Abstracts

Attentional deficits are common in epilepsy and neurodevelopmental disorders, occurring at rates several-fold above the general population. Core components of attention may be particularly vulnerable, including the detection (salience) and monitoring (vigilance) of behaviorally relevant stimuli. Vigilance, regulated by neuromodulatory arousal centers, fluctuates dynamically and can be continuously indexed via pupil diameter under constant luminance. Salience, hypothesized to be cortically driven, enables rapid orientation to relevant stimuli. Despite the prevalence of cognitive impairments in epilepsy, the mechanisms linking epileptiform activity to disruptions in vigilance and salience remain unclear. It is unknown how fluctuations in neuromodulatory tone influence transitions between normative and epileptiform states—or how these transitions impair stimulus-driven attentional responses. This work assesses how epileptiform activity modulates saliency processing in Scn8a^8J heterozygous mice, a model with a high burden of spike wave discharges (SWDs).

Scn8a^8J heterozygous and wild type (WT) mice were head-fixed and monitored with EEG, encoder for movement, and pupillometry during a passive auditory salience paradigm. Each session included a 20-minute resting state and then 280 trials of auditory stimuli (amplitude modulated white noise bursts: 0-60 dB SPL above baseline; 40 trials per stimulus level).  Salience was measured via stimulus-evoked pupil diameter. Analysis was restricted to trials with peri-stimulus still periods and pre-stimulus pupil diameters 20-50% of max. Linear mixed-effects (LME) models assessed effects of stimulus category, SWD status (none [WT], no-SWD [Scn8a^8J], SWD [Scn8a^8J]) and their interaction on pupil dilation (area under the curve, AUC) at trial and session levels, with mouse ID as a random intercept.

Two WT and four Scn8a^8J heterozygous mice each underwent 2-3 sessions (see Figure 1 for example session). Trial level LME (n = 2,841 trials) revealed a significant effect of stimulus intensity on pupil dilation (β = 3.70, 95% CI [2.79, 4.61], p < 0.001), indicating greater pupil responses with louder auditory stimuli. There was no significant main effect of SWD status, but significant interaction terms showed that both heterozygous groups exhibited blunted responses compared to WT mice. The reduction in pupil sensitivity was significant for both the no-SWD (β = –1.55, 95% CI [–2.75, –0.35], p = 0.012) and the SWD groups (β = –2.42, 95% CI [–3.98, –0.85], p = 0.003).

At the session level (Figure 2), where mean pupil responses were averaged per stimulus level, similar effects were observed. Pupil dilation increased with stimulus intensity (β = 0.30, 95% CI [0.07, 0.53], p = 0.010). The SWD group showed a trend toward reduced responsiveness (interaction β = –0.25, 95% CI [–0.55, 0.04], p = 0.090), although this did not reach statistical significance.

Scn8a^8J heterozygous mice demonstrate impaired stimulus evoked-pupil responses to novel auditory stimuli. Ongoing neuromodulatory imaging studies aim to clarify how epileptiform activity disrupts salience processing.