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SummaryBackgroundA retrospective, multi-site case control study was carried out to validate a set of candidate biomarkers of seizure susceptibility. The objective was to determine the robustness of these biomarkers derived from routinely collected EEG within a large cohort (both epilepsy and common alternative conditions which may present with a possible seizure, such as NEAD).MethodsThe database consisted of 814 EEG recordings from 648 subjects, collected from 8 NHS sites across the UK. Clinically non-contributory EEG recordings were identified by an experienced clinical scientist (N = 281; 152 alternative conditions, 129 epilepsy). Eight computational markers (spectral [N = 2], network-based [N = 4] and model-based [N = 2]) were calculated within each recording. Ensemble-based classifiers were developed using a two-tier cross-validation approach. We used standard regression methods in order to identify whether potential confounding variables (e.g. age, gender, treatment-status, comorbidity) impacted model performance.FindingsWe found levels of balanced accuracy of 68% across the cohort with clinically non-contributory normal EEGs (sensitivity: 61%, specificity: 75%, positive predictive value: 55%, negative predictive value: 79%, diagnostic odds ratio: 4.64). Group-level analysis found no evidence suggesting any of the potential confounding variables significantly impacted the overall performance.InterpretationThese results provide evidence that the set of biomarkers could provide additional value to clinical decision-making, providing the foundation for a decision support tool that could reduce diagnostic delay and misdiagnosis rates. Future work should therefore assess the change in diagnostic yield and time to diagnosis when utilising these biomarkers in carefully designed prospective studies.Research in ContextEvidence before this studyWe searched Google Scholar and Pubmed (March 21, 2022) for the following phrases ((“EEG” OR “electroencephalogram” OR “electroencephalography”) AND (“biomarker”) AND (“epilepsy” OR “seizure”) AND (“resting state” OR “resting-state”) OR (“normal”)). Several of the existing studies developed deep learning approaches for identifying the presence of interictal epileptiform discharges (IED), with the overarching aim to develop an automated stand-alone diagnostic tool. These approaches are particularly sensitive to the potential presence of artefacts in the EEG recordings and typically include spectral rather than network- or model-based features. We found no studies of more than 100 participants that assessed the cross-validated performance of candidate biomarkers on routine EEG recordings that were clinically non-contributory. One study found near-chance performance of a deep-learning based method using spectral features on a smaller cohort of people suspected of epilepsy (N=33 epilepsy; N=30 alternative conditions) with clinically non-contributory EEGs. Another study found overall accuracy of 69% (N=74 epilepsy; N=74 alternative conditions) but this framework did not use any independent cross-validation methods. Estimates of sensitivity of clinical markers of seizure susceptibility in routine EEG recordings vary between 17-56%. To the best of our knowledge no studies have assessed whether computational biomarkers offer sufficient discrimination between people with epilepsy and an alternative diagnosis to provide potential decision support for people with suspected epilepsy.Added value of this studyWe show that data-driven analysis of routinely collected EEGs that are currently considered clinically non-informative (i.e. absence of apparent epileptiform activity) can be used to distinguish EEGs from people with epilepsy from people with an alternative diagnosis with better-than-chance performance. To the best of our knowledge, this is the largest retrospective study assessing the performance of computational biomarkers derived from clinically non-contributory EEG recordings. The resulting statistical model is interpretable and relies on both spectral and computational (network- and model-based) features. We perform a series of validity and sensitivity analysis to assess the overall robustness of the final statistical model used for classification. We also conduct several statistical tests to analyse any shared characteristics (e.g. site, comorbidity) amongst the primary classes (FP, FN, TP, TN). These findings validate previous biomarker discovery- or development-studies, and provide evidence that they offer better-than-chance performance in a clinically relevant context. Future large-scale studies could consider combining these methods with interictal features for non-specialist settings.Implications of all the available evidenceOur study presents evidence that computational analysis of clinically non-contributory EEGs could provide additional decision support for both epilepsy and alternative conditions. Since the statistical model and underlying features are interpretable, they could provide the starting point for further exploring the mechanisms that drive overall seizure-likelihood. Future work should focus on prospective testing and validation (e.g. identification of specific situations or cases in which these methods could be of added value) as well as assessing heterogeneity across different syndromes and diagnoses (e.g. NEAD, focal vs generalised epilepsy).

Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy - so-called interictal epileptiform activity - with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy.Author summary65 million people have epilepsy worldwide. Many of these people report specific triggers that make their seizures (the primary symptom of epilepsy) more likely. Here, we use a mathematical model to understand the relationship between possible triggers and rhythms in epileptiform activity observed across the day.The mathematical model describes the activity of connected brain regions, and how the excitability of these regions can change in response to different stimuli. Based on data collected from people with idiopathic generalized epilepsy, we identify transitions between sleep stages and variation in concentration of the stress-hormone cortisol as candidate factors that influence how likely it is for epileptiform activity to occur. By including those factors into the model, we show they can explain most of the daily variability. More broadly, our approach provides a framework for better understanding what factors drive the occurrence of epileptiform activity and offers the potential to suggest experiments that can validate model predictions.

Chronotype - the relationship between the internal circadian physiology of an individual and the external 24-hour light-dark cycle - is increasingly implicated in mental health and cognition. Individuals presenting with a late chronotype have an increased likelihood of developing depression, and can display reduced cognitive performance during the societal 9-5 day. However, the interplay between physiological rhythms and the brain networks that underpin cognition and mental health are not well understood. To address this issue, we use resting state fMRI collected from 16 people with an early chronotype and 22 people with a late chronotype to study if differentiable information about chronotype is embedded in functional brain networks. We develop a classifier utilising the Network Based-Statistic (NBS) methodology, using rigorous selection criteria to select t-statistic thresholds within the NBS approach. We find significant differences in functional networks measured in early and late chronotypes and describe conditions under which the classifier achieves 97.3% accuracy. Revealing differences in functional brain networks based on extreme chronotype suggests future avenues of research that may ultimately better characterise the relationship between internal physiology, external perturbations, brain networks and disease.

Modelling the interactions that arise from neural dynamics in seizure genesis is challenging but important in the effort to improve the success of epilepsy surgery. Dynamical network models developed from physiological evidence offer insights into rapidly evolving brain networks in the epileptic seizure. A limitation of previous studies in this field is the dependence on invasive cortical recordings with constrained spatial sampling of brain regions that might be involved in seizure dynamics. Here, we propose virtual intracranial electroencephalography (ViEEG), which combines non-invasive ictal magnetoencephalographic imaging (MEG), dynamical network models and a virtual resection technique. In this proof-of-concept study, we show that ViEEG signals reconstructed from MEG alone preserve critical temporospatial characteristics for dynamical approaches to identify brain areas involved in seizure generation. We show the non-invasive ViEEG approach may have some advantage over intracranial electroencephalography (iEEG). Future work may be designed to test the potential of the virtual iEEG approach for use in surgical management of epilepsy.

This article describes source data from a systematic review and meta-analysis of electroencephalography (EEG) and magnetoencephalography (MEG) studies investigating functional connectivity in idiopathic generalized epilepsy. Data selection, analysis and reporting was performed according to PRISMA guidelines. Eligible studies for review were identified from human case-control, and cohort studies. Twenty-two studies were included in the review. Extracted descriptive data included sample characteristics, acquisition of EEG or MEG recordings and network construction. Reported differences between IGE and control groups in functional connectivity or network metrics were extracted as the main outcome measure. Qualitative group differences in functional connectivity were synthesized through narrative review. Meta-analysis was performed for group-level, quantitative estimates of common network metrics clustering coefficient, path length, mean degree and nodal strength. Six studies were included in the meta-analysis. Risk of bias was assessed across all studies. Raw and synthesized data for included studies are reported, alongside effect size and heterogeneity statistics from meta-analyses. Network neurosciences is a rapidly expanding area of research, with significant potential for clinical applications in epilepsy. This data article provides novel, statistical estimates of brain network differences from patients with IGE relative to healthy controls, across the existing literature. Increasing data accessibility supports study replication and improves study comparability for future reviews, enabling a better understanding of network characteristics in IGE.

For idiopathic generalized epilepsies (IGE), brain network analysis is emerging as a biomarker for potential use in clinical care. To determine whether people with IGE show alterations in resting-state brain connectivity compared to healthy controls, and to quantify these differences, we conducted a systematic review and meta-analysis of EEG and magnetoencephalography (MEG) functional connectivity and network studies. The review was conducted according to PRISMA guidelines. Twenty-two studies were eligible for inclusion. Outcomes from individual studies supported hypotheses for interictal, resting-state brain connectivity alterations in IGE patients compared to healthy controls. In contrast, meta-analysis from six studies of common network metrics clustering coefficient, path length, mean degree and nodal strength showed no significant differences between IGE and control groups (effect sizes ranged from -0.151 -1.78). The null findings of the meta-analysis and the heterogeneity of the included studies highlights the importance of developing standardized, validated methodologies for future research. Network neuroscience has significant potential as both a diagnostic and prognostic biomarker in epilepsy, though individual variability in network dynamics needs to be better understood and accounted for.

Objectives. There is emerging evidence that network/computer analysis of epileptiform discharge free electroencephalograms (EEGs) can be used to detect epilepsy, improve diagnosis and resource use. Such methods are automated and can be performed on shorter recordings of EEG. We assess the evidence and its strength in the area of seizure detection from network/computer analysis of epileptiform discharge free EEG. Methods. A scoping review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was conducted with a literature search of Embase, Medline and PsychINFO. Predesigned inclusion/exclusion criteria were applied to selected articles. Results. The initial search found 3398 articles. After duplicate removal and screening, 591 abstracts were reviewed, 64 articles were selected and read leading to 20 articles meeting the requisite inclusion/exclusion criteria. These were 9 reports and 2 cross-sectional studies using network analysis to compare and/or classify EEG. One review of 17 reports and 10 cross-sectional studies only aimed to classify the EEGs. One cross-sectional study discussed EEG abnormalities associated with autism. Conclusions. Epileptiform discharge free EEG features derived from network/computer analysis differ significantly between people with and without epilepsy. Diagnostic algorithms report high accuracies and could be clinically useful. There is a lack of such research within the intellectual disability (ID) and/or autism populations, where epilepsy is more prevalent and there are additional diagnostic challenges.

Modelling the interactions that arise from neural dynamics in seizure genesis is challenging but important in the effort to improve the success of epilepsy surgery. Dynamical network models developed from physiological evidence offer insights into rapidly evolving brain networks in the epileptic seizure. A major limitation of previous studies in this field is the dependence on invasive cortical recordings with constrained spatial sampling of brain regions that might be involved in seizure dynamics. Here, we propose a novel approach, virtual intracranial electroencephalography (ViEEG), that combines non-invasive ictal magnetoencephalographic imaging (MEG), dynamical network models and a virtual resection technique. In this proof-of-concept study, we show that ViEEG signals reconstructed from MEG alone preserve critical temporospatial characteristics for dynamical approaches to identify brain areas involved in seizure generation. Our findings demonstrate the advantages of non-invasive ViEEG over the current presurgical ‘gold-standard’ – intracranial electroencephalography (iEEG). Our approach promises to optimise the surgical strategy for patients with complex refractory focal epilepsy.

Objectives. There is growing evidence for the use of biofeedback (BF) in affective disorders, dissocial personality disorder, and in children with histories of abuse. Electroencephalogram (EEG) markers could be used as neurofeedback in emotionally unstable personality disorder (EUPD) management especially for those at high risk of suicide when emotionally aroused. This narrative review investigates the evidence for EEG markers in EUPD. Methods. PRISMA guidelines were used to conduct a narrative review. A structured search method was developed and implemented in collaboration with an information specialist. Studies were identified via 3 electronic database searches of MEDLINE, Embase, and PsycINFO. A predesigned inclusion/exclusion criterion was applied to selected papers. A thematic analysis approach with 5 criteria was used. Results. From an initial long list of 5250 papers, 229 studies were identified and screened, of which 44 met at least 3 of the predesigned inclusion criteria. No research to date investigates EEG-based neurofeedback in EUPD. A number of different EEG biomarkers are identified but there is poor consistency between studies. Conclusions. The findings heterogeneity may be due to the disorder complexity and the variable EEG related parameters studied. An alternative explanation may be that there are a number of different neuromarkers, which could be clustered together with clinical symptomatology, to give new subdomains. Quantitative EEGs in particular may be helpful to identify more specific abnormalities. EEG standardization of neurofeedback protocols based on specific EEG abnormalities detected may facilitate targeted use of neurofeedback as an intervention in EUPD.

Recent advances in knowledge relating to the organization of neural circuitry in the human brain have increased understanding of disorders involving brain circuit asymmetry. These asymmetries, which can be measured and identified utilizing EEG and LORETA analysis techniques, may be a factor in mental disorders. New treatments involving non-invasive brain stimulation (NIBS), including trans-cranial magnetic stimulation, direct current stimulation and vagal nerve stimulation, have emerged in recent years. We propose that EEG identification of circuit asymmetry geometries can direct non-invasive brain stimulation more specifically for treatments of mental disorders. We describe as a narrative review new NIBS therapies that have been developed and delivered, and suggest that they are proving effective in certain patient groups. A brief narrative of influence of classical and operant conditioning of neurofeedback on EEG coherence, phase, abnormalities and Loreta's significance is provided. We also discuss the role of Heart rate variability and biofeedback in influencing EEG co-relates. Clinical evidence is at an early stage, but the basic science evidence and early case studies suggest that this may be a promising new modality for treating mental disorders and merits further research.

ObjectiveCurrent explanatory concepts suggest seizures emerge from ongoing dynamics of brain networks. It is unclear how brain network properties determine focal or generalised seizure onset, or how network properties can be described in a clinically-useful manner. Understanding network properties would cast light on seizure-generating mechanisms and allow to quantify in the clinic the extent to which a seizure is focal or generalised.Methods68 people with epilepsy and 38 healthy controls underwent 19 channel scalp EEG recording. Functional brain networks were estimated in each subject using phase-locking between EEG channels in the 6-9Hz band from segments of 20s without interictal discharges. Simplified brain dynamics were simulated using a computer model. We introduce three concepts: Critical Coupling (Cc), the ability of a network to generate seizures; Onset Index (OI), the tendency of a region to generate seizures; and Participation Index (PI), the tendency of a region to become involved in seizures.ResultsCc was lower in both patient groups compared with controls. OI and PI were more variable in focal-onset than generalised-onset cases. No regions showed higher OI and PI in generalised-onset cases than in healthy controls; in focal cases, the regions with highest OI and PI corresponded to the side of seizure onset.ConclusionsProperties of interictal functional networks from scalp EEG can be estimated using a computer model and used to predict seizure likelihood and onset patterns. Our framework, consisting of three clinically-meaningful measures, could be implemented in the clinic to quantify the diagnosis and seizure onset pattern.

Epilepsy is one of the most common neurological conditions affecting over 65 million people worldwide. Over one third of people with epilepsy are considered refractory: they do not respond to drug treatments. For this significant cohort of people, surgery is a potentially transformative treatment. However, only a small minority of people with refractory epilepsy are considered suitable for surgery, and long-term seizure freedom is only achieved in half the cases. Recently, several computational approaches have been proposed to support presurgical planning. Typically, these approaches use a dynamic network model to explore the potential impact of surgical resection in silico. The network component of the model is informed by clinical imaging data and is considered static thereafter. This assumption critically overlooks the plasticity of the brain and, therefore, how continued evolution of the brain network post-surgery may impact upon the success of a resection in the longer term. In this work, we use a simplified dynamic network model, which describes transitions to seizures, to systematically explore how the network structure influences seizure propensity, both before and after virtual resections. We illustrate key results in small networks, before extending our findings to larger networks. We demonstrate how the evolution of brain networks post resection can result in a return to increased seizure propensity. Our results effectively determine the robustness of a given resection to possible network reconfigurations and so provide a potential strategy for optimizing long-term seizure freedom.

In this chapter we present a review of computational models for studying the dynamic mechanisms that describe the function of the human brain, with a specific focus on epilepsy. Epilepsy is a neurological disorder characterised by an increased likelihood of recurrent seizures, which in turn are characterised by transient, pathological episodes of hypersynchronised neural activity resulting in a variety of behavioural symptoms. Our chapter introduces some of the key concepts of epilepsy from a clinical perspective, before describing some of the classical approaches to modelling brain activity across multiple levels of description. We then focus on how these models have been used to explain and predict experimental and clinical phenomena within the field of epilepsy research. Here we focus on techniques that seek to integrate computational modelling with experimental and clinical measures, as we believe this “systems approach” to epilepsy research is from where the most significant new advances, particularly with regards model validation, will occur. We highlight some of the key studies, as well as emphasising more recent breakthroughs to provide a useful entry point into this rapidly expanding field of research.

Summary Epilepsy is one of the most common serious neurologic conditions. It is characterized by the tendency to have recurrent seizures, which arise against a backdrop of apparently normal brain activity. At present, clinical diagnosis relies on the following: (1) case history, which can be unreliable; (2) observation of transient abnormal activity during electroencephalography (EEG), which may not be present during clinical evaluation; and (3) if diagnostic uncertainty occurs, undertaking prolonged monitoring in an attempt to observe EEG abnormalities, which is costly. Herein, we describe the discovery and validation of an epilepsy biomarker based on computational analysis of a short segment of resting-state (interictal) EEG. Our method utilizes a computer model of dynamic networks, where the network is inferred from the extent of synchrony between EEG channels (functional networks) and the normalized power spectrum of the clinical data. We optimize model parameters using a leave-one-out classification on a dataset comprising 30 people with idiopathic generalized epilepsy (IGE) and 38 normal controls. Applying this scheme to all 68 subjects we find 100% specificity at 56.7% sensitivity, and 100% sensitivity at 65.8% specificity. We believe this biomarker could readily provide additional support to the diagnostic process.