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.

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.

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.

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 ).

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 ).

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.

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.

Neural processing of facial identity and expression in adults with and without autism: A multi-method approach.

The ability to recognize faces and facial expressions is a common human talent. It has, however, been suggested to be impaired in individuals with autism spectrum disorder (ASD). The goal of this study was to compare the processing of facial identity and emotion between individuals with ASD and neurotypicals (NTs). Behavioural and functional magnetic resonance imaging (fMRI) data from 46 young adults (aged 17-23 years, NASD = 22, NNT = 24) was analysed. During fMRI data acquisition, participants discriminated between short clips of a face transitioning from a neutral to an emotional expression. Stimuli included four identities and six emotions. We performed behavioural, univariate, multi-voxel, adaptation and functional connectivity analyses to investigate potential group differences. The ASD-group did not differ from the NT-group on behavioural identity and expression processing tasks. At the neural level, we found no differences in average neural activation, neural activation patterns and neural adaptation to faces in face-related brain regions. In terms of functional connectivity, we found that amygdala seems to be more strongly connected to inferior occipital cortex and V1 in individuals with ASD. Overall, the findings indicate that neural representations of facial identity and expression have a similar quality in individuals with and without ASD, but some regions containing these representations are connected differently in the extended face processing network.

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 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.

Adults with high functioning autism display idiosyncratic behavioral patterns, neural representations and connectivity of the 'Voice Area' while judging the appropriateness of emotional vocal reactions.

Understanding others in everyday situations requires multiple types of information processing (visual, auditory, higher order…) which implicates the use of multiple neural circuits of the human brain. Here, using a multisensory paradigm we investigate one aspect of social understanding less explored in the literature: instead of focusing on the capacity to infer what a specific person is thinking, we explore here how people with high functioning autism (HFA) and matched controls with typical development (TD) infer the "population thinking". For this we created an audio-visual 'social norm inference' task. Participants were required to imagine how most people would judge the appropriateness of vocal utterances in relation to different emotional visual contexts. Behavioral findings demonstrated that HFA individuals show more interindividual variability in these judgments despite equal within-participant reliability relative to TD. This was also the case for judgements of the valence of these vocalizations when presented in isolation. At the neural level, multivoxel pattern analysis of functional magnetic resonance imaging data revealed strikingly similar neural representations between HFA and TD participants at the group level across different hierarchical levels and neural systems. However, analyses at the individual-participant level revealed that the "Temporal Voice Area" (TVA) shows more interindividual variability in the HFA group, both for neural representations and functional connectivity. Thus, this larger neural idiosyncrasy in a high-level auditory area matches with the larger behavioral idiosyncrasy in HFA individuals, when judging auditory valence and its adequacy in different social scenarios. These results suggest that idiosyncrasy in task-relevant sensory areas in HFA participants could underlie their greater difficulties to estimate how others can think.

Mood congruency effects are mediated by shifts in salience and central executive network efficiency.

Emotions are not confined to short momentary states but carry on over time, facilitating the perception and interpretation of the environment in mood-congruent ways. Yet, the (neural) mechanism linking affective stimulation at a certain time-point to such altered, mood-congruent processing of stimuli presented at a subsequent time-point remains unknown. Recent research suggests that such a link could be explained by transient effects of affective stimulation on the organization of intrinsic macro-scale neural networks. It remains, however, unclear whether these changes in network organization are influencing subsequent perception in a mood-congruent way. Addressing this gap the current study investigated whether changes in network organization, measured in terms of network efficiency, mediate the relation between mood induction and mood-congruent processing as measured by reaction times during an emotional Stroop task. The results demonstrated that negative mood induction increased the efficiency of the salience network and decreased the efficiency of the central executive network. This modulation of network efficiency fully mediated the effects of mood induction on reaction times to negative words. These findings indicate that transient shifts in the organization of macro-scale neural networks are an essential part of the emotional response and can help to explain how affect shapes our interaction with the environment.

Amygdala-Hippocampal Connectivity Is Associated With Endogenous Levels of Oxytocin and Can Be Altered by Exogenously Administered Oxytocin in Adults With Autism.

BACKGROUND: Oxytocin (OT) plays a pivotal role in interpersonal bonding, affiliation, and trust, and its intranasal administration is increasingly considered as a potential treatment for autism spectrum disorder. METHODS: We explored whether variations in endogenous salivary OT concentration are related to interindividual differences in core autism symptoms and expressions of attachment in 38 male adults with autism spectrum disorder. Further, resting-state functional magnetic resonance imaging was adopted to specifically explore whether interindividual differences are reflected in the intrinsic network organization of key regions of the central oxytocinergic system. RESULTS: Positive correlations were identified between peripheral OT and expressions of secure attachment (the State Adult Attachment Measure and the Inventory of Peer Attachment), but no significant relationships were identified with scales assessing core autism symptom domains (the Social Responsiveness Scale and the Repetitive Behavior Scale). At the neural level, higher levels of endogenous OT were associated with lower degrees of interregional functional coupling between the amygdala and hippocampal regions. Interestingly, a single dose of exogenously administered OT induced a further reduction in amygdala-hippocampal connectivity, indicating that a higher availability of OT can alter the degree of amygdala-hippocampal connectivity. CONCLUSIONS: The identified associations between the oxytocinergic system, expressions of secure attachment, and amygdala-hippocampal pathways are anticipated to be of relevance for understanding the role of OT in modulating appropriate neural and physiological responses to stress and restoring homeostasis.

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.

Neural Representations Behind 'Social Norm' Inferences In Humans.

Humans are highly skilled in social reasoning, e.g., inferring thoughts of others. This mentalizing ability systematically recruits brain regions such as Temporo-Parietal Junction (TPJ), Precuneus (PC) and medial Prefrontal Cortex (mPFC). Further, posterior mPFC is associated with allocentric mentalizing and conflict monitoring while anterior mPFC is associated with self-reference (egocentric) processing. Here we extend this work to how we reason not just about what one person thinks but about the abstract shared social norm. We apply functional magnetic resonance imaging to investigate neural representations while participants judge the social congruency between emotional auditory utterances in relation to visual scenes according to how 'most people' would perceive it. Behaviorally, judging according to a social norm increased the similarity of response patterns among participants. Multivoxel pattern analysis revealed that social congruency information was not represented in visual and auditory areas, but was clear in most parts of the mentalizing network: TPJ, PC and posterior (but not anterior) mPFC. Furthermore, interindividual variability in anterior mPFC representations was inversely related to the behavioral ability to adjust to the social norm. Our results suggest that social norm inferencing is associated with a distributed and partially individually specific representation of social congruency in the mentalizing network.

Dyscalculia and dyslexia: Different behavioral, yet similar brain activity profiles during arithmetic.

Brain disorders are often investigated in isolation, but very different conclusions might be reached when studies directly contrast multiple disorders. Here, we illustrate this in the context of specific learning disorders, such as dyscalculia and dyslexia. While children with dyscalculia show deficits in arithmetic, children with dyslexia present with reading difficulties. Furthermore, the comorbidity between dyslexia and dyscalculia is surprisingly high. Different hypotheses have been proposed on the origin of these disorders (number processing deficits in dyscalculia, phonological deficits in dyslexia) but these have never been directly contrasted in one brain imaging study. Therefore, we compared the brain activity of children with dyslexia, children with dyscalculia, children with comorbid dyslexia/dyscalculia and healthy controls during arithmetic in a design that allowed us to disentangle various processes that might be associated with the specific or common neural origins of these learning disorders. Participants were 62 children aged 9 to 12, 39 of whom had been clinically diagnosed with a specific learning disorder (dyscalculia and/or dyslexia). All children underwent fMRI scanning while performing an arithmetic task in different formats (dot arrays, digits and number words). At the behavioral level, children with dyscalculia showed lower accuracy when subtracting dot arrays, and all children with learning disorders were slower in responding compared to typically developing children (especially in symbolic formats). However, at the neural level, analyses pointed towards substantial neural similarity between children with learning disorders: Control children demonstrated higher activation levels in frontal and parietal areas than the three groups of children with learning disorders, regardless of the disorder. A direct comparison between the groups of children with learning disorders revealed similar levels of neural activation throughout the brain across these groups. Multivariate subject generalization analyses were used to statistically test the degree of similarity, and confirmed that the neural activation patterns of children with dyslexia, dyscalculia and dyslexia/dyscalculia were highly similar in how they deviated from neural activation patterns in control children. Collectively, these results suggest that, despite differences at the behavioral level, the brain activity profiles of children with different learning disorders during arithmetic may be more similar than initially thought.

A Multitude of Neural Representations Behind Multisensory "Social Norm" Processing.

Humans show a unique capacity to process complex information from multiple sources. Social perception in natural environment provides a good example of such capacity as it typically requires the integration of information from different sensory systems, and also from different levels of sensory processing. Here, instead of studying one isolate system and level of representation, we focused upon a neuroimaging paradigm which allows to capture multiple brain representations simultaneously, i.e., low and high-level processing in two different sensory systems, as well as abstract cognitive processing of congruency. Subjects performed social decisions based on the congruency between auditory and visual processing. Using multivoxel pattern analysis (MVPA) of functional magnetic resonance imaging (fMRI) data, we probed a wide variety of representations. Our results confirmed the expected representations at each level and system according to the literature. Further, beyond the hierarchical organization of the visual, auditory and higher order neural systems, we provide a more nuanced picture of the brain functional architecture. Indeed, brain regions of the same neural system show similarity in their representations, but they also share information with regions from other systems. Further, the strength of neural information varied considerably across domains in a way that was not obviously related to task relevance. For instance, selectivity for task-irrelevant animacy of visual input was very strong. The present approach represents a new way to explore the richness of co-activated brain representations underlying the natural complexity in human cognition.