Alpha Auditory Entrainment for Cognitive Enhancement and Sensory Hypersensitivity in Youth With Developmental Disorders (ENTRAIN)

FX ENTRAIN: Perturbation of Neurodynamics Underlying Sensory Hyperarousal and Statistical Learning in Youth With FXS

Fragile X Syndrome (FXS) is a complex neurodevelopmental disorder caused by a mutation on the X chromosome. Scientists have investigated FXS extensively in both humans and animals. Thus far, phenotypic rescue in animal models has not resulted in treatment breakthroughs in humans, though some important discoveries have been made. Research has shown that individuals with FXS process sounds differently than those in the typical population, and they also show baseline differences in brain activity, including high gamma activity, increased theta activity, and decreased alpha activity. The investigators' central hypothesis is that these alterations in brain activity (specifically alpha and gamma activity) impair the brain's ability to process new information, thereby impeding cognitive functioning and increasing sensory sensitivity. The investigators propose that auditory entrainment, a technique that involves playing special sounds through headphones, will normalize brain activity in individuals with FXS and lead to increased cognitive function and decreased sensory hypersensitivity.

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder; Autistic Disorder; Fragile X Syndrome; Asperger Syndrome
• Intervention / Treatment: Other: Alpha Auditory Entrainment; Other: Sham

Detailed Description

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. The investigators' 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. This approach involves three scientific aims, which, if addressed, would ascertain underlying mechanisms that may alleviate sensory and cognitive impairments. First, the investigators 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), and 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, the research team 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, the investigators 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.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Grace Westerkamp; Phone Number: 513-636-2332; Email: grace.westerkamp@cchmc.org
• Study Contact Backup: Name: Jae Citarella; Phone Number: 513-636-0875; Email: Jae.Citarella@cchmc.org

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45226
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Grace Westerkamp; Email: grace.westerkamp@cchmc.org
      • Principal Investigator: Ernest V Pedapati, MD
      • Sub-Investigator: Craig Erickson, MD
      • Sub-Investigator: Elizabeth Smith, PhD
      • Sub-Investigator: Steve Wu, MD
      • Sub-Investigator: Meredith Will, PhD
      • Sub-Investigator: Rebecca Shaffer, PhD
      • Sub-Investigator: Makoto Miyakoshi, PhD
      • Sub-Investigator: Lauren Schmitt, PhD
      • Sub-Investigator: Kelli Dominick, MD, PhD
      • Contact: Jae Citarella; Phone Number: 513-636-0875; Email: Jae.Citarella@cchmc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• FXS Cohort: 1) Aged 5-10 years, inclusive; 2) Patient has full FMR1 mutation confirmed by genetic testing.
• ASD Cohort: 1) Aged 5-10 years, inclusive; 2) Have no known genetic mutation; 3) Have documentation of ASD diagnosis; 4) Score ≤ 15 on SCQ screen; 5) Be in good health per investigator.
• TDC Cohort: 1) Aged 5-10 years, inclusive; 2) Have no known genetic mutation; 3) Have documentation of ASD diagnosis; 4) Score ≤ 15 on SCQ screen; 5) Be in good health per investigator; 6) Patient has met normal developmental milestones; Patient has no family history of heritable neuropsychiatric disorders; 7) Patient has an IQ greater than 85 on the Stanford-Binet; 8) Score ≤8 on an SCQ screen.

Exclusion Criteria:

• All subjects: 1) Patient has auditory or visual impairments that cannot be corrected; 2) History of substance abuse or dependence within the past 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fragile X Syndrome; Fragile X Syndrome with full FMR1 mutations (>200 CGG repeats; at least partial FMR1 gene methylation)	Other: Alpha Auditory Entrainment; Alpha Brainwave Entrainment (AAE) stimulus: starts at high theta range (7-Hz) through high alpha (13-Hz) in 2 Hz steps on a 500 Hz sine carrier tone Target frequency: 10 Hz Delivery: headphones/speakers; Other Names: Alpha Brainwave Entrainment; Alpha Binaural Beats; Pulsed Sound Stimulation; Sonic Entrainment; Other: Sham; Sham stimulus: carrier tone alone Target frequency: N/A Delivery: headphones/speakers
Active Comparator: Autism Spectrum Disorder Controls; Age and sex-matched with FXS cohort	Other: Alpha Auditory Entrainment; Alpha Brainwave Entrainment (AAE) stimulus: starts at high theta range (7-Hz) through high alpha (13-Hz) in 2 Hz steps on a 500 Hz sine carrier tone Target frequency: 10 Hz Delivery: headphones/speakers; Other Names: Alpha Brainwave Entrainment; Alpha Binaural Beats; Pulsed Sound Stimulation; Sonic Entrainment; Other: Sham; Sham stimulus: carrier tone alone Target frequency: N/A Delivery: headphones/speakers
Active Comparator: Typically Developing Controls; Subjects with neither disorder who have met normal developmental milestones	Other: Alpha Auditory Entrainment; Alpha Brainwave Entrainment (AAE) stimulus: starts at high theta range (7-Hz) through high alpha (13-Hz) in 2 Hz steps on a 500 Hz sine carrier tone Target frequency: 10 Hz Delivery: headphones/speakers; Other Names: Alpha Brainwave Entrainment; Alpha Binaural Beats; Pulsed Sound Stimulation; Sonic Entrainment; Other: Sham; Sham stimulus: carrier tone alone Target frequency: N/A Delivery: headphones/speakers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alpha auditory entrainment versus sham effect on Word Learning Index during the Statistical Learning Passive Task.	The Statistical Learning Passive Task uses an EEG-based measure of neural entrainment that uses inter-trial coherence (ITC) to calculate Word Learning Index (WLI). Patterns of EEG phase-locking, corresponding to a shift in processing from raw syllable units to cohesive words, reflect gradual statistical learning in the brain. The WLI effect can be quantified by creating a ratio of the inter-trail coherence for words versus syllables, as follows: WLI = Inter-trial Coherence word rate / Inter-trial Coherence syllable rate A higher WLI indicates a relatively stronger response to tri-syllabic nonwords compared to raw syllables, reflecting stronger word segmentation due to statistical learning.	1 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alpha auditory entrainment versus sham effect on the Behavior Learning Effect during the Statistical Learning Active Task.	The Active SL Task based measure uses reaction time to estimate a behavioral measure of SL, the Behavioral Learning Effect BLE. BLE values indicate greater proportional facilitation to predictable words in the stream, indicative of stronger SL at the individual level. The Behavioral Learning effect is quantified as follows: BLE (in ms) = (Reaction time target syllable position 1)-(Reaction time target syllable position 3) Larger BLE values indicate greater proportional facilitation to predictable words in the stream, indicative of stronger SL at the individual level.	1 week

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Ernest V Pedapati, MD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2023
• Primary Completion (Estimated): May 24, 2027
• Study Completion (Estimated): May 24, 2028

Study Registration Dates

• First Submitted: November 16, 2023
• First Submitted That Met QC Criteria: January 18, 2024
• First Posted (Actual): January 29, 2024

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: ASD; Autism; Fragile X; Autism Spectrum Disorder; Autistic Disorder; Fragile X Syndrome; Neurodevelopmental Disorders; FXS; Asperger
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Congenital Abnormalities; Child Development Disorders, Pervasive; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Sex Chromosome Disorders; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; X-Linked Intellectual Disability; Autism Spectrum Disorder; Autistic Disorder; Neurodevelopmental Disorders; Fragile X Syndrome; Asperger Syndrome; salicylhydroxamic acid
• Other Study ID Numbers: 2022-0911; 1R01HD108222-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: all collected, deidentified IPD
• IPD Sharing Time Frame: upon publication of results
• IPD Sharing Access Criteria: Research data gathered as part of this study may be shared and provided to other investigators affiliated with the Neurobehavioral and Neurology Research Teams at CCHMC for the purpose of data sharing. If participants are enrolled in multiple studies, their research data will be shared across studies to reduce participant burden and avoid duplication of procedures. Only investigators/research team affiliated with CCHMC will have access to secured files and/or research data and will be well-informed regarding the protection of participants' rights to confidentiality.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No