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Abstract Background Biopsychosocial changes during adolescence are thought to confer risk for emotion dysregulation, and in particular, anxiety disorders. However, there are substantial gaps in our knowledge about the biological mechanisms underlying anxiety during adolescence, and whether this contributes to the higher prevalence in females. The Puberty and NeuroDevelopment in Adolescents (PANDA) study aims to examine links between biological (sex hormones, cortisol) and social environmental factors and brain function during adolescence, with a focus on key processes (emotion regulation, fear learning) identified as relevant for the development of anxiety disorders. Methods PANDA is a cross-sectional study with an observational design that aims to recruit a total of 175 adolescents aged 11-16 (majority female) and their parents/guardians, from the community. Brain function will be examined using magnetic resonance imaging (MRI), including functional MRI tasks of emotion regulation and fear learning. Hormones will be measured from hair (i.e., cortisol) and weekly saliva samples (i.e., oestradiol, progesterone, five across a month in females). Questionnaires and semi-structured interviews will be used to assess mental health and social environmental factors such as parenting and adverse childhood experiences. An online study of 113 adolescents was also incorporated during the COVID-19 pandemic as a questionnaire-only sub-study. Discussion Strengths of this study include the collection of multiple saliva samples to assess variability in hormone levels, examination of the timing of adverse childhood experiences, inclusion of both maternal and paternal parental factors, exploration of mechanisms through the examination of brain structure and function, and multi-method, multi-informant collection of mental health symptoms. This study addresses important gaps in the literature and will enhance knowledge of the biological and environmental contributors to emotion dysregulation and anxiety in adolescents.

IntroductionThe number of insular gyri is elevated in patients with schizophrenia. Thus, it has potential as a marker of early neurodevelopmental abnormalities. However, currently it remains unclear whether patients with other neuropsychiatric disorders, such as affective disorders, also have this gross brain anatomical feature.Materials and methodsThe macroscopic features of the insular cortex in 26 patients with bipolar disorder (BD), 56 with major depressive disorder (MDD), and control subjects for each clinical group (24 for BD and 33 for MDD) were assessed using magnetic resonance imaging.ResultsThe number of short insular gyri was higher in BD patients than in matched controls bilaterally with well-developed accessory and middle short gyri. Furthermore, the left middle short gyrus was more developed in MDD patients than in matched controls, and was weakly associated with the severity of depressive symptoms.DiscussionThe present results indicate that changes in the gross morphology of the insular cortex in BD and MDD is a potential vulnerability factor associated with their neurodevelopmental pathologies, and may also contribute to the severity of symptoms in MDD.

Introduction Coding has become burdensome to healthcare systems due to patient complexity and resource requirements. In Alberta, Intelligent Medical Objects (IMO), an interface terminology mapping product, is integrated within the new province-wide Clinical Information System, named Connect Care (CC), to support documentation by clinicians and map clinical terminologies to ICD-10. This study evaluates comparability of terminologies mapped ICD-10 codes to the ICD-10 codes in DAD. Approach We conducted a retrospective analysis by linking acute care hospital DAD with CC between April 2021 and December 2023. The primary outcome was the level of agreement between ‘hospital problem list’ of CC and DAD for ICD-10-CA codes at a 3-digit level. The number of diagnoses and rate of unspecified codes were also compared. The outcome measures were stratified by physician specialty, hospital type and location, and length-of-stay (LOS). Results A total of 498,834 unique hospital records were linked. The average level of agreement between CC and DAD at 3-digit level of ICD-10-CA code was 43.4%. The average number of diagnoses captured in CC (3.91) was slightly lower than DAD (4.06), and the average rate of unspecified codes was higher in CC (26.4%) compared to DAD (23.0%). The level of agreement varied by specialty and length-of-stay with specialties with more complex patients and longer lengths-of-stay having the lowest agreement (43% for generalists and internal medicine and 33% for LOS >3 months). Conclusion Level of agreement between CC and DAD for ICD-10 data was identified as low, indicating significant disparities between terminology mappings and the coding process.

Introduction Globally, differences in coding practices and guidelines lead to variations in hospital-administrative data. Studies on patient safety found that better hospital-data quality is associated with higher rates of patient safety events. This study outlines our process of creating a standardized tool for countries to assess their hospital-administrative data quality. Approach We developed 24 indicators across five different dimensions through a Delphi-consensus method. To test applicability of these indicators, we approached representatives from 50 countries with an online survey comprised of qualitative and quantitative questions. Characteristics of each country and indicator scores were noted. A data quality overall score, out of 20, was calculated for each country based on survey responses. The score was classified into 3 data quality categories: high (≥18), moderate (13-17.9), and low (

Abstract Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Alberta has rich clinical and health services data held under the custodianship of Alberta Health and Alberta Health Services (AHS), which is not only used for clinical and administrative purposes but also disease surveillance and epidemiological research. Alberta is the largest province in Canada with a single payer centralised health system, AHS, and a consolidated data and analytics team supporting researchers across the province. This paper describes Alberta's data custodians, data governance mechanisms, and streamlined processes followed for research data access. AHS has created a centralised data repository from multiple sources, including practitioner claims data, hospital discharge data, and medications dispensed, available for research use through the provincial Data and Research Services (DRS) team. The DRS team is integrated within AHS to support researchers across the province with their data extraction and linkage requests. Furthermore, streamlined processes have been established, including: 1) ethics approval from a research ethics board, 2) any necessary operational approvals from AHS, and 3) a tripartite legal agreement dictating terms and conditions for data use, disclosure, and retention. This allows researchers to gain timely access to data. To meet the evolving and ever-expanding big-data needs, the University of Calgary, in partnership with AHS, has built high-performance computing (HPC) infrastructure to facilitate storage and processing of large datasets. When releasing data to researchers, the analytics team ensures that Alberta's Health Information Act's guiding principles are followed. The principal investigator also ensures data retention and disposition are according to the plan specified in ethics and per the terms set out by funding agencies. Even though there are disparities and variations in the data protection laws across the different provinces in Canada, the streamlined processes for research data access in Alberta are highly efficient.

Background: Our understanding of the mechanisms relating pubertal timing to mental health problems via brain development remains rudimentary. Method: Longitudinal data was sourced from ∼11,500 children from the Adolescent Brain Cognitive Development (ABCD) Study (age 9–13years). We built models of “brain age” and “puberty age” as indices of brain and pubertal development. Residuals from these models were used to index individual differences in brain development and pubertal timing, respectively. Mixed-effects models were used to investigate associations between pubertal timing and regional and global brain development. Mediation models were used to investigate the indirect effect of pubertal timing on mental health problems via brain development. Results: Earlier pubertal timing was associated with accelerated brain development, particularly of subcortical and frontal regions in females and subcortical regions in males. While earlier pubertal timing was associated with elevated mental health problems in both sexes, brain age did not predict mental health problems, nor did it mediate associations between pubertal timing and mental health problems. Conclusion: This study highlights the importance of pubertal timing as a marker associated with brain maturation and mental health problems.

Empathy, which is important for social functioning and mental health, is recognized to have both cognitive and affective components. While several studies have demonstrated unique neural underpinnings of empathy components in adults, few have investigated this in young people. Investigating associations between empathy and brain functional connectivity during childhood is beneficial to begin to build a comprehensive picture of the neural correlates of empathy across the lifespan. One hundred and twelve children (52% female, mean age 10 years) underwent magnetic resonance imaging brain scans including a resting-state sequence and completed empathy self-report measures. Seed-to-whole-brain resting-state functional connectivity analyses demonstrated that higher affective empathy (affective sharing and empathic distress) was associated with weaker connectivity between key hubs of the default mode network (DMN) and other widespread areas in the brain. Analyses of resting-state networks demonstrated that higher cognitive empathy was associated with both stronger and weaker connectivity between dorsal and lateral regions of the DMN and regions outside of the DMN, including the pre- and postcentral gyrus, and the cerebellum. Higher affective sharing was associated with greater connectivity between the anterior salience network and the pre- and postcentral gyrus. However, these associations did not withstand correction for multiple models. While interpretations should be made cautiously, findings suggest wide-ranging and diffuse connectivity patterns may be related to several components of empathy in children. These findings could indicate a more complex picture of the neural correlates of empathy processes in childhood, with less specialization and more widespread involvement of regions and networks. Future studies should attempt to replicate these findings using different measurement approaches.

The negative impact of adverse experiences in childhood on neurodevelopment is well documented. Less attention however has been given to the impact of variations in “normative” parenting behaviors. The influence of these parenting behaviors is likely to be marked during periods of rapid brain reorganization, such as late childhood. The aim of the current study was to investigate associations between normative parenting behaviors and the development of structural brain networks across late childhood. Data were collected from a longitudinal sample of 114 mother-child dyads (54% female children, M age 8.41 years, SD = 0.32 years), recruited from low socioeconomic areas of Melbourne, Australia. At the first assessment parenting behaviors were coded from two lab-based interaction tasks and structural magnetic resonance imaging (MRI) scans of the children were performed. At the second assessment, approximately 18 months later (M age 9.97 years, SD = 0.37 years) MRI scans were repeated. Cortical thickness (CT) was extracted from T1-weighted images using FreeSurfer. Structural covariance (SC) networks were constructed from partial correlations of CT estimates between brain regions and estimates of network efficiency and modularity were obtained for each time point. The change in these network measures, from Time 1 to Time 2, was also calculated. At Time 2, less positive maternal affective behavior was associated with higher modularity (more segregated networks), while negative maternal affective behavior was not related. No support was found for an association between local or global efficacy and maternal affective behaviors at Time 2. Similarly, no support was demonstrated for associations between maternal affective behaviors and change in network efficiency and modularity, from Time 1 to Time 2. These results indicate that normative variations in parenting may influence the development of structural brain networks in late childhood and extend current knowledge about environmental influences on structural connectivity in a developmental context.

Abstract Structural covariance conceptualizes how morphologic properties of brain regions are related to one another (across individuals). It can provide unique information to cortical structure (e.g., thickness) about the development of functionally meaningful networks. The current study investigated how structural covariance networks develop during the transition from childhood to adolescence, a period characterized by marked structural re-organization. Participants (N = 192; scans = 366) completed MRI assessments between 8.5 and 14.5 years of age. A sliding window approach was used to create “age-bins”, and structural covariance networks (based on cortical thickness) were created for each bin. Next, generalized additive models were used to characterize trajectories of age-related changes in network properties. Results revealed nonlinear trajectories with “peaks” in mean correlation and global density that are suggestive of a period of convergence in anatomical properties across the cortex during early adolescence, prior to regional specialization. “Hub” regions in sensorimotor cortices were present by late childhood, but the extent and strength of association cortices as “hubs” increased into mid-adolescence. Moreover, these regional changes were found to be related to rates of thinning across the cortex. In the context of neurocognitive networks, the frontoparietal, default mode, and attention systems exhibited age-related increases in within-network and between-network covariance. These regional and modular developmental patterns are consistent with continued refinement of socioemotional and other complex executive functions that are supported by higher-order cognitive networks during early adolescence.

Abstract Parenting behavior has a vital role in the development of the brain and cognitive abilities of offspring throughout childhood and adolescence. While positive and aggressive parenting behavior have been suggested to impact neurobiology in the form of abnormal brain activation in adolescents, little work has investigated the links between parenting behavior and the neurobiological correlates of cognitive performance during this age period. In the current longitudinal fMRI study, associations between parenting behaviors and cognitive performance and brain activation across mid- and late-adolescence were assessed. Observed measures of maternal aggressive and positive behavior were recorded in early adolescence (12 years) and correlated with fMRI activation and in-scanner behavioral scores on the multi-source interference task (MSIT) during mid- (16 years; 95 participants) and late-adolescence (19 years; 75 participants). There was a significant reduction in inhibitory-control-related brain activation in posterior parietal and cingulate cortices as participants transitioned from mid- to late-adolescence. Positive maternal behavior in early-adolescence was associated with lower activation in the left parietal and DLPFC during the MSIT in mid-adolescence, whereas maternal aggressive behavior was associated with longer reaction time to incongruent trials in late-adolescence. The study supports the notion that maternal behavior may influence subsequent neurocognitive development during adolescence.

An increased prevalence of duplicated Heschl’s gyrus (HG) has been repeatedly demonstrated in various stages of schizophrenia as a potential neurodevelopmental marker, but it remains unknown whether other neuropsychiatric disorders also exhibit this macroscopic brain feature. The present magnetic resonance imaging study aimed to examine the disease specificity of the established finding of altered HG patterns in schizophrenia by examining independent cohorts of bipolar disorder (BD) and major depressive disorder (MDD). Twenty-six BD patients had a significantly higher prevalence of HG duplication bilaterally compared to 24 age- and sex-matched controls, while their clinical characteristics (e.g., onset age, number of episodes, and medication) did not relate to HG patterns. No significant difference was found for the HG patterns between 56 MDD patients and 33 age- and sex-matched controls, but the patients with a single HG were characterized by more severe depressive/anxiety symptoms compared to those with a duplicated HG. Thus, in keeping with previous findings, the present study suggests that neurodevelopmental pathology associated with gyral formation of the HG during the late gestation period partly overlaps between schizophrenia and BD, but that HG patterns may make a somewhat distinct contribution to the phenomenology of MDD.

Neighborhood disadvantage has consistently been linked to alterations in brain structure; however, positive environmental (e.g., positive parenting) and psychological factors (e.g., temperament) may buffer these effects. We aimed to investigate associations between neighborhood disadvantage and deviations from typical neurodevelopmental trajectories during adolescence, and examine the moderating role of positive parenting and temperamental effortful control (EC). Using a large dataset (n = 1313), a normative model of brain morphology was established, which was then used to predict the age of youth from a longitudinal dataset (n = 166, three time-points at age 12, 16, and 19). Using linear mixed models, we investigated whether trajectories of the difference between brain-predicted-age and chronological age (brainAGE) were associated with neighborhood disadvantage, and whether positive parenting (positive behavior during a problem-solving task) and EC moderated these associations. We found that neighborhood disadvantage was associated with positive brainAGE during early adolescence and a deceleration (decreasing brainAGE) thereafter. EC moderated this association such that in disadvantaged adolescents, low EC was associated with delayed development (negative brainAGE) during late adolescence. Findings provide evidence for complex associations between environmental and psychological factors, and brain maturation. They suggest that neighborhood disadvantage may have long-term effects on neurodevelopment during adolescence, but high EC could buffer these effects.

Early socioeconomic status (SES) has consistently been associated with child health and cognitive outcomes, in addition to alterations in brain function and connectivity. The goal of the present study was to probe the effects of different facets of SES (parent education, income, and neighborhood disadvantage), that likely represent varying aspects of the environment, on resting state functional connectivity (rsFC). We investigated this question in a large sample of 9475 children (aged 9–10 years) from the Adolescent Brain Cognitive Development (ABCD) Study. Specifically, we analyzed the association between household SES (parent education, income-to-needs ratio) and neighborhood disadvantage, and system-level rsFC using within-sample split-half replication. We then tested whether the associations were unique to each SES measure, and whether household SES and neighborhood disadvantage had interactive effects on rsFC. SES measures had both common and distinct effects on rsFC, with sensory-motor systems (e.g., sensorimotor network) and cognitive networks (e.g., front-parietal network) particularly implicated. Further, the association between neighborhood disadvantage and sensorimotor network connectivity was less pronounced in the presence of high income-to-needs. Findings demonstrate that different facets of SES have distinct and interacting effects on rsFC, highlighting the importance of considering different indicators when studying the effects of SES on the brain.

Puberty triggers a period of structural “re-organization” in the brain, when rising hormone levels act via receptors to influence morphology. However, our understanding of these neuroendocrine processes in humans remains poor. As such, the current longitudinal study characterized development of the human subcortex during puberty, including changes in relation to pubertal (Tanner) stage and hormone (testosterone, dehydroepiandrosterone [DHEA]) levels. Beyond normative group-level patterns of development, we also examined whether individual differences in the rate of pubertal maturation (i.e., “pubertal/hormonal tempo”) were associated with variations in subcortical trajectories. Participants (N = 192; scans = 366) completed up to three waves of MRI assessments between 8.5 and 14.5 years of age. Parents completed questionnaire assessments of pubertal stage at each wave, and adolescents provided hormone samples on a subset of waves. Generalized additive mixture models were used to characterize trajectories of subcortical development. Results showed that development of most subcortical structures was related to pubertal stage, although findings were mostly non-significant when controlling for age. Testosterone and DHEA levels were related to development of the amygdala, hippocampus and pallidum in both sexes, and findings in the amygdala remained significant when controlling for age. Additionally, we found that variability in hormonal (specifically testosterone) tempo was related to right hippocampal development in males, with an accelerated pattern of hippocampal development in those with greater increases in testosterone levels. Overall, our findings suggest prominent hormonal influences on the amygdala and hippocampus, consistent with the prevalence of androgen and estrogen receptors in these regions. We speculate that these findings are most likely reflective of the important role of adrenarcheal processes on adolescent brain development.

The brain undergoes extensive structural changes during adolescence, concurrent to puberty-related physical and hormonal changes. While animal research suggests these biological processes are related to one another, our knowledge of brain development in humans is largely based on age-related processes. Thus, the current study characterized puberty-related changes in human brain structure, by combining data from two longitudinal neuroimaging cohorts. Beyond normative changes in cortical thickness, we examined whether individual differences in the rate of pubertal maturation (or “pubertal tempo”) was associated with variations in cortical trajectories. Participants (N = 192; scans = 366) completed up to three waves of MRI assessments between 8.5 and 14.5 years of age, as well as questionnaire assessments of pubertal stage at each wave. Generalized additive mixture models were used to characterize trajectories of cortical development. Results revealed widespread linear puberty-related changes across much of the cortex. Many of these changes, particularly within the frontal and parietal cortices, were independent of age-related development. Males exhibiting faster pubertal tempo demonstrated greater thinning in the precuneus and frontal cortices than same-aged and -sex peers. Findings suggest that the unique influence of puberty on cortical development may be more extensive than previously identified, and also emphasize important individual differences in the coupling of these developmental processes.

The aim of the current study was to longitudinally examine how adrenarcheal hormones influence the development of white matter structure from age 8.5 to 10 years. Participants were 120 children (66 female; mean age 8.45 years at Time 1 and 9.97 years at Time 2) who completed two diffusion-weighted imaging scans 1.5 years apart. Morning saliva samples were taken at both assessment time points to measure levels of dehydroepiandrosterone (DHEA), its sulphate (DHEAS), and testosterone. Fixel-based analysis was performed to examine how changes in white matter fibre density (FD) and cross-section (FC) over time were associated with initial levels of hormones, and changes in hormone levels over time. Both FD and FC increased over time in a wide range of white matter tracts. Increases in testosterone over time were related to relatively weaker increases in FC in the inferior fronto-occipital fasciculus. Levels and change in DHEA and DHEAS were not related to FD or FC changes. The results demonstrated development of white matter fibre density and cross-section from age 8.5 to 10 years. Changes in adrenarcheal hormone levels showed limited, localized associations with development of white matter FC. Future research should examine the relevance of adrenarcheal hormone-related white matter development for cognitive functioning; as well as directly compare analysis techniques of white matter structure.

Abnormal melatonin secretion has been demonstrated in patients with affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). However, magnetic resonance imaging (MRI) studies that previously investigated the volume of the pineal gland, which regulates circadian rhythms by secreting melatonin, in these patients reported inconsistent findings. The present study employed MRI to examine pineal gland volumes and pineal cyst prevalence in 56 MDD patients (29 currently depressed and 27 remitted patients), 26 BD patients, and matched controls (33 for MDD and 24 for BD). Pineal volumes and cyst prevalence in the current MDD, remitted MDD, and BD groups did not significantly differ from those of the healthy controls. However, pineal gland volumes were significantly smaller in the current MDD subgroup of non-melancholic depression than in the melancholic MDD subgroup. Interestingly, pineal volumes correlated negatively with the severity of loss of interest in the current MDD group. Medication and the number of affective episodes were not associated with pineal volumes in the MDD or BD group. While these results do not suggest that pineal volumes reflect abnormal melatonin secretion in affective disorders, they do point to the possibility that pineal abnormalities are associated with clinical subtypes of MDD and its symptomatology.

Both depression and substance use problems have their highest incidence during youth (i.e., adolescence and emerging adulthood), and are characterized by emotion regulation deficits. Influential neurodevelopmental theories suggest that alterations in the function of limbic and frontal regions render youth susceptible to these deficits. However, whether depression and substance use in youth are associated with similar alterations in emotion regulation neural circuitry is unknown. In this systematic review we synthesized the results of functional magnetic resonance imaging (fMRI) studies investigating the neural correlates of emotion regulation in youth depression and substance use. Resting-state fMRI studies focusing on limbic connectivity were also reviewed. While findings were largely inconsistent within and between studies of depression and substance use, some patterns emerged. First, youth depression appears to be associated with exaggerated amygdala activity in response to negative stimuli; second, both depression and substance use appear to be associated with lower functional connectivity between the amygdala and prefrontal cortex during rest. Findings are discussed in relation to support for existing neurodevelopmental models, and avenues for future work are suggested, including studying neurodevelopmental trajectories from a network perspective.

Continued advances in neuroimaging technologies and statistical modelling capabilities have improved our knowledge of structural brain development in children and adolescents. While this has provided an increasingly nuanced understanding of brain development, the field is still plagued by inconsistent findings. This review highlights the methodological diversity in existing longitudinal magnetic resonance imaging (MRI) studies on structural brain development during childhood and adolescence, and addresses how such variation might contribute to inconsistencies in the literature. We discuss the impact of method choices at multiple decision points across the research process, from study design and sample selection, to image processing and statistical analysis. We also highlight the extent to which different methodological considerations have been empirically examined, drawing attention to specific areas that would benefit from future investigation. Where appropriate, we recommend certain best practices that would be beneficial for the field to adopt, including greater completeness and transparency in reporting methods, in order to ultimately develop an accurate and detailed understanding of normative child and adolescent brain development. Keywords: Structural MRI, Brain development, Longitudinal analyses, Methodology

Substantial hormonal and neurobiological changes occur during puberty, and are widely argued to render this period of life a sensitive period in terms of risk for mental health problems. However, there is a paucity of research focusing on adrenarche, the earlier phase of pubertal development. Furthermore, there is a limited understanding of the association between adrenarche and neural development during this phase of life. We systematically reviewed research examining human adrenarcheal development as operationalized by hormonal levels of DHEA and DHEA-S, in relation to indices of mental health (Systematic Review 1). We then reviewed the limited amount of literature that has examined the association between adrenarcheal development and brain structure or function (Systematic Review 2). In general, studies showed that earlier timing of adrenarche was associated with greater mental health symptoms, and there is emerging support that brain development plays a role in this relationship. However, several methodological inconsistencies were noted. We propose that future research in this area test a theoretical model of adrenarche as a sensitive period of neurobiological development, whereby timing of exposure to hormones interacts with brain development, biological sex, and psychosocial stress to influence environmental sensitivity and risk for mental health problems through adolescence. Keywords: Puberty, Adrenarche, Sensitive periods, Mental health, Brain development

Pituitary gland volume (PGV) increases during childhood and adolescence in a sex-specific manner, and previous research suggests that puberty may be associated with PGV development. However, existing research to date has focused on sex hormones associated with gonadarche. Given the role of the pituitary gland in hypothalamic-pituitary-adrenal (HPA) axis function, the present study investigated associations between PGV development and HPA hormones that play a role in the earlier pubertal phase of adrenarche.Participants were a community sample of 249 children and early adolescents who participated in longitudinal brain imaging and pubertal assessments. Each participant provided data at one or two waves 1.5–3 years apart, resulting in 409 datasets that covered the age range 8–13 years. PGV was estimated from T1-weighted Magnetic Resonance Imaging (MRI) scans, and dehydroepiandrosterone (DHEA), its sulfate (DHEA-S) and testosterone were measured from saliva. Estradiol was measured for a subset of females. Parents reported on physical pubertal development. Linear mixed modeling was used to investigate associations between age, pubertal measures and PGV development.DHEA, DHEA-S and testosterone (in addition to physical maturation) explained variance in PGV development over and above age, and in a sex-dependent fashion. In all cases, associations were stronger, or only present in females. Estradiol was associated with PGV in females, but this did not appear to account for adrenarcheal hormone effects.Our findings suggest a key role for the hormones of adrenarche, the first biochemical phase of puberty, in PGV development. Further research is required to understand the sex-specific role of adrenarcheal and gonadarcheal hormones on the PGV across development.

Investigating how brain development during adolescence and early adulthood underlies guilt- and shame-proneness may be important for understanding risk processes for mental disorders. The aim of this study was to investigate the neurodevelopmental correlates of interpersonal guilt- and shame-proneness in healthy adolescents and young adults using structural magnetic resonance imaging (sMRI). Sixty participants (age range: 15–25) completed sMRI and self-report measures of interpersonal guilt- and shame-proneness. Independent of interpersonal guilt, higher levels of shame-proneness were associated with thinner posterior cingulate cortex (PCC) thickness and smaller amygdala volume. Higher levels of shame-proneness were also associated with attenuated age-related reductions in thickness of lateral orbitofrontal cortex (lOFC). Our findings highlight the complexities in understanding brain–behavior relationships during the adolescent/young adult period. Results were consistent with growing evidence that accelerated cortical thinning during adolescence may be associated with superior socioemotional functioning. Further research is required to understand the implications of these findings for mental disorders characterized by higher levels of guilt and shame.

Background: Childhood peer victimization is a stressful life experience associated with long-lasting adverse psychological consequences. While there is some evidence that victimization is associated with alterations in brain function, little is known about effects on brain structure. This study explored the relationships between childhood peer victimization, cortisol, and adolescent ventrolateral prefrontal cortex (vlPFC) structure in a sample of healthy children.Methods: A total of 50 (Mage = 9.29 years at baseline) children participated in this longitudinal study. We examined whether diurnal cortisol levels (assessed at baseline) moderated the link between children’s self-reported peer victimization (assessed at baseline) and vlPFC surface area, gray matter volume, and thickness 5 years later.Results: For boys, cortisol levels moderated the association between victimization and brain structure. For boys with a low daily cortisol output (assessed as area under the curve; AUC), high victimization was associated with a smaller right vlPFC surface area, and for boys with a high AUC, high victimization was associated with a larger right vlPFC surface area. In addition, for boys with a steeper diurnal slope, high victimization was associated with a smaller right vlPFC surface area, and for boys with a low flatter diurnal slope, high victimization was associated with a larger right vlPFC surface area.Conclusion: These results indicate the differential influence of cortisol on the relationship between victimization and brain structure. Findings suggest that victimization may have differential effects on brain development in boys who are more versus less biologically sensitive to stress.

Inhibitory control describes the suppression of goal-irrelevant stimuli and behavioral responses. Current developmental taxonomies distinguish between Response Inhibition – the ability to suppress a prepotent motor response, and Attentional Inhibition – the ability to resist interference from distracting stimuli. Response Inhibition and Attentional Inhibition have exhibited moderately strong positive correlations in previous studies, suggesting they are closely related cognitive abilities. These results may reflect the use of cognitive tasks combining Stimulus–Stimulus- and Stimulus–Response-conflict as indicators of both constructs, which may have conflated their empirical association. Additionally, previous statistical modeling studies have not controlled for individual differences in Working Memory Capacity, which may account for some of the empirical overlap between Response Inhibition and Attentional Inhibition. The aim of the current study was to test a hierarchical model of inhibitory control that specifies Working Memory Capacity as a higher-order cognitive construct. Response Inhibition and Attentional Inhibition were conceptualized as lower-order cognitive mechanisms that should be empirically independent constructs apart from their shared reliance on Working Memory Capacity for active maintenance of goal-relevant representations. Measures of performance on modified stimulus–response compatibility tasks, complex memory span, and non-selective stopping tasks were obtained from 136 preadolescent children (M = 11 years, 10 months, SD = 8 months). Consistent with hypotheses, results from Structural Equation Modeling demonstrated that the Response Inhibition and Attentional Inhibition factors were empirically independent constructs that exhibited partial statistical dependence on the Working Memory Capacity factor. These findings have important implications for current theories and models of inhibitory control during development.

Little is known about the neural correlates of fear learning in adolescents, a population at increased risk for anxiety disorders. Healthy adolescents (mean age 16.26) and adults (mean age 29.85) completed a fear learning paradigm across two stages during functional magnetic resonance imaging (fMRI). Stage 1 involved conditioning and extinction, and stage 2 involved extinction recall, re-conditioning, followed by re-extinction. During extinction recall, we observed a higher skin conductance response to the CS+ relative to CS− in adolescents compared to adults, which was accompanied by a reduction in dorsolateral prefrontal cortex (dlPFC) activity. Relative to adults, adolescents also had significantly reduced activation in the ventromedial PFC, dlPFC, posterior cingulate cortex (PCC), and temporoparietal junction (TPJ) during extinction recall compared to late extinction. Age differences in PCC activation between late extinction and late conditioning were also observed. These results show for the first time that healthy adolescent humans show different behavioral responses, and dampened PFC activity during short-term extinction recall compared to healthy adults. We also identify the PCC and TPJ as novel regions that may be associated with impaired extinction in adolescents. Also, while adults showed significant correlations between differential SCR and BOLD activity in some brain regions during late extinction and recall, adolescents did not show any significant correlations. This study highlights adolescent-specific neural correlates of extinction, which may explain the peak in prevalence of anxiety disorders during adolescence.

Background: Altered basal ganglia function has been implicated in the pathophysiology of youth Major Depressive Disorder (MDD). Studies have generally focused on characterizing abnormalities in ventral “affective” corticostriatal loops supporting emotional processes. Recent evidence however, has implicated alterations in functional connectivity of dorsal “cognitive” corticostriatal loops in youth MDD. The contribution of dorsal versus ventral corticostriatal alterations to the pathophysiology of youth MDD remains unclear. Methods: Twenty-one medication-free patients with moderate-to-severe MDD between the ages of 15 and 24 years old were matched with 21 healthy control participants. Using resting-state functional connectivity magnetic resonance imaging we systematically investigated connectivity of eight dorsal and ventral subdivisions of the striatum. Voxelwise statistical maps of each subregion's connectivity with other brain areas were compared between the depressed and control groups. Results: Depressed youths showed alterations in functional connectivity that were confined to the dorsal corticostriatal circuit. Compared to controls, depressed patients showed increased connectivity between the dorsal caudate nucleus and ventrolateral prefrontal cortex bilaterally. Increased depression severity correlated with the magnitude of dorsal caudate connectivity with the right dorsolateral prefrontal cortex. There were no significant between-group differences in connectivity of ventral striatal regions. Conclusions: The results provide evidence that alterations in corticostriatal connectivity are evident at the early stages of the illness and are not a result of antidepressant treatment. Increased connectivity between the dorsal caudate, which is usually associated with cognitive processes, and the more affectively related ventrolateral prefrontal cortex may reflect a compensatory mechanism for dysfunctional cognitive-emotional processing in youth depression.

While deficits in fear extinction recall have been suggested to underlie vulnerability to anxiety disorders in adolescents, the neurobiology of these deficits remain underexplored. Here we investigate the functional connectivity (FC) of the ventromedial prefrontal cortex (vmPFC) and dorsolateral PFC (dlPFC) underlying extinction recall in healthy adolescents, and assess associations between FC and state/trait anxiety. Adolescents (17) and adults (14, for comparison) completed a fear-learning paradigm involving extinction and extinction recall during a functional magnetic resonance imaging session, in which skin conductance response (SCR) was recorded. Psychophysiological interaction analyses revealed that during extinction recall there was significant negative connectivity between the vmPFC and amygdala in adults, but not adolescents. vmPFC-amygdala connectivity was positively correlated with SCR. Adolescents showed significant negative FC between the dlPFC and the left and right hippocampus, and the amygdala, which was positively correlated with state anxiety. Recall was also associated with negative connectivity between the dlPFC and thalamus, posterior cingulate cortex, fusiform gyrus, and pallidum in adolescents. These results demonstrate that fear extinction recall in healthy adolescents is associated with FC between prefrontal and limbic brain regions, and suggest that alterations in connectivity may be associated with vulnerability to anxiety in adolescence.

This study investigated the relationship between the development of effortful control (EC), a temperamental measure of self-regulation, and concurrent development of three regions of the prefrontal cortex (anterior cingulate cortex, ACC; dorsolateral prefrontal cortex, dlPFC; ventrolateral prefrontal cortex, vlPFC) between early- and mid-adolescence. It also examined whether development of EC mediated the relationship between cortical maturation and emotional and behavioral symptoms. Ninety-two adolescents underwent baseline assessments when they were approximately 12 years old and follow-up assessments approximately 4 years later. At each assessment, participants had MRI scans and completed the Early Adolescent Temperament Questionnaire-Revised, as well as measures of depressive and anxious symptoms, and aggressive and risk taking behavior. Cortical thicknesses of the ACC, dlPFC and vlPFC, estimated using the FreeSurfer software, were found to decrease over time. EC also decreased over time in females. Greater thinning of the left ACC was associated with less reduction in EC. Furthermore, change in effortful control mediated the relationship between greater thinning of the left ACC and improvements in socioemotional functioning, including reductions in psychopathological symptoms. These findings highlight the dynamic association between EC and the maturation of the anterior cingulate cortex, and the importance of this relationship for socioemotional functioning during adolescence.

Little work has been conducted that examines the effects of positive environmental experiences on brain development to date. The aim of this study was to prospectively investigate the effects of positive (warm and supportive) maternal behavior on structural brain development during adolescence, using longitudinal structural MRI. Participants were 188 (92 female) adolescents, who were part of a longitudinal adolescent development study that involved mother–adolescent interactions and MRI scans at approximately 12 years old, and follow-up MRI scans approximately 4 years later. FreeSurfer software was used to estimate the volume of limbic-striatal regions (amygdala, hippocampus, caudate, putamen, pallidum, and nucleus accumbens) and the thickness of prefrontal regions (anterior cingulate and orbitofrontal cortices) across both time points. Higher frequency of positive maternal behavior during the interactions predicted attenuated volumetric growth in the right amygdala, and accelerated cortical thinning in the right anterior cingulate (males only) and left and right orbitofrontal cortices, between baseline and follow up. These results have implications for understanding the biological mediators of risk and protective factors for mental disorders that have onset during adolescence.

Background: There is growing interest in understanding the neurobiology of major depressive disorder (MDD) in youth, particularly in the context of neuroimaging studies. This systematic review provides a timely comprehensive account of the available functional magnetic resonance imaging (fMRI) literature in youth MDD. Methods: A literature search was conducted using PubMED, PsycINFO and Science Direct databases, to identify fMRI studies in younger and older youth with MDD, spanning 13–18 and 19–25 years of age, respectively. Results: Twenty-eight studies focusing on 5 functional imaging domains were identified, namely emotion processing, cognitive control, affective cognition, reward processing and resting-state functional connectivity. Elevated activity in “extended medial network” regions including the anterior cingulate, ventromedial and orbitofrontal cortices, as well as the amygdala was most consistently implicated across these five domains. For the most part, findings in younger adolescents did not differ from those in older youth; however a general comparison of findings in both groups compared to adults indicated differences in the domains of cognitive control and affective cognition. Conclusions: Youth MDD is characterized by abnormal activations in ventromedial frontal regions, the anterior cingulate and amygdala, which are broadly consistent with the implicated role of medial network regions in the pathophysiology of depression. Future longitudinal studies examining the effects of neurodevelopmental changes and pubertal maturation on brain systems implicated in youth MDD will provide a more comprehensive neurobiological model of youth depression.

Limited attention has been directed toward the influence of non-abusive parenting behaviour on brain structure in adolescents. It has been suggested that environmental influences during this period are likely to impact the way that the brain develops over time. The aim of this study was to investigate the association between aggressive and positive parenting behaviors on brain development from early to late adolescence, and in turn, psychological and academic functioning during late adolescence, using a multi-wave longitudinal design. Three hundred and sixty seven magnetic resonance imaging (MRI) scans were obtained over three time points from 166 adolescents (11-20 years). At the first time point, observed measures of maternal aggressive and positive behaviors were obtained. At the final time point, measures of psychological and academic functioning were obtained. Results indicated that a higher frequency of maternal aggressive behavior was associated with alterations in the development of right superior frontal and lateral parietal cortical thickness, and of nucleus accumbens volume, in males. Development of the superior frontal cortex in males mediated the relationship between maternal aggressive behaviour and measures of late adolescent functioning. We suggest that our results support an association between negative parenting and adolescent functioning, which may be mediated by immature or delayed brain maturation.

Introduction Endovenous therapy is the first choice management for symptomatic varicose veins in NICE guidelines, with 56–70 000 procedures performed annually in the UK. Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a known complication of endovenous therapy, occurring at a rate of up to 3.4%. Despite 73% of UK practitioners administering pharmacological thromboprophylaxis to reduce VTE, no high-quality evidence supporting this practice exists. Pharmacological thromboprophylaxis may have clinical and cost benefit in preventing VTE; however, further evidence is needed. This study aims to establish whether when endovenous therapy is undertaken: a single dose or course of pharmacological thromboprophylaxis alters the risk of VTE; pharmacological thromboprophylaxis is associated with an increased rate of bleeding events; pharmacological prophylaxis is cost effective.Methods and analysis A multi-centre, assessor-blind, randomised controlled trial (RCT) will recruit 6660 participants from 40 NHS and private sites across the UK. Participants will be randomised to intervention (single dose or extended course of pharmacological thromboprophylaxis plus compression) or control (compression alone). Participants will undergo a lower limb venous duplex ultrasound scan at 21–28 days post-procedure to identify asymptomatic DVT. The duplex scan will be conducted locally by blinded assessors. Participants will be contacted remotely for follow-up at 7 days and 90 days post-procedure. The primary outcome is imaging-confirmed lower limb DVT with or without symptoms or PE with symptoms within 90 days of treatment. The main analysis will be according to the intention-to-treat principle and will compare the rates of VTE at 90 days, using a repeated measures analysis of variance, adjusting for any pre-specified strongly prognostic baseline covariates using a mixed effects logistic regression.Ethics and dissemination Ethical approval was granted by Brent Research Ethics Committee (22/LO/0261). Results will be disseminated in a peer-reviewed journal and presented at national and international conferences.Trial registration number ISRCTN18501431.

Introduction Hospital-acquired thrombosis (HAT) is defined as any venous thromboembolism (VTE)-related event during a hospital admission or occurring up to 90 days post discharge, and is associated with significant morbidity, mortality and healthcare-associated costs. Although surgery is an established risk factor for VTE, operations with a short hospital stay (