An integrative model of the maturation of cognitive control.

Brains systems undergo unique and specific dynamic changes at the cellular, circuit, and systems level that underlie the transition to adult-level cognitive control. We integrate literature from these different levels of analyses to propose a novel model of the brain basis of the development of cognitive control. The ability to consistently exert cognitive control improves into adulthood as the flexible integration of component processes, including inhibitory control, performance monitoring, and working memory, increases. Unique maturational changes in brain structure, supported by interactions between dopaminergic and GABAergic systems, contribute to enhanced network synchronization and an improved signal-to-noise ratio. In turn, these factors facilitate the specialization and strengthening of connectivity in networks supporting the transition to adult levels of cognitive control. This model provides a novel understanding of the adolescent period as an adaptive period of heightened experience-seeking necessary for the specialization of brain systems supporting cognitive control.

The default mode network is associated with changes in internalizing and externalizing problems differently in adolescent boys and girls.

Internalizing and externalizing problems that emerge during adolescence differentially increase boys' and girls' risk for developing psychiatric disorders. It is not clear, however, whether there are sex differences in the intrinsic functional architecture of the brain that underlie changes in the severity of internalizing and externalizing problems in adolescents. Using resting-state fMRI data and self-reports of behavioral problems obtained from 128 adolescents (73 females; 9-14 years old) at two timepoints, we conducted multivoxel pattern analysis to identify resting-state functional connectivity markers at baseline that predict changes in the severity of internalizing and externalizing problems in boys and girls 2 years later. We found sex-differentiated involvement of the default mode network in changes in internalizing and externalizing problems. Whereas changes in internalizing problems were associated with the dorsal medial subsystem in boys and with the medial temporal subsystem in girls, changes in externalizing problems were predicted by hyperconnectivity between core nodes of the DMN and frontoparietal network in boys and hypoconnectivity between the DMN and affective networks in girls. Our results suggest that different neural mechanisms predict changes in internalizing and externalizing problems in adolescent boys and girls and offer insights concerning mechanisms that underlie sex differences in the expression of psychopathology in adolescence.

White Matter Microstructural Properties of the Cerebellar Peduncles Predict Change in Symptoms of Psychopathology in Adolescent Girls.

Internalizing symptoms typically emerge in adolescence and are more prevalent in females than in males; in contrast, externalizing symptoms typically emerge in childhood and are more commonly observed in males. Previous research has implicated aspects of white matter organization, including fractional anisotropy (FA), of cerebral tracts in both internalizing and externalizing symptoms. Although the cerebellum has been posited to integrate limbic and cortical regions, its role in psychopathology is not well understood. In this longitudinal study, we investigated whether FA of the superior (SCP), middle (MCP), and inferior cerebellar peduncles (ICP) predict change in symptoms and whether sex moderates this association. One hundred eleven adolescents completed the Youth Self-Report, assessing symptoms at baseline (ages 9-13 years) and again 2 years later. Participants also underwent diffusion-weighted imaging at baseline. We used deterministic tractography to segment and compute mean FA of the cerebellar peduncles. Lower FA of the right SCP at baseline predicted increases in internalizing symptoms in females only. Lower FA in the right SCP and ICP also predicted increases in externalizing symptoms in females, but these associations did not survive multiple comparison correction. There was no association between FA of the cerebellar peduncles and change in symptoms in males or between MCP FA and symptom changes in males or females. Organizational properties of the SCP may be a sex-specific marker of internalizing symptom changes in adolescence. The cerebellar peduncles should be explored further in future studies to elucidate sex differences in symptoms.

Early life stress, systemic inflammation, and neural correlates of implicit emotion regulation in adolescents.

Exposure to early life stress (ELS) increases the risk for developing psychopathology; however, the mechanisms underlying this association are not clear. In this study we examined systemic inflammation as a pathway that may link exposure to stress to altered neural correlates of implicit emotion regulation in adolescents with varying levels of exposure to ELS (n = 83; 52 females, 31 males; 15.63 ± 1.10 years). We measured ventrolateral prefrontal cortex (vlPFC) activation and functional connectivity (FC) between the bilateral amygdala and the vlPFC as adolescents completed an affect labeling task in the scanner and assessed concentrations of C-reactive protein (CRP) using a dried blood spot protocol. We found that CRP levels were negatively associated with vlPFC activation during implicit regulation of negatively-valenced stimuli, and that cumulative severity of ELS exposure moderated this neuroimmune association. Severity of ELS also significantly moderated the association between CRP levels and FC between the bilateral amygdala and l-vlPFC during implicit emotion regulation: in adolescents who had been exposed to more severe ELS, higher CRP was associated with more negative frontoamygdala FC during implicit regulation of negatively-valenced stimuli. Thus, ELS may disrupt the normative association between the immune system and the neural processes that underlie socioemotional functioning potentially increasing adolescents' risk for maladaptive outcomes.

Correlates and predictors of the severity of suicidal ideation in adolescence: an examination of brain connectomics and psychosocial characteristics.

BACKGROUND: Suicidal ideation (SI) typically emerges during adolescence but is challenging to predict. Given the potentially lethal consequences of SI, it is important to identify neurobiological and psychosocial variables explaining the severity of SI in adolescents. METHODS: In 106 participants (59 female) recruited from the community, we assessed psychosocial characteristics and obtained resting-state fMRI data in early adolescence (baseline: aged 9-13 years). Across 250 brain regions, we assessed local graph theory-based properties of interconnectedness: local efficiency, eigenvector centrality, nodal degree, within-module z-score, and participation coefficient. Four years later (follow-up: ages 13-19 years), participants self-reported their SI severity. We used least absolute shrinkage and selection operator (LASSO) regressions to identify a linear combination of psychosocial and brain-based variables that best explain the severity of SI symptoms at follow-up. Nested-cross-validation yielded model performance statistics for all LASSO models. RESULTS: A combination of psychosocial and brain-based variables explained subsequent severity of SI (R2 = .55); the strongest was internalizing and externalizing symptom severity at follow-up. Follow-up LASSO regressions of psychosocial-only and brain-based-only variables indicated that psychosocial-only variables explained 55% of the variance in SI severity; in contrast, brain-based-only variables performed worse than the null model. CONCLUSIONS: A linear combination of baseline and follow-up psychosocial variables best explained the severity of SI. Follow-up analyses indicated that graph theory resting-state metrics did not increase the prediction of the severity of SI in adolescents. Attending to internalizing and externalizing symptoms is important in early adolescence; resting-state connectivity properties other than local graph theory metrics might yield a stronger prediction of the severity of SI.

An exploration of dimensions of early adversity and the development of functional brain network connectivity during adolescence: Implications for trajectories of internalizing symptoms.

Different dimensions of adversity may affect mental health through distinct neurobiological mechanisms, though current supporting evidence consists largely of cross-sectional associations between threat or deprivation and fronto-limbic circuitry. In this exploratory three-wave longitudinal study spanning ages 9-19 years, we examined the associations between experiences of unpredictability, threat, and deprivation with the development of functional connectivity within and between three brain networks implicated in psychopathology: the salience (SAL), default mode (DMN), and fronto-parietal (FPN) networks, and tested whether network trajectories moderated associations between adversity and changes in internalizing symptoms. Connectivity decreased with age on average; these changes differed by dimension of adversity. Whereas family-level deprivation was associated with lower initial levels and more stability across most networks, unpredictability was associated with stability only in SAL connectivity, and threat was associated with stability in FPN and DMN-SAL connectivity. In youth exposed to higher levels of any adversity, lower initial levels and more stability in connectivity were related to smaller increases in internalizing symptoms. Our findings suggest that whereas deprivation is associated with widespread neurodevelopmental differences in cognitive and emotion processing networks, unpredictability is related selectively to salience detection circuitry. Studies with wider developmental windows should examine whether these neurodevelopmental alterations are adaptive or serve to maintain internalizing symptoms.

Negative caregiving and stress reactivity moderate the relation between early life stress and externalizing in adolescence.

Exposure to early life stress (ELS) is common and has been implicated in the development of psychopathology; importantly, however, many individuals who experience ELS do not develop emotional or behavioral difficulties. Prior research implicates stress exposure, negative caregiving behaviors, and patterns of physiological reactivity in predicting psychological well-being; however, the precise factors that contribute to resilience versus vulnerability to the adverse effects of stress exposures are not well understood. In a longitudinal study of adolescents (N = 120) assessed at three timepoints approximately every 2 years beginning at the ages of 913 years, we examined the roles of autonomic reactivity to social stress (assessed through skin conductance during the Trier Social Stress Task) and negative caregiving behaviors as moderators of the association between exposure to ELS and internalizing and externalizing symptoms. We found that the relation between ELS and externalizing symptoms was moderated by both negative caregiving and autonomic reactivity, such that the relation between ELS and externalizing was positive at low levels of negative caregiving and at high levels of autonomic reactivity; interactions predicting internalizing symptoms were not statistically significant. These findings highlight the importance of considering physiological and environmental variables that might contribute to susceptibility or resilience to symptoms of psychopathology following exposure to ELS.

Sex differences in pubertal associations with fronto-accumbal white matter morphometry: Implications for understanding sensitivity to reward and punishment.

Researchers have reported sex-differentiated maturation of white matter (WM) during puberty. It is not clear, however, whether such distinctions contribute to documented sex differences in sensitivity to reward and punishment during adolescence. Given the role of the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in reward and punishment-related behaviors, we tested in a cross-sectional study whether males and females (N = 156, 89 females; ages 9-14 years) differ in the association between pubertal stage and fixel-based morphometry of WM fibers connecting the OFC and NAcc (i.e., the fronto-accumbal tract). Further, we examined whether males and females differ in associations between fronto-accumbal WM measures and self-reported sensitivity to reward and punishment. Pubertal stage was positively associated with fronto-accumbal fiber density and cross-section (FDC) in males, but not in females. Consistent with previous reports, males reported higher reward sensitivity than did females, although fronto-accumbal combined FDC was not related to reward sensitivity in either sex. Meanwhile, only males showed a negative association between fronto-accumbal tract FDC and sensitivity to punishment. Follow-up analyses revealed that fiber cross-section, but not density, was related to pubertal stage and punishment sensitivity in males, as well as to reward sensitivity in all participants. Our findings suggest there are sex differences in puberty-related maturation of the fronto-accumbal tract, and this tract is related to lower punishment sensitivity in adolescent males compared to females.

Neural connectivity biotypes: associations with internalizing problems throughout adolescence.

BACKGROUND: Neurophysiological patterns may distinguish which youth are at risk for the well-documented increase in internalizing symptoms during adolescence. Adolescents with internalizing problems exhibit altered resting-state functional connectivity (RSFC) of brain regions involved in socio-affective processing. Whether connectivity-based biotypes differentiate adolescents' levels of internalizing problems remains unknown. METHOD: Sixty-eight adolescents (37 females) reported on their internalizing problems at ages 14, 16, and 18 years. A resting-state functional neuroimaging scan was collected at age 16. Time-series data of 15 internalizing-relevant brain regions were entered into the Subgroup-Group Iterative Multi-Model Estimation program to identify subgroups based on RSFC maps. Associations between internalizing problems and connectivity-based biotypes were tested with regression analyses. RESULTS: Two connectivity-based biotypes were found: a Diffusely-connected biotype (N = 46), with long-range fronto-parietal paths, and a Hyper-connected biotype (N = 22), with paths between subcortical and medial frontal areas (e.g. affective and default-mode network regions). Higher levels of past (age 14) internalizing problems predicted a greater likelihood of belonging to the Hyper-connected biotype at age 16. The Hyper-connected biotype showed higher levels of concurrent problems (age 16) and future (age 18) internalizing problems. CONCLUSIONS: Differential patterns of RSFC among socio-affective brain regions were predicted by earlier internalizing problems and predicted future internalizing problems in adolescence. Measuring connectivity-based biotypes in adolescence may offer insight into which youth face an elevated risk for internalizing disorders during this critical developmental period.

Heart rate variability moderates the effects of COVID-19-related stress and family adversity on emotional problems in adolescents: Testing models of differential susceptibility and diathesis stress.

The COVID-19 pandemic is a unique period of stress, uncertainty, and adversity that will have significant implications for adolescent mental health. Nevertheless, stress and adversity related to COVID-19 may be more consequential for some adolescents' mental health than for others. We examined whether heart rate variability (HRV) indicated differential susceptibility to mental health difficulties associated with COVID-19 stress and COVID-19 family adversity. Approximately 4 years prior to the pandemic, we assessed resting HRV and HRV reactivity to a well-validated stress paradigm in 87 adolescents. During the pandemic, these adolescents (ages 13-19) reported on their health-related stress and concerns about COVID-19, family adversity related to COVID-19, and their recent emotional problems. The association between COVID-19 stress and emotional problems was significantly stronger for adolescents who previously exhibited higher resting HRV or higher HRV reactivity. For adolescents who exhibited lower resting HRV or HRV augmentation, COVID-19 stress was not associated with emotional problems. Conversely, lower resting HRV indicated vulnerability to the effect of COVID-19 family adversity on emotional problems. Different patterns of parasympathetic functioning may reflect differential susceptibility to the effects of COVID-19 stress versus vulnerability to the effects of COVID-19 family adversity on mental health during the pandemic.

Research Review: Brain network connectivity and the heterogeneity of depression in adolescence - a precision mental health perspective.

BACKGROUND: Adolescence is a period of high risk for the onset of depression, characterized by variability in symptoms, severity, and course. During adolescence, the neurocircuitry implicated in depression continues to mature, suggesting that it is an important period for intervention. Reflecting the recent emergence of 'precision mental health' - a person-centered approach to identifying, preventing, and treating psychopathology - researchers have begun to document associations between heterogeneity in features of depression and individual differences in brain circuitry, most frequently in resting-state functional connectivity (RSFC). METHODS: In this review, we present emerging work examining pre- and post-treatment measures of network connectivity in depressed adolescents; these studies reveal potential intervention-specific neural markers of treatment efficacy. We also review findings from studies examining associations between network connectivity and both types of depressive symptoms and response to treatment in adults, and indicate how this work can be extended to depressed adolescents. Finally, we offer recommendations for research that we believe will advance the science of precision mental health of adolescence. RESULTS: Nascent studies suggest that linking RSFC-based pathophysiological variation with effects of different types of treatment and changes in mood following specific interventions will strengthen predictions of prognosis and treatment response. Studies with larger sample sizes and direct comparisons of treatments are required to determine whether RSFC patterns are reliable neuromarkers of treatment response for depressed adolescents. Although we are not yet at the point of using RSFC to guide clinical decision-making, findings from research examining the stability and reliability of RSFC point to a favorable future for network-based clinical phenotyping. CONCLUSIONS: Delineating the correspondence between specific clinical characteristics of depression (e.g., symptoms, severity, and treatment response) and patterns of network-based connectivity will facilitate the development of more tailored and effective approaches to the assessment, prevention, and treatment of depression in adolescents.

Girls' brain structural connectivity in late adolescence relates to history of depression symptoms.

BACKGROUND: Girls' depressive symptoms typically increase in adolescence, with individual differences in course and severity being key risk factors for impaired emotional functioning in young adulthood. Given the continued brain white matter (WM) maturation that occurs in adolescence, the present study tested whether structural connectivity patterns in late adolescence are associated with variation in the course of depression symptom severity throughout adolescence. METHOD: Participants were girls (N = 115) enrolled in a multiyear prospective cohort study of risk for depression. Initial depression severity (intercept) at age 10 and change in severity (linear slope) across ages 10-19 were examined in relation to WM tractography collected at age 19. Network-based statistic analyses were used to identify clusters showing variation in structural connectivity in association with depressive symptom intercept, slope, and their interaction. RESULTS: Higher initial depressive severity and steeper positive slope (separately) were associated with greater structural connectivity between temporal, subcortical socioaffective, and occipital regions. Intercept showed more connectivity associations than slope. The interaction effect indicated that higher initial symptom severity and a steeper negative slope (i.e., alleviating symptoms) were related to greater connectivity between cognitive control regions. Moderately severe symptoms that worsened over time were followed by greater connectivity between self-referential and cognitive regions (e.g., posterior cingulate and frontal gyrus). CONCLUSIONS: Higher depressive symptom severity in early adolescence and increasing symptom severity over time may forecast structural connectivity differences in late adolescence, particularly in pathways involving cognitive and emotion-processing regions. Understanding how clinical course relates to neurobiological correlates may inform new treatment approaches to adolescent depression.

Support, information, and integration of genetics for children with congenital lower limb deficiencies in British Columbia, Canada.

OBJECTIVES: Children and families affected by congenital limb deficiencies (CLD) require a unique level of emotional support from diagnosis through to adolescence. The following study aims to collect data on Canadian paediatric patients affected by a CLD followed at BC Children's Hospital (BCCH), Department of Orthopaedics. METHODS: Parents of children with a CLD were asked to complete a written questionnaire examining their experiences. Qualitative and quantitative data were collected concerning parent satisfaction with patient referrals, emotional support, and knowledge of their child's diagnosis. RESULTS: Twenty-five completed questionnaires were returned. Fifty per cent of the parents reported they were either very satisfied, or satisfied, with the emotional support provided by health care providers (HCPs). Twenty-five per cent of the parents were unsatisfied with the emotional support received by HCPs. Forty-eight per cent of the parents could not recall the specific name of their child's diagnosis; 20% of the parents reported their child did not have diagnosis. All the patients in our study had received a clinical diagnosis. Twenty-eight per cent of the parents in this study were also seen in medical genetics. CONCLUSIONS: Families require additional resources for emotional support, peer support, and referrals to support organizations. Gaps in parent knowledge regarding their child's CLD suggest the need for formalized communication strategies for HCPs. Furthermore, patients with CLDs and their families may benefit from improved communication between orthopaedic and medical genetic services at the time of diagnosis. Integration of genetic counsellors may improve emotional supports and education for families with regards to testing and reproductive planning.

Girls' pubertal development is associated with white matter microstructure in late adolescence.

Patterns of pubertal maturation have been linked to vulnerability for emotion dysregulation disorders in girls, as well as white matter (WM) development, suggestive of a potential mechanism between pubertal maturation and emotional health. Because pubertal processes begin at varying ages (i.e., status, timing) and proceed at varying rates (i.e., tempo), identifying individual differences in the pubertal course associated with subsequent WM microstructure development may reveal clues about neurobiological mechanisms of girls' emotional well-being. In a prospective cohort study of 107 girls, we examined associations between pubertal status at age 9, pubertal timing and tempo from ages 9-15, and WM microstructure at age 19. Tract-based spatial statistics revealed that girls with more advanced pubertal status at age 9, specific to gonadal-related physical changes, had higher fractional anisotropy, and lower mean diffusivity (MD) and radial diffusivity in tracts relevant to cognitive control and emotion regulation (e.g., the superior longitudinal fasciculus, external capsule, and uncinate fasciculus). Additionally, girls with earlier pubertal timing showed lower MD in the left anterior cingulum bundle. Tempo was unrelated to WM measures. These findings implicate specific aspects of pubertal maturation in subsequent neural signatures, suggesting possible neuroendocrine mechanisms relevant to emotional development. Future work incorporating longitudinal neuroimaging in parallel with pubertal measures may contribute to the understanding of individual variation in pubertal course and WM development.

Modulation of reward-related neural activation on sensation seeking across development.

Sensation seeking is a personality construct associated with an increased propensity for engaging in risk-taking. Associations with deleterious outcomes ranging from mental health impairments to increased mortality rates highlight important public health concerns related to this construct. Although some have suggested that increased neural responsivity to reward within the ventral striatum (e.g., nucleus accumbens) may drive sensation seeking behaviors, few studies have examined the neural mechanisms associated with stable individual differences in sensation seeking across development. To address this issue, the current study used functional magnetic resonance imaging to examine the association between neural responding to reward and stable patterns of sensation seeking across a three-year follow-up period among healthy adolescents and young adults (N = 139). Results indicated that during early adolescence (~ages 10-12), increased reactivity to reward within the nucleus accumbens (NAcc) was associated with lower levels of sensation seeking across a three-year follow-up. In middle adolescence (~ages 12-16), there was no evidence of a relationship between NAcc reactivity and sensation seeking. However, during the transition from late adolescence into adulthood (~ages 17-25), heightened reward-related reactivity in the NAcc was linked to increased sensation seeking. Findings suggest that the neural mechanisms underlying individual differences in trait-like levels of sensation seeking change from early to late adolescence.

Exploring sex differences in trajectories of pubertal development and mental health following early adversity.

Despite evidence that early life adversity (ELA) affects mental health in adolescence, we know little about sex differences in how distinct dimensions of adversity affect development and their corresponding effects on mental health. In this three-wave longitudinal study, 209 participants (118 females; ages 9-13 years at baseline) provided objective (salivary hormones, BMI, age of menarche) and subjective (perceived gonadal and adrenal status) measures of puberty and physical development, and reported on levels of internalizing and externalizing symptoms at all timepoints. Participants also reported lifetime exposure to three distinct types of ELA: deprivation, threat, and unpredictability. Using generalized additive mixed models, we tested within each sex whether dimensions of adversity were associated with longitudinal changes in measures of pubertal and physical development, and whether these indices of development were associated with trajectories of internalizing and externalizing symptoms. In females, experiences of threat and unpredictability were significantly associated with earlier pubertal timing (e.g., age of menarche) whereas experiences of deprivation were associated with steeper increases in BMI; further, faster pubertal tempo (i.e., steeper increases in pubertal stage) was associated with increases in internalizing and externalizing symptoms. In males, however, ELA was not associated with any measures of pubertal or physical development or with symptoms. Together, our results suggest that adverse experiences during early life have sex-selective consequences for pubertal and physical maturation and mental health trajectories in ways that may elucidate why females are at higher risk for mental health difficulties during puberty, particularly following exposure to unpredictable and threatening experiences of adversity.

Sex-Specific Vulnerability to Externalizing Problems: Sensitivity to Early Stress and Nucleus Accumbens Activation Over Adolescence.

BACKGROUND: Exposure and sensitivity to early-life stress (ELS) are related to increased risk for psychopathology in adolescence. While cross-sectional studies have reported blunted nucleus accumbens (NAcc) activation in the context of these associations, researchers have not yet assessed the effects of ELS on developmental trajectories of activation. We examined whether trajectories are affected by stress and the moderating role of biological sex in predicting vulnerability to symptoms of psychopathology. METHODS: Adolescents (n = 173) completed 3 assessments at 2-year intervals across puberty (ages 9-18 years). At baseline, we assessed objective ELS and stress sensitivity using the Traumatic Events Screening Inventory for Children. At all time points, we assessed NAcc activation using the Monetary Incentive Delay task and externalizing, internalizing, and total problems using the Youth Self-Report. We examined correlations between NAcc trajectories (extracted using linear mixed-effects models) with ELS and stress sensitivity and conducted multivariate regression analysis to examine the interaction of NAcc trajectories and biological sex in predicting symptoms of psychopathology. RESULTS: Symptoms increased over adolescence. Stress sensitivity, but not objective ELS, was associated with decreasing trajectories of NAcc activation. Biological sex interacted with NAcc trajectories to predict psychopathology; boys, but not girls, with decreasing NAcc activation had more severe externalizing problems in adolescence. These findings were replicated in the putamen and caudate but not in the medial prefrontal cortex or control brain regions. CONCLUSIONS: NAcc activation may be a sex-specific marker of externalizing problems in adolescence. Efforts to reduce stress sensitivity may help to decrease symptoms of psychopathology in adolescent boys.

Early Life Stress and Neurodevelopment in Adolescence: Implications for Risk and Adaptation.

An alarming high proportion of youth experience at least one kind of stressor in childhood and/or adolescence. Exposure to early life stress is associated with increased risk for psychopathology, accelerated biological aging, and poor physical health; however, it is important to recognize that not all youth who experience such stress go on to develop difficulties. In fact, resilience, or positive adaptation in the face of adversity, is relatively common. Individual differences in vulnerability or resilience to the effects of early stress may be represented in the brain as specific patterns, profiles, or signatures of neural activation, structure, and connectivity (i.e., neurophenotypes). Whereas neurophenotypes of risk that reflect the deleterious effects of early stress on the developing brain are likely to exacerbate negative outcomes in youth, neurophenotypes of resilience may reduce the risk of experiencing these negative outcomes and instead promote positive functioning. In this chapter we describe our perspective concerning the neurobiological mechanisms and moderators of risk and resilience in adolescence following early life stress and integrate our own work into this framework. We present findings suggesting that exposure to stress in childhood and adolescence is associated with functional and structural alterations in neurobiological systems that are important for social-affective processing and for cognitive control. While some of these neurobiological alterations increase risk for psychopathology, they may also help to limit adolescents' sensitivity to subsequent negative experiences. We also discuss person-centered strategies that we believe can advance our understanding of risk and resilience to early stress in adolescents. Finally, we describe ways in which the field can broaden its focus to include a consideration of other types of environmental factors, such as environmental pollutants, in affecting both risk and resilience to stress-related health difficulties in youth.

Sex-specific vulnerability to depressive symptoms across adolescence and during the COVID-19 pandemic: The role of the cingulum bundle.

Background: Females are at higher risk for developing depression during adolescence than are males, particularly during exposure to stressors like the COVID-19 pandemic. Examining structural connections between brain regions involved in executive functioning may advance our understanding of sex biases in stress and depression. Here, we examined the role of the cingulum bundle in differentiating trajectories of depressive symptoms in males and females across adolescence and during the pandemic. Methods: In a longitudinal study of 214 youth (121 females; ages 9-13 years at baseline), we examined whether fixel-based properties of the cingulum bundle at baseline predict changes in females' and males' severity of depressive symptoms across four timepoints (4-7 years) in adolescence, including during the COVID-19 pandemic. We also tested whether cingulum properties predict self-reported resilience and stress during the pandemic. Results: Females had lower fiber density and cross-section (FDC) of the cingulum than did males, a neural pattern that predicted greater increases in depressive symptoms, lower resilience, and higher stress during the COVID-19 pandemic. Cingulum morphometry predicted changes in depressive trajectories in females, but not in males; specifically, females with lower FDC had significant increases in symptoms throughout adolescence, whereas females with higher cingulum FDC did not. Conversely, males had low, stable depressive symptoms throughout adolescence and higher resilience and lower stress during the pandemic compared to females. Higher cingulum FDC predicted higher resilience and lower stress in both sexes. Conclusions: In adults, the cingulum has been implicated in sex differences in stress reactivity. We show that in adolescents, the cingulum reflects sex differences in reports of stress and resilience that might contribute to the increased risk of stress-related mood disorders in females. Adolescent females might benefit from cognitive interventions that strengthen the structural properties of the cingulum and increase their perceived resilience during periods of adversity and disruption.

Associations of Irritability With Functional Connectivity of Amygdala and Nucleus Accumbens in Adolescents and Young Adults With ADHD.

OBJECTIVE: Irritability is a common characteristic in ADHD. We examined whether dysfunction in neural connections supporting threat and reward processing was related to irritability in adolescents and young adults with ADHD. METHOD: We used resting-state fMRI to assess connectivity of amygdala and nucleus accumbens seeds in those with ADHD (n = 34) and an age- and gender-matched typically-developing comparison group (n = 34). RESULTS: In those with ADHD, irritability was associated with atypical functional connectivity of both seed regions. Amygdala seeds showed greater connectivity with right inferior frontal gyrus and caudate/putamen, and less connectivity with precuneus. Nucleus accumbens seeds showed altered connectivity with middle temporal gyrus and precuneus. CONCLUSION: The irritability-ADHD presentation is associated with atypical functional connectivity of reward and threat processing regions with cognitive control and emotion processing regions. These patterns provide novel evidence for irritability-associated neural underpinnings in adolescents and young adults with ADHD. The findings suggest cognitive and behavioral treatments that address response to reward, including omission of an expected reward and irritability, may be beneficial for ADHD.