This systematic review with a network meta-analysis included 12 randomized controlled trials with 284 participants examining the effect of tDCS on our primary outcome, that of ADL capacity. We found evidence of a significant moderate effect in favor of cathodal tDCS, whereas no significant effects were found for the other active tDCS (i.e., dual tDCS, anodal tDCS, and sham tDCS) or control interventions. Sixteen studies with 302 participants examined our secondary outcome, that of upper limb motor function as measured with Upper Extremity Fugl-Meyer Motor scores (UE-FM). We found no evidence of an effect of cathodal tDCS, dual tDCS, anodal tDCS, sham tDCS, or physical rehabilitation interventions. Finally, our analysis of 26 trials with 754 participants found no statistically significant differences between sham tDCS, physical rehabilitation interventions, cathodal tDCS, methylphenidate, dual tDCS, and anodal tDCS, regarding our other secondary outcome, that of the safety of tDCS or its control interventions as revealed by the number of dropouts and adverse events.

The results of this network meta-analysis in terms of our primary outcome, ADL capacity, are in line with a recent Cochrane review examining the effects of tDCS in improving activities, arm and lower extremity function, muscle strength, and cognition [16]. Due to the methodological limitations inherent in traditional pairwise meta-analyses the authors of that review could only draw pairwise comparisons, not taking into account the existing evidence network. Furthermore, in order to avoid multiple testing, the authors had to combine treatment groups with different types of tDCS into a single tDCS group, thus maybe masking possible differences between different tDCS types. In a pre-specified formal subgroup analysis for their primary outcome of activities, the authors tried to estimate the treatment effects of the different tDCS types (anodal, cathodal, and dual tDCS). The analysis suggested a favorable effect of cathodal tDCS for improving ADL after stroke (SMD 0.33, 95% CI 0.10 to 0.57; six studies with 301 participants), whereas there was no effect for anodal (SMD -0.04, 95% CI -0.35 to 0.27; five studies with 164 participants) or dual tDCS (SMD 0.30, 95% CI -0.39 to 0.99; two studies with 33 participants), which is in accordance with our findings.

The relative superiority of cathodal tDCS might be due to a downregulation of the overactive non-affected brain hemisphere as a result of insufficient interhemispheric inhibition and with that, restoring the balance of excitatory and inhibitory interactions between both hemispheres [64,65,66,67]. From this point of view, cathodal tDCS should rather be regarded as supporting the downregulation of overactivity of the non-lesioned hemisphere. This might contrast with the model of ‘vicariation of function’ [68, 69] which suggests that unaffected brain areas ‘take over’ functions of the affected hemisphere [64, 69]. Recently, doubts have been raised about whether this model may be oversimplified or even incorrect and new models have been proposed, such as the bimodal balance-recovery model, which links interhemispheric balancing to the brain’s remaining structural reserve [64].

The optimal stimulation paradigm, in terms of the selection of participants likely to benefit from tDCS, the electrode size and location, the amount of direct current applied and the duration of administration remains to be established [14, 64, 70]. Besides the above-mentioned neurophysiological explanation for the finding of superiority of cathodal tDCS, there might also be methodological reasons. For example, the majority of participants in randomised studies of tDCS for improving ADL capacity were treated with cathodal tDCS (167 out of 284 participants, 59%). Hence, this intervention might have the greatest statistical power in showing evidence, whereas dual tDCS was the least powered intervention.

Regarding our secondary outcome (i.e., function of the upper paretic limb), our results are in line with two systematic reviews with pairwise meta-analysis. Tedesco Triccas and colleagues (2015) included genuine RCTs with multiple sessions of tDCS for improving the function of the upper paretic limb after stroke [71]. They included nine studies with 371 participants. Their analysis did not reveal any statistically significant effect of active tDCS at the end of the intervention period (SMD 0.11, 95% CI -0.17 to 0.38). The other systematic review of the effects of anodal tDCS on upper extremity function and cortical excitability in people with stroke also yielded no evidence of effect (SMD 0.39, 95% CI -0.17 to 0.94) [72]. There have also been systematic reviews with contradicting results: Butler and colleagues (2013) examined the effect of anodal tDCS on upper limb motor recovery in people with stroke and included randomised controlled trials, non-randomised trials and pre–post trials. Their analyses revealed a statistically significant beneficial effect of tDCS on upper limb function (SMD 0.49, 95% CI 0.18 to 0.817; seven studies with 168 participants) [73]. One reason for the discrepancy between their results and ours might be that the authors also included non-randomised studies, and that their meta-analyses suffered from multiplicity.

We found evidence of an effect of tDCS for improving ADL capacity, but not for improving arm function. Since there is only a weak association between paresis of one upper limb after stroke and ADL scores, one could argue that the improvement in ADL capacity may be not based on an improvement of the paretic arm itself, but rather on a generalized treatment effect, or on chance.

A recent systematic review with pairwise meta-regression explored several stimulation variables, like electrode size, electric current, current density, tDCS duration, number of sessions, electric charge, total electric charge, and total electric charge density [74]. The authors included ten comparisons of eight RCTs with 213 participants which measured arm function after stroke. They identified pad size, charge density, and current density as potentially relevant effect modifiers in studies measuring arm function by UE-FM, by entering each of the variables in an inverse variance-weighted linear meta-regression. We incorporated 19 comparisons of 16 studies with 302 participants measuring arm function by UE-FM, and could not find any statistically significant potential effect modifier. This might be explained by our different sample as well as our different approach to data extraction and meta-regression analysis.

To our knowledge, our review, including 26 genuine RCTs with a total of 754 participants, is the most comprehensive review so far of the effects and safety of tDCS regarding ADL capacity and arm function. However, our study has several limitations. These concern the level of individual studies and outcomes in the review as well as that of the review itself. At the level of individual studies, there is the concern about overestimating treatment effects and safety due to unclear or sometimes even high risk of bias, and the fact that the reporting of adverse events was often unsatisfactory. However, our sensitivity analysis regarding methodological quality was in accordance with the results of our main analysis. Another aspect is that there was methodological and clinical heterogeneity among the included studies regarding study type (the majority of included studies were phase II studies with rather small sample sizes, hence prone to the risk of baseline imbalance), age of the participants, time since stroke, dosage of stimulation, electrode location, base therapy (i.e., concurrent treatment) and level of initial severity. This may be due to the fact that the optimal stimulation paradigm still has to be established, since theoretical assumptions about the interaction between motor learning and tDCS-enhanced brain plasticity are still weak. This includes the optimal electrode placement. In popular electrode settings most of the current is redirected by the skin covering the skull, hence being unable to ‘trigger’ neurons effectively [14]. Although tDCS easily could be coupled with novel technologies like, for example robot-assisted training, its added value to rehabilitation outcomes has been limited so far [15]. The bimodal balance recovery model might represent a further step towards a patient-tailored approach to tDCS. But if an interaction effect is assumed between motor learning (base therapy) and brain plasticity (tDCS), tDCS should start earlier. This, however, was not supported by our data.

All clinical trials did employ a simplistic dose strategy of tDCS, assuming increased or decreased excitability of stimulated brain areas under the anodal and cathodal electrode, respectively (a detailed qualitative description of interventions can be found in Additional file 2). However, recent dose-response studies suggest that anodal or cathodal tDCS follows a complex, non-linear intensity-dependent effect on neuronal networks [10, 75]. The electric fields induced by tDCS applied in current doses in humans are found not sufficient in themselves to trigger spikes but rather to activate neurons at subthreshold level [10, 64]. Current animal studies rather suggest that cathodal and anodal tDCS may respectively, introduce dendritic hyper- or depolarization of neural membranes [10, 64]. The tDCS induced polarization of membranes of the apical dendrite will differ from that of soma and basal dendrite and dependent on the direction (i.e., inward (anodal) or outward (cathodal) current [10]. In other words, the localization of hyper-and depolarization in the cortex will differ in the same neuron dependent on its cellular composition and its position in relation with the cortex surface. As a consequence, there is now strong evidence that tDCS may induce long-term potentiation (LTP) and long-term depression (LTD) of stimulated neuronal pools [10, 64], which are fundamental for Hebbian and non-Hebbian forms of neuronal plasticity [76]. Furthermore, anodal tDCS induced LTP may enhance the secretion of brain derived nerve growth factors (BDNF) such as GAP43 [77, 78], change interneuronal activity and metabolism of glia cells [10]. The complexity of neuromodulation by tDCS suggests that a more sophisticated approach of tDCS is required to target neural networks effectively in a functional way [10].

Regarding the review level, there is the concern about violating the transitivity assumption, which means that included studies lack comparability. Violating the assumption of transitivity is more likely in larger treatment networks or in systematically different study conditions, like a wide variation in dates of study performance [24]. Neither of these was the case in our analyses. Although our formal analyses regarding inconsistency in the treatment networks were negative, this does not automatically mean that no inconsistency occurred [21]. Another point is that network meta-analyses require reasonably homogeneous studies, which is why we restricted our analysis to the post-intervention effects of tDCS. Since stroke is often a chronic disease, future network meta-analyses could also focus on the sustainability of effects of cathodal tDCS, acknowledging that the number of published trials that included long-term outcomes is rather small.