Using Pupillometry to Assess the Atypical Pupillary Light Reflex and LC-NE System in ASD

Abstract

With recent advances in technology, there has been growing interest in use of eye-tracking and pupillometry to assess the visual pathway in autism spectrum disorder (ASD). Within emerging literature, an atypical pupillary light reflex (PLR) has been documented, holding potential for use as a clinical screening biomarker for ASD. This review outlines dominant theories of neuropathology associated with ASD and integrates underlying neuroscience associated with the atypical PLR through a reciprocal model of brainstem involvement and cortical underconnectivity. This review draws from animal models of ASD demonstrating disruption of cranial motor nuclei and brain imaging studies examining arousal and the influence of the locus coeruleus norepinephrine (LC-NE) system on the pupillary response. Pupillometry methods are explained in relation to existing data examining the PLR in ASD and pupillary parameters of constriction latency and tonic pupil diameter as key parameters for investigation. This focused review provides preliminary data toward future work developing pupillometry metrics and offers direction for studies aimed at rigorous study replication using pupillometry with the ASD population. Experimental conditions and testing protocol for capturing pupil parameters with this clinical population are discussed to promote clinical research and translational application.

Keywords: autism; biomarker; eye tracking; locus coeruleus; pupillary light reflex; screening.

Figure 1

LC-NE system eliciting PLR and efferent visual neural pathway–modulation of NMDA receptors and cranial nerves produce pupillary change; elevated Ca²⁺ at NMDA receptors increase NE levels = hyperarousal/sympathetic state in ASD, inducing sustained mydriasis in response to light stimuli. LC = locus coeruleus; NE = norepinephrine; BLA = basolateral amygdala; NMDA = N-methyl-D-aspartate; E-W = Edinger Westphal; ACh = acetylcholine.

Figure 2

Noradrenergic projections from the locus coeruleus, site of synthesis of NE, modulate CN II & CNIII, controlling the PLR. LC neurons located in the pons project to subcortical structures associated with hyperarousal modulating neural activity and extend throughout cortex also directly effecting pupillary response to a light stimulus. Image reproduced from Strawn & Geracioti (2008). Photograph: Patricia Brown, Ph.D., University of Cincinnati. Public domain.

Figure 3

Eye-tracking studies examining pupillary parameters constriction latency and tonic pupil diameter by age and sample size, reporting significance for differences in comparison to typical development.