Neurophysiological and Genetic Findings in Patients With Juvenile Myoclonic Epilepsy.

OBJECTIVE: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia. METHODS: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10-15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied. RESULTS: We identified increased polyphasia in patients (85%) and relatives (70%) compared to controls (47%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; p < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in SYT14 (Synaptotagmin 14), in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia. CONCLUSION: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives.

Functional brain networks of patients with epilepsy exhibit pronounced multiscale periodicities, which correlate with seizure onset.

Epileptic seizure detection and prediction by using noninvasive measurements such as scalp EEG signals or invasive, intracranial recordings, has been at the heart of epilepsy studies for at least three decades. To this end, the most common approach has been to consider short-length recordings (several seconds to a few minutes) around a seizure, aiming to identify significant changes that occur before or during seizures. An inherent assumption in this approach is the presence of a relatively constant EEG activity in the interictal period, which is interrupted by seizure occurrence. Here, we examine this assumption by using long-duration scalp EEG data (21-94 hr) in nine patients with epilepsy, based on which we construct functional brain networks. Our results reveal that these networks vary over time in a periodic fashion, exhibiting multiple peaks at periods ranging between 1 and 24 hr. The effects of seizure onset on the functional brain network properties were found to be considerably smaller in magnitude compared to the changes due to these inherent periodic cycles. Importantly, the properties of the identified network periodic components (instantaneous phase) were found to be strongly correlated to seizure onset, especially for the periodicities around 3 and 5 hr. These correlations were found to be largely absent between EEG signal periodicities and seizure onset, suggesting that higher specificity may be achieved by using network-based metrics. In turn, this implies that more robust seizure detection and prediction can be achieved if longer term underlying functional brain network periodic variations are taken into account.

Graph Theoretical Characteristics of EEG-Based Functional Brain Networks in Patients With Epilepsy: The Effect of Reference Choice and Volume Conduction.

It is well-established that both volume conduction and the choice of recording reference (montage) affect the correlation measures obtained from scalp EEG, both in the time and frequency domains. As a result, a number of correlation measures have been proposed aiming to reduce these effects. In our previous work, we have showed that scalp-EEG based functional brain networks in patients with epilepsy exhibit clear periodic patterns at different time scales and that these patterns are strongly correlated to seizure onset, particularly at shorter time scales (around 3 and 5 h), which has important clinical implications. In the present work, we use the same long-duration clinical scalp EEG data (multiple days) to investigate the extent to which the aforementioned results are affected by the choice of reference choice and correlation measure, by considering several widely used montages as well as correlation metrics that are differentially sensitive to the effects of volume conduction. Specifically, we compare two standard and commonly used linear correlation measures, cross-correlation in the time domain, and coherence in the frequency domain, with measures that account for zero-lag correlations: corrected cross-correlation, imaginary coherence, phase lag index, and weighted phase lag index. We show that the graphs constructed with corrected cross-correlation and WPLI are more stable across different choices of reference. Also, we demonstrate that all the examined correlation measures revealed similar periodic patterns in the obtained graph measures when the bipolar and common reference (Cz) montage were used. This includes circadian-related periodicities (e.g., a clear increase in connectivity during sleep periods as compared to awake periods), as well as periodicities at shorter time scales (around 3 and 5 h). On the other hand, these results were affected to a large degree when the average reference montage was used in combination with standard cross-correlation, coherence, imaginary coherence, and PLI, which is likely due to the low number of electrodes and inadequate electrode coverage of the scalp. Finally, we demonstrate that the correlation between seizure onset and the brain network periodicities is preserved when corrected cross-correlation and WPLI were used for all the examined montages. This suggests that, even in the standard clinical setting of EEG recording in epilepsy where only a limited number of scalp EEG measurements are available, graph-theoretic quantification of periodic patterns using appropriate montage, and correlation measures corrected for volume conduction provides useful insights into seizure onset.

Unsupervised detection and removal of muscle artifacts from scalp EEG recordings using canonical correlation analysis, wavelets and random forests.

OBJECTIVE: This paper proposes supervised and unsupervised algorithms for automatic muscle artifact detection and removal from long-term EEG recordings, which combine canonical correlation analysis (CCA) and wavelets with random forests (RF). METHODS: The proposed algorithms first perform CCA and continuous wavelet transform of the canonical components to generate a number of features which include component autocorrelation values and wavelet coefficient magnitude values. A subset of the most important features is subsequently selected using RF and labelled observations (supervised case) or synthetic data constructed from the original observations (unsupervised case). The proposed algorithms are evaluated using realistic simulation data as well as 30min epochs of non-invasive EEG recordings obtained from ten patients with epilepsy. RESULTS: We assessed the performance of the proposed algorithms using classification performance and goodness-of-fit values for noisy and noise-free signal windows. In the simulation study, where the ground truth was known, the proposed algorithms yielded almost perfect performance. In the case of experimental data, where expert marking was performed, the results suggest that both the supervised and unsupervised algorithm versions were able to remove artifacts without affecting noise-free channels considerably, outperforming standard CCA, independent component analysis (ICA) and Lagged Auto-Mutual Information Clustering (LAMIC). CONCLUSION: The proposed algorithms achieved excellent performance for both simulation and experimental data. Importantly, for the first time to our knowledge, we were able to perform entirely unsupervised artifact removal, i.e. without using already marked noisy data segments, achieving performance that is comparable to the supervised case. SIGNIFICANCE: Overall, the results suggest that the proposed algorithms yield significant future potential for improving EEG signal quality in research or clinical settings without the need for marking by expert neurophysiologists, EMG signal recording and user visual inspection.

Epileptic seizure onset correlates with long term EEG functional brain network properties.

We investigated the correlation of epileptic seizure onset times with long term EEG functional brain network properties. To do so, we constructed binary functional brain networks from long-term, multichannel electroencephalographic data recorded from nine patients with epilepsy. The corresponding network properties were quantified using the average network degree. It was found that the network degree (as well as other network properties such as the network efficiency and clustering coefficient) exhibited large fluctuations over time; however, it also exhibited specific periodic temporal structure over different time scales (1.5hr-24hr periods) that was consistent across subjects. We investigated the correlation of the phases of these network periodicities with the seizure onset by using circular statistics. The results showed that the instantaneous phases of the 3.5hr, 5.5hr, 12hr and 24hr network degree periodic components are not uniformly distributed, suggesting that functional network properties are related to seizure generation and occurrence.

Automatic detection and removal of muscle artifacts from scalp EEG recordings in patients with epilepsy.

Automatic detection and removal of muscle artifacts plays an important role in long-term scalp electroencephalography (EEG) monitoring, and muscle artifact detection algorithms have been intensively investigated. This paper proposes an algorithm for automatic muscle artifacts detection and removal using canonical correlation analysis (CCA) and wavelet transform (WT) in epochs from long-term EEG recordings. The proposed method first performs CCA analysis and then conducts wavelet decomposition on the canonical components within a specific frequency range and selects a subset of the wavelet coefficients for subsequent processing. A set of features, including the mean of wavelet coefficients and the canonical component autocorrelation values, are extracted from the above analysis and subsequently used as input in a random forest (RF) classifier. The RF classifier produces a similarity measure between observations and selects a subset of the most important features by comparing the original data with a set of synthetic data that is constructed based on the latter. The RF predictor output is finally used in combination with unsupervised clustering algorithms to discriminate between contaminated and non-contaminated EEG epochs. The proposed method is evaluated in epochs of 30 min from scalp EEG recordings obtained from three patients with epilepsy and yields a sensitivity of 71% and 80%, as well as a specificity of 81% and 85% for k-means and spectral clustering, respectively.

Cervical vestibular evoked myogenic potentials in cerebellar lesions.

INTRODUCTION: Reports about cervical vestibular evoked myogenic potentials (cVEMPs) in central nervous system lesions are scarce. Our experience with cerebellar lesions is still evolving, with only a few cases published. The purpose of this article is to present our cVEMP findings of 3 cases with cerebellar lesions. MATERIALS AND METHODS: cVEMPs were performed using unilateral 120-dB peak SPL intensity 1 kHz tone air-conducted sound stimulation with contralateral masking noise, with recording from the tonically active sternocleidomastoid muscle. RESULTS: Brain MRI scans showed a small focal lesion in the right middle cerebellar peduncle in our first case, 2 foci in the right middle cerebellar peduncle and cerebellar hemisphere in our second case, and lesions in the right superior and inferior cerebellar peduncles near the fourth ventricle in our final case. All cVEMPs were normal. DISCUSSION: cVEMPs seem to be unaffected by at least certain cerebellar peduncle and hemispheric lesions. Although an abnormal cVEMP result may suggest noncerebellar dysfunction, further work is needed, as the lesions reported may not be interrupting the known cerebellovestibular pathways. Normal cVEMP responses may also or otherwise be due to affected vestibular nuclei influenced by the above cerebellar lesions not being part of the cVEMP pathway.

International guidelines for the clinical application of cervical vestibular evoked myogenic potentials: an expert consensus report.

BACKGROUND: Cervical vestibular evoked myogenic potentials (cVEMPs) are electromyogram responses evoked by high-level acoustic stimuli recorded from the tonically contracting sternocleidomastoid (SCM) muscle, and have been accepted as a measure of saccular and inferior vestibular nerve function. As more laboratories are publishing cVEMP data, there is a wider range of recording methods and interpretation, which may be confusing and limit comparisons across laboratories. OBJECTIVE: To recommend minimum requirements and guidelines for the recording and interpretation of cVEMPs in the clinic and for diagnostic purposes. MATERIAL AND METHODS: We have avoided proposing a single methodology, as clinical use of cVEMPs is evolving and questions still exist about its underlying physiology and its measurement. The development of guidelines by a panel of international experts may provide direction for accurate recording and interpretation. RESULTS: cVEMPs can be evoked using air-conducted (AC) sound or bone conducted (BC) vibration. The technical demands of galvanic stimulation have limited its application. For AC stimulation, the most effective frequencies are between 400 and 800 Hz below safe peak intensity levels (e.g. 140 dB peak SPL). The highpass filter should be between 5 and 30 Hz, the lowpass filter between 1000 and 3000 Hz, and the amplifier gain between 2500 and 5000. The number of sweeps averaged should be between 100 and 250 per run. Raw amplitude correction by the level of background SCM activity narrows the range of normal values. There are few publications in children with consistent results. CONCLUSION: The present recommendations outline basic terminology and standard methods. Because research is ongoing, new methodologies may be included in future guidelines.

Periodicity in functional brain networks: application to scalp EEG from epilepsy patients.

Seizure detection and prediction studies using scalp- or intracranial-EEG measurements often focus on short-length recordings around the occurrence of the seizure, normally ranging between several seconds and up to a few minutes before and after the event. The underlying assumption in these studies is the presence of a relatively constant EEG activity in the interictal period, that is presumably interrupted by the occurrence of a seizure, at the time the seizure starts or slightly earlier. In this study, we put this assumption under test, by examining long-duration scalp EEG recordings, ranging between 22 and 72 hours, of five patients with epilepsy. For each patient, we construct functional brain networks, by calculating correlations between the scalp electrodes, and examine how these networks vary in time. The results suggest not only that the network varies over time, but it does so in a periodic fashion, with periods ranging between 11 and 25 hours.