Specific subcortical structures are activated during seizure-induced death in a model of sudden unexpected death in epilepsy (SUDEP): A manganese-enhanced magnetic resonance imaging study

Kommajosyula, Srinivasa P.; Randall, Marcus E.; Brozoski, Thomas J.; Odintsov, B. M.; Faingold, Carl L.

doi:10.1016/j.eplepsyres.2017.05.011

Cited by 24 publications

(65 citation statements)

References 86 publications

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“…25 Thus, significant fluoxetine-induced increases occurred in several of these ROIs in the Flx+Sz group as compared to the Sal+Sz+RA group. 25 Thus, significant fluoxetine-induced increases occurred in several of these ROIs in the Flx+Sz group as compared to the Sal+Sz+RA group.…”

Section: Discussionmentioning

confidence: 86%

“…17,18 S-IRA in DBA mice can be prevented by peripheral or central administration of certain selective serotonin reuptake inhibitors (SSRIs), including fluoxetine. 25 These results suggest that the seizure network interacts with specific brainstem structures, leading to impaired respiratory and arousal functions in this model of seizure-induced death. [19][20][21] The PAG plays a particularly important compensatory role for respiratory distress that occurs in numerous exigent situations.…”

Section: Introductionmentioning

confidence: 75%

“…25 Subsequently, a seizure was evoked in both Sz groups; the noSz control groups were placed in the stimulation chamber for the same period of time, but seizure was not evoked (Table 1). 25 Subsequently, a seizure was evoked in both Sz groups; the noSz control groups were placed in the stimulation chamber for the same period of time, but seizure was not evoked (Table 1).…”

Section: Manganese-enhanced Magnetic Resonance Imagingmentioning

confidence: 99%

“…25,36 Blood vessels and technical artifacts were excluded. 25,36 Blood vessels and technical artifacts were excluded.…”

Section: Image Analysismentioning

confidence: 99%

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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: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 75%

Section: Manganese-enhanced Magnetic Resonance Imagingmentioning

confidence: 99%

“…25,36 Blood vessels and technical artifacts were excluded. 25,36 Blood vessels and technical artifacts were excluded.…”

Section: Image Analysismentioning

confidence: 99%

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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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“…Serotonin is known to be an important transmitter that affects seizure networks, 34,35 and this transmitter has a well-established importance in the respiratory network unrelated to seizures. 40,41 Moreover, human SUDEP has been associated with subtherapeutic levels of antiepileptic drugs, and in at-risk patients it may be useful to add an additional antiepileptic drug, such as fenfluramine, to potentially reduce the incidence of SUDEP. When an agent blocks S-IRA without blocking any convulsive behavior, we posit that this is due to an action primarily on the respiratory network, which is supported by our recent neuroimaging data in this SUDEP model.…”

Section: Discussionmentioning

confidence: 99%

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

Tupal

Faingold

2019

Epilepsia

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Summary Objective Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure‐induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure‐induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure‐induced respiratory arrest (S‐IRA) in DBA/1 mice. Methods The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz‐induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi‐square test. Results Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S‐IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20‐40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S‐IRA susceptibility occurred, which were long‐lasting (≥48 hours). The median effective dose (ED50) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg. Significance This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S‐IRA susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block S‐IRA selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

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Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Mueller

Nei

Bateman

et al. 2018

Human Brain Mapping

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Observations in witnessed Sudden Unexpected Death in Epilepsy (SUDEP) suggest that a fatal breakdown of the central autonomic control could play a major role in SUDEP. A previous MR study found volume losses in the mesencephalon in focal epilepsy that were more severe and extended into the lower brainstem in two patients who later died of SUDEP. The aims of this study were to demonstrate an association (1) between brainstem volume loss and impaired autonomic control (reduced heart rate variability [HRV]); (2) between brainstem damage and time to SUDEP in patients who later died of SUDEP. Two populations were studied: (1) Autonomic system function population (ASF, 18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3 T MR exams. (2) SUDEP population (26 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion indicating significant volume loss or atrophy. The total number of regions with excessive expansion in ASF was negatively correlated with HRV (r = -.37, p = .03), excessive volume loss in periaqueductal gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r = -.82/.67, p < .001). The total number of regions with excessive expansion in SUDEP was negatively correlated with time to SUDEP (r = -.39, p = .03), excessive volume loss in the raphe/medulla oblongata at the obex level explained most of the variation of the time between MRI to SUDEP (r/r = -.60/.35,p = .001). Epilepsy is associated with brainstem atrophy that impairs autonomic control and can increase the risk for SUDEP if it expands into the mesencephalon.

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Specific subcortical structures are activated during seizure-induced death in a model of sudden unexpected death in epilepsy (SUDEP): A manganese-enhanced magnetic resonance imaging study

Cited by 24 publications

References 86 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

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

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