Can pupil size and pupil responses during visual scanning contribute to the diagnosis of autism spectrum disorder in children?

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Abstract

The purpose of this study was to determine whether baseline pupil size and pupil responses during visual scanning with eye-tracking technology could discriminate children with Autism Spectrum Disorder (ASD) from mental age-matched and chronological age-matched controls. To this end, we used stimuli consisting in still color photographs presented centrally to the participant’s midline on a stimulus monitor. Each child was presented with a series of neutral faces, virtual faces (avatars) and different objects, separated by black slides. We recorded the mean pupil size and pupil size changes over time in each of the three categories of stimuli and during exposure to the black slides. Fifty-seven children participated in study (19 ASD, mean age 118 months; 19 mental age-matched controls, mean age 87 months; and 19 chronological age-matched controls, mean age 118 months). We compared the baseline pupil size and pupil responses during visual scanning among the three diagnostic groups. During the presentation of slides, the mean pupil size in the ASD group was clearly smaller than in the MA-matched and CA-matched groups. Discriminate analysis of pupil size during the presentation of black slides and slides with visual stimuli successfully predicted group membership in 72% of the participants. Group membership was correctly classified in 89% of the participants in the ASD group, in 63% in the MA-matched group and in 63% in the CA-matched group. These potential biomarkers may contribute to our understanding of the differences in neurological development in the brain in autism and could prove useful as indicators of ASD.

Introduction

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder affecting between 1 in 165 (Fombonne, 2003) or even 1 in 90 children (King and Bearman, 2009). It is four times more prevalent in boys than in girls. The disorder was first described by Kanner (1943) who isolated three core features: impaired reciprocal social interactions, abnormal development and use of language; repetitive and ritualized behavior and a narrow range of interests (APA, 2000). ASD is usually diagnosed between the ages of 2 and 3 years, but early signs may be detectable by 12 months of age (Osterling and Dawson, 1994). Early recognition of the disorder is an important challenge since early treatment is more effective in helping children develop adaptation skills thus allowing them to attain a better level of integration into society. In addition, it can reduce the intensity of the condition and the level of handicap (Robel, 2009).

Previous studies on the pupil responses of children with autism have reported conflicting results. The first study was performed by Rubin (1961) who reported smaller pupil sizes in children with autism during pupil dilation. In a habituation paradigm, van Engeland et al. (1991) used geometric figures of differing complexity and found no significant differences in baseline pupil size or constriction amplitude in children with ASD. In another initial study, Anderson et al. (2006) investigated pupil responses to face and non-face stimuli in ASD children and found that the ASD group showed pupil constriction in response to children’s faces, whereas the control groups showed pupil dilation. In 2009, they analyzed tonic (baseline) pupil responses obtained from the previously mentioned investigation (Anderson and Colombo, 2009) and found that the ASD group exhibited a greater baseline pupil size than age-matched controls. Fan et al. (2009) did not observe any differences in resting pupil size in children with and without ASD, but participants with ASD showed a significantly longer PLR (pupillary light reflex) latency, smaller constriction amplitude and slower constriction velocity than children who had normal development. All these results suggest abnormal functioning in the autonomic nervous system (ANS). Reduced duration and quality of sleep (Daoust et al., 2004, Williams et al., 2004), heightened autonomic responses at rest such as increased skin conductance (Hirstein et al., 2001, Zahn et al., 1987), a decrease in skin conductance during emotional judgment (Hubert et al., 2009), increased heart-rate (Hirstein et al., 2001, Ming et al., 2005) and increased arterial blood pressure (Ming et al., 2005) and an increase in respiratory rate (Zahn et al., 1987) have been reported in ASD patients compared to controls and by consistent with the hypothesis of an altered balance in the inhibitory and excitatory activity within the sympathetic and parasympathetic divisions of the ANS. The purpose of this study was to determine whether baseline pupil size and pupil responses during visual scanning could discriminate between children with ASD and controls. We chose to measure pupil diameter because pupil size assessment has long been used to evaluate neurological functioning, alertness and cognitive functioning (Loewenfeld, 1999). Pupil responses have also been associated with attention and information processing (Hess, 1975). In addition, these measurements are more reliable and more sensitive than other autonomic measurements (Beatty and Lucero-Wagoner, 2000 for review). Since previous reports showed inconsistent results in resting pupil responses and task-evoked pupil responses, we chose to analyze baseline pupil size and pupil responses to the faces, objects and avatars used in a previous study (Hernandez et al., 2009).

Section snippets

Participants

The study sample consisted in 19 patients who had been diagnosed with ASD (American Psychiatric Association, 2000) at the University Hospital Center of Tours (France). Inclusion criteria included normal vision or vision correctable to 10/10 or better, no past history of any eye disorder and the ability to comply with the test procedure. The patients’ mean age was 118 months, chronological age (CA) between 41 and 181 months, mental age (MA) between 35 and 136 months and the gender ratio was 16

Responses to the black slides and other types of stimuli

One-way analysis of variance (ANOVA) demonstrated a significant difference between the groups in their responses to the black slides presented during the inter-stimulus intervals (F(2,54) = 18.194, p = 0.000001). The ASD group had a significantly smaller static baseline pupil size (M = 4.11 mm, Standard error of the mean (SEM) = 0.12) than either the MA-matched (M = 5.35; SEM = 0.10, Bonferroni test, p = 0.00002) or CA-matched groups (M = 5.46, SEM = 0.16, Bonferroni test, p = 0.000004),

Discussion

The results of this study are consistent with Rubin’s findings in his first report (1961) in which he found smaller pupils in children with autism during pupil dilation. However our results are not consistent with the findings published on static baseline pupil size (Anderson and Colombo, 2009); in that study the authors presented a blank, gray inter-stimulus slide between slides showing facial and non-facial social stimuli (faces of children and animals vs. Images of toys and landscapes).

Role of funding

Funding sources were: INSERM Unit 930; University Hospital of Tours; University François-Rabelais of Tours; Fondation Pour la Recherche Médicale; Fondation Planiol.

Conflict of interest

None declared.

Acknowledgements

We thank the Fondation Pour la Recherche Médicale and the Fondation Planiol for their financial support, and we greatly appreciate the support of INSERM Unit 930, the University Hospital of Tours and University François-Rabelais of Tours. We thank all of the participants for their cooperation, Ms. Doreen Raine and Dr Donald Schwartz for help with reviewing the English language.

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