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Seizure and SD phenotype of Scn1a +/RX mice before and after a hyperthermic seizure. (A) Electrode positions: from the top, #1 right anterior, #2 left anterior, #3 right posterior, #4 left posterior. (B) Compressed trace showing a 24-hour recording. SDs are reliably detected as sharp negative shift over stable baseline. (C-E) Expanded representative traces of SD, seizure, and seizure+SD complex. (F-H) Hyperthermic seizure robustly increased SD and seizure incidence. (F) Raster plots of seizure and SD incidence in WT and Scn1a +/RX mice. WT mice had no seizure or SD. Three mice exclusively had seizures ("seizure-only"). Seven mice died or became moribund during the study. The same Scn1a +/RX event data are presented in a cumulative histogram (G) and pie chart (H) showing proportion of seizure, SD, and seizure+SD events during baseline and after a hyperthermic seizure in Scn1a +/RX mice that survived the recording period, excluding the "seizure-only" mice. (I) Quantification of event frequencies. Frequencies of SD and total events were increased after a hyperthermic seizure. "Seizure-only" mice were excluded from this analysis. Two-way ANOVA and post hoc Tukey's test. (J) Chronological analysis of SD, seizure, and seizure+SD events.
Source publication
Spreading depolarization (SD) is a massive wave of cellular depolarization that slowly migrates across the brain gray matter. Cortical SD is frequently generated following brain injury, while less is understood about its potential contribution to genetic disorders of hyperexcitability, such as SCN1A-deficient epilepsy, in which febrile seizure ofte...
Contexts in source publication
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... results are summarized in Figure 1. We detected 3 abnormal baseline spontaneous events: isolated SD, seizures, and complexes of seizure with postictal SD (hereafter "seizure+SD") in which an SD emerged within minutes following a seizure (Figure 1, A-E). ...
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... results are summarized in Figure 1. We detected 3 abnormal baseline spontaneous events: isolated SD, seizures, and complexes of seizure with postictal SD (hereafter "seizure+SD") in which an SD emerged within minutes following a seizure (Figure 1, A-E). During the study, one Scn1a +/RX mouse died during hyperthermic seizure, and 6 mice died due to postictal sudden death or moribund condition ( Figure 1F). ...
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... detected 3 abnormal baseline spontaneous events: isolated SD, seizures, and complexes of seizure with postictal SD (hereafter "seizure+SD") in which an SD emerged within minutes following a seizure (Figure 1, A-E). During the study, one Scn1a +/RX mouse died during hyperthermic seizure, and 6 mice died due to postictal sudden death or moribund condition ( Figure 1F). While the baseline incidence of seizures and SD was relatively rare (mean of both events 0.57 ± 0.35 per day), SD was detected more commonly than seizures in most mice (Figure 1, H and I). ...
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... the study, one Scn1a +/RX mouse died during hyperthermic seizure, and 6 mice died due to postictal sudden death or moribund condition ( Figure 1F). While the baseline incidence of seizures and SD was relatively rare (mean of both events 0.57 ± 0.35 per day), SD was detected more commonly than seizures in most mice (Figure 1, H and I). No seizures or SD were detected in WT mice during the baseline or posthyperthermia periods ( Figure 1F). ...
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... the baseline incidence of seizures and SD was relatively rare (mean of both events 0.57 ± 0.35 per day), SD was detected more commonly than seizures in most mice (Figure 1, H and I). No seizures or SD were detected in WT mice during the baseline or posthyperthermia periods ( Figure 1F). ...
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... 7 days of baseline recording, mice were subjected to a hyperthermic seizure (see Methods), and its effect was continuously monitored for more than 10 days. Starting 1 day after the posthyperthermic seizure, SD frequency clearly increased in Scn1a +/RX mutants (Figure 1, F and G), even in 2 mice that had not shown any seizure or SD during baseline recording. This upsurge in SD frequency lasted for multiple days and up to a week, rendering SD the dominant abnormal EEG event ( Figure 1H). ...
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... 1 day after the posthyperthermic seizure, SD frequency clearly increased in Scn1a +/RX mutants (Figure 1, F and G), even in 2 mice that had not shown any seizure or SD during baseline recording. This upsurge in SD frequency lasted for multiple days and up to a week, rendering SD the dominant abnormal EEG event ( Figure 1H). Statistical analyses detected significant increases in the frequencies of spontaneous SD (4.2-fold) and total events (3.3-fold) following the hyperthermic seizure ( Figure 1I). ...
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... upsurge in SD frequency lasted for multiple days and up to a week, rendering SD the dominant abnormal EEG event ( Figure 1H). Statistical analyses detected significant increases in the frequencies of spontaneous SD (4.2-fold) and total events (3.3-fold) following the hyperthermic seizure ( Figure 1I). In the 2 exceptional "seizure-only" mice that did not show SD during baseline nor during the hyperthermic seizure, seizure frequency decreased after the hyperthermic seizure. ...
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... was a weak diurnal trend in the SD frequency in this monitoring cohort, with peaks detected at 6.5 hours and 17.8 hours, which correspond to light-dark cycle transitions ( Figure 1J). A similar circadian sudden unexpected death in epilepsy (SUDEP) mortality pattern was previously detected in the same Scn1a-deficient mouse model (29), implying the presence of a circadian vulnerability in this mutant mouse model. ...
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... on the increased spontaneous SD event frequency shown in Figure 1D, hyperthermic seizure might be expected to facilitate postictal SD generation by shortening the time to onset. However, the latency to postictal SD was significantly prolonged after hyperthermic seizure ( Figure 3D). ...
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... mice receiving saline before hyperthermic seizure showed a robust increase in the total number of events (P = 0.014; Figure 4A). In this control cohort, more mice later developed seizures compared with the initial cohort shown in Figure 1. A significant increase in total events was also seen in the pretreatment group (P = 0.030; Figure 4B), while the aftermath was absent in 1 mouse. ...
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... addition, 2 seizure-prone mice that had a reduced seizure frequency after JCI Insight 2023;8(15):e170399 https://doi.org/10.1172/jci.insight.170399 hyperthermic seizure (Figure 1) suggest that the effect of hyperthermic seizure could be altered in distinct disease conditions. Although the number is limited because of the rare chance to encounter these mice, they showed no SD during chronic monitoring and hyperthermic seizure. ...
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Background
The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014, eligibility for mandatory long-term care insurance (LTCI) was extended to people with dementia enabling access to appropriate long-term care including the cognitive function...
Citations
... Here, within 10 min of terminal SD in the ischemic hippocampus, a massive transient wave of neuronal depolarization consistent with an SD also appeared in the contralesional hippocampus. Seizures are often associated with SD in both rodents [49][50][51][52][53] and humans 54 . We observed contralesional electrographic seizure directly preceding SD when LFP was simultaneously recorded with neuronal Ca 2+ . ...
... Untreated seizure after stroke, can trigger post-stroke epilepsy 81 and is associated with neurological deterioration 78 . Seizure and SD can co-occur in both rodents and humans [49][50][51][52][53][54][82][83][84] . While a complex pattern between SDs and electrographic seizure exists in patients receiving neurocritical care, In pharmacologically induced preclinical seizure models 83 , focal seizures can trigger a transient SD, which, after a phase of activity depression, can at least temporarily restore normal spontaneous activity 50,85 . ...
Ischemic stroke, brain tissue infarction following obstructed cerebral blood flow, leads to long-term neurological deficits and death. While neocortex is a commonly affected region with established preclinical models, less is known about deeper brain strokes, despite having unique neurological outcomes. We induced focal ischemic stroke while simultaneously monitoring neuronal activity in awake behaving Thy1-GCaMP6f mice by delivering and collecting light through bilateral fiberoptic implants. Unilateral hippocampal stroke resulted in atypical wandering behavior coincident with ipsilesional terminal spreading depolarization (sustained increase in GCaMP6f fluorescence). Ischemia induced seizures that propagated to the contralesional hippocampus triggering a transient spreading depolarization, predominantly in females. Hippocampal stroke impaired contextual fear conditioning acquired pre-stroke. Yet, 7 days post-stroke, contextual fear conditioning was only improved in mice with contralesional spreading depolarization. Blunting peri-stroke contralesional spreading depolarization prevented recovery of hippocampus-dependent learning. Together, we show that regionally isolated deleterious and beneficial spreading depolarizations can occur concurrently in the murine brain during acute stroke.
... Challenging this interpretation, patients with intractable epilepsy without craniotomy showed DC-potential shifts and related suppression of faster activity indicating CSD prior to ictal activity (Bastany et al., 2020). Spontaneous CSDs related to seizure activity have been demonstrated in mouse models of Developmental and Epileptic Encephalopathy (Aiba et al., 2023, Aiba andNoebels, 2021). Relatively complex relationships between electrographic seizures and SDs have also been observed in patients with different brain injuries using invasive recordings (Dreier et al., 2012, Fabricius et al., 2008. ...
Like Janus, the Roman god of beginnings, transitions, and endings, spreading depolarizations (SDs) can be depicted with two faces: one looking backward, waving a symbolic farewell to the end of a cortical seizure; the other forward looking, opening a darker door for a fatal wave in the brainstem that ends life. There is good agreement on the distinct electrical nature of both events, but neither role is yet proven in patients. SD is a slow-moving wave of cellular depolarization that steadily silences neuronal networks and depresses EEG amplitude, whereas seizures represent fast, intermittent synchronization of neural networks with highly variable EEG activation patterns. However, the thresholds triggering both events are neither fixed nor inseparable; indeed, their co-occurrence and interaction depend on dimly-lit intrinsic brain pathophysiology. New insights into single gene control of SD and seizure thresholds are beginning to illuminate the darkness. Here, we review recent data and consider the title's question at the end.
Confusion, aphasia, and unaware wandering are prominent post-ictal symptoms regularly observed in temporal lobe epilepsy (TLE). Despite the potentially life-threatening nature of the immediate post-ictal state, its neurobiological underpinnings remain understudied. We provide evidence in mice and humans that seizure-associated focal spreading depolarization (sSD) is a pathoclinical key factor in epilepsy. Using two-photon or widefield imaging (hippocampus, neocortex), field potential and single unit recordings, and behavioral assessment in mice, we first studied seizures during viral encephalitis, and subsequently established an optogenetic approach to dissociate hippocampal seizures and SD. We find region-specific occurrence of sSD that displays distinct spatial trajectories to preceding seizures, and show that seizure-related and isolated hippocampal SD prompt post-ictal wandering. This clinically relevant locomotor phenotype occurred in the absence of hippocampal SD progression to the neocortex. Finally, we confirm sSD existence in human epilepsy, in a patient cohort with refractory focal epilepsy, via Behnke-Fried electrode recordings. In this cohort, sSD displayed a similar temporomesial propensity as in mice. This work uncovers sSD as a previously underrecognized pathoclinical entity underlying postictal behavioral abnormalities in epilepsy. Our results carry wide-reaching ramifications for epilepsy research and neurology, and challenge current EEG-standards.
A bstract
During cortical spreading depolarization (CSD), neurons exhibit a dramatic increase in cytosolic calcium, which may be integral to CSD-mediated seizure termination. This calcium increase greatly exceeds that during seizures, suggesting the calcium source may not be solely extracellular. Thus, we sought to determine if the endoplasmic reticulum (ER), the largest intracellular calcium store, is involved. We developed a two-photon calcium imaging paradigm to simultaneously record the cytosol and ER during seizures in awake mice. Paired with direct current recording, we reveal that CSD can manifest as a slow post-ictal cytosolic calcium wave with a concomitant depletion of ER calcium that is spatiotemporally consistent with a calcium-induced calcium release. Importantly, we observed both naturally occurring and electrically induced CSD suppressed post-ictal epileptiform activity. Collectively, this work links ER dynamics to CSD, which serves as an innate process for seizure suppression and a potential mechanism underlying therapeutic electrical stimulation for epilepsy.
The cortical microenvironment surrounding malignant glioblastoma is a source of depolarizing crosstalk favoring hyperexcitability, tumor expansion, and immune evasion. Neosynaptogenesis, excess glutamate, and altered intrinsic membrane currents contribute to excitability dyshomeostasis, yet only half of the cases develop seizures, suggesting that tumor and host genomics, along with location, rather than mass effect, play a critical role. We analyzed the spatial contours and expression of 358 clinically validated human epilepsy genes in the human glioblastoma transcriptome compared to non-tumor adult and developing cortex datasets. Nearly half, including dosage-sensitive genes whose expression levels are securely linked to monogenic epilepsy, are strikingly enriched and aberrantly regulated at the leading edge, supporting a complex epistatic basis for peritumoral epileptogenesis. Surround hyperexcitability induced by complex patterns of proepileptic gene expression may explain the limited efficacy of narrowly targeted antiseizure medicines and the persistence of epilepsy following tumor resection and clarify why not all brain tumors provoke seizures.
Background
Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke. Acquired and inherited prothrombotic conditions are the most common risk factors for CVST. Sometimes, an etiology is not found. Wide utilization of next generation sequencing technologies in clinical practice may lead to identification of risk factors other than those classically associated with CVST.
Method and Results
This retrospective clinical-laboratory observational study has a reference patient who presented with CVST as an adolescent. Work up for prothrombotic conditions showed high homocysteine level secondary to homozygosity for a common polymorphism, c.677 C > T in the methylenetetrahydrofolate reductase (MTHFR) gene. His older unaffected brother has a similar MTHFR genotype and high homocysteine. The whole exome sequencing revealed a likely pathogenic variant in the sodium voltage gated channel, alpha subunit 1(SCN1A) gene.
Conclusion
CVST is a multifactorial disease. Prothrombotic conditions are the most common risk factors for CVST. High homocysteine due to the common MTHFR polymorphisms was previously attributed to various thrombotic conditions including CVST. Although high homocysteine due to MTHFR polymorphism may be a contributing factor, additional risk factors such as blood flow abnormalities during SCN1A related seizures may be needed for thrombosis.
Graphene-enabled micro-transistor arrays can be used to improve our understanding of how infraslow brain signals relate to changes in cerebral blood flow.
