Transcranial magnetic stimulation-evoked electroencephalography responses as biomarkers for epilepsy: A review of study design and outcomes.

Transcranial magnetic stimulation (TMS) with electroencephalography (EEG), that is TMS-EEG, may assist in managing epilepsy. We systematically reviewed the quality of reporting and findings in TMS-EEG studies on people with epilepsy and healthy controls, and on healthy individuals taking anti-seizure medication. We searched the Cochrane Library, Embase, PubMed and Web of Science databases for original TMS-EEG studies comparing people with epilepsy and healthy controls, and healthy subjects before and after taking anti-seizure medication. Studies should involve quantitative analyses of TMS-evoked EEG responses. We evaluated the reporting of study population characteristics and TMS-EEG protocols (TMS sessions and equipment, TMS trials and EEG protocol), assessed the variation between protocols, and recorded the main TMS-EEG findings. We identified 20 articles reporting 14 unique study populations and TMS methodologies. The median reporting rate for the group of people with epilepsy parameters was 3.5/7 studies and for the TMS parameters was 13/14 studies. TMS protocols varied between studies. Fifteen out of 28 anti-seizure medication trials in total were evaluated with time-domain analyses of single-pulse TMS-EEG data. Anti-seizure medication significantly increased N45, and decreased N100 and P180 component amplitudes but in marginal numbers (N45: 8/15, N100: 7/15, P180: 6/15). Eight articles compared people with epilepsy and controls using different analyses, thus limiting comparability. The reporting quality and methodological uniformity between studies evaluating TMS-EEG as an epilepsy biomarker is poor. The inconsistent findings question the validity of TMS-EEG as an epilepsy biomarker. To demonstrate TMS-EEG clinical applicability, methodology and reporting standards are required.

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura.

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

Tracking cortical excitability dynamics with transcranial magnetic stimulation in focal epilepsy.

INTRODUCTION: The lack of reliable biomarkers constrain epilepsy management. We assessed the potential of repeated transcranial magnetic stimulation with electromyography (TMS-EMG) to track dynamical changes in cortical excitability on a within-subject basis. METHODS: We recruited people with refractory focal epilepsy who underwent video-EEG monitoring and drug tapering as part of the presurgical evaluation. We performed daily TMS-EMG measurements with additional postictal assessments 1-6 h following seizures to assess resting motor threshold (rMT), and motor evoked potentials (MEPs) with single- and paired-pulse protocols. Anti-seizure medication (ASM) regimens were recorded for the day before each measurement and expressed in proportion to the dosage before tapering. Additional measurements were performed in healthy controls to evaluate day-to-day rMT variability. RESULTS: We performed 77 (58 baseline, 19 postictal) measurements in 16 people with focal epilepsy and 35 in seven healthy controls. Controls showed minimal day-to-day rMT variation. Withdrawal of ASMs was associated with a lower rMT without affecting MEPs of single- and paired-pulse TMS-EMG paradigms. Postictal measurements following focal to bilateral tonic-clonic seizures demonstrated unaltered rMT and increased short interval intracortical inhibition, while measurements following focal seizures with impaired awareness showed decreased rMT's and reduced short and long interval intracortical inhibition. CONCLUSION: Serial within-subject rMT measurements yielded reproducible, stable results in healthy controls. ASM tapering and seizures had distinct effects on TMS-EMG excitability indices in people with epilepsy. Drug tapering decreased rMT, indicating increased overall corticospinal excitability, whereas seizures affected intracortical inhibition with contrasting effects between seizure types.

Cardiac arrhythmias in Dravet syndrome: an observational multicenter study.

OBJECTIVES: We ascertained the prevalence of ictal arrhythmias to explain the high rate of sudden unexpected death in epilepsy (SUDEP) in Dravet syndrome (DS). METHODS: We selected cases with clinical DS, ≥6 years, SCN1A mutation, and ≥1 seizure/week. Home-based ECG recordings were performed for 20 days continuously. Cases were matched for age and sex to two epilepsy controls with no DS and ≥1 major motor seizure during video-EEG. We determined the prevalence of peri-ictal asystole, bradycardia, QTc changes, and effects of convulsive seizures (CS) on heart rate, heart rate variability (HRV), and PR/QRS. Generalized estimating equations were used to account for multiple seizures within subjects, seizure type, and sleep/wakefulness. RESULTS: We included 59 cases. Ictal recordings were obtained in 45 cases and compared to 90 controls. We analyzed 547 seizures in DS (300 CS) and 169 in controls (120 CS). No asystole occurred. Postictal bradycardia was more common in controls (n = 11, 6.5%) than cases (n = 4, 0.7%; P = 0.002). Peri-ictal QTc-lengthening (≥60ms) occurred more frequently in DS (n = 64, 12%) than controls (n = 8, 4.7%, P = 0.048); pathologically prolonged QTc was rare (once in each group). In DS, interictal HRV was lower compared to controls (RMSSD P = 0.029); peri-ictal values did not differ between the groups. Prolonged QRS/PR was rare and more common in controls (QRS: one vs. none; PR: three vs. one). INTERPRETATION: We did not identify major arrhythmias in DS which can directly explain high SUDEP rates. Peri-ictal QTc-lengthening was, however, more common in DS. This may reflect unstable repolarization and an increased propensity for arrhythmias.

Phase clustering in transcranial magnetic stimulation-evoked EEG responses in genetic generalized epilepsy and migraine.

BACKGROUND: Epilepsy and migraine are paroxysmal neurological conditions associated with disturbances of cortical excitability. No useful biomarkers to monitor disease activity in these conditions are available. Phase clustering was previously described in electroencephalographic (EEG) responses to photic stimulation and may be a potential epilepsy biomarker. OBJECTIVE: The objective of this study was to investigate EEG phase clustering in response to transcranial magnetic stimulation (TMS), compare it with photic stimulation in controls, and explore its potential as a biomarker of genetic generalized epilepsy or migraine with aura. METHODS: People with (possible) juvenile myoclonic epilepsy (JME), migraine with aura, and healthy controls underwent single-pulse TMS with concomitant EEG recording during the interictal period. We compared phase clustering after TMS with photic stimulation across the groups using permutation-based testing. RESULTS: We included eight people with (possible) JME (five off medication, three on), 10 with migraine with aura, and 37 controls. The TMS and photic phase clustering spectra showed significant differences between those with epilepsy without medication and controls. Two phase clustering-based indices successfully captured these differences between groups. One participant was tested multiple times. In this case, the phase clustering-based indices were inversely correlated with the dose of antiepileptic medication. Phase clustering did not differ between people with migraine and controls. CONCLUSION: We present methods to quantify phase clustering using TMS-EEG and show its potential value as a measure of brain network activity in genetic generalized epilepsy. Our results suggest that the higher propensity to phase clustering is not shared between genetic generalized epilepsy and migraine.

Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study.

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.

Gap Junctions as Common Cause of High-Frequency Oscillations and Epileptic Seizures in a Computational Cascade of Neuronal Mass and Compartmental Modeling.

High frequency oscillations (HFO) appear to be a promising marker for delineating the seizure onset zone (SOZ) in patients with localization related epilepsy. It remains, however, a purely observational phenomenon and no common mechanism has been proposed to relate HFOs and seizure generation. In this work we show that a cascade of two computational models, one on detailed compartmental scale and a second one on neural mass scale can explain both the autonomous generation of HFOs and the presence of epileptic seizures as emergent properties. To this end we introduce axonal-axonal gap junctions on a microscopic level and explore their impact on the higher level neural mass model (NMM). We show that the addition of gap junctions can generate HFOs and simultaneously shift the operational point of the NMM from a steady state network into bistable behavior that can autonomously generate epileptic seizures. The epileptic properties of the system, or the probability to generate epileptic type of activity, increases gradually with the increase of the density of axonal-axonal gap junctions. We further demonstrate that ad hoc HFO detectors used in previous studies are applicable to our simulated data.