Sensory Processing Abnormalities, ASD Features, and Modulation of Auditory Evoked Potentials in Fragile X Syndrome

Background:  Sensory hypersensitivities are common, clinically distressing features of both Autism Spectrum Disorder (ASD) and the Fragile X Syndrome (FXS).  Preclinical evidence suggests that this symptom results from synaptic hyperexcitability in sensory systems.  Local circuit function in sensory networks is dependent on the dynamic balance of inhibitory/excitatory synapses in sensory cortex.  Shifts in this balance modulate stimulus selectivity and sensory habituation to a repeated stimulus. These processes can be selectively examined with sensory evoked potentials. 

Objectives:  The objective of this study was to examine local circuit function in auditory cortex by assessing sensory habituation, sensitivity and selectivity in FXS.

Methods:  Auditory evoked potential studies were completed with adolescent and adult individuals with FXS (N=17), and matched healthy controls (N=15).  Event-related potentials (ERPs) were examined during a passive auditory habituation task. Habituation trials (150 total) consisted of a train of four 1000 Hz beeps separated by a 500 ms inter-stimulus interval, with an inter-trial interval of 4 sec. Dense array EEG and spatial PCA were used to capture the ERP response to each stimulus in the 4 stimulus train. Absolute ERP amplitudes as well as percent reduction in amplitude to each repeated stimulus were compared between groups. 

Results:  FXS patients showed reduced habituation to repeated tones reflected in a significantly decreased level of N1 reduction over trials, t(30)=2.24, p=.03. A subset of FXS patients showed “giant” N1 amplitudes (more than 2x that of healthy controls) to all four repeated stimuli. Increased negative N1 amplitude was strongly correlated with increased clinical reports of auditory processing abnormalities on the Sensory Profile (rho=-.59, p=.02) which were in turn correlated with increased endorsement of ASD features on the Social Communication Questionnaire (SCQ; rho=.66, p=.03). FXS patients also showed significantly decreased N2 ERPs to each of the stimuli in the 4 stimulus train (p’s<.01). Abnormally decreased negative average N2 amplitude showed a strong correlation with increased Irritability scores on the Aberrant Behavior Checklist (rho=.75, p=.005) for FXS.

Conclusions:  FXS patients show hyperexcitability of the N1 ERP response and increased impairment in sensory habituation linked to clinical reports of auditory processing abnormalities and to the presence of ASD-like traits. Abnormalities in the N2 ERP response suggest a reduction in executive function associated with extended stimulus processing, potentially reflecting a reduction in the cognitive components associated with habituation to repeated stimuli which may contribute to the increased levels of irritability seen in these individuals.