Alpha Auditory Entrainment for Fragile X Syndrome
(ENTRAIN Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byErnest V Pedapati, MD
Age: < 18
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Children's Hospital Medical Center, Cincinnati
Disqualifiers: Auditory impairments, Visual impairments, Substance abuse, others
No Placebo Group
Trial Summary
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.
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.
12345How 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.
23456Eligibility 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
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Active Control
Group I: Fragile X SyndromeExperimental Treatment2 Interventions
Fragile X Syndrome with full FMR1 mutations (\>200 CGG repeats; at least partial FMR1 gene methylation)
Group II: Autism Spectrum Disorder ControlsActive Control2 Interventions
Age and sex-matched with FXS cohort
Group III: Typically Developing ControlsActive Control2 Interventions
Subjects with neither disorder who have met normal developmental milestones
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Cincinnati Children's Hospital Medical CenterCincinnati, OH
Elizabeth BlankCincinnati, OH
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Who Is Running the Clinical Trial?
Children's Hospital Medical Center, CincinnatiLead Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)Collaborator
References
Sensory Symptoms and Signs of Hyperarousal in Individuals with Fragile X Syndrome: Findings from the FORWARD Registry and Database Multisite Study. [2023]This study was designed to increase our understanding about characteristics and the impact of sensory symptoms (SS) and signs of hyperarousal (HA) in individuals with fragile X syndrome (FXS) from childhood through early adulthood and by gender. Data derived from the Fragile X Online Registry With Accessible Research Database (FORWARD), a natural history study of FXS, were analyzed using descriptive statistics and multivariate linear and logistic regression models to examine SS and signs of HA, their impact on behavioral regulation and limitations on the subject/family. The sample (N = 933) consisted of 720 males and 213 females. More males were affected with SS (87% vs. 68%) and signs of HA (92% vs. 79%). Subjects who were endorsed as having a strong sensory response had more comorbidities, including behavioral problems. The predominant SS was difficulty with eye gaze that increased with age in both genders. As individuals age, there was less use of non-medication therapies, such as occupational therapy (OT)/physical therapy (PT), but there was more use of psychopharmacological medications and investigational drugs for behaviors. Multiple regression models suggested that endorsing SS and signs of HA was associated with statistically significantly increased ABC-C-I subscale scores and limited participation in everyday activities. This study improves our understanding of SS and signs of HA as well as their impact in FXS. It supports the need for more research regarding these clinical symptoms, especially to understand how they contribute to well-known behavioral concerns.
Development of Neural Response to Novel Sounds in Fragile X Syndrome: Potential Biomarkers. [2022]Auditory processing abnormalities in fragile X syndrome (FXS) may contribute to difficulties with language development, pattern identification, and contextual updating. Participants with FXS (N = 41) and controls (N = 27) underwent auditory event-related potentials during presentation of an oddball paradigm. Data was adequate for analysis for 33 participants with FXS and 27 controls (age 4-51 y, 13 females [FXS]; 4-54 y, 11 females [control]). Participants with FXS showed larger N1 and P2 amplitudes, abnormal lack of modulation of P1 and P2 amplitudes and P2 latency in response to oddball stimuli ) relative to controls: Females with FXS were more similar to controls. Participants with FXS showed a marginal speeding of the P2 latency, suggesting potentiation to oddball stimuli rather than habituation. Participants with FXS showed a heightened N1 habituation effect compared to controls. Gamma power was significantly higher for participants with FXS. Groups did not differ on mismatch negativity. Both controls and participants with FXS showed similar developmental trajectories in P1 and N1 amplitude, P2 latency, and gamma power, but not for P2 amplitude. One month retest analyses performed in 14 participants suggest strong test-retest reliability for most measures. Individuals with FXS show previously demonstrated increased response amplitude and high frequency neural activity. Despite an overall normal developmental trajectory for most measures, individuals with FXS show age-independent but gender-dependent decreases in complex processing of novel stimuli. Many markers show strong retest reliability even in children and thus are potential biomarkers for clinical trials in FXS.
Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome. [2018]Label="BACKGROUND">Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS.
Augmentation of auditory N1 in children with fragile X syndrome. [2019]We compared the N1 responses of the auditory event-related brain potentials (ERPs) in school-aged children with fragile X syndrome to age-matched controls in order to assess auditory processing. Event-related potentials to non-attended standard and deviant tone stimuli were recorded with EEG electrodes and here the standard tones were analysed. The amplitude of the N1 component to standard tones was significantly larger in children with fragile X syndrome than in control children. In addition, the global field power maximum of ERP corresponding to the N2 component was significantly (p
Empirical Frequency Bound Derivation Reveals Prominent Mid-Frontal Alpha Associated with Neurosensory Dysfunction in Fragile X Syndrome. [2023]The FMR1 gene is inactive in Fragile X syndrome (FXS), resulting in low levels of FMRP and consequent neurochemical, synaptic, and local circuit neurophysiological alterations in the fmr1 KO mouse. In FXS patients, electrophysiological studies have demonstrated a marked reduction in global alpha activity and regional increases in gamma oscillations associated with intellectual disability and sensory hypersensitivity. Since alpha activity is associated with a thalamocortical function with widely distributed modulatory effects on neocortical excitability, insight into alpha physiology may provide insight into systems-level disease mechanisms. Herein, we took a data-driven approach to clarify the temporal and spatial properties of alpha and theta activity in participants with FXS. High-resolution resting-state EEG data were collected from participants affected by FXS (n = 65) and matched controls (n = 70). We used a multivariate technique to empirically classify neural oscillatory bands based on their coherent spatiotemporal patterns. Participants with FXS demonstrated: 1) redistribution of lower-frequency boundaries indicating a "slower" dominant alpha rhythm, 2) an anteriorization of alpha frequency activity, and 3) a correlation of increased individualized alpha power measurements with auditory neurosensory dysfunction. These findings suggest an important role for alterations in thalamocortical physiology for the well-established neocortical hyper-excitability in FXS and, thus, a role for neural systems level disruption to cortical hyperexcitability that has been studied primarily at the local circuit level in animal models.
Hemispheric Utilization of Alpha Oscillatory Dynamics as a Unique Biomarker of Neural Compensation in Females with Fragile X Syndrome. [2023]Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide expansion on the FMR1 gene and characterized by intellectual disability, sensory hypersensitivity, executive function difficulties, and social anxiety. Recently, efforts to define neural biomarkers for FXS have highlighted disruptions to power in the alpha frequency band; however the dynamic mechanisms supporting these findings are poorly understood. The current study aimed to explore the temporal and hemispheric dynamics supporting alpha phenotypes in FXS and their relationship with neural phenotypes related to auditory processing using electroencephalography during an auditory evoked task. Adolescents and adults (N = 36) with FXS and age/sex matched typically developing controls (N = 40) completed an auditory chirp task. Frontal alpha power in the prestimulus period was decomposed into "bursts" using percentile thresholding, then assessed for number of bursts per second (burst count) and burst length. Data were compared across left and right hemispheres to assess lateralization of neural activity. Individuals with FXS showed more differences in alpha power compared to TDC primarily in the right hemisphere. Notably, alpha hemisphere outcomes in males with FXS were driven by the number of times they entered a dynamically relevant period of alpha (burst count) rather than length of time spent in alpha. Females with FXS showed reduced burst counts but remained in sustained high alpha states for longer periods of time. Length of time spent in alpha may reflect a modulatory or compensatory mechanism capable of recovering sensory processing abilities in females with FXS resulting in a less severe clinical presentation. Right hemisphere abnormalities may impact sensory processing differences between males and females with FXS. The relationship between alpha burst length, count, sex, and hemisphere may shed light on underlying mechanisms for previously observed alpha power abnormalities in FXS and their variation by sex.