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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Neural responses to implicit forms of peer influence in young adults.

Young adults are acutely sensitive to peer influences. Differences have been found in neural sensitivity to explicit peer influences, such as seeing peer ratings on social media. The present study aimed to identify patterns of neural sensitivity to implicit peer influences, which involve more subtle cues that shape preferences and behaviors. Participants were 43 young adults (MAge = 19.2 years; 24 males) who underwent functional magnetic resonance imaging while completing a task used to assess neural responses to implicitly "socially tagged" symbols (previously judged by peers as liked vs. not liked, thus differing in apparent popularity) vs. novel symbols that carried no social meaning (not judged by peers). Results indicated greater activity in brain regions involved in salience detection (e.g., anterior cingulate cortex) and reward processing (e.g., caudate) to socially tagged vs. novel symbols, and particularly to unpopular symbols. Greater self-reported susceptibility to peer influence was related to more activity in the insula and caudate when viewing socially tagged vs. novel symbols. These results suggest that the brain is sensitive to even subtle cues varying in level of peer endorsement and neural sensitivity differed by the tendency to conform to peers' behaviors particularly in regions implicated in social motivation.

Greater age-related changes in white matter morphometry following early life stress: Associations with internalizing problems in adolescence.

Early life stress (ELS) is associated with increased risk for internalizing disorders and variations in gray matter development. It is unclear, however, whether ELS affects normative age-related changes in white matter (WM) morphology, and if such maturational differences are associated with risk for internalizing psychopathology. We conducted comprehensive interviews in a cross-sectional sample of young adolescents (N = 156; 89 F; Ages 9-14) to assess lifetime exposure to stress and objective cumulative ELS severity. We used diffusion-weighted imaging to measure WM fixel-based morphometry and tested the effects of age and ELS on WM fiber density and cross-section (FDC), and associations between WM FDC and internalizing problems. Age was positively associated with FDC in all WM tracts; greater ELS severity was related to stronger age-WM associations in several association tracts connecting the frontal lobes with limbic, parietal, and occipital regions, including bilateral superior and inferior longitudinal and uncinate fasciculi (UF). Among older adolescents with greater ELS severity, a higher UF FDC was associated with fewer internalizing problems. Greater ELS severity predicted more mature WM morphometry in tracts implicated in emotion regulation and cognitive processing. More phenotypically mature UF WM may be adaptive against internalizing psychopathology in adolescents exposed to ELS.

Higher Executive Control Network Coherence Buffers Against Puberty-Related Increases in Internalizing Symptoms During the COVID-19 Pandemic.

BACKGROUND: Early pubertal maturation has been posited to be a biopsychosocial risk factor for the onset of internalizing psychopathology in adolescence; further, early-maturing youths exhibit heightened reactivity to stressful events. School closures and enforced social distancing, as well as health and financial uncertainties, during the COVID-19 pandemic are expected to adversely affect mental health in youths, particularly adolescents who are already at risk for experiencing emotional difficulties. The executive control network (ECN) supports cognitive processes required to successfully navigate novel challenges and regulate emotions in stressful contexts. METHODS: We examined whether functional coherence of the ECN, measured using resting-state functional magnetic resonance imaging 5 years before the pandemic (T1), is a neurobiological marker of resilience to increases in the severity of internalizing symptoms during COVID-19 in adolescents who were in more advanced stages of puberty at T1 relative to their same-age peers (N = 85, 49 female). RESULTS: On average, participants reported an increase in symptoms from the 3 months before pandemic to the 2 most recent weeks during the pandemic. We found that early-maturing youths exhibited greater increases in internalizing symptoms during the pandemic if their ECN coherence was low; in contrast, relative pubertal stage was not associated with changes in internalizing symptoms in adolescents with higher ECN coherence at T1. CONCLUSIONS: These findings highlight the role of the functional architecture of the brain that supports executive functioning in protecting against risk factors that may exacerbate symptoms of internalizing psychopathology during periods of stress and uncertainty.

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.

Testing a Developmental Model of Positive Parenting, Amygdala-Subgenual Anterior Cingulate Cortex Connectivity, and Depressive Symptoms in Adolescents Before and During the COVID-19 Pandemic.

Background: Neurobiological measures may inform our understanding of individual differences in adolescents' general risk for and resilience to depressive symptoms, including during the COVID-19 pandemic. We tested a developmental model linking variation in amygdala-subgenual anterior cingulate cortex (sgACC) resting-state connectivity to perceived parenting experiences earlier in adolescence, to concurrent depressive symptoms before the pandemic, and to subsequent depressive symptoms during the pandemic. Methods: We used data from a longitudinal study that included three waves (N = 214 adolescents; ages 9-15 years at time 1 [T1], 11-17 years at T2, and 12-19 years during the pandemic at T3). We assessed positive parenting (warm and supportive) (T1), depressive symptoms (T1 to T3), and functional connectivity between the sgACC and basolateral (BLA) and centromedial amygdala (T1 and T2). We modeled associations among earlier positive parenting, amygdala-sgACC connectivity, and depressive symptoms before and during the pandemic. Results: Less positive parenting at T1 was associated prospectively with stronger BLA-sgACC connectivity at T2 (ß = -0.22) over and above the effect of BLA-sgACC connectivity at T1. Stronger BLA-sgACC connectivity, in turn, was associated with heightened depressive symptoms, both before the pandemic (r = 0.21) and during the pandemic (ß = 0.19; independent of the effect of pre-pandemic symptoms). Conclusions: Adolescents who experience less positive parenting may develop a pattern of BLA-sgACC connectivity that increases their risk for mental health problems. BLA-sgACC connectivity may be associated with depressive symptoms in general, including during periods of heightened risk for adolescents, such as the pandemic.

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.

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.

Early Life Stress Predicts Depressive Symptoms in Adolescents During the COVID-19 Pandemic: The Mediating Role of Perceived Stress.

BACKGROUND: Exposure to early life stress (ELS) is alarmingly prevalent and has been linked to the high rates of depression documented in adolescence. Researchers have theorized that ELS may increase adolescents' vulnerability or reactivity to the effects of subsequent stressors, placing them at higher risk for developing symptoms of depression. METHODS: We tested this formulation in a longitudinal study by assessing levels of stress and depression during the COVID-19 pandemic in a sample of adolescents from the San Francisco Bay Area (N = 109; 43 male; ages 13-20 years) who had been characterized 3-7 years earlier (M = 5.06, SD = 0.86 years) with respect to exposure to ELS and symptoms of depression. RESULTS: As expected, severity of ELS predicted levels of depressive symptoms during the pandemic [r(107) = 0.26, p = 0.006], which were higher in females than in males [t(107) = -3.56, p < 0.001]. Importantly, the association between ELS and depression was mediated by adolescents' reported levels of stress, even after controlling for demographic variables. CONCLUSIONS: These findings underscore the importance of monitoring the mental health of vulnerable children and adolescents during this pandemic and targeting perceived stress in high-risk youth.