Stroke is the number one cause of long-term disability in adults worldwide [
17 acute and subacute stroke patients undergoing a six-week in-patient neurological rehabilitation treatment for unilateral hemiplegia after a first unilateral stroke were included. Table
Subjects characteristics.
Pat. Nr. | Sex | Age (years) | Time from stroke (days) | Stroke location | Stroke aetiology | Affected hem. | Dominant hem. | NIHSS (score) | MRS (score) | SIS (score) | MMS (score) | WMFT (score) | ARAT (score) | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
NAH | AH | NAH | AH | ||||||||||||
P1 | m | 66 | 15 | CR | i | ri | le | 0 | 1 | na | na | 70 | 66 | 57 | 57 |
P2 | m | 64 | 48 | CR, GTS | h | le | le | 0 | 2 | 6 | 29 | 70 | 62 | 57 | 53 |
P3 | m | 78 | 15 | P | i | ri | le | 0 | 2 | 12 | 28 | 70 | 60 | 57 | 57 |
P4 | m | 70 | 14 | CR, GFS, pre-CG, post-CG | i | le | le | 3 | 2 | 21 | 30 | 70 | 52 | 57 | 37 |
P5 | f | 76 | 22 | BG | i | ri | le | 1 | 3 | 16 | 28 | 70 | 47 | 57 | 28 |
P6 | f | 89 | 29 | CR, pre-CG | i | le | le | 2 | 4 | 7 | 27 | 70 | 40 | 57 | 20 |
P7 | f | 49 | 22 | CR, GFI, GTS | i | ri | le | 4 | 4 | 23 | 27 | 70 | 36 | 57 | 19 |
P8 | f | 44 | 22 | CR, BG | i | ri | le | 3 | 3 | 10 | 30 | 70 | 32 | 57 | 19 |
P9 | m | 76 | 50 | CI, BG | i | le | le | 4 | 3 | 6 | 29 | 70 | 28 | 57 | 19 |
P10 | m | 40 | 19 | CR, BG | h | ri | le | 5 | 4 | 26 | 28 | 70 | 18 | 57 | 0 |
P11 | m | 30 | 25 | CI, GFI, GTS | i | le | le | 8 | 4 | 25 | 28 | 70 | 16 | 57 | 0 |
P12 | f | 75 | 32 | T, CI, CR | i | le | le | 10 | 4 | 22 | 21 | 70 | 16 | 57 | 0 |
P13 | m | 80 | 30 | BG | i | ri | le | na | na | na | na | 70 | 16 | 57 | 0 |
P14 | m | 74 | 57 | CR, post-CG | i | ri | le | 3 | 3 | 19 | 29 | 70 | 16 | 57 | 0 |
P15 | m | 63 | 14 | CR, BG, GFI, GFS, pre-CR, post-CG | i | ri | le | 10 | 4 | 27 | 30 | 70 | 15 | 57 | 0 |
P16 | w | 63 | 16 | CR, BG | h | ri | le | 6 | 4 | 32 | 30 | 70 | 15 | 57 | 0 |
P17 | f | 76 | 94 | CR, BG, pre-CG, post-CG | i | ri | le | na | na | na | na | 70 | 15 | 57 | 0 |
AH = affected hand/affected hemisphere; ARAT = Action Research Arm Test; BG = basal ganglia; CI = capsule internal; CR = corona radiate; f = female; GFI = gyrus frontal inferior; GFS = gyrus frontal superior; GTS = gyrus temporal superior; h = haemorrhage; i = ischemia; le = left; m = male; MMS = Mini Mental Status Examination Score; MRS = Modified Rankin Scale; NAH = nonaffected hand/nonaffected hemisphere; NIHSS = National Institute of Health Stroke Scale; ri = right; P = pons cerebri; pre CG = precentral gyrus; post-CG = postcentral gyrus; SIS = Sensibility Impairment Score; T = thalamus; WMFT = Wolf Motor Function Test.
Pat. Nr. | rMT (% of stimulator output) | MEP (mV) | MMA size (number of active sites) | MMA volume (mV) | COG anterior-posterior (cm) | COG medial-lateral (cm) | CSP (sec) | ISP (sec) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
NAH | AH | NAH | AH | NAH | AH | NAH | AH | NAH | AH | NAH | AH | NAH | AH | NAH | AH | |
P1 | 64 | >100 | 0.40 | 0.00 | 3 | 0 | 0.98 | 0.00 | 1.83 | na | 4.13 | na | 0.108 | na | 0.025 | na |
P2 | 85 | 75 | 0.84 | 0.23 | 9 | 5 | 4.35 | 1.02 | 2.18 | −0.23 | 5.17 | 5.04 | 0.085 | 0.263 | 0.029 | 0.025 |
P3 | 68 | 57 | 1.40 | 0.76 | 12 | 9 | 7.81 | 3.71 | 2.70 | 4.26 | 3.59 | 5.48 | 0.159 | 0.183 | 0.033 | 0.034 |
P4 | 73 | >100 | 0.53 | 0.00 | 8 | 0 | 2.53 | 0.00 | 1.95 | na | 5.27 | na | 0.187 | na | na | na |
P5 | 49 | >100 | 1.15 | 0.00 | 12 | 0 | 5.11 | 0.00 | 1.10 | na | 3.41 | na | 0.107 | na | na | na |
P6 | 45 | 47 | 1.64 | 0.53 | 13 | 11 | 7.64 | 2.73 | 0.46 | 0.63 | 2.90 | 3.95 | 0.184 | 0.103 | na | 0.025 |
P7 | 75 | >100 | 0.57 | 0.00 | 17 | 0 | 2.83 | 0.00 | 0.31 | na | 4.88 | na | 0.165 | na | na | na |
P8 | 66 | >100 | 0.96 | 0.00 | 13 | 0 | 5.43 | 0.00 | −0.15 | na | 5.55 | na | 0.158 | na | na | na |
P9 | 40 | >100 | 0.49 | 0.00 | 5 | 0 | 1.54 | 0.00 | 3.01 | na | 2.96 | na | 0.156 | na | na | na |
P10 | 55 | >100 | 1.11 | 0.00 | 7 | 0 | 4.30 | 0.00 | 1.03 | na | 4.01 | na | 0.160 | na | na | na |
P11 | 60 | >100 | 0.18 | 0.00 | 2 | 0 | 0.35 | 0.00 | 3.16 | na | 5.32 | na | 0.174 | na | na | na |
P12 | 49 | >100 | 0.71 | 0.00 | 7 | 0 | 3.50 | 0.00 | 1.38 | na | 2.89 | na | 0.183 | na | na | na |
P13 | 60 | >100 | 0.35 | 0.00 | 5 | 0 | 1.15 | 0.00 | 0.70 | na | 4.98 | na | 0.154 | na | na | na |
P14 | 48 | >100 | 0.21 | 0.00 | 1 | 0 | 0.21 | 0.00 | 0.00 | na | 4.24 | na | 0.091 | na | na | na |
P15 | 57 | >100 | 0.65 | 0.00 | 11 | 0 | 3.66 | 0.00 | 3.68 | na | 4.04 | na | 0.197 | na | na | na |
P16 | 67 | >100 | 0.28 | 0.00 | 4 | 0 | 0.82 | 0.00 | 1.45 | na | 2.98 | na | 0.163 | na | na | na |
P17 | 53 | >100 | 1.37 | 0.00 | 13 | 0 | 6.29 | 0.00 | −0.04 | na | 5.38 | na | 0.109 | na | na | na |
AH = affected hand/affected hemisphere; COG = center of gravity; CSP = cortical silent period; ISP = ipsilateral silent period; MEP = motor evoked potential; MMA = motor map area; mV = millivolt; na = not applicable/not available; NAH = nonaffected hand/nonaffected hemisphere; RMT = resting motor threshold.
This prospective longitudinal study evaluates the changes of motor function of the affected and the nonaffected hands as well as the changes of neurophysiology of the affected and nonaffected hemispheres during a six-week period in stroke patients. The evaluations were performed at the baseline, two weeks, four weeks, and six weeks after study inclusion (see Figure
Study design. ARAT = Action Research Arm Test; COG = center of gravity; CSP = cortical silent period; ISP = ipsilateral silent period; MEP = motor evoked potential; MMA = motor map area; MMS = Mini Mental Status Examination Score; MRS = Modified Rankin Scale; NIHSS = National Institute of Health Stroke Scale; RMT = resting motor threshold; SIS = Sensibility Impairment Score; WMFT = Wolf Motor Function Test.
Motor function of both the affected and unaffected hands was assessed using the Wolf Motor Function Test (WMFT) [
Neurophysiologic evaluations of the ipsilesional and the contralesional hemispheres comprised motor evoked potentials (MEP) recorded from the first dorsal interosseous (FDI) muscle, motor mapping of FDI muscle representation over the primary motor cortex, cortical silent period, and ipsilateral silent period. Transcranial magnetic stimulation was performed using a 70 mm figure-of-8 coil (Magstim, Dyfed, UK). Electromyographic activity was recorded using silver-silver-chloride electrodes positioned in a belly-tendon technique over the FDI muscle of the contralateral hand. The coil was placed tangentially in a posterior-anterior plane at a 45-degree angle from midline during all measures. For motor mapping a self-fabricated net cap was used. The cap consisted of one-by-one centimetre squares allowing an exact predefined positioning of the TMS coil over the scalp. TMS intensity was specified for each subject at baseline and kept constant during follow-up evaluations. LabChart and PowerLab software were used for data acquisition and analysis (AD-Instruments, Australia). Patients were seated in a comfortable chair during all experiments.
17 stroke patients were included. Four patients were lost during the six-week follow-up (see Figure
Patients demonstrated a broad spectrum of motor impairment of the affected hand, ranging from severe to mild as assessed by both hand motor function tests at baseline (see Table
At baseline, MEPs from the ipsilesional hemisphere were evocable in only three patients (P2, P3, and P6). All these patients suffered from a mild or moderate motor deficit of the upper limb. In one patient (P1) with a mild hand motor impairment MEPs from the ipsilesional hemisphere were evocable at the two-week evaluation and in one patient (P14, with a severe motor impairment) at the six-week evaluation. MEPs from the contralesional hemisphere were evocable in all patients at all time points.
Two patients (P2, P3) showed a higher rMT within the contralesional hemisphere compared to the ipsilesional hemisphere at baseline. Both patients suffered from a mild motor impairment of the affected hand. All remaining patients showed a higher rMT within the ipsilesional hemisphere compared to the contralesional hemisphere. These data imply that a severe motor impairment of the affected hand is associated with an interhemispheric imbalance of cortical excitability towards the contralesional hemisphere, whereas a mild motor impairment may be associated with a shift of cortical excitability towards the ipsilesional hemisphere.
The available data show greater MEP amplitudes after stimulation of the contralesional hemisphere, compared to stimulation of the ipsilesional hemisphere in all patients at baseline. The baseline data show positive correlations between MEP amplitudes within the contralesional hemisphere and motor function of the affected hand (see Figure
Correlation-coefficients between the neurophysiological values within the contralesional hemisphere and motor function of the affected hand.
Correlation-coefficients between changes of neurophysiological values within the contralesional hemisphere and motor function of the affected hand.
In addition, we found a number of nearly significant correlations between the changes of cortical excitability of the contralesional hemisphere and the changes of motor function of the affected hand (see Figure
Correlation-coefficients between changes of neurophysiological values within the contralesional hemisphere and changes in motor function of the affected hand.
At baseline MMA size was greater within the contralesional hemisphere compared to the ipsilesional hemisphere in all subjects. The correlation analyses showed positive correlations between MMA size within the contralesional hemisphere and motor function of the affected hand at baseline (see Figure
The changes of MMA size within the ipsilesional hemisphere were measurable in only three patients, who suffered from a mild to moderate hand motor impairment. The data showed a decrease of the cortical hand motor representation size within the ipsilesional hemisphere in all subjects.
At baseline the MMA volume within the contralesional hemisphere was greater than that in the ipsilesional hemisphere in all patients. The baseline data show significant correlations between MMA volume and hand motor function (Figure
The changes of ipsilesional MMA volume were obtained in only three patients, all suffering from a mild to moderate hand motor impairment. In general, they showed a decrease of MMA volume over time. The changes ranged between −3.5 mV (decrease) and +0.2 mV (increase).
The anterior-posterior shift of the MMA COG within the ipsilesional hemisphere was obtained in only three patients. The changes ranged between −2.8 cm (posterior shift) and +0.6 cm (anterior shift).
The medial-lateral shift of the MMA COG within the ipsilesional hemisphere was obtained in only two patients. The changes ranged between −1.24 cm (medial shift) and +0.43 cm (lateral shift).
The changes of the CSP after stimulation of the contralesional motor cortex ranged between −0.045 seconds (shortening) and +0.077 seconds (prolongation) over the follow-up period. Age of the included subjects correlated with the changes of the contralesional CSP duration from baseline to the four-week evaluation (
Follow-up measures of ipsilesional CSP were available in only three patients. The changes ranged between −0.042 seconds (shortening) and +0.31 seconds (prolongation).
The ISPs within the contralesional hemisphere were measurable in only three subjects. The follow-up changes ranged between −0.006 seconds (shortening) and +0.016 seconds (prolongation). The ISPs within the ipsilesional hemisphere were measurable in only two patients. The follow-up changes ranged between −0.009 seconds (shortening) and +0.005 seconds (prolongation).
The objective of this study was to describe the plastic changes in cortical excitability and cortical hand motor representation during recovery from stroke and to relate potential changes to the clinical impairment and recovery of hand function. The overall aim was to establish potential electrophysiological surrogate markers that may help to judge upon outcome of hand motor function in an affected individual.
Indeed we found strong relationships between motor function/motor recovery of the affected hand and (i) the reduction of cortical excitability, (ii) the reduction in size and volume of cortical hand motor representation, and (iii) the medial and anterior shift of cortical hand motor representation within the contralesional hemisphere. Based on these data, both maladaptive and beneficial roles of the contralesional motor cortex on hand motor recovery after stroke may be discussed.
On one hand, our follow-up data suggest a strong association between the reduction of motor cortex excitability (MEP size, MMA size, and MMA volume) within the contralesional hemisphere and a more favorable hand motor recovery. This may be interpreted as a maladaptive role of the contralesional motor cortex for the process of hand motor recovery after stroke. Support to this notion comes from numerous FMRI studies that describe a significant relationship between enhanced motor related neural activity within the contralesional hemisphere and the amount of motor deficit of the stroke-affected hand, as well as a clear relationship between reduction of contralesional neural activity and a successful recovery of impaired motor function over time [
On the other hand, our data also show a strong relationship between hand motor function and motor recovery of the affected hand. Patients with a more severe impairment of upper limb motor function exhibit a less favorable recovery than those with mild disability and this is coupled with persistent enhancement of cortical excitability (MEP size, MMA size, and MMA volume) within the contralesional hemisphere over the follow-up-period. Thus, the severity of motor impairment is the predominant surrogate marker for a less favorable recovery and it may also trigger enhanced motor cortex excitability within the contralesional hemisphere. Possibly, the increased neural activity within motor areas of the contralesional hemisphere may be essential for hand motor performance in those patients with a more severe motor deficit after stroke. This theory receives support from a study demonstrating that an increase of MMA size within the contralesional hemisphere is associated with a good hand motor recovery in patients, who received a hand motor training [
At baseline testing we found significant relationships between cortical excitability within the contralesional hemisphere (MEP size, MMA size, and MMA volume) and motor function of the affected hand function: the lower the cortical excitability, the more severe the hand motor impairment. In contrast, patients with moderate to mild hand motor impairment demonstrated a greater cortical excitability.
Collectively, these results are in accordance with a recent review that investigated the evolution of cortical hand motor representation during the course of motor recovery after stroke [
Another interesting observation of the present study was that patients with a well preserved hand function and good motor recovery exhibited an anterior-medial shift of contralesional cortical hand motor representation. In contrast, a posterior-lateral shift of contralesional hand motor representation was found in those patients with a less favorable function and recovery of the affected hand (Figure
Hand motor representation area (MMA) within the contralesional hemisphere at baseline and its changes after six weeks in two representative patients. P3 shows a good motor recovery of the affected hand between baseline and the six-week evaluation (WMFT score increases by 16 points; ARAT score increases by 19 points). This was associated with a decrease in size and volume of contralesional MMA, as well as with an anterior-medial shift of hand motor representation. P1 shows a poor motor recovery of the affected hand at the six-week evaluation (WMFT score and ARAT score did not change). This was associated with an increase in size and volume of contralesional MMA and a posterior-lateral shift of hand motor representation. A = anterior direction; Cz = vertex; P = posterior direction.
Our study protocol did not include neuronavigation based on brain imaging. Therefore we cannot comment on the exact anatomical landmarks of motor cortex plasticity within the contralesional hemisphere. Nevertheless, it appears as if a poor motor function and recovery were accompanied by an extension of contralesional hand motor representation towards the lateral surface of the frontal lobe and posterior towards the parietal lobe. In contrast, a favorable motor function and recovery were accompanied by a reduction of the cortical excitability within the aforementioned areas coupled with an extension towards premotor cortex and supplementary motor areas within the contralesional hemisphere.
In summary, we were able to show that recovery of motor function of the affected hand after stroke is accompanied by definite changes in excitability, size, volume, and location of hand motor representation within the contralesional primary motor cortex. These measures may be developed to serve as surrogate markers for motor outcome after stroke in the future. Acute stroke is within 2 weeks from symptom onset. Subacute stroke is 2 weeks to 3 months from symptom onset. Chronic stroke is more than 3 months from symptom onset.
The authors declare that there is no conflict of interests regarding the publication of this paper.