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.

The effects of oxytocin administration on social and routinized behaviors in autism: A preregistered systematic review and meta-analysis.

Oxytocin administration has demonstrated considerable promise for providing individualized support for autistic people. However, studies evaluating the effects of oxytocin administration on autistic characteristics have yielded inconsistent results. This systematic review and meta-analysis investigates the effect of oxytocin administration on social and routinized behaviors in autism using recently developed methods to accurately assess the potential impact of effect size dependency and publication bias. Our frequentist meta-analysis yielded a significant summary effect size estimate for the impact of oxytocin administration on social outcomes in autism (d = 0.22, p < 0.001). The summary effect size estimate for routinized behavior outcomes was not statistically significant (d = 0.14, p = 0.22), with a follow up test indicating that the effect size estimate was not either statistically equivalent (Z = -1.06, p = 0.2), assuming a smallest effect size of interest of 0.25. Frequentist and Bayesian assessments for publication bias, as well as results from Robust Bayesian meta-analysis of oxytocin effects on social outcomes in autism, indicated that summary effect sizes might be inflated due to publication bias. Future studies should aim to reduce bias by preregistering analysis plans and to increase precision with larger sample sizes.

Social functioning predicts individual changes in EEG microstates following intranasal oxytocin administration: A double-blind, cross-over randomized clinical trial.

Oxytocin (OXT) modulates social behaviors. However, the administration of exogenous OXT in humans produces inconsistent behavioral changes, affecting future consideration of OXT as a treatment for autism and other disorders with social symptoms. Inter-individual variability in social functioning traits might play a key role in how OXT changes brain activity and, therefore, behavior. Here, we investigated if inter-individual variability might dictate how single-dose intranasal OXT administration (IN-OXT) changes spontaneous neural activity during the eyes-open resting state. We used a double-blinded, randomized, placebo-controlled, cross-over design on 30 typically developing young adult men to investigate the dynamics of EEG microstates corresponding to activity in defined neural networks. We confirmed previous reports that, at the group level, IN-OXT increases the representation of the attention and salience microstates. Furthermore, we identified a decreased representation of microstates associated with the default mode network. Using multivariate partial least square statistical analysis, we found that social functioning traits associated with IN-OXT-induced changes in microstate dynamics in specific spectral bands. Correlation analysis further revealed that the higher the social functioning, the more IN-OXT increased the appearance of the visual network-associated microstate, and suppressed the appearance of a default mode network-related microstate. The lower the social functioning, the more IN-OXT increases the appearance of the salience microstate. The effects we report on the salience microstate support the hypothesis that OXT regulates behavior by enhancing social salience. Moreover, our findings indicate that social functioning traits modulate responses to IN-OXT and could partially explain the inconsistent reports on IN-OXT effects.

In the eye of the beholder: Social traits predict motor simulation during naturalistic action perception.

Previous research has robustly demonstrated that eye contact between actor and observer promotes the simulation of perceived actions into the observer's own motor system, which in turn facilitates social perception and communication. The socially relevant connotation embedded in eye contact may however be different for individuals with differing social traits. Here, we examined how "normal" (i.e. non-clinical) variability in self-reported social responsiveness/autistic traits, social anxiety and interpersonal relationship style (secure, avoidant or anxious attachment) influences neural motor simulation during action observation in different gaze conditions. To do so, we analyzed an existing dataset involving 124 adult participants (age range: 18-35 years) who underwent transcranial magnetic stimulation (TMS) while observing an actor performing simple hand actions and simultaneously engaging in eye contact or gazing away from the observer. Motor evoked potential (MEP) amplitudes were adopted as an index of motor resonance. Regression-based analyses highlighted the role of social responsiveness and secure attachment in shaping motor resonance, indicating that socially responsive motor resonance during dyadic gaze (i.e., MEPdirect > MEPaverted) was only observed in participants displaying high levels of these traits. Furthermore, a clustering analysis identified two to three distinct subgroups of participants with unique social trait profiles, showing a clear differentiation in motor resonant patterns upon different gaze cues that is in accordance with a recent neurobiological framework of attachment. Together, results demonstrate that motor resonance within a given social interaction may serve as a sensitive tracker of socio-interactive engagement, which allows to capture subclinical inter-individual variation in relevant social traits.

The Physiological and Clinical-Behavioral Effects of Heart Rate Variability Biofeedback in Adolescents with Autism: A Pilot Randomized Controlled Trial.

Adolescents with autism present lower levels of cardiac vagal modulation. It was hypothesized that Heart Rate Variability Biofeedback (HRVB) increases cardiac vagal modulation in adolescents with autism, resulting in positive effects on physiological and psychosocial parameters. It was also hypothesized that home-based HRVB training is feasible. In a single-blind, randomized sham-controlled pilot trial, adolescents with autism performed supervised HRVB (n = 24) or sham training (n = 20). Subsequently, half of the adolescents received HRVB training at home, whereas the other subset did not practice. Physiological, cortisol and behavioral data were collected during stress-provoking assessments before and after each training period. Supervised HRVB resulted in a late increase in cardiac vagal modulation in adolescents with autism. Heart rate increased and cortisol decreased significantly immediately after supervised HRVB, but none of these effects remained after follow-up. Following supervised HRVB, no significant change in psychosocial functioning was found. Home-based HRVB was feasible, adolescents reported lower symptoms of stress, but a significant decrease in compliance rate was found. HRVB is feasible and effective in adolescents with autism given the late-emerging increases in cardiac vagal modulation and decrease in stress symptoms. Replicating this study with a larger sample and further exploration of the working mechanisms of HRVB are recommended. ClinicalTrials.gov , NCT04628715.

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.

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.

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.

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.

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.

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.

Altered Dynamic Resting State Functional Connectivity Associated With Somatosensory Impairments in the Upper Limb in the Early Sub-Acute Phase Post-Stroke.

BACKGROUND.: Altered dynamic functional connectivity has been associated with motor impairments in the acute phase post-stroke. Its association with somatosensory impairments in the early sub-acute phase remains unexplored. OBJECTIVE.: To investigate altered dynamic functional connectivity associated with somatosensory impairments in the early sub-acute phase post-stroke. METHODS.: We collected resting state magnetic resonance imaging and clinical somatosensory function of the upper limb of 20 subacute stroke patients and 16 healthy controls (HC). A sliding-window approach was used to identify 3 connectivity states based on the estimated dynamic functional connectivity of sensorimotor related networks. Network components were subdivided into 3 domains: cortical and subcortical sensorimotor, as well as cognitive control network. Between-group differences were investigated using independent t-tests and Mann-Whitney-U tests. Analyzes were performed with correction for age, head motion and time post-stroke and corrected for multiple comparisons. RESULTS.: Stroke patients spent significantly less time in a weakly connected network state (state 3; dwell time: pstate3 = 0.003, meanstroke = 53.02, SDstroke = 53.13; meanHC = 118.92, SDHC = 72.84), and stayed shorter but more time intervals in a highly connected intra-domain network state (state 1; fraction time: pstate 1 < 0.001, meanstroke = 0.46, SDstroke = 0.26; meanHC = 0.26, SDHC = 0.21) compared to HC. After 8 weeks of therapy, improvements in wrist proprioception were moderately associated with decreases in dwell and fraction times toward a more normalized pattern. CONCLUSION.: Changes in temporal properties of large-scale network interactions are present in the early rehabilitation phase post-stroke and could indicate enhanced neural plasticity. These findings could augment the understanding of cerebral reorganization after loss of neural tissue specialized in somatosensory functions.

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 ).

A Systematic Review of Self-Reported Stress Questionnaires in People on the Autism Spectrum.

Background: The goal of this systematic review was to provide an overview of self-report measures of stress in populations on the autism spectrum. In addition, information regarding psychometric properties was discussed as well. Methods: Four databases were systematically searched following the PRISMA guidelines and using strict eligibility criteria. Risk of bias assessment was performed using the COSMIN checklist. Results: Eight questionnaires were previously used in populations on the autism spectrum, reported over 31 studies. Discussion: Future research should focus more on examining psychometric properties of these self-report measures in this population as current evidence is scarce. In addition, it is important to consider which concept of stress one aims to measure as not all questionnaires cover the same aspects of stress. Supplementary Information: The online version contains supplementary material available at 10.1007/s40489-021-00293-4.

Multimodal and multidomain lesion network mapping enhances prediction of sensorimotor behavior in stroke patients.

Beyond the characteristics of a brain lesion, such as its etiology, size or location, lesion network mapping (LNM) has shown that similar symptoms after a lesion reflects similar dis-connectivity patterns, thereby linking symptoms to brain networks. Here, we extend LNM by using a multimodal strategy, combining functional and structural networks from 1000 healthy participants in the Human Connectome Project. We apply multimodal LNM to a cohort of 54 stroke patients with the aim of predicting sensorimotor behavior, as assessed through a combination of motor and sensory tests. Results are two-fold. First, multimodal LNM reveals that the functional modality contributes more than the structural one in the prediction of sensorimotor behavior. Second, when looking at each modality individually, the performance of the structural networks strongly depended on whether sensorimotor performance was corrected for lesion size, thereby eliminating the effect that larger lesions generally produce more severe sensorimotor impairment. In contrast, functional networks provided similar performance regardless of whether or not the effect of lesion size was removed. Overall, these results support the extension of LNM to its multimodal form, highlighting the synergistic and additive nature of different types of network modalities, and their corresponding influence on behavioral performance after brain injury.

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.

Effects of single- and multiple-dose oxytocin treatment on amygdala low-frequency BOLD fluctuations and BOLD spectral dynamics in autism.

Prior neuroimaging clinical trials investigating the neural effects of intranasal administration of the neuropeptide oxytocin demonstrated a key role of the amygdala in oxytocin's neuromodulatory effects. These studies mostly demonstrated the acute effects of single-dose administrations, examining task-dependent effects of oxytocin on brain activity elicited during explicit experimental tasks or stimuli presentations. The increased consideration of oxytocin as a potential ameliorating treatment in autism spectrum disorder (ASD) requires a better understanding of how multiple-dose oxytocin administration affects intrinsic, task-free, amygdala function. In this double-blind, randomized, placebo-controlled trial with between-subject design, 38 adult men with ASD underwent resting-state fMRI scanning before and after oxytocin or placebo treatment. Effects were assessed either after a single-dose administration, consisting of 24 international units, or after multiple-dose treatment, consisting of 4 weeks of once-daily nasal spray administrations. Compared to placebo, oxytocin induced a decrease in intrinsic resting-state BOLD signal amplitudes of the bilateral amygdala (fractional amplitudes of low-frequency fluctuations) and modulated cross-frequency interactions between adjacent BOLD frequency components. The right amygdala showed a pattern of reduced cross-frequency harmonicity, while the left amygdala showed a relative increase in harmonic cross-frequency interactions after oxytocin treatment. Notably, the direction and magnitude of BOLD spectral changes induced after a single-dose were qualitatively similar to treatment effects induced after multiple-dose treatment. Furthermore, the identified spectral changes in amygdalar BOLD amplitude and cross-frequency harmonicity were associated with improved feelings of tension, reflecting oxytocin's anxiolytic, stress-reducing neuromodulatory role. The observed effects of oxytocin on amygdalar BOLD spectral characteristics and associated behaviors contribute to a deeper mechanistic understanding of the intrinsic, task-free neuromodulatory dynamics that underlie single- and multiple-dose oxytocin treatment in ASD. European Clinical Trial Registry (Eudract 2014-000586-45).

Broken or socially mistuned mirroring in ASD? An investigation via transcranial magnetic stimulation.

Individuals with an autism spectrum disorder (ASD) experience persistent difficulties during social interactions and communication. Previously, it has been suggested that deficits in the so-called "mirror system," active during both action execution and observation, may underlie these social difficulties. It is still a topic of debate however whether deficiencies in the simulation of others' actions (i.e., "broken" mirroring) forms a general feature of ASD, or whether these mostly reflect a lack of social attunement. The latter would suggest an overall intact mirror system, but an impaired modulation of mirror activity according to variable social contexts. In this study, 25 adults with ASD and 28 age- and IQ-matched control participants underwent transcranial magnetic stimulation during the observation of hand movements under variable conditions. Hand movements were presented via a live interaction partner, either without social context to assess basic motor mirroring or in combination with direct and averted gaze from the actor to assess socially modulated mirroring. Overall, no significant group differences were revealed, indicating no generally diminished mirror activity in ASD. Interestingly however, regression analyses revealed that, among ASD participants, higher symptom severity was associated with both reduced basic motor mirroring and aberrant socially modulated mirroring (i.e., no enhancement of mirror system activity upon observation of the interaction partner's direct vs. averted gaze). These findings further challenge the notion that mirror system dysfunctions constitute a principal feature of ASD, but demonstrate that variations in mirroring may be related to differential expressions of ASD symptom severity. LAY SUMMARY: Our findings show similar activity levels in brain regions responsible for action simulation and understanding in adults with autism, compared to adults without autism. However, the presence of more severe autism symptoms was linked to reduced activity in these regions. This suggests lower levels of brain activity during action understanding in some, but not all, persons with autism, which may contribute to the social difficulties these persons experience in daily life.

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.

Oxytocin enhances neural approach towards social and non-social stimuli of high personal relevance.

Oxytocin (OT) plays a pivotal role in a variety of complex social behaviors by modulating approach-avoidance motivational tendencies, but recently, its social specificity has been challenged. Here, a randomized, double-blind, placebo-controlled study was conducted with forty young adult men, investigating the effect of a single-dose of OT (24 IU) on behavioral and neural approach-avoidance. Frontal alpha asymmetry, indexing neurophysiological approach-avoidance, was obtained from electroencephalographic recordings while participants were presented with a series of pictures, individually rated in terms of personal relevance (i.e., high versus low positive/negative emotional evocativeness) and categorized as social or non-social. Additionally, participants could prolong (approach) or shorten (avoid) the viewing-time of each picture, providing a measure of behavioral approach-avoidance. Intranasal OT enhanced both behavioral and neural approach (increased viewing-time), particularly towards negatively valenced pictures of both social and non-social nature, thus challenging the notion that OT's effects are specific to social stimuli. Neurally, OT specifically amplified approach-related motivational salience of stimuli that were self-rated to have high personal relevance, but irrespective of their social nature or rated affective valence (positive/negative). Together, these findings provide support to the General Approach-Avoidance Hypothesis of OT, suggesting a role of OT in amplifying the motivational salience of environmental stimuli with high (personal) relevance, but irrespective of their social/non-social nature.Clinical Trial Number: The study design was registered at ClinicalTrials.gov (NCT04443647; 23/06/2020; https://clinicaltrials.gov/ct2/show/NCT04443647 ).