ORIGINAL ARTICLE
Inhibition of the contralesional dorsal premotor cortex improves motor function of the affected hand following stroke a, K. Bo €sla and D. A. Nowaka,b €demann-Podubecka J. Lu HELIOS Klinik Kipfenberg, Kipfenberg, Germany; and bDepartment of Neurology, University Hospital, Philipps-Universit€ at, Marburg, Germany
Keywords:
hand, motor function, repetitive transcranial magnetic stimulation, stroke Received 28 April 2015 Accepted 13 November 2015 European Journal of Neurology 2016, 23: 823–830 doi:10.1111/ene.12949
Background and purpose: Numerous studies have shown that repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) may improve motor function of the affected hand after stroke. The effects of 1 Hz rTMS applied over the contralesional dorsal premotor cortex (PMd) on hand function and cortical neurophysiology in subacute stroke were examined. Methods: Ten subacute stroke patients with mild hand motor impairment were enrolled in a prospective, double-blind, randomized, placebo-controlled, crossover study with two intervention sessions. 1 Hz rTMS was applied over the contralesional PMd (real rTMS, 900 pulses at 110% of the motor threshold; sham rTMS, 900 pulses at 0% of the motor threshold). Tests of hand function (Jebsen-Taylor hand function test, box and block test) and neurophysiological evaluations (resting motor threshold, motor evoked potentials, cortical silent period, ipsilateral silent period) were obtained from both hands and hemispheres prior to (baseline) and after each treatment. Results: Hand function tests revealed significant improvement of motor function of the affected but not of the unaffected hand after real rTMS only. Neither intervention changed the neurophysiological measures in comparison to baseline. Conclusion: One hertz rTMS over the contralesional PMd improves motor function of the affected hand in subacute stroke. The PMd may be a novel rTMS target to treat motor impairment after stroke.
Highlights
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A single session of 1 Hz rTMS over contralesional dorsal premotor cortex improves motor performance of the affected hand in subacute stroke with a mild hand motor deficit. A single session of 1 Hz rTMS over contralesional dorsal premotor cortex does not change corticospinal excitability, long-lasting cortical inhibition and interhemispheric inhibition of either and in between both M1. One hertz rTMS over the contralesional dorsal premotor cortex may positively influence motor
Correspondence: J. L€ udemann-Podubeck a, Helios Klinik Kipfenberg, Neurologische Fachklinik, Kindinger Strasse 13, D-85110 Kipfenberg, Germany (tel.: 0049 (0)8465-175-66131; fax: 0049 (0)8465-175-222; e-mail: [email protected]).
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recovery in subacute stroke, but the neurophysiological correlates of this phenomenon remain unclear.
Introduction About two-thirds of stroke survivors exhibit persistent disability with motor impairment being the most common [1]. Although exercise and training programmes are widely used for recovery of post-stroke motor function, approximately 60%–70% of stroke victims suffer from impaired hand function 6 months after the initial cerebrovascular incident [1]. Based on recent advances in our understanding of brain plasticity associated with post-stroke motor impairment novel electrophysiological treatment strategies, such as repetitive transcranial magnetic stimulation (rTMS), are currently under exploration [2,3].
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Enhanced neural activity and excitability within motor areas of the contralesional hemisphere for movements of the affected hand is a common finding after stroke. Numerous studies describe a negative correlation between enhanced activity of motor areas of the contralesional hemisphere and the amount of motor deficit of the affected hand after stroke [4–6]. Based on these data, the theory of a maladaptive role of the contralesional hemisphere for motor recovery after stroke was established (interhemispheric competition model). This theory suggests that increased excitability and neural activation within motor areas of the contralesional hemisphere may generate a pronounced inhibitory drive towards motor areas of the ipsilesional hemisphere, which may hamper motor recovery of the affected hand after stroke [4,7]. Several placebo-controlled intervention studies have shown that inhibition of the contralesional primary motor cortex (M1) or facilitation of the ipsilesional M1 by means of rTMS significantly improves motor function of the affected hand after stroke. On the other hand, a number of placebo-controlled trials showed no relevant effect of rTMS over M1 on motor function of the affected hand after stroke [8,9]. Consequently, one may ask whether – within the pertinent concept of interhemispheric competition after stroke – other cortical targets for rTMS may provide higher effectiveness to overcome stroke afflicted motor disability. The dorsal premotor cortex (PMd) is strongly interconnected with M1 and other motor areas within the cortical motor network of the frontal and parietal lobes [10]. These connections are plastic and can be modified in response to motor learning or brain injury. The influence of contralesional PMd on recovery of hand function after stroke is not completely understood and may vary with the severity of the motor deficit. For example, it has been shown that in patients with mild to moderate motor impairment of one hand after stroke involving small parts of M1 or cortico-spinal projections, the ipsilesional PMd is reorganized to support motor function [11]. In contrast, when a larger part of M1 or its cortico-spinal projections are involved in stroke, causing a more profound clinical hand motor deficit, the contralesional PMd may develop a positive influence on motor recovery [12]. That is, the influence of contralesional PMd on motor areas of the ipsilesional hemisphere is inhibitory (with a potentially negative effect on recovery) in those patients with mild to moderate motor impairment of one hand but more facilitatory in those with severe hand motor impairment after stroke [10]. Based on the concept of interhemispheric competition [7], it may be argued that inhibitory rTMS over the contralesional PMd may improve
motor function of the mild to moderately affected hand after stroke in a similar way as has been observed after inhibition of the contralesional M1 in this cohort [3]. Indeed, a recent study demonstrated that inhibition of contralesional PMd improves hand function in chronic stroke survivors [13]. Here it was tested whether 1 Hz rTMS over the contralesional PMd influences motor function of the affected hand in subacute stroke patients suffering from a mild motor deficit of one hand. In addition, it was tested whether 1 Hz rTMS over the contralesional PMd influences cortico-spinal excitability, long-lasting cortical inhibition and interhemispheric inhibition of either and in between both M1.
Methods Subjects
Ten subjects with sensorimotor impairment of one hand after a first middle cerebral artery stroke within 2–8 weeks (subacute phase) prior to study inclusion were enrolled. The diagnosis was made by clinical features and neuro-imaging studies. Patients were regarded as suitable to participate if they fulfilled the following criteria: (i) location of the lesion within the territory of the middle cerebral artery; (ii) presentation with mild to moderate motor and/or sensory deficits of one hand, defined as grasp strength ≥20% of the unaffected hand, preserved extension at the wrist (≥30°) and preserved abduction and elevation of the upper arm within the shoulder joint (≥90°); (iii) absence of aphasia, apraxia, neglect, visual field deficits, psychiatric or coexistent general neurological, medical or orthopaedic illness, and accepted contraindications for TMS (pacemakers, metallic objects in the head, history of epilepsy). Table 1 gives a summary of the clinical data. The study was approved by the ethics committee of the Bavarian Chamber of Physicians (EC no. 09083). Study design
The study was a prospective, randomized, doubleblind, sham-controlled crossover trial. All 10 subjects participated in two separate experimental sessions (1 Hz rTMS, sham rTMS). The two experimental sessions were conducted in random order (using sealed envelopes), with a ‘washout period’ of at least 48 h in between. Prior to (baseline) and after each intervention motor performance of each hand [Jebsen-Taylor hand function test (JTHF), box and block test (B&B)] was tested. In addition, cortico-spinal excitability [motor resting threshold, motor evoked potentials
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Table 1 Subject characteristics
Sex
Age (years)
Time from stroke (months)
M W W W M M
75 75 71 66 82 67
1 0.5 1 1 1 1.5
M W M
78 79 53
0.75 0.75 2
M Mean SD
73 71.9 7.9
0.75 1.0 0.4
Stroke location
Stroke aetiology
Affected hand
Dominant hand
MRS
NIHSS
MMS
BMRC
SIS
P BG,CR Th BG, IC BG, Th CR, preCG, postCG Th, IC IC, NC GTS, CR, GFS, preCG, postCG P
Ischaemic Ischaemic Ischaemic Ischaemic Haemorrhagic Ischaemic
Right Right Left Right Left Right
Right Left Right Right Right Right
3 2 1 2 4 2
0 0 0 2 5 15
29 28 29 26 26 29
4 4 4+ 4+ 4 4+
5 6 5 5 19
Ischaemic Ischaemic Ischaemic
Right Right Left
Right Right Right
1 2 3
0 1 0
30 26 29
4+ 4 4+
7 10 23
Ischaemic
Left
Left
2 2.2 0.9
0 2.3 4.5
29 28.1 1.4
4+ 4.0 0.0
6 9.6 6.4
BG, basal ganglia; BMRC, British Medical Research Council (hand extension) [17]; CR, corona radiata; GFS, gyrus frontalis superior; GTS, gyrus temporalis superior; IC, internal capsule; MMS, Mini Mental State Examination Score [14]; MRS, modified Rankin Scale [15]; NC, nucleus caudatus; NIHSS, National Institutes of Health Stroke Scale [16]; P, pons cerebri; postCG, gyrus postcentralis; preCG, gyrus precentralis; SIS, Sensibility Impairment Score [18]; Th, thalamus. Bold indicates ‘mean and SD’ values.
(MEPs)], long-lasting cortical inhibition [cortical silent period (CSP)] and interhemispheric inhibition [ipsilateral silent period (ISP)] of both hemispheres were assessed prior to (baseline) and after each intervention. Participating subjects and each experimenter involved in data assessment and data analysis were blinded to group allocation. Neurophysiological and motor evaluations
Neurophysiological evaluations Participants were seated in a comfortable chair during the experiments, resting their hands on their lap. For TMS a 70-mm figure-of-eight coil and a Magstim Super Rapid stimulator (Magstim Co., Dyfed, Whitland, UK) were used. Electromyography (EMG) activity was recorded using silver silver-chloride electrodes positioned in a belly-tendon technique on the skin overlying the first dorsal interosseous (FDI) muscle of the ipsilesional and contralesional hand. For the measurement of MEP, CSP and ISP the coil was placed tangentially in a posterior anterior plane at a 45° angle from midline over the hand area for the FDI muscle of the ipsilesional/contralesional M1. Resting motor threshold and motor evoked potentials. First, the hand area of the ipsilesional/contralesional M1 was located as defined by the location where single pulse supra-threshold TMS consistently elicited the largest MEP from the FDI muscle of the affected/ unaffected hand. Resting motor threshold was defined for each participant as the lowest stimulator output intensity that elicited MEP with peak-to-peak
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amplitude of at least 50 lV in the contralateral FDI muscle in at least five of 10 trials. MEPs were obtained from the FDI of the contralateral hand after single pulse stimulation of the hand area of the M1. Twenty MEPs were sampled during stimulation at 110% of the resting motor threshold (rMT). A series of 20 test TMS pulses was allowed for familiarization before the experimental recording was started. The patients were instructed to relax and rest their hands on their lap during the experiments. The peak-to-peak amplitudes for each MEP were calculated offline and averaged for each participant. The stimulation intensity was kept constant for each subject during the measures obtained at baseline and after the rTMS intervention. Cortical silent period. The CSP [19] was obtained from the actively contracted contralateral FDI after a stimulus of 130% of the rMT was applied over ipsilesional/contralesional M1. Participants were instructed to squeeze a force transducer in a lateral grasp between index finger and thumb. For each participant first the individual maximum voluntary contraction force was obtained. The force output was displayed on a computer screen. For CSP measures voluntary contraction of the FDI was set to 20%–30% of maximum voluntary contraction. Accurate matching of contraction force was continuously visually monitored throughout the experiments. The CSP duration was measured from the beginning of the MEP until return of continuous voluntary EMG activity. This is referred to as the absolute CSP and ends with a deflection of the EMG waveform [20]. Ten CSP recordings were obtained for each participant.
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Ipsilateral silent period. The ISP duration was obtained from the maximally contracted unaffected/affected FDI after a stimulus of 150% of the rMT applied over ipsilesional/contralesional M1. Maximal voluntary contraction of the FDI was visually monitored as described above. ISP duration was measured from rectified EMG recordings. The ISP onset, which reflects the onset latency of transcallosal inhibition, was determined as the time point after TMS stimulus application when the first sign of significant decrease (>25%) in the mean rectified EMG activity level occurred. The ISP duration was measured from ISP onset to the first sign of return of voluntary EMG activity. 10 ISP recordings were obtained for each participant. Calculation of CSP and ISP duration was performed offline and averaged for each participant. Hand motor function evaluations Motor function of both the affected and the unaffected hand was assessed using the JTHF and the B&B. The JTHF is an evaluation that tests manual activities of daily life [21]. Patients were instructed to perform the tasks as fast and accurately as possible. The total performance time was calculated as the sum of the performance times for all subtests for each participant. The B&B is scored by counting the number of blocks (2.5 cm edge length) picked up and transported from one container to another within 1 min [22]. The participants were instructed to move as many blocks as possible, one at a time. Both tests were performed three times with each hand prior to assessment to achieve a stable level of performance. Intervention
For rTMS the coil was placed tangentially with the handle directed at 45° to the posterior anterior plane over the contralesional PMd by locating it 2 cm anterior and 1 cm medial to the hand area of the contralesional M1 [23]. The site for premotor rTMS with reference to the FDI ‘motor hotspot’ of M1 was used based on previously published procedures [12,23,24]. The following rTMS parameters were used: intensity 0% (sham rTMS) or 110% (1 Hz rTMS) of the rMT, frequency 1 Hz, 900 stimuli as a single continuous train lasting 15 min. During the rTMS intervention participants were seated in a comfortable chair resting their arms on their lap. Analysis
For data analysis, absolute values were obtained for each behavioural test and participant; average values were calculated for each neurophysiological parame-
ter and participant. Separate repeated measures ANOVAs with Bonferroni correction were used to analyse behavioural and neurophysiological data for both hands and hemispheres with factors ‘time’ (baseline and after intervention) and ‘intervention’ (1 Hz rTMS and sham rTMS). A P value ≤0.05 was considered significant. Correlation analyses between the pre-post changes of the behavioural and the neurophysiological parameters were performed using Pearson tests.
Results Participants tolerated the intervention well without side effects. Table 2 summarizes average data of cortico-spinal excitability (rMT, MEP), long-lasting cortical inhibition (CSP) and interhemispheric inhibition (ISP) of both hemispheres and motor function of each hand as probed with the JTHF and the B&B. The baseline data were not significantly different between sham and 1 Hz rTMS sessions for both hand motor function (JTHF and B&B) and neurophysiological measures. Neurophysiological evaluations ANOVAs showed no significant effects of the tested factors on each neurophysiological value (MEP, CSP, ISP), regardless of the hemisphere tested.
Hand motor function
Affected hand ANOVAs showed significant effects of the interaction intervention 9 time (F1,9 = 7.7; P = 0.021) on JTHF and of the single factor time (F1,9 = 7.2; P = 0.025) and intervention 9 time interaction (F1,9 = 7.6; P = 0.022) on B&B. Figure 1 summarizes the absolute intervention-induced changes in motor performance of the affected hand as difference to baseline. Non-affected hand showed no significant effects of each factor or their interaction on motor performance of the nonaffected hand for both hand motor function tests (JTHF, B&B). ANOVAs
Correlation analysis
The correlation analysis between the pre-post changes of motor performance and the pre-post changes of neurophysiological measures showed no significant correlations, regardless of the hand or hemisphere tested.
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B&B, box and block test [22]; CSP, cortical silent period; ISP, ipsilateral silent period; JTHF, Jebsen-Taylor hand function test [21]; MEP, motor evoked potential; rMT, resting motor threshold; rTMS, repetitive transcranial magnetic stimulation.
9.56 5.40 10.93 6.90 6.06 0.67 6.51 0.93 9.27 4.73 9.88 6.07 6.1 0.77 6.27 0.96
0.23 0.046 0.008 14.8 0.37 0.178 0.027 49.4 0.18 0.055 0.06 14.2 0.38 0.176 0.030 44.8 0.50 0.043 0.006 10.8 0.74 0.148 0.029 60.8 0.45 0.045 0.008 8.6 0.74 0.150 0.031 58.2 0.21 0.056 0.006 14.5 0.29 0.180 0.028 47.9 0.24 0.047 0.006 13.7 0.34 0.177 0.029 47.9 0.53 0.141 0.027 59.1
0.23 0.041 0.007 9.8
0.63 0.140 0.027 61.8
0.43 0.045 0.009 10.3
66.1 15.1 66.1 15.1 60.0 9.3 60.0 9.3 66.1 15.1 66.1 15.1 60.0 9.3
Pre
Affected
Post Pre
60.0 9.3
rMT (stimulator output; %) MEP (amplitude; mV) CSP (duration; ms) ISP (duration; ms) B&B (performance; size) JTHF (time; s)
Pre Post Pre
Non-affected Non-affected
Post
Real rTMS Sham rTMS
Table 2 Mean values and standard deviations of motor function tests (B&B, JTHF) and neurophysiological evaluations (rMT, MEP, CSP, ISP)
Affected
Post
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Discussion The primary objective of this study was to investigate the efficiency of low-frequency (1 Hz) rTMS applied over the contralesional PMd on motor function of the affected hand in subacute stroke patients who suffer from a mild motor impairment of the affected upper limb. The rationale of this study was based on the apparent role of the PMd in motor learning [25,26] as well as on the theory of maladaptive over-activity within motor areas of the non-affected hemisphere (including the PMd) for motor recovery of the affected hand after stroke [4–6]. Within this theoretical framework it was predicted that inhibition of the contralesional PMd may improve motor performance of the affected hand after stroke. A second objective of this study was to investigate the rTMS-induced neurophysiological changes within both hemispheres and to describe their relationship to hand motor performance. This was based on the welldescribed shift of neural excitability and activation towards the non-affected hemisphere in stroke patients moving the affected hand. Within the concept of interhemispheric competition between motor areas of the two hemispheres the balance shift towards the unaffected hemisphere has been described to be detrimental for motor recovery [3,4]. It was therefore predicted that inhibition of the contralesional PMd may cause (i) a reduction of cortico-spinal excitability of the contralesional M1 with an enhancement of cortico-spinal excitability of the ipsilesional M1, (ii) an enhancement of long-lasting cortical inhibition of the contralesional M1 with a reduction of long-lasting cortical inhibition of the ipsilesional M1 and (iii) a reduction of interhemispheric inhibition from the contralesional towards the ipsilesional M1 and, at the same time, an increase of interhemispheric inhibition from the ipsilesional towards the contralesional M1. Correlations between the motor improvement of the affected upper limb and changes of the neurophysiological values within the theory of interhemispheric competition were also predicted. Effect of 1 Hz rTMS over the contralesional PMd on motor function of the affected hand
The results of our study show that 1 Hz rTMS over the contralesional PMd improves motor function of the affected hand in subacute stroke patients suffering from a mild to moderate motor impairment. Until today only one placebo-controlled study has investigated the efficiency of rTMS over the contralesional PMd for motor recovery of the affected hand after stroke [13]. This study included 44 chronic stroke
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Figure 1 Changes in motor performance of both hands in relation to baseline.
patients (3–12 months since stroke) and compared the effect of 10 sessions of inhibitory 1 Hz rTMS over the contralesional PMd with an inhibition of the contralesional M1. The authors demonstrated that – compared to sham stimulation – inhibition of the contralesional PMd resulted in a significant improvement of motor performance of the affected hand, but was inferior to M1 stimulation. Both studies demonstrated a consistent and positive effect of inhibitory 1 Hz rTMS over the contralesional PMd for motor recovery after stroke – our study in subacute stroke (2–8 weeks from the acute vascular incident) and Wang et al. in chronic stroke (3–12 months from the acute vascular incident) [13]. Numerous placebo-controlled trials have tested the effect of diverse brain stimulation protocols in an attempt to improve hand motor performance after stroke. The great majority of these studies applied rTMS over the primary motor area (M1) (but see [13,27,28]). More than 20 studies tested the efficiency of inhibitory 1 Hz rTMS over the contralesional M1 to improve hand motor function after stroke (for a review of the pertinent literature see [8,9]). However, higher motor areas such as the supplementary motor area or the premotor areas were less widely under investigation as targets for non-invasive brain stimulation [29]. Based on current knowledge on the essential role of the PMd in motor learning and motor control [10,25,26] it may be assumed that modulation of cortical excitability and neural processing in the PMd may be a potentially fruitful way to induce recovery of the affected hand after stroke. Recent research also
suggests that excessive activity in the contralesional PMd may be detrimental for restoration of hand motor function in those stroke survivors with mild to moderate impairment but supportive for those with a more severe impairment [12,23]. Bestmann et al. used paired pulse TMS to test the physiological influence of the contralesional PMd on ipsilesional M1 at rest and showed that it became less inhibitory/more facilitatory in those patients with a greater clinical impairment of hand motor function [23]. Another TMS functional magnetic resonance imaging (fMRI) experiment showed a greater hand-grip-related activation within the contralesional PMd in those patients suffering from a more severe hand dysfunction [23]. Johansen-Berg et al. demonstrated a prolongation of reaction times of the affected hand after a single supra-threshold TMS applied to the contralesional PMd and that the prolonged reaction times were positively correlated with the degree of hand motor impairment [12]. These findings suggest that a potentially supportive role of the contralesional PMd for motor function of the affected hand is evident in severely impaired patients, whereas this is not the case in stroke victims with a moderate or mild hand motor dysfunction. Taken together our and previous data imply that the contralesional PMd may develop differential roles on motor recovery of the affected hand after stroke depending on the degree of functional motor impairment and/or on the time from the acute vascular incident. Our cohort comprised mild to moderately impaired stroke patients in the subacute phase of stroke (2–8 weeks from symptom onset). In these
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the contralesional PMd may develop a maladaptive influence on ipsilesional motor areas, and disruption of neural processing in the contralesional PMd by inhibitory rTMS may therefore improve hand motor control after stroke. Such an interpretation receives strong support from an fMRI study which demonstrated that the amount of neural activity within the contralesional PMd was positively correlated with the improvement of hand motor function after 1 Hz rTMS over the contralesional M1 in stroke patients with mild to moderate hand motor impairment [29].
stimulation of the PMd activates a specific set of connections which are different from those influenced by stimulation of M1 [33] and may therefore be inaccessible to the neurophysiological tests used here. Connectivity between the PMd and M1 within and between both hemispheres (as obtained from measures of neurophysiology) is complex and also may change after a stroke. In addition, technical reasons such as pulse phase (monophasic or biphasic) and orientation of the TMS coil may account for the variable effects of PMd inhibition on neurophysiological measures.
Effect of 1 Hz rTMS over the contralesional PMd on cortical excitability and interhemispheric inhibition within and in between M1
Correlations between motor performance and neurophysiology
Despite significant effects on motor function of the affected hand, 1 Hz rTMS over the contralesional PMd did not change the raw data of MEP, CSP and ISP within the contralesional and ipsilesional M1 as could be expected from previous studies on healthy humans or derived from the interhemispheric competition model after stroke. It was hypothesized that, in our sample of stroke subjects, inhibition of the contralesional PMd may (i) reduce cortical excitability of the contralesional M1, (ii) reduce the inhibitory drive from the contralesional M1 towards ipsilesional M1, (iii) enhance cortical excitability of the ipsilesional hemisphere and (iv) enhance the inhibitory drive from the ipsilesional towards contralesional M1. Our hypothesis is based on the well-documented connectivity between M1 and PMd obtained from studies on healthy subjects [30,31]. Paired pulse TMS experiments demonstrated that cortical excitability of M1 can be modulated not only by applying the conditioning stimulus over the contralateral M1 but also when applying the conditioning stimulus over the contralateral PMd [32,33]. This implies a direct influence of the PMd on excitability of the contralateral M1. A combined TMS positron emission tomography study demonstrated a comparable modulation of cortical excitability (change of MEP size) in M1 after rTMS applied over the ipsilateral PMd [34]. Another study demonstrated that 1 Hz rTMS over the PMd reduced MEP size and increased CSP duration elicited from the ipsilateral M1, whereas 5 Hz rTMS over the PMd increased MEP size and reduced CSP duration elicited from the ipsilateral M1 [31]. However, no significant changes in MEP size, CSP or ISP durations were detected in our cohort of stroke patients, regardless of whether 1 Hz rTMS or sham rTMS was applied over the contralesional PMd. A possible explanation for these results may be that
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The correlation analysis between the changes of motor performance and the changes of neurophysiological values within/between both M1 (MEP, CSP, ISP) showed no significant results. The significant improvement of the affected hand was not associated with measurable changes in cortical excitability of M1 or a change in interhemispheric inhibitory interaction between both M1. These negative results suggest that despite behavioural effectiveness inhibition of the contralesional PMd does not generate reproducible changes in the neurophysiological markers used. However, our study is limited by the small sample size of stroke patients included. Further data on larger patient cohorts are needed until definitive conclusions can be drawn upon the effects of 1 Hz rTMS over the PMd of the contralesional hemisphere on (i) cortico-spinal excitability, (ii) interhemispheric inhibition and (iii) motor function of the affected hand after stroke.
Acknowledgements This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors.
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
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19. Inghilleri M, Berardelli A, Cruccu G, Manfredi M. Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction. J Physiol 1993; 466: 521–534. 20. Tergau F, Wandschura V, Canelo M, et al. Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation. Exp Brain Res 1999; 124: 447–454. 21. Jebsen RH, Taylor N, Trieschmann RB, Trotter MJ, Howard LA. An objective and standardized test of hand function. Arch Phys Med Rehabil 1969; 50: 311–319. 22. Desrosiers J, Bravo G, Hebert R, Dutil E, Mercier L. Validation of the box and block test as a measure of dexterity of elderly people: reliability, validity, and norms studies. Arch Phys Med Rehabil 1994; 75: 751–755. 23. Bestmann S, Swayne O, Blankenburg F, et al. The role of the contralesional dorsal premotor cortex after stroke as studied with concurrent TMS-fMRI. J Neurosci 2010; 30: 11926–11937. 24. Bestmann S, Baudewig J, Siebner HR, Rothwell JC, Frahm J. BOLD MRI responses to repetitive TMS over human dorsal premotor cortex. NeuroImage 2005; 28: 22–29. 25. Graziano MS, Aflalo TN. Mapping behavioral repertoire onto the cortex. Neuron 2007; 56: 239–251. 26. Hardwick RM, Rottschy C, Miall RC, Eickhoff SB. A quantitative meta-analysis and review of motor learning in the human brain. NeuroImage 2013; 67: 283–297. 27. Brodie SM, Borich MR, Boyd LA. Impact of 5-Hz rTMS over the primary sensory cortex is related to white matter volume in individuals with chronic stroke. Eur J Neurosci 2014; 40: 3405–3412. 28. Meehan SK, Dao E, Linsdell MA, Boyd LA. Continuous theta burst stimulation over the contralesional sensory and motor cortex enhances motor learning poststroke. Neurosci Lett 2011; 500: 26–30. 29. Plow EB, Cunningham DA, Varnerin N, Machado A. Rethinking stimulation of the brain in stroke rehabilitation: why higher motor areas might be better alternatives for patients with greater impairments. Neuroscientist 2015; 21: 225–240. 30. Gerschlager W, Siebner HR, Rothwell JC. Decreased corticospinal excitability after subthreshold 1 Hz rTMS over lateral premotor cortex. Neurology 2001; 57: 449–455. 31. Rizzo V, Siebner HR, Modugno N et al. Shaping the excitability of human motor cortex with premotor rTMS. J Physiol 2004; 554: 483–495. 32. B€ aumer T, Bock F, Koch G, et al. Magnetic stimulation of human premotor or motor cortex produces interhemispheric facilitation through distinct pathways. J Physiol 2006; 572: 857–868. 33. Mochizuki H, Huang YZ, Rothwell JC. Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex. J Physiol 2004; 561: 331–338. 34. Chouinard PA, Van Der Werf YD, Leonard G, Paus T. Modulating neural networks with transcranial magnetic stimulation applied over the dorsal premotor and primary motor cortices. J Neurophysiol 2003; 90: 1071–1083.
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Inhibition of the contralesional dorsal premotor cortex improves motor function of the affected hand following stroke a, K. Bo €sla and D. A. Nowaka,b €demann-Podubecka J. Lu HELIOS Klinik Kipfenberg, Kipfenberg, Germany; and bDepartment of Neurology, University Hospital, Philipps-Universit€ at, Marburg, Germany
Keywords:
hand, motor function, repetitive transcranial magnetic stimulation, stroke Received 28 April 2015 Accepted 13 November 2015 European Journal of Neurology 2016, 23: 823–830 doi:10.1111/ene.12949
Background and purpose: Numerous studies have shown that repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) may improve motor function of the affected hand after stroke. The effects of 1 Hz rTMS applied over the contralesional dorsal premotor cortex (PMd) on hand function and cortical neurophysiology in subacute stroke were examined. Methods: Ten subacute stroke patients with mild hand motor impairment were enrolled in a prospective, double-blind, randomized, placebo-controlled, crossover study with two intervention sessions. 1 Hz rTMS was applied over the contralesional PMd (real rTMS, 900 pulses at 110% of the motor threshold; sham rTMS, 900 pulses at 0% of the motor threshold). Tests of hand function (Jebsen-Taylor hand function test, box and block test) and neurophysiological evaluations (resting motor threshold, motor evoked potentials, cortical silent period, ipsilateral silent period) were obtained from both hands and hemispheres prior to (baseline) and after each treatment. Results: Hand function tests revealed significant improvement of motor function of the affected but not of the unaffected hand after real rTMS only. Neither intervention changed the neurophysiological measures in comparison to baseline. Conclusion: One hertz rTMS over the contralesional PMd improves motor function of the affected hand in subacute stroke. The PMd may be a novel rTMS target to treat motor impairment after stroke.
Highlights
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A single session of 1 Hz rTMS over contralesional dorsal premotor cortex improves motor performance of the affected hand in subacute stroke with a mild hand motor deficit. A single session of 1 Hz rTMS over contralesional dorsal premotor cortex does not change corticospinal excitability, long-lasting cortical inhibition and interhemispheric inhibition of either and in between both M1. One hertz rTMS over the contralesional dorsal premotor cortex may positively influence motor
Correspondence: J. L€ udemann-Podubeck a, Helios Klinik Kipfenberg, Neurologische Fachklinik, Kindinger Strasse 13, D-85110 Kipfenberg, Germany (tel.: 0049 (0)8465-175-66131; fax: 0049 (0)8465-175-222; e-mail: [email protected]).
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recovery in subacute stroke, but the neurophysiological correlates of this phenomenon remain unclear.
Introduction About two-thirds of stroke survivors exhibit persistent disability with motor impairment being the most common [1]. Although exercise and training programmes are widely used for recovery of post-stroke motor function, approximately 60%–70% of stroke victims suffer from impaired hand function 6 months after the initial cerebrovascular incident [1]. Based on recent advances in our understanding of brain plasticity associated with post-stroke motor impairment novel electrophysiological treatment strategies, such as repetitive transcranial magnetic stimulation (rTMS), are currently under exploration [2,3].
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Enhanced neural activity and excitability within motor areas of the contralesional hemisphere for movements of the affected hand is a common finding after stroke. Numerous studies describe a negative correlation between enhanced activity of motor areas of the contralesional hemisphere and the amount of motor deficit of the affected hand after stroke [4–6]. Based on these data, the theory of a maladaptive role of the contralesional hemisphere for motor recovery after stroke was established (interhemispheric competition model). This theory suggests that increased excitability and neural activation within motor areas of the contralesional hemisphere may generate a pronounced inhibitory drive towards motor areas of the ipsilesional hemisphere, which may hamper motor recovery of the affected hand after stroke [4,7]. Several placebo-controlled intervention studies have shown that inhibition of the contralesional primary motor cortex (M1) or facilitation of the ipsilesional M1 by means of rTMS significantly improves motor function of the affected hand after stroke. On the other hand, a number of placebo-controlled trials showed no relevant effect of rTMS over M1 on motor function of the affected hand after stroke [8,9]. Consequently, one may ask whether – within the pertinent concept of interhemispheric competition after stroke – other cortical targets for rTMS may provide higher effectiveness to overcome stroke afflicted motor disability. The dorsal premotor cortex (PMd) is strongly interconnected with M1 and other motor areas within the cortical motor network of the frontal and parietal lobes [10]. These connections are plastic and can be modified in response to motor learning or brain injury. The influence of contralesional PMd on recovery of hand function after stroke is not completely understood and may vary with the severity of the motor deficit. For example, it has been shown that in patients with mild to moderate motor impairment of one hand after stroke involving small parts of M1 or cortico-spinal projections, the ipsilesional PMd is reorganized to support motor function [11]. In contrast, when a larger part of M1 or its cortico-spinal projections are involved in stroke, causing a more profound clinical hand motor deficit, the contralesional PMd may develop a positive influence on motor recovery [12]. That is, the influence of contralesional PMd on motor areas of the ipsilesional hemisphere is inhibitory (with a potentially negative effect on recovery) in those patients with mild to moderate motor impairment of one hand but more facilitatory in those with severe hand motor impairment after stroke [10]. Based on the concept of interhemispheric competition [7], it may be argued that inhibitory rTMS over the contralesional PMd may improve
motor function of the mild to moderately affected hand after stroke in a similar way as has been observed after inhibition of the contralesional M1 in this cohort [3]. Indeed, a recent study demonstrated that inhibition of contralesional PMd improves hand function in chronic stroke survivors [13]. Here it was tested whether 1 Hz rTMS over the contralesional PMd influences motor function of the affected hand in subacute stroke patients suffering from a mild motor deficit of one hand. In addition, it was tested whether 1 Hz rTMS over the contralesional PMd influences cortico-spinal excitability, long-lasting cortical inhibition and interhemispheric inhibition of either and in between both M1.
Methods Subjects
Ten subjects with sensorimotor impairment of one hand after a first middle cerebral artery stroke within 2–8 weeks (subacute phase) prior to study inclusion were enrolled. The diagnosis was made by clinical features and neuro-imaging studies. Patients were regarded as suitable to participate if they fulfilled the following criteria: (i) location of the lesion within the territory of the middle cerebral artery; (ii) presentation with mild to moderate motor and/or sensory deficits of one hand, defined as grasp strength ≥20% of the unaffected hand, preserved extension at the wrist (≥30°) and preserved abduction and elevation of the upper arm within the shoulder joint (≥90°); (iii) absence of aphasia, apraxia, neglect, visual field deficits, psychiatric or coexistent general neurological, medical or orthopaedic illness, and accepted contraindications for TMS (pacemakers, metallic objects in the head, history of epilepsy). Table 1 gives a summary of the clinical data. The study was approved by the ethics committee of the Bavarian Chamber of Physicians (EC no. 09083). Study design
The study was a prospective, randomized, doubleblind, sham-controlled crossover trial. All 10 subjects participated in two separate experimental sessions (1 Hz rTMS, sham rTMS). The two experimental sessions were conducted in random order (using sealed envelopes), with a ‘washout period’ of at least 48 h in between. Prior to (baseline) and after each intervention motor performance of each hand [Jebsen-Taylor hand function test (JTHF), box and block test (B&B)] was tested. In addition, cortico-spinal excitability [motor resting threshold, motor evoked potentials
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Table 1 Subject characteristics
Sex
Age (years)
Time from stroke (months)
M W W W M M
75 75 71 66 82 67
1 0.5 1 1 1 1.5
M W M
78 79 53
0.75 0.75 2
M Mean SD
73 71.9 7.9
0.75 1.0 0.4
Stroke location
Stroke aetiology
Affected hand
Dominant hand
MRS
NIHSS
MMS
BMRC
SIS
P BG,CR Th BG, IC BG, Th CR, preCG, postCG Th, IC IC, NC GTS, CR, GFS, preCG, postCG P
Ischaemic Ischaemic Ischaemic Ischaemic Haemorrhagic Ischaemic
Right Right Left Right Left Right
Right Left Right Right Right Right
3 2 1 2 4 2
0 0 0 2 5 15
29 28 29 26 26 29
4 4 4+ 4+ 4 4+
5 6 5 5 19
Ischaemic Ischaemic Ischaemic
Right Right Left
Right Right Right
1 2 3
0 1 0
30 26 29
4+ 4 4+
7 10 23
Ischaemic
Left
Left
2 2.2 0.9
0 2.3 4.5
29 28.1 1.4
4+ 4.0 0.0
6 9.6 6.4
BG, basal ganglia; BMRC, British Medical Research Council (hand extension) [17]; CR, corona radiata; GFS, gyrus frontalis superior; GTS, gyrus temporalis superior; IC, internal capsule; MMS, Mini Mental State Examination Score [14]; MRS, modified Rankin Scale [15]; NC, nucleus caudatus; NIHSS, National Institutes of Health Stroke Scale [16]; P, pons cerebri; postCG, gyrus postcentralis; preCG, gyrus precentralis; SIS, Sensibility Impairment Score [18]; Th, thalamus. Bold indicates ‘mean and SD’ values.
(MEPs)], long-lasting cortical inhibition [cortical silent period (CSP)] and interhemispheric inhibition [ipsilateral silent period (ISP)] of both hemispheres were assessed prior to (baseline) and after each intervention. Participating subjects and each experimenter involved in data assessment and data analysis were blinded to group allocation. Neurophysiological and motor evaluations
Neurophysiological evaluations Participants were seated in a comfortable chair during the experiments, resting their hands on their lap. For TMS a 70-mm figure-of-eight coil and a Magstim Super Rapid stimulator (Magstim Co., Dyfed, Whitland, UK) were used. Electromyography (EMG) activity was recorded using silver silver-chloride electrodes positioned in a belly-tendon technique on the skin overlying the first dorsal interosseous (FDI) muscle of the ipsilesional and contralesional hand. For the measurement of MEP, CSP and ISP the coil was placed tangentially in a posterior anterior plane at a 45° angle from midline over the hand area for the FDI muscle of the ipsilesional/contralesional M1. Resting motor threshold and motor evoked potentials. First, the hand area of the ipsilesional/contralesional M1 was located as defined by the location where single pulse supra-threshold TMS consistently elicited the largest MEP from the FDI muscle of the affected/ unaffected hand. Resting motor threshold was defined for each participant as the lowest stimulator output intensity that elicited MEP with peak-to-peak
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amplitude of at least 50 lV in the contralateral FDI muscle in at least five of 10 trials. MEPs were obtained from the FDI of the contralateral hand after single pulse stimulation of the hand area of the M1. Twenty MEPs were sampled during stimulation at 110% of the resting motor threshold (rMT). A series of 20 test TMS pulses was allowed for familiarization before the experimental recording was started. The patients were instructed to relax and rest their hands on their lap during the experiments. The peak-to-peak amplitudes for each MEP were calculated offline and averaged for each participant. The stimulation intensity was kept constant for each subject during the measures obtained at baseline and after the rTMS intervention. Cortical silent period. The CSP [19] was obtained from the actively contracted contralateral FDI after a stimulus of 130% of the rMT was applied over ipsilesional/contralesional M1. Participants were instructed to squeeze a force transducer in a lateral grasp between index finger and thumb. For each participant first the individual maximum voluntary contraction force was obtained. The force output was displayed on a computer screen. For CSP measures voluntary contraction of the FDI was set to 20%–30% of maximum voluntary contraction. Accurate matching of contraction force was continuously visually monitored throughout the experiments. The CSP duration was measured from the beginning of the MEP until return of continuous voluntary EMG activity. This is referred to as the absolute CSP and ends with a deflection of the EMG waveform [20]. Ten CSP recordings were obtained for each participant.
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Ipsilateral silent period. The ISP duration was obtained from the maximally contracted unaffected/affected FDI after a stimulus of 150% of the rMT applied over ipsilesional/contralesional M1. Maximal voluntary contraction of the FDI was visually monitored as described above. ISP duration was measured from rectified EMG recordings. The ISP onset, which reflects the onset latency of transcallosal inhibition, was determined as the time point after TMS stimulus application when the first sign of significant decrease (>25%) in the mean rectified EMG activity level occurred. The ISP duration was measured from ISP onset to the first sign of return of voluntary EMG activity. 10 ISP recordings were obtained for each participant. Calculation of CSP and ISP duration was performed offline and averaged for each participant. Hand motor function evaluations Motor function of both the affected and the unaffected hand was assessed using the JTHF and the B&B. The JTHF is an evaluation that tests manual activities of daily life [21]. Patients were instructed to perform the tasks as fast and accurately as possible. The total performance time was calculated as the sum of the performance times for all subtests for each participant. The B&B is scored by counting the number of blocks (2.5 cm edge length) picked up and transported from one container to another within 1 min [22]. The participants were instructed to move as many blocks as possible, one at a time. Both tests were performed three times with each hand prior to assessment to achieve a stable level of performance. Intervention
For rTMS the coil was placed tangentially with the handle directed at 45° to the posterior anterior plane over the contralesional PMd by locating it 2 cm anterior and 1 cm medial to the hand area of the contralesional M1 [23]. The site for premotor rTMS with reference to the FDI ‘motor hotspot’ of M1 was used based on previously published procedures [12,23,24]. The following rTMS parameters were used: intensity 0% (sham rTMS) or 110% (1 Hz rTMS) of the rMT, frequency 1 Hz, 900 stimuli as a single continuous train lasting 15 min. During the rTMS intervention participants were seated in a comfortable chair resting their arms on their lap. Analysis
For data analysis, absolute values were obtained for each behavioural test and participant; average values were calculated for each neurophysiological parame-
ter and participant. Separate repeated measures ANOVAs with Bonferroni correction were used to analyse behavioural and neurophysiological data for both hands and hemispheres with factors ‘time’ (baseline and after intervention) and ‘intervention’ (1 Hz rTMS and sham rTMS). A P value ≤0.05 was considered significant. Correlation analyses between the pre-post changes of the behavioural and the neurophysiological parameters were performed using Pearson tests.
Results Participants tolerated the intervention well without side effects. Table 2 summarizes average data of cortico-spinal excitability (rMT, MEP), long-lasting cortical inhibition (CSP) and interhemispheric inhibition (ISP) of both hemispheres and motor function of each hand as probed with the JTHF and the B&B. The baseline data were not significantly different between sham and 1 Hz rTMS sessions for both hand motor function (JTHF and B&B) and neurophysiological measures. Neurophysiological evaluations ANOVAs showed no significant effects of the tested factors on each neurophysiological value (MEP, CSP, ISP), regardless of the hemisphere tested.
Hand motor function
Affected hand ANOVAs showed significant effects of the interaction intervention 9 time (F1,9 = 7.7; P = 0.021) on JTHF and of the single factor time (F1,9 = 7.2; P = 0.025) and intervention 9 time interaction (F1,9 = 7.6; P = 0.022) on B&B. Figure 1 summarizes the absolute intervention-induced changes in motor performance of the affected hand as difference to baseline. Non-affected hand showed no significant effects of each factor or their interaction on motor performance of the nonaffected hand for both hand motor function tests (JTHF, B&B). ANOVAs
Correlation analysis
The correlation analysis between the pre-post changes of motor performance and the pre-post changes of neurophysiological measures showed no significant correlations, regardless of the hand or hemisphere tested.
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B&B, box and block test [22]; CSP, cortical silent period; ISP, ipsilateral silent period; JTHF, Jebsen-Taylor hand function test [21]; MEP, motor evoked potential; rMT, resting motor threshold; rTMS, repetitive transcranial magnetic stimulation.
9.56 5.40 10.93 6.90 6.06 0.67 6.51 0.93 9.27 4.73 9.88 6.07 6.1 0.77 6.27 0.96
0.23 0.046 0.008 14.8 0.37 0.178 0.027 49.4 0.18 0.055 0.06 14.2 0.38 0.176 0.030 44.8 0.50 0.043 0.006 10.8 0.74 0.148 0.029 60.8 0.45 0.045 0.008 8.6 0.74 0.150 0.031 58.2 0.21 0.056 0.006 14.5 0.29 0.180 0.028 47.9 0.24 0.047 0.006 13.7 0.34 0.177 0.029 47.9 0.53 0.141 0.027 59.1
0.23 0.041 0.007 9.8
0.63 0.140 0.027 61.8
0.43 0.045 0.009 10.3
66.1 15.1 66.1 15.1 60.0 9.3 60.0 9.3 66.1 15.1 66.1 15.1 60.0 9.3
Pre
Affected
Post Pre
60.0 9.3
rMT (stimulator output; %) MEP (amplitude; mV) CSP (duration; ms) ISP (duration; ms) B&B (performance; size) JTHF (time; s)
Pre Post Pre
Non-affected Non-affected
Post
Real rTMS Sham rTMS
Table 2 Mean values and standard deviations of motor function tests (B&B, JTHF) and neurophysiological evaluations (rMT, MEP, CSP, ISP)
Affected
Post
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Discussion The primary objective of this study was to investigate the efficiency of low-frequency (1 Hz) rTMS applied over the contralesional PMd on motor function of the affected hand in subacute stroke patients who suffer from a mild motor impairment of the affected upper limb. The rationale of this study was based on the apparent role of the PMd in motor learning [25,26] as well as on the theory of maladaptive over-activity within motor areas of the non-affected hemisphere (including the PMd) for motor recovery of the affected hand after stroke [4–6]. Within this theoretical framework it was predicted that inhibition of the contralesional PMd may improve motor performance of the affected hand after stroke. A second objective of this study was to investigate the rTMS-induced neurophysiological changes within both hemispheres and to describe their relationship to hand motor performance. This was based on the welldescribed shift of neural excitability and activation towards the non-affected hemisphere in stroke patients moving the affected hand. Within the concept of interhemispheric competition between motor areas of the two hemispheres the balance shift towards the unaffected hemisphere has been described to be detrimental for motor recovery [3,4]. It was therefore predicted that inhibition of the contralesional PMd may cause (i) a reduction of cortico-spinal excitability of the contralesional M1 with an enhancement of cortico-spinal excitability of the ipsilesional M1, (ii) an enhancement of long-lasting cortical inhibition of the contralesional M1 with a reduction of long-lasting cortical inhibition of the ipsilesional M1 and (iii) a reduction of interhemispheric inhibition from the contralesional towards the ipsilesional M1 and, at the same time, an increase of interhemispheric inhibition from the ipsilesional towards the contralesional M1. Correlations between the motor improvement of the affected upper limb and changes of the neurophysiological values within the theory of interhemispheric competition were also predicted. Effect of 1 Hz rTMS over the contralesional PMd on motor function of the affected hand
The results of our study show that 1 Hz rTMS over the contralesional PMd improves motor function of the affected hand in subacute stroke patients suffering from a mild to moderate motor impairment. Until today only one placebo-controlled study has investigated the efficiency of rTMS over the contralesional PMd for motor recovery of the affected hand after stroke [13]. This study included 44 chronic stroke
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Figure 1 Changes in motor performance of both hands in relation to baseline.
patients (3–12 months since stroke) and compared the effect of 10 sessions of inhibitory 1 Hz rTMS over the contralesional PMd with an inhibition of the contralesional M1. The authors demonstrated that – compared to sham stimulation – inhibition of the contralesional PMd resulted in a significant improvement of motor performance of the affected hand, but was inferior to M1 stimulation. Both studies demonstrated a consistent and positive effect of inhibitory 1 Hz rTMS over the contralesional PMd for motor recovery after stroke – our study in subacute stroke (2–8 weeks from the acute vascular incident) and Wang et al. in chronic stroke (3–12 months from the acute vascular incident) [13]. Numerous placebo-controlled trials have tested the effect of diverse brain stimulation protocols in an attempt to improve hand motor performance after stroke. The great majority of these studies applied rTMS over the primary motor area (M1) (but see [13,27,28]). More than 20 studies tested the efficiency of inhibitory 1 Hz rTMS over the contralesional M1 to improve hand motor function after stroke (for a review of the pertinent literature see [8,9]). However, higher motor areas such as the supplementary motor area or the premotor areas were less widely under investigation as targets for non-invasive brain stimulation [29]. Based on current knowledge on the essential role of the PMd in motor learning and motor control [10,25,26] it may be assumed that modulation of cortical excitability and neural processing in the PMd may be a potentially fruitful way to induce recovery of the affected hand after stroke. Recent research also
suggests that excessive activity in the contralesional PMd may be detrimental for restoration of hand motor function in those stroke survivors with mild to moderate impairment but supportive for those with a more severe impairment [12,23]. Bestmann et al. used paired pulse TMS to test the physiological influence of the contralesional PMd on ipsilesional M1 at rest and showed that it became less inhibitory/more facilitatory in those patients with a greater clinical impairment of hand motor function [23]. Another TMS functional magnetic resonance imaging (fMRI) experiment showed a greater hand-grip-related activation within the contralesional PMd in those patients suffering from a more severe hand dysfunction [23]. Johansen-Berg et al. demonstrated a prolongation of reaction times of the affected hand after a single supra-threshold TMS applied to the contralesional PMd and that the prolonged reaction times were positively correlated with the degree of hand motor impairment [12]. These findings suggest that a potentially supportive role of the contralesional PMd for motor function of the affected hand is evident in severely impaired patients, whereas this is not the case in stroke victims with a moderate or mild hand motor dysfunction. Taken together our and previous data imply that the contralesional PMd may develop differential roles on motor recovery of the affected hand after stroke depending on the degree of functional motor impairment and/or on the time from the acute vascular incident. Our cohort comprised mild to moderately impaired stroke patients in the subacute phase of stroke (2–8 weeks from symptom onset). In these
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the contralesional PMd may develop a maladaptive influence on ipsilesional motor areas, and disruption of neural processing in the contralesional PMd by inhibitory rTMS may therefore improve hand motor control after stroke. Such an interpretation receives strong support from an fMRI study which demonstrated that the amount of neural activity within the contralesional PMd was positively correlated with the improvement of hand motor function after 1 Hz rTMS over the contralesional M1 in stroke patients with mild to moderate hand motor impairment [29].
stimulation of the PMd activates a specific set of connections which are different from those influenced by stimulation of M1 [33] and may therefore be inaccessible to the neurophysiological tests used here. Connectivity between the PMd and M1 within and between both hemispheres (as obtained from measures of neurophysiology) is complex and also may change after a stroke. In addition, technical reasons such as pulse phase (monophasic or biphasic) and orientation of the TMS coil may account for the variable effects of PMd inhibition on neurophysiological measures.
Effect of 1 Hz rTMS over the contralesional PMd on cortical excitability and interhemispheric inhibition within and in between M1
Correlations between motor performance and neurophysiology
Despite significant effects on motor function of the affected hand, 1 Hz rTMS over the contralesional PMd did not change the raw data of MEP, CSP and ISP within the contralesional and ipsilesional M1 as could be expected from previous studies on healthy humans or derived from the interhemispheric competition model after stroke. It was hypothesized that, in our sample of stroke subjects, inhibition of the contralesional PMd may (i) reduce cortical excitability of the contralesional M1, (ii) reduce the inhibitory drive from the contralesional M1 towards ipsilesional M1, (iii) enhance cortical excitability of the ipsilesional hemisphere and (iv) enhance the inhibitory drive from the ipsilesional towards contralesional M1. Our hypothesis is based on the well-documented connectivity between M1 and PMd obtained from studies on healthy subjects [30,31]. Paired pulse TMS experiments demonstrated that cortical excitability of M1 can be modulated not only by applying the conditioning stimulus over the contralateral M1 but also when applying the conditioning stimulus over the contralateral PMd [32,33]. This implies a direct influence of the PMd on excitability of the contralateral M1. A combined TMS positron emission tomography study demonstrated a comparable modulation of cortical excitability (change of MEP size) in M1 after rTMS applied over the ipsilateral PMd [34]. Another study demonstrated that 1 Hz rTMS over the PMd reduced MEP size and increased CSP duration elicited from the ipsilateral M1, whereas 5 Hz rTMS over the PMd increased MEP size and reduced CSP duration elicited from the ipsilateral M1 [31]. However, no significant changes in MEP size, CSP or ISP durations were detected in our cohort of stroke patients, regardless of whether 1 Hz rTMS or sham rTMS was applied over the contralesional PMd. A possible explanation for these results may be that
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The correlation analysis between the changes of motor performance and the changes of neurophysiological values within/between both M1 (MEP, CSP, ISP) showed no significant results. The significant improvement of the affected hand was not associated with measurable changes in cortical excitability of M1 or a change in interhemispheric inhibitory interaction between both M1. These negative results suggest that despite behavioural effectiveness inhibition of the contralesional PMd does not generate reproducible changes in the neurophysiological markers used. However, our study is limited by the small sample size of stroke patients included. Further data on larger patient cohorts are needed until definitive conclusions can be drawn upon the effects of 1 Hz rTMS over the PMd of the contralesional hemisphere on (i) cortico-spinal excitability, (ii) interhemispheric inhibition and (iii) motor function of the affected hand after stroke.
Acknowledgements This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors.
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
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