- Email: [email protected]
Transcranial Magnetic Stimulation After Spinal Cord Injury
PEER-REVIEW REPORTS
Transcranial Magnetic Stimulation After Spinal Cord Injury Basem I. Awad1,2, Margaret A. Carmody3, Xiaoming Zhang4, Vernon W. Lin4, Michael P. Steinmetz2
Key words Rehabilitation - Spinal cord injury - Transcranial magnetic stimulation -
Abbreviations and Acronyms CMCT: Central motor conduction time MEP: Motor-evoked potential rTMS: Repetitive transcranial magnetic stimulation SCI: Spinal cord injury TMS: Transcranial magnetic stimulation From the 1Department of Neurosurgery, Mansoura University School of Medicine, Mansoura, Egypt; 2Department of Neurosciences, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA; 3Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; and 4Department of Physical Medicine and Rehabilitation, Cleveland Clinic, Cleveland, Ohio, USA To whom correspondence should be addressed: Michael P. Steinmetz, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 83, 2:232-235. http://dx.doi.org/10.1016/j.wneu.2013.01.043 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com
- OBJECTIVE:
To review the basic principles and techniques of transcranial magnetic stimulation (TMS) and provide information and evidence regarding its applications in spinal cord injury clinical rehabilitation.
- METHODS:
A review of the available current and historical literature regarding TMS was conducted, and a discussion of its potential use in spinal cord injury rehabilitation is presented.
- RESULTS:
TMS provides reliable information about the functional integrity and conduction properties of the corticospinal tracts and motor control in the diagnostic and prognostic assessment of various neurological disorders. It allows one to follow the evolution of motor control and to evaluate the effects of different therapeutic procedures. Motor-evoked potentials can be useful in follow-up evaluation of motor function during treatment and rehabilitation, specifically in patients with spinal cord injury and stroke. Although studies regarding somatomotor functional recovery after spinal cord injury have shown promise, more trials are required to provide strong and substantial evidence.
- CONCLUSIONS:
TMS is a promising noninvasive tool for the treatment of spasticity, neuropathic pain, and somatomotor deficit after spinal cord injury. Further investigation is needed to demonstrate whether different protocols and applications of stimulation, as well as alternative cortical sites of stimulation, may induce more pronounced and beneficial clinical effects.
1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
INTRODUCTION More than 30 years ago, Merton asked Morton to build a high-voltage electrical stimulator that would have the ability to activate muscle directly rather than through small nerve branches. Once built, he had the idea that this device could also stimulate the motor areas of the human brain through intact scalp, that is, transcranial electrical stimulation (33). A brief, highvoltage electric shock applied over the primary motor cortex produced a brief, relatively synchronous muscle response. From that point forward, it was clear that transcranial electrical stimulation would prove valuable. However, it required large electric currents to be applied for a small proportion to penetrate into the patient’s brain, which would lead to painful contractions of scalp muscles and activation of sensory receptors in the skin. Five years later, Barker et al. (3) developed the principle of inductance (discovered by
232
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Michael Faraday in 1838) to transmit electrical energy across the scalp and skull through magnetic stimulation (transcranial magnetic stimulation, or TMS). TMS provided the same effect without the pain associated with percutaneous electrical stimulation. Since its introduction as a noninvasive method of brain stimulation, the use of TMS has spread widely in clinical practice. In this article we review the basic principles and techniques of repetitive TMS (rTMS) and provide information and evidence regarding its applications in the clinical rehabilitation of patients with spinal cord injury (SCI). BASIC PRINCIPLES OF TMS When a time-varying magnetic field is applied in the vicinity of a conductive structure, it induces an electrical field, the amplitude of which is related to the rate of change of the magnetic field and to the geometry of the conductive structure. This electrical field creates a current that, if of
appropriate amplitude and duration, can stimulate neuromuscular tissue as if it had been produced by electrodes (2). The magnetic fields generated from the motor cortex are able to pass through high-resistance structures such as bone, fat, skin, and clothing. Because TMS is noninvasive and painless, the number of clinical studies has increased over past decades, and many clinical applications have become available (48, 40, 14). The technique provides reliable information about the functional integrity and conduction properties of the corticospinal tracts and motor control in the diagnostic and prognostic assessment of various neurological disorders. It allows one to follow the evolution of motor control and to evaluate the effects of different therapeutic procedures. PHYSIOLOGICAL MECHANISMS When TMS is applied to the motor cortex at appropriate stimulation intensity, motorevoked potentials (MEPs) can be recorded
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2013.01.043
PEER-REVIEW REPORTS BASEM I. AWAD ET AL.
from contralateral extremity muscles. Motor threshold refers to the lowest TMS intensity necessary to evoke MEPs in the target muscle when single-pulse stimuli are applied to the motor cortex. When the central nervous system is stimulated, the stimulation threshold can be reduced by approximately 25%, the response amplitude can be increased, and the response latency reduced by some 1e3 ms through preactivation of the target muscle. This technique is referred to as “facilitation.” The phenomenon of facilitation was noted in an early stage of the original transcutaneous electrical stimulation studies of Merton and Morton and is equally prominent with magnetic brain stimulation (15). Compared with those of electrical stimulation, muscle responses to magnetic stimulation show longer onset latency by approximately 2 ms (in hand muscles), simpler waveform, shorter duration, and larger amplitude. These differences indicate that electrical and magnetic stimulation activates the motor pathways at different sites. Electrical stimulation excites corticospinal neurons directly, causing an initial D-wave and subsequent I-wave volleys, and magnetic stimulation acts transsynaptically, the better synchronized and longer latency response being caused by a more homogeneous site of excitation resulting in I waves, but no D wave, impinging on the spinal motor neuron. Another phenomenon (inhibitory) is the interruption of the ongoing voluntary muscle contraction produced by TMS of the motor cortex. When an individual is instructed to maintain muscle contraction and a single suprathreshold TMS pulse is applied to the motor cortex contralateral to the target muscle, the electromyographic activity is arrested for a few hundred milliseconds after the MEP. This period of electromyographic suppression is referred to as a silent period. This silent period is produced by a mixture of cortical and spinal inhibitory effects. Approximately the first 50 ms of the silent period are caused by both cortical and spinal mechanisms. From this point onward, spinal mechanisms are progressively less important, and the cortical inhibitory mechanisms act on the neural elements of the corticomotoneuronal system at motor cortical level: a magnetic stimulus given during the second half of the silent period does not produce MEP whereas electrical stimulation evokes almost
TMS AFTER SPINAL CORD INJURY
unchanged muscle responses. In other words, the unexcitability of the motor cortex after a second magnetic stimulus indicates that the motor cortex per se is inhibited, whereas the excitability with electrical stimulation implies that corticospinal axons and spinal motor neurons are not inhibited (5, 17, 41). Depending on the purpose of the test, there are many important parameters that can be measured in cortical stimulation, such as stimulation threshold, MEP latency, MEP amplitude, response morphology, central motor conduction time (CMCT), silent period duration, fatigue, intracortical inhibitory, and excitatory pathways. CMCT is defined as the latency difference between the MEPs induced by stimulation of the motor cortex and those evoked by spinal (motor root) stimulation and are calculated by subtracting the latency of the motor potential induced by stimulation of the spinal motor root from that of the response to motor cortex stimulation. CMCT can be calculated by subtracting the latency in response to spinal root stimulation from the latency in response to cortical stimulation (7, 35). The CMCT measurement can provide supporting evidence for the diagnosis and also can be used as an objective marker of disease progression and prognosis. MEP amplitude can be affected by the type of cortical stimulator (high-voltage electrical or magnetoelectrical) and by the stimulus intensity, as well as the activation of other muscles. MEP amplitude reflects not only the integrity of the corticospinal tract but also the excitability of motor cortex and nerve roots and the conduction along the peripheral motor pathway to the muscles. Patients with dysfunction at any level along the corticospinal pathway may display abnormal MEPs, whereas the presence of intact MEPs suggests integrity of the pyramidal tract. For example, contralateral MEPs acutely after a stroke relate to a favorable recovery, whereas the absence of MEPs suggests a poor outcome. CMCT can be increased and MEP amplitude reduced by several factors, such as reduced excitability of the motor cortex, slowed conduction between the motor cortex and spinal motor neurons, several factors at the motor neuron level, and reduced conduction velocities in motor axons.
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USES OF TMS AS A DIAGNOSTIC TOOL TMS delivered to different levels of the motor system (neuroaxis) can provide information about the excitability of the motor cortex; the functional integrity of intracortical neuronal structures; the conduction along corticospinal, corticonuclear, and callosal fibers; as well as the function of nerve roots and peripheral motor pathways to the muscles. The pattern of findings in these studies can help to localize the level of a lesion within the nervous system, distinguish between a predominantly demyelinating or axonal lesion in the motor tracts, or predict the functional motor outcome after an injury. The abnormalities revealed by TMS are not disease-specific, and the results should be interpreted in the context of other clinical data. Clinical applications of TMS include spinal cord injury, multiple sclerosis, anterior horn cell disorders, spondylotic myelopathy, stroke, various neuropathies, epilepsy (43), degenerative ataxic disorders such as cerebellar ataxia and Friedreich ataxia (8, 22, 44), cranial nerve disorders (mainly the facial nerve) (30, 36, 45), pathology of the respiratory muscles, and several others. It can also be used in the operating room, where monitoring motor conduction is a useful indicator of the integrity of the central motor pathways, specifically during neurosurgical operations (18, 31, 49), as well as in the intensive care unit (10). In SCI, good correlation was seen between MEP findings and motor function (12, 34, 50). Decreased MEP amplitudes or absent MEP responses are seen more frequently in neoplastic than inflammatory lesions, whereas in the latter increased latencies are seen more often (27). In high tetraplegic patients in whom the diaphragm is affected, MEPs can be recorded from the diaphragm as well as from other respiratory muscles to investigate the central motor conduction properties of the musculature (28, 29, 51). USE OF TMS AS A CLINICAL REHABILITATION TOOL AFTER SCI Neuropathic pain in patients with SCI is resistant to most treatments and has considerable impact on their quality of life (19, 42). Recently, studies of rTMS applied to the motor cortex that correspond to
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pain areas suggest that it has potential as a therapeutic tool to relieve chronic neuropathic pain (1, 9, 21, 25). Defrin et al. (9) studied the effect of rTMS on neuropathic pain after SCI. They applied the rTMS to the legs of paraplegic patients with chronic neuropathic pain. Targeting the areas that represented the leg, they used a figure-of-eight coil to stimulate the cortex. Pain reduction was demonstrated in both the real and sham rTMS groups, but no significant difference was documented. Kang et al. (20) also evaluated the analgesic effect of rTMS when applied to the hand motor cortical area in patients with SCI who had chronic neuropathic pain at multiple sites in the body. The average pain intensity during the subsequent 24 hours did not differ between the real and sham rTMS treatment groups, and therefore, the therapeutic efficacy of rTMS was not demonstrated. Spasticity is also a common disorder in patients with SCI. Its prevalence is reported to be approximately 65%e78% in this population (32). Spasticity is a major cause of long-term disability and significantly impacts daily activities and quality of life. A major challenge in rehabilitation is to induce active movement in the paretic extremities and reduce spasticity, which is hardly affected by traditional spasmolytic drugs (11). Previous authors have shown that highfrequency rTMS applied over the primary motor cortex can reduce H-reflex size in healthy subjects (37, 39, 46) and reduce spasticity in patients with multiple sclerosis (6), cerebral palsy and spastic quadriplegia (47). Kumru et al. (23) hypothesized that increasing the excitability of the primary motor cortex would modify descending corticospinal influences and increase inhibitory input, which would then reduce segmental spinal excitability and thus reduce limb spasticity in patients with incomplete SCI. All patients tolerated the high-frequency stimulation without complication or report of adverse effects, with the exception of three patients, who complained of facial twitching during the first session of active stimulation. Furthermore, all patients showed a significant and consistent clinical improvement in spasticity for at least 1 week after 5 days of daily rTMS sessions. However, they failed to demonstrate neurophysiologic changes after the intervention.
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TMS AFTER SPINAL CORD INJURY
Belci et al. (4) examined somatomotor functional recovery in patients after incomplete SCI. They showed short term reduction in cortical inhibition during treatment with rTMS, as well as improved ASIA impairment scale measures of sensory and motor function and improved hand function that lasted into a recovery period. Furthermore, Kuppuswamy et al. (24) assessed the effectiveness of physiological outcome measures in detecting functional change in the degree of impairment of SCI after rTMS of the sensorimotor cortex. They reported no significant differences in American Spinal Injury Association impairment scale outcomes between real and sham rTMS. The Action Research Arm Test was increased at 1 hour after rTMS compared with baseline. Active motor threshold for the most caudally innervated hand muscle was increased at 72 and 120 hours compared with baseline. Persistent reductions in electrical perceptual test to rTMS occurred in two individuals. These changes in cortical motor threshold measures may add support to the idea of functional gain after rTMS in SCI patients.
CONCLUSION MEPs can be useful in follow-up evaluation of motor function during treatment and rehabilitation, specifically in patients with SCI and strokes. This is not only useful for the therapeutic staff but also improves patient motivation (13, 16, 26, 38). The enhancement of motor excitability is also associated with an improvement of motor function. Further investigation is needed to demonstrate whether different protocols and applications of stimulation, as well as alternative cortical sites of stimulation may induce more pronounced and beneficial clinical effects. REFERENCES 1. Andre-Obadia N, Peyron R, Mertens P, Mauguiere F, Laurent B, Garcia-Larrea L: Transcranial magnetic stimulation for pain control: double blind study of different frequencies against placebo, and correlation with motor cortex stimulation efficacy. Clin Neurophysiol 117:1536-1544, 2006.
2. Barker AT, Freeston IL, Jalinous R, Jarratt JA: Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of an initial clinical evaluation. Neurosurgery 20:100-109, 1987.
3. Barker AT, Jalinous R, Freeston IL: Noninvasive magnetic stimulation of human motor cortex. Lancet 1:1106-1107, 1985. 4. Belci M, Catley M, Husain M, Frankel HL, Davey NJ: Magnetic brain stimulation can improve clinical outcome in incomplete spinal cord injured patients. Spinal Cord 42:417-419, 2004. 5. Cantello R, Gianelli M, Civardi C, Mutani R: Magnetic brain stimulation: the silent period after the motor evoked potential. Neurology 42: 1951-1959, 1992. 6. Centonze D, Koch G, Versace V, Mori F, Rossi S, Brusa L, Grossi K, Torelli F, Prosperetti C, Cervellino A, Marfia GA, Stanzione P, Marciani MG, Boffa L, Bernardi G: Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis. Neurology 68: 1045-1050, 2007. 7. Claus D: Central motor conduction: method and normal results. Muscle Nerve 13:1125-1132, 1990. 8. Claus D, Harding AE, Hess CW, Mills KR, Murray NM, Thomas PK: Central motor conduction in degenerative ataxic disorders: a magnetic stimulation study. J Neurol Neurosurg Psychiatry 51:790-795, 1988. 9. Defrin R, Grunhaus L, Zamir D, Zeilig G: The effect of a series of repetitive transcranial magnetic stimulations of the motor cortex on central pain after spinal cord injury. Arch Phys Med Rehabil 88:1574-1580, 2007. 10. Demoule A, Morelot-Panzini C, Prodanovic H, Cracco C, Mayaux J, Duguet A, Similowski T: Identification of prolonged phrenic nerve conduction time in the ICU: magnetic versus electrical stimulation. Intensive Care Med 37: 1962-1968, 2011. 11. Dietz V: Gait disorder in spasticity and Parkinson’s disease. Adv Neurol 87:143-154, 2001. 12. Dimitrijevic MR, Kofler M, McKay WB, Sherwood AM, Van der Linden C, Lissens MA: Early and late lower limb motor evoked potentials elicited by transcranial magnetic motor cortex stimulation. Electroencephalogr Clin Neurophysiol 85:365-373, 1992. 13. Dominkus M, Grisold W, Jelinek V: Transcranial electrical motor evoked potentials as a prognostic indicator for motor recovery in stroke patients. J Neurol Neurosurg Psychiatry 53:745-748, 1990. 14. Ellaway PH, Catley M, Davey NJ, Kuppuswamy A, Strutton P, Frankel HL, Jamous A, Savic G: Review of physiological motor outcome measures in spinal cord injury using transcranial magnetic stimulation and spinal reflexes. J Rehabil Res Dev 44:69-76, 2007. 15. Hess CW, Mills KR, Murray NM: Responses in small hand muscles from magnetic stimulation of the human brain. J Physiol 388:397-419, 1987. 16. Hummelsheim H, Hauptmann B, Neumann S: Influence of physiotherapeutic facilitation techniques on motor evoked potentials in centrally paretic hand extensor muscles. Electroencephalogr Clin Neurophysiol 97:18-28, 1995.
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17. Inghilleri M, Berardelli A, Cruccu G, Manfredi M: Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction. J Physiol 466:521-534, 1993. 18. Jacobs MJ, Mess W, Mochtar B, Nijenhuis RJ, Statius van Eps RG, Schurink GW: The value of motor evoked potentials in reducing paraplegia during thoracoabdominal aneurysm repair. J Vasc Surg 43:239-246, 2006. 19. Jensen MP, Hoffman AJ, Cardenas DD: Chronic pain in individuals with spinal cord injury: a survey and longitudinal study. Spinal Cord 43: 704-712, 2005. 20. Kang BS, Shin HI, Bang MS: Effect of repetitive transcranial magnetic stimulation over the hand motor cortical area on central pain after spinal cord injury. Arch Phys Med Rehabil 90:1766-1771, 2009. 21. Khedr EM, Kotb H, Kamel NF, Ahmed MA, Sadek R, Rothwell JC: Longlasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain. J Neurol Neurosurg Psychiatry 76:833-838, 2005. 22. Kikuchi S, Mochizuki H, Moriya A, NakataniEnomoto S, Nakamura K, Hanajima R, Ugawa Y: Ataxic hemiparesis: neurophysiological analysis by cerebellar transcranial magnetic stimulation. Cerebellum 11:259-263, 2012. 23. Kumru H, Murillo N, Samso JV, Valls-Sole J, Edwards D, Pelayo R, Valero-Cabre A, Tormos JM, Pascual-Leone A: Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury. Neurorehabil Neural Repair 24:435-441, 2010. 24. Kuppuswamy A, Balasubramaniam AV, Maksimovic R, Mathias CJ, Gall A, Craggs MD, Ellaway PH: Action of 5 Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in human spinal cord injury. Clin Neurophysiol 122:2452-2461, 2011. 25. Lefaucheur JP, Drouot X, Menard-Lefaucheur I, Zerah F, Bendib B, Cesaro P, Keravel Y, Nguyen JP: Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry 75:612-616, 2004. 26. Liepert J: Transcranial magnetic stimulation in neurorehabilitation. Acta Neurochir Suppl 93: 71-74, 2005. 27. Linden D, Berlit P: Magnetic motor evoked potentials (MEP) in diseases of the spinal cord. Acta Neurol Scand 90:348-353, 1994. 28. Lissens MA: Motor evoked potentials of the human diaphragm elicited through magnetic transcranial brain stimulation. J Neurol Sci 124: 204-207, 1994.
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29. Lissens MA, Vanderstraeten GG: Motor evoked potentials of the respiratory muscles in tetraplegic patients. Spinal Cord 34:673-678, 1996.
prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103: 249-257, 2003.
30. Lo YL, Fook-Chong S: Magnetic brainstem stimulation of the facial nerve. J Clin Neurophysiol 24: 44-47, 2007.
43. Tassinari CA, Michelucci R, Forti A, Plasmati R, Troni W, Salvi F, Blanco M, Rubboli G: Transcranial magnetic stimulation in epileptic patients: usefulness and safety. Neurology 40:11321-11323, 1990.
31. Macdonald DB, Al Zayed Z, Al Saddigi A: Four-limb muscle motor evoked potential and optimized somatosensory evoked potential monitoring with decussation assessment: results in 206 thoracolumbar spine surgeries. Eur Spine J 16:171-187, 2007. 32. Maynard FM, Karunas RS, Waring WP: Epidemiology of spasticity following traumatic spinal cord injury. Arch Phys Med Rehabil 71:566-569, 1990. 33. Merton PA, Morton HB: Stimulation of the cerebral cortex in the intact human subject. Nature 285:227, 1980. 34. Meyer B, Zentner J: Do motor evoked potentials allow quantitative assessment of motor function in patients with spinal cord lesions? Eur Arch Psychiatry Clin Neurosci 241:201-204, 1992. 35. Misra UK, Mathur VN, Kalita J: Central motor conduction in motor neuron disease. Electromyogr Clin Neurophysiol 35:485-490, 1995. 36. Nowak DA, Linder S, Topka H: Diagnostic relevance of transcranial magnetic and electric stimulation of the facial nerve in the management of facial palsy. Clin Neurophysiol 116:2051-2057, 2005. 37. Perez MA, Lungholt BK, Nielsen JB: Short-term adaptations in spinal cord circuits evoked by repetitive transcranial magnetic stimulation: possible underlying mechanisms. Exp Brain Res 162:202-212, 2005.
44. Ugawa Y, Terao Y, Hanajima R, Sakai K, Furubayashi T, Machii K, Kanazawa I: Magnetic stimulation over the cerebellum in patients with ataxia. Electroencephalogr Clin Neurophysiol 104: 453-458, 1997. 45. Urban PP: Transcranial magnetic stimulation in brainstem lesions and lesions of the cranial nerves. Suppl Clin Neurophysiol 56:341-357, 2003. 46. Valero-Cabre A, Oliveri M, Gangitano M, PascualLeone A: Modulation of spinal cord excitability by subthreshold repetitive transcranial magnetic stimulation of the primary motor cortex in humans. Neuroreport 12:3845-3848, 2001. 47. Valle AC, Dionisio K, Pitskel NB, PascualLeone A, Orsati F, Ferreira MJ, Boggio PS, Lima MC, Rigonatti SP, Fregni F: Low and high frequency repetitive transcranial magnetic stimulation for the treatment of spasticity. Dev Med Child Neurol 49:534-538, 2007. 48. Wassermann EM, Zimmermann T: Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps. Pharmacol Ther 133:98-107, 2012. 49. Zentner J: Noninvasive motor evoked potential monitoring during neurosurgical operations on the spinal cord. Neurosurgery 24:709-712, 1989.
38. Piron L, Piccione F, Tonin P, Dam M: Clinical correlation between motor evoked potentials and gait recovery in poststroke patients. Arch Phys Med Rehabil 86:1874-1878, 2005.
50. Zentner J, Rieder G: Diagnostic significance of motor evoked potentials in space-occupying lesions of the brain stem and spinal cord. Eur Arch Psychiatry Neurol Sci 239:285-289, 1990.
39. Quartarone A, Bagnato S, Rizzo V, Morgante F, Sant’angelo A, Battaglia F, Messina C, Siebner HR, Girlanda P: Distinct changes in cortical and spinal excitability following highfrequency repetitive TMS to the human motor cortex. Exp Brain Res 161:114-124, 2005.
51. Zifko U, Remtulla H, Power K, Harker L, Bolton CF: Transcortical and cervical magnetic stimulation with recording of the diaphragm. Muscle Nerve 19:614-620, 1996.
40. Rossi S, Hallett M, Rossini PM, Pascual-Leone A: Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 120:2008-2039, 2009.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 11 July 2012; accepted 11 January 2013; published online 12 January 2013
41. Saisanen L, Pirinen E, Teitti S, Kononen M, Julkunen P, Maatta S, Karhu J: Factors influencing cortical silent period: optimized stimulus location, intensity and muscle contraction. J Neurosci Methods 169:231-238, 2008.
Available online: www.sciencedirect.com
42. Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ: A longitudinal study of the
1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY 83 [2]: 232-235, FEBRUARY 2015
Citation: World Neurosurg. (2015) 83, 2:232-235. http://dx.doi.org/10.1016/j.wneu.2013.01.043 Journal homepage: www.WORLDNEUROSURGERY.org
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Transcranial Magnetic Stimulation After Spinal Cord Injury Basem I. Awad1,2, Margaret A. Carmody3, Xiaoming Zhang4, Vernon W. Lin4, Michael P. Steinmetz2
Key words Rehabilitation - Spinal cord injury - Transcranial magnetic stimulation -
Abbreviations and Acronyms CMCT: Central motor conduction time MEP: Motor-evoked potential rTMS: Repetitive transcranial magnetic stimulation SCI: Spinal cord injury TMS: Transcranial magnetic stimulation From the 1Department of Neurosurgery, Mansoura University School of Medicine, Mansoura, Egypt; 2Department of Neurosciences, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA; 3Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; and 4Department of Physical Medicine and Rehabilitation, Cleveland Clinic, Cleveland, Ohio, USA To whom correspondence should be addressed: Michael P. Steinmetz, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 83, 2:232-235. http://dx.doi.org/10.1016/j.wneu.2013.01.043 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com
- OBJECTIVE:
To review the basic principles and techniques of transcranial magnetic stimulation (TMS) and provide information and evidence regarding its applications in spinal cord injury clinical rehabilitation.
- METHODS:
A review of the available current and historical literature regarding TMS was conducted, and a discussion of its potential use in spinal cord injury rehabilitation is presented.
- RESULTS:
TMS provides reliable information about the functional integrity and conduction properties of the corticospinal tracts and motor control in the diagnostic and prognostic assessment of various neurological disorders. It allows one to follow the evolution of motor control and to evaluate the effects of different therapeutic procedures. Motor-evoked potentials can be useful in follow-up evaluation of motor function during treatment and rehabilitation, specifically in patients with spinal cord injury and stroke. Although studies regarding somatomotor functional recovery after spinal cord injury have shown promise, more trials are required to provide strong and substantial evidence.
- CONCLUSIONS:
TMS is a promising noninvasive tool for the treatment of spasticity, neuropathic pain, and somatomotor deficit after spinal cord injury. Further investigation is needed to demonstrate whether different protocols and applications of stimulation, as well as alternative cortical sites of stimulation, may induce more pronounced and beneficial clinical effects.
1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
INTRODUCTION More than 30 years ago, Merton asked Morton to build a high-voltage electrical stimulator that would have the ability to activate muscle directly rather than through small nerve branches. Once built, he had the idea that this device could also stimulate the motor areas of the human brain through intact scalp, that is, transcranial electrical stimulation (33). A brief, highvoltage electric shock applied over the primary motor cortex produced a brief, relatively synchronous muscle response. From that point forward, it was clear that transcranial electrical stimulation would prove valuable. However, it required large electric currents to be applied for a small proportion to penetrate into the patient’s brain, which would lead to painful contractions of scalp muscles and activation of sensory receptors in the skin. Five years later, Barker et al. (3) developed the principle of inductance (discovered by
232
www.SCIENCEDIRECT.com
Michael Faraday in 1838) to transmit electrical energy across the scalp and skull through magnetic stimulation (transcranial magnetic stimulation, or TMS). TMS provided the same effect without the pain associated with percutaneous electrical stimulation. Since its introduction as a noninvasive method of brain stimulation, the use of TMS has spread widely in clinical practice. In this article we review the basic principles and techniques of repetitive TMS (rTMS) and provide information and evidence regarding its applications in the clinical rehabilitation of patients with spinal cord injury (SCI). BASIC PRINCIPLES OF TMS When a time-varying magnetic field is applied in the vicinity of a conductive structure, it induces an electrical field, the amplitude of which is related to the rate of change of the magnetic field and to the geometry of the conductive structure. This electrical field creates a current that, if of
appropriate amplitude and duration, can stimulate neuromuscular tissue as if it had been produced by electrodes (2). The magnetic fields generated from the motor cortex are able to pass through high-resistance structures such as bone, fat, skin, and clothing. Because TMS is noninvasive and painless, the number of clinical studies has increased over past decades, and many clinical applications have become available (48, 40, 14). The technique provides reliable information about the functional integrity and conduction properties of the corticospinal tracts and motor control in the diagnostic and prognostic assessment of various neurological disorders. It allows one to follow the evolution of motor control and to evaluate the effects of different therapeutic procedures. PHYSIOLOGICAL MECHANISMS When TMS is applied to the motor cortex at appropriate stimulation intensity, motorevoked potentials (MEPs) can be recorded
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2013.01.043
PEER-REVIEW REPORTS BASEM I. AWAD ET AL.
from contralateral extremity muscles. Motor threshold refers to the lowest TMS intensity necessary to evoke MEPs in the target muscle when single-pulse stimuli are applied to the motor cortex. When the central nervous system is stimulated, the stimulation threshold can be reduced by approximately 25%, the response amplitude can be increased, and the response latency reduced by some 1e3 ms through preactivation of the target muscle. This technique is referred to as “facilitation.” The phenomenon of facilitation was noted in an early stage of the original transcutaneous electrical stimulation studies of Merton and Morton and is equally prominent with magnetic brain stimulation (15). Compared with those of electrical stimulation, muscle responses to magnetic stimulation show longer onset latency by approximately 2 ms (in hand muscles), simpler waveform, shorter duration, and larger amplitude. These differences indicate that electrical and magnetic stimulation activates the motor pathways at different sites. Electrical stimulation excites corticospinal neurons directly, causing an initial D-wave and subsequent I-wave volleys, and magnetic stimulation acts transsynaptically, the better synchronized and longer latency response being caused by a more homogeneous site of excitation resulting in I waves, but no D wave, impinging on the spinal motor neuron. Another phenomenon (inhibitory) is the interruption of the ongoing voluntary muscle contraction produced by TMS of the motor cortex. When an individual is instructed to maintain muscle contraction and a single suprathreshold TMS pulse is applied to the motor cortex contralateral to the target muscle, the electromyographic activity is arrested for a few hundred milliseconds after the MEP. This period of electromyographic suppression is referred to as a silent period. This silent period is produced by a mixture of cortical and spinal inhibitory effects. Approximately the first 50 ms of the silent period are caused by both cortical and spinal mechanisms. From this point onward, spinal mechanisms are progressively less important, and the cortical inhibitory mechanisms act on the neural elements of the corticomotoneuronal system at motor cortical level: a magnetic stimulus given during the second half of the silent period does not produce MEP whereas electrical stimulation evokes almost
TMS AFTER SPINAL CORD INJURY
unchanged muscle responses. In other words, the unexcitability of the motor cortex after a second magnetic stimulus indicates that the motor cortex per se is inhibited, whereas the excitability with electrical stimulation implies that corticospinal axons and spinal motor neurons are not inhibited (5, 17, 41). Depending on the purpose of the test, there are many important parameters that can be measured in cortical stimulation, such as stimulation threshold, MEP latency, MEP amplitude, response morphology, central motor conduction time (CMCT), silent period duration, fatigue, intracortical inhibitory, and excitatory pathways. CMCT is defined as the latency difference between the MEPs induced by stimulation of the motor cortex and those evoked by spinal (motor root) stimulation and are calculated by subtracting the latency of the motor potential induced by stimulation of the spinal motor root from that of the response to motor cortex stimulation. CMCT can be calculated by subtracting the latency in response to spinal root stimulation from the latency in response to cortical stimulation (7, 35). The CMCT measurement can provide supporting evidence for the diagnosis and also can be used as an objective marker of disease progression and prognosis. MEP amplitude can be affected by the type of cortical stimulator (high-voltage electrical or magnetoelectrical) and by the stimulus intensity, as well as the activation of other muscles. MEP amplitude reflects not only the integrity of the corticospinal tract but also the excitability of motor cortex and nerve roots and the conduction along the peripheral motor pathway to the muscles. Patients with dysfunction at any level along the corticospinal pathway may display abnormal MEPs, whereas the presence of intact MEPs suggests integrity of the pyramidal tract. For example, contralateral MEPs acutely after a stroke relate to a favorable recovery, whereas the absence of MEPs suggests a poor outcome. CMCT can be increased and MEP amplitude reduced by several factors, such as reduced excitability of the motor cortex, slowed conduction between the motor cortex and spinal motor neurons, several factors at the motor neuron level, and reduced conduction velocities in motor axons.
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USES OF TMS AS A DIAGNOSTIC TOOL TMS delivered to different levels of the motor system (neuroaxis) can provide information about the excitability of the motor cortex; the functional integrity of intracortical neuronal structures; the conduction along corticospinal, corticonuclear, and callosal fibers; as well as the function of nerve roots and peripheral motor pathways to the muscles. The pattern of findings in these studies can help to localize the level of a lesion within the nervous system, distinguish between a predominantly demyelinating or axonal lesion in the motor tracts, or predict the functional motor outcome after an injury. The abnormalities revealed by TMS are not disease-specific, and the results should be interpreted in the context of other clinical data. Clinical applications of TMS include spinal cord injury, multiple sclerosis, anterior horn cell disorders, spondylotic myelopathy, stroke, various neuropathies, epilepsy (43), degenerative ataxic disorders such as cerebellar ataxia and Friedreich ataxia (8, 22, 44), cranial nerve disorders (mainly the facial nerve) (30, 36, 45), pathology of the respiratory muscles, and several others. It can also be used in the operating room, where monitoring motor conduction is a useful indicator of the integrity of the central motor pathways, specifically during neurosurgical operations (18, 31, 49), as well as in the intensive care unit (10). In SCI, good correlation was seen between MEP findings and motor function (12, 34, 50). Decreased MEP amplitudes or absent MEP responses are seen more frequently in neoplastic than inflammatory lesions, whereas in the latter increased latencies are seen more often (27). In high tetraplegic patients in whom the diaphragm is affected, MEPs can be recorded from the diaphragm as well as from other respiratory muscles to investigate the central motor conduction properties of the musculature (28, 29, 51). USE OF TMS AS A CLINICAL REHABILITATION TOOL AFTER SCI Neuropathic pain in patients with SCI is resistant to most treatments and has considerable impact on their quality of life (19, 42). Recently, studies of rTMS applied to the motor cortex that correspond to
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pain areas suggest that it has potential as a therapeutic tool to relieve chronic neuropathic pain (1, 9, 21, 25). Defrin et al. (9) studied the effect of rTMS on neuropathic pain after SCI. They applied the rTMS to the legs of paraplegic patients with chronic neuropathic pain. Targeting the areas that represented the leg, they used a figure-of-eight coil to stimulate the cortex. Pain reduction was demonstrated in both the real and sham rTMS groups, but no significant difference was documented. Kang et al. (20) also evaluated the analgesic effect of rTMS when applied to the hand motor cortical area in patients with SCI who had chronic neuropathic pain at multiple sites in the body. The average pain intensity during the subsequent 24 hours did not differ between the real and sham rTMS treatment groups, and therefore, the therapeutic efficacy of rTMS was not demonstrated. Spasticity is also a common disorder in patients with SCI. Its prevalence is reported to be approximately 65%e78% in this population (32). Spasticity is a major cause of long-term disability and significantly impacts daily activities and quality of life. A major challenge in rehabilitation is to induce active movement in the paretic extremities and reduce spasticity, which is hardly affected by traditional spasmolytic drugs (11). Previous authors have shown that highfrequency rTMS applied over the primary motor cortex can reduce H-reflex size in healthy subjects (37, 39, 46) and reduce spasticity in patients with multiple sclerosis (6), cerebral palsy and spastic quadriplegia (47). Kumru et al. (23) hypothesized that increasing the excitability of the primary motor cortex would modify descending corticospinal influences and increase inhibitory input, which would then reduce segmental spinal excitability and thus reduce limb spasticity in patients with incomplete SCI. All patients tolerated the high-frequency stimulation without complication or report of adverse effects, with the exception of three patients, who complained of facial twitching during the first session of active stimulation. Furthermore, all patients showed a significant and consistent clinical improvement in spasticity for at least 1 week after 5 days of daily rTMS sessions. However, they failed to demonstrate neurophysiologic changes after the intervention.
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Belci et al. (4) examined somatomotor functional recovery in patients after incomplete SCI. They showed short term reduction in cortical inhibition during treatment with rTMS, as well as improved ASIA impairment scale measures of sensory and motor function and improved hand function that lasted into a recovery period. Furthermore, Kuppuswamy et al. (24) assessed the effectiveness of physiological outcome measures in detecting functional change in the degree of impairment of SCI after rTMS of the sensorimotor cortex. They reported no significant differences in American Spinal Injury Association impairment scale outcomes between real and sham rTMS. The Action Research Arm Test was increased at 1 hour after rTMS compared with baseline. Active motor threshold for the most caudally innervated hand muscle was increased at 72 and 120 hours compared with baseline. Persistent reductions in electrical perceptual test to rTMS occurred in two individuals. These changes in cortical motor threshold measures may add support to the idea of functional gain after rTMS in SCI patients.
CONCLUSION MEPs can be useful in follow-up evaluation of motor function during treatment and rehabilitation, specifically in patients with SCI and strokes. This is not only useful for the therapeutic staff but also improves patient motivation (13, 16, 26, 38). The enhancement of motor excitability is also associated with an improvement of motor function. Further investigation is needed to demonstrate whether different protocols and applications of stimulation, as well as alternative cortical sites of stimulation may induce more pronounced and beneficial clinical effects. REFERENCES 1. Andre-Obadia N, Peyron R, Mertens P, Mauguiere F, Laurent B, Garcia-Larrea L: Transcranial magnetic stimulation for pain control: double blind study of different frequencies against placebo, and correlation with motor cortex stimulation efficacy. Clin Neurophysiol 117:1536-1544, 2006.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 11 July 2012; accepted 11 January 2013; published online 12 January 2013
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