Reduced short-interval intracortical inhibition (SICI) in motor neuron disease has been demonstrated by amplitude changes (A-SICI) and threshold-tracking (T-SICI) using 10 stimuli per inter-stimulus interval (ISI). To test whether fewer stimuli would suffice, A-SICI and T-SICI were recorded twice from 30 healthy subjects using 6 and 10 stimuli per ISI. Using fewer stimuli increased mean A-SICI variances by 23.8% but the 7.3% increase in T-SICI variance was not significant. We conclude that our new parallel threshold-tracking SICI protocol, with 6 stimuli per ISI, can reduce time and stimulus numbers by 40% without appreciable loss of accuracy

Bostock, H

Cengiz, B

Howells, J

Koltzenburg, M

Samusyte, G

Tankisi, H

English

UCL Discovery

ARTICLE IN PRESSJID: NEUCLI [mEU6P;January 6, 2022;14:17]Neurophysiologie Clinique 000 (xxxx) 14Available online atScienceDirectwww.sciencedirect.comTECHNICAL NOTEShort interval intracortical inhibition:Variability of amplitude and threshold-tracking measurements with 6 or 10 stimuliper pointHatice Tankisia, B€ulent Cengizb, Gintaute Samusytec, James Howellsd,Martin Koltzenburge,f, Hugh Bostockg,*a Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmarkb Department of Neurology, Gazi University Faculty of Medicine, Beşevler, 06500 Ankara, Turkeyc Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuaniad Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australiae Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, WC1N 3BG London,United Kingdomf Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG London,United Kingdomg Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N 3BG London, UnitedKingdomReceived 20 September 2021; accepted 16 November 2021Available online xxxList of abbreviations: A-SICI, short-stimuli per ISI; A-SICI-T, A-SICI transformotor neuron disease; MSO, maximumstandard error of measurement; SICI,old tracking different ISIs in parallel; Trequired to evoke 1 mV MEP.* Corresponding author.E-mail address: H.Bostock@ucl.ac.https://doi.org/10.1016/j.neucli.20210987-7053/© 2021 The Author(s). Publ(http://creativecommons.org/licensePlease cite this article in press asof amplitude and threshold-trachttps://doi.org/10.1016/j.neuclAbstract Reduced short-interval intracortical inhibition (SICI) in motor neuron disease hasbeen demonstrated by amplitude changes (A-SICI) and threshold-tracking (T-SICI) using 10 stimuliper inter-stimulus interval (ISI). To test whether fewer stimuli would suffice, A-SICI and T-SICIwere recorded twice from 30 healthy subjects using 6 and 10 stimuli per ISI. Using fewer stimuliincreased mean A-SICI variances by 23.8% but the 7.3% increase in T-SICI variance was not signifi-cant. We conclude that our new parallel threshold-tracking SICI protocol, with 6 stimuli per ISI,can reduce time and stimulus numbers by 40% without appreciable loss of accuracy.KEYWORDSShort-interval intra-cortical inhibition;Parallel threshold-tracking versus con-ventional TMS;SICI variabilityinterval intracortical inhibition obtained by amplitude measurements; A-SICI(n), A-SICI recorded with nmed into equivalent threshold changes; ISI, inter-stimulus interval; MEP, motor evoked potential; MND,stimulator output; RMT200, stimulus required to evoke 200 mV MEP; SD, standard deviation; SEMeas,short-interval intracortical inhibition; T-SICI, short-interval intracortical inhibition obtained by thresh--SICI(n), T-SICI recorded with n stimuli per ISI; TMS, transcranial magnetic stimulation; TS1mV, stimulusuk (H. Bostock)..11.006ished by Elsevier Masson SAS. This is an open access article under the CC BY licenses/by/4.0/).: H. Tankisi, B. Cengiz, G. Samusyte et al., Short interval intracortical inhibition: Variabilityking measurements with 6 or 10 stimuli per point, Neurophysiologie Clinique (2021),i.2021.11.006ARTICLE IN PRESSJID: NEUCLI [mEU6P;January 6, 2022;14:17]H. Tankisi, B. Cengiz, G. Samusyte et al.© 2021 The Author(s). Published by Elsevier Masson SAS. This is an open access article under theCC BY license (http://creativecommons.org/licenses/by/4.0/).IntroductionThe transcranial magnetic stimulation (TMS) technique ofshort-interval intracortical inhibition (SICI) can be recordedby using constant stimuli, and measuring the effect of theconditioning stimulus on the amplitude of the response tothe test stimulus (i.e. amplitude SICI: A-SICI), or by trackingthe effect of the conditioning stimulus on the thresholdstimulus required to elicit a constant target response (i.e.threshold-tracking SICI: T-SICI). Both methods showedreduced inhibition in patients with motor neuron disease(MND), with high specificity and sensitivity, using 10 stimuliat each of nine inter-stimulus intervals (ISI) from 1 to 7 ms[9]. This study was undertaken to determine how much lossin accuracy would result from using only 6 stimuli per ISI.MethodsThe study was carried out in accordance with the Declara-tion of Helsinki and approved by The Central DenmarkRegion Committees on Health Research Ethics and the localethics committee in Ankara. All participants gave their writ-ten informed consent before the investigations.SubjectsThirty healthy volunteers (9 men, 21 women) were recruitedwho had no known neurological disorder or contraindicationsfor TMS, and were not on any regular medication. They wereaged 37.6 § 11.7 years (mean § S.D., range 2463).TMS and SICIThe methods were described previously [8,9]. Briefly, aMagstim D70 figure-of-8 coil was positioned on the contra-lateral hemisphere, to excite motor evoked potentials(MEPs) of the right first dorsal interosseus (FDI) muscle. Thecoil current was generated by two Magstim 2002 stimula-tors in BiStim configuration. After identifying the hotspot,all the stimulation sequences were controlled automaticallyby QtracW software ( UCL, London, UK), using QTMSG-12protocols ( QTMS Science Ltd.).For A-SICI, resting motor thresholds were first deter-mined for 200mV (RMT200) and 1 mV (TS1mV) peak-to-peakMEPs, using a ‘4!2!10 tracking rule [8]. The TS1mV teststimulus was then preceded by conditioning stimuli at 70%RMT200, at the nine ISIs (1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7 ms)presented in pseudo-random order, while every fourth teststimulus was delivered alone. Ten stimuli were delivered ateach ISI, then A-SICI(10) data was generated from the geo-metric means of all 10 conditioned and all 30 unconditionedMEPs, while A-SICI(6) data was generated from the first 6 con-ditioned and first 18 unconditioned MEPs.For T-SICI, RMT200 was estimated as above, then trackedcontinuously with 1% of maximum stimulator output (MSO)steps as every fourth stimulus, and the conditioning stimuli2were set to 70% of the updated RMT200. The conditionedtest stimuli were delivered at the same pseudo-randomised9 ISIs after the conditioning stimuli as for A-SICI, and initiallyset to 106% RMT200. Thresholds for the 9 ISIs were estimatedindependently in parallel by proportional tracking, with themaximum permitted change in stimulus diminishing from 6to 2%MSO (6!5.5!5!4.5!4!3.5!3!2.5!2%MSO forT-SICI(10) and 6!5!4!3!2%MSO for T-SICI(6)). The T-SICI(10) protocol was previously designated T-SICIp2 [8] anddistinct from the earlier serial threshold-tracking protocolT-SICIs [4,5,8,10].All 120 A-SICI and T-SICI(10) stimuli (each comprising 90paired and 30 single pulses) and 72 T-SICI(6) stimuli wereapplied to each of the 30 subjects twice. The coil wasremoved from the hotspot after each protocol, and otherprotocols interposed before a repetition.Data analysisA-SICI amplitudes were averaged as geometric means, and T-SICI thresholds were estimated by log regression [4,8]. Forcomparison with T-SICI thresholds, A-SICI amplitudes were nor-malized by log conversion and scaled, using the relationshipfound previously [8]:A-SICI-T = 100  17.85 £ Log10(A-SICI/100).For statistical tests, P<0.05 was considered significant.ResultsVariability of A-SICI, A-SICI-Tand T-SICI estimatesFor each type of recording, there were 2 measurementsfrom each of 30 subjects, so Fig. 1A shows the geometricmeans and geometric means £ / geometric SD for all 60recordings with n = 10 stimuli per ISI, and 60 recordings withn = 6. Similarly, Fig. 1C shows means § SDs for the 60 T-SICIrecordings with n = 6 and n = 10 stimuli per ISI. To enable thevariability of the A-SICI recordings to be compared morereadily with the T-SICI ones, the transformed A-SICI-T valuesare shown in Fig. 1B. Although the A-SICI-T means closelyresemble the T-SICI ones, the SDs are smaller, and this isshown more clearly in Fig. 2, where SDs of the 1st and 2ndmeasurements are shown separately.The variances averaged over the two measurements at 9ISIs were 24.37 for A-SICI-T(10), 30.18 for A-SICI-T(6), 64.58for T-SICI(10) and 69.28 for T-SICI(6) (all in [%RMT200]2). TheT-SICI/A-SICI-T differences were highly significant:P = 9.32 £ 108 for n = 10 and P = 5.27 £ 109 for n = 6 bypaired t-tests). The n = 6/n = 10 differences (calculated bycomparing 1st measurement at n = 10 with 2nd measurementat n = 6, and vice versa, to avoid comparing overlappingobservations) were much smaller. The null hypothesis thatn = 6 observations were no more variable than n = 10 onescould be rejected for A-SICI-T (P = 0.0248) but not for T-SICIFigure 1 Means and variabilities for 60 SICI recordings made with 10 or 6 stimuli per ISI. A: Conventional amplitude SICI, with geo-metric means £ / geometric SDs. B: Amplitude SICI normalized by log conversion to resemble threshold tracking SICI (mean § SD).C: Threshold-tracking SICI (mean § SD).ARTICLE IN PRESSJID: NEUCLI [mEU6P;January 6, 2022;14:17]Neurophysiologie Clinique 00 (xxxx) 14(P = 0.187). Although the percentage differences in theabove variances were much greater for A-SICI-T (23.8%) thanT-SICI (7.3%), the absolute differences were similar (5.81 forA-SICI and 4.71 for T-SICI).Within-subject and between-subject variabilitySince each recording was repeated, the sources of varia-tion can be separated into within-subject and between-subject components. Whereas between-subject variabilitycan help determine whether a patient’s SICI is abnormalor not, within-subject variability determines how manysubjects are needed to demonstrate differences overtime due to disease progression or treatment interven-tions. The within-subject SD or standard error of mea-surement (SEMeas), is simply related to the MinimalDetectable Change (MDC):MDC = SEMeas £ x2 £ 1.96 [7]Figure 2 Variability of two sets of SICI estimates made with 10 atracking SICI. Filled symbols: first measurement. Open symbols: seco3MDC is the minimal change that can be detected in anindividual with 95% probability, and is a measure of absolutereliability for TMS outcomes [1]. For a group of size n, theminimal detectable change reduces to:MDCn = MDC/xn [7]From which it follows that:n ¼ ðMDC=MDCnÞ2 ¼ 2  ðSEMeas  1:96=MDCnÞ2This enables us to compare the 4 SICI methods used inthis study and estimate how many more subjects will beneeded to compensate for the shorter A-SICI(6) and T-SICI(6)protocols.All 4 methods give a mean threshold increase from 1 to3.5 ms (a useful SICI measure for MND studies) of 10.5%RMT200. The within-subject SDs or SEMeas values for A-SICI-T(10), A-SICI-T(6), T-SICI(10) and T-SICI(6) from 1 to 3.5 ms werend 6 stimuli per ISI. A: Normalized amplitude SICI. B: Thresholdnd measurement. Black circles: n = 10. Red squares: n = 6.ARTICLE IN PRESSJID: NEUCLI [mEU6P;January 6, 2022;14:17]H. Tankisi, B. Cengiz, G. Samusyte et al.2.18, 2.49, 3.33 and 3.15% RMT200 respectively. From the for-mulae above, we can estimate the numbers of subjects requiredto detect a change in SICI over time of 20% or 2.1% RMT200 as9, 11, 20 and 18 (rounded to the next highest integer).DiscussionThe main aim of this study was to determine whetherfewer stimuli could be used in clinical tests of SICI with-out seriously impairing their reliability. This would savetime (especially when using TMS equipment limited toone stimulus every 4 or 5 s), improve patient tolerance,and reduce coil heating. One way to reduce stimulusnumbers is to limit the ISI range, and for MND, ISIs47 ms can be omitted without impairing discrimination[9]. Here we tested reducing the number of stimuli perISI, both for conventional A-SICI measurements and thenew parallel method of T-SICI [8,9] which requires similarstimulus numbers. Previous A-SICI versus ISI studies haveused between 6 [3] and 20 [2] paired stimuli per ISI, with10, as used in our previous studies [8,9] the most popularnumber [6,11]. Boroojerdi and colleagues [2] showedthat the coefficient of variation of their responsesincreased, as expected, when calculations were based on20, 15, 10 or 5 trials. As in that study, our estimates ofA-SICI variability with different numbers of stimuli werenot independent, since A-SICI(6) variability was estimatedfrom a subset of A-SICI(10) measurements, invalidatingdirect A-SICI(6)/A-SICI(10) comparisons. By comparing non-overlapping recordings, however, we could demonstratethat averaging only 6 stimuli increased the variance ofthe observations. On the other hand, despite making 30recordings at each ISI, we were unable to demonstrateany disadvantage in using 6 rather than 10 stimuli per ISIfor the T-SICI measurements. Analysis of variances indi-cated that this was mainly due to the higher variabilityof the T-SICI measurements.As previously reported [8], the A-SICI-T measurementswere consistently less variable than the T-SICI ones using thesame number of stimuli, indicating that conventional ampli-tude measurements provide a more efficient means of mea-suring intra-cortical inhibition than these threshold-trackingmethods, so that approximately twice the number of sub-jects are expected to be needed to demonstrate a compara-ble change in SICI due, for example to a drug. This does not,however, mean that threshold-tracking SICI is less efficientas a clinical biomarker. Our recent comparison of these twomethods in MND patients found that T-SICI was much betterthan A-SICI at detecting abnormal corticospinal excitabilityin patients with few upper motor neuron signs, since thresh-old-tracking is sensitive to changes in fewer neurons [9].Consequently, the two techniques had comparable overallsensitivity and specificity as biomarkers [9].In conclusion, whereas reducing stimulus numbers by 40%incurs a small loss in A-SICI accuracy, our new 6-stimulusT-SICI protocol carries no appreciable penalty, and can berecommended for future MND studies.4Declaration Competing of InterestHB and JH receive from UCL shares of the royalties for salesof the Qtrac software used in this study. HB, HT, BC, and MKare shareholders of QTMS Science Ltd., which licences theQTMSG-12 recording protocols used. GS has no potentialconflict of interest to declare.AcknowledgementsThis work was supported by the Lundbeck Foundation (Grantnumber: R2902018751) and the Independent ResearchFund Denmark (Grant number: 903900272B).References[1] Beaulieu L-D, Flamand VH, Masse-Alarie H, Schneider C. Reli-ability and minimal detectable change of transcranial magneticstimulation outcomes in healthy adults: a systematic review.Brain Stim 2017;10:196–213.[2] Boroojerdi B, Kopylev L, Battaglia F, Facchini S, Ziemann U,Muellbacher W, et al. Reproducibility of intracortical inhibitionand facilitation using the paired-pulse paradigm. Muscle Nerve2000;23:1594–7.[3] Du X, Summerfelt A, Chiappelli J, Holcomb HH, Hong LE. Indi-vidualized brain inhibition and excitation profile in response topaired-pulse TMS. J Mot Behav 2014;46:39–48.[4] Fisher RJ, Nakamura Y, Bestmann S, Rothwell JC, Bostock H.Two phases of intracortical inhibition revealed by transcranialmagnetic threshold tracking. Exp Brain Res 2002;143:240e8.[5] Ørskov S, Bostock H, Howells J, Pugdahl K, Fuglsang-Frederik-sen A, Nielsen CSZ, et al. Comparison of figure-of-8 and circularcoils for threshold tracking transcranial magnetic stimulationmeasurements. Neurophysiol Clin 2021;51:153–60.[6] Peinemann A, Lehner C, Conrad B, Siebner HR. Age-relateddecrease in paired-pulse intracortical inhibition in the humanprimary motor cortex. Neurosci Lett 2001;313:33–6.[7] Schambra HM, Ogden RT, Martinez-Hernandez IE, Lin X, ChangeYB, Rahman A, et al. The reliability of repeated TMS measuresin older adults and in patients with subacute and chronicstroke. Front Cell Neurosci 2015;9:335.[8] Tankisi H, Cengiz B, Howells J, Samusyte G, Koltzenburg M,Bostock H. Short-interval intracortical inhibition as a functionof inter-stimulus interval: three methods compared. Brain Stim2021;14:22–32.[9] Tankisi H, Nielsen CS, Howells J, Cengiz B, Samusyte G, Kolt-zenburg M, et al. Early diagnosis of amyotrophic lateral sclero-sis by threshold tracking and conventional transcranialmagnetic stimulation. Eur J Neurology 2021;28:3030–9.[10] Vucic S, Howells J, Trevillion L, Kiernan MC. Assessment of cor-tical excitability using threshold tracking techniques. MuscleNerve 2006;33:477–86.[11] Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, PaulusW. Impaired motor cortex inhibition in patients with amyotro-phic lateral sclerosis. Evidence from paired transcranial mag-netic stimulation. Neurology 1997;49:1292–8.

Short interval intracortical inhibition: Variability of amplitude and threshold-tracking measurements with 6 or 10 stimuli per point

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Short interval intracortical inhibition: Variability of amplitude and threshold-tracking measurements with 6 or 10 stimuli per point

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