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SD generation during hyperthermic seizures induced with a heating lamp in Scn1a +/RX mice. (A and B) Representative EEG showing seizure and SD. Top: DC; middle: high pass (>1 Hz); bottom: power spectrum of EEG (anterior electrode). (C) Postictal SD was less common in WT mice: 77% (10/13) of Scn1a +/RX mice developed SD following seizure, while 27% (3/11) of WT mice did so. (D) Consistent with previous studies, Scn1a +/RX mice showed a lowered thermal threshold for seizure. WT: n = 11; Scn1a +/RX : n = 13; P = 0.007, Mann-Whitney U test. **P < 0.01.
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
Context 1
... Chronological analysis of SD, seizure, and seizure+SD events. clonic seizure, and was electrographically detected as a train of ictal spiking that resulted within less than 1 minute in a temporally coupled SD (Figure 2A). Mice are usually unconscious or semiconscious during the minutes-long postictal period. ...
Context 2
... are usually unconscious or semiconscious during the minutes-long postictal period. SD was detected in 77% (10/13) of the Scn1a +/RX mice during hyperthermic seizure induction ( Figure 2C) and was usually associated with postictal loss of voluntary motor behavior and an occasional myoclonic jerk. SD always appeared after the electrographic seizure and was likely generated as a secondary consequence of neuronal discharges, while brain hyperthermia might facilitate it. ...
Context 3
... 3 Scn1a +/RX mice that did not display SD during hyperthermic seizure were "seizure-only" mice, and 1 of these died shortly after this period. In WT mice, ictal SD was less common during the hyperthermic period (27% [3/11], P = 0.037 vs. Scn1a +/RX , Fisher's exact test; Figure 2, B and C). Consistent with earlier studies (30), the hyperthermic seizure threshold was significantly higher in WT littermates (WT: 43.0°C ± 1.0°C, n = 11; Scn1a +/RX : 41.7°C ± 0.7°C, n = 12; P = 0.007, Mann-Whitney test), which also required longer heat exposures (>30 minutes) until a seizure emerged ( Figure 2D). ...
Context 4
... WT mice, ictal SD was less common during the hyperthermic period (27% [3/11], P = 0.037 vs. Scn1a +/RX , Fisher's exact test; Figure 2, B and C). Consistent with earlier studies (30), the hyperthermic seizure threshold was significantly higher in WT littermates (WT: 43.0°C ± 1.0°C, n = 11; Scn1a +/RX : 41.7°C ± 0.7°C, n = 12; P = 0.007, Mann-Whitney test), which also required longer heat exposures (>30 minutes) until a seizure emerged ( Figure 2D). ...
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Citations
... 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. ...
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.
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