Empirical Frequency Bound Derivation Reveals Prominent Mid-Frontal Alpha Associated with Neurosensory Dysfunction in Fragile X Syndrome

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 of have demonstrated a marked reduction in global alpha activity and regional increases in gamma oscillations that have been associated with intellectual disability and sensory hypersensitivity. Since alpha activity is associated with thalamocortical function that has 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 was 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) a 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 mouse model research.