Increased Spontaneous Blink Rate Suggests Dopaminergic Function Abnormalities in Individuals with Fragile X Syndrome:

Background: Spontaneous blink rate (SBR) stands as a non-invasive measure of central dopaminergic function that has been studied in the context of a variety of neurological disorders; increased SBR is associated with increased dopaminergic activity and has been found in schizophrenia, and anxiety disorders. The relative ease of carrying out these studies offers a promising, cost-effective method to evaluate a possible role of dopaminergic dysfunction and anxiety in Autism Spectrum Disorders or related neuropathologies such as Fragile X Syndrome (FXS).

Objectives: To verify that a difference exists between spontaneous blink rates in FXS individuals relative to neurotypical controls, and identify any correlations between SBR and aberrant behavioral or electrophysiological measures associated with FXS, which would suggest a possible role of hyper- or hypo-dopaminergic states in specific FXS-related deficits.

Methods: EEG data was collected on 13 FXS patients and 12 matched controls (ages 14-56) while conducting a passive auditory habituation task consisting of 150 stimulus trains of four tones presented 500ms apart with an inter-train interval of 4000 ms. Virtual EOG channels produced from recorded EEG data, along with the EEG spatial topographies were used to identify blinks. Blinks were manually identified by evaluating EOG waveforms and verifying the topographical distribution of EEG activity at the peak waveform amplitude.

Results: Preliminary results indicate that FXS has a higher overall blink rate (mean = 0.58 blinks/sec, Mann-whitney U test p=0.03) compared to controls (mean = 0.32 blinks/sec). Blink rate during stimulus train presentation did not differ from overall blink rate for either group. In neurotypical controls, induced gamma EEG activity was negatively associated with SBR (r= -0.580 , p= 0.048 ), consistent with studies reporting DRD4-modulated gamma inhibition in fast-spiking interneuron/excitatory pyramidal cell networks in auditory cortex. While FXS exhibited overall higher induced gamma activity, F(1,27)=10.1, p=.004, they did not show a relationship between gamma and SBR, suggesting a breakdown in dopaminergic regulation of network inhibition.

Conclusions: Spontaneous blink rate may offer a simple, non-invasive measure of dopaminergic function that can be taken during passive tasks making this approach valuable to research involving very young, or intellectually disabled individuals. FXS showed increased SBR throughout the task but did not show a further enhancement of blink rate during stimulus presentation, indicating no enhanced startle response to the auditory stimuli. The combined results provide evidence for dopaminergic dysfunction which may be related to EEG phenotypes and potentially anxiety phenotypes in FXS but may only indirectly relate to sensory hypersensitivity associated with FXS. SBR combined with EEG easily translates to mouse models of FXS, suggesting a potentially powerful mechanism for exploring receptor-level dopamine dysfunction in FXS and its associated behaviors.