# Metabolomic predictors of circadian vulnerabilities in epilepsy

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $460,625

## Abstract

PROJECT SUMMARY
Many physiological processes and diseases exhibit intriguing rhythmic patterns such as cortisol secretion,
body temperature, sleep/wakefulness, and epilepsy. With respect to epilepsy, it is well-known that seizures can
occur in clusters, followed by long periods of seizure freedom, and many focal epilepsies exhibit approximately
24-h oscillations of seizure vulnerability. However, the mechanisms underlying periodicity in epilepsy are
incompletely understood, and a detailed understanding of these mechanisms is important because this could
result in more effective antiseizure interventions. Such interventions could be to increase the dose of
antiseizure drugs or to change brain stimulation parameters during periods of heightened seizure susceptibility
(i.e. chronotherapy), or to manipulate specific seizure-triggering chemistry perturbations using
pharmacological, dietary, or even microbiological approaches. The long-term goal of the present project is
twofold: first to understand the mechanisms of periodic vulnerabilities to seizures; second, to use this
information to develop more effective and specific antiseizure therapies. The objective here is to identify
circadian changes in the extracellular brain chemistry (metabolome) in humans with focal epilepsies and a
translationally relevant rodent model of mesial temporal lobe epilepsy. To this end, we will track and quantify
about 100 brain chemicals, including neurotransmitters, melatonin, adenosine, orexin, histamine, steroid
hormones, and microbial metabolites. The central hypothesis is that numerous brain chemicals exhibit distinct
circadian patterns associated with periods of increased seizure susceptibility, biological sex, brain region,
neuropathology, sleep/wakefulness, light/dark cycle, antiepileptic drug therapy, and the host microbiota. The
specific aim is to use in vivo brain microdialysis and mass spectrometry to explore changes in the extracellular
brain metabolome during the circadian cycle in humans with epilepsy and a translationally relevant rodent
model of mesial temporal lobe epilepsy. With respect to outcomes, this project is expected to identify multiple
patterns of brain chemistry oscillations that correlate with periods of increased seizure vulnerability and many
other biological parameters. The project will likely have a high positive impact because the identified rhythmic
changes may be better understood and targeted to treat epileptic seizures more effectively than currently
possible. Furthermore, the research is expected to markedly advance the field of chronobiology by revealing a
complexity of novel circadian changes associated with key biological parameters such as sex, brain region,
sleep/wakefulness, and the host microbiota. The proposal addresses the following 2014 NINDS Benchmark for
Epilepsy Research: (IIIE) Identify, develop, and improve anti-seizure therapies that target (either alone, or in
combination) novel or multiple seizure mechanisms.

## Key facts

- **NIH application ID:** 9979128
- **Project number:** 1R21NS109734-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** TORE EID
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,625
- **Award type:** 1
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979128

## Citation

> US National Institutes of Health, RePORTER application 9979128, Metabolomic predictors of circadian vulnerabilities in epilepsy (1R21NS109734-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9979128. Licensed CC0.

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