Epilepsy Research 72 (2006) 18–24

A single dose of sulthiame induces a selective increase inresting motor threshold in human motor cortex: A transcranial

magnetic stimulation study

Michael Siniatchkin a,∗, Sergey Groppa a, Hartwig Siebner b, Ulrich Stephani a

a Neuropediatric Department, Christian-Albrechts-University, Kiel, Germanyb Department of Neurology, Christian-Albrechts-University, Kiel, Germany

Received 28 March 2006; received in revised form 3 June 2006; accepted 4 July 2006Available online 22 August 2006

Abstract

Sulthiame is a carbonic anhydrase inhibitor that is widely used to treat partial and myoclonic seizures. In 11 healthy adults,we applied transcranial magnetic stimulation (TMS) to the primary motor cortex. Using a cross-over study design, we foundthat a single oral dose of sulthiame (5 mg/kg) produced a significant increase of resting motor threshold relative to placebo. Noother TMS measure of corticomotor excitability was altered after a single dose of sulthiame. The selective increase in motorthreshold suggests that sulthiame produces its antiepileptic effect by reducing the axonal excitability of cortical neurons.

© 2006 Published by Elsevier B.V.

Keywords: Sulthiame; Transcranial magnetic stimulation; Cortical excitabi

Abbreviations: AED, antiepileptic drugs; APB, abductor policisbrevis; CSP, cortical silent period; EMG, electromyography; ICI,intracortical inhibition; ICF, intracortical facilitation; MEP, motorevoked potential; RMT, resting motor threshold; TMS, transcranialmagnetic stimulation

∗ Corresponding author at: Pediatric Neurology, Schwanenweg 20,D-24105 Kiel, Germany. Tel.: +49 431 597 1771;fax: +49 431 5497 1659.

E-mail address: m.siniatchkin@pedneuro.uni-kiel.de(M. Siniatchkin).

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0920-1211/$ – see front matter © 2006 Published by Elsevier B.V.doi:10.1016/j.eplepsyres.2006.07.001

lity; Ion channels

. Introduction

Sulthiame (STM) has been used since 1960 for treat-ent of benign focal epilepsies in childhood (Bast et

l., 2003; Rating et al., 2000), West syndrome (Debusnd Kurlemann, 2004), myoclonic seizures (Gross-elbeck, 1995), and as add-on therapy for children withefractory epilepsies (Brockmeier, 2003). The anti-onvulsant effect of this sulfonamide derivative has

een reproduced in several in vitro and animal mod-ls of epileptic activity. It has been demonstrated thatulthiame inhibits the enzyme carbonic anhydrase inlial cells, increases the carbon dioxide concentration

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nd leads to an acidification of the extracellular fluidLeniger et al., 2002). This results in a reduction ofhe inward currents operated by NMDA receptors andalcium currents, causing a depression of intrinsic neu-onal excitability (Iijima et al., 1986; Tang et al., 1990).ulthiame has also been found to alter voltage-operatedodium currents (Madeja et al., 2001) and to reduce theoncentration of the excitatory neurotransmitter gluta-ate (Patsalos and Lascelles, 1981) in the hippocam-

us of rats and guinea pigs, as well as the concentrationf the inhibitory neurotransmitter �-aminobutyric acidGABA) in cerebral hemispheres of mice (Saad, 1976).owever, it is still unclear which effect accounts for the

nticonvulsant properties of sulthiame in humans.Transcranial magnetic stimulation (TMS) of the

ntact human motor cortex offers an array of measures,hich can be used to investigate distinct aspects of

ortical excitability. For instance, the threshold inten-ity that is necessary to induce a motor responsemotor threshold) depends on the axonal excitabil-ty of the cortical neuronal elements that are primar-ly activated by the transcranial magnetic stimulus,hile other TMS measures allow to assess distinct

orms of inhibitory and excitatory synaptic excitabil-ty (Ziemann et al., 2004). This array of TMS mea-ures has been successfully used to characterize theode of action of antiepileptic drugs (AEDs) in vivo

Ziemann, 2004). Several TMS studies have consis-ently shown that drugs which block voltage-gatedodium channels such as carbamazepine (Ziemann etl., 1996; Schulze-Bonhage et al., 1996), phenytoinMavroudakis et al., 1994; Chen et al., 1997), lamot-igine (Ziemann et al., 1996a; Boroojerdi et al., 2001;ergau et al., 2003), and levitiracetam (Reis et al.,004) primarily increase the motor threshold withoutroducing consistent effects on paired-pulse inhibitorynd excitatory synaptic excitability. Conversely, AEDsith GABA-ergic and glutamate-antagonistic proper-

ies such as topiramate (Reis et al., 2002), vigabatrinMavroudakis et al., 1997) and diazepam (Inghillerit al., 1996) have no effect on the motor thresh-ld but modify measures of intracortical synapticxcitability such as short-latency intracortical inhibi-ion (SICI) or intracortical facilitation (ICF). Addition-

lly, some GABA-ergic compounds such as lorazepamZiemann et al., 1996b) and tiagabin (Werhahn etl., 1999) increase the duration of the cortical silenteriod (CSP), which is thought to depend on synaptic

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xcitability of GABA-B ergic circuits (Siebner et al.,998).

In the present study, we used an array of well-definedMS measures to characterize the acute effects of sulth-

ame on motor cortex excitability in healthy adults. Weeasoned that the profile of acute excitability changesould provide important insights into the anticonvul-

ant mode of action of sulthiame.

. Subjects and methods

.1. Subjects

Eleven healthy, right-handed volunteers (seven mannd four women, mean age 28.7 ± 7.9, range 22–42ears) were recruited from the hospital staff. Allubjects fulfilled the following criteria: no metallicmplants or electrical devices, no previous history ofny neurological or psychiatric disorder, drug abuse, orlcoholism. Participants were interviewed about theirtate of health and were not taking any medicationn the days of experiment. None of the subjects hadny experience with AEDs and TMS. All gave writtennformed consent. The study was conducted accordingo the Declaration of Helsinki and was approved by thenstitutional review board.

.2. Measures of motor cortex excitability

TMS measurements were performed according tohe procedures that have been used in previous neu-opharmacological TMS studies (Reis et al., 2002,004; Tergau et al., 2003; Ziemann et al., 1996a,). TMS was given to the right primary motor handrea using a standard figure-of-eight-shaped coil and aagstim 200 magnetic stimulator (Magstim, Whitland,yfed, UK, peak magnetic field 2.2 T). The magnetic

timulus had a nearly monophasic pulse configurationith a rise time of approximately 100 �s, decayingack to zero over approximately 0.8 ms. The coil cur-ent during the rising phase of the magnetic field flowedoward the handle. The coil was placed tangentially tohe scalp with the handle pointing antero-medially at a

5◦ angle from the midline. The monophasic stimulusnduced a current in the brain flowing from posterioro anterior, approximately perpendicular to the cen-ral sulcus. We determined the optimal position for

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timulation by moving the coil in 0.5 cm steps aroundhe presumed primary motor hand area. The coil waslaced over the site where slightly suprathreshold stim-li evoked a maximal EMG response in the relaxed leftPB muscle (referred to as motor hot spot). The motorot spot was marked with a pen by drawing a semilunarine following the anterior bifurcation of the coil and atraight line indicating the orientation of the coil han-le. This enabled us to maintain a constant coil positionhroughout the experiment.

Motor-evoked potentials (MEP) were recorded withg/AgCl surface EMG electrodes (9 mm diameter)

rom the left abductor policis brevis (APB) musclesing a belly-tendon montage. The EMG raw sig-al was amplified (EMG device Neuropack 2, Nihonodhen, Shinjukuku, Tokyo, Japan), bandpass-filtered

1 Hz–10 kHz), digitized at a frequency of 5 kHz, andtored on a PC (CED 1622 Micro and Signal 3.0 soft-are, Cambridge Electronic Design, Cambridge, UK).he absence of any voluntary activity in the APB mus-le was continuously monitored to ensure completeelaxation throughout the TMS measurements.

First, we measured the resting motor thresholdRMT), which has been used in previous neurophar-acological studies to probe drug induced changes in

ortical axonal excitability (Ziemann et al., 2004). TheMT was defined as the minimum stimulation intensityecessary to induce a MEP in five out of 10 consecu-ive trials (Rossini et al., 1999). During measurementsf RMT, we first used a suprathreshold intensity, whichas gradually reduced in 1% steps of maximal stim-lator output until this criterion was met. We did noterform additional measurements of the motor thresh-ld during tonic pre-activation of the target muscleecause in previous neuropharmacological TMS stud-es, drug effects always produced analogous changes in

otor threshold at rest and during tonic pre-activationZiemann et al., 1996a; Manganotti et al., 1999; Reist al., 2004).

To estimate the relationship between stimulus inten-ity and the MEP amplitude, we applied single-pulsetimuli at 110%, 130% and 150% of individual RMT.t any stimulus intensity, we recorded 10 consecutiveEPs in the relaxed APB muscle. For any stimulus

ntensity, the mean MEP amplitude was calculated tostimate the stimulus–response curve. The same TMSrotocol was repeated while participants performed aoderate tonic contraction of the left APB muscle at

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0% of maximum force level. We recorded 10 consec-tive EMG traces (400 ms) which were triggered byingle-pulse TMS at 110%, 130% and 150% of indi-idual RMT. The duration of the cortical silent periodCSP) was measured in each trial and defined as theeriod between the first turning point of the MEP andhe first reoccurrence of voluntary EMG activity. The

ean duration of the CSP was calculated for any inten-ity of stimulation.

The paired-pulse technique described by Kujirait al. (1993) was employed to probe intracorticalxcitability of the right motor cortex Paired magneticulses were generated by two high power Magstim 200timulators connected by a Bistim module and deliv-red to the motor hot spot through the same figure-of-ight coil that was used for single-pulse TMS (Magstimompany, Whitland, Dyfed, UK). The intensity of theonditioning stimulus was adjusted to 70% of individ-al RMT, while the intensity of the test stimulus waset at 120% of individual RMT. Paired-pulse TMS usednterstimulus intervals (ISIs) of 2 or 15 ms. An ISI ofms was chosen to assess intracortical inhibition (ICI),nd an ISI of 15 ms was used to probe intracortical facil-tation (ICF). In addition, we applied single pulses at20% of RMT without a conditioning stimulus (i.e. testtimulus alone). Stimulation conditions were pseudo-andomly intermingled and 15 MEPs were recorded forach stimulation condition. The inter-trial interval wasandomly jittered between 7 and 15 s. To measure theelative strength of ICI and ICF, the amplitudes of theonditioned MEPs were measured from peak to peakmV) and averaged for each condition. Mean peak-to-eak amplitude of the conditioned MEP responses werexpressed as a percentage of the unconditioned MEPesponse (=100%).

.3. Experimental procedures and statistics

Using a placebo-controlled, cross-over studyesign, we measured corticomotor excitability imme-iately before and 2 h after a single oral dose of 5 mg/kgulthiame or placebo. Each subject participated in twoeasurements (verum versus placebo), which were

erformed in a counterbalanced order at least 1 week

part. The dosage of sulthiame as well as the tim-ng of TMS was based on the known pharmacoki-etics and pharmacodynamics of sulthiame. The com-only prescribed single oral dosage is 5 mg/kg, and the

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aximal dose of sulthiame is 10 mg/kg a day dividednto two single dosages (Bast et al., 2003; Debus andurlemann, 2004; Gross-Selbeck, 1995; Rating et al.,000). TMS measurements were performed 2 h aftersingle oral dose of sulthiame or placebo, because

eak concentrations and the maximal effect is reachedpproximately 2 h after drug intake (May et al., 1991).

Though blinded assessment of cortical excitabilityould have been desirable, this was not possible in

he present study because almost all subjects exhibitedbvious side effects after taking sulthiame but not afterlacebo medication. These side effects included mildyperventilation, paraesthesia, nausea, restlessness butone of the participants reported significant sedation.owever, since the within-subject test–retest reliabil-

ty of TMS measures has shown to be high (Maeda etl., 2002; Wassermann, 2002; Malcolm et al., 2006),nblinded assessment of corticospinal excitability wastill reliable. It should also be noted that we had nopriori prediction regarding the pattern of excitability

hanges caused by sulthiame, which might have biasedhe experimenter towards a specific change in excitabil-ty.

Because the data were normally distributednd characterized by homogenous variancesKolmogorov–Smirnoff test), five separate repeated-easures analyses of variance (ANOVA) were

erformed using the RMT, stimulus–response curve,SP, ICI and ICF as dependent variables. The ANOVAodel was two-factorial with the within-subject

actors time of measurement (before medicationersus 2 h after medication) and drug (sulthiameersus placebo). For the stimulus–response curvend the CSP measurements, the intensity of TMS

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able 1eans and SD of TMS measures of corticospinal excitability before and 2 h

Sulthiame

Before medication During

MT (% of stimulator output) 43.3 ± 5.7 45.8 ±EP at 110% (mV) 0.29 ± 0.19 0.37 ±EP at 130% (mV) 0.86 ± 0.47 1.14 ±EP at 150% (mV) 2.13 ± 1.29 2.15 ±SP at 110% (ms) 73.3 ± 35.5 78.2 ±SP at 130% (ms) 113.1 ± 44.4 124.1 ±SP at 150% (ms) 144.3 ± 45.4 145.9 ±

CI (conditioning/test ratio) 0.30 ± 0.16 0.41 ±CF (conditioning/test ratio) 1.35 ± 0.25 1.53 ±

esearch 72 (2006) 18–24 21

as included as additional factor in the ANOVAodel. Significance level was corrected for multiple

omparisons using the Bonferroni method and wasccepted at p < 0.010.

. Results and discussion

Table 1 summarizes the mean data for each exper-mental condition. Using the RMT as dependent vari-ble, ANOVA revealed no main effect of time ofeasurement or drug for any measure of cortico-otor excitability (p > 0.2). There was, however, an

nteraction between time of measurement and drugF (1, 11) = 13.57; p = 0.004]. Fig. 1 illustrates indi-idual changes in RMT after a single dose of sulth-ame and placebo. Sulthiame led to an increase inhe motor threshold in nine out of 11 participants,hereas placebo had no consistent effect on the RMT.or the other measures of corticomotor excitability,NOVA showed no main effects time of measurement

nd drug as well as no interaction between time ofeasurement and drug (p > 0.2) indicating that sulth-

ame specifically increased the RMT without modi-ying the stimulus–response curve, ICI, ICF or CSPompared with placebo. The main effect intensity ofMS was significant for both the CSP duration [F (2,2) = 67.12, p < 0.001] and MEP amplitudes within thetimulus–response curve [F (2, 22) = 18.74; p < 0.001].his effect underlines the validity of TMS data demon-

trating a significant increase of the CSP duration and

EP amplitude with increasing TMS intensity. Thereere no significant interaction between intensity ofMS and other factors.

after a single dose of sulthiame or placebo

Placebo

medication Before medication During medication

5.6 42.2 ± 5.9 42.1 ± 5.80.13 0.33 ± 0.16 0.35 ± 0.180.97 0.81 ± 0.46 1.12 ± 0.981.41 1.98 ± 1.51 1.99 ± 1.8331.7 93.3 ± 29.2 85.5 ± 30.943.3 137.3 ± 37.3 139.7 ± 43.249.2 163.3 ± 40.3 154.8 ± 45.90.24 0.46 ± 0.31 0.57 ± 0.470.58 1.47 ± 0.92 1.39 ± 0.56

22 M. Siniatchkin et al. / Epilepsy Research 72 (2006) 18–24

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Our results show that a single dose of sulthiameauses an acute decrease in axonal excitability asndexed by an increase in RMT, but did not modifyMS measures of intracortical synaptic excitability.his profile is identical to the acute cortical effects ofnticonvulsive drugs that block voltage-gated sodiumhannels (Boroojerdi et al., 2001; Chen et al., 1997;avroudakis et al., 1997; Reis et al., 2004; Schulze-onhage et al., 1996; Tergau et al., 2003; Ziemann etl., 1996a). Though we did not assess changes in spinalnd peripheral excitability, we propose that sulthi-me influences the excitability of cortico-cortical andortico-spinal axons because previous studies did notemonstrate any effect of sodium channel blockers onpinal or peripheral excitability (Ziemann et al., 1996;oroojerdi et al., 2001). It is also unlikely that the

ncrease in RMT was caused by an unspecific sedativeffect of sulthiame, because sulthiame produced no orittle sedation in our participants. Moreover, other seda-ive antiepileptic drugs, which influence the GABA-rgic system have no effect on the motor threshold butodify the strength of intracortical inhibition or facil-

tation (Ziemann, 2004).In the present study, hyperventilation was a fre-

uent side effect of sulthiame. This begs the questionhether drug induced hyperventilation contribute to

he changes in RMT after sultiame intake? Several stud-es have used TMS to assess the impact of hyperventi-ation on corticospinal excitability in healthy subjects.

hese studies reported an increase in MEP amplitudet rest (Kukumberg et al., 1996; Seyal et al., 1998) orshortening of the CSP (Priori et al., 1995), but foundo effects on RMT. Since a single dose of sulthiame

B

ose of sulthiame (A) or placebo (B) in 11 healthy subjects.

roduced no effects on the mean MEP amplitude andhe duration of the CSP, the increase in RMT cannot bettributed to hyperventilation.

Our results would be compatible with the notionhat sulthiame exerts its anticonvulsive effect in humansy reducing the conductivity of voltage-gated sodiumhannels. In good agreement with this hypothesis,ulthiame has been shown to reduce voltage-operatedodium currents in isolated hippocampal neurons fromuinea pig (Madeja et al., 2001). This mechanismlocked the generation of repetitive action poten-ials in cortico-cortical axonal connections. Lenigert al. (2002) demonstrated that sulthiame induces aodest intracellular acidification of CA3 hippocam-

al neurons. This acidification was accompanied byreversible decrease in epileptiform activity, whichas related to blocking axonal bursts of action poten-

ials. The shift in intracellular pH value has been showno produce multiple inhibitory effects on the functionf sodium and calcium channels (Traynelis, 1998).herefore, we propose that the inhibition of carbonicnhydrase activity lowers the intracellular pH and thus,educes the amount of transmembrane ion currents andncreases the threshold for generating action potentials.his mechanism may explain the selective increase inMT after a single oral dose of sulthiame.

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