Clinical Neurophysiology 115 (2004) 1717–1729

www.elsevier.com/locate/clinph

Invited review

TMS and drugs

Ulf Ziemann*
Motor Cortex Laboratory, Clinic of Neurology, Johann Wolfgang Goethe University Frankfurt,
Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany

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Accepted 5 March 2004

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Available online 10 April 2004

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Abstract

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The application of a single dose of a CNS active drug with a well-defined mode of action on a neurotransmitter or neuromodulator system
may be used for testing pharmaco-physiological properties of transcranial magnetic stimulation (TMS) measures of cortical excitability.
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Conversely, a physiologically well-defined single TMS measure of cortical excitability may be used as a biological marker of acute drug
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effects at the systems level of the cerebral cortex. An array of defined TMS measures may be used to study the pattern of effects of a drug with
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unknown or multiple modes of action. Acute drug effects may be rather different from chronic drug effects. These differences can also be
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studied by TMS measures. Finally, TMS or repetitive TMS by themselves may induce changes in endogenous neurotransmitters or
neuromodulators. All these possible interactions are the focus of this in-depth review on TMS and drugs.
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q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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Keywords: Transcranial magnetic stimulation; Neuropharmacology; CNS active drugs; Motor cortical excitability; Motor evoked potential; Corticospinal
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projection; Human
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1. Introduction anaesthetics may acutely reduce corticospinal excitability.

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The knowledge, to which extent different anaesthetics are

What are the main topics that come to mind when doing this, is very important in the setting of intraoperative
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thinking about transcranial magnetic stimulation (TMS) and monitoring of corticospinal tract integrity. Sixth, TMS and
drugs? First, drugs with a known mode of action may be repetitive TMS (RTMS) by themselves may result in
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used to explore physiological properties of TMS measures changes in the concentration and release of endogenous
of motor excitability. The typical experimental setting is the CNS active substances, such as neurotransmitters and
administration of a single dose of the study drug and to neuromodulators. Knowledge about these effects would be
obtain TMS measures before and at one or several time important, if TMS and RTMS are used for therapeutic
points after drug intake. This application proved to be purposes. This review will present an in-depth survey on all
extremely useful in promoting a better understanding of of these topics. It will be limited to research in healthy
what is measured with TMS. Second, a single well-defined subjects though because drug effects on TMS measures in
TMS measure may be used as biological marker of acute patients with CNS disorders may deviate unpredictably
drug effects. Typically, this is tested in drug concentration— from the effects obtained in the intact brain.
drug effect relationships. Third, an array of well-defined
TMS measures may be used to identify modes of action of a
study drug at the systems level of the human motor cortex, if
2. Effects of CNS active drugs with a known mode
these modes of action are not known or complex. Fourth,
of action on TMS measures of motor excitability
chronic drug effects on TMS measures may be different
from acute ones. Knowledge about chronic versus acute
drug effects is important, if drug effects in the setting of The reviewed studies were always designed to compare
long-term treatment shall be predicted. Fifth, particular TMS measures at one or several time points after drug
intake with one baseline measure before drug intake. Some
* Tel.: þ49-69-6301-5739; fax: þ49-69-6301-6842. studies added a placebo control in a randomised and blinded
E-mail address: u.ziemann@em.uni-frankfurt.de (U. Ziemann). parallel or crossover design to minimise experimenter bias.
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2004.03.006
1718 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729

This chapter will review drug effects separately for (benzodiazepines, barbiturates), DA agonists (cabergoline,
the different TMS measures of motor cortical and own unpublished observation) and one NE antagonist
corticospinal excitability. (guanfacine). In contrast, MEP amplitude increases after
application of DA antagonists (haloperidol, own unpublished
2.1. Motor threshold observation), various NE agonists (methylphenidate,
d-amphetamine, reboxetine, yohimbine), one serotonin
Motor threshold is most often defined as the minimum re-uptake inhibitor (sertraline), and one muscarinic receptor
intensity that is necessary to elicit a small (usually (M1) antagonist (scopolamine) (Table 1). These effects are
. 50 mV) motor evoked potential (MEP) in the target most likely explained by the complex and hitherto only
muscle in at least half of the trials (Rossini et al., 1999). incompletely understood modulating effects of DA, NE,
Motor threshold is lower in the voluntarily contracting 5-HT and ACh on inhibitory and excitatory synaptic
muscle (active motor threshold, AMT) compared to the transmission in neocortical neuronal networks (Hasselmo,
resting muscle (resting motor threshold, RMT), usually by 1995). In several instances, changes in MEP amplitude
about 10% of maximum stimulator output (Devanne et al., occurred without significant changes in motor threshold

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(Table 1), supporting the notion (see above) of a fundamental
1997). It may be expected that motor threshold depends on

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difference in physiology between the two measures.
the excitability of those elements, which are activated by
TMS. Most likely, these are cortico-cortical axons

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2.3. Cortical silent period
(Amassian et al., 1987; Shimazu et al., 2004), and their

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excitatory synaptic contacts with the corticospinal neur-
Cortical silent period (CSP) refers to a TMS induced
ones. Voltage-gated sodium channels are crucial in
regulating axon excitability (Hodgkin and Huxley, 1952), h
interruption of voluntary activity in the EMG of the target
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muscle. CSP duration increases approximately linearly
while ionotropic non-NMDA glutamate receptors are
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with stimulus intensity and may reach 200– 300 ms in hand
responsible for fast excitatory synaptic neurotransmission
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muscles (Cantello et al., 1992). While spinal inhibition

in neocortex (Douglas and Martin, 1998). Accordingly, it
contributes to the early part of the CSP, the late part
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was found that drugs which block voltage-gated sodium

originates in supraspinal structures, most likely the motor
channels (Boroojerdi et al., 2001; Chen et al., 1997;
cortex (Fuhr et al., 1991; Inghilleri et al., 1993; Ziemann
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Mavroudakis et al., 1994; Ziemann et al., 1996c) elevate

et al., 1993). It was proposed that the late part of the CSP is
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motor threshold, while the NMDA antagonist ketamine that

caused by a long-lasting cortical inhibition mediated by
may indirectly increase neurotransmission through the
GABAB receptors because the GABA re-uptake inhibitor
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AMPA receptor decreases it (Di Lazzaro et al., 2003)

tiagabine lengthened the CSP (Werhahn et al., 1999). This
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(Table 1). Acute modulation of other neurotransmitter and

is consistent with the duration of the inhibitory post-
neuromodulator systems (GABA, dopamine (DA), norepi-
synaptic potentials (IPSPs) elicited by GABAB receptor
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nephrine (NE), serotonin (5-HT) or acetylcholine (ACh))

activation, which is in the range of several hundred
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has no significant effects on motor threshold (Table 1).

milliseconds (Connors et al., 1988). The meta-analytic
evidence from pharmacological TMS experiments in
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2.2. Motor evoked potential amplitude

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favour of a GABAB receptor mediated inhibition is

relatively weak, though (Table 1). In two studies, the
Motor evoked potential (MEP) amplitude increases with GABAB receptor agonist baclofen did not lead to a
stimulus intensity in a sigmoid fashion (Devanne et al., lengthening of the CSP (Inghilleri et al., 1996; Ziemann
1997). At low stimulus intensity, the corticospinal volley et al., 1996c). However, the applied dosages were probably
resulting in the MEP often consists of only one single wave too low to result in an effective drug concentration in the
(I1-wave if the current induced by TMS in the brain runs in brain. One patient with generalised dystonia who was
posterior-to-anterior direction), while the corticospinal treated with incremental doses of intrathecal baclofen
volley becomes more complex and consists of multiple showed a significant lengthening of the CSP, starting at
I-waves (I2 – I4 in addition to I1) at higher stimulus intensity 1.000 mg/d (Siebner et al., 1998). However, a contribution
(Di Lazzaro et al., 2004). In contrast to the I1-wave the later by an increase in GABAB mediated spinal inhibition to
I-waves are modifiable by many processes, and it is very that effect was not ruled out. Furthermore, L-DOPA and
likely that they originate through a chain of cortical DA agonists appear to lengthen the CSP (Priori et al.,
excitatory inter-neurones (Amassian et al., 1987; Ziemann 1994; Ziemann et al., 1996a), which is consistent with a
and Rothwell, 2000). Accordingly, it may be expected that dopamine-induced enhancement of post-synaptic sensi-
neurotransmitters (glutamate, GABA) and modulators of tivity to GABA in animal preparations (Beauregard and
neurotransmission (DA, NE, 5-HT, ACh) influence MEP Ferron, 1991), and the shortened CSP in patients with a
amplitude, particularly in the high-stimulus intensity range. cortical dopaminergic deficit, such as patients with
It was found that MEP amplitude decreases after Parkinson’s disease (Cantello et al., 2002). One important
application of allosteric modulators of the GABAA receptor potential confounding effect in CSP measurements is
 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729 1719

Table 1
Acute drug effects on TMS measures of motor cortical excitability

Drug Mode of action MT MEP CSP SICI ICF SICF Literature

Carbamazepine Naþ OW W W WW WP W Ziemann et al. (1996c)

Schulze-Bonhage et al. (1996)
Phenytoin Naþ OO WW WW Chen et al. (1997)
Mavroudakis et al. (1994)
Lamotrigine Naþ OOO P W WW WW W Ziemann et al. (1996c)
Boroojerdi et al. (2001)
Tergau et al. (2003)
Valproic acid Na þ /GABA W W W W Ziemann et al. (1999)
Lorazepam GABAA WWW PP O OOW PW P Ziemann et al. (1996b)
Boroojerdi et al. (2001)
Di Lazzaro et al. (2000a)
Diazepam GABAA WW PW PW OW P P Inghilleri et al. (1996)

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Palmieri et al. (1999)

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Ilic et al. (2002b)
Thiopental GABAA W P W Inghilleri et al. (1996)
Ethanol GABAA W W O O P Ziemann et al. (1995)

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Progesterone GABAA W O W Smith et al. (1999)

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Flumazenil GABAA antagonist W W W W W Jung et al. (2004)
Vigabatrin GABA W WW WW W P P Ziemann et al. (1996c)

h Mavroudakis et al. (1997)

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Tiagabine GABA W W O P O Werhahn et al. (1999)
Baclofen GABAB WW WW WW O P W Ziemann et al. (1996c)
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Inghilleri et al. (1996)
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Dextrometorphan NMDA antagonist W W W O P Ziemann et al. (1998a)

Memantine NMDA antagonist WW W W O P W Ziemann et al. (1998c)
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Schwenkreis et al. (1999)

Riluzole Anti-GLU WW WW OW PP Liepert et al. (1997)
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Schwenkreis et al. (2000)

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Ketamine NMDA antagonist P O W W W Di Lazzaro et al. (2003)

L-DOPA DA precursor W W O W W Priori et al. (1994)
Ziemann et al. (1997)
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Bromocriptine DA agonist W O W Ziemann et al. (1997)

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Pergolide DA agonist W W O O W Ziemann et al. (1996a)

Cabergoline DA agonist W P W O P P (own unpublished observations)
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Selegiline MAO-B inhibitor W W W Ziemann et al. (1997)

Haloperidol DA antagonist WW O W PW O Ziemann et al. (1997)
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(own unpublished observations)

Daskalakis et al. (2003)
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Sulipiride DA antagonist W W W Ziemann et al. (1997)

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Olanzapine DA/5HT2A antagonist W W W Daskalakis et al. (2003)

Methylphenidate NE agonist WW O W PW WO Ilic et al. (2003)
Moll et al. (2003)
d-Amphetamine NE/DA agonist W O W O Boroojerdi et al. (2001)
Reboxetine NE re-uptake inhibitor WP O PW OO Plewnia et al. (2002)
Herwig et al. (2002)
Yohimbine a2 Antagonist W O W O Plewnia et al. (2001)
Prazosin a1 Antagonist W W W W Sawaki et al. (2003)
Guanfacine a2 Agonist W P O P Korchounov et al. (2003)
Sertraline SSRI W O W W P Ilic et al. (2002a)
Citalopram SSRI W O W Eichhammer et al. (2003)
Zolmitriptan 5-HT1B/1D agonist W W W P W Werhahn et al. (1998)
Atropine M1/M2 antagonist W W W P O Liepert et al. (2001)
Scopolamine M1 antagonist P O W W W Di Lazzaro et al. (2000b)

Drugs are grouped according to main mode of action. W, no effect; P, reduction; O, increase; Naþ, blockade of voltage-gated sodium channels; GABAA, agonist
at the GABAA receptor; GABAB, agonist at the GABAB receptor; GABA, increase of GABA in the synaptic cleft; GLU, glutamate; SSRI, serotonin re-uptake
inhibitor; M, muscarinic receptor. A study is included only when it was primarily devoted to the testing of drug effects on TMS measures of motor excitability.

the influence of motor set and motor attention (Classen which is most likely unspecific because these drugs do not
et al., 1997; Mathis et al., 1998). This may explain the act at GABAB receptors but may reduce motor attention.
lengthening of the CSP by drugs, such as ethanol (Ziemann Other drug effects on CSP duration were inconsistent
et al., 1995) or benzodiazepines (Ziemann et al., 1996b), (Table 1).
1720 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729

2.4. Short-interval intracortical inhibition largely unaffected by neurotransmitter or neuromodulator

systems in those studies which differentiated between SICI
Short-interval intracortical inhibition (SICI) is measured at 1 ms versus longer intervals of 2-5 ms.
in a paired-pulse TMS protocol, using a sub-threshold first
(conditioning) pulse followed after a short inter-stimulus 2.5. Intracortical facilitation (ICF)
interval of , 2 –5 ms by a supra-threshold second (test)
pulse (Kujirai et al., 1993). It is currently believed that the ICF is tested by the same protocol as SICI, but longer
sub-threshold first pulse produces an IPSP at the corticosp- inter-stimulus intervals of 7– 20 ms are used (Kujirai et al.,
inal neurones through activation of a low-threshold cortical 1993; Ziemann et al., 1996d). Compared to SICI, the
inhibitory circuit, which inhibits action potential generation physiology of ICF is less clear. The leading hypothesis is
by excitatory post-synaptic potentials (EPSPs) elicited by that ICF tests excitability of excitatory neuronal circuits in
the supra-threshold second pulse (Ilic et al., 2002b; Kujirai motor cortex, which are at least in part dissociable from the
et al., 1993). Consistent with this hypothesis, GABAA SICI network (Ziemann et al., 1996d). It is likely that ICF is
agonists enhance SICI (Di Lazzaro et al., 2000a; Ilic et al., a net facilitation consisting of prevailing facilitation and

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2002b; Ziemann et al., 1996b). The GABAA antagonist weaker inhibition. The inhibition probably comes from the

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flumazenil does not alter SICI, suggesting that there is no tail of the GABAA mediated IPSP, which has a duration of
tonic activity at the benzodiazepine binding site of the approximately 20 ms (Connors et al., 1988). Consistent with

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GABAA receptor in normal human motor cortex (Jung et al., this, the range of effective inter-stimulus intervals for

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2004). Furthermore, in contrast, the GABA re-uptake inhibition of the I3-wave in human motor cortex reaches up
inhibitor tiagabine decreases SICI (Werhahn et al., 1999). to 20 ms (Hanajima et al., 1998). EPSPs in neurones of
This is best explained by activation of pre-synaptic GABAB
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motor cortex may consist of a fast component mediated by
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auto-receptors on nerve terminals of GABAergic inhibitory non-NMDA receptors and a slower component mediated by
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interneurones, resulting in auto-inhibition. SICI is a net NMDA receptors (Hwa and Avoli, 1992). The latency to
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inhibition consisting of strong inhibitory effects and weaker onset of the EPSP mediated by the NMDA receptor is in the
facilitatory effects of the conditioning pulse on the test MEP order of 10 ms, which would be consistent with the time
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(Ilic et al., 2002b). A decrease of the facilitatory effects may course of ICF. This idea is supported by the majority of the
best explain why glutamate antagonists lead to an apparent pharmacological studies, demonstrating a decrease of ICF
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enhancement of SICI (Ziemann et al., 1998a; Schwenkreis by NMDA antagonists (Schwenkreis et al., 1999; Ziemann
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et al., 1999, 2000). In agreement with animal experiments, et al., 1998a), although this was not a unanimous finding
which show that neuromodulators strongly influence GABA (Di Lazzaro et al., 2003). GABAA agonists also decrease
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and glutamate neurotransmitter systems in the cerebral ICF (Ziemann et al., 1995, 1996b), supporting a contri-
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cortex (Hasselmo, 1995), most TMS studies demonstrate bution of inhibition through the GABAA receptor to the
significant effects of neuromodulators on SICI (Table 1). magnitude of ICF. A synopsis shows (Table 1), that the
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DA agonists and NE antagonists (guanfacine) increase SICI, pharmacological profiles of ICF and SICI are similar though
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while DA antagonists (haloperidol) and NE agonists not identical, indicating similarity but also dissociability of
decrease SICI (Table 1). The effects of neuromodulators the underlying mechanisms.
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on TMS measures may depend on genetic polymorphisms

of the receptors and transporters involved in the neuro- 2.6. Short-interval intracortical facilitation
modulator system under study, and this may explain some of
the variability of findings reported in Table 1. One first study Short-interval intracortical facilitation (SICF) is also
to support this notion demonstrates that the selective measured in a paired-pulse TMS protocol, but in contrast to
serotonin re-uptake inhibitor citalopram increases SICI, SICI and ICF the first pulse is supra-threshold and the
but only in those subjects who are homozygotic for the long second pulse is sub-threshold (Ziemann et al., 1998b), or
variant of the 5-HT transporter gene (Eichhammer et al., both pulses are approximately of threshold intensity
2003). This is explained by the fact that homozygosity for (Tokimura et al., 1996). SICF occurs at discrete inter-
the long variant is associated with a two times more efficient stimulus intervals of about 1.1 – 1.5 ms, 2.3 –2.9 ms and
5-HT re-uptake compared to the short variant. Finally, it 4.1– 4.4 ms. The inter-peak latency between these facil-
should be noted that all reported findings refer to SICI as itatory intervals is about 1.5 ms, which led to the hypothesis
tested at inter-stimulus intervals of 2 – 5 ms between that SICF originates in those neural elements which are
conditioning and test pulse. Another type of inhibition at responsible for the generation of the I-waves (Tokimura
very short intervals of , 1 ms is most likely caused by et al., 1996; Ziemann et al., 1998b). It is currently thought
different inhibitory circuits (Roshan et al., 2003), and by that the second pulse directly excites the initial axon
relative refractoriness of neural elements in the cortex segments of those excitatory interneurones, which are
activated by the conditioning pulse and the resulting depolarised by EPSPs from the first pulse but did not fire
desynchronisation of the corticospinal volley (Fisher et al., an action potential (Hanajima et al., 2002; Ilic et al., 2002b).
2002; Hanajima et al., 2003). This process was found to be Allosteric GABAA agonists reduce SICF (Ilic et al., 2002b;
 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729 1721

Ziemann et al., 1998c), which is in accordance with the Ideally, a study should be randomised and placebo-
hypothesis that the first pulse elicits a GABAA dependent controlled to exclude or reduce experimenter bias. One
short-latency IPSP in corticospinal and/or first order important issue is to select an appropriate drug dose. A
excitatory interneurones, which inhibits the facilitatory drug effect on a TMS measure increases with drug dose
interaction with the second pulse. Other drug effects on (see below, pt. 3). However, the minimal dose to reach a
SICF are summarised in Table 1. threshold drug effect may vary considerably between
subjects (Tergau et al., 2003), and the individual relation
2.7. Long-interval intracortical inhibition between drug dose and drug effect may be non-linear due
to complex drug pharmacodynamics (see below, pt. 3).
Long-interval intracortical inhibition (LICI) is tested in a Therefore, there is always the risk to miss a drug effect on
paired-pulse TMS protocol by using two pulses of supra- TMS measures due to inappropriately low dosing. Another
threshold stimulus intensity (Claus et al., 1992; Valls-Sole critical issue of drug dose is to produce ‘unwanted’ drug
et al., 1992). Duration and magnitude of LICI depend on the effects when a drug has more than one mode of action
intensity of the conditioning and test stimulus. In healthy (‘dirty drug’). Usually, these different modes of action

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subjects, LICI typically occurs at inter-stimulus intervals come into play at different drug doses due to, for instance,

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between 50 and 200 ms, when stimulus intensity is adjusted differences in receptor density and/or drug-receptor
to produce unconditioned MEP amplitudes of approxi- affinity. This implies the risk to contaminate expected

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mately 1 mV (Valls-Sole et al., 1992). This range of drug effects with unwanted drug effects due to inappropri-

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effective inter-stimulus intervals shows that LICI is a long- ately high dosing. A reasonable way to account for these
lasting inhibition, which is distinct from SICI (Sanger et al., potential problems in drug dosing is the inclusion of
2001) but similar to the CSP (Valls-Sole et al., 1992).
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different or incremental doses into the study design (see
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Accordingly, it was proposed that LICI is mediated by slow below, pt. 3). Another critical issue is the timing of TMS
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IPSPs via activation of the GABAB receptor (Werhahn measurements. While most studies chose timing according
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et al., 1999). This is supported by an increase of the to the pharmacokinetics, i.e. the course of the plasma level
magnitude of LICI by the GABA re-uptake inhibitor of the drug under study, this may be inappropriate for
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tiagabine (Werhahn et al., 1999). However, LICI was not drugs, which produce their effect through complex
tested as of yet under exposure with a selective GABAB pharmacodynamic action. A good example is the anti-
d

agonist. epileptic drug vigabatrin. Its effect is exerted via

an

irreversible inhibition of the GABA-degrading enzyme

2.8. Short latency afferent inhibition GABA-transaminase, which has a much slower and longer
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time course than the vigabatin plasma concentration

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Short latency afferent inhibition (SAI) is defined as an (Ben-Menachem, 1995). GABA concentration in the
MEP inhibition produced by a conditioning afferent pulse brain peaks 24 h after intake of a single dose of vigabatrin
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applied to the median nerve at the wrist approximately (Petroff et al., 1996), while vigabatrin concentration in the
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20 ms prior to TMS of the hand area of the contralateral plasma peaks after 1 h and the plasma half-life is 6– 8 h
motor cortex (Tokimura, 2000). Pharmacological exper- (Ben-Menachem, 1995). Accordingly, a significant vigaba-
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iments revealed that SAI is distinct from SICI because SAI trin-induced decrease in ICF was observed 24 h after intake
is reduced by the ACh antagonist scopolamine, while SICI only, and not already after 6 h (Ziemann et al., 1996c). As
remains unaffected (Di Lazzaro et al., 2000b). The effects of a consequence, good knowledge about the pharmacokinetic/
scopolamine suggest that SAI may be useful to probe the pharmacodynamic (PK/PD) actions of the drug under study
integrity of cholinergic neural circuits. This idea is is required in order not to miss drug effects by
supported by an abnormal reduction of SAI in patients inappropriate timing of TMS testing. Finally, the selection
with Alzheimer’s disease (Di Lazzaro et al., 2002). Effects of subjects may play a pivotal role on the study results. It is
of other drugs on SAI have as of yet not been tested. possible that the level of a TMS measure at baseline
influences its responsiveness to experimental manipulation,
2.9. Issues of study design and pitfalls although this was as of yet not directly explored in
pharmacological TMS studies. The level of a TMS
The typical study design includes a baseline measure- measure at baseline can be affected by many sources,
ment before drug application and at least one measurement such as anxiety-related personality trait (Wassermann et al.,
after drug application. The statistical analysis uses a 2001), age (Peinemann et al., 2001) or phase of the
repeated measures test (usually a paired t test for two menstrual cycle (Smith et al., 1999). As a consequence, a
time points, and a repeated measures ANOVA with time as careful definition of the properties of the study population
the within-subject effect for more than two time points) to is important. Finally, it is very likely that subjects with
evaluate the effect of drug. This is a valid procedure neurological or psychiatric disease show drug effects on
because the within-subject test – retest reliability of TMS TMS measures that are different from healthy subjects. For
measures is high (Maeda et al., 2002; Wassermann, 2002). instance, in patients with attention-deficit hyperactivity
1722 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729

disorder, where there is pathologically reduced SICI, the the blood brain barrier, or kinetics of drug – receptor
indirect DA and NE agonist methylphenidate resulted in an interaction. The relation is usually sigmoid and can be
increase of SICI towards normalisation (Moll et al., 2000), described by pharmacokinetic/pharmacodynamic (PK/PD)
whereas a significant decrease in SICI was observed in modelling (e.g. (Della Paschoa et al., 2000)).
healthy subjects (Ilic et al., 2003). Therefore, results in Only few TMS studies in humans have explored the
healthy subjects do not predict drug effects in patients with relation between drug dose or drug plasma concentration
brain disease. and drug effects on TMS measures. These data are
summarised in Table 2. Most of the studies provided only
2.10. Summary semi-quantitative data, which show that a given drug effect
increased with drug dose (Table 2). Only two studies have
TMS now offers a broad array of measures of motor so far provided quantitative correlation analyses between
cortical excitability, which covers various aspects of drug plasma concentration and drug effect. One study
excitability, such as axon excitability, and inhibitory and showed that RMT increases linearly with phenytoin plasma
excitatory synaptic excitability. Synaptic excitability can be concentration (Chen et al., 1997), the other demonstrated

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dissected into, for instance, distinct forms of cortical that ICF decreases linearly with riluzole plasma concen-

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inhibition, such as SICI (GABAA dependent), CSP and tration (Schwenkreis et al., 2000). One limitation of both
LICI (GABAB dependent) and SAI (ACh dependent). studies is that the correlation analyses were calculated not

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Further experiments showed that these forms of inhibition within individuals, but at the group level, i.e. all individuals

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interact in a complex manner (for recent review, (Chen, received the same dose and only a single data point per
2004)). Pharmacology has helped to characterise these individual entered the analysis.
measures and it can be expected that the combination of
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One recent study found a linear increase in RMT with
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TMS and drugs will further advance this field in the near lamotrigine plasma concentration at the group level, if the
a
future. drug was taken in incremental divided doses (Tergau et al.,
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2003). Multiple data points per individual, one at each of the

incremental doses entered the analysis. This study is of
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3. TMS measures as biological markers of drug effects particular interest because, in a post-hoc analysis, subjects
were divided into four groups depending on the minimal
d
an

A biological marker is defined as a characteristic that is cumulative dose, which produced a significant increase in
objectively measured and evaluated as an indicator of RMT. This analysis revealed that all groups had a sigmoid
normal biological processes, pathogenic processes, or relationship between cumulative dose and RMT increase,
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pharmacological responses to a therapeutic intervention while the relation between cumulative dose and lamotrigine
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(Biomarkers Definitions Working Group, 2001). The plasma concentration was linear (Tergau et al., 2003). This
relation between drug plasma concentration and drug effect strongly suggests that the individual relationship between
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may be complex, for instance due to characteristics of drug plasma concentration and drug effect on RMT is
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the drug related to plasma protein binding, crossing of sigmoid. A good explanation for this characteristic provides
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Table 2
Acute drug effects on TMS measures of motor cortical excitability as a function of drug dose

Drug Dose Plasma concentration RMT MEP CSP SICI ICF Literature

Phenytoin 18 mg/kg 12 –23 mg/ml LINO W W W W Chen et al. (1997)

Lamotrigine Incremental dose 430 –2500 ng/ml LINOa Tergau et al. (2003)
25,50,100,150 mg SIGOb
Ethanol 0.35 l wine 0.3 ml/l W W O O P Ziemann et al. (1995)
0.70 l wine 0.8 ml/l W W OO OO PP
Tiagabine 5, 10, 15 mg W W LINO NOP LINO Werhahn et al. (1999)
Riluzole 100 mg/7d 10 –440 ng/ml W W NOO LINP Schwenkreis et al. (2000)
Ketamine 0.01–0.04 mg/kg/min LINP LINO LINO W W Di Lazzaro et al. (2003)
Reboxetine 4 mg 102 ^ 20 ng/ml W O W O Plewnia et al. (2002)
8 mg 250 ^ 88 ng/ml W OO W OO
Yohimbine 20 mg W W W W Plewnia et al. (2001)
40 mg W O W O
Atropine 1 mg W W W P W Liepert et al. (2001)
2 mg W W W PP O

LIN, linear correlation between drug dose and change in TMS measure; SIG, sigmoid correlation between drug dose and change in TMS measure; NO, drug
effect, but no correlation with drug dose; W, no drug effect; O, increase; OO, strong increase; P, decrease; PP, strong decrease.
a
Correlation analysis at the group level.
b
Correlation analysis at the individual (sub-group) level.
 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729 1723

the model of PK/PD relationship, which may lead to a non- (Shank et al., 2000)). These include: (1) blockade of
linear transformation of drug concentration into drug effect voltage-gated Naþ channels; (2) enhancement of neuro-
(see above). With the individual correlation analysis transmission through the GABAA receptor; (3) inhibition of
between drug plasma concentration and drug effect on a neurotransmission through non-NMDA glutamate receptors
TMS measure it may become possible to predict the of the kainate and AMPA subtypes; (4) inhibition of
individual therapeutic effect of this drug. This vision voltage-gated Caþ þ channels of the L-type. It was found
needs to be explored in systematic future trials. If it that a single oral dose of 50 or 200 mg of topiramate dose-
becomes reality then TMS measures will develop into dependently increased SICI and tended to decrease ICF,
surrogate endpoints. These are defined as biomarkers that while RMT and CSP remained unaffected (Reis et al.,
are intended to substitute for a clinical endpoint (e.g. 2002). From this distinct pattern of effects it was concluded
decrease in seizure frequency in response to anti-epileptic that a single dose of topiramate exerts significant effects at
drug treatment) (Biomarkers Definitions Working Group, the level of human cortex through enhancement of GABAA
2001). Such a development would be extremely helpful for and/or suppression of glutamate dependent mechanisms
the clinician because it is currently often impossible to without detectable action on voltage-gated Naþ channels or

ly
predict an individual’s therapeutic response. GABAB receptors (Reis et al., 2002). A vision for future

on
investigations may be that, through refinement of TMS
protocols, measures become even more specific towards

e
4. Effects of CNS active drugs with incompletely known particular mechanisms to facilitate further the identification

us
or multiple modes of action on motor cortical excitability of drug mechanisms at the systems level in humans.

Many of the TMS measures are by now well defined in h

rc
terms of their physiological and pharmacological properties 5. Chronic versus acute effects on TMS measures
a
(see pt. 2 and Table 1). This knowledge may be used to of motor cortical excitability
se

identify the most prominent actions of CNS active drugs

re

with multiple or incompletely known mechanisms at the Chronic drug effects may be fundamentally different
systems level of human motor cortex. The available data of from acute ones. There are several processes, which can
d

this approach are summarised in Table 3. potentially alter the response of the human brain to a drug, if
an

As a clear example along this avenue, one study tested chronically administered: (1) pharmacokinetic tolerance.
the effects of the novel anti-epileptic drug topiramate on a This refers to changes in the distribution or metabolism of a
al

broad array of TMS measures (Reis et al., 2002). drug induced by repeated application. The most common
on

Topiramate demonstrated a wide spectrum of anti-epileptic mechanism is an increase in the rate of metabolism;
activities in pre-clinical animal experimental models of (2) pharmacodynamic tolerance. This refers to adaptive
rs

epilepsy and in clinical studies. Several different modes of changes within the system affected by the drug. In the CNS,
pe

action were identified at the cellular level (for review, the most common mechanism are drug-induced changes in
r
Fo

Table 3
Effects of CNS active drugs with incompletely known or multiple modes of action on motor cortical excitability

Drug Mode(s) of action MT MEP CSP SICI ICF SICF Literature

Losigamone ? Naþ, ? Caþ þ O W W W Ziemann et al. (1996c)

Gabapentin Caþ þ W O O P Ziemann et al. (1996c)
Increase of GABA synthesis W O O P Rizzo et al. (2001)
Increase of GLU release
Levetiracetam Reversal of negative allosteric W P W W W Sohn et al. (2001)
modulators at GABAA

? High voltage-gated Caþþ

? Inhibition Ik
Piracetam ? P Wischer et al. (2001)
Acamprosate NMDA antagonist O W W Wohlfarth et al. (2000)
Caþ þ
Topiramate Naþ, GABAA W W O (P) Reis et al. (2002)
Non-NMDA antagonist
Caþ þ (L-type)
Theophylline Adenosine antagonist W W P W Nardone et al. (2004)
þþ
?, mode of action unclear; Ca , blockade of voltage-gated calcium channels; Ik ; delayed rectifier potassium current. For other abbreviations, see legend to
Table 1.
1724 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729

receptor density, or efficiency of receptor coupling to signal analgesics is not different (Kalkman et al., 1992) (Table 4).
transduction pathways; (3) sensitisation. This refers to an This review is limited to studies of healthy subjects and
increase in drug effect with repeated application. patients without significant affection of the corticospinal
Naturally, only very few studies have investigated system before surgery. Only those studies are selected
chronic drug effects on TMS measures in healthy subjects. that allow assessment of the effects of a given anaesthetic or
The anti-glutamate drug riluzole results in an increase in analgesic on MEP amplitude. This requires a comparison of
SICI (Schwenkreis et al., 2000) and a decrease in ICF after a MEP amplitude before (baseline) and after introduction
single oral dose of 100 – 150 mg (Liepert et al., 1997; of the study drug, or an analysis of MEP amplitude
Schwenkreis et al., 2000). Both effects are maintained if as a function of drug dose (Table 4), using the same
riluzole is administered daily over a period of 1 week stimulus parameters throughout. Many studies added the
(Schwenkreis et al., 2000). In addition, a slight but anaesthetic under study to a maintenance regimen of other
significant increase in RMT occurs after 1 week that was anaesthetics (usually nitrous oxide, cf. Table 4). Most
not seen after the first day (Schwenkreis et al., 2000). These studies agree that it is possible to elicit relatively stable
data suggest that pharmacodynamic tolerance does not MEP under maintenance anaesthesia with nitrous oxide. In

ly
develop during chronic riluzole treatment. This is an contrast, most volatile (isoflurane) or intravenous anaes-

on
important piece of information for the clinical setting, thetics (propofol, etomidate, thiopental, pentobarbital,
where riluzole is used for treatment of various neurodegen- methohexital, midazolam) lead to severe depression of the

e
erative disorders, such as amyotrophic lateral sclerosis. MEP (Table 4). The MEP depression under intravenous

us
More such studies are desirable in order to learn more about anaesthesia is much more profound compared with the MEP
chronic versus acute drugs effects at the systems level of the decrease observed after a single non-aesthetic dose of
human motor cortex. This may also help to understand
h
benzodiazepines or barbiturates (cf. pt. 2.2. and Table 1).
rc
better the contribution of chronic drug treatment to This difference is due to a dose effect as shown by a
a
abnormal TMS measures in neurological or psychiatric progressive decline of MEP amplitude during continuous
se

patients. infusion of midazolam associated with a continuous

Drug effects on TMS measures may be evaluated also increase in midazolam blood level (Schönle et al., 1989).
re

outside of the motor system. One first example is a study on One important finding is that the MEP depression by
the effects of chronic ecstasy use on phosphene threshold in intravenous anaesthetics can be rescued, at least to some
d

the visual cortex (Oliveri and Calvo, 2003). Phosphene extent, by using high-frequency (200 –500 Hz) trains of
an

threshold was found to be lower in ecstasy users than stimuli instead of single-pulse TMS or TES, whereas this
controls and correlated negatively with frequency of ecstasy is not possible, or only to a lesser extent, when volatile
al

use. Furthermore, those ecstasy users with visual hallucina- anaesthetics were used ((Pechstein et al., 1998; Scheufler
on

tions had a lower phosphene threshold compared to those and Zentner, 2002; Rohde et al., 2003), Table 4). It is very
without hallucinations (Oliveri and Calvo, 2003). Extension likely that this difference is caused by differences in the
rs

of TMS measures into visual cortex can provide substantial main modes of action of intravenous versus volatile
pe

additional information because a within-subject comparison anaesthetics. Intravenous anaesthetics strongly enhance
showed no correlation of phosphene threshold with motor neurotransmission through the GABAA receptor while
r

blockade of voltage-gated Naþ channels is less prominent

Fo

threshold (Stewart et al., 2001), indicating assessment of

different systems, and because, on the grounds of regional (Lingamaneni and Hemmings, 2003). Intravenous anaes-
differences in cytoarchitecture and distribution of receptor thetics (propofol, thiopental) result in suppression of late
binding sites, it is likely that the drug under study affects the I-waves whereas the D-wave remains unaffected
different regions of the human cerebral cortex rather (Woodforth et al., 1999). This is consistent with previous
differently. observations that late I-waves are suppressed by the
GABA system (Di Lazzaro et al., 2000a). In contrast,
preservation of the D-wave suggests that axon excitability
6. Effects of anaesthetics and analgesics on motor is maintained. High-frequency pulse trains imitate the
cortical excitability multiple corticospinal discharges (D- and I-waves) and
their temporal summation at spinal alpha-motoneurones
MEP recordings are increasingly employed to monitor (Pechstein et al., 1996; Taylor et al., 1993). Therefore, it
corticospinal tract integrity during surgery of brainstem and is very plausible that high-frequency pulse trains help to
spinal cord. In the intraoperative setting, transcranial elicit stable MEPs in a context of preserved axon
electrical stimulation (TES) is more often used than TMS excitability but suppressed I-waves. In contrast, volatile
because it is less bulky and the electrodes can remain on the anaesthetics are essentially equipotent at voltage-gated
scalp once they have been fixed there so that continuous Naþ channels and GABAA receptors (Lingamaneni and
access to the patient’s head is no longer necessary. It Hemmings, 2003). Accordingly, volatile anaesthetics also
appeared that the sensitivity of TES and TMS to detect lead to strong suppression of late I-waves (Burke et al.,
changes in motor excitability induced by anaesthetics or 1993; Hicks et al., 1992; Kitagawa et al., 1995).
 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729 1725

Table 4
Effects of anaesthetics and analgesics on MEP amplitude

Drug Mode of action Dose Stimulation MEP Literature

IFL Naþ .GABAA 1.9–3.7% ETC TMS, 1P P (100%) Schmid et al. (1992)
N2O(66%) þ IFL 0.24% ETC TES, 1P P (100%) Kalkman et al. (1991)
N2O(66%) þ IFL 0.5% ETC TES, 1P P (93%) Calancie et al. (1991)
N2O(70%) þ IFL 0.5% ETC TES, 1P P (100%) Woodforth et al. (1996)
N2O(50%) þ IFL 0.2/0.4/0.6% ETC TES, 1-5P 500 Hz P (78%) Ubags et al. (1998)
N2O(60%) þ PFL þ IFL 0.5% ETC TES, 5P 200 Hz P (91–100%) Zhou and Zhu (2000)
IFL 1.2% ETC TMS, 4P 200–333 Hz P (100%) Rohde et al. (2003)
N2O Opioid peptide release N2O(66%) TES, 1P P (91%) Zentner et al. (1989)
N2O N2O(79%) TMS, 1P P (20%) Schmid et al. (1992)
PFL GABAA, Naþ 2 mg/kg B TMS, 1P P (100%) Schmid et al. (1992)
PFL 2 mg/kg Ba TES/TMS, 1P P (99/93%) Kalkman et al. (1992)
PFL 13 mg/minb TMS, 1P P (98%) Taniguchi et al. (1993)

ly
N2O(50%) þ PFL 0.7 ! 1.4 mg/ml TES, 6P 500 Hz P (30–50%) van Dongen et al. (2000)

on
PFL 6 mg/ml TMS, 1P P (97%) Scheufler and Zentner (2002)
PFL 6 mg/ml TMS, 2P 500 Hz P (99%) Scheufler and Zentner (2002)
PFL 6 mg/ml TMS, 4P 500 Hz P (94%) Scheufler and Zentner (2002)

e
N2O(50%) þ KET þ PFL 2 mg/kg/h TES, 1P P (100%) Kawaguchi et al. (2000)

us
N2O(50%) þ KET þ PFL 2 mg/kg/h TES, 5P 500 Hz P (72%) Kawaguchi et al. (2000)
ETM GABAA 0.3 mg/kg Ba TES/TMS, 1P P (70/53%) Kalkman et al. (1992)
ETM 2.18 mg/minb TMS, 1P
h P (63%) Taniguchi et al. (1993)
rc
ETM 0.25–0.5 mg/kg/h TMS, 1P P (64%) Herdmann et al. (1993)
N2O(50%) þ ETM 0.1 mg/kg B TES, 2P 333 Hz P (28%) Ubags et al. (1997)
a
TP GABAA 25.6 mg/minb TMS, 1P P (96%) Taniguchi et al. (1993)
se

TP 10 mg/kg CD TMS, 1P P (100%) Kawaguchi et al. (1993)

MHX GABAA 12.3 mg/minb TMS, 1P P (72%) Taniguchi et al. (1993)
re

PB GABAA 8 mg/kg B TMS, 1P P (96%) Schmid et al. (1992)

MZL GABAA 0.3 ml/kg/hc TMS, 1P P (90%) Schönle et al. (1989)
d

MZL 0.4 ml/kg B TMS, 1P P (83%) Schmid et al. (1992)

an

MZL 0.05 mg/kg Ba TES/TMS, 1P P (73/73%) Kalkman et al. (1992)

KET NMDA-ant, NE-agonist 3 mg/kg TMS, 1P W Kothbauer et al. (1993)
al

KET 1 mg/kg B TMS, 1P W /O Kalkman et al. (1994)

N2O(50%) þ KET 0.5 mg/kg B TES, 2P 333 Hz W Ubags et al. (1997)
on

FEN Opioid agonist 8 mg/kg B TMS, 1P W Schmid et al. (1992)

FEN 3 mg/kg Ba TES/TMS, 1P W Kalkman et al. (1992)
rs

B, bolus; CD, cumulative dose; ETC, end tidal concentration; ETM, etomidate; FEN, fentanyl; IFL, isoflurane; KET, ketamine; MHX, methohexital; MZL,
pe

midazolam; N2O, nitrous oxide; P, pulses; PFL, propofol; PT, pentobarbital; TP, thiopental. The anaesthetic in bold indicates the test agent (the other
anaesthetics are used for maintenance of anaesthesia and are not changed during introduction of the test agent). Doses and/or stimulation settings in bold
r

indicate those to which the given reduction in MEP amplitude refers to. P(n%), reduction in MEP amplitude by n% from baseline. W, no significant change in
Fo

MEP amplitude. For other abbreviations, see legend to Table 1.

a
Measured 1 –2 min after bolus application.
b
Mean infusion rate at the time of anaesthesia induction.
c
Infusion given at this rate for 30 min.

The D-wave is also suppressed, if tested at stimulus The intravenous anaesthetic ketamine does not suppress
intensity around threshold (liminal D-wave) (Hicks et al., MEP amplitude, but may even lead to MEP facilitation
1992), while D-waves tested at far above threshold (Table 4). Besides blocking the NMDA receptor, ketamine
stimulus intensity are less affected (Hicks et al., 1992; exerts multiple other actions in the CNS, in particular by
Woodforth et al., 1999). Another elegant demonstration increasing the release and inhibiting the re-uptake of NE
that volatile anaesthetics (sevoflurane) decrease corticosp- and 5-HT. These latter actions would explain the increase
inal axon excitability was provided by strength– duration in MEP amplitude (cf. 2.2 and Table 1). Opioid analgesics
curves, which show a decrease of the strength– duration (fentanyl) do not alter MEP amplitude (Table 4). In
time constant and an increase in rheobase (Burke et al., summary, this synopsis shows that the differential
2000). Both findings are consistent with a depression of potential of high-frequency multi-pulse stimulation to
Naþ currents at corticospinal axons (Bostock and overcome MEP suppression by intravenous versus volatile
Rothwell, 1997; Burke et al., 2000). The depression of anaesthetics supports the known differences in the main
axon excitability in addition to I-wave excitability may mode of action of these two classes of anaesthetics at the
explain why high-frequency pulse trains are less effective systems level of human motor cortex. In the setting
under volatile anaesthetics to maintain MEP amplitude. of intraoperative monitoring of the corticospinal tract,
1726 U. Ziemann / Clinical Neurophysiology 115 (2004) 1717–1729

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a
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Fo

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