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BACKGROUND: A diagnostic criterion for Major Depressive Disorder (MDD) is difficulty concentrating and increased distractibility. One form of distraction that occurs in everyday life is mind-wandering. The current study aims to test how individuals with MDD and healthy controls differ in their mind-wandering in everyday life. METHODS: Adults diagnosed with MDD (n = 53) and healthy controls (n = 53) completed a week of experience sampling, with prompts administered up to eight times per day. At each prompt, participants reported the occurrence and characteristics of their mind-wandering. They also reported levels of momentary negative affect (NA), positive affect (PA), and rumination. RESULTS: MDD participants reported mind-wandering almost twice as often as healthy control participants. Compared to healthy participants, MDD participants rated their mind-wandering as more negative, but did not differ in terms of temporal orientation. Higher NA and lower PA predicted mind-wandering in the MDD group but not healthy controls, even after controlling for rumination. Time-lagged analyses revealed that current mind-wandering predicted future levels of PA in MDD participants but not in healthy controls; in contrast, current NA and PA did not predict future mind-wandering. LIMITATIONS: Limitations include our examination of specific forms of mind-wandering (i.e., we did not sample the full spectrum of this construct). CONCLUSIONS: Individuals with MDD frequently report engaging in mind-wandering in everyday life, and this appears to be coupled with affect. Mind-wandering may have maladaptive effects in MDD and could serve as a target for intervention.
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Background: Exposure to environmental pollutants early in life has been associated with increased prevalence and severity of depression in adolescents; however, the neurobiological mechanisms underlying this association are not well understood. In the current longitudinal study, we investigated whether pollution burden in early adolescence (9-13 years) was associated with altered brain activation and connectivity during implicit emotion regulation and changes in depressive symptoms across adolescence. Methods: One hundred forty-five participants (n = 87 female; 9-13 years) provided residential addresses, from which we determined their relative pollution burden at the census tract level, and performed an implicit affective regulation task in the scanner. Participants also completed questionnaires assessing depressive symptoms at 3 time points, each approximately 2 years apart, from which we calculated within-person slopes of depressive symptoms. We conducted whole-brain activation and connectivity analyses to examine whether pollution burden was associated with alterations in brain function during implicit emotion regulation of positively and negatively valenced stimuli and how these effects were related to slopes of depressive symptoms across adolescence. Results: Greater pollution burden was associated with greater bilateral medial prefrontal cortex activation and stronger bilateral medial prefrontal cortex connectivity with regions within the default mode network (e.g., temporoparietal junction, posterior cingulate cortex, precuneus) during implicit regulation of negative emotions, which was associated with greater increases in depressive symptoms across adolescence in those exposed to higher pollution burden. Conclusions: Adolescents living in communities characterized by greater pollution burden showed altered default mode network functioning during implicit regulation of negative emotions that was associated with increases in depressive symptoms across adolescence.
Exposure to environmental pollution is related to increased risk for depression in youth; however, the neurobiological mechanisms underlying this association are unknown. We found that adolescents living in neighborhoods with greater census tractlevel pollution burden had stronger functional connectivity between the medial prefrontal cortex and regions within the default mode network during implicit regulation of negative emotions, which in turn was associated with greater increases in depressive symptoms across adolescence in these pollution-exposed youths.
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Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples (N = 1,384) of medication-free individuals with first-episode and recurrent MDD (N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls (N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals (N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter (N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter (N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) (ß = -18.3, 95% CI (-34.3 to -2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.
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BACKGROUND: Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging. STUDY DESIGN: Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma). RESULTS: Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta -496.1, 95 % confidence interval [CI] -891.1, -101.1, p = 0.01) and beyond (adjusted beta -396.8; 95 % CI -727.2, -66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction. CONCLUSION: Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted.
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Cesárea , Parto Obstétrico , Leucocitos , Periodo Posparto , Humanos , Femenino , Adulto , Embarazo , Estudios Prospectivos , TelómeroRESUMEN
OBJECTIVE: Adolescents face significant changes in many domains of their daily lives that require them to flexibly adapt to changing environmental demands. To shift efficiently among various goals, adolescents must reconfigure their brains, disengaging from previous tasks and engaging in new activities. METHOD: To examine this reconfiguration, we obtained resting-state and task-based functional magnetic resonance imaging (fMRI) scans in a community sample of 164 youths. We assessed the similarity of functional connectivity (FC) of the reward network between resting state and a reward-processing state, indexing the degree of reward network reconfiguration required to meet task demands. Given research documenting relations among reward network function, early life stress (ELS), and adolescent depression, we examined the association of reconfiguration efficiency with age across adolescence, the moderating effect of ELS on this association, and the relation between reconfiguration efficiency and depressive symptoms. RESULTS: We found that older adolescents showed greater reconfiguration efficiency than younger adolescents and, furthermore, that this age-related association was moderated by the experience of ELS. CONCLUSION: These findings suggest that reconfiguration efficiency of the reward network increases over adolescence, a developmental pattern that is attenuated in adolescents exposed to severe ELS. In addition, even after controlling for the effects of age and exposure to ELS, adolescents with higher levels of depressive symptoms exhibited greater reconfiguration efficiency, suggesting that they have brain states at rest that are more strongly optimized for reward processing than do asymptomatic youth. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science.
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The Coronavirus disease (COVID-19) pandemic led to heightened anxiety in adolescents. The basolateral amygdala (BLA) and the nucleus accumbens (NAcc) are implicated in response to stress and may contribute to anxiety. The role of threat- and reward-related circuitry in adolescent anxiety during the COVID-19 pandemic, however, is not clear. Ninety-nine adolescents underwent resting-state fMRI â¼1 year before the pandemic. Following shelter-in-place orders, adolescents reported their perceived stress and, 1 month later, their anxiety. Generalized multivariate analyses identified BLA and NAcc seed-based whole-brain functional connectivity maps with perceived stress. In the resulting significant clusters, we examined the association between seed-based connectivityand subsequent anxiety. Perceived stress was associated with bilateral BLA and NAcc connectivity across distributed clusters that included prefrontal, limbic, temporal, and cerebellar regions. Several NAcc connectivity clusters located in ventromedial prefrontal, parahippocampal, and temporal cortices were positively associated with anxiety; NAcc connectivity with the inferior frontal gyrus was negatively associated. BLA connectivity was not associated with anxiety. These results underscore the integrative role of the NAcc in responding to acute stressors and its relation to anxiety in adolescents. Elucidating the involvement of subcortical-cortical circuitry in adolescents' capacity to respond adaptively to environmental challenges can inform treatment for anxiety-related disorders.
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Ansiedad , COVID-19 , Imagen por Resonancia Magnética , Recompensa , Estrés Psicológico , Humanos , COVID-19/psicología , Adolescente , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Estrés Psicológico/fisiopatología , Ansiedad/fisiopatología , Ansiedad/psicología , Estudios Longitudinales , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Núcleo Accumbens/diagnóstico por imagen , Núcleo Accumbens/fisiopatología , Complejo Nuclear Basolateral/fisiología , SARS-CoV-2 , Mapeo EncefálicoRESUMEN
There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.
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Ansiedad , Encéfalo , Depresión , Imagen por Resonancia Magnética , Humanos , Masculino , Femenino , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Adulto , Depresión/fisiopatología , Depresión/diagnóstico por imagen , Depresión/terapia , Ansiedad/fisiopatología , Persona de Mediana Edad , Medicina de Precisión , Adulto Joven , Cognición/fisiologíaRESUMEN
Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.
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Trastorno Bipolar , Imagen por Resonancia Magnética , Obesidad , Análisis de Componente Principal , Humanos , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/patología , Adulto , Femenino , Masculino , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Obesidad/diagnóstico por imagen , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/patología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Análisis por Conglomerados , Adulto Joven , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
BACKGROUND: Research has demonstrated an association between elevated systemic inflammation and changes in brain function. Affective areas of the brain involved in processing threat (e.g., amygdala) and reward (e.g., nucleus accumbens) appear to be sensitive to inflammation. Early-life stress, such as experiencing low socioeconomic status (SES), may also potentiate this association, but relevant evidence has come primarily from cross-sectional studies of brain function. It is unclear whether similar associations are present between early-life stress, inflammation, and brain structure, particularly in typically developing populations. METHODS: We recruited and assessed 50 adolescents (31 females/19 males) from the community (mean [SD] age = 15.5 [1.1] years, range = 13.1-17.5 years) and examined in exploratory analyses whether changes in C-reactive protein (ΔCRP) from blood spots predict changes in gray matter volume (ΔGMV) in the bilateral amygdala and nucleus accumbens over a 2-year period. We also investigated whether experiencing early-life stress, operationalized using a comprehensive composite score of SES disadvantage at the family and neighborhood levels, significantly moderated the association between ΔCRP and ΔGMV. RESULTS: We found that ΔCRP was negatively associated with Δamygdala GMV (i.e., increasing CRP levels were associated with decreasing amygdala volume; ß = -0.84, p = .012). This effect was stronger in youths who experienced greater SES disadvantage (ß = -0.56, p = .025). CONCLUSIONS: These findings suggest that increases in systemic inflammation are associated with reductions in amygdala GMV in adolescents, potentially signaling accelerated maturation, and that these neuroimmune processes are compounded in adolescents who experienced greater SES disadvantage. Our findings are consistent with theoretical frameworks of neuroimmune associations and suggest that they may influence adolescent neurodevelopment.
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Early life adversity has been posited to influence the pace of structural neurodevelopment. Most research, however, has relied on cross-sectional data, which do not reveal whether the pace of neurodevelopmental change is accelerated or slowed following early exposures. In a birth cohort study that included neuroimaging data obtained at 4.5, 6, and 7.5 years of age (N = 784), we examined associations among a cumulative measure of perinatal adversity relative to resources, nonlinear trajectories of hippocampal and amygdala volume, and children's subsequent depressive symptoms at 8.5 years of age. Greater adversity was associated with reduced bilateral hippocampal body volume in early childhood, but also to faster growth in the right hippocampal body across childhood. Further, the association between adversity and childhood depressive symptoms was mediated by faster hippocampal body growth. These findings suggest that perinatal adversity is biologically embedded in hippocampal structure development, including an accelerated pace of change in the right hippocampal body that is implicated in children's psychopathology risk. In addition, our findings suggest that reduced hippocampal volume is not inconsistent with accelerated hippocampal change; these aspects of structural development may typically co-occur, as smaller regional volumes in early childhood were associated with faster growth across childhood.
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Experiencias Adversas de la Infancia , Depresión , Hipocampo , Imagen por Resonancia Magnética , Humanos , Hipocampo/crecimiento & desarrollo , Hipocampo/diagnóstico por imagen , Femenino , Masculino , Niño , Preescolar , Amígdala del Cerebelo/crecimiento & desarrollo , Amígdala del Cerebelo/diagnóstico por imagen , Desarrollo Infantil/fisiología , Cohorte de Nacimiento , EmbarazoRESUMEN
The field of developmental psychopathology has grown exponentially over the past decades, and has become increasingly multifaceted. The initial focus on understanding abnormal child psychology has broadened to the study of the origins of psychopathology, with the goals of preventing and alleviating disorder and promoting healthy development. In this paper, we discuss how technological advances and global events have expanded the questions that researchers in developmental psychopathology can address. We do so by describing a longitudinal study that we have been conducting for the past dozen years. We originally planned to examine the effects of early adversity on trajectories of brain development, endocrine function, and depressive symptoms across puberty; it has since become an interdisciplinary study encompassing diverse domains like inflammation, sleep, biological aging, the environment, and child functioning post-pandemic, that we believe will advance our understanding of neurobehavioral development. This increase in the breadth in our study emerged from an expansion of the field; we encourage researchers to embrace these dynamic changes. In this context, we discuss challenges, opportunities, and institutional changes related to the growing interdisciplinarity of the field with respect to training the next generation of investigators to mitigate the burden of mental illness in youth.
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BACKGROUND: Despite evidence that early life stress (ELS) can influence the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and increase maladaptive behaviors in adolescence, less attention has been paid to the role of the coordinated effects of the two primary adrenal hormones, cortisol and dehydroepiandrosterone (DHEA), in these associations. METHODS: 138 typically developing adolescents (76 females) reported the stressful events experienced during childhood and early adolescence across 30 domains. Two years later we assessed levels of externalizing problems and obtained salivary levels of cortisol and DHEA. Using causal moderated mediation analyses, we examined whether the ratio of cortisol to DHEA (CD ratio) mediates the association between ELS and subsequent externalizing problems. RESULTS: We found that ELS is associated with both a lower CD ratio and more externalizing problems. Importantly, a lower CD ratio mediated the association between ELS and externalizing problems in boys. CONCLUSIONS: An imbalance in adrenal hormones may be a mechanism through which ELS leads to an increase in externalizing problems in adolescent boys. These findings underscore the utility of using the CD ratio to index HPA-axis functioning.
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Experiencias Adversas de la Infancia , Deshidroepiandrosterona , Hidrocortisona , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Saliva , Estrés Psicológico , Humanos , Masculino , Hidrocortisona/metabolismo , Hidrocortisona/análisis , Adolescente , Deshidroepiandrosterona/metabolismo , Deshidroepiandrosterona/análisis , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Saliva/química , Saliva/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Femenino , Niño , Conducta del Adolescente/fisiología , Conducta del Adolescente/psicología , Problema de Conducta/psicologíaRESUMEN
We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments (SJs). We found significantly increased high-frequency activity (HFA) in â¼13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than that in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and SJ conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.
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Epilepsia , Memoria Episódica , Humanos , Masculino , Femenino , Juicio , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiología , Encéfalo/fisiología , Mapeo Encefálico , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Understanding the prenatal origins of children's psychopathology is a fundamental goal in developmental and clinical science. Recent research suggests that inflammation during pregnancy can trigger a cascade of fetal programming changes that contribute to vulnerability for the emergence of psychopathology. Most studies, however, have focused on a handful of proinflammatory cytokines and have not explored a range of prenatal biological pathways that may be involved in increasing postnatal risk for emotional and behavioral difficulties. METHODS: Using extreme gradient boosted machine learning models, we explored large-scale proteomics, considering over 1,000 proteins from first trimester blood samples, to predict behavior in early childhood. Mothers reported on their 3- to 5-year-old children's (N = 89, 51% female) temperament (Child Behavior Questionnaire) and psychopathology (Child Behavior Checklist). RESULTS: We found that machine learning models of prenatal proteomics predict 5%-10% of the variance in children's sadness, perceptual sensitivity, attention problems, and emotional reactivity. Enrichment analyses identified immune function, nervous system development, and cell signaling pathways as being particularly important in predicting children's outcomes. CONCLUSIONS: Our findings, though exploratory, suggest processes in early pregnancy that are related to functioning in early childhood. Predictive features included far more proteins than have been considered in prior work. Specifically, proteins implicated in inflammation, in the development of the central nervous system, and in key cell-signaling pathways were enriched in relation to child temperament and psychopathology measures.
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Aprendizaje Automático , Primer Trimestre del Embarazo , Proteómica , Temperamento , Humanos , Femenino , Temperamento/fisiología , Preescolar , Embarazo , Masculino , Primer Trimestre del Embarazo/sangre , Conducta Infantil/fisiología , Adulto , Efectos Tardíos de la Exposición Prenatal/fisiopatologíaRESUMEN
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.
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Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/psicología , Benchmarking , Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Aprendizaje Automático , Imagen por Resonancia Magnética/métodosRESUMEN
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.
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Salud Mental , Caracteres Sexuales , Adolescente , Humanos , Masculino , Femenino , Estudios Longitudinales , Pubertad/psicología , MenarquiaRESUMEN
OBJECTIVE: Network analysis may identify specific symptoms involved in the maintenance and development of psychopathology. This approach, however, has not been applied to the study of young Black children, a population facing unique challenges and developmental risks. It is also unclear whether network analysis identifies early symptoms in Black children that are linked to their longer-term difficulties and strengths in adolescence. METHODS: We conducted a network analysis of emotional and behavioral difficulties in 1238 Black (non-Hispanic) children from the age-3 assessment in the Future of Families and Child Wellbeing Study (47 % female). We also explored whether early childhood symptoms predict subsequent caregiver-reported internalizing and externalizing problems, and youth-reported social competencies and extracurricular and community involvement, at the age-15 assessment. RESULTS: We identified specific symptoms of externalizing and emotional reactivity as central in the network. Symptoms of emotional reactivity were also involved in comorbidity, bridging different communities of symptoms. Using elastic net models, we identified specific central and bridge symptoms, but also peripheral network symptoms, that contributed uniquely to the prediction of internalizing and externalizing problems in adolescence. Early childhood symptoms were less predictive of positive outcomes in adolescence. CONCLUSIONS: This study identified central and bridge symptoms in young Black children, an underrepresented population in network analysis research. Some of these central and bridge symptoms, but also peripheral network symptoms, may be useful targets in early interventions to prevent long-term difficulties. Conversely, network approaches to understanding early psychopathology may have less utility for predicting Black children's subsequent strengths in adolescence.
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Emociones , Trastornos Mentales , Humanos , Niño , Preescolar , Adolescente , Femenino , Masculino , Estudios Longitudinales , Psicopatología , Comorbilidad , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiologíaRESUMEN
Elevated levels of systemic inflammation are associated with altered reward-related brain function in ventral striatal areas of the brain like the nucleus accumbens (NAcc). In adolescents, cross-sectional research indicates that exposure to early life stress (ELS) can moderate the relation between inflammation and neural activation, which may contribute to atypical reward function; however, no studies have tested whether this moderation by ELS of neuroimmune associations persists over time. Here, we conducted a cross-sectional analysis and the first exploratory longitudinal analysis testing whether cumulative severity of ELS moderates the association of systemic inflammation with reward-related processing in the NAcc in adolescents (n = 104; 58F/46M; M[SD] age = 16.00[1.45] years; range = 13.07-19.86 years). For the cross-sectional analysis, we modeled a statistical interaction between ELS and levels of C-reactive protein (CRP) predicting NAcc activation during the anticipation and outcome phases of a monetary reward task. We found that higher CRP was associated with blunted NAcc activation during the outcome of reward in youth who experienced higher levels of ELS (ß = -0.31; p = 0.006). For the longitudinal analysis, we modeled an interaction between ELS and change in CRP predicting change in NAcc activation across 2 years. This analysis similarly showed that increasing CRP over time was associated with decreasing NAcc during reward outcomes in youth who experienced higher levels of ELS (ß = -0.47; p = 0.022). Both findings support contemporary theoretical frameworks involving associations among inflammation, reward-related brain function, and ELS exposure, and suggest that experiencing ELS can have significant and enduring effects on neuroimmune function and adolescent neurodevelopment.
Asunto(s)
Experiencias Adversas de la Infancia , Humanos , Adolescente , Estudios Transversales , Encéfalo/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Proteína C-Reactiva/metabolismo , Imagen por Resonancia Magnética , Inflamación/metabolismoRESUMEN
BACKGROUND: Exposure to adversity early in life (ELA) has been associated with elevated risk for depression during adolescence, particularly for females; the mechanisms underlying this association, however, are poorly understood. One potential mechanism linking ELA and sex differences in depressive symptoms is sleep disturbances, which increase during adolescence and are more common in females. Here, we examined whether sleep disturbances mediate the association between ELA and increases in depressive symptoms during adolescence and whether this mediation differs by sex. METHODS: 224 (N = 132 females) youth were recruited at age 9-13 years and assessed every 2 years across three timepoints. At the first timepoint, we conducted extensive interviews about stressful events participants experienced; participants provided subjective severity ratings of events and we objectively scored the severity of each event. Self-reported sleep disturbances and depressive symptoms were assessed at all timepoints. We conducted linear mixed models to estimate both initial levels and changes in sleep disturbances and depressive symptoms, and moderated mediation analyses to test whether initial levels and/or changes in sleep disturbances mediated the association of ELA (objective and subjective) with increases in depressive symptoms across adolescence and whether the mediations differed by sex. RESULTS: While higher initial levels and increases in sleep problems were uniquely associated with increases in depressive symptoms for males and females, they were related to ELA differently by sex. For females, greater ELA (both objectively and subjectively rated) was associated with higher initial levels of sleep problems, which in turn were associated with increases in depressive symptoms from early to late adolescence. In contrast, for males, ELA exposure was not associated with either initial levels of, or increases in, sleep problems. CONCLUSIONS: These findings highlight the role of sleep disturbances during the transition to adolescence in mediating sex differences in the effects of ELA on depressive symptoms.