Adaptive Remote Sensing Paradigm for Real-Time Alerting of Convulsive Epileptic Seizures.

Epilepsy is a debilitating neurological condition characterized by intermittent paroxysmal states called fits or seizures. Especially, the major motor seizures of a convulsive nature, such as tonic-clonic seizures, can cause aggravating consequences. Timely alerting for these convulsive epileptic states can therefore prevent numerous complications, during, or following the fit. Based on our previous research, a non-contact method using automated video camera observation and optical flow analysis underwent field trials in clinical settings. Here, we propose a novel adaptive learning paradigm for optimization of the seizure detection algorithm in each individual application. The main objective of the study was to minimize the false detection rate while avoiding undetected seizures. The system continuously updated detection parameters retrospectively using the data from the generated alerts. The system can be used under supervision or, alternatively, through autonomous validation of the alerts. In the latter case, the system achieved self-adaptive, unsupervised learning functionality. The method showed improvement of the detector performance due to the learning algorithm. This functionality provided a personalized seizure alerting device that adapted to the specific patient and environment. The system can operate in a fully automated mode, still allowing human observer to monitor and override the decision process while the algorithm provides suggestions as an expert system.

Validation of virtual resection on intraoperative interictal data acquired during epilepsy surgery.

Objective. A 'Virtual resection' consists of computationally simulating the effect of an actual resection on the brain. We validated two functional connectivity based virtual resection methods with the actual connectivity measured using post-resection intraoperative recordings.Approach. A non-linear association index was applied to pre-resection recordings from 11 extra-temporal focal epilepsy patients. We computed two virtual resection strategies: first, a 'naive' one obtained by simply removing from the connectivity matrix the electrodes that were resected; second, a virtual resection with partialization accounting for the influence of resected electrodes on not-resected electrodes. We validated the virtual resections with two analysis: (1) we tested with a Kolmogorov-Smirnov test if the distributions of connectivity values after the virtual resections differed from the actual post-resection connectivity distribution; (2) we tested if the overall effect of the resection measured by contrasting pre-resection and post-resection connectivity values is detectable with the virtual resection approach using a Kolmogorv-Smirnov test.Main results. The estimation of post-resection connectivity values did not succeed for both methods. In the second analysis, the naive method failed completely to detect the effect found between pre-resection and post-resection connectivity distributions, while the partialization method agreed with post-resection measurements in detecting a drop connectivity compared to pre-resection recordings. Our findings suggest that the partialization technique is superior to the naive method in detecting the overall effect after the resection.Significance. We pointed out how a realistic validation based on actual post-resection recordings reveals that virtual resection methods are not yet mature to inform the clinical decision-making.

The value of intra-operative electrographic biomarkers for tailoring during epilepsy surgery: from group-level to patient-level analysis.

Signal analysis biomarkers, in an intra-operative setting, may be complementary tools to guide and tailor the resection in drug-resistant focal epilepsy patients. Effective assessment of biomarker performances are needed to evaluate their clinical usefulness and translation. We defined a realistic ground-truth scenario and compared the effectiveness of different biomarkers alone and combined to localize epileptogenic tissue during surgery. We investigated the performances of univariate, bivariate and multivariate signal biomarkers applied to 1 min inter-ictal intra-operative electrocorticography to discriminate between epileptogenic and non-epileptogenic locations in 47 drug-resistant people with epilepsy (temporal and extra-temporal) who had been seizure-free one year after the operation. The best result using a single biomarker was obtained using the phase-amplitude coupling measure for which the epileptogenic tissue was localized in 17 out of 47 patients. Combining the whole set of biomarkers provided an improvement of the performances: 27 out of 47 patients. Repeating the analysis only on the temporal-lobe resections we detected the epileptogenic tissue in 29 out of 30 combining all the biomarkers. We suggest that the assessment of biomarker performances on a ground-truth scenario is required to have a proper estimate on how biomarkers translate into clinical use. Phase-amplitude coupling seems the best performing single biomarker and combining biomarkers improves localization of epileptogenic tissue. Performance achieved is not adequate as a tool in the operation theater yet, but it can improve the understanding of pathophysiological process.

Automated video-based detection of nocturnal motor seizures in children.

Seizure detection devices can improve epilepsy care, but wearables are not always tolerated. We previously demonstrated good performance of a real-time video-based algorithm for detection of nocturnal convulsive seizures in adults with learning disabilities. The algorithm calculates the relative frequency content based on the group velocity reconstruction from video-sequence optical flow. We aim to validate the video algorithm on nocturnal motor seizures in a pediatric population. We retrospectively analyzed the algorithm performance on a database including 1661 full recorded nights of 22 children (age = 3-17 years) with refractory epilepsy at home or in a residential care setting. The algorithm detected 118 of 125 convulsions (median sensitivity per participant = 100%, overall sensitivity = 94%, 95% confidence interval = 61%-100%) and identified all 135 hyperkinetic seizures. Most children had no false alarms; 81 false alarms occurred in six children (median false alarm rate [FAR] per participant per night = 0 [range = 0-0.47], overall FAR = 0.05 per night). Most false alarms (62%) were behavior-related (eg, awake and playing in bed). Our noncontact detection algorithm reliably detects nocturnal epileptic events with only a limited number of false alarms and is suitable for real-time use.

Epilepsy as a manifestation of a multistate network of oscillatory systems.

The human brain, largely accepted as the most complex biological system known, is still far from being understood in its parts or as a whole. More specifically, biological mechanisms of epileptic states and state transitions are not well understood. Here, we explore the concept of the epilepsy as a manifestation of a multistate network composed of coupled oscillatory units. We also propose that functional coupling between neuroglial elements is a dynamic process, characterized by temporal changes both at short and long time scales. We review various experimental and modelling data suggesting that epilepsy is a pathological manifestation of such a multistate network - both when viewed as a coupled oscillatory network, and as a system of multistate stable state attractors. Based on a coupled oscillators model, we propose a significant role for glial cells in modulating hyperexcitability of the neuroglial networks of the brain. Also, using these concepts, we explain a number of observable phenomena such as propagation patterns of bursts within a seizure in the isolated intact hippocampus in vitro, postictal generalized suppression in human encephalographic seizure data, and changes in seizure susceptibility in epileptic patients. Based on our conceptual model we propose potential clinical applications to estimate brain closeness to ictal transition by means of active perturbations and passive measures during on-going activity.

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.

Automated remote fall detection using impact features from video and audio.

Elderly people and people with epilepsy may need assistance after falling, but may be unable to summon help due to injuries or impairment of consciousness. Several wearable fall detection devices have been developed, but these are not used by all people at risk. We present an automated analysis algorithm for remote detection of high impact falls, based on a physical model of a fall, aiming at universality and robustness. Candidate events are automatically detected and event features are used as classifier input. The algorithm uses vertical velocity and acceleration features from optical flow outputs, corrected for distance from the camera using moving object size estimation. A sound amplitude feature is used to increase detector specificity. We tested the performance and robustness of our trained algorithm using acted data from a public database and real life data with falls resulting from epilepsy and with daily life activities. Applying the trained algorithm to the acted dataset resulted in 90% sensitivity for detection of falls, with 92% specificity. In the real life data, six/nine falls were detected with a specificity of 99.7%; there is a plausible explanation for not detecting each of the falls missed. These results reflect the algorithm's robustness and confirms the feasibility of detecting falls using this algorithm.

Automated video-based detection of nocturnal convulsive seizures in a residential care setting.

People with epilepsy need assistance and are at risk of sudden death when having convulsive seizures (CS). Automated real-time seizure detection systems can help alert caregivers, but wearable sensors are not always tolerated. We determined algorithm settings and investigated detection performance of a video algorithm to detect CS in a residential care setting. The algorithm calculates power in the 2-6 Hz range relative to 0.5-12.5 Hz range in group velocity signals derived from video-sequence optical flow. A detection threshold was found using a training set consisting of video-electroencephalogaphy (EEG) recordings of 72 CS. A test set consisting of 24 full nights of 12 new subjects in residential care and additional recordings of 50 CS selected randomly was used to estimate performance. All data were analyzed retrospectively. The start and end of CS (generalized clonic and tonic-clonic seizures) and other seizures considered desirable to detect (long generalized tonic, hyperkinetic, and other major seizures) were annotated. The detection threshold was set to the value that obtained 97% sensitivity in the training set. Sensitivity, latency, and false detection rate (FDR) per night were calculated in the test set. A seizure was detected when the algorithm output exceeded the threshold continuously for 2 seconds. With the detection threshold determined in the training set, all CS were detected in the test set (100% sensitivity). Latency was ≤10 seconds in 78% of detections. Three/five hyperkinetic and 6/9 other major seizures were detected. Median FDR was 0.78 per night and no false detections occurred in 9/24 nights. Our algorithm could improve safety unobtrusively by automated real-time detection of CS in video registrations, with an acceptable latency and FDR. The algorithm can also detect some other motor seizures requiring assistance.

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.

Dynamics of convulsive seizure termination and postictal generalized EEG suppression.

It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression.

Multimodal, automated detection of nocturnal motor seizures at home: Is a reliable seizure detector feasible?

Objective: Automated seizure detection and alarming could improve quality of life and potentially prevent sudden, unexpected death in patients with severe epilepsy. As currently available systems focus on tonic-clonic seizures, we want to detect a broader range of seizure types, including tonic, hypermotor, and clusters of seizures. Methods: In this multicenter, prospective cohort study, the nonelectroencephalographic (non-EEG) signals heart rate and accelerometry were measured during the night in patients undergoing a diagnostic video-EEG examination. Based on clinical video-EEG data, seizures were classified and categorized as clinically urgent or not. Seizures included for analysis were tonic, tonic-clonic, hypermotor, and clusters of short myoclonic/tonic seizures. Features reflecting physiological changes in heart rate and movement were extracted. Detection algorithms were developed based on stepwise fulfillment of conditions during increases in either feature. A training set was used for development of algorithms, and an independent test set was used for assessing performance. Results: Ninety-five patients were included, but due to sensor failures, data from only 43 (of whom 23 patients had 86 seizures, representing 402 h of data) could be used for analysis. The algorithms yield acceptable sensitivities, especially for clinically urgent seizures (sensitivity = 71-87%), but produce high false alarm rates (2.3-5.7 per night, positive predictive value = 25-43%). There was a large variation in the number of false alarms per patient. Significance: It seems feasible to develop a detector with high sensitivity, but false alarm rates are too high for use in clinical practice. For further optimization, personalization of algorithms may be necessary.

Non-harmonicity in high-frequency components of the intra-operative corticogram to delineate epileptogenic tissue during surgery.

OBJECTIVE: We aimed to test the potential of auto-regressive model residual modulation (ARRm), an artefact-insensitive method based on non-harmonicity of the high-frequency signal, to identify epileptogenic tissue during surgery. METHODS: Intra-operative electrocorticography (ECoG) of 54 patients with refractory focal epilepsy were recorded pre- and post-resection at 2048Hz. The ARRm was calculated in one-minute epochs in which high-frequency oscillations (HFOs; fast ripples, 250-500Hz; ripples, 80-250Hz) and spikes were marked. We investigated the pre-resection fraction of HFOs and spikes explained by the ARRm (h2-index). A general ARRm threshold was set and used to compare the ARRm to surgical outcome in post-resection ECoG (Pearson X2). RESULTS: ARRm was associated strongest with the number of fast ripples in pre-resection ECoG (h2=0.80, P<0.01), but also with ripples and spikes. An ARRm threshold of 0.47 yielded high specificity (95%) with 52% sensitivity for channels with fast ripples. ARRm values >0.47 were associated with poor outcome at channel and patient level (both P<0.01) in post-resection ECoG. CONCLUSIONS: The ARRm algorithm might enable intra-operative delineation of epileptogenic tissue. SIGNIFICANCE: ARRm is the first unsupervised real-time analysis that could provide an intra-operative, 'on demand' interpretation per electrode about the need to remove underlying tissue to optimize the chance of seizure freedom.

Automated Video Detection of Epileptic Convulsion Slowing as a Precursor for Post-Seizure Neuronal Collapse.

Automated monitoring and alerting for adverse events in people with epilepsy can provide higher security and quality of life for those who suffer from this debilitating condition. Recently, we found a relation between clonic slowing at the end of a convulsive seizure (CS) and the occurrence and duration of a subsequent period of postictal generalized EEG suppression (PGES). Prolonged periods of PGES can be predicted by the amount of progressive increase of interclonic intervals (ICIs) during the seizure. The purpose of the present study is to develop an automated, remote video sensing-based algorithm for real-time detection of significant clonic slowing that can be used to alert for PGES. This may help preventing sudden unexpected death in epilepsy (SUDEP). The technique is based on our previously published optical flow video sequence processing paradigm that was applied for automated detection of major motor seizures. Here, we introduce an integral Radon-like transformation on the time-frequency wavelet spectrum to detect log-linear frequency changes during the seizure. We validate the automated detection and quantification of the ICI increase by comparison to the results from manually processed electroencephalography (EEG) traces as "gold standard". We studied 48 cases of convulsive seizures for which synchronized EEG-video recordings were available. In most cases, the spectral ridges obtained from Gabor-wavelet transformations of the optical flow group velocities were in close proximity to the ICI traces detected manually from EEG data during the seizure. The quantification of the slowing-down effect measured by the dominant angle in the Radon transformed spectrum was significantly correlated with the exponential ICI increase factors obtained from manual detection. If this effect is validated as a reliable precursor of PGES periods that lead to or increase the probability of SUDEP, the proposed method would provide an efficient alerting device.

Preventive and Abortive Strategies for Stimulation Based Control of Epilepsy: A Computational Model Study.

Epilepsy is a condition in which periods of ongoing normal EEG activity alternate with periods of oscillatory behavior characteristic of epileptic seizures. The dynamics of the transitions between the two states are still unclear. Computational models provide a powerful tool to explore the underlying mechanisms of such transitions, with the purpose of eventually finding therapeutic interventions for this debilitating condition. In this study, the possibility to postpone seizures elicited by a decrease of inhibition is investigated by using external stimulation in a realistic bistable neuronal model consisting of two interconnected neuronal populations representing pyramidal cells and interneurons. In the simulations, seizures are induced by slowly decreasing the conductivity of GABA[Formula: see text] synaptic channels over time. Since the model is bistable, the system will change state from the initial steady state (SS) to the limit cycle (LS) state because of internal noise, when the inhibition falls below a certain threshold. Several state-independent stimulations paradigms are simulated. Their effectiveness is analyzed for various stimulation frequencies and intensities in combination with periodic and random stimulation sequences. The distributions of the time to first seizure in the presence of stimulation are compared with the situation without stimulation. In addition, stimulation protocols targeted to specific subsystems are applied with the objective of counteracting the baseline shift due to decreased inhibition in the system. Furthermore, an analytical model is used to investigate the effects of random noise. The relation between the strength of random noise stimulation, the control parameter of the system and the transitions between steady state and limit cycle are investigated. The study shows that it is possible to postpone epileptic activity by targeted stimulation in a realistic neuronal model featuring bistability and that it is possible to stop seizures by random noise in an analytical model.

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.

Automated Seizure Onset Zone Approximation Based on Nonharmonic High-Frequency Oscillations in Human Interictal Intracranial EEGs.

A novel automated algorithm is proposed to approximate the seizure onset zone (SOZ), while providing reproducible output. The SOZ, a surrogate marker for the epileptogenic zone (EZ), was approximated from intracranial electroencephalograms (iEEG) of nine people with temporal lobe epilepsy (TLE), using three methods: (1) Total ripple length (TRL): Manually segmented high-frequency oscillations, (2) Rippleness (R): Area under the curve (AUC) of the autocorrelation functions envelope, and (3) Autoregressive model residual variation (ARR, novel algorithm): Time-variation of residuals from autoregressive models of iEEG windows. TRL, R, and ARR results were compared in terms of separability, using Kolmogorov-Smirnov tests, and performance, using receiver operating characteristic (ROC) curves, to the gold standard for SOZ delineation: visual observation of ictal video-iEEGs. TRL, R, and ARR can distinguish signals from iEEG channels located within the SOZ from those outside it (p < 0.01). The ROC AUC was 0.82 for ARR, while it was 0.79 for TRL, and 0.64 for R. ARR outperforms TRL and R, and may be applied to identify channels in the SOZ automatically in interictal iEEGs of people with TLE. ARR, interpreted as evidence for nonharmonicity of high-frequency EEG components, could provide a new way to delineate the EZ, thus contributing to presurgical workup.

Multiple oscillatory states in models of collective neuronal dynamics.

In our previous studies, we showed that the both realistic and analytical computational models of neural dynamics can display multiple sustained states (attractors) for the same values of model parameters. Some of these states can represent normal activity while other, of oscillatory nature, may represent epileptic types of activity. We also showed that a simplified, analytical model can mimic this type of behavior and can be used instead of the realistic model for large scale simulations. The primary objective of the present work is to further explore the phenomenon of multiple stable states, co-existing in the same operational model, or phase space, in systems consisting of large number of interconnected basic units. As a second goal, we aim to specify the optimal method for state control of the system based on inducing state transitions using appropriate external stimulus. We use here interconnected model units that represent the behavior of neuronal populations as an effective dynamic system. The model unit is an analytical model (S. Kalitzin et al., Epilepsy Behav. 22 (2011) S102-S109) and does not correspond directly to realistic neuronal processes (excitatory-inhibitory synaptic interactions, action potential generation). For certain parameter choices however it displays bistable dynamics imitating the behavior of realistic neural mass models. To analyze the collective behavior of the system we applied phase synchronization analysis (PSA), principal component analysis (PCA) and stability analysis using Lyapunov exponent (LE) estimation. We obtained a large variety of stable states with different dynamic characteristics, oscillatory modes and phase relations between the units. These states can be initiated by appropriate initial conditions; transitions between them can be induced stochastically by fluctuating variables (noise) or by specific inputs. We propose a method for optimal reactive control, allowing forced transitions from one state (attractor) into another.