Tese de Doutoramento Medicina 2023 Faculdade de Ciências Médicas, Universidade NOVA de Lisboa

Social cognition concerns the processes that make it possible to identify, understand and judge one's own and others' social behaviours, allowing for the integration and functioning in a social group. Social cognition encompasses a set of cognitive skills that include facial processing, emotion perception, attributive style or Theory of Mind (ToM), defined as the ability to infer the mental states (beliefs, desires, intentions) of the self and others. Both schizophrenia and autism spectrum disorder (ASD) are chronic psychiatric conditions characterized by difficulties in social cognition. In both conditions, these difficulties have been associated with impaired social functioning and a worse functional prognosis. Given the similarities in genetic, pathophysiological, and phenotypic aspects between the two conditions, the characterization of the mechanisms underlying difficulties in social cognition may help clarify whether schizophrenia and ASD constitute two effectively distinct clinical entities or if they are part of a continuum, a question that remains a matter for debate in specialized literature. However, despite multiple studies showing that social cognitive performance is consistently more impaired in individuals with schizophrenia and ASD compared to neurotypical populations, identifying differences in social cognitive performance between the two conditions has proved notoriously difficult. A meta-analysis of direct comparisons between the two clinical conditions, carried out within the framework of this research project, found that, although participants with schizophrenia performed better than autistic* individuals in tasks of emotion perception from faces, no differences in performance were observed in the other dimensions of social cognition that were assessed (including ToM tasks, emotional intelligence or social skills). Interestingly, age of the participants was found to be a significant moderator of effect size on emotion perception from faces and on the attribution of mental states (assessed by the Reading the Mind in the Eyes [RMET] scale), so that, with increasing age, the differences between autistic individuals and those with schizophrenia became blurred, suggesting the existence of different trajectories in terms of social cognitive functioning. The difficulty in distinguishing social cognitive performance between individuals with schizophrenia and autistic subjects based on the currently available assessment instruments, as well as the need to clarify the mechanisms underlying social cognitive processes in autism, motivated this research project. For the first objective, I present data on a social cognitive task able to assess both social cognitive capacity and bias in schizophrenia - the Waiting Room Task (WRT). Then, I report the results of an experimental study involving 21 adult male autistic participants and 30 adult male controls with neurotypical development, using the same social cognition assessment scale. In an exploratory comparative analysis, combining data obtained from individuals with schizophrenia and autistic participants, I also sought to understand whether the WRT is an instrument capable of distinguishing groups with ASD and schizophrenia, with regards to their social cognitive performance. Regarding the second objective, data were collected using two psychophysiological techniques – event-related potentials (ERP) and eye-tracking – while participants performed several social cognition tasks. In addition to their intrinsic value for exploring the mechanisms underlying the identified social cognitive deficits, these tools may allow for the identification of reliable biomarkers, capable of identifying particular phenotypes that facilitate the recruitment of more homogeneous samples for research, essential to deepen the study of biological mechanisms. In the WRT task, the participant was asked to identify, in a series of 26 short sequential videos, whether the person who appeared in the video (imagining that he/she is sitting in front of the participant in a waiting room) looked at the participant, elaborated a thought about him, and what emotion was expressed. After being translated and adapted to Portuguese, I showed that the WRT is an adequate tool for collecting data on social cognition in the neurotypical population and in ASD. The exploratory analysis of the comparative performance between participants with schizophrenia, ASD, and neurotypical individuals found that the schizophrenia group had a worse performance (lower rate of correct answers and higher proportion of false alarms) than neurotypical adults and autistic adults. These results support the usefulness of the WRT task as an instrument for assessing social cognitive capacity and bias with specificity for individuals with schizophrenia, probably due to its ability to detect the self-relational bias that characterizes this condition. In the eye-tracking study, participants were asked to complete the tasks RMET (a task in which the participant is asked to identify the mental state - 1 correct out of 4 possible - in 36 photographs restricted to the eye region) and WRT under eye tracking. In the RMET task, the ASD group performed significantly worse than neurotypical controls. Eye-tracking showed that participants with ASD had a higher number of fixations than the neurotypical group, although the duration of individual fixations was comparable between groups. This finding suggests greater hesitation/doubt when assessing task items in the clinical group, in line with the circumspect reasoning bias characteristic of autism. Additionally, the higher proportion of omissions in regions of interest in the ASD group, along with the higher proportion of fixations outside the regions of interest, may reflect difficulties in organizing the visual search pattern as a function of the spatial structure of the stimulus. In WRT, no differences were observed between groups in the number or duration of fixations. However, I found an interesting positive correlation in the ASD group between fixations on the mouth region and age, in line with previous evidence showing an increase in fixation on the mouth region as autistic individuals grow older and which is thought to represent a possible compensation strategy when collecting social information due to a recognized difficulty to establish eye contact. In the assessment of the electrophysiological correlates of a non-verbal task to evaluate the attribution of intentions (Comic Strips Task [CST]), I found that, compared to neurotypical participants, autistic participants were significantly less accurate in correctly identifying congruence in situations of attribution of intentions (AI), but not in situations of physical causality (with no social cognitive component involved). In the AI condition, a bilateral posterior positive ERP occurring 200-400 ms post-stimulus (the “intention ERP effect”) emerged in both groups. This ERP comprised a P200 component and a P300 component, with the P200 component being larger for the AI condition in neurotypical volunteers, but not in autistic individuals, who also showed higher latency for this component. Between-group differences in ERP amplitude became particularly evident when comparing autistic participants with a subgroup of neurotypical participants with a similar level of behavioural performance, suggesting that the atypical ERP observed in ASD is a group effect rather than a marker of low performance on the task. These results suggest that the ASD group's lower accuracy in the AI task may result from ineffective early attentional processing and contextual integration of socially relevant cues. Taken together, the results obtained within the scope of this research project lead to the conclusion that many of the instruments commonly used to assess social cognition differentiate poorly between individuals with schizophrenia and ASD, and that it is important to develop new tasks to assess specific dimensions of social cognition that mays be compromised in one of these disorders but not in the other. In this context, the WRT stands out as an instrument that may be able to detect social cognitive deficits in schizophrenia that are not present in ASD, namely those related to self-relational biases. On the other hand, it was possible to reinforce the usefulness and feasibility of combining neurophysiological techniques, specifically ERP and eye-tracking, with behavioural social cognitive tasks for the characterization of social cognition in ASD. In the ERP study, I showed that the greatest difficulties in inferring intentions in autistic individuals may result from atypical early attentional processing and contextual integration of socially relevant cues. On the other hand, the eye-tracking data obtained reinforced the presence of a circumspect bias (need to collect more data before reaching a conclusion) in autism, as well as the compensatory effects of age in the collection of socially relevant information. In addition to the necessary replication of these findings in larger studies, the application of the experimental protocol (in particular, of the psychophysiological studies) to other populations, namely to individuals with schizophrenia, but also to individuals with other conditions where there is evidence of difficulties in social cognition (e.g. (e.g., bipolar disorder or borderline personality disorder), as well as in female participants from clinical and non-clinical populations, will contribute to a better characterization of social cognitive processes, paving the way for the development of more specific and tailored interventions. Future studies may also help clarify if the atypical ERP that was observed in the autistic group is valid as a biomarker for the condition, given the current need to identify suitable biomarkers in ASD