Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study

Prisca R. Bauer, Annika A. de Goede, William M. Stern, Adam D. Pawley, Fahmida A. Chowdhury, Robert M. Helling, Romain Bouet, Stiliyan N. Kalitzin, Gerhard H. Visser, Sanjay M. Sisodiya, John C. Rothwell, Mark P. Richardson, Michel J.A.M. van Putten, Josemir W. Sander (Corresponding Author)

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Abstract

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.
Original languageEnglish
Pages (from-to)409-421
Number of pages13
JournalBrain
Volume141
Issue number2
Early online date11 Jan 2018
DOIs
Publication statusPublished - 1 Feb 2018

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Generalized Epilepsy
Partial Epilepsy
Transcranial Magnetic Stimulation
Epilepsy
Biomarkers
Electromyography
Linear Models

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Bauer, P. R., de Goede, A. A., Stern, W. M., Pawley, A. D., Chowdhury, F. A., Helling, R. M., ... Sander, J. W. (2018). Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study. Brain, 141(2), 409-421. https://doi.org/10.1093/brain/awx343
Bauer, Prisca R. ; de Goede, Annika A. ; Stern, William M. ; Pawley, Adam D. ; Chowdhury, Fahmida A. ; Helling, Robert M. ; Bouet, Romain ; Kalitzin, Stiliyan N. ; Visser, Gerhard H. ; Sisodiya, Sanjay M. ; Rothwell, John C. ; Richardson, Mark P. ; van Putten, Michel J.A.M. ; Sander, Josemir W. / Long-interval intracortical inhibition as biomarker for epilepsy : a transcranial magnetic stimulation study. In: Brain. 2018 ; Vol. 141, No. 2. pp. 409-421.
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abstract = "Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.",
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Bauer, PR, de Goede, AA, Stern, WM, Pawley, AD, Chowdhury, FA, Helling, RM, Bouet, R, Kalitzin, SN, Visser, GH, Sisodiya, SM, Rothwell, JC, Richardson, MP, van Putten, MJAM & Sander, JW 2018, 'Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study' Brain, vol. 141, no. 2, pp. 409-421. https://doi.org/10.1093/brain/awx343

Long-interval intracortical inhibition as biomarker for epilepsy : a transcranial magnetic stimulation study. / Bauer, Prisca R.; de Goede, Annika A.; Stern, William M.; Pawley, Adam D. ; Chowdhury, Fahmida A.; Helling, Robert M.; Bouet, Romain; Kalitzin, Stiliyan N.; Visser, Gerhard H.; Sisodiya, Sanjay M.; Rothwell, John C.; Richardson, Mark P.; van Putten, Michel J.A.M.; Sander, Josemir W. (Corresponding Author).

In: Brain, Vol. 141, No. 2, 01.02.2018, p. 409-421.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Long-interval intracortical inhibition as biomarker for epilepsy

T2 - a transcranial magnetic stimulation study

AU - Bauer, Prisca R.

AU - de Goede, Annika A.

AU - Stern, William M.

AU - Pawley, Adam D.

AU - Chowdhury, Fahmida A.

AU - Helling, Robert M.

AU - Bouet, Romain

AU - Kalitzin, Stiliyan N.

AU - Visser, Gerhard H.

AU - Sisodiya, Sanjay M.

AU - Rothwell, John C.

AU - Richardson, Mark P.

AU - van Putten, Michel J.A.M.

AU - Sander, Josemir W.

PY - 2018/2/1

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N2 - Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.

AB - Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.

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DO - 10.1093/brain/awx343

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