Transcranial Direct Current Stimulation (tDCS)/Transcranial Alternating Current Stimulation (tACS)Original ArticleImmediate and Late Modulation of Interhemipheric Imbalance With Bilateral Transcranial Direct Current Stimulation in Acute Stroke
Introduction
In recent years, several small studies have reported positive effects of non-invasive cortical stimulation, in the form of repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), to enhance recovery in patients with acute or subacute stroke [1], [2], [3]. However, it is still unknown whether these interventions will be useful in the clinical setting. Neuromodulation techniques can induce long-lasting changes in the excitability of the synapses in motor cortical areas in a manner which might be biologically similar to the long-term potentiation/depression (LTP/LTD) phenomena described at cellular level [4]. LTP/LTD are important for learning and memory and are likely involved in reacquisition of skill after stroke.
Considering that, in the acute phase of stroke, animal and in vitro models have showed that various markers of plasticity are shown to be at higher levels both in perilesional territories of affected hemisphere (AH) [5], [6] and remotely in the contralateral unaffected hemisphere (UH) [7], it is reasonable that, during this phase, the effects of neuromodulatory therapy might be maximized.
One of the most influential models of stroke recovery is based on the inter-hemispheric rivalry or competition hypothesis: the AH becomes doubly disabled, both by its own damage and by the increased hindering output from UH, no longer inhibited by the hypo-functioning AH [8], [9]. Although other possible explanations may account for the imbalance of excitability between the two hemispheres (i.e. vicariation of the AH), the inter-hemispheric competition has been exploited so far as rationale by most of the neuromodulatory interventions aimed at improving stroke motor recovery [41]. According to this model, recovery can be favored by increasing the cortical excitability on the affected side and/or reducing the excitability of the unaffected side.
It may then be the case that the bilateral application of tDCS over the motor cortices, with anodal tDCS over the AH and cathodal tDCS over the UH, results in a useful strategy to induce an additive effect compared to unilateral stimulation [10], [11], [12].
We designed two experiments to assess whether tDCS-induced bihemispheric modulation in acute stroke patients (tested within 48–96 h of stroke) would modify neuroplasticity and clinical outcomes. In the preliminary small double-blind, randomized, placebo controlled experiment (experiment 1) we evaluated the short-term effects of bilateral tDCS alone on recovery. Since this experiment was negative, we designed another experiment as to assess further plasticity and long-term effects by combining tDCS with constraint-induced movement therapy. Our initial hypothesis was that active tDCS would induce larger motor gains and enhanced neuroplasticity as compared to sham tDCS.
Given the two main techniques of non-invasive brain stimulation, we chose tDCS. Although these two techniques seem to have a final common effect on neuroplasticity, their effects are mediated by different mechanisms of action. A recent experimental study has shown that direct current stimulation applied to rat brain slices has a direct effect on the amount of LTP that can be induced by repetitive stimulation [13]. This is increased by anodal and reduced by cathodal DCS. In analogy with these experimental data, it can be speculated that in the intact human brain, tDCS, even though via subthreshold modulation, can enhance the propensity of the cortex to undergo LTP-like plasticity after rTMS [14], [15]. This latter approach means that tDCS exerts his effect especially when coupled with other interventions, thus it might be useful to promote relearning of skills when associated with motor rehabilitation, given also that tDCS is feasible simultaneously with behavioral therapies [16]. Therefore, by combining non-invasive brain stimulation and motor training/learning it should be possible to increase the modulatory effects on the motor neural network and thus increase clinical gains.
We conducted a detailed neurophysiological and clinical assessment. In fact, given the possibility that the assessment of the clinical outcome would not be sensitive enough to all the aspects of the effects induced by tDCS, we evaluated also changes in motor cortex excitability of both hemispheres.
Along this line, we recently showed that the level of LTP-like activity promoted by intermittent theta burst stimulation (iTBS), a robust form of rTMS, delivered to the affected hemisphere (AH) during the acute phase of human stroke correlates with long-term functional recovery [17]. Similarly, suppressive rTMS of the unaffected hemisphere (UH) resulted in the reduction of the AH motor threshold that correlated with recovery [18]. Thus, the neuroplasticity response to neuromodulatory protocols in the acute phase of stroke over both hemispheres is a parameter that might be useful as a surrogate marker of recovery. Accordingly, in this experiment, we also evaluated whether five consecutive days of bilateral tDCS could increase the propensity of the hemispheres to undergo LTP-like plasticity. We used iTBS, which is able to promote LTP-like activity lasting up to 1 h [19], to investigate how tDCS changes iTBS-promoted LTP-like activity.
Section snippets
Patients
Patients with a history of first ischemic cerebral infarct admitted to the Stroke Unit were enrolled in the study. Inclusion criteria were: (1) Age 18–90; (2) Clinical first ever ischemic cerebrovascular accident – confirmed by MRI; (3) Acute phase of stroke (treatment was started 48–96 h after the stroke onset).
Exclusion criteria: (1) Pre-stroke disability; (2) Any substantial decrease in alertness, language reception, or attention that might interfere with understanding instructions for motor
Clinical outcome
Experiment 1 – For each clinical measure (NIHSS, mRS, ARAT, NHPT, NIHSS, MAL (AOU), MAL (QOM)) we computed a repeated measure ANOVA with Time as within subject factor (2 levels: baseline, 1 week) and tDCS (two levels: real and sham) as between subject factors. tDCS had no effect on clinical outcome (tDCS and the tDCS by Time interaction: P > 0.200 consistently). We confirmed the expected and well-known time-related clinical improvement (factor Time P < 0.001 for all the measures considered) (
Discussion
Our first important conclusion, from the assessment of all clinical instruments in both experiments, is that, in acute stroke, our strategy of tDCS does not result in significant clinical improvements, at 1 week and/or at three months, due to five-daily bilateral tDCS sessions, either administered alone or in association with CIMT, beyond the ones achieved by the physical therapy alone or through the spontaneous recovery.
However, it might be the case that the clinical instruments, or the
Conclusions
This study shows two important novel findings: (i) the addition of bilateral tDCS to the CIMT significantly reduces inter-hemispheric imbalance between AH and UH as indexed by TMS induced neurophysiologic outcomes and this effect is maximal at three-month follow-up; (ii) tDCS does not lead to additional clinical benefits in acute stroke despite the positive neurophysiologic findings. However, inter-hemispheric imbalance is widely considered as an important predictor of poor rehabilitation
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