NAVIGATED TRANSCRANIAL MAGNETIC STIMULATION IN AMYOTROPHIC LATERAL SCLEROSIS
1
PhD Alexander V. Chervyakov, 2Ilya S. Bakulin, 1 PhD Natalia G. Savitskaya, 2 PhD Ivan V.
Arkhipov, 2 PhD Andrey V. Gavrilov, 1 PhD, MD, professor Maria N. Zakharova, 1 PhD, MD, professor Michael A. Piradov
1
Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia 2
Moscow State University, Moscow, Russia
Acknowledgments The authors are grateful to Prof. S.S. Nikitin and Prof. A.L. Kurenkov for fruitful discussion of the results and for valuable advice concerning further investigations.
Alexander V. Chervyakov, 123181, Moscow, Marshala Katukova Street, 13-2-124 [email protected]
Running title: Navigated TMS in ALS
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24345
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2
NAVIGATED TRANSCRANIAL MAGNETIC STIMULATION IN AMYOTROPHIC LATERAL SCLEROSIS Introduction: Amyotrophic lateral sclerosis (ALS) is a set of disorders associated with preferential degeneration of both upper and lower motor neurons. Navigated transcranial magnetic stimulation (nTMS) is a tool used to perform noninvasive functional brain mapping. Objective: To evaluate the function of upper motor neurons in ALS. Methods: nTMS was performed on 30 patients with ALS (mean age 54.4 ± 12.1 years) and 24 healthy volunteers (mean age 32.7 ± 13.3 years). Results: The resting motor threshold (MT) was significantly higher in ALS patients than in controls (P < 0.001). The mean map areas were smaller in patients with ALS than in healthy individuals, although some patients with short disease duration had extended maps. Discussion: Motor area maps serve as markers of upper motor neuron damage in ALS. Further research may elucidate the pathogenic mechanisms of the neurodegenerative process and aid in development of diagnostic and prognostic markers.
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3 Abbreviations.
ALS, amyotrophic lateral sclerosis; ALSFRS-R - ALS Functional Rating Scale, revised; EMG, electromyography; MMT, manual muscle testing; MT, motor threshold; MEP, motor evoked potential; nTMS, navigated transcranial magnetic stimulation; TMS, transcranial magnetic stimulation
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4 Keywords:
ALS,
navigated
transcranial
magnetic
neurodegeneration
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stimulation,
TMS,
brain
mapping,
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5 INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a disease associated with preferental degeneration of both upper and lower motor neurons.1 An important area of investigation in ALS research is the identification of biological markers of the disease.2 In the absence of these markers, ALS diagnosis relies currently on clinical evidence of combined upper and lower motor neuron involvement at various levels of the motor cortex, brain stem, and spinal cord. Involvement of peripheral motor neurons can be confirmed using needle electromyography (EMG), but signs of pyramidal dysfunction must be based exclusively on clinical findings.3 However, some patients fail to exhibit these signs for a considerable period of time. In addition, pronounced lower motor neuron dysfunction can also mask pyramidal signs in ALS.4 Transcranial magnetic stimulation (TMS) is a technique used to investigate upper motor neuron function.5,6 Studies conducted over the last few decades have shown that ALS affects multiple TMS parameters. Motor threshold (MT) is decreased during the early stages of ALS and increases during advanced disease, motor evoked potential (MEP) amplitude is decreased, central motor conduction time is increased, and cortical inhibition in response to paired stimulation is impaired.7-18 The use of TMS in ALS research has significantly improved our understanding of the pathogenesis of motor cortex damage. One promising TMS application is constructing cortical maps of individual muscles. In a single study of motor maps in ALS patients, maps were shown to diminish in size with disease progression, and it was suggested that this method could offer a more sensitive marker of ALS progression than current measures.19 An important shortcoming of conventional TMS-based mapping is its inability to precisely match target anatomical entities with their corresponding stimulation sites. However, such a match is essential given the individual variations and inevitable alterations in brain topography caused by the disease. This problem can be overcome largely by employing navigated TMS (nTMS), which uses the individual brain MRI scan of the patient for targeted stimulation.20
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6 We performed a PubMed search using the following search terms: “amyotrophic lateral sclerosis”, “motor neuron disease”, “navigated transcranial magnetic stimulation,” and “brain mapping” and did not find any studies concerning the use of nTMS in ALS research. The purpose of this study was to evaluate the functional condition of upper motor neurons in ALS and to obtain motor maps of target muscles using nTMS. MATERIALS AND METHODS Subjects. Patients treated at the Research Centre of Neurology at the Russian Academy of Medical Science between 2011 and 2013 were included in the study. The diagnosis of ALS was made according to the revised El Escorial criteria,21 The neurological status of each patient was evaluated using the revised ALS Functional Rating Scale (ALSFRS-R).
22
Manual muscle testing (MMT) was performed in 23
patients (muscle strength score in 18 muscle groups on the left and right)23. Each muscle group was measured on a 10-point scale, and the highest possible score was 360. None of the patients participated in other research studies or clinical trials. The control group consisted of healthy volunteers. The study was approved by the local Ethics Committee of Research at the Center of Neurology, Russian Academy of Medical Science. All subjects provided informed consent. nTMS. All participants underwent nTMS using an NBS eXimia Nexstim system (Finland). During the study period, none of the subjects were taking any medications that affected cerebral cortex excitability. Navigated TMS was performed bilaterally in all ALS patients. In healthy volunteers, stimulation of the hemispheres was bilateral in 6 participants, on the left in 8, and on the right in 10. First, all subjects underwent an MRI investigation on a Magnetom Symphony 1.5 T scanner (Siemens, Germany) using a T1 multiplanar reconstruction regime (MPR); the data were loaded into the NBS eXimia Nexstim system to obtain an individual 3D brain model for each subject. Next, the real anatomical entities were matched to their MRI representations.
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7 MEPs were recorded by placing 0.6 cm2 surface EMG electrodes over the target muscle being mapped (abductor pollicis brevis) using belly-tendon recording. The ground electrode was placed on the right clavicle or on the upper third of the right forearm. TMS was performed using a 70 mm figure-eight-shaped BiPulse Nexstim coil, with a maximal magnetic field strength of 199 V/m and a magnetic impulse duration of 280 µs. The imported MR images were used to identify the potential cortical representation area of the abductor pollicis brevis muscle in the lower part of the anterior central gyrus, corresponding to Brodmann area 4. Areas of interest were stimulated initially using a magnetic field of 80–110 V/m to detect MEPs of 100–500 µV. The coil was placed anteromedially at a 45° angle from the midline. The MEPs were recorded using a standard EMG machine (Nexstim, EMD, Finland). This procedure ensured stimulation over the precentral gyrus. We then determined the resting MT, defined as the lowest stimulation intensity able to evoke motor responses of a 50 µV peak-to-peak amplitude in 5/10 trials with the patient at rest.24 Resting MT was measured as the percent of the maximum intensity of the magnetic stimulator (1.5 Tesla). Next, the cortical representation of the abductor pollicis brevis muscle was mapped. Stimulation with a magnetic field of 110% of the motor threshold was used to identify the sites that evoked a motor response of at least 50 µV. This procedure allowed us to construct a cortical map of motor areas. All MEP responses were selected manually and/or the markers were readjusted to avoid including the traces with artifacts. Post-processing analysis. The volume of the motor representations was calculated using Multivox, a program developed at Moscow State University, Moscow, Russia (http://www.multivox.ru/). A workstation Multivox module has been developed that allows direct loading of anatomical MRI, magnetic stimulation, and functional MRI data. After cortical mapping, the Nexstim device could import the stimulation session (and points) as DICOME format files. Every point has its own coordinate in the MR-scanner coordinate system and its own MEP amplitude value. This package file was uploaded using a
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8 Multivox system. The software breaks the metric space into 2 mm³ cubes and counts the number of cubes that are selected in terms of stimulation volume. For each set of points selected, the module assesses the number of stimulation zones under the assumption that each stimulation point has a volume of 2 mm³ (the error value during the stimulation of certain Nexstim LTD). A finite sum of multiple points is calculated so that if 2 points belong to the same 2 mm³ cell, the contribution of the second point to the end sum is ignored. Statistical analysis was performed using Statistica 6.1 (StatSoft, Inc., USA). Data are presented as medians and 25% and 75% quartiles. Data sets were compared using nonparametric tests: the Mann– Whitney test for comparison of 2 independent groups and the Kruskal–Wallis test for comparisons of several independent groups. Correlations were analysed using Spearman correlation coefficients. Differences were considered significant at P < 0.05.
RESULTS Demographics There were 30 ALS patients: 20 men (66.7%) and 10 women (33.3%) aged 31 to 88 years (mean 54.4 ± 12.1). All patients were right-handed. By El Escorial criteria, ALS was definite in 16 (53.3%), probable in 9 (30.0%), probable laboratory-supported in 3 (10.0%), and possible in 1. Progressive muscular atrophy was diagnosed in 1 patient. There were 13 patients (43.3%) with lower limb onset, 7 (23.3%) with upper limb onset, and 10 (33.4%) with bulbar onset. The disease duration ranged from 4 to 160 months (median, 12 months), with a duration of less than 1 year in 18 patients (60.0%), 1 to 2 years in 7 (23.3%), and more than 2 years in 5 (16.7%). Among the latter 5 patients, 2 had durations of 160 and 135 months. ALSFRS-R scores ranged from 12 to 45 (median, 39). MMT scores ranged from 90 to 360. The control group consisted of 24 volunteers, all right-handed: 11 men (45.8%) and 13 women (54.2%) aged 32.7 ± 13.3 years. There were no significant age differences between the bilateral, left and right-sided controls. In addition, there were no significant differences between groups with respect to gender or age.
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9 Resting MT We found that MT was increased significantly in ALS patients for both right and left hemisphere stimulation compared to controls (Table 1). Resting MT values did not correlate with disease duration but did show an inverse correlation with total ALSFRS-R scores (patients with more severe neurological deficits had higher motor thresholds) and MMT scores (Table 2). The inverse correlation between MT and the strength of the contralateral abductor pollicis brevis muscle was also significant. MT was not significantly correlated with site of onset (P = 0.64 for the right hemisphere, and P = 0.21 for the left hemisphere, Kruskal–Wallis test) but tended to be higher in patients with upper limb onset than in patients with lower limb or bulbar onset. Mapping the cortical representation of the abductor pollicis brevis muscle We obtained individual cortical representation maps of the abductor pollicis brevis muscle in ALS patients and healthy individuals. The cortical representation of a muscle is the set of sites that can be stimulated to produce an MEP of at least 50 µV in the contralateral muscle. Individual maps obtained for healthy control subjects were located within Brodmann areas 4 and 6, which correspond to the anterior central gyrus and the premotor cortex (Fig. 1, A). In these regions, ALS patients exhibited a significant decrease in the volume of individual maps in both hemispheres (Table 1, Fig. 1, B). A significant correlation was found between the volume of the cortical representation maps and the clinical features of the disease [total scores on the ALSFRS-R and MMT (right alone) and the strength in the contralateral abductor pollicis brevis muscle] (Table 2). At a resting MT, MEP volume maps did not depend upon the site of onset (P = 0.66 and P = 0.88 for right and left hemispheres, respectively, Kruskal–Wallis test) and were not correlated with disease duration. A significant correlation was found between the volume of the cortical map and the resting MT (Fig. 2). In addition to a reduced map size, the individual motor representations had a considerably altered form in a number of cases. In these cases, the maps were arranged into distinct functional zones (where stimulation could induce MEPs) and interspersing lacunae (where a motor response could not
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10 be evoked). We describe this phenomenon as sparseness (or patchiness) of cortical representations (Fig. 3, A). In several ALS patients, we observed a broadening of individual cortical representations; MEPs were recorded in response to stimulation of the upper and lower part of the anterior central gyrus (Brodmann area 4), the posterior central gyrus (Brodmann area 1), and the frontal and temporal parasagittal regions (Fig. 3, B). In other patients, similar MEPs (with identical amplitudes and latencies) were recorded when various motor cortical areas were stimulated; in some, the phenomenon was restricted to only 1 hemisphere. It was also noted that in several patients, TMS produced an increase in fasciculation potentials, which caused considerable difficulties during data analysis. The fasciculation potentials decreased gradually after stimulation was interrupted. Adverse Events None of the experiments were associated with any major adverse effects (such as seizures). Several participants complained of mild, short-term headaches following the experiment but did not require any pharmacological treatment.
DISCUSSION One of the central unsolved problems concerning ALS pathogenesis is how to identify the site of neurodegenerative onset. To date, 3 principal hypotheses have been proposed: 1) upper motor neuron damage precedes lower motor neuron damage; 2) lower motor neuron damage precedes upper motor neuron damage; and 3) both motor neuron populations are affected independently.5 The first of these theories suggests that ALS affects cortical motor neurons initially and subsequently triggers the death of anterior horn motor neurons by excitotoxicity of glutamate transported from hyperactive cortical motor neurons.25 TMS data indicate that this hyperactivity is observed during early disease stages as decreased MT, which has been observed in a number of studies involving
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11 patients with sporadic and familial ALS.8,10,15 Numerous studies have also demonstrated involvement of glutamate excitotoxicity in ALS neurodegeneration at the molecular level.26 The death of cortical motor neurons during the course of ALS progression increasingly elevates MT.27 However, the growth rate depends on the individual characteristics of the neurodegenerative process in each individual. The group of patients who participated in our study was heterogeneous with respect to disease course (in particular, there was no correlation between total ALSFRS-R score and disease duration), which most likely explains the lack of a significant correlation between resting MT and disease duration despite the fact that such a link was reported in an earlier study.27 Similar results were also obtained by other groups.13,14 In a study by Khedr et al.,18 there were no significant differences in resting MT values between ALS patients and healthy volunteers, but MT did correlate with neurological deficit according to the ALSFRS-R. A similar association was also observed in our study. The association of MT with the clinical presentation of ALS (such as an inverse relationship with the total ALSFRS-R score, MMT score or target muscle strength) makes it possible to consider this parameter as a neurophysiological marker of ALS disease severity. Heterogeneity of the clinical course of ALS may be affected by polymorphisms in genes that encode ion channels and proteins that regulate motor cortex excitability. Mori et al.28 showed that polymorphisms in the gene encoding the TRPV1 (transient receptor potential vanilloid 1) ion channel can affect resting motor thresholds, contributing to the molecular basis of cortical excitability. The observed increase in fasciculations in response to magnetic stimuli has been described previously.29,30 However, in these studies, the phenomenon was observed in patients with low motor thresholds. Although it was not our goal to analyze spontaneous activity, we noted that it can also increase in patients with high motor thresholds and considerable weakness in the respective muscle, which is in agreement with the data reported by de Carvalho et al.31 The ability to match TMS and MRI scans of a particular individual using the navigation system enabled us to evaluate not only the conventional neurophysiological parameters but also the size and shape of cortical muscle representations. Several studies have reported changes in the size and
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12 position of cortical muscle representations associated with CNS diseases or various types of training and neurorehabilitation procedures.32,33 In ALS patients, we observed individual motor representations that were at times diminished in size and sometimes significantly broadened. The first phenomenon is most likely related to cortical motor neuron depletion, but we believe the second phenomenon can be attributed to neuroplasticity. Functional MRI studies have shown that the regions activated during a motor task are larger in ALS patients.34,35 The characteristics of neuroplastic processes may play a central role in progression of ALS by determining its rate. Broadened individual representations were only observed in patients with recent ALS onset or a relatively benign disease course. Cortical map enlargement could not be correlated with an increase in the stimulation intensity because we detected resting MT for every person. Enlargements of the cortical motor area were only observed in 2 patients and failed to correlate with stimulation intensity.
The correlation between the volumes of the nTMS maps and clinical signs of the disease confirms the utility of nTMS mapping and may potentially serve as a neurophysiological marker of the severity of neurodegeneration. In addition, the expansion, reduction, and sparseness of nTMS maps implicate neuroplasticity in neurodegenerative diseases and the severity of the upper motor neuron component. The mechanisms underlying spatial expansion of neurodegeneration in ALS are currently unknown. On the one hand, it has been observed that the evolution of clinical signs in ALS commonly reflects
the anatomy of the motor system, and the neurodegenerative process can spread both synaptically and
nonsynaptically from the initial point of onset to neighboring regions of the nervous system.36 On the
other hand, it has been suggested that neurodegeneration begins independently in each individual
motor neuron, attributing a crucial role to congenital and/or acquired metabolic deficiencies.37
The temporal development of clinical signs in some patients cannot be explained by continuous
spread; for example, a patient with bulbar onset ALS can subsequently develop weakness in the
lower but not upper limbs.
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13
The phenomenon of cortical representation patchiness described in this study suggests that the
pathological process lacks a single initial locus and that neurodegeneration proceeds independently
on various levels in individual motor neurons. However, the 3D anatomy of the process of
pathological spread during ALS is complex and may involve both mechanisms described above.
Alternatively, cortical representation patchiness could be due to variable resistance to the disease
process, e.g. some cortical motor neurons may be more resistant to the disease process than others,
comparable to the situation in spinal motor neurons. Further studies will be required to clarify this
issue.
Limitations.
The main limitation of this study is the significant age difference between healthy individuals and
ALS patients. Rossini et al. demonstrated in 1992 that resting MT decreases with age38 because of
age-related changes in the corticospinal tract.39 However, this finding could not be replicated in other
studies.40,41 In addition, there were no correlations betweenage, gender, and resting MT in 1 of the
largest studies (n=141).42 Conclusions. nTMS is a promising method for assessing upper motor neuron function in ALS. Further studies involving the computation of individual cortical representations of various muscles, a dynamic investigation of the parameters analyzed and a comparison of nTMS data to lower motor neuron status may elucidate the pathogenic mechanisms underlying neurodegenerative processes.
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14 References. 1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O et al. Amyotrophic lateral sclerosis. Lancet 2011;377:942-55. 2. Bowser R. Turner M., Shefner J. Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nat Rev Neurol. 2011;7:631-8. 3. De Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008;119:497-503. 4. Swash M Why are upper motor neuron signs difficult to elicit in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2012;83:659-62. 5. Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC et al. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg Psychiatry. 2013;84(10):1161-70. 6. De Carvalho M Testing upper motor neuron function in amyotrophic lateral sclerosis: the most difficult task of neurophysiology. Brain 2012;135(Pt 9):2581-2. 7. Eisen A, Shytbel W, Murphy K, Hoirch M Cortical magnetic stimulation in amyotrophic lateral sclerosis. Muscle Nerve. 1990;13:146–151. 8. Caramia MD, Cicinelli P, Paradiso C. Excitability changes of muscular responses to magnetic brain stimulation in patients with central motor disorders. Electroencephalogr Clin Neurophysiol 1991;81:243–50. 9. Ziemann U, Rothwell JC, Ridding MC Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 1996;496:873–81. 10. Mills K, Nithi K Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve 1997;20:1137-41. 11. Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology 1997;49:1292–1298.
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15 12. Triggs WJ, Menkes D, Onorato J, Yan RS, Young MS, Newell K et al. Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease. Neurology 1999;53:605–611. 13. De Carvalho M, Evangelista T, Sales-Luís ML The corticomotor threshold is not dependent on disease duration in amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Other Motor Neuron Disord 2002;3:39-42. 14. De Carvalho M, Turkman A, Swash Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion. J Neurol Sci 2003;210:183-90. 15. Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 2008;131:1540–50. 16. Floyd AG, Yu QP, Piboolnurak P Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology 2009;72:498-504. 17. Vucic S, Cheah BC, Kiernan MC Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis. Exp Neurol 2009;220:177-82. 18. Khedr EM, Ahmed MA, Hamdy A, Shawky OA Cortical excitability of amyotrophic lateral sclerosis: transcranial magnetic stimulation study. Neurophysiol Clin 2011;41:73-9. 19. de Carvalho M, Miranda PC, Luís ML, Ducla-Soares E Cortical muscle representation in amyotrophic
lateral
sclerosis
patients:
changes
with
disease
evolution.
Muscle
Nerve1999;22:1684-92. 20. Ruohonen J, Karhu J Navigated transcranial magnetic stimulation. Neurophysiol Clin 2010;40:717. 21. Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293-9.
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16 22. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999;169:13-21. 23. Florence JM, Pandya S., King WM, Robison JD, Signore LC, Wentzell M et al. Clinical trials in Duchenne dystrophy. Standardization and reliability of evaluation procedures. Phys Ther 1984;64:41-5. 24. Rossini PM, Barker AT, Berardelli A, et al. 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. Electroencephalogr Clin Neurophysiol 1994;91:79–92. 25. Eisen A, Kim S, Pant B. Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron? Muscle Nerve 1992;15:219–24. 26. Bogaert E, d'Ydewalle C, Van Den Bosch L. Amyotrophic lateral sclerosis and excitotoxicity: from pathological mechanism to therapeutic target. CNS Neurol Disord Drug Targets 2010;9:297-304 27. Eisen A, Pant B, Stewart H Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci 1993;20:11-6. 28. Mori F, Ribolsi M, Kusayanagi H, Monteleone F, Mantovani V, Buttari F et al. TRPV1 Channels Regulate Cortical Excitability in Humans. JNeurosci January 2012;32:873– 879. 29. Kaji R, Kohara N, Kimura J. Fasciculations evoked by magnetic cortical stimulation in patients with amyotrophic lateral sclerosis. Neurology 1993;43(suppl 2):A257-258. 30. Mills KR. Motor neuron disease: studies of the corticospinal excitation of single motor neurons by magnetic brain stimulation. Brain:1995;118:971-982. 31. de Carvalho M. Neurophysiological features of fasciculation potentials evoked by transcranial magnetic stimulation in amyotrophic lateral sclerosis. J Neurol. 2000;247:189-94. 32. Rossini PM, Caltagirone C, Castriota-Scanderbeg A, Cicinelli P, Del Gratta C, Demartin M et al. Hand motor cortical area reorganization in stroke: a study with fMRI, MEG and TCS maps.
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17 Neuroreport 1998;9:2141-6. 33. Tyč F, Boyadjian A. Plasticity of motor cortex induced by coordination and training. Clin Neurophysiol 2011;122:153-62. 34. Konrad C, Henningsen H, Bremer J, Mock B, Deppe M, Buchinger C et al. Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Exp Brain Res 2002;143:51-6 35. Mohammadi B, Kollewe K, Samii A, Dengler R, Münte TF. Functional neuroimaging at different disease stages reveals distinct phases of neuroplastic changes in amyotrophic lateral sclerosis. Hum Brain Mapp 2011;32:750-8. 36. Kanouchi T, Ohkubo T, Yokota T. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation? J Neurol Neurosurg Psychiatry. 2012;83:73945. 37. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 2009;73:805-11. 38. Rossini PM, Desiato MT, Caramia MD. Age-related changes of motor evoked potentials in healthy humans: non-invasive evaluation of central and peripheral motor tracts excitability and conductivity. Brain Res 1992; 593:14–9. 39. Clark BC, Taylor JL. Age-related changes in motor cortical properties and voluntary activation of skeletal muscle. Curr Aging Sci 2011; 4(3):192-9. 40. Pitcher JB, Ogston KM, Miles TS. Age and sex differences in human motor cortex input-output characteristics. J Physiol 2003; 546 (Pt 2):605-13. 41. Bernard JA, Seidler RD. Evidence for motor cortex dedifferentiation in older adults. Neurobiol Aging 2012; 33(9):1890-9. 42. Wassermann EM. Variation in the response to transcranial magnetic brain stimulation in the general population. Clin Neurophysiol 2002; 113(7): 1165-71.
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18
Table 1. Electrophysiological data of patients with ALS and control subjects ALS patients, n=30
Control
P-value
Medians [lower;
Medians [lower;
(U-test)
upper quartiles]
upper quartiles]
Right MT, %
78 [57; 100]
45 [40; 56.5] (n=16)
1
PhD Alexander V. Chervyakov, 2Ilya S. Bakulin, 1 PhD Natalia G. Savitskaya, 2 PhD Ivan V.
Arkhipov, 2 PhD Andrey V. Gavrilov, 1 PhD, MD, professor Maria N. Zakharova, 1 PhD, MD, professor Michael A. Piradov
1
Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia 2
Moscow State University, Moscow, Russia
Acknowledgments The authors are grateful to Prof. S.S. Nikitin and Prof. A.L. Kurenkov for fruitful discussion of the results and for valuable advice concerning further investigations.
Alexander V. Chervyakov, 123181, Moscow, Marshala Katukova Street, 13-2-124 [email protected]
Running title: Navigated TMS in ALS
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24345
Muscle & Nerve
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2
NAVIGATED TRANSCRANIAL MAGNETIC STIMULATION IN AMYOTROPHIC LATERAL SCLEROSIS Introduction: Amyotrophic lateral sclerosis (ALS) is a set of disorders associated with preferential degeneration of both upper and lower motor neurons. Navigated transcranial magnetic stimulation (nTMS) is a tool used to perform noninvasive functional brain mapping. Objective: To evaluate the function of upper motor neurons in ALS. Methods: nTMS was performed on 30 patients with ALS (mean age 54.4 ± 12.1 years) and 24 healthy volunteers (mean age 32.7 ± 13.3 years). Results: The resting motor threshold (MT) was significantly higher in ALS patients than in controls (P < 0.001). The mean map areas were smaller in patients with ALS than in healthy individuals, although some patients with short disease duration had extended maps. Discussion: Motor area maps serve as markers of upper motor neuron damage in ALS. Further research may elucidate the pathogenic mechanisms of the neurodegenerative process and aid in development of diagnostic and prognostic markers.
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3 Abbreviations.
ALS, amyotrophic lateral sclerosis; ALSFRS-R - ALS Functional Rating Scale, revised; EMG, electromyography; MMT, manual muscle testing; MT, motor threshold; MEP, motor evoked potential; nTMS, navigated transcranial magnetic stimulation; TMS, transcranial magnetic stimulation
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4 Keywords:
ALS,
navigated
transcranial
magnetic
neurodegeneration
John Wiley & Sons, Inc.
stimulation,
TMS,
brain
mapping,
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5 INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a disease associated with preferental degeneration of both upper and lower motor neurons.1 An important area of investigation in ALS research is the identification of biological markers of the disease.2 In the absence of these markers, ALS diagnosis relies currently on clinical evidence of combined upper and lower motor neuron involvement at various levels of the motor cortex, brain stem, and spinal cord. Involvement of peripheral motor neurons can be confirmed using needle electromyography (EMG), but signs of pyramidal dysfunction must be based exclusively on clinical findings.3 However, some patients fail to exhibit these signs for a considerable period of time. In addition, pronounced lower motor neuron dysfunction can also mask pyramidal signs in ALS.4 Transcranial magnetic stimulation (TMS) is a technique used to investigate upper motor neuron function.5,6 Studies conducted over the last few decades have shown that ALS affects multiple TMS parameters. Motor threshold (MT) is decreased during the early stages of ALS and increases during advanced disease, motor evoked potential (MEP) amplitude is decreased, central motor conduction time is increased, and cortical inhibition in response to paired stimulation is impaired.7-18 The use of TMS in ALS research has significantly improved our understanding of the pathogenesis of motor cortex damage. One promising TMS application is constructing cortical maps of individual muscles. In a single study of motor maps in ALS patients, maps were shown to diminish in size with disease progression, and it was suggested that this method could offer a more sensitive marker of ALS progression than current measures.19 An important shortcoming of conventional TMS-based mapping is its inability to precisely match target anatomical entities with their corresponding stimulation sites. However, such a match is essential given the individual variations and inevitable alterations in brain topography caused by the disease. This problem can be overcome largely by employing navigated TMS (nTMS), which uses the individual brain MRI scan of the patient for targeted stimulation.20
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6 We performed a PubMed search using the following search terms: “amyotrophic lateral sclerosis”, “motor neuron disease”, “navigated transcranial magnetic stimulation,” and “brain mapping” and did not find any studies concerning the use of nTMS in ALS research. The purpose of this study was to evaluate the functional condition of upper motor neurons in ALS and to obtain motor maps of target muscles using nTMS. MATERIALS AND METHODS Subjects. Patients treated at the Research Centre of Neurology at the Russian Academy of Medical Science between 2011 and 2013 were included in the study. The diagnosis of ALS was made according to the revised El Escorial criteria,21 The neurological status of each patient was evaluated using the revised ALS Functional Rating Scale (ALSFRS-R).
22
Manual muscle testing (MMT) was performed in 23
patients (muscle strength score in 18 muscle groups on the left and right)23. Each muscle group was measured on a 10-point scale, and the highest possible score was 360. None of the patients participated in other research studies or clinical trials. The control group consisted of healthy volunteers. The study was approved by the local Ethics Committee of Research at the Center of Neurology, Russian Academy of Medical Science. All subjects provided informed consent. nTMS. All participants underwent nTMS using an NBS eXimia Nexstim system (Finland). During the study period, none of the subjects were taking any medications that affected cerebral cortex excitability. Navigated TMS was performed bilaterally in all ALS patients. In healthy volunteers, stimulation of the hemispheres was bilateral in 6 participants, on the left in 8, and on the right in 10. First, all subjects underwent an MRI investigation on a Magnetom Symphony 1.5 T scanner (Siemens, Germany) using a T1 multiplanar reconstruction regime (MPR); the data were loaded into the NBS eXimia Nexstim system to obtain an individual 3D brain model for each subject. Next, the real anatomical entities were matched to their MRI representations.
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7 MEPs were recorded by placing 0.6 cm2 surface EMG electrodes over the target muscle being mapped (abductor pollicis brevis) using belly-tendon recording. The ground electrode was placed on the right clavicle or on the upper third of the right forearm. TMS was performed using a 70 mm figure-eight-shaped BiPulse Nexstim coil, with a maximal magnetic field strength of 199 V/m and a magnetic impulse duration of 280 µs. The imported MR images were used to identify the potential cortical representation area of the abductor pollicis brevis muscle in the lower part of the anterior central gyrus, corresponding to Brodmann area 4. Areas of interest were stimulated initially using a magnetic field of 80–110 V/m to detect MEPs of 100–500 µV. The coil was placed anteromedially at a 45° angle from the midline. The MEPs were recorded using a standard EMG machine (Nexstim, EMD, Finland). This procedure ensured stimulation over the precentral gyrus. We then determined the resting MT, defined as the lowest stimulation intensity able to evoke motor responses of a 50 µV peak-to-peak amplitude in 5/10 trials with the patient at rest.24 Resting MT was measured as the percent of the maximum intensity of the magnetic stimulator (1.5 Tesla). Next, the cortical representation of the abductor pollicis brevis muscle was mapped. Stimulation with a magnetic field of 110% of the motor threshold was used to identify the sites that evoked a motor response of at least 50 µV. This procedure allowed us to construct a cortical map of motor areas. All MEP responses were selected manually and/or the markers were readjusted to avoid including the traces with artifacts. Post-processing analysis. The volume of the motor representations was calculated using Multivox, a program developed at Moscow State University, Moscow, Russia (http://www.multivox.ru/). A workstation Multivox module has been developed that allows direct loading of anatomical MRI, magnetic stimulation, and functional MRI data. After cortical mapping, the Nexstim device could import the stimulation session (and points) as DICOME format files. Every point has its own coordinate in the MR-scanner coordinate system and its own MEP amplitude value. This package file was uploaded using a
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8 Multivox system. The software breaks the metric space into 2 mm³ cubes and counts the number of cubes that are selected in terms of stimulation volume. For each set of points selected, the module assesses the number of stimulation zones under the assumption that each stimulation point has a volume of 2 mm³ (the error value during the stimulation of certain Nexstim LTD). A finite sum of multiple points is calculated so that if 2 points belong to the same 2 mm³ cell, the contribution of the second point to the end sum is ignored. Statistical analysis was performed using Statistica 6.1 (StatSoft, Inc., USA). Data are presented as medians and 25% and 75% quartiles. Data sets were compared using nonparametric tests: the Mann– Whitney test for comparison of 2 independent groups and the Kruskal–Wallis test for comparisons of several independent groups. Correlations were analysed using Spearman correlation coefficients. Differences were considered significant at P < 0.05.
RESULTS Demographics There were 30 ALS patients: 20 men (66.7%) and 10 women (33.3%) aged 31 to 88 years (mean 54.4 ± 12.1). All patients were right-handed. By El Escorial criteria, ALS was definite in 16 (53.3%), probable in 9 (30.0%), probable laboratory-supported in 3 (10.0%), and possible in 1. Progressive muscular atrophy was diagnosed in 1 patient. There were 13 patients (43.3%) with lower limb onset, 7 (23.3%) with upper limb onset, and 10 (33.4%) with bulbar onset. The disease duration ranged from 4 to 160 months (median, 12 months), with a duration of less than 1 year in 18 patients (60.0%), 1 to 2 years in 7 (23.3%), and more than 2 years in 5 (16.7%). Among the latter 5 patients, 2 had durations of 160 and 135 months. ALSFRS-R scores ranged from 12 to 45 (median, 39). MMT scores ranged from 90 to 360. The control group consisted of 24 volunteers, all right-handed: 11 men (45.8%) and 13 women (54.2%) aged 32.7 ± 13.3 years. There were no significant age differences between the bilateral, left and right-sided controls. In addition, there were no significant differences between groups with respect to gender or age.
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9 Resting MT We found that MT was increased significantly in ALS patients for both right and left hemisphere stimulation compared to controls (Table 1). Resting MT values did not correlate with disease duration but did show an inverse correlation with total ALSFRS-R scores (patients with more severe neurological deficits had higher motor thresholds) and MMT scores (Table 2). The inverse correlation between MT and the strength of the contralateral abductor pollicis brevis muscle was also significant. MT was not significantly correlated with site of onset (P = 0.64 for the right hemisphere, and P = 0.21 for the left hemisphere, Kruskal–Wallis test) but tended to be higher in patients with upper limb onset than in patients with lower limb or bulbar onset. Mapping the cortical representation of the abductor pollicis brevis muscle We obtained individual cortical representation maps of the abductor pollicis brevis muscle in ALS patients and healthy individuals. The cortical representation of a muscle is the set of sites that can be stimulated to produce an MEP of at least 50 µV in the contralateral muscle. Individual maps obtained for healthy control subjects were located within Brodmann areas 4 and 6, which correspond to the anterior central gyrus and the premotor cortex (Fig. 1, A). In these regions, ALS patients exhibited a significant decrease in the volume of individual maps in both hemispheres (Table 1, Fig. 1, B). A significant correlation was found between the volume of the cortical representation maps and the clinical features of the disease [total scores on the ALSFRS-R and MMT (right alone) and the strength in the contralateral abductor pollicis brevis muscle] (Table 2). At a resting MT, MEP volume maps did not depend upon the site of onset (P = 0.66 and P = 0.88 for right and left hemispheres, respectively, Kruskal–Wallis test) and were not correlated with disease duration. A significant correlation was found between the volume of the cortical map and the resting MT (Fig. 2). In addition to a reduced map size, the individual motor representations had a considerably altered form in a number of cases. In these cases, the maps were arranged into distinct functional zones (where stimulation could induce MEPs) and interspersing lacunae (where a motor response could not
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10 be evoked). We describe this phenomenon as sparseness (or patchiness) of cortical representations (Fig. 3, A). In several ALS patients, we observed a broadening of individual cortical representations; MEPs were recorded in response to stimulation of the upper and lower part of the anterior central gyrus (Brodmann area 4), the posterior central gyrus (Brodmann area 1), and the frontal and temporal parasagittal regions (Fig. 3, B). In other patients, similar MEPs (with identical amplitudes and latencies) were recorded when various motor cortical areas were stimulated; in some, the phenomenon was restricted to only 1 hemisphere. It was also noted that in several patients, TMS produced an increase in fasciculation potentials, which caused considerable difficulties during data analysis. The fasciculation potentials decreased gradually after stimulation was interrupted. Adverse Events None of the experiments were associated with any major adverse effects (such as seizures). Several participants complained of mild, short-term headaches following the experiment but did not require any pharmacological treatment.
DISCUSSION One of the central unsolved problems concerning ALS pathogenesis is how to identify the site of neurodegenerative onset. To date, 3 principal hypotheses have been proposed: 1) upper motor neuron damage precedes lower motor neuron damage; 2) lower motor neuron damage precedes upper motor neuron damage; and 3) both motor neuron populations are affected independently.5 The first of these theories suggests that ALS affects cortical motor neurons initially and subsequently triggers the death of anterior horn motor neurons by excitotoxicity of glutamate transported from hyperactive cortical motor neurons.25 TMS data indicate that this hyperactivity is observed during early disease stages as decreased MT, which has been observed in a number of studies involving
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11 patients with sporadic and familial ALS.8,10,15 Numerous studies have also demonstrated involvement of glutamate excitotoxicity in ALS neurodegeneration at the molecular level.26 The death of cortical motor neurons during the course of ALS progression increasingly elevates MT.27 However, the growth rate depends on the individual characteristics of the neurodegenerative process in each individual. The group of patients who participated in our study was heterogeneous with respect to disease course (in particular, there was no correlation between total ALSFRS-R score and disease duration), which most likely explains the lack of a significant correlation between resting MT and disease duration despite the fact that such a link was reported in an earlier study.27 Similar results were also obtained by other groups.13,14 In a study by Khedr et al.,18 there were no significant differences in resting MT values between ALS patients and healthy volunteers, but MT did correlate with neurological deficit according to the ALSFRS-R. A similar association was also observed in our study. The association of MT with the clinical presentation of ALS (such as an inverse relationship with the total ALSFRS-R score, MMT score or target muscle strength) makes it possible to consider this parameter as a neurophysiological marker of ALS disease severity. Heterogeneity of the clinical course of ALS may be affected by polymorphisms in genes that encode ion channels and proteins that regulate motor cortex excitability. Mori et al.28 showed that polymorphisms in the gene encoding the TRPV1 (transient receptor potential vanilloid 1) ion channel can affect resting motor thresholds, contributing to the molecular basis of cortical excitability. The observed increase in fasciculations in response to magnetic stimuli has been described previously.29,30 However, in these studies, the phenomenon was observed in patients with low motor thresholds. Although it was not our goal to analyze spontaneous activity, we noted that it can also increase in patients with high motor thresholds and considerable weakness in the respective muscle, which is in agreement with the data reported by de Carvalho et al.31 The ability to match TMS and MRI scans of a particular individual using the navigation system enabled us to evaluate not only the conventional neurophysiological parameters but also the size and shape of cortical muscle representations. Several studies have reported changes in the size and
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12 position of cortical muscle representations associated with CNS diseases or various types of training and neurorehabilitation procedures.32,33 In ALS patients, we observed individual motor representations that were at times diminished in size and sometimes significantly broadened. The first phenomenon is most likely related to cortical motor neuron depletion, but we believe the second phenomenon can be attributed to neuroplasticity. Functional MRI studies have shown that the regions activated during a motor task are larger in ALS patients.34,35 The characteristics of neuroplastic processes may play a central role in progression of ALS by determining its rate. Broadened individual representations were only observed in patients with recent ALS onset or a relatively benign disease course. Cortical map enlargement could not be correlated with an increase in the stimulation intensity because we detected resting MT for every person. Enlargements of the cortical motor area were only observed in 2 patients and failed to correlate with stimulation intensity.
The correlation between the volumes of the nTMS maps and clinical signs of the disease confirms the utility of nTMS mapping and may potentially serve as a neurophysiological marker of the severity of neurodegeneration. In addition, the expansion, reduction, and sparseness of nTMS maps implicate neuroplasticity in neurodegenerative diseases and the severity of the upper motor neuron component. The mechanisms underlying spatial expansion of neurodegeneration in ALS are currently unknown. On the one hand, it has been observed that the evolution of clinical signs in ALS commonly reflects
the anatomy of the motor system, and the neurodegenerative process can spread both synaptically and
nonsynaptically from the initial point of onset to neighboring regions of the nervous system.36 On the
other hand, it has been suggested that neurodegeneration begins independently in each individual
motor neuron, attributing a crucial role to congenital and/or acquired metabolic deficiencies.37
The temporal development of clinical signs in some patients cannot be explained by continuous
spread; for example, a patient with bulbar onset ALS can subsequently develop weakness in the
lower but not upper limbs.
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13
The phenomenon of cortical representation patchiness described in this study suggests that the
pathological process lacks a single initial locus and that neurodegeneration proceeds independently
on various levels in individual motor neurons. However, the 3D anatomy of the process of
pathological spread during ALS is complex and may involve both mechanisms described above.
Alternatively, cortical representation patchiness could be due to variable resistance to the disease
process, e.g. some cortical motor neurons may be more resistant to the disease process than others,
comparable to the situation in spinal motor neurons. Further studies will be required to clarify this
issue.
Limitations.
The main limitation of this study is the significant age difference between healthy individuals and
ALS patients. Rossini et al. demonstrated in 1992 that resting MT decreases with age38 because of
age-related changes in the corticospinal tract.39 However, this finding could not be replicated in other
studies.40,41 In addition, there were no correlations betweenage, gender, and resting MT in 1 of the
largest studies (n=141).42 Conclusions. nTMS is a promising method for assessing upper motor neuron function in ALS. Further studies involving the computation of individual cortical representations of various muscles, a dynamic investigation of the parameters analyzed and a comparison of nTMS data to lower motor neuron status may elucidate the pathogenic mechanisms underlying neurodegenerative processes.
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14 References. 1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O et al. Amyotrophic lateral sclerosis. Lancet 2011;377:942-55. 2. Bowser R. Turner M., Shefner J. Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nat Rev Neurol. 2011;7:631-8. 3. De Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008;119:497-503. 4. Swash M Why are upper motor neuron signs difficult to elicit in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2012;83:659-62. 5. Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC et al. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg Psychiatry. 2013;84(10):1161-70. 6. De Carvalho M Testing upper motor neuron function in amyotrophic lateral sclerosis: the most difficult task of neurophysiology. Brain 2012;135(Pt 9):2581-2. 7. Eisen A, Shytbel W, Murphy K, Hoirch M Cortical magnetic stimulation in amyotrophic lateral sclerosis. Muscle Nerve. 1990;13:146–151. 8. Caramia MD, Cicinelli P, Paradiso C. Excitability changes of muscular responses to magnetic brain stimulation in patients with central motor disorders. Electroencephalogr Clin Neurophysiol 1991;81:243–50. 9. Ziemann U, Rothwell JC, Ridding MC Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 1996;496:873–81. 10. Mills K, Nithi K Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve 1997;20:1137-41. 11. Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology 1997;49:1292–1298.
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15 12. Triggs WJ, Menkes D, Onorato J, Yan RS, Young MS, Newell K et al. Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease. Neurology 1999;53:605–611. 13. De Carvalho M, Evangelista T, Sales-Luís ML The corticomotor threshold is not dependent on disease duration in amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Other Motor Neuron Disord 2002;3:39-42. 14. De Carvalho M, Turkman A, Swash Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion. J Neurol Sci 2003;210:183-90. 15. Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 2008;131:1540–50. 16. Floyd AG, Yu QP, Piboolnurak P Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology 2009;72:498-504. 17. Vucic S, Cheah BC, Kiernan MC Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis. Exp Neurol 2009;220:177-82. 18. Khedr EM, Ahmed MA, Hamdy A, Shawky OA Cortical excitability of amyotrophic lateral sclerosis: transcranial magnetic stimulation study. Neurophysiol Clin 2011;41:73-9. 19. de Carvalho M, Miranda PC, Luís ML, Ducla-Soares E Cortical muscle representation in amyotrophic
lateral
sclerosis
patients:
changes
with
disease
evolution.
Muscle
Nerve1999;22:1684-92. 20. Ruohonen J, Karhu J Navigated transcranial magnetic stimulation. Neurophysiol Clin 2010;40:717. 21. Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293-9.
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Muscle & Nerve
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16 22. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999;169:13-21. 23. Florence JM, Pandya S., King WM, Robison JD, Signore LC, Wentzell M et al. Clinical trials in Duchenne dystrophy. Standardization and reliability of evaluation procedures. Phys Ther 1984;64:41-5. 24. Rossini PM, Barker AT, Berardelli A, et al. 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. Electroencephalogr Clin Neurophysiol 1994;91:79–92. 25. Eisen A, Kim S, Pant B. Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron? Muscle Nerve 1992;15:219–24. 26. Bogaert E, d'Ydewalle C, Van Den Bosch L. Amyotrophic lateral sclerosis and excitotoxicity: from pathological mechanism to therapeutic target. CNS Neurol Disord Drug Targets 2010;9:297-304 27. Eisen A, Pant B, Stewart H Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci 1993;20:11-6. 28. Mori F, Ribolsi M, Kusayanagi H, Monteleone F, Mantovani V, Buttari F et al. TRPV1 Channels Regulate Cortical Excitability in Humans. JNeurosci January 2012;32:873– 879. 29. Kaji R, Kohara N, Kimura J. Fasciculations evoked by magnetic cortical stimulation in patients with amyotrophic lateral sclerosis. Neurology 1993;43(suppl 2):A257-258. 30. Mills KR. Motor neuron disease: studies of the corticospinal excitation of single motor neurons by magnetic brain stimulation. Brain:1995;118:971-982. 31. de Carvalho M. Neurophysiological features of fasciculation potentials evoked by transcranial magnetic stimulation in amyotrophic lateral sclerosis. J Neurol. 2000;247:189-94. 32. Rossini PM, Caltagirone C, Castriota-Scanderbeg A, Cicinelli P, Del Gratta C, Demartin M et al. Hand motor cortical area reorganization in stroke: a study with fMRI, MEG and TCS maps.
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17 Neuroreport 1998;9:2141-6. 33. Tyč F, Boyadjian A. Plasticity of motor cortex induced by coordination and training. Clin Neurophysiol 2011;122:153-62. 34. Konrad C, Henningsen H, Bremer J, Mock B, Deppe M, Buchinger C et al. Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Exp Brain Res 2002;143:51-6 35. Mohammadi B, Kollewe K, Samii A, Dengler R, Münte TF. Functional neuroimaging at different disease stages reveals distinct phases of neuroplastic changes in amyotrophic lateral sclerosis. Hum Brain Mapp 2011;32:750-8. 36. Kanouchi T, Ohkubo T, Yokota T. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation? J Neurol Neurosurg Psychiatry. 2012;83:73945. 37. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 2009;73:805-11. 38. Rossini PM, Desiato MT, Caramia MD. Age-related changes of motor evoked potentials in healthy humans: non-invasive evaluation of central and peripheral motor tracts excitability and conductivity. Brain Res 1992; 593:14–9. 39. Clark BC, Taylor JL. Age-related changes in motor cortical properties and voluntary activation of skeletal muscle. Curr Aging Sci 2011; 4(3):192-9. 40. Pitcher JB, Ogston KM, Miles TS. Age and sex differences in human motor cortex input-output characteristics. J Physiol 2003; 546 (Pt 2):605-13. 41. Bernard JA, Seidler RD. Evidence for motor cortex dedifferentiation in older adults. Neurobiol Aging 2012; 33(9):1890-9. 42. Wassermann EM. Variation in the response to transcranial magnetic brain stimulation in the general population. Clin Neurophysiol 2002; 113(7): 1165-71.
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18
Table 1. Electrophysiological data of patients with ALS and control subjects ALS patients, n=30
Control
P-value
Medians [lower;
Medians [lower;
(U-test)
upper quartiles]
upper quartiles]
Right MT, %
78 [57; 100]
45 [40; 56.5] (n=16)
