Post-ictal Generalized EEG Suppression is reduced by Enhancing Dorsal Raphe Serotonergic Neurotransmission

Petrucci, Alexandra N.; Joyal, Katelyn G.; Chou, Jonathan W; Li, Rui; Vencer, Kimberly M.; Buchanan, Gordon F.

doi:10.1016/j.neuroscience.2020.11.029

Cited by 23 publications

(23 citation statements)

References 105 publications

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“…MRI studies found brainstem atrophy from the medulla into the midbrain in SUDEP cases, 8 activation of DR serotonergic neurons in an animal epilepsy model suppressed tonic seizures and respiratory arrest, 23 and DR activation reduced PGES length. 24 We did not detect changes related to serotonin signalling (TPH2 and SERT were not different, serotonin receptors were not detected). The midbrain of epilepsy patients is structurally normal.…”

Section: Discussionmentioning

confidence: 69%

“… 21 , 22 In a SUDEP animal model, optogenetic activation of midbrain dorsal raphe (DR) serotonergic neurons suppressed tonic seizures and respiratory arrest, 23 and another study showed decreased PGES length. 24 The DR plays a role in arousal response to hypercapnia, with reciprocal projections to multiple regions in the forebrain, hippocampus and brainstem. 18 , 25–27 There have been no brainstem proteomics studies in SUDEP or epilepsy cases to date.…”

Section: Introductionmentioning

confidence: 99%

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Raphe and ventrolateral medulla proteomics in epilepsy and sudden unexpected death in epilepsy

Leitner

Kanshin

Askenazi

et al. 2022

Brain Communications

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Brainstem nuclei dysfunction is implicated in sudden unexpected death in epilepsy. In animal models, deficient serotonergic activity is associated with seizure-induced respiratory arrest. In humans, glia are decreased in the ventrolateral medullary pre-Botzinger complex that modulate respiratory rhythm, as well as in the medial medullary raphe that modulate respiration and arousal. Finally, sudden unexpected death in epilepsy cases have decreased midbrain volume. To understand the potential role of brainstem nuclei in sudden unexpected death in epilepsy, we evaluated molecular signaling pathways using localized proteomics in microdissected midbrain dorsal raphe and medial medullary raphe serotonergic nuclei, as well as the ventrolateral medulla in brain tissue from epilepsy patients who died of sudden unexpected death in epilepsy and other causes in diverse epilepsy syndromes, and non-epilepsy control cases (n = 15-16 cases per group/region). Compared to the dorsal raphe of non-epilepsy controls, we identified 89 proteins in non-sudden unexpected death in epilepsy and 219 proteins in sudden unexpected death in epilepsy that were differentially expressed. These proteins were associated with inhibition of EIF2 signaling (p value of overlap = 1.29 × 10−8, z = -2.00) in non-sudden unexpected death in epilepsy. In sudden unexpected death in epilepsy, there were 10 activated pathways (top pathway: gluconeogenesis I, p value of overlap = 3.02 × 10−6, z = 2.24) and 1 inhibited pathway (fatty acid beta-oxidation, p value of overlap = 2.69 × 10−4, z = -2.00). Comparing sudden unexpected death in epilepsy and non-sudden unexpected death in epilepsy, 10 proteins were differentially expressed but there were no associated signaling pathways. In both medullary regions, few proteins showed significant differences in pairwise comparisons. We identified altered proteins in the raphe and ventrolateral medulla of epilepsy patients, including some differentially expressed in sudden unexpected death in epilepsy cases. Altered signaling pathways in the dorsal raphe of sudden unexpected death in epilepsy indicate a shift in cellular energy production and activation of G-protein signaling, inflammatory response, stress response, and neuronal migration/outgrowth. Future studies should assess the brain proteome in relation to additional clinical variables (e.g. recent tonic-clonic seizures) and in more of the reciprocally connected cortical and subcortical regions to better understand the pathophysiology of epilepsy and sudden unexpected death in epilepsy.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Raphe and ventrolateral medulla proteomics in epilepsy and sudden unexpected death in epilepsy

Leitner

Kanshin

Askenazi

et al. 2022

Brain Communications

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“… 52 Indeed, pharmacological and optogenetic enhancement of DR serotonergic neurotransmission before seizure induction can reduce postictal generalized EEG suppression duration and block seizure-induced respiratory arrest. 15 , 16 , 53 A previous study using single-unit recording of serotonergic neurons in DR of rats revealed variable firing with a mixture of increases and decreases during seizures induced by hippocampal electric stimulation, suggesting other types of neurons may also contribute to the overall suppression of DR population neuronal activity measured by LFP. 17 Future work is needed to better understand the cellular contribution to SUDEP by using cell type-specific manipulations in DR.…”

Section: Discussionmentioning

confidence: 97%

Ictal neural oscillatory alterations precede sudden unexpected death in epilepsy

Levine

et al. 2022

Brain Communications

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Sudden unexpected death in epilepsy is the most catastrophic outcome of epilepsy. Each year there are as many as 1.65 cases of such death for every 1000 individuals with epilepsy. Currently, there are no methods to predict or prevent this tragic event, due in part to a poor understanding of the pathologic cascade that leads to death following seizures. We recently identified enhanced seizure-induced mortality in four inbred strains from the genetically diverse Collaborative Cross mouse population. These mouse models of sudden unexpected death in epilepsy provide a unique tool to systematically examine the physiological alterations during fatal seizures, which can be studied in a controlled environment and with consideration of genetic complexity. Here we monitored the brain oscillations and heart functions before, during, and after nonfatal and fatal seizures using a flurothyl-induced seizure model in freely moving mice. Compared to mice that survived seizures, non-survivors exhibited significant suppression of brainstem neural oscillations that coincided with cortical epileptic activities and tachycardia during the ictal phase of a fatal seizure. Non-survivors also exhibited suppressed delta (0.5–4 Hz)/gamma (30–200 Hz) phase-amplitude coupling in cortex but not in brainstem. A connectivity analysis revealed elevated synchronization of cortex and brainstem oscillations in the delta band during fatal seizures compared to nonfatal seizures. The dynamic ictal oscillatory and connectivity features of fatal seizures provide insights into sudden unexpected death in epilepsy and may suggest biomarkers and eventual therapeutic targets.

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“… 18 Moreover, increased serotonin transmission shortens post-ictal suppression and does not cause burst suppression. 19 Neither case had a history of seizures or epilepsy prior to arrest.…”

Section: Discussionmentioning

confidence: 98%

Awakening from post anoxic coma with burst suppression with identical bursts

et al. 2021

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Background Electroencephalography (EEG) is commonly used after cardiac arrest. Burst suppression with identical bursts (BSIB) has been reported as a perfectly specific predictor of poor outcome but published case series are small. We describe two patients with BSIB who awakened from coma after cardiac arrest. Methods We identified two out-of-hospital cardiac arrest (OHCA) patients with coma and BSIB. We determined the etiology of arrest, presenting neurological examination, potential confounders to neurological assessment, neurodiagnostics and time to awakening. We reviewed and interpreted EEGs using 2021 American Clinical Neurophysiology Society guidelines. We quantified identicality of bursts by calculating pairwise correlation coefficients between the first 500 ms of each aligned burst. Results In case one we present a 62-year-old man with OHCA secondary to septic shock. EEG showed burst suppression pattern, with bursts consisted of high amplitude generalized spike waves in lock-step with myoclonus (inter-burst correlation = 0.86). He followed commands 3 days after arrest, when repeat EEG showed a continuous, variable and reactive background without epileptiform activity. Case two was a 49-year-old woman with OHCA secondary to polysubstance overdose. Initial EEG revealed burst suppression with high amplitude generalized polyspike-wave bursts with associated myoclonus. She followed commands on post-arrest day 4, when repeat EEG showed a continuous, variable and reactive background with frequent runs of bifrontal predominant sharply contoured rhythmic delta activity. Conclusion These cases highlight the perils of prognosticating with a single modality in comatose cardiac arrest patients.

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Post-ictal Generalized EEG Suppression is reduced by Enhancing Dorsal Raphe Serotonergic Neurotransmission

Cited by 23 publications

References 105 publications

Raphe and ventrolateral medulla proteomics in epilepsy and sudden unexpected death in epilepsy

Raphe and ventrolateral medulla proteomics in epilepsy and sudden unexpected death in epilepsy

Ictal neural oscillatory alterations precede sudden unexpected death in epilepsy

Awakening from post anoxic coma with burst suppression with identical bursts

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