Clinical Neurophysiology xxx (2014) xxx–xxx

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Clinical Neurophysiology

journal homepage: www.elsevier .com/locate /c l inph

On the estimation of silent period thresholds in transcranialmagnetic stimulation

http://dx.doi.org/10.1016/j.clinph.2014.03.0121388-2457/� 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

⇑ Corresponding author at: Department of Clinical Neurophysiology, KuopioUniversity Hospital, POB 100, FI-70029 KYS, Finland. Tel.: +358 503687356.

E-mail address: elisa.kallioniemi@kuh.fi (E. Kallioniemi).

Please cite this article in press as: Kallioniemi E et al. On the estimation of silent period thresholds in transcranial magnetic stimulation. Clin Neuro(2014), http://dx.doi.org/10.1016/j.clinph.2014.03.012

Elisa Kallioniemi a,b,⇑, Laura Säisänen a,c, Mervi Könönen a,d, Friedemann Awiszus e, Petro Julkunen a,b

a Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finlandb Department of Applied Physics, University of Eastern Finland, Kuopio, Finlandc Institute of Biomedicine, University of Eastern Finland, Kuopio, Finlandd Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finlande Department of Orthopaedics, Otto-von-Guericke-University, Magdeburg, Germany

a r t i c l e i n f o h i g h l i g h t s

Article history:Accepted 10 March 2014Available online xxxx

Keywords:Transcranial magnetic stimulationNeuronavigationMotor cortexThreshold curvesElectromyographySilent period

� We evaluated novel individual thresholds in measurements of corticospinal silent periods (SPs) toassess the subject-specific inhibition with transcranial magnetic stimulation.

� The use of the measured SP-thresholds decreased the inter-individual variation in SP durations whencompared with those induced in relation to the individual resting motor threshold.

� By using individual SP-thresholds the assessment of corticospinal inhibition may be improved and theeffects of excitatory components have less influence on the measurements.

a b s t r a c t

Objective: We evaluated the induction of corticospinal silent period (SP) using transcranial magneticstimulation (TMS) at stimulation intensities normalized to resting motor threshold (rMT) or silent periodthresholds (SPTs). The aim was to reduce the characteristic inter-individual variation in SP measurementsin healthy population to improve the sensitivity of such measurements.Methods: The cortical representation area of the right hand musculature of 12 healthy subjects was stim-ulated with navigated TMS with varying stimulating intensities. Subsequently, the individual SPTs foreliciting SPs of 20, 30, and 50 ms in duration were determined from the input–output characteristics.Results: While SPT for 20 and 50 ms SPs differed from rMT, the SPT for 30 ms was similar to rMT. Never-theless, the inter-individual variation in SP duration was reduced significantly at 120% of SPT30 whencompared with SP durations obtained at 120% of rMT.Conclusions: Inter-individual variation in the SP duration decreases when applying TMS at stimulationintensities normalized to the individual SPTs instead to the rMT. This makes the SP duration more specificto inhibition and less affected by changes in cortical excitability.Significance: Use of individual SPTs may improve the sensitivity of the SP measures in studies with inter-individual design.� 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights

reserved.

1. Introduction

Transcranial magnetic stimulation (TMS) is a noninvasive meth-od suitable for the assessment of motor pathways (Barker et al.,

1985). TMS focused on the motor cortex with sufficient stimulationintensity induces motor evoked potentials (MEPs) observed inelectromyography (EMG) of the contralateral muscles. An MEP re-flects the motor cortex excitability in the stimulated cortical area.The lowest stimulation intensity capable of producing an MEP ofpredefined amplitude at a 50% probability in a resting muscle(Groppa et al., 2012) is called the motor threshold (MT). The MThas a relatively constant value within a subject, but it varies greatly

physiol

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between subjects (Wassermann, 2002; Danner et al., 2008, 2012;Säisänen et al., 2008). When TMS is applied on the cortical repre-sentation area of a voluntarily contracted muscle, an MEP maybe followed by a disruption in the muscle activity, called the corti-cospinal silent period (SP) (Fuhr et al., 1991), presented in Fig. 1.With a low stimulation intensity, an SP may occur without a pre-ceding MEP (Ikeda et al., 2000). The SP is considered to reflectthe activity of inhibitory cortical gamma-aminobutyric (GABA)interneurons (Daskalakis et al., 2007), and there are indicationson the influence of both the GABAA (Inghilleri et al., 1993) andGABAB (Nakamura et al., 1997) system. The SP duration can lastup to a few hundred milliseconds. Furthermore, the SP durationis task-dependent (Tinazzi et al., 2003) and tends to increase withage (Sale and Semmler, 2005).

The SP has often been used to assess cortical inhibition (Fuhret al., 1991; Radhu et al., 2013) and plasticity (Stefan et al., 2000,2004; Quartarone et al., 2003). Abnormalities in the SP durationhave been identified in some brain disorders, such as in Parkinson’sdisease (Cantello et al., 1991), primary dystonia (Mavroudakiset al., 1995), stroke (Liepert et al., 2000), epilepsy (Kim et al.,2008) and Huntington’s disease (Priori et al., 1994). The SP dura-tion is affected strongly by the stimulation intensity (Cantelloet al., 1992; Chin et al., 2012) and muscle fatigue (Hunter et al.,2006), but it is practically independent of the strength of the con-traction force (Cantello et al., 1992; Säisänen et al., 2008). Despitethe large inter-individual variability in the SP duration, theintra-individual durations are repeatable (Roick et al., 1993).

Conventionally, SPs are induced with a suprathreshold stimula-tion intensity related to the resting MT (rMT) (Schnitzler andBenecke, 1994) or to the active MT (aMT) (Ziemann et al.,1996a), which is measured during voluntary contraction of the tar-get muscle. In addition, a few studies have introduced the conceptof SP thresholds (SPTs) that reflect directly the induction of SPs(Tergau et al., 1999; Kimiskidis et al., 2005; Lo and Fook-Chong,2005; Badawy et al., 2007). No consensus, however, exists on theoptimal way to induce SPs. Previous SP studies in neurological dis-orders and pharmaceuticals demonstrate that the neural processesbehind the SPs and the MEPs differ (Maccabee et al., 2000).Moreover, during voluntary muscle contraction the threshold foreliciting MEPs is lower than in a resting muscle, as contractiondepolarizes both corticospinal and spinal motoneurons (Hesset al., 1986; Mills and Kimiskidis, 1996). Based on these differencesbetween SP and MEP, as well as rMT and aMT, using stimulationintensities based on the rMT or aMT may not lead to reliableresults on the SP duration, and an approach based on SPTs would

Fig. 1. SP after an MEP. Data from a single subject data measured from FDI. TMSpulse was given at a time 0 ms. The vertical dashed lines indicate the beginning andthe end of the absolute SP.

Please cite this article in press as: Kallioniemi E et al. On the estimation of silen(2014), http://dx.doi.org/10.1016/j.clinph.2014.03.012

be preferable. In principle, the use of SPTs in relating stimulationintensities to induce an SP would make the measurements of SPsmore specific to the cortical inhibitory mechanisms than whenmixing the SP measurements with measures of excitability byrelating the SP induction stimulation intensities to MTs.

The SP input–output curves describe the behaviour of SP dura-tion at different stimulation intensities (Kimiskidis et al., 2005). Byconstructing these curves, it is possible to acquire more informa-tion about the behaviour of cortical inhibitory mechanisms(Kimiskidis et al., 2005). In addition, the input–output curves allowthe determination of the individual SPTs for predefined SP dura-tions in a similar fashion to the MEP input–output curves (Devanneet al., 1997; Ridding and Rothwell, 1997; Awiszus, 2005; Julkunenet al., 2011).

In the present study, we examined healthy subjects with single-pulse TMS to assess the input–output characteristics of MEP andSP. The rationale behind this was to evaluate the importance ofusing individual SPTs instead of stimulation intensities related torMT in the induction of SPs. Our objective was to improve the po-tential of SP measurements in the assessment of corticospinal inhi-bition by reducing the characteristic inter-individual variation andthereby improving specificity of the measurement to inhibitoryprocesses. This could increase the possibilities of SP in clinicalapplications by increasing both the sensitivity and the specificityin defining abnormal SPs.

2. Methods

2.1. Subjects

We studied 12 healthy right-handed volunteers (8 women, 4men, age range 22–59 years). None of the subjects suffered fromneurological diseases or had any other contraindications for TMS(Rossi et al., 2009). All the subjects signed a written informed con-sent, and the study was conducted with the approval of the localethical board (8/2012). Due to uncharacteristic SP behaviour, onefemale subject was excluded from the analysis.

2.2. Measurements

Before the TMS experiment, 3D T1-weighted magnetic reso-nance images (MRIs) were scanned of all the subjects to allowco-registration of the head of each subject and the MRIs in navi-gated TMS. The stimulation was performed with an eXimia TMSstimulator and a biphasic figure-of-eight coil (Nexstim Oy,Helsinki, Finland). During the TMS experiment, EMG was recordedfrom the right hand muscles: first dorsal interosseous (FDI), abduc-tor pollicis brevis (APB) and abductor digiti minimi (ADM) with aneXimia EMG device (Nexstim Oy, Helsinki, Finland). Analysis ofEMG was performed offline in MegaWin (version 2.5, MegaElectronics Ltd, Kuopio, Finland).

2.3. Stimulation at rest

The subjects were seated in a chair with both hands restingcomfortably on a firm pillow. The measurement session was begunby mapping the optimal representation site of the FDI on the leftM1, i.e., mapping the cortical location and electric field vector, bothof which elicited the largest amplitude MEP for FDI. To find theoptimal site, a suprathreshold stimulation intensity was used. Typ-ically, maximum MEPs at the representation area were between1–2 mV during the mapping. The individual rMT was estimatedby the TMS Motor Threshold Assessment Tool (MTAT) 2.0(Awiszus, 2003; Awiszus and Borckardt, 2012). Only MEPs of atleast 50 lV in amplitude were accepted as responses

t period thresholds in transcranial magnetic stimulation. Clin Neurophysiol

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(Groppa et al., 2012). To study the MEP input–output characteris-tics of all three muscles, the stimulations were performed atstimulation intensities of 90–150% of individual rMT at 10% inter-vals. Stimulation was provided as single-pulses with an intertrial-interval (ITI) of 4–6 s, and the order of the stimulation intensitieswas randomized. Ten pulses were given at each stimulation inten-sity (Julkunen et al., 2011). However, if the subject had trouble inmaintaining the target muscles relaxed some extra pulses were gi-ven to compensate the loss of data due to passing muscle tension.

2.4. Stimulation during voluntary contraction

Single-pulse TMS was applied to the optimal representation siteof FDI at randomized stimulation intensities varying between60–130% of rMT at steps of 10%. Ten stimuli were given per inten-sity with a fixed ITI of 12 s. Subjects were asked to squeeze a softball in both hands with equal force exerted by each finger and tokeep a constant contraction of peak-to-peak EMG of about1–2 mV. The contraction level was adjusted from the EMG displayonline and sufficient contraction in all the muscles was verifiedbefore giving a TMS pulse to ensure similar activation in each mus-cle during TMS. Both hands were activated in order to minimiseinterhemispheric inhibition as both hands had the same movementgoals (Stinear and Byblow, 2002; Giovannelli et al., 2009). Theexperimenter instructed the subject to begin muscle contractionabout 3 s before the TMS and continue the contraction until about3 s after the TMS. This stimulation experiment was divided intotwo parts with a brief break in between in order to avoid musclefatigue.

2.5. Data analysis

2.5.1. Resting motor evoked potentialContinuous EMG was divided into epochs of 150 ms, with 50 ms

before the TMS pulse and 100 ms after. The data was visually in-spected, and epochs with pre-existing muscle tension were dis-carded. Responses above 50 lV in peak-to-peak amplitude wereaccepted as MEPs, and the stimulation intensities were normalizedbased on the individual rMTs. The resting input–output character-istics of all muscles were assessed through threshold curves(Awiszus, 2005; Julkunen et al., 2011, 2012), in which the single-trial MEP amplitudes are examined as a function of stimulationintensity. The principle difference between these techniques is thatMTAT is used to determine a rMT value in an iterative manner,while a threshold curve is constructed to determine threshold val-ues based on a predetermined set of stimulation intensities. Bothmethods employ maximum likelihood estimation of threshold(Awiszus, 2003). Threshold-curve data was used to estimate SPthresholds with certain duration criteria and rMT from all studiedmuscles. From the MEP threshold curves, the estimated rMT(rMT50) was calculated for each muscle. In the analyses, the mus-cle specific rMT50 was used instead of rMT, as the rMT50 for FDIexhibited similar values to rMT (intraclass correlation = 0.99,F(10,10) = 128.92, p < 0.001). The MEP and SP threshold curveswere constructed in Matlab (version 7.5, The Mathworks, Inc.Natick, MA, USA).

2.5.2. Silent periodFor the SP analysis, the recorded EMG was divided into epochs

of 400 ms, 100 ms pre-stimulus and 300 ms post-stimulus. Theepoch length used was longer than in the resting condition to facil-itate the SP detection. The data was visually inspected, and epochswith insufficient muscle contraction were ignored. To assess theabsolute SP duration, the onset of the SP was visually defined asthe end of the TMS-induced MEP where EMG crossed the baselineand the offset as the recovery of EMG activity. For a successful SP, a

Please cite this article in press as: Kallioniemi E et al. On the estimation of silen(2014), http://dx.doi.org/10.1016/j.clinph.2014.03.012

minimum duration of 10 ms was required, and SPs shorter andmissing SPs were set to zero. From the SP data, an SP thresholdcurve similar to the MEP curve was constructed with SP durationas a function of the estimated threshold stimulation intensity.The SP threshold curve was used to calculate SP thresholds for SPdurations of 20 ms (SPT20), 30 ms (SPT30) and 50 ms (SPT50).

2.6. Statistical analysis

For statistical tests, SPSS Statistics 21.0 (IBM Corporation, Som-ers, NY) was used. Data were analysed with repeated measures AN-OVA with Least Significant Difference (LSD) post hoc test. For allinvestigated variables Mauchly’s Test of Spherity was conductedand in case the sphericity assumptions were violated, degrees offreedom were Greenhouse-Geisser corrected. The Levene test forequality of variances was used to compare inter-individual vari-ances of SPT-based with rMT50-based SP durations. The signifi-cance level in all the analyses was set to 0.05.

3. Results

3.1. Threshold curves

Threshold curves for both the resting MEP and SP are presentedin Fig. 2. The curves differed from each other; however, they had asimilar shape. With the lowest stimulation intensities, only a fewsubjects exhibited SPs. The mean values for SP durations at anintensity of rMT50 were for FDI 35.0 ± 3.5 ms, for APB31.6 ± 3.6 ms and for ADM 40.0 ± 4.0 ms.

3.2. rMT and SP thresholds

The mean and standard deviation of measured rMT, rMT50 andthe SPTs (SPT20, SPT30, and SPT50) are presented in Fig. 3. Themuscle type had a significant effect on the thresholds(F(1.16,12.74) = 6.73, p = 0.019). According to the post hoc testthere was significant difference between FDI and APB (p = 0.002),while no difference existed between FDI and ADM (p = 0.243). Thethreshold type demonstrated a significant effect (F(1.82,20.01) =20.39, p < 0.001). On a group-level the SPT20 was lower than allthe other thresholds (p6 0.002), SPT50 was greater than all theother thresholds (p6 0.019), while no significant difference wasfound between rMT50 and SPT30 (p = 0.274). Furthermore, muscleby threshold type had a significant interaction (F(6,66) = 2.62,p = 0.024).

The comparison in the inter-individual variation was comparedbetween SPT30 and rMT50, since they were most alike on thegroup-level and were hence most comparable. In the individual-levelthe inter-individual variation between SP durations at stimulationintensity of 120% of SPT30 was significantly lower than in SPs in-duced at rMT50 (F(1, 64) = 5.57, p = 0.021, Levene test) in all muscles(Fig. 4). A considerable reduction in the range of SP values was ob-served when using SPT30 instead of rMT50 (23% reduction for FDI(from 75.5 ms to 58.4 ms); 31% reduction for APB (from 78.4 ms to54 ms); 15% reduction for ADM (from 69.4 ms to 58.8 ms)).

4. Discussion

In the present study, we investigated the relevance of usingindividual SPTs in determining SP durations, whether the inter-individual variation, partly caused by the connection to MTs, couldbe reduced. SPs from the threshold curves at 120% of the SPT30were compared with SP durations at 120% of the rMT50. The mainfinding was that by applying stimulation intensity related to theindividual SPT30 instead of the rMT50, the inter-individual

t period thresholds in transcranial magnetic stimulation. Clin Neurophysiol

(A) (B)

(C)

Fig. 2. Threshold curves (Julkunen et al., 2011) for both the SP and resting MEP in FDI (A), APB (B) and ADM (C) as a function of SI normalized to the individual rMT. The curvespresent the grand average (bold and dotted line), and inter-individual variation (shaded area around the mean) which is shown as standard error of the mean.

Fig. 3. Mean and standard deviation for rMT, rMT evaluated for each muscleseparately from the threshold curve (rMT50), and SPT values for eliciting SPs of20 ms (SPT20), 30 ms (SPT30), and 50 ms (SPT50). The threshold values are shownas a percentage of maximum stimulator output (%-MSO). Significant differencesassessed with ANOVA are indicated with asterisks: p < 0.05 (⁄), p < 0.01 (⁄⁄),p < 0.001 (⁄⁄⁄).

Fig. 4. Inter-individual variation in SP duration at 120% of rMT50 and 120% ofSPT30 for FDI, APB and ADM muscle. Median and the range of individual SPdurations are shown.

4 E. Kallioniemi et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

Please cite this article in press as: Kallioniemi E et al. On the estimation of silen(2014), http://dx.doi.org/10.1016/j.clinph.2014.03.012

variability in SP duration is reduced. This may be because the SPTscan account for the inter-individual variations in the inhibition-excitation balance (Vaalto et al., 2011).

The results support the previous findings in that the origin andprocesses behind the MEP and SP differ (Maccabee et al., 2000). Inaddition, such a distinction is also supported by earlier studieswhich have observed that SPs can be induced with lower intensi-ties than MEPs (Triggs et al., 1992; Wassermann et al., 1993) andvoluntary contraction levels affect differently to MEP and SP(Cantello et al., 1991, 1992; Inghilleri et al., 1993). Moreover, theSPs and the MEPs do not have similar dependence on stimulationintensity (Inghilleri et al., 1993). There is also some evidencethat SPs and MEPs might have a different cortical topography(Wassermann et al., 1993). However, there are also studies wheresimilar topographies have been revealed (Wilson et al., 1993). The

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duration of SPs can vary largely, and the time course of GABAreceptors have been addressed to explain this variability as GABAA

modulates short-lasting potentials and GABAB, on the other hand,modulates long-lasting potentials (Keller, 1993). This view on theGABA origin of SPs is also supported by pharmacological studies(Werhahn et al., 1999). The characteristics of MEPs, on the con-trary, are influenced by voltage-gated ion channels (Ziemannet al., 1996b). In agreement with this contrast, we found that aver-age rectified values (ARV) of pre-stimulus EMG and active MEPswere affected by muscle fatigue, which did not affect SP durations(data not shown). This suggests SP to be a purely inhibitory phe-nomenon and it is not confused by voluntary excitation parameterslike the ARV or the active MEP. Importantly, all these mentioneddifferences propose that using personalized stimulation intensitiesrelated to SPTs may lead to more sensitive SP measurements andprovides information more specifically about the corticospinalinhibition unlike when relating SPs to MTs, which could potentiallymake SP measurements prone to errors caused by changes purelyin the excitatory system.

Several approaches to SPTs have previously been presented.SPTs have been characterized as a predefined intensity level(Ahonen et al., 1998), as an intensity eliciting a certain durationof SP in a percentage of epochs (Badawy et al., 2007), as an inten-sity inducing a certain reduction in voluntary EMG (Tergau et al.,1999), or through stimulus–response curves (Kimiskidis et al.,2005). Our findings suggest that SPTs need to be individualized,and therefore the use of pre-set stimulation intensities should beavoided. Use of fixed intensities might lead to inaccurate resultson the cortical inhibitory state as they do not consider the inter-individual variability in SP duration (Roick et al., 1993).

In this study, the mean rMT50 was significantly higher than themean of the smallest SPT, SPT20, for the target muscle FDI. Expect-edly, the SPTs of all the studied muscles rose with an increasingthreshold criterion for SP duration resulting from the known stim-ulation intensity dependence of the SP duration (Kimiskidis et al.,2005; Säisänen et al., 2008). The SPTs determined with differentthreshold duration criteria (20, 30 or 50 ms) differed from eachother. Instead, rMT50 and SPT30 demonstrated similar values.After comparing the variation of the individual SP duration, wefound that with SPT30 the inter-individual variation in SP durationwas lower than with rMT50 (Fig. 4). This is because the SPTs takeinto account the within-individual variation in the inhibition–exci-tation balance.

A limitation of this study is that we did not test, if aMT wouldprovide a better dose scaling for SP compared to rMT or SPT30.Our experiments were performed at such high contraction levelsthat meaningful estimates for aMT were not obtainable. However,we consider it unlikely that aMT could outperform SPT30 as it is anexcitatory measure that has a limited sensitivity for inhibitory net-work investigations (Groppa et al., 2012).

The SP threshold curves (Julkunen et al., 2011) may be a reliablemethod to quantify the behaviour of SP and monitor the corticospi-nal inhibition by quite effectively excluding the excitatory corticaleffects. In addition, threshold curves reduce the time needed to ob-tain MTs of several muscles and the analysis can be made automat-ically. Obviously, some excitatory effect may be observed since thepre-SP muscle activation level can be predefined, and the muscleactivation level may have a mild to practically negligible effecton the detected SP duration (Inghilleri et al., 1993; Wu et al.,2002). In addition, there are subjects having an abnormal SPbehaviour for which the threshold curve is not suitable.

In conclusion, the present study emphasizes the importance ofusing individual SPTs in the assessment of SPs. We demonstratedthat the use of these SPTs assessed individually will reduce the in-ter-individual variation in SP durations by reducing the excitatoryvariation component conventionally included in the SP duration

Please cite this article in press as: Kallioniemi E et al. On the estimation of silen(2014), http://dx.doi.org/10.1016/j.clinph.2014.03.012

measurements via inclusion of MTs in the assessment methodol-ogy. These findings demonstrate that SP durations could be a moresensitive measure in studies investigating inter-individual effectsin corticospinal inhibition.

Acknowledgements

The study was funded by the Kuopio University Hospital, Kuo-pio, Finland (EVO 5041730 and 5041736), Orion-Farmos ResearchFoundation, Espoo, Finland, Kaute Foundation, Helsinki, Finland,and The Finnish Brain Research and Rehabilitation Center Neuron,Kuopio, Finland.

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