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

Abstract

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.

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

“…Previous evidence in the psychiatric literature links changes in frontal asymmetry to anxiety and depression (Smith et al, 2017), and frontal asymmetry differences have been described in full mutation FXS (Norris et al, 2022). Frontal alpha asymmetry has shown high internal consistency and moderate test-retest reliability in populations with depression, particularly greater right hemisphere frontal activity (Allen et al, 2004;Coan and Allen, 2004;Thibodeau et al, 2006;Stewart et al, 2010;van der Vinne et al, 2017).…”

“…Frontal asymmetry measures have previously been linked to variations in mood and anxiety (Allen et al, 2004;Coan and Allen, 2004;Thibodeau et al, 2006;Stewart et al, 2010;Smith et al, 2017;van der Vinne et al, 2017), relevant to individuals with the FXS premutation. Changes in frontal asymmetry have also been reported in full 10.3389/fnint.2023.898215 mutation FXS, related to sensory processing and adaptive behavior (Norris et al, 2022). Use of predefined clustering may provide insight into the neural basis of sensory, mood, and anxiety processing in adult PMCs specific to the features that defined each cluster and provide defined neural pathways and behavioral alterations associated with varying clinical profiles.…”

Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice

“…A recent human study discovered a prolonged alpha state during the pre-stimulus period of an auditory evoked task in females with FXS. Norris et al (2022) hypothesized that the length of time spent in alpha may reflect a compensatory mechanism that could potentially ‘rescue’ sensory processing abilities [ 127 ]. Therefore, the sustained alpha state identified in females could account for improvements seen in females versus males with FXS.…”

Validating brain activity measures as reliable indicators of individual diagnostic group and genetically mediated sub-group membership Fragile X Syndrome

“…The cross-validation error term for this measure was somewhat increased relative to those for other best-performing sub-group analyses, however, which may be re ective of the smaller sample size for females with FXS and must be interpreted with caution. Regardless, absolute power, particularly in the frontal region in which the chirp data was measured, has been recently found to differ in dynamic utilization and timing between males and females with FXS, and may re ect different underlying mechanistic and compensatory processes [35].…”