Archives of Physical Medicine and Rehabilitation journal homepage: www.archives-pmr.org Archives of Physical Medicine and Rehabilitation 2015;96:69-75
ORIGINAL ARTICLE
Corticospinal Integrity and Motor Impairment Predict Outcomes After Excitatory Repetitive Transcranial Magnetic Stimulation: A Preliminary Study Chih-Jou Lai, MD, MS,a,b Chih-Pin Wang, MD,c Po-Yi Tsai, MD,a,b Rai-Chi Chan, MD,a,b Shan-Hui Lin, MD,a Fu-Gong Lin, PhD,d Chin-Yi Hsieh, MDc From the aDepartment of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei; bNational Yang-Ming University, School of Medicine, Taipei; cDepartment of Emergency, Mackay Memorial Hospital, Taipei; and dSchool of Public Health, National Defense Medical Center, Taipei, Taiwan.
Abstract Objective: To identify the effective predictors for therapeutic outcomes based on intermittent theta-burst stimulation (iTBS). Design: A sham-controlled, double-blind parallel study design. Setting: A tertiary hospital. Participants: People with stroke (NZ72) who presented with unilateral hemiplegia. Interventions: Ten consecutive sessions of real or sham iTBS were implemented with the aim of enhancing hand function. Patients were categorized into 4 groups according to the presence (MEPþ) or absence (MEP) of motor-evoked potentials (MEPs) and grip strength according to the Medical Research Council (MRC) scale. Main Outcome Measures: Cortical excitability, Wolf Motor Function Test (WMFT), finger-tapping task (FT), and simple reaction time were performed before and after the sessions. Results: MEPs and the MRC scale were predictive of iTBS therapeutic outcomes. Group A (MEPþ, MRC>1) exhibited the greatest WMFT change (7.62.3, P1; 5.22.2 score change) and group C (MEP, MRCZ0; 2.31.5 score change). These improvements were correlated significantly with baseline motor function and ipsilesional maximum MEP amplitude. Conclusions: The effectiveness of iTBS modulation for poststroke motor enhancement depends on baseline hand grip strength and the presence of MEPs. Our findings indicate that establishing neurostimulation strategies based on the proposed electrophysiological and clinical criteria can allow iTBS to be executed with substantial precision. Effective neuromodulatory strategies can be formulated by using electrophysiological features and clinical presentation information as guidelines. Archives of Physical Medicine and Rehabilitation 2015;96:69-75 ª 2015 by the American Congress of Rehabilitation Medicine
Stroke is a major medical problem and the leading cause of disability worldwide.1 Motor recovery after a stroke depends on the reorganization of the perilesional region, axonal regeneration within connected motor networks, and the unmasking of the potential secondary motor areas.2,3 The postulated role of synaptic plasticity in poststroke motor recovery has awakened great interest in the applicability of noninvasive brain stimulation,4,5 including repetitive transcranial magnetic stimulation (rTMS), which has Supported by the Taipei Veterans General Hospital (grant no. V103C-168). Clinical Trial Registration No.: NCT02006615. Disclosures: none.
shown promise in promoting motor relearning and enhancing neurologic recovery.6 This is because rTMS generates long-term potentiation and long-term depression-like synaptic plasticity, which are associated with augmented neural plasticity.7,8 The N-methyl-D-aspartate receptoredependent aftereffects of highfrequency rTMS have been shown to upregulate cortical plasticity, leading to the consolidation of adaptive neuromodulation.9,10 Participant responses to rTMS vary greatly; possible modulatory factors include the participant’s age, the duration of the poststroke period, the lesion location, and the severity of baseline motor impairment.10-12 Identifying the receptiveness of patients with various characteristics to rTMS
0003-9993/14/$36 - see front matter ª 2015 by the American Congress of Rehabilitation Medicine http://dx.doi.org/10.1016/j.apmr.2014.08.014
70 Table 1
C.-J. Lai et al Demographic data and clinical characteristics of all patients
Characteristics
Group A (nZ21)
Group B (nZ17)
Group C (nZ17)
Group D (nZ17)
Age (y) M/F Ischemic/hemorrhagic CorticalCR/BG CR/BG Right/left brain lesion Lesion volume (cm3) NIHSS Months poststroke
62.611.6 17/4 15/6 8 13 11/10 37.021.4 11.83.8 10.45.8
60.410.4 14/3 12/5 6 11 9/8 39.528.4 11.44.1 9.75.1
63.412.1 13/4 13/4 7 10 10/7 34.723.6 12.13.7 11.44.3
62.110.5 13/4 13/4 6 11 8/9 38.220.6 11.43.5 10.64.6
NOTE. Values are mean SD or n. Abbreviations: BG, basal ganglia; CR, corona radiata; F, female; M, male; NIHSS, National Institutes of Health Stroke Scale.
conditioning may help determine which stroke patients should be targeted for conditioning and help predict therapeutic outcomes. Elicited motor-evoked potentials (MEPs) recorded in the targeted muscles represent the excitability of intracortical connections, indicating the functional integrity of the corticospinal tract (CST).13 The absence of detectable MEPs after ipsilesional stimulation soon after a stroke is considered a predictor of poor functional outcomes.14,15 Applying focal rTMS to the target primary motor cortex activates both neural synaptic transmission to remote motor networks and crucial elements involved in the effective neural regeneration of new functions.16 The connection between a disrupted CST and the efficacy of intermittent theta-burst stimulation (iTBS), an excitatory rTMS paradigm for motor enhancement, has not been examined. We hypothesized that by determining the integrity of the CST and the severity of baseline motor impairment, the effectiveness of iTBS treatment in motor recovery could be predicted. Thus, we compared groups of motor-impaired stroke patients with variously categorized MEPs; we also sought to identify other possible contributing factors underlying the receptiveness of stroke patients to iTBS treatment.
Methods Participants Seventy-two stroke patients (15 women; mean age, 62.5y) who presented with unilateral hemiplegia secondary to a first-ever stroke were recruited from a rehabilitation center at a tertiary hospital. All fulfilled the following conditions: (1) a diagnosis of
List of abbreviations: aMT CST FDI fMRI FT iTBS MEP MRC MT RT rTMS WMFT
active motor threshold corticospinal tract first dorsal interosseous functional magnetic resonance imaging finger-tapping task intermittent theta-burst stimulation motor-evoked potential Medical Research Council motor threshold reaction time repetitive transcranial magnetic stimulation Wolf Motor Function Test
unilateral, ischemic, or hemorrhagic supratentorial stroke at least 2 months prior, as confirmed by magnetic resonance imaging; (2) no history of concomitant neurodegenerative diseases or brain surgery; (3) no aphasia, spatial neglect, visual field deficit, emotional problems, or communication problems; and (4) no rTMS contraindications. All patients underwent detailed clinical and neurologic examinations including the National Institutes of Health Stroke Scale, the distal Medical Research Council (MRC) scale of 0 to 5 points,17 the FIM system,18 and electroencephalography. All the patients recruited to the study gave their written informed consent before participating, in accordance with the 2008 Declaration of Helsinki. The study was approved by the local institutional review board. Fifty-three patients were diagnosed with ischemic stroke and 27 with cortical involvement (with or without subcortical lesion). All patients were in the chronic stage of stroke, with a mean poststroke duration SD of 10.55.0 months. Other baseline demographic and clinical features are presented in table 1. Electrophysiological measures and motor assessments were performed at inception (baseline), midterm in the 10-session intervention, and immediately after the 10 sessions of intervention. We divided the patients into 4 groups: 3 groups received a real iTBS treatment, and 1 group received a sham iTBS intervention. The real iTBS groups included patients (group A, nZ21) who had inducible MEPs (MEPþ) recorded from the paretic first dorsal interosseous (FDI) and exhibited preserved hand grip strength (MRC>1) before iTBS intervention; group B (nZ17) included patients who had undetectable MEPs (MEP) but exhibited preserved hand grip strength (MRC>1); and group C (nZ17) included patients with undetectable MEPs and no evidence of hand grip strength (MEP and MRCZ0). Group D (nZ17), to which the sham treatment was administered, had a patient composition similar to that of group A and included patients who exhibited positive MEPs (MEPþ) and positive grip strength (MRC>1), but underwent a placebo iTBS treatment. Patients with both MEPþ and MRC>1 were randomly assigned to either group A or group D. No patient with a totally paretic hand grip presented with elicited MEPs. Figure 1 summarizes the criteria used for group categorization.
Interventions Patients in the experimental groups underwent a real iTBS protocol administered using the Magstim Rapid2,a with a 70-mm www.archives-pmr.org
Outcome predictors of repetitive transcranial magnetic stimulation
71
Fig 1 Criteria for patient allocation, proposed adjustment, and adjuvant therapy to augment the effects of iTBS. Group A showed favorable outcomes post-iTBS conditioning following the original settings of the iTBS paradigm. Group B, whose motor control may emerge from the more distant secondary motor area, showed a pronounced response to adopting a high-intensity paradigm (such as 5-Hz rTMS), or determined the stimulation loci according to the functional neuroimaging assessment. Group C, without any motor control from either cortex, was supposed to show a high likelihood of benefiting from adjuvant physiotherapy and advanced protocols. Abbreviations: AH, affected hemisphere; rTMSexc, excitatory rTMS; rTMSinh, inhibitory rTMS; UH, unaffected hemisphere.
figure-8 coil. We adopted the iTBS as our intervention paradigm because it induces long-lasting changes in excitability in stimulated areas.19 Bursts of 3 pulses at 50Hz were administered to the FDI hot spot at 80% of the active motor threshold (aMT) at 200-millisecond intervals for 2 seconds. A 2-second train of iTBS was repeated every 10 seconds for a total of 190 seconds and 600 pulses. All patients underwent 10 intervention sessions that were conducted 5 days per week for 2 weeks. A placebo coila was used for the sham stimulation, which produced a scalp sensation and an audible click on discharge but did not allow the electrical current to penetrate into the brain tissue. For patients in groups B and C, for whom MEPs could not be elicited by using the maximal stimulator output on their affected hemispheres, the target area was homologous to the FDI hot spot in an unaffected hemisphere.20,21 In these cases, we determined the stimulus intensity as 49% stimulator output based on the mean intensity averaged from the patients with positive MEPs elicited from the affected cortex. This dosage was identical to the mean conditioned intensity used in group A. All the patients continued the same amount of daily physical rehabilitation programs. The conventional physiotherapy program included strength training for the shoulder, wrist, finger flexors, and extensors, combined with repetitive and augmentative training and active participation. These sessions were conducted for 1 hour daily, 5 times per week, immediately after the intervention.
www.archives-pmr.org
Assessments Cortical excitability To evaluate cortical excitability, we measured the MEP parameters and motor map area at the baseline, midterm in the 10-session intervention, and immediately after the 10 sessions of intervention using the monophasic Magstim 2002,a and standard procedures.22,23 Patients were instructed to sit in an armchair and to keep their eyes open. An elastic cap was attached to the head of each patient and placed based on the nasion-inion line and the interaural line. A grid (99cm) was drawn over the frontal area along the interaural and nasion-inion lines and labeled with numbers on both sides. MEPs were recorded from FDI muscles using bilateral surface Ag/AgCl electrodes. A Dantec Keypoint electromyographb connected to the stimulator was used to record the MEP signals. The raw signals were amplified (50mV to 1mV per division), bandpass filtered (1e2000Hz), and digitized at a 2-kHz sampling rate. The resting motor threshold (MT) and aMT for FDI were determined based on the lowest intensity required to elicit MEPs of >100mV in 5 of 10 consecutive trials, respectively, at rest or during weak voluntary hand contraction (5%e15% of maximal force). The maximum MEP amplitude for each patient was obtained using 100% of maximal stimulator output. If we were not able to obtain the maximum MEP using this method, the patient was instructed to contract the affected FDI at maximal force during stimulation. If MEPs were still absent after stimulation, the
72
C.-J. Lai et al
Table 2 Results of hierarchical multiple linear regression analyses on improvement of WMFT in iTBS groups WMFT (Postbaseline)
b Coefficients
SE
Constant Pathology (ischemic, hemorrhagic) Cortical involvement Time poststroke WMFT (baseline) Group B vs C A vs C
2.69 2.71
1.40 2.0
.068 .197
2.18 0.067 0.14
1.87 0.064 0.04
.248 .301 .001*
7.59 13.17
2.38 2.93
including WMFT, FT, RT, and motor map area, were found to be significantly altered relative to baseline levels for all patients in groups A, B, and C (P
ORIGINAL ARTICLE
Corticospinal Integrity and Motor Impairment Predict Outcomes After Excitatory Repetitive Transcranial Magnetic Stimulation: A Preliminary Study Chih-Jou Lai, MD, MS,a,b Chih-Pin Wang, MD,c Po-Yi Tsai, MD,a,b Rai-Chi Chan, MD,a,b Shan-Hui Lin, MD,a Fu-Gong Lin, PhD,d Chin-Yi Hsieh, MDc From the aDepartment of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei; bNational Yang-Ming University, School of Medicine, Taipei; cDepartment of Emergency, Mackay Memorial Hospital, Taipei; and dSchool of Public Health, National Defense Medical Center, Taipei, Taiwan.
Abstract Objective: To identify the effective predictors for therapeutic outcomes based on intermittent theta-burst stimulation (iTBS). Design: A sham-controlled, double-blind parallel study design. Setting: A tertiary hospital. Participants: People with stroke (NZ72) who presented with unilateral hemiplegia. Interventions: Ten consecutive sessions of real or sham iTBS were implemented with the aim of enhancing hand function. Patients were categorized into 4 groups according to the presence (MEPþ) or absence (MEP) of motor-evoked potentials (MEPs) and grip strength according to the Medical Research Council (MRC) scale. Main Outcome Measures: Cortical excitability, Wolf Motor Function Test (WMFT), finger-tapping task (FT), and simple reaction time were performed before and after the sessions. Results: MEPs and the MRC scale were predictive of iTBS therapeutic outcomes. Group A (MEPþ, MRC>1) exhibited the greatest WMFT change (7.62.3, P1; 5.22.2 score change) and group C (MEP, MRCZ0; 2.31.5 score change). These improvements were correlated significantly with baseline motor function and ipsilesional maximum MEP amplitude. Conclusions: The effectiveness of iTBS modulation for poststroke motor enhancement depends on baseline hand grip strength and the presence of MEPs. Our findings indicate that establishing neurostimulation strategies based on the proposed electrophysiological and clinical criteria can allow iTBS to be executed with substantial precision. Effective neuromodulatory strategies can be formulated by using electrophysiological features and clinical presentation information as guidelines. Archives of Physical Medicine and Rehabilitation 2015;96:69-75 ª 2015 by the American Congress of Rehabilitation Medicine
Stroke is a major medical problem and the leading cause of disability worldwide.1 Motor recovery after a stroke depends on the reorganization of the perilesional region, axonal regeneration within connected motor networks, and the unmasking of the potential secondary motor areas.2,3 The postulated role of synaptic plasticity in poststroke motor recovery has awakened great interest in the applicability of noninvasive brain stimulation,4,5 including repetitive transcranial magnetic stimulation (rTMS), which has Supported by the Taipei Veterans General Hospital (grant no. V103C-168). Clinical Trial Registration No.: NCT02006615. Disclosures: none.
shown promise in promoting motor relearning and enhancing neurologic recovery.6 This is because rTMS generates long-term potentiation and long-term depression-like synaptic plasticity, which are associated with augmented neural plasticity.7,8 The N-methyl-D-aspartate receptoredependent aftereffects of highfrequency rTMS have been shown to upregulate cortical plasticity, leading to the consolidation of adaptive neuromodulation.9,10 Participant responses to rTMS vary greatly; possible modulatory factors include the participant’s age, the duration of the poststroke period, the lesion location, and the severity of baseline motor impairment.10-12 Identifying the receptiveness of patients with various characteristics to rTMS
0003-9993/14/$36 - see front matter ª 2015 by the American Congress of Rehabilitation Medicine http://dx.doi.org/10.1016/j.apmr.2014.08.014
70 Table 1
C.-J. Lai et al Demographic data and clinical characteristics of all patients
Characteristics
Group A (nZ21)
Group B (nZ17)
Group C (nZ17)
Group D (nZ17)
Age (y) M/F Ischemic/hemorrhagic CorticalCR/BG CR/BG Right/left brain lesion Lesion volume (cm3) NIHSS Months poststroke
62.611.6 17/4 15/6 8 13 11/10 37.021.4 11.83.8 10.45.8
60.410.4 14/3 12/5 6 11 9/8 39.528.4 11.44.1 9.75.1
63.412.1 13/4 13/4 7 10 10/7 34.723.6 12.13.7 11.44.3
62.110.5 13/4 13/4 6 11 8/9 38.220.6 11.43.5 10.64.6
NOTE. Values are mean SD or n. Abbreviations: BG, basal ganglia; CR, corona radiata; F, female; M, male; NIHSS, National Institutes of Health Stroke Scale.
conditioning may help determine which stroke patients should be targeted for conditioning and help predict therapeutic outcomes. Elicited motor-evoked potentials (MEPs) recorded in the targeted muscles represent the excitability of intracortical connections, indicating the functional integrity of the corticospinal tract (CST).13 The absence of detectable MEPs after ipsilesional stimulation soon after a stroke is considered a predictor of poor functional outcomes.14,15 Applying focal rTMS to the target primary motor cortex activates both neural synaptic transmission to remote motor networks and crucial elements involved in the effective neural regeneration of new functions.16 The connection between a disrupted CST and the efficacy of intermittent theta-burst stimulation (iTBS), an excitatory rTMS paradigm for motor enhancement, has not been examined. We hypothesized that by determining the integrity of the CST and the severity of baseline motor impairment, the effectiveness of iTBS treatment in motor recovery could be predicted. Thus, we compared groups of motor-impaired stroke patients with variously categorized MEPs; we also sought to identify other possible contributing factors underlying the receptiveness of stroke patients to iTBS treatment.
Methods Participants Seventy-two stroke patients (15 women; mean age, 62.5y) who presented with unilateral hemiplegia secondary to a first-ever stroke were recruited from a rehabilitation center at a tertiary hospital. All fulfilled the following conditions: (1) a diagnosis of
List of abbreviations: aMT CST FDI fMRI FT iTBS MEP MRC MT RT rTMS WMFT
active motor threshold corticospinal tract first dorsal interosseous functional magnetic resonance imaging finger-tapping task intermittent theta-burst stimulation motor-evoked potential Medical Research Council motor threshold reaction time repetitive transcranial magnetic stimulation Wolf Motor Function Test
unilateral, ischemic, or hemorrhagic supratentorial stroke at least 2 months prior, as confirmed by magnetic resonance imaging; (2) no history of concomitant neurodegenerative diseases or brain surgery; (3) no aphasia, spatial neglect, visual field deficit, emotional problems, or communication problems; and (4) no rTMS contraindications. All patients underwent detailed clinical and neurologic examinations including the National Institutes of Health Stroke Scale, the distal Medical Research Council (MRC) scale of 0 to 5 points,17 the FIM system,18 and electroencephalography. All the patients recruited to the study gave their written informed consent before participating, in accordance with the 2008 Declaration of Helsinki. The study was approved by the local institutional review board. Fifty-three patients were diagnosed with ischemic stroke and 27 with cortical involvement (with or without subcortical lesion). All patients were in the chronic stage of stroke, with a mean poststroke duration SD of 10.55.0 months. Other baseline demographic and clinical features are presented in table 1. Electrophysiological measures and motor assessments were performed at inception (baseline), midterm in the 10-session intervention, and immediately after the 10 sessions of intervention. We divided the patients into 4 groups: 3 groups received a real iTBS treatment, and 1 group received a sham iTBS intervention. The real iTBS groups included patients (group A, nZ21) who had inducible MEPs (MEPþ) recorded from the paretic first dorsal interosseous (FDI) and exhibited preserved hand grip strength (MRC>1) before iTBS intervention; group B (nZ17) included patients who had undetectable MEPs (MEP) but exhibited preserved hand grip strength (MRC>1); and group C (nZ17) included patients with undetectable MEPs and no evidence of hand grip strength (MEP and MRCZ0). Group D (nZ17), to which the sham treatment was administered, had a patient composition similar to that of group A and included patients who exhibited positive MEPs (MEPþ) and positive grip strength (MRC>1), but underwent a placebo iTBS treatment. Patients with both MEPþ and MRC>1 were randomly assigned to either group A or group D. No patient with a totally paretic hand grip presented with elicited MEPs. Figure 1 summarizes the criteria used for group categorization.
Interventions Patients in the experimental groups underwent a real iTBS protocol administered using the Magstim Rapid2,a with a 70-mm www.archives-pmr.org
Outcome predictors of repetitive transcranial magnetic stimulation
71
Fig 1 Criteria for patient allocation, proposed adjustment, and adjuvant therapy to augment the effects of iTBS. Group A showed favorable outcomes post-iTBS conditioning following the original settings of the iTBS paradigm. Group B, whose motor control may emerge from the more distant secondary motor area, showed a pronounced response to adopting a high-intensity paradigm (such as 5-Hz rTMS), or determined the stimulation loci according to the functional neuroimaging assessment. Group C, without any motor control from either cortex, was supposed to show a high likelihood of benefiting from adjuvant physiotherapy and advanced protocols. Abbreviations: AH, affected hemisphere; rTMSexc, excitatory rTMS; rTMSinh, inhibitory rTMS; UH, unaffected hemisphere.
figure-8 coil. We adopted the iTBS as our intervention paradigm because it induces long-lasting changes in excitability in stimulated areas.19 Bursts of 3 pulses at 50Hz were administered to the FDI hot spot at 80% of the active motor threshold (aMT) at 200-millisecond intervals for 2 seconds. A 2-second train of iTBS was repeated every 10 seconds for a total of 190 seconds and 600 pulses. All patients underwent 10 intervention sessions that were conducted 5 days per week for 2 weeks. A placebo coila was used for the sham stimulation, which produced a scalp sensation and an audible click on discharge but did not allow the electrical current to penetrate into the brain tissue. For patients in groups B and C, for whom MEPs could not be elicited by using the maximal stimulator output on their affected hemispheres, the target area was homologous to the FDI hot spot in an unaffected hemisphere.20,21 In these cases, we determined the stimulus intensity as 49% stimulator output based on the mean intensity averaged from the patients with positive MEPs elicited from the affected cortex. This dosage was identical to the mean conditioned intensity used in group A. All the patients continued the same amount of daily physical rehabilitation programs. The conventional physiotherapy program included strength training for the shoulder, wrist, finger flexors, and extensors, combined with repetitive and augmentative training and active participation. These sessions were conducted for 1 hour daily, 5 times per week, immediately after the intervention.
www.archives-pmr.org
Assessments Cortical excitability To evaluate cortical excitability, we measured the MEP parameters and motor map area at the baseline, midterm in the 10-session intervention, and immediately after the 10 sessions of intervention using the monophasic Magstim 2002,a and standard procedures.22,23 Patients were instructed to sit in an armchair and to keep their eyes open. An elastic cap was attached to the head of each patient and placed based on the nasion-inion line and the interaural line. A grid (99cm) was drawn over the frontal area along the interaural and nasion-inion lines and labeled with numbers on both sides. MEPs were recorded from FDI muscles using bilateral surface Ag/AgCl electrodes. A Dantec Keypoint electromyographb connected to the stimulator was used to record the MEP signals. The raw signals were amplified (50mV to 1mV per division), bandpass filtered (1e2000Hz), and digitized at a 2-kHz sampling rate. The resting motor threshold (MT) and aMT for FDI were determined based on the lowest intensity required to elicit MEPs of >100mV in 5 of 10 consecutive trials, respectively, at rest or during weak voluntary hand contraction (5%e15% of maximal force). The maximum MEP amplitude for each patient was obtained using 100% of maximal stimulator output. If we were not able to obtain the maximum MEP using this method, the patient was instructed to contract the affected FDI at maximal force during stimulation. If MEPs were still absent after stimulation, the
72
C.-J. Lai et al
Table 2 Results of hierarchical multiple linear regression analyses on improvement of WMFT in iTBS groups WMFT (Postbaseline)
b Coefficients
SE
Constant Pathology (ischemic, hemorrhagic) Cortical involvement Time poststroke WMFT (baseline) Group B vs C A vs C
2.69 2.71
1.40 2.0
.068 .197
2.18 0.067 0.14
1.87 0.064 0.04
.248 .301 .001*
7.59 13.17
2.38 2.93
including WMFT, FT, RT, and motor map area, were found to be significantly altered relative to baseline levels for all patients in groups A, B, and C (P
