Fragile X SyndromeENTRAINNCT06227780
Alpha Auditory Entrainment for Cognitive Enhancement and Sensory Hypersensitivity in Youth With Developmental Disorders
A study testing Alpha Auditory Entrainment in people with Fragile X Syndrome and Autism Spectrum Disorder, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 5 to 10 yearsHealthy volunteers can take part
- Conditions the study is for
- Fragile X Syndrome, Autism Spectrum Disorder, Autistic Disorder
- What is being tested?
- Alpha Auditory Entrainment
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 180 participants
- Where
- 1 siteUnited States
- Study dates
- 24 May 2023to 24 May 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 10 years
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45226
Jae Citarella, 513-636-0875, Jae.Citarella@cchmc.org
Grace Westerkamp, grace.westerkamp@cchmc.org
About this study
Official title: 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.
Read the 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.
- Being tested
- Alpha Auditory Entrainment, Sham
- Keywords
- Neurodevelopmental Disorders, Autistic Disorder, Autism Spectrum Disorder, Fragile X Syndrome, Fragile X, FXS, ASD, Asperger, Autism
- Medical subject headings
- Fragile X Syndrome, Autism Spectrum Disorder, Autistic Disorder, Asperger Syndrome, Neurodevelopmental Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Alpha Auditory EntrainmentOther
Also called Alpha Brainwave Entrainment, Alpha Binaural Beats, Pulsed Sound Stimulation, Sonic 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
ShamOther
Sham stimulus: carrier tone alone
Target frequency: N/A
Delivery: headphones/speakers
| Study group | Role | What they receive |
|---|---|---|
| Fragile X Syndrome | Experimental | Fragile X Syndrome with full FMR1 mutations (>200 CGG repeats; at least partial FMR1 gene methylation) Receives: Other: Alpha Auditory Entrainment; Other: Sham |
| Autism Spectrum Disorder Controls | Active comparator | Age and sex-matched with FXS cohort Receives: Other: Alpha Auditory Entrainment; Other: Sham |
| Typically Developing Controls | Active comparator | Subjects with neither disorder who have met normal developmental milestones Receives: Other: Alpha Auditory Entrainment; Other: Sham |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 1 week
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2024
- Study start24 May 2023
- Primary completion24 May 2027 (estimated)
- Study completion24 May 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Fragile X SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 180 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Ernest Pedapati, MD, Children's Hospital Medical Center, Cincinnati
- Investigators
- Ernest V Pedapati, MD, Principal investigator, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06227780
- Sponsor's protocol ID
- 2022-0911
- Other IDs
- 1R01HD108222-01
- Acronym
- ENTRAIN
- Status last verified
- Mar 2026
- First submitted
- 16 Nov 2023
- Last updated
- 30 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: all collected, deidentified IPD
Study at a glance
From the registry record, last updated by the sponsor on 30 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- FX ENTRAIN: Perturbation of Neurodynamics Underlying Sensory Hyperarousal and Statistical Learning in Youth With FXS
- ClinicalTrials.gov ID
- NCT06227780
- Acronym / sponsor ID
- ENTRAIN / 2022-0911
- Keywords
- Neurodevelopmental Disorders, Autistic Disorder, Autism Spectrum Disorder, Fragile X Syndrome, Fragile X, FXS, ASD, Asperger
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 180 participants (estimated)
- Lead sponsor
- Children's Hospital Medical Center, CincinnatiUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- 24 May 2023 (actual)
- Primary completion
- 24 May 2027 (estimated)
- Study completion
- 24 May 2028 (estimated)
- First posted
- 29 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Fragile X Syndrome | Experimental | Other: Alpha Auditory Entrainment, Other: ShamFragile X Syndrome with full FMR1 mutations (>200 CGG repeats; at least partial FMR1 gene methylation) |
| Autism Spectrum Disorder Controls | Active comparator | Other: Alpha Auditory Entrainment, Other: ShamAge and sex-matched with FXS cohort |
| Typically Developing Controls | Active comparator | Other: Alpha Auditory Entrainment, Other: ShamSubjects with neither disorder who have met normal developmental milestones |
Who may qualify
- Ages
- 5 to 10 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (1 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Alpha Auditory EntrainmentAlso: Alpha Brainwave Entrainment, Alpha Binaural Beats, Pulsed Sound Stimulation, Sonic EntrainmentAlpha 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 | Autism Spectrum Disorder Controls, Fragile X Syndrome, Typically Developing Controls |
| ShamSham stimulus: carrier tone alone Target frequency: N/A Delivery: headphones/speakers | Other | Autism Spectrum Disorder Controls, Fragile X Syndrome, Typically Developing Controls |
Primary outcome
Alpha auditory entrainment versus sham effect on Word Learning Index during the Statistical Learning Passive Task.
Time frame: 1 week
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.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Mar 2026.
- Individual participant dataSharing planned: Yes. all collected, deidentified IPD
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Ernest V Pedapati, MD principal investigator
Children's Hospital Medical Center, Cincinnati
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Alpha Auditory Entrainment in people with Fragile X Syndrome and Autism Spectrum Disorder, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 30 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jae Citarella (513-636-0875, Jae.Citarella@cchmc.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Alpha auditory entrainment versus sham effect on Word Learning Index during the Statistical Learning Passive Task. (time frame: 1 week). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Mar 2026.