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Altered Cortical Excitability and Inhibition in Patients with Primary Dystonia: A Transcranial Magnetic Stimulation Study

Published online by Cambridge University Press:  19 March 2025

Debjyoti Dhar ,
Nitish Kamble ,
Amitabh Bhattacharya Open the ORCID record for Amitabh Bhattacharya [Opens in a new window] ,
Vikram Holla ,
Ravi Yadav Open the ORCID record for Ravi Yadav [Opens in a new window]  and
Pramod Kumar Pal Open the ORCID record for Pramod Kumar Pal [Opens in a new window]
Debjyoti Dhar
Affiliation:
Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, Karnataka, India
Nitish Kamble
Affiliation:
Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, Karnataka, India
Amitabh Bhattacharya
Affiliation:
Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, Karnataka, India
Vikram Holla
Affiliation:
Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, Karnataka, India
Ravi Yadav
Affiliation:
Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, Karnataka, India
Pramod Kumar Pal*
Affiliation:
Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, Karnataka, India
*
Corresponding author: Pramod Kumar Pal; Email: palpramod@hotmail.com
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Abstract

Background:

The literature on cortical excitability, inhibitory and facilitatory properties of the brain in patients with primary dystonia is not well elucidated. We aimed to study the changes in these neurophysiological parameters in patients with dystonia using transcranial magnetic stimulation (TMS).

Methods:

Patients with primary dystonia of presumed genetic etiology (n = 36) and an equal number of healthy controls (HC) (n = 36) were recruited from May 2021 to September 2022. TMS was done using single and paired pulse paradigms. The left motor cortex was stimulated, and responses were recorded from the contralateral first dorsal interosseus muscle. Resting motor threshold (RMT), central motor conduction time, contralateral silent period (cSP), ipsilateral silent period (iSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were recorded. All patients underwent whole exome sequencing.

Results:

The mean age of patients was 36.6 ± 13.5 years. There was a significant reduction of cSP (79.5 ± 33.8 vs 97.5 ± 25.4, p = 0.02) and iSP (42.3 ± 13.5 vs 53.8 ± 20.8, p = 0.003) in patients compared to HC. SICI was significantly enhanced in patients (0.38 ± 0.23) compared to HC (0.51 ± 0.24, p = 0.006). RMT was higher (42.1 ± 7.9 vs 37.1 ± 6.4%, p = 0.032) with enhanced SICI (0.36 ± 0.21 vs 0.56 ± 0.25, p = 0.004) in patients with generalized dystonia (n = 20) compared to HC. The genetically determined subgroup (n = 13) had significantly enhanced SICI compared to HC (0.23 ± 0.15 vs 0.51 ± 0.23, p = 0.001).

Conclusions:

Patients with primary dystonia have altered cortical excitability and inhibition with significantly reduced silent period and enhanced intracortical inhibition suggestive of impaired GABAergic neurotransmission.

Résumé :

RÉSUMÉ :

Altération de l’excitabilité et de l’inhibition corticales chez les patients atteints de dystonie primaire : une étude par stimulation magnétique transcrânienne.

Contexte :

La littérature portant sur l’excitabilité corticale, ainsi que sur les propriétés inhibitrices et facilitatrices du cerveau chez les patients atteints de dystonie primaire, n’est pas encore bien comprise. Nous avons ainsi cherché à étudier les changements de ces paramètres neurophysiologiques chez les patients atteints de dystonie en utilisant la stimulation magnétique transcrânienne (SMT).

Méthodes :

Des patients atteints de dystonie primaire chez lesquels on a présumé une étiologie génétique (n = 36), de même qu’un nombre égal de témoins en bonne santé (TBS) (n = 36), ont été recrutés de mai 2021 à septembre 2022. La SMT a été effectuée en utilisant des paradigmes impulsionnels uniques et appariés. À cet égard, le cortex moteur gauche a été stimulé et les réponses ont été enregistrées à partir du premier muscle interosseux dorsal controlatéral. Le seuil moteur au repos (resting motor threshold)), le temps de conduction dans le système nerveux central (central motor conduction), la période silencieuse controlatérale (PSC), la période silencieuse ipsilatérale (PSI), l’inhibition intra-corticale à intervalle court (IICIC) et la facilitation intra-corticale (FIC) ont été enregistrés. Notons enfin que tous les patients ont subi un séquençage de l’exome entier (SEE).

Résultats :

L’âge moyen des patients était de 36,6 ± 13,5 ans. Une réduction significative de la PSC (79,5 ± 33,8 contre 97,5 ± 25,4 ; p = 0,02) et de la PSI (42,3 ± 13,5 contre 53,8 ± 20,8 ; p = 0,003) a été observée chez les patients comparés ensuite aux TBS. L’IICIC s’est révélée significativement plus élevée chez les patients (0,38 ± 0,23) par rapport aux TBS (0,51 ± 0,24 ; p= 0,006). Le seuil moteur au repos était plus élevé (42,1 ± 7,9 contre 37,1 ± 6,4 % ; p = 0,032) avec une IICIC améliorée (0,36 ± 0,21 contre 0,56 ± 0,25 ; p = 0,004) chez les patients atteints de dystonie généralisée (n = 20) par rapport aux TBS. Finalement, le sous-groupe génétiquement déterminé (n = 13) a donné à voir une IICIC notablement plus élevée que celle des TBS (0,23 ± 0,15 contre 0,51 ± 0,23 ; p= 0,001).

Conclusions :

Les patients atteints de dystonie primaire ont présenté une altération de l’excitabilité et de l’inhibition corticales avec une période silencieuse significativement réduite et une inhibition intra-corticale accrue, ce qui suggère une neurotransmission gabaergique altérée.

Keywords

cortical excitabilitydystoniageneticsintracortical facilitationshort-interval intracortical inhibitiontranscranial magnetic stimulation
Type
Original Article
Information
Canadian Journal of Neurological Sciences , First View , pp. 1 - 8
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation

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Footnotes

†

Both authors contributed equally. Hence, both are to be considered as first authors.

References

Albanese, A, Bhatia, K, Bressman, SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013;28:863–873. doi: 10.1002/mds.25475.Google Scholar
Hallett, M. Transcranial magnetic stimulation: a primer. Neuron. 2007;55:187–199. doi: 10.1016/j.neuron.2007.06.026.Google Scholar
Kobayashi, M, Pascual-Leone, A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2:145–156. doi: 10.1016/s1474-4422(03)00321-1.Google Scholar
McDonnell, MN, Thompson, PD, Ridding, MC. The effect of cutaneous input on intracortical inhibition in focal task-specific dystonia. Mov Disord. 2007;22:1286–1292. doi: 10.1002/mds.21508.Google Scholar
Priori, A, Berardelli, A, Inghilleri, M, Polidori, L, Manfredi, M. Electromyographic silent period after transcranial brain stimulation in Huntington’s disease. Mov Disord. 1994;9:178–182. doi: 10.1002/mds.870090209.Google Scholar
Valls-Solé, J, Pascual-Leone, A, Brasil-Neto, JP, Cammarota, A, McShane, L, Hallett, M. Abnormal facilitation of the response to transcranial magnetic stimulation in patients with Parkinson’s disease. Neurology. 1994;44:735–735. doi: 10.1212/wnl.44.4.735.Google Scholar
Berardelli, A, Abbruzzese, G, Chen, R, et al. Consensus paper on short-interval intracortical inhibition and other transcranial magnetic stimulation intracortical paradigms in movement disorders. Brain Stimul. 2008;1:183–191. doi: 10.1016/j.brs.2008.06.005.Google Scholar
Mcclelland, V, Mills, K, Siddiqui, A, Selway, R, Lin, JP. Central motor conduction studies and diagnostic magnetic resonance imaging in children with severe primary and secondary dystonia. Dev Med Child Neurol. 2011;53:757–763. doi: 10.1111/j.1469-8749.2011.03981.x.Google Scholar
Stinear, CM, Byblow, WD. Impaired modulation of intracortical inhibition in focal hand dystonia. Cereb Cortex. 2004;14:555–561. doi: 10.1093/cercor/bhh017.Google Scholar
Bütefiscch, CM, Boroojerdi, B, Chen, R, Battaglia, F, Hallet, M. Task-dependent intracortical inhibition is impaired in focal hand dystonia. Mov Disord. 2005;20:545–551. doi: 10.1002/mds.20367.Google Scholar
Hallett, M. The neurophysiology of dystonia. Arch Neurol. 1998;55(5):601–603. doi: 10.1001/archneur.55.5.601.Google Scholar
Richardson, SP, Bliem, B, Lomarev, M, Shamim, E, Dang, N, Hallett, M. Changes in short afferent inhibition during phasic movement in focal dystonia. Muscle Nerve. 2008;37:358–363. doi: 10.1002/mus.20943.Google Scholar
Kimberley, TJ, Borich, MR, Prochaska, KD, Mundfrom, SL, Perkins, AE, Poepping, JM. Establishing the definition and inter-rater reliability of cortical silent period calculation in subjects with focal hand dystonia and healthy controls. Neurosci Lett. 2009;464:84–87. doi: 10.1016/j.neulet.2009.08.029.Google Scholar
Sommer, M, Ruge, D, Tergau, F, Beuche, W, Altenmüller, E, Paulus, W. Intracortical excitability in the hand motor representation in hand dystonia and blepharospasm. Mov Disord. 2002;17:1017–1025. doi: 10.1002/mds.10205.Google Scholar
Sohn, YH, Hallett, M. Disturbed surround inhibition in focal hand dystonia. Ann Neurol. 2004;56:595–599. doi: 10.1002/ana.20270.Google Scholar
Ridding, MC, Sheean, G, Rothwell, JC, Inzelberg, R, Kujirai, T. Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry. 1995;59(5):493–498. doi: 10.1136/jnnp.59.5.493.Google Scholar
Edwards, MJ, Huang, YZ, Wood, NW, Rothwell, JC, Bhatia, KP. Different patterns of electrophysiological deficits in manifesting and non-manifesting carriers of the DYT1 gene mutation. Brain. 2003;126:2074–2080. doi: 10.1093/brain/awg209.Google Scholar
Edwards, MJ, Huang, YZ, Mir, P, Rothwell, JC, Bhatia, KP. Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers. Mov Disord. 2006;21:2181–2186. doi: 10.1002/mds.21160.Google Scholar
Huang, YZ, Edwards, MJ, Bhatia, KP, Rothwell, JC. One-Hz repetitive transcranial magnetic stimulation of the premotor cortex alters reciprocal inhibition in DYT1 dystonia. Mov Disord. 2004;19:54–59. doi: 10.1002/mds.10627.Google Scholar
Li, JY, Cunic, DI, Paradiso, G, et al. Electrophysiological features of myoclonus-dystonia. Mov Disord. 2008;23:2055–2061. doi: 10.1002/mds.22273.Google Scholar
Groppa, S, Oliviero, A, Eisen, A, et al. A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol. 2012;123:858–882. doi: 10.1016/j.clinph.2012.01.010.Google Scholar
Kujirai, T, Caramia, MD, Rothwell, JC, et al. Corticocortical inhibition in human motor cortex. J Physiol. 1993;471:501–519. doi: 10.1113/jphysiol.1993.sp019912.Google Scholar
Li, H, Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589–595. doi: 10.1093/bioinformatics/btp698.Google Scholar
DePristo, MA, Banks, E, Poplin, R, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–498. doi: 10.1038/ng.806.Google Scholar
Wang, K, Li, M, Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164–e164. doi: 10.1093/nar/gkq603.Google Scholar
Sim, N-L, Kumar, P, Hu, J, Henikoff, S, Schneider, G, Ng, PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40:W452–W457. doi: 10.1093/nar/gks539.Google Scholar
Schwarz, JM, Rödelsperger, C, Schuelke, M, Seelow, D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7:575–576. doi: 10.1038/nmeth0810-575.Google Scholar
Adzhubei, IA, Schmidt, S, Peshkin, L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–249. doi: 10.1038/nmeth0410-248.Google Scholar
Richards, S, Aziz, N, Bale, S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424. doi: 10.1038/gim.2015.30.Google Scholar
Quartarone, A. Transcranial magnetic stimulation in dystonia. In: Handbook of Clinical Neurology. 2013;116:543–553. doi: 10.1016/B978-0-444-53497-2.00043-7.Google Scholar
Rona, S, Berardelli, A, Vacca, L, Inghilleri, M, Manfredi, M. Alterations of motor cortical inhibition in patients with dystonia. Mov Disord. 1998;13:118–124. doi: 10.1002/mds.870130123.Google Scholar
Brighina, F, Romano, M, Giglia, M, et al. Effects of cerebellar TMS on motor cortex of patients with focal dystonia: a preliminary report. Exp Brain Res. 2009;192:651–656. doi: 10.1007/s00221-008-1572-9.Google Scholar
Stinear, CM, Byblow, WD. Elevated threshold for intracortical inhibition in focal hand dystonia. Mov Disord. 2004;19(11):1312–1317. doi: 10.1002/mds.20160.Google Scholar
Meunier, S, Lourenco, G, Roze, E, Apartis, E, Trocello, JM, Vidailhet, M. Cortical excitability in DYT-11 positive myoclonus dystonia. Mov Disord. 2008;23:761–764. doi: 10.1002/mds.21954.Google Scholar
van der Salm, SMA, van Rootselaar, AF, Foncke, EMJ, et al. Normal cortical excitability in myoclonus-dystonia - a TMS study. Exp Neurol. 2009;216:300–305. doi: 10.1016/j.expneurol.2008.12.001.Google Scholar
Nikolov, P, Hassan, SS, Aytulun, A, et al. Cerebellar involvement in DYT-THAP1 dystonia. Cerebellum. 2019;18:969–971. doi: 10.1007/s12311-019-01062-0.Google Scholar
Balint, B, Mencacci, NE, Valente, EM, et al. Dystonia. Nat Rev Dis Primers. 2018;4(1):25. doi: 10.1038/s41572-018-0023-6.Google Scholar
Berardelli, A, Rothwell, JC, Hallett, M, Thompson, PD, Manfredi, M, Marsden, CD. The pathophysiology of primary dystonia. Brain. 1998;121:1195–1212. doi: 10.1093/brain/121.7.1195.Google Scholar
Ikoma, K, Samii, A, Mercuri, B, Wassermann, EM, Hallett, M. Abnormal cortical motor excitability in dystonia. Neurology. 1996;46:1371–1371. doi: 10.1212/wnl.46.5.1371.Google Scholar
Berardelli, A, Rothwell, JC, Day, BL, Marsden, CD. Pathophysiology of blepharospasm and oromandibular dystonia. Brain. 1985;108:593–608. doi: 10.1093/brain/108.3.593.Google Scholar
Lozeron, P, Poujois, A, Richard, A, et al. Contribution of TMS and rTMS in the understanding of the pathophysiology and in the treatment of dystonia. Front Neural Circuits. 2016;10:90. doi: 10.3389/fncir.2016.00090.Google Scholar
Beck, S, Richardson, SP, Shamim, EA, Dang, N, Schubert, M, Hallett, M, et al. Short intracortical and surround inhibition are selectively reduced during movement initiation in focal hand dystonia. J Neurosci. 2008;28:10363–10369. doi: 10.1523/jneurosci.3564-08.2008.Google Scholar