565465

research-article2015

NNRXXX10.1177/1545968314565465Neurorehabilitation and Neural RepairSattler et al

Original Research Article

Anodal tDCS Combined With Radial Nerve Stimulation Promotes Hand Motor Recovery in the Acute Phase After Ischemic Stroke

Neurorehabilitation and Neural Repair 1­–12 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1545968314565465 nnr.sagepub.com

Virginie Sattler, MD1,2,3, Blandine Acket, MD1,2,3, Nicolas Raposo, MD1,2, Jean-François Albucher, MD1,2, Claire Thalamas, MD4, Isabelle Loubinoux, PhD2, François Chollet, MD, PhD1,2,3, and Marion Simonetta-Moreau, MD, PhD1,2,3

Abstract Background and Objective. The question of the best therapeutic window in which noninvasive brain stimulation (NIBS) could potentiate the plastic changes for motor recovery after a stroke is still unresolved. Most of the previous NIBS studies included patients in the chronic phase of recovery and very few in the subacute or acute phase. We investigated the effect of transcranial direct current stimulation (tDCS) combined with repetitive peripheral nerve stimulation (rPNS) on the time course of motor recovery in the acute phase after a stroke. Methods. Twenty patients enrolled within the first few days after a stroke were randomized in 2 parallel groups: one receiving 5 consecutive daily sessions of anodal tDCS over the ipsilesional motor cortex in association with rPNS and the other receiving the same rPNS combined with sham tDCS. Motor performance (primary endpoint: Jebsen and Taylor Hand Function Test [JHFT]) and transcranial magnetic stimulation cortical excitability measures were obtained at baseline (D1), at the end of the treatment (D5), and at 2 and 4 weeks’ follow-up (D15 and D30). Results. The time course of motor recovery of the 2 groups of patients was different and positively influenced by the intervention (Group × Time interaction P = .01). The amount of improvement on the JHFT was greater at D15 and D30 in the anodal tDCS group than in the sham group. Conclusion. These results show that early cortical neuromodulation with anodal tDCS combined with rPNS can promote motor hand recovery and that the benefit is still present 1 month after the stroke. Keywords acute phase, tDCS, stroke, rehabilitation, peripheral nerve stimulation

Introduction Although the usefulness of classical physical therapies to promote the recovery of upper limb function after a stroke is well established,1 additional therapeutic approaches are clearly needed to enhance it. In this context and based on functional imaging data providing insight into both the pathophysiology of stroke-induced cortical network disturbances and a better understanding of the mechanisms underlying neuromodulation, noninvasive brain stimulation (NIBS) appears to be an interesting option as an add-on intervention. Among NIBS techniques, transcranial direct current stimulation (tDCS) is a safe,2,3 painless, and inexpensive method that induces prolonged cortical excitability modifications in humans through a combination of glutamatergic and polarity-driven alterations of resting membrane

mechanisms, resulting in LTP/LTD-like synaptic changes.4 These changes are NMDA-receptor dependent and mediated by secretion of brain-derived neurotrophic factor in rodent M1 slices.5 Several studies, mainly performed in the chronic or subacute recovery phase after a stroke, have reported a tDCSinduced functional motor improvement of the paretic hand 1

Centre Hospitalier Universitaire de Toulouse, Toulouse, France Inserm, Imagerie cérébrale et handicaps neurologiques UMR 825, Toulouse, France 3 Université de Toulouse, Toulouse, France 4 Centre d’Investigation Clinique, CHU Purpan, Toulouse, France 2

Corresponding Author: Marion Simonetta-Moreau, Service de Neurologie, CHU Purpan, place du Dr Baylac, 31059 Toulouse cedex TSA40031, France. Email: [email protected]

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Neurorehabilitation and Neural Repair 

(chronic6-9 and subacute9-11). Various tDCS strategies that follow a model of interhemispheric rivalry between the damaged and the intact hemispheres have been tested to promote motor recovery and suggest that motor recovery might be facilitated by upregulating the excitability of the affected motor cortex through anodal tDCS6,7,12 or by downregulating the excitability of the intact motor cortex through cathodal tDCS,6,7,12 or, more recently, by the use of bihemispheric anodal/cathodal tDCS.13-17 Besides NIBS, repetitive peripheral nerve stimulation (rPNS) has been proposed to enhance motor recovery: in chronic stroke patients, 2 hours of stimulation of the median nerve,18 the median + ulnar nerves combined,19 or the median + ulnar + radial nerves combined20 was able to transiently improve the paretic hand performance and this was also observed in the acute or subacute phase.21 Finally, the combination of central and peripheral stimulation has been successfully used to enhance motor recovery in chronic poststroke patients.22 However, the question of the best NIBS strategy remains open. Some studies have tried to address it7,23,24 but have failed to reach a consensus probably because of the different methodologies used (crossover or parallel studies, single or multiple sessions) and different outcome measures. The question of the best therapeutic window in which NIBS could potentiate the plastic changes for motor recovery is still unresolved. Animal models show that, after focal ischemic damage, there is a brief, approximately 3- to 4-week window of heightened plasticity.25 Analogously, almost all recovery from impairment in humans occurs in the first 3 months after stroke,25 although functional motor improvement can be obtained later. In the present double-blind controlled pilot study, we investigated the effect of 5 daily sessions of anodal tDCS, applied over the ipsilesional primary motor cortex (M1) combined with rPNS, on the time course of the paretic hand motor recovery in patients in the acute phase of recovery after an ischemic stroke. Behavioral outcome measures associated with transcranial magnetic stimulation (TMS) study were recorded at baseline and repeated at the end of the intervention, at 2 and 4 weeks’ follow-up. The rationale for targeting ipsilesional motor regions was that previous functional neuroimaging studies had shown reactivation of intact portions of the ipsilesional motor cortex to be associated with better outcome after stroke.26,27 The anodal-stimulation-induced behavioral gains in chronic stroke are associated with a functionally relevant increase in activity within the ipsilesional primary motor cortex.28 We chose the radial nerve because the aim was to improve the recovery of wrist extension, which is crucial for the recovery of skilled hand prehension.29,30 Our hypothesis was that NIBS intervention proposed during the acute phase after a stroke, as add-on treatment to the

classical rehabilitation program, could potentially enhance motor recovery.

Patients and Methods Patients Inclusion criteria were the following: first-ever, single, unilateral hemispheric ischemic stroke within 4 weeks with mild to moderate motor deficit. Exclusion criteria were the following: cortical infarct with large hand/wrist M1 involvement, major depression or other severe psychiatric comorbidity, alcohol abuse, TMS contraindications.31 The study was performed in accordance with the Declaration of Helsinki, registered in the ClinicalTrials.gov Web site (no. NCT01007136) and approved by the local ethics committee (CPP Sud Ouest et Outre-mer 1). Written informed consent was obtained from all participants before their inclusion in the study.

Transcranial Direct Current Stimulation tDCS was applied with the anode placed over the ipsilesional motor cortex (M1) at the hotspot of the extensor carpi radialis muscle (ECR, previously determined by the baseline TMS study, see below) and the cathode over the contralesional supraorbital region. Anodal stimulation was delivered by a Magstim Eldith DC stimulator plus through a pair of 35 cm2 saline-soaked sponge surface electrodes. For the active condition, patients received 5 consecutive daily sessions of 1.2 mA anodal tDCS for 13 minutes each, while for the sham condition, the stimulation (same site and same parameters) was turned off after 60 seconds of stimulation.

Repetitive Peripheral Nerve Stimulation Repetitive electrical (DIGITIMER DS7A) stimulation (5 Hz) was delivered to the radial nerve through bipolar round brass electrodes (2 cm diameter) placed in the spiral grove of the paretic side and was applied at the same time as the real or sham tDCS stimulation. It was applied similarly in both active and sham conditions for 13 minutes. The intensity of the rPNS was adjusted to be below the threshold for direct M response (0.7 × MT).

Outcome Measures The Jebsen Taylor Hand Function Test (JHFT) was used as the primary outcome measure32 (with exclusion of the writing task). It measures hand function in real-life activities by evaluating the time required to perform various tasks (turning cards, lifting objects, feeding simulation, stacking checkers, moving light and heavy cans). As secondary outcomes,

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Sattler et al we used the Hand Dynamometer (maximum grip force of the hand, DYN) (JAMAR), the Nine Hole Peg Test (9HPT), the Hand Tapping test (HTap, number of palm taps on a mechanical hand tapping for 10 seconds), and the Upper Limb Fugl-Meyer (ULFM) scale.33 All the tests were performed 3 times with the affected hand, and the mean of 3 trials was taken as the result— except for the 9HPT, which was performed only twice.

Corticomotor Excitability Using TMS, we determined the presence or absence of a motor evoked potential (MEP) and resting and active motor thresholds (RMT, AMT) in the affected motor cortex. TMS was delivered using a Magstim 200 stimulator (Magstim Co, Whitland, UK) through a 70 mm figure-of-eight–shaped magnetic coil, held with the handle pointing backward at approximately 45° from the sagittal midline, over the cortical ECR Hotspot on the affected hemisphere. Electromyographic (EMG) activity was recorded from Ag–AgCl surface disposable electrodes pasted on the skin over the muscle belly of the paretic ECR muscle, with the reference electrode placed between EMG and radial nerve stimulation electrodes. During the experiments, EMG activity was continuously monitored with visual (oscilloscope) feedback to ensure complete relaxation at rest. The optimal scalp position for the coil was defined as the site of stimulation that consistently yielded the largest ECR MEP.

Rest and Active Motor Threshold The resting motor threshold (RMT) was defined as the minimum TMS intensity (measured to the nearest 1% of the maximum output of the magnetic stimulator) required to elicit an MEP of at least 50 µV in the relaxed ECR in at least 5 of 10 trials with an intertrial interval of 6 seconds. The active motor threshold (AMT) was defined as the minimum intensity required to elicit at least 5 out of 10 MEPs of at least 200 µV in the ECR during a weak voluntary contraction of the ECR (10% to 20% of maximal isometric voluntary muscle contraction).

Study Design Patients included in this double-blind, sham-controlled, pilot study first participated in a familiarization session in which they trained themselves on the motor tests 3 times with each hand. They were randomized in 2 parallel groups (anodal tDCS or sham tDCS group), without stratification regarding the severity of their baseline motor impairment. The randomization list was created by the Clinical Research Center of Toulouse using Rand List Software V1.2 (Dat Inf GmbH; www.randomisation.eu), which provided 5 blocks of 4 patients, each balanced between the sham and active

interventions. All the investigators were blinded to the patient’s allocation except the doctor who applied the stimulation. Each patient received 5 consecutive daily sessions of tDCS (anodal or sham), combined with rPNS on the paretic side. The peripheral and cortical stimulations were applied at the same time. Motor performance and TMS measures were obtained at baseline (D1) before the first stimulation session, at the end of the treatment (D5), and at 2 and 4 weeks’ follow-up (D15 and D30). The ULFM was not recorded at D15. The assessment of motor functions and the TMS study were performed by trained doctors, blinded to group assignment. Conventional occupational therapy sessions (from 3 to 5 times per week) started at the in-patient stroke clinic, independently of the tDCS sessions, most often at D4 or D5, and lasted 30 minutes. After discharge, outpatient therapy sessions were given 3 to 5 times per week (45-90 minutes/session) until the end of the follow-up period. Therapists were blinded to group allocation.

Data Analysis The comparison of the baseline clinical motor performance, TMS parameters, and therapy doses between groups were performed using unpaired t tests. Because the baseline motor performance of the patients enrolled differed widely, we calculated the differences between baseline and D5, D15, and D30 data (Δt5, Δt15, Δt30) for each patient and each motor test. These Δt values were input to the general linear mixed-factors variance analysis (repeated measures ANOVA) with GROUP (anodal tDCS/sham tDCS), as the between-subject factor, and TIME (Δt5, Δt15, Δt30), as the within-subject factor, and baseline JHFT as covariate. The primary outcome for analysis was the mean change in motor performance as indexed by the decrease in time needed to perform the JHFT between baseline (D1) and respectively D5, D15, and D30. TMS data (RMT, AMT) were tested using repeated-measures ANOVA with GROUP as the between-subject factor and TIME (D1, D5, D15, D30) as the within-subject factor. Appropriate post hoc comparisons were carried out using a Bonferroni correction. Results are reported as means and standard deviations. Statistical significance refers to a 2-tailed P value