# Mechanisms for Improving Cognitive Outcome in Pediatric Epilepsy with ACTH

> **NIH NIH K22** · NEMOURS CHILDREN'S HOSPITAL, DELAWARE · 2022 · $242,406

## Abstract

Epilepsy, particularly pediatric epilepsy, is associated with a very high incidence of cognitive, behavioral and
psychiatric comorbidities that are often more detrimental to overall quality of life than the seizures themselves.
Aggressive treatment of seizures has been the gold standard, with the belief that this will also minimize
cognitive and psychiatric comorbidities. However, very little focus has been placed on treatment of these
comorbidities directly and clinical data suggest that focusing on seizure treatment alone does not effectively
treat cognitive impairment. We have recently found that ACTH, an endogenous part of the hypothalamic-
pituitary-adrenal axis that is often exogenously administered to children with severe epilepsies, can improve
cognitive outcome in rats without altering seizure parameters. While it was previously thought that the primary
mechanism of action for ACTH was through the release of corticosteroids, new research suggests that
melanocortin 4 receptor (MC4R) activation in neuronal and glial populations is neuroprotective and can
improve outcomes in other disease models.
We hypothesize that MC4R agonism in the CNS with ACTH is a key mechanism of action by which it
can improve cognitive outcomes after early life seizures (ELS). We further hypothesize that early
treatment with ACTH will normalized functional organization of neural networks within and between the
prefrontal cortex and the hippocampus, and that this improvement will provide a systems-level
mechanism underpinning its mechanism of action. Understanding how ACTH can prevent cognitive
deficits without altering seizure parameters is crucial for finding novel treatment approaches for these deficits.
Therefore, the scientific aims of this study are to: 1) (Phase I) determine the role of MC4R signaling in the brain
on subsequent cognition in control animals and (Phase II) ELS animals, 2) (Phase I) determine the effect of
early treatment with ACTH on synaptic plasticity in adult neuronal networks in the PFC after ELS and finally 3)
(Phase II) determine the effect of early treatment with ACTH on adult neuronal networks in vivo and executive
dysfunction associated with ELS.
To achieve these goals, I require additional training, both formal through a “Methods in Computational
Neuroscience” course at the Marine Biological Laboratory and informal with my co-mentor, Dr. Mahoney, in
order to develop the neurocomputational modeling tools necessary for exploring the systems-level
mechanisms of cognitive impairment after ELS and the prevention of such impairments with ACTH. The
studies proposed are designed to understand the developmental role of ACTH and MC4Rs on cognitive
networks in ELS. Successful completion of this project has the potential to change the way we think about
treatment of pediatric epilepsy, and may have implications for the treatment of other neurodevelopmental
disorders as well.

## Key facts

- **NIH application ID:** 10232148
- **Project number:** 7K22NS104230-05
- **Recipient organization:** NEMOURS CHILDREN'S HOSPITAL, DELAWARE
- **Principal Investigator:** Amanda Hernan
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $242,406
- **Award type:** 7
- **Project period:** 2017-09-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232148

## Citation

> US National Institutes of Health, RePORTER application 10232148, Mechanisms for Improving Cognitive Outcome in Pediatric Epilepsy with ACTH (7K22NS104230-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10232148. Licensed CC0.

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