Title Participants Abstract "Chronic oxytocin administration stimulates the oxytocinergic system in children with autism" "Matthijs Moerkerke, Nicky Daniels, Laura Tibermont, Tiffany Tang, Margaux Evenepoel, Stephanie Van der Donck, Edward Debbaut, Jellina Prinsen, Stephan Claes, Bart Vanaudenaerde, Lynn Willems, Jean Steyaert, Bart Boets, Kaat Alaerts" "Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene (OXTR) epigenetics (DNA-methylation), oxytocin-induced reductions in OXTR DNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism." "Can repeated intranasal oxytocin administration affect reduced neural sensitivity towards expressive faces in autism? A randomized controlled trial" "Matthijs Moerkerke, Nicky Daniels, Stephanie Van der Donck, Laura Tibermont, Tiffany Tang, Edward Debbaut, Jellina Prinsen, Jean Steyaert, Kaat Alaerts, Bart Boets" "BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication and interaction. Crucial for efficient social interaction is the ability to quickly and accurately extract information from a person's face. Frequency-tagging electroencephalography (EEG) is a novel tool to quantify face-processing sensitivity in a robust and implicit manner. In terms of intervention approaches, intranasal administration of oxytocin (OT) is increasingly considered as a potential pharmacological approach for improving socio-communicative difficulties in ASD, through enhancing social salience and/or reducing (social) stress and anxiety. METHODS: In this randomized, double-blind, placebo-controlled, mechanistic pharmaco-neuroimaging clinical trial, we implemented frequency-tagging EEG to conduct an exploratory investigation into the impact of repeated OT administration (4 weeks, 12 IU, twice daily) on neural sensitivity towards happy and fearful facial expressions in children with ASD (8-12 years old; OT: n = 29; placebo: n = 32). Neural effects were assessed at baseline, post-nasal spray (24 hr after the last nasal spray) and at a follow-up session, 4 weeks after the OT administration period. At baseline, neural assessments of children with ASD were compared with those of an age- and gender-matched cohort of neurotypical (NT) children (n = 39). RESULTS: Children with ASD demonstrated reduced neural sensitivity towards expressive faces, as compared to NT children. Upon nasal spray administration, children with ASD displayed a significant increase in neural sensitivity at the post- and follow-up sessions, but only in the placebo group, likely reflecting an implicit learning effect. Strikingly, in the OT group, neural sensitivity remained unaffected from the baseline to the post-session, likely reflecting a dampening of an otherwise typically occurring implicit learning effect. CONCLUSIONS: First, we validated the robustness of the frequency-tagging EEG approach to assess reduced neural sensitivity towards expressive faces in children with ASD. Furthermore, in contrast to social salience effects observed after single-dose administrations, repeated OT administration dampened typically occurring learning effects in neural sensitivity. In line with OT's social anxiolytic account, these observations possibly reflect a predominant (social) stress regulatory effect towards emotionally evocative faces after repeated OT administration." "Neural sensitivity to facial identity and facial expression discrimination in adults with autism" "Stephanie Van der Donck, Hans Op de Beeck, Bart Boets" "The fluent processing of faces can be challenging for autistic individuals. Here, we assessed the neural sensitivity to rapid changes in subtle facial cues in 23 autistic men and 23 age and IQ matched non-autistic (NA) controls using frequency-tagging electroencephalography (EEG). In oddball paradigms examining the automatic and implicit discrimination of facial identity and facial expression, base rate images were presented at 6 Hz, periodically interleaved every fifth image with an oddball image (i.e. 1.2 Hz oddball frequency). These distinctive frequency tags for base rate and oddball stimuli allowed direct and objective quantification of the neural discrimination responses. We found no large differences in the neural sensitivity of participants in both groups, not for facial identity discrimination, nor for facial expression discrimination. Both groups also showed a clear face-inversion effect, with reduced brain responses for inverted versus upright faces. Furthermore, sad faces generally elicited significantly lower neural amplitudes than angry, fearful and happy faces. The only minor group difference is the larger involvement of high-level right-hemisphere visual areas in NA men for facial expression processing. These findings are discussed from a developmental perspective, as they strikingly contrast with robust face processing deficits observed in autistic children using identical EEG paradigms." "Effects of multiple-dose intranasal oxytocin administration on social responsiveness in children with autism: a randomized, placebo-controlled trial" "Nicky Daniels, Matthijs Moerkerke, Jean Steyaert, Edward Debbaut, Jellina Prinsen, Tiffany Tang, Stephanie Van der Donck, Bart Boets, Kaat Alaerts" "BACKGROUND: Intranasal administration of oxytocin is increasingly explored as a new approach to facilitate social development and reduce disability associated with a diagnosis of autism spectrum disorder (ASD). The efficacy of multiple-dose oxytocin administration in children with ASD is, however, not well established. METHODS: A double-blind, randomized, placebo-controlled trial with parallel design explored the effects of a 4-week intranasal oxytocin administration (12 IU, twice daily) on parent-rated social responsiveness (Social Responsiveness Scale: SRS-2) in pre-pubertal school-aged children (aged 8-12 years, 61 boys, 16 girls). Secondary outcomes included a questionnaire-based assessment of repetitive behaviors, anxiety, and attachment. Effects of oxytocin were assessed immediately after the administration period and at a follow-up, 4 weeks after the last administration. The double-blind phase was followed by a 4-week single-blind phase during which all participants received intranasal oxytocin. RESULTS: In the double-blind phase, both the oxytocin and placebo group displayed significant pre-to-post-improvements in social responsiveness and secondary questionnaires, but improvements were not specific to the intranasal oxytocin. Notably, in the single-blind phase, participants who were first allocated to intranasal placebo and later changed to intranasal oxytocin displayed a significant improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. Participants receiving oxytocin in the first phase also showed a significant further improvement upon receiving a second course of oxytocin, but only at the 4-week follow-up. Further, exploratory moderator analyses indicated that children who received psychosocial trainings (3 or more sessions per month) along with oxytocin administration displayed a more pronounced improvement in social responsiveness. LIMITATIONS: Future studies using larger cohorts and more explicitly controlled concurrent psychosocial trainings are warranted to further explore the preliminary moderator effects, also including understudied populations within the autism spectrum, such as children with co-occurring intellectual disabilities. CONCLUSIONS: Four weeks of oxytocin administration did not induce treatment-specific improvements in social responsiveness in school-aged children with ASD. Future studies are warranted to further explore the clinical efficacy of oxytocin administration paired with targeted psychosocial trainings that stimulate socio-communicative behaviors. Trial registration The trial was registered with the European Clinical Trial Registry (EudraCT 2018-000769-35) on June 7th, 2018 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000769-35/BE )." """FEELING INVISIBLE"": INDIVIDUALS WITH BORDERLINE PERSONALITY DISORDER UNDERESTIMATE THE TRANSPARENCY OF THEIR EMOTIONS" "Celine De Meulemeester, Benedicte Lowyck, Bart Boets, Stephanie Van der Donck, Yannic Verhaest, Patrick Luyten" "The present study investigated transparency estimation, that is, the ability to estimate how observable one's emotions are, in patients diagnosed with borderline personality disorder (BPD) (n = 35) and healthy controls (HCs; n = 35). Participants watched emotionally evocative video clips and estimated the transparency of their own emotional experience while watching the clip. Facial expression coding software (FaceReader) quantified their objective transparency. BPD patients felt significantly less transparent than HCs, but there were no differences in objective transparency. BPD patients tended to underestimate the transparency of their emotions compared to HCs, who in turn overestimated their transparency. This suggests that BPD patients expect that others will not know how they feel, irrespective of how observable their emotions actually are. We link these findings to low emotional awareness and a history of emotional invalidation in BPD, and we discuss their impact on BPD patients' social functioning." "Frequency-Tagging EEG of Superimposed Social and Non-Social Visual Stimulation Streams Provides No Support for Social Salience Enhancement after Intranasal Oxytocin Administration" "Zhiling Qiao, Stephanie Van der Donck, Matthijs Moerkerke, Sofie Vettori, Ruud van Winkel, Kaat Alaerts, Bart Boets" "The social salience hypothesis proposes that the neuropeptide oxytocin (OT) can impact human social behavior by modulating the salience of social cues. Here, frequency-tagging EEG was used to quantify the neural responses to social versus non-social stimuli while administering a single dose of OT (24 IU) versus placebo treatment. Specifically, two streams of faces and houses were superimposed on one another, with each stream of stimuli tagged with a particular presentation rate (i.e., 6 and 7.5 Hz or vice versa). These distinctive frequency tags allowed unambiguously disentangling and objectively quantifying the respective neural responses elicited by the different streams of stimuli. This study involved a double-blind, placebo-controlled, cross-over trial with 31 healthy adult men. Based on four trials of 60 s, we detected robust frequency-tagged neural responses in each individual, with entrainment to faces being more pronounced in lateral occipito-temporal regions and entrainment to houses being focused in medial occipital regions. However, contrary to our expectation, a single dose of OT did not modulate these stimulus-driven neural responses, not in terms of enhanced social processing nor in terms of generally enhanced information salience. Bayesian analyses formally confirmed these null findings. Possibly, the baseline ceiling level performance of these neurotypical adult participants as well as the personal irrelevance of the applied stimulation streams might have hindered the observation of any OT effect." "Monitoring the effect of oxytocin on the neural sensitivity to emotional faces via frequency-tagging EEG: A double-blind, cross-over study" "Stephanie Van der Donck, Matthijs Moerkerke, Sofie Vettori, Kaat Alaerts, Bart Boets" "The neuropeptide oxytocin (OXT) is suggested to exert an important role in human social behaviors by modulating the salience of social cues. To date, however, there is mixed evidence whether a single dose of OXT can improve the behavioral and neural sensitivity for emotional face processing. To overcome difficulties encountered with classic event-related potential studies assessing stimulus-saliency, we applied frequency-tagging EEG to implicitly assess the effect of a single dose of OXT (24 IU) on the neural sensitivity for positive and negative facial emotions. Neutral faces with different identities were presented at 6 Hz, periodically interleaved with an expressive face (angry, fearful, and happy, in separate sequences) every fifth image (i.e., 1.2 Hz oddball frequency). These distinctive frequency tags for neutral and expressive stimuli allowed direct and objective quantification of the neural expression-categorization responses. The study involved a double-blind, placebo-controlled, cross-over trial with 31 healthy adult men. Contrary to our expectations, we did not find an effect of OXT on facial emotion processing, neither at the neural, nor at the behavioral level. A single dose of OXT did not evoke social enhancement in general, nor did it affect social approach-avoidance tendencies. Possibly ceiling performances in facial emotion processing might have hampered further improvement." "Do my emotions show or not? Problems with transparency estimation in women with borderline personality disorder features" "Celine De Meulemeester, Benedicte Lowyck, Bart Boets, Stephanie Van der Donck, Patrick Luyten" "Transparency estimation, that is, estimating the extent to which one’s mental states are observable to others, requires the simultaneous representation of the self and of others’ perspective on the self. Individuals with borderline personality disorder (BPD) have difficulty integrating multiple perspectives when mentalizing, which may be reflected in impaired transparency estimation. Sixty-two participants high and low in BPD features watched emotionally evocative video clips, and estimated the transparency of their emotional experience while facial expression coding software (FaceReader) quantified their objective transparency. Individuals high in BPD features showed a larger discrepancy between estimated and objective transparency than individuals low in BPD features, showing that they both over- and underestimated their transparency. Indeed, estimated transparency positively predicted objective transparency in individuals low in BPD features, but not in individuals high in BPD features. Moreover, the ability to estimate intraindividual variability in one’s own objective transparency was moderated by self-reported arousal in the participants high in BPD features. Impairments in transparency estimation were correlated with self-report measures of borderline features, attachment, and mentalizing. In conclusion, we found that borderline features relate to a reduced capacity to estimate the extent to which one’s own emotional states are observable to others. Although replication in clinical samples of BPD patients is needed, the present study provides evidence for problems in mentalizing the (embodied) self from another person’s perspective in BPD." "Investigating automatic emotion processing in boys with autism via eye tracking and facial mimicry recordings" "Stephanie Van der Donck, Sofie Vettori, Milena Dzhelyova, Soha Sadat Mahdi, Peter Claes, Jean Steyaert, Bart Boets" "Difficulties in automatic emotion processing in individuals with autism spectrum disorder (ASD) might remain concealed in behavioral studies due to compensatory strategies. To gain more insight in the mechanisms underlying facial emotion recognition, we recorded eye tracking and facial mimicry data of 20 school-aged boys with ASD and 20 matched typically developing controls while performing an explicit emotion recognition task. Proportional looking times to specific face regions (eyes, nose, and mouth) and face exploration dynamics were analyzed. In addition, facial mimicry was assessed. Boys with ASD and controls were equally capable to recognize expressions and did not differ in proportional looking times, and number and duration of fixations. Yet, specific facial expressions elicited particular gaze patterns, especially within the control group. Both groups showed similar face scanning dynamics, although boys with ASD demonstrated smaller saccadic amplitudes. Regarding the facial mimicry, we found no emotion specific facial responses and no group differences in the responses to the displayed facial expressions. Our results indicate that boys with and without ASD employ similar eye gaze strategies to recognize facial expressions. Smaller saccadic amplitudes in boys with ASD might indicate a less exploratory face processing strategy. Yet, this slightly more persistent visual scanning behavior in boys with ASD does not imply less efficient emotion information processing, given the similar behavioral performance. Results on the facial mimicry data indicate similar facial responses to emotional faces in boys with and without ASD. LAY SUMMARY: We investigated (i) whether boys with and without autism apply different face exploration strategies when recognizing facial expressions and (ii) whether they mimic the displayed facial expression to a similar extent. We found that boys with and without ASD recognize facial expressions equally well, and that both groups show similar facial reactions to the displayed facial emotions. Yet, boys with ASD visually explored the faces slightly less than the boys without ASD." "Facial Expression Processing Across the Autism–Psychosis Spectra: A Review of Neural Findings and Associations With Adverse Childhood Events" "Celine Samaey, Stephanie Van der Donck, Ruud van Winkel, Bart Boets" "Autism spectrum disorder (ASD) and primary psychosis are classified as distinct neurodevelopmental disorders, yet they display overlapping epidemiological, environmental, and genetic components as well as endophenotypic similarities. For instance, both disorders are characterized by impairments in facial expression processing, a crucial skill for effective social communication, and both disorders display an increased prevalence of adverse childhood events (ACE). This narrative review provides a brief summary of findings from neuroimaging studies investigating facial expression processing in ASD and primary psychosis with a focus on the commonalities and differences between these disorders. Individuals with ASD and primary psychosis activate the same brain regions as healthy controls during facial expression processing, albeit to a different extent. Overall, both groups display altered activation in the fusiform gyrus and amygdala as well as altered connectivity among the broader face processing network, probably indicating reduced facial expression processing abilities. Furthermore, delayed or reduced N170 responses have been reported in ASD and primary psychosis, but the significance of these findings is questioned, and alternative frequency-tagging electroencephalography (EEG) measures are currently explored to capture facial expression processing impairments more selectively. Face perception is an innate process, but it is also guided by visual learning and social experiences. Extreme environmental factors, such as adverse childhood events, can disrupt normative development and alter facial expression processing. ACE are hypothesized to induce altered neural facial expression processing, in particular a hyperactive amygdala response toward negative expressions. Future studies should account for the comorbidity among ASD, primary psychosis, and ACE when assessing facial expression processing in these clinical groups, as it may explain some of the inconsistencies and confound reported in the field."