FX ENTRAIN: Scientific Context, Study Design, and Biomarker Driven Brain-Computer Interfaces in Neurodevelopmental Conditions

Jae Citarella^1*Lauren Ethridge^2,3Grace Westerkamp^1*Yanchen Liu¹Elizabeth Blank¹Laura Batterink⁴Stephanie R. Jones^5,6Elizabeth Smith¹Debra Reisinger¹Meredith Nelson¹Devin Binder⁷Khaleel Razak⁸Makoto Miyakoshi^1,9Steve Wu^10,11Donald Gilbert^10,11Paul Horn^10,11Lisa De Stefano^12,13Craig Erickson^1,14Ernest Pedapati^10,13,14

• ¹Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
• ²Section on Developmental and Behavioral Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
• ³Department of Psychology, University of Oklahoma, Norman, Oklahoma, United States
• ⁴Department of Psychology, Western University, London, Ontario, Canada
• ⁵Department of Neuroscience, Brown University, Providence, Rhode Island, United States
• ⁶Carney Institute for Brain Science, Brown University, Providence, Rhode Island, United States
• ⁷Division of Biomedical Sciences, University of California, Riverside, Riverside, California, United States
• ⁸Psychology Department, University of California, Riverside, Riverside, California, United States
• ⁹University of Cincinnati, Cincinnati, Ohio, United States
• ¹⁰Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
• ¹¹Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States
• ¹²Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
• ¹³Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
• ¹⁴Department of Psychiatry, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States

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. Clinical Trial Registration: clinicaltrials.gov. Identifier: NCT06227780.