# Remote effects of focal hippocampal seizures on neocortical function

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $363,878

## Abstract

PROJECT SUMMARY / ABSTRACT
Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy is a common
and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including
the hippocampus. Interestingly, focal temporal lobe seizures often cause functional deficits such as impaired
consciousness, which is not expected from local hippocampal impairment alone. Human focal temporal lobe
seizures with impaired consciousness show slow waves on electro-encephalography (EEG) and decreased
cerebral blood flow in the neocortex, distant from the hippocampus. The mechanisms by which focal seizures
in the hippocampus cause depressed function in the neocortex are not known. We established a rat model with
focal limbic seizures exhibiting high frequency discharges in the hippocampus, but slow 1-3 Hz activity in the
neocortex, decreased cortical blood flow and metabolism, as well as decreased behavioral responsiveness
resembling the human disorder. In this model we found that important subcortical arousal systems including
brainstem and basal forebrain cholinergic neurons are depressed. These finding suggest that sleep-like cortical
slow waves may occur in focal limbic seizures because of decreased subcortical arousal. In addition we found
that putative descending GABAergic systems including the lateral septum and anterior hypothalamus are
strongly activated by focal limbic seizures. Based on these findings, our central hypothesis is that focal limbic
seizures activate inhibitory systems which depress subcortical arousal leading to sleep-like cortical slow waves
and impaired consciousness. We plan to investigate this hypothesis at the level of neurons, networks, and
behavior in a rodent model. Recent work has also raised the exciting prospect of restoring subcortical arousal
to improve cortical function during seizures. Therefore, our aims are to first investigate the inputs to subcortical
arousal systems using whole-cell electrophysiology to determine incoming synaptic activity; and using
optogenetics to selectively activate or inhibit input pathways. Second, we will determine which subcortical
arousal systems are critical for depressed cortical function by electrically or optogenetically restoring outputs
from these systems during focal limbic seizures, and measure effects on the cortex through electrophysiology
recordings and high-field functional magnetic resonance imaging (fMRI). Third, we will examine the effects of
focal limbic seizures on attention and decision-making tasks and investigate the ability of restored subcortical
arousal to improve behavioral responsiveness during seizures. The integration of information across these
levels will increase our understanding of abnormal long-range network changes in epilepsy, potentially leading
to new therapeutic options in the treatment of this disorder.

## Key facts

- **NIH application ID:** 9989185
- **Project number:** 5R01NS066974-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** HAL BLUMENFELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,878
- **Award type:** 5
- **Project period:** 2011-02-01 → 2021-12-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989185

## Citation

> US National Institutes of Health, RePORTER application 9989185, Remote effects of focal hippocampal seizures on neocortical function (5R01NS066974-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989185. Licensed CC0.

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