Cortical excitability as a potential clinical marker of epilepsy: a review of the clinical application of transcranial magnetic stimulation.

2nd Reading January 10, 2014 16:46 1430001

Review Article

International Journal of Neural Systems, Vol. 24, No. 2 (2014) 1430001 (21 pages) c World Scientific Publishing Company DOI: 10.1142/S0129065714300010

Int. J. Neur. Syst. 2014.24. Downloaded from www.worldscientific.com by CARNEGIE MELLON UNIVERSITY on 11/09/14. For personal use only.

CORTICAL EXCITABILITY AS A POTENTIAL CLINICAL MARKER OF EPILEPSY: A REVIEW OF THE CLINICAL APPLICATION OF TRANSCRANIAL MAGNETIC STIMULATION PRISCA R. BAUER∗ and STILIYAN KALITZIN SEIN - Epilepsy Institute in the Netherlands Foundation Heemstede, The Netherlands P.O. Box 540, 2130 AM Hoofddorp, The Netherlands ∗ [email protected] MAEIKE ZIJLMANS SEIN - Epilepsy Institute in the Netherlands Foundation Heemstede, The Netherlands P.O. Box 540, 2130 AM Hoofddorp, The Netherlands Department of Neurology, Brain Center Rudolf Magnus University Medical Centre Utrecht Utrecht, The Netherlands JOSEMIR W. SANDER SEIN - Epilepsy Institute in the Netherlands Foundation Heemstede, The Netherlands P.O. Box 540, 2130 AM Hoofddorp, The Netherlands NIHR University College London Hospitals Biomedical Research Centre UCL Institute of Neurology, Queen Square London WC1N 3BG, United Kingdom Epilepsy Society, Chalfont St Peter SL9 0RJ United Kingdom GERHARD H. VISSER SEIN - Epilepsy Institute in the Netherlands Foundation Heemstede, The Netherlands P.O. Box 540, 2130 AM Hoofddorp, The Netherlands Accepted 23 November 2013 Published Online 14 January 2014 Transcranial magnetic stimulation (TMS) can be used for safe, noninvasive probing of cortical excitability (CE). We review 50 studies that measured CE in people with epilepsy. Most showed cortical hyperexcitability, which can be corrected with anti-epileptic drug treatment. Several studies showed that decrease of CE after epilepsy surgery is predictive of good seizure outcome. CE is a potential biomarker for epilepsy. Clinical application may include outcome prediction of drug treatment and epilepsy surgery. Keywords: TMS; epilepsy; cortical excitability; TMS-EEG.

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1.

Introduction

In the past three decades, neuroscience research has increasingly focused on cortical excitability (CE), which can be defined as the readiness of a neuron to generate an action potential when triggered, usually by an excitatory post-synaptic potential.1,2 Changes in CE can help explain physiologic and pathophysiologic mechanisms. We review the measurement of CE using transcranial magnetic stimulation (TMS) in the context of epilepsy. Factors that influence CE are briefly discussed. A review of TMS studies in people with epilepsy is reported, after which its potential role in the clinical evaluation of epilepsy, treatment monitoring and outcome prediction is explored. We do not review studies investigating the therapeutic use of TMS, such as repetitive stimulation. 1.1. Cortical excitability CE depends on the membrane potential that directly influences how close a neuron is to firing threshold. The membrane potential in the brain is kept constant through tight regulation of ion balance by ion channels. Even when sudden changes in ion concentration occur in the body, ion concentration in the brain is unaffected.2,3 The main players in this process are K+ , Na+ , Ca2+ , H+ , Mg+ , Cl− and HCO3− . Ion channels and neurotransmitters are functionally interconnected. Some ion channels are neurotransmitter-gated, and Ca2+ influx into a neuron causes release of neurotransmitter into the synaptic cleft, in turn influencing other neurons and their ion channels. The main neurotransmitters influencing CE are GABA, which has an inhibitory effect, and glutamate, which has an excitatory effect.3,4 1.2. Measuring CE 1.2.1. TMS CE can be measured in vivo using transcranial electrical stimulation (TES), and TMS.5 Since first described in 1985,6 TMS has developed into a valuable tool.7 TMS has some advantages over TES as stimulation is not painful and study subjects do not need to be sedated. TMS, like TES, has excellent temporal resolution. Spatial resolution is around 1 cm but as TMS only reaches 2 cm from the skull only superficial brain areas can be investigated. A TMS pulse activates all neurons within reach,

without differentiating between inhibitory, excitatory or modulating neurons. The resulting effect is always a nonspecific sum of the effects of the activated neuron population.8 A TMS pulse depolarizes neurons by inducing electric fields in the tissue that cause neurons to fire and the pulse to spread to neighboring neurons, causing descending volleys of action potentials from the cerebral cortex via the spinal cord to peripheral nerves. Descending volleys can be measured using epidural recordings. There are two types of volleys: direct (D), originating from direct stimulation of corticospinal neurons, or indirect (I), originating from synaptic activation of corticospinal neurons.4,7 In the hand area, TMS stimulation perpendicular to the central sulcus preferentially generates I-waves; D-waves are found at higher stimulus intensity.5 This is probably due to the orientation of the neuronal population activated. The interneurons activating the hand corticospinal neurons are orientated parallel to the skull surface, making them more sensitive to magnetic field impulses. In contrast, latero-medial stimulation preferentially generates D-waves.5 The effect of a TMS pulse on the cortex, and thus CE, can be measured in several ways. The most commonly used method is by measuring a motor evoked potential (MEP) using surface electromyographic (EMG) recordings (and documented as compound muscle action potential; CMAP) of the muscle group that is centrally stimulated. Both D- and I-waves contribute to the EMG response, and excitability of both spinal and cortical motor neurons influence the MEP.5 1.2.2. Motor evoked potential and motor threshold Key TMS measures are listed in Table 1. Several parameters of MEP can be measured. MEP amplitude is influenced by the number of motor neurons recruited in the spinal chord, the number of motor neurons discharging more than once upon the stimulus, and the synchronization of discharges of the motor neuron upon the TMS pulse. The MEP amplitude is proportional to the stimulus intensity and saturation occurs at high intensities, but highly variable from pulse to pulse, and between individuals. The main cause of the high variability is desynchronization and phase cancellation of the action potentials within the corticospinal tract and at spinal level. The varying degrees of synchronization

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Cortical Excitability as Marker of Epilepsy

Table 1.

Key TMS measures, mechanisms and interpretation of findings in the context of CE.

Mechanism

Increased cortical excitability

Membrane potential Membrane potential GABA-B receptor GABA-A receptor GABA-B receptor NMDA Glutamate receptor

Increased amplitude Lower threshold Shorter Lower Lower Higher

TMS measure


Motor evoked potential (MEP) Motor threshold (MT) Cortical silent period (cSP) Short intracortical inhibition (SICI) Long intracortical inhibition (LICI) Intracortical facilitation (ICF)

influence MEP amplitude.9 In addition, cortical stimulation causes repetitive — but asynchronous — discharges of spinal motor neurons.10 MEP amplitude is not often used as a clinical marker of CE due to the great variability of the amplitude. The resting motor threshold (rMT) is the lowest TMS pulse intensity that triggers reproducible MEPs, typically of >50 uV, in a fully relaxed target muscle in 50% of at least 20 trials.11 This has proven to be a reliable and repeatable measure of CE.12 The active motor threshold (aMT) represents the motor threshold of a slightly contracted muscle and is lower than rMT. It is defined as the required stimulus intensity to elicit reproducible MEPs of 200–300 uV in 50% of consecutive trials.13 The amplitude of MEP at aMT is higher than that at rMT, due to spinal facilitation. MT also decreases when a subject imagines contracting the target muscle. This facilitation is thought to originate entirely from cortical mechanisms.5 1.2.3. Cortical inhibition and facilitation Paired-pulse TMS protocols are widely used to study excitability of the motor cortex and its underlying mechanisms.14 To this end, two sub- or suprathreshold pulses are applied, with an Inter Stimulus Interval (ISI) of 2 to 400 ms. After a single TMS pulse, a MEP is followed by a silent period (SP) lasting up to 300 ms in which there is no EMG signal. The length of the SP is directly related to the stimulus intensity.15 The mechanism underlying the SP is complex. During the first 50 ms post-stimulus, the amplitude of the peripheral Hoffmann reflex also decreases or disappears, pointing towards a spinal origin of this first part of the silent period.16 Paired-pulse stimulation has shed more light on the later part of the silent period. When two suprathreshold stimuli are applied with

Decreased cortical excitability Decreased amplitude Higher threshold Longer Higher Higher Lower

an interstimulus interval of 50 to 150 ms, MEPs remained constant. A subthreshold stimulus following 50–150 ms after a suprathreshold stimulus however, showed inhibition of the response.17 Subthreshold stimuli activate neurons indirectly, probably through trans-synaptic mechanisms, whereas suprathreshold stimulation can directly activate corticospinal neurons.18 Thus, it is probable that the later part of the silent period originates from transsynaptic activation in the cortex, therefore it is termed cortical silent period (cSP). As the duration of cSP coincides with the timing of GABA(B) receptor activation, the later part of the cSP is believed to be GABA(B) mediated.19 Pharmacological evidence is somewhat conflicting: The selective GABA(B) agonist baclofen was shown to increase cSP,20,21 whereas other studies did not show any effect.22,23 This may have been due to the way the drug was administered, as the two studies that showed lengthening of cSP administered baclofen intrathecally, whereas the other studies used oral or intravenous administration. GABA(A) agonists such as lorazepam and ethanol have also been shown to increase cSP length.24 At higher stimulus intensities, however, lorazepam reduced cSP length, possibly reflecting an interaction between GABA(A)- and GABA(B)-receptors.25 Tiagabine, a GABA re-uptake inhibitor, lengthens the cSP.26 Short-interval intracortical inhibition (SICI) is studied with a first stimulus at subthreshold intensity and a second, suprathreshold, stimulus 1 to 6 ms before the test stimulus. SICI has two distinct phases.27,28 At an ISI of 1 ms both I- and D-waves are suppressed, which may be caused by axonal refractoriness.28 At an ISI of 3–5 ms, I waves (especially the later I3 waves) are selectively inhibited.28 This inhibition lasts 20 ms and is thought to be mediated

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by GABA(A).14,28 This notion was supported by pharmaceutical evidence as GABA(A) agonists such as diazepam, lorazepam and ethanol increase SICI.29 Intracortical facilitation (ICF) occurs when the test stimulus follows the conditioning stimulus after 10 to 15 ms.14 It was assessed less extensively than SICI and its exact mechanism of action is unknown. The Hoffmann reflex is not facilitated by the conditioning stimulus, making a cortical origin of this mechanism likely.30 It was, however, never demonstrated that the I-waves were increased in number or amplitude at ISIs of 10–15 ms, such that a spinal mechanism may be involved in ICF, although this is unlikely.31 NMDA-receptor antagonists such as dextromethorphan reduce ICF32 as well as GABA(A) receptor agonists.29 The glutamate antagonist riluzole strongly suppresses ICF.33 With two suprathreshold pulses, long-interval intracortical inhibition (LICI) can be demonstrated at interstimulus intervals (ISI) of 50 to 200 ms. This is likely a phenomenon of cortical origin as the I-waves, but not the D-wave, are affected.34 Baclofen increases LICI.22 These findings, taken together, suggest that LICI is probably GABA(B) mediated.13,34 GABA(A) receptors are ligand-gated ion channels and act faster than the G-protein coupled GABA(B) receptors, explaining part of the different timing between SICI and LICI.34

1.2.4. Threshold tracking TMS Measuring the change in MEP response after various combinations of conditioning and test stimuli is limited by the inter-individual variability of the MEP response in each set of conditioning/test stimuli and the ensuing requirement for several consecutive measurements.35 An alternative is to target a constant MEP amplitude output, set as a percentage of the maximum response of a baseline test, and to track this by changing the test stimulus intensity. Changes in CE are now reflected by the required change in test stimulus intensity to result in the preset output.36–38 With this threshold tracking technique (or “threshold hunting”), there is tighter control of the necessary pulse and small differences in CE can be measured more easily. Moreover, spinal and peripheral influences on measurements are reduced. It has been demonstrated that this method is a

valid alternative to constant stimulus methods.37 Recently, this method has suggested different mechanisms influencing CE.27,39 1.2.5. TMS-EEG CE in behaviorally silent areas can be measured by combining TMS with electroencephalography (EEG).40,41 This is technically challenging as TMS pulses can lead to large artefacts on EEG recordings,40,42,43 but the combination of these techniques is valuable in uncovering neural mechanisms, including changes in CE.44–46 The EEG response to TMS over the motor cortex in healthy individuals consists of positive peaks at 30, 60 and 150 ms after the TMS pulse, and negative peaks at 15, 45 and 100 ms.47 TMS-EEG responses have been shown to be repeatable and stable over time.48,49 1.2.6. TMS Safety Single- and paired-pulse TMS are considered a safe diagnostic tool.50 A handful of seizures have been reported in healthy subjects, but most seizures occurred in people with underlying brain pathology or taking neuroactive medication.11,50,51 Syncope may occur but is assumed not to be a direct effect of TMS but probably related to anxiety and stress during the examination.11,52 Transient hearing loss may occur due to the coil click if no hearing protection is used and stimulation can cause transient headache, local pain and paresthesias.50 No histologic changes of brain tissue (temporal lobes) after TMS have been seen.53 In people with epilepsy, no adverse effects of single-pulse TMS have been observed in the vast majority of studies.54,55 The risk of TMS-associated seizures in people with epilepsy is unclear, as adverse effects of TMS are not always reported. A total 49 articles reporting on 712 people with epilepsy who underwent single and paired pulse TMS were systematically reviewed.56 Only 22 studies (with 458 subjects) reported specifically on adverse effects of TMS. In these studies, altogether seven subjects had a seizure (1.5%), of whom five were from the same clinic.57 Group analysis suggested that the crude risk of seizure occurrence during TMS was lowest (0%) for single- and paired-pulse TMS in people with well-controlled epilepsy.56 The risk of seizure

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occurrence was highest (2.8%) if anti-epileptic drugs (AEDs) were tapered. No explanation was found for the described center-to-center variability. It may be that seizure occurrence during TMS is coincidental and not causative.56

it is paramount to take these potential confounders into account. Several studies evaluating the effects on TMS parameters in healthy individuals are listed in Table 2. The most important influences are discussed below.

2. Influences on CE

2.1. Circadian rhythm

CE is dynamic and varies depending on physiological as well as external conditions. When applying TMS

Muscle power increases over the day but MEP latency and cSP,58 and ICF and SICI,59 stay


Table 2. Influence Circardian rhythm– change over day

Sleep deprivation

Early follicular phase

Late follicular phase

Luteal phase

Na+ /Ca+ blockers GABAaRagonist Coffee

Alcohol Cannabis Cocaine Ketogenic diet Mobile phone use Meditation

Study

MEP ampl

Influences on CE. MEP latency

rMT

aMT

cSP

↔

↓

65

↔ ↔

Ziemann et al.73 Fitzgerald et al.74 Boutros et al.75 Cantello et al.76 Ferreri et al.77 Guglietti et al.78

↑

↓

↑∗∗

↑ ↑

↑

↔

↔

↓ ↑

↔

↑∗ ↓ ↓

↔

↔

↔

↔

↑ ↓ ↓

↑

↓

↔

↔

↔

↔ ↔

Paulus et al.29 Cerqueira et al.69 Carvalho et al.70 Orth et al.71 Specterman et al.72

↔

TEP

↔

↓ ↓

↓

ICF

↔

Civardi et al.62 Kreuzer et al.63 DeGennaro et al.64

Smith et al.65 Smith et al.66 Inghilleri et al.67 Hattemer et al.68 Smith et al.65 Smith et al.66 Inghilleri et al.67 Hattemer et al.68

LICI

↔

Doeltgen and Ridding59 Strutton et al.58 Huber et al.60 Lang et al.61

Smith et al. Smith et al.66 Inghilleri et al.67 Hattemer et al.68

SICI

↑

↓

↑

↔

↑ ↔ ↔ ↑∧ ↔

↔

↑

↔ ↔ ↑

↑ ↔ ↔ ↔ ↑

↑ ↑ ↑ ↓ ↔

↓

↔

↓ ↔ ↔ ↑

Note: ∗ Only significant effect during anovulatory phase. No effect in ovulatory phase. ∗∗ Only in female subjects. ∧ Right hemisphere. MEP amplitude: amplitude of motor evoked potential. MEP latency: latency of motor evoked potential. rMT: resting motor threshold. aMT: active motor threshold. cSP: cortical silent period. SICI: short-interval intracortical inhibition. LICI: long-interval intracortical inhibition. ICF: intracortical facilitation. TEP: TMS-induced EEG potential. 1430001-5


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relatively constant. Using TMS-EEG, the TMS Evoked Potential (TEP) slope and amplitude have been shown to increase over the day.60 LICI and CSP decreased over the course of a day.6 Sleep deprivation seems to increase CE. It has been shown to reduce intracortical inhibition62,63 and to increase TEP slope and amplitude.60 Sleep deprivation increased ICF only in women, raising questions about the underlying mechanisms.64


2.2. Hormones CE varies with the menstrual cycle. Estrogens have an excitatory effect while progesterone has an inhibitory effect.65,79 In the early follicular phase, when both hormone levels are relatively low, the tendency is towards inhibition. In the late follicular phase, with high estradiol and low progesterone levels, excitability rises. In the luteal phase, progesterone levels are higher than estradiol levels and excitability returns to around the same levels as during the early follicular phase.65 In women with anovulatory cycles, inhibition is increased during menstruation, possibly reflecting the withdrawal of estrogens and their excitatory effect.68 One study did not find significantly different rMT during the menstrual cycle in healthy subjects and women suffering from migraine. In this study, no significant difference was seen in CE between women taking oral contraceptives and those who did not.80 2.3. Medication Many pharmacologic substances that act on the central nervous system were assessed with TMS and good overviews of these assessments are available.24,29 We will only discuss the most important AEDs, without aiming to provide an exhaustive list. Na+ blockers such as lamotrigine, carbamazepine and phenytoin increase the motor threshold, but do not affect other TMS parameters.81–84 Benzodiazepines such as diazepam and lorazepam are GABA(A) receptor agonists. They have no effect on the MT but increase SICI.23,25,85 Diazepam decreases cSP whereas lorazepam increases cSP at high stimulus intensities but decreases cSP at low stimulus intensities.23–25 Tiagabine, a GABA-reuptake inhibitor, and vigabatrin, an inhibitor of the GABA transaminase that breaks down GABA, both enhance GABA function,

resulting in prolonged cSP and stronger LICI.86,87 Valproic acid acts on sodium and calcium channels, and also inhibits GABA transaminase, enhancing GABA-ergic inhibition. Only one TMS study is available on this drug, that showed an increase of MT and no effect on cSP.81 The mechanism of effect of topiramate is not well known, it increases SICI but has no measurable effect on MT and cSP.88 The mechanism of action of levetiracetam is unknown, TMS studies have demonstrated increased MT and cSP duration upon levetiracetam administration, but no effect on SICI and ICF.89,90 AED thus reduce CE by various mechanisms. 2.4. Neuroactive substances Coffee is the most widely used neurostimulative substance. Two studies demonstrated a reduction of the CSP after administration of caffeine but no influence on other CE measures.69,70 An earlier study showed no significant effect of caffeine on resting or active MT, SICI or ICF.71 Another study showed an increase in MEP size after administration of an energy drink containing water, sugar and caffeine, an effect which was not seen when subjects were given water alone.72 Spinal excitability was increased by caffeine.91 Alcohol decreases CE, especially in right prefrontal areas.92–95 This is reflected by an increase of cSP and SICI, whereas ICF is decreased.29 The effect of smoking and nicotine use was assessed in one study that showed that CE is lower in chronic smokers than in nonsmokers.96 Few studies have investigated the effect of drugs of abuse on CE. In chronic cannabis users, excitability is increased; users were found to have reduced SICI, irrespective of cannabis use around the time of the experiment. Other measures of CE are not affected by cannabis use.74 Schizophrenia and substance abuse often co-exist; people who suffered from their first schizophrenic episode and who had a history of cannabis use had increased CE. Cannabis users had lower cortical inhibition and higher ICF than people who suffered from a first schizophrenic episode but had no history of cannabis use.97 Cocaine increases the active and resting MT, reflecting a decrease of CE. cSP was not significantly different between cocaine users and healthy controls.75

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2.5. Other external influences

contribute to epilepsy. Generalized epilepsy commonly arises due to genetic causes, ensuing ion channel dysfunction and cortical hyperexcitability. Focal epilepsy is most often the result of a structural defect in the brain, in combination with a predisposition to develop epilepsy.99,102

As electromagnetic fields can alter CE, the effect of mobile phone use has been investigated. Mobile phone use significantly increases CE in the exposed hemisphere, reflected by an enhanced ICF and reduced SICI.77 These findings were replicated in a group of people with focal epilepsy, although increase of CE was only evident in the hemisphere contralateral to the epileptic hemisphere.98 To date, there is, however, no evidence or reported trend of actual increase in seizures related to mobile-phone usage, even though mobile phones are increasingly used in day-to-day life. Recently, the effect of meditation on TMS parameters was studied.78 There was an increase of the cSP compared to the control group who watched television, indicating decrease of excitability. SICI was not altered in the people who meditated.

3.1. CE in different types of epilepsy Many studies of TMS in people with epilepsy have been published. A PubMed search conducted in November 2012 in PubMed using the search terms “transcranial magnetic stimulation” and “epilepsy”; this identified 381 articles. The following selection criteria were applied: original research, written in English, either single-pulse TMS or pairedpulse TMS protocols, people with epilepsy. After excluding studies using repetitive TMS, and casereports including fewer than five subjects, 63 articles remained for further reading. By checking the reference lists, four more articles were added. A further 17 articles were excluded; nine reported on fewer than five subjects, three reported on people without epilepsy, two did not report primary data, one concerned TMS-EEG findings and for two studies, only the abstract was available. 50 articles were included for review, shown in Tables 3(a)–3(c).

3. Epilepsy and CE Seizures are the common symptom of many conditions grouped under the name “epilepsy”. “Misfiring” of neurons and increased CE are thought to be key to the generation of seizures.4,99–101 A complex interplay of genetic and environmental factors

Table 3a.

TMS measures in generalized epilepsy.

Study

Epilepsy type

N

AED

rMT

Aguglia et al.124

IGE with versive seizures IGE (7JME)

10

Y

↑

13

Y

↑

IGE (5JME) IGE + sleep deprivation

15

N N

↔ ↔

Badawy et al.104 Badawy et al.125

IGE (11JME) IGE morning IGE afternoon

35 10

N N N

↔ ↔ ↔

Badawy et al.123

IGE pre-ictal IGE post-ictal

23

N N

Badawy et al.115

IGE IGE + AED

59

Badawy et al.105

Lennox-Gastaut IGE (refractory) IGE (4 JME) IGE IGE

Badawy et al.

103

Badawy et al.12 Badawy and Jackson120 Brodtmann et al.126

SICI

LICI

ICF

↓

↓∗

↑

↓ ↓ ↓

↓∗ ↓ ↓

↑ ↑ ↑

↓∧ ↑∧

↓∧ ↑∧

↓∧ ↑∧

↑∧ ↓∧

N Y

↓ ↑

↓ ↑

↓∗∗ ↑

↑ ↓

18 20

Y Y

↑ ↔

↑ ↓↓

↑ ↑

↓

13 28 7

N N N

↔ ↔ ↔

↓ ↓

↓∗ ↓∗ ↓∗∗∗

↑ ↑

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aMT

MEP

cSP

↔

↓↓


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Table 3a. Study

Epilepsy type

N

AED

rMT

Cantello et al.106

IGE before AED

8

N

aMT

MEP

cSP

SICI

↔

↔

↔

↑

↔

Y

↔

Delvaux et al.119

Within 48 h of 1st TC seizure

18

N

↑

Ertas et al.117 Groppa et al.118

IGE IGE − PPR

10 12

N N/Y

↑

↔ ↔

IGE + PPR

13

N/Y

↔

↔

IGE IGE + Zonisamide

15

N Y

↔ ↔

IGE (7JME) IGE (7JME) VPA 4 weeks IGE (7JME) VPA 25 weeks

30

N

↓ Y Y

Klimpe et al.108 Macdonell et al.109 Molnar et al.122

IGE IGE (9JME) IGE + DBS off IGE + DBS on IGE + DBS cyclic

15 21 5

N N Y Y Y

↔ ↔ ↑ ↑ ↑

↔

M¨ unchau et al.121

IGE + depression − mirtazapine IGE + depression + mirtazapine 3 weeks Controls + 1 dose mirtazapine

7

Y

↔

↑

↔

↓

Y

↔

↓

↔

↔

N

↔

↔

↑

↔

IGE 12 weeks VPA

Joo et al.

107

Kazis et al.112 Int. J. Neur. Syst. 2014.24. Downloaded from www.worldscientific.com by CARNEGIE MELLON UNIVERSITY on 11/09/14. For personal use only.

(Continued)

Reutens and Berkonic et al.113

IGE − AED IGE + AED

11 34

N Y

↓ ↑

Reutens et al.114

IGE − AED IGE + AED

20 36

N Y

↓ ↑

Tataroglu et al.116

IGE

50

N/A

↑

↑ ↓

↑ ↑

↔ ↔

↑ ↑ ↑

LICI

ICF

↔

↔

↔

↓

↔ ↔

↔ ↔

↓ ↓ ↔ ↑

↓ ↔ ↔ ↔

↓↓ ↓ ↓

↔ ↔ ↔

↑

Note: ∗ At 250 ms. ∗∗ At 150 and 250 ms. ∗∗∗ At 175 and 250 ms. ∧ Compared to interictal state. Correlated with seizure freedom after 1 year of treatment. IGE: idiopathic generalized epilepsy. JME: juvenile myoclonic epilepsy. AED: antiepileptic drugs. VPA: valproic acid. TC: tonic-clonic. PPR: paroxysmal photic reaction. DBS: deep brain stimulator. N/Y: included people with and without medication. N/A: information on medication not available. rMT: resting motor threshold. MEP: Motor evoked potential. cSP: cortical silent period. SICI: short-interval intracortical inhibition. LICI: long-interval intracortical inhibition. ICF: intracortical facilitation. All data are compared to healthy controls. If no control group was included, this is stated.

It was not possible to determine whether studies from the same authors used overlapping subject groups. The study results are diverse, and sometimes conflicting. Methods vary too widely across centers to make a meta-analysis valid.

3.2. Generalized epilepsy MT was normal in most studies that included untreated subjects with idiopathic generalized

epilepsy (IGE, see Table 3(a)).12,103–109 Some studies that included a larger number of people however, found decreased MT.111–114 This contradictory findings may thus be due to a lack of statistical power.112,115 Evidence concerning CSP is conflicting. It was increased in some studies,107,109,116 but normal in the majority of studies.104,106,108,117,118 SICI and LICI were normal in three relatively small studies (N < 15),106,107,119 but most studies showed reduced inhibition.12,103–105,108,115,120–122 It has to

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Table 3b.

TMS measures in JME.

Study

Epilepsy type

N

Akgun et al.129

JME Asymptomatic siblings of people

21 21

Y N

↑ ↑

JME morning JME afternoon

10

N N

↔ ↔

↓↓ ↓

↓↓ ↓

Badawy et al.111

PME JME refractory JME well-controlled

6 9 10

Y Y Y

↔ ↔ ↔

↓↓↓ ↓↓ ↓

↓↓↓ ↓↓ ↓

Brown et al.130

Cortical Myoclonus (generalized jerks) 8 Cortical Myoclonus (focal jerks) 10 Epilepsy + cortical myoclonus 9

Y Y

↑ ↑↑ ↑

↓ ↔ ↔

Canafoglia et al.131

Unverricht-lundborg disease Lafora body disease JME Unverricht-Lundborg disease Benign myoclonus epilepsy n.o.s. JME JME JME + sleep deprivation JME morning JME evening Myoclonic epilepsy n.o.s. PME

Y Y Y Y Y Y Y Y Y Y N/A Y

↔ ↔

↑ ↑

↑

↑∗ ↔

AED rMT aMT MEP CSP SICI LICI ICF ↔ ↔

↑ ↑

with JME


Badawy et al.

125

Caramia et al.132 Danner et al.128 Hanajima et al.139 Manganotti et al.134 Manganotti et al.135 Pf¨ utze et al.136 Tataroglu et al.116 Valzania et al.137

10 5 7 24 11 9 10 12 12 12

↔ ↔ ↑ ↔ ↔ ↓ ↔

↔ ↔

↔ ↔ ↔ ↔

↑ ∗∗

↔

↑ ↔

↓ ↓ ↓

↑↑ ↑

↔ ↓

↔ ↓

↓ ↓ ↓ ↓↓ ↔ ↔

↔ ↓ ↔ ↔ ↔ ↓

↑∗∗∗

Note: ∗ In abductor digiti minimi not abductor pollicis brevis. ∗∗ In controls: decrease with age, not in patient group. ∗∗∗ At 50 ms. JME: juvenile myoclonic epilepsy. PME: progressive myoclonic epilepsy. AED: anti-epileptic drugs. N.o.s.: not otherwise specified. N/Y: included people with and without medication. N/A: information on medication not available. rMT: resting motor threshold. MEP: Motor evoked potential. cSP: cortical silent period. SICI: short-interval intracortical inhibition. LICI: long-interval intracortical inhibition. ICF: intracortical facilitation. BECT: benign childhood epilepsy with centro-temporal spikes. All data are compared to healthy controls. If no control group was included, this is stated.

Table 3c. rMT Study

Epilepsy type

TMS measures in focal epilepsy. aMT

MEP

cSP

SICI

LICI

ICF

N AED ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra 15 15

N N

↔ ↔

↔ ↔

— ↓

↔

— ↓

↓∧

— ↑

↔

Badawy Focal 27 et al.104 Badawy Focal morning 10 et al.125 Focal afternoon

N

↔

↓

↓

↔

↓

↔

↑

↔

N N

↔ ↔

↔ ↔

↓ ↔

Badawy Focal pre-ictal 35 et al.123 Focal post-ictal

N N

↓ ↑

↔ ↑

Badawy Focal et al.115 Focal + AED

N Y

↑ ↑

↓ ↑

Badawy Focal et al.103 Focal + sleep deprivation

47

↑

↓

↑

↓ ↔

1430001-9

↓ˆ ↔

↑ ↔

↔ ↔

↓↓ ↑↑

↔ ↔

↑ ↓

↔ ↔

↔ ↔

↓↓ ↔

↔ ↔

↑ ↔

↔ ↔


P. R. Bauer et al.

Table 3c.


rMT

(Continued )

aMT

MEP

cSP

SICI

LICI

ICF

Study

Epilepsy type

N AED ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra

Badawy et al.105

Focal (refractory) 3 AED

20

Y

↑

Badawy et al.12

Focal

11

N

↔

Badawy and Focal Jackson120

22

N

↔

Cantello et al.146

Cryptogenic partial

18

Y

↔

↔

↔

↔

↓

↔

Cantello et al.106

Focal before VPA Focal 12 weeks VPA

7

N

↔

↔

↔

↔

↔

Y

↑

↑

↔

↔

↔ —

↓

↔

↓

↓↓

↔

↓

Cicinelli et al.147

Cryptogenic focal

16

Y

↑

↑

↓

↔

Cincotta et al.148

Partial 8 myoclonic Partial 10 nonmyoclonic

Y

↑

↑

↑∗

↑

Y

↔

↔

↔

↔

↔

—

↑

↔

↔

↔

↔

↔

↔

↔

—

Y

↔

↔

↓

↔

↔

↔

Hattemer et al.151

Focal catamenial

6

Y

↔

↔

↓#

↔

↔

↔

Hufnagel et al.145

Focal (TLE) + 18 AED Focal (TLE) − AED

Y

↑

↑

N

↑

↑

Focal (TLE)

53

Y

↑

↑

Focal − zonisamide Focal + zonisamide

24

N

no controls

↔

↔

↔

↔

↔

Y

↔

↔

↓

↔

↔

↔

Kessler et al.152

Post-stroke focal no controls

6

N

↔

↔

↓

↔

↓

↔

Kim et al.144

Post-stroke focal no controls Focal

18

Y

↑

↔

↔∗

↓∗

↑

↑

10

N

↔$

Kotova168

Focal − AED Focal + AED

13 20

N Y

↓$ ↔$

Manganotti et al.169

Partial − AED Partial + 5 weeks AED

6

N Y

no controls ↑% ↑%

Klimpe et al.108

↑ ↑

Focal 2AED no 23 controls

↔

↔

↓

Hamer et al.141

Hufnagel et al.149 Joo et al.150

↓

↑

—

↔

↔

↔

↔

↔

↔

↔

↔

↔

↔

↔

↑∗

↓∗

↔

↔$

↔$

↔%

1430001-10

↔%

↔$




rMT

Table 3c.

(Continued )

aMT

MEP

cSP

SICI

LICI

ICF

Study

Epilepsy type N AED ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra ipsi contra

Nezu et al.110 Tataroglu et al.116 Turazzini et al.138

BECT − AED 5 BECT + AED 8 Partial 48

N Y Y

↔ ↑ ↑

Post-stroke 8 focal − AED Post-stroke focal CBZ Focal 21

N

no controls

Y

↑%

N

↔

15

N

↔

Varrasi et al.142 Werhahn Focal − AED et al.143 Wright Refractory et al.167 TLE

18

↑

↔

↑%

↔%

↔

↔% ↔% ↔

↔

↔

↔

↔

↔% ↔% ↓

↔

↔

↔

↓

↑∗∗

no controls

↔% ↔R ↑L ↓↓

↓

↓∗∗

Note: ∗ Increased interhemispheric difference. ∗∗ Peri-ictally, correlated positively with seizure occurrence within 48 h. ∧ At 250 ms. # During luteal phase and menstruation. $ Only dominant hemisphere studied, regardless epilepsy side. % Side not specified. AED: anti-epileptic drugs. VPA: Valproic acid. CBZ: carbamazepine. TLE: temporal lobe epilepsy. N/Y: included people with and without medication. N/A: information on medication not available. rMT: resting motor threshold. MEP: Motor evoked potential. cSP: cortical silent period. SICI: short-interval intracortical inhibition. LICI: long-interval intracortical inhibition. ICF: intracortical facilitation. All data are compared to healthy controls. If no control group was included, this is stated.

be noted, however, that eight of these studies were conducted by one group. It is unclear whether their data overlaps from one study to another. ICF was increased in most studies,12,103–106,115,120 again, mostly from the same authors, and normal in two studies.107,122 Cortical recovery curves display the Test Response/Conditioned Response ratio (TR/CR) plotted against an ISIs range. In these studies people with IGE displayed a peak at ISI 250 ms where the TR/CR is around 200%, compared to 100% in healthy subjects. People with IGE also display a smaller peak at an ISI of 150–175 ms. Cortical recovery curves have not been widely studied by other authors, but appear to provide valuable additional information. The pathophysiologic significance of the facilitation or decrease in inhibition in people with epilepsy has not yet been completely elucidated. The fact that it is maximal at a long ISI suggests defective GABA(B) inhibition as one of the possible mechanisms.103,120,123 Further study, especially of the recovery curve and the long ISIs is needed to confirm these results and understand the underlying mechanisms.

In Lennox–Gastaut syndrome, a severe form of epilepsy characterized by frequent and refractory seizures and mental handicap, the balance tilts towards inhibition, reflected by an increased rMT, increased SICI and LICI and reduced ICF (see Table 3(a)).105 In this study, an attempt was made to correct for medication use by comparing people with Lennox–Gastaut who used two or more AEDs with people suffering from other types of refractory epilepsy who also used two or more AEDs. The authors corrected for peri-ictal changes in excitability by ensuring seizure freedom around the TMS measurements.105 It remains unclear why this disease shows hypo-excitability, whereas other types of epilepsy show cortical hyperexcitability. 3.2.1. Myoclonic epilepsies (juvenile and progressive myoclonic epilepsy (JME and PME )) Juvenile myoclonic epilepsy (JME) and progressive myoclonic epilepsy (PME) were repeatedly studied separately from other forms of IGE. JME is one of the most common forms of IGE with a

1430001-11



P. R. Bauer et al.

comparatively well-defined genetic profile.127 For these reasons, and to improve readability of the results, we have chosen to keep this separation in this review. In people with JME, rMT seems to be normal or increased although most studies have been carried out in people taking medication (see Table 3(b)).111,128–137 The only study in which people with JME did not take AEDs showed a normal rMT.125 In people with JME the balance was more towards excitability, with most studies, except two showing decreased inhibition reflected by lower SICI and LICI.111,131,132,135,138,139 One study found no differences in excitability between patients and healthy controls.136 It is argued that this may be due to the fact that the patients were on AEDs. In the studies that showed decreased SICI patients were on AEDs. Circadian rhythms were taken into account by measuring once in the evening and once in the morning, but seizure occurrence around TMS measurements is not mentioned. Another study only found reduced SICI in people with generalized myoclonus.130 Decrease of SICI and LICI was more marked in people with JME after sleep deprivation.135 One study found decreased ICF in JME and one found decreased ICF in Lafora body PME.131,135 Another study showed that in people with PME, SICI and LICI decrease was more pronounced than in people with JME.111 Studies investigating rMT in drug-na¨ıve people with IGE were compared in a recent metaanalysis.140 Data on JME were extracted from studies that included people with different types of IGE. It suggested that rMT was significantly lower in drug-na¨ıve people with JME (40 people) than in controls (161). In people with IGE other than JME, however, rMT did not significantly differ from controls (41 with IGE, 130 controls). The most consistent finding in people with JME is reduction in SICI (and LICI when studied), despite use of medication. In other forms of IGE, this finding is less consistent. SICI is probably GABA(A) mediated, and impaired GABA(A) mediated inhibition is in line with some reports of mutations of GABA(A) receptor subunits in cases of JME.127

and without (contralateral) the seizure focus separately. Results regarding rMT are conflicting (see Table 3(c)). Most studies did not find significant differences in rMT either between hemispheres or between people with and without epilepsy.12,103,104,108,110,120,141–143 Others found significant differences between ipsi- and contralateral rMT.104,115,144 In some studies no difference was found between the hemispheres, but rMT was found to be increased bilaterally compared with controls.115,116,145–149 Most of these studies included people who were treated with AEDs at the time of the investigation. cSP was normal in most studies.106,142,143,146,150 Two studies found prolonged cSP,144,148 while three studies found a shorter cSP, especially ipsilaterally.141,147,151 cSP was also reduced in post-stroke epilepsy152 but this was not confirmed by other studies.138,144 SICI was found to be decreased in people with focal epilepsy, especially in the ipsilateral hemisphere.12,103–105,115,120,123,125,142 All but two of these studies are from the same group, and were mainly conducted in drug-na¨ıve people. In these studies, ICF was increased ipsilaterally.12,103–105,115,120,123,125,142,144,146 Other studies, some of which were also conducted in drug-na¨ıve people, found no difference in SICI (bilaterally) or ICF between people with focal epilepsy and healthy controls.106,108,138,141,143,144,150,151 One study found decreased ICF ipsilaterally.143 The cortical recovery curves of people with focal epilepsy also shows a peak at an ISI of 250 ms that is somewhat smaller than in people with IGE.103,120,123 The peak at an ISI of 150– 175 ms, which is seen in people with IGE, is absent in people with focal epilepsy. Summarizing, although not unequivocal, the findings in people with focal epilepsy seem to point towards hyperexcitability of the hemisphere ipsilaterally to the epileptic focus, especially when considering the studies of Badawy et al.12,103–105,115,120,123,125 4.

TMS-EEG in Epilepsy

4.1. Assessment of CE 3.3. Focal epilepsy Inter-hemispheric difference in excitability appears to be crucial in focal epilepsy, and most groups have studied the hemispheres with (ipsilateral)

TMS-EEG in epilepsy is relatively novel. This noninvasive active method may offer advantages over passive mathematical EEG markers.153 The response to TMS on the EEG in people with focal epilepsy

1430001-12




and healthy controls has been assessed.154 Two phenomena were seen exclusively in 11 of 15 people with epilepsy. In three, stimulation of the epileptogenic area triggered a delayed response with spikes and sharp waves, sometimes similar to the person’s epileptiform discharges. In nine people, including one showing a delayed response, extra-temporal TMS stimulation triggered a new EEG rhythm that differed from the background EEG. Both phenomena were correlated with seizure lateralization. Another study found that the late EEG response to TMS was increased in amplitude after sleep deprivation in people with JME more than in controls.155 In a study of people with PME, it was shown that the power of oscillations in the alpha, beta and gamma band of the EEG upon TMS stimulation were lower in people with PME, than in controls. People with PME showed less synchronization of the alpha and beta bands than controls. The P30 response in people with PME was increased, which was interpreted as a sign of hyperexcitability. The N100/P180 peak was decreased in people with PME, indicating defective inhibition.156 TMS-EEG can be valuable to study brain connectivity in epilepsy.157,158 A recent study showed that during an epileptic discharge, there is an increase in information flow from the epileptic focus to other areas of the epileptogenic region. When TMS is applied after the start of the epileptic discharge however, this flow is reduced. Application of a short train of TMS stimuli at 3–5 Hz just after the start of epileptic discharges significantly shortens the duration of epileptic discharges. More research is needed to deepen understanding of this phenomenon.157 5. Potential Clinical Application of Diagnostic TMS 5.1. Prediction of AED response A potential clinical application of TMS is the prediction of AED treatment outcome. A significant effect at group level of AED on CE has been consistently shown.110,112–115,121 Treatment with AED increases rMT, even if this was low or normal prior to treatment,110,112–115,121 although in one study an AED failed to increase MT significantly.107 This was probably due to the fact that zonisamide was used in this study, whereas the others included sodium valproate, carbamazepine and lamotrigine. Zonisamide

has complex and multiple modes of action and may not directly affect MT.159 It caused, however, MEP reduction and lengthening of cSP. Significant increase of the rMT to above normal level after AED treatment initiation has been positively correlated with seizure reduction (and freedom) after one year.115 This opens the opportunity for personalized treatment in epilepsy. Epilepsy is often caused by multiple genetic and environmental factors. Knowledge of epilepsy is advancing, but it is not possible yet to determine all the factors involved in its pathophysiology, let alone on an individual basis. So far, treatment decisions in epilepsy are made mostly on empirical grounds. With TMS, reliable assessment of the inhibition/excitation balance is possible and the effect of medication can be assessed within 24 h. TMS may have the potential to guide treatment decisions in epilepsy. It could be of use in determining the doses needed, or TMS could help choosing the right drug. Several doses or drugs could be tried sequentially in a person with epilepsy, and instead of awaiting the clinical effect on the number of seizures, excitability could be tested after several weeks. A substantial decrease of excitability may mean that the drug is effective. TMS may also be used to study the temporal dynamics of CE in response to AED or candidate drugs. Further research is warranted to assess TMS reliability on individual rather than group basis and to determine what magnitude of decrease in CE is associated with seizure freedom. 5.2. Pre- and post epilepsy surgery CE evidence Focal epilepsy can be treated by surgery. CE measured with TMS pre- and post-operatively can predict the surgical outcome in some cases.160,161 Decrease of excitability of the epileptic hemisphere was correlated with significant seizure reduction (mean follow-up 16 months). One person, who did not show reduction of excitability, had a suboptimal post-operative outcome.161 These results were replicated for the nonepileptic hemisphere.160,162 Epilepsy surgery seems to change interhemispheric inhibitory interactions between the motor cortices.163 A case report discussed two people with cerebral tumors (glioblastoma multiforme WHO IV and metastasis) with focal motor seizures in whom TMS showed loss of SICI and strongly increased facilitation. The CSP was normal in both.164

1430001-13



P. R. Bauer et al.

Another report on two people with meningioma and simple and complex partial seizures showed lengthening of CSP in the person with simple partial seizures. Post-surgically, CSP returned to normal levels in this individual with no CSP changes seen in the other.165 Hyperexcitability was shown to normalize after subpial transection in an individual with simple partial seizures.166 One of the issues in post-operative management of people with epilepsy is the subsequent treatment with AED. Often AED treatment is continued until at least the first year after the operation, and some people will never stop taking AEDs in fear of new seizures. TMS could help decision making in the post-operative phase, and may help differentiate between the people who are at risk of relapse and who should continue taking AEDs and those who are likely to stay seizure free without medication. 5.3. Seizure prediction There is some evidence that CE significantly rises in the 24 h preceding a seizure, reflected by lower SICI and LICI and higher ICF.123,167 24 h post-ictally, excitability is lower than inter-ictally.115,119 TMS could, theoretically, help predict seizure occurrence, for example in the setting of pre-surgical evaluation. In this setting, time is limited, and ictal recordings are necessary to accurately determine the epileptic source. AED are tapered to increase the likelihood of a seizure that can be recorded. TMS could guide clinicians in the decisions regarding the doses of medication. Before this is possible further research will need to demonstrate that pre-ictal rise of excitability is significant in individuals and not only on group level. TMS is not a technique that could likely be used for seizure prediction in an out-patient setting, but has potential in a clinical environment. 6.

the human brain influenced by internal and external factors. Imbalance of inhibitory and excitatory factors seems to be key to the development of epilepsy. People with epilepsy (apart from those with Lennox–Gastaut syndrome) have a hyperexcitable cortex compared with healthy subjects. AEDs have an important role in reducing this cortical hyperexcitability. CE may be used as a marker of disease activity. Single- and paired-pulse TMS have the potential to help reduce the disease burden of epilepsy by predicting outcome of AED treatment in individuals. Findings are, however, sometimes contradictory and TMS is not as of yet ready to be used in clinical practice. The challenge that lies ahead is to investigate whether TMS can assess changes in CE at an individual level and whether these changes are strong enough to predict treatment outcome. More clinical studies that correlate individual changes in CE to disease activity are necessary. CE assessment may also be valuable for early prediction of post-operative outcome as well as for decision making regarding post-operative continuation of AED treatment. Prospective studies are needed to investigate the predictive power of pre- and postoperative CE measured by TMS. TMS-EEG offers exciting new opportunities to study the key features of the epileptic cortex — increased excitability and inappropriate firing of neurons. Future research will without doubt further develop this technique, as well as its application in epilepsy. One prospect is the possibility of assessing connectivity in epileptic circuits, offering insights into pathophysiology. In future, this information may help guide and evaluate epilepsy surgery and new therapies for the condition. Acknowledgments

Conclusion

Responses to TMS are fairly stable. Even when using a coil with focused beam, TMS typically recruits a large ensemble of neuronal cells, including neurons with excitatory and inhibitory properties. It is plausible that stimulating a relatively large area results in a consistent net response, while in some cases of direct cortical stimulation variability in the response may be due to insufficient neuronal recruitment.170 Research of CE, spurred by the development of TMS, suggests that CE is a dynamic feature of

This work was supported by the Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie (Nederland). We are grateful to Dr. G. S. Bell for reviewing the manuscript. We have no conflict of interest to declare in relation to this work. References

1430001-14

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42.

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