Neuropsychiatric feature-based subgrouping reveals neural sensory processing spectrum in female FMR1 premutation carriers: A pilot study

Jordan E Norris; Lauren M Schmitt; Lisa A De Stefano; Ernest V Pedapati; Craig A Erickson; John A Sweeney; Lauren E Ethridge

doi:10.3389/fnint.2023.898215

Neuropsychiatric feature-based subgrouping reveals neural sensory processing spectrum in female FMR1 premutation carriers: A pilot study

Front Integr Neurosci. 2023 Feb 3:17:898215. doi: 10.3389/fnint.2023.898215. eCollection 2023.

Authors

Jordan E Norris¹, Lauren M Schmitt^{2

3}, Lisa A De Stefano², Ernest V Pedapati^{4

5

6}, Craig A Erickson^{4

6}, John A Sweeney⁶, Lauren E Ethridge^{1

7}

Affiliations

¹ Department of Psychology, The University of Oklahoma, Norman, OK, United States.
² Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
³ Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States.
⁴ Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
⁵ Division of Child Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
⁶ Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States.
⁷ Department of Pediatrics, Section on Developmental and Behavioral Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.

Abstract

Introduction: Fragile X Syndrome (FXS) is rare genetic condition characterized by a repeat expansion (CGG) in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene where individuals with greater than 200 repeats are defined as full mutation. FXS clinical presentation often includes intellectual disability, and autism-like symptoms, including anxiety and sensory hypersensitivities. Individuals with 55 to <200 CGG repeats are said to have the FMR1 premutation, which is not associated with primary characteristics of the full mutation, but with an increased risk for anxiety, depression, and other affective conditions, as well as and impaired cognitive processing differences that vary in severity. Defining subgroups of premutation carriers based on distinct biological features may identify subgroups with varying levels of psychiatric, cognitive, and behavioral alterations.

Methods: The current pilot study utilized 3 cluster subgroupings defined by previous k means cluster analysis on neuropsychiatric, cognitive, and resting EEG variables in order to examine basic sensory auditory chirp task-based EEG parameters from 33 females with the FMR1 premutation (ages 17-78).

Results: Based on the predefined, neuropsychiatric three-cluster solution, premutation carriers with increased neuropsychiatric features and higher CGG repeat counts (cluster 1) showed decreased stimulus onset response, similar to previous ERP findings across a number of psychiatric disorders but opposite to findings in individuals with full mutation FXS. Premutation carriers with increased executive dysfunction and resting gamma power (cluster 2) exhibited decreased gamma phase locking to a chirp stimulus, similar to individuals with full mutation FXS. Cluster 3 members, who were relatively unaffected by psychiatric or cognitive symptoms, showed the most normative task-based EEG metrics.

Discussion: Our findings suggest a spectrum of sensory processing characteristics present in subgroups of premutation carriers that have been previously understudied due to lack of overall group differences. Our findings also further validate the pre-defined clinical subgroups by supporting links between disturbances in well-defined neural pathways and behavioral alterations that may be informative for identifying the mechanisms supporting specific risk factors and divergent therapeutic needs in individuals with the FMR1 premutation.

Keywords: EEG; FMR1 premutation carrier; clustering analysis; neural oscillations and entrainment; sensory processing.

Grants and funding

This research study was supported by the U54 Fragile X Center (U54HD082008, JS and U54HD104461, CE) and the University of Oklahoma Libraries’ Open Access Fund.