Alpha Auditory Entrainment for Fragile X Syndrome

(ENTRAIN Trial)

Recruiting at 1 trial location

Overseen By Jae Citarella

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Children's Hospital Medical Center, Cincinnati

Disqualifiers: Auditory impairments, Visual impairments, Substance abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 week

180 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment Alpha Auditory Entrainment for Fragile X Syndrome?

Research shows that individuals with Fragile X Syndrome have altered brain activity, including changes in alpha and gamma oscillations, which are linked to sensory hypersensitivity and intellectual disability. Alpha Auditory Entrainment may help by targeting these brain wave patterns, potentially improving sensory processing and reducing hyper-excitability. ^{1 2 3 4 5}

How is Alpha Auditory Entrainment treatment different from other treatments for Fragile X Syndrome?

Alpha Auditory Entrainment is unique because it targets the brain's alpha waves, which are often disrupted in Fragile X Syndrome, to help manage symptoms like sensory hypersensitivity and intellectual disability. This approach focuses on modulating brain activity through sound, rather than using medication, making it a novel non-drug therapy for this condition. ^{2 3 4 5 6}

What is the purpose of this trial?

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.

Research Team

Ernest V Pedapati, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

This trial is for young individuals with developmental disorders such as Autism Spectrum Disorder, Asperger Syndrome, and Fragile X Syndrome. It's designed to help those who have cognitive challenges and are overly sensitive to sensory input.

Inclusion Criteria

TDC Cohort: Aged 5-15 years, inclusive; Have no known genetic mutation; Have documentation of ASD diagnosis; Score ≤ 15 on SCQ screen; Be in good health per investigator; Patient has met normal developmental milestones; Patient has no family history of heritable neuropsychiatric disorders; Patient has an IQ greater than 85 on the Stanford-Binet; Score ≤8 on an SCQ screen.

I am aged 5-15, have ASD without genetic mutations, scored ≤ 15 on SCQ, and am in good health.

I am between 5 and 15 years old with a confirmed full FMR1 mutation.

Exclusion Criteria

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo alpha auditory entrainment to normalize brain activity and improve cognitive function and sensory hypersensitivity

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alpha Auditory Entrainment

Trial Overview The study tests Alpha Auditory Entrainment—a technique using special sounds played through headphones—to see if it can improve brain activity, cognition, and reduce sensory hypersensitivity in participants with these conditions.

Participant Groups

Group I: Fragile X Syndrome Experimental Treatment 2 Interventions

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

Group II: Autism Spectrum Disorder Controls Active Control 2 Interventions

Age and sex-matched with FXS cohort

Group III: Typically Developing Controls Active Control 2 Interventions

Subjects with neither disorder who have met normal developmental milestones

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

In a study of 933 individuals with fragile X syndrome (FXS), sensory symptoms (SS) and signs of hyperarousal (HA) were more prevalent in males, with 87% of males experiencing SS compared to 68% of females, indicating a gender difference in symptom expression.

The presence of strong sensory responses was linked to more behavioral problems and limited participation in daily activities, highlighting the need for further research on how these symptoms affect individuals with FXS and their families.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensory Symptoms and Signs of Hyperarousal in Individuals with Fragile X Syndrome: Findings from the FORWARD Registry and Database Multisite Study. Lachiewicz, AM., Stackhouse, TM., Burgess, K., et al.[2023]

Individuals with fragile X syndrome (FXS) exhibit distinct auditory processing abnormalities, including larger N1 and P2 amplitudes and abnormal modulation of these responses, which may impact language development and pattern recognition.

Despite showing a normal developmental trajectory for most auditory measures, participants with FXS demonstrate age-independent and gender-dependent challenges in processing novel stimuli, suggesting potential biomarkers for clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Neural Response to Novel Sounds in Fragile X Syndrome: Potential Biomarkers. Ethridge, L., Thaliath, A., Kraff, J., et al.[2022]

The study found that adolescents and adults with fragile X syndrome (FXS) exhibited decreased gamma band phase-locking in their auditory cortex, indicating altered neural entrainment compared to healthy controls.

These neural abnormalities were linked to heightened sensory sensitivities and social communication deficits, suggesting that targeting the functionality of fast-spiking interneurons could be a potential therapeutic strategy for FXS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome. Ethridge, LE., White, SP., Mosconi, MW., et al.[2018]

Children with fragile X syndrome showed significantly larger N1 responses to standard auditory tones compared to age-matched controls, indicating heightened auditory processing sensitivity.

The study also found that fragile X children did not exhibit habituation of the N1 response or sensitization of the N2 response to repeated tones, suggesting abnormal auditory stimulus processing in their brains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentation of auditory N1 in children with fragile X syndrome. Castrén, M., Pääkkönen, A., Tarkka, IM., et al.[2019]

In individuals with Fragile X syndrome (n = 65), there is a notable alteration in brain activity, characterized by a slower dominant alpha rhythm and a shift in alpha frequency towards the front of the brain, which may contribute to sensory processing issues.

These changes in alpha activity suggest that disruptions in thalamocortical physiology play a significant role in the heightened excitability of the neocortex observed in Fragile X syndrome, indicating a need for further exploration of these neural mechanisms beyond what has been studied in animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Empirical Frequency Bound Derivation Reveals Prominent Mid-Frontal Alpha Associated with Neurosensory Dysfunction in Fragile X Syndrome. Pedapati, EV., Sweeney, JA., Schmitt, LM., et al.[2023]

In a study of 36 adolescents and adults with Fragile X syndrome (FXS) compared to 40 typically developing controls, individuals with FXS exhibited significant differences in alpha brain wave activity, particularly in the right hemisphere, which may affect sensory processing.

Males with FXS showed more frequent bursts of alpha activity, while females had fewer bursts but maintained high alpha states longer, suggesting different mechanisms of sensory processing and clinical presentation between sexes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemispheric Utilization of Alpha Oscillatory Dynamics as a Unique Biomarker of Neural Compensation in Females with Fragile X Syndrome. Norris, JE., DeStefano, LA., Schmitt, LM., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Sensory Symptoms and Signs of Hyperarousal in Individuals with Fragile X Syndrome: Findings from the FORWARD Registry and Database Multisite Study. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Development of Neural Response to Novel Sounds in Fragile X Syndrome: Potential Biomarkers. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Augmentation of auditory N1 in children with fragile X syndrome. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Empirical Frequency Bound Derivation Reveals Prominent Mid-Frontal Alpha Associated with Neurosensory Dysfunction in Fragile X Syndrome. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Hemispheric Utilization of Alpha Oscillatory Dynamics as a Unique Biomarker of Neural Compensation in Females with Fragile X Syndrome. [2023]