Uncharacteristic Task-Evoked Pupillary Responses Implicate Atypical Locus Ceruleus Activity in Autism

Abstract

Autism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, reflected in exaggerated and variable responses to sensory stimuli. Attentional engagement is known to be regulated by the locus ceruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether, under different attentional task demands, individuals with ASD exhibit a different profile of LC activity compared with typically developing controls. Males and females with ASD and age-and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses, an established correlate for LC activity, were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared with controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed specifically in response to task-relevant events, providing confirmation that the group differences most likely were specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.

Autism spectrum disorder and pupillometry: A systematic review and meta-analysis

“…Cortical gain increases behavioural flexibility, exploration of the task environment and as such to relevant and irrelevant stimuli. When phasic responses decrease, the focus shifts only to task-relevant stimuli, according to Granovetter et al (Granovetter et al, 2020). In their study, the ASD group showed inflexibility of regulation of the LC activity, they conclude based on a lower pupil reactivity in the presence of distractions, which is not expected when the LC would be regulated correctly.…”

“…Laeng et al (2018) hypothesized this constriction would be reduced or absent in the ASD group, but found no differences between the ASD and the TD group. The inability to distinguish relevant from irrelevant stimuli as found by Granovetter et al (2020) impedes the creation of priors and expectations and the ability to learn from novel environmental input and consequently could cause increased attention to particular environmental stimuli that other don't consider relevant and this explain the fixated interests in ASD, as well as increased sensitivity to sensory stimuli. They confirmed this in their results, as a smaller pupil response amplitude, which shows low phasic LC activity and increased cortical gain, was associated higher ADOS-RRB scores (Granovetter et al, 2020).…”

“…Daluwatte suggests that it is likely that medication does affect the ANS function in a subtle way, even though medication did not show a significant effect on either sensory scores or PLR parameters (Daluwatte et al, 2015). Granovetter et al included medication use in their model, they even investigated adrenergic-related medication separately, and found no effect on their results (Granovetter et al, 2020). In other studies, medication effect is either not present, or only in a group with low functioning ASD, where it complicates the relation between IQ and PLR latency outcomes.…”

Atypical alert state control in adult patients with ADHD: A pupillometry study

“…For example, elevation in tonic pupil size has also been found in children with ASD [36,37] (but see [38]). On the other hand, findings on phasic pupil response in individuals with ASD are inconclusive [37][38][39]. As ADHD is the most common comorbidity in children with ASD [40,41], it is possible that ADHD traits might play an important role in atypical pupillary responses in ASD.…”

“…A recent review suggests that atypical pupillary responses in autism spectrum disorder (ASD) might be associated with atypical attentional functions [35]. For example, elevation in tonic pupil size has also been found in children with ASD [36,37] (but see [38]). On the other hand, findings on phasic pupil response in individuals with ASD are inconclusive [37][38][39].…”