# Network mechanisms of seizure-induced cardiorespiratory impairment

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $363,955

## Abstract

PROJECT SUMMARY / ABSTRACT
Seizures have both local and remote effects on nervous system function. Focal seizures can propagate from
the site of onset to engage a larger network and induce severe consequences including impaired arousal,
cardiorespiratory changes and in some cases death. Impaired cardiorespiratory function during and following
seizures may contribute to chronic hypoxic brain damage and to long-term deficits in epilepsy. In addition,
sudden unexpected death in epilepsy (SUDEP) is thought to arise from a state in the post-ictal period in which
cardiovascular, breathing and arousal functions are impaired. Although cardiac, autonomic, breathing and
arousal effects of seizures have long been recognized, the specific mechanisms by which seizures cause
these changes have been relatively neglected. Our prior work investigating impaired consciousness in epilepsy
suggests that seizures can depress subcortical arousal circuits including the upper brainstem. Human and
animal model studies led to the network inhibition hypothesis, in which seizures inhibit brainstem arousal
during and following seizures. Our preliminary data extend this work, showing that decreased ictal and post-
ictal cardiorespiratory function in a rodent model is associated with markedly suppressed firing of medullary
serotonergic neurons in the lower brainstem. Based on these findings, our central hypothesis is that seizures
propagate to inhibitory circuits which depress lower brainstem neuromodulatory and control systems; this in
turn impairs cardiorespiratory functions significant for seizure morbidity and mortality. We plan to investigate
this hypothesis in detail through a combination of neuroimaging, electrophysiology, and neurotransmitter
studies in a rodent model. Our aims are to first define the network of cortical and subcortical structures which
cause impaired cardiorespiratory function during and following seizures using fMRI, local field and multiunit
recordings, local electrical and optogenetic stimulation and inactivation experiments. Next, we will investigate
the neurotransmitters producing impaired cardiorespiratory function using in vivo biosensor probe
measurements. Finally, we will determine the changes in firing patterns of identified brainstem serotonergic
and other modulatory neurons as well as cardiorespiratory control neurons using juxtacellular recordings
during and following seizures. The integration of information across these levels will increase our
understanding of abnormal long-range network changes underlying impaired ictal and post-ictal breathing and
cardiac function, potentially leading to new treatment options to prevent seizure-related morbidity and mortality.

## Key facts

- **NIH application ID:** 9991927
- **Project number:** 5R01NS096088-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** HAL BLUMENFELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,955
- **Award type:** 5
- **Project period:** 2016-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991927

## Citation

> US National Institutes of Health, RePORTER application 9991927, Network mechanisms of seizure-induced cardiorespiratory impairment (5R01NS096088-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9991927. Licensed CC0.

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