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Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

Abstract Many children who experience childhood adversity, whether in the form of threat or deprivation, develop adaptive competencies that lead to resilient functioning. Still, research has not succeeded in accurately predicting the level of resilient functioning by any kind of biomarkers, likely because it has sidelined the flexibility inherent in a construct that is situationally and developmentally variable. Whilst recent research acknowledges the importance of redefining resilience in order to reflect its dynamic nature after adversity, evidence for specific behaviors that are developmentally adaptive and dynamic throughout the lifespan is limited. We here propose a model in which resilient functioning is crucially dependent on the individual’s capability to flexibly synchronize with and segregate from another’s cognitive-affective, behavioral, and physiological states, known as ‘biobehavioral synchrony’. Such an adaptive interpersonal skill is rooted in (a) the early caregiving experience and its regulatory effects on an individual’s physiological stress reactivity, as well as (b) the development of self–other distinction which can be affected by childhood maltreatment. Bridging the gap between accounts of flexible resilient functioning and the latest thinking in biobehavioral synchrony, we will review behavioral and neurobiological evidence that threat and deprivation in childhood interfere with the development of dynamic, context-sensitive boundaries between self and other, mediated by the (right) tempo-parietal junction (a central neural hub for interpersonal synchronization), which puts the individual at risk for affective fusion or cut-off from others’ arousal states. Our proposed model charts a path for investigating the differential effects of maltreatment experiences and mechanisms for intergenerational transmission of non-sensitive caregiving. We conclude with metrics, data analysis methods, and strategies to facilitate flexible biobehavioral synchrony.

Introduction: The motor system undergoes significant development throughout childhood and adolescence. The contingent negative variation (CNV), a brain response reflecting preparation for upcoming actions, offers valuable insights into these changes. However, previous CNV studies of motor preparation have primarily focused on adults, leaving a gap in our understanding of how cortical activity related to motor planning and execution matures in children and adolescents. Methods: The study addresses this gap by investigating the maturation of motor preparation, pre-activation, and post-processing in 46 healthy, right-handed children and adolescents aged 5–16 years. To overcome the resolution limitations of previous studies, we combined 64-electrode high-density Electroencephalography (EEG) and advanced analysis techniques, such as event-related potentials (ERPs), mu-rhythm desynchronization as well as source localization approaches. The combined analyses provided an in-depth understanding of cortical activity during motor control. Results: Our data showed that children exhibited prolonged reaction times, increased errors, and a distinct pattern of cortical activation compared to adolescents. The findings suggest that the supplementary motor area (SMA) plays a progressively stronger role in motor planning and response evaluation as children age. Additionally, we observe a decrease in sensory processing and post-movement activity with development, potentially reflecting increased efficiency. Interestingly, adolescent subjects, unlike young adults in previous studies, did not yet show contralateral activation of motor areas during the motor preparation phase (late CNV). Conclusion: The progressive increase in SMA activation and distinct cortical activation patterns in younger participants suggest immature motor areas. These immature regions might be a primary cause underlying the age-related increase in motor action control efficiency. Additionally, the study demonstrates a prolonged maturation of cortical motor areas, extending well into early adulthood, challenging the assumption that motor control is fully developed by late adolescence. This research, extending fundamental knowledge of motor control development, offers valuable insights that lay the foundation for understanding and treating motor control difficulties.

IntroductionInterpersonal synchronization involves the alignment of behavioral, affective, physiological, and brain states during social interactions. It facilitates empathy, emotion regulation, and prosocial commitment. Mental disorders characterized by social interaction dysfunction, such as Autism Spectrum Disorder (ASD), Reactive Attachment Disorder (RAD), and Social Anxiety Disorder (SAD), often exhibit atypical synchronization with others across multiple levels. With the introduction of the “second-person” neuroscience perspective, our understanding of interpersonal neural synchronization (INS) has improved, however, so far, it has hardly impacted the development of novel therapeutic interventions.MethodsTo evaluate the potential of INS-based treatments for mental disorders, we performed two systematic literature searches identifying studies that directly target INS through neurofeedback (12 publications; 9 independent studies) or brain stimulation techniques (7 studies), following PRISMA guidelines. In addition, we narratively review indirect INS manipulations through behavioral, biofeedback, or hormonal interventions. We discuss the potential of such treatments for ASD, RAD, and SAD and using a systematic database search assess the acceptability of neurofeedback (4 studies) and neurostimulation (4 studies) in patients with social dysfunction.ResultsAlthough behavioral approaches, such as engaging in eye contact or cooperative actions, have been shown to be associated with increased INS, little is known about potential long-term consequences of such interventions. Few proof-of-concept studies have utilized brain stimulation techniques, like transcranial direct current stimulation or INS-based neurofeedback, showing feasibility and preliminary evidence that such interventions can boost behavioral synchrony and social connectedness. Yet, optimal brain stimulation protocols and neurofeedback parameters are still undefined. For ASD, RAD, or SAD, so far no randomized controlled trial has proven the efficacy of direct INS-based intervention techniques, although in general brain stimulation and neurofeedback methods seem to be well accepted in these patient groups.DiscussionSignificant work remains to translate INS-based manipulations into effective treatments for social interaction disorders. Future research should focus on mechanistic insights into INS, technological advancements, and rigorous design standards. Furthermore, it will be key to compare interventions directly targeting INS to those targeting other modalities of synchrony as well as to define optimal target dyads and target synchrony states in clinical interventions.

Abstract Mother–child interaction has been characterized by a fine-tuning of behavior and physiological activity. Yet, little is known about the dynamics of mother–child physiological synchrony during early school age and their associations to positive affect. To investigate these processes, 42 mother–child dyads, with children aged 8 to 10 years, played an interactive game while their interbeat intervals (IBI) and respiratory sinus arrhythmia (RSA) were measured simultaneously. IBI/RSA synchrony was calculated using cross-correlations of the IBI/RSA second-by-second time series for lags − 3 to + 3 seconds. Mother’s and child’s individual and shared positive affect were microcoded. During the interactive tasks, IBI and RSA synchrony significantly increased compared to control conditions. RSA and affect synchrony were significantly stronger for negative compared to positive lags indicating a stronger child leads/mother follows covariation. Further, dyad’s IBI and RSA synchrony were significantly associated to mother’s and child’s individual positive affect. Our data suggest that in low-risk community samples, mothers may respond to their children’s positive affect by matching their own affect and physiology. Investigating these temporally precise, concurrent and lagged synchrony processes may open up new avenues for understanding the ways in which parent–child interactions contribute to child developmental outcomes.

Abstract Theoretical and empirical accounts suggest that adolescence is associated with heightened reward learning and impulsivity. Experimental tasks and computational models that can dissociate reward learning from the tendency to initiate actions impulsively (action initiation bias) are thus critical to characterise the mechanisms that drive developmental differences. However, existing work has rarely quantified both learning ability and action initiation, or it has relied on small samples. Here, using computational modelling of a learning task collected from a large sample (N = 742, 9-18 years, 11 countries), we test differences in reward and punishment learning and action initiation from childhood to adolescence. Computational modelling reveals that whilst punishment learning rates increase with age, reward learning remains stable. In parallel, action initiation biases decrease with age. Results are similar when considering pubertal stage instead of chronological age. We conclude that heightened reward responsivity in adolescence can reflect differences in action initiation rather than enhanced reward learning.

Diffusion tensor imaging (DTI) enables the assessment of changes in brain tissue microstructure during maturation and ageing. In general, patterns of cerebral maturation and decline render non-monotonic lifespan trajectories of DTI metrics with age, and, importantly, the rate of microstructural changes is heterochronous for various white matter fibres. Recent studies have demonstrated that diffusion kurtosis imaging (DKI) metrics are more sensitive to microstructural changes during ageing compared to those of DTI. In a previous work, we demonstrated that the Cohen’s d of mean diffusional kurtosis (dMK) represents a useful biomarker for quantifying maturation heterochronicity. However, some inferences on the maturation grades of different fibre types, such as association, projection, and commissural, were of a preliminary nature due to the insufficient number of fibres considered. Hence, the purpose of this follow-up work was to further explore the heterochronicity of microstructural maturation between pre-adolescence and middle adulthood based on DTI and DKI metrics. Using the effect size of the between-group parametric changes and Cohen’s d, we observed that all commissural fibres achieved the highest level of maturity, followed by the majority of projection fibres, while the majority of association fibres were the least matured. We also demonstrated that dMK strongly correlates with the maxima or minima of the lifespan curves of DTI metrics. Furthermore, our results provide substantial evidence for the existence of spatial gradients in the timing of white matter maturation. In conclusion, our data suggest that DKI provides useful biomarkers for the investigation of maturation spatial heterogeneity and heterochronicity.

ObjectiveThis study tested the reactivity of motor cortex inhibition to different intensities of external stimulation by transcranial magnetic stimulation (TMS) and its internal modulation during different motor states in children and adolescents with Tourette syndrome.MethodsTMS-evoked N100 served as an indirect measure of GABAB receptor function which is related to cortical inhibition. Combined TMS/EEG was used to analyze the TMS-evoked N100 component evoked by different stimulation intensities as well as during resting condition, movement preparation (contingent negative variation task) and movement execution. The study included 18 early adolescents with Tourette syndrome and 15 typically developing control subjects.ResultsTMS-evoked N100 showed a less steep increase with increasing TMS intensity in Tourette syndrome together with less modulation (disinhibition) over the primary motor cortex during the motor states movement preparation and movement execution. Children with Tourette syndrome showed equally high N100 amplitudes at 110% resting motor threshold (RMT) intensity during resting condition and a parallel decline of RMT and N100 amplitude with increasing age as control subjects.ConclusionOur study yields preliminary evidence that modulation of motor cortical inhibitory circuits, during external direct stimulation by different TMS intensities and during volitional movement preparation and execution is different in children and adolescents with Tourette syndrome compared to controls. These results suggest that a reduced resting motor cortical inhibitory “reserve” could contribute to the production of unwanted movements. Our findings are compatible with increased regulation of motor cortex excitability by perception-action binding in Tourette syndrome instead of top-down / motor regulation and need to be replicated in further studies.

AimsHeart rate variability (HRV) measures have been suggested in healthy individuals as a potential index of self-regulation skills, which include both cognitive and emotion regulation aspects. Studies in patients with a range of psychiatric disorders have however mostly focused on the potential association between abnormally low HRV at rest and specifically emotion regulation difficulties. Emotion regulation deficits have been reported in patients with Conduct Disorder (CD) however, the association between these emotion regulation deficits and HRV measures has yet to be fully understood. This study investigates (i) the specificity of the association between HRV and emotion regulation skills in adolescents with and without CD and (ii) the association between HRV and grey matter brain volumes in key areas of the central autonomic network which are involved in self-regulation processes, such as insula, lateral/medial prefrontal cortices or amygdala.MethodsRespiratory sinus arrhythmia (RSA) measures of HRV were collected from adolescents aged between 9–18 years (693 CD (427F)/753 typically developing youth (TD) (500F)), as part of a European multi-site project (FemNAT-CD). The Inverse Efficiency Score, a speed-accuracy trade-off measure, was calculated to assess emotion and cognitive regulation abilities during an Emotional Go/NoGo task. The association between RSA and task performance was tested using multilevel regression models. T1-weighted structural MRI data were included for a subset of 577 participants (257 CD (125F); 320 TD (186F)). The CerebroMatic toolbox was used to create customised Tissue Probability Maps and DARTEL templates, and CAT12 to segment brain images, followed by a 2 × 2 (sex × group) full factorial ANOVA with RSA as regressor of interest.ResultsThere were no significant associations between RSA and task performance, neither during emotion regulation nor during cognitive regulation trials. RSA was however positively correlated with regional grey matter volume in the left insula (pFWE = 0.011) across all subjects.ConclusionRSA was related to increased grey matter volume in the left insula across all subjects. Our results thus suggest that low RSA at rest might be a contributing or predisposing factor for potential self-regulation difficulties. Given the insula’s role in both emotional and cognitive regulation processes, these brain structural differences might impact either of those.

Although home visiting programs have generally shown small overall effects on the prevention of child maltreatment, at-risk families with severe strain do not seem to benefit sufficiently from this support. A crucial factor for success seems to be the quality of the service system. The aim of the current study is to evaluate the effects of mentalization-based team supervision on the already existing welfare service of a German early prevention program (EPP). This will be a non-randomized, open-label, single-arm feasibility study. The EPP staff will be trained according to the mentalization-based team approach (MB-TA) and regularly receive MFT supervision by a trained and experienced child and adolescent psychiatrist. A minimum of eighty-four families with defined risk factors with children below 24 months of age and pregnant women in the third trimester will be included. Assessments will take place at T0 (after inclusion in the study), at T1 (after family care ends, as an intermediate assessment,) and at T2 (as a follow-up). We hypothesize that the risk of maltreatment can be reduced by strengthening the skills and capacities of the primary care system. This will be evaluated at the end of the follow-up period by comparing the Parental Stress Index (PSI) scores of all participants pre- and postintervention. Stress levels and mentalization abilities will be assessed as feasibility endpoints for the participating EPP teams.

Abstract Background Anorexia nervosa (AN) is a severe psychiatric disease that often takes a chronic course due to insufficient treatment options. Emerging evidence on the gut-brain axis offers the opportunity to find innovative treatments for patients with psychiatric disorders. The gut microbiome of patients with AN shows profound alterations that do not completely disappear after weight rehabilitation. In previous studies, the administration of polyunsaturated fatty acids (PUFA) resulted in effects that might be beneficial in the treatment of AN, affecting the microbiome, body weight and executive functions. Therefore, the MiGBAN study aims to examine the effects of a nutritional supplementation with PUFA on the gut microbiome and body mass index (BMI) in patients with AN. Methods This is a longitudinal, double-blind, randomized, placebo-controlled trial. Within 2 years, 60 adolescent patients aged 12 to 19 years with AN will receive either PUFA or placebo for 6 months additional to treatment as usual. After 1 year, the long-term effect of PUFA on the gut microbiome and consecutively on BMI will be determined. Secondary outcomes include improvement of gastrointestinal symptoms, eating disorder psychopathology, and comorbidities. Additionally, the interaction of the gut microbiome with the brain (microbiome-gut-brain axis) will be studied by conducting MRI measurements to assess functional and morphological changes and neuropsychological assessments to describe cognitive functioning. Anti-inflammatory effects of PUFA in AN will be examined via serum inflammation and gut permeability markers. Our hypothesis is that PUFA administration will have positive effects on the gut microbiota and thus the treatment of AN by leading to a faster weight gain and a reduction of gastrointestinal problems and eating disorder psychopathology. Discussion Due to previously heterogeneous results, a systematic and longitudinal investigation of the microbiome-gut-brain axis in AN is essential. The current trial aims to further analyse this promising research field to identify new, effective therapeutic tools that could help improve the treatment and quality of life of patients. If this trial is successful and PUFA supplementation contributes to beneficial microbiome changes and a better treatment outcome, their administration would be a readily applicable additional component of multimodal AN treatment. Trial registration German Clinical Trials Register DRKS00017130 . Registered on 12 November 2019.

ObjectivesLeveraging a large population-level morphologic, microstructural, and functional neuroimaging dataset, we aimed to elucidate the underlying neurobiology of attention-deficit hyperactivity disorder (ADHD) in children. In addition, we evaluated the applicability of machine learning classifiers to predict ADHD diagnosis based on imaging and clinical information.MethodsFrom the Adolescents Behavior Cognitive Development (ABCD) database, we included 1,798 children with ADHD diagnosis and 6,007 without ADHD. In multivariate logistic regression adjusted for age and sex, we examined the association of ADHD with different neuroimaging metrics. The neuroimaging metrics included fractional anisotropy (FA), neurite density (ND), mean-(MD), radial-(RD), and axial diffusivity (AD) of white matter (WM) tracts, cortical region thickness and surface areas from T1-MPRAGE series, and functional network connectivity correlations from resting-state fMRI.ResultsChildren with ADHD showed markers of pervasive reduced microstructural integrity in white matter (WM) with diminished neural density and fiber-tracks volumes – most notable in the frontal and parietal lobes. In addition, ADHD diagnosis was associated with reduced cortical volume and surface area, especially in the temporal and frontal regions. In functional MRI studies, ADHD children had reduced connectivity among default-mode network and the central and dorsal attention networks, which are implicated in concentration and attention function. The best performing combination of feature selection and machine learning classifier could achieve a receiver operating characteristics area under curve of 0.613 (95% confidence interval = 0.580–0.645) to predict ADHD diagnosis in independent validation, using a combination of multimodal imaging metrics and clinical variables.ConclusionOur study highlights the neurobiological implication of frontal lobe cortex and associate WM tracts in pathogenesis of childhood ADHD. We also demonstrated possible potentials and limitations of machine learning models to assist with ADHD diagnosis in a general population cohort based on multimodal neuroimaging metrics.

Abstract Conduct disorder (CD), a psychiatric disorder characterized by a repetitive pattern of antisocial behaviors, results from a complex interplay between genetic and environmental factors. The clinical presentation of CD varies both according to the individual’s sex and level of callous-unemotional (CU) traits, but it remains unclear how genetic and environmental factors interact at the molecular level to produce these differences. Emerging evidence in males implicates methylation of genes associated with socio-affective processes. Here, we combined an epigenome-wide association study with structural neuroimaging in 51 females with CD and 59 typically developing (TD) females to examine DNA methylation in relation to CD, CU traits, and gray matter volume (GMV). We demonstrate an inverse pattern of correlation between CU traits and methylation of a chromosome 1 region in CD females (positive) as compared to TD females (negative). The identified region spans exon 1 of the SLC25A24 gene, central to energy metabolism due to its role in mitochondrial function. Increased SLC25A24 methylation was also related to lower GMV in multiple brain regions in the overall cohort. These included the superior frontal gyrus, prefrontal cortex, and supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex, which are regions that have previously been implicated in CD and CU traits. While our findings are preliminary and need to be replicated in larger samples, they provide novel evidence that CU traits in females are associated with methylation levels in a fundamentally different way in CD and TD, which in turn may relate to observable variations in GMV across the brain.

Abstract Background Reduced birthweight is associated with adverse physical and mental health outcomes later in life. Children of adolescent mothers are at higher risk for reduced birthweight. The current study aimed to identify the key risk factors affecting birthweight in a well-characterized sample of adolescent mothers to inform preventive public health efforts. Methods Sixty-four adolescent mothers (≤ 21 years of age) provided detailed data on pregnancy, birth and psychosocial risk. Separate regression analyses with (1) birthweight and (2) low birthweight (LBW) as outcomes, and pregnancy complications, prenatal care, maternal age, substance abuse during pregnancy, socioeconomic risk, stressful life events and the child’s sex as independent variables were conducted. Exploratively, a receiver operating characteristic (ROC) analysis was performed to investigate the quality of the discriminatory power of the risk factors. Results The following variables explained variance in birthweight significantly: prenatal care attendance (p = .006), pregnancy complications (p = .006), and maternal substance abuse during pregnancy (p = .044). Prenatal care attendance (p = .023) and complications during pregnancy (p = .027) were identified as significant contributors to LBW. Substance abuse (p = .013), pregnancy complications (p = .022), and prenatal care attendance (p = .044) showed reasonable accuracy in predicting low birthweight in the ROC analysis. Conclusions Among high-risk adolescent mothers, both biological factors, such as pregnancy complications, and behavioural factors amenable to intervention, such as substance abuse and insufficient prenatal care, seem to contribute to reduced birthweight in their children, a predisposing factor for poorer health outcomes later in life. More tailored intervention programmes targeting the specific needs of this high-risk group are needed.

Financial risk-taking and loss aversion are multifaceted phenomena that are the focus of neuroscience, psychology, and economics research. A growing number of studies highlighted the role of hormones (particularly of testosterone) on socio-economic decision-making. However, the effects of testosterone on risk-taking under framing and consumer-based choices and preferences are inconclusive. We investigated the effects of 100 mg testosterone administration on aspects of decision-making within the Prospect Theory framework which is the most used descriptive model of decision-making under risk. We assessed risk-taking under framing and the endowment effect (effect of possession) using Bayesian modeling. Forty men participated in this double-blind placebo-controlled fully-randomized cross-over experiment and performed two tasks. One was a risk-taking task with binary choices under positive and negative framing associated with different probabilities. In the second task participants had to bid money for hedonic and utilitarian items. We observed a significant increase in serum testosterone concentrations after transdermal application. Compared to placebo, testosterone administration increased risk-taking under the positive framing (very large effect size) and decreased under the negative framing (moderate to small). The sensitivity to gain was positive in each framing. Our model showed that decision-making is jointly influenced by testosterone and the trade-off between gains and losses. However, while the endowment effect was more pronounced for hedonic than for utilitarian items, the effect was independent of testosterone. The findings provide novel information on the complex modulatory role of testosterone on risk-taking within the framework of prospect theory and shed light on mechanisms of behavioral economic biases. The proposed models of effects of individual differences in testosterone on risk-taking could be used as predictive models for reference-depended behavior under positive and negative framing with low and high probabilities.

Although there is evidence that testosterone has deteriorating effects on cognitive and affective empathy, whether testosterone administration influences both routes to understanding others has not yet been simultaneously investigated.We conducted a functional magnetic resonance imaging (fMRI) pharmacological study using a within-subjects, randomized, placebo-controlled, double-blind crossover design to examine the effects of 100 mg transdermal testosterone administration on brain activation during a task that examines affective and cognitive empathy simultaneously in a sample of 23 healthy right-handed adult men.Relative to placebo, testosterone did not alter affective or cognitive empathy functional brain networks. Instead, the task yielded activation in the canonical networks associated with both types of empathy. Affective empathy yielded activation in the inferior and middle frontal gyri, inferior temporal gyri, and the cingulate cortex. Cognitive empathy was associated with activation of the temporoparietal junction, medial prefrontal cortex, middle and inferior temporal gyri, and temporal pole. Behaviourally, testosterone administration decreased error rates and increased participants’ confidence in their responses regardless of response accuracy. Independent of testosterone administration, participants reported higher affective responses during emotionally negative scenarios.Even though our results provide further evidence that testosterone administration in healthy men does not alter brain activity underlying cognitive and affective empathy, testosterone administration does influence the empathic concern and hence socio-cognitive processes. The reproducibility and variability of the current and previous findings should nevertheless be addressed in upcoming studies.

Hyperscanning studies have begun to unravel the brain mechanisms underlying social interaction, indicating a functional role for interpersonal neural synchronization (INS), yet the mechanisms that drive INS are poorly understood. The current study, thus, addresses whether INS is functionally-distinct from synchrony in other systems – specifically the autonomic nervous system and motor behavior. To test this, we used concurrent functional near-infrared spectroscopy - electrocardiography recordings, while N = 34 mother-child and stranger-child dyads engaged in cooperative and competitive tasks. Only in the neural domain was a higher synchrony for mother-child compared to stranger-child dyads observed. Further, autonomic nervous system and neural synchrony were positively related during competition but not during cooperation. These results suggest that synchrony in different behavioral and biological systems may reflect distinct processes. Furthermore, they show that increased mother-child INS is unlikely to be explained solely by shared arousal and behavioral similarities, supporting recent theories that postulate that INS is higher in close relationships.

Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5' of the neurite modulator SLITRK5 (FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely mediated by epigenetic mechanisms impairing specific brain developmental networks and therefore exerting a long-term effect on neural functions in CD. Our results are exploratory and thus, further replication is needed.

Background: The previous and current studies highlight the psychological distress caused by coronavirus disease 2019 (COVID-19)-associated restrictions among the general population, especially among children and adolescents; however, few studies have examined children and adolescents with a mental disorder. The current study aimed to explore whether youth with mental disorders show a higher pandemic-associated psychological burden than healthy children and adolescents and to determine which psychiatric diagnoses are particularly associated with a higher distress level.Methods: In this study, 144 children and adolescents between the ages of 6 and 18 years with a mental disorder and 48 children and adolescents within the same age range without a mental disorder, and their caregivers, completed questionnaires assessing the pandemic-associated trauma symptoms (the Child Report of Post-Traumatic Symptoms [CROPS] and the Parents Report of Post-Traumatic Symptoms [PROPS]). Additionally, we asked specific questions about the pandemic-associated stress factors, such as financial problems, prolonged screen times, or loneliness.Results: Children and adolescents with a mental illness showed a significantly higher psychological burden than their mentally healthy peers. Female gender was a risk factor for a higher self-reported psychological burden, and younger age was associated with a more extensive parent-reported psychological burden. The patients with a depressive disorder showed significantly higher levels of psychological distress associated with the COVID-19 pandemic than the patients with an attention deficit and/or a conduct disorder.Conclusions: Children and adolescents with a mental illness, particularly, female children and individuals with a depressive disorder, are at an increased risk of suffering from pandemic-associated psychological distress. Adequate mental health care options, such as telepsychiatry, are indispensable.

Cognitive flexibility helps us to navigate through our ever-changing environment and has often been examined by reversal learning paradigms. Performance in reversal learning can be modeled using computational modeling which allows for the specification of biologically plausible models to infer psychological mechanisms. Although such models are increasingly used in cognitive neuroscience, developmental approaches are still scarce. Additionally, though most reversal learning paradigms have a comparable design regarding timing and feedback contingencies, the type of feedback differs substantially between studies. The present study used hierarchical Gaussian filter modeling to investigate cognitive flexibility in reversal learning in children and adolescents and the effect of various feedback types. The results demonstrate that children make more overall errors and regressive errors (when a previously learned response rule is chosen instead of the new correct response after the initial shift to the new correct target), but less perseverative errors (when a previously learned response set continues to be used despite a reversal) adolescents. Analyses of the extracted model parameters of the winning model revealed that children seem to use new and conflicting information less readily than adolescents to update their stimulus-reward associations. Furthermore, more subclinical rigidity in everyday life (parent-ratings) is related to less explorative choice behavior during the probabilistic reversal learning task. Taken together, this study provides first-time data on the development of the underlying processes of cognitive flexibility using computational modeling.

Background: At the group level, youths with conduct disorder (CD) show deficient emotion processing across various tasks compared to typically developing controls (TDC). But little is known about neuropsychological subgroups within the CD population, the clinical correlates of emotion processing deficits [for instance, with regard to the presence or absence of the DSM-5 Limited Prosocial Emotions (LPE) specifier], and associated risk factors.Methods: 542 children and adolescents with CD (317 girls) and 710 TDCs (479 girls), aged 9–18 years, were included from the FemNAT-CD multisite study. All participants completed three neuropsychological tasks assessing emotion recognition, emotion learning, and emotion regulation. We used a self-report measure of callous-unemotional traits to create a proxy for the LPE specifier.Results: Relative to TDCs, youths with CD as a group performed worse in all three emotion domains. But using clinically based cut-off scores, we found poor emotion recognition skills in only 23% of the participants with CD, followed by emotion regulation deficits in 18%, and emotion learning deficits in 13% of the CD group. Critically, the majority of youths with CD (~56%) did not demonstrate any meaningful neuropsychological deficit, and only a very small proportion showed pervasive deficits across all three domains (~1%). Further analyses indicate that established DSM-5 subtypes of CD are not tightly linked to neurocognitive deficits in one particular emotion domain over another (i.e., emotion recognition deficits in CD+LPE vs. emotion regulation deficits in CD–LPE).Conclusions: Findings from this large-scale data set suggest substantial neuropsychological diversity in emotion processing in the CD population and, consequently, only a subgroup of youths with CD are likely to benefit from additional behavioral interventions specifically targeting emotion processing mechanisms.

Background: The effects of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI)-neurofeedback on brain activation and behaviors have been studied extensively in the past. More recently, researchers have begun to investigate the effects of functional near-infrared spectroscopy-based neurofeedback (fNIRS-neurofeedback). FNIRS is a functional neuroimaging technique based on brain hemodynamics, which is easy to use, portable, inexpensive, and has reduced sensitivity to movement artifacts.Method: We provide the first systematic review and database of fNIRS-neurofeedback studies, synthesizing findings from 22 peer-reviewed studies (including a total of N = 441 participants; 337 healthy, 104 patients). We (1) give a comprehensive overview of how fNIRS-neurofeedback training protocols were implemented, (2) review the online signal-processing methods used, (3) evaluate the quality of studies using pre-set methodological and reporting quality criteria and also present statistical sensitivity/power analyses, (4) investigate the effectiveness of fNIRS-neurofeedback in modulating brain activation, and (5) review its effectiveness in changing behavior in healthy and pathological populations.Results and discussion: (1–2) Published studies are heterogeneous (e.g., neurofeedback targets, investigated populations, applied training protocols, and methods). (3) Large randomized controlled trials are still lacking. In view of the novelty of the field, the quality of the published studies is moderate. We identified room for improvement in reporting important information and statistical power to detect realistic effects. (4) Several studies show that people can regulate hemodynamic signals from cortical brain regions with fNIRS-neurofeedback and (5) these studies indicate the feasibility of modulating motor control and prefrontal brain functioning in healthy participants and ameliorating symptoms in clinical populations (stroke, ADHD, autism, and social anxiety). However, valid conclusions about specificity or potential clinical utility are premature.Conclusion: Due to the advantages of practicability and relatively low cost, fNIRS-neurofeedback might provide a suitable and powerful alternative to EEG and fMRI neurofeedback and has great potential for clinical translation of neurofeedback. Together with more rigorous research and reporting practices, further methodological improvements may lead to a more solid understanding of fNIRS-neurofeedback. Future research will benefit from exploiting the advantages of fNIRS, which offers unique opportunities for neurofeedback research.

Background: A deficit in empathy has repeatedly been described in individuals with conduct disorder (CD), and in particular in those with callous unemotional traits. Until now, little is known about the neural basis of empathy in children and adolescents with early onset conduct disorder. The aim of this study was to examine neural responses during empathizing in children and adolescents with CD with a task that allowed to differentiate between the judgment of the emotional states of other people and the own emotional response to other people's emotional state. Moreover, we investigated associations of callous-unemotional traits and neural activations during empathizing.Methods: Using functional magnetic resonance imaging (fMRI) we investigated 14 boys with early onset CD and 15 typically developing (TDC) age matched controls between 8 and 16 years of age. Happy and sad faces were presented, and participants were asked to either infer the emotional state from the face (other-task) or to judge their own emotional response (self-task). A perceptual decision on faces was used as a control task. Individual empathic abilities and callous unemotional traits were assessed.Results: During the other task, TDC boys showed significantly larger right amygdala responses than CD boys. Higher empathic abilities (as assessed with the Bryant Index of Empathy) were associated with higher responses in the right amygdala within the CD boys and across the entire sample. Moreover, across the entire sample, callous-unemotional traits were negatively related to the BOLD-response in the right amygdala. CD boys showed larger responses in the dorsal and ventral medial prefrontal cortex across tasks and increased activation in dorsal medial prefrontal cortex specifically during the self-conditions, which were also related to empathic abilities within the CD boys.Conclusions: The data emphasize the important role of the amygdala in empathy related emotional processing. Diminished amygdala responses and their association with low empathy suggest a pivotal influence of impaired amygdala processing in early-onset CD, in particular for deficits in empathic behavior and related callous-unemotional-traits. Elevated response in the medial prefrontal cortex in boys with CD point toward increased involvement of brain areas related to self-referential processing and cognitive empathy during empathizing.

Abstract Categorical diagnoses from the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) manuals are increasingly found to be incongruent with emerging neuroscientific evidence that points towards shared neurobiological dysfunction underlying attention deficit/hyperactivity disorder and autism spectrum disorder. Using resting-state functional magnetic resonance imaging data, functional connectivity of the default mode network, the dorsal attention and salience network was studied in 1305 typically developing and diagnosed participants. A transdiagnostic hierarchical Bayesian modeling framework combining Indian Buffet Processes and Latent Dirichlet Allocation was proposed to address the urgent need for objective brain-derived measures that can acknowledge shared brain network dysfunction in both disorders. We identified three main variation factors characterized by distinct coupling patterns of the temporoparietal cortices in the default mode network with the dorsal attention and salience network. The brain-derived factors were demonstrated to effectively capture the underlying neural dysfunction shared in both disorders more accurately, and to enable more reliable diagnoses of neurobiological dysfunction. The brain-derived phenotypes alone allowed for a classification accuracy reflecting an underlying neuropathology of 67.33% (+/−3.07) in new individuals, which significantly outperformed the 46.73% (+/−3.97) accuracy of categorical diagnoses. Our results provide initial evidence that shared neural dysfunction in ADHD and ASD can be derived from conventional brain recordings in a data-led fashion. Our work is encouraging to pursue a translational endeavor to find and further study brain-derived phenotypes, which could potentially be used to improve clinical decision-making and optimize treatment in the future.

Callous-unemotional traits are characterized by a lack of empathy, a disregard for others' feelings and shallow or deficient affect, such as a lack of remorse or guilt. Neuroanatomical correlates of callous-unemotional traits have been demonstrated in clinical samples (i.e., adolescents with disruptive behavior disorders). However, it is unknown whether callous-unemotional traits are associated with neuroanatomical correlates within normative populations without clinical levels of aggression or antisocial behavior. Here we investigated the relationship between callous-unemotional traits and gray matter volume using voxel-based morphometry in a large sample of typically-developing boys and girls (N=189). Whole-brain multiple regression analyses controlling for site, total intracranial volume, and age were conducted in the whole sample and in boys and girls individually. Results revealed that sex and callous-unemotional traits interacted to predict gray matter volume when considering the whole sample. This interaction was driven by a significant positive correlation between callous-unemotional traits and bilateral anterior insula volume in boys, but not girls. Insula gray matter volume explained 19% of the variance in callous-unemotional traits for boys. Our results demonstrate that callous-unemotional traits are related to variations in brain structure beyond psychiatric samples. This association was observed for boys only, underlining the importance of considering sex as a factor in future research designs. Future longitudinal studies should determine whether these findings hold over childhood and adolescence, and whether the neuroanatomical correlates of callous-unemotional traits are predictive of future psychiatric vulnerability. General scientific summary: This study suggests that callous-unemotional traits have a neuroanatomical correlate within typically developing boys, but not girls. Bilateral anterior insula volume explains up to 19% of the variance in callous-unemotional traits in boys. Keywords: Callous-unemotional traits, Insula, Pediatric neuroimaging, Sex differences, Voxel-based morphometry

Abstract Background This study focuses on children living in foster families with a history of maltreatment or neglect. These children often show adverse mental health outcomes reflected in increased externalizing and internalizing problems. It is expected that these adverse outcomes are associated with increased parental stress levels experienced by foster mothers as well as foster fathers. Methods The study sample included 79 children living in foster families and 140 children living in biological families as comparison group. The age of the children ranged from 2 to 7 years. Mental health problems were assessed with the Child Behavior Checklist, while parenting stress was measured with a parenting stress questionnaire including subscales on the amount of experienced stress and the amount of perceived support. The Child Behavior Checklist assessments were based mainly on maternal reports, while the parental stress assessments were based on maternal as well as paternal reports. Results As expected the results showed increased externalizing and internalizing scores for the foster children accompanied by increased parental stress experiences in the foster family sample (however only in the maternal, but not in the paternal stress reports). The stress differences between the foster and biological family groups disappeared, when the children’s mental health problem scores were included as covariates. Moreover, especially the externalizing scores were strong predictors of parental stress in both, the groups of foster and biological parents. The amount of perceived social support was associated with reduced parental stress, but only in the group of biological fathers. Conclusion The emergence of parental stress in biological as well as foster parents is closely related to child characteristics (mainly externalizing child problems). Possible implications for the reduction of parental stress are discussed as a consequence of the present results.

The growing interest in testosterone's effects on men's social behaviors, in particular aggressive, risk-taking, or status maintenance behaviors, is accompanied by a paucity of dose-dependent pharmacokinetic data. Examining the neurophysiological effects of transdermal testosterone typically includes a 4h delay before further brain-behavior measurements. Nevertheless, high heterogeneity regarding the timing of follow-up measurements and dosage remains. In a double-blind placebo-controlled design, we examined the short-term pharmacokinetic profile of 100-mg transdermal testosterone (Testotop®) to determine the optimal time for detecting testosterone-mediated effects. Across two studies, 35 healthy men received a single dose of testosterone and placebo in two separate sessions. In study one (n = 16), serum testosterone and cortisol were assessed serially every 30 min up to 2 h posttreatment. In study two (n = 19), we assessed serum testosterone and cortisol at baseline, 2 h, and 4.15 h (255 min) posttreatment. Relative to baseline and placebo, transdermal testosterone significantly increased total serum testosterone concentrations 90 min posttreatment, reaching maximum concentration between 2 h and 3 h posttreatment. Albeit elevated, serum testosterone levels gradually decreased between 2 h and 4 h following treatment. Transdermal testosterone did not suppress cortisol release. Instead, cortisol concentrations decreased according to cortisol's known circadian rhythm. Unlike previous findings showing significant testosterone concentration increases as soon as 60 min and as late as 3 h post 150-mg testosterone treatment, our 100-mg testosterone manipulation significantly increased testosterone concentrations 90 min following treatment. These pharmacokinetic data are important in facilitating the optimization of timing parameters for future testosterone challenge studies.

One of the most significant effects of neural plasticity manifests in the case of sensory deprivation when cortical areas that were originally specialized for the functions of the deprived sense take over the processing of another modality. Vision and audition represent two important senses needed to navigate through space and time. Therefore, the current systematic review discusses the cross-modal behavioral and neural consequences of deafness and blindness by focusing on spatial and temporal processing abilities, respectively. In addition, movement processing is evaluated as compiling both spatial and temporal information. We examine whether the sense that is not primarily affected changes in its own properties or in the properties of the deprived modality (i.e., temporal processing as the main specialization of audition and spatial processing as the main specialization of vision). References to the metamodal organization, supramodal functioning, and the revised neural recycling theory are made to address global brain organization and plasticity principles. Generally, according to the reviewed studies, behavioral performance is enhanced in those aspects for which both the deprived and the overtaking senses provide adequate processing resources. Furthermore, the behavioral enhancements observed in the overtaking sense (i.e., vision in the case of deafness and audition in the case of blindness) are clearly limited by the processing resources of the overtaking modality. Thus, the brain regions that were previously recruited during the behavioral performance of the deprived sense now support a similar behavioral performance for the overtaking sense. This finding suggests a more input-unspecific and processing principle-based organization of the brain. Finally, we highlight the importance of controlling for and stating factors that might impact neural plasticity and the need for further research into visual temporal processing in deaf subjects.

A negative mood-congruent attention bias has been consistently observed, for example, in clinical studies on major depression. This bias is assumed to be dysfunctional in that it supports maintaining a sad mood, whereas a potentially adaptive role has largely been neglected. Previous experiments involving sad mood induction techniques found a negative mood-congruent attention bias specifically for young individuals, explained by an adaptive need for information transfer in the service of mood regulation. In the present study we investigated the attentional bias in typically developing children (aged 6–12 years) when happy and sad moods were induced. Crucially, we manipulated the age (adult vs. child) of the displayed pairs of facial expressions depicting sadness, anger, fear and happiness. The results indicate that sad children indeed exhibited a mood specific attention bias toward sad facial expressions. Additionally, this bias was more pronounced for adult faces. Results are discussed in the context of an information gain which should be stronger when looking at adult faces due to their more expansive life experience. These findings bear implications for both research methods and future interventions.

Background: Anorexia nervosa (AN) often begins in adolescence, however, the understanding of the underlying pathophysiology at this developmentally important age is scarce, impeding early interventions. We used diffusion tensor imaging (DTI) to investigate microstructural white matter (WM) brain changes including an experimental longitudinal follow-up. Methods: We acquired whole brain diffusion-weighted brain scans of 22 adolescent female hospitalized patients with AN at admission and nine patients longitudinally at discharge after weight rehabilitation. Patients (10–18 years) were compared to 21 typically developing controls (TD). Tract-based spatial statistics (TBSS) were applied to compare fractional anisotropy (FA) across groups and time points. Associations between average FA values of the global WM skeleton and weight as well as illness duration parameters were analyzed by multiple linear regression. Results: We observed increased FA in bilateral frontal, parietal and temporal areas in AN patients at admission compared to TD. Higher FA of the global WM skeleton at admission was associated with faster weight loss prior to admission. Exploratory longitudinal analysis showed this FA increase to be partially normalized after weight rehabilitation. Conclusions: Our findings reveal a markedly different pattern of WM microstructural changes in adolescent AN compared to most previous results in adult AN. This could signify a different susceptibility and reaction to semi-starvation in the still developing brain of adolescents or a time-dependent pathomechanism differing with extend of chronicity. Higher FA at admission in adolescents with AN could point to WM fibers being packed together more closely.

The integration of virtual acoustic environments (VAEs) with functional near-infrared spectroscopy (fNIRS) offers novel avenues to investigate behavioral and neural processes of speech-in-noise (SIN) comprehension in complex auditory scenes. Particularly in children with hearing aids (HAs), the combined application might offer new insights into the neural mechanism of SIN perception in simulated real-life acoustic scenarios. Here, we present first pilot data from six children with normal hearing (NH) and three children with bilateral HAs to explore the potential applicability of this novel approach. Children with NH received a speech recognition benefit from low room reverberation and target-distractors’ spatial separation, particularly when the pitch of the target and the distractors was similar. On the neural level, the left inferior frontal gyrus appeared to support SIN comprehension during effortful listening. Children with HAs showed decreased SIN perception across conditions. The VAE-fNIRS approach is critically compared to traditional SIN assessments. Although the current study shows that feasibility still needs to be improved, the combined application potentially offers a promising tool to investigate novel research questions in simulated real-life listening. Future modified VAE-fNIRS applications are warranted to replicate the current findings and to validate its application in research and clinical settings.

Children fitted with hearing aids (HAs) and children with attention deficit/hyperactivity disorder (ADHD) often have marked difficulties concentrating in noisy environments. However, little is known about the underlying neural mechanism of auditory and visual attention deficits in a direct comparison of both groups. The current functional near-infrared spectroscopy (fNIRS) study was the first to investigate the behavioral performance and neural activation during an auditory and a visual go/nogo paradigm in children fitted with bilateral HAs, children with ADHD and typically developing children (TDC). All children reacted faster, but less accurately, to visual than auditory stimuli, indicating a sensory-specific response inhibition efficiency. Independent of modality, children with ADHD and children with HAs reacted faster and tended to show more false alarms than TDC. On a neural level, however, children with ADHD showed supra-modal neural alterations, particularly in frontal regions. On the contrary, children with HAs exhibited modality-dependent alterations in the right temporopolar cortex. Higher activation was observed in the auditory than in the visual condition. Thus, while children with ADHD and children with HAs showed similar behavioral alterations, different neural mechanisms might underlie these behavioral changes. Future studies are warranted to confirm the current findings with larger samples. To this end, fNIRS provided a promising tool to differentiate the neural mechanisms underlying response inhibition deficits between groups and modalities.