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Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke.

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Differential Effects of High-Frequency
Repetitive Transcranial Magnetic Stimulation
Over Ipsilesional Primary Motor Cortex in
Cortical and Subcortical Middle Cerebral
Artery Stroke
Mitra Ameli, MD,1 Christian Grefkes, MD,1,2 Friederike Kemper, MD,1 Florian P. Riegg, MS,1
Anne K. Rehme, MS,2 Hans Karbe, MD, PhD,3 Gereon R. Fink, MD, PhD,1,4
and Dennis A. Nowak, MD, PhD1,3,4
Objective: Facilitation of cortical excitability of the ipsilesional primary motor cortex (M1) may improve dexterity of the affected
hand after stroke. The effects of 10Hz repetitive transcranial magnetic stimulation (rTMS) over ipsilesional M1 on movement
kinematics and neural activity were examined in patients with subcortical or cortical stroke.
Methods: Twenty-nine patients with impaired dexterity after stroke (16 subcortical middle cerebral artery [MCA] strokes, 13
MCA strokes involving subcortical tissue and primary or secondary cortical sensorimotor areas) received 1 session of 10Hz rTMS
(5-second stimulation, 25-second break, 1,000 pulses, 80% of the resting motor threshold) applied over: 1) ipsilesional M1 and
2) vertex (control stimulation). For behavioral testing, 29 patients performed index finger and hand tapping movements with the
affected and unaffected hand prior to and following each rTMS application. For functional magnetic resonance imaging, 18
patients performed index finger tapping movements with the affected and unaffected hand before and after each rTMS application.
Results: Ten-Hz rTMS over ipsilesional M1, but not over vertex, improved movement kinematics in 14 of 16 patients with
subcortical stroke, but not in patients with additional cortical stroke. Ten-Hz rTMS slightly deteriorated dexterity of the affected
hand in 7 of 13 cortical stroke patients. At a neural level, rTMS over ipsilesional M1 reduced neural activity of the contralesional
M1 in 11 patients with subcortical stroke, but caused a widespread bilateral recruitment of primary and secondary motor areas
in 7 patients with cortical stroke. Activity in ipsilesional M1 at baseline correlated with improvement of index finger tapping
frequency induced by rTMS.
Interpretation: The beneficial effects of 10Hz rTMS over ipsilesional M1 on motor function of the affected hand depend on
the extension of MCA stroke. Neural activity in ipsilesional M1 may serve as a surrogate marker for the effectiveness of
facilitatory rTMS.
Ann Neurol 2009;66:298 –309
Recovery of hand motor function following stroke is
usually incomplete; 6 months following the cerebrovascular incident about two-thirds of patients still suffer
from profoundly impaired dexterity, which significantly impacts the individual’s disability and activities
of daily living.1 Thus, novel concepts beyond current
strategies for hand motor rehabilitation after stroke are
needed.
Repetitive transcranial magnetic stimulation (rTMS)
is a noninvasive and painless procedure to modulate
cortical excitability of motor areas,2 and has the potential to improve dexterity of the affected hand after
stroke.3– 8 The concept underlying the use of rTMS in
hand motor rehabilitation after stroke is based on the
model of interhemispheric competition for sensory and
motor processing.9 –11 Within this concept, a stroke in
one hemisphere may shift the equilibrium of cortical
excitability within the motor areas of both hemispheres
From the 1Department of Neurology, University Hospital Cologne, Cologne, Germany; 2Max-Planck-Institute for Neurological
Research, Cologne, Germany; 3Neurological Rehabilitation Hospital Godeshöhe, Bonn, Germany; and 4Cognitive Neurology Section, Institute of Neuroscience and Medicine—INM-3, Research
Center Jülich, Jülich, Germany.
13, D-85110 Kipfenberg. E-mail: dennis.nowak@neurologiekipfenberg.de
Address correspondence to Dr Nowak, Klinik Kipfenberg, Neurochirurgische und Neurologische Fachklinik, Kindinger Strasse
298
© 2009 American Neurological Association
Potential conflict of interest: Nothing to report.
Received Dec 10, 2008, and in revised form Mar 8, 2009. Accepted for
publication Apr 3, 2009. Published online in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21725
toward the contralesional hemisphere.10,12 Enhanced
excitability of the primary motor cortex (M1) of the
contralesional hemisphere is a frequent finding after
stroke, and probably results from abnormally decreased
transcallosal inhibition from the lesioned M1 for
movements of the affected hand.12–15 Two therapeutic
strategies may be pursued to interfere with motor function of the affected hand following stroke: upregulation
of excitability of the ipsilesional M1 or downregulation
of excitability of the contralesional M1. Indeed, a series
of proof-of-principle studies has demonstrated that inhibitory rTMS applied over the contralesional
M13– 6,16 or facilitatory rTMS applied over the ipsilesional M17,8,17 may improve dexterity of the affected
hand following stroke.
Although rTMS is increasingly used in stroke rehabilitation, the mechanism underlying the changes of
cortical excitability within the cortical motor network
of both hemispheres and their impact on motor behavior remain to be elucidated. For example, it is unclear
to what extent stroke location and distribution determines the individual response to the application of
rTMS. Recent rTMS studies examining stroke-induced
functional changes in cortical excitability in subcortical
and cortical stroke suggest differential functional interference with neural activation and motor function depending on stroke location and distribution.18,19 We
investigated the effect of lesion site and distribution
(subcortical stroke or both subcortical and cortical
stroke)1 within the middle cerebral artery (MCA) territory on 1) the behavioral response to facilitatory
rTMS applied over ipsilesional M1 as measured by kinematic motion analysis and 2) the associated changes
in neural activity as measured by functional magnetic
resonance imaging (fMRI).
Materials and Methods
Subjects and Clinical Data
Twenty-nine patients (13 females; mean age, 56 ⫾ 13 years;
age range, 35–78 years) with sensorimotor impairment of 1
hand after a first left (n ⫽ 13) or right (n ⫽ 16) ischemic
MCA stroke participated. High-resolution structural MRI
was used to differentiate 2 groups of patients: 16 subjects
had a subcortical stroke without involvement of cortical motor areas (subcortical stroke), whereas 13 patients showed infarction of cortical primary or secondary sensorimotor areas
in addition to subcortical infarction (cortical stroke).
Twenty-seven participants had a right hand and 2 a left hand
preference as determined by a handedness questionnaire.20
Patients in the acute and chronic stage of their disease were
included (time from stroke, 1– 88 weeks; on average, 22 ⫾
1
In the following we refer to lesion site and distribution of stroke as
subcortical and cortical for sake of simplicity. However, there is additional subcortical damage in the majority of patients classified as
cortical stroke (see also Figure 1).
26 weeks). Time from stroke was not statistically different
between the 2 patient groups (unpaired t test, p ⫽ 0.5). Patients were included according to the following criteria: 1)
location of the ischemic lesion within the territory of the
MCA; 2) presentation with mild to moderate motor and/or
sensory deficits of 1 hand; 3) preserved motor evoked potentials (MEP) at the first dorsal interosseus (FDI) muscle of the
affected hand after single-pulse TMS applied over the hand
area of the ipsilesional M1; 4) a score of ⱖ24 points on the
Folstein Mini-Mental Status Examination21; 5) absence of a
relevant depression as indexed by a score of ⬍18 points on
the Beck Depression Inventory22; 6) absence of mirror movements of the unaffected hand for movements of the affected
hand; 7) absence of aphasia, apraxia, and neglect; 8) no visual field deficits; and 9) no psychiatric or coexistent general
neurological, medical, or orthopedic illness. The study was
approved by the Ethics committee of the Medical faculty of
the University of Cologne (EK 072/06).
The following clinical scores were assessed: modified
Rankin Scale,23 Action Research Arm Test,24 Medical Research Council scale for wrist extension of the affected
hand,25 National Institute of Health Stroke Scale,26 and a
sensibility impairment score to rate cutaneous and proprioceptive sensibility of the affected hand.27 For a summary of
clinical data, see Table 1.
Repetitive Transcranial Magnetic Stimulation
The rTMS protocol consisted of 1,000 pulses applied over
the ipsilesional M1 at a frequency of 10Hz (trains of 5 seconds of stimulation, followed by 25 seconds of intertrain interval; stimulus intensity, 80% of the resting motor threshold
of the contralesional M1). Based on previous work,7 stimulation intensity was set to 80% of the resting motor threshold of the contralesional M1 to reduce overall stimulation
intensity and thus minimize the risk of rTMS-provoked seizures, which is thought to be higher in patients with stroke
lesions involving the cortex.28 Stimulation intensities did not
differ for patients with (rTMS responders) or without behavioral improvement (rTMS nonresponders) of the affected
hand (Table 1). Stimulation was performed using a 70mm
figure-of-eight coil and a Magstim Super Rapid stimulator
(Magstim Company, Dyfed, UK). The handle of the coil
pointed backward and laterally at a 45° angle to the sagittal
plane. The coil was placed tangentially over the hand area of
M1 at the optimal site for the response of the FDI muscle.
Hence, the site of stimulation was defined as the location
where single-pulse suprathreshold TMS consistently elicited
the largest MEP from the FDI muscle of the contralateral
hand. Electromyographic activity was recorded using silversilver-chloride electrodes positioned in a belly-tendon technique on the skin overlying the FDI muscle of the contralateral hand. Resting motor threshold was defined for each
patient as the lowest stimulator output intensity that elicited
MEP with peak-to-peak amplitude of at least 50␮V in the
contralateral FDI muscle in at least 5 of 10 trials. For control
condition, the coil was placed over the vertex several centimeters posterior in the y-axis to avoid interference with neuronal processing in cortical motor areas such as the supplementary motor area (SMA). The order of the stimulation
sites was counterbalanced across patients.
Ameli et al: Differential rTMS Effects in Stroke
299
Table 1. Clinical Details of Stroke Patients
Patient/Sex/Age, yr
Stroke
Location
Affected
Hand
MMS
Score
NIHSS
Score
mRS
Score
ARAT
Score
MRC
Score
Time
From
Stroke
(wk)
SIS
%
Improvement
to rTMS
Over
Ipsilesional
M1
rTMS
Stimulation
Intensity
(% of
Stimulator
Output)
1/M/58
sc/CR; BG
2/F/52
sc/BG
Left
28
4
2
46
3
83
8
47.0
63
Right
27
6
2
54
4
24
7
40.4
3/F/35
41
sc/CR; BG
Right
30
8
3
27
3
3
6
38.1
52
4/M/41
sc/BG
Left
30
2
1
53
5
14
0
35.9
50
5/M/55
sc/CR
Left
26
2
1
52
5
46
0
35.8
50
6/F/77
sc/T
Left
30
5
3
31
4
65
20
31.9
49
7/F/36
sc/CR
Left
29
3
2
57
4
1
9
23.3
50
8/M/54
sc/CR
Right
30
4
1
54
4
8
4
18.0
55
9/F/50
sc/T
Left
30
4
1
51
4
7
6
15.8
45
10/M/46
sc/CR
Left
28
5
1
55
4
9
13
15.7
50
11/F/49
sc/CR
Right
29
5
1
40
4
37
7
14.8
50
12/M/65
sc/CR
Right
30
4
2
49
4
40
10
13.8
55
13/M/53
sc/CR
Right
30
3
1
54
4
6
1
13.1
49
14/F/55
sc/CR
Right
25
2
2
55
5
23
10
11.0
52
15/M/46
c/preCG; IFG;
Left
30
4
2
42
3
53
0
8.9
34
16/M/47
c/postCG;
SPL; IPL; IFG
Right
28
5
1
56
5
51
17
8.1
48
17/F/58
c/preCG;
postCG; IFG
Right
28
6
2
57
4
2
8
6.2
52
18/M/53
c/preCG;
postCG; SPL;
IFG
Left
30
1
1
56
5
7
3
5.8
47
19/F/71
c/preCG;
postCG;
Right
26
5
3
27
3
2
20
4.4
45
20/M/61
c/preCG;
postCG, SPL
Right
30
3
2
40
3
4
11
3.0
43
21/F/27
sc/CR
Left
28
2
1
57
5
2
3
1.5
43
22/M/56
c/preCG;
postCG; IPL
Left
30
5
3
28
4
4
19
⫺2.3
45
23/F/76
c/preCG;
postCG; IPL
Right
28
0
1
48
4
2
9
⫺2.3
50
24/F/78
c/preCG;
postCG
Right
25
3
2
52
4
6
15
⫺3.1
55
rTMS responders
rTMS non-responders
25/M/55
sc/IC
Right
28
3
3
31
3
3
9
⫺6.7
49
26/F/68
c/preCG; IFG;
Left
29
2
1
56
5
4
10
⫺7.9
52
27/M/72
c/preCG;
postCG; SPL;
IPL
Right
28
6
3
29
5
88
26
⫺14.0
50
28/M/52
c/preCG;
postCG
Right
30
1
1
51
5
47
2
⫺29.2
52
29/M/67
c/preCG; SPL;
IPL
Right
27
6
1
55
4
3
14
⫺37.8
49
MMS ⫽ Mini Mental Status Examination Score; NIHSS26 ⫽ National Institute of Health Stroke Scale; mRS23 ⫽ Modified Rankin
Scale; ARAT24 ⫽ Action Research Arm Test; MRC25 ⫽ Medical Research Council Score of wrist extension; SIS27⫽ Sensibility
Impairment Score, rated as described previously (0 ⫽ normal; greater score indicates more significant impairment; maximum score: 35
points); rTMS ⫽ repetitive transcranial magnetic stimulation; M1 ⫽ primary motor cortex; M ⫽ male; sc ⫽ subcortical stroke; CR ⫽
corona radiata; BG ⫽ basal ganglia; F ⫽ female; T ⫽ thalamus; c ⫽ cortical stroke location; IFG ⫽ inferior frontal gyrus; SPL ⫽
superior parietal lobule; IPL ⫽ inferior parietal lobule; preCG ⫽ gyrus precentralis; postCG⫽ gyrus postcentralis; IC ⫽ internal
capsule.
Experimental Procedure
Patients participated in behavioral and fMRI experiments
separated by at least 24 hours. Stimulation sessions were
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counterbalanced across subjects. For the fMRI experiments,
subjects were tested under 3 conditions: 1) immediately prior
to rTMS (baseline condition), 2) following rTMS applied
over ipsilesional M1, and 3) following rTMS applied over
vertex (control stimulation). For the behavioral experiments,
after patients had been familiarized with the motor tasks, 2
baseline conditions were assessed to exclude learning effects.
Participants were tested at 4 time points: 1) 1 hour prior to
rTMS (baseline 1), 2) immediately prior to rTMS (baseline
2), 3) following rTMS applied over ipsilesional M1, and 4)
following rTMS applied over the vertex. M1 and vertex stimulation sessions were separated by at least 120 minutes to
avoid carryover effects. rTMS was performed in front of the
scanner room, and the time between the end of rTMS and
the onset of fMRI (echo planar imaging [EPI]) was approximately 2–3 minutes due to optimized positioning procedures (parameters such as mirror position and field of view
were copied from the baseline fMRI session).
Subjects performed repetitive 1 joint movements in terms of
1) index finger tapping movements and 2) hand tapping
movements (total duration of the experiment, approximately
7 minutes). Movement kinematics were recorded using an
ultrasonic motion analyzer.27 Three 5-second trials of index
finger and hand tapping movements were performed. Movements were performed as fast as possible. Peak movement
amplitude was specified to 1.5cm for index finger tapping
and 4cm for hand tapping. To quantify motor performance,
movement frequency (in hertz) and peak movement amplitude (in millimeters) were assessed. All parameters were averaged across all trials for each patient. There were no statistical differences between baseline conditions for index finger
tapping and hand tapping movements ( p ⫽ 0.6). The second baseline condition was used for further analysis.
Changes in behavior, that is, percentage changes of tapping
frequency in relation to baseline performance, were calculated for every trial (using the formula: tapping frequency
after rTMS stimulation minus tapping frequency at baseline,
divided by tapping frequency at baseline). Average data were
calculated for each patient.
Behavioral data were analyzed for all 29 patients participating in the behavioral experiments and, in addition, for the
subgroup of 18 patients participating in both the behavioral
and fMRI experiments. After verification of normal distribution and homogeneity of variance, repeated measures analyses of variance (ANOVAs) were calculated for each parameter with the factors “hand” (levels: affected hand and
unaffected hand), “lesion distribution” (levels: subcortical
stroke and cortical stroke), and “intervention” (levels: baseline, rTMS applied over vertex, and rTMS applied over ipsilesional M1). “Time from stroke” (in weeks) and “patient
age” (in years) were added as fixed covariates into the model.
Post hoc pair-wise comparisons between conditions were performed using t tests. A p value of 0.05 was considered significant after Bonferroni correction for multiple comparisons.
tapping frequency after M1 stimulation in relation to baseline condition, subjects were divided into 2 subgroups:
“rTMS responder” and “rTMS nonresponder.” The rTMS
responder subgroup contained those 14 patients with the
strongest changes in behavior (average: 25.3 ⫾ 3.2% standard error of the mean [SEM]); the rTMS nonresponder
subgroup contained those patients with the weakest changes
in behavior (average: ⫺4.4 ⫾ 3.4% SEM). This classification
was used for the generation of lesion maps as well as for
fMRI analysis. Comparing the rTMS-induced changes in
motor performance, a significant difference between the
rTMS responder and rTMS nonresponder subgroups was evident ( p ⱕ 0.001).
fMRI was performed in only 21 patients, as 8 patients had
contraindication for fMRI or claustrophobia. Three of the
21 subjects were excluded from analysis due to excessive
movements during scanning as assessed from the image realignment procedure. An fMRI block design with 2 experimental conditions (block length, 15 seconds) and interleaved
resting baselines was employed. In the experimental conditions, subjects were asked to perform index finger tapping
movements as fast as possible in the magnetic resonance
scanner (Siemens Trio 3.0 T, Siemens, Erlangen, Germany)
with their affected or unaffected hand with 15-second tapping periods separated by 15-second resting baselines. Subjects were informed via a goggle system (VisualSystem, NordicNeuroLab, Bergen, Norway) attached to the head coil of
the scanner which hand (affected or unaffected) to move in
the upcoming activation block (arrow to the left or right for
1.5 seconds). The finger tapping performance was visually
monitored for each patient by a blinded experimenter. The
sequence of right hand and left hand blocks was pseudorandomized and counterbalanced across patients. The whole
experiment comprised 2 ⫻ 8 activation blocks and 17 baseline conditions (each lasting 15 seconds, including the instruction period).
A gradient EPI sequence with the following imaging parameters was used: repetition time (TR) ⫽ 1,820 milliseconds, echo time (TE) ⫽ 30 milliseconds, 30 axial slices, slice
thickness ⫽ 3.0mm, in-plane resolution ⫽ 3.1 ⫻ 3.1mm,
EPI volumes ⫽ 288 for each session. The slices covered a
region extending from the dorsolateral prefrontal cortex to
mid parts of the cerebellum. High-resolution T1-weighted
images were acquired via a 3-dimensional (3-D) magnetization prepared rapid gradient echo sequence with the following parameters: TR ⫽ 2,250 milliseconds, TE ⫽ 3.93 milliseconds, 176 sagittal slices, slice thickness ⫽ 1.0mm, inplane resolution ⫽ 1.0 ⫻ 1.0mm. T2–fluid-attenuated
inversion recovery images were acquired for all subjects to
identify brain lesions not visible on the T1 volume images:
TR ⫽ 9,000 milliseconds, TE ⫽ 100 milliseconds, 25 axial
slices, slice thickness ⫽ 4mm, in-plane resolution ⫽ 0.9 ⫻
0.9mm.
fMRI Experiments
fMRI Data Analysis
Based on the median value of rTMS induced changes in behavior (8.9 %), that is, percentage change of index finger
For imaging data preprocessing and statistical analysis, the
SPM software package (SPM5; Wellcome Department of
Behavioral Experiments
Ameli et al: Differential rTMS Effects in Stroke
301
Imaging Neuroscience, London, UK, http://www.fil.ion.ucl.ac.uk) was used. Images from patients with right-sided lesions were flipped at the midsagittal plane, so that the affected hemisphere corresponded to the left side of the brain
for all patients. After realignment of the EPI volumes of each
session and coregistration with the anatomical 3D image, lesion masks were interactively constructed from the mean EPI
of all realigned images in combination with the T1 and
FLAIR volume (using the software MRICRON, version
beta, University of South Carolina, Columbia, SC). All volumes were spatially normalized to the standard template of
the Montreal Neurological Institute (MNI, Montreal, Quebec, Canada), employing the unified segmentation approach29 with masked lesions. Finally, data were smoothed
using an isotropic kernel of 8mm full width half maximum.
Box-car vectors for each condition were convolved with a
canonical hemodynamic response function including temporal derivatives. The times series was high-pass filtered at
1/128Hz. Movement parameters of the head were used as
additional regressors to exclude movement-related variance
from the image time series. In the first-level analysis, linear
contrast images were computed for the conditions “affected
hand vs resting” and “unaffected hand vs resting” for each
patient.
For the second-level analysis, patients were divided into 2
subgroups according to their individual response to rTMS
applied over ipsilesional M1 (“rTMS responder,” “rTMS
nonresponder”) as described above. The parameter estimates
for all conditions were subsequently compared between patients in an ANOVA with the factor “intervention” (levels
“baseline,” “rTMS applied over vertex,” “rTMS applied over
ipsilesional M1”) for “rTMS responder” and “rTMS nonresponder”, thereby effecting a random effects model, allowing
inference to the general population. To account for differences in terms of lesion age, we added “time from stroke” (in
weeks) as a covariate to the ANOVA. Furthermore, the “order of intervention” (“rTMS applied over vertex,” “rTMS
applied over ipsilesional M1”) and “patient age” (in years)
were used as covariates to remove age-dependent or stimulation order–dependent effects from the statistical analysis.
The t statistics for the linear contrasts versus resting baseline
were then interpreted by referring to the probabilistic behavior of Gaussian random fields. Voxels were identified as significant if their t values passed a threshold of p ⱕ 0.05 (false
discovery rate [FDR] corrected for multiple comparisons).
Lesion Maps
To compute lesion maps of the current sample of patients,
each lesion mask was spatially normalized to the MNI reference brain using the deformation field computed from the
EPI normalization procedure. Then, the normalized lesion
masks were superimposed in 3-D space. The degree of overlap was color coded in a spectral sequence.
Correlation Analysis
To identify regions in which neural activity prior to intervention (ie, baseline) correlated with the behavioral improvements after rTMS applied over ipsilesional M1, the contrast
images of the contrast “affected hand vs baseline” were entered in a regression analysis with the percentage change in
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September 2009
behavior as covariate. Voxels were considered significant
when passing a height threshold of t ⫽ 3.65 ( p ⱕ 0.001).
Correction for multiple comparisons ( p ⱕ 0.05, FDR corrected) was achieved by applying a small volume correction
over the rTMS stimulation site with a search radius of
30mm around the hand knob in the precentral gyrus.
Results
Behavioral Experiments
The majority of patients with subcortical stroke, but
none of the patients with additional cortical stroke,
showed a behavioral improvement of movement kinematics of the affected hand after rTMS applied over
ipsilesional M1 (Table 1). This observation is supported by the lesion maps contrasting lesion location
and extension for rTMS responders and rTMS nonresponders (Fig 1) in those 18 patients where an MRI
could be obtained. In only 2 of 16 patients with subcortical stroke, rTMS applied over ipsilesional M1
failed to increase the frequencies of index finger and
hand tapping movements (Table 1).
The performance deficit of the affected hand was
stable, as suggested by similar frequencies at both baseline investigations in each group ( p ⱖ 0.5 for each
comparison), suggesting there was no learning effect.
The second baseline condition was used for further
analysis. Frequencies and amplitudes of index finger
tapping and hand tapping movements of the affected
hand were smaller compared to those of the unaffected
hand for both subcortical and cortical stroke patients,
as evidenced by a significant effect of “hand” on frequency (F2,26 ⫽ 27.4, p ⱕ 0.001 for index finger tapping; F2,26 ⫽ 28.7, p ⱕ 0.001 for hand tapping) and
amplitude (F2,26 ⫽ 12, p ⱕ 0.05 for index finger tapping; F2,26 ⫽ 6.3, p ⱕ 0.05 for hand tapping). Movement kinematics of the affected hand, but not of the
unaffected hand, were influenced when rTMS was applied over ipsilesional M1, but not when rTMS was
applied over the vertex (“hand” ⫻ “intervention” interaction: F2,26 ⫽ 6.05, p ⱕ 0.01 for index finger tapping; F2,26 ⫽ 43.7, p ⱕ 0.05 for hand tapping). Importantly, the fixed covariates “time from stroke” and
“patient age” alone or in interaction with any of the
other factors (“hand,” “lesion distribution,” or “intervention”) did not develop significant effects on any of
the behavioral measures.
Ten-hertz rTMS applied over ipsilesional M1 evoked
differential effects on index finger and hand tapping
movements of the affected hand, but not of the unaffected hand, depending on stroke location, as evidenced by a significant “lesion location” ⫻ “intervention” interaction (all 29 patients participating in the
behavioral experiments: F2,26 ⫽ 4.2, p ⱕ 0.05 for index finger tapping; F2,26 ⫽ 3.7, p ⱕ 0.05 for hand
tapping; 18 patients participating in behavioral and
Fig 1. After normalization to the Montreal Neurological Institute space using the SPM software package, lesion maps of repetitive
transcranial magnetic stimulation (rTMS) responders and rTMS nonresponders were superimposed on a canonical T1 image and
color-coded using MRIcron (version Beta, January 7, 2007, www.mricro.com).
fMRI experiments: F2,15 ⫽ 10.4, p ⫽ 0.01 for index
finger tapping; F2,15 ⫽ 13.8, p ⱕ 0.001 for hand tapping) and “hand” ⫻ “lesion location” ⫻ “intervention”
interaction (all 29 patients participating in the behavioral experiments: F2,26 ⫽ 10.4, p ⱕ 0.001 for index
finger tapping; F2,26 ⫽ 5.5, p ⱕ 0.01 for hand tapping; 18 patients participating in behavioral and fMRI
experiments: F2,15 ⫽ 6.5, p ⱕ 0.01 for index finger
tapping; F2,15 ⫽ 2.1, p ⫽ 0.05 for hand tapping) in
the frequencies of tapping movements. The movement
amplitudes were not significantly influenced by rTMS
applied over either ipsilesional M1 or vertex both for
all patients and for the subgroup undergoing behavioral and fMRI experiments ( p ⬎ 0.05 for all comparisons), indicating that movement frequencies did not
increase simply as a result of reduction in movement
amplitude. Movement frequencies of index finger and
hand tapping movements performed with the affected
hand improved after rTMS applied over ipsilesional
M1 in subcortical stroke patients in comparison to the
baseline condition (all 29 patients participating in the
behavioral experiments: p ⱕ 0.001 for index finger and
hand tapping; 18 patients participating in behavioral
and fMRI experiments: p ⱕ 0.001 for index finger and
hand tapping) and vertex stimulation (all 29 patients
participating in the behavioral experiments: p ⱕ 0.01
for index finger and p ⱕ 0.001 for hand tapping; 18
patients participating in behavioral and fMRI experiments: p ⱕ 0.05 for index finger and hand tapping;
Table 2). Ten-hertz rTMS applied over the vertex developed no significant effects on movement kinematics
of both index finger tapping and hand tapping movements in subcortical stroke patients ( p ⱖ 0.05 for each
comparison within each group). Figure 2 demonstrates
the percentage change of index finger (Fig 2A) and
hand tapping (Fig 2B) frequencies compared to the
baseline condition for all patients undergoing the behavioral testing, respectively.
In contrast, in the patients suffering from stroke affecting cortical motor areas, neither rTMS applied over
ipsilesional M1 nor over the vertex induced a significant increase of the frequencies of index finger and
hand tapping movements compared to baseline condition ( p ⱖ 0.05 for each comparison within each
group). In 7 of the 13 cortical stroke patients, rTMS
applied over ipsilesional M1 was associated with a decrease of index finger and hand tapping frequencies,
suggesting deterioration (Tables 1 and 2, Fig 2). Comparing the percentage change of index finger and hand
tapping frequencies in relation to baseline, a significant
difference between the groups of subcortical and cortical stroke was evident after rTMS applied over ipsilesional M1 (all 29 patients participating in the behavioral experiments: p ⱕ 0.001 for index finger tapping,
p ⱕ 0.01 for hand tapping; 18 patients participating in
behavioral and fMRI experiments: p ⱕ 0.001 for index
finger tapping; Fig 2).
Ameli et al: Differential rTMS Effects in Stroke
303
Table 2. Mean Values of Index Finger and Hand Tapping Frequencies and Amplitudes ⴞ SEM
Affected Hand
Subcortical stroke
Index finger
tapping
Frequency, Hz
Amplitude, mm
Hand tapping
Frequency, Hz
Amplitude, mm
Cortical stroke
Index finger
tapping
Frequency, Hz
Amplitude, mm
Hand tapping
Frequency, Hz
Amplitude, mm
rTMS
Applied
Over
Vertex
Unaffected Hand
Baseline
1
Baseline
2
rTMS Applied
Over
Ipsilesional
M1
Baseline
1
Baseline2
rTMS
Applied
Over
Vertex
rTMS Applied
Over
Ipsilesional
M1
3.3 ⫾ 0.3
22.1 ⫾ 2.1
3.2 ⫾ 0.3
22.1 ⫾ 2.1
3.3 ⫾ 0.3
21.2 ⫾ 1.4
3.8 ⫾ 0.3a,b
21.9 ⫾ 2.6
4.5 ⫾ 0.3
23.7 ⫾ 1.3
4.6 ⫾ 0.2
23.1 ⫾ 2.2
4.6 ⫾ 0.2
26.2 ⫾ 3.9
4.7 ⫾ 0.2
24.0⫾1.5
3.6 ⫾ 0.4
28.0⫾3.0
3.4 ⫾ 0.3
33.3 ⫾ 4.3
3.6 ⫾ 0.4
33.5 ⫾ 4.1
4.0 ⫾ 0.4a,c
35.0 ⫾ 4.0
5.0 ⫾ 10.3
33,8 ⫾ 2.4
5.0 ⫾ 0.3
36,3 ⫾ 3.2
5.0 ⫾ 0.3
37,0 ⫾ 2.9
5.0 ⫾ 0.3
39,3 ⫾ 4.2
3.3 ⫾ 0.5
21.4 ⫾ 2.2
3.3 ⫾ 0.5
20.6 ⫾ 2.1
3.4 ⫾ 0.5
20.8 ⫾ 3.2
3.3 ⫾ 0.5
20.5⫾2.7
4.6 ⫾ 0,4
25.5 ⫾ 2.6
4.9 ⫾ 0,2
26.1 ⫾ 1.8
4.9 ⫾ 0,3
26.1 ⫾ 2.6
5,0 ⫾ 0,2
26.8 ⫾ 1.9
3.9 ⫾ 0.5
28.4 ⫾ 2.6
3.9 ⫾ 0.6
29.7⫾3.1
3.9 ⫾ 0.6
28.6 ⫾ 4.2
3.8 ⫾ 0.6
26.0 ⫾ 2.7
5.1 ⫾ 0.4
33.4 ⫾ 4.4
5.5 ⫾ 0.2
35.7 ⫾ 4.5
5.4 ⫾ 0.2
30.3 ⫾ 3.0
5.4 ⫾ 0.2
36.5 ⫾ 3.6
Significant difference in comparison to baseline 2; p ⱕ 0.001.
Significant difference in comparison to rTMS applied over vertex; p ⱕ 0.01.
c
Significant difference in comparison to rTMS applied over vertex; p ⱕ 0.001.
SEM ⫽ standard error of the mean; rTMS ⫽ repetitive transcranial magnetic stimulation; M1 ⫽ primary motor cortex.
a
b
fMRI Experiments
Note that not all patients included in the behavioral
analysis participated in the fMRI study (see Materials
and Methods). In both groups, movements of the unaffected hand were associated with increased neural activity in contralesional M1, contralesional somatosensory cortex, bilateral premotor cortex (dorsal and
ventral), SMA and pre-SMA, contralesional posterior
parietal cortex along the intraparietal sulcus, bilateral
dorsolateral prefrontal cortex, and bilateral visual cortex
(V1–V5), as well as subcortical regions, such as bilateral putamen, contralesional thalamus, and ipsilesional
superior cerebellum ( p ⱕ 0.05, FDR corrected). For
both groups, activity did not differ between baseline
and the two stimulation conditions for index finger
tapping movements with the unaffected hand ( p ⬎
0.05, corrected).
Neural Activity in rTMS Responders
Movements of the affected hand differed between
rTMS responders and rTMS nonresponders in the
baseline condition, that is, prior to an intervention. In
rTMS responders, movements of the affected hand
were associated with widespread activation clusters in
the ipsilesional hemisphere extending into frontal and
parietal areas (Fig 3A). Unlike movements of the unaffected index finger, finger movements of the affected
hand were also associated with significant neural activity in the contralesional hemisphere, with clusters of
activation around the central sulcus, precentral gyrus,
and the inferior parietal cortex. After vertex stimulation, this bilateral activation pattern did not change
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significantly. In contrast, rTMS applied over ipsilesional M1 significantly reduced neural overactivity in
the contralesional hemisphere, especially in the premotor cortex and posterior parietal cortex. Furthermore,
neural activity in ipsilesional motor areas tended to be
more focused, compared to baseline or after vertex
stimulation (Fig 3A).
Neural Activity in rTMS Nonresponders
rTMS nonresponders presented with a different neural
response pattern for movements of the affected hand
(Fig 3B). At baseline, neural activity was generally
weaker in both ipsilesional and contralesional motor
areas, especially in ipsilesional M1 ( p ⱕ 0.05, corrected). Compared to baseline, the application of
rTMS over the vertex had no significant impact on
neural activation for movements of the affected hand
(Fig 3B). Directly contrasting both these conditions
did not yield significant differences in BOLD (blood
oxygen level dependent) activity, even at uncorrected p
values ( p ⱕ 0.001). In contrast, when patients were
stimulated over ipsilesional M1, BOLD activity was increased in both hemispheres, with maximal increase in
contralesional ventral premotor cortex, dorsolateral premotor cortex, and parietal cortex ( p ⱕ 0.05, corrected). In other words, whereas rTMS responders, that
is, subcortical stroke patients, showed a decrease in
overactivity, especially in contralesional motor areas,
rTMS nonresponders showed the opposite behavior,
with widespread increases in activity, especially in the
contralesional hemisphere.
Fig 2. Repetitive transcranial magnetic stimulation (rTMS)induced percentage change (⫹ standard error of mean) of (A)
index finger and (B) hand tapping frequency of the affected
and unaffected hand after rTMS was applied over the vertex
(grey columns) and after rTMS was applied over the ipsilesional primary motor cortex (M1) (black columns) in relation
to the baseline. **p ⱕ 0.01; ***p ⱕ 0.001.
Correlation Between Baseline fMRI Activity and
Changes in Behavior
A correlation analysis between baseline activity and
rTMS-induced changes in behavior for all patients
scanned with fMRI showed that the neural activity in
ipsilesional M1 correlated with a change in motor behavior after rTMS applied over ipsilesional M1 ( p ⱕ
0.05, corrected; Spearman rho ⫽ 0.83, p ⱕ 0.01, Fig
4), that is, the better subjects were able to activate the
ipsilesional motor cortex before stimulation, the greater
was the beneficial effect of rTMS applied over ipsilesional M1.
Discussion
This study was designed to investigate the impact of
high-frequency (10Hz) rTMS applied over ipsilesional
M1 on movement kinematics and neural activation in
patients having suffered from MCA stroke involving either subcortical brain tissue only or both subcortical
and cortical brain tissue. We show that facilitatory
rTMS applied over ipsilesional M1, but not over the
vertex, causes a significant improvement of motor performance of the affected hand in patients with subcortical stroke, but not in patients with additional cortical
stroke. At the neural level, rTMS applied over ipsilesional M1, but not over the vertex, resulted in a significant reduction of neural activity in the contralesional hemisphere for movements of the affected hand
in subcortical, but not in cortical, MCA stroke. In patients with an ischemic stroke involving cortical motor
areas, rTMS rather enhanced a maladaptive pattern of
bilateral neural activation. Neural activation of the ipsilesional M1 prior to rTMS (at baseline) was indicative of an improvement of dexterity of the affected
hand induced by facilitatory rTMS applied over ipsilesional M1, suggesting that the effectiveness of facilitatory rTMS applied over ipsilesional M1 depends on
the functional integrity of the stimulation site, which
on one hand might influence recruitment of corticospinal projections, and on the other hand might enable
a stronger “network shaping effect” by propagating the
rTMS effects to other nodes of the motor network.
The latter hypothesis fits well with data showing that
focal stimulation of M1 has not only local, but also
remote effects in various motor areas of both hemispheres.30
Consistent with previous studies,7,17,31 14 of the 16
subcortical stroke patients responded to high-frequency
rTMS applied over ipsilesional M1 with an improvement of movement kinematics of the affected hand. In
contrast, none of the stroke patients with involvement
of cortical areas showed an improvement, and some
showed even a deterioration of movement kinematics
of the affected hand after 10Hz rTMS applied over ipsilesional M1. Importantly, at baseline cortical and
subcortical stroke patients did not differ statistically regarding the degree of motor and/or sensory impairment of the affected hand, patient age, or the time
from stroke. Thus, the relevant factor determining the
efficiency of facilitatory rTMS applied over ipsilesional
M1 seems to be the amount of neural activity of M1 of
the lesioned hemisphere at baseline, which is probably
predetermined by the site and distribution of the lesion, that is, whether or not cortical motor areas are
involved. To the best of our knowledge, previous studies employing facilitatory rTMS applied over ipsilesional M1 did not differentiate between patients with
subcortical and cortical stroke lesions.7,8,17 Our data
speak against the application of high-frequency rTMS
over the ipsilesional M1 in stroke patients with cortical
lesions in an attempt to improve motor function of the
affected hand after stroke.
The variety of lesion locations and therefore the resulting simplistic anatomical classification of “cortical”
and “subcortical” stroke may represent an important
Ameli et al: Differential rTMS Effects in Stroke
305
Fig 3. Illustration of neural activity within the cortical motor areas for the subgroups of (A) repetitive transcranial magnetic stimulation (rTMS) responders and (B) rTMS nonresponders during index finger tapping movements with the affected hand following
rTMS applied over the vertex or rTMS applied over the ipsilesional primary motor cortex (M1) versus baseline. Significant clusters
are projected on the SPM smoothed average template (p ⱕ 0.05, false discovery rate corrected). front. ⫽ frontal; occ. ⫽ occipital.
Fig 4. Correlation between neural activity within ipsilesional primary motor cortex (M1) at baseline (prior to repetitive transcranial magnetic stimulation [rTMS]) and the behavioral changes in the affected hand induced by rTMS applied over the ipsilesional
M1 (percentage change of index finger tapping frequency after rTMS was applied over the ipsilesional M1 in relation to baseline);
p ⱕ 0.01, Spearman rho ⫽ 0.83. front. ⫽ frontal; occ. ⫽ occipital. CS ⫽ central sulcus.
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limitation of our study. The amount of damage to the
corticospinal tract may be one key factor regarding the
effectiveness of high-frequency rTMS applied over ipsilesional M1. The presence or absence of motorevoked responses in the affected upper limb following
single-pulse suprathreshold transcranial magnetic stimulation over ipsilesional M132,33 and the structural integrity of the corticospinal tract as assessed using MRI
and diffusion tensor imaging32 have been shown to be
reliable indicators of motor recovery of the affected
arm and hand after stroke. In case motor-evoked responses in the affected upper limb are absent after
stroke, the possibility as to a relevant functional recovery may decline with increasing corticospinal tract disruption as detected by diffusion tensor imaging.32 The
presence of motor evoked responses in the affected upper limb is a predictor for a relevant motor recovery
even in the chronic phase after stroke.32 Impaired
functional integrity of the corticospinal tract after
stroke, as probed by MEP from the affected hand after
suprathreshold transcranial magnetic stimulation over
the ipsilesional M1, is also associated with an enhanced
neural activation of secondary motor areas in both
hemispheres, as assessed by fMRI.34 Impaired functional integrity of the corticospinal tract of the strokelesioned hemisphere correlates with the magnitude and
extension of neural activation in several motor-related
areas, including ipsilesional posterior M1, contralesional anterior M1, bilateral premotor cortex, supplementary motor area, intraparietal sulcus, dorsolateral
prefrontal cortex, and contralesional superior cingulate
sulcus, during a motor task performed with the affected hand. The widespread neural activation of secondary motor areas in both hemispheres to be found in
our patients with combined subcortical and cortical
stroke, in comparison to patients with only subcortical
stroke, may be the result of a more pronounced functional damage to the ipsilesional corticospinal tract.
Importantly, the preserved MEP in all patients with
cortical MCA stroke participating in the current study
indicate at least a partial preservation of functionally
excitable tissue within the ipsilesional M1. This suggests that in cortical stroke patients next to a loss of
excitable neural tissue, a change of neural connectivity
between ipsilesional M1 and the cortical motor network may be an additional factor for the lack of improvement. Within this context, several studies put forward that a “homeostatic plasticity mechanism” adjusts
the magnitude and direction of synaptic connectivity
dependent on the recent history of postsynaptic activity
to stabilize corticospinal excitability within a physiologically useful range.35,36 In line with the concept of homeostatic plasticity, it has been shown that the magnitude and direction of rTMS-induced aftereffects
depend on the state of cortical excitability.37,38 The
gamma-aminobutyric acid (GABA)-ergic intracortical
inhibition is typically suppressed in cortical stroke,11,12
and a consecutive downregulation of GABAA receptors
has been observed for both the ipsi- and contralesional
hemispheres.39,40 The loss of GABA-ergic intracortical
inhibition has been described to be associated with an
enhancement of glutamatergic activity in the immediate neighborhood of a cortical stroke.41,42 Such mechanisms may play a role in the lack of rTMS-induced
behavioral improvement (6 of 13 patients) or even deterioration (7 of 13 patients) of motor function of the
affected hand and divergent modulation of neural activity in cortical stroke.
Two of the 16 subcortical stroke subjects did not
respond to 10Hz rTMS applied over ipsilesional M1.
In one of the two nonresponders, a marked degeneration of the corticospinal tract was evident in structural
MRI, suggesting significant functional disconnection
with the spinal motor neuron pool. However, MRI
scans did not reveal similar corticospinal degeneration
in the second patient with subcortical stroke not responding to rTMS. Rather, the clinical hand motor
dysfunction in this patient resulted primarily from a
somatosensory deficit. It is well conceivable that given
the marginal motor impairment of the affected hand, a
significant rTMS effect should not have been expected
(Table 1; Patient 21).
At the neural level, subcortical stroke patients
showed a clear reduction of neural activity in the contralesional hemisphere for movements of the affected
hand after facilitatory rTMS, which has been shown to
correlate with motor recovery after stroke.16,43,44 The
global increase in neural activity in a number of frontal
and parietal motor areas (clearly differing from a physiological neural activation pattern) induced by facilitatory rTMS applied over ipsilesional M1 in patients
with additional cortical stroke could represent mechanisms that attempt to counteract the disturbing effect
evoked by rTMS itself. Alternatively, an increase in
neural activity might also result from a pathological
propagation of enhanced, but unphysiological, cortical
motor network excitability. Both hypotheses would be
compatible with the finding that the strength of ipsilesional M1 activation, which depends at least in part on
the integrity of the motor network, was highly correlated with the subsequent rTMS effect on motor behavior of the affected hand. Earlier TMS-fMRI studies
frequently demonstrated that stimulation of M1 may
increase BOLD activity in areas interconnected with
M1, such as SMA and lateral premotor cortex.30,45
Hence, applying rTMS over ipsilesional M1 not only
modulates cortical excitability of the cortex underneath
the stimulation coil, but also interacts with remote areas interconnected with the stimulation site. This hypothesis is in good accordance with our finding that an
intact M1 is a crucial prerequisite for the facilitatory
Ameli et al: Differential rTMS Effects in Stroke
307
effects of rTMS to be propagated throughout the
whole motor network.
Earlier studies have shown that the excitability of the
ipsilesional M1 and the distribution of neural activation change over time from stroke.43,44,46 We accounted for such confounding effects by using “time
from stroke” as a covariate to the imaging data. Nevertheless, the combined investigation of subacute and
chronic stroke patients (see time from stroke in Table
1) may be a limitation of our study. Relevant differences in the time from stroke within the study population may be associated with confounding factors,
such as the amount of restoration of brain tissue homeostasis, active participation in a rehabilitation program, and intake of medication, which, among others,
could influence cortical excitability of the ipsilesional
M1 and, consequently, the individual response to facilitatory rTMS. Future studies should address this issue by a thorough age-stratification of the study cohort
under investigation.
The concept of interhemispheric competition offers
two different strategies to rebalance the disturbed equilibrium of cortical excitability within the motor areas
of both hemispheres: upregulation of excitability in the
M1 of the lesioned hemisphere, under investigation
here, and downregulation of excitability in the M1 of
the contralesional hemisphere.47 Our data speak for a
detailed extension of the concept of interhemispheric
competition as a theoretical framework to test for the
effectiveness of noninvasive neuromodulation. Functional imaging studies,34,46 as well as electrophysiological examination of intracortical inhibition and interhemispheric inhibition,18,19 have shown that the
location and distribution of a stroke significantly impacts the disequilibrium of excitability within motor
areas of both hemispheres. Future research addressing
the relation between stroke-induced changes in neural
activation and interhemispheric balance, the exact
stroke location, and rTMS-induced changes in neural
activity and behavior is needed to unravel the myths of
maladaptive changes in cortical excitability and connectivity after stroke. The current data suggest that a multimodal approach combining behavioral testing with
fMRI may help to evaluate the impact of lesion location and distribution on the motor cortical network
pathology and the response to rTMS treatment after
stroke. Neural activity in ipsilesional M1 for movements of the affected hand after stroke may be used as
a functional surrogate marker to predict a prospective
improvement of motor function induced by facilitatory
rTMS applied over the ipsilesional M1. This may allow
for an individual selection of patients most suited for
facilitatory rTMS procedures.
This study was supported by grants of the Köln Fortune Stiftung,
the Deutsche Forschungsgemeinschaft (DFG NO 737/5-1) to
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September 2009
D.A.N., and the Bundesministerium für Biklung und Forschung
(BMBF; 01GO0509) to G.R.F.
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