Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients.

Abstract

Motor recovery after stroke depends on the integrity of ipsilesional motor circuits and interactions between the ipsilesional and contralesional hemispheres. In this sham-controlled randomized trial, we investigated whether noninvasive modulation of regional excitability of bilateral motor cortices in combination with physical and occupational therapy improves motor outcome after stroke.
Twenty chronic stroke patients were randomly assigned to receive 5 consecutive sessions of either 1) bihemispheric transcranial direct current stimulation (tDCS) (anodal tDCS to upregulate excitability of ipsilesional motor cortex and cathodal tDCS to downregulate excitability of contralesional motor cortex) with simultaneous physical/occupational therapy or 2) sham stimulation with simultaneous physical/occupational therapy. Changes in motor impairment (Upper Extremity Fugl-Meyer) and motor activity (Wolf Motor Function Test) assessments were outcome measures while functional imaging parameters were used to identify neural correlates of motor improvement.
The improvement of motor function was significantly greater in the real stimulation group (20.7% in Fugl-Meyer and 19.1% in Wolf Motor Function Test scores) when compared to the sham group (3.2% in Fugl-Meyer and 6.0% in Wolf Motor Function Test scores). The effects outlasted the stimulation by at least 1 week. In the real-stimulation group, stronger activation of intact ipsilesional motor regions during paced movements of the affected limb were found postintervention whereas no significant activation changes were seen in the control group.
The combination of bihemispheric tDCS and peripheral sensorimotor activities improved motor functions in chronic stroke patients that outlasted the intervention period. This novel approach may potentiate cerebral adaptive processes that facilitate motor recovery after stroke. Classification of evidence: This study provides Class I evidence that for adult patients with ischemic stroke treated at least 5 months after their first and only stroke, bihemispheric tDCS and simultaneous physical/occupational therapy given over 5 consecutive sessions significantly improves motor function as measured by the Upper Extremity Fugl-Meyer assessment (raw change treated 6.1 ± 3.4, sham 1.2 ± 1.0).

Full text

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Bihemispheric brain stimulation facilitates
motor recovery in chronic stroke patients
R. Lindenberg, MD
V. Renga, MD
L.L. Zhu
D. Nair, MD
G. Schlaug, MD, PhD
ABSTRACT
Objective: Motor recovery after stroke depends on the integrity of ipsilesional motor circuits and
interactions between the ipsilesional and contralesional hemispheres. In this sham-controlled ran-
domized trial, we investigated whether noninvasive modulation of regional excitability of bilateral
motor cortices in combination with physical and occupational therapy improves motor outcome
after stroke.
Methods: Twenty chronic stroke patients were randomly assigned to receive 5 consecutive
sessions of either 1) bihemispheric transcranial direct current stimulation (tDCS) (anodal
tDCS to upregulate excitability of ipsilesional motor cortex and cathodal tDCS to downregu-
late excitability of contralesional motor cortex) with simultaneous physical/occupational ther-
apy or 2) sham stimulation with simultaneous physical/occupational therapy. Changes in
motor impairment (Upper Extremity Fugl-Meyer) and motor activity (Wolf Motor Function Test)
assessments were outcome measures while functional imaging parameters were used to
identify neural correlates of motor improvement.
Results: The improvement of motor function was significantly greater in the real stimulation group
(20.7% in Fugl-Meyer and 19.1% in Wolf Motor Function Test scores) when compared to the
sham group (3.2% in Fugl-Meyer and 6.0% in Wolf Motor Function Test scores). The effects
outlasted the stimulation by at least 1 week. In the real-stimulation group, stronger activation of
intact ipsilesional motor regions during paced movements of the affected limb were found
postintervention whereas no significant activation changes were seen in the control group.
Conclusions: The combination of bihemispheric tDCS and peripheral sensorimotor activities im-
proved motor functions in chronic stroke patients that outlasted the intervention period. This novel
approach may potentiate cerebral adaptive processes that facilitate motor recovery after stroke.
Classification of evidence: This study provides Class I evidence that for adult patients with isch-
emic stroke treated at least 5 months after their first and only stroke, bihemispheric tDCS and
simultaneous physical/occupational therapy given over 5 consecutive sessions significantly im-
proves motor function as measured by the Upper Extremity Fugl-Meyer assessment (raw change
treated 6.1 ? 3.4, sham 1.2 ? 1.0). Neurology®2010;75:1–1
GLOSSARY
CST ? corticospinal tract; FLAIR ? fluid-attenuated inversion recovery; LI ? laterality index; MRC ? Medical Research
Council; PT/OT ? physical/occupational therapy; rTMS ? repetitive transcranial magnetic stimulation; tDCS ? transcranial
direct current stimulation; UE-FM ? Upper Extremity Fugl-Meyer assessment; WMFT ? Wolf Motor Function Test.
Motor impairment due to ischemic stroke is one of the leading disabilities in adults in
Western countries.1In addition to established means of facilitating motor recovery after
stroke such as physical and occupational therapy, a variety of experimental rehabilitation
approaches have been tested.2Recent developments include noninvasive brain stimulation
techniques such as repetitive transcranial magnetic stimulation (rTMS)3and transcranial
direct current stimulation (tDCS).4The use of these tools is based on neurophysiologic
e-Pub ahead of print on November 10, 2010, at www.neurology.org.
From the Department of Neurology, Neuroimaging and Stroke Recovery Laboratories, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston, MA.
Study funding: Supported by the NIH/NINDS (NS045049).
Disclosure: Author disclosures are provided at the end of the article.
Editorial,pageXXX
Address correspondence and
reprint requests to Dr. Gottfried
Schlaug, Department of
Neurology, Beth Israel Deaconess
Medical Center and Harvard
Medical School, 330 Brookline
Ave., Boston, MA 02215
gschlaug@bidmc.harvard.edu
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Copyright © 2010 by AAN Enterprises, Inc.
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studies demonstrating an imbalance of in-
terhemispheric interactions which appears
to interfere with the recovery process.5,6
The model of interhemispheric imbalance
provides a framework for developing hypoth-
eses based on its 2 facets: 1) upregulating ex-
citability of intact portions of the ipsilesional
motor cortex and 2) downregulating excit-
ability of the contralesional motor cortex to
modulate its unrestrained inhibitory influence
on ipsilesional regions.2,4Pilot and proof-of-
principle studies, using either rTMS7-10or
tDCS,11-14have shown both approaches to
have beneficial effects on motor skills and mo-
tor learning. Furthermore, the combination
of tDCS and peripheral stimulation (e.g., pe-
ripheral nerve stimulation or peripheral senso-
rimotor activities) seems to enhance the
effects of each intervention by itself.13,14
To date, however, no study has tested the
efficacy of bihemispheric stimulation, i.e.,
upregulation of ipsilesional and simulta-
neous downregulation of contralesional
motor regions, in combination with periph-
eral sensorimotor activities in chronic
stroke patients. Bihemispheric tDCS may
potentiate the effects of anodal stimulation
to the lesional hemisphere11,14through ad-
ditional modulation of interhemispheric in-
teractions15via cathodal stimulation to the
contralesional motor cortex.12
METHODS Subjects. Twenty chronic stroke patients par-
ticipated in the study (see table 1 for demographic, clinical,
and imaging data; figure 1 for individual lesion maps). Inclu-
sion criteria consisted of occurrence of ischemic stroke in the
territory of the medial cerebral artery at least 5 months prior
to enrollment; no previous or subsequent strokes; Medical
Research Council (MRC) strength grade of ?3/5 in extensor
muscles of the affected upper extremity in the acute phase
with at least 15 degrees of active wrist dorsiflexion at enroll-
ment; no additional neurologic or psychiatric disorders; and
no concurrent use of CNS-affecting drugs.
Sample size calculations were based on a previous unihemi-
spheric tDCS study (cathodal stimulation of the contralesional
motor cortex), in which patients improved by 4 points on the
Upper Extremity Fugl-Meyer assessment (UE-FM) after 5 days
of treatment.4,16Since bihemispheric tDCS was shown to be
about 50% more effective than unihemispheric tDCS in healthy
subjects,17we assumed an improvement of about 6 ? 3 points in
our real stimulation group and, according to this previous study,
1 ? 2 points in our control group. A power analysis revealed the
necessary sample size to be n ? 8 per group to achieve a statisti-
cal power of at least 95% (2-tailed ? ? 0.05).
Standard protocol approvals, registrations, and patient
consents. The study was approved by the local Institutional
Review Board, and all patients gave written informed consent.
Thistrial isregistered at
(NCT00792428).
the publictrials registry
Study design. Patients were randomly assigned to one of two
groups—real tDCS with physical/occupational therapy (PT/
OT) or sham tDCS with PT/OT—using a block randomization
with 3 strata of impairment based on UE-FM score (13–28,
29–41, and 42–56 points) to achieve similar distributions of
impairment between the 2 groups.
Each patient underwent motor impairment assessments and
MRI at baseline and after the intervention, conducted by trained
individuals who were blinded to the type of intervention the
patients received.
For both conditions, tDCS (30 minutes) and PT/OT (60
minutes) commenced at the same time. An experienced occu-
pational therapist used a combination of PT/OT techniques
including functional motor tasks to promote sensory-motor
integration, coordination of movement, and goal-directed ac-
tivities of practical relevance (e.g., reaching, grasping, or ob-
ject manipulation). All patients received similar exercises
within their own capabilities. The patients and the therapist
were blinded as to whether the patients received real or sham
tDCS.
Transcranial direct current stimulation. Direct current
was delivered using a Phoresor®II autostimulator (IOMED,
Salt Lake City, UT) through 2 saline-soaked surface gel-
sponge electrodes (16.3 cm2active area).4Real stimulation
consisted of 30 minutes of 1.5 mA direct current with the
anode placed over the ipsilesional and the cathode over the
contralesional motor cortex (C3 and C4 of the international
10–20 EEG electrode system). For sham stimulation, the
same electrode positions were used. The current was ramped
up to 1.5 mA and slowly decreased over 30 seconds to ensure
the typical initial tingling sensation.18
Motor impairment and motor activity assessments.
Each patient underwent the UE-FM,19a standardized motor im-
pairment scale (primary outcome measure), and the Wolf Mo-
tor Function Test (WMFT),20a battery of proximal and distal
motor activity tasks (secondary outcome measure), on 2 dif-
ferent days prior to the intervention to assure measurement
stability at baseline.21Patients were assessed again 3 days (post
1) and 7 days (post 2) after the last intervention session. A
2-tailed paired t test revealed no difference between baseline
assessments (p ? 0.62) so the 2 preintervention tests were
averaged for the overall analysis.
A generalized linear mixed-effects regression model with robust
variance estimation was used to evaluate the association between
treatment assignment (dual vs sham) and outcome measures over
time (pre, post 1, post 2) while controlling for age, time poststroke,
and lesion size. All statistical analyses were performed using Stata
10.0 (StataCorp, College Station, TX).
Functional MRI tasks. Prior to and following the experi-
mental intervention, all patients were scanned while performing
repetitive elbow and wrist extension/flexion movements, which
were paced auditorily by a metronome, delivered through MRI-
compatible headphones. Subjects were asked to close their eyes,
listen to the metronome, and alternate between flexion and ex-
tension up to the maximal excursion they could perform while
still synchronizing with the auditory pacer at a rate of 1 Hz. The
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Table 1
Demographic, imaging, and behavioral motor dataa
ID
Age,
y
Tpost,
mo
Sex
HD
Hem
WM
Size,
cc
CST-LL,
cc
UE-FM
WMFT
Pre
(max ? 66)
Post 1
(max ? 66)
Post 2
(max ? 66)
Pre
(sec[log])
Post 1
(sec[log])
Post 2
(sec[log])
D1
65.1
65.0
M
R
L
3
245.4
3.19
32.5
41.0
41.0
1.18
1.10
1.05
D2
76.1
10.6
F
R
R
6
19.2
1.15
40.5
46.0
47.0
0.89
0.73
0.64
D3
44.2
12.4
M
R
L
5
35.5
0.47
45.0
49.0
49.0
1.00
0.95
0.90
D4
76.2
62.5
F
R
R
8
62.3
2.11
13.0
20.0
20.0
1.96
1.60
1.60
D5
68.2
46.0
M
R
L
4
4.9
0.20
52.5
57.0
59.0
0.22
0.15
0.15
D6
76.5
29.3
M
R
R
4
79.8
0.33
47.0
52.0
52.0
0.29
0.26
0.23
D7
52.1
5.3
M
R
R
2
199.2
0.20
27.0
35.0
41.0
0.95
0.79
0.66
D8
54.0
34.9
M
R
L
2
167.5
0.10
48.0
51.0
51.0
0.48
0.35
0.35
D9
69.6
22.3
M
R
L
5
8.6
0.10
53.0
60.0
56.0
0.39
0.24
0.35
D10
34.6
16.5
M
R
L
4
199.8
2.73
23.5
27.0
27.0
1.38
1.28
1.37
Mean
61.7 ? 14.7
30.5 ? 21.4
4.4 ? 1.9
102.2 ? 91.5
1.06 ? 1.19
38.2 ? 13.3
43.8 ? 12.3
44.3 ? 11.5
0.87 ? 0.55
0.74 ? 0.49
0.73 ? 0.49
S1
77.8
64.5
F
A
L
7
108.8
0.66
56.0
58.0
58.0
0.30
0.24
0.25
S2
58.7
56.8
F
R
L
4
93.3
4.58
44.0
46.0
46.0
0.26
0.26
0.25
S3
69.8
20.6
M
R
L
6
113.1
0.22
51.5
52.0
51.0
0.36
0.36
0.39
S4
49.1
35.0
M
R
R
2
10.7
0.90
28.0
28.0
28.0
1.28
1.26
1.25
S5
50.6
51.0
M
R
R
2
15.1
0.98
34.0
34.0
34.0
1.14
1.14
1.12
S6
39.6
10.3
F
R
L
6
9.7
0.38
38.0
39.0
39.0
1.19
1.10
1.14
S7
40.6
45.6
M
R
L
2
303.2
1.43
30.5
31.0
32.0
0.97
0.97
0.94
S8
55.4
81.0
M
R
L
5
143.3
0.74
48.5
50.0
51.0
0.34
0.28
0.25
S9
68.8
24.7
M
R
L
7
6.5
0.87
20.0
22.0
22.0
1.62
1.46
1.44
S10
47.7
13.4
M
R
R
4
2.7
0.55
47.0
49.0
48.0
0.84
0.83
0.82
Mean
55.8 ? 12.9
40.3 ? 23.4
4.5 ? 2.0
80.6 ? 95.0
1.13 ? 1.26
39.8 ? 11.5
41.0 ? 11.8
40.9 ? 11.7
0.83 ? 0.48
0.79 ? 0.47
0.78 ? 0.46
Abbreviations:A?ambidextrous;CST-LL?lesionloadofthecorticospinaltract;D?dual(i.e.,bihemispheric)transcranialdirectcurrentstimulationgroup;HD?handedness;Hem?lesionedhemisphere;post1?
assessment at 3rd day post intervention; post 2 ? assessment at 7th day post intervention; S ? sham transcranial direct current stimulation group; Tpost? time post stroke; UE-FM ? Upper Extremity Fugl-Meyer
assessment (averaged across 2 baseline assessments); WM ? white matter damage (scores are based on the modified Scheltens Scale24); WMFT ? Wolf Motor Function Test.
aValues are mean ? SD.
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fMRI session consisted of alternating 35-second epochs of elbow
or wrist movements.
Each active task was followed by a nonmovement rest condi-
tion (elbow and wrist in neutral position), resulting in 20 vol-
umes each for affected limb movements, unaffected limb
movements, and rest conditions in each run. To minimize train-
ing effects and their influence on the activation pattern,22pa-
tients practiced until they were able to perform the movements
at the required pace and at maximal excursion without mirror
movements. An investigator remained in the scanner room to
observe whether the tasks were performed as instructed. No mir-
ror movements were detected.
MRI acquisition, preprocessing, and analysis. All pa-
tients underwent MRI using a 3-T GE scanner, which included
a set of highly T1-weighted images (0.93 ? 0.93 ? 1.5 mm3), a
fluid-attenuated inversion recovery (FLAIR) sequence (0.5 ?
0.5 ? 5 mm3), and a gradient echo T2*-weighted EPI sequence.
Head motion was minimized using foam pads and forehead re-
straining straps. The T1-weighted images were spatially normal-
ized (2-mm isotropic voxels). Each patient’s stroke lesion was
mapped using the coregistered FLAIR images as an additional
guide to confirm the location and extent of the chronic lesion
(figure 1). We calculated an overlap of each lesion with a canon-
ical corticospinal tract (CST) derived from a group of 10 age-
Figure 1Representative individual lesion maps
After spatial normalization to the Montreal Neurological Institute space using SPM5, individual lesion maps of patients in
the real stimulation group (dual) and control group (sham) were drawn and superimposed onto a canonical T1-weighted image.
Thesliceclosesttotheinternalcapsulelevelwiththegreatestlesionexpansionisshowntoillustrateeachpatient’slesion.
Figure 2Change in motor impairment scores and fMRI laterality index
(A) Proportional change of motor impairment scores from baseline to postintervention assessments ([post ? pre]/pre ?
100). Note that an increase in Upper Extremity Fugl-Meyer assessment (UE-FM) scores reflects an improvement in impair-
ment of the affected limb and that a decrease in logarithmized Wolf Motor Function Test (WMFT) scores indicates a better
function of the affected limb (i.e., shorter completion times). (B) Linear regression of change in the precentral gyrus activa-
tion laterality index (LI) and WMFT change (sec[log]) in the real stimulation group (Pearson coefficient r ? 0.72, p ? 0.029).
No significant correlation between functional imaging measures and behavioral motor measures were found in the sham
group.
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matched healthy control subjects (58.2 ? 12.2 years) using
diffusion tensor imaging.23We used lesion volume as well as
CST lesion load, a combined measure of lesion site and size that
has been shown to be an excellent predictor of motor impair-
ment in chronic stroke patients, to test for group differences at
baseline. Furthermore, we rated white matter hyperintensities on
the FLAIR images using the modified Scheltens scale24in order
to test for differences in the presence and severity of small vessel
disease between the 2 groups.
Functional imaging data were acquired with the following
parameters: field of view ? 64 ? 64, 32 contiguous axial slices
covering the whole brain (voxel size 3.75 ? 3.75 ? 4 mm3). We
used a sparse temporal design with clustered volume acquisition
(acquisition time of 2.6 seconds and effective repetition time of 7
seconds). A long repetition time was chosen to ensure that pa-
tients heard the metronome during the interscan intervals and to
exclude the possibility that the scanner noise would serve as a
guide for movements.
Preprocessing (including realignment, spatial normalization,
and smoothing using a kernel size of 8 mm) and statistical anal-
ysis were done with SPM5 (Wellcome Department of Neurol-
ogy, London, UK) implemented in Matlab (The Mathworks
Inc., Sherborn, MA). In the elbow task, 3 patients’ imaging stud-
ies had to be excluded due to head motion that could not be
adequately corrected, resulting in 9 sets of preintervention and
postintervention data for the dual group and 8 for the sham
group. Only 7 patients in each group could perform the wrist
task at the required pace and were included in this analysis.
Voxels with task-related activity were identified using a Gen-
eral Linear Model approach.25For the first level group analysis
data were high-pass filtered (128 seconds) and modeled with the
standard canonical hemodynamic response function. The analy-
ses were conducted using a threshold of p ? 0.05 (corrected for
family-wise error).
The images of patients with right hemispheric lesions
were mirrored so that all lesions were displayed on the left
side. In addition to group analyses for the dual and sham
groups, we extracted individual regional ? parameters using
WFU Pick Atlas templates of the precentral gyri in order to
compare changes in laterality indices (LI) from preinterven-
tion to postintervention:
LI ? (contralesional ? ipsilesional)/(contralesional ?
ipsilesional)26
Correlation analyses were used to examine changes in LI
with respect to changes in motor impairment/motor activity
scores.
RESULTS No adverse effects were observed by the
investigators or reported by the patients except a
mild tingling sensation at the site of the electrodes at
the beginning of the stimulation, which is a common
finding across different studies.18
Motor assessments and demographic data. The groups
did not differ with respect to age, time poststroke,
gender distribution, presence and severity of small
vessel disease,24lesion volume, CST lesion load,23or
baseline motor scores (all p ? 0.35; table 1). In the
dual group, we observed an increase in UE-FM from
38.2 ? 13.3 to 43.8 ? 12.3 (post 1) and 44.3 ?
11.5 (post 2) and a decrease in WMFT scores from
0.87 ? 0.55 to 0.74 ? 0.48 (post 1) and 0.73 ?
Table 2
Within-group comparisonsa
Upper Extremity Fugl-Meyer assessment
Wolf Motor Function Test
Post 1 vs pre, Z score
Post 2 vs pre, Z score
Post 2 vs post 1, Z score
Post 1 vs pre, Z score
Post 2 vs pre, Z score
Post 2 vs post 1, Z score
Dual
9.19
5.76
0.64
?4.37
?3.90
?0.64
95% CI (p value)
4.40 to 6.79 (?0.001)
4.02 to 8.18 (?0.001)
?1.03 to 2.03 (0.521)
?0.19 to ?0.07 (?0.001)
?0.21 to ?0.07 (?0.001)
?0.06 to ?0.03 (0.520)
Sham
4.27
3.53
0.00
?2.33
?2.15
0.00
95% CI (p value)
0.62 to 1.68 (?0.001)
0.51 to 1.79 (?0.001)
0.41 to 0.41 (1.000)
?0.68 to ?0.01 (0.020)
?0.07 to ?0.00 (0.031)
?0.12 to ?0.12 (1.000)
Abbreviation: CI ? confidence interval.
aCovariates: age, time poststroke, and lesion size.
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