Parkinson disease (PD) is a progressive neurological disorder resulting from the death of dopamine-producing cells in the substantia nigra, an area in the brainstem. It mainly affects the motor system and causes difficulties in mobility and walking, decreasing the quality of daily life. The mean (SD) walking speed of healthy people between the ages of 40 to 80 yrs is 1.19 (0.11) m/sec,1 whereas that of patients with PD is 0.94 (0.21) m/sec,2 which is significantly slower.
Levodopa is the most effective medication for patients with PD and is considered the criterion standard intervention. It is usually prescribed with other medications such as monoamine oxidase type B inhibitors, catechol-O-methyltransferase inhibitors, the N-Methyl-D-aspartate receptor antagonist, amantadine, and dopamine receptor agonists.3,4 However, some limitations have been noted with levodopa because some patients react differently to it and it may even be ineffective sometimes.3–5 In addition, its adverse effects were also common such as dizziness, gastrointestinal irritation, and cognitive dysfunction. Long-term use of levodopa is associated with the development of motor disorders including dyskinesia.4,5 Deep brain stimulation, a surgical intervention used to treat PD, involves surgically implanting a device to stimulate specific groups of neurons such as the subthalamic nucleus or globus pallidus; the results of deep brain stimulation have been well established.3,6,7 However, the risk of surgery-related complications such as intracranial hemorrhage, seizure, or cerebritis cannot be avoided6,8,9; hence, this technique can only be used in a few select patients.
Currently, noninvasive brain stimulation techniques are used to treat patients with neurological illnesses. These procedures, such as transcranial direct current stimulation (tDCS) at the motor cortex, are fairly easier to perform and safer to administer. Previous studies have reported fewer and relatively mild adverse effects of tDCS; for example, tingling sensation on the scalp has been observed with this technique,10,11 compared with the more serious surgical complications of deep brain stimulation as mentioned previously. Research has shown that tDCS can increase the efficiency of the motor system among both healthy people and patients with central nervous system diseases such as stroke, dementia, and PD.10,12,13 Benninger et al.10 used the tDCS method—using 2 mA of electric current to stimulate the lower extremity motor cortex area of the brain—in 25 patients with PD for 20 minutes/session, for a total of 8 sessions for 3 wks. The results revealed a significant reduction in walking time of 10 meters. McCreery et al.14 studied the safety of tDCS and discovered that an electric current as high as 25 mA/cm2 can be used without harming the brain tissue. Typically, in clinical research, 1 to 2 mA of current is used with a 35-cm2 electrode because it has been proven to be the safest maximum level that can be used. Various tDCS studies have established its effectiveness in improving the strength of the muscles and the gait speed.10,13,15 However, the stimulation parameters such as intensity of current, duration of each session, and the total number of sessions used to treat in previous studies were different and, hence, remain inconclusive.
Apart from medications and tDCS, rehabilitation has also been used in patients with PD to reduce muscle tightness, prevent joint stiffness, improve muscle power, correct postural instability, and correct gait abnormalities. However, it is only used as a symptomatic adjunct therapy and has not been approved as a standard intervention.3,16 According to a systematic review,17 physical therapy can improve the problems in gait abnormality and postural instability when the following five key factors are targeted: joint range of motion, body flexibility, muscle strength of the lower limbs, cardiovascular fitness, and balance. These exercises are conducted with the patients at least three times weekly, for a minimum of 6 to 12 wks by a professional physical therapist. Subsequently, patients are strongly encouraged to continue the exercises at home to maintain the positive effects of rehabilitation.
However, no data are available about the efficacy of using a combination of both tDCS and physical therapy in patients with PD. Therefore, the authors investigated the effects of combined tDCS and physical therapy on the walking ability of patients with PD.
This study was approved by the institution review board and strictly followed the procedures in accordance with ethical standards and complied with the Helsinki Declaration of 1975, as revised in 1983. The study employed an experimental, double-blinded, randomized controlled trial design and was registered in the Thai Clinical Trials Registry (20160330002). It was conducted according to the ICH8 and conformed to all CONSORT guidelines, and it reports the required information accordingly (see Checklist, Supplemental Digital Content, http://links.lww.com/PHM/A447). Detailed information about the study was provided to all the participants before the screening process, and written informed consent was obtained from them, and/or their relatives, before any procedures were performed.
This study was conducted in patients with PD attending the King Chulalongkorn Memorial Hospital from October 2012 to September 2014. Subjects enrolled were between the ages of 40 to 80 yrs, with a documented diagnosis of PD using the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria for Parkinson's Disease.18 The severity of their illness was either stage 2 or 3 of PD, according to the modified Hoehn & Yahr Staging criterion,19 and they were on medical treatment with no changes in medication throughout the study period. In addition, they had slower average walking speed than normal elderly by 0.4 to 0.9 m/sec and agreed to participate in the study including the follow-up period. Patients who were unable to walk on a flat surface by themselves, required to use a gait aid, previously had epilepsy or had undergone surgery around the skull area, and were being treated with either sodium channel blocker or calcium channel blocker medication were excluded from the study. Furthermore, patients having other co-morbidities that may affect the motor system and communication skills such as dementia or stroke, and patients with diseases of the bones or eyes that affected their visual acuity were also excluded from the study.
Patients who met the inclusion criteria were block randomized into three groups by a computer, and blinding was also maintained. Group 1 (tDCS) was treated with only anodal tDCS. Group 2 (combination) was treated with a combination of anodal tDCS followed by physical therapy. Group 3 (PT) received sham tDCS followed by physical therapy. Details of the interventions are described in the following section. A definite tDCS regimen has not been established, and the physical therapy treatment for patients with PD is recommended for at least three sessions per week. Therefore, we decided to use 30-min long sessions for a total of six sessions for 2 wks (three sessions weekly), delivered by the same therapist using the same protocols.
Transcranial Direct Current Stimulation
The transcranial electrical stimulator model “Magstim eldith DC-stimulator plus” manufactured by Magstim Company Ltd, England, was used. The stimulator has two electrodes, 35 cm2 (5 × 7 cm) in size. The electrodes were placed according to the International 10-20 EEG System.20 The anodal electrode was attached at Cz position on the scalp, which corresponds to the lower limb motor cortex. The cathodal electrode was attached at the supraorbital area on the forehead. For groups 1 and 2, a direct current of 2 mA was applied for 30 minutes and the total duration of stimulation was 3 hrs (30 mins × 6 sessions). For group 3, sham tDCS was applied; the current was initiated at 2 mA and gradually decreased to 0 mA within a minute. The electrodes were not removed but left in place at 0 mA for 30 minutes.
Physical Therapy Intervention
Patients in groups 2 and 3 were treated by 2 professional physical therapists, who are specialists in neurological rehabilitation. The physical therapy program comprised joint range of motion and body flexibility, strengthening leg muscles, and balance and gait training. Each physical therapy session was conducted for 30 minutes and modified according to each patient's requirements.
Our primary objective was to explore the walking speed in patients with PD after receiving different treatment protocols. The Gait & Motion Analysis model Qualisys Track Manager (Qualisys AB, Gothenburg, Sweden) was used to evaluate gait parameters. Participants were instructed to walk on a flat surface at their own normal pace three times. The average of their gait speed, step length, step width, and cadence was reported. A baseline assessment was conducted before the designated interventions and the postintervention assessments were performed three times during the follow-up at 2, 4, and 8 wks. All the assessments were conducted 1 to 2 hrs after the patients had taken their usual dopamine medication to maintain a consistency in the effect of the dopamine because the peak effect of the dopamine drugs occurs 1 to 2 hrs after ingestion and it needed to be controlled to avoid intervention bias. The participants and the assessor were blinded to the information regarding the treatment groups.
Unified Parkinson's Disease Rating Scale
The Unified Parkinson's Disease Rating Scale (UPDRS) is the most commonly used scale to assess the clinical course of a patient with PD.21 Part II (13 items) and part III (14 items) were used to assess the activities of daily living and motor function, respectively. Each item had a scale of 0 to 4 ratings; a higher score reflects higher severity. The assessment and motion analysis were performed during the same visit.
Sample Size Calculation
The sample size was calculated on the basis of the data obtained from Benninger et al.10 The calculation used an α value of 0.05 and β value of 0.2 (power = 80%), indicating that a total of 48 participants were needed for the study. The authors estimated that approximately 20% of the participants may discontinue or withdraw from the study and, therefore, increased the required sample size to a total of 60 patients (20 patients/group).
SPSS Program Version 17.0 was used, and a P value of 0.05 was considered to be statistically significant. One-way analysis of variance (ANOVA) was used to find dissimilarities among the three groups, and repeated measure ANOVA with pairwise comparison was used to analyze the differences between the findings of preintervention and postintervention.
From October 2012 to September 2014, a total of 186 patients with PD and interested in participating in the study were identified. Through the screening process, 126 patients were ineligible according to the inclusion/exclusion criteria; 56 patients did not have stage 2 or stage 3 PD, 33 patients had other abnormalities that would potentially affect the outcomes, and other reasons for exclusion are shown in Figure 1. The remaining 60 patients were block randomized into three groups (20 patients/group). During the follow-up period, seven participants (11.7%) dropped out of the study. The main reason for withdrawing was the inconvenience due to the follow-up visits. One patient from group 3 (sham group) developed a stroke 4 wks after intervention. The authors have confirmed that the stroke was not caused by tDCS. Overall, 18, 17, and 18 patients from groups 1, 2, and 3, respectively, completed the study. Per-protocol analysis was used to examine the data from these 53 participants. During the intervention period, two participants, who received the anodal tDCS intervention for the first time, reported a burning sensation on their forehead where the stimulator was attached. As the day progressed, it subsided without any treatment. For the subsequent anodal tDCS interventions, more water was added to the electrodes and the two patients did not experience recurrence of the symptom.
Among 53 participants, 33 were male and 20 were female with an average age of 65.0 yrs. The mean duration of PD was 7.9 yrs. A total of 28 and 25 patients had PD stage 2 and 3, respectively. The dopamine medications were measured in units of levodopa equivalent dose, and the average levodopa equivalent dose was 864.0 mg daily. The gait parameters revealed that the average walking speed, step length, step width, and cadence were 0.69 m/sec, 42.83 cm, 8.87 cm, and 98.99 steps/min, respectively. The baseline data and demographic data were comparable among the three groups (Table 1).
Comparison of Gait Outcomes After Intervention Within the Groups
Postintervention gait parameters were compared with the baseline data of each group. The tDCS group demonstrated a significant increase in walking speed and step length in a relatively sustained pattern from 2 to 8 wks after intervention, but without any significant change in step width and cadence. Walking speed improved from 0.73 to 0.87 m/sec (an increase of 0.14 m/sec or 19.17% from baseline). In addition, the step length improved from 42.28 cm to more than 48 cm (an increase of 5.91–6.14 cm or approximately 14.12 % from baseline). Step width and cadence showed an insignificant change from baseline at every postintervention visit (Table 2).
The combination group also demonstrated significant increases in walking speed and step length at 2, 4, and 8 wks after intervention, but without significant changes in step width and cadence. The walking speed was the highest in the fourth week at 0.80 m/sec (an increase of 0.13 m/sec or 19.4% from baseline). The step length was the highest at 47.77 cm at the second week after intervention (an increase of 5.41 cm or 12.77% from baseline) and dropped minimally to 46.85 cm in the eighth week. The cadence gradually increased from 96.76 steps/min to 101.03 steps/min in the eighth week but was not statistically significant. Step width was relatively constant throughout the 8 wks and not significantly different from the baseline at 8.38 cm.
The PT group demonstrated significant progressive improvement in walking speed and step length at 2, 4, and 8 wks after intervention. The gait speed improved to 0.83 m/sec at 4 and 8 wks (an increase of 0.14 m/sec or 20.29% from baseline) and step length improved to 49.21 cm at 8 wks (an increase of 5.38 cm or 12.27% from baseline). A significant improvement in cadence was also detected at 4 and 8 wks after intervention and was the highest at 104.61 steps/min (an increase of 9.64 steps/min or 10.15% from baseline). Step width at baseline was 8.32 cm and unchanged throughout the 8 wks after intervention.
The UPDRS Parts II and III Post Intervention, Within Group Comparison
The UPDRS scores of part II and part III, in all the groups, demonstrated significant reduction at 2 and 4 wks after intervention compared with baseline. The PT group and tDCS group demonstrated significantly lower UPDRS scores of part II at 8 wks. The details are described in Table 3.
Outcome Comparisons Between Groups
To measure the effect of the treatment, outcomes from each group (walking speed, step length, step width, cadence, and UPDRS parts II and III) were calculated as mean difference from the respective baseline data and were compared among the three groups. For each postintervention evaluation, no significant difference was observed among the three groups (Table 4).
All groups demonstrated that walking speed increased by 0.09 to 0.15 m/sec in postintervention evaluations. The mean difference of step length was 2.97 to 6.14 cm longer than the baseline. Step width and cadence were statistically unchanged in this study. Notably, every intervention group had similar positive outcomes, but the differences did not reach statistical significance among the three protocols.
The scores for the UPDRS (Table 4) decreased at all time points after intervention for all groups, but this did not significantly differ between the groups. The decrement in UPDRS scores was in the range of 0 to 2 points on average, which was difficult to interpret whether it was clinically helpful.
Gait Speed, Step Length, and Step Width
Our findings indicated that all interventions were effective in improving the gait of patients with PD, particularly the walking speed and the step length. The result from the combination group, providing both tDCS and physical therapy, did not show better outcomes than the other two groups, which received either tDCS or physical therapy. The goal of the study was to explore the effect of treatment modalities among patients with PD with walking impairment. Hence, the walking speed of the participants must be lower than the average walking speed of the patients with PD, which is 0.94 (0.21) m/sec according to Sofuwa et al.2 and 0.92 (0.05) m/sec according to Hass et al.22 Participants in groups 1 and 3, who were treated with only one type of intervention, demonstrated postintervention gait speeds of 0.87 (0.20) and 0.83 (0.17) m/sec, respectively, which was comparable with the normal walking speed of patients with PD. The same result was also found in step length. The mean (SD) step length, according to Sofuwa,2 is 51.5 (8.0) cm; whereas after treatment, the mean (SD) step length of the tDCS group was 48.14 (8.06) cm and that of the PT group was 49.21 (8.39) cm. However, the average step width did not change significantly from the baseline value in all the three groups throughout the 8 wks after intervention but was within the normal limit.22 This could be interpreted as receiving either tDCS or physical therapy for 2 wks could improve the walking capacity of walking-impaired patients with PD to almost normal. For elderly patients experiencing chronic neurological diseases that interfere with mobility or walking ability, especially those with PD, improving the pattern of walking and a return to normal walking pattern and quality is very difficult and challenging. This could explain why the combination group did not produce a better outcome, because receiving a single treatment could improve walking ability with acceptable results.
For cadence, the only group that showed significant improvement was the PT group, where it improved from 94.97 steps/min at baseline to 104.61 steps/min at fourth week and 102.29 steps/min at the eighth week. However, no significant difference was found among groups. This could be explained by the observation that the baseline data of PT group was slightly lower, when compared with the other groups (Tables 1, 2). In conclusion, the present study was unable to confirm the effects of the interventions on cadence. This is not unusual among patients in the early stages of PD because cadence abnormality is rarely found or is mildly present.23 For this study, the mean (SD) cadence in patients with PD of stage 2 and 3 were 98.99 (15.87) steps/min, which is comparable with that of the normal population (115.3 [6.6]). This finding corroborates with the previously reported data.2,22
At the moment, the international standard guideline considers physical therapy an adjunct treatment for patients with PD.3 It is possible that results from systematic reviews and meta-analyses16,24 may have influenced the guidelines because the data may be difficult to interpret when the study populations are heterogeneous. Moreover, different medical modalities were used and different measurements of the outcomes were analyzed. Nevertheless, the findings from all of these studies showed that physical therapy programs for patients with PD were highly beneficial in improving the patients' physical performance and activities of daily living. However, it should be noted that the intensity, type, and duration of the physical therapy program are crucial; hence, additional attention is warranted when designing a program to see positive and effective results. For this study, a total of six sessions for 2 wks were sufficient to detect an improvement in gait of patients with PD.
Transcranial Direct Current Stimulation
Equally effective as PT, the tDCS intervention used in this study helped patients with PD to walk faster and increased their step length at 2, 4, and 8 wks after intervention (Table 2). Only 2 of the 35 participants from groups 1 and 2 (5.7%) experienced burning pain at the sites where the electrodes were attached, which had been reported previously10,11 and resolved spontaneously with time. Apart from this, no serious or severe adverse effects of tDCS were observed. Less severe complication is one of the greatest advantages for tDCS over deep brain stimulation, which may have adverse effects such as intracranial hemorrhage, cerebritis, seizure, and other surgery-related complications.6,8,25 The mechanisms and technical aspects of each brain stimulation technique were reviewed by Klooster et al.,25 who reported that at the moment, no definite protocol exists for tDCS. The most commonly used current intensity is 0.5 to 2 mA for approximately 20 minutes and the number of sessions required is still undefined. These findings confirm that tDCS stimulation through the scalp can enable the motor neurons inside the brain to become more active resulting in better neural modulation and plasticity.25,26 The physiological mechanism of tDCS in stimulating the brains of patients with PD has been proposed; that tDCS can penetrate deep into the cortex of the brain and effectively reach the neural networks, i.e., the cortico-subthalamic projection, which is specific for motor coordination.27 The use of tDCS can calibrate and enhance a neuron's networking abilities even in advanced stages of PD with cortical and basal ganglion dysfunctions.25,27
Our study demonstrated that both tDCS and physical therapy are effective in improving the walking ability in patients with PD. A combination of the treatments did not demonstrate a significantly better outcome.
Kaski et al.28 also studied the combination treatment of physical therapy and tDCS and its effect on improving the walking speed among patients with PD and reported that the combination treatment had a greater effect on walking speed compared with using tDCS or physical therapy alone. Furthermore, they reported that using tDCS alone resulted in no significant benefit. However, a single session of 15-min stimulation was used, without any long-term evaluation. Our study differed in that a 30-minute stimulation was applied for a total of six sessions for 2 wks and demonstrated a positive outcome on gait with no difference from the combination group. This could imply that tDCS has a positive treatment effect when adequate dose-related stimulation is reached.
In resource-limited settings without access to tDCS, the physical therapy protocols used in this study could help improve the gait of patients with PD, albeit the effects resulted at a slightly slower pace compared with those of tDCS. If a setting has access to tDCS devices, using the tDCS, which can be easily performed by trained physical therapists or medical personnel and also can be performed upon multiple patients at the same time, supervised by a single therapist, has a great advantage over physical therapy. This usually requires a one-on-one training regimen, especially in a rehabilitation center that has a limited number of therapists compared with a high number of patients.
As far as home treatment is considered, the physical therapist can provide instructions about what exercise can be performed by patients by themselves at home or with assistance from the caregivers. Currently, no recommendation has been established to allow patients to use tDCS without the supervision of trained medical personnel, at a hospital or at home. Klooster et al.25 described the possibility that in the future, self-delivery of tDCS with patient-specific stimulation protocol in a home environment could be the most important advantage of noninvasive brain stimulation treatment.
Some limitations were observed in the study. First, the patients from this study had mild to moderate PD and were on medications that had already been adjusted for the optimal dose for individual patients. Medication remains the most effective treatment for PD and is considered the criterion standard treatment for controlling both motor and nonmotor symptoms.3,5,29 Thus, all the results from gait evaluation performed in this study were the result of medication treatment plus additional treatment protocols given to each group. This may explain why the authors were not able to detect any significant difference between groups. The best method to explore the effect of tDCS and/or PT might include instructing the patients to stop taking such medications, but this would be unethical and is not clinically practical. Second, the treatment regimen in the combination group was applying tDCS followed by physical therapy and not simultaneously. The technique of using tDCS during physical therapy has been reported.28,30 Hypothetically, if tDCS and physical therapy are performed simultaneously, the neural networking might be enhanced further, but this could also increase the chance of the electrodes shifting position or losing contact while performing the exercises because they are attached to the patient's scalp using Velcro straps.
All interventions in this study could be used alone or together as a combination treatment protocol to improve walking speed and step length among patients with PD. The effects of a 2-wk course or a total of 6 sessions could last up to at least 8 wks. The intervention of anodal tDCS with physical therapy was not superior to the use of tDCS or physical therapy alone in improving the gait of patients with PD.
The authors thank all of the patients for participating in this study.
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