A unified physiological framework of transitions between seizures, sustained ictal activity and depolarization block at the single neuron level

The majority of seizures recorded in humans and experimental animal models can be described by a generic phenomenological mathematical model, the Epileptor. In this model, seizure-like events (SLEs) are driven by a slow variable and occur via saddle node (SN) and homoclinic bifurcations at seizure onset and offset, respectively. Here we investigated SLEs at the single cell level using a biophysically relevant neuron model including a slow/fast system of four equations. The two equations for the slow subsystem describe ion concentration variations and the two equations of the fast subsystem delineate the electrophysiological activities of the neuron. Using extracellular K+ as a slow variable, we report that SLEs with SN/homoclinic bifurcations can readily occur at the single cell level when extracellular K+ reaches a critical value. In patients and experimental models, seizures can also evolve into sustained ictal activity (SIA) and depolarization block (DB), activities which are also parts of the dynamic repertoire of the Epileptor. Increasing extracellular concentration of K+ in the model to values found during experimental status epilepticus and DB, we show that SIA and DB can also occur at the single cell level. Thus, seizures, SIA, and DB, which have been first identified as network events, can exist in a unified framework of a biophysical model at the single neuron level and exhibit similar dynamics as observed in the Epileptor.Author Summary: Epilepsy is a neurological disorder characterized by the occurrence of seizures. Seizures have been characterized in patients in experimental models at both macroscopic and microscopic scales using electrophysiological recordings. Experimental works allowed the establishment of a detailed taxonomy of seizures, which can be described by mathematical models. We can distinguish two main types of models. Phenomenological (generic) models have few parameters and variables and permit detailed dynamical studies often capturing a majority of activities observed in experimental conditions. But they also have abstract parameters, making biological interpretation difficult. Biophysical models, on the other hand, use a large number of variables and parameters due to the complexity of the biological systems they represent. Because of the multiplicity of solutions, it is difficult to extract general dynamical rules. In the present work, we integrate both approaches and reduce a detailed biophysical model to sufficiently low-dimensional equations, and thus maintaining the advantages of a generic model. We propose, at the single cell level, a unified framework of different pathological activities that are seizures, depolarization block, and sustained ictal activity.

Ictal Blinking: Reappraisal of the Lateralization and Localization Value in Focal Seizures

Introduction. Although ictal blinking is significantly more frequent in generalized epilepsy, it has been reported as a rare but useful lateralizing sign in focal seizures when it is not associated with facial clonic twitching. This study aimed to raise awareness of eye blinking as a semiological lateralizing sign. Method. Our database over an 11-year period reviewed retrospectively to assess patients who had ictal blinking associated with focal seizures. Results. Among 632 patients, 14 (2.2%), who had 3 to 13 (7 ± 3) seizures during video-EEG monitoring, were included. Twenty-five percent of all 92 seizures displayed ictal blinking and each patient had one to five seizures with ictal blinking. Ictal blinking was unilateral in 17%, asymmetrical in 22% and symmetrical in 61%. The blinking appeared with a mean latency of 6.3 s (range 0-39) after the clinical seizure-onset, localized most often to fronto-temporal, then in frontal or occipital regions. Blinking was ipsilateral to ictal scalp EEG lateralization side in 83% (5/6) of the patients with unilateral/asymmetrical blinking. The exact lateralization and localization of ictal activity could not have been determined via EEG in most of the patients with symmetrical blinking, remarkably. Conclusions. Unilateral/asymmetrical blinking is one of the early components of the seizures and appears as a useful lateralizing sign, often associated with fronto-temporal seizure-onset. Symmetrical blinking, on the other hand, did not seem to be valuable in lateralization and localization of focal seizures. Future studies using invasive recordings and periocular electrodes are needed to evaluate the value of blinking in lateralization and localization.

Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis

Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

Multiscale criticality measures as general-purpose gauges of proper brain function

The brain is universally regarded as a system for processing information. If so, any behavioral or cognitive dysfunction should lend itself to depiction in terms of information processing deficiencies. Information is characterized by recursive, hierarchical complexity. The brain accommodates this complexity by a hierarchy of large/slow and small/fast spatiotemporal loops of activity. Thus, successful information processing hinges upon tightly regulating the spatiotemporal makeup of activity, to optimally match the underlying multiscale delay structure of such hierarchical networks. Reduced capacity for information processing will then be expressed as deviance from this requisite multiscale character of spatiotemporal activity. This deviance is captured by a general family of multiscale criticality measures (MsCr). MsCr measures reflect the behavior of conventional criticality measures (such as the branching parameter) across temporal scale. We applied MsCr to MEG and EEG data in several telling degraded information processing scenarios. Consistently with our previous modeling work, MsCr measures systematically varied with information processing capacity: MsCr fingerprints showed deviance in the four states of compromised information processing examined in this study, disorders of consciousness, mild cognitive impairment, schizophrenia and even during pre-ictal activity. MsCr measures might thus be able to serve as general gauges of information processing capacity and, therefore, as normative measures of brain health.

Neurophysiological phenotypes of pharmacoresistant temporal lobe epilepsy

Patients with a drug-resistant form of epilepsy can be treated by neurosurgery through the destruction or separation of the epileptic focus. If the results of clinical, neuro-imaging and neurophysiological methods are discordant, then the localization of the epileptogenic zone is performed based on the results of long-term invasive monitoring of the bioelectrical activity of the cortex and deep structures of the brain. The aim of this work was the retrospective analysis of the results of invasive monitoring of the bioelectrical activity of the brain to clarify the mechanisms of the formation of patterns of interictal and ictal activity in structural epilepsy. The study included 35 patients (18 men, 17 women) with drug-resistant temporal lobe epilepsy, who were treated at the Polenov Neurosurgical Institute. The examination included video-EEG monitoring, long-term invasive monitoring of bioelectrical activity of the cortex, and deep brain structures. The patients were divided into two groups according to the type of surgical treatment: 1) micro-surgical resection of the epileptic focus, including the zone of structural changes (24 patients); 2) stereotactic destruction of the amygdala-hippocampal complex (6 patients). The follow-up of the outcomes of the surgical treatment took place over 2-3 years. Depending on the results of the surgical treatment, the patients were divided into two groups: 1) patients with a favorable outcome (Engel 1–2) — 15 patients and 2) patients with no positive dynamics and a relatively poor outcome (Engel 3–4) — 15 patients. The results obtained showed that the patterns of interictal and ictal activity in their totality determine the neurophysiology, i.e the phenotype of temporal lobe epilepsy, reflecting the interference of pathogenetic and sanogenetic mechanisms. The localization of the epileptogenic zone should be based on the cumulative assessment of interictal and ictal activity. The presence of more than one focus of interictal activity, the secondary spread of epileptiform activity from the primary focus, are prognostically unfavorable factors.

Traveling waves reveal a dynamic seizure source in human focal epilepsy

Treatment of patients with drug resistant focal epilepsy relies upon accurate seizure localization. Ictal activity captured in intracranial EEG (iEEG) has traditionally been interpreted to suggest that the underlying cortex is actively involved in seizures. Here, we hypothesize that such activity instead reflects propagated activity from a relatively focal seizure source, even during later time points when ictal activity is more widespread. We use the time differences observed between ictal discharges in adjacent electrodes to estimate the location of the hypothesized focal source. We demonstrate that the seizure source, localized in this manner, closely matches the clinically- and neurophysiologically-determined brain region giving rise to seizures. Moreover, this focal source is a dynamic entity that moves and evolves over the time course of a seizure. Our results offer an interpretation of ictal activity observed in iEEG that challenges the traditional conceptualization of the seizure source.

Quantification of seizure termination patterns reveals limited pathways to seizure end

Seizures result from a variety of pathologies and exhibit great diversity in their dynamics. Although many studies have examined the dynamics of seizure initiation, few have investigated the mechanisms leading to seizure termination. We examined intracranial recordings from patients with intractable focal epilepsy to differentiate seizure termination patterns and investigate whether these termination patterns are indicative of different underlying mechanisms. Seizures (n=710) were recorded intracranially from 104 patients and visually classified as focal or secondarily generalized. Only two patterns emerged from this analysis: (a) those that end simultaneously across the brain (synchronous termination), and (b) those whose ictal activity terminates in some regions but continues in others (asynchronous termination). Finally, seizures ended with either an intermittent bursting pattern (burst suppression pattern), or continuous activity (continuous bursting). These findings allowed for a classification and quantification of the burst suppression ratio, absolute energy and network connectivity of all seizures and comparison across different seizure termination patterns. We found that different termination patterns can manifest within a single patient, even in seizures originating from the same onset locations. Most seizures terminate with patterns of burst suppression regardless of generalization but that seizure that secondarily generalize show burst suppression patterns in 90% of cases, while only 60% of focal seizures exhibit burst suppression. Interestingly, we found similar absolute energy and burst suppression ratios in seizures with synchronous and asynchronous termination, while seizures with continuous bursting were found to be different from seizures with burst suppression, showing lower energy during seizure and lower burst suppression ratio at the start and end of seizure. Finally, network density was observed to increase with seizure progression, with significantly lower densities in seizures with continuous bursting compared to seizures with burst suppression. Our study demonstrates that there are a limited number of seizure termination patterns, suggesting that, unlike seizure initiation, the number of mechanisms underlying seizure termination is constrained. The study of termination patterns may provide useful clues about how these seizures may be managed, which in turn may lead to more targeted modes of therapy for seizure control.