**5. Conclusions and future perspectives**

Motor cortex hyperexcitability in ALS patients is a well-studied phenomenon that can be of significant interest as a biomarker of neurodegeneration. However, despite the large number of studies, the reasons and sequelae currently remain poorly studied. Since motor cortex hyperexcitability in ALS patients was first described, this phenomenon has been attributed to the development of excitotoxicity and weakening of inhibitory neurotransmission in the neocortex, thus ensuring its pathogenetic role in the development of neurodegeneration. However, no direct evidence to the fact that motor cortex hyperexcitability in ALS patients attests to development of excitotoxicity and precedes its degeneration has been obtained yet. Meanwhile, hyperexcitability can be one of the mechanisms of neuroplastic alterations, thus having the compensatory (sanogenetic) rather than pathogenetic value. This theory has been supported by the data on interaction between decreased motor cortex excitability and neuro‐ plasticity in the norm and in some pathologic conditions such as Alzheimer's disease and vascular dementia. Furthermore, expansion of the cortical representation of certain muscles was demonstrated for ALS patients in fMRI and nTMS studies, which can be a manifestation of neuroplasticity and related to increased motor cortex excitability.

It should be mentioned that hyperexcitability is not a specific sign of ALS and is also revealed in other neurodegenerative diseases. More and more data supporting the similarity between pathophysiology of neurodegeneration in various diseases and its relationship with intracel‐ lular accumulation of abnormal proteins have been obtained. This may result in dysfunction of synaptic connections and a compensatory increase in expression of the genes ensuring increased excitability and synaptic plasticity.

A hypothesis can be put forward based on these data that hyperexcitability plays different roles at different stages of the disease (**Figure 4**). At onset of the disease, this phenomenon can develop via the compensatory mechanism in response to reduced number of functioning motor neurons and disruption of synaptic connections. Hence, increased hyperexcitability can be regarded as a method for maintaining functioning of the system as the number of its components decreases. In addition, hyperexcitability can have a protective effect at the cellular level as it prevents accumulation of pathologically altered proteins. As the disease progresses, hyperexcitability may start to have a pathological effect and induce excitotoxicity. Does this mean that our effect on motor cortex excitability in ALS patients needs to be differentiated depending on disease stage? Further research involving various methods and focusing on patients at different stages of the disease needs to be carried out to answer this question.

Motor Cortex Hyperexcitability, Neuroplasticity, and Degeneration in Amyotrophic Lateral Sclerosis http://dx.doi.org/10.5772/63310 63

**Figure 4.** A link between excitability and function.

## **Author details**

demonstrate that displacement of the boundaries of cortical representation as a result of neuroplastic alterations can be caused by decreased motor cortex excitability. Hence, the phenomenon of motor cortex hyperexcitability can have the compensatory function in ALS

Motor cortex hyperexcitability in ALS patients is a well-studied phenomenon that can be of significant interest as a biomarker of neurodegeneration. However, despite the large number of studies, the reasons and sequelae currently remain poorly studied. Since motor cortex hyperexcitability in ALS patients was first described, this phenomenon has been attributed to the development of excitotoxicity and weakening of inhibitory neurotransmission in the neocortex, thus ensuring its pathogenetic role in the development of neurodegeneration. However, no direct evidence to the fact that motor cortex hyperexcitability in ALS patients attests to development of excitotoxicity and precedes its degeneration has been obtained yet. Meanwhile, hyperexcitability can be one of the mechanisms of neuroplastic alterations, thus having the compensatory (sanogenetic) rather than pathogenetic value. This theory has been supported by the data on interaction between decreased motor cortex excitability and neuro‐ plasticity in the norm and in some pathologic conditions such as Alzheimer's disease and vascular dementia. Furthermore, expansion of the cortical representation of certain muscles was demonstrated for ALS patients in fMRI and nTMS studies, which can be a manifestation

It should be mentioned that hyperexcitability is not a specific sign of ALS and is also revealed in other neurodegenerative diseases. More and more data supporting the similarity between pathophysiology of neurodegeneration in various diseases and its relationship with intracel‐ lular accumulation of abnormal proteins have been obtained. This may result in dysfunction of synaptic connections and a compensatory increase in expression of the genes ensuring

A hypothesis can be put forward based on these data that hyperexcitability plays different roles at different stages of the disease (**Figure 4**). At onset of the disease, this phenomenon can develop via the compensatory mechanism in response to reduced number of functioning motor neurons and disruption of synaptic connections. Hence, increased hyperexcitability can be regarded as a method for maintaining functioning of the system as the number of its components decreases. In addition, hyperexcitability can have a protective effect at the cellular level as it prevents accumulation of pathologically altered proteins. As the disease progresses, hyperexcitability may start to have a pathological effect and induce excitotoxicity. Does this mean that our effect on motor cortex excitability in ALS patients needs to be differentiated depending on disease stage? Further research involving various methods and focusing on patients at different stages of the disease needs to be carried out to answer this question.

patients.

62 Update on Amyotrophic Lateral Sclerosis

**5. Conclusions and future perspectives**

of neuroplasticity and related to increased motor cortex excitability.

increased excitability and synaptic plasticity.

Ilya S. Bakulin, Alexander V. Chervyakov\* , Natalia A. Suponeva, Maria N. Zakharova and Michael A. Piradov

\*Address all correspondence to: tchervyakovav@gmail.com

Research Center of Neurology, Moscow, Russia

#### **References**


[16] Stephens B, Guiloff RJ, Navarrete R, Newman P, Nikhar N, Lewis P. Widespread loss of neuronal populations in the spinal ventral horn in sporadic motor neuron disease. A morphometric study. J. Neurol. Sci. 2006;244(1-2):41–58.

[4] Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimula‐ tion and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg

[5] Menon P, Kiernan MC, Vucic S. Cortical hyperexcitability precedes lower motor neuron dysfunction in ALS. Clin Neurophysiol. 2015;126(4):803–9. DOI: 10.1016/j.clinph.

[6] Zanette G, Tamburin S, Manganotti P, Refatti N, Forgione A, Rizzuto N. Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral

[7] Bae JS, Simon NG, Menon P, Vucic S, Kiernan MC. The puzzling case of hyperexcita‐ bility in amyotrophic lateral sclerosis. J Clin Neurol. 2013;9(2):65–74. DOI: 10.3988/jcn.

[8] King AE, Woodhouse A, Kirkcaldie MT, Vickers JC. Excitotoxicity in ALS: Overstimu‐ lation, or overreaction? Exp Neurol. 2016;275(1):162–71. DOI: 10.1016/j.expneurol.

[9] Blasco H, Mavel S, Corcia P, Gordon PH. The glutamate hypothesis in ALS: patho‐

[10] Fray AE, Ince, PG, Banner SJ, Milton ID, Usher PA, Cookson MR, Shaw PJ. The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease:

[11] Sasaki S, Komori T, Iwata M. Excitatory amino acid transporter 1 and 2 immunoreac‐ tivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol. 2000;100(2):

[12] Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic

[13] Velasco I, Tapia R, Massieu L. Inhibition of glutamate uptake induces progressive accumulation of extracellular glutamate and neuronal damage in rat cortical cultures.

[14] Benkler C, Ben-Zur T, Barhum Y, Offen D. Altered astrocytic response to activation in SOD1(G93A) mice and its implications on amyotrophic lateral sclerosis pathogenesis.

[15] Ince P, Stout N, Shaw P, Slade J, Hunziker W, Heizmann CW, Baimbridge KG. Parvalbumin and calbindin D-28k in the human motor system and in motor neuron

lateral sclerosis (ALS). Proc. Natl. Acad. Sci. U. S. A. 2002;99(3):1604–1609.

physiology and drug development. Curr Med Chem. 2014;21(31):3551–75.

an immunohistochemical study. Eur. J. Neurosci. 1998;10(8):2481–2489.

Psychiatry. 2013;84(10):1161–70. DOI: 10.1136/jnnp-2012-304019.

sclerosis. Clin Neurophysiol. 2002;113(11):1688–97.

2014.04.023.

64 Update on Amyotrophic Lateral Sclerosis

2013.9.2.65.

2015.09.019.

138–44.

J. Neurosci. Res. 1996;44(6):551–561.

Glia. 2013;61(3):312–326. DOI: 10.1002/glia.22428.

disease. Neuropathol. Appl. Neurobiol. 1993;19(4):291–299.


nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015;126(6):1071– 107. DOI: 10.1016/j.clinph.2015.02.001.


[40] Khedr EM, Ahmed MA, Hamdy A, Shawky OA. Cortical excitability of amyotrophic lateral sclerosis: transcranial magnetic stimulation study. Neurophysiol Clin. 2011;41(2):73–9. DOI: 10.1016/j.neucli.2011.03.001.

nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015;126(6):1071–

[28] Di Lazzaro V. Biological effects of non-invasive brain stimulation. Handb Clin Neurol.

[29] Chervyakov AV, Bakulin IS, Savitskaya NG, Arkhipov IV, Gavrilov AV, Zakharova MN, Piradov MA. Navigated transcranial magnetic stimulation in amyotrophic lateral

[30] de Carvalho M, Turkman A, Swash M. 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

[31] Miscio G, Pisano F, Mora G, Mazzini L. Motor neuron disease: usefulness of transcranial magnetic stimulation in improving the diagnosis. Clin Neurophysiol. 1999;110(5):975–

[32] Eisen A, Shytbel W, Murphy K, Hoirch M. Cortical magnetic stimulation in amyotro‐

[33] Mills KR. The natural history of central motor abnormalities in amyotrophic lateral

[34] 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

[35] Urban PP, Wicht S, Hopf HC. Sensitivity of transcranial magnetic stimulation of corticobulbar vs. cortico-spinal tract involvement in Amyotrophic Lateral Sclerosis (ALS). J

[36] Vucic S, Cheah BC, Kiernan MC. Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis. Exp Neurol. 2009;220(1):177–82. DOI:

[37] Caramia MD, Cicinelli P, Paradiso C, Mariorenzi R, Zarola F, Bernardi G, Rossini PM. Excitability changes of muscular responses to magnetic brain stimulation in patients with central motor disorders. Electroencephalogr Clin Neurophysiol. 1991;81(4):243–

[38] Vucic S, Kiernan MC. Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain. 2006;129(Pt 9):2436–

[39] Mills KR, Nithi KA. Corticomotor threshold is reduced in early sporadic amyotrophic

lateral sclerosis. Muscle Nerve. 1997;20(9):1137–41.

2013;2013(116):367-74. DOI: 10.1016/B978-0-444-53497-2.00030-9.

sclerosis. Muscle Nerve. 2015;51(1):125–31. DOI: 10.1002/mus.24345.

phic lateral sclerosis. Muscle Nerve. 1990;13(2):146–51.

sclerosis. Brain. 2003;126(Pt 11):2558–66.

disease. Neurology. 1999;53(3):605–11.

Neurol. 2001;248(10):850–5.

10.1016/j.expneurol.2009.08.017.

107. DOI: 10.1016/j.clinph.2015.02.001.

66 Update on Amyotrophic Lateral Sclerosis

Neurol Sci. 2003;210(1–2):83–90.

81.

50.

46.


[65] Bromberg MB. The cart or the horse first? Did Charcot have it right? Clin Neurophysiol. 2015;126(4):647–8. DOI: 10.1016/j.clinph.2014.07.019.

[52] Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol.

[53] Vucic S, Cheah BC, Yiannikas C, Kiernan MC. Cortical excitability distinguishes ALS from mimic disorders. Clin Neurophysiol. 2011;122(9):1860–6. DOI: 10.1016/j.clinph.

[54] 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

[55] Yokota T, Yoshino A, Inaba A, Saito Y. Double cortical stimulation in amyotrophic

[56] Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S. Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol. 2015;14(5):478–84.

[57] Geevasinga N, Menon P, Yiannikas C, Kiernan MC, Vucic S. Diagnostic utility of cortical excitability studies in amyotrophic lateral sclerosis. Eur J Neurol. 2014;21(12):

[58] Clark R, Blizzard C, Dickson T. Inhibitory dysfunction in amyotrophic lateral sclerosis: future therapeutic opportunities. Neurodegener Dis Manag. 2015;5(6):511–25. DOI:

[59] Martin LJ, Chang Q. Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis. Mol Neurobiol. 2012;45(1):30–42.

[60] Turner MR, Kiernan MC. Does interneuronal dysfunction contribute to neurodegen‐ eration in amyotrophic lateral sclerosis? Amyotroph Lateral Scler 2012;13(3):245–50.

[61] Nihei K, McKee AC, Kowall NW. Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol. (Berl.) 1993;86(1):55–64.

[62] Leroy F, Zytnicki D. Is hyperexcitability really guilty in amyotrophic lateral sclerosis?

[63] van Zundert B, Izaurieta P, Fritz E, Alvarez FJ. Early pathogenesis in the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J Cell Biochem. 2012;113(11):

[64] Jia M, Njapo SA, Rastogi V, Hedna VS. Taming glutamate excitotoxicity: strategic pathway modulation for neuroprotection CNS Drugs. 2015;29(2):153–62. DOI: 10.1007/

Neural Regen Res. 2015;10(9):1413–5. DOI: 10.4103/1673-5374.165308.

transcranial magnetic stimulation. Neurology. 1997;49(5):1292–8.

lateral sclerosis. J Neurol Neurosurg Psychiatry. 1996;61(6):596–600.

1997;498 (Pt 3):817–23.

DOI: 10.1016/S1474-4422(15)00014-9.

1451–7. DOI: 10.1111/ene.12422.

DOI: 10.1007/s12035-011-8217-x.

DOI: 10.3109/17482968.2011.636050.

3301–12. DOI: 10.1002/jcb.24234.

s40263-015-0225-3.

10.2217/nmt.15.49.

2010.12.062.

68 Update on Amyotrophic Lateral Sclerosis


[91] Ferreri F, Pasqualetti P, Määttä S, Ponzo D, Guerra A, Bressi F, Chiovenda P, Del Duca M, Giambattistelli F, Ursini F, Tombini M, Vernieri F, Rossini PM. Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation follow-up study. Neurosci Lett. 2011;492(2):94–8. DOI: 10.1016/j.neulet.2011.01.064.

[78] Svensson P, Romaniello A, Wang K, Arendt-Nielsen L, Sessle BJ. One hour of tonguetask training is associated with plasticity in corticomotor control of the human tongue

[79] Classen J, Liepert J, Hallett M, Cohen L. Plasticity of movement representation in the human motor cortex. Electroencephalogr Clin Neurophysiol Suppl. 1999;51(1):162–73.

[80] Tyč F, Boyadjian A. Plasticity of motor cortex induced by coordination and training.

[81] Perez MA, Lungholt BK, Nyborg K, Nielsen JB. Motor skill training induces changes in the excitability of the leg cortical area in healthy humans. Exp Brain Res. 2004;159(2):

[82] Mokienko OA, Chervyakov AV, Kulikova SN, Bobrov PD, Chernikova LA, Frolov AA, Piradov MA. Increased motor cortex excitability during motor imagery in braincomputer interface trained subjects. Front Comput Neurosci. 2013;7:168. DOI: 10.3389/

[83] Rosenkranz K, Williamon A, Rothwell JC. Motorcortical excitability and synaptic plasticity is enhanced in professional musicians. J Neurosci. 2007;27(19):5200–6.

[84] Pearce AJ, Thickbroom GW, Byrnes ML, Mastaglia FL. Functional reorganisation of the corticomotor projection to the hand in skilled racquet players. Exp Brain Res.

[85] Funkenstein HH, Albert MS, Cook NR, West CG, Scherr PA, Chown MJ, Pilgrim D, Evans DA. Extrapyramidal signs and other neurological findings in clinically diag‐

[86] Rogers J, Morrison JH. Quantitative morphology and regional and laminar distribution

[87] Pennisi G, Ferri R, Lanza G, Cantone M, Pennisi M, Puglisi V, Malaguarnera G, Bella R. Transcranial magnetic stimulation in Alzheimer's disease: a neurophysiological marker of cortical hyperexcitability. J Neural Transm (Vienna). 2011;118(4):587–98.

[88] Guerra A, Assenza F, Bressi F, Scrascia F, Del Duca M, Ursini F, Vollaro S, Trotta L, Tombini M, Chisari C, Ferreri F. Transcranial magnetic stimulation studies in Alz‐ heimer's disease. Int J Alzheimers Dis. 2011; 2011:263817. DOI: 10.4061/2011/263817.

[89] Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Daniele A, Ghirlanda S, Gainotti G, Tonali PA. Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004; 75(4):555–9.

[90] Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, Rossini PM. Motor cortex excita‐ bility in Alzheimer's disease: a transcranial magnetic stimulation study. Ann Neurol.

of senile plaques in Alzheimer's disease. J Neurosci. 1985;5(10):2801–8.

nosed Alzheimer's disease. Arch Neurol. 1993;50(1):51–6.

Clin Neurophysiol. 2011;122(1):153–62. DOI: 10.1016/j.clinph.2010.05.022.

musculature. Exp Brain Res. 2006;173(1):165–73.

197–205.

70 Update on Amyotrophic Lateral Sclerosis

fncom.2013.00168.

2000;130(2):238–43.

DOI: 10.1007/s00702-010-0554-9.

2003;53(1):102–8.

