonic seizures and are not associated with epileptiform discharges or alterations in consciousness 70 . PxDs is subdivided into four subgroups based on their precipitating factors: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exercise-induced dyskinesia (PED), and paroxysmal hypnogenic dyskinesia (PHD). The association between PxDs and other neurological disorders, such as epilepsy or ataxia occasionally observed within one individual or family. Mutations in SLC2A1 are the main cause of PED, which can be isolated or be a part of a more complex phenotype 18,71,72 . Mutations in GCH1, PARK2 (encoding Parkin), or other genes involved in recessive juvenile PD can occasionally cause PED 73 . Rare genetic causes include modifications in PRRT2 74 , ATP1A3 75 , ADCY5 76 , PDHA1, and PDHX (pyruvate dehydrogenase deficiency) 76 . Symptomatic treatment with antiepileptics, levodopa, or acetazolamide can be useful 15 .
Interestingly, in contrast to LID, only physical activities such as domestic activities in patients with PED can activate dyskinesias, a rarer and less welldocumented group. Many studies of genetic studies have been carried out to understand the pathophysiol-ogy of the attacks. In summary, the attacks are triggered by prolonged exercise like walking or running characterized by attacks of dystonia and chorea, typically lasting for 5-30 min 14 . The attacks often start in the body part involved in the activity and last for 10-15 min after stopping the exercise. PED made walking impossible and caused falls in some of the patients. Some patients were able to stand despite the PED, or walk with difficulty, but most patients had to sit down until the movements subsided. A summary of the studies is shown in Table 3.
The co-occurrence of PED and epilepsy is frequently. The frequency of attacks is variable, depending on the routine level of physical exercise. These attacks may be accompanied by migraine without aura 77 or a combination of alternating hemiplegia, epilepsy, and ataxia 78 . Epilepsy and writer's cramp combination was reported is these patients 79 . In some patients, PED presenting signs of young-onset idiopathic PD due to the Parkin gene 80 . PED and epilepsy are associated with a low glucose concentration in the presence of normoglycaemia. Although several family members reported that glucose and sugar alleviated symptoms, carbohydrate-rich diets are unsuccessful. Although some pharmacological treatments with anticonvulsants had no effect on some patients, others the anticonvulsants, such as carbamazepine 18,73 , clonazepan 79 , and sodium valproate, decrease the occurrence of attacks 77 . A previos study has shown that 15 patients had no effet with any anticonvulsants. One case was reported improvement with the use of the steroidal anti-inflammatory drug (Prednisolone) in a 20-year-old woman. However, studies show that the cessation of attacks occurs spontaneously after a few years. Interestingly, in experimental models, using mouse mutants, tottering and lethargic mice, have shown the same pattern of response. Two studies show that after evaluation with short motor tests and after physical exercise on a treadmill or motor task for a brief moment, animals present dyskinetic attacks for minutes and sometimes for hours 72,81 .

Conclusions
In our mini-review, we show that exercise improves LID and motor impairments of PD patients and PD animal models. This decrease in LID is likely as consequence of dopaminergic normalization and an increase of neurotrophic factors. Although this type of intervention has a beneficial effects on patients with TD, few studies are available because some patients have mental problems making diificult the approach with physical exercise and/ or physical activity. Eventually, PED is an entirely different pattern from the other dyskinesias and physical exercise. This condition can worsen the symptoms after physical activity performance. A schematic conclusion is shown in Figure 5.