Hannah, R

Rocchi, L

Rothwell, JC

Tremblay, S

Wilson, E

English

UCL Discovery

lable at ScienceDirectBrain Stimulation 13 (2020) 536e538Contents lists avaiBrain Stimulationjournal homepage: http: / /www.journals .e lsevier .com/brain-st imulat ionPulse width biases the balance of excitation and inhibition recruited bytranscranial magnetic stimulationKeywords:Short-interval intracortical inhibitionMotor cortexControllable pulse parameter TMShttps://doi.org/10.1016/j.brs.2020.01.0111935-861X/© 2020 The Authors. Published by Elsevierdorsal inered viaA single transcranial magnetic stimulation (TMS) pulse isthought to recruit a mixture of excitation and inhibition in humancortex. Therefore, both the assessment of cortical excitability andthe response to repetitive TMS protocols depend on the relativerecruitment of a range of neuronal populations, each with differentphysiological characteristics. Currently, the only method for modu-lating the balance of excitation/inhibition recruited is to manipu-late pulse amplitude: some forms of inhibition in primary motorcortex have a lower threshold for recruitment than the excitationinvolved in generating a motor evoked potential (MEP) [1,2].Here, we build on recent work showing that other pulse parame-ters, such as shape and duration, influence the relative recruitmentof different excitatory neuronal populations [3e5], and test the ideathat pulse duration can be used to modulate the relative recruit-ment of excitation and inhibition.We used the short-interval intracortical inhibition (SICI) para-digm, where a sub-motor threshold pulse (conditioning pulse)has the effect of suppressing the MEP generated by a subsequentsupra-motor threshold pulse (test pulse) delivered a few millisec-onds later [2]. Our aim was to examine the effects of different con-ditioning pulse durations on the level of MEP suppression, with thefollowing rationale. First, we know that motor thresholds vary as afunction of pulse duration: brief pulses require greater pulse ampli-tudes to produce an MEP [3,5]. Second, the amplitude of the condi-tioning pulse in the SICI paradigm is typically set as a percentage ofthe motor threshold. The question then is whether different condi-tioning pulse durations, delivered at the same relative intensity (%motor threshold), produce similar SICI. If they do, then thethreshold for inhibition (SICI) and excitation (MEP) would seemto scale with one another across pulse durations, the implicationbeing that the balance of excitation/inhibition recruited by a singlepulse is preserved. Alternatively, if the inhibition differs acrosspulse durations, then excitation/inhibition thresholds do not scalewith one another. In this case, different pulse durations presumablyrecruit a different balance of excitation/inhibition.28 right-handed volunteers (13 females; age 25 ± 4 years), whoreported no contraindications to TMS, participated in two experi-ments involving TMS over the representation of the right firstInc. This is an open access article uterosseous (FDI) muscle. Conditioning pulses were deliv-a figure-of-eight coil (70mm; Magstim Company Ltd, UK)connected to a prototype controllable-pulse parameter TMS device(cTMS3, Rogue Research Inc., Canada; [6]) secured over the top of aflat, elliptical coil connected to a standard TMS device (Magstim2002, Magstim Company Ltd., UK) (Fig. 1A), which delivered testpulses. MEPs were recorded via surface electromyography.Two current directions were applied for the test and condition-ing pulses (Fig. 1A), and two pulse durations were used for the con-ditioning pulses (Fig.1B). In experiment 1 (n¼ 15), we assessed SICIat intervals corresponding to the peaks/troughs of each partici-pant’s short-interval intracortical facilitation curve (SICF; [7],Fig. 1D), using standard posterior-anterior induced currents andwith the FDI muscle at rest. These intervals were chosen to assesswhether any differences in SICI between pulse widths could infact be explained by a differential recruitment of overlapping facil-itation [8]. In experiment 2 (n ¼ 15), we wanted to explore the fulltime course of SICI, which can last up to 20 ms [9]. This is best donewith anterior-posterior pulses during weak muscle contraction(10% maximum voluntary electromyogram amplitude [9]), andsince we found no evidence of overlapping SICF in experiment 1(see Fig. 1E), we used a pragmatic range of inter-stimulus intervalsup to 20 ms (Fig. 1F).Resting and active motor thresholds (RMT and AMT) and testpulse intensity, defined at that required to produce a ~1mV MEPat rest in experiment 1 or during voluntary contraction in experi-ment 2, were determined at the start of each experiment. Followingthat, a SICI recruitment curve (2 ms inter-stimulus interval,50e110% AMT conditioning pulse intensities) was generated usingthe standard TMS device. The relative intensity (%AMT) producing~50% inhibition (experiment 1) or the greatest inhibition (experi-ment 2, because SICI can sometimes appear weaker during contrac-tion) was selected for use as the conditioning pulse in the mainexperiments. Conditioning pulse intensities for brief (30 ms) andlong (120 ms) pulses were therefore equivalent in relative terms(%AMT), despite being different in absolute terms (i.e. % maximumstimulator output, %MSO; Fig. 1C). The SICF recruitment curve inexperiment 2 was generated using 0.3 ms inter-stimulus intervals,1mV test pulse and 90%RMT conditioning pulse.Repeated-measures ANOVAwere used to evaluate the influenceof pulse width and inter-stimulus interval on SICI (expressed asMEP amplitudes normalised to the amplitude of unconditionedtest MEPs). Paired-sample t-tests were used to compare stimulusintensities and to follow-up interactions in the repeated-measures ANOVA.Data are shownmean ± SEM andMEP amplitudes are expressedrelative to those obtained with the test pulse alone. Absolute testnder the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Fig. 1. A. TMS-induced current flow for conditioning pulses and test pulses in the SICI paradigm. Curved white arrows indicate the orientation of current in the coil, whilst thestraight arrows indicate orientation of current induced in the brain. The hotspot of the conditioning coil was fixed over the centre-left part of the test coil. B. Electric fields inducedin a copper wire illustrating the waveform of the short (30 ms) and long (120 ms) duration pulses. C. Conditioning pulse intensities in Experiments 1 (posterior-anterior inducedcurrent delivered with the muscles at rest) and 2 (anterior-posterior induced current delivered with weak muscle contraction). Intensities were set at an individually determinedproportion of active motor threshold. Intensities for each pulse duration were therefore the same in relative terms (%AMT), but differed in absolute terms (%MSO). D. SICF inter-stimulus interval recruitment curve illustrating peaks and troughs of facilitation in Experiment 1. These were used to determine the SICI inter-stimulus intervals for each participant(peak 1, trough 1, peak 2, trough 2, peak 3 and trough 3). E. SICI in Experiment 1 with posterior-anterior conditioning pulses delivered at intervals corresponding to the peaks andtroughs of SICF. Repeated measures ANOVA revealed that short duration pulses elicited less SICI than long duration pulses (main effect of pulse duration: F[1,14] ¼ 8.426, P ¼ 0.012;main effect of inter-stimulus interval: F[2.79,39.07] ¼ 14.35, P < 0.001; pulse duration  inter-stimulus interval interaction: F[5,70] ¼ 0.851, P ¼ 0.519). The fact that the SICI was notsystematically different at intervals corresponding to the peaks versus troughs of SICF indicates SICF was not recruited by the conditioning pulses, and thus did not contaminate ourassessments of SICI. F. SICI in Experiment 2 with anterior-posterior conditioning pulses delivered at intervals up to 20 ms prior to the test pulse. Repeated measures ANOVA revealedthat short duration pulses elicited less SICI than long duration pulses (main effect of pulse duration: F[1,14] ¼ 12.368, P ¼ 0.003; main effect of inter-stimulus interval: F[6,84] ¼ 8.83,P < 0.001). Moreover, an interaction of pulse duration  inter-stimulus interval (F[3.67,51.34] ¼ 2.785, P ¼ 0.04) indicated that the recruitment of SICI at 2 ms was particularly weak forshort compared to long duration pulses. Significance for paired t-test indicated as follows: ***P < 0.001, *P < 0.05.R. Hannah et al. / Brain Stimulation 13 (2020) 536e538 537pulse MEP amplitudes were similar across different conditionswithin each experiment (both P > 0.19). As expected [3,5], AMTwas greater for brief pulses compared to long pulses in each exper-iment (both P < 0.001). Thus, within each experiment, the intensityof the conditioning pulse was greater for brief compared to longpulses in absolute terms (%MSO; Fig. 1C), but identical in relativeterms (%AMT; Fig. 1C).In experiment 1, brief conditioning pulses were associated withless SICI compared to longer pulses (Fig. 1E; see legend for results ofANOVA). In experiment 2, brief conditioning pulses were againassociated with less SICI compared to longer pulses (Fig. 1F; seelegend for results of ANOVA). However, an interaction ofconditioning pulse duration and inter-stimulus interval, also indi-cated that the reduction in SICI for brief pulses was particularlyprominent at 2 ms.We show for the first time that the extent and duration of SICI isinfluenced by the duration of the conditioning pulse: brief pulsesrecruit less pronounced SICI. The reason for this is probably becausethe neurones responsible for SICI are not the same as those thatgenerate MEPs, and must differ in how they respond to pulses ofdifferent duration (i.e. their stimulus strength-duration behaviour[5]). Consequently, setting the conditioning pulse intensity as a pro-portion of the motor threshold results in differential recruitment ofinhibition for different pulse durations. The main implication ofR. Hannah et al. / Brain Stimulation 13 (2020) 536e538538these results is that even when using a single TMS pulse, one willrecruit a different balance of inhibition and excitation dependingon pulse duration. This could, in part, explain why the outcomesof rTMS differ according to the pulse duration [10]. Additionally,it suggests that, similar to what has been done for excitatory neuro-nes generating the MEP [5], we might now be able to quantify thestrength-duration behavior of inhibitory neurones by tracking thethreshold required to produce inhibition of voluntary EMG [1] orSICI [2] across pulse durations.SICI at ~1 ms (including SICF peak 1 in experiment 1) appearedbroadly similar across the different pulsewidths. This confirms pre-vious work suggesting that its mechanism is different from that atlater intervals [2]. Furthermore, given that this early inhibition per-sists for both directions of current pulses (experiment 1 and 2), it isconsistent with the possibility that it relates to the neuronal refrac-tory period [2].A curious finding was that SICI with brief anterior-posteriordirected pulses produced very little inhibition at 2 ms by compari-son with the longer-lasting pulse (Fig. 1F). This suggests that briefanterior-posterior conditioning pulses recruit a distinct form of in-hibition with a later onset than typical posterior-anterior or evenlong-duration anterior-posterior pulses, though the issue requiresmore thorough investigation.We conclude that pulse duration offers a potential method withwhich to bias the relative ratio of inhibition and excitation recruitedby a TMS pulse, and that this has relevance to assessments ofcortical circuitry as well as the outcomes of rTMS protocols.Declaration of competing interestThere are no known conflicts of interest associated with thispublication and there has been no significant financial supportfor this work that could have influenced its outcome.AcknowledgementsRH and JCR were supported by a Biotechnology and BiologicalSciences Research Council grant (BB/N016793/1). ST was supportedby a Canadian Institutes of Health Research fellowship award(#MFE-14096). EW was supported by the Wolfson Foundation.References[1] Davey NJ, Romaiguere P, Maskill DW, Ellaway PH. Suppression of voluntarymotor activity revealed using transcranial magnetic stimulation of the motorcortex in man. J Physiol 1994;477(2):223e35.[2] Kujirai BT, Caramia MD, Rothwell J, Day BL, Thompson PD, Ferbert A, et al. Cor-ticocortical inhibition in human motor cortex. J Physiol 1993;471:501e19.[3] Hannah R, Rothwell J. Pulse duration as well as current direction determinesthe specificity of transcranial magnetic stimulation of motor cortex duringcontraction. Brain Stimul 2017;10(1):106e15.[4] Sommer M, Ciocca M, Chieffo R, Hammond P, Neef A, Paulus W, et al. TMS ofprimary motor cortex with a biphasic pulse activates two independent sets ofexcitable neurones. Brain Stimul 2018;11(3):558e65.[5] D’Ostilio K, Goetz SM, Hannah R, Ciocca M, Chieffo R, Chen JCA, et al. Effect ofcoil orientation on strength-duration time constant and I-wave activationwith controllable pulse parameter transcranial magnetic stimulation. ClinNeurophysiol 2016;127(1):675e83.[6] Peterchev A, D’Ostilio K, Rothwell J, Murphy D. Controllable pulse parametertranscranial magnetic stimulator with enhanced circuit topology and pulseshaping. J Neural Eng 2014;11:056023.[7] Ziemann U, Tergau F, Wassermann EM, Wischer S, Hildebrandt J, Paulus W.Demonstration of facilitatory I wave interaction in the human motor cortexby paired transcranial magnetic stimulation. J Physiol 1998;511(1):181e90.[8] Peurala SH, Müller-Dahlhaus JFM, Arai N, Ziemann U. Interference of short-interval intracortical inhibition (SICI) and short-interval intracortical facilita-tion (SICF). Clin Neurophysiol 2008;119(10):2291e7.[9] Hanajima R, Ugawa Y, Terao Y, Sakai K, Furubayashi T, Machii K, et al. Paired-pulse magnetic stimulation of the human motor cortex: differences among Iwaves. J Physiol 1998;509(Pt 2):607e18.[10] Halawa I, Shirota Y, Neef A, Sommer M, Paulus W. Longer cTMS pulse widthswitches 1 Hz inhibitory motor cortex rTMS aftereffects to excitation. BrainStimul 2019 Mar;12(2):589.Ricci Hannah*Department of Clinical and Movement Neurosciences, UCL QueenSquare Institute of Neurology, London, UKDepartment of Psychology, University of San Diego California, La Jolla,USALorenzo RocchiDepartment of Clinical and Movement Neurosciences, UCL QueenSquare Institute of Neurology, London, UKSara TremblayDepartment of Clinical and Movement Neurosciences, UCL QueenSquare Institute of Neurology, London, UKThe Royal’s Institute of Mental Health Research, Ottawa, CanadaEleanor Wilson, John C. RothwellDepartment of Clinical and Movement Neurosciences, UCL QueenSquare Institute of Neurology, London, UK* Corresponding author. University of San Diego California, La Jolla,92093, USA.E-mail address: rhannah@ucsd.edu (R. Hannah).20 December 2019Available online 14 January 2020

Pulse width biases the balance of excitation and inhibition recruited by transcranial magnetic stimulation

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Pulse width biases the balance of excitation and inhibition recruited by transcranial magnetic stimulation

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