Alterations in the brain's oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.
Similar to the gut microbiome, oral microbiome compositions have been suggested to play an important role in the etiology of autism. However, empirical research on how variations in the oral microbiome relate to clinical-behavioral difficulties associated with autism remains sparse. Furthermore, it is largely unknown how potentially confounding lifestyle variables, such as oral health and nutrition, may impact these associations. To fill this gap, the current study examined diagnosis-related differences in oral microbiome composition between 80 school-aged autistic children (8-12 years; 64 boys, 16 girls) versus 40 age-matched typically developing peers (32 boys, 8 girls). In addition, associations with individual differences in social functioning (SRS-2), repetitive behavior (RBS-R) and anxiety (SCARED) were explored, as well as the impact of several lifestyle variables regarding nutrition and oral health. Results provide important indications that the bacterial genera
Children born very preterm (VPT, < 32 weeks of gestation) have an increased risk of developing socio-emotional difficulties. Possible neural substrates for these socio-emotional difficulties are alterations in the structural connectivity of the social brain due to premature birth. The objective of the current study was to study microstructural white matter integrity in VPT versus full-term born (FT) school-aged children along twelve white matter tracts involved in socio-emotional processing. Diffusion MRI scans were obtained from a sample of 35 VPT and 38 FT 8-to-12-year-old children. Tractography was performed using TractSeg, a state-of-the-art neural network-based approach, which offers investigation of detailed tract profiles of fractional anisotropy (FA). Group differences in FA along the tracts were investigated using both a traditional and complementary functional data analysis approach. Exploratory correlations were performed between the Social Responsiveness Scale (SRS-2), a parent-report questionnaire assessing difficulties in social functioning, and FA along the tract. Both analyses showed significant reductions in FA for the VPT group along the middle portion of the right SLF I and an anterior portion of the left SLF II. These group differences possibly indicate altered white matter maturation due to premature birth and may contribute to altered functional connectivity in the Theory of Mind network which has been documented in earlier work with VPT samples. Apart from reduced social motivation in the VPT group, there were no significant group differences in reported social functioning, as assessed by SRS-2. We found that in the VPT group higher FA values in segments of the left SLF I and right SLF II were associated with better social functioning. Surprisingly, the opposite was found for segments in the right IFO, where higher FA values were associated with worse reported social functioning. Since no significant correlations were found for the FT group, this relationship may be specific for VPT children. The current study overcomes methodological limitations of previous studies by more accurately segmenting white matter tracts using constrained spherical convolution based tractography, by applying complementary tractometry analysis approaches to estimate changes in FA more accurately, and by investigating the FA profile along the three components of the SLF.
Objectives Recent magnetic resonance imaging (MRI) studies implicate structural alterations of amygdala, a brain region responsible for processing and experiencing negative emotions, in adolescents with attention-deficit/hyperactivity disorder (ADHD). Here we examined ADHD-related structural correlates of amygdala functional activity elicited during a functional MRI task designed to test behavioural and brain responses to the imposition of delay – an event known to both elicit amygdala hyperactivation and aversity in ADHD.Methods Structural MRI scans from 28 right-handed male adolescents with combined type ADHD and 32 age-matched controls were analysed. Regional grey matter volumes of ADHD and control participants (P[FWE] < 0.05) were correlated with delay aversion self-ratings and neural activity in response to delay-related cues on the Escape Delay Incentive fMRI task.Results ADHD was associated with significantly reduced volumes in bilateral amygdala, parahippocampal and temporal gyrus (P[FWE] < 0.05), greater basolateral amygdala activation to delay-related cues (P[FWE] < 0.05) and higher delay aversion self-ratings. Amygdala volume reductions were significantly correlated with, and statistically mediated the pathway from ADHD to, delay-cue-related amygdala hyperactivity (P < 0.01) and self-reported delay aversion (P < 0.01).Conclusions We provide the first evidence of the functional significance of reduced amygdala volumes in adolescents with ADHD by highlighting its relation to delay-induced brain activity that is linked to delay aversion.
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.
Abstract 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.
Introduction. Intranasal administration of oxytocin presents a promising new approach to reduce disability associated with an autism spectrum disorder diagnosis. Previous investigations have emphasized the amygdala as the neural foundation for oxytocin’s acute effects. To fully understand oxytocin’s therapeutic potential however, it is crucial to gain insight into the neuroplastic changes in amygdala circuitry induced from chronic oxytocin administrations, particularly in pediatric populations. Objective. We aimed to examine the impact of a four-week course of intranasal oxytocin on amygdala functional connectivity in children with autism, compared to placebo. Additionally, we investigated whether oxytocin improves cardiac autonomic arousal, as indexed by high-frequency heart rate variability. Methods. Fifty-seven (45 boys, 12 girls) children with autism aged 8-12 years participated in a double-blind, randomized pharmaco-neuroimaging trial involving twice-daily administrations of intranasal oxytocin or placebo. Resting-state fMRI scans and simultaneous, in-scanner heart rate recordings were obtained before, immediately after and four weeks after the nasal spray administration period. Results. Significant reductions in intrinsic amygdala-orbitofrontal connectivity were observed, particularly at the four-week follow-up session. These reductions correlated with improved social symptoms and lower cardiac autonomic arousal. Further, oxytocin’s neural and cardiac autonomic effects were modulated by epigenetic modifications of the oxytocin receptor gene. The effects were more pronounced in children with reduced epigenetic methylation, signifying heightened expression of the oxytocin receptor. Conclusion. These findings underscore that a four-week oxytocin administration course decreases amygdala connectivity and improves cardiac autonomic balance. Epigenetic modulators may explain inter-individual variation in responses to oxytocin.
Abstract 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 ).
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