Transcranial direct current stimulation (tDCS) for idiopathic Parkinson's disease
Abstract
Background
Idiopathic Parkinson's disease (IPD) is a neurodegenerative disorder, with the severity of the disability usually increasing with disease duration. IPD affects patients' health‐related quality of life, disability, and impairment. Current rehabilitation approaches have limited effectiveness in improving outcomes in patients with IPD, but a possible adjunct to rehabilitation might be non‐invasive brain stimulation by transcranial direct current stimulation (tDCS) to modulate cortical excitability, and hence to improve these outcomes in IPD.
Objectives
To assess the effectiveness of tDCS in improving motor and non‐motor symptoms in people with IPD.
Search methods
We searched the following databases (until February 2016): the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library ; 2016 , Issue 2), MEDLINE, EMBASE, CINAHL, AMED, Science Citation Index, the Physiotherapy Evidence Database (PEDro), Rehabdata, and Inspec. In an effort to identify further published, unpublished, and ongoing trials, we searched trial registers and reference lists, handsearched conference proceedings, and contacted authors and equipment manufacturers.
Selection criteria
We included only randomised controlled trials (RCTs) and randomised controlled cross‐over trials that compared tDCS versus control in patients with IPD for improving health‐related quality of life , disability, and impairment.
Data collection and analysis
Two review authors independently assessed trial quality (JM and MP) and extracted data (BE and JM). If necessary, we contacted study authors to ask for additional information. We collected information on dropouts and adverse events from the trial reports.
Main results
We included six trials with a total of 137 participants. We found two studies with 45 participants examining the effects of tDCS compared to control (sham tDCS) on our primary outcome measure, impairment, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS). There was very low quality evidence for no effect of tDCS on change in global UPDRS score ( mean difference (MD) ‐7.10 %, 95% confidence interval (CI ‐19.18 to 4.97; P = 0.25, I² = 21%, random‐effects model). However, there was evidence of an effect on UPDRS part III motor subsection score at the end of the intervention phase (MD ‐14.43%, 95% CI ‐24.68 to ‐4.18; P = 0.006, I² = 2%, random‐effects model; very low quality evidence). One study with 25 participants measured the reduction in off and on time with dyskinesia, but there was no evidence of an effect (MD 0.10 hours, 95% CI ‐0.14 to 0.34; P = 0.41, I² = 0%, random‐effects model; and MD 0.00 hours, 95% CI ‐0.12 to 0.12; P = 1, I² = 0%, random‐ effects model, respectively; very low quality evidence).
Two trials with a total of 41 participants measured gait speed using measures of timed gait at the end of the intervention phase, revealing no evidence of an effect ( standardised mean difference (SMD) 0.50, 95% CI ‐0.17 to 1.18; P = 0.14, I² = 11%, random‐effects model; very low quality evidence). Another secondary outcome was health‐related quality of life and we found one study with 25 participants reporting on the physical health and mental health aspects of health‐related quality of life (MD 1.00 SF‐12 score, 95% CI ‐5.20 to 7.20; I² = 0%, inverse variance method with random‐effects model; very low quality evidence; and MD 1.60 SF‐12 score, 95% CI ‐5.08 to 8.28; I² = 0%, inverse variance method with random‐effects model; very low quality evidence, respectively). We found no study examining the effects of tDCS for improving activities of daily living. In two of six studies, dropouts , adverse events, or deaths occurring during the intervention phase were reported. There was insufficient evidence that dropouts , adverse effects, or deaths were higher with intervention (risk difference (RD) 0.04, 95% CI ‐0.05 to 0.12; P = 0.40, I² = 0%, random‐effects model; very low quality evidence).
We found one trial with a total of 16 participants examining the effects of tDCS plus movement therapy compared to control (sham tDCS) plus movement therapy on our secondary outcome, gait speed at the end of the intervention phase, revealing no evidence of an effect (MD 0.05 m/s, 95% CI ‐0.15 to 0.25; inverse variance method with random‐effects model; very low quality evidence). We found no evidence of an effect regarding differences in dropouts and adverse effects between intervention and control groups (RD 0.00, 95% CI ‐0.21 to 0.21; Mantel‐Haenszel method with random‐effects model; very low quality evidence).
Authors' conclusions
There is insufficient evidence to determine the effects of tDCS for reducing off time ( when the symptoms are not controlled by the medication) and on time with dyskinesia ( time that symptoms are controlled but the person still experiences involuntary muscle movements ) , and for improving health‐ related quality of life, disability, and impairment in patients with IPD. Evidence of very low quality indicates no difference in dropouts and adverse events between tDCS and control groups.
PICOs
Plain language summary
Non‐invasive electrical brain stimulation for improving rehabilitation outcomes in patients with idiopathic Parkinson's disease (IPD)
Review question
To assess the effectiveness of electrical brain stimulation in improving motor and non‐motor symptoms in people with idiopathic Parkinson's disease (IPD) .
Background
IPD is a neurodegenerative disorder, with the severity of the disability usually increasing with disease duration. IPD affects patients' health‐related quality of life, disability, and impairment. Current rehabilitation strategies have limited effectiveness in improving these outcomes. One possibility for enhancing the effects of rehabilitation might be the addition of non‐invasive electrical brain stimulation through a technique known as transcranial direct current stimulation (tDCS). This technique can alter how the brain works and may improve health‐related quality of life, disability, and impairment in function in patients with IPD. However, the effectiveness of this intervention for improving rehabilitation outcomes is still unknown.
Search date
The latest search was performed on 17 February 2016.
Study characteristics
We included six trials involving 137 participants. The duration of treatment in the included trials ranged from a single session to five consecutive sessions of tDCS.
Key results
From the six trials involving 137 participants, we found there was insufficient evidence to determine how much of an effect there is from tDCS in enhancing rehabilitation outcomes regarding reduction in off time (when the symptoms are not controlled by the medication) and on time with dyskinesia (time that symptoms are controlled but the person still experiences involuntary muscle movements) , and for improving health‐ related quality of life, disability, and impairment in patients with IPD. However, tDCS may improve impairment regarding motor symptoms in patients with IPD. We found no study examining the effects of tDCS for improving activities of daily living. Proportions of adverse events and people discontinuing the study were comparable between groups.
Quality of evidence
All findings are based on evidence of very low quality. That means that we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Authors' conclusions
Summary of findings
| Transcranial direct current stimulation (tDCS) versus sham tDCS for patients with odiopathic Parkinson's disease | ||||||
| Patient or population: Patients with idiopathic Parkinson's disease Comparison: sham tDCS | ||||||
| Outcomes | Illustrative comparative risks/scores* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
| Assumed risk/scores | Corresponding risk/scores | |||||
| Control (sham tDCS) | Transcranial Direct Current Stimulation (tDCS) | |||||
| Impairment/ disability | The mean impairment/disability in the control groups was | The mean impairment/disability in the intervention groups was | 45 | ⊕⊝⊝⊝ | ||
| Off time | The mean off time in the control groups was | The mean off time in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| On time with dyskinesia | The mean on time with dyskinesia in the control groups was | The mean on time with dyskinesia in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| Gait speed at the end of the intervention phase | The mean gait speed at the end of the intervention phase in the control groups was | The mean gait speed at the end of the intervention phase in the intervention groups was | 41 | ⊕⊝⊝⊝ | SMD 0.50 (‐0.17 to 1.18; a standard deviation of 0.50 represents a moderate effect (Cohen 1988)) | |
| Health‐related quality of life ‐ physical health (scores less than 50 indicate health above the mean and scores less than 50 indicate health below the mean) | The mean health‐related quality of life ‐ physical health in the control groups was | The mean health‐related quality of life ‐ physical health in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| Health‐related quality of life ‐ mental health | The mean health‐related quality of life ‐ mental health in the control groups was | The mean health‐related quality of life ‐ mental health in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| Safety/ acceptability | Study population | See comment | 101 | ⊕⊝⊝⊝ | Risks were calculated from pooled RDs RD 0.04, 95% CI ‐0.05 to 0.12; I² = 0% | |
| 0 per 1000 | 4 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to serious risk of bias (allocation sequence generation, concealment, and blinding of outcome assessors unclear). | ||||||
Background
Description of the condition
Idiopathic Parkinson' s disease (IPD) is a degenerative disorder that is characterised clinically by tremor, rigidity, bradykinesia (slowness of movement) , and postural instability.
Parkinson' s disease is estimated to have a crude incidence rate of 4.5 to 19 per 100,000 population per year (Baker 2006). Age‐adjusted prevalence estimations range between 72 and 258.8 per 100,000 population, and age‐adjusted incidence rates range from 9.7 to 13.8 per 100,000 population per year (Baker 2006). The male‐to‐female ratio is estimated to be 1.9 (Baker 2006). A recent study from Scotland found no association between incidence and socioeconomic status (Caslake 2013).
People suffering from Parkinson' s disease utilise health services significantly more often than healthy individuals, and this is associated with costs that are approximately double that the of a control population (Baker 2006). Almost every second US Dollar (USD) of associated annual direct and indirect costs of the disease is generated by productivity loss, and every fifth USD of associated costs is generated by inpatient and uncompensated care (Huse 2005).
At all stages of the disease, disability occurs, and the severity of disability usually increases with disease duration. Pain, motor impairment, depression, and insomnia affect the health‐related quality of life of people with IPD (Shearer 2012), particularly in the early stages of the disease. During disease progression, other factors become more important, particularly dementia (Schrag 2000a), and the prevalence of psychosis increases (Aarsland 1999). Patients usually have gait impairment, difficulty linking movements together smoothly, and episodes of freezing. These problems, together with balance disturbances, lead to an increased incidence of falls with concurrent risk of fractures. Nearly one‐third of patients with IPD have had a hip fracture within 10 years of their diagnosis (Johnell 1992).
Current management of IPD focuses on pharmacological therapy; at present, levodopa is regarded as the most effective treatment, and is prescribed most often (Crosby 2003). However, many patients suffer from side effects of levodopa, including abnormal involuntary movements known as dyskinesias (Jankovic 2000). Drugs other than levodopa, such as dopamine agonists are used increasingly as first‐line treatment to reduce motor complications, but with the tradeoff of generating other relevant side effects, and leading to poorer symptom control (Stowe 2008).
A large proportion of patients taking medication suffer from significant motor complications, such as motor fluctuation or dyskinesias (Nutt 1990). These complications cause functional disability, affect the person's quality of life, and are difficult to manage with available drug strategies (Motto 2003). These patients could be considered candidates for deep brain stimulation of the basal ganglia (Motto 2003). However, debate continues concerning risks and benefits of this surgical approach; whereas motor symptoms can be improved by deep brain stimulation , evidence is insufficient to show improvement in non‐motor symptoms (Fasano 2012).
Despite optimal medical and surgical therapies for IPD, patients develop progressive disability (Deane 2001). Hence, novel treatment approaches, aimed at reducing movement disorders in IPD are needed (Mehrholz 2010).
Description of the intervention
Non‐invasive brain stimulation by transcranial direct current stimulation (tDCS) might offer such a treatment approach. tDCS modulates cortical excitability by applying a direct current to the skull (Bindman 1964; Nowak 2009; Purpura 1965). Stimulation of the central nervous system by tDCS is relatively inexpensive and easy to administer when compared with other techniques for brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS) and epidural stimulation (Hesse 2011). tDCS usually is delivered via saline‐soaked surface sponge electrodes, which are connected to a direct current stimulator that produces low intensities of a current (Lang 2005). Different techniques might be applied: the anodal electrode might be placed over the presumed area of interest of the brain and the cathodal electrode placed above the contralateral orbit (anodal stimulation), or vice versa (cathodal stimulation) (Hesse 2011), or both at the same time (bi‐hemispheric or dual stimulation) (Lindenberg 2010).
How the intervention might work
Depending on the type of stimulation (anodal or cathodal), tDCS might lead to increased or decreased cortical excitability, respectively (Bindman 1964; Purpura 1965). This might be due to a shift in the resting potential of the brain's nerves (Purpura 1965). Stimulation lasting for longer than five minutes might induce significant after‐effects, which could last up to several hours (Nitsche 2001; Nitsche 2003). Anodal stimulation might lead to depolarisation of the neuronal membranes, and therefore may result in greater cortical excitability, and vice versa (Bindman 1964). This effect might be used to facilitate motor learning in healthy people (Boggio 2006; Jeffery 2007; Reis 2009), and seems therefore to be a promising option in neurorehabilitation of individuals with movement disorders because it could be delivered with standard rehabilitation simultaneously, and is inexpensive.
Why it is important to do this review
Recent studies have suggested that tDCS might be beneficial for improving movement disorders in people with Parkinson's disease (Benninger 2010; Fregni 2006; Gruner 2010; Wu 2008). However, no systematic review has examined the available literature on the effectiveness and acceptability of this treatment option.
Objectives
To assess the effectiveness of transcranial direct current stimulation (tDCS) in improving motor and non‐motor symptoms in people with idiopathic Parkinson's disease (IPD) in comparison to any active or passive comparator.
Methods
Criteria for considering studies for this review
Types of studies
We included genuine randomised controlled trials (RCTs) with parallel‐group or cross‐over designs. We did not include quasi‐RCTs.
Types of participants
We included adult participants (18+ years of age) with idiopathic Parkinson's disease (IPD) who have been diagnosed by the UK Parkinson' s Disease Brain Bank criteria (Hughes 1992), or by a clinical definition, regardless of medication, duration of illness, presence of motor fluctuations, duration of treatment, or level of initial impairment.
Types of interventions
We compared any kind of truly active transcranial direct current stimulation (tDCS) for improving movement disorders versus any kind of placebo or control intervention (i.e. sham tDCS or no intervention). We defined active tDCS as the longer‐lasting (longer than one minute) application of a direct current to the brain to stimulate the affected hemisphere or to inhibit the healthy hemisphere, or to do both simultaneously. We defined sham tDCS as a short‐term direct current stimulation (less than one minute; this is approximately the time it usually takes to fade in and fade out the current in sham‐controlled tDCS trials without producing perceivable sensations on the skin (Gandiga 2006)), or the placement of electrodes with no application of direct current.
Types of outcome measures
Primary outcomes
As primary outcomes, we considered the following.
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Impairment/disability, measured by the Unified Parkinson's Disease Ranking Scale (UPDRS; Fahn 1987).
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Reduction in off time (when the symptoms are not controlled by the medication)
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Reduction in on time with dyskinesia (time that symptoms are controlled but the person still experiences involuntary muscle movements) .
We classified the clinically important difference in UPDRS change according to Shulman 2010 (i.e. 2.5 points for a minimal, 5.2 points for a moderate, and 10.8 points for a large clinically important difference ).
We reported primary outcome measures at the end of the intervention phase, and if sufficient data were available, at least three months after the end of the intervention phase.
Secondary outcomes
As secondary outcomes, we considered the following.
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Specific measures of impairment.
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Timed tests of gait.
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Stride length.
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Cadence.
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Bradykinesia in the upper extremity.
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Health‐related quality of life; possible outcome measures include the following.
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PDQ‐39 (Marinus 2002).
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PDQL (Marinus 2002).
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EQ‐5D (Schrag 2000b).
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Activities of daily living; a possible outcome measure is:
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the Schwab and England A ctivities of D aily L iving scale (Schwab 1969).
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Safety/acceptability .
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Dropouts .
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A dverse events (including death from al l causes) .
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Search methods for identification of studies
Electronic searches
We used a modified search strategy developed by the Cochrane Stroke Group to search the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library ; 2016 , Issue 2 ), MEDLINE (from 1948 to 16 February 2016), EMBASE (from 1980 to 16 February 2016), CINAHL (from 1982 to 16 February 2016), AMED (from 1985 to 16 February 2016), Web of Science Core Collection (from 1900 to 16 February 2016), the Physiotherapy Evidence Database (PEDro; www.pedro.org.auto 16 February 2016), Rehabdata (from 1956 to 16 February 2016), and the engineering database Inspec (from 1969 to 16 February 2016 ).
The search strategy can be found in Appendix 1.
We identified and searched the following ongoing trial and research registers.
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Current Controlled Trials (http://www.controlled‐trials.com/).
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ClinicalTrials.gov (http://clinicaltrials.gov/ct2/home).
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European Union (EU) Clinical Trials Register (https://www.clinicaltrialsregister.eu/).
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World Health Organization (WHO) International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/).
Searching other resources
To identify further published, unpublished, and ongoing trials not available in the aforementioned databases, we:
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identified and handsearched relevant conference proceedings;
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screened reference lists of relevant articles, reviews, and textbooks;
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contacted authors of identified trials and other researchers in the field;
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searched the Science Citation Index cited references;
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contacted the following equipment manufacturers:
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DJO global http://djoglobal.com/contact‐us;
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Grindhouse http://www.grindhousewetware.com;
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Trans Cranial Technologies http://www.trans‐cranial.com;
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Soterix Medical http://soterixmedical.com/;
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Activatek http://activatekinc.com;
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Zhinheng Electronics http://cszhineng.diytrade.com;
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Magstim www.magstim.com;
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Neuroelectrics www.neuroelectrics.com;
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Neuroconn www.neuroconn.de;
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Newronika www.newronika.it;
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and searched Google Scholar (http://scholar.google.com/).
We searched for relevant trials in all languages and arranged translation of trial reports published in languages other than English.
Data collection and analysis
Selection of studies
Two review authors (BE and JM) read the titles and abstracts of the records identified through the electronic searches and eliminated irrelevant references that clearly did not match our inclusion criteria. We retrieved the full‐ text of the remaining studies, and two review authors (JK and MP) independently checked relevant studies for inclusion according to our inclusion criteria (types of studies, participants, and aims of interventions). We resolved disagreements by discussion with all review authors. If we needed further information to resolve disagreements concerning including or excluding a study, we contacted the trial authors to request the required information. We listed in the 'Characteristics of excluded studies' table all studies that appeared to match our inclusion criteria regarding type of study, participants, or types of interventions, but did not actually match them.
Data extraction and management
Two review authors (BE and JM) independently extracted trial and outcome data from the selected trials. If one of the review authors was involved in an included trial, another review author extracted trial and outcome data from such a trial.
We used checklists to independently extract data regarding the following aspects and provided them in the 'Characteristics of included studies' table.
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Methods of random sequence generation.
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Methods of allocation concealment.
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Blinding of assessors.
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Use of an intention‐to‐treat (ITT) analysis.
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Adverse effects and dropouts.
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Important differences in prognostic factors.
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Participants (country, number of participants, age, gender, stage of Parkinson's disease as assessed by Hoehn and Yahr at entry to the study ( Hoehn 1967 ), 'on' / 'off' state of dopaminergic medication, inclusion and exclusion criteria).
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Comparison (details of interventions in treatment and control groups, duration of treatment, and details of co‐interventions in study groups).
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Outcomes.
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Time point of measurement.
Further, we extracted data of initial functional ability and of initial level of function, and we presented the content of each included study in detail in a table.
All review authors checked the extracted data for agreement. If necessary, we contacted trialists to request more information.
Assessment of risk of bias in included studies
Two review authors (JK and MP) assessed the risk of bias in the included trials according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We categorise d the risk of bias as ‘low’, ‘high’ or ‘unclear’ for the following domains.
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Random sequence generation.
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Allocation concealment.
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Blinding of participants and personnel.
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Blinding of outcome assessment.
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Selective outcome reporting.
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Incomplete outcome data.
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Other bias.
We described the agreement between review authors for assessment of methodological quality, and we resolved disagreements in methodological assessment by reaching consensus through discussion. We contacted trialists for clarification and to request missing information.
Measures of treatment effect
For outcomes measured with continuous data, we used means and standard deviations (SDs) to generate effect estimates. We calculated a summary estimate of the mean difference (MD) with 95% confidence intervals (CIs). If studies assessing the same outcome used different scales, we calculated standardised mean differences (SMDs) instead of MDs. For all binary outcomes, we calculated risk ratios (RRs) with 95% CIs. If only few events occurred, we calculated risk differences (RDs) with 95% CIs instead.
For all statistical comparisons, we used the current version of Review Manager 5 (RevMan 2014).
Unit of analysis issues
We analysed both periods of randomised cross‐over trials. If sham or active control groups from the same study investigated the same content, we combined these into one group for each (e.g. if two sham control groups were used, we combined these into a single group for comparison with the intervention group).
Dealing with missing data
In case of missing information, we contacted the authors of the respective studies to ask for further clarification. If we were not able to receive the missing data of a study from the authors, we classified the study as 'awaiting classification'.
Assessment of heterogeneity
We used the I² statistic to assess heterogeneity. In cases in which I² was greater than 50%, we assumed substantial heterogeneity.
Assessment of reporting biases
We examined the presence of a reporting bias by visual inspection of funnel plots using all studies that met basic entry criteria, if appropriate (Sterne 2011).
Data synthesis
We used a random‐effects model, regardless of the level of heterogeneity. Thus, in the case of heterogeneity, we did not violate the preconditions of a fixed‐effect model approach.
'Summary of findings' table and assessing the quality of evidence
We assessed the quality of evidence using the grading system developed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) collaboration (Guyatt 2008). Following the methods developed by the GRADE Working Group, two review authors independently judged the quality of the body of evidence using a transparent structure that involved appraising factors such as research design, implementation, imprecision, inconsistency, indirectness, and reporting bias. We used the software, GRADEprofiler, to assist in the process of a GRADE assessment ( GRADEproGDT 2015). We implemented a 'S ummary of findings' table to describe the quality of the evidence for the main comparison 'transcranial direct current stimulation (tDCS) versus sham tDCS' . If data on more than seven outcomes had to be reported, we presented the outcomes with the highest prioritisation in the 'Summary of findings' table , regardless of the availability of data.
Subgroup analysis and investigation of heterogeneity
If sufficient data were available, we conducted an analysis of the following subgroups for our primary outcome, impairment/disability, measured by the UPDRS .
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On/off state of the illness.
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Type of stimulation: cathodal versus anodal.
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Type of control intervention (sham tDCS or nothing).
All stratified (subgroup) analyses were accompanied by appropriate tests for interaction (statistical tests for subgroup differences as described in the Cochrane Handbook for Systematic Review of Interventions (Deeks 2011), and as implemented in Review Manager 5 (RevMan 2014).
Sensitivity analysis
We intended to undertake a sensitivity analysis regarding the risk of bias of included studies to assess the robustness of our results. We planned to analyse the influence of studies that did not clearly state or did not utilise proper methods for: (1) generating the randomisation schedule; (2) allocation concealment; and (3) did not use an intention‐to‐treat analysis.
Results
Description of studies
Results of the search
See Characteristics of included studies, Characteristics of excluded studies, Characteristics of studies awaiting classification , and Characteristics of ongoing studies. We identified a total of 4420 unique records through the searches. After screening titles and abstracts, we excluded 4167 records and obtained the full‐ text of the remaining 53 articles. After further assessment, we determined that six studies met the review inclusion criteria. The flow of references is shown in Figure 1.
Study flow diagram. Please note, that the number of full‐texts may be unequal to the number of studies (i.e. the studies Kaski 2014a and Kaski 2014b have been reported in a single full‐text).
Included studies
We included six studies involving a total of 137 participants (Benninger 2010; Kaski 2014a ; Kaski 2014b; Monte‐Silva 2013; Valentino 2014; Verheyden 2013 ; see Characteristics of included studies). Kaski 2014a; and Kaski 2014b are two arms of the same study. Four studies investigated the effects of transcranial direct current stimulation (tDCS) versus sham tDCS (Benninger 2010; Kaski 2014b; Valentino 2014; Verheyden 2013), whereas two trials with 28 participants investigated the effects of tDCS plus movement therapy versus sham tDCS plus movement therapy (Kaski 2014a; Monte‐Silva 2013). Four trials with 92 participants were randomly assigned cross‐over trials (Kaski 2014a; Kaski 2014b; Valentino 2014; Verheyden 2013), whereas the remaining two, with 45 analysed participants, were randomised parallel‐group trials (RCTs) (Benninger 2010; Monte‐Silva 2013). All six studies included one intervention group and one control group, or the patients received the intervention and served as their own control, respectively. Benninger 2010, Monte‐Silva 2013 and Valentino 2014 were the only studies that examined the effects of tDCS on the Unified Parkinson's Disease Ranking Scale (UPDRS) or UPDRS motor subscore , and four studies examined the effects of tDCS on gait speed (Benninger 2010; Kaski 2014a; Kaski 2014b; Verheyden 2013). One of the included studies was conducted in Italy, one in the USA, one in Brazil, and one in the UK. In two studies, the country was not clearly stated. Widely used outcomes were measures of timed gait and the UPDRS. For a comprehensive summary of participant characteristics, please see Table 1; for a comprehensive summary of intervention characteristics, dropouts and adverse events, please see Table 2.
| Study | EXP: age, | CTL: age, | Hoehn and | EXP: duration of disease | CTL: duration of disease | EXP: female/male | CON: female/male |
| 64 (9) years | 64 (9) years | 2 to 3 | 11 (7) months | 9 (3) years | 5/7 | 4/9 | |
| No demographical data provided | |||||||
| No demographical data provided | |||||||
| No demographical data provided | |||||||
| 72 (4) years | 2.5 to 4 | 11 (5) years | 5/5 | ||||
| 71 (7) years | 1 to 4 | 9 (4) years | not reported | ||||
CTL: control group
EEG: electroencephalography
EXP: experimental group
NA: not applicable
SD: standard deviation
| Study | Type of stimulation (polarity) | Electrode position and size | Treatment intensity | Base treatment | Dropouts | Adverse events | Reasons for dropouts and adverse events in the experimental group | Reasons for dropouts and adverse events in the control group | Source of information | |
| Anodal tDCS | Anode and cathode were placed on the forehead | 2 mA for 20 minutes | Anodal or sham tDCS for 4 days once a day | None | None | 1 | Skin defect (similar to 1st degree burn) due to malpositioned electrodes | NA | Published | |
| Sham tDCS | 1 mA for 1 to 2 minutes | None | ||||||||
| Anodal tDCS | Saline‐soaked 40 cm² sponge electrode was placed over the Cz area of international 10‐20 EEG electrode placement system (anode) and over the inion (cathode), respectively | 2 mA for 15 minutes | Anodal or sham tDCS once | 15 minutes of physical training, focusing on improvement on gait initiation, stride length, gait velocity, arm swing and balance | None | Not reported | NA | NA | Published | |
| Sham tDCS | 2 mA for 30 seconds | |||||||||
| Anodal tDCS | Saline‐soaked 40 cm² sponge electrode was placed over the Cz area of international 10‐20 EEG electrode placement system (anode) and over the inion (cathode), respectively | 2 mA for 15 minutes | Anodal or sham tDCS once | None | None | Not reported | NA | NA | Published | |
| Sham tDCS | 2 mA for 30 seconds | |||||||||
| Not reported | Unpublished | |||||||||
| Anodal tDCS | Anode was positioned in anterioposterior orientation over M1 corresponding to the leg with which the patient usually started walking after a freezing of gait period and the cathode at the contralateral supraorbital region | 2 mA for 20 minutes | Anodal or sham tDCS for five consecutive days | None | None | None | NA | NA | Published | |
| Sham tDCS | 2 mA for 1 minute | |||||||||
| Anodal tDCS | Anode was positioned over M1 of the dominant hemisphere with the cathode placed on the contralateral supraorbital region | 1 mA for 15 minutes | Anodal or sham tDCS once | None | 1 in EXP group | None | Feeling of heat underneath the active electrode | NA | Publisihed and unpublished | |
| Sham tDCS | 1 mA for 10 seconds (plus ramps) | |||||||||
EEG: electroencephalography
EXP: experimental
M1: primary motor cortex
NA: not applicable
Excluded studies
Altogether we excluded 48 full‐text articles (Figure 1), as they did not fulfil our inclusion criteria. We have listed ten of them in the Characteristics of excluded studies t ables as these studies did not obviously violate our inclusion criteria, but were not suitable for inclusion in this review (Baijens 2012; Biundo 2015; Boggio 2006; Fregni 2006; Gruner 2010; Manenti 2014; Pereira 2013; Schollmann 2015; von Papen 2014; Yu 2011).
Risk of bias in included studies
We provided information about the risk of bias in the Characteristics of included studies tables. To complete the rating of methodological quality, we contacted principal investigators of the included trials, and of trials awaiting classification, to request further information about methodological issues, if necessary. We made contact via letter and email, including email reminders once a month, if we received no response. Some trialists provided all requested information, and some did not answer our requests. We used the 'Risk of bias' tool, as implemented in Review Manager 5 ( RevMan 2014 ), to assess risk of bias according to the aspects listed under Methods. Two review authors (BE and JM) independently assessed risk of bias of the included trials, and two other review authors (JK and MP) checked the extracted data for agreement. Information on risk of bias at the study level is provided in Figure 2. All review authors discussed disagreements and, if necessary, sought arbitration by another review author. A detailed description of risk of bias can be found in the 'Risk of bias' tables in Characteristics of included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Four of the six included studies ( 66 %) described a low risk of bias for sequence generation (Benninger 2010; Kaski 2014a; Kaski 2014b; Verheyden 2013), whereas two studies (34%) described a low risk of bias for allocation concealment (Monte‐Silva 2013; Verheyden 2013).
Blinding
We rated five of the six included studies (83%) at low risk of performance bias for blinding of participants and personnel (objective outcome measures) (Benninger 2010; Kaski 2014a; Kaski 2014b; Valentino 2014; Verheyden 2013); we rated Monte‐Silva 2013 at unclear risk of bias. For the subjective measures of blinding of participants and personnel , we judged Kaski 2014a and Kaski 2014b at low risk of performance bias; we rated all other studies at unclear risk of performance bias. Four studies (67%) described low risk of bias for blinding of outcome assessment ( objective out come measures ) (Benninger 2010; Kaski 2014a; Kaski 2014b; Verheyden 2013), whereas we judged one study (17%) to have high risk of bias for subjective outcomes (Valentino 2014), and one study at unclear risk of bias for both objective and subjective outcomes (Monte‐Silva 2013).
Incomplete outcome data
Four of the six included studies (67%) were at low risk of bias for incomplete outcome data (Benninger 2010; Kaski 2014a; Kaski 2014b; Valentino 2014).
Selective reporting
One of the five included studies (17%) was at low risk of bias for selective outcome reporting (Benninger 2010), whereas we rated the remaining five (83%) at unclear risk of bias.
Effects of interventions
A summary of this review's main findings can be found in summary of findings Table for the main comparison.
Comparison 1. transcranial direct current stimulation (tDCS) versus sham tDCS
Outcome 1.1. Unified Parkinson's Disease Ranking Scale (UPDRS; change in global UPDRS score)
We found two studies with 45 participants examining the effects of tDCS on impairment, as measured by UPDRS (Benninger 2010; Valentino 2014). We used percentage change, rather than absolute UPDRS change because one trial only provided percentage change from baseline ( Valentino 2014 ). We found no evidence of effect regarding impairment ( mean difference (MD) ‐7.10%, 95% confidence interval (CI) ‐19.18 to 4.97; P = 0.25, I² = 21%, inverse variance method with random‐effects model; very low quality evidence) (Analysis 1.1).
Outcome 1.2. Unified Parkinson's Disease Ranking Scale (UPDRS; change in part III (motor section) score)
Two studies with 45 participants used UPDRS part III motor subsection to evaluate the effects of tDCS on (motor) impairment (Benninger 2010; Valentino 2014). We found evidence of an effect (MD ‐14.43%, 95% CI ‐24.68 to ‐4.18; P = 0.006, I² = 2%, inverse variance method with random‐effects model; very low quality evidence), but the confidence interval was wide (Analysis 1.2).
Outcome 1.3 Off time and on time with dyskinesia
1.3.1 Off time (when the symptoms are not controlled by the medication)
We found one study with 25 participants examining the reduction in off time (Benninger 2010). We found no evidence of an effect (MD 0.10 hours, 95% CI ‐0.14 to 0.34; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence) (Analysis 1.3).
1.3.2 On time with dyskinesia (time that symptoms are controlled but the person still experiences involuntary muscle movements)
We found one study with 25 participants examining the reduction in on time with dyskinesia (Benninger 2010). We found no evidence of an effect (MD 0.00 hours, 95% CI ‐0.12 to 0.12; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence) (Analysis 1.3).
Outcome 1.4 Gait speed at the end of the intervention phase
We found two studies with 41 participants examining the effects of tDCS on gait speed, measured by timed tests of gait (Benninger 2010; Kaski 2014b). We found no evidence of effect regarding impairment ( standardised mean difference (SMD) 0.50, 95% CI ‐0.17 to 1.18; P = 0.14, I2 = 11%, inverse variance method with random‐effects model; very low quality evidence) (Analysis 1.4).
Outcome 1.5 Health‐related quality of life
1.5.1 Physical health
We found one study with 25 participants examining the physical health aspect of health‐related quality of life (Benninger 2010). We found no evidence of an effect (MD 1.00 SF‐12 score, 95% CI ‐5.20 to 7.20; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence) (Analysis 1.5).
1.5.2 Mental health
We found one study with 25 participants examining the mental health aspect of health‐related quality of life (Benninger 2010). We found no evidence of an effect (MD 1.60 SF‐12 score, 95% CI ‐5.08 to 8.28; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence) (Analysis 1.5).
Outcome 1.6 Activities of daily living
We found no study examining the effects of tDCS for improving activities of daily living.
Outcome 1.7 Dropouts and adverse events
We found four studies with 101 participants examining the effects of tDCS on dropouts and adverse events (Benninger 2010; Kaski 2014a; Valentino 2014; Verheyden 2013). We found no evidence of effect regarding dropouts and adverse events ( risk difference (RD) 0.04, 95% CI ‐0.05 to 0.12; P = 0.40, I2 = 0%, Mantel‐Haenszel method with random‐effects model; very low quality evidence) (Analysis 1.6).
Comparison 2. transcranial direct current stimulation (tDCS) plus movement therapy versus sham tDCS plus movement therapy
Outcome 2.1. Unified Parkinson's Disease Ranking Scale (UPDRS; change in global UPDRS score)
We found no study examining the effects of tDCS for improving UPDRS global score.
Outcome 2.2. Unified Parkinson's Disease Ranking Scale (UPDRS; change in part III (motor section) score)
We found no study examining the effects of tDCS for improving UPDRS part III (motor section) score.
Outcome 2.3 Reduction in off time and on time with dyskinesia
We found no study examining the effects of tDCS for improving off time (when the symptoms are not controlled by the medication) and on time with dyskinesia (when the symptoms are not controlled by the medication) (for people with more advanced disease).
Outcome 2.4 Gait speed at the end of the intervention phase
We found one randomised cross‐over study with eight participants examining the effects of tDCS on gait speed, measured by timed tests of gait (Kaski 2014a). We found no evidence of effect regarding impairment (MD 0.05 m/s, 95% CI ‐0.15 to 0.25; P = 0.62, I2 = 0%, inverse variance method with random‐effects model; very low quality evidence) (Analysis 2.1).
Outcome 2.5 Health‐related quality of life
We found no study examining the effects of tDCS for improving health‐related quality of life.
Outcome 2.6 Activities of daily living
We found no study examining the effects of tDCS for improving activities of daily living.
Outcome 2.7 Dropouts and adverse events
We found one randomised cross‐over study with eight participants examining the effects of tDCS on dropouts and adverse events (Kaski 2014a). We found no evidence of effect regarding dropouts and adverse events (RD 0.00, 95% CI ‐0.21 to 0.21; I2 = 0%, Mantel‐Haenszel method with random‐effects model; very low quality evidence) (Analysis 2.2).
Sensitivity analyses
We discarded our planned sensitivity analysis, because there were too few included trials.
Discussion
Summary of main results
This review focused on evaluating the effectiveness of transcranial direct current stimulation (tDCS) (anodal, cathodal, or dual) versus control ( sham tDCS, any other approach, or no intervention) for improving health‐related quality of life, disability, and impairment in patients with idiopathic Parkinson's disease (IP D). We included six trials with a total of 137 participants.
tDCS versus sham tDCS
We found two studies with 45 participants examining the effects of tDCS on our primary outcome measure, impairment, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS). We found no evidence of effect regarding impairment at the end of the intervention phase for global UPDRS score ( mean difference (MD) ‐7.10%, 95% confidence interval (CI) ‐19.18 to 4.97; inverse variance method with random‐effects model; very low quality evidence), whereas we found evidence of an effect of tDCS on UPDRS part III motor subsection score (MD ‐14.43%, 95% CI ‐24.68 to ‐4.18; inverse variance method with random‐effects model; very low quality evidence), but the CI was wide. We found one study with 25 participants examining the reduction in off time and in on time with dyskinesia. We found no evidence of an effect (MD 0.10 hours, 95% CI ‐0.14 to 0.34; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence; and MD 0.00 hours, 95% CI ‐0.12 to 0.12; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence, respectively).
One of our secondary outcome measures was gait speed: two trials with a total of 41 participants measured gait speed using measures of timed gait at the end of the intervention phase, revealing no evidence of an effect (standardised mean difference (SMD) 0.50, 95% CI ‐0.17 to 1.18; inverse variance method with random‐effects model; very low quality evidence). Another secondary outcome was health‐related quality of life and we found one study with 25 participants reporting on the physical health and mental health aspects of health‐related quality of life (MD 1.00 SF‐12 score, 95% CI ‐5.20 to 7.20; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence; and MD 1.60 SF‐12 score, 95% CI ‐5.08 to 8.28; I2 = 0%, inverse variance method with random‐effects model; very low quality evidence, respectively). We found no study examining the effects of tDCS for improving activities of daily living. In two of six studies (33%), dropouts and adverse events occurring during the intervention phase were reported. We found no evidence of an effect regarding differences in dropouts and adverse effects between intervention and control groups ( risk difference (RD) 0.04, 95% CI ‐0.05 to 0.12; Mantel‐Haenszel method with random‐effects model; very low quality evidence).
A summary of this comparison's main findings can be found in summary of findings Table for the main comparison.
tDCS plus movement therapy versus sham tDCS plus movement therapy
One of our secondary outcome measures was gait speed: one trial with a total of 16 participants measured gait speed using measures of timed gait at the end of the intervention phase, revealing no evidence of an effect (MD 0.05 m/s, 95% CI ‐0.15 to 0.25; inverse variance method with random‐effects model; very low quality). We found no evidence of an effect regarding differences in dropouts and adverse effects between intervention and control groups (RD 0.00, 95% CI ‐0.21 to 0.21; Mantel‐Haenszel method with random‐effects model; very low quality evidence).
Overall completeness and applicability of evidence
Some factors suggest uncertainty in generalisations, for example, two studies had examined change in UPDRS scores ( Benninger 2010 ; Valentino 2014 ), which is appropriate for early patients with IPD. We only found one study that assessed the reduction in off time and on time with dyskinesia ( Benninger 2010), which are outcome measures suitable for people with more advanced disease. Completeness of evidence generally is lacking regarding studies on the non‐motor aspects of the disease and measures of health‐ related quality of life as well. The majority of patients have been analysed in the on‐state of the disease. Hence, the results may not be applicable to patients in the off‐state of the disease.
Quality of the evidence
Based on our assessments of the quality of evidence provided in summary of findings Table for the main comparison, we downgraded quality of evidence due to unclear or high risk of bias (this would overestimate our findings) and the imprecision of effect estimates. We also found heterogeneity regarding trial design (parallel‐group or cross‐over design), therapy variables (active/passive comparator, location of stimulation, dosage of stimulation, base treatment), and participant characteristics (age, disease duration, severity of disease).
Potential biases in the review process
The methodological rigour of Cochrane reviews minimises bias during the process of conducting systematic reviews. However it is possible that publication bias could have affected our results. However, according to the Cochrane Handbook for Systematic Reviews of Interventions, methods for detecting publication bias, such as funnel plots and linear regression tests, as a rule of thumb, do not work properly in cases where there are less than ten included studies ( Sterne 2011) ; therefore we have not included such methods .
Another potential fact that could have introduced bias is the analysis of both periods of randomised cross‐over trials. On the one hand, the natural course of the disease as well as carry‐over effects are not regarded as a problem in this case. However, the analysis of both periods of randomised controlled trials (RCTs) as if they were a parallel‐ group trial may be too conservative, resulting in wide CIs, and giving too little weight to these studies.
Agreements and disagreements with other studies or reviews
Although there are systematic reviews dealing with the effects of repetitive transcranial magnetic stimulation (rTMS) in IPD (for example, Elahi 2009), we were not able to identify any systematic reviews dealing with the effects of tDCS on IPD. However, the results of our review seem to reflect the ambiguous results across clinical studies dealing with this topic. The apparent lack of benefit may be due to variations in the implementation of tDCS, since it is not known which are the optimal stimulation protocols for IPD (Chen 2010; Koch 2013). The results of Monte‐Silva 2013 corroborate the findings of Analysis 1.1.
There are two recent Cochrane reviews about the contemporary approach of tDCS for improving activities of daily living, function, and aphasia after stroke (Elsner 2013a; Elsner 2013b), which also revealed small or no effects of tDCS following stroke.
Study flow diagram. Please note, that the number of full‐texts may be unequal to the number of studies (i.e. the studies Kaski 2014a and Kaski 2014b have been reported in a single full‐text).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Transcranial Direct Current Stimulation (tDCS) versus sham tDCS, Outcome 1 Unified Parkinson's Disease Ranking Scale (UPDRS; change in global UPDRS score).
Comparison 1 Transcranial Direct Current Stimulation (tDCS) versus sham tDCS, Outcome 2 Unified Parkinson's Disease Ranking Scale (UPDRS; change in part III (motor section) score).
Comparison 1 Transcranial Direct Current Stimulation (tDCS) versus sham tDCS, Outcome 3 Off time and on time with dyskinesia.
Comparison 1 Transcranial Direct Current Stimulation (tDCS) versus sham tDCS, Outcome 4 Gait speed at the end of intervention phase.
Comparison 1 Transcranial Direct Current Stimulation (tDCS) versus sham tDCS, Outcome 5 Health‐related quality of life.
Comparison 1 Transcranial Direct Current Stimulation (tDCS) versus sham tDCS, Outcome 6 Dropouts and adverse events.
Comparison 2 Transcranial Direct Current Stimulation (tDCS) plus movement therapy versus sham tDCS plus movement therapy, Outcome 1 Gait speed at the end of intervention phase.
Comparison 2 Transcranial Direct Current Stimulation (tDCS) plus movement therapy versus sham tDCS plus movement therapy, Outcome 2 Dropouts and adverse events.
| Transcranial direct current stimulation (tDCS) versus sham tDCS for patients with odiopathic Parkinson's disease | ||||||
| Patient or population: Patients with idiopathic Parkinson's disease Comparison: sham tDCS | ||||||
| Outcomes | Illustrative comparative risks/scores* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
| Assumed risk/scores | Corresponding risk/scores | |||||
| Control (sham tDCS) | Transcranial Direct Current Stimulation (tDCS) | |||||
| Impairment/ disability | The mean impairment/disability in the control groups was | The mean impairment/disability in the intervention groups was | 45 | ⊕⊝⊝⊝ | ||
| Off time | The mean off time in the control groups was | The mean off time in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| On time with dyskinesia | The mean on time with dyskinesia in the control groups was | The mean on time with dyskinesia in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| Gait speed at the end of the intervention phase | The mean gait speed at the end of the intervention phase in the control groups was | The mean gait speed at the end of the intervention phase in the intervention groups was | 41 | ⊕⊝⊝⊝ | SMD 0.50 (‐0.17 to 1.18; a standard deviation of 0.50 represents a moderate effect (Cohen 1988)) | |
| Health‐related quality of life ‐ physical health (scores less than 50 indicate health above the mean and scores less than 50 indicate health below the mean) | The mean health‐related quality of life ‐ physical health in the control groups was | The mean health‐related quality of life ‐ physical health in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| Health‐related quality of life ‐ mental health | The mean health‐related quality of life ‐ mental health in the control groups was | The mean health‐related quality of life ‐ mental health in the intervention groups was | 25 | ⊕⊝⊝⊝ | ||
| Safety/ acceptability | Study population | See comment | 101 | ⊕⊝⊝⊝ | Risks were calculated from pooled RDs RD 0.04, 95% CI ‐0.05 to 0.12; I² = 0% | |
| 0 per 1000 | 4 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to serious risk of bias (allocation sequence generation, concealment, and blinding of outcome assessors unclear). | ||||||
| Study | EXP: age, | CTL: age, | Hoehn and | EXP: duration of disease | CTL: duration of disease | EXP: female/male | CON: female/male |
| 64 (9) years | 64 (9) years | 2 to 3 | 11 (7) months | 9 (3) years | 5/7 | 4/9 | |
| No demographical data provided | |||||||
| No demographical data provided | |||||||
| No demographical data provided | |||||||
| 72 (4) years | 2.5 to 4 | 11 (5) years | 5/5 | ||||
| 71 (7) years | 1 to 4 | 9 (4) years | not reported | ||||
| CTL: control group | |||||||
| Study | Type of stimulation (polarity) | Electrode position and size | Treatment intensity | Base treatment | Dropouts | Adverse events | Reasons for dropouts and adverse events in the experimental group | Reasons for dropouts and adverse events in the control group | Source of information | |
| Anodal tDCS | Anode and cathode were placed on the forehead | 2 mA for 20 minutes | Anodal or sham tDCS for 4 days once a day | None | None | 1 | Skin defect (similar to 1st degree burn) due to malpositioned electrodes | NA | Published | |
| Sham tDCS | 1 mA for 1 to 2 minutes | None | ||||||||
| Anodal tDCS | Saline‐soaked 40 cm² sponge electrode was placed over the Cz area of international 10‐20 EEG electrode placement system (anode) and over the inion (cathode), respectively | 2 mA for 15 minutes | Anodal or sham tDCS once | 15 minutes of physical training, focusing on improvement on gait initiation, stride length, gait velocity, arm swing and balance | None | Not reported | NA | NA | Published | |
| Sham tDCS | 2 mA for 30 seconds | |||||||||
| Anodal tDCS | Saline‐soaked 40 cm² sponge electrode was placed over the Cz area of international 10‐20 EEG electrode placement system (anode) and over the inion (cathode), respectively | 2 mA for 15 minutes | Anodal or sham tDCS once | None | None | Not reported | NA | NA | Published | |
| Sham tDCS | 2 mA for 30 seconds | |||||||||
| Not reported | Unpublished | |||||||||
| Anodal tDCS | Anode was positioned in anterioposterior orientation over M1 corresponding to the leg with which the patient usually started walking after a freezing of gait period and the cathode at the contralateral supraorbital region | 2 mA for 20 minutes | Anodal or sham tDCS for five consecutive days | None | None | None | NA | NA | Published | |
| Sham tDCS | 2 mA for 1 minute | |||||||||
| Anodal tDCS | Anode was positioned over M1 of the dominant hemisphere with the cathode placed on the contralateral supraorbital region | 1 mA for 15 minutes | Anodal or sham tDCS once | None | 1 in EXP group | None | Feeling of heat underneath the active electrode | NA | Publisihed and unpublished | |
| Sham tDCS | 1 mA for 10 seconds (plus ramps) | |||||||||
| EEG: electroencephalography | ||||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Unified Parkinson's Disease Ranking Scale (UPDRS; change in global UPDRS score) Show forest plot | 2 | 45 | Mean Difference (IV, Random, 95% CI) | ‐7.10 [‐19.18, 4.97] |
| 2 Unified Parkinson's Disease Ranking Scale (UPDRS; change in part III (motor section) score) Show forest plot | 2 | 45 | Mean Difference (IV, Random, 95% CI) | ‐14.43 [‐24.68, ‐4.18] |
| 3 Off time and on time with dyskinesia Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 3.1 Off time | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.14, 0.34] |
| 3.2 On time with dyskinesia | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐0.12, 0.12] |
| 4 Gait speed at the end of intervention phase Show forest plot | 1 | Std. Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 5.1 Physical health | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 1.0 [‐5.20, 7.20] |
| 5.2 Mental health | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 1.60 [‐5.08, 8.28] |
| 6 Dropouts and adverse events Show forest plot | 3 | 85 | Risk Difference (M‐H, Random, 95% CI) | 0.04 [‐0.05, 0.13] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Gait speed at the end of intervention phase Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Dropouts and adverse events Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
