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Facilitation of motor evoked potentials in ischemic stroke patients: prognostic value and neurophysiologic correlations
Clinical Neurophysiology 114 (2003) 2370–2375 www.elsevier.com/locate/clinph
Facilitation of motor evoked potentials in ischemic stroke patients: prognostic value and neurophysiologic correlations B. Dachya,b,*, E. Biltiaub, E. Bouillota, B. Danc, P. Deltenrea,b a Laboratory of Clinical Neurophysiology, CHU Brugmann, Place Van Gehuchten 4, B-1020 Brussels, Belgium Department of Rehabilitation for Neurologic Diseases, CHU Brugmann, Universite´ Libre de Bruxelles, Place Van Gehuchten 4, B-1020 Brussels, Belgium c Department of Neurology, Hoˆpital Universitaire des Enfants Reine Fabiola, Universite´ Libre de Bruxelles, Place Van Gehuchten 4, B-1020 Brussels, Belgium b
Accepted 10 July 2003
Abstract Objective: To investigate the predictive value of paired transcranial magnetic stimulation (TMS) at rest in stroke patients in comparison with the predictive value derived from data obtained by single TMS during facilitation. Methods: Fifty-six patients with a single ischemic lesion and no electromyographic responses from single TMS in the resting affected hand muscles participated in the study. TMS assessment was performed 32 days post-stroke. It consisted of a single stimulation at maximal output during facilitation (controlateral hand grip and elbow flexion) and a paired-pulse stimulation at rest with two stimuli at maximal output at interstimulus intervals ranging from 15 to 100 ms. Two blind clinical assessments using the ‘motricity index’ were carried out 26 and 76 days post-stroke. Results: Thirty-seven percent of patients were responsive to single TMS during facilitation, had better clinical scores at both evaluations and better clinical recovery. Fifty-four percent of patients responded to paired TMS, had better clinical scores at the second evaluation and better clinical recovery. All patients who responded to the single stimulation paradigm also responded to the paired one. Conclusions: A positive correlation was found between the responsiveness to both the TMS paradigms (facilitation procedure and paired stimulation) and clinical recovery. This underlines the importance of facilitation during single TMS in stroke patients and suggests that paired TMS at rest might supplement this procedure in stroke studies. q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Transcranial magnetic stimulation; Stroke; Prognosis; Facilitation
1. Introduction As a non-invasive method of evaluation of the central motor pathways, transcranial magnetic stimulation (TMS) has been proposed as a prognostic tool in stroke patients (Catano et al., 1996; Pennisi et al., 1999). Nevertheless, some conflicting results have been reported (Trompetto et al., 2000), probably because of the variability of patients included and differences in the techniques used. The results of the initial basic studies designed to investigate the predictive value of TMS have led to categorize stroke patients in two groups: patients with preserved motor evoked potential at rest had a more complete return of function and patients with absent MEP were at high risk of poor functional recovery (Heald et al., 1993). The prognostic value of a MEP * Corresponding author. Tel.: þ 32-2-477-2446; fax: þ 32-2-477-2456. E-mail address: [email protected] (B. Dachy).
reappearing following a facilitatory technique has been approached in few studies (Macdonell and Donnan, 1992; Catano et al., 1995; Escudero et al., 1998). On the other hand, TMS responses have been studied in order to explore the physiologic mechanisms underlying physiotherapeutic interventions in stroke patients and in normal subjects (Hummelsheim et al., 1992; Hauptmann and Hummelsheim, 1996; Hummelsheim and Hauptmann, 1999). In this context, it would appear relevant to study stroke patients with absent MEP following single TMS at rest in order to confirm the predictive value of MEP facilitation and to relate it to the physiotherapeutic technique applied during the test (Hummelsheim and Hauptmann, 1999). Paired-pulse TMS techniques may be useful as they might detect residual corticospinal function and provide a standardized electrophysiologic equivalent to physiotherapeutic facilitation. To assess cortical excitability, the most commonly used paradigm consists of a subthreshold conditioning stimulus
1388-2457/$30.00 q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1388-2457(03)00252-9
B. Dachy et al. / Clinical Neurophysiology 114 (2003) 2370–2375
followed at short interstimulus intervals (ISIs) by a suprathreshold test stimulus in order to explore intracortical inhibition and intracortical facilitation (Chen, 2000). Studies using paired TMS to investigate cortical excitability in stroke patients have demonstrated a decrease in intracortical motor inhibition in both the affected and unaffected hemispheres. However, intracortical inhibition cannot be evaluated in the affected hemisphere when resting motor responses are absent or severely reduced. In such cases, it is hazardous to attribute eventual MEP changes to recovery processes (Manganotti et al., 2002). Intracortical facilitation has been evaluated in normal subjects with two nearthreshold stimuli, either at short ISIs (Tokimura et al., 1996) or at longer ISIs (Valls-Sole´ et al., 1992). In stroke patients, the comparison between MEP results obtained by single TMS with facilitation and by paired TMS at rest could refine theoretical assumptions about the modulation of the corticospinal output and practical arguments concerning physiotherapeutic interventions. In this study, we investigated whether a facilitatory effect of paired TMS was present in a group of stroke patients with a substantial motor deficit and whether this could have a predictive value for recovery.
2. Subjects and methods 2.1. Patients The study concerned patients admitted in the rehabilitation unit after a stroke. The inclusion criteria were: (1) computerized tomography or magnetic resonance imaging showing a single ischemic monohemispheric lesion; (2) first-ever stroke; and (3) no MEP at rest in the affected hand during the electrophysiological assessment. The exclusion criteria were concomitant neuropathies, dementia, epilepsy and the presence of intracerebral clips or cardiac pacemaker. Fifty-six patients (25 women, 31 men), aged from 22 to 92 years (mean 65), were entered into the study. Thirty-six patients had a left-sided lesion and 20 a right-sided lesion. The site of the lesion was cortical in 5 patients, corticosubcortical in 30 patients and subcortical in 21 patients. The patients were not receiving any drugs interfering with cortical excitability. During their stay in the rehabilitation unit, they underwent physiotherapeutic treatment performed twice daily by the same physiotherapist. 2.2. Control subjects This group consisted of 16 healthy subjects (9 women, 7 men) aged from 23 to 78 years (mean 47). 2.3. Clinical assessment Two evaluations of the muscle power in the affected upper limb were performed during the study using the ‘motricity index’ (Demeurisse et al., 1980). Power was
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assessed for pinch grip, elbow flexion and shoulder abduction while the patient was sitting. This provided a weighted score ranging from 0 (no muscle power) to 100 (normal muscle power). The physiotherapists scoring the patient strength were unaware of the neurophysiological results. Evaluations were performed at an early and a late stage of rehabilitation and labeled as index 1 and index 2. The second value was missing if, at that time, the patient was already discharged from the hospital. The gain in muscle strength as recovery rating was calculated as {index 2 –index 1}. 2.4. TMS procedures TMS was performed with a circular coil (90 mm diameter) connected to a Magstim 200 (2.0 Tesla). For paired TMS, two Magstim 200 were connected to one coil by means of a Bistim device. The same coil was used as for single TMS, accordingly to previous studies (Shimuzu et al., 1999). The coil was held flat over the vertex with the current flowing in an anticlockwise direction to preferentially activate the left hemisphere or in a clockwise direction to stimulate the right hemisphere. MEPs were recorded on the abductor digiti minimi muscles with surface electrodes, connected to a Nicolet Viking IV. The reliability of TMS responses was assessed by 3 stimulations in each condition. Whenever it was needed, the resting state of target muscles was assessed by visual and auditory feedback (on-line free running electromyographic channel). 2.4.1. Patients Two procedures were successively performed during the same session. The first procedure was a single TMS at maximal output stimulation at rest (according to inclusion criteria) and during facilitation. The latter consisted of maximal isometric flexion of the elbow against resistance combined with maximal handgrip of the unaffected side. If a MEP appeared, its shortest latency and its maximal amplitude were noted. The second procedure was a paired TMS at rest, with two equal stimuli at maximal output at ISIs ranging from 15 to 100 ms (ISI of 15, 30, 45, 60, 75 and 100 ms). If a MEP appeared during this test, its shortest latency (calculated from the second stimulus), its maximal amplitude and the ISIs allowing maximal MEP amplitude were noted. MEP recording from the unaffected hand assessed the integrity of controlateral corticospinal tract. A peripheral cause of MEP absence was excluded by nerve conduction studies and by magnetic stimulation of the cervical roots. This TMS session lasted 35– 45 min. 2.4.2. Control subjects The excitability threshold values at rest were defined according to standard procedures (Rossini et al., 1994). Paired TMS with two stimuli at 0.8 £ threshold at rest was performed; ISIs ranging from 15 to 100 ms (15, 30, 45, 60, 75
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and 100 ms). The excitation threshold was controlled at the beginning and at the end of the paired TMS procedure. The occurrence of MEP and ISI corresponding values were noted. 2.5. Statistical analysis All statistical analyzes were performed using the Statistical Package for the Social Sciences statistical package. Student’s t test for independent samples (two-tailed) was applied for comparisons of clinical scores between groups of patients. Student’s t test for paired samples (two-tailed) was used for the comparison of mean MEP latencies and amplitudes obtained by the two TMS procedures and for the comparison between index 1 and index 2 in groups of patients defined by electrophysiological results. A Levene’s test was done before in order to assess the equality of variances. The occurrence of MEP with paired TMS in patients and in control subjects was compared using a chisquare test. Values of P , 0:05 were considered significant. When not specified, values are given as mean ^ SD. 2.6. Ethical aspects The local Ethics Committee approved this project. Informed consent was obtained from the patients and from the healthy controls after the nature of the procedure had been explained. 3. Results 3.1. Clinical assessment The main results of the clinical evaluation are summarized in Table 1. 3.1.1. First evaluation (index 1) The 56 patients were evaluated at 26 ^ 16 days poststroke. The mean value of the ‘motricity index’ was 14 ^ 19. No significant difference was found in function of the side of the lesion (P ¼ 0:716, t test).
3.1.2. Second evaluation (index 2) Forty-eight patients were evaluated at 76 ^ 17 days post-stroke. The mean value of the ‘motricity index’ was 26 ^ 24. No significant difference was found in function of the side of the lesion (P ¼ 0:825, t test). Nevertheless, recovery {index 2 –index 1} was better for right-sided lesions (P ¼ 0:038, t test). 3.2. TMS results The neurophysiological testing was performed at 32 ^ 17 days post-stroke. The patients were divided in groups according to the presence of MEP or not during each of TMS procedures. 3.2.1. Single TMS results In two patients, the facilitation procedure could not be performed satisfactorily because of limb pain on the unaffected side. They were then excluded from this section of data analysis. In 20 of the other 54 patients (37%), a consistent MEP appeared during facilitation. The mean latency of these responses was 25 ^ 4.7 ms. The mean MEP amplitude was 358 ^ 743 mV. An example of facilitated MEPs is shown in Fig. 1. 3.2.2. Paired TMS results In 30 of 56 patients (54%), two successive stimuli evoked a response. The paired TMS recording of the patient illustrated in Fig. 1 is shown in Fig. 2. The mean MEP latency was 26.1 ^ 5.8 ms, which is not significantly different from that obtained with the single pulse paradigm (P ¼ 0:404, paired t test). The mean MEP amplitude was 269 ^ 532 mV, not significantly different from that obtained with the single pulse paradigm (P ¼ 0:45, paired t test). All patients who responded to the first paradigm also responded to the second one. The mean value of optimal ISIs for a maximal MEP amplitude was 44 ^ 20 ms. Fig. 3 illustrates the influence of ISI on MEP amplitude and the presence of a late component, observed in few patients.
Table 1 ‘Motricity index’ scores in function of the presence of motor evoked potentials after single transcranial magnetic stimulation during facilitation and paired transcranial magnetic stimulation at rest (mean value ^ SD) Single TMS
Paired TMS
MEP
Absent
Present
P
Absent
Present
P
Index 1 Index 2 {Index 2– Index 1} P
9.9 ^ 16.3 (n ¼ 34) 18.7 ^ 22.4 (n ¼ 30) 9.5 ^ 11.5 **
23.1 ^ 21.4 (n ¼ 20) 42 ^ 19.2 (n ¼ 16) 18.9 ^ 17.5 **
* ** *
11.3 ^ 17.7 (n ¼ 26) 18 ^ 22.5 (n ¼ 23) 7.8 ^ 9.9 **
16.7 ^ 20.2 (n ¼ 30) 32.6 ^ 23.7 (n ¼ 25) 16.2 ^ 16.7 **
NS * *
Index 1 ¼ first clinical evaluation. Index 2 ¼ second clinical evaluation. {Index 2–Index 1} ¼ strength recovery between the two evaluations. Statistical analysis: independent samples t test for comparison of ‘motricity index’ values between groups and paired samples t test for evolution of ‘motricity index’ values in each group defined by transcranial magnetic stimulation (TMS) results. * ¼ P value ,0.05. ** ¼ P value ,0.01. NS ¼ not statistically significant.
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Fig. 1. Example of single transcranial magnetic stimulation recording. Motor evoked potentials recordings on the affected side before (upper traces) and during (lower traces) facilitation. Three successive trials at 100% maximal output are superimposed.
3.2.3. Control subjects In the control subjects, the resting motor threshold values were 54 ^ 12% for the right hand and 52 ^ 11% for the left hand. In 3 (19%) of the 16 subjects, two successive subthreshold stimuli evoked a response. The occurrence of MEP was lower than in the patient group (P ¼ 0:014, chisquare test). The mean value of corresponding ISI was 35 ^ 35 ms.
Fig. 3. Example of paired transcranial magnetic stimulation recording. The uppermost trace was obtained with a single pulse transcranial magnetic stimulation at 100% maximal output. Lower traces correspond to paired transcranial magnetic stimulation (each at 100% maximal output) with interstimulus intervals of 15, 30, 45, 60, 75 and 100 ms. The maximal motor evoked potential amplitude was obtained at an interstimulus interval of 45 ms. Note the late component that may reflect activation of slow conducting cortical motor neuronal connections.
3.3. Correlations between clinical and neurophysiological data The distribution of clinical scores in function of TMS results is summarized in Table 1. 3.3.1. Single TMS results Fig. 2. Example of paired transcranial magnetic stimulation recording (same patient as in Fig. 1). Three successive trials for each condition are superimposed. Upper traces were obtained with a single pulse transcranial magnetic stimulation at 100% maximal output. Lower traces demonstrate motor evoked potentials evoked by paired transcranial magnetic stimulation (each at 100% maximal output) at an interstimulus interval of 30 ms.
Patients with MEP appearing during facilitation had ‘motricity index’ values significantly higher at index 1 (23.1 ^ 21.4 versus 9.9 ^ 16.3, P ¼ 0:014, t test), at index 2 (42 ^ 19.2 versus 18.7 ^ 22.4, P ¼ 0:001, t test) and for {index 2 – index 1} (18.9 ^ 17.5 versus 9.5 ^ 11.5, P ¼ 0:034, t test).
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3.3.2. Paired TMS results When positive, results of this procedure were not linked to a better score at index 1 (16.7 ^ 20.2 versus 11.3 ^ 17.7, P ¼ 0:293, t test), in contrast with index 2 (32.6 ^ 23.7 versus 18 ^ 22.5, P ¼ 0:034, t test) and {index 2– index 1} (16.2 ^ 16.7 versus 7.8 ^ 9.9, P ¼ 0:043, t test).
4. Discussion For single TMS procedure, our results confirm the important role of a facilitation technique for patients unresponsive at rest. As previously described (Heald et al., 1993), patients with MEP appearing during contraction of the unaffected limb had a better recovery prognosis. The same group of patients was also responsive to paired TMS performed at rest. This technique has a prognostic value similar to single TMS during facilitation, with the advantages of being independent from the patient’s collaboration and by-passing some clinical limitations, such as joint pain as in our study. The facilitatory effect of paired TMS at rest was found in 54% of patients. This was greater than the effect of the physiotherapeutic technique combined with single TMS, seen in 37% of patients. The relatively low effect of the latter facilitation technique, namely controlateral preinnervation, has been demonstrated by comparing it to direct activation of the target muscle, proximal preinnervation and cutaneous/proprioceptive stimulation (Hummelsheim and Hauptmann, 1999). However, none of these approaches would be applicable in patients with severe deficit such as our study group. In this context, paired TMS appears as a relevant approach. The mechanisms underlying facilitation during single TMS are not entirely understood. They likely include increased cortical and spinal excitability (Weber and Eisen, 2002). This would result in increased firing of residual corticospinal neurons, facilitating response to the magnetic stimulation, thus enhancing the descending volley onto the spinal motoneurons (Catano et al., 1995). The data obtained by Hauptmann and Hummelsheim (1996) in hemiparetic stroke patients suggest that most of the MEP amplitude facilitation is of cortical origin. Nevertheless, the recruitment of a greater number of spinal motoneurons has been linked to increased spinal excitability or to increased synchronization of spinal motoneuron firing (Weber and Eisen, 2002). This duality of facilitation sites could have therapeutic implications. Indeed, physiotherapeutic interventions including synergistic associated patterns are based on central facilitation, whereas peripheral facilitation procedures involve cutaneous and proprioceptive afferents (Hummelsheim and Hauptmann, 1999). Previous TMS studies suggested that central facilitation procedures as proposed by Brunnstrom were the most effective way to raise the discharge probability of spinal motoneurons, at least in completely paralyzed muscles (Hummelsheim et al., 1992).
To our knowledge, the use of paired TMS in stroke patients with a cortical threshold at rest above maximal output using two equal stimuli at subthreshold intensity has not been described before. The site (cortical versus spinal) of the facilitation resulting from paired TMS has been discussed in many studies carried out with healthy subjects. With a paired TMS technique involving two near-threshold stimuli, Tokimura et al. (1996) observed MEP facilitation at short ISIs between 1.1 and 4.5 ms. This facilitation probably reflects an interaction between circuits producing the indirect corticospinal waves (I waves) (Chen, 2000). Performing paired TMS at near-threshold stimulus intensities (90 and 100%), Valls-Sole´ et al. (1992) observed facilitation at ISIs of 50– 90 ms. The probability of eliciting the test MEP at 90% of the threshold was in the range of our normal subjects (20 ^ 10%). The motor disinhibition observed in motor areas in acute stroke (Liepert et al., 2000; Manganotti et al., 2002) can explain that two equal subthreshold stimuli generated a MEP more frequently in our stroke patients than in control subjects during paired TMS. However, a refined study of the excitability of intracortical inhibitory circuits in the affected hemisphere was not feasible in our study as motor inhibition cannot be measured in patients with absent MEP at rest. In few patients, MEP appearing during our paired TMS procedure included late components, as illustrated in Fig. 3. These components are also observed in single TMS recordings in amyotrophic lateral sclerosis patients. Using peristimulus time histograms in this condition, Weber and Eisen (1999) attributed the temporal dispersion of excitatory postsynaptic potentials generated at the anterior horn level to motor cortex hyperexcitability. The late components of MEP were linked to the activation of slow conducting and/or indirect cortical motor neuronal connections (Weber and Eisen, 2002). Studying ipsilateral responses to focal TMS in healthy subjects and stroke patients, Alagona et al. (2001) suggested that hyperexcitability of the lateral premotor cortex and supplementary motor area on the affected side could compensate damage to the corticospinal pathway. As regard the spinal level, it is generally considered that an initial subthreshold conditioning stimulus has no influence on the descending pathways (Hallett, 2000). However, on the basis of simultaneous recordings of the corticospinal volley and of EMG response following paired TMS, Nakamura et al. (1997) demonstrated that stimulation below threshold with respect to EMG response is above threshold for the corticospinal volley. At ISIs of 25 and 50 ms, there was slight facilitation of the volley. They concluded that the enlargement of the EMG responses could not be linked only to facilitation of the motor cortex, but presumably also to the temporal summation of the multiple descending I waves at the spinal level. Ziemann et al. (1996) noted that when the intensity of the conditioning stimulus is below the threshold needed to evoke responses in relaxed muscles but greater than the threshold needed to evoke responses in active muscles, then
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some part of the facilitation can be linked to changes in spinal cord excitability. Kujirai et al. (1993) studied the influence of the intensity of the conditioning stimuli. When this intensity raised, a small corticospinal volley appear to produce subthreshold facilitation of spinal motoneurons, contributing to the facilitation of test responses at interstimulus intervals of 10 and 15 ms.
5. Conclusion Our findings in stroke patients responsive to single TMS with facilitatory technique and to paired TMS at rest are consistent with a cortical excitability threshold slightly above 100% output of the stimulator. The thresholdlowering effect of muscle contraction allows to unmask residual corticospinal projections, which seem to play a significant role in muscle power recovery as demonstrated by group comparisons. In addition to theoretical hypotheses on the respective role of cortical and spinal factors in facilitation, these techniques may help to select the most appropriate physiotherapeutic intervention. We therefore suggest that paired TMS might be used as a prognostic neurophysiological marker for better outcome in stroke patients with severe initial impairment.
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Heald A, Bates D, Cartlidge NEF, French JM, Miller S. Longitudinal study of central motor conduction time following stroke. Brain 1993;116:1355–85. Hummelsheim H, Hauptmann B. Transcranial magnetic stimulation and motor rehabilitation. In: Paulus W, Hallett M, Rossini PM, Rothwell JC, editors. Transcranial magnetic stimulation. Electroenceph clin Neurophysiol Suppl. 51. Amsterdam: Elsevier; 1999. p. 221 –32. Hummelsheim H, Mu¨nch B, Bu¨tefisch C, Hoppe S, Neumann S. Transcranial magnetic stimulation in rehabilitation and physiotherapy evaluation in hemiparetic stroke patients. In: Lissens MA, editor. Clinical applications of magnetic transcranial stimulation. Leuven: Peeters Press; 1992. p. 290–300. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD. Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501–19. Liepert J, Storch P, Fritsch A, Weiller C. Motor disinhibition in acute stroke. Clin Neurophysiol 2000;111:671 –6. Macdonell RAL, Donnan GA. The clinical applications of transcranial stimulation in localization and prognosis of stroke. In: Lissens MA, editor. Clinical applications of magnetic transcranial stimulation. Leuven: Peeters Press; 1992. p. 166 –73. Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol 2002;113:936–43. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol 1997;498:817 –23. Pennisi G, Rapisarda G, Bella R, Calabrese V, Maertens de Noordhout A, Delwaide PJ. Absence of response to early transcranial magnetic stimulation in ischemic stroke patients. Prognostic value for hand recovery. Stroke 1999;30:2666–70. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, Dimitrijevic MR, Hallett M, Katayama Y, Lu¨cking CH, Maertens de Noordhout AL, Marsden CD, Murray NMF, Rothwell JC, Swash M, Tomberg C. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroenceph clin Neurophysiol 1994;91:79 –92. Shimuzu T, Filippi MM, Palmieri MG, Olivieri M, Vernieri F, Pasqualetti P, Rossini PM. Modulation of intracortical excitability for different muscles in the upper extremity: paired magnetic stimulation study with focal versus non-focal coils. Clin Neurophysiol 1999;110:575–81. Tokimura H, Ridding MC, Tokimura Y, Ammassian VE, Rothwell JC. Short latency facilitation between pairs of threshold magnetic stimuli applied to human motor cortex. Electroenceph clin Neurophysiol 1996; 101:263–72. Trompetto C, Assini A, Buccolieri A, Marchese R, Abbruzzese G. Motor recovery following stroke: a transcranial magnetic stimulation study. Clin Neurophysiol 2000;111:1860– 7. Valls-Sole´ J, Pascual-Leone A, Wasserman EM, Hallett M. Human motor evoked responses to paired transcranial magnetic stimuli. Electroenceph clin Neurophysiol 1992;85:355– 64. Weber M, Eisen AA. Assessment of upper and lower motor neurons in Kennedy’s disease: implications for corticomotoneuronal PSTH studies. Muscle Nerve 1999;22:299 –306. Weber M, Eisen AA. Magnetic stimulation of the central and peripheral nervous systems. Muscle Nerve 2002;25:160–75. Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 1996;496: 873– 81.
Facilitation of motor evoked potentials in ischemic stroke patients: prognostic value and neurophysiologic correlations B. Dachya,b,*, E. Biltiaub, E. Bouillota, B. Danc, P. Deltenrea,b a Laboratory of Clinical Neurophysiology, CHU Brugmann, Place Van Gehuchten 4, B-1020 Brussels, Belgium Department of Rehabilitation for Neurologic Diseases, CHU Brugmann, Universite´ Libre de Bruxelles, Place Van Gehuchten 4, B-1020 Brussels, Belgium c Department of Neurology, Hoˆpital Universitaire des Enfants Reine Fabiola, Universite´ Libre de Bruxelles, Place Van Gehuchten 4, B-1020 Brussels, Belgium b
Accepted 10 July 2003
Abstract Objective: To investigate the predictive value of paired transcranial magnetic stimulation (TMS) at rest in stroke patients in comparison with the predictive value derived from data obtained by single TMS during facilitation. Methods: Fifty-six patients with a single ischemic lesion and no electromyographic responses from single TMS in the resting affected hand muscles participated in the study. TMS assessment was performed 32 days post-stroke. It consisted of a single stimulation at maximal output during facilitation (controlateral hand grip and elbow flexion) and a paired-pulse stimulation at rest with two stimuli at maximal output at interstimulus intervals ranging from 15 to 100 ms. Two blind clinical assessments using the ‘motricity index’ were carried out 26 and 76 days post-stroke. Results: Thirty-seven percent of patients were responsive to single TMS during facilitation, had better clinical scores at both evaluations and better clinical recovery. Fifty-four percent of patients responded to paired TMS, had better clinical scores at the second evaluation and better clinical recovery. All patients who responded to the single stimulation paradigm also responded to the paired one. Conclusions: A positive correlation was found between the responsiveness to both the TMS paradigms (facilitation procedure and paired stimulation) and clinical recovery. This underlines the importance of facilitation during single TMS in stroke patients and suggests that paired TMS at rest might supplement this procedure in stroke studies. q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Transcranial magnetic stimulation; Stroke; Prognosis; Facilitation
1. Introduction As a non-invasive method of evaluation of the central motor pathways, transcranial magnetic stimulation (TMS) has been proposed as a prognostic tool in stroke patients (Catano et al., 1996; Pennisi et al., 1999). Nevertheless, some conflicting results have been reported (Trompetto et al., 2000), probably because of the variability of patients included and differences in the techniques used. The results of the initial basic studies designed to investigate the predictive value of TMS have led to categorize stroke patients in two groups: patients with preserved motor evoked potential at rest had a more complete return of function and patients with absent MEP were at high risk of poor functional recovery (Heald et al., 1993). The prognostic value of a MEP * Corresponding author. Tel.: þ 32-2-477-2446; fax: þ 32-2-477-2456. E-mail address: [email protected] (B. Dachy).
reappearing following a facilitatory technique has been approached in few studies (Macdonell and Donnan, 1992; Catano et al., 1995; Escudero et al., 1998). On the other hand, TMS responses have been studied in order to explore the physiologic mechanisms underlying physiotherapeutic interventions in stroke patients and in normal subjects (Hummelsheim et al., 1992; Hauptmann and Hummelsheim, 1996; Hummelsheim and Hauptmann, 1999). In this context, it would appear relevant to study stroke patients with absent MEP following single TMS at rest in order to confirm the predictive value of MEP facilitation and to relate it to the physiotherapeutic technique applied during the test (Hummelsheim and Hauptmann, 1999). Paired-pulse TMS techniques may be useful as they might detect residual corticospinal function and provide a standardized electrophysiologic equivalent to physiotherapeutic facilitation. To assess cortical excitability, the most commonly used paradigm consists of a subthreshold conditioning stimulus
1388-2457/$30.00 q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1388-2457(03)00252-9
B. Dachy et al. / Clinical Neurophysiology 114 (2003) 2370–2375
followed at short interstimulus intervals (ISIs) by a suprathreshold test stimulus in order to explore intracortical inhibition and intracortical facilitation (Chen, 2000). Studies using paired TMS to investigate cortical excitability in stroke patients have demonstrated a decrease in intracortical motor inhibition in both the affected and unaffected hemispheres. However, intracortical inhibition cannot be evaluated in the affected hemisphere when resting motor responses are absent or severely reduced. In such cases, it is hazardous to attribute eventual MEP changes to recovery processes (Manganotti et al., 2002). Intracortical facilitation has been evaluated in normal subjects with two nearthreshold stimuli, either at short ISIs (Tokimura et al., 1996) or at longer ISIs (Valls-Sole´ et al., 1992). In stroke patients, the comparison between MEP results obtained by single TMS with facilitation and by paired TMS at rest could refine theoretical assumptions about the modulation of the corticospinal output and practical arguments concerning physiotherapeutic interventions. In this study, we investigated whether a facilitatory effect of paired TMS was present in a group of stroke patients with a substantial motor deficit and whether this could have a predictive value for recovery.
2. Subjects and methods 2.1. Patients The study concerned patients admitted in the rehabilitation unit after a stroke. The inclusion criteria were: (1) computerized tomography or magnetic resonance imaging showing a single ischemic monohemispheric lesion; (2) first-ever stroke; and (3) no MEP at rest in the affected hand during the electrophysiological assessment. The exclusion criteria were concomitant neuropathies, dementia, epilepsy and the presence of intracerebral clips or cardiac pacemaker. Fifty-six patients (25 women, 31 men), aged from 22 to 92 years (mean 65), were entered into the study. Thirty-six patients had a left-sided lesion and 20 a right-sided lesion. The site of the lesion was cortical in 5 patients, corticosubcortical in 30 patients and subcortical in 21 patients. The patients were not receiving any drugs interfering with cortical excitability. During their stay in the rehabilitation unit, they underwent physiotherapeutic treatment performed twice daily by the same physiotherapist. 2.2. Control subjects This group consisted of 16 healthy subjects (9 women, 7 men) aged from 23 to 78 years (mean 47). 2.3. Clinical assessment Two evaluations of the muscle power in the affected upper limb were performed during the study using the ‘motricity index’ (Demeurisse et al., 1980). Power was
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assessed for pinch grip, elbow flexion and shoulder abduction while the patient was sitting. This provided a weighted score ranging from 0 (no muscle power) to 100 (normal muscle power). The physiotherapists scoring the patient strength were unaware of the neurophysiological results. Evaluations were performed at an early and a late stage of rehabilitation and labeled as index 1 and index 2. The second value was missing if, at that time, the patient was already discharged from the hospital. The gain in muscle strength as recovery rating was calculated as {index 2 –index 1}. 2.4. TMS procedures TMS was performed with a circular coil (90 mm diameter) connected to a Magstim 200 (2.0 Tesla). For paired TMS, two Magstim 200 were connected to one coil by means of a Bistim device. The same coil was used as for single TMS, accordingly to previous studies (Shimuzu et al., 1999). The coil was held flat over the vertex with the current flowing in an anticlockwise direction to preferentially activate the left hemisphere or in a clockwise direction to stimulate the right hemisphere. MEPs were recorded on the abductor digiti minimi muscles with surface electrodes, connected to a Nicolet Viking IV. The reliability of TMS responses was assessed by 3 stimulations in each condition. Whenever it was needed, the resting state of target muscles was assessed by visual and auditory feedback (on-line free running electromyographic channel). 2.4.1. Patients Two procedures were successively performed during the same session. The first procedure was a single TMS at maximal output stimulation at rest (according to inclusion criteria) and during facilitation. The latter consisted of maximal isometric flexion of the elbow against resistance combined with maximal handgrip of the unaffected side. If a MEP appeared, its shortest latency and its maximal amplitude were noted. The second procedure was a paired TMS at rest, with two equal stimuli at maximal output at ISIs ranging from 15 to 100 ms (ISI of 15, 30, 45, 60, 75 and 100 ms). If a MEP appeared during this test, its shortest latency (calculated from the second stimulus), its maximal amplitude and the ISIs allowing maximal MEP amplitude were noted. MEP recording from the unaffected hand assessed the integrity of controlateral corticospinal tract. A peripheral cause of MEP absence was excluded by nerve conduction studies and by magnetic stimulation of the cervical roots. This TMS session lasted 35– 45 min. 2.4.2. Control subjects The excitability threshold values at rest were defined according to standard procedures (Rossini et al., 1994). Paired TMS with two stimuli at 0.8 £ threshold at rest was performed; ISIs ranging from 15 to 100 ms (15, 30, 45, 60, 75
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and 100 ms). The excitation threshold was controlled at the beginning and at the end of the paired TMS procedure. The occurrence of MEP and ISI corresponding values were noted. 2.5. Statistical analysis All statistical analyzes were performed using the Statistical Package for the Social Sciences statistical package. Student’s t test for independent samples (two-tailed) was applied for comparisons of clinical scores between groups of patients. Student’s t test for paired samples (two-tailed) was used for the comparison of mean MEP latencies and amplitudes obtained by the two TMS procedures and for the comparison between index 1 and index 2 in groups of patients defined by electrophysiological results. A Levene’s test was done before in order to assess the equality of variances. The occurrence of MEP with paired TMS in patients and in control subjects was compared using a chisquare test. Values of P , 0:05 were considered significant. When not specified, values are given as mean ^ SD. 2.6. Ethical aspects The local Ethics Committee approved this project. Informed consent was obtained from the patients and from the healthy controls after the nature of the procedure had been explained. 3. Results 3.1. Clinical assessment The main results of the clinical evaluation are summarized in Table 1. 3.1.1. First evaluation (index 1) The 56 patients were evaluated at 26 ^ 16 days poststroke. The mean value of the ‘motricity index’ was 14 ^ 19. No significant difference was found in function of the side of the lesion (P ¼ 0:716, t test).
3.1.2. Second evaluation (index 2) Forty-eight patients were evaluated at 76 ^ 17 days post-stroke. The mean value of the ‘motricity index’ was 26 ^ 24. No significant difference was found in function of the side of the lesion (P ¼ 0:825, t test). Nevertheless, recovery {index 2 –index 1} was better for right-sided lesions (P ¼ 0:038, t test). 3.2. TMS results The neurophysiological testing was performed at 32 ^ 17 days post-stroke. The patients were divided in groups according to the presence of MEP or not during each of TMS procedures. 3.2.1. Single TMS results In two patients, the facilitation procedure could not be performed satisfactorily because of limb pain on the unaffected side. They were then excluded from this section of data analysis. In 20 of the other 54 patients (37%), a consistent MEP appeared during facilitation. The mean latency of these responses was 25 ^ 4.7 ms. The mean MEP amplitude was 358 ^ 743 mV. An example of facilitated MEPs is shown in Fig. 1. 3.2.2. Paired TMS results In 30 of 56 patients (54%), two successive stimuli evoked a response. The paired TMS recording of the patient illustrated in Fig. 1 is shown in Fig. 2. The mean MEP latency was 26.1 ^ 5.8 ms, which is not significantly different from that obtained with the single pulse paradigm (P ¼ 0:404, paired t test). The mean MEP amplitude was 269 ^ 532 mV, not significantly different from that obtained with the single pulse paradigm (P ¼ 0:45, paired t test). All patients who responded to the first paradigm also responded to the second one. The mean value of optimal ISIs for a maximal MEP amplitude was 44 ^ 20 ms. Fig. 3 illustrates the influence of ISI on MEP amplitude and the presence of a late component, observed in few patients.
Table 1 ‘Motricity index’ scores in function of the presence of motor evoked potentials after single transcranial magnetic stimulation during facilitation and paired transcranial magnetic stimulation at rest (mean value ^ SD) Single TMS
Paired TMS
MEP
Absent
Present
P
Absent
Present
P
Index 1 Index 2 {Index 2– Index 1} P
9.9 ^ 16.3 (n ¼ 34) 18.7 ^ 22.4 (n ¼ 30) 9.5 ^ 11.5 **
23.1 ^ 21.4 (n ¼ 20) 42 ^ 19.2 (n ¼ 16) 18.9 ^ 17.5 **
* ** *
11.3 ^ 17.7 (n ¼ 26) 18 ^ 22.5 (n ¼ 23) 7.8 ^ 9.9 **
16.7 ^ 20.2 (n ¼ 30) 32.6 ^ 23.7 (n ¼ 25) 16.2 ^ 16.7 **
NS * *
Index 1 ¼ first clinical evaluation. Index 2 ¼ second clinical evaluation. {Index 2–Index 1} ¼ strength recovery between the two evaluations. Statistical analysis: independent samples t test for comparison of ‘motricity index’ values between groups and paired samples t test for evolution of ‘motricity index’ values in each group defined by transcranial magnetic stimulation (TMS) results. * ¼ P value ,0.05. ** ¼ P value ,0.01. NS ¼ not statistically significant.
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Fig. 1. Example of single transcranial magnetic stimulation recording. Motor evoked potentials recordings on the affected side before (upper traces) and during (lower traces) facilitation. Three successive trials at 100% maximal output are superimposed.
3.2.3. Control subjects In the control subjects, the resting motor threshold values were 54 ^ 12% for the right hand and 52 ^ 11% for the left hand. In 3 (19%) of the 16 subjects, two successive subthreshold stimuli evoked a response. The occurrence of MEP was lower than in the patient group (P ¼ 0:014, chisquare test). The mean value of corresponding ISI was 35 ^ 35 ms.
Fig. 3. Example of paired transcranial magnetic stimulation recording. The uppermost trace was obtained with a single pulse transcranial magnetic stimulation at 100% maximal output. Lower traces correspond to paired transcranial magnetic stimulation (each at 100% maximal output) with interstimulus intervals of 15, 30, 45, 60, 75 and 100 ms. The maximal motor evoked potential amplitude was obtained at an interstimulus interval of 45 ms. Note the late component that may reflect activation of slow conducting cortical motor neuronal connections.
3.3. Correlations between clinical and neurophysiological data The distribution of clinical scores in function of TMS results is summarized in Table 1. 3.3.1. Single TMS results Fig. 2. Example of paired transcranial magnetic stimulation recording (same patient as in Fig. 1). Three successive trials for each condition are superimposed. Upper traces were obtained with a single pulse transcranial magnetic stimulation at 100% maximal output. Lower traces demonstrate motor evoked potentials evoked by paired transcranial magnetic stimulation (each at 100% maximal output) at an interstimulus interval of 30 ms.
Patients with MEP appearing during facilitation had ‘motricity index’ values significantly higher at index 1 (23.1 ^ 21.4 versus 9.9 ^ 16.3, P ¼ 0:014, t test), at index 2 (42 ^ 19.2 versus 18.7 ^ 22.4, P ¼ 0:001, t test) and for {index 2 – index 1} (18.9 ^ 17.5 versus 9.5 ^ 11.5, P ¼ 0:034, t test).
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3.3.2. Paired TMS results When positive, results of this procedure were not linked to a better score at index 1 (16.7 ^ 20.2 versus 11.3 ^ 17.7, P ¼ 0:293, t test), in contrast with index 2 (32.6 ^ 23.7 versus 18 ^ 22.5, P ¼ 0:034, t test) and {index 2– index 1} (16.2 ^ 16.7 versus 7.8 ^ 9.9, P ¼ 0:043, t test).
4. Discussion For single TMS procedure, our results confirm the important role of a facilitation technique for patients unresponsive at rest. As previously described (Heald et al., 1993), patients with MEP appearing during contraction of the unaffected limb had a better recovery prognosis. The same group of patients was also responsive to paired TMS performed at rest. This technique has a prognostic value similar to single TMS during facilitation, with the advantages of being independent from the patient’s collaboration and by-passing some clinical limitations, such as joint pain as in our study. The facilitatory effect of paired TMS at rest was found in 54% of patients. This was greater than the effect of the physiotherapeutic technique combined with single TMS, seen in 37% of patients. The relatively low effect of the latter facilitation technique, namely controlateral preinnervation, has been demonstrated by comparing it to direct activation of the target muscle, proximal preinnervation and cutaneous/proprioceptive stimulation (Hummelsheim and Hauptmann, 1999). However, none of these approaches would be applicable in patients with severe deficit such as our study group. In this context, paired TMS appears as a relevant approach. The mechanisms underlying facilitation during single TMS are not entirely understood. They likely include increased cortical and spinal excitability (Weber and Eisen, 2002). This would result in increased firing of residual corticospinal neurons, facilitating response to the magnetic stimulation, thus enhancing the descending volley onto the spinal motoneurons (Catano et al., 1995). The data obtained by Hauptmann and Hummelsheim (1996) in hemiparetic stroke patients suggest that most of the MEP amplitude facilitation is of cortical origin. Nevertheless, the recruitment of a greater number of spinal motoneurons has been linked to increased spinal excitability or to increased synchronization of spinal motoneuron firing (Weber and Eisen, 2002). This duality of facilitation sites could have therapeutic implications. Indeed, physiotherapeutic interventions including synergistic associated patterns are based on central facilitation, whereas peripheral facilitation procedures involve cutaneous and proprioceptive afferents (Hummelsheim and Hauptmann, 1999). Previous TMS studies suggested that central facilitation procedures as proposed by Brunnstrom were the most effective way to raise the discharge probability of spinal motoneurons, at least in completely paralyzed muscles (Hummelsheim et al., 1992).
To our knowledge, the use of paired TMS in stroke patients with a cortical threshold at rest above maximal output using two equal stimuli at subthreshold intensity has not been described before. The site (cortical versus spinal) of the facilitation resulting from paired TMS has been discussed in many studies carried out with healthy subjects. With a paired TMS technique involving two near-threshold stimuli, Tokimura et al. (1996) observed MEP facilitation at short ISIs between 1.1 and 4.5 ms. This facilitation probably reflects an interaction between circuits producing the indirect corticospinal waves (I waves) (Chen, 2000). Performing paired TMS at near-threshold stimulus intensities (90 and 100%), Valls-Sole´ et al. (1992) observed facilitation at ISIs of 50– 90 ms. The probability of eliciting the test MEP at 90% of the threshold was in the range of our normal subjects (20 ^ 10%). The motor disinhibition observed in motor areas in acute stroke (Liepert et al., 2000; Manganotti et al., 2002) can explain that two equal subthreshold stimuli generated a MEP more frequently in our stroke patients than in control subjects during paired TMS. However, a refined study of the excitability of intracortical inhibitory circuits in the affected hemisphere was not feasible in our study as motor inhibition cannot be measured in patients with absent MEP at rest. In few patients, MEP appearing during our paired TMS procedure included late components, as illustrated in Fig. 3. These components are also observed in single TMS recordings in amyotrophic lateral sclerosis patients. Using peristimulus time histograms in this condition, Weber and Eisen (1999) attributed the temporal dispersion of excitatory postsynaptic potentials generated at the anterior horn level to motor cortex hyperexcitability. The late components of MEP were linked to the activation of slow conducting and/or indirect cortical motor neuronal connections (Weber and Eisen, 2002). Studying ipsilateral responses to focal TMS in healthy subjects and stroke patients, Alagona et al. (2001) suggested that hyperexcitability of the lateral premotor cortex and supplementary motor area on the affected side could compensate damage to the corticospinal pathway. As regard the spinal level, it is generally considered that an initial subthreshold conditioning stimulus has no influence on the descending pathways (Hallett, 2000). However, on the basis of simultaneous recordings of the corticospinal volley and of EMG response following paired TMS, Nakamura et al. (1997) demonstrated that stimulation below threshold with respect to EMG response is above threshold for the corticospinal volley. At ISIs of 25 and 50 ms, there was slight facilitation of the volley. They concluded that the enlargement of the EMG responses could not be linked only to facilitation of the motor cortex, but presumably also to the temporal summation of the multiple descending I waves at the spinal level. Ziemann et al. (1996) noted that when the intensity of the conditioning stimulus is below the threshold needed to evoke responses in relaxed muscles but greater than the threshold needed to evoke responses in active muscles, then
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some part of the facilitation can be linked to changes in spinal cord excitability. Kujirai et al. (1993) studied the influence of the intensity of the conditioning stimuli. When this intensity raised, a small corticospinal volley appear to produce subthreshold facilitation of spinal motoneurons, contributing to the facilitation of test responses at interstimulus intervals of 10 and 15 ms.
5. Conclusion Our findings in stroke patients responsive to single TMS with facilitatory technique and to paired TMS at rest are consistent with a cortical excitability threshold slightly above 100% output of the stimulator. The thresholdlowering effect of muscle contraction allows to unmask residual corticospinal projections, which seem to play a significant role in muscle power recovery as demonstrated by group comparisons. In addition to theoretical hypotheses on the respective role of cortical and spinal factors in facilitation, these techniques may help to select the most appropriate physiotherapeutic intervention. We therefore suggest that paired TMS might be used as a prognostic neurophysiological marker for better outcome in stroke patients with severe initial impairment.
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