Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome

Abstract

Sensory hypersensitivities are common, clinically distressing features of Fragile X Syndrome (FXS). Preclinical evidence suggests this abnormality may result from synaptic hyper-excitability in sensory systems. This model predicts reduced sensory habituation to repeated stimulus presentation. Fourteen adolescents and adults with FXS and 15 age-matched controls participated in a modified auditory gating task using trains of 4 identical tones during dense array electroencephalography (EEG). Event-related potential and single trial time-frequency analyses revealed decreased habituation of the N1 event-related potential response in FXS, and increased gamma power coupled with decreases in gamma phase-locking during the early-stimulus registration period. EEG abnormalities in FXS were associated with parent reports of heightened sensory sensitivities and social communication deficits. Reduced habituation and altered gamma power and phase-locking to auditory cues demonstrated here in FXS patients parallels preclinical findings with Fmr1 KO mice. Thus, the EEG abnormalities seen in FXS patients support the model of neocortical hyper-excitability in FXS, and may provide useful translational biomarkers for evaluating novel treatment strategies targeting its neural substrate.

Figure 1

ERP grand average PCA-weighted virtual channel plot for FXS and matched controls, with inset PCA spatial component topography. Small black bars indicate presentation of the auditory stimulus. ERP, event-related potential; FXS, Fragile X Syndrome; PCA, principal components analysis.

Figure 2

(a) ITC. (b) Single trial power. (c) Baseline-corrected single trial power. Black boxes in the difference maps indicate clusters with significant group differences. Warmer colors in the difference maps (right column) indicate higher phase-locking or higher power for FXS and cooler colors indicate higher values for healthy controls. FXS, Fragile X Syndrome; ITC, inter-trial coherence.

Figure 3

Relationship of excitatory (gamma single trial power, N1 amplitude to initial stimulus) and inhibitory (gamma phase-locking during ‘gamma spike' for initial stimulus and first repetition) activity in response to trains of auditory stimuli. Units for both x and y axes represent averaged rank scores from lowest (1) to highest (29) for the composite variables. Controls show high inhibitory, organized activity and low background excitatory noise. In contrast, most FXS participants have both higher excitatory response and lower inhibitory activity. FXS, Fragile X Syndrome.