Motor cortical excitability in patients with poststroke epilepsy

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1 FULL-LENGTH ORIGINAL RESEARCH Motor cortical excitability in patients with poststroke epilepsy Jee Hyun Kim, Hyang Woon Lee, Leonardo G. Cohen, Kee-Duk Park, and Kyoung-Gyu Choi Department of Neurology and Ewha Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea; and Human Cortical Physiology Section and Stroke Neurorehabilitation Clinic, National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A. SUMMARY Purpose: To gain insight into the mechanisms underlying poststroke epilepsy (PSE), we evaluated motor cortical function in chronic stroke patients with (N = 18) and without (N = 18) PSE. Methods: We measured resting motor threshold (RMT), motor evoked potential (MEP) amplitudes, cortical silent period (CSP), intracortical inhibition (ICI), influenced by GABAergic neurotransmission, and intracortical facilitation (ICF), influenced by glutamatergic activity, to transcranial magnetic stimulation. Results: We found (1) larger MEP amplitudes and ICF, in the affected than unaffected hemispheres of patients in the PSE group but not in patients without epilepsy, and (2) comparably higher RMT and longer CSP in the absence of differences in ICI, H- reflexes or F-waves in the affected and unaffected hemispheres of both PSE and non-pse patients. Conclusions: Enhanced cortical excitability in the affected hemisphere, possibly related to increased glutamatergic activity, could be one of the mechanisms contributing to the development of poststroke epilepsy. KEY WORDS: Cortical excitability, Poststroke epilepsy, Transcranial magnetic stimulation, Motor evoked potentials. Stroke leads to structural and functional changes including cortical reorganization in perilesional brain areas (Fridman et al., 2004; Johansen-Berg et al., 2004), and interconnected neuronal circuits, that may undergo selective neuronal cell death, changes in membrane properties, and collateral axonal sprouting (Luhmann et al., 1995; Stroemer et al., 1995; Kelly et al., 2001; Jin et al., 2006). Motor cortical excitability changes after stroke, as indicated by the modulation of intracortical inhibitory and excitatory circuits in both cerebral hemispheres (Liepert et al., 2000; Ward and Cohen, 2004; Talelli et al., 2006), as well as in abnormalities of interhemispheric interactions (Murase et al., 2004; Jin et al., 2006). Approximately 2 4% of patients with stroke develop epilepsy (Kessler et al., Accepted May 15, 2007; Online Early Publication August 2, Address correspondence and reprint requests to Hyang Woon Lee, MD, PhD, Associate Professor at Epilepsy and Sleep Disorder, Department of Neurology and Ewha Medical Research Institute, School of Medicine, Ewha Womans University, 911-1, Mok-dong, Yangcheon-gu, Seoul, , Korea. leeh@ewha.ac.kr Blackwell Publishing, Inc. C 2008 International League Against Epilepsy 2002; Epsztein et al., 2006), more commonly with severe, large, disabling lesions, often hemorrhagic, and predominantly cortical involvement (Lossius et al., 2005). The mechanisms mediating the development of PSE are not well understood but may include differential changes in cortical function in stroke patients with seizures relative to those patients without epilepsy. The purpose of this investigation was to evaluate motor cortical excitability in chronic stroke patients with and without PSE using transcranial magnetic stimulation (TMS). METHODS Subjects Thirty-six right handed patients with chronic stroke with (n = 18, mean age, 60.4 ± 9.8 years; 3 females and 15 males) and without (n = 18; mean age 67.4 ± 12.0 years; 6 females and 12 males) epilepsy participated in this study at Ewha Womans University Hospital between January 2001 and July

2 118 J. H. Kim et al. Patients with PSE were included if they (1) had two or more seizures at least one week after an ischemic stroke consistent with the definition of poststroke epilepsy according to the Guidelines developed by the International League Against Epilepsy (Commission on Epidemiology and Prognosis, International League Against Epilepsy, 1993); (2) had unilateral single cortical (or combined corticosubcortical) infarction considered epileptogenic; and (3) had no history of seizures or epileptogenic lesion preceding the stroke. The control group included patients with a single unilateral stroke without seizures. Vascular territories, cortical and corticosubcortical lesion locations, and motor function (by motricity index) affected were matched in both groups. The patients enrolled had been followed for at least 1-year after stroke onset. Informed consent was obtained from all patients and the study protocol was approved by our local Institutional Review Board based on the ethical principles of the Declaration of Helsinki (1964). Clinical assessments, which included medical records, seizure classifications, brain MRI or CT findings, EEG, and antiepileptic drug medications, were reviewed. Hand muscle strength was assessed on the MRC scale (0, no movement and 5, normal strength) and the Motricity indices (0, absent movement of both arm and leg and 99, normal strength) (Demeurisse et al., 1980). Stroke severity was evaluated with the Modified Rankin Scale and the National Institutes of Health Stroke Scale. Deep tendon reflexes were graded from 0 to 4 (0, absent to 4, hyperreflexia), and the severity of spasticity was evaluated by the Modified Aschworth Scale from 0 to 5 (0, no spasticity to 5, severe spasticity). Global quality of life was measured with the Barthel index. The Edinburgh Handedness Scale was assessed to determine a dominant hemisphere (Oldfield, 1971). Within the PSE group, seizures were well controlled by pharmacological medications in all but three patients. Transcranial magnetic stimulation Motor evoked potentials (MEPs) were recorded using surface EMG Ag-AgCl electrodes placed over the first dorsal interosseous (FDI) muscle in a belly-tendon montage. EMG raw signals were amplified, bandpass-filtered (5 Hz to 5 khz), and recorded on a personal computer using data collection and averaging software (Neuroscreen plus, Toennies, Germany). TMS was delivered through a figure of eight magnetic coil (15 cm external diameter) connected to a Cadwell High Speed Magnetic Stimulator (Cadwell Laboratories, Inc., Kennewick, WA, U.S.A.) discharging a maximum output of 2.0 T. Subjects were seated in an armchair. The intersection of the two wings of the coil was placed tangentially to the scalp with the handle pointing backward and laterally at a 45 away from the midline to activate optimally the corticospinal pathways (Brasil-Neto et al., 1992). The TMS coil was placed flat on the skull over the optimal scalp positions to activate the contralateral FDI muscles. The following measures were determined in every patient: Resting motor threshold (RMT) was defined as the minimal stimulus intensity required to induce a MEP > 50 µv peak to peak amplitude in at least five of ten consecutive trials in the contralateral FDI (Rossini et al., 1994). Stimulus intensities were changed in steps of 1%. Recruitment curve (RC) to TMS was determined at 100%, 120%, and 140% of the RMT intensity in each subject. Ten consecutive MEPs were recorded at each stimulus intensity. Peak to peak amplitudes were measured in each trial and later averaged to characterize amplitudes at each stimulus intensity. Absolute MEP amplitudes were expressed relative to the maximal peripheral M response evoked by stimulation of ulnar nerve at the wrist. Cortical silent period (CSP) was measured for each of 10 trials at 140% RMT stimulus intensity. Subjects were asked to maintain a voluntary contraction of the FDI muscle at 50% of maximal force under visual feedback. CSP duration was measured in individual trials from the beginning of the MEP to the recurrence of voluntary EMG activity displayed at high magnification on an EMG screen. This measure could only be obtained in patients with sufficient hand motor function to maintain the required background contraction (13 with and 13 without PSE). Intracortical inhibition (ICI) and facilitation (ICF) were measured using well described paired pulse protocols at 2 ms for ICI and 15 ms for ICF (Chen et al., 1998). The intensity of the conditioning stimulus was 70% of the RMT of the FDI, and the intensity of the test stimulus was adjusted to produce MEPs of approximately 1 mv peak-topeak amplitude in the resting FDI. Mean intertrial interval was 5 seconds. The amplitude of the conditioned MEP was expressed relative to the unconditioned MEP for each ISI. All excitability measures (other than CSP, see above) were measured in all patients. Side-to-side ratios were determined for each measure of corticomotor excitability to evaluate interhemispheric differences; values of the affected hemisphere relative to those in the unaffected hemisphere (e.g. MEP amplitudes at 120% RMT of the affected hemisphere divided by MEPs at 120% RMT of the unaffected hemisphere) (Traversa et al., 1999). H-reflexes and F-waves, which convey information on the excitability of the alpha motor neuron pool, were also measured to determine to which extent changes in MEP amplitudes to TMS could be secondary to changes in spinal instead of cortical excitability. Statistical analysis RMT, MEP amplitudes, CSP, ICI, ICF, H and F responses in each side were analyzed using Mann Whitney U test. The Wilcoxon signed ranks test was used to compare each TMS index between the PSE and non-pse groups. Repeated measures ANOVA were used to analyze recruitment curves across groups. Pearson correlation test was used to examine if there was a correlation between

3 119 Cortical Excitability in Poststroke Epilepsy Table 1. Clinical characteristics of PSE patients Time course No. Age (years) Sex Arterial territory Lesion M1 (months) MRS MI MAS BI 1 72 M Rt MCA (C) F-T N M Rt MCA (C) F-T-P N F Lt MCA (C) Ant. F N M Lt MCA (C) Ant. F N M Rt ACA (C) Med. F N F Lt ACA (C) Med. F N M Rt MCA (C) P N M Rt MCA (C) T-P N M Rt MCA (C) T-P N M Lt MCA (C) F Y F Lt MCA (CS) F-T-P Y M Rt MCA (CS) F-T-P Y M Lt MCA (CS) F-T-P Y M Lt MCA (CS) F-T-P Y M Lt MCA (CS) F-T-P Y M Lt MCA (CS) F-T-P Y M Rt MCA (CS) F-T-P Y M Rt MCA (CS) F-T-P Y Mean SD Lt, left; Rt, right; C, cortical; CS, corticosubcortical; F, frontal; T, temporal; P, parietal; F-T-P, frontotemporoparietal; F-P, frontoparietal; F-T, frontotemporal; T-P, temporoparietal; Ant., anterior; Med., medial; M1, primary motor cortex; Y, involvement of primary motor cortex; N, no involvement; MRS, modified Rankin Scale; MI, motricity index; MAS, modified Ashworth scale; BI, Barthel index; SD, standard deviation. abnormalities in cortical excitability and motor function. Data is displayed as mean ± standard deviation and differences are assigned significance if p < RESULTS Patient characteristics There were no significant differences between PSE and non-pse patients in clinical profiles including age, time after stroke, and functional indices (see Tables 1 and 2). Of the 18 PSE patients, 6 had partial seizures (simple and/or complex), and 12 had secondary generalized tonic-clonic (sgtc) seizures (Table 3). In the PSE group, 15/18 patients were receiving one or more antiepileptic drugs at the time of the study (valproic acid, 8/15; phenytoin, 2/15; carbamazepine, 1/15; topiramate, 1/15; gabapentin, 1/15; phenytoin + gabapentin, 1/15; valproic acid + carbamazepine + gabapentin, 1/15). Plasma drug levels were 58.2 ± 21.9 mg/dl for valproic acid, 10.2 ± 5.0 mg/dl for phenytoin, and 6.7 ± 2.5 mg/dl for carbamazepine. Thirteen of 18 patients showed EEG abnormalities including regional spikes (3/18), continuous or intermittent lateralized hemispheric slow waves (5/18), continuous or intermittent regional slow waves (3/18), and intermittent generalized slow waves (2/18) (Table 3). Twelve of 15 patients with medications were seizure free, and two of the three patients with occasional seizures had their seizures when they skipped the medications. Figure 1. Resting motor thresholds (RMTs) in patients of poststroke epilepsy (PSE) and non-pse groups. RMTs increased in the affected hemispheres (AH, black bars) compared with unaffected hemispheres (UH, white bars) in the PSE and non-pse groups ( p < 0.05 level). Epilepsia C ILAE Motor cortical excitability Motor thresholds RMTs were significantly higher in the affected (AH) than in the unaffected hemisphere (UH) in PSE patients (p = 0.030), with a similar nonsignificant trend in the non-pse group (p = 0.344, Fig. 1). Comparable

4 120 J. H. Kim et al. Table 2. Clinical characteristics of non-pse control patients No. Age (years) Sex Arterial territory Lesion M1 Time course (months) MRS MI MAS BI 1 86 M Lt MCA (C) F-T N F Rt MCA (C) F-T N M Rt MCA (C) Ant. F N M Lt MCA (C) Ant. F N F Rt ACA (C) Med. F N F Lt ACA (C) Med. F N M Lt MCA (C) P N M Rt MCA (C) T-P N M Lt MCA (C) T-P N M Lt MCA (C) F Y M Rt MCA (CS) F-T-P Y F Lt MCA (CS) F-T-P Y M Lt MCA (CS) F-T-P Y M Rt MCA (CS) F-T-P Y M Rt MCA (CS) F-T-P Y F Lt MCA (CS) F-T-P Y M Rt MCA (CS) F-T-P Y F Lt MCA (CS) F-T-P Y Mean SD Lt, left; Rt, right; C, cortical; CS, corticosubcortical; F, frontal; T, temporal; P, parietal; F-T-P, frontotemporoparietal; F-P, frontoparietal; F-T, frontotemporal; T-P, temporoparietal; Ant., anterior; Med., medial; M1, primary motor cortex; Y, involvement of primary motor cortex; N, no involvement; MRS, modified Rankin Scale; MI, motricity index; MAS, modified Ashworth scale; BI, Barthel index; SD, standard deviation. Table 3. Seizure classification and antiepileptic drugs in PSE patients Seizure Seizure Antiepileptic Last seizure No. Age Sex Lesion onset Classification drug EEG finding before TMS (months) 1 72 M F-T 15 months sgtc DPH CS, right hemi M F-T-P 6 months sgtc VPA CS, right hemi F Ant. F 10 months SPS VPA Normal M Ant. F 2 weeks sgtc None Normal M Med. F 1 month SPS TPM CS, right F-T F Med. F 8 months CPS DPH Normal M P 3 months sgtc VPA Spike, right P M T-P 2 weeks sgtc GBP Normal M T-P 2 weeks SPS None IS, right hemi M F 2 weeks sgtc VPA IS, gen F F-P-T 36 months sgtc DPH + GBP Normal M F-T-P 6 months sgtc VPA CS, right F-T M F-T-P 1 month sgtc VPA CS, left hemi M F-T-P 2 weeks CPS None Spike, left frontopolar M F-T-P 16 months sgtc CBZ IS, gen M F-T-P 5 months sgtc VPA CS, left hemi M F-T-P 2 months CPS VPA+CBZ+GBP Spike, right F M F-T-P 5 months sgtc VPA CS, right F-T 1 Ant., anterior; Med., medial; F, frontal; T, temporal; P, parietal; F-T, frontotemporal; T-P, temporoparietal; F-T-P, frontotemporoparietal; SPS, simple partial seizure; CPS, complex partial seizure; sgtc, secondarily generalized tonic clonic seizures; DPH, phenytoin; VPA, valproic acid; GBP, Gabapentin; CBZ, carbamazepine; TPM, topiramate; CS, continuous slow; IS, intermittent slow; hemi., hemisphere; gen., generalized. nonsignificant trends were seen in PSE patients with partial and sgtc seizures (p = and 0.059, respectively). Side-to-side ratios were also comparable in both groups, with a significant correlation between side-to-side RMT ratios and motricity indices for the paretic arm (R = 0.605, p < ). The weaker the paretic arm, the more marked the side-to-side RMT ratio.

5 121 Cortical Excitability in Poststroke Epilepsy Figure 2. Recruitment curves (expressing MEP amplitudes as % RMT). MEP amplitudes from FDI muscles at intensities of 100%, 120% and 140% RMT in the affected (AH) and unaffected hemisphere (UH) in a patient with poststroke epilepsy (PSE) (A)the recruitment curves group data (B)and side to side MEP ratio AH/UH (C) in PSE and non-pse groups. Note the larger MEP amplitudes elicited at 120% and 140% RMT intensities in the AH than in the UH in PSE patients (A and B), whereas the opposite effect (smaller MEPs at 120% and 140% RMT in the AH than the UH) was seen in the non-pse group (B). The AH/UH MEP amplitude ratio increased with increasing stimulus intensities in the PSE group, while it decreased in the non-pse group (C) ( p < 0.05 and p < 0.01 levels). Epilepsia C ILAE Recruitment curves RCs were larger in the AH than in the UH in PSE patients only an effect more prominent at 120% and 140% RMT (p = and 0.009, Fig. 2B) that appeared to be present in patients with partial seizures (i.e., ± mv in the AH to ± mv in the UH at 140% RMT, p = 0.034) and also in those with sgtcs (i.e., ± mv in the AH to ± mv in the UH at 140% RMT, p = 0.080). Considering only the AH, MEP amplitudes were higher in PSE patients than in non-pse patients (Figs. 2A and 2B, p = 0.033). The side-to-side ratio in MEP amplitudes at 140% RMT was significantly higher in the PSE than in the non-pse group (p = 0.007, Fig. 2C). A repeated measures ANOVA, showed that the MEP amplitudes of the AH and side-to-side ratio in the PSE group increased with increasing stimulus intensities (p = and 0.063, respectively) relative to the non-pse group. No significant differences were observed between MEP amplitudes of the UH in both groups (p = 0.605, Figs. 2B and 2C). Similar results were observed in the subgroups with relatively preserved hand motor function. MEP amplitudes in the AH increased with increasing stimulus intensities more prominently in the PSE than in the non-pse group at intensities of 120% RMT (0.118 ± mv and ± mv, p = 0.047) and 140% RMT (0.209 ± mv and ± mv, p = 0.046).

6 122 J. H. Kim et al. Figure 3. Cortical silent periods (CSP) in patients of poststroke epilepsy (PSE) and non-pse groups. CSP prolonged in the affected hemispheres (AH, black bars) relative to the unaffected hemispheres (UH, white bars) in the PSE group with a similar trend in the non-pse group ( p < 0.05 level). Epilepsia C ILAE Cortical silent periods Mean CSP durations were longer in the AH than in the UH within the PSE group (p = 0.011) with a similar nonsignificant trend in the non-pse group (Fig. 3). No difference was found between the PSE and non-pse groups in side-to-side CSP duration ratios. Prolonged CSPs in the AH relative to the UH in PSE patients were evident in subjects with sgtcs (217.4 ± 94.1 ms in the AH and ± 68.5 ms in the UH, p = 0.008), but not in those with partial seizures (144.5 ± 42.0 ms and ± 53.0 ms, p = 0.465). Intracortical inhibitions and facilitations ICI was comparable in the AH and the UH of PSE and non-pse (p = and 096 respectively, Fig. 4B) patients. ICF, on the other hand, was larger in the AH than in the UH of PSE patients (p = 0.001) (Fig. 4A), in the absence of differences in non-pse patients (p = 0.300) (Fig. 4C). There were no significant differences in ICI or ICF of each hemisphere between PSE and non-pse groups, or between subgroups with partial and sgtcs. The latency of the first seizures after stroke onset was not correlated with any of the TMS indices. H-reflexes and F-waves There was no difference in H-reflexes between the two sides of PSE (13.94 ± 0.76 µv and ± 1.33 µv respectively, p = 0.736) and non-pse (13.14 ± 0.95 µv and ± 1.29 µv respectively, p = 0.556) patients. F- waves were also comparable in the two sides of PSE (27.12 ± 1.45 µv and ± 6.74 µv respectively, p = 0.523) and non-pse (26.36 ± 1.11 µv and ± 0.91 µv respectively, p = 0.408) patients. DISCUSSION The main findings of this study were (1) larger RC and ICF in the affected than unaffected hemispheres of patients in the PSE group but not in patients without epilepsy, and (2) comparably higher RMT and longer CSP in the absence of differences in ICI in the affected and unaffected Figure 4. Intracortical inhibition (ICI) at 2 ms and facilitation (ICF) at 15 ms interstimulus intervals (ISI). ICI and ICF in the affected (AH) and the unaffected hemispheres (UH) of a patient with PSE (A), and group data of ICI (B) and ICF (C) in the PSE and non-pse groups. Note the larger ICF in the AH than the UH, in the absence of differences in ICI, in the PSE patient (A). There was no interhemispheric differences of ICI in the PSE and non-pse groups (B), while ICF was larger in the AH (black bars) than in the UH (white bars) in the PSE group ( p < 0.01 level) (C). Epilepsia C ILAE

7 123 Cortical Excitability in Poststroke Epilepsy hemispheres of both PSE and non-pse patients. These findings were also present when including only patients with relatively intact hand motor functions in the analysis. Longer CSP in the affected hemisphere was present in PSE patients with secondary generalized seizures, but not in those with partial seizures. Patients in the two groups were matched for vascular territory affected (all middle cerebral artery territory except two), lesion site (whether cortical lesions included primary motor cortex or not, and whether the lesions involved both cortical and subcortical structures), and motor impairment, reducing to some extent the unavoidable heterogeneity implicit in this type of investigation (Liepert et al., 2005). In our study, the main differences between the two groups were larger recruitment curves and increased intracortical facilitation in the affected than unaffected hemispheres of patients in the PSE group but not in patients without epilepsy. Recruitment curves in small hand muscles, show a sigmoid increase of MEP amplitudes with increasing stimulus intensities until they reach a plateau level (Hess et al., 1987; Devanne et al., 1997), which provides information about the physiological strength of corticospinal connections (Devanne et al., 1997; Ridding et al., 1997; Boroojerdi et al., 2001). Recruitment curves have multifactorial influences; enhanced by D-amphetamine, and influenced by GABAergic/monoaminergic neurotransmission as well as changes in Na + /Ca ++ channel properties (Boroojerdi et al., 2001). Increased MEP amplitudes could reflect enhanced cortical excitability and increased recruitment of cortical neurons at suprathreshold TMS stimulations in the affected hemisphere of PSE patients. It is unlikely that medications taken by these patients influenced our results since all these drugs elicit the opposite effect: decrease motor cortical excitability (Ziemann et al., 1996a,b, 1999), contrary to our findings of increased recruitment curves. Intracortical facilitation is predominantly influenced by intracortical glutamatergic function (Ziemann, 2003, 2004). A conditioning stimulus capable of producing ICF has been reported to induce modifications partially mediated at subcortical levels (Di Lazzaro et al., 2006). Our finding that neither H nor F responses differed between the two sides in either patient group indicates that differences in ICF could not be explained by higher excitability at the alpha motor neuron level. More likely, the difference between the two groups, in addition to the interaction of factors like lesion size and location (Liepert et al., 2005; Lossius et al., 2005), could represent the consequence of differential glutamatergic activity in intracortical circuits of the affected hemisphere, more prominent in PSE subjects. Up-regulation of NMDA receptor dependent function has been documented in ischemic cores and neighboring cortical areas in animal models of ischemic stroke (Qu et al., 1998). Collateral sprouting and synaptogenesis are known to increase more in the chronic than in the subacute phase after rat neocortical infarction (Stroemer et al., 1995). These microstructural changes can facilitate the recruitment of cortical neurons when stimulated, which can be comparable with our findings in ICF, together with the increment of RC curves. Common to both patient groups, PSE and non-pse, was the higher RMT and longer CSP in the absence of differences in ICI between the affected and unaffected hemispheres. These findings suggest that abnormalities in Na + and Ca 2+ channels, which influence prominently RMT (Ziemann et al., 1996a, 1996b), and in GABAergic functions, which influence heavily ICI and CSP (Chen et al., 1999; Ziemann et al., 1996a, 1996b; Ziemann, 2003, 2004), as far as they are evaluated with RMT and ICI, could not account alone for the expression of seizures in PSE patients. Interestingly, CSP prolongation was observed only in patients with secondary generalized seizures within the PSE group. The reason why CSP prolongation was not observed in patients with partial seizures remains to be determined. All patients in the present study have been tested more than one year after the stroke. Therefore, across group differences in motor cortical function were stable (Delvaux et al., 2003), and clearly did not rely on motor impairment levels or lesion locations (matched as part of the experimental design). A previous study showed that stroke patients with a shortened CSP in the affected hemisphere during the acute stage of MCA infarction have an increased risk of developing seizures later on, suggesting the association of PSE with reduced intracortical inhibition during the early stages after cortical infarction (Kessler et al., 2002). Lack of correlation in our results would be probably because our study had been done in the chronic stage after at least one year of stroke onset. One limitation of this study is that we have not evaluated patients with seizures in the acute period after stroke, a situation in which the mechanisms underlying the epileptic event may differ substantially from those present in the chronic stage. In summary, our results of differential changes in RC and particularly ICF in PSE patients relative to those without seizures raise the hypothesis that enhanced cortical excitability, possibly related to increased expression of intracortical glutamatergic activity in the affected hemisphere, could contribute to the development of poststroke epilepsy in the chronic stage. ACKNOWLEDGMENTS Hyang Woon Lee was supported by a Korean Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF E00156) and Ewha Medical Research Institute. REFERENCES Brasil-Neto JP, Cohen LG, Panizza M, Nilsson J, Roth BJ, Hallett M. (1992) Optimal focal transcranial magnetic activation of the human

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