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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

180 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-05-24

Study Completion Date

2028-05-24

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Fragile X Syndrome Autism Spectrum Disorder Autistic Disorder Asperger Syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

All visits across all arms will follow identical procedures. Aim 1 and Aim 2 consist of a case-control study that will be completed over two visits, in which baseline data will be collected from participants that will be used to optimize the intervention delivered in Aim 3. Aim 3 consists of a two-visit, randomized controlled, crossover acute perturbation study to study the effect of alpha auditory entrainment (AAE) or sham stimulation on brain activity. AAE will be performed in two visits as a double-blind, sham-controlled crossover study such that each participant will receive AAE and sham in random order.

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

As the randomization and "dispensing" of the intervention is conducted via software, investigators, study staff, and study subjects will all be blinded to the randomized study treatment assignments.

Study Groups

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Fragile X Syndrome

Fragile X Syndrome with full FMR1 mutations (\>200 CGG repeats; at least partial FMR1 gene methylation)

Group Type EXPERIMENTAL

Alpha Auditory Entrainment

Intervention Type OTHER

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

Sham

Intervention Type OTHER

Sham stimulus: carrier tone alone

Target frequency: N/A

Delivery: headphones/speakers

Autism Spectrum Disorder Controls

Age and sex-matched with FXS cohort

Group Type ACTIVE_COMPARATOR

Alpha Auditory Entrainment

Intervention Type OTHER

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

Sham

Intervention Type OTHER

Sham stimulus: carrier tone alone

Target frequency: N/A

Delivery: headphones/speakers

Typically Developing Controls

Subjects with neither disorder who have met normal developmental milestones

Group Type ACTIVE_COMPARATOR

Alpha Auditory Entrainment

Intervention Type OTHER

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

Sham

Intervention Type OTHER

Sham stimulus: carrier tone alone

Target frequency: N/A

Delivery: headphones/speakers

Interventions

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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

Intervention Type OTHER

Sham

Sham stimulus: carrier tone alone

Target frequency: N/A

Delivery: headphones/speakers

Intervention Type OTHER

Other Intervention Names

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Alpha Brainwave Entrainment Alpha Binaural Beats Pulsed Sound Stimulation Sonic Entrainment

Eligibility Criteria

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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

Minimum Eligible Age

5 Years

Maximum Eligible Age

10 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes