Multi-scale modelling of the epileptic brain: advantages of computational therapy exploration.

Objective: Epilepsy is a complex disease spanning across multiple scales, from ion channels in neurons to neuronal circuits across the entire brain. Over the past decades, computational models have been used to describe the pathophysiological activity of the epileptic brain from different aspects. Traditionally, each computational model can aid in optimizing therapeutic interventions, therefore, providing a particular view to design strategies for treating epilepsy. As a result, most studies are concerned with generating specific models of the epileptic brain that can help us understand the certain machinery of the pathological state. Those specific models vary in complexity and biological accuracy, with system-level models often lacking biological details.Approach: Here, we review various types of computational model of epilepsy and discuss their potential for different therapeutic approaches and scenarios, including drug discovery, surgical strategies, brain stimulation, and seizure prediction. We propose that we need to consider an integrated approach with a unified modelling framework across multiple scales to understand the epileptic brain. Our proposal is based on the recent increase in computational power, which has opened up the possibility of unifying those specific epileptic models into simulations with an unprecedented level of detail.Main results: A multi-scale epilepsy model can bridge the gap between biologically detailed models, used to address molecular and cellular questions, and brain-wide models based on abstract models which can account for complex neurological and behavioural observations.Significance: With these efforts, we move toward the next generation of epileptic brain models capable of connecting cellular features, such as ion channel properties, with standard clinical measures such as seizure severity.

Structural and functional reorganization of inhibitory synapses by activity-dependent cleavage of neuroligin-2.

Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating synaptic strength in excitatory synapses. However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated. In this study, we utilized an engineered proteolysis technique to investigate the effects of acute cleavage of neuroligin-2 (NL2) on synaptic transmission. Our results show that the rapid cleavage of NL2 led to impaired synaptic transmission by reducing both neurotransmitter release probability and quantum size. These changes were attributed to the dispersion of RIM1/2 and GABAA receptors and a weakened spatial alignment between them at the subsynaptic scale, as observed through superresolution imaging and model simulations. Importantly, we found that endogenous NL2 undergoes rapid MMP9-dependent cleavage during epileptic activities, which further exacerbates the decrease in inhibitory transmission. Overall, our study demonstrates the significant impact of nanoscale structural reorganization on inhibitory transmission and unveils ongoing modulation of mature GABAergic synapses through active cleavage of NL2 in response to hyperactivity.

Post-stroke epilepsy: From clinical predictors to possible mechanisms.

BACKGROUND: Stroke is the most common cause of newly diagnosed epilepsy in the elderly, ahead of degenerative disorders, brain tumors, and head trauma. Stroke accounts for 30-50% of unprovoked seizures in patients aged ≥ 60 years. This review discusses the current understanding of epidemiology, risk factors, mechanisms, prevention, and treatment opportunities for post-stroke epilepsy (PSE). METHODS: We performed a literature search in the PubMed and Cochrane Library databases. The keywords "stroke, epilepsy", "stroke, seizure", "post-stroke seizure", "post-stroke epilepsy" were used to identify the clinical and experimental articles on PSE. All resulting titles and abstracts were evaluated, and any relevant article was considered. The reference lists of all selected papers and reference lists of selected review papers were manually analyzed to find other potentially eligible articles. RESULTS: PSE occurs in about 6% of stroke patients within several years after the event. The main risk factors are cortical lesion, initial stroke severity, young age and seizures in acute stroke period (early seizures, ES). Other risk factors, such as a cardioembolic mechanism or circulation territory involvement, remain debated. The role of ES as a risk factor of PSE could be underestimated especially in young age. Mechanism of epileptogenesis may involve gliosis scarring, alteration in synaptic plasticity, etc.; and ES may enhance these processes. Statins especially in the acute period of stroke are possible agents for PSE prevention presumably due to their anticonvulsant and neuroprotection effects. Antiepileptic drugs (AED) monotherapy is enough for seizure prevention in most cases of PSE; but no evidence was found for its efficiency against epileptic foci formation. The growing interest in PSE has led to a notable increase in the number of published articles each year. To aid in navigating this expanding body of literature, several tables are included in the manuscript. CONCLUSION: Further studies are needed for better understanding of the pathophysiology of PSE and searching the prevention strategies.

Seizure-induced strengthening of a recurrent excitatory circuit in the dentate gyrus is proconvulsant.

Epilepsy is a devastating brain disorder for which effective treatments are very limited. There is growing interest in early intervention, which requires a better mechanistic understanding of the early stages of this disorder. While diverse brain insults can lead to epileptic activity, a common cellular mechanism relies on uncontrolled recurrent excitatory activity. In the dentate gyrus, excitatory mossy cells (MCs) project extensively onto granule cells (GCs) throughout the hippocampus, thus establishing a recurrent MC-GC-MC excitatory loop. MCs are implicated in temporal lobe epilepsy, a common form of epilepsy, but their role during initial seizures (i.e., before the characteristic MC loss that occurs in late stages) is unclear. Here, we show that initial seizures acutely induced with an intraperitoneal kainic acid (KA) injection in adult mice, a well-established model that leads to experimental epilepsy, not only increased MC and GC activity in vivo but also triggered a brain-derived neurotrophic factor (BDNF)-dependent long-term potentiation (LTP) at MC-GC excitatory synapses. Moreover, in vivo induction of MC-GC LTP using MC-selective optogenetic stimulation worsened KA-induced seizures. Conversely, Bdnf genetic removal from GCs, which abolishes LTP, and selective MC silencing were both anticonvulsant. Thus, initial seizures are associated with MC-GC synaptic strengthening, which may promote later epileptic activity. Our findings reveal a potential mechanism of epileptogenesis that may help in developing therapeutic strategies for early intervention.

Does epileptic activity impair sleep-related memory consolidation in epilepsy? A critical and systematic review.

STUDY OBJECTIVES: People with epilepsy often complain about disturbed sleep and cognitive impairment. Beyond seizures, the occurrence of interictal epileptic activity during sleep is also increasingly recognized to negatively impact cognitive functioning, including memory processes. The aim of this study was to critically review the effect of interictal epileptic activity on sleep-related memory consolidation. METHODS: PubMed and PsychINFO databases were systematically searched to identify experimental studies that investigated sleep-related memory consolidation and the relationships between sleep-related epileptic activity and memory in adults and children with epilepsy. This review also highlights hypotheses regarding the potential pathophysiological mechanisms. RESULTS: A total of 261 studies were identified; 27 of these met selection criteria. Only 13 studies prospectively assessed the effect of sleep on memory in epilepsy. Most studies reported no alteration of sleep-related memory consolidation in patients, with either similar retention levels following a period containing sleep (n = 5) or improved memory performance postsleep (n = 4). Two studies in children with epilepsy found impaired sleep-related memory consolidation. Ten studies, of which 6 were in childhood epilepsy syndromes, reported a debilitating effect of sleep-related epileptic activity on memory functioning. CONCLUSIONS: Conclusions from existing studies were hampered by small sample sizes, heterogeneous patient groups, and variations in memory assessment techniques. Overall, results to date preclude any definitive conclusions on the alteration of sleep-related memory consolidation in epilepsy. We discuss methodological considerations specific to people with epilepsy and provide suggestions on how to best investigate the relationship between epileptic activity, sleep, and memory consolidation in future studies. CITATION: Latreille V, Schiller K, Peter-Derex L, Frauscher B. Does epilepticimpair sleep-related memory consolidation in epilepsy? A critical and systematic review. J Clin Sleep Med. 2022;18(10):2481-2495.

Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature.

BACKGROUND: IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein. OBJECTIVE: To analyses the clinical characteristics of the patients reported in the literature and of an additional patient we observed in order to better delineate the phenomenological spectrum of the disease and provide indications to improve clinical recognition and facilitate diagnosis. METHODS: We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers (n.27), using PUBMED as the search engine, and in our hospital (n. 1). RESULTS: All patients shared developmental delay/regression. Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances. Correlation analysis suggested a significant positive correlation between the number of affected neurological domains and the presence of MRI abnormalities (rho = 0.45, p = 0.02), while no significant correlation emerged between the number of affected clinical domains and age at disease onset (rho = 0.18, p = 0.35) or variant type (rho = 0.30, p = 0.12). CONCLUSIONS: Our analysis highlights that the IRF2BPL mutation syndrome is highly specific to the central nervous system. Diagnostic work-up should consider the clinical picture of the IRF2BPL mutation syndrome herein delineated and the existence of conditions that share developmental delay/regression and result from acquired/genetic or unidentifiable underlying etiology.

Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis.

Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development.

Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes.

Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.

Masking for School-Age Children With Epilepsy: We Do Have Consensus!

INTRODUCTION: This study was designed to assess current recommendations from child neurologists and epileptologists on masking for school-age children with epilepsy. METHODS: A 7-item survey was created and sent out to members of the Child Neurology Society and Pediatric Epilepsy Research Consortium in August of 2021 to assess current practice and provider recommendations on masking. RESULTS: One hundred four individuals participated with representation from all regions of the United States. Masking was recommended by 95.1%, with 63.4% (n = 66) noting exception of those with severe intellectual disability, autism, and behavioral problems. Of those who write exemption letters, 54% write these <5% of the time. Only 3% reported potential adverse events associated with masking. CONCLUSION: Nearly all respondents recommended masking for school-age children with epilepsy. Potential risks of masking and adverse events were low. Improved guidance on masking is needed to ensure academic success of our patients with epilepsy.

Mapping whole brain seizure network recruitment with optogenetic kindling.

Epilepsy is often labeled as a network disorder, though a common view of seizures holds that they initiate in a singular onset zone before expanding contiguously outward. A recent report by Choy et al. (Choy M, Dadgar-Kiani E, Cron GO, Duffy BA, Schmid F, Edelman BJ, Asaad M, Chan RW, Vahdat S, Lee JH. Neuron 2021 Oct 23: S0896-6273(21)00778-9.) leverages new tools to study whole brain dynamics during epileptic seizures originating in the hippocampus. Cell-type-specific kindling and functional imaging revealed how various brain regions were recruited to seizures and uncovered a novel form of migrating seizure core.

Reliability of patient self-report of cognition, awareness, and consciousness during seizures.

OBJECTIVE: Clinicians rely on patient self-report of impairment during seizures for decisions including driving eligibility. However, the reliability of patient reports on cognitive and behavioral functions during seizures remains unknown. METHODS: We administered a daily questionnaire to epilepsy patients undergoing continuous video-EEG monitoring, asking about responsiveness, speech, memory, awareness, and consciousness during seizures in the preceding 24 hours. We also administered a questionnaire upon admission about responsiveness, speech, and awareness during seizures. Subjective questionnaire answers were compared with objective behavioral ratings on video review. Criteria for agreement were Cohen's kappa >0.60 and proportions of positive and negative agreement both >0.75. RESULTS: We analyzed 86 epileptic seizures in 39 patients. Memory report on the daily questionnaire met criteria for agreement with video review (κ = 0.674 for early, 0.743 for late recall). Subjective report of awareness also met agreement criteria with video ratings of memory (κ = 0.673 early, 0.774 late). Concordance for speech was relatively good (κ = 0.679) but did not meet agreement criteria, nor did responsiveness or consciousness. On the admission questionnaire, agreement criteria were met for subjective report of awareness versus video ratings of memory (κ = 0.814 early, 0.806 late), but not for other comparisons. INTERPRETATION: Patient self-report of memory or awareness showed the best concordance with objective memory impairment during seizures. Self-report of impairment in other categories was less reliable. These findings suggest that patient reports about impaired memory during seizures may be most reliable, and otherwise determining functional impairments should be based on objective observations.

Variation of scalp EEG high frequency oscillation rate with sleep stage and time spent in sleep in patients with pediatric epilepsy.

OBJECTIVE: High frequency oscillations (HFO) in scalp EEG are a new and promising epilepsy biomarker. However, considerable fluctuations of HFO rates have been observed through sleep stages and cycles. Here, we aimed to identify the optimal timing within sleep and the minimal data length for sensitive and reproducible HFO detection. METHODS: We selected 16 whole-night scalp EEG recordings of paediatric patients with a focal structural epilepsy. We used an automated clinically validated HFO detector to determine HFO rates (80-250 Hz). We evaluated the reproducibility of HFO detection across intervals. RESULTS: HFO rates were higher in N3 than in N2 and REM (rapid eye movement) sleep and highest in the first sleep cycle, decreasing with time in sleep. In N3 sleep, the median reliability of HFO detection increased from 67% (interquartile range: iqr 57) to 78% (iqr 59) to 100% (iqr 70%) for 5-, 10-, and 15-min data intervals, improving significantly (p = 0.004, z = 2.9) from 5 to 10 min but not from 10 to 15 min. CONCLUSIONS: We identified the first N3 sleep stage as the most sensitive time window for HFO rate detection. At least 10 min N3 data intervals are required and sufficient for reliable measurements of HFO rates. SIGNIFICANCE: Our study provides a robust and reliable framework for scalp HFO detection that may facilitate their implementation as an EEG biomarker in paediatric epilepsy.

Phase synchronization and measure of criticality in a network of neural mass models.

Synchronization has an important role in neural networks dynamics that is mostly accompanied by cognitive activities such as memory, learning, and perception. These activities arise from collective neural behaviors and are not totally understood yet. This paper aims to investigate a cortical model from this perspective. Historically, epilepsy has been regarded as a functional brain disorder associated with excessive synchronization of large neural populations. Epilepsy is believed to arise as a result of complex interactions between neural networks characterized by dynamic synchronization. In this paper, we investigated a network of neural populations in a way the dynamics of each node corresponded to the Jansen-Rit neural mass model. First, we study a one-column Jansen-Rit neural mass model for four different input levels. Then, we considered a Watts-Strogatz network of Jansen-Rit oscillators. We observed an epileptic activity in the weak input level. The network is considered to change various parameters. The detailed results including the mean time series, phase spaces, and power spectrum revealed a wide range of different behaviors such as epilepsy, healthy, and a transition between synchrony and asynchrony states. In some points of coupling coefficients, there is an abrupt change in the order parameters. Since the critical state is a dynamic candidate for healthy brains, we considered some measures of criticality and investigated them at these points. According to our study, some markers of criticality can occur at these points, while others may not. This occurrence is a result of the nature of the specific order parameter selected to observe these markers. In fact, The definition of a proper order parameter is key and must be defined properly. Our view is that the critical points exhibit clear characteristics and invariance of scale, instead of some types of markers. As a result, these phase transition points are not critical as they show no evidence of scaling invariance.

Dynamic training of a novelty classifier algorithm for real-time detection of early seizure onset.

OBJECTIVE: To develop an adaptive framework for seizure detection in real-time that is practical to use in the Epilepsy Monitoring Unit (EMU) as a warning signal, and whose output helps characterize epileptiform activity. METHODS: Our algorithm was tested on intracranial EEG from epilepsy patients admitted to the EMU for presurgical evaluation. Our framework uses a one-class Support Vector Machine (SVM) that is being trained dynamically according to past activity in all available channels to classify the novelty of the current activity. In this study we compared multiple configurations using a one-class SVM to assess if there is significance over specific neural features or electrode locations. RESULTS: Our results show that the algorithm reaches a sensitivity of 87% for early-onset seizure detection and of 97.7% as a generic seizure detection. CONCLUSIONS: Our algorithm is capable of running in real-time and achieving a high performance for early seizure-onset detection with a low false positive rate and robustness in detection of different type of seizure-onset patterns. SIGNIFICANCE: This algorithm offers a solution to warning systems in the EMU as well as a tool for seizure characterization during post-hoc analysis of intracranial EEG data for surgical resection of the epileptogenic network.

Human interictal epileptiform discharges are bidirectional traveling waves echoing ictal discharges.

Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Although they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus.

The Anti-Epileptic Effects of Carbenoxolone In Vitro and In Vivo.

Gap junctions (GJs) are intercellular junctions that allow the direct transfer of ions and small molecules between neighboring cells, and GJs between astrocytes play an important role in the development of various pathologies of the brain, including regulation of the pathological neuronal synchronization underlying epileptic seizures. Recently, we found that a pathological change is observed in astrocytes during the ictal and interictal phases of 4-aminopyridin (4-AP)-elicited epileptic activity in vitro, which was correlated with neuronal synchronization and extracellular epileptic electrical activity. This finding raises the question: Does this signal depend on GJs between astrocytes? In this study we investigated the effect of the GJ blocker, carbenoxolone (CBX), on epileptic activity in vitro and in vivo. Based on the results obtained, we came to the conclusion that the astrocytic syncytium formed by GJ-associated astrocytes, which is responsible for the regulation of potassium, affects the formation of epileptic activity in astrocytes in vitro and epileptic seizure onset. This effect is probably an important, but not the only, mechanism by which CBX suppresses epileptic activity. It is likely that the mechanisms of selective inhibition of GJs between astrocytes will show important translational benefits in anti-epileptic therapies.

Ictal wavefront propagation in slices and simulations with conductance-based refractory density model.

The mechanisms determining ictal discharge (ID) propagation are still not clear. In the present study, we aimed to examine these mechanisms in animal and mathematical models of epileptiform activity. Using double-patch and extracellular potassium ion concentration recordings in rat hippocampal-cortical slices, we observed that IDs moved at a speed of about 1 mm/s or less. The mechanisms of such slow propagation have been studied with a mathematical, conductance-based refractory density (CBRD) model that describes the GABA- and glutamatergic neuronal populations' interactions and ion dynamics in brain tissue. The modeling study reveals two main factors triggerring IDs: (i) increased interneuronal activity leading to chloride ion accumulation and a consequent depolarizing GABAergic effect and (ii) the elevation of extracellular potassium ion concentration. The local synaptic transmission followed by local potassium ion extrusion and GABA receptor-mediated chloride ion accumulation underlies the ID wavefront's propagation. In contrast, potassium ion diffusion in the extracellular space is slower and does not affect ID's speed. The short discharges, constituting the ID, propagate much faster than the ID front. The accumulation of sodium ions inside neurons due to their hyperactivity and glutamatergic currents boosts the Na+/K+ pump, which terminates the ID. Knowledge of the mechanism of ID generation and propagation contributes to the development of new treatments against epilepsy.

Intracranial electrophysiological recordings from the human brain during memory tasks with pupillometry.

Data comprise intracranial EEG (iEEG) brain activity represented by stereo EEG (sEEG) signals, recorded from over 100 electrode channels implanted in any one patient across various brain regions. The iEEG signals were recorded in epilepsy patients (N = 10) undergoing invasive monitoring and localization of seizures when they were performing a battery of four memory tasks lasting approx. 1 hour in total. Gaze tracking on the task computer screen with estimating the pupil size was also recorded together with behavioral performance. Each dataset comes from one patient with anatomical localization of each electrode contact. Metadata contains labels for the recording channels with behavioral events marked from all tasks, including timing of correct and incorrect vocalization of the remembered stimuli. The iEEG and the pupillometric signals are saved in BIDS data structure to facilitate efficient data sharing and analysis.

Minimum standards for inpatient long-term video-EEG monitoring: A clinical practice guideline of the international league against epilepsy and international federation of clinical neurophysiology.

The objective of this clinical practice guideline is to provide recommendations on the indications and minimum standards for inpatient long-term video-electroencephalographic monitoring (LTVEM). The Working Group of the International League Against Epilepsy and the International Federation of Clinical Neurophysiology develop guidelines aligned with the Epilepsy Guidelines Task Force. We reviewed published evidence using The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. We found limited high-level evidence aimed at specific aspects of diagnosis for LTVEM performed to evaluate patients with seizures and nonepileptic events (see Table S1). For classification of evidence, we used the Clinical Practice Guideline Process Manual of the American Academy of Neurology. We formulated recommendations for the indications, technical requirements, and essential practice elements of LTVEM to derive minimum standards used in the evaluation of patients with suspected epilepsy using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Further research is needed to obtain evidence about long-term outcome effects of LTVEM and establish its clinical utility.