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Address correspondence to: Jamie L. Hanson, Ph.D., Duke University, Department of Psychology & Neuroscience, 417 Chapel Drive, Duke West Campus, Sociology-Psychology Building, Room 07A, Durham, NC 27710.
Department of Psychiatry, University of Texas Health Sciences Center at San Antonio, San Antonio, TexasSouth Texas Veterans Health Care System, San Antonio, Texas
Emotional neglect is associated with multiple negative outcomes, particularly increased risk for depression. Motivated by increasing evidence of reward-related ventral striatum (VS) dysfunction in depression, we investigated the role of developmental changes in VS activity on the emergence of depressive symptomatology as a function of emotional neglect.
Methods
We examined relationships between longitudinal neuroimaging of reward-related VS activity, assessments of mood, and measures of emotional neglect in 106 participants first scanned between ages 11 to 15 and then 2 years later.
Results
We found that greater levels of emotional neglect were associated with blunted development of reward-related VS activity between the first and second assessments (as indexed by lower residualized change scores). Additionally, we found that decreases in this reward-related VS activity were related to greater depressive symptomatology and partially mediated the association between emotional neglect and subsequent depressive symptomatology.
Conclusions
Our results provide an important demonstration that blunted development of reward-related VS activity as a function of emotional neglect predicts the emergence of depressive symptoms in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related VS dysfunction in the etiology and pathophysiology of depression. These results are a first step toward developing the ability to predict, prevent, and treat stress-related psychopathology through the targeting of specific neural phenotypes.
Shonkoff JP, Garner AS (2012): Committee on Psychosocial Aspects of Child and Family Health; Committee on Early Childhood, Adoption, and Dependent Care, Section on Developmental and Behavioral Pediatrics: The lifelong effects of early childhood adversity and toxic stress. Pediatrics 129:e232–e246. http://dx.doi.org/10.1542/peds.2011-2663.
). In regard to mental health, meta-analyses suggest over a 65% increase in the risk for major depressive disorder (MDD) following ELS such as abuse or neglect (
). Though well studied and well replicated in psychological and epidemiological research, the exact neurobiological mechanisms mediating the association between such adverse experiences and later depression remain unclear. ELS is associated with sensitization of the neuroendocrine stress response (
Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene–environment interactions, and epigenetics.
). However, further mechanistic clarification is crucial for advancing efforts to establish predictive biomarkers of relative risk and resilience. Targeted neurobiological investigations, particularly those employing neuroimaging, could also aid in developing the next generation of intervention strategies.
In considering the various forms of ELS, psychological maltreatment, such as emotional neglect (EN) may be of particular concern, as this adversity is prevalent, often goes unreported, and is associated with a twofold increase in adolescent mental illness (
Sedlak AJ, Mettenburg J, Basena M, Petta I, McPherson K, Greene A, Li S (2010): Fourth National Incidence Study of Child Abuse and Neglect (NIS-4): Report to Congress, Executive Summary. Washington, DC: US Department of Health and Human Services, Administration for Children and Families.
). Emotional neglect, which is characterized by emotional unresponsiveness, unavailability, and limited emotional interactions between parent and child (
), has been associated with the development of a host of psychological difficulties including increased shame, humiliation, anger, and feelings of worthlessness (
To date, the majority of investigations into neural mechanisms of risk related to forms of ELS have focused on dysfunction of brain circuits involved with threat processing and stress responsiveness such as the amygdala (
). VS dysfunction has been theorized to underlie symptoms of MDD (including anhedonia and apathy), and neuroimaging studies have reported decreased reward-related VS activity in depressed individuals (
). Furthermore, there is evidence that psychological factors protective against MDD, including maintaining optimism and a positive self-concept, are associated with increased activity of the VS and interconnected neural circuitry (
). In support of these clinical studies, preclinical animal models have found associations between depressive behavior and VS functioning as assessed by levels of transcription factors and gene expression (
). Further work has found antidepressive-like effects after manipulation of VS neurobiology, such as changing the levels of transcription factors or the firing rates of neurons that project to the VS (
), again underscoring a central role of the functioning of this brain region in the pathophysiology of depression.
Despite the links suggested by the work described above, few investigations have directly examined associations between EN, VS dysfunction, and depression. One study reported behavioral deficits in reward processing in children who suffered maltreatment (
). The dearth of clinical research in this area is further surprising, given robust findings from preclinical models linking ELS to alterations in reward-related neural circuitry, particularly dopaminergic modulation of VS activity (
). Additionally, changes in reward-related behaviors, such as weakened conditioned place preferences, have been consistently noted in these preclinical models of ELS (
The limited available research, though informative, has not investigated whether differences in reward-related VS function specifically predict later mood disturbances related to EN or other types of ELS. Prospective work is critically needed, particularly during adolescence. Initial episodes of depression are likely to occur during this developmental transition (
). Furthermore, focusing on reward during this time period may be particularly important, given that anhedonia and low positive affect in adolescence predicts later MDD (
The core of loneliness: Lack of pleasurable engagement--more so than painful disconnection--predicts social impairment, depression onset, and recovery from depressive disorders among adolescents.
). Emotionally unresponsive caregiving during childhood and adolescence could influence the development of this circuitry, leading to difficulties in emotion processing and regulation (
). When examining these possible developmental pathways, it will be important to carefully consider seminal studies examining structural brain development that have found trajectories of neurobiological change may be more predictive of outcomes than a single measurement at one time point (
). Here, we report on such a prospective study. Specifically, we used longitudinal neuroimaging and behavioral data to test the hypothesis that changes in reward-related VS activity would mediate the relationship between emotional neglect and the emergence of later depressive symptomatology. We predicted that higher levels of EN would be related to greater decreases in reward-related VS activity over time and that this change in activity would partially explain the association between depressive symptoms and EN. Finally, we examined neural responses to specific valences of feedback (i.e., positive or negative) to more fully understand potential relationships between EN, symptoms of depression, and VS activity. Based on past theoretical and empirical reports linking lower VS activity to anhedonic elements of depression, we predicted lower VS activity to positive feedback in individuals reporting higher levels of EN.
Methods and Materials
Participants
Longitudinal data were available for 106 adolescents (51 female adolescents; mean age at scan 1 = 13.67 years; range at scan 1 = 11.88–15.45 years of age) who were initially recruited as part of a study designed to investigate factors contributing to risk for psychopathology, with an emphasis on depression and alcohol use disorders. After providing consent/assent, adolescent participants without magnetic resonance imaging (MRI) contraindications (e.g., braces) then completed in-person interviews, self-report behavioral assessments, and MRI scanning. Participants were re-contacted annually to complete diagnostic interviews and questionnaires and also underwent a follow-up MRI scanning session (mean time between scanning sessions = 2.09 ± .37 years; range = 1.32–3.13 years; age range at scan 2 = 13.77–18.25 years). A distinctive feature of our recruitment and sampling strategy was an ability to capture increases in rates of depression between adolescence and early adulthood (
Inclusion criteria required that all participants be free of psychopathology, with the exception of anxiety disorder diagnoses, at the baseline. Diagnoses were assessed using structured clinical interviews (
Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data.
J Am Acad Child Adolesc Psychiatry.1997; 36: 980-988
). Sixteen participants had an anxiety disorder at the start of the project and nine participants developed MDD between neuroimaging scans. Within the study population, participants with a family history of MDD were oversampled. Those with both a first- and second-degree relative with a history of MDD were classified as high risk, and those with no first- or second-degree relatives with a history of MDD were classified as low risk.
Measures of Depression and Anxiety
Depressive symptoms were measured with the child-report version of the Mood and Feelings Questionnaire (
), the EN subscale exhibited greater variability in scores. This measure was collected at the baseline scanning session and the second scanning session and then averaged together to yield a composite measure of EN. Analyses were also conducted related to stressful life events occurring during the past year assessed using the interviewer-based Stressful Life Events Schedule (
To probe reward circuitry, participants completed a functional MRI (fMRI) card-guessing paradigm consisting of three blocks each of predominantly positive feedback (80% correct guess), predominantly negative feedback (20% correct guess), and no feedback. Participants were told that their performance on this game would determine a monetary reward to be received and were unaware of the fixed outcome probabilities associated with each block. Instead, all participants received $10. One incongruent trial was included within each task block (e.g., one of five trials during positive feedback blocks was incorrect, resulting in negative feedback) and all blocks were pseudorandomly ordered to minimize expectancy effects and to increase participant engagement throughout the task. A number of past studies have employed this block design task to elicit robust VS activity associated with positive feedback in contrast to negative feedback within the broader context of monetary reward (
Blood oxygen level-dependent functional neuroimaging data were acquired for each participant and then processed in SPM8 (University College London, London, United Kingdom) using standard preprocessing parameters. Following preprocessing, linear contrasts employing canonical hemodynamic response functions were used to estimate the effects of different forms of feedback (e.g., positive, negative) for each individual. Next, a second-level whole-brain analysis of variance (flexible factorial) with a 2 (positive feedback, negative feedback) × 2 (scan 1, scan 2) design was utilized to isolate regions consistently activated in the contrast of positive feedback > negative feedback. This analytic strategy was employed because of the heterogeneity of reward-related VS activation reported across adolescence, with some studies finding relative increases (
) in comparison with adults. Multiple comparison correction was conducted via cluster-size thresholding based on Monte Carlo simulation to yield a corrected p ≤ .05 (details in Supplement 1). Additional analyses were also conducted with regions of interest (ROI) not reaching statistical significance but previously implicated with reward processing (additional details in Supplement 1).
Statistical Analyses
Parameter estimates were extracted for use outside of SPM8 using MarsBaR (
Region of interest analysis using an SPM toolbox. Presented at the International Conference on Functional Mapping of the Human Brain, June 2-6, Sendai.
) by averaging across every voxel in clusters that survived multiple comparisons correction in each region of interest. The same masks were used at scan 1 and scan 2 for all analyses. Before all analyses and similar to past studies (
), mean parameter estimates were winsorized to minimize the effects of potential outliers, with values that were greater than 3 SDs above or below the mean set to the closest observed value within 3 SDs of the mean. Next, to measure change in VS activity over time, linear regression models in R (R: a language and environment for statistical computing; R Core Team, Vienna, Austria; http://cran.r-project.org) were constructed with parameter estimates for scan 2 as the dependent variable and parameter estimates for scan 1 as the independent variable. Residuals for this model (the difference between observed activity and predicted scores for scan 2) were then saved and used in subsequent analyses. These scores carry the advantage of controlling for the influence of baseline values on change over time and can be interpreted as changing more or less than expected (
). Negative residuals (or lower values) would therefore represent greater decreases than expected in activity over time.
Next, bivariate correlations were calculated to assess the relationship between change in activity and depressive symptoms and also EN, controlling for age and sex. To investigate the potential mediating role of change in VS activity, path analyses tested whether EN (X) was associated with depression symptomatology (Y) and whether the observed association was mediated by change in activity (M). Statistical testing of mediation was done by nonparametric bootstrapping, with 95% confidence interval for indirect (a × b) mediation effects. Mediation modeling was completed in R and included age (at scan 1 and scan 2), time between scans, sex, anxiety symptoms (Screen for Child Anxiety Related Disorders at scans 1 and 2), and depressive symptomatology (scan 1 Mood and Feelings Questionnaire) as covariates.
To probe the specificity of effects, mediation modeling was also completed controlling for recent life stress and other forms of trauma (details in Supplement 1). Furthermore, additional analyses were also conducted 1) in relation to symptoms of anxiety; 2) reversing potential mediators (change in depression symptoms as the potential mediator); and 3) in relation to familial history of MDD (all detailed in Supplement 1).
Exploratory Analyses Related to Feedback Valance
To better understand the effects of EN on reward-related brain function, we investigated the effects of feedback valence (positive or negative) by extracting the contrasts of positive feedback > control blocks and negative feedback > control blocks for the VS clusters that survived multiple comparisons for the contrast positive > negative feedback. For these analyses, change scores were calculated for each of these metrics and bivariate correlations were computed with our variables of interest (details in Supplement 1). Due to the brief nature of our task and limited past research studies focused on such effects, this analysis was considered exploratory. Analyses examining psychophysiological interactions were also conducted and are discussed in Supplement 1.
Results
Neuroimaging Quality Control and Task Validation
All participants included in our analyses had two waves of fMRI data that met stringent quality control procedures (Supplement 1). Attrition and exclusion for data quality were not related to variables of interest [additional information including demographic and recruitment information available in Supplement 1; also in (
), our fMRI paradigm elicited robust reward-related (i.e., positive > negative feedback) VS activity (main effect of task shown in Figure 1). In fact, the VS was the only brain area that survived whole-brain multiple comparison correction, p < .05, corrected (max voxel x = −8, y = +14, z = −2, t = 5.2, k = 328 voxels). Mean blood oxygen level-dependent parameter estimates for this VS cluster were used in all statistical analyses, conducted in R. Analyses with additional ROIs not reaching statistical significance are included in the Supplement 1.
Figure 1Ventral striatum activity for the contrast of positive > negative feedback, controlling for multiple comparisons; p = .05 corrected.
Association between Stress Exposure, Depressive Symptomatology, and VS Activity
Bivariate correlations indicated EN was associated with greater depressive symptoms at scan 2 (r = .266, p = .004) but not anxiety symptoms (all ps > .08; details in Supplement 1). EN was associated with changes in VS activity (r = −.234, p = .015), with greater levels of this adversity being related to lower VS activity change (Figure 2A). This relationship remained significant when participants with any diagnosis of anxiety (p = .044) or depression (p = .026) were removed from the analyses. Depressive symptomatology (at scan 2) was associated with changes in VS activity (r = −.215, p = .02), with greater depressive symptomatology being related to lower VS activity change (Figure 2B). This relationship remained significant when participants with any diagnosis of anxiety (p = .025) or depression (p = .01) were removed from the analyses. Similar results were found using robust regression techniques to control for any potential outliers in VS activity (Supplement 1). Levels of anxiety (at scan 2) were also associated with changes in VS activity (r = −.19, p = .048), with greater symptoms being related to lower VS activity change. This association, however, became nonsignificant when participants with any diagnosis of anxiety (p = .12) or depression (p = .17) were removed from analyses. Of important note, change in VS activity was not related to recent stressful life events, familial risk, or the interaction of familial risk by time (all ps > .8, Supplement 1). Also, no differences in levels of EN were found between these groups (p = .845).
Figure 2Scatter plots showing change in ventral striatum (VS) activity (vertical axis) (A, B) and emotional neglect (horizontal axis) (A) and depressive symptoms at scan 2 (horizontal axis) (B). CTQ, Childhood Trauma Questionnaire.
After finding the associations reported above, we next investigated whether individual differences in changes in reward-related VS activity mediated the effects of EN on depression symptomatology. Similar to the correlations reported above, a linear regression model where EN predicted depressive symptomatology at scan 2 yielded a β = .26 (covariates: age at each scan, time between scans, and participant sex). When change in VS activity was entered into this model, the relationship between EN and depressive symptomatology at scan 2 fell to β = .22 (covariates: age at each scan, time between scans, participant sex, depressive symptoms at scan 1, and anxiety symptoms at scans 1 and 2). In support of our principal hypothesis, nonparametric bootstrapped models indicated the change in VS activity mediated 18.6% of the association between EN and depressive symptoms (variance mediated by the VS = .186; 95% confidence interval = .002–.83, p = .04; Figure 3). Additional mediation models employing additional covariates (e.g., pubertal status) and different metrics of VS change are detailed in Supplement 1.
Figure 3Results from a path analysis testing a model wherein changes in ventral striatum (VS) activity mediate the relationship between emotional neglect (EN) and later depressive symptoms. Standardized regression estimates are shown for the relationship between EN and VS change (path a), between VS change and depressive symptoms at scan 2 (path b), and between EN and depressive symptoms. The latter is shown without (path c) and also while accounting for VS change (path c’). CI, confidence interval.
Factors Contributing to Differences in Reward-Related VS Activity
Regarding VS activity to valence-specific feedback, we found that the change in VS activity to positive feedback was inversely related to EN (r = −.209, p = .03) and depressive symptoms (r = −.259, p = .007). Change in VS activity to negative feedback, however, was not related to either EN (r = −.049, p = .6) or depressive symptoms (r = −.14, p = .12). Analyses examining psychophysiological interactions with the VS and other brain regions are discussed in Supplement 1.
Discussion
Our current results demonstrate that blunted development of reward-related VS activity significantly mediates the expression of depressive symptomatology as a function of emotional neglect in early life. These patterns of lower residuals of VS activity change (which can be conceptualized as greater decreases over time) are consistent with prior neuroimaging studies linking lower reward-related activity of the VS specifically with anhedonic symptoms of depression (
), as well as research from our group demonstrating that lower reward-related VS activity explains reductions in positive affect after stressful events in young adults (
) that posit brain reward function may be a key component of resilience to MDD following EN or other forms of ELS. In particular, VS activity may be critically related to psychological aspects of resiliency, including maintaining optimism, hopefulness, and a positive self-concept after exposure to extreme stress (
). Our data and such ideas ally with the finding that initial episodes of MDD may be more strongly related to anhedonia and low positive affect in adolescence (
This work begins to fill in important gaps in the understanding of the sequelae of ELS and also the emergence of MDD. While it is clear that both stress and reward deficiencies contribute to depression, debate is ongoing regarding the sequencing of such risk factors. Stress may contribute to reward dysfunction, which then increases risk for MDD. Alternatively, preexisting reward dysfunction may amplify risk for MDD subsequent to stress (
). Our data suggest that reward-related neural dysfunction subsequent to stress exposure is associated with later depression symptomatology. However, further prospective investigations are needed to fully rule out that vulnerability to MDD is not due to the interactions between stress exposure and reward dysfunction. Further research and clarification of these pathways may have important implications for clinical practice, as adults exposed to abuse or neglect have more recurrent, persistent, and treatment-resistant depressive episodes (
). Decreases in reward-related VS activity following EN may represent a neurobiological mechanism for such clinical phenomena. Augmenting treatment with therapeutic modules related to positive affect and reward functioning may be particularly efficacious in samples exposed to EN or other forms of ELS.
In thinking about the phenomenology of EN, a paucity of emotionally responsive caregiving, especially during crucial early periods of development, could increase risk factors for MDD. Emotional unavailability and unresponsiveness in parents may result in poor emotion regulation, as parents help children learn how to adaptively respond to their environment (
). The lack of rich emotional interactions may also contribute to feelings of worthlessness and other cognitive risk factors for depression (e.g., negative attributional style). These cognitive biases may then give way to reduced optimism and greater hopelessness, processes related to VS functioning. Past investigations have found early emotional experiences and forms of emotional maltreatment significantly increase risk for symptoms of depression, as well as clinical disorder (
). These cognitive vulnerabilities may be a unique pathway linking early EN to MDD, as opposed to other forms of ELS such as physical abuse.
The lack of associations between EN, anxiety, and VS activity in the current work is important to discuss, particularly in light of reports finding anxiety often predates MDD during development [for review, see (
)]. Anxiety in childhood and depression in adolescence, however, may not always reflect the same constellation of risk factors. Behavioral genetics research suggests MDD and forms of anxiety may partially reflect different genetic risk variables (
). Furthermore, environmental factors, such as EN or maltreatment, significantly influence the covariation of anxiety and depression symptoms during development (
). Research suggests that life stress may be more predictive of MDD, particularly the first onset of the disorder, rather than specific forms of anxiety (
). Such patterns could be due to cognitive or emotional vulnerabilities related to EN, noted previously. More broadly, relationships between pediatric anxiety and VS functioning have been mixed, with higher, lower, and no differences in reward-related activity reported between healthy participants and those with anxiety disorders (
As adolescence represents a period of major neurobiological change within brain reward circuitry, it is important to consider our study in the emerging subdiscipline of developmental cognitive neuroscience. A growing body of research in this field suggests major changes in VS function are a normative part of brain development (
A systematic review of fMRI reward paradigms used in studies of adolescents vs. adults: The impact of task design and implications for understanding neurodevelopment.
). Initial theoretical models conceptualized increases in reward-related VS activity as an explanation for the elevated risk taking seen during adolescence (
). More recent longitudinal work has, however, found VS increases may be protective in nature, with greater increases across development related to self-reports of less risky decision making (
) finding that lower reward-related VS activity is related to MDD in adolescence. Additional research focused on the VS is needed to explicate these differences, particularly in regard to interactions with the medial prefrontal cortex (mPFC), as increased activity has been found in this region during reward processing for those at risk for depression (
). In exploratory ROI analyses, we did not find any differences in the mPFC related to EN (details in Supplement 1). Lower VS activity during development, however, may lead to aberrant corticostriatal connectivity, which is related to MDD clinical symptomatology and treatment response (
) supports the importance of better understanding the development of reward circuitry in the development of depression.
Our study is not without limitations, many of which suggest specific directions for future research. First, the experimental paradigm employed here assays only one facet of reward processing. Recent work has noted that such processing is a complex, nonunitary phenomenon (
A systematic review of fMRI reward paradigms used in studies of adolescents vs. adults: The impact of task design and implications for understanding neurodevelopment.
). Future work focused on reward anticipation, modulation, and other components of reward processing may aid in explaining the effects of ELS and/or connections with different forms of psychopathology. Second, our sample consisted of individuals with and without a familial history of MDD; this risk factor was, however, not related to reward activity. We discuss these null findings in relation to past research reports in Supplement 1. Third, the participants in our study are still developing, and the differences highlighted here may lessen (or increase) later in adolescence and adulthood. A blunting of VS activity during development may emerge as reduced engagement in rewarding experiences or with peers, each of which put individuals at elevated risk for MDD (
). Additional longitudinal investigations are needed, particularly those connecting earlier measures of brain functioning with later behavioral outcomes. Fourth, no information was available about the timing of EN. ELS during specific periods in development may uniquely impact facets of reward processing, further influencing stress-related affective psychopathology. Finally, the preponderance of our analyses centered on the VS and depression symptomatology. Though important, the VS does not act in isolation and interactions between the VS and interconnected corticostriatal structures, particularly the ventral tegmental area, amygdala, and mPFC, likely further mediate the effects of EN on psychopathology through alterations in reward processing. Interestingly, we find relationships between EN and VS-amygdala functional connectivity (details in Supplement 1). Such results connect with cross-sectional (
) investigations focused on corticolimbic alterations after ELS. Conceptual models of ELS should consider differences in reward-related VS activity and also threat-related amygdala activity, as dynamic interactions between these systems may better predict maladaptive responses to stress exposure (
These limitations notwithstanding, our results provide the first empirical demonstration that changes in reward-related VS activity as a function of EN predict relative risk for stress-related depressive symptomatology in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related VS dysfunction in the etiology and pathophysiology of depression and suggest that targeting this neural phenotype may advance efforts for early intervention in those experiencing EN or forms of ELS. More broadly, aspects of the early environment, specifically parent-child interactions, may uniquely shape the processing of important environmental (reward) cues, creating vulnerabilities for later negative outcomes. Additional research is needed to clarify the complex relationships between ELS and related long-term physical and mental difficulties, and our data are a needed first step in the ability to predict, prevent, and treat stress-related affective psychopathology.
Acknowledgments and Disclosures
This work was supported by the National Institute on Alcohol Abuse and Alcoholism (Grant R01AA016274 to DEW), the Genetic and Environmental Risk endowment from the Dielmann Family (DEW), the National Institute on Drug Abuse (Grants R01DA033369 and R01DA031579 to ARH), the National Institute of Mental Health (Grant MH087493 to Consuelo Walss-Bass), a Postdoctoral Fellowship provided by the National Institute on Drug Abuse through the Center for the Study of Adolescent Risk and Resilience (Grant P30DA023026 to JLH), and a postdoctoral fellowship provided by the National Institute of Child Health and Human Development (Grant T32HD0737625) through the Center for Developmental Science, University of North Carolina at Chapel Hill, to JLH.
JLH performed statistical analyses and helped draft the manuscript. ARH conceived of the study, participated in study design, aided with statistical analyses, and helped draft the manuscript. DEW conceived of the study, participated in study design and data collection, aided with statistical analyses, and helped draft the manuscript.
We thank the Teen Alcohol Outcomes Study research staff and participating families for their contributions to this work.
All authors report no biomedical financial interests or potential conflicts of interest.
Shonkoff JP, Garner AS (2012): Committee on Psychosocial Aspects of Child and Family Health; Committee on Early Childhood, Adoption, and Dependent Care, Section on Developmental and Behavioral Pediatrics: The lifelong effects of early childhood adversity and toxic stress. Pediatrics 129:e232–e246. http://dx.doi.org/10.1542/peds.2011-2663.
Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene–environment interactions, and epigenetics.
Sedlak AJ, Mettenburg J, Basena M, Petta I, McPherson K, Greene A, Li S (2010): Fourth National Incidence Study of Child Abuse and Neglect (NIS-4): Report to Congress, Executive Summary. Washington, DC: US Department of Health and Human Services, Administration for Children and Families.
The core of loneliness: Lack of pleasurable engagement--more so than painful disconnection--predicts social impairment, depression onset, and recovery from depressive disorders among adolescents.
Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data.
J Am Acad Child Adolesc Psychiatry.1997; 36: 980-988
Region of interest analysis using an SPM toolbox. Presented at the International Conference on Functional Mapping of the Human Brain, June 2-6, Sendai.
A systematic review of fMRI reward paradigms used in studies of adolescents vs. adults: The impact of task design and implications for understanding neurodevelopment.
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