Neural circuit disruptions of eye gaze processing in autism spectrum disorder and schizophrenia: An activation likelihood estimation meta-analysis

Abstract

Background: Impairment in social cognition, particularly eye gaze processing, is a shared feature common to autism spectrum disorder (ASD) and schizophrenia. However, it is unclear if a convergent neural mechanism also underlies gaze dysfunction in these conditions. The present study examined whether this shared eye gaze phenotype is reflected in a profile of convergent neurobiological dysfunction in ASD and schizophrenia.

Methods: Activation likelihood estimation (ALE) meta-analyses were conducted on peak voxel coordinates across the whole brain to identify spatial convergence. Functional coactivation with regions emerging as significant was assessed using meta-analytic connectivity modeling. Functional decoding was also conducted.

Results: Fifty-six experiments (n = 30 with schizophrenia and n = 26 with ASD) from 36 articles met inclusion criteria, which comprised 354 participants with ASD, 275 with schizophrenia and 613 healthy controls (1242 participants in total). In ASD, aberrant activation was found in the left amygdala relative to unaffected controls during gaze processing. In schizophrenia, aberrant activation was found in the right inferior frontal gyrus and supplementary motor area. Across ASD and schizophrenia, aberrant activation was found in the right inferior frontal gyrus and right fusiform gyrus during gaze processing. Functional decoding mapped the left amygdala to domains related to emotion processing and cognition, the right inferior frontal gyrus to cognition and perception, and the right fusiform gyrus to visual perception, spatial cognition, and emotion perception. These regions also showed meta-analytic connectivity to frontoparietal and frontotemporal circuitry.

Conclusion: Alterations in frontoparietal and frontotemporal circuitry emerged as neural markers of gaze impairments in ASD and schizophrenia. These findings have implications for advancing transdiagnostic biomarkers to inform targeted treatments for ASD and schizophrenia.

Keywords: Amygdala; Autism spectrum disorder; Cognitive control; Eye gaze; Lateral prefrontal cortex; Schizophrenia.

Figure 1.

Regions of aberrant activation within ASD during gaze processing. Aberrant activation in the left amygdala emerged in ASD. Sub-analyses pooled coordinates across hyper- and hypoactivation in ASD vs healthy controls. The right panel indicates the contribution of paradigm type or gaze subdomains, age group, and contrast (indicating hyper- vs hypoactivation in ASD) to the convergence on this region.

Figure 2.

Regions of aberrant activation across ASD and schizophrenia during gaze processing. Aberrant activation in the right inferior frontal gyrus and right fusiform gyrus emerged across ASD and schizophrenia. Primary ALE analyses pooled coordinates across hyper- and hypoactivation in ASD and schizophrenia vs healthy controls. The right panel indicates the contribution of gaze subdomains and disorder subgroups to the convergence on these regions.

Figure 3.

Regions of disruption based on hypoactivation across ASD and schizophrenia during gaze processing. Hypoactivation in the right inferior frontal gyrus and right supplementary motor area emerged in ASD and schizophrenia. Sub-analyses pooled coordinates across gaze processing tasks and across ASD and schizophrenia vs healthy controls. The right panel indicates the contribution of gaze subdomains and disorder subgroups to the convergence on these regions.

Figure 4.

Aberrant activation in the right inferior frontal gyrus and supplementary motor area in schizophrenia during gaze processing. Sub-analyses pooled coordinates across hyper- and hypoactivation in schizophrenia vs healthy controls. The right panel indicates the contribution of paradigm type or gaze subdomains and contrast (indicating hyper- vs hypoactivation in schizophrenia) to the convergence on these regions.

Figure 5.

Connectivity maps for the volumes of interest emerging as significant clusters in ALE analyses. Depicted are coactivation maps for the left amygdala (A), right inferior frontal gyrus (IFG) (B), the right fusiform gyrus (FG) (C), and the supplementary motor area (SMA) (D). For comparison of findings, results are also shown with a modified version of MACM using the specific co-activation likelihood estimation algorithm (SCALE). Coactivation patterns are labelled in blue and seed volumes of interest are labelled in yellow.

Figure 6.

Functional characterization of the four core regions from the ALE meta-analysis. Behavioral domain meta-data from BrainMap were used for quantitative forward (left panels in A-D) and reverse (right panels in A-D) inference on significant functional associations of each region or volume of interest (corrected FDR < 0.05). Values at the bottom of each figure represent the likelihood of activation. For example, considering forward inference, 0.01 means that one in 100 studies features an activation in that particular cluster; for the significant domains/paradigms, their likelihoods are higher than the base rate. For reverse inference, the value represents the probability that this task was present given activation in that particular cluster.