Our data demonstrate that constraining individuals with ASD to look into the eyes of dynamic faces expressing different emotions results in aberrant activation of the subcortical pathway, such that higher activation was found generally in the ASD group. An abnormality of the subcortical system in autism during face processing was first hypothesized by Senju and Johnson25, and our data not only confirm this hypothesis, but specify it to a considerable degree: our direct comparison of the same dynamic facial expression seen freely or with a fixation cross is the most direct evidence of the mechanisms by which direct eye-contact may be experienced as stressful in autism.

ASD participants had higher pulvinar activation than controls in both conditions, and it seems that activity in this structure is less consistently modulated by eye contact. The pulvinar can be considered as a central forebrain hub and its input from the superior colliculus may be critical in shaping the functional specialization of the cortex during early development (for review, see ref. 46). One of the roles of the pulvinar is to filter distracting stimuli47, and recently morphological alterations of this structure have been reported in ASD, with an expanded surface area48. The thalamic hyperactivation evidenced here has been hypothesized as one of the substrates of higher-order social cognition deficits in ASD, potentially through its dysregulatory impact on the dorsolateral prefrontal cortex49. The role of the pulvinar in both the higher-order cognitive and the basic socio-affective profile in ASD will need to be examined in future studies.

As could be expected from previous studies (e.g. ref. 26), the effect of constraining gaze in the eyes had the strongest effect for ASD in the amygdala, and although group differences were most marked for fearful faces, the difference between free and constrained gaze was also remarkable for happy faces. This shows that the subcortical system in ASD over-reacts not only to threat-related stimuli, but also to stimuli that should be considered as positively engaging and socially rewarding.

Our findings deepen our understanding of the mechanisms at play in the social deficits of individuals with autism. Traditional accounts have suggested that ASD is characterized by a fundamental lack of interpersonal interest2; however, the results of our study align with other recent studies showing oversensitivity to socio-affective stimuli (e.g. refs 50, 51). In everyday life, such oversensitivity may lead to attempts to decrease one’s arousal levels, and first-hand reports suggest that simply avoiding to attend to the eyes of others is one common strategy among individuals with ASD1. Such a strategy is unlikely, however, to come without costs, since the eyes carry important interpersonal and deictic information during social interaction and communication, and eye-avoidance may result in cascading effects leading to improper development of the social brain.

Limitations

There are several limitations in this work. First, we did not collect eye-tracking data in the scanner, and hence we never directly correlated subcortical brain activation with the amount of time spent in the eye-region26. However, while interesting, the relative merits of that approach should not be overstated. Indeed, abnormal gaze patterns in ASD during spontaneous face viewing has been demonstrated repeatedly, and although not all studies find evidence of reduced eye gaze in ASD samples, more robust differences in how they distribute their attention within the central areas of the face has been described52, 53. Moreover, while there are current developments in fixation-based54 and event-related55 fMRI, challenges still exists when trying to associate a hemodynamic response (that lasts ca 10 seconds) with fixation-based metrics (which averages 300 msec during scene viewing)54.

Second, we only tested constrained gaze with a face, and not with a blank screen or with non-face stimuli, so part of our results may be due to a general effect of constraining gaze. One can perhaps expect that fixating a cross might introduce some level of cognitive control in the task. Future research should use free-viewing vs. constrained gaze for non-face stimuli as well, so as to better determine whether part of the effect observed can be attributed to this factor. Still, there are to our knowledge no theoretical or empirical reasons to predict an enhanced activation of the face-specific subcortical system following a fixed gaze in general.

Third, although we and others have plenty of clinical evidence for the notion that many individuals with ASD find eye contact stressful, no research study, including the one presented, have actually linked subjective reports of discomfort with neural activity patterns during eye gaze. This would be an important area of future research (though one also needs to hold in mind the potential limitations of self-reports in a condition that is very often associated with alexithymia)56.

Finally, as is most often done in this kind of technically challenging studies, we only examined participants with normal intelligence, so we do not know whether these results generalize to the full spectrum of ability in the ASD population. We hope that further studies using less invasive techniques such as eye-tracking with galvanic skin response will help us investigate a wider range of ASD individuals.

Despite these caveats, the results have potential clinical implications: during behavioral therapy, forcing individuals with autism to look in the eyes might be counterproductive and elicit more anxiety - however, by not looking at the eyes, the person with ASD will continue to miss critical social information, and somehow one has to help them to gather all these important cues. One possible strategy could consist in progressively habituating individuals with ASD to look into the eyes, analogous to the way surgeons habituate to look at open bleeding bodies, and then in incentivizing them to look at the eyes, finding a way to make eye contact somehow less stressful.