Transcranial direct current stimulation combined with physical or cognitive training in people with Parkinson’s disease: a systematic review

Two of the authors (VSB and NRC) created a search strategy, which was approved by all authors, to identify all potentially relevant studies. Table 1 shows the terms and synonyms used to search papers in the databases in the title, abstract or keywords. The search strategy included three fields (connected with “AND”) with independent search terms. Terms in the same field were connected with the conjunction “OR”. The first search field focused on the population (i.e. Parkinson’s disease). The second search field comprised types of non-pharmacologic treatments (i.e. motor/physical therapies, rehabilitation, cognitive therapies, and exercises). The third search field focused on tDCS. The search terms were combined and explored with the medical subject headings (MeSH) in different databases (Pubmed, Scopus, Embase, Web of Science and PsycNET). Manuscripts identified through databases search were downloaded to a reference manager software where duplicates were excluded. Two authors (VSB and NRC) performed the initial screen by reviewing the titles and abstracts and when necessary a third author (RV) made the final decision. However, in cases that the eligibility of the study was not clear by the information provided in the title and abstract, a review of the full text was performed. Additional sourced articles were acquired by screening reference lists.

Articles were included if they investigated the effects of tDCS combined with physical and/or cognitive therapies on motor, cognitive, neuropsychiatric, quality of life, and others outcomes in people with PD (only human participants). Only articles written in English were considered for the review. Any open-label studies, review papers, book chapters, commentaries, study protocols, or clinical trials registers were excluded. Articles that analyzed the effects of tDCS as a stand-alone intervention and those involving other techniques of transcranial stimulation (e.g., transcranial alternating current stimulation, transcranial magnetic stimulation, etc.) were also excluded to avoid confusion with the reviewed topic.

Data were extracted by five reviewers (VSB, NRC, PNS, DOS, LKBFD) and synthesized into a table format. Data entry was confirmed by another reviewer (RV). Data included authors, year of publication, groups and participants characteristics (number of participants, score of Unified Parkinson’s Disease Rating Scale motor section (UPDRS III), years since the diagnosis, levodopa equivalent daily dosage), study design, tDCS protocol (current stimulation, sham characteristics, electrode placement, stimulation intensity and duration, electrode size and number of sessions), therapy protocol (type, characteristics, volume, intensity, duration, moment and number of sessions), assessment (period; medication state and outcomes), main findings and occurrence of adverse effects of tDCS.

The flow chart with information regarding the different phases of the search and screening process is shown in Fig. 1. The search strategy yielded 408 studies from publication databases. One hundred and sixty-four duplicates were removed. After further review of title and abstract, 20 articles were included by consensus of the reviewers. After full text review, three studies were excluded, one because it did not involve people with PD [32], and two because they did not have control group or sham condition [26, 27]. Table 2 shows the extracted data regarding the methodological aspects of the studies included in the present systematic review.

The sample size varied from 1 to 53 participants, with a mean age between 56.67 and 79 years. The mean of the UPDRS motor section (part III) score ranged from 10.9 to 47.7. The disease duration ranged from 4.4 to 9.4 years and Levodopa Equivalent Dose (LED) ranged from 251.56 to 912 mg/day.

Seven studies had cross-over design [25, 28, 34, 37, 39‐41] and ten were controlled trials with parallel arms. Three studies did not mention information regarding how or if experiments were blinded [37, 40, 42], three studies consisted of single-blind experiments [28, 34, 36] and eleven studies consisted of double-blind experiments. It is worth mentioning that all the included studies randomly assigned participants into groups/conditions.

tDCS protocols were combined with motor interventions in thirteen studies [25, 28, 29, 31, 34‐41, 45], cognitive interventions in three studies [33, 42, 43] and motor-cognitive intervention in one study [44].

Seven studies combined tDCS protocols with acute interventions [25, 28, 34, 36, 37, 39, 41] and in all of them tDCS was applied concurrently (not as a priming technique). Ten studies combined tDCS protocols with chronic interventions [29, 31, 33, 35, 38, 40, 42‐45]. Five of the chronic studies applied tDCS as a priming technique [31, 35, 38, 42, 45] while five studies applied tDCS during the combined intervention [29, 33, 40, 43, 44]. Chronic interventions varied between 3 and 5 sessions per week (between 5 and 16 sessions in total), with total duration (not only tDCS) between 15 and 60 min [29, 31, 33, 35, 38, 40, 42‐45].

Fifteen studies carried out pre- and post-assessments [25, 29, 31, 33‐35, 37, 38, 41, 42, 44, 45] and seven chronic studies also included follow-up assessments after 4 [31, 35] or 12 weeks [29, 38, 42‐44]. Twelve studies assessed patients while ON medication [25, 28, 29, 34‐37, 41‐45], two studies while OFF medication [39, 40], one study assessed patients in both ON and OFF states [31] and two studies did not report medication state [33, 38]. Although the methods used for assessment varied in the included studies, a few tests were repeated. The Timed Up and Go test (TUG) was used in six studies [25, 29, 31, 35, 36, 44], the UPDRS motor section was used in seven studies [29, 33, 35, 39, 40, 43, 45], Parkinson’s Disease Quality of Life Questionnaire-39 (PDQ-39) was used in four studies [29, 35, 42, 43] and Mini Mental State Examination (MMSE) and Parkinson’s Disease – Cognitive Rating Scale (PD-CRS) were used in three studies [29, 42, 43].

Table 3 presents the main results regarding the effects of tDCS when combined with motor and/or cognitive interventions. Figure 2 summarizes the main findings of the 17 included studies separately for gait/mobility, postural control, upper limb movements, other motor symptoms, cognition, neuropsychiatric symptoms and others (including quality of life, fatigue and sleep disorders).

The included studies were consistent with regards to tDCS polarity and site of stimulation. In all studies, the anode electrode was placed in order to target brain area related to motor or cognitive functions. Studies aiming to improve cognition targeted DLPFC while those aiming to improve motor aspects of PD targeted M1, SMA and/or PMC. As PD is characterized by reduced dopaminergic signaling by the substantia nigra pars compacta and the consequent increased GABAergic signaling from the basal ganglia to other encephalic regions, it makes sense to use anodal tDCS for rehabilitation in PD. Anodal tDCS has been shown to increase extracellular dopamine levels in the striatum [21] and inhibit GABAergic neurons [22, 23]. However, it is somewhat surprising that only one of the reviewed studies used cathodal tDCS [40]. Ishikuro et al. [40] applied the cathodal tDCS over the occipital area. A growing body of evidence supports the hypothesis that the functional interhemispheric imbalance contributes to the clinical motor deficits in PD. For example, PD is associated with asymmetry in M1 excitability [47, 48], with the more-affected hemisphere showing decreased excitability in comparison to the less-affected one. Thus, cathodal tDCS applied to the less-affected hemisphere (as well as anodal tDCS on the more-affected hemisphere) may also benefit patients with PD by leading to a more balanced interhemispheric activity. Cosentino et al. (2017) [49] observed that anodal tDCS of the more-affected M1 and cathodal tDCS of the less-affected M1 were able to induce polarity-specific changes in cortical excitability, leading to a more balanced interhemispheric excitability. These authors also observed that motor performances of both hands improved after both stimulation protocols [49]. Additional studies investigating the effects of cathodal tDCS in PD is required, especially when applied in combination with physical or cognitive interventions.

Another consistent aspect of the intervention protocols of the reviewed studies refers to current intensity. Thirteen studies used 2 mA and none compared the effects of different tDCS intensities when applied in combination with other interventions. The choice for 2 mA may be justified by the fact that some neurophysiological studies have shown greater increase in cortical excitability after 2 mA tDCS when compared to 1 mA [50, 51]. Also, longer lasting effects have been associated with greater current intensities [15]. However, other studies have found no differences in cortical excitability when comparing 2 mA and 1 mA [52‐54]. Further research is required to understand if current intensity is a moderator factor when tDCS is applied in combination with other complementary interventions. Tolerability and safety of current intensities greater than 2 mA are still to be investigated in this kind of interventions in PD.

Consistent synergistic effects were reported for cognition when tDCS was applied in combination with other modalities of complementary interventions. All six studies reporting synergistic effects on cognition used multiple sessions (4 to 16 sessions). Current intensity included 1.0, 1.5 or 2.0 mA. The reported synergistic effects were consistent with the area targeted by tDCS. Four studies targeted the DLPFC and one study target the frontal polar area, cortical regions known to be involved in executive function and working memory [29, 33, 42]. Interestingly, one study that stimulated M1 observed increased number of correct responses provided while performing the TUG test under dual-task condition (i.e., concomitant cognitive task) [44]. Authors argued that individuals with PD improved their ability to dual task when walking due to improved movement automaticity after the intervention. It is possible that anodal tDCS on M1 improved the efficiency of the direct locomotor pathway (i.e. neuronal commands are transmitted directly from M1 to the spinal cord), leading to a more automatic control [55, 56]. Then, the attentional and executive resources previously required for the control of movements could be reallocated to the performance of the concomitant cognitive task, which led to better performance of such task.

Upper limb function and motor symptoms (as assessed by UPDRS-III) respond differently to combined interventions involving tDCS. Consistent synergistic effects were reported for upper limb function [28, 34, 39, 40]. Since methods of the studies reporting the synergistic effects on upper limb function varied, it is difficult to establish associations with results. Overall, synergistic effects were observed after a single or multiple sessions, with tDCS targeting DLPFC or M1. On the other hand, motor symptoms as assessed by UPDRS-III seem to not benefit from the addition of tDCS on physical/cognitive interventions. Only one (out of five) study observed synergistic effects on motor symptoms [40]. UPDRS-III may miss subtle motor improvements and, therefore, we suggest future studies to use more objective assessments of clinical motor symptoms (e.g., inertial sensors, electromyography, etc.).

Although inconsistent, synergistic effects were also reported for gait and mobility when tDCS was combined with other complementary interventions in people with PD. Two out of eight studies reported synergistic effects of tDCS on gait and mobility at post-test [25, 41]. These two studies involved immediate physical interventions (i.e. gait training and tango dance) with stimulation targeting bilateral M1 and PMC. Studies targeting one cortical area (i.e. unilateral M1 or prefrontal cortex - PFC) observed similar results for both active and sham tDCS. Given the multiple cortical regions involved in gait and the bilateral representation of these regions [55, 57], it is possible that bilateral stimulation of multiple cortical areas is required to provide synergistic immediate effects (i.e. at post-test) to gait in people with PD. Also, two studies observed synergistic effects on gait and mobility at follow-up assessment [31, 35]. Costa-Ribeiro et al. [31, 35] observed that tDCS (applied before the physical intervention) prolonged the effects of cued gait training on functional mobility and that this benefit is independent of dopaminergic medication. The synergistic effects on mobility at follow-up assessment could be explained by the changes in cortical excitability. While both sham and active tDCS groups increased cortical excitability and improved mobility at post assessment, only the gait training plus active tDCS group maintained the benefits at the follow-up assessment [31]. Thus, there seems to be a positive relationship between increased cortical excitability and improvement in mobility in patients with PD [11, 31].

Synergistic effects on postural control were also reported when tDCS was combined with physical interventions in people with PD. Four studies assessed postural control, but only two studies presented synergistic effects of active tDCS combined with gait training and tango dance [25, 41]. These studies involved a single session of intervention and stimulated motor areas (i.e. M1 and PMC) bilaterally. The other two studies that reported no synergistic effects at the post and follow-up assessments involved 10 sessions of physical interventions (i.e. physical therapy and cued gait training) and stimulated M1 and PFC unilaterally (contralateral to the most affected body side). Postural control involves several cortical areas (i.e. PFC, PMC, SMA, M1, and primary sensory cortex – S1) in both hemispheres and the cerebellum [2, 58]. Therefore, it is possible that bilateral stimulation of multiple areas is necessary for the synergistic immediate effects to postural control in patients with PD. Besides, it should be noted that the synergistic effects were evidenced by studies that performed the stimulation during the physical intervention. Physical training has been shown to normalize M1 excitability in people with PD [59], while tDCS may decrease the threshold for these changes to occur, facilitating long-lasting effects [11, 25].