Deficient post-ictal cardiorespiratory compensatory mechanisms mediated by the periaqueductal gray may lead to death in a mouse model of SUDEP

Kommajosyula, Srinivasa P.; Tupal, Srinivasan; Faingold, Carl L.

doi:10.1016/j.eplepsyres.2018.08.005

Cited by 11 publications

(24 citation statements)

References 72 publications

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“…This is consistent with recent evidence indicating that this compensatory role of the PAG may be deficient in DBA/1 mice. 42 The significant activity increases in the amygdala in both the Flx-noSz and Flx+Sz groups indicate that fluoxetine is exerting an effect on this structure, which may be consistent with previous findings regarding a proposed role of the amygdala in respiratory modulation, [43][44][45][46] as well as the role of serotonin in emotion processing by this structure. 47 However, the finding that there is no significant difference between these groups is not conclusive as to the importance of this structure in blockade of RA by fluoxetine.…”

Section: Discussionsupporting

confidence: 90%

“…42 This duration is consistent with the critical period during which resuscitation must be initiated to successfully prevent seizure-induced death in DBA/1 mice in previous studies. 42 This duration is consistent with the critical period during which resuscitation must be initiated to successfully prevent seizure-induced death in DBA/1 mice in previous studies.…”

Section: Discussionsupporting

confidence: 89%

“…A recent study found significantly reduced effectiveness of PAG electrical stimulation-induced increases in respiration in DBA/1 mice, as compared to non-seizure-prone mice, which lasted for 10 seconds after stimulation. 42 This duration is consistent with the critical period during which resuscitation must be initiated to successfully prevent seizure-induced death in DBA/1 mice in previous studies. 3 These findings suggest that PAG-mediated respiratory stimulation that may involve serotonin is deficient, 55 and this deficiency may be important to DBA/1 mouse susceptibility to S-IRA.…”

Section: Discussionsupporting

confidence: 89%

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Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

Kommajosyula

Faingold

2019

Epilepsia

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Objective Sudden unexpected death in epilepsy (SUDEP) is a critical issue in epilepsy, and DBA/1 mice are a useful animal model of this devastating epilepsy sequela. The serotonin hypothesis for SUDEP proposes that modifying serotonergic function significantly alters susceptibility to seizure‐induced respiratory arrest (S‐IRA). Agents that enhance serotonergic function, including a selective serotonin reuptake inhibitor, fluoxetine, selectively prevent S‐IRA in DBA/1 mice. This study examined fluoxetine‐induced changes in brain activity using manganese‐enhanced magnetic resonance imaging (MEMRI) to reveal sites in the DBA/1 mouse brain where fluoxetine acts to prevent S‐IRA. Methods DBA/1 mice were subjected to audiogenic seizures (Sz) after saline or fluoxetine (45 mg/kg, intraperitoneal) administration. Control DBA/1 mice received fluoxetine or saline, but Sz were not evoked. A previous MEMRI study established the regions of interest (ROIs) for Sz in the DBA/1 mouse brain, and the present study examined MEMRI differences in the ROIs of these mouse groups. Results The neural activity in several ROIs was significantly increased in fluoxetine‐treated DBA/1 mice that exhibited Sz but not S‐IRA when compared to the saline‐treated mice that exhibited both Sz and respiratory arrest. These structures included the periaqueductal gray (PAG), amygdala, reticular formation (sensorimotor‐limbic network), Kölliker‐Fuse nucleus, facial‐parafacial group (respiratory network), and pontine raphe. Of these ROIs, only the PAG showed significantly decreased neural activity with saline pretreatment when seizure‐induced respiratory arrest occurred as compared to saline treatment without seizure. Significance The PAG is known to play an important compensatory role for respiratory distress caused by numerous exigent situations in normal animals. The pattern of fluoxetine‐induced activity changes in the present study suggests that PAG may be the most critical target for fluoxetine's action to prevent seizure‐induced sudden death. These findings have potential clinical importance, because there is evidence of anomalous serotonergic function and PAG imaging abnormalities in human SUDEP.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

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Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

Kommajosyula

Faingold

2019

Epilepsia

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“…The ventrolateral PAG can elicit substantial increases in sustained (ie, “freezing”) muscle tone via the lateral vermis of the cerebellum, a source of concern when attempting to initiate cyclic breathing during an ictal event . Deficient cardiorespiratory compensatory mechanisms mediated by the PAG have been shown to contribute to SUDEP in mice …”

Section: Discussionmentioning

confidence: 99%

“…29 Deficient cardiorespiratory compensatory mechanisms mediated by the PAG have been shown to contribute to SUDEP in mice. 30 Volume loss of PAG, posterior cingulate, left posterior thalamus, and hippocampus raises the possibility that compromised excitatory or timing signals from descending influences on the cerebellum may further blunt central breathing control.…”

Section: Descending Influences From Damaged Structuresmentioning

confidence: 99%

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy

et al. 2019

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Summary Objective The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk. Methods We retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high‐risk (n = 25) or low‐risk (n = 23), and age‐ and sex‐matched healthy controls (n = 25) with identical high‐resolution T1‐weighted scans. Regional gray matter volume, determined by voxel‐based morphometry, and segmentation‐derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex. Results Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high‐risk subjects and absent in low‐risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High‐risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high‐risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging. Significance SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

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Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology

Akyüz

Uner

Köklü

et al. 2021

J of Neuroscience Research

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Epilepsy is a debilitating disorder of uncontrollable recurrent seizures that occurs as a result of imbalances in the brain excitatory and inhibitory neuronal signals, that could stem from a range of functional and structural neuronal impairments. Globally, nearly 70 million people are negatively impacted by epilepsy and its comorbidities. One such comorbidity is the effect epilepsy has on the autonomic nervous system (ANS), which plays a role in the control of blood circulation, respiration and gastrointestinal function. These epilepsy‐induced impairments in the circulatory and respiratory systems may contribute toward sudden unexpected death in epilepsy (SUDEP). Although, various hypotheses have been proposed regarding the role of epilepsy on ANS, the linking pathological mechanism still remains unclear. Channelopathies and seizure‐induced damages in ANS‐control brain structures were some of the causal/pathological candidates of cardiorespiratory comorbidities in epilepsy patients, especially in those who were drug resistant. However, emerging preclinical research suggest that neurotransmitter/receptor dysfunction and synaptic changes in the ANS may also contribute to the epilepsy‐related autonomic disorders. Thus, pathological mechanisms of cardiorespiratory dysfunction should be elucidated by considering the modifications in anatomy and physiology of the autonomic system caused by seizures. In this regard, we present a comprehensive review of the current literature, both clinical and preclinical animal studies, on the cardiorespiratory findings in epilepsy and elucidate the possible pathological mechanisms of these findings, in hopes to prevent SUDEP especially in patients who are drug resistant.

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Deficient post-ictal cardiorespiratory compensatory mechanisms mediated by the periaqueductal gray may lead to death in a mouse model of SUDEP

Cited by 11 publications

References 72 publications

Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy

Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology

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