Upper Limb Recovery After Stroke Is Associated With Ipsilesional Primary Motor Cortical Activity A Meta-Analysis Isabelle Favre, MD; Thomas A. Zeffiro, MD, PhD; Olivier Detante, MD, PhD; Alexandre Krainik, MD, PhD; Marc Hommel, MD; Assia Jaillard, MD, PhD Background and Purpose—Although neuroimaging studies have revealed specific patterns of reorganization in the sensorimotor control network after stroke, their role in recovery remains unsettled. To review the existing evidence systematically, we performed activation likelihood estimation meta-analysis of functional neuroimaging studies investigating upper limb movement-related brain activity after stroke. Methods—Twenty-four studies using sensorimotor tasks in standardized coordinates were included, totaling 255 patients and 145 healthy controls. Across the entire brain, we compared task-related activity patterns in good and poor recovery and assessed the magnitude of spatial shifts in sensorimotor activity in cortical motor areas after stroke. Results—When compared with healthy controls, patients showed higher activation likelihood estimation values in contralesional primary motor soon after stroke that abated with time, but were not related to motor outcome. The observed activity changes were consistent with restoration of typical interhemispheric balance. In contrast, activation likelihood estimation values in ipsilesional medial-premotor and primary motor cortex were associated with good outcome, reorganization that may reflect vicarious processes associated with ventral activity shifts from BA4a to 4p. In the anterior cerebellum, a novel finding was the association of poor recovery with increased vermal activity, possibly reflecting behaviorally inadequate compensatory strategies engaging the fastigio-thalamo-cortical and corticoreticulospinal systems. Conclusions—Activity in ipsilesional primary motor and medial-premotor cortices in chronic stroke signals good motor recovery, whereas cerebellar vermis activity signals poor recovery. Functional MRI may be useful in identifying recovery biomarkers. (Stroke. 2014;45:1077-1083.) Key Words: biomarkers ◼ functional neuroimaging ◼ magnetic resonance imaging ◼ motor cortex ◼ positron-emission tomography
S
ensorimotor deficits after stroke are common and disabling contributors to global functional impairment. Moreover, at the time of the stroke, it is difficult to make accurate prognostic assessments on eventual motor recovery. Although the extent and degree of performance impairment in the subacute period after stroke provide useful information in forming predictions about recovery, the clinical assessment of sensorimotor performance used in forming these predictions is subjective, complex, and time intensive, suggesting that discovery and characterization of biomarkers, predicting either the course of recovery or response to specific therapies, would be of great clinical use.1 Functional neuroimaging allows rapid assessment of the neural mechanisms associated with stroke recovery,2,3 suggesting that sensorimotor neural activity measured noninvasively with functional MRI (fMRI) could be used to identify potential surrogate end points predicting recovery.
Although the empirical findings related to neural activity changes after stroke have been complex and sometimes contradictory, 2 related mechanisms have been advanced to explain sensorimotor recovery after stroke. In the first theory, behavioral recovery is supported by a sensorimotor network in the lesioned hemisphere, including medialpremotor (medial-PMC), lateral premotor (lateral-PMC), primary motor (MI), and primary somatosensory (SI) cortices.4–7 A second hypothesis posits that reorganization in the undamaged contralesional hemisphere supports motor recovery.8–10 Studies in support of this theory have shown that recovery of motor performance after unilateral stroke is associated with greater activity in contralesional MI and dorsolateral-PMC.10,11 Establishing a role of fMRI as a biomarker of motor recovery will require sensitive, specific, and efficient measurement
Received August 12, 2013; final revision received January 7, 2014; accepted January 14, 2014. From the Unité Neurovasculaire, Pôle Psychiatrie-Neurologie (I.F., O.D.), Unité IRM, Pôle Radiologie (A.K.), Unité IRM 3T Recherche IRMaGe - Inserm US17/CNRS UMS 3552 (A.K., A.J.), and Pôle Recherche (M.H., A.J.), CHU de Grenoble, Grenoble, France; and Neural Systems Group, Massachusetts General Hospital, Charlestown (T.A.Z.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 113.003168/-/DC1. Correspondence to Assia Jaillard, MD, PhD, Unité IRM 3T—Recherche CHU Grenoble CS 10217, 38043 Grenoble Cedex 9, France. E-mail [email protected] © 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.003168
Downloaded from http://stroke.ahajournals.org/ at BIBLIOTHEQUE DE L'UNIV LAVAL on December 1, 2014 1077
1078 Stroke April 2014 of sensorimotor neural activity.1 Identifying the specific neuroanatomical targets useful for assessment of stroke recovery involves overcoming the limitations of functional neuroimaging studies with respect to their capacity to include large samples of patients with homogeneous lesions, characteristics that would result in higher and more reliable detection sensitivity.2 One approach to this problem involves the use of quantitative neuroimaging meta-analysis, a technique that combines results from many studies and thereby has more power to detect subtle effects that may be difficult to identify in individual studies.12 Meta-analysis offers a principled and efficient procedure for dealing with sometimes inconstant results among studies jointly characterized by small sample sizes, variable times between stroke and study entry, diverse stroke locations, varying degrees of sensorimotor impairment, sensorimotor task variations, and different fMRI acquisition techniques. A recent quantitative coordinate-based activation likelihood estimation (ALE) meta-analysis suggested that a return to typical task-related activity spatial patterns constitutes a key process in effective functional recovery after stroke. Evidence in support of this conclusion was that less impaired patients showed higher activity not only in ipsilesional-MI and contralesional cerebellum but also in the contralesional hemisphere in the dorsolateral-PMC, anteromedial-PMC, and secondary somatosensory cortex, suggesting that fuller motor recovery might be dependent on contributions from several cortical systems in both hemispheres.13 However, many of these recovery-related effects were statistically weak not surviving family-wise error critical threshold correction. Furthermore, the meta-analysis included data from duplicate patients from 7 of the 36 included publications, possibly resulting in selection bias as a consequence of overweighting the contributions of the duplicated patients. In addition, between-group effects were estimated using foci computed from between-group contrasts reported in the individual studies rather than performing the between-group contrast at the meta-analysis level in a way that would allow direct group comparisons. Including only studies reporting results of between-group comparisons could introduce a false-positive bias because studies showing between-group differences are much more likely to be reported than those that show no significant differences.14 Finally, subsequent studies have appeared, including larger numbers of patients and associated outcome data15,16 and personal communication (A. Jaillard et al, unpublished data, 2014). The above considerations motivated a re-examination of the existing data on stroke recovery designed to avoid the described limitations. Therefore, we performed an ALE metaanalysis based on a selective and systematic review of the literature, including data from recent studies, with the goal of identifying robust fMRI predictors of motor recovery that might be useful in clinical research and practice. In our meta-analysis, we sought to (1) characterize sensorimotor system activity changes related to stroke, (2) describe how poststroke delay influences task-related sensorimotor activity patterns in patients with stroke, (3) determine which sensorimotor areas were associated with good or bad behavioral outcome 6 months after stroke, (4) determine if stroke
induces spatial shifts in ipsilesional sensorimotor cortical activity, and (5) determine whether these effects are present in a subset of patients with pure subcortical lesions sparing the overlying sensorimotor cortices, as ischemic lesions extending to the cortex could affect accurate identification of cortical activity patterns.17
Methods
The experimental methods are described in more detail in the Materials in the online-only Data Supplement. We selected functional neuroimaging studies published from January 1995 to April 2012, investigating upper limb movements and motor recovery after stroke using fMRI or positron-emission tomography. Studies were selected by searching the PubMed database (www.pubmed.org) using 5 keywords: stroke, fMRI, PET, recovery, and motor. Thirty-four studies met our inclusion criteria: (1) patients assessed at acute, subacute, or chronic stages and having motor impairments of the upper limb with partial or complete recovery, (2) a sample size exceeding 5, (3) the use of active or passive sensorimotor tasks involving the upper limb, (4) neuroimaging using positron-emission tomography or fMRI, and (5) voxel-wise whole brain analysis. The time after stroke was divided into 2 categories: 155 subjects were included in the acute group (stroke delay 3 months; second time-point). Thirty-two subjects with a delay after stroke between 35 days and 3 months were included only in the global analysis (Figure I in the online-only Data Supplement). Next, duplicate results arising from incorporation of the same fMRI data in multiple studies were excluded, resulting in the 25 remaining studies listed in Table I in the online-only Data Supplement. As we included studies with lesions affecting both right and left hemispheres, when the right hemisphere was affected the x coordinates were flipped about the y axis. Therefore, the left hemisphere corresponded to the affected hemisphere and the right limb corresponded to the affected limb for all contrasts included in the meta-analysis. We then performed a voxel-based ALE meta-analysis using GingerALE 2.1 (http://www.brainmap.org).12,18 Five related model families were run to examine task-related (1) effects related to between-group differences in the healthy and total patient group with stroke, (2) effects of time after stroke, (3) effects of behavioral outcome, (4) spatial shifts in activity compared between stroke and healthy groups, and (5) effect differences with respect to subcortical stroke location. In addition, passive and active sensorimotor tasks were compared among the patient and healthy groups. Time after stroke was divided into 2 categories: an acute group (poststroke delay 3 months). To avoid duplication, data from each patient were assigned to only 1 temporal category. As functional outcome was assessed using a variety of research scales assessing upper limb functional impairment, sensorimotor outcome measures were recoded and then used to split the sample into 2 subgroups, corresponding to good and bad recovery by 2 neurologists with expertise in stroke research. Good outcome or recovery was defined as National Institutes of Health Stroke Scale 40, Barthel Index >90, European Stroke Scale ≥85, Motricity Index-Upper-Limb >80, Ashworth Scale ≤2, Upper-Limb-Motor Assessment Scale >13, or modified Rankin Scale ≤2. The relationship between sensorimotor activity and behavioral outcome was only assessed at the chronic stage because outcome is rarely reported in acute stage studies. We analyzed spatial differences between control and patient groups with stroke in ipsilesional-MI and medial-PMC sensorimotor activity related to active movement tasks. The Montreal Neurological Institute coordinates of task-related activity maxima were obtained for each experimental contrast. Using t tests, we compared MI and medial-PMC maxima locations among the total stroke, subcortical stroke, and healthy groups. In addition, we explored effects of motor recovery in the chronic stroke group using outcome as a factor in an ANOVA with size and number of maxima as nuisance variables. Statistical analyses of spatial shifts in ALE value peaks were performed with SPSS (version 11.5) using a critical threshold of P1322 and the modified Rankin Score≤2.23 For more details about these scales, go to http://www.strokecenter.org/professionals/stroke-diagnosis/stroke-assessment-scales/. 2
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The relationship between motor activity and behavioral outcome was assessed only at the chronic stage, because outcome was reported at the acute stage in very few studies. To examine the effect of motor task type on activity, we ran separate analyses comparing the active and passive tasks. When subjects were duplicated, we selected the earliest scan for the first time-point. Comparison between groups was based on subtraction analysis. Since the nature of the sensorimotor task can influence the spatial pattern of activity, only studies including an active movement condition were included in the group comparisons. Maps reflected regions of convergence both within- and between-groups, using maxima drawn from all three processing domains. 3. Analyses of activity spatial changes We analyzed shifts in activity related to movements of the affected hand between controls and stroke patients within primary sensorimotor cortex and medial-PMC. First, MNI coordinates obtained for each study in the patient group for each spatial axis (x,y,z) at each time were recorded. Then a univariate GLM (one-way ANOVA) was performed using SPSS 11.5.24 To determine whether the peak coordinates were normally distributed for each group we used the Kolmogorov–Smirnov test (K–S test). Homogeneity of variance was tested using Levene's Test for Equality of Variances. We tested sample sizes and age as covariates to control for effects that could influence the dependent ‘peak coordinates’ variable. When more than two groups for the independent variable were assessed, we performed post-hoc tests (such as the LSD test) that compared individual group results. A critical threshold of p< 0.05 was used. We tested the effect of recovery on the M1 and on the medial-PMC shifts in the chronic stroke patients using the same procedure.
3
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SUPPLEMENTAL TABLES Table I. Studies included in the ALE meta-analysis Study
Stroke Patients Foci
Askim, 20098 "
12 (session 1) 12 (session 2)
17 11
/ /
/ /
MRI 1,5 MRI 1.5
Active Active
Self-paced, thumb-index finger opposition Self-paced, thumb-index finger opposition
Butefish, 200525
5
12
9
14
MRI 1,5
Active
Visually-paced, 1 Hz, thumb opposing the other fingers
Calautti, 20012
5 (session 1)
13
/
/
PET
Active
" Calautti, 200726
5 (session 2) 19
10 5
/ /
/ /
MRI 1.5 PET
Active Active
Auditory-paced, 1,26 Hz, thumb-index finger opposition All stages " Chronic Auditory-paced, 1,26 Hz, thumb-index finger opposition Chronic
Carey, 200627
9 (session 1)
4
10
3
PET
Active
Self-paced, index-tapping
Acute
"
5 (session 2)
3
/
/
PET
Active
Self-paced, index-tapping
Chronic
"
4 (session 2)
3
/
/
PET
Active
Self-paced, index-tapping
Chronic
6 (session 1)
6
/
/
MRI 1,5
Passive
Wrist flexion-extension, 1Hz
7 (session 2) 7 (session 2)
4 5
/ /
/ /
MRI 1.5 MRI 1.5
Passive Passive
Wrist flexion-extension, 1Hz Wrist flexion-extension, 1Hz
Jaillard, 200529 " Jaillard (in prep) " Lindberg, 200730 Lindberg, 200931 Lotze,` 20123
4 (session 1) 4 (session 2) 19 (session 1) 19 (session 2) 7 / 14
5 5 9 7 9 / 7
12 12 44 / 6 12 /
3 3 7 / 9 24 /
MRI 1,5 MRI 1,5 MRI 1,5 MRI 1.5 MRI 1,5 MRI 1,5
Active Active Active Active Passive Passive Active
Loubinoux, 200332 "
9 (session 1) 9 (session 2)
8 7
/ /
/ /
MRI 1,5 MRI 1.5
Dechaumont, 200828 " "
Controls Foci Imaging
MRI 1,5
Condition
Passive Passive
Task
Stage Acute Chronic Acute
Acute
Acute Sub. Self-paced, 1.33 Hz, thumb opposing the other fingers Acute Self-paced, 1.33 Hz, thumb opposing the other fingers Chronic Self-paced, sequential finger tapping Acute Self-paced, sequential finger tapping Chronic Wrist flexion-extension, 0,25 Hz Chronic Wrist flexion-extension, 0,25 Hz / Auditory-paced, fist clenching around a rubber ball, 1 Chronic Hz Wrist flexion-extension, 1 Hz Acute Wrist flexion-extension, 1 Hz Sub.
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
Luft, 200433 " Marshall, 200934 Nelles, 201135
STROKE 2014
9 (cortical) 11 (subcortical) 23 10 (session 1)
7 21 7 4
8 / / /
7 / / /
"
5 (session 2)
3
/
/
PET
Act+pass
0,5 Hz, elbow flexion-extension
Chronic
"
5 (session 2)
7
/
/
PET
Act+pass
0,5 Hz, elbow flexion-extension
Chronic
10 (session 1)
4
5
6
PET
Passive
0,5 Hz, elbow flexion-extension
Acute
"
5 (session 2)
3
/
/
PET
Passive
0,5 Hz, elbow flexion-extension
Sub.
"
5 (session 2)
9
/
/
PET
Passive
0,5 Hz, elbow flexion-extension
Sub.
6 (session 1)
6
3
8
PET
Passive
0,5 Hz, elbow flexion-extension
Acute
6 (session 2)
4
/
PET
Passive
0,5 Hz, elbow flexion-extension
Sub.
Nelles, 200136
Nelles, 199911 " Pariente, 2001
37
MRI 1,5 MRI 1 MRI 1,5 PET
Active Active Active Passive
Auditory-paced, 0,3 Hz, elbow flexion-extension Chronic Auditory-paced, 0,3 Hz, elbow flexion-extension Chronic Auditory-paced, 1 Hz, hand flexion-extension Acute 0,5 Hz, elbow flexion-extension Acute
8
9
/
/
MRI 1.5
Active
Auditory-paced, 1 Hz, hand flexion-extension
Acute
Rehme, 201138
11
9
15
16
MRI 3,0
Active
Visually-paced, 1 Hz, whole hand - fist closures
Acute
Riecker, 201039
8
5
8
4
MRI 1,5
Active
Auditory-paced FT, 2 to 6 Hz
Chronic
6
/
Active
Self-paced, finger-tapping
All stage
8
17
8
Active
Auditory-paced, 1 Hz, thumb-index finger opposition
All stage
Active
Auditory-paced, index-tapping
Chronic
Active Act+ pass Act+ pass
Auditory-paced, 1 Hz, hand flexion-extension
Acute
Auditory-paced, 1 Hz, hand flexion-extension
Acute
Auditory-paced, 1 Hz, hand flexion-extension
Chronic
Seitz, 1998
40
7
PET
Sharma, 200912
12
Struppler, 200741
8
8
/
/
8
4
/
/
MRI 1,5
13
8
12
MRI 1,5
9
/
/
MRI 1.5
Tardy, 2006
42 43
Tombari, 2004 "
8 (session 1) 8 (session 2)
MRI 3,0 PET
Twenty four studies were included. The term ‘foci’ refers to the three-dimensional coordinates of the active areas reported. In each study, one or more sets of foci can be reported. A patient can have one or more fMRI/ PET sessions in longitudinal studies and therefore be included in both acute and chronic groups. For more details on motor task and stroke staging (see Methods).
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table II. Stroke patient characteristics Study
Stroke Lesion side Lesion location patients
Mean age ± SD (y)
Sex
Askim,2009 8
12
5R, 7L
cortical (2)/subcortical (10)
67.2 ± 4.9
9M, 3W
Butefish, 200525
5
3R, 2L
cortical (2) /subcortical (2) /combined (1)
54.2 ± 11.4
1M, 4W
Calautti, 20012
5
0R, 5L
subcortical(5)
59.2 ± 13
4M, 1 W
Calautti, 200726
19
14R, 5L
Cortical (2)/subcortical (17)
61 ± 10
14M, 5W
Carey, 200627
9
4R, 5L
Cortical (3)/subcortical (6)
72 ± 9.8
7M, 2W
Dechaumont, 200828
6
4R, 2L
Subcortical (6)
58.8 ± 8
4M, 2W
Dechaumont, 200828
7
4R, 3L
Subcortical (7)
64 ± 12
4M, 3W
Jaillard (in prep)
19
7R, 12L
subcortical(19)
47.8 ± 16.3
15M, 4W
Jaillard, 200529
4
4L
Cortical (4)
61.3 ± 9.7
3M, 1W
Lindberg, 200730
7
2R, 5L
subcortical (6) /cortical (1)
59.4 ± 7.4
7M, 0W
Lotze, 20123
14
7R, 7L
Subcortical (14)
58 ± 14.4
10M, 4W
Loubinoux, 200332
9
5R, 4L
Subcortical (9)
59 ± 7
5M, 4W
Luft, 200433
20
11R, 9L
Subcortical (11)/cortical (9)
62 ± 9
11M, 9W
Marshall, 200934
23
12 R, 11 L
Subcortical (16)/cortical (3) /combined (4)
59 ± 10.5
16M, 7W
Nelles, 200136
5
4R, 1L
Subcortical (5)
68 ± 3.6
3M, 2W
Nelles, 200136
5
3R, 2L
Subcortical (5)
63 ± 3
3M, 1W
Nelles, 199911
6
2R, 4L
Subcortical (6)
62 ± 9.4
4M, 2W
Nelles, 201135
5
2R, 3L
Subcortical (5)
54-85
4M, 1W
Nelles, 201135
5
4R, 1L
Subcortical (5)
48-78
2M, 3W
Pariente, 200137
8
3R, 5L
Subcortical (8)
61.7 ± 11.1
5M, 3W
Rheme, 201138
11
7R, 4L
cortical (3)/subcortical (8)
65 ± 10
7M, 4W
Seitz, 199840
8
0R, 8L
subcortical(8)
58,9 ± ,8
4M, 4W
Sharma, 200912
7
5R, 2L
Cortical (7)
53,9 ± 8
6M, 1W
Struppler, 200741
12
4R, 8L
Subcortical (12)
66 ± 8,8
6M, 6W
Tardy, 200642
8
4R, 4L
Subcortical (8)
55 ± 8
6M, 2W
Tombari, 200443
8
4R, 4L
Subcortical (8)
60.5 ±9,4
8M, 0W
Riecker, 201039
8
3R, 5L
Subcortical (8)
62 ± 11
5M, 3W
6
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Stroke vs. Healthy Control Group Effects Table III. ALE-maxima MNI coordinates for stroke patients. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIA) Region
Side
Precentral gyrus Medial sup. frontal gyrus Medial sup. frontal gyrus Cingulate gyrus Inferior parietal lobule Postcentral gyrus Middle cerebellar peduncle Superior temporal gyrus Precentral gyrus Inferior parietal lobule Insula Inferior parietal lobule Cerebellum lobule V Vermis lobule IV-V Supramarginal gyrus Insula Inferior frontal gyrus
L L L L L L L L R R R R R R R R R
BA 4 6 6 24 40 2 22 4 40 13 40 40 13 44
ALE Value 522 345 270 118 156 99 131 123 225 167 151 145 224 104 137 122 115
x -34 2 -4 -4 -50 -42 -22 -54 42 50 54 52 16 2 64 36 54
y -24 -4 -14 -20 -28 -18 -40 6 -8 -30 -34 -30 -54 -60 -40 0 6
z 56 52 56 36 28 30 -34 6 56 28 20 40 -22 -18 34 0 16
Table IV. ALE-maxima MNI coordinates for healthy subjects. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIB) Region Precentral gyrus Precentral gyrus Medial sup. frontal gyrus Medial sup. frontal gyrus Insula Pre-motor cortex Cerebellum lobule V Cerebellum lobule V Thalamus VPL nucleus Insula Cerebellum lobule V Cingulate gyrus Cerebellum lobule IV-V Postcentral gyrus Inferior parietal lobule
Side L L L L L L L L L R R R R R R
BA 4 4 6 6 13 6 13 32 2 40
ALE Value 248 201 226 85 138 120 100 87 100 184 203 120 135 95 94
x -36 -38 0 -4 -50 -52 -26 -36 -16 60 18 4 6 56 52
y -16 -12 4 -6 -22 -4 -56 -58 -18 -30 -48 16 -62 -20 -26
z 60 54 58 68 24 40 -24 -26 0 22 -20 42 -14 42 46
7
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table V. ALE-maxima MNI coordinates for the contrast stroke patients > healthy subjects. Affected upper limb versus rest contrast. FDR pID 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
ALE Value
x
y
z
Precentral gyrus
L
3
2.07
-26
-28
48
Precentral gyrus
L
4
2.05
-28
-26
52
Postcentral gyrus
L
3
2.12
-48
-20
42
Postcentral gyrus
L
2
1.92
-48
-20
52
Medial sup. frontal gyrus
R
6
3.036
4
-20
50
Medial sup. frontal gyrus
R
6
2.89
6
-16
50
Cingulate gyrus
R
23
2.70
10
-22
36
Cingulate gyrus
R
31
3.54
17
-23
46
Precentral gyrus
R
6
3.35
18
-22
50
Paracentral lobule
R
5
2.82
20
-30
50
Precentral gyrus
R
4
2.09
26
-22
52
Table VI. ALE-maxima MNI coordinates for the contrast healthy subjects > stroke patients. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Side
BA
ALE Value
x
Precentral gyrus
L
6
3.89
-27
-13.5
69.5
Precentral gyrus
L
4
3.54
-28
-16
74
Precentral gyrus
L
4
2.75
-34
-10
52
Precentral gyrus
L
4
2.13
-42
-16
62
Medial sup. frontal gyrus
L
6
2.85
-2
-2
62
Medial sup. frontal gyrus
L
6
2.72
0
0
66
Inferior parietal lobule
L
40
3.72
-62
-22.67
24.67
Inferior parietal lobule
L
40
2.32
-47
-24
20
Sup. temporal gyrus
L
41
2.29
-48
-26
16
Cerebellum lobule VI
L
-
2.76
-32
-55
-26
Cerebellum lobule VI
L
-
2.71
-30
-56
-22
Cerebellum lobule VI
L
-
2.57
-26
-58
-25
Cerebellum lobule VIIa
L
-
1.90
-38
-59
-30
Precentral gyrus
L
6
2.67
-56
2
40
Precentral gyrus
L
4
1.99
-56
-10
36
Precentral gyrus
L
4
1.93
-58
-6
36
Medial sup. frontal gyrus
R
6
2.37
6
-6
74
Inferior parietal lobule
R
40
3.54
63
-31
21
Cingulate gyrus
R
32
2.62
10
14
40
Cingulate gyrus
R
24
2.62
8
10
42
Cingulate gyrus
R
32
2.29
6
16
46
Cerebellum lobule V
R
-
2.89
17
-43
-15
Region
y
z
8
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Acute and Chronic Stage Effects
Table VII. ALE-maxima MNI coordinates for the acute stroke patients. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIIA) Region
Side
BA
Ale Value
x
y
z
Cerebellum lobule V
L
-
93
-24
-42
-34
Cingulate gyrus
L
24
88
-2
-2
42
Insula
L
13
80
-52
-40
26
Parietal inferior lobule
L
40
95
-50
-30
28
Postcentral gyrus
L
2
95
-42
-18
32
Precentral gyrus
L
4
233
-34
-24
54
Cingulate gyrus
L
6
83
-4
-20
46
Cerebellum lobule V
R
-
127
18
-50
-28
Cerebellum lobule V
R
-
80
14
-54
-20
Medial sup. frontal gyrus
R
6
180
2
-4
52
Parietal inferior lobule
R
40
112
50
-30
30
Precentral gyrus
R
4
100
38
-10
52
Table VIII. ALE-maxima MNI coordinates for the chronic stroke subjects. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIIB) Region
Side
BA
Ale Value
x
y
z
Vermis lobule IV-V
L
-
90
0
-60
-14
Frontal operculum
L
44
110
-52
6
6
Medial sup. frontal gyrus
L
6
193
-4
-14
58
Postcentral gyrus
L
3
213
-44
-16
52
Precentral gyrus
L
4
275
-36
-20
56
Cerebellum lobule V
R
-
145
16
-56
-22
Insula
R
13
93
54
-34
22
Medial sup. frontal gyrus
R
6
157
2
-2
54
Premotor cortex
R
6
129
42
-6
58
Thalamus VL nucleus
R
-
88
10
-12
10
9
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table IX. ALE-maxima MNI coordinates for the contrast acute > chronic stroke patients. Affected upper limb (active tasks) versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected cluster level. (Figure IIIC) Region
Side
Precentral gyrus Precentral gyrus Postcentral gyrus Postcentral gyrus Cerebellum lobule VI Postcentral gyrus Postcentral gyrus Postcentral gyrus Middle Frontal gyrus Precentral gyrus Precentral gyrus Middle Frontal gyrus Middle cerebellar peduncle Cerebellum lobule VI Cerebellum lobule VI Cerebellum lobule V Inferior parietal lobule Inferior parietal lobule
BA
L L L L L L L L R R R R R R R R R R
6 6 2 2 3 2 2 6 6 6 6 40 40
Ale Value 2.29 2.05 2.05 1.99 2.10 1.89 1.72 1.71 2.83 2.73 2.73 2.52 1.82 1.75 1.75 1.74 1.94 1.90
x -46 -42 -45 -40 -32 -32 -38 -40 32 38 38 26 16 24 22 22 36 39.33
y -8 -9 -16 -20 -50 -22 -24 -24 -4 -4 -8 -2 -44 -50 -48 -44 -46 -44
z 32 30 30 32 -18 44 40 46 42 38 38 42 -30 -32 -32 -26 42 41
Table X. ALE-maxima MNI coordinates for the differential contrast chronic > acute stroke patients. Affected upper limb (active tasks) versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level (Figure IIIC). Region Side BA Ale Value x y z
Precentral gyrus
L
4
2.09
-46
-18
54
Precentral gyrus
L
4
2.01
-40
-18
56
Behavioral Outcome Effects
Table XI. ALE-maxima MNI coordinates for the stroke patients with good outcome. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure 1A) Ale Value (10-4) Region
Side
BA
x
y
z
Medial sup. frontal gyrus
L
6
148
2
-2
54
Medial sup. frontal gyrus
L
6
115
-4
-14
56
Precentral gyrus
L
4
251
-36
-20
56
Cerebellum lobule V
R
-
145
16
-56
-22
Inferior parietal lobule
R
40
103
52
-30
42
Precentral gyrus
R
6
126
42
-6
58
10
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table XII. ALE-maxima MNI coordinates for the stroke subjects with bad outcome (Figure 1B). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Ale Value (10-4) Region Thalamus VPL
Side L
BA -
70
x -19
y -21
z 0
Vermis lobule IV-V
L
-
78
0
-60
-12
Vermis lobule IV-V
L
-
87
-10
-60
-8
Postcentral gyrus
L
40
98
-36
-30
60
Cingulate gyrus
L
24
68
0
-38
20
Premotor cortex
L
6
95
-2
-14
58
Thalamus, VPL
R
-
70
19
-23
0
Table XIII. ALE-maxima MNI coordinates for the contrast good recovery > bad recovery (Figure 1C). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Precentral gyrus
L
4
Precentral gyrus
L
Precentral gyrus
Ale Value
x
y
z
2.71
-36
-22
52
4
1.83
-38
-14
46
L
4
1.78
-40
-14
50
Cingulate gyrus
L
24
2.09
-2
-6
44
Medial sup. frontal gyrus
L
6
2.07
-2
-6
50
Medial sup. frontal gyrus
L
6
2.03
-4
-4
54
Cingulate gyrus
L
24
1.78
-10
-2
50
Cingulate gyrus
L
24
1.76
-10
-4
44
Cingulate gyrus
L
24
1.75
-5
3
45
Table XIV. ALE-maxima MNI coordinates for the contrast bad > good recovery (Figure 1D). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Ale Value
x
y
z
Brainstem
R
-
2.29
30
-15
-8
Thalamus VPL
R
-
1.88
19
-23
0
Vermis lobule IV-V
L
-
1.93
-5
-62
-6
Cerebellum lobule VI
L
-
1.93
-17
-74
-13
11
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Subcortical Lesion Location Effects Table XV. ALE-maxima MNI coordinates for all subcortical stroke patients (Figure VA). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Ale Value
Precentral gyrus
L
4
439
Medial Sup. Frontal gyrus
L
6
276
Cingulate gyrus
L
31
118
Cingulate gyrus
L
24
117
Cingulate gyrus
L
31
103
Insula
L
13
156
x
y
z
-34
-22
56
0
0
52
-2
-18
48
-4
-20
36
-6
-22
42
-50
-28
28
Superior temporal gyrus
L
22
89
-48
-18
20
Inferior parietal lobule
L
40
122
-54
6
6
Inferior parietal lobule
R
40
166
50
-30
28
Inferior parietal lobule
R
40
144
52
-30
40
Inferior parietal lobule
R
40
137
64
-40
34
Postcentral gyrus
R
2
102
60
-24
36
Postcentral gyrus
R
2
102
64
-16
34
Precentral gyrus
R
4
125
38
-16
54
Precentral gyrus
R
6
120
44
-4
58
Vermis lobule IV-V
R
-
103
2
-60
-18
Cerebellum lobule V
R
-
113
18
-54
-20
Precentral gyrus
R
9
101
42
12
32
Cingulate gyrus
R
31
101
26
-36
44
Table XVI. ALE maxima MNI coordinates for the contrast healthy subjects > stroke subcortical patients (Figure VB). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region Side BA ALE Value x y z Precentral gyrus Precentral gyrus Precentral gyrus Postcentral gyrus Medial Sup. Frontal gyrus
L L L L L
4 6 4 3 6
3.72 3.54 2.48 2.02 2.69
-28 -24 -34 -42 -3
-19 -10 -10 -18 -2
72 71 52 62 62
Medial Sup. Frontal gyrus Medial Sup. Frontal gyrus Cerebellum lobule VI Cerebellum lobule V Cerebellum lobule VI Cerebellum lobule VI Superior temporal gyrus Precentral gyrus Medial Sup. Frontal gyrus
L L L L L R L L R
6 6 41 6 6
1.92 1.85 2.49 2.27 1.89 3.35 1.93 2.35 2.15
2 2 -30.12 -24.57 -37 20 -48 -56 8
8 12 -53.62 -58 -59.5 -62 -25 2 -8
64 60 -23.06 -22.86 -21 -22 18 40 72
Inferior parietal lobule Superior temporal gyrus
R R
40 22
3.72 3.43
68 66.94
-22 -27.88
16 16.12
12
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Inferior parietal lobule Cerebellum lobule V
R R
40 -
3.35 2.62
62 16
-28 -46
19 -22
Cerebellum lobule V Cerebellum lobule V Cingulate gyrus Medial Sup. Frontal gyrus
R R R R
32 6
2.60 2.59 2.16 2.04
17.5 16 8 6
-44.5 -44 14 18
-18 -14 40 46
Table XVII. ALE maxima of MNI coordinates for the contrast stroke subcortical patients > healthy subjects (Figure VB). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
ALE Value
x
y
z
Cingulate gyrus
L
23
2.11
0
-20
30
Cingulate gyrus
R
23
2.72
12
-20
34
Paracentral lobule
R
31
2.62
4
-20
50
Inferior parietal lobule
R
40
2.12
62
-44
36
Inferior parietal lobule
R
40
2.10
64
-42
32
Supramarginal gyrus
R
40
2.10
64
-46
32
Supramarginal gyrus
R
40
2.10
62
-40
36
Inferior parietal lobule
R
40
1.88
64
-34
38
Precentral gyrus
R
4
1.88
34
-14
42
Precentral gyrus
R
4
1.84
30
-14
48
Table XVIII. ALE-maxima MNI coordinates for the acute subcortical stroke patients. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Ale Value x y z Region Side BA Precentral gyrus
L
4
178
-36
-24
54
Inferior parietal lobule
L
40
95
-50
-30
28
Postcentral gyrus
L
2
95
-42
-18
32
Superior temporal gyrus
L
13
80
-52
-40
26
Medial Sup. Frontal gyrus
L
6
125
2
-4
52
Medial Sup. Frontal gyrus
L
6
64
-4
4
56
Cingulate gyrus
L
31
79
-6
-22
44
Inferior parietal lobule
R
40
111
50
-30
30
Precentral gyrus
R
4
80
34
-10
44
Cerebellum lobule HVIIa
R
-
88
32
-70
-32
Inferior parietal lobule
R
40
90
64
-40
34
13
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table XIX. Maxima MNI coordinates for the chronic subcortical stroke subjects. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
BA
Side
Precentral gyrus
4
L
Postcentral gyrus
3
Precentral gyrus
Ale Value
x
y
z
205
-36
-20
58
L
111
-46
-16
48
4
L
89
-44
-10
48
Medial Sup. Frontal gyrus
6
L
119
0
2
54
Vermis lobule IV-V
-
L
90
0
-60
-14
44
L
110
-52
6
6
Medial Sup. Frontal gyrus
6
L
110
-2
-14
58
Cerebellum, lobule IV
-
L
87
-10
-60
-8
Precentral gyrus
6
R
87
40
-4
58
Cerebellum lobule V-VI
-
R
109
18
-54
-20
Inferior parietal lobule
40
R
103
52
-30
42
Insula
13
R
93
54
-34
22
Precentral gyrus
Table XX. ALE-maxima MNI coordinates for the contrast acute > chronic subcortical stroke patients (Figure VC). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Side
BA
Ale Value
Inferior parietal lobule
L
40
3.72
-51.33
-28.33
32.67
Inferior parietal lobule
L
40
3.24
-54
-28
26
Inferior parietal lobule
L
40
2.82
-51.33
-38
31.33
Inferior parietal lobule
L
40
2.79
-52
-42
30
Inferior parietal lobule
L
40
2.72
-58
-42
30
Inferior parietal lobule
L
40
2.54
-54.67
-45.33
26
Insula
L
13
2.40
-46
-38
29
Postcentral gyrus
L
2
2.362
-36
-22
36
Precentral gyrus
L
4
2.03
-34
-22
46
Precentral gyrus
L
4
1.77
-44
-14
34
Inferior parietal lobule
L
40
3.29
-60
-31
34
Inferior parietal lobule
L
40
2.81
-62
-34
40
Middle frontal gyrus
R
6
2.34
20
-2
38
Region
x
y
z
14
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table XXI. ALE-maxima MNI coordinates for the contrast chronic > acute in subcortical stroke patients (Figure VC). Affected upper limb versus rest contrast. FDR pID0.05 voxel-level, FWE-corrected cluster level. Region Side BA Ale Value x y z Vermis lobule IV-V Vermis lobule IV-V
L L
-
2.19 2.10
0 -1
-57 -64
-13 -6
Vermis lobule IV-V
L
-
Cerebellum lobule IV-V
L
-
1.97
-4.57
-62.43
-13.43
1.84
-10.49
-60.28
-7.12
Precentral gyrus
L
4
2.36
-35
-14
60
Cerebellum lobule IV-V
R
-
2.73
11.63
-58.21
-7.15
Vermis lobule IV-V
R
-
2.52
4
-58
Vermis lobule IV-V
R
-
2.42
4.67
-62.89
-12.89
Cerebellum lobule IV-V
R
-
2.40
12
-54
-16
Vermis lobule IV-V
R
-
2.28
3.56
-66.22
-4.67
Cerebellum lobule V
R
-
2.13
13
-58
-20
Cerebellum lobule V
R
-
2.05
12
-52
-20
Cerebellum lobule V
R
-
1.77
21
-53
-16
Inferior frontal gyrus
R
44
2.31
53
11
12.33
Inferior frontal gyrus
R
44
1.84
56
6.4
15.2
Insula
R
13
2.34
38.46
5.85
2.92
Insula
R
13
2.31
40
8
8
Insula
R
13
2.10
42
10
4
-
-8
Active and Passive Task Comparisons
Table XXII. ALE-maxima MNI coordinates for the contrast stroke patients > healthy subjects performing an active task. Affected upper limb versus rest contrast. FDR pID0.05 voxel-level, FWE-corrected cluster level. Region
Side
BA
Ale Value
x
y
Z
Cingulate gyrus
L
31
2.49
-18
-26
42
Paracentral lobule
L
5
2.32
-12
-28
50
Medial sup. frontal gyrus
L
6
2.04
-6
-22
50
Medial sup. frontal gyrus
L
6
1.84
-2
-20
54
Cingulate gyrus
L
31
1.83
-4
-22
46
Cingulate gyrus
L
23
1.82
-6
-22
36
Cingulate gyrus
L
23
1.82
-3.71
-21.43
32
Precentral gyrus
R
4
2.11
30
-14
50
Precentral gyrus
R
6
1.83
32
-14
58
Cingulate gyrus
R
24
2.45
20
-14
40
Cingulate gyrus
R
24
2.26
24
-10
38
Cingulate gyrus
R
31
3.04
18
-22
48
Cingulate gyrus
R
31
2.85
19
-26
47
Cingulate gyrus
R
23
2.02
10
-18
34
Cingulate gyrus
R
23
1.95
9.33
-20.67
30
15
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table XXIII. ALE-maxima MNI coordinates for the contrast healthy subjects > stroke patients performing an active task. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWEcorrected at the cluster level. Region
Side
BA
Ale Value
x
y
Z
Precentral gyrus
L
4
2.95
-35
-10
53
Precentral gyrus
L
6
2.54
-28
-8
66
Precentral gyrus
L
6
2.46
-30
-10
67
Precentral gyrus
L
4
2.44
-40
-16
58
Precentral gyrus
L
4
2.06
-34
-18
66
Precentral gyrus
L
6
2.02
-30
-4
70
Precentral gyrus
L
6
2.44
-4
-2
64
Cerebellum lobule V
L
-
2.75
16
-42.4
-18.8
Cerebellum lobule VI
L
-
2.09
-27.96
-56.26
-24.4
Precentral gyrus
L
6
2.58
-56
Insula
L
13
2.07
-47.12
-25.75
21.38
Inferior parietal lobule
L
40
1.89
-53
-23
24
Superior temporal gyrus
L
41
1.82
-48
-25
16
Medial sup. frontal gyrus
R
6
2.12
4
6
58
Medial sup. frontal gyrus
R
6
2.23
6
14
46
Inferior parietal lobule
R
40
2.29
52
-38
56
Inferior parietal lobule
R
40
2.28
48
-39
54
Inferior parietal lobule
R
40
2.28
52
-42
52
Inferior parietal lobule
R
40
2.32
66
-22
26
Inferior parietal lobule
R
40
1.88
62
-28
22
2
40
16
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table XXIV. ALE-maxima MNI coordinates for the contrast active > passive task. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
BA
Side
Postcentral gyrus
3
L
Postcentral gyrus
3
Precentral gyrus
x
y
z
2.82
-42
-18
58
L
2.74
-34
-30
64
4
L
2.41
-34
-12
48
Postcentral gyrus
2
L
2.33
-42
-20
48
Cingulate gyrus
24
L
2.89
-12
-4
48
6
L
2.57
-6
-6
58
Cingulate gyrus
24
L
2.48
-14
2
44
Precentral gyrus
4
L
2.30
-48
4
48
Medial Sup. Frontal gyrus
6
R
2.26
6
-12
62
Medial Sup. Frontal gyrus
6
R
2.25
4
-8
64
Precentral gyrus
4
R
2.47
34
-16
60
Precentral gyrus
6
R
2.27
34
-8
56
Precentral gyrus
6
R
2.21
36
-6
64
Precentral gyrus
6
R
2.19
42
-12
60
Cerebellum lobule V
-
R
2.39
16
-54
-22
Cerebellum lobule V
-
R
2.17
14
-60
-18
Cerebellum lobule V
-
R
2.16
12
-54
-28
Cerebellum lobule V
-
R
2.02
12
-50
-26
Cerebellum lobule V
-
R
1.75
10
-60
-4
Medial Sup. Frontal gyrus
Ale Value
Table XXV. ALE-maxima MNI coordinates for the contrast passive > active task. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Superior temporal gyrus Cingulate gyrus
L L
41 24
Superior parietal lobule
L
Insula
Ale Value
x
y
z
3.89 1.76
-53 -24
-35 -38
28 46
7
1.71
-29
-45
45
R
13
2.68
50
-25
26
Inferior parietal Lobule
R
40
2.88
61
-46
37
Inferior parietal Lobule
R
40
2.67
62
-38
32
17
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Table XXVI. MNI coordinates for ALE-maxima in acute stage stroke patients performing an active task (n=103, 9 experiments, 85 reported foci). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxellevel, FWE-corrected at the cluster level. Region
Side
BA
Ale Value
x
y
z
Postcentral gyrus Postcentral gyrus
L L
3 3
174 106
-34 -38
-26 -20
56 46
Medial Sup. Frontal gyrus
L
6
105
-4
-2
52
Medial Sup. Frontal gyrus
L
6
101
-4
-8
50
Postcentral gyrus
L
2
90
-42
-18
32
Precentral gyrus
L
4
Cerebellum lobule V
L
Medial Sup. Frontal gyrus
R
Cerebellum lobule V
74
-44
-8
28
93
-24
-42
-34
6
100
4
-8
56
R
-
127
18
-50
-28
Cerebellum lobule V
R
-
79
14
-54
-20
Precentral gyrus
R
4
95
36
-10
50
Table XXVII. MNI coordinates for ALE-maxima in chronic stage stroke patients performing an active task (n=113, 13 experiments, 98 reported foci). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Precentral gyrus
L
4
Postcentral gyrus
L
Medial Sup. Frontal Gyrus
Ale Value (104)
x
y
z
275
-36
-20
56
3
213
-44
-16
52
L
6
193
-4
-14
58
Medial Sup. Frontal Gyrus
L
6
157
2
-2
54
Precentral gyrus
L
44
110
-52
6
6
Vermis lobule IV-V
L
-
90
0
-60
-14
Precentral gyrus
R
6
129
42
-6
58
Cerebellum lobule V
R
-
145
16
-56
-22
Inferior parietal lobule
R
40
103
52
-30
42
Insula
R
13
93
54
-34
22
18
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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SUPPLEMENTAL FIGURES
Figure I. Categorization of the included patients according to time after stroke
Session 1
Session 2
All stages (n=24) All patients (n=255)
Acute (n=151)
Subacute (n=32)
Chronic (n=76)
Chronic (n=63)
Chronic (n=139) The included patients are divided into three groups shown in the gray boxes. Three stages were utilized. In the chronic group, 63 patients were the same as those included in the acute stage group (imaging session 1 and 2 of longitudinal studies) and 76 came from additional studies.
19
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Figure II. Activity patterns for the right/affected upper limb. (A) For stroke patients at all stages (red-yellow): ‘movement tasks vs. rest’ contrast. (B) For healthy subjects (green): ‘movement tasks vs. rest’ contrast. (C) Contrast of ‘stroke patients vs. healthy controls’ (red-yellow) and ‘healthy controls vs. stroke patients’ (green). The right hemisphere is shown on the right side.
20
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Figure III. Effect of post-stroke delay in patients for the right/affected upper-limb. ‘Motor task vs. rest’ contrast at: (A) acute stage (red); (B) chronic stage (blue). (C) ‘acute vs. chronic stage’ (red) and ’chronic vs. acute stage’ (blue).
21
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Figure IV. Overlay maps of ALE maxima for the right/affected upper-limb reveal a ventral shift within primary sensorimotor cortex and a caudal shift within medial premotor cortex. ‘Motor task vs. rest’ contrast: (A) Acute stage in stroke patients (red) and healthy subjects (green). (B) Chronic stage in stroke patients (blue) and healthy subjects (green). (C-D) Both cute (red) and chronic (blue) stage in stroke patients and in healthy subjects (green); (C) Sagittal view and (D) Axial view.
22
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Figure V. Effect of subcortical lesions on activity related to right/affected upper-limb movements. ‘Motor task vs. rest’ contrast in subcortical patients: (A) All stages (red-yellow);
(B) ‘Stroke patients vs. healthy’ (yellow) and ’Healthy vs. stroke patients’ (green). (C) ‘Acute vs. chronic’ stages (red) and ‘Chronic vs. acute stages’ (blue).
23
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Figure VI. Comparison between good and bad outcome related-activity in subcortical stroke patients for right/affected upper-limb movements: ‘Good vs. bad outcome’ contrast (cyan) and ‘Bad vs. good outcome’ (pink).
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SUPPLEMENTAL REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13. 14. 15.
Calautti C, Baron JC. Functional neuroimaging studies of motor recovery after stroke in adults: A review. Stroke; a journal of cerebral circulation. 2003;34:1553-1566 Calautti C, Leroy F, Guincestre JY, Baron JC. Dynamics of motor network overactivation after striatocapsular stroke: A longitudinal pet study using a fixedperformance paradigm. Stroke; a journal of cerebral circulation. 2001;32:2534-2542 Lotze M, Beutling W, Loibl M, Domin M, Platz T, Schminke U, et al. Contralesional motor cortex activation depends on ipsilesional corticospinal tract integrity in wellrecovered subcortical stroke patients. Neurorehabil Neural Repair. 2012;26:594-603 Lotze M, Grodd W, Rodden FA, Gut E, Schonle PW, Kardatzki B, et al. Neuroimaging patterns associated with motor control in traumatic brain injury. Neurorehabil Neural Repair. 2006;20:14-23 Bestmann S, Swayne O, Blankenburg F, Ruff CC, Teo J, Weiskopf N, et al. The role of contralesional dorsal premotor cortex after stroke as studied with concurrent tmsfmri. J Neurosci. 2010;30:11926-11937 Manganotti P, Storti SF, Formaggio E, Acler M, Zoccatelli G, Pizzini FB, et al. Effect of median-nerve electrical stimulation on bold activity in acute ischemic stroke patients. Clin Neurophysiol. 2012;123:142-153 Pineiro R, Pendlebury S, Johansen-Berg H, Matthews PM. Altered hemodynamic responses in patients after subcortical stroke measured by functional mri. Stroke; a journal of cerebral circulation. 2002;33:103-109 Askim T, Indredavik B, Haberg A. Internally and externally paced finger movements differ in reorganization after acute ischemic stroke. Archives of physical medicine and rehabilitation. 2010;91:1529-1536 Calautti C, Jones PS, Naccarato M, Sharma N, Day DJ, Bullmore ET, et al. The relationship between motor deficit and primary motor cortex hemispheric activation balance after stroke: Longitudinal fmri study. Journal of neurology, neurosurgery, and psychiatry. 2010;81:788-792 Loubinoux I, Dechaumont-Palacin S, Castel-Lacanal E, De Boissezon X, Marque P, Pariente J, et al. Prognostic value of fmri in recovery of hand function in subcortical stroke patients. Cereb Cortex. 2007;17:2980-2987 Nelles G, Spiekramann G, Jueptner M, Leonhardt G, Muller S, Gerhard H, et al. Evolution of functional reorganization in hemiplegic stroke: A serial positron emission tomographic activation study. Annals of neurology. 1999;46:901-909 Sharma N, Simmons LH, Jones PS, Day DJ, Carpenter TA, Pomeroy VM, et al. Motor imagery after subcortical stroke: A functional magnetic resonance imaging study. Stroke; a journal of cerebral circulation. 2009;40:1315-1324 Wang LE, Fink GR, Diekhoff S, Rehme AK, Eickhoff SB, Grefkes C. Noradrenergic enhancement improves motor network connectivity in stroke patients. Annals of neurology. 2011;69:375-388 Rehme AK, Eickhoff SB, Wang LE, Fink GR, Grefkes C. Dynamic causal modeling of cortical activity from the acute to the chronic stage after stroke. NeuroImage. 2011;55:1147-1158 Brott T, Adams HP, Jr., Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements of acute cerebral infarction: A clinical examination scale. Stroke; a journal of cerebral circulation. 1989;20:864-870
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16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
29. 30.
31. 32.
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Fugl-Meyer AR, Jaasko L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. A method for evaluation of physical performance. Scand J Rehabil Med. 1975;7:13-31 Duncan PW, Propst M, Nelson SG. Reliability of the fugl-meyer assessment of sensorimotor recovery following cerebrovascular accident. Phys Ther. 1983;63:16061610 Mahoney FI, Barthel DW. Functional evaluation: The barthel index. Md State Med J. 1965;14:61-65 Hantson L, De Weerdt W, De Keyser J, Diener HC, Franke C, Palm R, et al. The european stroke scale. Stroke; a journal of cerebral circulation. 1994;25:2215-2219 Sunderland A, Tinson D, Bradley L, Hewer RL. Arm function after stroke. An evaluation of grip strength as a measure of recovery and a prognostic indicator. Journal of neurology, neurosurgery, and psychiatry. 1989;52:1267-1272 Bohannon RW, Smith MB. Interrater reliability of a modified ashworth scale of muscle spasticity. Phys Ther. 1987;67:206-207 Kurinnyi IM. [the quantitative assessment of functional disorders of the hand and upper limb]. Likars'ka sprava / Ministerstvo okhorony zdorov'ia Ukrainy. 1999:99105 Rankin J. Cerebral vascular accidents in patients over the age of 60. Ii. Prognosis. Scottish medical journal. 1957;2:200-215 SPSS I. Spss graduate pack 11.5 for windows. 2002 Butefisch CM, Kleiser R, Korber B, Muller K, Wittsack HJ, Homberg V, et al. Recruitment of contralesional motor cortex in stroke patients with recovery of hand function. Neurology. 2005;64:1067-1069 Calautti C, Naccarato M, Jones PS, Sharma N, Day DD, Carpenter AT, et al. The relationship between motor deficit and hemisphere activation balance after stroke: A 3t fmri study. NeuroImage. 2007;34:322-331 Carey LM, Abbott DF, Egan GF, O'Keefe GJ, Jackson GD, Bernhardt J, et al. Evolution of brain activation with good and poor motor recovery after stroke. Neurorehabil Neural Repair. 2006;20:24-41 Dechaumont-Palacin S, Marque P, De Boissezon X, Castel-Lacanal E, Carel C, Berry I, et al. Neural correlates of proprioceptive integration in the contralesional hemisphere of very impaired patients shortly after a subcortical stroke: An fmri study. Neurorehabil Neural Repair. 2008;22:154-165 Jaillard A, Delon-Martin C, Garambois K, Lebas JF, Hommel M. Vicarious function within the human primary motor cortex? A longitudinal fmri stroke study. Brain. 2005;128:1122-1138 Lindberg PG, Skejo PH, Rounis E, Nagy Z, Schmitz C, Wernegren H, et al. Wallerian degeneration of the corticofugal tracts in chronic stroke: A pilot study relating diffusion tensor imaging, transcranial magnetic stimulation, and hand function. Neurorehabil Neural Repair. 2007;21:551-560 Lindberg PG, Gaverth J, Fagergren A, Fransson P, Forssberg H, Borg J. Cortical activity in relation to velocity dependent movement resistance in the flexor muscles of the hand after stroke. Neurorehabil Neural Repair. 2009;23:800-810 Loubinoux I, Carel C, Pariente J, Dechaumont S, Albucher JF, Marque P, et al. Correlation between cerebral reorganization and motor recovery after subcortical infarcts. NeuroImage. 2003;20:2166-2180
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33. 34. 35. 36. 37. 38. 39. 40. 41.
42. 43.
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Luft AR, Buitrago MM, Ringer T, Dichgans J, Schulz JB. Motor skill learning depends on protein synthesis in motor cortex after training. J Neurosci. 2004;24:65156520 Marshall RS, Zarahn E, Alon L, Minzer B, Lazar RM, Krakauer JW. Early imaging correlates of subsequent motor recovery after stroke. Annals of neurology. 2009;65:596-602 Nelles G, Jentzen W, Bockisch A, Diener HC. Neural substrates of good and poor recovery after hemiplegic stroke: A serial pet study. Journal of neurology. 2011;258:2168-2175 Nelles G, Jentzen W, Jueptner M, Muller S, Diener HC. Arm training induced brain plasticity in stroke studied with serial positron emission tomography. NeuroImage. 2001;13:1146-1154 Pariente J, Loubinoux I, Carel C, Albucher JF, Leger A, Manelfe C, et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Annals of neurology. 2001;50:718-729 Rehme AK, Fink GR, von Cramon DY, Grefkes C. The role of the contralesional motor cortex for motor recovery in the early days after stroke assessed with longitudinal fmri. Cereb Cortex. 2011;21:756-768 Riecker A, Groschel K, Ackermann H, Schnaudigel S, Kassubek J, Kastrup A. The role of the unaffected hemisphere in motor recovery after stroke. Hum Brain Mapp. 2010;31:1017-1029 Seitz RJ, Hoflich P, Binkofski F, Tellmann L, Herzog H, Freund HJ. Role of the premotor cortex in recovery from middle cerebral artery infarction. Archives of neurology. 1998;55:1081-1088 Struppler A, Binkofski F, Angerer B, Bernhardt M, Spiegel S, Drzezga A, et al. A fronto-parietal network is mediating improvement of motor function related to repetitive peripheral magnetic stimulation: A pet-h2o15 study. NeuroImage. 2007;36 Suppl 2:T174-186 Tardy J, Pariente J, Leger A, Dechaumont-Palacin S, Gerdelat A, Guiraud V, et al. Methylphenidate modulates cerebral post-stroke reorganization. NeuroImage. 2006;33:913-922 Tombari D, Loubinoux I, Pariente J, Gerdelat A, Albucher JF, Tardy J, et al. A longitudinal fmri study: In recovering and then in clinically stable sub-cortical stroke patients. NeuroImage. 2004;23:827-839
27
Upper Limb Recovery After Stroke Is Associated With Ipsilesional Primary Motor Cortical Activity: A Meta-Analysis Isabelle Favre, Thomas A. Zeffiro, Olivier Detante, Alexandre Krainik, Marc Hommel and Assia Jaillard Stroke. 2014;45:1077-1083; originally published online February 13, 2014; doi: 10.1161/STROKEAHA.113.003168 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/45/4/1077
Data Supplement (unedited) at: http://stroke.ahajournals.org/content/suppl/2014/02/13/STROKEAHA.113.003168.DC1.html
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S
ensorimotor deficits after stroke are common and disabling contributors to global functional impairment. Moreover, at the time of the stroke, it is difficult to make accurate prognostic assessments on eventual motor recovery. Although the extent and degree of performance impairment in the subacute period after stroke provide useful information in forming predictions about recovery, the clinical assessment of sensorimotor performance used in forming these predictions is subjective, complex, and time intensive, suggesting that discovery and characterization of biomarkers, predicting either the course of recovery or response to specific therapies, would be of great clinical use.1 Functional neuroimaging allows rapid assessment of the neural mechanisms associated with stroke recovery,2,3 suggesting that sensorimotor neural activity measured noninvasively with functional MRI (fMRI) could be used to identify potential surrogate end points predicting recovery.
Although the empirical findings related to neural activity changes after stroke have been complex and sometimes contradictory, 2 related mechanisms have been advanced to explain sensorimotor recovery after stroke. In the first theory, behavioral recovery is supported by a sensorimotor network in the lesioned hemisphere, including medialpremotor (medial-PMC), lateral premotor (lateral-PMC), primary motor (MI), and primary somatosensory (SI) cortices.4–7 A second hypothesis posits that reorganization in the undamaged contralesional hemisphere supports motor recovery.8–10 Studies in support of this theory have shown that recovery of motor performance after unilateral stroke is associated with greater activity in contralesional MI and dorsolateral-PMC.10,11 Establishing a role of fMRI as a biomarker of motor recovery will require sensitive, specific, and efficient measurement
Received August 12, 2013; final revision received January 7, 2014; accepted January 14, 2014. From the Unité Neurovasculaire, Pôle Psychiatrie-Neurologie (I.F., O.D.), Unité IRM, Pôle Radiologie (A.K.), Unité IRM 3T Recherche IRMaGe - Inserm US17/CNRS UMS 3552 (A.K., A.J.), and Pôle Recherche (M.H., A.J.), CHU de Grenoble, Grenoble, France; and Neural Systems Group, Massachusetts General Hospital, Charlestown (T.A.Z.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 113.003168/-/DC1. Correspondence to Assia Jaillard, MD, PhD, Unité IRM 3T—Recherche CHU Grenoble CS 10217, 38043 Grenoble Cedex 9, France. E-mail [email protected] © 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.003168
Downloaded from http://stroke.ahajournals.org/ at BIBLIOTHEQUE DE L'UNIV LAVAL on December 1, 2014 1077
1078 Stroke April 2014 of sensorimotor neural activity.1 Identifying the specific neuroanatomical targets useful for assessment of stroke recovery involves overcoming the limitations of functional neuroimaging studies with respect to their capacity to include large samples of patients with homogeneous lesions, characteristics that would result in higher and more reliable detection sensitivity.2 One approach to this problem involves the use of quantitative neuroimaging meta-analysis, a technique that combines results from many studies and thereby has more power to detect subtle effects that may be difficult to identify in individual studies.12 Meta-analysis offers a principled and efficient procedure for dealing with sometimes inconstant results among studies jointly characterized by small sample sizes, variable times between stroke and study entry, diverse stroke locations, varying degrees of sensorimotor impairment, sensorimotor task variations, and different fMRI acquisition techniques. A recent quantitative coordinate-based activation likelihood estimation (ALE) meta-analysis suggested that a return to typical task-related activity spatial patterns constitutes a key process in effective functional recovery after stroke. Evidence in support of this conclusion was that less impaired patients showed higher activity not only in ipsilesional-MI and contralesional cerebellum but also in the contralesional hemisphere in the dorsolateral-PMC, anteromedial-PMC, and secondary somatosensory cortex, suggesting that fuller motor recovery might be dependent on contributions from several cortical systems in both hemispheres.13 However, many of these recovery-related effects were statistically weak not surviving family-wise error critical threshold correction. Furthermore, the meta-analysis included data from duplicate patients from 7 of the 36 included publications, possibly resulting in selection bias as a consequence of overweighting the contributions of the duplicated patients. In addition, between-group effects were estimated using foci computed from between-group contrasts reported in the individual studies rather than performing the between-group contrast at the meta-analysis level in a way that would allow direct group comparisons. Including only studies reporting results of between-group comparisons could introduce a false-positive bias because studies showing between-group differences are much more likely to be reported than those that show no significant differences.14 Finally, subsequent studies have appeared, including larger numbers of patients and associated outcome data15,16 and personal communication (A. Jaillard et al, unpublished data, 2014). The above considerations motivated a re-examination of the existing data on stroke recovery designed to avoid the described limitations. Therefore, we performed an ALE metaanalysis based on a selective and systematic review of the literature, including data from recent studies, with the goal of identifying robust fMRI predictors of motor recovery that might be useful in clinical research and practice. In our meta-analysis, we sought to (1) characterize sensorimotor system activity changes related to stroke, (2) describe how poststroke delay influences task-related sensorimotor activity patterns in patients with stroke, (3) determine which sensorimotor areas were associated with good or bad behavioral outcome 6 months after stroke, (4) determine if stroke
induces spatial shifts in ipsilesional sensorimotor cortical activity, and (5) determine whether these effects are present in a subset of patients with pure subcortical lesions sparing the overlying sensorimotor cortices, as ischemic lesions extending to the cortex could affect accurate identification of cortical activity patterns.17
Methods
The experimental methods are described in more detail in the Materials in the online-only Data Supplement. We selected functional neuroimaging studies published from January 1995 to April 2012, investigating upper limb movements and motor recovery after stroke using fMRI or positron-emission tomography. Studies were selected by searching the PubMed database (www.pubmed.org) using 5 keywords: stroke, fMRI, PET, recovery, and motor. Thirty-four studies met our inclusion criteria: (1) patients assessed at acute, subacute, or chronic stages and having motor impairments of the upper limb with partial or complete recovery, (2) a sample size exceeding 5, (3) the use of active or passive sensorimotor tasks involving the upper limb, (4) neuroimaging using positron-emission tomography or fMRI, and (5) voxel-wise whole brain analysis. The time after stroke was divided into 2 categories: 155 subjects were included in the acute group (stroke delay 3 months; second time-point). Thirty-two subjects with a delay after stroke between 35 days and 3 months were included only in the global analysis (Figure I in the online-only Data Supplement). Next, duplicate results arising from incorporation of the same fMRI data in multiple studies were excluded, resulting in the 25 remaining studies listed in Table I in the online-only Data Supplement. As we included studies with lesions affecting both right and left hemispheres, when the right hemisphere was affected the x coordinates were flipped about the y axis. Therefore, the left hemisphere corresponded to the affected hemisphere and the right limb corresponded to the affected limb for all contrasts included in the meta-analysis. We then performed a voxel-based ALE meta-analysis using GingerALE 2.1 (http://www.brainmap.org).12,18 Five related model families were run to examine task-related (1) effects related to between-group differences in the healthy and total patient group with stroke, (2) effects of time after stroke, (3) effects of behavioral outcome, (4) spatial shifts in activity compared between stroke and healthy groups, and (5) effect differences with respect to subcortical stroke location. In addition, passive and active sensorimotor tasks were compared among the patient and healthy groups. Time after stroke was divided into 2 categories: an acute group (poststroke delay 3 months). To avoid duplication, data from each patient were assigned to only 1 temporal category. As functional outcome was assessed using a variety of research scales assessing upper limb functional impairment, sensorimotor outcome measures were recoded and then used to split the sample into 2 subgroups, corresponding to good and bad recovery by 2 neurologists with expertise in stroke research. Good outcome or recovery was defined as National Institutes of Health Stroke Scale 40, Barthel Index >90, European Stroke Scale ≥85, Motricity Index-Upper-Limb >80, Ashworth Scale ≤2, Upper-Limb-Motor Assessment Scale >13, or modified Rankin Scale ≤2. The relationship between sensorimotor activity and behavioral outcome was only assessed at the chronic stage because outcome is rarely reported in acute stage studies. We analyzed spatial differences between control and patient groups with stroke in ipsilesional-MI and medial-PMC sensorimotor activity related to active movement tasks. The Montreal Neurological Institute coordinates of task-related activity maxima were obtained for each experimental contrast. Using t tests, we compared MI and medial-PMC maxima locations among the total stroke, subcortical stroke, and healthy groups. In addition, we explored effects of motor recovery in the chronic stroke group using outcome as a factor in an ANOVA with size and number of maxima as nuisance variables. Statistical analyses of spatial shifts in ALE value peaks were performed with SPSS (version 11.5) using a critical threshold of P1322 and the modified Rankin Score≤2.23 For more details about these scales, go to http://www.strokecenter.org/professionals/stroke-diagnosis/stroke-assessment-scales/. 2
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The relationship between motor activity and behavioral outcome was assessed only at the chronic stage, because outcome was reported at the acute stage in very few studies. To examine the effect of motor task type on activity, we ran separate analyses comparing the active and passive tasks. When subjects were duplicated, we selected the earliest scan for the first time-point. Comparison between groups was based on subtraction analysis. Since the nature of the sensorimotor task can influence the spatial pattern of activity, only studies including an active movement condition were included in the group comparisons. Maps reflected regions of convergence both within- and between-groups, using maxima drawn from all three processing domains. 3. Analyses of activity spatial changes We analyzed shifts in activity related to movements of the affected hand between controls and stroke patients within primary sensorimotor cortex and medial-PMC. First, MNI coordinates obtained for each study in the patient group for each spatial axis (x,y,z) at each time were recorded. Then a univariate GLM (one-way ANOVA) was performed using SPSS 11.5.24 To determine whether the peak coordinates were normally distributed for each group we used the Kolmogorov–Smirnov test (K–S test). Homogeneity of variance was tested using Levene's Test for Equality of Variances. We tested sample sizes and age as covariates to control for effects that could influence the dependent ‘peak coordinates’ variable. When more than two groups for the independent variable were assessed, we performed post-hoc tests (such as the LSD test) that compared individual group results. A critical threshold of p< 0.05 was used. We tested the effect of recovery on the M1 and on the medial-PMC shifts in the chronic stroke patients using the same procedure.
3
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SUPPLEMENTAL TABLES Table I. Studies included in the ALE meta-analysis Study
Stroke Patients Foci
Askim, 20098 "
12 (session 1) 12 (session 2)
17 11
/ /
/ /
MRI 1,5 MRI 1.5
Active Active
Self-paced, thumb-index finger opposition Self-paced, thumb-index finger opposition
Butefish, 200525
5
12
9
14
MRI 1,5
Active
Visually-paced, 1 Hz, thumb opposing the other fingers
Calautti, 20012
5 (session 1)
13
/
/
PET
Active
" Calautti, 200726
5 (session 2) 19
10 5
/ /
/ /
MRI 1.5 PET
Active Active
Auditory-paced, 1,26 Hz, thumb-index finger opposition All stages " Chronic Auditory-paced, 1,26 Hz, thumb-index finger opposition Chronic
Carey, 200627
9 (session 1)
4
10
3
PET
Active
Self-paced, index-tapping
Acute
"
5 (session 2)
3
/
/
PET
Active
Self-paced, index-tapping
Chronic
"
4 (session 2)
3
/
/
PET
Active
Self-paced, index-tapping
Chronic
6 (session 1)
6
/
/
MRI 1,5
Passive
Wrist flexion-extension, 1Hz
7 (session 2) 7 (session 2)
4 5
/ /
/ /
MRI 1.5 MRI 1.5
Passive Passive
Wrist flexion-extension, 1Hz Wrist flexion-extension, 1Hz
Jaillard, 200529 " Jaillard (in prep) " Lindberg, 200730 Lindberg, 200931 Lotze,` 20123
4 (session 1) 4 (session 2) 19 (session 1) 19 (session 2) 7 / 14
5 5 9 7 9 / 7
12 12 44 / 6 12 /
3 3 7 / 9 24 /
MRI 1,5 MRI 1,5 MRI 1,5 MRI 1.5 MRI 1,5 MRI 1,5
Active Active Active Active Passive Passive Active
Loubinoux, 200332 "
9 (session 1) 9 (session 2)
8 7
/ /
/ /
MRI 1,5 MRI 1.5
Dechaumont, 200828 " "
Controls Foci Imaging
MRI 1,5
Condition
Passive Passive
Task
Stage Acute Chronic Acute
Acute
Acute Sub. Self-paced, 1.33 Hz, thumb opposing the other fingers Acute Self-paced, 1.33 Hz, thumb opposing the other fingers Chronic Self-paced, sequential finger tapping Acute Self-paced, sequential finger tapping Chronic Wrist flexion-extension, 0,25 Hz Chronic Wrist flexion-extension, 0,25 Hz / Auditory-paced, fist clenching around a rubber ball, 1 Chronic Hz Wrist flexion-extension, 1 Hz Acute Wrist flexion-extension, 1 Hz Sub.
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
Luft, 200433 " Marshall, 200934 Nelles, 201135
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9 (cortical) 11 (subcortical) 23 10 (session 1)
7 21 7 4
8 / / /
7 / / /
"
5 (session 2)
3
/
/
PET
Act+pass
0,5 Hz, elbow flexion-extension
Chronic
"
5 (session 2)
7
/
/
PET
Act+pass
0,5 Hz, elbow flexion-extension
Chronic
10 (session 1)
4
5
6
PET
Passive
0,5 Hz, elbow flexion-extension
Acute
"
5 (session 2)
3
/
/
PET
Passive
0,5 Hz, elbow flexion-extension
Sub.
"
5 (session 2)
9
/
/
PET
Passive
0,5 Hz, elbow flexion-extension
Sub.
6 (session 1)
6
3
8
PET
Passive
0,5 Hz, elbow flexion-extension
Acute
6 (session 2)
4
/
PET
Passive
0,5 Hz, elbow flexion-extension
Sub.
Nelles, 200136
Nelles, 199911 " Pariente, 2001
37
MRI 1,5 MRI 1 MRI 1,5 PET
Active Active Active Passive
Auditory-paced, 0,3 Hz, elbow flexion-extension Chronic Auditory-paced, 0,3 Hz, elbow flexion-extension Chronic Auditory-paced, 1 Hz, hand flexion-extension Acute 0,5 Hz, elbow flexion-extension Acute
8
9
/
/
MRI 1.5
Active
Auditory-paced, 1 Hz, hand flexion-extension
Acute
Rehme, 201138
11
9
15
16
MRI 3,0
Active
Visually-paced, 1 Hz, whole hand - fist closures
Acute
Riecker, 201039
8
5
8
4
MRI 1,5
Active
Auditory-paced FT, 2 to 6 Hz
Chronic
6
/
Active
Self-paced, finger-tapping
All stage
8
17
8
Active
Auditory-paced, 1 Hz, thumb-index finger opposition
All stage
Active
Auditory-paced, index-tapping
Chronic
Active Act+ pass Act+ pass
Auditory-paced, 1 Hz, hand flexion-extension
Acute
Auditory-paced, 1 Hz, hand flexion-extension
Acute
Auditory-paced, 1 Hz, hand flexion-extension
Chronic
Seitz, 1998
40
7
PET
Sharma, 200912
12
Struppler, 200741
8
8
/
/
8
4
/
/
MRI 1,5
13
8
12
MRI 1,5
9
/
/
MRI 1.5
Tardy, 2006
42 43
Tombari, 2004 "
8 (session 1) 8 (session 2)
MRI 3,0 PET
Twenty four studies were included. The term ‘foci’ refers to the three-dimensional coordinates of the active areas reported. In each study, one or more sets of foci can be reported. A patient can have one or more fMRI/ PET sessions in longitudinal studies and therefore be included in both acute and chronic groups. For more details on motor task and stroke staging (see Methods).
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Table II. Stroke patient characteristics Study
Stroke Lesion side Lesion location patients
Mean age ± SD (y)
Sex
Askim,2009 8
12
5R, 7L
cortical (2)/subcortical (10)
67.2 ± 4.9
9M, 3W
Butefish, 200525
5
3R, 2L
cortical (2) /subcortical (2) /combined (1)
54.2 ± 11.4
1M, 4W
Calautti, 20012
5
0R, 5L
subcortical(5)
59.2 ± 13
4M, 1 W
Calautti, 200726
19
14R, 5L
Cortical (2)/subcortical (17)
61 ± 10
14M, 5W
Carey, 200627
9
4R, 5L
Cortical (3)/subcortical (6)
72 ± 9.8
7M, 2W
Dechaumont, 200828
6
4R, 2L
Subcortical (6)
58.8 ± 8
4M, 2W
Dechaumont, 200828
7
4R, 3L
Subcortical (7)
64 ± 12
4M, 3W
Jaillard (in prep)
19
7R, 12L
subcortical(19)
47.8 ± 16.3
15M, 4W
Jaillard, 200529
4
4L
Cortical (4)
61.3 ± 9.7
3M, 1W
Lindberg, 200730
7
2R, 5L
subcortical (6) /cortical (1)
59.4 ± 7.4
7M, 0W
Lotze, 20123
14
7R, 7L
Subcortical (14)
58 ± 14.4
10M, 4W
Loubinoux, 200332
9
5R, 4L
Subcortical (9)
59 ± 7
5M, 4W
Luft, 200433
20
11R, 9L
Subcortical (11)/cortical (9)
62 ± 9
11M, 9W
Marshall, 200934
23
12 R, 11 L
Subcortical (16)/cortical (3) /combined (4)
59 ± 10.5
16M, 7W
Nelles, 200136
5
4R, 1L
Subcortical (5)
68 ± 3.6
3M, 2W
Nelles, 200136
5
3R, 2L
Subcortical (5)
63 ± 3
3M, 1W
Nelles, 199911
6
2R, 4L
Subcortical (6)
62 ± 9.4
4M, 2W
Nelles, 201135
5
2R, 3L
Subcortical (5)
54-85
4M, 1W
Nelles, 201135
5
4R, 1L
Subcortical (5)
48-78
2M, 3W
Pariente, 200137
8
3R, 5L
Subcortical (8)
61.7 ± 11.1
5M, 3W
Rheme, 201138
11
7R, 4L
cortical (3)/subcortical (8)
65 ± 10
7M, 4W
Seitz, 199840
8
0R, 8L
subcortical(8)
58,9 ± ,8
4M, 4W
Sharma, 200912
7
5R, 2L
Cortical (7)
53,9 ± 8
6M, 1W
Struppler, 200741
12
4R, 8L
Subcortical (12)
66 ± 8,8
6M, 6W
Tardy, 200642
8
4R, 4L
Subcortical (8)
55 ± 8
6M, 2W
Tombari, 200443
8
4R, 4L
Subcortical (8)
60.5 ±9,4
8M, 0W
Riecker, 201039
8
3R, 5L
Subcortical (8)
62 ± 11
5M, 3W
6
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Stroke vs. Healthy Control Group Effects Table III. ALE-maxima MNI coordinates for stroke patients. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIA) Region
Side
Precentral gyrus Medial sup. frontal gyrus Medial sup. frontal gyrus Cingulate gyrus Inferior parietal lobule Postcentral gyrus Middle cerebellar peduncle Superior temporal gyrus Precentral gyrus Inferior parietal lobule Insula Inferior parietal lobule Cerebellum lobule V Vermis lobule IV-V Supramarginal gyrus Insula Inferior frontal gyrus
L L L L L L L L R R R R R R R R R
BA 4 6 6 24 40 2 22 4 40 13 40 40 13 44
ALE Value 522 345 270 118 156 99 131 123 225 167 151 145 224 104 137 122 115
x -34 2 -4 -4 -50 -42 -22 -54 42 50 54 52 16 2 64 36 54
y -24 -4 -14 -20 -28 -18 -40 6 -8 -30 -34 -30 -54 -60 -40 0 6
z 56 52 56 36 28 30 -34 6 56 28 20 40 -22 -18 34 0 16
Table IV. ALE-maxima MNI coordinates for healthy subjects. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIB) Region Precentral gyrus Precentral gyrus Medial sup. frontal gyrus Medial sup. frontal gyrus Insula Pre-motor cortex Cerebellum lobule V Cerebellum lobule V Thalamus VPL nucleus Insula Cerebellum lobule V Cingulate gyrus Cerebellum lobule IV-V Postcentral gyrus Inferior parietal lobule
Side L L L L L L L L L R R R R R R
BA 4 4 6 6 13 6 13 32 2 40
ALE Value 248 201 226 85 138 120 100 87 100 184 203 120 135 95 94
x -36 -38 0 -4 -50 -52 -26 -36 -16 60 18 4 6 56 52
y -16 -12 4 -6 -22 -4 -56 -58 -18 -30 -48 16 -62 -20 -26
z 60 54 58 68 24 40 -24 -26 0 22 -20 42 -14 42 46
7
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Table V. ALE-maxima MNI coordinates for the contrast stroke patients > healthy subjects. Affected upper limb versus rest contrast. FDR pID 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
ALE Value
x
y
z
Precentral gyrus
L
3
2.07
-26
-28
48
Precentral gyrus
L
4
2.05
-28
-26
52
Postcentral gyrus
L
3
2.12
-48
-20
42
Postcentral gyrus
L
2
1.92
-48
-20
52
Medial sup. frontal gyrus
R
6
3.036
4
-20
50
Medial sup. frontal gyrus
R
6
2.89
6
-16
50
Cingulate gyrus
R
23
2.70
10
-22
36
Cingulate gyrus
R
31
3.54
17
-23
46
Precentral gyrus
R
6
3.35
18
-22
50
Paracentral lobule
R
5
2.82
20
-30
50
Precentral gyrus
R
4
2.09
26
-22
52
Table VI. ALE-maxima MNI coordinates for the contrast healthy subjects > stroke patients. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Side
BA
ALE Value
x
Precentral gyrus
L
6
3.89
-27
-13.5
69.5
Precentral gyrus
L
4
3.54
-28
-16
74
Precentral gyrus
L
4
2.75
-34
-10
52
Precentral gyrus
L
4
2.13
-42
-16
62
Medial sup. frontal gyrus
L
6
2.85
-2
-2
62
Medial sup. frontal gyrus
L
6
2.72
0
0
66
Inferior parietal lobule
L
40
3.72
-62
-22.67
24.67
Inferior parietal lobule
L
40
2.32
-47
-24
20
Sup. temporal gyrus
L
41
2.29
-48
-26
16
Cerebellum lobule VI
L
-
2.76
-32
-55
-26
Cerebellum lobule VI
L
-
2.71
-30
-56
-22
Cerebellum lobule VI
L
-
2.57
-26
-58
-25
Cerebellum lobule VIIa
L
-
1.90
-38
-59
-30
Precentral gyrus
L
6
2.67
-56
2
40
Precentral gyrus
L
4
1.99
-56
-10
36
Precentral gyrus
L
4
1.93
-58
-6
36
Medial sup. frontal gyrus
R
6
2.37
6
-6
74
Inferior parietal lobule
R
40
3.54
63
-31
21
Cingulate gyrus
R
32
2.62
10
14
40
Cingulate gyrus
R
24
2.62
8
10
42
Cingulate gyrus
R
32
2.29
6
16
46
Cerebellum lobule V
R
-
2.89
17
-43
-15
Region
y
z
8
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
-
STROKE 2014
Acute and Chronic Stage Effects
Table VII. ALE-maxima MNI coordinates for the acute stroke patients. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIIA) Region
Side
BA
Ale Value
x
y
z
Cerebellum lobule V
L
-
93
-24
-42
-34
Cingulate gyrus
L
24
88
-2
-2
42
Insula
L
13
80
-52
-40
26
Parietal inferior lobule
L
40
95
-50
-30
28
Postcentral gyrus
L
2
95
-42
-18
32
Precentral gyrus
L
4
233
-34
-24
54
Cingulate gyrus
L
6
83
-4
-20
46
Cerebellum lobule V
R
-
127
18
-50
-28
Cerebellum lobule V
R
-
80
14
-54
-20
Medial sup. frontal gyrus
R
6
180
2
-4
52
Parietal inferior lobule
R
40
112
50
-30
30
Precentral gyrus
R
4
100
38
-10
52
Table VIII. ALE-maxima MNI coordinates for the chronic stroke subjects. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure IIIB) Region
Side
BA
Ale Value
x
y
z
Vermis lobule IV-V
L
-
90
0
-60
-14
Frontal operculum
L
44
110
-52
6
6
Medial sup. frontal gyrus
L
6
193
-4
-14
58
Postcentral gyrus
L
3
213
-44
-16
52
Precentral gyrus
L
4
275
-36
-20
56
Cerebellum lobule V
R
-
145
16
-56
-22
Insula
R
13
93
54
-34
22
Medial sup. frontal gyrus
R
6
157
2
-2
54
Premotor cortex
R
6
129
42
-6
58
Thalamus VL nucleus
R
-
88
10
-12
10
9
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Table IX. ALE-maxima MNI coordinates for the contrast acute > chronic stroke patients. Affected upper limb (active tasks) versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected cluster level. (Figure IIIC) Region
Side
Precentral gyrus Precentral gyrus Postcentral gyrus Postcentral gyrus Cerebellum lobule VI Postcentral gyrus Postcentral gyrus Postcentral gyrus Middle Frontal gyrus Precentral gyrus Precentral gyrus Middle Frontal gyrus Middle cerebellar peduncle Cerebellum lobule VI Cerebellum lobule VI Cerebellum lobule V Inferior parietal lobule Inferior parietal lobule
BA
L L L L L L L L R R R R R R R R R R
6 6 2 2 3 2 2 6 6 6 6 40 40
Ale Value 2.29 2.05 2.05 1.99 2.10 1.89 1.72 1.71 2.83 2.73 2.73 2.52 1.82 1.75 1.75 1.74 1.94 1.90
x -46 -42 -45 -40 -32 -32 -38 -40 32 38 38 26 16 24 22 22 36 39.33
y -8 -9 -16 -20 -50 -22 -24 -24 -4 -4 -8 -2 -44 -50 -48 -44 -46 -44
z 32 30 30 32 -18 44 40 46 42 38 38 42 -30 -32 -32 -26 42 41
Table X. ALE-maxima MNI coordinates for the differential contrast chronic > acute stroke patients. Affected upper limb (active tasks) versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level (Figure IIIC). Region Side BA Ale Value x y z
Precentral gyrus
L
4
2.09
-46
-18
54
Precentral gyrus
L
4
2.01
-40
-18
56
Behavioral Outcome Effects
Table XI. ALE-maxima MNI coordinates for the stroke patients with good outcome. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. (Figure 1A) Ale Value (10-4) Region
Side
BA
x
y
z
Medial sup. frontal gyrus
L
6
148
2
-2
54
Medial sup. frontal gyrus
L
6
115
-4
-14
56
Precentral gyrus
L
4
251
-36
-20
56
Cerebellum lobule V
R
-
145
16
-56
-22
Inferior parietal lobule
R
40
103
52
-30
42
Precentral gyrus
R
6
126
42
-6
58
10
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Table XII. ALE-maxima MNI coordinates for the stroke subjects with bad outcome (Figure 1B). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Ale Value (10-4) Region Thalamus VPL
Side L
BA -
70
x -19
y -21
z 0
Vermis lobule IV-V
L
-
78
0
-60
-12
Vermis lobule IV-V
L
-
87
-10
-60
-8
Postcentral gyrus
L
40
98
-36
-30
60
Cingulate gyrus
L
24
68
0
-38
20
Premotor cortex
L
6
95
-2
-14
58
Thalamus, VPL
R
-
70
19
-23
0
Table XIII. ALE-maxima MNI coordinates for the contrast good recovery > bad recovery (Figure 1C). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Precentral gyrus
L
4
Precentral gyrus
L
Precentral gyrus
Ale Value
x
y
z
2.71
-36
-22
52
4
1.83
-38
-14
46
L
4
1.78
-40
-14
50
Cingulate gyrus
L
24
2.09
-2
-6
44
Medial sup. frontal gyrus
L
6
2.07
-2
-6
50
Medial sup. frontal gyrus
L
6
2.03
-4
-4
54
Cingulate gyrus
L
24
1.78
-10
-2
50
Cingulate gyrus
L
24
1.76
-10
-4
44
Cingulate gyrus
L
24
1.75
-5
3
45
Table XIV. ALE-maxima MNI coordinates for the contrast bad > good recovery (Figure 1D). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Ale Value
x
y
z
Brainstem
R
-
2.29
30
-15
-8
Thalamus VPL
R
-
1.88
19
-23
0
Vermis lobule IV-V
L
-
1.93
-5
-62
-6
Cerebellum lobule VI
L
-
1.93
-17
-74
-13
11
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Subcortical Lesion Location Effects Table XV. ALE-maxima MNI coordinates for all subcortical stroke patients (Figure VA). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Ale Value
Precentral gyrus
L
4
439
Medial Sup. Frontal gyrus
L
6
276
Cingulate gyrus
L
31
118
Cingulate gyrus
L
24
117
Cingulate gyrus
L
31
103
Insula
L
13
156
x
y
z
-34
-22
56
0
0
52
-2
-18
48
-4
-20
36
-6
-22
42
-50
-28
28
Superior temporal gyrus
L
22
89
-48
-18
20
Inferior parietal lobule
L
40
122
-54
6
6
Inferior parietal lobule
R
40
166
50
-30
28
Inferior parietal lobule
R
40
144
52
-30
40
Inferior parietal lobule
R
40
137
64
-40
34
Postcentral gyrus
R
2
102
60
-24
36
Postcentral gyrus
R
2
102
64
-16
34
Precentral gyrus
R
4
125
38
-16
54
Precentral gyrus
R
6
120
44
-4
58
Vermis lobule IV-V
R
-
103
2
-60
-18
Cerebellum lobule V
R
-
113
18
-54
-20
Precentral gyrus
R
9
101
42
12
32
Cingulate gyrus
R
31
101
26
-36
44
Table XVI. ALE maxima MNI coordinates for the contrast healthy subjects > stroke subcortical patients (Figure VB). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region Side BA ALE Value x y z Precentral gyrus Precentral gyrus Precentral gyrus Postcentral gyrus Medial Sup. Frontal gyrus
L L L L L
4 6 4 3 6
3.72 3.54 2.48 2.02 2.69
-28 -24 -34 -42 -3
-19 -10 -10 -18 -2
72 71 52 62 62
Medial Sup. Frontal gyrus Medial Sup. Frontal gyrus Cerebellum lobule VI Cerebellum lobule V Cerebellum lobule VI Cerebellum lobule VI Superior temporal gyrus Precentral gyrus Medial Sup. Frontal gyrus
L L L L L R L L R
6 6 41 6 6
1.92 1.85 2.49 2.27 1.89 3.35 1.93 2.35 2.15
2 2 -30.12 -24.57 -37 20 -48 -56 8
8 12 -53.62 -58 -59.5 -62 -25 2 -8
64 60 -23.06 -22.86 -21 -22 18 40 72
Inferior parietal lobule Superior temporal gyrus
R R
40 22
3.72 3.43
68 66.94
-22 -27.88
16 16.12
12
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Inferior parietal lobule Cerebellum lobule V
R R
40 -
3.35 2.62
62 16
-28 -46
19 -22
Cerebellum lobule V Cerebellum lobule V Cingulate gyrus Medial Sup. Frontal gyrus
R R R R
32 6
2.60 2.59 2.16 2.04
17.5 16 8 6
-44.5 -44 14 18
-18 -14 40 46
Table XVII. ALE maxima of MNI coordinates for the contrast stroke subcortical patients > healthy subjects (Figure VB). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
ALE Value
x
y
z
Cingulate gyrus
L
23
2.11
0
-20
30
Cingulate gyrus
R
23
2.72
12
-20
34
Paracentral lobule
R
31
2.62
4
-20
50
Inferior parietal lobule
R
40
2.12
62
-44
36
Inferior parietal lobule
R
40
2.10
64
-42
32
Supramarginal gyrus
R
40
2.10
64
-46
32
Supramarginal gyrus
R
40
2.10
62
-40
36
Inferior parietal lobule
R
40
1.88
64
-34
38
Precentral gyrus
R
4
1.88
34
-14
42
Precentral gyrus
R
4
1.84
30
-14
48
Table XVIII. ALE-maxima MNI coordinates for the acute subcortical stroke patients. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Ale Value x y z Region Side BA Precentral gyrus
L
4
178
-36
-24
54
Inferior parietal lobule
L
40
95
-50
-30
28
Postcentral gyrus
L
2
95
-42
-18
32
Superior temporal gyrus
L
13
80
-52
-40
26
Medial Sup. Frontal gyrus
L
6
125
2
-4
52
Medial Sup. Frontal gyrus
L
6
64
-4
4
56
Cingulate gyrus
L
31
79
-6
-22
44
Inferior parietal lobule
R
40
111
50
-30
30
Precentral gyrus
R
4
80
34
-10
44
Cerebellum lobule HVIIa
R
-
88
32
-70
-32
Inferior parietal lobule
R
40
90
64
-40
34
13
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Table XIX. Maxima MNI coordinates for the chronic subcortical stroke subjects. Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
BA
Side
Precentral gyrus
4
L
Postcentral gyrus
3
Precentral gyrus
Ale Value
x
y
z
205
-36
-20
58
L
111
-46
-16
48
4
L
89
-44
-10
48
Medial Sup. Frontal gyrus
6
L
119
0
2
54
Vermis lobule IV-V
-
L
90
0
-60
-14
44
L
110
-52
6
6
Medial Sup. Frontal gyrus
6
L
110
-2
-14
58
Cerebellum, lobule IV
-
L
87
-10
-60
-8
Precentral gyrus
6
R
87
40
-4
58
Cerebellum lobule V-VI
-
R
109
18
-54
-20
Inferior parietal lobule
40
R
103
52
-30
42
Insula
13
R
93
54
-34
22
Precentral gyrus
Table XX. ALE-maxima MNI coordinates for the contrast acute > chronic subcortical stroke patients (Figure VC). Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Side
BA
Ale Value
Inferior parietal lobule
L
40
3.72
-51.33
-28.33
32.67
Inferior parietal lobule
L
40
3.24
-54
-28
26
Inferior parietal lobule
L
40
2.82
-51.33
-38
31.33
Inferior parietal lobule
L
40
2.79
-52
-42
30
Inferior parietal lobule
L
40
2.72
-58
-42
30
Inferior parietal lobule
L
40
2.54
-54.67
-45.33
26
Insula
L
13
2.40
-46
-38
29
Postcentral gyrus
L
2
2.362
-36
-22
36
Precentral gyrus
L
4
2.03
-34
-22
46
Precentral gyrus
L
4
1.77
-44
-14
34
Inferior parietal lobule
L
40
3.29
-60
-31
34
Inferior parietal lobule
L
40
2.81
-62
-34
40
Middle frontal gyrus
R
6
2.34
20
-2
38
Region
x
y
z
14
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
STROKE 2014
Table XXI. ALE-maxima MNI coordinates for the contrast chronic > acute in subcortical stroke patients (Figure VC). Affected upper limb versus rest contrast. FDR pID0.05 voxel-level, FWE-corrected cluster level. Region Side BA Ale Value x y z Vermis lobule IV-V Vermis lobule IV-V
L L
-
2.19 2.10
0 -1
-57 -64
-13 -6
Vermis lobule IV-V
L
-
Cerebellum lobule IV-V
L
-
1.97
-4.57
-62.43
-13.43
1.84
-10.49
-60.28
-7.12
Precentral gyrus
L
4
2.36
-35
-14
60
Cerebellum lobule IV-V
R
-
2.73
11.63
-58.21
-7.15
Vermis lobule IV-V
R
-
2.52
4
-58
Vermis lobule IV-V
R
-
2.42
4.67
-62.89
-12.89
Cerebellum lobule IV-V
R
-
2.40
12
-54
-16
Vermis lobule IV-V
R
-
2.28
3.56
-66.22
-4.67
Cerebellum lobule V
R
-
2.13
13
-58
-20
Cerebellum lobule V
R
-
2.05
12
-52
-20
Cerebellum lobule V
R
-
1.77
21
-53
-16
Inferior frontal gyrus
R
44
2.31
53
11
12.33
Inferior frontal gyrus
R
44
1.84
56
6.4
15.2
Insula
R
13
2.34
38.46
5.85
2.92
Insula
R
13
2.31
40
8
8
Insula
R
13
2.10
42
10
4
-
-8
Active and Passive Task Comparisons
Table XXII. ALE-maxima MNI coordinates for the contrast stroke patients > healthy subjects performing an active task. Affected upper limb versus rest contrast. FDR pID0.05 voxel-level, FWE-corrected cluster level. Region
Side
BA
Ale Value
x
y
Z
Cingulate gyrus
L
31
2.49
-18
-26
42
Paracentral lobule
L
5
2.32
-12
-28
50
Medial sup. frontal gyrus
L
6
2.04
-6
-22
50
Medial sup. frontal gyrus
L
6
1.84
-2
-20
54
Cingulate gyrus
L
31
1.83
-4
-22
46
Cingulate gyrus
L
23
1.82
-6
-22
36
Cingulate gyrus
L
23
1.82
-3.71
-21.43
32
Precentral gyrus
R
4
2.11
30
-14
50
Precentral gyrus
R
6
1.83
32
-14
58
Cingulate gyrus
R
24
2.45
20
-14
40
Cingulate gyrus
R
24
2.26
24
-10
38
Cingulate gyrus
R
31
3.04
18
-22
48
Cingulate gyrus
R
31
2.85
19
-26
47
Cingulate gyrus
R
23
2.02
10
-18
34
Cingulate gyrus
R
23
1.95
9.33
-20.67
30
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Table XXIII. ALE-maxima MNI coordinates for the contrast healthy subjects > stroke patients performing an active task. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWEcorrected at the cluster level. Region
Side
BA
Ale Value
x
y
Z
Precentral gyrus
L
4
2.95
-35
-10
53
Precentral gyrus
L
6
2.54
-28
-8
66
Precentral gyrus
L
6
2.46
-30
-10
67
Precentral gyrus
L
4
2.44
-40
-16
58
Precentral gyrus
L
4
2.06
-34
-18
66
Precentral gyrus
L
6
2.02
-30
-4
70
Precentral gyrus
L
6
2.44
-4
-2
64
Cerebellum lobule V
L
-
2.75
16
-42.4
-18.8
Cerebellum lobule VI
L
-
2.09
-27.96
-56.26
-24.4
Precentral gyrus
L
6
2.58
-56
Insula
L
13
2.07
-47.12
-25.75
21.38
Inferior parietal lobule
L
40
1.89
-53
-23
24
Superior temporal gyrus
L
41
1.82
-48
-25
16
Medial sup. frontal gyrus
R
6
2.12
4
6
58
Medial sup. frontal gyrus
R
6
2.23
6
14
46
Inferior parietal lobule
R
40
2.29
52
-38
56
Inferior parietal lobule
R
40
2.28
48
-39
54
Inferior parietal lobule
R
40
2.28
52
-42
52
Inferior parietal lobule
R
40
2.32
66
-22
26
Inferior parietal lobule
R
40
1.88
62
-28
22
2
40
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Table XXIV. ALE-maxima MNI coordinates for the contrast active > passive task. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
BA
Side
Postcentral gyrus
3
L
Postcentral gyrus
3
Precentral gyrus
x
y
z
2.82
-42
-18
58
L
2.74
-34
-30
64
4
L
2.41
-34
-12
48
Postcentral gyrus
2
L
2.33
-42
-20
48
Cingulate gyrus
24
L
2.89
-12
-4
48
6
L
2.57
-6
-6
58
Cingulate gyrus
24
L
2.48
-14
2
44
Precentral gyrus
4
L
2.30
-48
4
48
Medial Sup. Frontal gyrus
6
R
2.26
6
-12
62
Medial Sup. Frontal gyrus
6
R
2.25
4
-8
64
Precentral gyrus
4
R
2.47
34
-16
60
Precentral gyrus
6
R
2.27
34
-8
56
Precentral gyrus
6
R
2.21
36
-6
64
Precentral gyrus
6
R
2.19
42
-12
60
Cerebellum lobule V
-
R
2.39
16
-54
-22
Cerebellum lobule V
-
R
2.17
14
-60
-18
Cerebellum lobule V
-
R
2.16
12
-54
-28
Cerebellum lobule V
-
R
2.02
12
-50
-26
Cerebellum lobule V
-
R
1.75
10
-60
-4
Medial Sup. Frontal gyrus
Ale Value
Table XXV. ALE-maxima MNI coordinates for the contrast passive > active task. Affected upper limb versus rest contrast. FDR pID0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Superior temporal gyrus Cingulate gyrus
L L
41 24
Superior parietal lobule
L
Insula
Ale Value
x
y
z
3.89 1.76
-53 -24
-35 -38
28 46
7
1.71
-29
-45
45
R
13
2.68
50
-25
26
Inferior parietal Lobule
R
40
2.88
61
-46
37
Inferior parietal Lobule
R
40
2.67
62
-38
32
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Table XXVI. MNI coordinates for ALE-maxima in acute stage stroke patients performing an active task (n=103, 9 experiments, 85 reported foci). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxellevel, FWE-corrected at the cluster level. Region
Side
BA
Ale Value
x
y
z
Postcentral gyrus Postcentral gyrus
L L
3 3
174 106
-34 -38
-26 -20
56 46
Medial Sup. Frontal gyrus
L
6
105
-4
-2
52
Medial Sup. Frontal gyrus
L
6
101
-4
-8
50
Postcentral gyrus
L
2
90
-42
-18
32
Precentral gyrus
L
4
Cerebellum lobule V
L
Medial Sup. Frontal gyrus
R
Cerebellum lobule V
74
-44
-8
28
93
-24
-42
-34
6
100
4
-8
56
R
-
127
18
-50
-28
Cerebellum lobule V
R
-
79
14
-54
-20
Precentral gyrus
R
4
95
36
-10
50
Table XXVII. MNI coordinates for ALE-maxima in chronic stage stroke patients performing an active task (n=113, 13 experiments, 98 reported foci). Affected upper limb versus rest contrast. FDR pN 0.05 at the voxel-level, FWE-corrected at the cluster level. Region
Side
BA
Precentral gyrus
L
4
Postcentral gyrus
L
Medial Sup. Frontal Gyrus
Ale Value (104)
x
y
z
275
-36
-20
56
3
213
-44
-16
52
L
6
193
-4
-14
58
Medial Sup. Frontal Gyrus
L
6
157
2
-2
54
Precentral gyrus
L
44
110
-52
6
6
Vermis lobule IV-V
L
-
90
0
-60
-14
Precentral gyrus
R
6
129
42
-6
58
Cerebellum lobule V
R
-
145
16
-56
-22
Inferior parietal lobule
R
40
103
52
-30
42
Insula
R
13
93
54
-34
22
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SUPPLEMENTAL FIGURES
Figure I. Categorization of the included patients according to time after stroke
Session 1
Session 2
All stages (n=24) All patients (n=255)
Acute (n=151)
Subacute (n=32)
Chronic (n=76)
Chronic (n=63)
Chronic (n=139) The included patients are divided into three groups shown in the gray boxes. Three stages were utilized. In the chronic group, 63 patients were the same as those included in the acute stage group (imaging session 1 and 2 of longitudinal studies) and 76 came from additional studies.
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Figure II. Activity patterns for the right/affected upper limb. (A) For stroke patients at all stages (red-yellow): ‘movement tasks vs. rest’ contrast. (B) For healthy subjects (green): ‘movement tasks vs. rest’ contrast. (C) Contrast of ‘stroke patients vs. healthy controls’ (red-yellow) and ‘healthy controls vs. stroke patients’ (green). The right hemisphere is shown on the right side.
20
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Figure III. Effect of post-stroke delay in patients for the right/affected upper-limb. ‘Motor task vs. rest’ contrast at: (A) acute stage (red); (B) chronic stage (blue). (C) ‘acute vs. chronic stage’ (red) and ’chronic vs. acute stage’ (blue).
21
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Figure IV. Overlay maps of ALE maxima for the right/affected upper-limb reveal a ventral shift within primary sensorimotor cortex and a caudal shift within medial premotor cortex. ‘Motor task vs. rest’ contrast: (A) Acute stage in stroke patients (red) and healthy subjects (green). (B) Chronic stage in stroke patients (blue) and healthy subjects (green). (C-D) Both cute (red) and chronic (blue) stage in stroke patients and in healthy subjects (green); (C) Sagittal view and (D) Axial view.
22
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Figure V. Effect of subcortical lesions on activity related to right/affected upper-limb movements. ‘Motor task vs. rest’ contrast in subcortical patients: (A) All stages (red-yellow);
(B) ‘Stroke patients vs. healthy’ (yellow) and ’Healthy vs. stroke patients’ (green). (C) ‘Acute vs. chronic’ stages (red) and ‘Chronic vs. acute stages’ (blue).
23
MOTOR STROKE META‐ANALYSIS SUPPLEMENTAL MATERIAL
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Figure VI. Comparison between good and bad outcome related-activity in subcortical stroke patients for right/affected upper-limb movements: ‘Good vs. bad outcome’ contrast (cyan) and ‘Bad vs. good outcome’ (pink).
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Upper Limb Recovery After Stroke Is Associated With Ipsilesional Primary Motor Cortical Activity: A Meta-Analysis Isabelle Favre, Thomas A. Zeffiro, Olivier Detante, Alexandre Krainik, Marc Hommel and Assia Jaillard Stroke. 2014;45:1077-1083; originally published online February 13, 2014; doi: 10.1161/STROKEAHA.113.003168 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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