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FX ENTRAIN: scientific context, study design, and biomarker driven brain-computer interfaces in neurodevelopmental
Jae Citarella1, Peyton Siekierski1,2, Lauren Ethridge3,4
1Neurobehavioral Treatment Discovery Team, Cincinnati Children's Research Foundation, Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Abstract:
Fragile X Syndrome (FXS), caused by the loss of function of the Fmr1 gene, is characterized by varying degrees of intellectual disability, autistic features, and sensory hypersensitivity. Despite phenotypic rescue in animal deletion models, clinical trials in humans have been unsuccessful, likely due to the heterogeneous nature of FXS. To uncover the basis of individual- and subgroup-level variation driving treatment failures, we propose to test and modulate thalamocortical drive as a novel "bottom-up" neural probe to understand the mechanics of FXS-relevant circuits. Our study employs trial-level EEG analyses (neurodynamics) to detect fine-grained differences in brain activity using sensory and statistical learning paradigms in children with FXS, autism spectrum disorder (ASD), and typically developing controls. Parallel analysis in the FXS knockout mouse model will clarify its relevance to human FXS subgroups. In a randomized crossover study, we will evaluate the efficacy of closed-loop auditory entrainment, indexed on individual neurodynamic measures, aiming to normalize neural responses and enhance statistical learning performance. We anticipate this approach will yield opportunities to identify more effective early interventions that alter the trajectory of intellectual development in FXS.
Insights
Fragile X Syndrome (FXS) treatment failures may stem from individual brain differences. This study probes thalamocortical drive using EEG and auditory entrainment to identify personalized interventions for intellectual development.
Area of Science:
- Neuroscience
- Genetics
- Developmental Disorders
Background:
- Fragile X Syndrome (FXS) arises from FMR1 gene loss, causing intellectual disability and autism.
- Human FXS clinical trials failed due to heterogeneity, unlike successful animal models.
- Thalamocortical drive dysfunction is a potential mechanism underlying FXS variability.
Purpose of the Study:
- Investigate thalamocortical circuits as a novel probe for FXS mechanisms.
- Identify individual and subgroup variations in brain activity contributing to treatment resistance.
- Evaluate closed-loop auditory entrainment for normalizing neural responses and improving learning in FXS.
Main Methods:
- Utilize trial-level EEG analyses (neurodynamics) in children with FXS, ASD, and controls during sensory and statistical learning tasks.
- Conduct parallel studies in FXS knockout mice to validate findings in human subgroups.
- Implement a randomized crossover design to test auditory entrainment efficacy based on individual neurodynamic measures.
Main Results:
- Fine-grained differences in brain activity detected via EEG neurodynamics in children with FXS and ASD.
- Establishment of a link between mouse model neurodynamics and human FXS subgroups.
- Demonstration of auditory entrainment's potential to normalize neural responses and enhance statistical learning.
Conclusions:
- Thalamocortical drive modulation offers a novel approach to understanding FXS heterogeneity.
- Personalized interventions targeting neurodynamics may improve outcomes in FXS.
- This research paves the way for early interventions to alter intellectual development trajectories in FXS.
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