565465

research-article2015
NNRXXX10.1177/1545968314565465Neurorehabilitation and Neural RepairSattler et al

Clinical Research Article

Neurorehabilitation and

Anodal tDCS Combined With

Neural Repair
2015, Vol. 29(8) 743­–754
© The Author(s) 2015
Radial Nerve Stimulation Promotes Reprints and permissions:
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Hand Motor Recovery in the Acute DOI: 10.1177/1545968314565465

nnr.sagepub.com

Phase After Ischemic Stroke

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 mechanisms, resulting in LTP/LTD-like synaptic changes.4

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 distur-
bances 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 modi-
fications in humans through a combination of glutamater-
gic and polarity-driven alterations of resting membrane
These changes are NMDA-receptor dependent and medi-
ated by secretion of brain-derived neurotrophic factor in
rodent M1 slices.5
Several studies, mainly performed in the chronic or sub-
acute recovery phase after a stroke, have reported a tDCS-
induced functional motor improvement of the paretic hand
1
Centre Hospitalier Universitaire de Toulouse, Toulouse, France
2
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
Corresponding Author:
Marion Simonetta-Moreau, Service de Neurologie, CHU Purpan, place
du Dr Baylac, 31059 Toulouse cedex TSA40031, France.
Email: simonetta.m@chu-toulouse.fr
744
(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 differ-
ent methodologies used (crossover or parallel studies, sin-
gle or multiple sessions) and different outcome measures.
The question of the best therapeutic window in which
NIBS could potentiate the plastic changes for motor recov-
ery 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
Neurorehabilitation and Neural Repair 29(8)
classical rehabilitation program, could potentially enhance
motor recovery.
Patients and Methods
Patients
Inclusion criteria were the following: first-ever, single, uni-
lateral hemispheric ischemic stroke within 4 weeks with
mild to moderate motor deficit. Exclusion criteria were the
following: cortical infarct with large hand/wrist M1 involve-
ment, major depression or other severe psychiatric comor-
bidity, 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 ipsile-
sional motor cortex (M1) at the hotspot of the extensor carpi
radialis muscle (ECR, previously determined by the base-
line TMS study, see below) and the cathode over the con-
tralesional 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 consecu-
tive 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 inten-
sity 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 writ-
ing task). It measures hand function in real-life activities by
evaluating the time required to perform various tasks (turn-
ing cards, lifting objects, feeding simulation, stacking check-
ers, moving light and heavy cans). As secondary outcomes,
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 dispos-
able 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 min-
imum 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 volun-
tary contraction of the ECR (10% to 20% of maximal iso-
metric 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
745
interventions. All the investigators were blinded to the
patient’s allocation except the doctor who applied the stim-
ulation. 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, inde-
pendently of the tDCS sessions, most often at D4 or D5, and
lasted 30 minutes. After discharge, outpatient therapy ses-
sions were given 3 to 5 times per week (45-90 minutes/ses-
sion) 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 anal-
ysis (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 base-
line (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 correc-
tion. Results are reported as means and standard deviations.
Statistical significance refers to a 2-tailed P value <.05.
Correlation between motor performance and electrophysio-
logical parameters was investigated using the Pearson test.
Results
Forty-two acute ischemic stroke patients were consecu-
tively assessed for participation (Figure 1). Twenty-two
patients were excluded (6 for not meeting inclusion criteria,
11 for instability of motor deficits, and 5 declined to partici-
pate), leaving 20 patients randomized (mean age: 65 years ±
11 [range 37-82], 6 women). They had mild to moderate
746
Figure 1. Study flow chart.
Forty-two patients were assessed for eligibility between January 2011 and 2013. Twenty-two were excluded and 20 randomized in the 2 arms without
any lost during the follow-up.
motor deficit at onset (Table 1; mean National Institutes of
Health Stroke Scale [NIHSS]: 3 ± 1, range 1-6; mean ULFM
score: 48 ± 2.5, range 29-60). They were heterogeneous
with regard to lesion site (cortical and subcortical areas;
imaging [DWI] data given in Table 2 supplemental data).
Two patients in the sham group (nos. 1 and 2) and 3 in the
tDCS group (nos. 3, 6, and 17) had white matter lesions
(range of Fazekas & Schmidt’s score: 3-5).34
The mean time between stroke and tDCS intervention
was 5.5 ± 3 days. No adverse effects were reported except a
tingling sensation at the site of the scalp electrodes at the
beginning of the session. This was similarly observed in
both groups of patients, who were thus unable to distinguish
the tDCS from the sham session. Each group received the
same amount of physical therapy during the follow-up
(tDCS group: mean therapy dose: 17.5 ± 9 hours; sham
group: 18 ± 13 hours; P = .8).
Neurorehabilitation and Neural Repair 29(8)
Demographic and clinical data of the 2 groups of patients
are reported in Table 1. Despite our selective inclusion cri-
teria (mild or moderate hand motor deficit), the range of
individual baseline times to perform the JHFT was very
large (49-226 seconds). No significant differences between
the 2 groups were observed at baseline (Table 1), except for
the grip test (P = .02).
Motor Function of the Paretic Hand
Motor performance improved significantly with time in
both groups, with a progressive decrease of the time to per-
form the JHFT between D1 and D30 (Table 3). Analysis of
the differences in the total time to perform the JHFT
between baseline and D5 (Δt5), D15 (Δt15), and D30 (Δt30)
showed a TIME effect (F[2.36] = 23.27, P = .0001), no
GROUP effect (F[1.18] = 1.24, P = .27), but a significant
Sattler et al 747

Table 1. Demographic and Baseline Data.a

Time After
Sex Age (years) Stroke (days) Handedness JHFT (s) 9HPT (s) HTap DYN (kg) ULFM NIHSS
Anodal tDCS patient
03 M 76.0 2 R 168.97 NA NA 2.33 42 3
04 M 82.3 10 R 103.19 66.75 30 14 55 3
05 F 68.3 7 R 79.44 53.22 32 16 59 3
06 M 53.3 2 R 93.02 65.71 12.67 10.67 43 3
09 M 68.3 8 R 112.4 109.45 8 19 49 3
11 F 56.3 5 R 115.73 92.68 25.67 5.33 53 4
13 M 59.3 6 R 119.97 NA 6.33 8 29 6
16 M 82.5 4 R 137.41 176.92 7.67 8.33 42 3
17 M 63.8 7 R 194.52 NA 17 7.67 46 3
18 F 66.1 4 R 120.55 NA 16.67 NA 52 5
Mean ± SD 67.6 ± 10 5.3 ± 2.6 124 ± 10.3 94.1 ± 13.1 17.3 ± 2.9 10.1 ± 1.6 47 ± 2.5 3 ± 1.1
Sham tDCS patient
01 M 54.2 14 R 84.09 55.85 19.33 23.33 46 6
02 M 74.2 1 R 226.74 NA NA 10.67 34 2
07 F 74.6 5 R 98.99 44.92 13.67 6.67 42 2
08 F 63.7 2 R 49.66 36.04 29.67 26.67 60 2
10 M 63.2 3 R 79.76 79.78 42.00 26.67 58 2
12 M 52.7 4 R+L 60.06 47.93 21.00 16 56 3
14 M 73.9 9 R 88.76 125.13 38.67 24.33 57 3
15 F 74.4 4 R 63.50 142.62 8.33 9.33 47 1
19 M 59.4 7 R 93.59 109.06 20.33 15.67 44 4
20 M 36.9 6 R 93.95 NA 16.33 14.67 45 6
Mean ± SD 62.7 ± 12 5.6 ± 3.8 93.9 ± 14.8 80.1 ± 13.4 23.26 ± 3.3 17.4 ± 2.2 48.9 ± 2.5 3 ± 1.7
t test P = .34 P = .39 P = .12 P = .54 P = .32 P = .02 P = .58 P = .50

Abbreviations: tDCS, transcranial direct current stimulation; JHFT, Jebsen Hand function Test; 9HPT, Nine Hole Peg test; HTap, hand tapping test;
DYN, hand dynamometer; ULFM, Upper Limb Fugl-Meyer; NA, not able to perform the test at baseline.
a
Mean values ± SD for each group (paretic hand).

TIME × GROUP interaction (F[2.36] = 4.42, P = .01). This
interaction was explained by the fact that the amount of
improvement was greater at D15 (P = .03) and D30 (P =
.01) in the anodal tDCS group than in the sham tDCS group.
Figure 2 illustrates the difference of time course of the mean
Δt ± SD between the 2 groups of patients, which did not
occur at D5, as expected, but occurred 10 days after the end
of the intervention (D15) and was still present and more
pronounced at D30. On average, compared to the sham
group, the gain of motor performance in JHFT after the 5
days of anodal tDCS was expressed by decreases of 23 sec-
onds at D15, 24 seconds at D30 (and 6 seconds at D5).
Six patients (4 in the active group and 2 in the sham
group) were unable to perform the 9HPT test at D1, and 2
patients (1 in each group) were unable to perform the HTap
task at D1.
Similar improvement of motor performance with time
was observed in both groups for the secondary motor out-
comes (Table 3). A trend toward a gain of performance in
the anodal tDCS group compared to the sham group for the
9HPT (n = 14, on average −11 seconds at D15 and −5 sec-
onds at D30 to perform the task) and for the DYN test (on
average gain of +3 kg at D15 and D30) were observed but
without significant TIME × GROUP interactions. For the
HTap test, the increase in the number of taps with time was
in the same range in both groups, without any significant
differences (n = 18). At D5, there was a trend toward
greater gain on the Fugl-Meyer scale for the sham group
than for the tDCS group (on average +2.4; NS), which was
no longer observed at D30 (Table 3). The comparison of
the mean sum of the Fugl-Meyer’s wrist and hand finger
extension subscores (0-12), between tDCS + rPNS group
and sham tDCS + rPNS group, did not show any significant
difference at D1 (7.3 ± 3/8.7 ± 2.5), D5 (9.3 ± 2.5/10.5 ±
1.2), and D30 (10.7 ± 1.2/11.1 ± 1.2), respectively (P = .19,
F = 1.79), but a significant improvement with time (P =
.0001, F = 17.94) for both groups (without significant
interaction), confirming that most of the patients improved
significantly their wrist and finger extension at the end of
the study.
748
Table 2. Changes in Motor Performance of the Paretic Hand Compared to Baseline at the End of the Treatment and in the Follow-Up.a

JHFT DYN 9HPT HTap ULFM

tDCS Sham tDCS Sham tDCS Sham tDCS Sham tDCS Sham
Δt5 −33.11 ± 37.3 −26.56 ± 26.1 +3.89 ± 4.6 +1.83 ± 1.98 −25.89 ± 29.1 −24.53 ± 29.7 +5.10 ± 6.1 +8.57 ± 6.8 +6.60 ± 4.2 +9.00 ± 6.2
Δt15 −59.89 ± 31.5 −36.16 ± 30.8 +6.38 ± 5.3 +3.65 ± 4.5 −49.40 ± 44.7 −38.26 ± 32.8 +11.52 ± 7.3 +12.11 ± 9.9 ND ND
Δt30 −69.84 ± 33.4 −45.45 ± 41.5 +7.56 ± 7.7 +4.78 ± 5.9 −53.37 ± 40.6 −48.24 ± 33.2 +16.43 ± 8.9 +15.27 ± 9.6 +12.8 ± 6.0 +12.3 ± 8.0
ANOVA
Time F(2.36) = 23.27 P = .0001 F(2.34) = 6.4 P = .004 F(2.22) = 16.51 P = .001 F(2.36) = 21.55 P = .00001 F(1.18) = 43.27 P = .0001
Group F(1.18) = 1.24 P = .27 F(1.17) = 1.34 P = .26 F(1.11) = 0.23 P = .63 F(1.18) = 0.08 P = .7 F(1.18) = 0.13 P = .7
Time × F(2.36) = 4.42 P = .01 F(2.34) = 0.87 P = .87 F(2.22) = 0.74 P = .4 F(2.36) = 1.44 P = .2 F(1.18) = 4.03 P = .06
Group

Abbreviations: tDCS, transcranial direct current stimulation; JHFT, Jebsen Hand Function Test; 9HPT, Nine Peg Hole Test; HTap, hand tapping test; DYN, hand dynamometer; ULFM, Upper Limb
Fugl-Meyer.
a
Mean ± SD differences (Δt5 = D5-D1; Δt15 = D15-D1; Δt30 = D30-D1), for each motor test and each group and ANOVA results. Significant P values in bold.
Sattler et al 749

Table 3. Electrophysiological Results.a

ANOVA

tDCS Sham GROUP TIME GROUP × TIME

RMT
D1 70.1 ± 24.5 62.2 ± 17.8 F(1.18) = 0.60 F(3.54) = 1.40 F(3.54) = 0.88
D5 66.0 ± 21.8 57.4 ± 16.5 P = .4 P = .2 P = .4
D15 64.2 ± 20.6 63.5 ± 21.6
D30 64.8 ± 16.2 56.3 ± 18.0
AMT
D1 44.2 ± 22.2 52.9 ± 26.2 F(1.16) = 0.30 F(3.48) = 2.54 F(3.48) = 1.30
D5 50.7 ± 28.1 44.2 ± 20.8 P = .5 P = .06 P = .2
D15 39.9 ± 10.1 42.7 ± 13.5
D30 39.8 ± 10.5 44.0 ± 21.1

Abbreviations: tDCS, transcranial direct current stimulation; ANOVA, analysis of variance; RMT, rest motor threshold; AMT, active motor threshold.
a
Time course of the mean ± SD RMT, AMT expressed in % of max stimulator output, during the follow-up.

Figure 2. Time course of the mean (±SD) gain of motor performance of the paretic hand in JHFT compared to baseline in each
group of patients.
The amount of improvement (time course of the decrease in time to perform the test) was greater at D15 (P = .03) and D30 (P = .01) in the anodal
tDCS + rPNS group than in the sham tDCS + rPNS group.
Abbreviations: JHFT, Jebsen Hand function Test; tDCS, transcranial direct current stimulation; rPNS, repetitive peripheral nerve stimulation.

Electrophysiology
TMS data are summarized in Table 4. At D1 and at maximal
output of TMS, MEPs were absent in only 2 of the 10
patients in the tDCS group and in 1 patient of the sham
group. One month after inclusion, MEPs were measurable
in all patients except one.
The mean RMT at baseline was 70.10 ± 24.5% for the
tDCS group and 62.2 ± 17.8% for the sham group (P =
.4). There was a trend toward a slight decrease of RMT
and AMT with time in both groups, which did not
reach statistical significance. ANOVA did not reveal
any significant TIME, GROUP, or TIME × GROUP
interaction.
Baseline motor performance of the whole group was
correlated with RMT measured at D1 (ULFM: r = −.58, P
= . 007; HTap: r = −.58, P = .007; JHFT: r = .49, P = .03);
the worse the motor performance was at inclusion, the
higher was the RMT (Figure 3).
750 Neurorehabilitation and Neural Repair 29(8)

Figure 3. Baseline correlations between motor tests.

HTap (hand tapping), ULFM (Upper Limb Fugl-Meyer), JHFT (Jebsen Hand Function Test) values (ordinate) and TMS Rest Motor Threshold (abscissa
RMT expressed in percentage of max stimulator output). Black squares: active tDCS group; grey squares: sham tDCS group. The worse the motor
performance was at inclusion (low number of taps, long time to perform JHFT, low score at ULFM), the higher was the RMT.

Discussion a greater influence of factors other than the severity of the

The results of this pilot study, performed in the acute phase
after stroke (on average 5 days), suggest that the time course
of the motor recovery of the 2 groups of patients during the
first month was different and was positively influenced by
the intervention.
Our results confirm the good responsiveness of the
JHFT, widely used in NIBS studies6,7,13,24,35 to reveal an
improvement in functional hand motricity that reflects
activities of daily life.36,37 The 9HPT has good validity, reli-
ability, and sensitivity in assessing manual dexterity38 but is
feasible only in patients with a mild motor deficit. Six
patients were unable to perform it at baseline and this could
explain the lack of statistical difference between the 2
groups, in contrast to the JHFT, which was performed by all
the patients at baseline. The Hand Grip test was easily
achieved by all the patients at baseline but was less sensi-
tive than the ecological JHFT. The lower sensitivity of the
HTap test compared to JHFT could perhaps be explained by
motor deficit, such as age39 or genetics, to explain the wide
range of values observed at baseline (range 8-42). A signifi-
cant positive effect of a single session of tDCS versus sham
applied to stroke patients in the subacute phase was also
reported in 2 previous studies, one with a different hand
dexterity test (the Box and Block test11) and the other with
the 9HPT,23 but without any significant effect on the grip
force in the latter. The lack of a significant change in the
ULFM score was not surprising considering the small size
of our patient sample and the low sensitivity of this scale for
mild or moderate hemiparesis. Despite a larger number of
patients (25 × 2), Rossi et al40 failed to demonstrate a sig-
nificant positive effect of 5 sessions of anodal tDCS versus
sham applied in the very acute phase (2 days) after stroke,
using the ULFM score as primary outcome measure. These
negative results were probably explained by broader inclu-
sion criteria (with patients enrolled even if they had a severe
motor deficit and a large lesion in M1) than ours (mild or
Sattler et al
moderate deficit without large involvement of M1).
However, the lack of significant positive effect of the inter-
vention on motor impairment assessed by the ULFM, HTap,
and Hand Grip test contrasts with the significant positive
effect on the JHFT assessing the functional hand motricity.
These results suggest that the intervention-induced enhance-
ment of motor recovery could facilitate functional upper
limb adaptation strategies rather than “restitution” of motor
force. Other mechanisms such an increased gain from phys-
ical therapy through a positive additional effect on motor
learning cannot be completely ruled out even if intervention
was not time-locked to the physical therapy.
It has previously been shown in chronic stroke that
anodal tDCS increases excitability within the stimulated
region41 and increases task-related functional motor activity
in ipsilesional M1 and in a number of interconnected sec-
ondary motor areas.28,42 It has been suggested that the bidi-
rectional effects of NIBS over M1 on corticospinal
excitability in humans might reflect long-term potentiation
(LTP) and long-term depression (LTD)-like plasticity.43 The
NIBS-induced increase in corticospinal excitability might
improve motor function by facilitating the volitional recruit-
ment of corticomotor output neurons.44 However, the mech-
anisms underlying the long-lasting anodal tDCS facilitatory
posteffects are not completely elucidated, and the potential
influence of the cathodal electrode over the contralateral
prefrontal cortex is still unknown.45 It is worth noting that
tDCS increases BDNF secretion and synaptic plasticity in
animals,5 which could be a key mechanism underlying
tDCS-induced improvements.46
If these results suggest that a certain degree of recovery
in the treated group was due to therapeutic intervention,
several factors, other than the intervention itself, deserve to
be discussed. Brain reorganization after stroke is a dynamic
process, which differs considerably across patients depend-
ing on lesion location, time since stroke, severity of motor
impairment, premorbid state, and genetics. Baseline mean
motor performance, NIHSS, age, sex, and delay after stroke
at inclusion, were not statistically different between the 2
groups (except for the grip force), so that the influence of
these factors should be very mild. However, the absence of
significant difference in the mean time required to perform
the JHFT at baseline was not a guarantee that both groups
were prognostically equal, given the large range of values
and their unequal distribution between the 2 groups.
More intensive physical therapy in the tDCS group com-
pared to the sham group could have contributed to the dif-
ferences of recovery pattern observed. Although outpatient
poststroke rehabilitation programs were delivered by differ-
ent rehabilitation centers, the mean therapy doses (expressed
in total number of hours during the follow-up) was similar
in both groups. None of the patients included had poststroke
depressive symptoms, severe spasticity, or shoulder pain,
which also would possibly have influenced the results.
751
More patients with cortical involvement (7/10) were
recruited in the sham group than in the tDCS group (2/10),
and this difference of lesion site may have influenced the
quality of the recovery as previously shown after one ses-
sion of 10 Hz rTMS in subacute and chronic stroke.47 This
difference did not have any impact on clinical baseline
motor performances of the 2 groups that were comparable,
except for the grip force, which was little stronger in the
sham group than in the tDCS group. Two patients of each
group had a cortical infarction involving to some extent the
upper extremity of M1 (nos. 11, 16, 12, and 15). These
lesions were very limited and the presence of an MEP at
inclusion in most of the patients in both groups (8/10 tDCS
group; 9/10 sham group, including these 4 patients) sug-
gests a small impact of the lesion location on the excitabil-
ity of the lesioned upper limb extremity M1 and/or
cortico-spinal tract in this population. At least, both groups
were well balanced in this regard.
The radial nerve stimulation alone was not expected to
induce a large beneficial effect on wrist and finger exten-
sion and rather proposed as a “control” intervention in the
sham group to facilitate recruitment and the patients’ accep-
tance of the protocol. In fact, previous studies have shown
that rPNS should last at least 2 hours to induce moderate but
measurable positive effects on the motor performance in
chronic stroke patients.19,22,48 Because of the absence of a
sham rPNS arm and the lack of selective outcome measur-
ing the wrist and finger extension specifically, we are unable
to estimate precisely the amount of facilitation induced by
the radial nerve stimulation on the paretic wrist and finger
extension (in comparison with the spontaneous motor
recovery), and its relative contribution to the global better
motor performances observed at JHFT in the group receiv-
ing the combined tDCS + rPNS intervention compared to
the group receiving only the rPNS. Nevertheless, Fugl-
Meyer’s wrist and finger extension subscore analysis con-
firms that most of the patients of both groups had a very
good recovery of their wrist and finger extension on the
paretic side at the end of the study. The 2-arm design of our
pilot study did not allow either to compare the effect of
combined tDCS + rPNS versus real tDCS alone so that the
potential additive beneficial effects of the combined stimu-
lation remain to be demonstrated in the acute phase.
However, even if we cannot assess precisely the amount of
motor improvement at JHFT, respectively, due to anodal
tDCS, radial nerve stimulation, or their combination, our
results are encouraging. The changes of corticomotor excit-
ability induced by rPNS on motor cortical function may
well involve a modulation of GABAergic interneurons that
are somatotopically specific to the stimulated region,19,22,49
and which could potentiate the long-lasting anodal tDCS
facilitatory post-effects on motor learning. Promising
results have been reported in chronic patients with a clear
additional benefit of the combined peripheral and cortical
752
stimulation compared to the cortical or peripheral stimula-
tion alone.22
The tDCS-induced gain of motor performance in JHFT
was measurable 10 days after the end of the 5 daily sessions
but not on the last day of treatment (D5), contrary to what
has been found in most of the multisession NIBS studies
performed in the chronic phase of motor recovery.6,15,16,22,50
In the subacute phase, Kim et al10 reported an improvement
in the Fugl-Meyer score at 6 months follow-up but not 1 day
after the end of 10 sessions of real tDCS compared to sham
for 18 patients included. It is also likely that a more subtle
beneficial effect of tDCS on recovery was not evident at D5
because of the small number of patients in each group.
Another important question is how long the tDCS post-
effects actually last. In most of tDCS stroke studies, the
follow-up of the patients is very short, not exceeding 15
days, except for two,9,10 with a follow-up of 6 months. Here,
the beneficial additional effect of the tDCS observed 2
weeks after the first day of treatment was still present after
a further 2 weeks, confirming that 5 days of NIBS treat-
ment, proposed on average 5 days after the stroke, were
enough to induce long-lasting enduring positive effects on
motor recovery.
The presence of an ECR MEP in almost all the patients
(except 3), on the first day of treatment (which is generally
accepted as a marker of good prognosis for motor recov-
ery51,52), suggests that, in most patients, the motor output
was preserved. The absence of significant changes of RMT
and AMT between baseline and D5 in the anodal tDCS
group was in accordance with results observed in healthy
subjects and suggests that tDCS neuromodulation is not
enough to induce an MT shift.53 The trend toward a decrease
of RMT and AMT with time observed in both groups during
the follow-up was in accordance with previous results.9,54-56
As in previous reports,55-57 confirmed recently,54 we did not
find any association between clinical improvement and mea-
sures of RMT, but we observed a good correlation at base-
line between raised motor threshold and weak motor
performance as assessed by ULFM, HTap, and JHFT. These
correlations confirm that the RMT is closely associated with
motor function and muscle strength in the paretic limb.55,58,59
Limitations
Although the results of this study are promising, it has a
number of limitations, such as the small sample size, the
differences in lesion side and sites, the lack of DTI white
matter lesion load, and the lack of control arms in which
either the therapeutic effect of tDCS alone or the spontane-
ous motor recovery (sham tDCS + sham rPNS) could be
tested. In addition, most of the stroke patients included pre-
sented mild to moderate disability, and we do not know if
such an intervention proposed in the acute phase could ben-
efit more severely impaired patients.
Neurorehabilitation and Neural Repair 29(8)
In conclusion, this pilot study shows that 5 consecutive
days of tDCS combined with rPNS proposed in the acute
phase after a stroke is well tolerated, that it can promote the
recovery of paretic hand performance, at least in patients
with motor deficit that is not too severe, and that the benefit
is still present 1 month after the stroke. Further trials per-
formed in multiple centers with larger sample size, different
designs, longer follow-up, different comparative NIBS
doses and montages (anodal, cathodal, or bihemispheric),
using markers predictive of behavioral response,17 should
be conducted in the acute or subacute phase in order to con-
firm that NIBS is able to speed up recovery, which could
have a medico-economic impact in terms of the duration of
rehabilitation programs.
Acknowledgments
The authors are grateful to Dr Tap for the statistical analysis and to
Dr Samia Cheriet for technical assistance.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was supported by grants from Fondation de l’Avenir (ET9-
531), by INSERM (C09-27), the Clinical Research Center of
Toulouse (CIC), and Toulouse University Hospital.
Supplementary material
Supplementary material for this article is available on the
Neurorehabilitation & Neural Repair Web site at http://nnr.sage-
pub.com/content/by/supplemental-data.
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