Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs.

Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector (IE) cells have shown benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. Although the short-term complications of IE cells are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IE cells genetically modified with γ-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1027 years of long-term follow-up, 13 patients (3.8%) developed another cancer with a total of 16 events (4 hematologic malignancies and 12 solid tumors). The 5-year cumulative incidence of a first subsequent malignancy in the recipients of genetically modified IE cells was 3.6% (95% confidence interval, 1.8% to 6.4%). For 11 of the 16 subsequent tumors, biopsies were available, and no sample was transgene positive by polymerase chain reaction. Replication-competent retrovirus testing of peripheral blood mononuclear cells was negative in the 13 patients with subsequent malignancies tested. Rates of subsequent malignancy were low and comparable to standard chemotherapy. These results suggest that the administration of IE cells genetically modified with γ retroviral vectors does not increase the risk for subsequent malignancy.

Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors.

BACKGROUND AIMS: The success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited. OBJECTIVE: We compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors. METHODS: A retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion. RESULTS: Of 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome. CONCLUSIONS: Immune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors.

"Puberty age gap": new method of assessing pubertal timing and its association with mental health problems.

Puberty is linked to mental health problems during adolescence, and in particular, the timing of puberty is thought to be an important risk factor. This study developed a new measure of pubertal timing that was built upon multiple pubertal features and their nonlinear changes over time (i.e., with age), and investigated its association with mental health problems. Using the Adolescent Brain Cognitive Development (ABCD) cohort (N ~ 9900, aged 9-13 years), we employed three different models to assess pubertal timing. These models aimed to predict chronological age based on: (i) observed physical development, (ii) hormone levels (testosterone and dehydroepiandrosterone [DHEA]), and (iii) a combination of both physical development and hormones. To achieve this, we utilized a supervised machine learning approach, which allowed us to train the models using the available data and make age predictions based on the input pubertal features. The accuracy of these three models was evaluated, and their associations with mental health problems were examined. The new pubertal timing model performed better at capturing age variance compared to the more commonly used linear regression method. Further, the model based on physical features accounted for the most variance in mental health, such that earlier pubertal timing was associated with higher symptoms. This study demonstrates the utility of our new model of pubertal timing and suggests that, relative to hormonal measures, physical measures of pubertal maturation have a stronger association with mental health problems in early adolescence.

Research Review: Child emotion regulation mediates the association between family factors and internalizing symptoms in children and adolescents - a meta-analysis.

BACKGROUND: Parental influence on children's internalizing symptoms has been well established; however, little is known about the underlying mechanisms. One possible mechanism is child emotion regulation given evidence (a) of its associations with internalizing symptoms and (b) that the development of emotion regulation during childhood and adolescence is influenced by aspects of the family environment. This meta-analysis aimed to systematically investigate the mediating role of child emotion regulation in the relationship between various family factors and internalizing symptoms in children and adolescents. METHODS: We searched Medline, Embase, PsychInfo, and Web of Science for English articles up until November 2022. We included studies that examined child emotion regulation as a mediator between a family factor and child/adolescent internalizing symptoms. Random-effects models were used to calculate pooled indirect effects and total effects for nine family factors. Heterogeneity and mediation ratio were also calculated. RESULTS: Of 49 studies with 24,524 participants in this meta-analysis, family factors for which emotion regulation mediated the association with child/adolescent internalizing symptoms included: unsupportive emotion socialization, psychological control, secure attachment, aversiveness, family conflict, parent emotion regulation and parent psychopathology, but not supportive emotion socialization and behavioral control. CONCLUSIONS: Various family factors impact children's emotion regulation development, and in turn, contribute to the risk of internalizing symptoms in young people. Findings from this study highlight the need for interventions targeting modifiable parenting behaviors to promote healthy emotion regulation and better mental health in children and adolescents.

Family and parenting factors are associated with emotion regulation neural function in early adolescent girls with elevated internalizing symptoms.

A prominent tripartite model proposes that parent role modeling of emotion regulation, emotion socialization behaviors, and the emotional climate of the family are important for young people's emotional development. However, limited research has examined the neural mechanisms at play. Here, we examined the associations between family and parenting factors, the neural correlates of emotional reactivity and regulation, and internalizing symptoms in early adolescent girls. Sixty-four female adolescents aged 10-12 years with elevated internalizing symptoms completed emotional reactivity, implicit (affect labeling) and explicit (cognitive reappraisal) emotion regulation tasks during functional magnetic resonance imaging. Positive family emotional climate was associated with greater activation in the anterior cingulate and middle temporal cortices during emotional reactivity. Maternal emotion regulation difficulties were associated with increased frontal pole and supramarginal gyrus activation during affect labeling, whereas supportive maternal emotion socialization and positive family emotional climate were associated with activation in prefrontal regions, including inferior frontal and superior frontal gyri, respectively, during cognitive reappraisal. No mediating effects of brain function were observed in the associations between family/parenting factors and adolescent symptoms. These findings highlight the role of family and parenting behaviors in adolescent emotion regulation neurobiology, and contribute to prominent models of adolescent emotional development.

Longitudinal changes in within-salience network functional connectivity mediate the relationship between childhood abuse and neglect, and mental health during adolescence.

BACKGROUND: Understanding the neurobiological underpinnings of childhood maltreatment is vital given consistent links with poor mental health. Dimensional models of adversity purport that different types of adversity likely have distinct neurobiological consequences. Adolescence is a key developmental period, during which deviations from normative neurodevelopment may have particular relevance for mental health. However, longitudinal work examining links between different forms of maltreatment, neurodevelopment, and mental health is limited. METHODS: In the present study, we explored associations between abuse, neglect, and longitudinal development of within-network functional connectivity of the salience (SN), default mode (DMN), and executive control network in 142 community residing adolescents. Resting-state fMRI data were acquired at age 16 (T1; M = 16.46 years, s.d. = 0.52, 66F) and 19 (T2; mean follow-up period: 2.35 years). Mental health data were also collected at T1 and T2. Childhood maltreatment history was assessed prior to T1. RESULTS: Abuse and neglect were both found to be associated with increases in within-SN functional connectivity from age 16 to 19. Further, there were sex differences in the association between neglect and changes in within-DMN connectivity. Finally, increases in within-SN connectivity were found to mediate the association between abuse/neglect and lower problematic substance use and higher depressive symptoms at age 19. CONCLUSIONS: Our findings suggest that childhood maltreatment is associated with altered neurodevelopmental trajectories, and that changes in salience processing may be linked with risk and resilience for the development of depression and substance use problems during adolescence, respectively. Further work is needed to understand the distinct neurodevelopmental and mental health outcomes of abuse and neglect.

A longitudinal study of childhood maltreatment, subcortical development, and subcortico-cortical structural maturational coupling from early to late adolescence.

BACKGROUND: Examining neurobiological mechanisms that may transmit the effects of childhood maltreatment on mental health in youth is crucial for understanding vulnerability to psychopathology. This study investigated associations between childhood maltreatment, adolescent structural brain development, and mental health trajectories into young-adulthood. METHODS: Structural magnetic resonance imaging data was acquired from 144 youth at three time points (age 12, 16, and 18 years). Childhood maltreatment was reported to occur prior to the first scan. Linear mixed models were utilized to examine the association between total childhood maltreatment, neglect, abuse and (i) amygdala and hippocampal volume development, and (ii) maturational coupling between amygdala/hippocampus volume and the thickness of prefrontal regions. We also examined whether brain development mediated the association between maltreatment and depressive and anxiety symptoms trajectories from age 12 to 28. RESULTS: Total maltreatment, and neglect, were associated with positive maturational coupling between the amygdala and caudal anterior cingulate cortex (cACC), whereby at higher and lower levels of amygdala growth, maltreatment was associated with lower and higher PFC thinning, respectively. Neglect was also associated with maturational coupling of the hippocampus with prefrontal regions. While positive amygdala-cACC maturational coupling was associated with greater increases in anxiety symptoms, it did not significantly mediate the association between maltreatment and anxiety symptom trajectories. CONCLUSION: We found maltreatment to be associated with altered patterns of coupling between subcortical and prefrontal regions during adolescence, suggesting that maltreatment is associated with the development of socio-emotional neural circuitry. The implications of these findings for mental health require further investigation.

Corticolimbic connectivity mediates the relationship between pubertal timing and mental health problems.

BACKGROUND: Undergoing puberty ahead of peers ('earlier pubertal timing') is an important risk factor for mental health problems during early adolescence. The current study examined pathways between pubertal timing and mental health via connectivity of neural systems implicated in emotional reactivity and regulation (specifically corticolimbic connections) in 9- to 14-year-olds. METHOD: Research questions were examined in the Adolescent Brain Cognitive Development (ABCD) Study, a large population representative sample in the United States. Linear mixed models examined associations between pubertal timing and resting-state corticolimbic connectivity. Significant connections were examined as potential mediators of the relationship between pubertal timing and mental health (withdrawn depressed and rule-breaking) problems. Exploratory analyses interrogated whether the family environment moderated neural risk patterns in those undergoing puberty earlier than their peers. RESULTS: Earlier pubertal timing was related to decreased connectivity between limbic structures (bilateral amygdala and right hippocampus) and the cingulo-opercular network, left amygdala and somatomotor (mouth) network, as well as between the left hippocampus and ventral attention network and visual network. Corticolimbic connections also mediated the relationship between earlier pubertal timing and increased withdrawn depressed problems (but not rule-breaking problems). Finally, parental acceptance buffered against connectivity patterns that were implicated in withdrawn depressed problems in those undergoing puberty earlier than their peers. CONCLUSION: Findings highlight the role of decreased corticolimbic connectivity in mediating pathways between earlier pubertal timing and withdrawn depressed problems, and we present preliminary evidence that the family environment may buffer against these neural risk patterns during early adolescence.

Development of morning-eveningness in adolescence: implications for brain development and psychopathology.

BACKGROUND: Morning-evening preference is defined as an individual's preference for a morning- or evening-oriented rhythm. Across adolescence, a preference for eveningness becomes more predominant. Although eveningness is cross-sectionally associated with internalizing and externalizing psychopathology, few studies have examined developmental changes in eveningness and its potential biological substrates. Here, we investigated the longitudinal relationships among the trajectory of eveningness preference, internalizing and externalizing psychopathology and white matter development, across adolescence. METHODS: Two-hundred and nine adolescents (49% male) were assessed longitudinally at four separate time points between 12 and 19 years of age. Morning-evening preference and internalizing and externalizing symptoms were assessed at each time point. Diffusion-weighted images were acquired on a subset of participants at the final two time points to estimate changes in global mean fractional anisotropy (FA). Linear mixed models were performed to estimate the change in eveningness over time. A series of linear regression models assessed the influence of change in eveningness on psychopathology and white matter development at age 19. RESULTS: Across the sample, a preference for eveningness became more predominant by 19 years of age. Greater individual-level change towards eveningness significantly predicted greater severity in externalizing, but not internalizing, symptoms at 19 years of age. In contrast, change in psychopathology from 12 to 19 years of age was not associated with morning-eveningness at age 19. A change towards eveningness predicted an attenuated increase in FA between 17 and 19 years of age. CONCLUSIONS: This study suggests that developmental changes in morning-evening preference may predict both neurodevelopmental and psychological outcomes in adolescents.

Individual differences in brain structure and self-reported empathy in children.

Empathy refers to the understanding and sharing of others' emotions and comprises cognitive and affective components. Empathy is important for social functioning, and alterations in empathy have been demonstrated in many developmental or psychiatric disorders. While several studies have examined associations between empathy and brain structure in adults, few have investigated this relationship in children. Investigating associations between empathy and brain structure during childhood will help us to develop a deeper understanding of the neural correlates of empathy across the lifespan. A total of 125 children (66 females, mean age 10 years) underwent magnetic resonance imaging brain scans. Grey matter volume and cortical thickness from structural images were examined using the Computational Anatomy Toolbox (CAT12) within Statistical Parametric Mapping (SPM12) software. Children completed questionnaire measures of empathy (cognitive empathy, affective empathy: affective sharing, empathic concern, and empathic distress). In hypothesised region of interest analyses, individual differences in affective and cognitive empathy were related to grey matter volume in the insula and the precuneus. Although these relationships were of similar strength to those found in previous research, they did not survive correction for the total number of models computed. While no significant findings were detected between grey matter volume and empathy in exploratory whole-brain analysis, associations were found between cortical thickness and empathic concern in the right precentral gyrus. This study provides preliminary evidence that individual differences in self-reported empathy in children may be related to aspects of brain structure. Findings highlight the need for more research investigating the neurobiological correlates of empathy in children.

Management of early treated adolescents and young adults with phenylketonuria: Development of international consensus recommendations using a modified Delphi approach.

BACKGROUND: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. METHODS: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. RESULTS: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. CONCLUSIONS: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.

Soft Tissue and Visceral Organ Sarcomas With BCOR Alterations.

Sarcomas with BCOR alteration are a heterogenous group characterized by changes including internal tandem duplications (ITDs) and recurring fusions with CCNB3, ZC3H7B, and other rare partners. With widespread genomic testing, these alterations are now associated with histologies such as Ewing-like sarcoma (BCOR::CCNB3), high-grade endometrial stromal sarcoma (ZC3H7B::BCOR), and clear cell sarcoma of kidney (BCOR-ITD). BCOR altered sarcomas of soft tissues and organs were identified through PubMed using keywords "Sarcoma (AND) BCOR" from 2005 through October 2021. Summary statistics and outcome data were calculated using STATA v12.1. Forty-one publications described 190 patients with BCOR altered soft tissue or organ sarcomas. BCOR-ITD was most common, followed by BCOR::CCNB3, ZC3H7B::BCOR. BCOR-ITD tumors occurred mainly in infants, BCOR::CCNB3 commonly occurred in adolescent young adults, and ZC3H7B::BCOR only in adults. The most common site for BCOR::CCNB3 fused tumors was extremity, BCOR-ITD kidney and ZC3H7B::BCOR uterus. Metastasis was rare in patients with BCOR::CCNB3. While most underwent resection and chemotherapy, few received radiation. Median follow-up of survivors was 24 months. Five year overall survival for patients with BCOR::CCNB3 fusions was 68% (95% confidence interval [CI]: 46%-83%). Patients with BCOR-ITD and ZC3H7B::BCOR had worse prognoses with 5 years overall survival of 35% (95% CI: 15%-56%) and 41% (95% CI: 11%-71%), respectively, demonstrating need for collaborative efforts identifying optimal treatments to improve outcomes.

A longitudinal analysis of puberty-related cortical 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.

Towards understanding neurocognitive mechanisms of parenting: Maternal behaviors and structural brain network organization in late childhood.

A substantial body of knowledge suggests that exposure to adverse family environments - including violence and neglect - influences many aspects of brain development. Relatively less attention has been directed toward the influence of "normative" differences in parenting behaviors. Given the rapid brain reorganization during late childhood, parenting behaviors are particularly likely to impact the structure of the brain during this time. This study investigated associations between maternal parenting behaviors and the organization of structural brain networks in late childhood, as measured by structural covariance. One hundred and forty-five typically developing 8-year-olds and their mothers completed questionnaire measures and two observed interaction tasks; magnetic resonance imaging (MRI) scans were obtained from the children. Measures of maternal negative, positive, and communicative behavior were derived from the interaction tasks. Structural covariance networks based on partial correlations between cortical thickness estimates were constructed and estimates of modularity were obtained using graph theoretical analysis. High levels of negative maternal behavior were associated with low modularity. Minimal support was found for an association between positive maternal behaviors and modularity and between maternal communicative behaviors and modularity. Our findings suggest that variation in negative maternal behavior is associated with the structural organization of brain networks in children.

Structural Brain Development and Aggression: A Longitudinal Study in Late Childhood.

This longitudinal study examined the neurodevelopmental correlates of aggression in children, focusing on structural brain properties. A community sample of 110 (60 females) children participated at age 8 years and again at age 10 years. Brain structure was assessed by using magnetic resonance imaging (MRI), and parents reported on child aggression using the Child Behavior Checklist. Analyses examined the relationship between aggression and development of volume of subcortical regions, cortical thickness, and subcortical-cortical structural coupling. Females with relatively high aggression exhibited reduced right hippocampal growth over time. Across males and females, aggression was associated with amygdala- and hippocampal-cortical developmental coupling, with findings for amygdala-cortical coupling potentially indicating reduced top-down prefrontal control of the amygdala in those with increasing aggression over time. Findings suggest that aggressive behaviors may be associated with alterations in normative brain development; however, results were not corrected for multiple comparisons and should be interpreted with caution.

Pediatric liposarcoma: A case series and literature review.

Liposarcoma is arare soft tissue sarcoma in children. While prognosis, clinical behavior, and response to therapy among the various histologic subtypes are well described in adults, data in children are limited. Here, we describe our experience treating 14 children with liposarcoma at a large, academic pediatric center and review the available pediatric literature. This comprehensive report adds treatment, survival, and genomic data to pediatric liposarcoma literature.

Charting a path for prioritization of novel agents for clinical trials in osteosarcoma: A report from the Children's Oncology Group New Agents for Osteosarcoma Task Force.

Osteosarcoma is the most common bone tumor in children and young adults. Metastatic and relapsed disease confer poor prognosis, and there have been no improvements in outcomes for several decades. The disease's biological complexity, lack of drugs developed specifically for osteosarcoma, imperfect preclinical models, and limits of existing clinical trial designs have contributed to lack of progress. The Children's Oncology Group Bone Tumor Committee established the New Agents for Osteosarcoma Task Force to identify and prioritize agents for inclusion in clinical trials. The group identified multitargeted tyrosine kinase inhibitors, immunotherapies targeting B7-H3, CD47-SIRPα inhibitors, telaglenastat, and epigenetic modifiers as the top agents of interest. Only multitargeted tyrosine kinase inhibitors met all criteria for frontline evaluation and have already been incorporated into an upcoming phase III study concept. The task force will continue to reassess identified agents of interest as new data become available and evaluate novel agents using this method.

Associations between early life stress and anterior pituitary gland volume development - A novel index of long-term hypothalamic-pituitary-adrenal axis functioning.

Previous research has established associations between early life stress (ELS) and altered pituitary gland volume (PGV) growth during adolescence. The pituitary gland, however, is composed of an anterior and a posterior lobe with distinct histological and neuroendocrinological properties. While the anterior (but not posterior) pituitary gland is directly involved in the hypothalamic-pituitary-adrenal axis (HPAA) stress response, no studies have examined the effects of ELS on anterior PGV (aPGV). The present study investigated whether previously reported associations between ELS and PGV development during adolescence were driven by aPGV versus posterior PGV (pPGV). Ninety-one adolescents (49 males) were included from a longitudinal, community-based adolescent development study investigating risk for psychopathology. ELS (maternal affective behavior, childhood maltreatment, stressful life events) was assessed during early adolescence. Participants underwent two waves of structural magnetic resonance imaging during mid- and late-adolescence, and aPGV and pPGV were manually traced. Regression analyses showed that childhood maltreatment predicted greater aPGV growth in females. This finding was stronger than that previously reported for PGV. No associations were found between ELS and pPGV development. Neither aPGV nor pPGV changes mediated associations between ELS and psychopathology. Results suggest that ELS may accelerate aPGV (but not pPGV) growth throughout adolescence. Investigating the development of aPGV, rather than PGV, represents a novel approach to studying the effects of stress on HPAA functioning.

Pubertal hormones predict sex-specific trajectories of pituitary gland volume during the transition from childhood to adolescence.

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.

Adrenarcheal hormone-related development of white matter during late childhood.

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.