Chronic oxytocin improves neural decoupling at rest in children with autism: an exploratory RCT.

BACKGROUND: Shifts in peak frequencies of oscillatory neural rhythms are put forward as a principal mechanism by which cross-frequency coupling/decoupling is implemented in the brain. During active neural processing, functional integration is facilitated through transitory formations of "harmonic" cross-frequency couplings, whereas "nonharmonic" decoupling among neural oscillatory rhythms is postulated to characterize the resting, default state of the brain, minimizing the occurrence of spurious, noisy, background couplings. METHODS: Within this exploratory, randomized, placebo-controlled trial, we assessed whether the transient occurrence of nonharmonic and harmonic relationships between peak-frequencies in the alpha (8-14 Hz) and theta (4-8 Hz) bands is impacted by intranasal administration of oxytocin, a neuromodulator implicated in improving homeostasis and reducing stress/anxiety. To do so, resting-state electroencephalography was acquired before and after 4 weeks of oxytocin administration (12 IU twice-daily) in children with autism spectrum disorder (8-12 years, n = 33 oxytocin; n = 34 placebo). At the baseline, neural assessments of children with autism were compared with those of a matched cohort of children without autism (n = 40). RESULTS: Compared to nonautistic peers, autistic children displayed a lower incidence of nonharmonic alpha-theta cross-frequency decoupling, indicating a higher incidence of spurious "noisy" coupling in their resting brain (p = .001). Dimensionally, increased neural coupling was associated with more social difficulties (p = .002) and lower activity of the parasympathetic "rest & digest" branch of the autonomic nervous system (p = .018), indexed with high-frequency heart-rate-variability. Notably, after oxytocin administration, the transient formation of nonharmonic cross-frequency configurations was increased in the cohort of autistic children (p < .001), indicating a beneficial effect of oxytocin on reducing spurious cross-frequency-interactions. Furthermore, parallel epigenetics changes of the oxytocin receptor gene indicated that the neural effects were likely mediated by changes in endogenous oxytocinergic signaling (p = .006). CONCLUSIONS: Chronic oxytocin induced important homeostatic changes in the resting-state intrinsic neural frequency architecture, reflective of reduced noisy oscillatory couplings and improved signal-to-noise properties.

Can repeated intranasal oxytocin administration affect reduced neural sensitivity towards expressive faces in autism? A randomized controlled trial.

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.

At the Head and Heart of Oxytocin's Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism.

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. However, to fully understand oxytocin's therapeutic potential, 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 4-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 children with autism aged 8-12 years (45 boys, 12 girls) 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 4 weeks after the nasal spray administration period. RESULTS: Significant reductions in intrinsic amygdala-orbitofrontal connectivity were observed, particularly at the 4-week follow-up session. These reductions were 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 4-week oxytocin administration course decreases amygdala connectivity and improves cardiac autonomic balance. Epigenetic modulators may explain inter-individual variation in responses to oxytocin.

Dissociating brain systems that respond to contingency and valence during monetary loss avoidance in adolescence.

Negative reinforcement processes allow individuals to avoid negative and/or harmful outcomes. They depend on the brain's ability to differentiate; (i) contingency from non-contingency, separately from (ii) judgements about positive and negative valence. Thirty-three males (8-18 years) performed a cued reaction-time task during fMRI scanning to differentiate the brain's responses to contingency and valence during loss avoidance. In two conditions, cues indicated no -contingency between participants' responses and monetary loss - (1) CERTAIN LOSS (negative valence) of €0.20, €1 or €5 or (2) CERTAIN LOSS AVOIDANCE (positive valence). In a third condition, cues indicated a contingency between short reaction times and avoidance of monetary loss. As expected participants had shorter reaction times in this latter condition where CONDITIONAL LOSS AVOIDANCE cues activated salience and motor-response-preparation brain networks - independent of the relative valence of the contrast (CERTAIN LOSS or CERTAIN LOSS AVOIDANCE). Effects of valence were seen toward the session's end where CERTAIN LOSS AVOIDANCE cues activated ventral striatum, medial-orbitofrontal cortex and medial-temporal areas more than CERTAIN LOSS. CONDITIONAL LOSS AVOIDANCE trials with feedback indicating "success" activated ventral striatum more than "failure feedback". The findings support the hypothesis that brain networks controlling contingency and valence processes during negative reinforcement are dissociable.

Subtle microstructural alterations in white matter tracts involved in socio-emotional processing after very preterm birth.

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 (FT) born 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 deconvolution 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.

Oral microbiota in autistic children: Diagnosis-related differences and associations with clinical characteristics.

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 Solobacterium, Stomatobaculum, Ruminococcaceae UCG.014, Tannerella and Campylobacter were significantly more abundant in autistic compared to non-autistic children. Furthermore, the former four bacteria that were significantly more abundant in the autistic children showed significant associations with parent-reported social difficulties, repetitive and restrictive behavior and with parent-reported anxiety-like behavior. Importantly, associations among oral microbiome and quantitative diagnostic characteristics were not significantly driven by differences in lifestyle variables. This exploratory study reveals significant differences in oral microbiome composition between autistic and non-autistic children, even while controlling for potential confounding lifestyle variables. Furthermore, the significant associations with clinical characteristics suggest that individual differences in microbiome composition might be involved in shaping the clinical phenotype of autism. However, these associations warrant further exploration of the oral microbiome's potential beyond the oral cavity and specifically with respect to neuropsychiatric conditions.

Chronic oxytocin administration stimulates the oxytocinergic system in children with autism.

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.

Effects of multiple-dose intranasal oxytocin administration on social responsiveness in children with autism: a randomized, placebo-controlled trial.

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 ).

Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation.

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.

Monitoring the effect of oxytocin on the neural sensitivity to emotional faces via frequency-tagging EEG: A double-blind, cross-over study.

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.

Frequency-Tagging EEG of Superimposed Social and Non-Social Visual Stimulation Streams Provides No Support for Social Salience Enhancement after Intranasal Oxytocin Administration.

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.

The limits of motivational influence in ADHD: no evidence for an altered reaction to negative reinforcement.

Functional magnetic resonance imaging studies have reported a diminished response in the brain's reward circuits to contingent cues predicting future monetary gain in adolescents with attention-deficit/hyperactivity disorder (ADHD). The situation with regard to monetary loss is less clear, despite recognition that both positive and negative consequences impact ADHD behaviour. Here, we employ a new Escape Monetary Loss Incentive task in an MRI scanner, which allows the differentiation of contingency and valence effects during loss avoidance, to examine ADHD-related alterations in monetary loss processing. There was no evidence of atypical processing of contingent or non-contingent monetary loss cues in ADHD - either in terms of ratings of emotional and motivational significance or brain responses. This suggests that the ability to process contingencies between performance and negative outcomes is intact in ADHD and that individuals with ADHD are no more (or less) sensitive to negative outcomes than controls. This latter finding stands in stark contrast to recent evidence from a similar task of atypical emotion network recruitment (e.g. amygdala) in ADHD individuals to cues predicting another negative event, the imposition of delay, suggesting marked specificity in the way they respond to negative events.

Endogenous Oxytocin Levels in Autism-A Meta-Analysis.

Oxytocin (OT) circuitry plays a major role in the mediation of prosocial behavior. Individuals with autism spectrum disorder (ASD) are characterized by impairments in social interaction and communication and have been suggested to display deficiencies in central OT mechanisms. The current preregistered meta-analysis evaluated potential group differences in endogenous OT levels between individuals with ASD and neurotypical (NT) controls. We included 18 studies comprising a total of 1422 participants. We found that endogenous OT levels are lower in children with ASD as compared to NT controls (n = 1123; g = -0.60; p = 0.006), but this effect seems to disappear in adolescent (n = 152; g = -0.20; p = 0.53) and adult populations (n = 147; g = 0.27; p = 0.45). Secondly, while no significant subgroup differences were found in regard to sex, the group difference in OT levels of individuals with versus without ASD seems to be only present in the studies with male participants (n = 814; g = -0.44; p = 0.08) and not female participants (n = 192; g = 0.11; p = 0.47). More research that employs more homogeneous methods is necessary to investigate potential developmental changes in endogenous OT levels, both in typical and atypical development, and to explore the possible use of OT level measurement as a diagnostic marker of ASD.

The amygdala in adolescents with attention-deficit/hyperactivity disorder: Structural and functional correlates of delay aversion.

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.

Waiting impulsivity: a distinctive feature of ADHD neuropsychology?

Impulsivity is a core feature of attention-deficit hyperactivity disorder (ADHD). It has been conceptualized in a number of different ways. In the current article, we examine how the new concept of "waiting impulsivity", which refers to premature responding before a scheduled target appears, adds to our understanding of impulsivity in ADHD. Sixty children (8-12 years old; 30 ADHD; 30 typically developing controls) completed the 4-choice serial reaction time task, a measure of waiting impulsivity, alongside tasks measuring inhibitory control and temporal discounting and questionnaires measuring behavioral disorder symptoms, delay aversion, and various aspects of impulsivity. A multiple logistic regression model was used to explore the contribution of the primary task outcomes to predict group membership. Children with ADHD displayed more waiting impulsivity and less inhibitory control; they did not differ in temporal discounting. There was no correlation between waiting impulsivity and inhibitory control. Waiting impulsivity was correlated with parent-reported ratings of hyperactivity/impulsivity, inattention, oppositional defiant disorder (ODD), and conduct disorder (CD) and with self-reported delay aversion ratings. Only waiting impulsivity was a significant predictor of ADHD status. In conclusion, waiting impulsivity is distinct from inhibitory control deficits and predicts ADHD status independently of it. Future research needs to examine the relationship with delay aversion and ODD/CD more thoroughly.