Abstract
We used transcranial magnetic stimulation (TMS) of motor cortex, including a novel four-pulse superconditioning (TMSsc) paradigm, in repeated examinations of motor-evoked potentials (MEPs) in eight subjects with motor neuron disease (MND), including seven with amyotrophic lateral sclerosis (ALS). The goals were: (1) to look for evidence of cortical hyperexcitability, including a reduction in short-interval intracortical inhibition (SICI); and (2) to examine the utility of using TMSsc for quantifying upper motor neuron function during MND progression. Testing of abductor pollicis brevis (APB) and tibialis anterior (TA) muscles bilaterally was carried out every 3 months in MND subjects for up to 2 years; results were compared to those from a cohort of 15 control subjects. Measures of SICI were not significantly different between control and MND subjects for either APB or TA muscles. Other measures of cortical excitability, including TMS threshold and MEP amplitude, were consistent with lowered cortical excitability in MND subjects. Certain combinations of superconditioning TMS were capable of causing stronger inhibition or facilitation of MEPs compared to dual-pulse TMS, for both APB and TA target muscles. Moreover, there were multiple cases in which target muscles unresponsive to strong single-pulse TMS, whether at rest or when tested with an active contraction, showed an MEP in response to TMSsc optimized for facilitation. Our findings suggest that a multi-faceted neurophysiologic protocol for examining upper motor neuron function in MND subjects might benefit from inclusion of TMSsc testing.
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References
Attarian S, Pouget J, Schmied A (2009) Changes in cortically induced inhibition in amyotrophic lateral sclerosis with time. Muscle Nerve 39:310–317
Awiszus F, Feistner H (1995) Comparison of single motor unit responses to transcranial magnetic and peroneal nerve stimulation in the tibialis anterior muscle of patients with amyotrophic lateral sclerosis. Electroencephalogr Clin Neurophysiol 97:90–95
Awiszus F, Feistner H, Urbach D, Bostock H (1999) Characterisation of paired-pulse transcranial magnetic stimulation conditions yielding intracortical inhibition or I-wave facilitation using a threshold-hunting paradigm. Exp Brain Res 129:317–324
Bakkar N, Boehringer A, Bowser R (2015) Use of biomarkers in ALS drug development and clinical trials. Brain Res 1607:94–107. https://doi.org/10.1016/j.brainres.2014.10.031
Bawa P, Calancie B (2004) Rate-coding of spinal motoneurons with high frequency magnetic stimulation of human motor cortex. Can J Physiol Pharmacol 82:740–748
Berardelli A, Inghilleri M, Cruccu G, Mercuri B, Manfredi M (1991) Electrical and magnetic transcranial stimulation in patients with corticospinal damage due to stroke or motor neurone disease. Electroencephalogr Clin Neurophysiol 81:389–396
Bickford RG, Guidi M, Fortesque P, Swenson M (1987) Magnetic stimulation of human peripheral nerve and brain: response enhancement by combined magnetoelectrical technique. Neurosurgery 20:110–116
Brasil-Neto JP, McShane LM, Fuhr P, Hallett M, Cohen LG (1992) Topographic mapping of the human motor cortex with magnetic stimulation: factors affecting accuracy and reproducibility. Electroencephalogr Clin Neurophysiol 85:9–16
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron D (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299
Butefisch CM, Netz J, Wessling M, Seitz RJ, Hömberg V (2003) Remote changes in cortical excitability after stroke. Brain 126:470–481
Calancie B (2017) Intraoperative neuromonitoring and alarm criteria for judging MEP responses to transcranial electric stimulation: the threshold-level method. J Clin Neurophysiol 34:12–21. https://doi.org/10.1097/WNP.0000000000000339
Calancie B, Molano MDR, Broton JG, Bean JA (2001) Relationship between EMG and muscle force after spinal cord injury. J Spinal Cord Med 24:19–25
Calancie B, Wang D, Young E, Alexeeva N (2018) Four-pulse transcranial magnetic stimulation using multiple conditioning inputs. Normative MEP responses. Exp Brain Res 236:1205–1218. https://doi.org/10.1007/s00221-018-5212-8
Caramia MD, Cicinelli P, Paradiso C, Mariorenzi R, Zarola F, Bernardi G, Rossini PM (1991) Excitability changes of muscular responses to magnetic brain stimulation in patients with central motor disorders. Electroencephalogr Clin Neurophysiol 81:243–250
Caramia MD, Palmieri MG, Desiato MT, Iani C, Scalise A, Telera S, Bernardi G (2000) Pharmacologic reversal of cortical hyperexcitability in patients with ALS. Neurology 54:58–64
de Carvalho M, Scotto M, Swash M (2007) Clinical patterns in progressive muscle atrophy (PMA): a prospective study. Amyotroph Lateral Scler 8(5):296–299
de Carvalho M, Dengler R, Eisen A et al (2008) Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 119:497–503
Di Lazzaro V, Restuccia D, Oliviero A et al (1998) Magnetic transcranial stimulation at intensities below active motor threshold activates intracortical inhibitory circuits. Exp Brain Res 119:265–268
Di Lazzaro V, Dileone M, Pilato F et al (2006) Repetitive transcranial magnetic stimulation for ALS. A preliminary controlled study. Neurosci Lett 408:135–140. https://doi.org/10.1016/j.neulet.2006.08.069
Dubach P, Guggisberg AG, Rosler KM, Hess CW, Mathis J (2004) Significance of coil orientation for motor evoked potentials from nasalis muscle elicited by transcranial magnetic stimulation. Clin Neurophysiol 115:862–870. https://doi.org/10.1016/j.clinph.2003.11.033
Eisen A, Pant B, Stewart H (1993) Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci 20:11–16
Eisen A, Entezari-Taher M, Stewart H (1996) Cortical projections to spinal motoneurons: changes with aging and amyotrophic lateral sclerosis. Neurology 46:1396–1404
Enterzari-Taher M, Eisen A, Stewart H, Nakajima M (1997) Abnormalities of cortical inhibitory neurons in amyotrophic lateral sclerosis. Muscle Nerve 20:65–71
Fischer U, Hess CW, Rosler KM (2005) Uncrossed cortico-muscular projections in humans are abundant to facial muscles of the upper and lower face, but may differ between sexes. J Neurol 252:21–26. https://doi.org/10.1007/s00415-005-0592-7
Fisher RJ, Nakamura Y, Bestmann S, Rothwell JC, Bostock H (2002) Two phases of intracortical inhibition revealed by transcranial magnetic threshold tracking. Exp Brain Res 143:240–248
Floyd AG, Yu QP, Piboolnurak P et al (2009) Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology 72:498–504. https://doi.org/10.1212/01.wnl.0000341933.97883.a4
Furby A, Bourriez JL, Jacquesson JM, Mounier-Vehier F, Guieu JD (1992) Motor evoked potentials to magnetic stimulation: technical considerations and normative data from 50 subjects. J Neurol 239:152–156
Geevasinga N, Menon P, Yiannikas C, Kiernan MC, Vucic S (2014) Diagnostic utility of cortical excitability studies in amyotrophic lateral sclerosis. Eur J Neurol 21:1451–1457
Groiss SJ, Mochizuki H, Hanajima R, Trenado C, Nakatani-Enomoto S, Otani K, Ugawa Y (2017) Impairment of triad conditioned facilitation in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 18:604–610. https://doi.org/10.1080/21678421.2017.1321676
Hanajima R, Ugawa Y, Terao Y, Ogata K, Kanazawa I (1996) Ipsilateral cortico-cortical inhibition of the motor cortex in various neurological disorders. J Neurol Sci 140:109–116
Hanajima R, Ugawa Y, Terao Y, Sakai K, Furubayashi T, Machii K, Kanazawa I (1998) Paired-pulse magnetic stimulation of the human motor cortex: differences among I waves. J Physiol 509(Pt 2):607–618
Hufnagel A, Jaeger M, Elger CE (1990) Transcranial magnetic stimulation: specific and non-specific facilitation of magnetic motor evoked potentials. J Neurol 1990:416–419
Keel JC, Smith MJ, Wassermann EM (2001) A safety screening questionnaire for transcranial magnetic stimulation. Clin Neurophysiol 112:720
Kiers L, Cros D, Chiappa KH, Fang J (1993) Variability of motor potentials evoked by transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol 89:415–423
Kohara N, Kaji R, Kojima Y et al (1996) Abnormal excitability of the corticospinal pathway in patients with amyotrophic lateral sclerosis: a single motor unit study using transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol 101:32–41
Kujirai T, Caramia MD, Rothwell JC et al (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519
Mills KR (1995) Motor neuron disease. Studies of the corticospinal excitation of single motor neurons by magnetic brain stimulation. Brain 118(Pt 4):971–982
Mills KR (2003) The natural history of central motor abnormalities in amyotrophic lateral sclerosis. Brain 126:2558–2566
Mills KR, Nithi KA (1997a) Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve 20:1137–1141
Mills KR, Nithi KA (1997b) Corticomotor threshold to magnetic stimulation: normal values and repeatability. Muscle Nerve 20:570–576
Mitsumoto H, Brooks BR, Silani V (2014) Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 13:1127–1138
Munneke MA, Rongen JJ, Overeem S, Schelhaas HJ, Zwarts MJ, Stegeman DF (2013) Cumulative effect of 5 daily sessions of theta burst stimulation on corticospinal excitability in amyotrophic lateral sclerosis. Muscle Nerve 48:733–738
Ni Z, Chen R (2008) Short-interval intracortical inhibition: a complex measure. Clin Neurophysiol 119:2175–2176
Nihei K, McKee AC, Kowall NW (1993) Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol 86:55–64
Paradiso GO, Cunic DI, Gunraj CA, Chen R (2005) Representation of facial muscles in human motor cortex. J Physiol 567:323–336
Peurala SH, Muller-Dahlhaus JF, Arai N, Ziemann U (2008) Interference of short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF). Clin Neurophysiol 119:2291–2297. https://doi.org/10.1016/j.clinph.2008.05.031
Sasaki S, Iwata M (2000) Immunocytochemical and ultrastructural study of the motor cortex in patients with lower motor neuron disease. Neurosci Lett 281:45–48
Schady W, Dick JPR, Sheard A, Crampton S (1991) Cental motor conduction studies in hereditary spastic paralegia. J Neurol Neurosurg Psychiatry 54:775–779
Schmied A, Attarian S (2008) Enhancement of single motor unit inhibitory responses to transcranial magnetic stimulation in amyotrophic lateral sclerosis. Exp Brain Res 189:229–242
Schriefer TN, Hess CW, Mills KR, Murray NMF (1989) Central motor conduction studies in motor neurone disease using magnetic brain stimulation. Electroencephalogr Clin Neurophysiol 74:431–437
Stefan K, Kunesch E, Benecke R, Classen J (2001) Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis. Ann Neurol 49:536–539
Swash M (1998) Early diagnosis of ALS/MND. J Neurol Sci 160(Suppl 1):S33–S36
Swash M, Ingram D (1988) Preclinical and subclinical events in motor neuron disease. J Neurol Neurosurg Psychiatry 51:165–168
Triggs WJ, Menkes D, Onorato J et al (1999) Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease. Neurology 53:605–611
Turner MR, Kiernan MC, Leigh PN, Talbot K (2009) Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 8:94–109. https://doi.org/10.1016/S1474-4422(08)70293-X
Uozumi T, Tsuji S, Murai Y (1991) Motor potentials evoked by magnetic stimulation of the motor cortex in normal subjects and patients with motor disorders. Electroencephalogr Clin Neurophysiol 81:251–256
Urban PP, Wicht S, Hopf HC (2001) Sensitivity of transcranial magnetic stimulation of cortico-bulbar vs. cortico-spinal tract involvement in amyotrophic lateral sclerosis (ALS). J Neurol 248:850–855
Van den Bos MAJ, Higashihara M, Geevasinga N, Menon P, Kiernan MC, Vucic S (2018) Imbalance of cortical facilitatory and inhibitory circuits underlies hyperexcitability in ALS. Neurology 91:e1669–e1676. https://doi.org/10.1212/WNL.0000000000006438
Vucic S, Kiernan MC (2006) Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 129:2436–2446. https://doi.org/10.1093/brain/awl172
Vucic S, Nicholson GA, Kiernan MC (2008) Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131:1540–1550. https://doi.org/10.1093/brain/awn071
Vucic S, Cheah BC, Kiernan MC (2009) Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis. Exp Neurol 220:177–182. https://doi.org/10.1016/j.expneurol.2009.08.017
Vucic S, Cheah BC, Yiannikas C, Kiernan MC (2011) Cortical excitability distinguishes ALS from mimic disorders. Clin Neurophysiol 122:1860–1866
Yokota T, Yoshino A, Inaba A, Saito Y (1996) Double cortical stimulation in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 61:596–600
Ziemann U, Rothwell JC, Ridding MC (1996) Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 496:873–881
Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W (1997) Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology 49:1292–1298
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Calancie, B., Young, E., Watson, M.L. et al. Superconditioning TMS for examining upper motor neuron function in MND. Exp Brain Res 237, 2087–2103 (2019). https://doi.org/10.1007/s00221-019-05573-4
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DOI: https://doi.org/10.1007/s00221-019-05573-4