OBJECTIVE:Childhood inhibited temperament (cIT) is associated with an increased risk for developing internalizing psychopathology. Neurobiological characteristics identified by structural magnetic resonance imaging (MRI) may elucidate the neural substrates for cIT, but studies are scarce and often focus on particular regions of interest. Moreover, current findings lack replication. This preregistered analysis from the ENIGMA-Anxiety Working Group examined structural brain characteristics associated with cIT using a comprehensive whole-brain approach. METHOD:Temperament assessments (behavioral observations, parent/teacher reports or self-reports on cIT before age 13 years) and MRI data (age at scan, 6-25 years) from international research sites (Europe, North America, South America) were pooled for mega-analysis. Following image processing and quality control, associations between cIT and brain structure were examined in 3,803 participants. Subcortical volumes, cortical thickness, and surface area (main analyses) and detailed subcortical characteristics (eg, subnuclei, subfields, partial volume effects; exploratory analyses) were considered. RESULTS:In the full sample, cIT showed no relation with brain structure, either as a main effect or in interactions with sex or age. Subgroup analyses (based on cIT assessment type) revealed cIT by sex interactions on mean cortical thickness (pMC-FWER = .037) and thickness of the right superior parietal region (pMC-FWER = .029) in youth with parent/teacher reports on cIT levels. Exploratory analyses revealed findings in the hippocampus, putamen, and caudate, but most did not survive statistical correction for multiple testing. CONCLUSION:This mega-analysis found no consistent associations between cIT and regional brain structure, although the role of parietal regions warrants further investigation. Future studies should consider brain function in cIT, preferably using longitudinal designs. PLAIN LANGUAGE SUMMARY:Inhibited temperament during childhood is a risk factor for the development of anxiety and depression later in life. A preregistered study from the international ENIGMA-Anxiety Working Group investigated whether characteristics of brain structure are associated with the level of childhood inhibited temperament, using brain scans and data on temperamental traits from participants aged 6 to 25 years, which have been previously acquired at research sites worldwide (total sample > 3,800 subjects). Analyses revealed no consistent correlations between brain structure and inhibited temperament. STUDY REGISTRATION INFORMATION:Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis. https://www.jaacap.org/article/S0890-8567(22)00299-4/fulltext.

Background: Digital phenotyping is an emerging field that aims to contribute to the clinical care of patients with mental disorders by offering objective, passive behavioural monitoring. This monitoring could be used for applications such as predicting the onset of episodes of mental illness. However, behaviours are often not unique to clinical disorders, and other factors in a person's life may contribute to their digital phenotyping behavioural pattern. Objective: We aimed to investigate non-clinical factors that may be relevant for personalisation in digital phenotyping, such as the area in which participants live and their regular phone habits, and discussed their implications in a depression relapse case study. Methods: In the MENTALPRECISION study we collected passive smartphone data (phone usage and location behaviours) in a predominantly healthy cohort (n=73) using the Behapp application. We administered a novel questionnaire, the "Smartphone Usage and Lifestyle Questionnaire" (SULQ), to the participants to gather information on their phone usage and lifestyle habits that could impact their digital phenotyping data. We trained a hidden Markov model (HMM) on the smartphone data and developed two types of digital phenotyping measures from the identified hidden behavioural states of the HMM. The "total dwell time" gave the percentage of time each participant spent in each state. The "individual transition probability" was extracted from the HMM itself for each participant, giving their personalised probabilities of transitioning between each of the hidden states. We compared the HMM-generated hidden state sequences and reported events such as holidays and illness. We carried out logistic regression between the digital phenotyping measures and various SULQ measures. We then provide a proof-of-concept for predicting depression relapse in recurrent depression using a HMM and consider the implication of non-clinical factors for this clinical application. Results: Visible differences in behaviour surrounding holidays and illness were observed in the generated hidden state sequences from the MENTALPRECISION study, as well as surrounding the depression relapse in the proof-of-concept. Participants who use another phone in addition to their personal smartphone spent significantly less time in the "socially inactive home time" state (FDR-corrected P=0.03, odds ratio 0.9196, 95% CI 0.8583-0.9808). iOS users spent significantly less time in the "socially active home time" state (FDR-corrected P=0.04, odds ratio 0.9330, 95% CI 0.8804-0.9857) than Android users, and participants reporting a smartphone addiction spent significantly more time in this state (FDR-corrected P=0.009, odds ratio 1.0787, 95% CI 1.0301-1.1272) when compared to participants reporting no smartphone addiction. Relationships between the mean transition probabilities and SULQ measures did not survive multiple comparison correction. We observed decreases in the monthly likelihood surrounding the depression relapse period, providing a possible metric for relapse prediction. Conclusions: When searching for clinically relevant behavioural signals, digital phenotyping researchers should consider additional non-clinical factors that may be contributing to the measured digital signal. Including this additional information could be used to improve personalisation of digital phenotyping models, leading to improved modelling abilities for goals such as depression relapse prediction. ### Competing Interest Statement Christian Beckmann is a director of SBGNeuro. Henricus Ruhé received grants from the Hersenstichting, ZonMw, the Dutch Ministry of Health and an unrestricted educational grant from Janssen. In addition he received speaking fees from Lundbeck, Janssen, Benecke and Prelum; all outside the current work. All other authors declare no conflicts of interest. ### Funding Statement The MENTALPRECISION study was funded by the European Research Council (consolidator grant 101001118). The SMARD study was funded by the Hersenstichting (Dutch Brain Foundation) (HA2015.01.07). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: MENTALPRECISION: the Medical Ethics Committee for the East of the Netherlands ("METC Oost Nederland") gave ethical approval for this work (MENTALPRECISION dossier number: NL82527.091.22). SMARD: the Medical Ethics Committee for the East of the Netherlands ("METC Oost Nederland") gave ethical approval for this work (SMARD dossier number: NL60033.091.16). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets analysed during the current study are available from the corresponding author on reasonable request.

Digital phenotyping has broad clinical potential, providing low-burden objective measures of behaviour as individuals go about their day. However, progress in making clinical inferences from these data is severely challenged by the common occurrence of missing data. We investigated non-homogeneous Poisson Point Process Models (PPPMs) as a method for imputing missing temporal digital phenotyping data, considering smartphone-based activities as 'points'. We assessed the inclusion of time-varying covariates ('hour' and 'day') in personalised PPPMs. We used participants from SMARD (n=26) for a ground truth evaluation, and PRISM (n=65) and Hersenonderzoek (n=283) for a replication analysis involving Hidden Markov Models, evaluating the effectiveness of PPPMs for imputation and their influence on downstream analysis. In the ground truth evaluation, PPPMs using one-hot encoded hour provided the highest out-of-sample likelihood. We successfully replicated findings from our prior work using this method, demonstrating that PPPMs using covariates are a promising imputation tool for digital phenotyping. ### Competing Interest Statement Christian Beckmann is a director of SBGNeuro. Henricus Ruhé received grants from the Hersenstichting, ZonMw, the Dutch Ministry of Health and an unrestricted educational grant from Janssen. In addition he received speaking fees from Lundbeck, Janssen, Benecke and Prelum; all outside the current work. All other authors declare no conflicts of interest. ### Funding Statement This study was funded by the European Research Council (consolidator grant 101001118). The SMARD study was funded by the Hersenstichting (Dutch Brain Foundation) (HA2015.01.07). The Dutch Brain Research Registry (Hersenonderzoek.nl) is supported by ZonMw‐Memorabel (project no 73305095003), Alzheimer Nederland, Amsterdam Neuroscience, and Hersenstichting. The PRISM project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 115916. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. This study reflects only the authors' view and the European Commission is not responsible for any use that may be made of the information it contains. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: SMARD: The ethics committee of the Radboudumc (Radboudumc ethics review board (2016-3009; NL60033.091.16)) gave ethical approval for this work. PRISM: The ethics committee of the University Medical Centre of Utrecht (Ethical Review Board University Medical Centre of Utrecht (17-021/D)) gave ethical approval for this work at the involved Dutch research centres. The ethics committee of Hospital General Universitario Gregorio Marañón (Comité Ético de Investigación Clínica Hospital General Universitario Gregorio Marañón (59359)) gave ethical approval for this work at the involved Spanish research centres. Hersenonderzoek: The ethics committee of VU University Medical Centre (Ethical Review Board VU University Medical Centre (2017.254)) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets analysed during the current study are available from the corresponding author on reasonable request.

Stereotypes can exert a powerful influence on our interactions with others, potentially leading to prejudice when factual evidence is ignored. Here, we identify neuroanatomical and developmental factors that influence the real-time integration of stereotypes and factual evidence during live social interactions. The study uses precisely quantified communicative exchanges in a longitudinal cohort of seventeen-year-olds followed since infancy, testing their ability to moderate stereotype tendencies toward children as contrary evidence accumulates. Our results indicate that the impact of stereotypes on communicative behavior is linked to individual variations in gray matter density and cortical thickness in the right anterior cingulate gyrus. In contrast, the ability to moderate stereotype tendencies is influenced by developmental exposure to social interactions during the initial years of life, beyond the effects of familial environment and later experiences. These findings pinpoint a key brain structure underlying stereotype tendencies and suggest that early-life social experiences have lasting consequences on how individuals integrate factual evidence in interpersonal communication.

Animal studies show that early life environmental factors, such as stress and trauma, can have a significant impact on a variety of bodily processes, including cellular aging and brain development. However, whether cellular wear-and-tear effects are also associated with individual differences in brain structures in humans, remains unknown. In this pre-registered study in a community sample of children (N=94, Mean age=12.71 years), we prospectively investigated the predictive value of two markers of cellular aging in childhood (at age 6 and 10) for brain morphology in early adolescence (age 12). More specifically, we associated buccal cell telomere length and epigenetic age in childhood to individual differences in adolescent whole-brain grey matter volume (GMV) including volumes of three regions of interest that have been found to be sensitive to effects of early life stress (i.e. amygdala, hippocampus, (pre)frontal cortex -PFC). Multiple regression analyses revealed no significant associations between childhood cellular aging (at 6 and 10 years) and early adolescent brain morphology. Exploratory Bayesian analyses indicated moderate to strong evidence for the null-findings. These results suggest that although our sample is modest, the associations between middle childhood cellular aging and early adolescent brain morphology are, if they do exist, likely not particularly large in community children. Future work should investigate whether these effects are similarly absent in large samples, in samples with a higher risk profile and in samples characterized by different age ranges. Highlights (3-5) - Investigation of cellular aging in relation to brain morphology in a community sample (N=95) - Epigenetic aging and telomere shortening were not associated with brain structure - Exploratory Bayesian Analyses reveal moderate to strong evidence for null findings - No association was found between cellular aging and white matter volume

Structural plasticity changes and functional differences in executive control tasks have been reported in bilinguals compared to monolinguals, supporting a proposed bilingual ‘advantage’ in executive control functions (e.g., task switching) due to continual usage of control mechanisms that inhibit one of the coexisting languages. However, it remains unknown whether these differences are also apparent in the spatial domain. The present fMRI study explores the use of spatial cues in 15 bilinguals and 14 monolinguals while navigating in an open-field virtual environment. In each trial, participants had to navigate towards a target object that was visible during encoding but hidden in retrieval. An extensive network was activated in bilinguals compared to monolinguals in the encoding and retrieval phase. During encoding, bilinguals activated the right temporal and left parietal regions (object trials) and left inferior frontal, precentral, and lingual regions more than monolinguals. During retrieval, the same contrasts activated the left caudate nucleus and the right dorsolateral prefrontal cortex (DLPFC), the left parahippocampal gyrus, as well as caudate regions. These results suggest that bilinguals may recruit neural networks known to subserve not only executive control processes but also spatial strategies.

A paradox of testosterone effects is seen in adolescents versus adults in social emotional approach-avoidance behavior. During adolescence, high testosterone levels are associated with increased anterior prefrontal (aPFC) involvement in emotion control, whereas during adulthood this neuro-endocrine relation is reversed. Rodent work shows that, during puberty, testosterone transitions from a neuro-developmental to a social-sexual activating hormone. In this study, we explored whether this functional transition is also present in human adolescents and young adults. Using a prospective longitudinal design, we investigated the role of testosterone on neural control of social emotional behavior during the transitions from middle to late adolescence and into young adulthood. Seventy-one individuals (tested at ages 14, 17, and 20 years) performed an fMRI-adapted approach-avoidance (AA) task involving automatic and controlled actions in response to social emotional stimuli. In line with predictions from animal models, the effect of testosterone on aPFC engagement decreased between middle and late adolescence, and shifted into an activational role by young adulthood-impeding neural control of emotions. This change in testosterone function was accompanied by increased testosterone-modulated amygdala reactivity. These findings qualify the testosterone-dependent maturation of the prefrontal-amygdala circuit supporting emotion control during the transition from middle adolescence into young adulthood.

There is accumulating evidence for positive effects of green spaces on mental and brain health. Here we investigated whether differentiating the types of green spaces may be relevant. On longitudinal data of children (N = 95) from the Netherlands, we quantified the link between green space exposure at home from birth onwards and MRI brain structure at 12.5 years. We differentiated between green space resulting from trees versus open green spaces and also associated visibility of sky (sky view factor) with brain structure (200 m buffer around home address). We observed a positive association between grey matter volume in different prefrontal clusters and green open space coverage as well as sky view, but a negative association within prefrontal clusters for tree cover density. Most importantly, in the medial prefrontal cortex, the only region in which all three analyses overlapped, the visibility of sky was the most important predictor. Our findings advance knowledge on health-promoting, evidence-based urban planning.

Recurrence in major depressive disorder (MDD) is common, but neurobiological models capturing vulnerability for recurrences are scarce. Disturbances in multiple resting‐state networks have been linked to MDD, but most approaches focus on stable (vs. dynamic) network characteristics. We investigated how the brain's dynamical repertoire changes after patients transition from remission to recurrence of a new depressive episode. Sixty two drug‐free, MDD‐patients with ≥2 episodes underwent a baseline resting‐state fMRI scan when in remission. Over 30‐months follow‐up, 11 patients with a recurrence and 17 matched‐remitted MDD‐patients without a recurrence underwent a second fMRI scan. Recurrent patterns of functional connectivity were characterized by applying Leading Eigenvector Dynamics Analysis (LEiDA). Differences between baseline and follow‐up were identified for the 11 non‐remitted patients, while data from the 17 matched‐remitted patients was used as a validation dataset. After the transition into a depressive state, basal ganglia‐anterior cingulate cortex (ACC) and visuo‐attentional networks were detected significantly more often, whereas default mode network activity was found to have a longer duration. Additionally, the fMRI signal in the basal ganglia‐ACC areas underlying the reward network, were significantly less synchronized with the rest of the brain after recurrence (compared to a state of remission). No significant changes were observed in the matched‐remitted patients who were scanned twice while in remission. These findings characterize changes that may be associated with the transition from remission to recurrence and provide initial evidence of altered dynamical exploration of the brain's repertoire of functional networks when a recurrent depressive episode occurs.

Defensive stress reactions, such as freezing and active fight-or-flight, are relevant for coping with threat. Action-preparatory activity supporting these reactions, including the amygdala, has been posited as a potential marker for stress-resilience. We considered the successive COVID-19 lockdowns as two pervasive stressors, to prospectively investigate the predictive value of neural threat-responses towards symptom development. Five years prior to the COVID-19 pandemic, 17-year-old adolescents (n = 64, Baseline-17) performed the fMRI-adapted Go/Nogo Under Threat (GUNT) task, where threat-anticipatory freezing reactions and transition to action are evoked to avoid a shock. A majority (n = 44) made themselves available for follow-up assessments before COVID (Baseline-20, age 20), during the first COVID-19 lockdown in the Netherlands (LD1, age 22.5), and during a second lockdown (LD2, age 23). The GUNT task quantified neural (thalamic, subcortical, amygdala) and physiological (bradycardia) markers of threat-anticipatory freezing and transition to action (mediated by anterior cingulate cortex). Threat-anticipatory amygdala responses (Baseline-17) were linked to stressor resilience, as quantified by self-reported anxiety symptoms between LD1 and LD2. However, stronger amygdala responses to low threat cues (Baseline-17) were associated with stronger anxiety symptoms. These effects occurred over and above early-life stress, COVID-19 stress burden, and overall symptom changes between age 17 and 20. These findings suggest that amygdala responses to acute threat provide a marker for resilience against real-life stressors, with adequate threat discrimination signaling resilience and stronger amygdala responses to low threat predicting vulnerability. The findings support the notion that neural responses to threat are instrumental for adaptive coping with pervasive stress.

A compelling amount of animal and human research has shown that perceived maternal stress during pregnancy can affect the neurodevelopment of the offspring. Prenatal maternal cortisol is frequently proposed as the biological key mechanism underlying this link; however, literature that investigates the effects of prenatal cortisol on subsequent neurodevelopment in humans is scarce. By using longitudinal data from a relatively large community sample of mother-child dyads (N = 73), this pre-registered study prospectively examined the role of maternal prenatal cortisol concentrations on subsequent individual differences in gray matter volume (GMV) and hippocampal subfield volumes at the onset of puberty of the offspring (12 years of age). Two markers of cortisol, that is, evening cortisol and circadian decline over the day, were used as indicators of maternal physiological stress during the last trimester of pregnancy. The results indicate that prenatal maternal cortisol levels were not associated with GMV or hippocampal subfield volumes of the children. These findings suggest that late pregnancy maternal cortisol may not be related to the structural development of the offspring's brain, at least not in healthy community samples and at the onset of puberty. When examining the influence of prenatal stress on offspring neurodevelopment, future investigations should delineate gestational timing effects of the cortisol exposure, cortisol assessment method, and impact of additional biomarkers, as these were not investigated in this study.

Callous-unemotional (CU) traits predict behavioral problems in adolescence. But little is known about early modulatory factors. Behavioral Inhibition (BI) in particular has been suggested to protect against the development of CU-traits. This temperamental predisposition is characterized by heightened environmental sensitivity. The current prospective longitudinal study examined whether BI at 15 months of age predicted lower CU-traits across development to age 21. A longitudinal sample of normatively developing children (n = 125) was used. BI was assessed at 15 months using a standard stranger/robot paradigm. CU-traits were assessed at 2, 5, 9, 12, 14, 17, and 21 years with parent, teacher, and self-reports. Developmental pathways across all available data points were examined using Bayesian mixed models and k-means cluster analysis. Infant BI predicted lower CU-traits across development for girls, suggesting that BI buffers the long-term development of CU-traits for girls. CU-traits peaked in early adulthood. Boys scored higher and showed higher increases in CU-traits than girls from childhood onward. There was no gender difference regarding infant BI. Together, the findings demonstrated gender differences in the development of CU-traits, with a protective role of BI for girls. These results shed new light on the developmental trajectories and protective factors of CU-traits and provide starting points for interventions aiming at increasing children's responsiveness to external cues to prevent antisocial traits and conduct problems.

Introduction Recurrence in major depression disorder (MDD) is common, but neurobiological models capturing vulnerability for recurrences are scarce. Disturbances in multiple resting-state networks have been linked to MDD, but most approaches focus on stable (vs. dynamic) network characteristics. We investigated how the brain’s dynamical repertoire changes after patients transition from remission to recurrence of a new depressive episode. Methods Sixty drug-free, MDD-patients with ≥2 episodes underwent a baseline resting-state fMRI scan when in remission. Over 30-months follow-up, 11 patients with a recurrence and 17 matched-remitted MDD-patients without a recurrence underwent a second fMRI scan. Recurrent patterns of functional connectivity were characterized by applying leading eigenvector dynamics analysis (LEiDA). Differences between baseline and follow-up were identified for the 11 non-remitted patients, while data from the 17 matched-remitted patients was used as a validation dataset. Results After the transition into a depressive state, the reward and a visuo-attentional networks were detected significantly more often, whereas default mode network activity was found to have a longer duration. Additionally, the fMRI signal in the areas underlying the reward network were significantly less synchronized with the rest of the brain after recurrence (compared to a state of remission). These changes were not observed in the matched-remitted patients who were scanned twice while in remission. Conclusion These findings characterize the changes that are specifically associated with the transition from remission to recurrence and provide first evidence of increased segregation in the brain’s dynamical repertoire when a recurrent depressive episode occurs. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Netherlands Trial Register trial number: NTR3768 ### Clinical Protocols ### Funding Statement The DELTA-neuroimaging study was funded by the Dutch Brain Foundation [Hersenstichting; Grant #2009(2)-72]. Further support was obtained by unrestricted personal grants from the AMC to RJTM (AMC PhD Scholarship) and CAF (AMC MD-PhD Scholarship). HGR is supported by a NWO/ZonMW VENI-grant (#016.126.059). AT and NI are partly funded by the Dutch Brain Foundation [Hersenstichting; Grant #HA2015.01.07; SMARD]. RJTM is supported by an unrestricted ABC Talent Grant. MLK is supported by the Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117), and Centre for Eudaimonia and Human Flourishing at Linacre College funded by the Pettit and Carlsberg Foundations. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local Medical Ethical Committee of Amsterdam University Medical Centre. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is available upon request via the Donders Repository (). Data can be provided by the Donders Institute for Brain, Cognition, and Behaviour pending scientific review and a completed data transfer agreement in collaboration with AmsterdamUMC. Requests for the data should be submitted to HR. The MATLAB scripts used to analyse the data in this study are publicly available at .

Defining predictors of recurrence might help reduce the huge burden of (recurrent) Major Depressive Disorder. Apart from the classical number of previous episodes and residual symptoms, mood fluctuations, (hot) neuropsychological tasks and (dynamic) resting-state connectivity patterns might be useful markers associated with recurrences.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

The COVID-19 pandemic has led to unprecedented societal changes limiting us in our mobility and our ability to connect with others in person. These unusual but widespread changes provide a unique opportunity for studies using digital phenotyping tools. Digital phenotyping tools, such as mobile passive monitoring platforms (MPM), provide a new perspective on human behavior and hold promise to improve human behavioral research. However, there is currently little evidence that these tools can reliably detect changes in behavior. Considering the Considering the COVID-19 pandemic as a high impact common environmental factor we studied potential impact on behavior of participants using our mobile passive monitoring platform BEHAPP that was ambulatory tracking them during the COVID-19 pandemic. We pooled data from three MPM studies involving Schizophrenia (SZ), Major Depressive Disorder (MDD) and Bipolar Disorder (BD) patients (N = 12). We compared the data collected on weekdays during three weeks prior and three weeks subsequent to the start of the quarantine. We hypothesized an increase in communication and a decrease in mobility. We observed a significant increase in the total time spent on communication applications (median 179 and 243 min per week respectively, p = 0.005), and a significant decrease in the number of unique places visited (median 6 and 3 visits per week respectively, p = 0.007), while the total time spent at home did not change significantly (median 64 and 77 h per week, respectively, p = 0.594). The data provides a proof of principle that digital phenotyping tools can identify changes in human behavior incited by a common external environmental factor.

It is clear that the steroid hormone testosterone plays an important role in the regulation of social emotional behavior, but it remains unknown which neural circuits mediate these hormonal influences in humans. We investigated the modulatory effects of endogenous testosterone on the control of social emotional behavior by applying functional magnetic resonance imaging while healthy male participants performed a social approach-avoidance task. This task operationalized social emotional behavior by having participants approach and avoid emotional faces by pulling and pushing a joystick, respectively. Affect-congruent trials mapped the automatic tendency to approach happy faces and avoid angry faces. Affect-incongruent trials required participants to override those automatic action tendencies and select the opposite response (approach-angry, avoid-happy). The social emotional control required by affect-incongruent responses resulted in longer reaction times (RTs) and increased activity at the border of the ventrolateral prefrontal cortex and frontal pole (VLPFC/FP). We show that endogenous testosterone modulates these cerebral congruency effects through 2 mechanisms. First, participants with lower testosterone levels generate larger VLPFC/FP responses during affect-incongruent trials. Second, during the same trials, endogenous testosterone modulates the effective connectivity between the VLPFC/FP and the amygdala. These results indicate that endogenous testosterone influences local prefrontal activity and interregional connectivity supporting the control of social emotional behavior.

An interesting factor explaining recurrence risk in Major Depressive Disorder (MDD) may be neuropsychological functioning, i.e., processing of emotional stimuli/information. Negatively biased processing of emotional stimuli/information has been found in both acute and (inconclusively) remitted states of MDD, and may be causally related to recurrence of depression. We aimed to investigate self-referent, memory and interpretation biases in recurrently depressed patients in remission and relate these biases to recurrence. We included 69 remitted recurrent MDD-patients (rrMDD-patients), 35–65 years, with ≥2 episodes, voluntarily free of antidepressant maintenance therapy for at least 4 weeks. We tested self-referent biases with an emotional categorization task, bias in emotional memory by free recall of the emotion categorization task 15 min after completing it, and interpretation bias with a facial expression recognition task. We compared these participants with 43 never-depressed controls matched for age, sex and intelligence. We followed the rrMDD-patients for 2.5 years and assessed recurrent depressive episodes by structured interview. The rrMDD-patients showed biases toward emotionally negative stimuli, faster responses to negative self-relevant characteristics in the emotional categorization, better recognition of sad faces, worse recognition of neutral faces with more misclassifications as angry or disgusting faces and less misclassifications as neutral faces (0.001 < p < 0.05). Of these, the number of misclassifications as angry and the overall performance in the emotional memory task were significantly associated with the time to recurrence (p ≤ 0.04), independent of residual symptoms and number of previous episodes. In a support vector machine data-driven model, prediction of recurrence-status could best be achieved (relative to observed recurrence-rate) with demographic and childhood adversity parameters (accuracy 78.1%; 1-sided p = 0.002); neuropsychological tests could not improve this prediction. Our data suggests a persisting (mood-incongruent) emotional bias when patients with recurrent depression are in remission. Moreover, these persisting biases might be mechanistically important for recurrence and prevention thereof.

Animal and human studies have shown that both early-life traumatic events and ongoing stress episodes affect neurodevelopment, however, it remains unclear whether and how they modulate normative adolescent neuro-maturational trajectories. We characterized effects of early-life (age 0–5) and ongoing stressors (age 14–17) on longitudinal changes (age 14 to17) in grey matter volume (GMV) of healthy adolescents (n = 37). Timing and stressor type were related to differential GMV changes. More personal early-life stressful events were associated with larger developmental reductions in GMV over anterior prefrontal cortex, amygdala and other subcortical regions; whereas ongoing stress from the adolescents’ social environment was related to smaller reductions over the orbitofrontal and anterior cingulate cortex. These findings suggest that early-life stress accelerates pubertal development, whereas an adverse adolescent social environment disturbs brain maturation with potential mental health implications: delayed anterior cingulate maturation was associated with more antisocial traits – a juvenile precursor of psychopathy.