Effect of Different Frequencies of Repetitive Transcranial Magnetic Stimulation on Motor Function Recovery after Acute Ischemic Stroke

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1 M.A. Etribi et al. Effect of Different Frequencies of Repetitive Transcranial Magnetic Stimulation on Motor Function Recovery after Acute Ischemic Stroke M.A. Etribi 1, E.M. Khedr 2, M.H. Elrakawy 1, A.M. Nassef 1, A.A. Osman 2 Department of Neurology, Ain Shams University 1, Assiut University 2 ABSTRACT Background and Purpose: Although there is some early evidence showing the value of repetitive transcranial magnetic stimulation (rtms) in stroke rehabilitation, the therapeutic effect of high-frequency rtms, has not been established. The aim of this study is to investigate the effect of different frequencies of rtms on motor cortical excitability on the affected and non affected hemisphere and to detect the best frequency used to enhance motor recovery in acute stroke patients. Methods: Forty eight patients with acute ischemic stroke of middle cerebral artery territory participated in the study (24) males and (24) females. The patients were randomly classified into three groups: Group 1 (included sixteen patients who received real rtms with 3Hz). Group 2 (included sixteen patients who received real rtms with 10 Hz). Group 3 (included sixteen patients who received sham rtms with 3 Hz) for five consecutive days. Otherwise, patients continued their medical treatment. Each patient underwent complete neurological examination, CT and/or MRI of the brain, motor disability and functional ability, EEG and neurophysiological assessment before and after rtms s. Results: There was significant improvement in patients who received real rtms in comparison to the sham rtms group regarding motor power recovery and all stroke scales scores. The improvement was concomitantly associated with cortical excitability changes. Conclusions: High-frequency rtms provides a fast, effective, painless, non invasive treatment for motor disorders during the rehabilitation of acute stroke patients. (Egypt J. Neurol. Psychiat. Neurosurg., 2008, 45(2): ) INTRODUCTION Stroke is the second commonest cause of death and the principal cause of adult disability in the world 1. Stroke is also a major cause of prolonged neurologic disability in adults 2. Fortunately the brain is plastic and is able to reorganize itself up to a certain degree of damage. Many studies have documented the changes in cortical organization that occur after motor stroke, particularly on the side of the lesion 3. In addition, there is a balance of function between the two hemispheres that is controlled by interhemispheric inhibition. The stroke-affected hemisphere can be doubly disabled, by the stroke itself and by an imbalanced inhibition from the non-stroke hemisphere. In this model, increased activity in the affected hemisphere will promote recovery of the paretic limbs, as well as decreased inhibition from the non-stroke hemisphere 4. Repetitive transcranial magnetic stimulation (rtms) has been identified as a mean of altering excitability in the motor cortex. Based on this ability to change excitability, rtms has been proposed as a potential treatment for various disorders with putatively altered level of activity in cortical circuits including stroke 5. The development of rtms and transcranial direct current stimulation (tdcs) allowed the imbalance of activity between hemispheres to be modulated for enhancing stroke recovery. For instance, post-stroke motor performance improved after inhibiting the unaffected hemisphere by lowfrequency rtms 6,7 or cathodal tdcs 8 or exciting the affected hemisphere by high-frequency rtms 9,10 or anodal tdcs 8,11 469

2 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 The aim of the present study is to evaluate the effect of different frequencies of rtms on motor cortical excitability on both the affected and unaffected hemisphere and to detect the best frequency used to enhance motor recovery in patients with acute ischemic stroke. SUBJECTS AND METHODS Forty eight patients with first ever acute ischemic stroke of middle cerebral artery territory participated in the study; (24) males and (24) females. The patients were selected consecutively from those who were admitted at stroke unit, department of neurology, Assiut University Hospital, from March 2006 to July 2007 in cooperation with Department of Neurology, Ain Shams university Hospital. Inclusion criteria were acute hemiplegia with single thromboembolic non hemorrhagic infarction documented by CT and /or MRI in the distribution of middle cerebral artery. Exclusion criteria were massive hemispheric infarction, brainstem infarction, unstable cardiac dysrhythmia, previous administration of tranquilizer and patients who were unable to give informed consent because of severe aphasia, anosognosia, or cognitive deficit. Each patient was submitted to complete neurological examination (we used Hemispheric stroke scale 12 in the assessment of the motor power). Motor disability and functional ability were assessed using National Institutes of Health Stroke Scale (NIHSS), Barthel index scale (BI) and Modified Rankin scale (MR). EEG was done for each patient before the first and after the fifth one. Cortical excitability was studied by of the resting motor threshold (RMT), active motor threshold (AMT) and motor evoked potentials size- (amplitude)- (MEP) (for the unaffected hemisphere as well as affected hemisphere if possible), cortical silent period (for the unaffected hemisphere only). The assessment was done before the first and after the second and the fifth one for all the parameters. TMS used as diagnostic tool for estimation of motor threshold (RMT and AMT), cortical silent period (CSP) and MEP amplitude and as a therapeutic tool through rtms. A Dantec keypoint EMG was utilized to collect the signal (Dantec, Skovlunde, Denmark). EMG parameters included a bandpass of Hz, and a recording time window of 200 ms. Assessment of cortical excitability of the M1Hand. Measurements were performed with a High Power Magstim 200 machine and a figure-of-eight coil with mean loop diameters of 9 cm. The coil was placed tangentially to the scalp with the junction region pointing backwards and laterally at a 45 degree angle away from the mid-line, approximately perpendicular to the line of the central sulcus, inducing a posterior anterior current in the brain. We have chosen this orientation because motor threshold is minimum when the induced electrical current in the brain flows approximately perpendicular to the line of the central sulcus 13,14. The provisional hot spot of the hand area was determined 5 cm lateral to the sagittal plane and 1 cm anterior to the pre auricular line 9 (Khedr et al., 2005). Intensity was gradually increased until a 50 µv (in amplitude) signal was produced on 5 out of 10 trials. The site at which stimuli of slightly suprathreshold intensity consistently produced the largest MEPs in the target muscle was marked with a red color as the motor hot spot. Baseline and postrtms s were performed over this marked area. Resting motor threshold (RMT) was defined as the minimum output of the stimulator that induced a reliable MEP (about 50 µv in amplitude) in at least five of ten consecutive trials when the first dorsal interosseous (FDI) muscle was completely relaxed. Active motor threshold (AMT) was defined as the lowest stimulus intensity at which five of ten consecutive stimuli elicited reliable MEPs (about 200 µv in amplitude) during slight (10 15% maximum) tonic contraction of the target muscle. Cortical silent period. Single TMS stimuli were also delivered during isometric voluntary contraction (70% maximal contraction) of the right FDI muscle in order to measure the duration of the cortical silent period. The intensity of stimulation was 130% of RMT. Sex trials were collected with intertrial intervals of 5 seconds. The duration of the silent period was measured in each patient from the onset of the MEP elicited by the suprathreshold TMS (130% of resting motor threshold) pulse to the onset of continuous EMG activity after the period of EMG suppression. 470

3 M.A. Etribi et al. MEP: The motor evoked potential amplitude was measured peak to peak (mv). The patients were randomly classified into three groups according to the type of the rtms to the affected hemisphere. During rtms, all patients were earpluged. Group 1: included sixteen patients who received real rtms with 3Hz, 5 sec., 50 trains, total : 750 pulses at 130% of RMT of the unaffected hemisphere for five consecutive days. Group 2: included sixteen patients who received real rtms with 10Hz, 2 sec., 37 trains, total : 750 pulses at 100% of RMT of the unaffected hemisphere for five consecutive days). Group 3: included sixteen patients who received sham rtms with 3Hz, 5 sec., 50 trains, total, 750 pulses at 130% of RMT of the unaffected hemisphere for five consecutive days. rtms was delivered through a figure of 8 coil (the outer diameter of each wing is 9 cm, the maximum field strength = 2.5 tesla) attached to a maglite r 25 stimulator (Dantec Medical, Skovelund, Denmark) rtms was applied over the FDI area of the stroke hemisphere. If MEPs were absent to stimulation of the stroke hemisphere, the motor "hot spot" was defined as being symmetric to the nonstroke hemisphere. If MEPs appeared during recovery, the optimal site for stimulation of the stroke hemisphere was reidentified. The three groups received the same conventional medical treatment (anticoagulant 'low molecular weight heparin' in the first week plus acetyl salicylic acid and one nootropic drug and then to continue on the acetyl salicylic acid and the nootropic drug) and rehabilitation (Passive limb movement beginning on the 2 nd day, modifying to a more active one as the patient improves). In the present study we followed up the patients clinically at the end of s then monthly for the first three months and at the end of the first year using motor disability and functional activity scales with assessment of the motor power. Evaluation was performed blindly by the neurologist without knowing the type of rtms. Data analysis Before starting rtms, after the second and fifth and at the end of the first, second and third month and at the end of the first year, disability was assessed using the three scales (NIHSS, BI and modified Rankin scale) and hemispheric stroke scale. Mean±SD was used to represent data. At the baseline assessment, the mean values of different disability scales (NIHSS, BI and modified Rankin scale) and hemispheric stroke scale between groups were compared by using one-way ANOVA for independent samples. The level of significance is set at P<0.05. Statistical analysis of the scores in each test was done with two ways ANOVA with time point as within subject factor, and patient group as between subject measure. The Greenhouse- Geisser degree of freedom corrections was applied to correct for nonsphericity of the data. Pearson s correlation coefficient was done between neurophysiological data and disability scales. RESULTS All the patients tolerated rtms well without any adverse effects. Tables (1) and (2) give clinical details of the examined patients. There were no significant differences between the studied groups in different demographic data and in risk factors. There were no significant differences between the studied groups regarding the baseline clinical assessment of different scores (hemispheric stroke scale, NIHSS, Barthel index scale and Modified Rankin scale (Tables 3 and 4) and baseline neurophysiological assessment of the unaffected hemisphere ( tables 5) and affected hemisphere (Table 6 ). Clinical follow up of the studied groups through the first year after stroke. In our study we did not find significant changes between group 1and 2 (3 Hz and 10 Hz groups) both clinically and neurophysiologically. For that we grouped them in one group in a comparison to the sham group to increase the power of the statistics (real and sham). There was significant improvement in patients who received real rtms in comparison to the sham rtms group regarding motor power recovery, (P = 0.033, 0.002,) for the hand grip and shoulder abduction respectively (Figs. 1 and 2). Significant improvement in real rtms was also observed in NIHSS after the first month (P=0.023) but not after the first year. (P=0.090) (Fig. 3). Significant 471

4 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 improvement was also observed in Barthel index scale (P=0.026) and in Modified Rankin scale (P=.031) (Figs. 4 and 5). This improvement was associated with cortical excitability changes indicating increased excitability of the motor cortex of the affected hemisphere after real rtms. Neurophysiological changes before and after rtms. Tables (7) and (8) show changes of the RMT and AMT of the unaffected hemisphere after the fifth. There were no significant changes in the first and second groups. In the third group there was significant decreased in RMT and AMT. Regarding the changes of the CSP of the unaffected hemisphere after the fifth, there were no significant changes in the real groups. But in the sham group, the duration of CSP was significantly decreased (P=0.028). Tables (9) and (10) show the changes of the RMT and AMT of the affected hemisphere after the fifth. There was significance decrease in the RMT and AMT in the first and second groups. In the third group there was no significant changes, while the changes between real rtms groups and the sham rtms group were statistically significant. There was significant increase in the amplitude of the MEP in the first group. The changes were not significant in the other groups. Also there were no significant changes between real and sham groups (Table 11). Table (12) and figure (6) show that there were positive correlations between MEP and clinical outcome. Details are illustrated in the table. EEG was done before s and after the fifth one. Sixteen patients had normal EEG before and after s. Fifteen patients had lateralizing slowing related to the site of infarction. One patient had mild irritative cerebral dysrythmia (non specific short episodes of sharp activity) before and after s. None of the patients developed any new irritative cerebral dysrythmias post s. Table 1. The age, sex and duration of illness among the studied groups. Item Group 1 Group 2 Group 3 Total no. P value Age (years) mean±sd 58.25± ± ± ± Sex (Male/female) 8/8 7/9 9/7 24/ Duration of illness (days):mean±sd 8± ± ± ± The significance depends on one way ANOVA. Table 2. The side of stroke and risk factors among the studied groups. Item Group 1 Group 2 Group 3 Total no. P value Site of stroke Rt/Lt 4/12 10/6 7/9 21/ Risk factors HTN D M Smoker 5 (31.25) 3 (18.75) 3 (18.25) 6 (37.5%) 3 (18.75%) 4 (25%) 1 (6.25%) 5 (31.25%) 5 (31.25%) 12 (25%) 11 (22.92%) 12 (25%) RHD,MS - (0%) 1 (6.25%) - (0%) 1 (2.08%) The significance depends on one way ANOVA. HTN; hypertension, DM; diabetis mellitus, RHD; rheumatic heart disease, MS; mitral stenosis. 472

5 M.A. Etribi et al. Table 3. Baseline assessment of the motor power (proximal and distal) of the hemiplegic side among the studied groups according to hemispheric stroke scale. Group 1 Group 2 Group 3 P-value Hand grip 4.56± ± ± Shoulder abduction 4.63± ± ± Ankle dorsiflexion 3.75± ± ± Hip flexion 3.88± ± ± The data presented as mean ± standard deviation. -The significance depends on one way ANOVA. Table 4. Baseline assessment of the stroke scales among the studied groups. Group 1 Group 2 Group 3 P-value NIH stroke scale 9.00± ± ± Barthel index scale 48.44± ± ± Modified Rankin scale 3.81± ± ± The data presented as mean ± standard deviation. -The significance depends on one way ANOVA. Table (5): Baseline assessment of (RMT, AMT, CSP and MEP) of the unaffected hemisphere among the studied groups. Group 1 Group 2 Group 3 P-value RMT 53.94± ± ± AMT 46.56± ± ± MEP 3.48± ± ± CSP ± ± ± RMT; resting motor threshold, AMT; active motor threshold, MEP; motor evoked potential at 130% RMT, CSP; cortical silent period.-the significance depends on one way ANOVA. Table 6. Baseline assessment of (RMT and MEP) of the affected hemisphere among the studied groups. Group 1 Group 2 Group 3 P-value RMT 64.22± (9) ±15.26 (9) 67.60±14.36 (5).078 MEP 1.04 ±.8299 (9).45±0.48 (9) 1.45±1.03 (5).072 The data presented as mean ± standard deviation. Number in parenthesis indicates number of the patients who had motor evoked response. RMT; resting motor threshold ; MEP; motor evoked potential at 130% RMT, The significance depends on one way ANOVA. 473

6 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July Pre Post 5 1m 2m 3m 1 y Fig. (1): Follow up study of power of the hand grip of the studied groups through the first year after stroke. 3Hz 10Hz Sham Pre Post 5 1m 2m 3m 1 y 3Hz 10Hz Sha m Fig. (2): Follow up study of power of the shoulder abduction of the studied groups through the first year after stroke Pre Post 5 1m 2m 3m 1 y 3Hz 10Hz Sham Fig. (3): Follow up study of NIH stroke scale among the studied groups through the first year after stroke. 474

7 M.A. Etribi et al Pre Post 5 1m 2m 3m 1 y 3Hz 10Hz Sha m Fig. (4): Follow up study of Barthel index scale among the studied groups through the first year after stroke Pre Post 5 1m 2m 3m 1 y 3Hz 10Hz Sha m Fig. (5): Follow up study of Modified Rankin scale among the studied groups through the first year after stroke. Table 7. Changes of the RMT of the unaffected hemisphere after the fifth among the studied groups. Pre Mean±SD Post second Mean±SD Post fifth Mean±SD P -value Repeated time time (3 Hz Vs 10 Hz) Group ± ± ± Group ± ± ± Group ± ± ± RMT; resting motor threshold.- The data presented as mean ± standard deviation (SD). The significance depends on two ways ANOVA. time Vs groups

8 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 Table 8. Changes of the AMT of the unaffected hemisphere after the fifth among the studied groups. Pre Mean±SD Post second Mean±SD Post fifth Mean±SD P -value Repeated time Group ± ± ± Group ± ± ± Group ± ± ± AMT; active motor threshold. The data presented as mean ± standard deviation (SD). The significance depends on two ways ANOVA. time (3 Hz Vs 10 Hz) time Vs groups Table 9. Changes of RMT of the affected hemisphere after the fifth among the studied groups. Pre s Post second Post fifth P -value Repeated Measurement time Group ± (9) 52.00± ± Group ±15.26 (9) 73.22± ± Group ±14.36 (5) 68.80± ± RMT; resting motor threshold. The data presented as mean ± standard deviation (SD). Number in parenthesis indicates number of the patients who had motor evoked response. The significance depends on two ways ANOVA. time (3 Hz Vs 10 Hz) time Vs groups Table 10. Changes of AMT of the affected hemisphere after the fifth among the studied groups. Pre s Post second Session Post fifth P value Repeated time Group ±14.40 (9) 40.33± ± Group ±18.92 (9) 66.11± ± Group ±17.46 (5) 60.40± ± time (3Hz Vs 10Hz) AMT; active motor threshold. The data presented as mean ± standard deviation (SD). Number in parenthesis indicates number of the patients who had motor evoked response. The significance depends on two ways ANOVA time Vs groups

9 ME.A.PO5 M.A. Etribi et al. Table 11. Changes of MEP of the affected hemisphere after the fifth among the studied groups. Pre s Post second Post fifth P -value Repeated time time (3 Hz Vs 10 Hz) Group ±.83 (9) 0.90± ± Group ±.48 (9) 0.80± ± Group ±1.03 (5) 1.13± ± MEP; motor evoked potential at 130% RMT. The data presented as mean ± standard deviation (SD). Number in parenthesis indicates number of the patients who had motor evoked response. The significance depends on two ways ANOVA. time Vs groups Table 12. Correlations between Motor evoked potentials (MEP) and clinical outcome in real rtms groups. Items Correlations Post fifth r= -550 P=0.003 First month r= -499 P=0.009 MEP and hand grip Second month r= -551 P=0.012 Third month r= -539 P=0.014 First year r= -463 P=0.071 MEP and modified Rankin scale Second month r= -444 P=0.050 MEP; motor evoked potentials MR.PO5 ME.A.PO5; motor evoked potential of the affected hemisphere, post fifth. MR.PO5; modified Rankin scale, post fifth. Fig. (6): Correlations between MEP and Modified Rankin scale in real rtms groups after the fifth. 477

10 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 DISCUSSION Fortunately the brain is plastic and able to reorganize itself up to a certain degree of damage. This is especially true for the motor cortex, which can be modified by sensory input, experience and learning, as well as in response to brain lesions. An important factor is the exogenous application of treatment, either through behavioral therapy or pharmacological treatment. These and other factors strongly influence the brains ability of plasticity and functional reorganization. 15,16 Many studies have documented the changes in cortical organization that occur after motor stroke, particularly on the side of the lesion 3. In addition, there is a balance of function between the two hemispheres that is controlled by interhemispheric inhibition. The stroke-affected hemisphere can be doubly disabled, by the stroke itself and by an imbalanced inhibition from the non-stroke hemisphere. In this model, increased activity in the affected hemisphere will promote recovery of the paretic limbs, as well as decreased inhibition from the non-stroke hemisphere 4. To our knowledge our study is the longest follow up study done up till now (along one year) on the therapeutic effect of high frequency repetitive transcranial magnetic stimulation of the affected hemisphere after acute ischemic stroke. We have chosen for rtms parameters governed by three considerations. First, given the increased risk of seizures after stroke, we chose rtms parameters that were safe within current safety guidelines 17.Second, to influence as much of the remaining intact tissue as possible, we employed a stimulus intensity of 130% RMT in case of 3 Hz and 100% in case of 10 Hz, which can spread as much as 2 to 3 cm from the coil in healthy subjects. Third, to increase excitability of remaining motor areas, we used a relatively high frequency of rtms (3 Hz and 10 Hz). In our study we confirmed the significant improvement in patients who received real rtms in comparison to the sham rtms group regarding motor power recovery and all stroke scales scores. This improvement was associated with cortical excitability changes. In the present study we found that the improvement in the real rtms groups started immediately after the first, while in the sham group it started only after the fifth and the improvement was progressive through the study with permanent significant difference.also we found that the improvement in the 3 Hz group was better than 10 Hz group, but the difference was insignificant, which might be due to the higher intensity used in the 3 Hz group. In the present study we found significant improvement in stroke scales in real rtms groups in comparison to shame group throughout the study which can be explained by increasing excitability of remaining pathways from the damaged hemisphere with real rtms. In agreement with our result, Khedr et al. 9 reported that 10 consecutive days of high-frequency rtms applied at 3Hz with intensity 120% RMT on the affected motor area improved the clinical outcome in early stroke patients. Kim et al., 10 reported enhanced motor accuracy and significant increased in corticomotor excitability in 15 patients who received rtms 3 months after stroke onset. In the present study we observed that the maximum improvement was in the first three months, and then minor improvement was recorded. In agreement with our results, Auri, 18 believes that the course of motor recovery reaches a plateau after an early phase of progressive improvement. Most recovery takes place in the first 3 months, and only minor additional measurable improvement occurs after 6 months following onset. However, recovery may continue over a longer period of time in some patients who have significant partial return of voluntary movement. So, we recommend repeated rtms after 3 months after declining of the maximum improvement. Cortical excitability in acute stroke and the effects of rtms: In the present study we found that; In patients who received real rtms, there was significant increased of the motor cortex excitability in the affected hemisphere (decreased RMT and AMT) in both groups and significant increased in the amplitude of the MEP in the first group only, while there were no significant changes in the unaffected hemisphere, which means that hyperexcitable motor cortex of the affected hemisphere after rtms may be due to the effects of modulation of the affected motor cortex by high frequency rtms. 478

11 M.A. Etribi et al. The results of the present study are supported by finding reported by Kim et al. 10 who reported that the effects of modulation of the affected motor cortex by high frequency rtms may directly affect the corticospinal excitability and also indirectly via an interhemispheric reciprocal mechanism. Previous neurophysiological studies have shown that there may be an imbalance between the 2 hemispheres after stroke, with disinhibition in the nonlesioned motor cortex 19 and an inability to remove interhemispheric inhibitory drive from the intact motor cortex to the affected motor cortex before movement of the paretic hand 20. The results of the present study are consistent with Kaoru et al., 21 who found that 5 Hz rtms at 110% ATM for the hand muscle in normal individuals can increase the amplitude of the MEPs evoked from the M1 hand. In patients who received sham rtms, there was significant increased of the motor cortex excitability (decreased RMT, AMT, CSP) of the unaffected hemisphere while there were no significant changes in the affected hemisphere regarding RMT and AMT, which means that hyperexcitable motor cortex of the unaffected hemisphere after stroke may be due to reduction in the transcallosal inhibition from the damaged hemisphere.this was supported by liepert et al., 19 who found similar results. In the present study we found positive correlations between MEP and clinical outcome. Our results are consistence with Palliyath, 22 who found that central conduction time and MEP amplitude correlate with the percentage of clinical motor improvement in three months after the stroke. But khedr et al., 9 did not found significant correlations between MEP and clinical recovery. Chu Vang et al., 23 documented that there is a close relationship between clinical and electrophysiological improvement and that MEP is a useful prognostic indicator of clinical outcome. There were no significant changes in the EEG after rtms s, which confirm the safety of the TMS. Our results are supported by the results of Fregni et al. 6, in which they confirmed that increased dose of rtms is not associated with cognitive adverse effects and/or epileptogenic activity. rtms can affect synaptic long term potentiating and depression by modulating neurotransmitter availability and postsynaptic receptor density both in cortical neurons directly underlying the stimulus and among those connected to them. 9,24 Trains of rtms can induce short and long-term changes in cortical excitability 25. The cumulative effect of the r-tms can be due to expansion of the short-term range of plasticity 26. Such expansion called metaplasticity and could be due to upregulation of NMDA receptors 27. Animal studies suggested that modulation of 28 neurotransmitters and gene induction may contribute to these long lasting modulatory effects of the rtms 29. In conclusions, patients who received real rtms has better outcome than sham group, which confirms the therapeutic effect of the TMS. Transcranial magnetic stimulation can manipulate cortical excitability and the results are long lasting. Highfrequency rtms provides a fast, effective, painless, non invasive treatment for motor disorders during the rehabilitation of acute stroke patients and is recommended to be repeated every 3 months if needed. REEFRENCES 1. Pablo M Lavados, Anselm J M Hennis, Jeff erson G Fernandes, Marco T Medina, Branca Legetic, Arnold Hoppe, Claudio Sacks, Liliana Jadue and Rodrigo Salinas: Stroke epidemiology, prevention, and management strategies at a regional level: Latin America and the Caribbean.Lancet Neurol 2007; 6: Zweifler RM.Management of acute stroke. South Med J 2003 Apr; 96(4): Ward NS and Cohen LG: Mechanisms underlying recovery of motor function after stroke. Arch Neurol 2004;61: Jean-Pascal L. and Khedr E.M. (2007): rtms in non psychiatric disorders: Pain, Parkinson, Stroke, Tinnitus.In Marcolin MA,Padberg F(eds):Transcranial for treatment in mental disorders.adv Biol Psychiatr. Basel, Karger, 2007, Vol. 23, pp Tergau F, Wassermann EM, Paulus W and Ziemann U: Lack of clinical improvement in patients with Parkinson s disease after low and high frequency repetitive transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol Suppl 1999; 51:

12 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJL, Wagner T, Fecteau S, Rigonatti SP, Riberto M, Freedman SD and Pascual-Leone A: A sham-controlled trial of 5- day course of rtms of the unaffected hemisphere in stroke patients. Stroke 2006 ;37: Takeuchi N, Chuma T, Matsuo Y, Watanabe I and Ikoma K: Repetitive transcranial magnetic stimulation of contralesional primary motor cortex improves hand function after stroke. Stroke 2005;36: Fregni F, Boggio PS, Mansur CG, Wagner T, Ferreira MJ, Lima MC, Rigonatti SP, Marcolin MA, Freedman SD, Nitsche MA and Pascual- Leone A: Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. NeuroReport 2005;16: Khedr EM, Ahmed MA, Fathy N and Rothwell JC: Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology 2005;65: Kim YH, You SH, Ko MH, Park JW, Lee KH, Jang SH, Yoo WK and Hallett M: Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor skill acquisition in chronic stroke. Stroke 2006; 37(6), Hummel F, Celnik P, Giraux P, Floel A, Wu WH, Gerloff C and Cohen LG: Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 2005;128; Adams RJ, Meador KJ, Sethi KD and Thomson DS: Graded neurologic scale for use in acute hemispheric stroke treatment protocol. Stroke 1987; 18: Brasil-Neto JP, Cohen LG, Panizza M, Nilsson J, Roth BJ and Hallett M: Optimal focal transcranial magnetic activation of the human motor cortex: effects of coil orientation shape of the induced current pulse, and stimulus intensity. J Clin Neurophysiol 1992; 9: Cited in Kaoru et al., Mills KR, Boniface SJ and Schubert M: Magnetic brain stimulation with a double coil: the importance of coil orientation. Electroencephalogr Clin Neurophysiol 1992; 85: Kujirai T, Caramia MD and Rothwell JC: Corticocortical inhibition in human motor cortex. J Physiol 1993;471: Cited in Miglė Ališauskienė et al., Robertson IH and Murre JMJ: Rehabilitation of brain damage: Brain plasticity and principles of guided recovery. Psychological Bulletin 1999; 125 (5): Wassermann EM:Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the international workshop on the safety of repetitive transcranial magnetic stimulation, Electroencephalogr Clin Neurophysiol 1998 Jan;108(1): Auri A Bruno, MD, MS, Sao Paulo Federal University, Brazil. Motor Recovery In Stroke. December 9, Liepert J, Storch P, Fritsch A and Weiller C: Motor cortex disinhibition in acute stroke. Clin Neurophysiol 2000; 111: Murase N, Duque J, Mazzocchio R and Cohen LG: Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol 2004;55: Kaoru M, Atsuo M, Toshiyuki F, Ryoji N and Sadatoshi T:Increased cortical excitability after 5 Hz rtms over the human supplementary motor area.j Physiol 2004;562.1 pp Palliyath M.:Role of central conduction time and motor evoked response amplitude in predicting stroke outcome. Electromyogr.Clin.Neurophysiol 2000;40: Chu Vang A., David D. and David K.: Correlation Between Functional and Electrophysiological Recovery in Acute Ischemic Stroke. Stroke 1999; abstr.,30: Pascual-Leone A, Valls-Sole J, Wassermann EM and Hallett M: Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 1994; 117 : Berardelli A, Inghilleri M, Rothwell JC, Romeo S, Curra A, Gilio F, et al: Facilitation of muscle evoked responses after repetitive cortical stimulation in man. Exp Brain Res 1998; 122: Lomarev MP, Kanchana S, Bara-Jimenez W, Iyer M, Wassermann EM and Hallett M: Placebo-controlled study of rtms for the treatment of Parkinson's disease. Mov Disord 2006; 21: Abraham WC, Mason-Parker SE, Bear MF, Webb S and Tate WP: Heterosynaptic metaplasticity in the hippocampus in vivo: a BCM-like modifiable threshold for LTP. Proc Natl Acad Sci U S A 2001; 98: Benjamin D, Philpot JS and Espinosa MF: Bear evidence for altered NMDA receptor function as a basis for metaplasticity in visual cortex. J Neurosci 2003; 23: Masahito Kobayashi and Alvaro Pascual-Leone. Transcranial magnetic stimulation in neurology. The Lancet Neurology March 2003; 2(3). 480

13 M.A. Etribi et al. الملخص العربى