Transcranial direct current stimulation of the affected hemisphere does not accelerate recovery of acute stroke patients

Abstract

Background and purpose:  Transcranial direct current stimulation (TDCS) is a potential tool to improve motor deficits in chronic stroke patients. Safety and efficacy of this procedure in acute stroke patients have not yet been addressed.

Methods:  We performed in our stroke unit a single-centre randomized, double-blind, sham-controlled study to investigate safety and efficacy of anodal TDCS of the affected hemisphere in acute stroke patients. The second day from stroke onset, 50 acute stroke patients received either five-daily sessions of anodal (n = 25) at 2 mA for 20 min or sham TDCS (n = 25) to the ipsilesional primary motor cortex (M1). Motor deficit was assessed by the short form of the Fugl–Meyer motor scale (FM) and overall neurological deficit by the National Institute of Health Stroke Scale (NIHSS) at onset, at 5 days after stroke and after 3 months.

Results:  No side effects were detected during either TDCS or sham. In both groups, there was a significant improvement in NIHSS and FM scores, which did not significantly differ when comparing TDCS and sham.

Conclusions:  Five-daily sessions of anodal TDCS to the ipsilesional M1 appear to be safe in acute stroke patients but do not improve clinical outcome.

Introduction

Non-invasive brain stimulation techniques such as transcranial direct current stimulation (TDCS) may have a potential impact in improving motor deficits in stroke patients. So far, most of the studies used TDCS to modulate motor functions in chronic stroke patients with encouraging results [1]. Two different approaches have been adopted: one using TDCS over the ipsilesional primary motor cortex (M1), to induce a long-lasting increase in cortical excitability over the affected hemisphere, and the other using TDCS at the aim to induce a long-lasting decrease in cortical excitability over the unaffected hemisphere, to modulate its unrestrained inhibitory influence on ipsilesional regions [2–4]. However, the use of TDCS in acute stroke patients has not yet been examined. Therefore, in the current study, we aimed to investigate the safety and efficacy of anodal TDCS of the affected hemisphere in patients with acute ischaemic stroke.

Methods

Inclusion criteria were as follows: age between 18 and 80 years; acute ischaemic lesion in the territory of the middle cerebral artery; a score between 6 and 20 at the National Institute of Health Stroke Scale (NIHSS); and an Fugl–Meyer (FM) motor score in the arm between 15 and 55 out of 66 [5]. Exclusion criteria were as follows: pre-stroke modified Rankin Scale > 1; treatment with thrombolysis; history of seizure; advanced systemic disease; coexistent neurological/psychiatric disease; and current treatment with antidepressants, antipsychotics or benzodiazepines. Stroke aetiology was based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria [6] on completion of diagnostic tests. All patients gave informed consent for participation in the study. Experimental procedures were approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki.

The second day after stroke onset, 50 patients were randomized to five-daily sessions of either anodal TDCS (n = 25) or sham stimulation (n = 25). Sample calculation was based on a previous study in which repetitive transcranial magnetic stimulation was demonstrated to improve clinical outcome in acute stroke patients [4]. Systolic and diastolic blood pressure, heart frequency and oxymetry were monitored during the stimulation sessions. TDCS (2-mA intensity for 20 min once a day for five consecutive days) was transferred by a pair of saline-soaked surface sponge electrodes (35 cm²) positioned in the M1 cortex by using the C3 or C4 position of the 10–20 EEG system [3] of the affected hemisphere (anode) and over the contralateral supraorbital area (cathode). For sham stimulation, the current was ramped up to 2 mA and slowly decreased over 30 s to ensure the typical initial tingling sensation. The FM scale was the primary outcome measure, whilst the NIHSS, the Barthel Index and the modified Rankin Scale were used as secondary outcome measures. These scales were assessed at onset, at 5 days after stroke and after 3 months.

Results

Demographics and clinical and imaging baseline characteristics in patients treated with real or sham TDCS are shown in Table 1. We did not detect any significant differences in baseline evaluation between the two groups. There were no witnessed adverse events during and after each TDCS session. No change was observed for systolic blood pressure, diastolic blood pressure, heart rate or oxygen saturation. NIHSS scores decreased significantly in both groups as revealed by anova, showing a significant TIME main factor (F = 6.25; P < 0.01) but not a significant TIME × GROUP interaction. FM scores increased significantly in both groups as revealed by anova, showing a significant TIME main factor (F = 4.31; P < 0.01) but not a significant TIME × GROUP interaction. No significant differences were observed in clinical and outcome measures during the study period between the two groups, as shown in Table 2. There were no significant changes, nor significant differences between the two groups in systolic and diastolic blood pressure, heart frequency and oxygenation during the stimulation sessions.

Table 1. Differences between TDCS and SHAM patients in demographic and clinical baseline characteristics

	TDCS (n = 25)	Sham (n = 25)	P-value
TOAST, Trial of Org 10172 in Acute Stroke Treatment; ^aKnown before stroke.
Age, years (±SD)	66.1 (±14.3)	70.3 (±13.5)	0.64
Male sex, n (%)	12 (48%)	14 (56%)	0.57
Left hemispheric lesion, n (%)	18 (72%)	16 (64%)	0.54
Previous ischaemic lesions	21 (84%)	17 (68%)	0.18
Vascular risk factors^a
Atrial fibrillation	4 (16%)	7 (28%)	0.34
Hypertension	11 (44%)	13 (52%)	0.45
Diabetes	4 (16%)	3 (12%)	0.33
Hyperlipidaemia	8 (32%)	6 (24%)	0.51
TOAST criteria
Large artery	15 (60%)	9 (36%)	0.27
Cardioembolic	6 (24%)	9 (36%)
Small vessels	0	1 (4%)
Undetermined causes	4 (16%)	4 (16%)
Other determined causes	0	3 (12%)
Lesion characteristics
Cortical	1 (4%)	2 (8%)	0.29
Cortico-subcortical	17 (68%)	18 (72%)	0.31
Subcortical	7 (28%)	5 (20%)	0.45
Admission duration, days (±SD)	9.8 (±2.4)	9.5 (±2.8)	0.45

Table 2. Differences between TDCS and SHAM patients in stroke severity and clinical and functional outcome

	Anodal, N = 25	Sham, N = 25	P-value
FM, Fugel–Meyer; NIHSS, National Institute and Health Stroke Scale; mRS, modified Rankin Scale; BI, Barthel Index; ^aTIME × GROUP interaction; ^bPaired t-test.
FM total onset (±SD)	4.1 (±6.4)	4.6 (±7.8)	0.82^a
FM total 5 days (±SD)	7.5 (±10.1)	9.6 (±10.3)
FM total (±SD) 3 months	13.6 (±11.2)	15.2 (±9.3)
NIHSS onset (±SD)	15.4 (±4.9)	14.1 (±3.5)	0.75^a
NIHSS 5 days (±SD)	12.4 (±5.3)	11.4 (±4.5)
NIHSS (±SD) 3 months	8.1 (±4.9)	7.1 (±4.6)
Pre-stroke mRS (±SD)	0.7 (±1.1)	0.9 (±1.3)	0.34^b
mRS ≤ 2 3-months	10 (40%)	15 (60%)	0.15^b
BI (±SD) 3 months	70.6 (±15.8)	65.2 (±20.3)	0.91^b
Mortality 3 months	2 (8%)	1 (4%)	0.35^b

Discussion

In chronic stroke patients, it has been shown that TDCS may be able to improve motor function either by the upregulation of excitability of the lesioned motor cortex or the downregulation of the homologue area in the intact hemisphere [7]. The current study demonstrates that this procedure can be safe also in acute stroke patients when a 5-day course of TDCS is initiated as soon as 48 h after stroke. Anodal TDCS did not induce any effect on the clinical vital parameters examined in the current study, in line with that observed in other TDCS investigations performed in neurological patients [1]. There was an expected improvement in both NIHSS and FM scales that, however, did not differ between patients treated with real or sham TDCS.

There could be several reasons to account for these negative results. First, it is important to notice that we did not include only patients with subcortical lesions and with an intact M1 as in previous studies [1,2]. We decided by purpose to apply TDCS in a real-world clinical setting, including patients with severe motor deficit, assuming that this procedure could be potentially effective for larger series of patients. It may well be that TDCS could still lead to some favourable results in selected populations of stroke patients. Second, we only tested anodal TDCS of the affected hemisphere. However, it remains to be investigated whether other approaches such as non-invasive modulation of the contralesional hemisphere [3] or bihemispheric stimulation designs used, affecting both components of the hypothesized imbalance of interhemispheric interactions after stroke [8], could be more effective than the strategy adopted here. Third, we only tested one intensity of stimulation (2 mA). Yet, it is possible that huge cortical–subcortical lesions could have profound effect on resulting current flow, implying that computational models could be needed for the design of individualized TDCS stroke therapy [9]. Further studies performed in large samples of patients, with a blinded placebo-controlled design, are needed to verify the potential clinical impact of other approaches based on non-invasive brain stimulation in acute stroke patients.

Acknowledgements

The authors report no conflict of interest. GK and PS conceived the study. GK, SDL and FS wrote the manuscript. CR, SDL, GK and FS performed the TDCS experiments and collected the data.

Disclosure of Conflict of Interest

The authors declare no financial or other conflict of interests.