Brain Stimulation xxx (2015) 1e8
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Original Research
The Effectiveness of 1Hz rTMS Over the Primary Motor Area of the Unaffected Hemisphere to Improve Hand Function After Stroke Depends on Hemispheric Dominance Jitka Lüdemann-Podubecká a, *, Kathrin Bösl a, Steven Theilig a, Ralf Wiederer a, Dennis Alexander Nowak a, b a b
Helios Klinik Kipfenberg, Neurologische Fachklinik, Kipfenberg, Germany Department of Neurology, University Hospital, Philips-University, Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 October 2014 Received in revised form 4 February 2015 Accepted 8 February 2015 Available online xxx
Objective: Inhibition of motor cortex excitability of the contralesional hemisphere may improve dexterity of the affected hand after stroke. Methods: 40 patients (17 dominant hemispheric stroke, 23 non-dominant hemispheric stroke) with a mild to moderate upper limb motor impairment were enrolled in a double-blind, randomized, placebocontrolled trial with two parallel-groups. Both groups received 15 daily sessions of motor training preceded by either 1Hz rTMS or sham rTMS. Behavioral and neurophysiological evaluations were performed at baseline, after the first week and after the third week of treatment, and after a 6 months follow-up. Results: In both groups motor function of the affected hand improved significantly. Patients with stroke of the non-dominant hemisphere made a similar improvement, regardless of whether the motor training was preceded by sham or 1Hz rTMS. Patients with stroke of the dominant hemisphere had a less favorable improvement than those with stroke of the non-dominant hemisphere after motor training preceded by sham rTMS. However, when 1Hz rTMS preceded the motor training, patients with stroke of the dominant hemisphere made a similar improvement as those with stroke of the non-dominant hemisphere. Interpretation: Motor recovery of the affected upper limb after stroke is determined by dominance of the affected hemisphere. Stroke of the dominant hemisphere is associated with per se poorer improvement of the affected hand. 1Hz rTMS over the contralesional M1 significantly improves dexterity of the affected hand in patients with stroke of the dominant hemisphere, but not in those with stroke of the nondominant hemisphere. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Stroke Repetitive transcranial magnetic stimulation Motor impairment Upper limb Hand dominance
Introduction More than 50% of stroke-victims retain permanent neurological impairments with motor impairment being the most frequent. Abbreviations: Dominant hemisphere, left hemisphere by right-handed volunteers, right hemisphere by left-handed volunteers; TMS, transcranial magnetic stimulation; rTMS, repetitive transcranial magnetic stimulation; MEP, Motor Evoked Potential; FDI, first dorsal interosseus muscle; BL, baseline evaluation; W1, evaluation after the first week of treatment; W3, evaluation after the third week of treatment; M6, follow-up examination 6 months after the last treatment; DA, dominant hemisphere affected; NDA, non-dominant hemisphere affected; M1, primary motor cortex; rMT, resting motor threshold; WMFT, Wolf Motor Function Test; MESUPES, Motor Evaluation Scale for Upper Extremity in Stroke Patients. * Corresponding author. Helios Klinik Kipfenberg, Neurologische Fachklinik, Kindingerstraße 13, D-85110 Kipfenberg, Germany. Tel.: þ49 (0)8465 175 66 131; fax: þ49 (0)8465 175 184. E-mail address: [email protected] (J. Lüdemann-Podubecká). http://dx.doi.org/10.1016/j.brs.2015.02.004 1935-861X/Ó 2015 Elsevier Inc. All rights reserved.
Among these patients, about 80% suffer from grasping deficits [1]. In about two thirds of stroke-victims impaired dexterity persists for up to 6 months after the stroke [2]. Given these epidemiological facts, novel treatment concepts for upper limb rehabilitation after stroke are urgently needed. The increasing interest in the application of rTMS in stroke rehabilitation is based on the fact that rTMS modulates excitability within the cortical motor network and thereby allows direct interference with neural plasticity [3]. Several changes in neural activity have been observed after unilateral stroke and until today, it is unclear if theses represent beneficial or detrimental plasticity [4]. Nevertheless, rTMS to promote motor recovery of the affected hand after stroke is widely used in reference to a so called interhemispheric imbalance model [3]. This concept describes the plastic changes within the cerebral motor network induced by stroke as a “disruption of the physiological balance” between both
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hemispheres with a “shift” of neural activity towards the nonlesioned hemisphere for movements of the affected hand. Within this concept of maladaptive plasticity after stroke it has been postulated that the increased activity within motor areas of the contralesional hemisphere and the inhibitory influence towards motor areas of the ipsilesional hemisphere may have a negative impact on recovery of the affected hand [4]. In this context, it has been demonstrated e on a group level e that either up-regulation of excitability of the ipsilesional primary motor area (M1) or down-regulation of excitability of contralesional M1 may improve dexterity of the affected hand after stroke [5e7]. Although rTMS is increasingly used in stroke rehabilitation, the mechanisms underlying the plastic changes of neural activity within the motor network of both hemispheres after stroke and their impact on motor recovery of the affected hand are not completely understood [4]. In particular, the above mentioned changes in neural activation throughout the cortical motor network develop in dependence of the hemisphere affected [8,9], the location and distribution of the lesion [10] and the time from stroke [11], among other factors, which may then again influence the effectiveness of an rTMS treatment. Consequently, pertinent metaanalyses are inconclusive, suggesting either a positive effect of rTMS on motor recovery of the stroke affected hand or no effect at all [5e7]. Given the short-living effects of rTMS on motor cortex excitability [12], an increasing number of studies apply rTMS over several sessions in combination with motor training for the affected hand after stroke [5e7]. Here we investigated the long-term effectiveness of preconditioning a three-week motor training for the stroke affected hand by inhibitory (1Hz) rTMS in a double-blind sham-controlled trial. We will show that e after a sub-classification of the cohort e 1Hz rTMS over the contralesional M1 significantly improves dexterity of the affected hand in patients with stroke of the dominant hemisphere, but not in those with stroke of the non-dominant hemisphere. Methods Participants 40 patients with a mild to moderate sensory-motor deficit of the hand after stroke were consecutively enrolled. 38 of them were right handed and two were left handed. Hand dominance was tested by a self-report questionnaire [13]. Demographic details of each patient are summarized in Table 1. Inclusion criteria were: 1) first-ever stroke within the last 6 months, 2) location of the lesion within the territory of the middle cerebral artery, 3) mild to moderate motor and/or sensory deficit of one hand, 4) preserved motor evoked potentials (MEP) at the first dorsal interosseus (FDI) muscle of the affected hand after single pulse TMS applied over the hand area of the ipsilesional M1. We excluded patients with relevant aphasia or cognitive impairments, which might interfere with the understanding of instructions for motor testing. None of the participants had apraxia, neglect, visual field deficits, psychiatric or coexistent general neurological, medical or orthopedic illness or accepted contraindications for TMS (pacemakers, metallic objects in the head, history of epilepsy, etc.). The study was approved by the local Ethics committee. All patients gave their written informed consent prior to participation. Each patient was informed about the possibility to be randomized in the sham rTMS group (Table 2) Study design The study was a prospective, randomized, double-blind, longitudinal, parallel- and factorial-design, sham-controlled trial that
had several phases: (1) randomization, (2) baseline evaluation (BL), (3) treatment during the first week, (4) evaluation after the first week of treatment (W1), (5) treatment during the second and third week, (6) evaluation after the third week of treatment (W3), (7) follow-up examination 6 months after the last treatment (M6). Using sealed envelopes, the subjects were randomly assigned to one of two experimental groups (real rTMS, sham rTMS) in a 1:1 ratio (see Fig. 1). Intervention Treatment lasted 15 working days with two time-locked daily interventions: 1) 15 min of real/sham 1Hz rTMS and 2) 30 min of standard task-oriented upper-limb motor-training. RTMS was performed using a 70-mm figure-of-eight coil connected to a Magstim Super Rapid stimulator (Magstim Company, Dyfed, UK). Participants were instructed to sit in a comfortable chair with both hands placed on the armrest in a relaxed position, and they were asked to stay awake during the procedure. Adherence to these instructions was supervised by the experimenter throughout the experiments. The coil was placed tangentially in a posterioreanterior plane over the motor representation of the first dorsal interosseous muscle (FDI) of the contralesional M1. For real rTMS a single train of 900 pulses at 100% of the resting motor threshold (rMT) was administered. For sham rTMS a single train of 900 pulses at 0% of rMT was applied at the very same position. RMT was defined as the lowest stimulator output intensity that elicited a motor evoked potential (MEP) in the contralateral FDI with a peak-to-peak amplitude of at least 50 mV in at least 5 out of 10 trials. All participants were blinded to the rTMS condition and none of them had any experience with rTMS before study participation. The motor training aimed to exercise hand dexterity with a set of different daily routine tasks, including grasping and manipulating objects, e.g. folding a towel, modeling with modeling clay, donning a t-shirt, opening and closing a tube or a bottle, drawing, playing “memory”. The tasks were selected according to the subject’s actual functional status and increased in difficulty and complexity on a day by day basis (shaping). The training was applied by an experienced occupational therapist, who was completely blind regarding group allocation of the individual subject, in one-to-one daily training sessions lasting 30 min each. Assessments Outcome assessments included measures of hand dexterity and cortical excitability. These were obtained by a different therapist blinded to group allocation. Motor function of both the affected and the unaffected hands were assessed. The Wolf Motor Function Test (WMFT) [20], the Motor Evaluation Scale for Upper Extremity in Stroke Patients (MESUPES) [21] and the velocity of index finger tapping were used. The velocity of finger tapping was recorded using an ultrasonic motion analyzer described in detail elsewhere [19]. Peak movement amplitude was specified to 2.0 cm. For cortical excitability measures the same stimulation system, coil placement and recording procedure were used, as detailed above. Volunteers were instructed to sit in a comfortable chair with both hands placed on the armrest in a relaxed position, and they were asked to stay awake during the procedure. The coil was placed tangentially in a posterioreanterior plane on the skull overlying the area representing the FDI of the contralesional M1. Electromyographic activity was recorded from silveresilver-chloride electrodes positioned in a belly-tendon montage on the skin overlying the FDI. Stimulation intensity was individually defined once for each patient during the baseline evaluations as the intensity to evoke a peak-to-peak MEP of 1 mV size. This stimulation intensity
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Table 1 Demographic data and lesion location for each participant. Age (years)
Sex
rTMS sham 76 w 50 w 71 m 74 m 55 w 86 w 48 m 58 m 65 m 84 w 58 m 62 m 76 w 65 m 76 m 65 m 79 w 73 w 63 m
Time from stroke (months)
Stroke location
Stroke etiology
Affected hand
Dominant hand
MRS
0.5 1 1 0.5 1.25 1.5 1.75 1 1 1.5 1.5 5 3 1 3.5 0.25 1.5 3 2
IC, BG P preCG, postCG, CR T, BG, IC BG, IC CR, BG, IFG CR IFG, CR, preCG preCG, CR CR, BG preCG, CR, IFG BG, CR, IC CR preCG, IFG SFG, CR T T, IC IC, CR preCG, postCG, CR, BG, SFG, IFG, STL, IPL CR 12 subcortical/8 cortical
I I I H I I H I I I I I I H I I I I I
Left Left Left Left Left Right Left Right Left Left Left Left Right Right Left Right Right Right Right
right right right right right right right right right right right right right right right right right right right
4 4 2 4 3 4 3 2 4 4 3 2 1 4 4 2 4 4 4
I 17 I/3H
Left 12 left/8 right
right 20 right
4 3.3 1.0
BG, CI, CR GTS, CR, T preCG SMA, FSG, preCG CR, preCG, postCG, SPL preCG, CR preCG, CR T CR BG, CR, T BG, CR BG, IC, CR preCG, CR
H I I I I
Left Right Left Right Left
Right Right Right Right Left
4 4 4 4 4
H H I H H H I I I H H I H H I 10 I/10H
Right Right Left Left Right Right Right Left Right Left Right Left Left Left Left 11 left/9 right
Right Right Right Right Right Right Right Right Right Right Left Right Right Right Right 18 right/2 left
3 4 1 2 4 4 4 4 3 2 2 4 4 4 3 3.4 0.9
81 m 68.3 12 m/8 w 10.8 rTMS real 55 w 77 m 73 m 54 w 66 m
0.5 1.6 1.2
74 73 66 47 64 54 77 77 69 52 56 73 68 57 81 65.7 9.9
0.75 4 0.5 1.25 0.75 5 1 2 1 2 1 1.5 2.25 2 2 1.7 1.1
w w m m m w w m w m m m m m m 13 m/7 w
1 0.5 1 3 2
BG, CR GTS, CR, SPL CR, IC Th, IC BG, IC preCG, CR 10 subcortical/9 cortical/1 NA
NIHSS
MMS
BDI
BMRC
SIS
WMFT change to baseline at W3 (points)
6 5 6 7 3 5 7 5 2 6 2 2 0 5 6 1 6 2 6
27 30 27 25 30 17 27 29 29 26 29 30 29 20
8 17 6 9 13
22 2 17 34 4 29 21 17 10 22 20 21 12 21
30 22 29
2 3 0 7
3 4 1 2 1 3 4 3.5 3.5 2 3.5 4.5 5 2 2 4.5 4.5 1 0
20 22 8 21
17 16 15 10 10 10 8 6 4 3 3 2 2 2 1 1 1 1 2
0 4.1 2.3
30 27.0 3.7
16 9.2 8.3
4 2.9 1.4
13 17.7 7.8
8 Mean SD
26 22 28 26 19
1 24 5 0 1
2 3 2 2 1
16 10 17 7 24
25 24 19 15 14
28 29 28 28 25 14 27 25 21 27 29 18 26 22 26 24.7 4.0
19 8 5 8 6 7 14 13 1 9 2 31 17 13 8 9.6 8.0
3 4 4.5 3.5 3 0 1 2 4.5 3.5 4.5 4.5 4.5 3.5 4.5 3.0 1.3
23 4 5 22 28 37 26 25 11 4 8 4 29 31 7 16.9 10.3
13 12 12 12 9 7 4 4 3 3 3 1 0 1 2 Mean SD
3 6 10 7 7 1 2 1 3 6 9 7 6 0 3 0 3 6 8 1 4.5 3.0
5 7 4 37 1 6 14 11
Dominant hand [13]; MMS [14] ¼ Mini Mental Status Examination Score; MRS [15] ¼ Modified Rankin Scale; NIHSS [16] ¼ National Institute of Health Stroke Scale; BDI [17] ¼ Beck’s Depression Inventory; BMRC [18] ¼ British Medical Research Council (wrist extension); SIS [19] ¼ Sensibility Impairment Score; WMFT [20] ¼ Wolf Motor Function Test; T ¼ thalamus; BG ¼ basal ganglia; IC ¼ internal capsule; preCG ¼ gyrus precentralis; postCG ¼ gyrus postzentralis; CR ¼ corona radiata; P ¼ pons; IFG ¼ inferior frontal gyrus; SFG ¼ superior frontal gyrus; STL ¼ superior temporal lobule; IPL ¼ inferior parietal lobule; GTS ¼ gyrus temporalis superior; SPL ¼ superior parietal lobule; SMA ¼ supplementary motor area; I ¼ ischemic; H ¼ haemorrhagic.
was kept constant for each patient during the later evaluation sessions. 20 MEPs were sampled by single pulse TMS for each session and the MEP size was averaged. All evaluations were performed at baseline, after the first week of treatment, after the third week of treatment and 6 months after the last treatment. Analysis All data were analyzed with SPSS Statistics 21. Preliminary analyses assured that the sham rTMS group and 1Hz rTMS group did not differ in age, time from stroke or any of the clinical measures obtained at the baseline assessment (see Table 1). The effect of treatment was evaluated as follows: for each measure, evaluation
after the first week, the third week of training and 6 months later was expressed as the difference to baseline. 7 patients (4 randomized in the 1Hz rTMS group and 3 randomized in the sham rTMS group) were unavailable for the follow-up assessment 6 months after the treatment period. Given obvious differences in the intervention induced behavioral changes of the affected hand in patients with stroke of the dominant (DA) or non-dominant hemisphere (NDA) an additional sub-classification into four subgroups was performed (DA sham, DA 1Hz, NDA sham, NDA 1Hz). The parameter estimates for all conditions were subsequently compared between patients in repeated measures ANOVA, with the factors “intervention” (1Hz rTMS, sham rTMS), “affected hemisphere” (DA, NDA) and “time” (baseline, 1st
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Table 2 Mean values and standard deviation of motor functions tests (WMFT, MESUPES, finger tapping) and cortical excitability measures (MEP). Affected hand Baseline Non dominant hemisphere affected sham rTMS WMFT (points) 42.0 MESUPES (points) 37.4 Finger tapping (speed m/s) 179.5 MEP (size mV) 1Hz rTMS WMFT (points) 44.5 MESUPES (points) 40.6 Finger tapping (speed m/s) 201.2 MEP (size mV) Dominant hemisphere affected sham rTMS WMFT (points) 49.0 MESUPES (points) 44.5 Finger tapping (speed m/s) 162.5 MEP (size mV) 1Hz rTMS WMFT (points) 38.7 MESUPES (points) 35.4 Finger tapping (speed m/s) 138.1 MEP (size mV)
Non affected hand 1 week
3 weeks
6 months
Baseline
1 week
3 weeks
6 months
17.1 13.0 186.6
44.7 17.2a 41.6 12.8c,f 169.2 178.3
48.8 17.1b 45.3 12.1c,f 177.1 143.2
60.2 13.7c,f 49.9 8.3b 277.7 213.7
72.9 58.0 450.4 1.10
2.6 0.0 113.0 0.82
72.9 58.0 420.5 0.84
2.6 0.0 187.5 0.64
72.9 58.0 431.2 1.14
2.6 0.0 155.7 0.60
73.5 58.0 528.5 0.83
2.4 0.0 213.9 0.96
17.0 11.8 178.5
46.8 14.4 44.2 10.9b 204.4 177.2
51.4 14.7a 47.7 8.8c 229.9 170.6
60.1 9.3b 51.9 4.9c 284.9 186.5a
72.3 58.0 420.9 0.96
2.6 0.0 120.0 0.13
72.3 58.0 460.8 1.01
2.6 0.0 119.9a 0.37
72.3 58.0 460.6 0.91
2.6 0.0 111.7 0.47
73.5 58.0 477.1 0.34
2.4 0.0 159.7 0.24c
15.8 12.7 150.8
51.4 16.7 45.4 12.4 178.3 166.4
51.1 15.9 47.4 11.2 187.0 175.7
57.0 17.5 49.2 11.8 224.7 218.1
73.75 58.0 442.4 1.26
2.3 0.0 79.3 0.58
73.75 58.0 452.8 1.45
2.3 0.0 86.7 1.25
73.75 58.0 458.4 1.28
2.3 0.0 82.1 0.83
75.0 58.0 470.6 0.77
0.0 0.0 68.3 1.00
15.4 13.5 161.4
42.3 17.1 40.6 12.6b,d 176.8 194.7
49.9 14.6c,e 43.7 12.6b 206.5 219.0a
56.6 13.8b,d 47.3 11.7b 229.4 181.6a
70.6 58.0 410.0 1.00
1.7 0.0 135.0 0.21
70.6 58.0 465.9 0.85
1.7 0.0 140.2 0.39
70.6 58.0 449.2 0.84
1.7 0.0 86.9 0.37
70.0 58.0 403.9 0.35
0.0 0.0 85.2 0.23c
P 0.05a, P 0.01b, P 0.001c; significant differences in comparison to sham rTMS P 0.05d, P 0.01e; significant difference between non-dominant and dominant hemispheric stroke P 0.05f; WMFT [20] ¼ Wolf Motor Function Test; MESUPES [21] ¼ Motor Evaluation Scale for Upper Extremity in Stroke patients; MEP ¼ Motor Evoked Potentials.
week of treatment, 3rd week of treatment, 6 months after the least treatment). Between groups differences (DA sham vs DA rTMS, NDA sham vs NDA rTMS, DA sham vs NDA sham and DA rTMS vs NDA rTMS) were analyzed using the independent-sample t-tests. The comparisons between pre and post treatment (baseline versus 1st week, baseline versus 3rd week, baseline versus 6 months after the training) were analyzed by means of dependent-sample t-test within each group (DA sham, DA 1Hz, NDA sham, NDA 1Hz). Post hoc tests were carried out using Bonferroni correction. A P-value of 0.05 was considered statistically significant. Using Pearson correlation tests, correlations between changes of motor function of the affected hand and changes in cortical excitability of contralesional M1 were calculated for each intervention group. A correlation coefficient (r) of 0.9e1.0 indicated high correlation, 0.5e0.7 moderate correlation and 0.3e5.0 low correlation. The affected and unaffected hands were tested separately. Results Participants tolerated the interventions well without serious adverse events. There were no significant differences between the interventions groups (DA sham, DA 1Hz, NDA sham, NDA 1Hz) regarding demographic variables, clinical features, affected upper limb function or cortical excitability of the contralesional M1 at the baseline assessment before treatment. Table 2 presents mean values and standard deviations of motor function tests (WMFT, MESUPES and finger tapping) and cortical excitability measures (MEP) for each assessment session (baseline, 1st week of treatment, 3rd week of treatment and 6 months after the last treatment). Figure 2 shows changes of hand motor function and changes of cortical excitability for each evaluation session expressed as absolute difference to the baseline assessment. Affected hand motor function The repeated measures ANOVAs showed significant effects of the factor “time” on WMFT (F3,12 ¼ 19.5; P < 0.001), MESUPES
(F3,12 ¼ 20.3; P < 0.001) and finger tapping (F3,12 ¼ 8.1; P ¼ 0.010). The interaction “intervention” “time” was significant for MESUPES (F3,12 ¼ 67.4; P ¼ 0.017) and the interaction “affected hemisphere” “intervention” “time” was significant for WMFT (F3,12 ¼ 4.9; P ¼ 0.007) and MESUPES (F3,12 ¼ 3.8; P ¼ 0.020). The results of post hoc tests are presented in Fig. 2. Post hoc between groups analyses (independent-sample t-tests) showed no significant differences of the intervention induced behavioral changes of the affected hand between the NDA sham- and NDA rTMS-groups. In contrast, the changes in motor function of the affected hand differed significantly between the DA sham- and DA rTMS-groups for WMFT (W3 and M6) and for MESUPES (W1). Post hoc within group analyses (dependent-sample t-test) for MESUPES, WMFT and finger tapping of the affected hand showed significant changes in motor function of the affected hand only for the DA 1Hz-, NDA sham- and NDA 1Hz-groups over the three weeks training period and 6 months thereafter. The DA sham-group showed no significant change of motor function of the affected upper limb over three weeks of treatment or 6 months later. The change of motor performance of the affected upper limb was significantly greater in the DA rTMS group when compared to the DA sham-group for each motor evaluation. However, the change of motor performance of the affected hand did not differ between the DA rTMS-, NDA sham- and NDA rTMS-groups. The between-groupanalyses showed additional significant differences (P 0.05) between the DA sham- and NDA sham-groups for WMFT (M6) and MESUPES (W1, W3), but no significant difference between the DA sham- and NDA rTMS-groups.
Unaffected hand motor function The repeated measures ANOVA showed no significant effect of any factor or their interactions on motor performance of the unaffected hand. The independent-samples t-test showed no significant between-groups-differences. The dependent-sample t-tests showed a significant improvement of motor performance of the unaffected upper limb for finger tapping (W1) in the NDA 1Hz-group.
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Figure 1. Study protocol: Note that the sub-classification of the intervention groups into stroke of the dominant and non-dominant hemisphere was performed post hoc. NDA ¼ non-dominant hand affected; DA ¼ dominant hand affected; MMS [14] ¼ Mini Mental Status Examination Score; MRS [15] ¼ Modified Rankin Scale; NIHSS [16] ¼ National Institute of Health Stroke Scale; BDI [17] ¼ Beck’s Depression Inventory; BMRC [18] ¼ British Medical Research Council (hand extension); SIS [19] ¼ Sensibility Impairment Score; WMFT [20] ¼ Wolf Motor Function Test; MESUPES [21] ¼ Motor Evaluation Scale for Upper Extremity in Stroke patients; MEP ¼ Motor Evoked Potentials.
Cortical excitability The repeated measures ANOVA did not show significant effects of each factor or their interaction on cortical excitability measures. The independent-sample t-test showed no significant betweengroup-differences. The dependent-sample t-test showed a significant decrease of motor evoked potentials elicited after stimulation of the contralesional M1 for the DA rTMS- and NDA rTMS-groups only at six months follow up. Both sham-groups
showed no significant compared to baseline.
differences
of
cortical
excitability
Correlation Table 3 summarizes the correlation coefficients between changes of motor function of the affected hand and changes in cortical excitability of the contralesional hemisphere for each parameter assessed. There is a consistent negative correlation
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Figure 2. Changes of affected hand motor performance and changes of cortical excitability within contralesional M1 in relation to baseline; significant differences in comparison to baseline P 0.05a, P 0.01b, P 0.001c; significant differences in comparison to sham rTMS P 0.05d, P 0.01e; significant difference between non-dominant and dominant hemispheric stroke P 0.05f.
between changes in motor function and changes in cortical excitability of contralesional M1 at M6, suggesting that the more MEPs reduced in size, the greater hand motor function improved over time. For the assessment at W1 and W3 both negative and positive correlations were found. Discussion The objective of this study was to examine the short and longterm behavioral and neurophysiological effects of a motor
training for the affected hand, preconditioned by either 1Hz rTMS or sham rTMS over the contralesional M1 after stroke affecting either the dominant or non-dominant hemisphere. In summary, our data show e for the first time e that inhibitory rTMS preconditioning of a motor training for the stroke affected hand is useful for patients with stroke of the dominant, but not for those with stroke of the non-dominant hemisphere. It appears as if patients with stroke of the dominant hemisphere make an inferior motor recovery of the affected hand during motor training, which can be enhanced by inhibition of M1 of the contralesional
J. Lüdemann-Podubecká et al. / Brain Stimulation xxx (2015) 1e8 Table 3 Correlation coefficients between changes of motor function of the affected hand and changes of cortical excitability of contralesional M1. sham rTMS W1
W3
Non-dominant hemisphere affected WMFT e MEP 0.04 0.31 MESUPES e MEP 0.07 0.24 Finger Tapping e MEP 0.00 0.19 Dominant hemisphere affected WMFT e MEP 0.18 0.20 MESUPES e MEP 0.07 0.29 Finger Tapping e MEP 0.41 0.07
1Hz rTMS M6
W1
W3
M6
0.18 0.50 0.64
0.57 0.36 0.15
0.56 0.23 0.21
0.21 0.43 0.31
0.72 0.34 0.42
0.41 0.33 0.20
0.20 0.20 0.44
0.34 0.26 0.25
WMFT [20] ¼ Wolf Motor Function Test; MESUPES [21] ¼ Motor Evaluation Scale for Upper Extremity in Stroke patients; MEP ¼ Motor Evoked Potentials.
hemisphere. In contrast, patients with stroke of the non-dominant hemisphere respond well to a motor training for the affected hand, which cannot be enhanced by inhibition of M1 of the contralesional hemisphere. Earlier data suggest that motor recovery after stroke is influenced by dominance or non-dominance of the affected hemisphere, and that stroke of the dominant hemisphere is commonly associated with a less favorable motor outcome of the affected hand. For example, a study in monkeys showed a strong negative correlation between the degree of handedness and the recovery of the affected hand following brain injury of the hemisphere contralateral to the preferred hand [22]. Also a human study showed that patients with left (dominant) hemispheric stroke took two to three times longer to learn a sequential finger movement task with either hand in comparison to those with stroke of the non-dominant hemisphere [23]. Until today, only a few studies addressed the issue of how noninvasive brain stimulation interferes with motor performance and motor learning in healthy humans in dependence of hemispheric dominance [24]. In particular, motor skill learning was significantly greater with facilitatory transcranial direct current stimulation applied over the left (dominant) M1 compared to application over the right (non-dominant) M1. Similar data on the influence of hemispheric dominance on the effectiveness of non-invasive brain stimulation for motor recovery of the affected hand after stroke do not exist. Our data imply that the dominant hemisphere plays a crucial role for motor re-learning after brain injury and are of high relevance for motor rehabilitation after stroke. A reasonable explanation for the differential effectiveness of rTMS preconditioning of a motor training in dominant and non-dominant hemispheric stroke may be an asymmetric motor representation of the upper limb within both hemispheres [25e27]. A TMS study demonstrated greater interhemispheric inhibition from the dominant towards the non-dominant hemisphere during activation of the contralateral hand in healthy subjects [8]. Another TMS study demonstrated greater increases of cortical excitability in dominant (left) M1 than non-dominant (right) M1 during ipsilateral hand movements [25]. After stroke, interhemispheric inhibition from the contralesional towards the ipsilesional hemisphere is influenced by hemispheric dominance in a way that interhemispheric inhibition is greater when the non-dominant hemisphere is affected [8]. In a recent fMRI study reduced ipsilateral premotor and increased contralateral sensorimotor neural activations have been found in patients with dominant (left) hemispheric stroke, compared to those with non-dominant (right) hemispheric stroke [9]. Within the concept of interhemispheric inhibition, this may be interpreted to be the result of a stronger transcallosal inhibitory drive towards the ipsilesional hemisphere after stroke in the dominant hemisphere. Our neurophysiological data showed no significant short-term, but a significant long-term effect of 1Hz rTMS preconditioning of
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a motor training for the affected hand, e.g. a decrease of cortical excitability of the contralesional M1 at 6 months after the intervention. The inhibitory effect of 1Hz rTMS has also been demonstrated by numerous previous studies [12]. A major finding of our study was that despite differential effects on motor recovery of the affected hand, preconditioning with inhibitory rTMS did not cause similar differential effects on changes of cortical excitability in dependence on lesion site. Indeed, the results of our correlation analyses were highly variable and inconclusive for weeks one and three of the intervention. A possible explanation for this may be an obvious limitation of the explanation model of interhemispheric rivalry after stroke, which addresses an inferior motor improvement of the affected hand simply to an enhanced cortical excitability of the contralesional hemisphere. Recent fMRI and TMS studies, however, describe stroke induced changes of functional and effective neural connectivity within a huge variety of sensorimotor brain areas of both hemispheres and came up with novel surrogate markers of both beneficial and maladaptive plasticity [4]. For example, the amount of motor impairment was associated with reduced functional connectivity between ipsi- and contralesional M1 and also with changes of functional connectivity between ipsilesional M1 and several other brain areas [25e27]. At 6 months after the intervention a negative correlation between the change of motor performance of the affected hand and the change in cortical excitability was found. This observation holds true for both sham and 1Hz rTMS preconditioning and for both dominant and non-dominant hemispheric stroke. One may consider to interpret these data in accordance with the theory that cortical excitability enhancement within the contralesional hemisphere is maladaptive for motor recovery after stroke.
References [1] Jørgensen HS, Nakayama H, Raaschou HO, Vive-Larsen J, Støier M, Olsen TS. Outcome and time course of recovery in stroke. Part II: time course of recovery. The Copenhagen Stroke Study. Arch Phys Med Rehabil 1995;76:406e12. [2] Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to the TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001;32:2735e40. [3] Nowak DA, Grefkes C, Ameli M, Fink GR. Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair 2009;23:641e56. [4] Grefkes C, Ward NS. Cortical reorganization after stroke: how much and how functional? Neuroscientist 2014;20:56e70. [5] Lüdemann-Podubecká J, Bösl K, Nowak DA. Repetitive transcranial magnetic stimulation for motor recovery of the upper limb after stroke. A Review. Prog Brain Res 2015 [In press]. [6] Hsu WY, Cheng CH, Liao KK, Lee IH, Lin YY. Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: a metaanalysis. Stroke 2012;43:1849e57. [7] Hao Z, Wang D, Zeng Y, Liu M. Repetitive transcranial magnetic stimulation for improving function after stroke. Cochrane Database Syst Rev 2013;5: CD008862. [8] Lewis GN, Perreault EJ. Side of lesion influences interhemispheric inhibition in subjects with post-stroke hemiparesis. Clin Neurophysiol 2007;118:2656e63. [9] Zemke AC, Heagerty PJ, Lee C, Cramer SC. Motor cortex organization after stroke is related to side of stroke and level of recovery. Stroke 2003;34:23e8. [10] Ameli M, Grefkes C, Kemper F, et al. Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke. Ann Neurol 2009;66:298e309. [11] 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;55:1147e58. [12] Fitzgerald PB, Fountain S, Daskalakis ZJ. A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Clin Neurophysiol 2006;117:2584e96. [13] Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97e113.
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[14] Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189e98. [15] van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604e7. [16] Brott T, Adams Jr HP, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864e70. [17] Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. San Antonio: Psychological Corporation; 1996. [18] Medical Research Council. Aids to the examination of the peripheral nervous system. Memorandum No. 45. London: Her Majesty’s Stationery Office; 1981. [19] Nowak DA, Grefkes C, Dafotakis M, Küst J, Karbe H, Fink GR. Dexterity is impaired at both hands following unilateral subcortical middle cerebral artery stroke. Eur J Neurosci 2007;25:3173e84. [20] Wolf SL, Catlin PA, Ellis M, Archer AL, Morgan B, Piacentino A. Assessing Wolf motor function test as outcome measure for research in patients after stroke. Stroke 2001;32:1635e9. [21] Van de Winckel A, Feys H, van der Knaap S, et al. Can quality of movement be measured? Rasch analysis and inter-rater reliability of the Motor Evaluation
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Scale for Upper Extremity in Stroke Patients (MESUPES). Clin Rehabil 2006;20:871e84. Darling WG, Helle N, Pizzimenti MA, et al. Laterality affects spontaneous recovery of contralateral hand motor function following motor cortex injury in rhesus monkeys. Exp Brain Res 2013;228:9e24. Kimura D. Acquistion of motor skill after left-hemisphere damage. Brain 1997;100:527e42. Schambra HM, Abe M, Luckenbaugh DA, Reis J, Krakauer JW, Cohen LG. Probing for hemispheric specialization for motor skill learning: a transcranial direct current stimulation study. J Neurophysiol 2011;106:652e61. Bai O, Mari Z, Vorbach S, Hallett M. Asymmetric spatiotemporal pattern of event-related desynchronization preceding voluntary sequential finger movements: a high-resolution EEG study. Clin Neurophysiol 2005;116: 1213e21. Bensmail D, Sarfeld AS, Ameli M, Fink GR, Nowak DA. Arbitrary visuomotor mapping in the grip-lift task: dissociation of performance deficits in right and left middle cerebral artery stroke. Neuroscience 2012;210:128e36. Ziemann U, Halett M. Hemispheric asymmetry of ipsilateral motor cortex activation during unimanual motor task further evidence for motor dominance. Clin Neurophysiol 2001;112:107e13.
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Original Research
The Effectiveness of 1Hz rTMS Over the Primary Motor Area of the Unaffected Hemisphere to Improve Hand Function After Stroke Depends on Hemispheric Dominance Jitka Lüdemann-Podubecká a, *, Kathrin Bösl a, Steven Theilig a, Ralf Wiederer a, Dennis Alexander Nowak a, b a b
Helios Klinik Kipfenberg, Neurologische Fachklinik, Kipfenberg, Germany Department of Neurology, University Hospital, Philips-University, Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 October 2014 Received in revised form 4 February 2015 Accepted 8 February 2015 Available online xxx
Objective: Inhibition of motor cortex excitability of the contralesional hemisphere may improve dexterity of the affected hand after stroke. Methods: 40 patients (17 dominant hemispheric stroke, 23 non-dominant hemispheric stroke) with a mild to moderate upper limb motor impairment were enrolled in a double-blind, randomized, placebocontrolled trial with two parallel-groups. Both groups received 15 daily sessions of motor training preceded by either 1Hz rTMS or sham rTMS. Behavioral and neurophysiological evaluations were performed at baseline, after the first week and after the third week of treatment, and after a 6 months follow-up. Results: In both groups motor function of the affected hand improved significantly. Patients with stroke of the non-dominant hemisphere made a similar improvement, regardless of whether the motor training was preceded by sham or 1Hz rTMS. Patients with stroke of the dominant hemisphere had a less favorable improvement than those with stroke of the non-dominant hemisphere after motor training preceded by sham rTMS. However, when 1Hz rTMS preceded the motor training, patients with stroke of the dominant hemisphere made a similar improvement as those with stroke of the non-dominant hemisphere. Interpretation: Motor recovery of the affected upper limb after stroke is determined by dominance of the affected hemisphere. Stroke of the dominant hemisphere is associated with per se poorer improvement of the affected hand. 1Hz rTMS over the contralesional M1 significantly improves dexterity of the affected hand in patients with stroke of the dominant hemisphere, but not in those with stroke of the nondominant hemisphere. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Stroke Repetitive transcranial magnetic stimulation Motor impairment Upper limb Hand dominance
Introduction More than 50% of stroke-victims retain permanent neurological impairments with motor impairment being the most frequent. Abbreviations: Dominant hemisphere, left hemisphere by right-handed volunteers, right hemisphere by left-handed volunteers; TMS, transcranial magnetic stimulation; rTMS, repetitive transcranial magnetic stimulation; MEP, Motor Evoked Potential; FDI, first dorsal interosseus muscle; BL, baseline evaluation; W1, evaluation after the first week of treatment; W3, evaluation after the third week of treatment; M6, follow-up examination 6 months after the last treatment; DA, dominant hemisphere affected; NDA, non-dominant hemisphere affected; M1, primary motor cortex; rMT, resting motor threshold; WMFT, Wolf Motor Function Test; MESUPES, Motor Evaluation Scale for Upper Extremity in Stroke Patients. * Corresponding author. Helios Klinik Kipfenberg, Neurologische Fachklinik, Kindingerstraße 13, D-85110 Kipfenberg, Germany. Tel.: þ49 (0)8465 175 66 131; fax: þ49 (0)8465 175 184. E-mail address: [email protected] (J. Lüdemann-Podubecká). http://dx.doi.org/10.1016/j.brs.2015.02.004 1935-861X/Ó 2015 Elsevier Inc. All rights reserved.
Among these patients, about 80% suffer from grasping deficits [1]. In about two thirds of stroke-victims impaired dexterity persists for up to 6 months after the stroke [2]. Given these epidemiological facts, novel treatment concepts for upper limb rehabilitation after stroke are urgently needed. The increasing interest in the application of rTMS in stroke rehabilitation is based on the fact that rTMS modulates excitability within the cortical motor network and thereby allows direct interference with neural plasticity [3]. Several changes in neural activity have been observed after unilateral stroke and until today, it is unclear if theses represent beneficial or detrimental plasticity [4]. Nevertheless, rTMS to promote motor recovery of the affected hand after stroke is widely used in reference to a so called interhemispheric imbalance model [3]. This concept describes the plastic changes within the cerebral motor network induced by stroke as a “disruption of the physiological balance” between both
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hemispheres with a “shift” of neural activity towards the nonlesioned hemisphere for movements of the affected hand. Within this concept of maladaptive plasticity after stroke it has been postulated that the increased activity within motor areas of the contralesional hemisphere and the inhibitory influence towards motor areas of the ipsilesional hemisphere may have a negative impact on recovery of the affected hand [4]. In this context, it has been demonstrated e on a group level e that either up-regulation of excitability of the ipsilesional primary motor area (M1) or down-regulation of excitability of contralesional M1 may improve dexterity of the affected hand after stroke [5e7]. Although rTMS is increasingly used in stroke rehabilitation, the mechanisms underlying the plastic changes of neural activity within the motor network of both hemispheres after stroke and their impact on motor recovery of the affected hand are not completely understood [4]. In particular, the above mentioned changes in neural activation throughout the cortical motor network develop in dependence of the hemisphere affected [8,9], the location and distribution of the lesion [10] and the time from stroke [11], among other factors, which may then again influence the effectiveness of an rTMS treatment. Consequently, pertinent metaanalyses are inconclusive, suggesting either a positive effect of rTMS on motor recovery of the stroke affected hand or no effect at all [5e7]. Given the short-living effects of rTMS on motor cortex excitability [12], an increasing number of studies apply rTMS over several sessions in combination with motor training for the affected hand after stroke [5e7]. Here we investigated the long-term effectiveness of preconditioning a three-week motor training for the stroke affected hand by inhibitory (1Hz) rTMS in a double-blind sham-controlled trial. We will show that e after a sub-classification of the cohort e 1Hz rTMS over the contralesional M1 significantly improves dexterity of the affected hand in patients with stroke of the dominant hemisphere, but not in those with stroke of the non-dominant hemisphere. Methods Participants 40 patients with a mild to moderate sensory-motor deficit of the hand after stroke were consecutively enrolled. 38 of them were right handed and two were left handed. Hand dominance was tested by a self-report questionnaire [13]. Demographic details of each patient are summarized in Table 1. Inclusion criteria were: 1) first-ever stroke within the last 6 months, 2) location of the lesion within the territory of the middle cerebral artery, 3) mild to moderate motor and/or sensory deficit of one hand, 4) preserved motor evoked potentials (MEP) at the first dorsal interosseus (FDI) muscle of the affected hand after single pulse TMS applied over the hand area of the ipsilesional M1. We excluded patients with relevant aphasia or cognitive impairments, which might interfere with the understanding of instructions for motor testing. None of the participants had apraxia, neglect, visual field deficits, psychiatric or coexistent general neurological, medical or orthopedic illness or accepted contraindications for TMS (pacemakers, metallic objects in the head, history of epilepsy, etc.). The study was approved by the local Ethics committee. All patients gave their written informed consent prior to participation. Each patient was informed about the possibility to be randomized in the sham rTMS group (Table 2) Study design The study was a prospective, randomized, double-blind, longitudinal, parallel- and factorial-design, sham-controlled trial that
had several phases: (1) randomization, (2) baseline evaluation (BL), (3) treatment during the first week, (4) evaluation after the first week of treatment (W1), (5) treatment during the second and third week, (6) evaluation after the third week of treatment (W3), (7) follow-up examination 6 months after the last treatment (M6). Using sealed envelopes, the subjects were randomly assigned to one of two experimental groups (real rTMS, sham rTMS) in a 1:1 ratio (see Fig. 1). Intervention Treatment lasted 15 working days with two time-locked daily interventions: 1) 15 min of real/sham 1Hz rTMS and 2) 30 min of standard task-oriented upper-limb motor-training. RTMS was performed using a 70-mm figure-of-eight coil connected to a Magstim Super Rapid stimulator (Magstim Company, Dyfed, UK). Participants were instructed to sit in a comfortable chair with both hands placed on the armrest in a relaxed position, and they were asked to stay awake during the procedure. Adherence to these instructions was supervised by the experimenter throughout the experiments. The coil was placed tangentially in a posterioreanterior plane over the motor representation of the first dorsal interosseous muscle (FDI) of the contralesional M1. For real rTMS a single train of 900 pulses at 100% of the resting motor threshold (rMT) was administered. For sham rTMS a single train of 900 pulses at 0% of rMT was applied at the very same position. RMT was defined as the lowest stimulator output intensity that elicited a motor evoked potential (MEP) in the contralateral FDI with a peak-to-peak amplitude of at least 50 mV in at least 5 out of 10 trials. All participants were blinded to the rTMS condition and none of them had any experience with rTMS before study participation. The motor training aimed to exercise hand dexterity with a set of different daily routine tasks, including grasping and manipulating objects, e.g. folding a towel, modeling with modeling clay, donning a t-shirt, opening and closing a tube or a bottle, drawing, playing “memory”. The tasks were selected according to the subject’s actual functional status and increased in difficulty and complexity on a day by day basis (shaping). The training was applied by an experienced occupational therapist, who was completely blind regarding group allocation of the individual subject, in one-to-one daily training sessions lasting 30 min each. Assessments Outcome assessments included measures of hand dexterity and cortical excitability. These were obtained by a different therapist blinded to group allocation. Motor function of both the affected and the unaffected hands were assessed. The Wolf Motor Function Test (WMFT) [20], the Motor Evaluation Scale for Upper Extremity in Stroke Patients (MESUPES) [21] and the velocity of index finger tapping were used. The velocity of finger tapping was recorded using an ultrasonic motion analyzer described in detail elsewhere [19]. Peak movement amplitude was specified to 2.0 cm. For cortical excitability measures the same stimulation system, coil placement and recording procedure were used, as detailed above. Volunteers were instructed to sit in a comfortable chair with both hands placed on the armrest in a relaxed position, and they were asked to stay awake during the procedure. The coil was placed tangentially in a posterioreanterior plane on the skull overlying the area representing the FDI of the contralesional M1. Electromyographic activity was recorded from silveresilver-chloride electrodes positioned in a belly-tendon montage on the skin overlying the FDI. Stimulation intensity was individually defined once for each patient during the baseline evaluations as the intensity to evoke a peak-to-peak MEP of 1 mV size. This stimulation intensity
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Table 1 Demographic data and lesion location for each participant. Age (years)
Sex
rTMS sham 76 w 50 w 71 m 74 m 55 w 86 w 48 m 58 m 65 m 84 w 58 m 62 m 76 w 65 m 76 m 65 m 79 w 73 w 63 m
Time from stroke (months)
Stroke location
Stroke etiology
Affected hand
Dominant hand
MRS
0.5 1 1 0.5 1.25 1.5 1.75 1 1 1.5 1.5 5 3 1 3.5 0.25 1.5 3 2
IC, BG P preCG, postCG, CR T, BG, IC BG, IC CR, BG, IFG CR IFG, CR, preCG preCG, CR CR, BG preCG, CR, IFG BG, CR, IC CR preCG, IFG SFG, CR T T, IC IC, CR preCG, postCG, CR, BG, SFG, IFG, STL, IPL CR 12 subcortical/8 cortical
I I I H I I H I I I I I I H I I I I I
Left Left Left Left Left Right Left Right Left Left Left Left Right Right Left Right Right Right Right
right right right right right right right right right right right right right right right right right right right
4 4 2 4 3 4 3 2 4 4 3 2 1 4 4 2 4 4 4
I 17 I/3H
Left 12 left/8 right
right 20 right
4 3.3 1.0
BG, CI, CR GTS, CR, T preCG SMA, FSG, preCG CR, preCG, postCG, SPL preCG, CR preCG, CR T CR BG, CR, T BG, CR BG, IC, CR preCG, CR
H I I I I
Left Right Left Right Left
Right Right Right Right Left
4 4 4 4 4
H H I H H H I I I H H I H H I 10 I/10H
Right Right Left Left Right Right Right Left Right Left Right Left Left Left Left 11 left/9 right
Right Right Right Right Right Right Right Right Right Right Left Right Right Right Right 18 right/2 left
3 4 1 2 4 4 4 4 3 2 2 4 4 4 3 3.4 0.9
81 m 68.3 12 m/8 w 10.8 rTMS real 55 w 77 m 73 m 54 w 66 m
0.5 1.6 1.2
74 73 66 47 64 54 77 77 69 52 56 73 68 57 81 65.7 9.9
0.75 4 0.5 1.25 0.75 5 1 2 1 2 1 1.5 2.25 2 2 1.7 1.1
w w m m m w w m w m m m m m m 13 m/7 w
1 0.5 1 3 2
BG, CR GTS, CR, SPL CR, IC Th, IC BG, IC preCG, CR 10 subcortical/9 cortical/1 NA
NIHSS
MMS
BDI
BMRC
SIS
WMFT change to baseline at W3 (points)
6 5 6 7 3 5 7 5 2 6 2 2 0 5 6 1 6 2 6
27 30 27 25 30 17 27 29 29 26 29 30 29 20
8 17 6 9 13
22 2 17 34 4 29 21 17 10 22 20 21 12 21
30 22 29
2 3 0 7
3 4 1 2 1 3 4 3.5 3.5 2 3.5 4.5 5 2 2 4.5 4.5 1 0
20 22 8 21
17 16 15 10 10 10 8 6 4 3 3 2 2 2 1 1 1 1 2
0 4.1 2.3
30 27.0 3.7
16 9.2 8.3
4 2.9 1.4
13 17.7 7.8
8 Mean SD
26 22 28 26 19
1 24 5 0 1
2 3 2 2 1
16 10 17 7 24
25 24 19 15 14
28 29 28 28 25 14 27 25 21 27 29 18 26 22 26 24.7 4.0
19 8 5 8 6 7 14 13 1 9 2 31 17 13 8 9.6 8.0
3 4 4.5 3.5 3 0 1 2 4.5 3.5 4.5 4.5 4.5 3.5 4.5 3.0 1.3
23 4 5 22 28 37 26 25 11 4 8 4 29 31 7 16.9 10.3
13 12 12 12 9 7 4 4 3 3 3 1 0 1 2 Mean SD
3 6 10 7 7 1 2 1 3 6 9 7 6 0 3 0 3 6 8 1 4.5 3.0
5 7 4 37 1 6 14 11
Dominant hand [13]; MMS [14] ¼ Mini Mental Status Examination Score; MRS [15] ¼ Modified Rankin Scale; NIHSS [16] ¼ National Institute of Health Stroke Scale; BDI [17] ¼ Beck’s Depression Inventory; BMRC [18] ¼ British Medical Research Council (wrist extension); SIS [19] ¼ Sensibility Impairment Score; WMFT [20] ¼ Wolf Motor Function Test; T ¼ thalamus; BG ¼ basal ganglia; IC ¼ internal capsule; preCG ¼ gyrus precentralis; postCG ¼ gyrus postzentralis; CR ¼ corona radiata; P ¼ pons; IFG ¼ inferior frontal gyrus; SFG ¼ superior frontal gyrus; STL ¼ superior temporal lobule; IPL ¼ inferior parietal lobule; GTS ¼ gyrus temporalis superior; SPL ¼ superior parietal lobule; SMA ¼ supplementary motor area; I ¼ ischemic; H ¼ haemorrhagic.
was kept constant for each patient during the later evaluation sessions. 20 MEPs were sampled by single pulse TMS for each session and the MEP size was averaged. All evaluations were performed at baseline, after the first week of treatment, after the third week of treatment and 6 months after the last treatment. Analysis All data were analyzed with SPSS Statistics 21. Preliminary analyses assured that the sham rTMS group and 1Hz rTMS group did not differ in age, time from stroke or any of the clinical measures obtained at the baseline assessment (see Table 1). The effect of treatment was evaluated as follows: for each measure, evaluation
after the first week, the third week of training and 6 months later was expressed as the difference to baseline. 7 patients (4 randomized in the 1Hz rTMS group and 3 randomized in the sham rTMS group) were unavailable for the follow-up assessment 6 months after the treatment period. Given obvious differences in the intervention induced behavioral changes of the affected hand in patients with stroke of the dominant (DA) or non-dominant hemisphere (NDA) an additional sub-classification into four subgroups was performed (DA sham, DA 1Hz, NDA sham, NDA 1Hz). The parameter estimates for all conditions were subsequently compared between patients in repeated measures ANOVA, with the factors “intervention” (1Hz rTMS, sham rTMS), “affected hemisphere” (DA, NDA) and “time” (baseline, 1st
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Table 2 Mean values and standard deviation of motor functions tests (WMFT, MESUPES, finger tapping) and cortical excitability measures (MEP). Affected hand Baseline Non dominant hemisphere affected sham rTMS WMFT (points) 42.0 MESUPES (points) 37.4 Finger tapping (speed m/s) 179.5 MEP (size mV) 1Hz rTMS WMFT (points) 44.5 MESUPES (points) 40.6 Finger tapping (speed m/s) 201.2 MEP (size mV) Dominant hemisphere affected sham rTMS WMFT (points) 49.0 MESUPES (points) 44.5 Finger tapping (speed m/s) 162.5 MEP (size mV) 1Hz rTMS WMFT (points) 38.7 MESUPES (points) 35.4 Finger tapping (speed m/s) 138.1 MEP (size mV)
Non affected hand 1 week
3 weeks
6 months
Baseline
1 week
3 weeks
6 months
17.1 13.0 186.6
44.7 17.2a 41.6 12.8c,f 169.2 178.3
48.8 17.1b 45.3 12.1c,f 177.1 143.2
60.2 13.7c,f 49.9 8.3b 277.7 213.7
72.9 58.0 450.4 1.10
2.6 0.0 113.0 0.82
72.9 58.0 420.5 0.84
2.6 0.0 187.5 0.64
72.9 58.0 431.2 1.14
2.6 0.0 155.7 0.60
73.5 58.0 528.5 0.83
2.4 0.0 213.9 0.96
17.0 11.8 178.5
46.8 14.4 44.2 10.9b 204.4 177.2
51.4 14.7a 47.7 8.8c 229.9 170.6
60.1 9.3b 51.9 4.9c 284.9 186.5a
72.3 58.0 420.9 0.96
2.6 0.0 120.0 0.13
72.3 58.0 460.8 1.01
2.6 0.0 119.9a 0.37
72.3 58.0 460.6 0.91
2.6 0.0 111.7 0.47
73.5 58.0 477.1 0.34
2.4 0.0 159.7 0.24c
15.8 12.7 150.8
51.4 16.7 45.4 12.4 178.3 166.4
51.1 15.9 47.4 11.2 187.0 175.7
57.0 17.5 49.2 11.8 224.7 218.1
73.75 58.0 442.4 1.26
2.3 0.0 79.3 0.58
73.75 58.0 452.8 1.45
2.3 0.0 86.7 1.25
73.75 58.0 458.4 1.28
2.3 0.0 82.1 0.83
75.0 58.0 470.6 0.77
0.0 0.0 68.3 1.00
15.4 13.5 161.4
42.3 17.1 40.6 12.6b,d 176.8 194.7
49.9 14.6c,e 43.7 12.6b 206.5 219.0a
56.6 13.8b,d 47.3 11.7b 229.4 181.6a
70.6 58.0 410.0 1.00
1.7 0.0 135.0 0.21
70.6 58.0 465.9 0.85
1.7 0.0 140.2 0.39
70.6 58.0 449.2 0.84
1.7 0.0 86.9 0.37
70.0 58.0 403.9 0.35
0.0 0.0 85.2 0.23c
P 0.05a, P 0.01b, P 0.001c; significant differences in comparison to sham rTMS P 0.05d, P 0.01e; significant difference between non-dominant and dominant hemispheric stroke P 0.05f; WMFT [20] ¼ Wolf Motor Function Test; MESUPES [21] ¼ Motor Evaluation Scale for Upper Extremity in Stroke patients; MEP ¼ Motor Evoked Potentials.
week of treatment, 3rd week of treatment, 6 months after the least treatment). Between groups differences (DA sham vs DA rTMS, NDA sham vs NDA rTMS, DA sham vs NDA sham and DA rTMS vs NDA rTMS) were analyzed using the independent-sample t-tests. The comparisons between pre and post treatment (baseline versus 1st week, baseline versus 3rd week, baseline versus 6 months after the training) were analyzed by means of dependent-sample t-test within each group (DA sham, DA 1Hz, NDA sham, NDA 1Hz). Post hoc tests were carried out using Bonferroni correction. A P-value of 0.05 was considered statistically significant. Using Pearson correlation tests, correlations between changes of motor function of the affected hand and changes in cortical excitability of contralesional M1 were calculated for each intervention group. A correlation coefficient (r) of 0.9e1.0 indicated high correlation, 0.5e0.7 moderate correlation and 0.3e5.0 low correlation. The affected and unaffected hands were tested separately. Results Participants tolerated the interventions well without serious adverse events. There were no significant differences between the interventions groups (DA sham, DA 1Hz, NDA sham, NDA 1Hz) regarding demographic variables, clinical features, affected upper limb function or cortical excitability of the contralesional M1 at the baseline assessment before treatment. Table 2 presents mean values and standard deviations of motor function tests (WMFT, MESUPES and finger tapping) and cortical excitability measures (MEP) for each assessment session (baseline, 1st week of treatment, 3rd week of treatment and 6 months after the last treatment). Figure 2 shows changes of hand motor function and changes of cortical excitability for each evaluation session expressed as absolute difference to the baseline assessment. Affected hand motor function The repeated measures ANOVAs showed significant effects of the factor “time” on WMFT (F3,12 ¼ 19.5; P < 0.001), MESUPES
(F3,12 ¼ 20.3; P < 0.001) and finger tapping (F3,12 ¼ 8.1; P ¼ 0.010). The interaction “intervention” “time” was significant for MESUPES (F3,12 ¼ 67.4; P ¼ 0.017) and the interaction “affected hemisphere” “intervention” “time” was significant for WMFT (F3,12 ¼ 4.9; P ¼ 0.007) and MESUPES (F3,12 ¼ 3.8; P ¼ 0.020). The results of post hoc tests are presented in Fig. 2. Post hoc between groups analyses (independent-sample t-tests) showed no significant differences of the intervention induced behavioral changes of the affected hand between the NDA sham- and NDA rTMS-groups. In contrast, the changes in motor function of the affected hand differed significantly between the DA sham- and DA rTMS-groups for WMFT (W3 and M6) and for MESUPES (W1). Post hoc within group analyses (dependent-sample t-test) for MESUPES, WMFT and finger tapping of the affected hand showed significant changes in motor function of the affected hand only for the DA 1Hz-, NDA sham- and NDA 1Hz-groups over the three weeks training period and 6 months thereafter. The DA sham-group showed no significant change of motor function of the affected upper limb over three weeks of treatment or 6 months later. The change of motor performance of the affected upper limb was significantly greater in the DA rTMS group when compared to the DA sham-group for each motor evaluation. However, the change of motor performance of the affected hand did not differ between the DA rTMS-, NDA sham- and NDA rTMS-groups. The between-groupanalyses showed additional significant differences (P 0.05) between the DA sham- and NDA sham-groups for WMFT (M6) and MESUPES (W1, W3), but no significant difference between the DA sham- and NDA rTMS-groups.
Unaffected hand motor function The repeated measures ANOVA showed no significant effect of any factor or their interactions on motor performance of the unaffected hand. The independent-samples t-test showed no significant between-groups-differences. The dependent-sample t-tests showed a significant improvement of motor performance of the unaffected upper limb for finger tapping (W1) in the NDA 1Hz-group.
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Figure 1. Study protocol: Note that the sub-classification of the intervention groups into stroke of the dominant and non-dominant hemisphere was performed post hoc. NDA ¼ non-dominant hand affected; DA ¼ dominant hand affected; MMS [14] ¼ Mini Mental Status Examination Score; MRS [15] ¼ Modified Rankin Scale; NIHSS [16] ¼ National Institute of Health Stroke Scale; BDI [17] ¼ Beck’s Depression Inventory; BMRC [18] ¼ British Medical Research Council (hand extension); SIS [19] ¼ Sensibility Impairment Score; WMFT [20] ¼ Wolf Motor Function Test; MESUPES [21] ¼ Motor Evaluation Scale for Upper Extremity in Stroke patients; MEP ¼ Motor Evoked Potentials.
Cortical excitability The repeated measures ANOVA did not show significant effects of each factor or their interaction on cortical excitability measures. The independent-sample t-test showed no significant betweengroup-differences. The dependent-sample t-test showed a significant decrease of motor evoked potentials elicited after stimulation of the contralesional M1 for the DA rTMS- and NDA rTMS-groups only at six months follow up. Both sham-groups
showed no significant compared to baseline.
differences
of
cortical
excitability
Correlation Table 3 summarizes the correlation coefficients between changes of motor function of the affected hand and changes in cortical excitability of the contralesional hemisphere for each parameter assessed. There is a consistent negative correlation
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Figure 2. Changes of affected hand motor performance and changes of cortical excitability within contralesional M1 in relation to baseline; significant differences in comparison to baseline P 0.05a, P 0.01b, P 0.001c; significant differences in comparison to sham rTMS P 0.05d, P 0.01e; significant difference between non-dominant and dominant hemispheric stroke P 0.05f.
between changes in motor function and changes in cortical excitability of contralesional M1 at M6, suggesting that the more MEPs reduced in size, the greater hand motor function improved over time. For the assessment at W1 and W3 both negative and positive correlations were found. Discussion The objective of this study was to examine the short and longterm behavioral and neurophysiological effects of a motor
training for the affected hand, preconditioned by either 1Hz rTMS or sham rTMS over the contralesional M1 after stroke affecting either the dominant or non-dominant hemisphere. In summary, our data show e for the first time e that inhibitory rTMS preconditioning of a motor training for the stroke affected hand is useful for patients with stroke of the dominant, but not for those with stroke of the non-dominant hemisphere. It appears as if patients with stroke of the dominant hemisphere make an inferior motor recovery of the affected hand during motor training, which can be enhanced by inhibition of M1 of the contralesional
J. Lüdemann-Podubecká et al. / Brain Stimulation xxx (2015) 1e8 Table 3 Correlation coefficients between changes of motor function of the affected hand and changes of cortical excitability of contralesional M1. sham rTMS W1
W3
Non-dominant hemisphere affected WMFT e MEP 0.04 0.31 MESUPES e MEP 0.07 0.24 Finger Tapping e MEP 0.00 0.19 Dominant hemisphere affected WMFT e MEP 0.18 0.20 MESUPES e MEP 0.07 0.29 Finger Tapping e MEP 0.41 0.07
1Hz rTMS M6
W1
W3
M6
0.18 0.50 0.64
0.57 0.36 0.15
0.56 0.23 0.21
0.21 0.43 0.31
0.72 0.34 0.42
0.41 0.33 0.20
0.20 0.20 0.44
0.34 0.26 0.25
WMFT [20] ¼ Wolf Motor Function Test; MESUPES [21] ¼ Motor Evaluation Scale for Upper Extremity in Stroke patients; MEP ¼ Motor Evoked Potentials.
hemisphere. In contrast, patients with stroke of the non-dominant hemisphere respond well to a motor training for the affected hand, which cannot be enhanced by inhibition of M1 of the contralesional hemisphere. Earlier data suggest that motor recovery after stroke is influenced by dominance or non-dominance of the affected hemisphere, and that stroke of the dominant hemisphere is commonly associated with a less favorable motor outcome of the affected hand. For example, a study in monkeys showed a strong negative correlation between the degree of handedness and the recovery of the affected hand following brain injury of the hemisphere contralateral to the preferred hand [22]. Also a human study showed that patients with left (dominant) hemispheric stroke took two to three times longer to learn a sequential finger movement task with either hand in comparison to those with stroke of the non-dominant hemisphere [23]. Until today, only a few studies addressed the issue of how noninvasive brain stimulation interferes with motor performance and motor learning in healthy humans in dependence of hemispheric dominance [24]. In particular, motor skill learning was significantly greater with facilitatory transcranial direct current stimulation applied over the left (dominant) M1 compared to application over the right (non-dominant) M1. Similar data on the influence of hemispheric dominance on the effectiveness of non-invasive brain stimulation for motor recovery of the affected hand after stroke do not exist. Our data imply that the dominant hemisphere plays a crucial role for motor re-learning after brain injury and are of high relevance for motor rehabilitation after stroke. A reasonable explanation for the differential effectiveness of rTMS preconditioning of a motor training in dominant and non-dominant hemispheric stroke may be an asymmetric motor representation of the upper limb within both hemispheres [25e27]. A TMS study demonstrated greater interhemispheric inhibition from the dominant towards the non-dominant hemisphere during activation of the contralateral hand in healthy subjects [8]. Another TMS study demonstrated greater increases of cortical excitability in dominant (left) M1 than non-dominant (right) M1 during ipsilateral hand movements [25]. After stroke, interhemispheric inhibition from the contralesional towards the ipsilesional hemisphere is influenced by hemispheric dominance in a way that interhemispheric inhibition is greater when the non-dominant hemisphere is affected [8]. In a recent fMRI study reduced ipsilateral premotor and increased contralateral sensorimotor neural activations have been found in patients with dominant (left) hemispheric stroke, compared to those with non-dominant (right) hemispheric stroke [9]. Within the concept of interhemispheric inhibition, this may be interpreted to be the result of a stronger transcallosal inhibitory drive towards the ipsilesional hemisphere after stroke in the dominant hemisphere. Our neurophysiological data showed no significant short-term, but a significant long-term effect of 1Hz rTMS preconditioning of
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a motor training for the affected hand, e.g. a decrease of cortical excitability of the contralesional M1 at 6 months after the intervention. The inhibitory effect of 1Hz rTMS has also been demonstrated by numerous previous studies [12]. A major finding of our study was that despite differential effects on motor recovery of the affected hand, preconditioning with inhibitory rTMS did not cause similar differential effects on changes of cortical excitability in dependence on lesion site. Indeed, the results of our correlation analyses were highly variable and inconclusive for weeks one and three of the intervention. A possible explanation for this may be an obvious limitation of the explanation model of interhemispheric rivalry after stroke, which addresses an inferior motor improvement of the affected hand simply to an enhanced cortical excitability of the contralesional hemisphere. Recent fMRI and TMS studies, however, describe stroke induced changes of functional and effective neural connectivity within a huge variety of sensorimotor brain areas of both hemispheres and came up with novel surrogate markers of both beneficial and maladaptive plasticity [4]. For example, the amount of motor impairment was associated with reduced functional connectivity between ipsi- and contralesional M1 and also with changes of functional connectivity between ipsilesional M1 and several other brain areas [25e27]. At 6 months after the intervention a negative correlation between the change of motor performance of the affected hand and the change in cortical excitability was found. This observation holds true for both sham and 1Hz rTMS preconditioning and for both dominant and non-dominant hemispheric stroke. One may consider to interpret these data in accordance with the theory that cortical excitability enhancement within the contralesional hemisphere is maladaptive for motor recovery after stroke.
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