Emotion dysregulation and functional connectivity in children with and without a history of major depressive disorder.

Recent interest has emerged in understanding the neural mechanisms by which deficits in emotion regulation (ER) early in development may relate to later depression. Corticolimbic alterations reported in emotion dysregulation and depression may be one possible link. We examined the relationships between emotion dysregulation in school age, corticolimbic resting-state functional connectivity (rs-FC) in preadolescence, and depressive symptoms in adolescence. Participants were 143 children from a longitudinal preschool onset depression study who completed the Children Sadness Management Scale (CSMS; measuring ER), Child Depression Inventory (CDI-C; measuring depressive symptoms), and two resting-state MRI scans. Rs-FC between four primary regions of interest (ROIs; bilateral dorsolateral prefrontal cortex [dlPFC] and amygdala) and six target ROIs thought to contribute to ER were examined. Findings showed that ER in school age did not predict depressive symptoms in adolescence, but did predict preadolescent increases in dlPFC-insula and dlPFC-ventromedial PFC rs-FC across diagnosis, as well as increased dlPFC-dorsal anterior cingulate cortex (dACC) rs-FC in children with a history of depression. Of these profiles, only dlPFC-dACC rs-FC in preadolescence predicted depressive symptoms in adolescence. However, dlPFC-dACC connectivity did not mediate the relationship between ER in school age and depressive symptoms in adolescence. Despite the absence of a direct relationship between ER and depressive symptoms and no significant rs-FC mediation, the rs-FC profiles predicted by ER are consistent with the hypothesis that emotion dysregulation is associated with abnormalities in top-down control functions. The extent to which these relationships might confer greater risk for later depression, however, remains unclear.

Shyness and Trajectories of Functional Network Connectivity Over Early Adolescence.

High shyness during early adolescence is associated with impaired peer relationships and risk for psychiatric disorders. Little is known, however, about the relation between shyness and trajectories of brain development over early adolescence. The current study longitudinally examined trajectories of resting-state functional connectivity (rs-fc) within four brain networks in 147 adolescents. Subjects underwent functional magnetic resonance imaging at three different time points, at average ages 10.5 (range = 7.8-13.0), 11.7 (range = 9.3-14.1), and 12.9 years (range = 10.1-15.2). Multilevel linear modeling indicated that high shyness was associated with a less steep negative slope of default mode network (DMN) rs-fc over early adolescence relative to low shyness. Less steep decreases in DMN rs-fc may relate to increased self-focus in adolescents with high shyness.

Variation in common preschool sleep problems as an early predictor for depression and anxiety symptom severity across time.

BACKGROUND: Child and adolescent psychopathology has been linked to increased sleep problems, but there has been less investigation of this relationship in younger samples with early-onset psychopathology. This study examined three specific but commonly observed aspects of sleep behaviors in young children - (i) Sleep onset latency, (ii) Refusal to sleep alone, and (iii) Nighttime awakenings - measured during preschool, and investigated whether these sleep problems predicted anxiety and/or depression across the next 6 years until school age (ages 9-13). METHODS: Data were analyzed from N = 292 participants from a prospective longitudinal study of preschool-age children (ages 3-6). At baseline, parent-reported clinical interviews of psychiatric symptoms, as well as sleep problems were conducted using the Preschool-Age Psychiatric Assessment (PAPA). Follow-up clinical interviews were also conducted annually through school age using the Childhood and Adolescent Psychiatric Assessment (CAPA). RESULTS: Parent-reported sleep onset latency and refusal to sleep alone were significant independent predictors of MDD and anxiety severity, but not ADHD severity across time, even after controlling for family income-to-needs ratio and maternal internalizing psychopathology. In exploratory analyses using only healthy preschoolers, parent-reported sleep onset latency and refusal to sleep alone also predicted anxiety severity. CONCLUSIONS: We demonstrate that specific, yet relatively common sleep problems predict diagnostic severity of depression and anxiety across time, but not ADHD. Increased clinical attention to and screening for sleep onset latency and refusal to sleep alone during preschool may be warranted.

Early Adversity, Psychopathology, and Latent Class Profiles of Global Physical Health From Preschool Through Early Adolescence.

OBJECTIVE: The purpose of the present report was to describe the longitudinal trajectories of physical health beginning during preschool and continuing into early adolescence; explore whether these trajectories were predicted by psychosocial adversity, family income-to-needs ratio, and psychiatric disorders occurring during the preschool period; and determine whether psychiatric disorders mediated these relations. METHODS: Participants included 296 children participating in a longitudinal study of early-onset psychopathology spanning 10 years. Semistructured clinical interviews were conducted with caregivers to determine children's psychiatric diagnoses between ages 3 and 6 years. Caregivers also completed annual assessments of their child's physical health problems (ages 3-13) and reported on the family's income and indicators of psychosocial adversity. RESULTS: Growth mixture modeling revealed 2 trajectories of physical health problems: a stable, low group (n = 199) and a high, increasing group (n = 57) indicating linear increases in physical health problems from ages 3 to 13. Preschool psychiatric diagnoses (Estimate [Est] = 0.05, p < .001), family income-to-needs ratio (Est = -0.01, p = .012), and psychosocial adversity (Est = 0.02, p = .015) predicted membership in the high, increasing trajectory of physical health problems. Early-onset psychopathology mediated relations between psychosocial adversity and physical health problems (αß = 0.31, p = .050) and between income-to-needs ratio and physical health problems (αß = -0.29, p < .021). CONCLUSIONS: These findings indicate the importance of early indicators of risk: low income-to-needs ratios, high psychosocial adversity, and psychiatric disorders occurring during the preschool period for contributing to increasing physical health problems from preschool through early adolescence. Early-onset psychiatric disorders also mediated relations between psychosocial adversity, income-to-needs ratio, and physical health problems.

Latent class profiles of depressive symptoms from early to middle childhood: predictors, outcomes, and gender effects.

BACKGROUND: There has been little available data to inform the predictors and outcomes of latent class trajectories of depressive symptoms beginning during preschool and continuing throughout school age. Further, the extant literature in this domain has been limited by the use of parent report checklists of nonspecific 'internalizing' psychopathology rather than diagnostic interviews for depression. METHODS: To address these gaps in the literature, this study applied growth mixture modeling to depressive symptom severity endorsed by children and/or their caregivers (N = 348) during a structured clinical interview in a 10-year longitudinal dataset spanning from preschool into late school age. RESULTS: Three distinct trajectories of depressive symptom severity were found in boys and girls. For boys, but not girls, the high depression severity latent class increased in depressive symptoms from preschool through school age, followed by a decline in depressive symptom severity during later school age. For girls, the high depression severity latent class remained stable across time. Early childhood social adversity, familial history of affective disorder, preschool-onset ODD/CD, and school age functional impairment differentiated high-risk trajectory classes among both boys and girls. CONCLUSIONS: Extending the literature on trajectories of depressive symptoms to the preschool period, these findings incorporate structured clinical interviews of depressive symptom severity and indicate gender differences as well as psychosocial predictors and functional outcomes among children in high severity latent classes. The findings from this study suggest that increased attention to screening for depressive symptoms in early childhood is of significant public health importance.

Emotion Awareness Predicts Body Mass Index Percentile Trajectories in Youth.

OBJECTIVE: To examine the rate of change in body mass index (BMI) percentile across 3 years in relation to emotion identification ability and brain-based reactivity in emotional processing regions. STUDY DESIGN: A longitudinal sample of 202 youths completed 3 functional magnetic resonance imaging-based facial processing tasks and behavioral emotion differentiation tasks. We examined the rate of change in the youth's BMI percentile as a function of reactivity in emotional processing brain regions and behavioral emotion identification tasks using multilevel modeling. RESULTS: Lower correct identification of both happiness and sadness measured behaviorally predicted increases in BMI percentile across development, whereas higher correct identification of both happiness and sadness predicted decreases in BMI percentile, while controlling for children's pubertal status, sex, ethnicity, IQ score, exposure to antipsychotic medication, family income-to-needs ratio, and externalizing, internalizing, and depressive symptoms. Greater neural activation in emotional reactivity regions to sad faces also predicted increases in BMI percentile during development, also controlling for the aforementioned covariates. CONCLUSION: Our findings provide longitudinal developmental data demonstrating links between both emotion identification ability and greater neural reactivity in emotional processing regions with trajectories of BMI percentiles across childhood.

Structural-functional correlations between hippocampal volume and cortico-limbic emotional responses in depressed children.

Although hippocampal atrophy and altered functional brain responses to emotional stimuli have been found in major depressive disorder (MDD), the relationship between the two is not yet well understood. The present study focused on children with and without a history of preschool onset MDD (PO-MDD) and directly examined the relations between hippocampal volume and functional brain activation to affect-eliciting stimuli. Children completed annual diagnostic assessments starting at preschool. When children were school-aged, high-resolution structural MRI and task-related functional MRI data were acquired from N = 64 nonmedicated children. During fMRI, subjects were shown emotional faces. Results from the total sample indicated that smaller bilateral hippocampal volumes were associated with greater cortico-limbic (e.g., amygdala, hippocampus, dorsolateral prefrontal cortex) activation to sad or negative faces versus neutral faces. Left hippocampal volume was negatively associated with the cortico-limbic activation in both the PO-MDD and healthy children. Right hippocampal volume was negatively correlated with amygdala responses in the PO-MDD group, but not in the healthy comparison group. These findings suggest that there may be important interrelationships between reduced hippocampal volume and hyperactivation of brain responses in children, both those with and those without a history of PO-MDD.

The clinical significance of preschool depression: impairment in functioning and clinical markers of the disorder.

OBJECTIVE: While much is now known about depression during school age and adolescence, whether clinical depression can onset even earlier in development during the preschool period remains under explored. The earliest possible identification of depression may be important for the design of prevention and early developmental intervention programs. This study investigated functional impairment associated with depression, symptoms that served as the best markers of depression vs. other disorders, as well as depression severity between two depressed sub-groups and other diagnostic comparison groups. METHOD: Three hundred and five preschoolers between the ages of 3.0 and 6.0 and their primary caregivers were recruited using a depression screening checklist distributed at community sites. The Preschool Age Psychiatric Assessment (PAPA) was used to derive psychiatric diagnoses in the study sample. Multivariate analyses of covariance were used to investigate the effects of depression on independent measures of functional impairment while controlling for the effects of co-morbidities. RESULTS: Functional impairment specifically associated with depression was found in multiple domains and contexts, however depressed preschoolers were not developmentally delayed. The symptoms of guilt and extreme fatigue were found to be highly specific for preschool depression. A statistically significant hierarchy of depression severity was found between diagnostic comparison groups, in the expected direction with the highest in a melancholic subgroup. CONCLUSIONS: Validation for preschool depression with associated functional impairment across contexts was found in preschool children. These findings replicate and extend earlier evidence for validity of MDD diagnosed in the preschool period and highlight the need for clinical attention. The finding that these depressed and impaired preschoolers were not yet developmentally delayed may have important public health significant significance as it suggests a possible window of opportunity for early intervention. Study findings were limited by reliance on parent and teacher informants and a cross-sectional view.

Temper tantrums in healthy versus depressed and disruptive preschoolers: defining tantrum behaviors associated with clinical problems.

OBJECTIVE: To investigate whether differences in the tantrum behaviors of healthy versus mood and disruptive disordered preschoolers can be detected. STUDY DESIGN: Caregivers of 279 preschool children (3 to 6 years old) completed the Preschool-Age Psychiatric Assessment (Egger HL, Ascher B, Angold A. Preschool Age Psychiatric Assessment (PAPA): version1.1. Durham, NC: Center for Developmental Epidemiology, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center; 1999), which was used to determine preschoolers' diagnostic classification and to measure tantrum behaviors. Preschoolers were placed in 1 of 4 diagnostic groups, healthy, pure depressed, pure disruptive, and comorbid depressed/disruptive, on the basis of the application of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition algorithms. Parametric and non-parametric analyses were used to examine characteristics of children's tantrums: intensity, frequency, context, and recovery ability. RESULTS: Disruptive preschoolers displayed violence during tantrums significantly more often than the depressed and healthy groups. The disruptive group had significantly more tantrums at school/daycare than the depressed and healthy groups. The disruptive group had a more difficult time recovering from tantrums than healthy preschoolers. In addition, depressed preschoolers were more aggressive toward objects and other people than healthy children. Finally, depressed preschoolers displayed significantly more self-harmful tantrum behaviors than preschoolers in the healthy and disruptive groups. CONCLUSION: These findings provide preliminary guidelines to parents, teachers, and practitioners in identifying tantrum behaviors that may be markers of a psychiatric disorder and therefore require mental health referral.

Early Childhood Adverse Experiences, Inferior Frontal Gyrus Connectivity, and the Trajectory of Externalizing Psychopathology.

OBJECTIVE: Early adverse childhood experiences (ACEs) have been linked to the development of both internalizing and externalizing psychopathology. In our prior work, we found that ACEs predicted reductions in the volume of the inferior frontal gyrus (IFG), a brain region important for impulse control and emotion regulation. Here we tested the hypothesis that ACEs might influence child behavioral outcomes through an impact on IFG functional connectivity, which may influence impulsive or risk-taking behavior. METHOD: We examined the effects of prospectively assessed ACEs on IFG connectivity in childhood, and their relationship to the trajectory of subsequent psychopathology from late school age and early adolescence, using data from an 11-year longitudinal study of children starting in preschool that included 3 waves of resting state functional connectivity across childhood and early adolescence. RESULTS: ACEs predicted functional connectivity of both left and right IFG. Multi-level modeling of symptoms across 3 waves of assessments indicated that more ACEs predicted both internalizing and externalizing symptoms. However, altered IFG connectivity specifically predicted greater externalizing symptoms over time in middle childhood and early adolescence, as compared to internalizing symptoms. Longitudinal modeling indicating that the relationships between externalizing and functional connectivity were maintained across 3 waves of functional connectivity assessment. CONCLUSION: These findings underscore the relationship of ACEs to later psychopathology, and suggest that connectivity of the IFG, a region known to play an important role in impulse control and emotion regulation, may play a key role in the risk trajectory of ACEs to externalizing problems. However, further work is needed to understand whether these relationships reflect a direct effect of ACEs or whether ACEs are a marker for other environmental or genetic factors that may also influence brain development and behavior.

Psychotropic prescriptions in a sample including both healthy and mood and disruptive disordered preschoolers: relationships to diagnosis, impairment, prescriber type, and assessment methods.

OBJECTIVE: Epidemiological data has shown that psychotropic medications are being prescribed to preschoolers at increasing rates. The diagnostic context and functional impairment of these preschoolers remains unknown. This investigation aimed to address these questions in a sample of preschoolers who were either without symptoms (healthy) or with mood and disruptive disorders by assessing them using a structured diagnostic interview and measure of impairment. METHOD: Preschoolers aged 3.0 to 5.11 without symptoms and those with symptoms of mood and disruptive disorders were recruited from primary care and daycare sites in the St. Louis area to participate in a psychiatric evaluation that included information about psychotropic prescriptions from community practitioners. RESULTS: Seven percent of preschoolers (n = 19) out of a total sample of n = 267 were prescribed psychotropic medications. Fifty-two percent of preschoolers in the total sample met criteria for an Axis I psychiatric disorder. Presence of an Axis I disorder was significantly related to psychotropic prescription (p < 0.01). Among preschoolers who met criteria for an Axis I disorder 12% received psychotropics (Dx/Rx group). The Dx/Rx group was more impaired than those with a diagnosis who were not prescribed psychotropics (p < 0.001). Among preschoolers taking psychotropic medications, two failed to meet criteria for any Axis I disorder. CONCLUSION: In this sample, most psychotropic medications were prescribed for impaired preschoolers with an Axis I diagnosis. These findings shed some light on the prescribing trends among mood and disruptive disordered preschoolers.

Preschoolers' depression severity and behaviors during dyadic interactions: the mediating role of parental support.

OBJECTIVE: To investigate the relationship between preschool depression severity, observed behavior, and parental emotional support in a population of 3.0- to 5.6-year-olds and their mothers. METHOD: One hundred fifty preschoolers who underwent a comprehensive mental health assessment during which DSM-IV diagnoses were derived were included in this analysis. Child and parent behaviors during challenging structured dyadic tasks were systematically coded. Dyads with preschoolers in three diagnostic groups of interest were explored: depression, disruptive, and healthy. Depression severity sum scores were derived for children in all of the groups. RESULTS: Depression severity accounted for a significant (p < .05) portion of the variance in preschoolers' persistence, compliance, and enthusiasm during dyadic tasks after controlling for the effects of age and gender. Depression severity was also significantly associated with parental emotional support, which was itself associated with all three preschool behaviors. When the effect of parental support was controlled for statistically, however, preschoolers' depression severity was no longer significantly associated with observed persistence or compliance, whereas the relationship between depression severity and enthusiasm remained significant. CONCLUSIONS: Maternal emotional support mediated the relationship between preschoolers' depression severity and their persistence and compliance but not the relationship between depression severity and enthusiasm. Findings have important clinical implications because they suggest that both external relational and internal child factors may be operating in preschool depression.

Cognitive Control Deficits in Shifting and Inhibition in Preschool Age Children are Associated with Increased Depression and Anxiety Over 7.5 Years of Development.

Although depression and anxiety are common in youth (Costello et al. 2003), factors that put children at risk for such symptoms are not well understood. The current study examined associations between early childhood cognitive control deficits and depression and anxiety over the course of development through school age. Participants were 188 children (at baseline M = 5.42 years, SD = 0.79 years) and their primary caregiver. Caregivers completed ratings of children's executive functioning at preschool age and measures of depression and anxiety severity over seven assessment waves (a period of approximately 7.5 years). Longitudinal multilevel linear models were used to examine the effect of attention shifting and inhibition deficits on depression and anxiety. Inhibition deficits at preschool were associated with significantly greater depression severity scores at each subsequent assessment wave (up until 7.5 years later). Inhibition deficits were associated with greater anxiety severity from 3.5 to 7.5 years later. Greater shifting deficits at preschool age were associated with greater depression severity up to 5.5 years later. Shifting deficits were also associated with significantly greater anxiety severity up to 3.5 years later. Importantly, these effects were significant even after accounting for the influence of other key predictors including assessment wave/time, gender, parental education, IQ, and symptom severity at preschool age, suggesting that effects are robust. Overall, findings indicate that cognitive control deficits are an early vulnerability factor for developing affective symptoms. Timely assessment and intervention may be beneficial as an early prevention strategy.

Functional connectivity of the amygdala and subgenual cingulate during cognitive reappraisal of emotions in children with MDD history is associated with rumination.

Major Depressive Disorder (MDD) is characterized by poor emotion regulation. Rumination, a maladaptive strategy for dealing with negative emotions, is common in MDD, and is associated with impaired inhibition and cognitive inflexibility that may contribute to impaired emotion regulation abilities. However, it is unclear whether rumination is differently associated with emotion regulation in individuals with MDD history (MDD-ever) and healthy individuals. In this study, children (8-15 years old) performed a cognitive reappraisal task in which they attempted to decrease their emotional response to sad images during fMRI scanning. Functional connectivity (FC) between both the amygdala and subgenual anterior cingulate (sACC) increased with cortical control regions during reappraisal as rumination increased in MDD-ever, while connectivity between those regions decreased during reappraisal as rumination increased in healthy controls. As the role of cortical control regions is to down-regulate activity of emotion processing regions during reappraisal, this suggests that rumination in MDD-ever, but not controls, is associated with inefficient regulation. This finding suggests that rumination may be particularly associated with poor emotion regulation in MDD-ever, and may also indicate qualitative group differences in whether rumination is maladaptive. These differences in rumination may provide important insight into depressive risk and potential avenues for treatment.

Breastfeeding and Childhood IQ: The Mediating Role of Gray Matter Volume.

OBJECTIVE: A substantial body of literature has established the positive effect of breastfeeding on child developmental outcomes. There is increasing consensus that breastfed children have higher IQs after accounting for key variables, including maternal education, IQ, and socioeconomic status. Cross-sectional investigations of the effects of breastfeeding on structural brain development suggest that breastfed infants have larger whole brain, cortical, and white matter volumes. To date, few studies have related these measures of brain structure to IQ in breastfed versus nonbreastfed children in a longitudinal sample. METHOD: Data were derived from the Preschool Depression Study (PDS), a prospective longitudinal study in which children and caregivers were assessed annually for 8 waves over 11 years. A subset completed neuroimaging between the ages of 9.5 and 14.11 years. A total of 148 individuals had breastfeeding data at baseline and complete data on all variables of interest, including IQ and structural neuroimaging. General linear models and process mediation models were used. RESULTS: Breastfed children had significantly higher IQ scores and larger whole brain, total gray matter, total cortical gray matter, and subcortical gray matter volumes compared with the nonbreastfed group in models that covaried for key variables. Subcortical gray matter volume significantly mediated the association between breastfeeding and children's IQ scores. CONCLUSION: The study findings suggest that the effects of breastfeeding on child IQ are mediated through subcortical gray volume. This effect and putative mechanism is of public health significance and further supports the importance of breastfeeding in mental health promotion.

Early Childhood Depression and Alterations in the Trajectory of Gray Matter Maturation in Middle Childhood and Early Adolescence.

IMPORTANCE: The trajectory of cortical gray matter development in childhood has been characterized by early neurogenesis and volume increase, peaking at puberty followed by selective elimination and myelination, resulting in volume loss and thinning. This inverted U-shaped trajectory, as well as cortical thickness, has been associated with cognitive and emotional function. Synaptic pruning-based volume decline has been related to experience-dependent plasticity in animals. To date, there have been no data to inform whether and how childhood depression might be associated with this trajectory. OBJECTIVE: To examine the effects of early childhood depression, from the preschool age to the school age period, on cortical gray matter development measured across 3 waves of neuroimaging from late school age to early adolescence. DESIGN, SETTING, AND PARTICIPANTS: Data were collected in an academic research setting from September 22, 2003, to December 13, 2014, on 193 children aged 3 to 6 years from the St Louis, Missouri, metropolitan area who were observed for up to 11 years in a longitudinal behavioral and neuroimaging study of childhood depression. Multilevel modeling was applied to explore the association between the number of childhood depression symptoms and prior diagnosis of major depressive disorder and the trajectory of gray matter change across 3 scan waves. Data analysis was conducted from October 29, 2014, to September 28, 2015. MAIN OUTCOMES AND MEASURES: Volume, thickness, and surface area of cortical gray matter measured using structural magnetic resonance imaging at 3 scan waves. RESULTS: Of the 193 children, 90 had a diagnosis of major depressive disorder; 116 children had 3 full waves of neuroimaging scans. Findings demonstrated marked alterations in cortical gray matter volume loss (slope estimate, -0.93 cm³; 95% CI, -1.75 to -0.10 cm³ per scan wave) and thinning (slope estimate, -0.0044 mm; 95% CI, -0.0077 to -0.0012 mm per scan wave) associated with experiencing an episode of major depressive disorder before the first magnetic resonance imaging scan. In contrast, no significant associations were found between development of gray matter and family history of depression or experiences of traumatic or stressful life events during this period. CONCLUSIONS AND RELEVANCE: This study demonstrates an association between early childhood depression and the trajectory of cortical gray matter development in late school age and early adolescence. These findings underscore the significance of early childhood depression on alterations in neural development.

Neural Correlates of Reward Processing in Depressed and Healthy Preschool-Age Children.

OBJECTIVE: Adults and adolescents with major depressive disorder (MDD) show a blunted neural response to rewards. Depression has been validated in children as young as age 3; however, it remains unclear whether blunted response to reward is also a core feature of preschool-onset depression. If so, this would provide further validation for the continuity of the neural correlates of depression across the life span and would identify a potential target for treatment in young children. METHOD: Fifty-three 4- to 7-year-old children with depression and 25 psychiatrically healthy 4- to 7-year-old children completed a simple guessing task in which points could be won or lost on each trial while event-related potentials (ERPs) were recorded. Psychiatric diagnosis was established using a preschool version of the Kiddie Schedule for Affective Disorders and Depression. RESULTS: Young children with depression showed a reduced differentiation between response to gains and losses, and this finding was driven by a blunted response to reward (i.e., the reward positivity [RewP]). These findings held even when controlling for co-occurring attention-deficit/hyperactivity disorder, oppositional defiant disorder, and generalized anxiety disorder. The RewP did not vary as a function of depression severity within the group with depression. CONCLUSION: Similar to adults and adolescents with depression, preschoolers with depression display reductions in responsivity to rewards as indexed by the RewP. These findings provide further evidence for continuity in the neural mechanisms associated with depression across the lifespan, and point to altered reward sensitivity as an early-emerging potential target for intervention in preschool-onset depression. Clinical trial registration information-A Randomized Controlled Trial of PCIT-ED for Preschool Depression; http://clinicaltrials.gov/; NCT02076425.

Early Childhood Behavioral Inhibition Predicts Cortical Thickness in Adulthood.

OBJECTIVE: Behavioral inhibition (BI) during early childhood predicts risk for anxiety disorders and altered cognitive control in adolescence. Although BI has been linked to variation in brain function through adulthood, few studies have examined relations between early childhood BI and adult brain structure. METHOD: The relation between early childhood BI and cortical thickness in adulthood was examined in a cohort of individuals followed since early childhood (N = 53, mean age 20.5 years). Analyses tested whether anxiety and/or cognitive control during adolescence moderated relations between BI and cortical thickness. Cognitive control was measured with the Eriksen Flanker Task. Initial analyses examined cortical thickness in regions of interest previously implicated in BI, anxiety disorders, and cognitive control: dorsal anterior cingulate (dACC), anterior insula (aI), and subgenual anterior cingulate (sgACC); and volumes of the amygdala and hippocampus. Exploratory analyses examined relations across the prefrontal cortex. RESULTS: BI during early childhood related to thinner dACC in adulthood. Neither anxiety nor cognitive control moderated this relation. A stronger congruency effect on the Eriksen Flanker Task during adolescence independently related to thinner dACC in adulthood. Higher anxiety during adolescence related to thicker cortex in the right ventrolateral prefrontal cortex (VLPFC) in adulthood among those with low BI as children. CONCLUSION: Temperament in early childhood and the interaction between temperament and later anxiety relate to adult brain structure. These results are consistent with prior work associating BI and anxiety with functional brain variability in the dACC and VLPFC.

Neural Activation During Cognitive Emotion Regulation in Previously Depressed Compared to Healthy Children: Evidence of Specific Alterations.

OBJECTIVE: Impairments in cognitive emotion regulation (CER) have been linked to functional neural abnormalities and the pathogenesis of major depressive disorder (MDD). Few functional magnetic resonance imaging (fMRI) studies have investigated the neural underpinnings of CER in samples with depression. As CER develops in childhood, understanding dysfunctional CER-related alterations in brain function during this period could advance knowledge of the developmental psychopathology of MDD. METHOD: This study tested whether neural activity in brain regions known to support cognitive reappraisal differed between healthy 7- to 15-year-old children and same-age peers with a history of MDD (MDD-ever). A total of 64 children participated in this event-related fMRI study, which used a developmentally appropriate and validated fMRI reappraisal task. Children were instructed to passively view sad or neutral images and to decrease negative emotions using cognitive reappraisal. RESULTS: MDD-ever and healthy children showed similar patterns of cortical activation during reappraisal, but with a significant difference found in 1 key CER region, the left inferior frontal gyrus (IFG). In addition, individual differences in CER were associated with left IFG activity during reappraisal. CONCLUSION: Alterations in the neurocircuitry of reappraisal are evident in children with a depression history compared to healthy controls. The finding that MDD-ever children showed reappraisal-related neural responses in many regions similar to healthy controls has clinical implications. Findings suggest that identification of alterations in reappraisal in children with remitted depression, for whom much, although not all, of the neural circuitry remains intact, may be an important window of opportunity for intervention.

Anterior insula volume and guilt: neurobehavioral markers of recurrence after early childhood major depressive disorder.

IMPORTANCE: This is the first study to date to examine volumetric alterations in the anterior insula (AI) as a potential biomarker for the course of childhood major depressive disorder (MDD). OBJECTIVES: To examine whether children with a history of preschool-onset (PO) MDD show reduced AI volume, whether a specific symptom of PO MDD (pathological guilt) is related to AI volume reduction (given the known relationship between AI and guilt processing), and whether AI volumes predict subsequent likelihood of having an episode of MDD. DESIGN, SETTING, AND PARTICIPANTS: In a prospective longitudinal study, 306 children (age range, 3.00-5.11 years) and caregivers completed DSM diagnostic assessments at 6 annual time points during 10 years as part of the Preschool Depression Study. Magnetic resonance imaging was completed on a subset of 145 school-age children (age range, 6.11-12.11 years). MAIN OUTCOMES AND MEASURES: Whole-brain-adjusted AI volume measured using magnetic resonance imaging at school age and children's diagnosis of MDD any time after their imaging. RESULTS: Compared with children without a history of PO MDD, school-age children previously diagnosed as having PO MDD had smaller left and right AI volumes (Wilks Λ = 0.94, F2,124 = 3.37, P = .04, Cohen d = 0.23). However, the effect of PO MDD on reduced AI volumes was better explained by children's experience of pathological guilt during preschool (Λ = 0.91, F2,120 = 6.17, P = .003, d = .30). When covarying for children's lifetime history of MDD episodes, their experience of pathological guilt during preschool, as well as their sex and age at the time of imaging, schoolchildren's right-side AI volume was a significant predictor of being diagnosed as having an MDD episode after imaging (odds ratio, 0.96; 95% CI, 0.01-0.75; P = .03). CONCLUSIONS AND RELEVANCE: These results provide evidence that structural abnormalities in AI volume are related to the neurobiology of depressive disorders starting in early childhood. The present findings are consistent with mounting research in adult MDD suggesting that insula function and structure may be a target biomarker for major depression.