# FX ENTRAIN: Perturbation of neurodynamics underlying sensory hyperarousal and statistical learning in Youth with FXS

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $712,967

## Abstract

Contact PI/PD: Pedapati, Ernest
PROJECT SUMMARY
Fragile X Syndrome (FXS) is an exemplar monogenetic neurodevelopmental disorder (NDD) where a
tremendous body of multi-species translational research has elucidated the underlying molecular
pathophysiology, and more recently, in-depth electrophysiology of cortical function. Thus far,
phenotypic rescue in animal models has not resulted in treatment breakthroughs in humans. Central to
this discrepancy is a poor understanding of the constituent neurodynamics of averaged group effects
and individual variability in human brain activity as related to higher-level cognitive symptomatology
and clinical phenotype. Our large collection of preliminary data demonstrates that individuals with FXS
do not mount precise neural responses to the sensory auditory chirp and, instead, have “noisy”
asynchronous gamma activity. Furthermore, a marked reduction in alpha power suggests altered
thalamocortical function, reducing the ability to detect signal from noise and representing potential
tractable targets for “bottom-up” entrainment. Our approach involves three scientific aims, which, if
addressed, would ascertain underlying mechanisms that may alleviate sensory and cognitive
impairments. First, we will study transient, non-continuous features (neurodynamics) of alpha and
gamma oscillations in resting-state EEG and sensory auditory chirp that model patient-level
heterogeneity and constitute group effects (Aim 1A). We will also identify what, if any, of these novel
features are conserved in the Fmr1-/- KO using preexisting murine EEG data and represent patient
subgroups (Aim 1B). Second, we will extend into cognition by studying neurodynamics and circuit
modeling associated with statistical learning (SL), which shares similar neural mechanisms to the
sensory auditory chirp (Aim 2). Third, we will use individualized closed-loop alpha auditory entrainment
(AAE) to attempt the normalization of neural signatures of the sensory auditory chirp and SL tasks (Aim
3). Aim 1 and 2 findings will provide critical data to optimize closed-loop parameters of AAE to serve
as a “bottom-up” neural probe to understand the mechanics of disorder-relevant circuit activity through
perturbation of thalamocortical drive. Ascertaining the mechanisms underlying these alterations would
have a high clinical impact, especially to enhance early intervention to alter the trajectory of intellectual
development in which no definitive treatments are available.

## Key facts

- **NIH application ID:** 10899435
- **Project number:** 5R01HD108222-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Ernest Vijay Pedapati
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $712,967
- **Award type:** 5
- **Project period:** 2023-08-07 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899435

## Citation

> US National Institutes of Health, RePORTER application 10899435, FX ENTRAIN: Perturbation of neurodynamics underlying sensory hyperarousal and statistical learning in Youth with FXS (5R01HD108222-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899435. Licensed CC0.

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