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This study aimed to examine changes in depression and anxiety symptoms from before to during the first 6 months of the COVID-19 pandemic in a sample of 1,339 adolescents (9-18 years old, 59% female) from three countries. We also examined if age, race/ethnicity, disease burden, or strictness of government restrictions moderated change in symptoms. Data from 12 longitudinal studies (10 U.S., 1 Netherlands, 1 Peru) were combined. Linear mixed effect models showed that depression, but not anxiety, symptoms increased significantly (median increase = 28%). The most negative mental health impacts were reported by multiracial adolescents and those under 'lockdown' restrictions. Policy makers need to consider these impacts by investing in ways to support adolescents' mental health during the pandemic.

BackgroundWhile identifying risk factors for adolescent depression is critical for early prevention and intervention, most studies have sought to understand the role of isolated factors rather than across a broad set of factors. Here, we sought to examine multi-level factors that maximize the prediction of depression symptoms in US children participating in the Adolescent Brain and Cognitive Development (ABCD) study.MethodsA total of 7,995 participants from ABCD (version 3.0 release) provided complete data at baseline and 1-year follow-up data. Depression symptoms were measured with the Child Behavior Checklist. Predictive features included child demographic, environmental, and structural and resting-state fMRI variables, parental depression history and demographic characteristics. We used linear (elastic net regression, EN) and non-linear (gradient-boosted trees, GBT) predictive models to identify which set of features maximized prediction of depression symptoms at baseline and, separately, at 1-year follow-up.ResultsBoth linear and non-linear models achieved comparable results for predicting baseline (EN: MAE = 3.757; R2  = 0.156; GBT: MAE = 3.761; R2  = 0.147) and 1-year follow-up (EN: MAE = 4.255; R2  = 0.103; GBT: MAE = 4.262; R2  = 0.089) depression. Parental history of depression, greater family conflict, and shorter child sleep duration were among the top predictors of concurrent and future child depression symptoms across both models. Although resting-state fMRI features were relatively weaker predictors, functional connectivity of the caudate was consistently the strongest neural feature associated with depression symptoms at both timepoints.ConclusionsConsistent with prior research, parental mental health, family environment, and child sleep quality are important risk factors for youth depression. Functional connectivity of the caudate is a relatively weaker predictor of depression symptoms but may represent a biomarker for depression risk.

Background/aimsTo assess the accuracy of real-time telemedicine to diagnose and manage paediatric eye conditions.MethodsDesign: Prospective, non-inferiority study analysing agreement in diagnoses and management plans between telemedicine and in-person examinations. Setting: Paediatric ophthalmology clinic. Population: Children 0-17 years, English-speaking or Spanish-speaking, able to participate in age-appropriate manner, either previously seen by the optometrist and required ophthalmology referral or newly referred from outside source. Procedures: Paediatric optometrist conducted examinations using digital equipment and streamed live to a paediatric ophthalmologist who recorded diagnoses and management plans, then re-examined patients in-person. Subjects were masked to the fact they would see the ophthalmologist in-person, same-day. Main outcome measures: Discrepancy in management plan or diagnosis between telemedicine and in-person examinations. Non-inferiority threshold was

Frustration is common in adolescence and often interferes with executive functioning, particularly reward-based decision-making, and yet very little is known about how incidental frustrating events (independent of task-based feedback) disrupt the neural circuitry of reward processing in this important age group. While undergoing functional magnetic resonance imaging (fMRI), 45 healthy adolescents played a card game in which they had to guess between two options to earn points, in low- and high-stake conditions. Functioning of button presses through which they made decisions was intermittently blocked, thereby increasing frustration potential. Neural deactivation of the precuneus, a Default Mode Network region, was observed during obstructed action blocks across stake conditions, but less so on high- relative to low-stake trials. Moreover, less deactivation in goal-directed reward processing regions (i.e., caudate), frontoparietal "task control" regions, and interoceptive processing regions (i.e., somatosensory cortex, thalamus) were observed on high-stake relative to low-stake trials. These findings are consistent with less disruption of goal-directed reward seeking during blocked action efficacy in high-stake conditions among healthy adolescents. These results provide a roadmap of neural systems critical to the processing of frustrating events during reward-based decision-making in youths and could help to characterize how frustration regulation is altered in a range of pediatric psychopathologies.

Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize the importance of considering multidimensional factors in understanding risk for suicidal thoughts and behaviors (STBs) during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal events that occur during puberty have significant effects on the organization and development of brain systems implicated in the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing, warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more effective, sex-specific, psychiatric interventions for adolescents.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Mindfulness-based approaches show promise to improve emotional health in youth and may help treat and prevent adolescent depression and anxiety. However, there is a fundamental gap in understanding the neural reorganization that takes place as a result of such interventions. The Training for Awareness, Resilience, and Action (TARA) program, initially developed for depressed adolescents, uses a framework drawn from neuroscience, mindfulness, yoga, and modern psychotherapeutic techniques to promote emotional health. The goal of this study was to assess the effects of the TARA training on emotional health and structural white matter brain networks in healthy youth. We analyzed data from 23 adolescents who underwent the 12-week TARA training in a controlled within-subject study design and whose brain networks were assessed using diffusion MRI connectomics. Compared to the control time period, adolescents showed a significant decrease in anxiety symptoms with TARA (Cohen's d = -0.961, p = 0.006); moreover, the node strength of the Right Amygdala decreased significantly after TARA (Cohen's d = -1.026, p = 0.004). Post-hoc analyses indicated that anxiety at baseline before TARA was positively correlated with Right Amygdala node strength (r = 0.672, p = 0.001). While change in Right Amygdala node strength with TARA was not correlated with change in anxiety (r = 0.146, p = 0.51), it was associated with change in depression subscale of Anhedonia / Negative Affect (r = 0.575, p = 0.004, exploratory analysis), possibly due to overlapping constructs captured in our anxiety and depression scales. Our results suggest that increased structural connectivity of Right Amygdala may underlie increased anxiety in adolescents and be lowered through anxiety-reducing training such as TARA. The results of this study contribute to our understanding of the neural mechanisms of TARA and may facilitate neuroscience-based prevention and treatment of adolescent anxiety and depression.

Early exposure to psychosocial adversity is among the most potent predictors of depression. Because depression commonly emerges prior to adulthood, we must consider the fundamental principles of developmental neuroscience when examining how experiences of childhood adversity, including abuse and neglect, can lead to depression. Considering that both the environment and the brain are highly dynamic across the period spanning gestation through adolescence, the purpose of this review is to discuss and integrate stress-based models of depression that center developmental processes. We offer a general framework for understanding how psychosocial adversity in early life disrupts or calibrates the biobehavioral systems implicated in depression. Specifically, we propose that the sources and nature of the environmental input shaping the brain, and the mechanisms of neuroplasticity involved, change across development. We contend that the effects of adversity largely depend on the developmental stage of the organism. First, we summarize leading neurobiological models that focus on the effects of adversity on risk for mental disorders, including depression. In particular, we highlight models of allostatic load, acceleration maturation, dimensions of adversity, and sensitive or critical periods. Second, we expound on and review evidence for the formulation that distinct mechanisms of neuroplasticity are implicated depending on the timing of adverse experiences, and that inherent within certain windows of development are constraints on the sources and nature of these experiences. Finally, we consider other important facets of adverse experiences (e.g., environmental unpredictability, perceptions of one's experiences) before discussing promising research directions for the future of the field.

Suicidal ideation (SI) and non-suicidal self-injury (NSSI) are two distinct yet often co-occurring risk factors for suicide deaths in adolescents. Elucidating the neurobiological patterns that specifically characterize SI and NSSI in adolescents is needed to inform the use of these markers in intervention studies and to develop brain-based treatment targets. Here, we clinically assessed 70 adolescents-49 adolescents with depression and 21 healthy controls-to determine SI and NSSI history. Twenty-eight of the depressed adolescents had a history of SI and 29 had a history of NSSI (20 overlapping). All participants underwent a resting-state fMRI scan. We compared groups in network coherence of subdivisions of the central executive network (CEN), default mode network (DMN), and salience network (SN). We also examined group differences in between-network connectivity and explored brain-behavior correlations. Depressed adolescents with SI and with NSSI had lower coherence in the ventral DMN compared to those without SI or NSSI, respectively, and healthy controls (all ps

Adolescence is characterized by rapid brain development in white matter (WM) that is attributed in part to surges in gonadal hormones. To date, however, there have been few longitudinal investigations relating changes in gonadal hormones and WM development in adolescents. We acquired diffusion-weighted MRI to estimate mean fractional anisotropy (FA) from 10 WM tracts and salivary testosterone from 51 females and 29 males (ages 9-14 years) who were matched on pubertal stage and followed, on average, for 2 years. We tested whether interactions between sex and changes in testosterone levels significantly explained changes in FA. We found positive associations between changes in testosterone and changes in FA within the corpus callosum, cingulum cingulate, and corticospinal tract in females (all ps

BackgroundChildhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.MethodsWithin the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.ResultsCM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.ConclusionsSeverity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate (1) the effects of edge weighting schemes and (2) the effects of varying interscan periods on graph metrics within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count, and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62 ± 1.10 years) or within the same scanning session (30 min apart) (16.65 ± 1.14 years). The intraclass correlation coefficient was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA weights are more suited for DTI connectome studies in adolescents.

BackgroundAdolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group.MethodsThe first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents.ResultsThere were no diagnosis-specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto-occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn.LimitationsUndifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations.ConclusionsThe results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population.

Recent evidence suggests that anterior cingulate cortex (ACC) maturation during adolescence contributes to or underlies the development of major depressive disorder (MDD) during this sensitive period. The ACC is a structure that sits at the intersection of several task-positive networks (eg, central executive network, CEN), which are still developing during adolescence. While recent work using seed-based approaches indicate that depressed adolescents show limited task-evoked vs resting-state connectivity (termed 'inflexibility') between the ACC and task-negative networks, no study has used network-based approaches to investigate inflexibility of the ACC in task-positive networks to understand adolescent MDD. Here, we used graph theory to compare flexibility of network-level topology in eight subregions of the ACC (spanning three task-positive networks) in 42 unmedicated adolescents with MDD and 53 well-matched healthy controls. All participants underwent fMRI scanning during resting state and a response inhibition task that robustly engages task-positive networks. Relative to controls, depressed adolescents were characterized by inflexibility in local efficiency of a key ACC node in the CEN: right dorsal anterior cingulate cortex/medial frontal gyrus (R dACC/MFG). Furthermore, individual differences in flexibility of local efficiency of R dACC/MFG significantly predicted inhibition performance, consistent with current literature demonstrating that flexible network organization affords successful cognitive control. Finally, reduced local efficiency of dACC/MFG during the task was significantly associated with an earlier age of depression onset, consistent with prior work suggesting that MDD may alter functional network development. Our results support a neurodevelopmental hypothesis of MDD wherein dysfunctional self-regulation is potentially reflected by altered ACC maturation.

BackgroundThe incidence of major depressive disorder (MDD) rises during adolescence, yet the neural mechanisms of MDD during this key developmental period are unclear. Altered amygdala resting-state functional connectivity (RSFC) has been associated with both adolescent and adult MDD, as well as symptom improvement in response to treatment in adults. However, no study to date has examined whether amygdala RSFC is associated with changes in depressive symptom severity in adolescents.MethodWe examined group differences in amygdala RSFC between medication-naïve depressed adolescents (N=48) and well-matched healthy controls (N=53) cross-sectionally. We then longitudinally examined whether baseline amygdala RSFC was associated with change in depression symptoms three months later in a subset of the MDD group (N=24).ResultsCompared to healthy controls, depressed adolescents showed reduced amygdala-based RSFC with the dorsolateral prefrontal cortex (DLPFC)and the ventromedial prefrontal cortex (VMPFC). Within the depressed group, more positive baseline RSFC between the amygdala and insulae was associated with greater reduction in depression symptoms three months later.LimitationsOnly a subset of depressed participants was assessed at follow-up and treatment type and delivery were not standardized.ConclusionsAdolescent depression may be characterized by dysfunction of frontolimbic circuits (amygdala-DLPFC, amygdala-VMPFC) underpinning emotional regulation, whereas those circuits (amygdala-insula) subserving affective integration may index changes in depression symptom severity and may therefore potentially serve as a candidate biomarker for treatment response. Furthermore, these results suggest that the biomarkers of MDD presence are distinct from those associated with change in depression symptoms over time.

Background: Suicidal behaviours are a major source of mortality and morbidity among adolescents. Given the maturational changes that occur in cortical and subcortical structures during adolescence, we tested whether atypical brain structural measurements were associated with a history of suicide attempt. Methods: We assessed 3 groups of adolescents (n = 92; 79% female, mean age 15.9 years, range 11.6-18.1 years): patients with a depressive disorder and a history of suicide attempt (n = 28); patient controls, who had a depressive disorder but no history of suicide attempt (n = 34); and healthy controls (n = 30). We derived regional cortical thickness and surface area, and subcortical volumes, from [T.sub.1]-weighted anatomic MRI scans acquired at 3 T. Results: We found significant group differences in surface area in the prefrontal, temporal and parietal regions, as well as in the volume of several subcortical nuclei ([p.sub.FDR] [less than or equal to] 0.05), but not in cortical thickness. Post hoc analyses indicated that morphological alterations primarily differentiated patients with a history of suicide attempt from healthy controls, but not from patient controls. However, patients with a history of suicide attempt exhibited positive correlations between age and cortical thickness in the temporal cortices and right insula, and between age and right putamen volume (i.e., thicker regional cortex and larger subcortical volumes with age). These correlations were negative in both patient controls and healthy controls (i.e., thinner regional cortex and smaller subcortical volumes). Limitations: Sample sizes, cross-sectional findings and psychiatric heterogeneity were limitations of this study. Conclusion: Macroscopic structural differences in several brain regions differentiated adolescents with a history of suicide attempt from healthy controls, but not from patient controls. However, adolescents with a history of suicide attempt may present with atypical maturation of specific cortical and subcortical regions that might contribute to the risk of suicidal behaviour., Introduction Suicide is the second leading cause of death in adolescents. (1) A recent survey of college students showed that lifetime prevalence of suicidal ideation, plans and attempts were 32.7%, [...]

Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p

Neuroscientists are increasingly using advanced neuroimaging methods to elucidate the intergenerational transmission of human brain circuitry. This new line of work promises to shed light on the ontogeny of complex behavioral traits, including psychiatric disorders, and possible mechanisms of transmission. Here we highlight recent intergenerational neuroimaging studies and provide recommendations for future work.