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.

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.

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.

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 ).

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.

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 ).

Tracking transient changes in the intrinsic neural frequency architecture: Oxytocin facilitates non-harmonic relationships between alpha and theta rhythms in the resting brain.

Shifts in the peak frequencies of oscillatory neural rhythms have been put forward as a principal mechanism by which cross-frequency coupling and decoupling is implemented in the brain. This notion is based on the mathematical reality that neural oscillations can only fully synchronize when their peak frequencies form harmonic 2:1 relationships (e.g., f2=f1/2). Non-harmonic cross-frequency relationships, on the other hand (based on the irrational golden mean 1.618.:1), provide the highest physiologically possible desynchronized state (reducing the occurrence of spurious, noisy, background coupling), and are therefore anticipated to characterize the resting state of the brain, in which no selective information processing takes place. The present study sought to assess whether the transient occurrence of 1.6:1 non-harmonic and 2:1 harmonic relationships between peak frequencies in the alpha (8-14 Hz) and theta (4-8 Hz) bands - respectively facilitating states of decoupling or coupling between oscillatory rhythms - are impacted by the intranasal administration of a single-dose of oxytocin (OT) or placebo. To do so, continuous resting-state electroencephalography (5 min eyes open, 19 electrodes) was obtained from 96 healthy adult men before and after nasal spray administration. The transient formation of non-harmonic cross-frequency configurations between alpha and theta peak frequencies was significantly increased after OT nasal spray administration, indicating an effect of OT on reducing the intrinsic occurrence of spurious (noisy) background phase synchronizations during resting-state. As a group, the OT group also showed a significant parallel increase in high-frequency and decrease in low-frequency heart rate variability, confirming a homeostatic role of OT in balancing parasympathetic drive. Overall, non-harmonic cross-frequency configurations have been put forward to lay the ground for a healthy neural network allowing the opportunity for an efficient transition from resting state to activity. The observed effects of OT on cross-frequency dynamics are therefore interpreted to reflect a homeostatic role of OT in increasing the signal-to-noise properties of the intrinsic EEG neural frequency architecture, i.e., by precluding the occurrence of 'noisy', unwanted, spurious couplings among neural rhythms in the resting brain.

Enhanced mirroring upon mutual gaze: multimodal evidence from TMS-assessed corticospinal excitability and the EEG mu rhythm.

Previous research has demonstrated that eye contact between actor and observer specifically enhances the 'mirroring' of others' actions, as measured by transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). However, it remains unknown whether other markers of mirror system activation, such as suppression of the EEG mu rhythm (8-13 Hz) over the sensorimotor strip, are also susceptible to perceived eye contact. Here, both TMS-induced MEPs and EEG mu suppression indices were assessed (in separate sessions) while 32 participants (mean age: 24y; 8m) observed a simple hand movement combined with direct or averted gaze from the actor. Both measures were significantly modulated by perceived eye gaze during action observation; showing an increase in MEP amplitude and an attenuation of the mu rhythm during direct vs. averted gaze. Importantly, while absolute MEP and mu suppression scores were not related, a significant association was identified between gaze-related changes in MEPs and mu suppression, indicating that both measures are similarly affected by the modulatory impact of gaze cues. Our results suggest that although the neural substrates underlying TMS-induced MEPs and the EEG mu rhythm may differ, both are sensitive to the social relevance of the observed actions, which might reflect a similar neural gating mechanism.

Oxytocin enhances the recovery of eye-contact induced autonomic arousal: A treatment mechanism study with placebo-controlled design.

The neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. OT has also been proposed to modulate activity of the autonomic nervous system. Here, a randomized double-blind, placebo-controlled study (with parallel design) was conducted with 56 healthy adult men to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electrodermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a two-person social context. In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the skin conductance response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (reduced recovery time), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness, indicating that person-dependent factors play an important role in determining OT treatment-responses. Exploratory, it was shown that OT also significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself. Together, these observations add further evidence to a role of OT in modulating activity of the autonomic nervous system, primarily by facilitating a restoration of homeostatic balance after stimulus-induced increases in sympathetically-driven autonomic arousal.

Intranasal oxytocin enhances approach-related EEG frontal alpha asymmetry during engagement of direct eye contact.

The neuropeptide oxytocin is suggested to play a major role in a variety of complex human behaviours, including interpersonal bonding, trust and attachment. Recent theories have suggested that the role oxytocin plays in these complex social behaviours involves a modulation of motivational tendencies of approach-/avoidance-related behaviours. However, to date, direct neurophysiological evidence supporting this notion is limited. In this double-blind, randomized, placebo-controlled study with parallel design, we assessed the effects of administered intranasal oxytocin in 40 adult men on gaze behaviour and a neural marker of approach/avoidance motivational tendencies. Specifically, electroencephalography recordings were performed during the engagement of eye contact with a live model in a naturalistic two-person social context and electroencephalographic frontal alpha asymmetry, an established neurophysiological index of motivational tendencies for approach-/avoidance-related behaviours, was assessed. Compared to placebo, a single dose of oxytocin (24 international units) was shown to increase relative left-sided frontal asymmetry upon direct eye contact with a live model, which is indicative of an increase in approach-related motivational tendencies towards the presented eye contact stimulus. Notably, the treatment effect was most prominently observed in participants with lower self-reported social motivation (higher Motivation subscale scores on the Social Responsiveness Scale), indicating that participants with lower social motivation benefitted the most from the administered oxytocin. No treatment-specific changes were identified in terms of gaze behaviour towards the eye region of the live model. Together, these observations add neurophysiological evidence to the hypothesized role of oxytocin in modulating approach-/avoidance-related tendencies and suggest that inter-subject variability in person-dependent factors need to be considered to evaluate the potential benefit of intranasal oxytocin as a treatment. This notion is of particular relevance to the variety of neuropsychiatric populations such as autism spectrum disorder, social anxiety disorder and depression, for which intranasal oxytocin is increasingly considered a potential treatment.

Oxytocin induces long-lasting adaptations within amygdala circuitry in autism: a treatment-mechanism study with randomized placebo-controlled design.

Intranasal administration of the neuropeptide oxytocin (IN-OT) is increasingly explored as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD). To date, however, the impact of multiple-dose IN-OT treatment on human neural circuitry is largely unknown, and also the possibility that long-term IN-OT use may induce long-lasting neural adaptations remains unexplored. Using a double-blind, randomized, placebo-controlled, between-subject design (including 38 adult men with ASD), this treatment-mechanism study showed that 4 weeks of daily oxytocin administration (24 IU/day) significantly altered intrinsic (resting-state fMRI) functional connectivity of the amygdala to core regions of the "social brain" (particularly orbitofrontal cortex and superior temporal sulcus) up to 4 weeks and 1 year post treatment. The neural adaptations in functional coupling of the amygdala to the orbitofrontal cortex were associated with reduced feelings of avoidance toward others and-at the trend level-reduced repetitive behaviors. These observations contribute to a deeper mechanistic understanding of the neural substrates that underlie behavioral effects of multiple-dose IN-OT treatment, and provide initial insights into the long-lasting neural consequences of chronic IN-OT use on amygdala circuitry. Future studies are however warranted to further elucidate the long-term impact of IN-OT treatment on human neural circuitry and its behavioral consequences.

Eye contact enhances interpersonal motor resonance: comparing video stimuli to a live two-person action context.

Previous research has shown a link between eye contact and interpersonal motor resonance, indicating that the mirroring of observed movements is enhanced when accompanied with mutual eye contact between actor and observer. Here, we further explored the role of eye contact within a naturalistic two-person action context. Twenty-two participants observed simple hand movements combined with direct or averted gaze presented via a live model in a two-person setting or via video recordings, while transcranial magnetic stimulation was applied over the primary motor cortex (M1) to measure changes in M1 excitability. Skin conductance responses and gaze behavior were also measured to investigate the role of arousal and visual attention herein. Eye contact significantly enhanced excitability of the observer's M1 during movement observation within a two-person setting. Notably, participants with higher social responsiveness (Social Communication subscale of the Social Responsiveness Scale) displayed a more pronounced modulation of M1 excitability by eye gaze. Gaze-related modulations in M1 excitability were, however, not associated with differences in visual attention or autonomic arousal. In summary, the current study highlights the effectiveness and feasibility of adopting paradigms with high ecological validity for studying the modulation of mirror system processes by subtle social cues, such as eye gaze.

Attachment styles have a modulatory impact on psychophysiological arousal evoked by reciprocated and unreciprocated gaze.

Gaze processing plays an essential role during social interactions. Here, it was investigated whether variations in attachment style (secure, anxious and avoidant) were associated with differential expressions of sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, 47 participants were presented with either reciprocated or unreciprocated eye gaze from a live model and skin conductance responses (SCRs) were collected. In line with previous observations, SCRs and subjective ratings of arousal were higher in response to reciprocated, compared to unreciprocated gaze. In terms of the modulation by attachment style, it was shown that participants with low attachment security and high attachment avoidance displayed overall higher sympathetic arousal upon the presentation of the live dyadic gaze cues, irrespective of whether the observed model showed reciprocal or unreciprocated gaze. Together, these observations indicate that attachment styles have a modulatory effect on individuals' psychophysiological responses to dyadic gaze interactions.

Multi-method brain imaging reveals impaired representations of number as well as altered connectivity in adults with dyscalculia.

Two hypotheses have been proposed about the etiology of neurodevelopmental learning disorders, such as dyslexia and dyscalculia: representation impairments and disrupted access to representations. We implemented a multi-method brain imaging approach to directly investigate these representation and access hypotheses in dyscalculia, a highly prevalent but understudied neurodevelopmental disorder in learning to calculate. We combined several magnetic resonance imaging methods and analyses, including univariate and multivariate analyses, functional and structural connectivity. Our sample comprised 24 adults with dyscalculia and 24 carefully matched controls. Results showed a clear deficit in the non-symbolic magnitude representations in parietal, temporal and frontal regions, as well as hyper-connectivity in visual brain regions in adults with dyscalculia. Dyscalculia in adults was thereby related to both impaired number representations and altered connectivity in the brain. We conclude that dyscalculia is related to impaired number representations as well as altered access to these representations.

To mirror or not to mirror upon mutual gaze, oxytocin can pave the way: A cross-over randomized placebo-controlled trial.

The eyes constitute a highly salient cue to communicate social intent. Previous research showed that direct eye contact between two individuals can readily evoke an increased propensity to 'mirror' other peoples' actions. Considering the implicated role of the prosocial neuropeptide oxytocin (OXT) in enhancing the saliency of social cues and modulating approach/avoidance motivational tendencies, the current study adopted the non-invasive brain stimulation technique transcranial magnetic stimulation (TMS) to explore whether a single dose of intranasal OXT (24 IU) modulated (enhanced) a person's propensity to show heightened mirroring or motor resonance upon salient social cues, such as eye contact. The study involved a double-blind, placebo-controlled, cross-over trial with twenty-seven healthy adult men (19-32 y). By applying single-pulse TMS over the primary motor cortex during movement observation, it was shown that motor resonance was significantly higher when movement observation was accompanied by direct, compared to averted gaze, but that a single dose of OXT did not uniformly enhance this effect. Significant moderations of the treatment effect were noted however, indicating that participants with high self-reports of attachment avoidance displayed a stronger OXT-treatment effect (enhancement of motor resonance upon direct eye contact), compared to participants with low attachment avoidance. Particularly, while participants with high attachment avoidance initially displayed a reduced propensity to increase their motor resonance upon direct eye contact, a single dose of OXT was able to promote an otherwise avoidant individual's propensity to engage in motor resonance upon a salient social cue such as eye contact.