# Inhibitory Control and Externalizing Behaviors in Youth at Risk for Huntington Disease

> **NIH NIH K23** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $176,796

## Abstract

PROJECT SUMMARY/ABSTRACT
 The treatment of patients with Huntington disease (HD) is quickly entering a new era, with gene-
silencing and disease-modifying therapies now in clinical trials. While current studies include patients with
motor manifest disease, future clinical trials will require interventions in presymptomatic HD gene carriers in the
hope of altering the course of the disease prior to the onset of motor symptoms. However, the critical question
remains how to target potential therapies and measure outcomes in the large and heterogenous population of
youth and young adults at risk for HD. Recent longitudinal studies have shown that cognitive and behavioral
changes emerge decades before motor symptom onset, but the full spectrum of these symptoms has not yet
been well-defined, and precisely which symptoms occur first and how to measure them remain matters of
debate in the field. Furthermore, data on individuals under age 18 are largely lacking.
 Our preliminary data demonstrate that children who are at risk for HD face a multitude of challenges,
including executive dysfunction, chronic stress, impaired coping skills, and significantly elevated
neuropsychiatric symptoms, including depression, anxiety, and impulsive behaviors. However, the
neurobiological basis of these symptoms, social and environmental contributing factors, and the potential
impacts of mutant huntingtin protein and aberrant neurodevelopment remain unknown.
 The aims of this career development award are (1) to investigate the association between CAG repeat
expansion, adverse childhood experiences, and externalizing risk-taking behavior in youth at risk for HD; (2) to
examine alterations in response inhibition that may underlie impulsive behaviors in this cohort; and (3) to
identify neurophysiological markers of inhibitory control that may represent modifiable treatment targets for
future therapeutic trials.
 This proposal is supported by a multidisciplinary team of mentors with expertise in neuropsychiatric
manifestations of neurodegenerative disorders, child psychology and human development, and
electrophysiology. My overarching goal is to become an independent physician-scientist with unique expertise
in the assessment of prodromal behavioral manifestations as early markers of neurodegenerative conditions.
This proposal will build on my previous experience and will provide a unique training opportunity to develop
new skills in neurophysiology, longitudinal data analysis, and the application of current neurodevelopmental
models of psychological disorders that will allow me to conduct future independent investigations examining
the developmental course of aberrant behaviors and impulse control in a prospective, longitudinal cohort from
youth to adulthood. This work will fill a critical gap in our knowledge regarding the earliest manifestations of HD
and will help to better target potential treatments during the premanifest phase of the disease.

## Key facts

- **NIH application ID:** 10428289
- **Project number:** 1K23NS126628-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Katherine McDonell
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $176,796
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428289

## Citation

> US National Institutes of Health, RePORTER application 10428289, Inhibitory Control and Externalizing Behaviors in Youth at Risk for Huntington Disease (1K23NS126628-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10428289. Licensed CC0.

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