Michael S. Gaffrey

Maternal support in early childhood predicts larger hippocampal volumes at school age

Early maternal support has been shown to promote specific gene expression, neurogenesis, adaptive stress responses, and larger hippocampal volumes in developing animals. In humans, a relationship between psychosocial factors in early childhood and later amygdala volumes based on prospective data has been demonstrated, providing a key link between early experience and brain development. Although much retrospective data suggests a link between early psychosocial factors and hippocampal volumes in humans, to date there has been no prospective data to inform this potentially important public health issue. In a longitudinal study of depressed and healthy preschool children who underwent neuroimaging at school age, we investigated whether early maternal support predicted later hippocampal volumes. Maternal support observed in early childhood was strongly predictive of hippocampal volume measured at school age. The positive effect of maternal support on hippocampal volumes was greater in nondepressed children. These findings provide prospective evidence in humans of the positive effect of early supportive parenting on healthy hippocampal development, a brain region key to memory and stress modulation.

Atypical network connectivity for imitation in autism spectrum disorder

Imitation has been considered as one of the precursors for sociocommunicative development. Impairments of imitation in autism spectrum disorder (ASD) could be indicative of dysfunctional underlying neural processes. Neuroimaging studies have found reduced activation in areas associated with imitation, but a functional connectivity MRI network perspective of these regions in autism is unavailable. Functional and effective connectivity was examined in 14 male participants with ASD and 14 matched typically developing (TD) participants. We analyzed intrinsic, low-frequency blood oxygen level dependent (BOLD) fluctuations of three regions in literature found to be associated with imitation (inferior frontal gyrus [IFG], inferior parietal lobule [IPL], superior temporal sulcus [STS]). Direct group comparisons did not show significantly reduced functional connectivity within the imitation network in ASD. Conversely, we observed greater connectivity with frontal regions, particularly superior frontal and anterior cingulate gyri, in the ASD compared to TD group. Structural equation modeling of effective connectivity revealed a significantly reduced effect of IPL on IFG together with an increased influence of a region in dorsal prefrontal cortex (dPFC) on IFG in the ASD group. Our results suggest atypical connectivity of the imitation network with an enhanced role of dPFC, which may relate to behavioral impairments.

Stress-System Genes and Life Stress Predict Cortisol Levels and Amygdala and Hippocampal Volumes in Children

Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structures. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, and FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3–5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7–12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3–5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.

Trajectories of Preschool Disorders to Full DSM Depression at School Age and Early Adolescence: Continuity of Preschool Depression

OBJECTIVE Preschool-onset depression, a developmentally adapted form of depression arising between ages 3 and 6, has demonstrated numerous validated features, including characteristic alterations in stress reactivity and brain function. This syndrome is characterized by subthreshold DSM criteria for major depressive disorder, raising questions about its clinical significance. To clarify the utility and public health significance of the preschool-onset depression construct, the authors investigated diagnostic outcomes of preschool children at school age and in adolescence. METHOD In a longitudinal prospective study of preschool children, the authors assessed the likelihood of meeting full criteria for major depressive disorder at age 6 or later as a function of preschool depression, other preschool axis I disorders, maternal history of depression, nonsupportive parenting, and traumatic life events. RESULTS Preschool-onset depression emerged as a robust predictor of major depressive disorder in later childhood even after accounting for the effect of maternal history of depression and other risk factors. Preschool-onset conduct disorder also predicted major depression in later childhood, but this association was partially mediated by nonsupportive parenting, reducing by 21% the effect of preschool conduct disorder in predicting major depression. CONCLUSIONS Study findings provide evidence that this preschool depressive syndrome is a robust risk factor for developing full criteria for major depression in later childhood, over and above other established risk factors. The results suggest that attention to preschool depression and conduct disorder in addition to maternal history of depression and exposure to trauma may be important in identifying young children at highest risk for later major depression and applying early interventions.

Association between depression severity and amygdala reactivity during sad face viewing in depressed preschoolers: An fMRI study

BACKGROUND Previous research has indicated that symptom severity and amygdala reactivity during the viewing of facial expressions of emotion are related in depression. However, it remains unclear how early in development this can be detected. METHODS A sample of 11 depressed preschoolers (4.5±0.8; 6 males) participated in an fMRI experiment where they viewed facial expressions of emotion. A region of interest approach was used in order to examine the relationship between amygdala activation and depression severity. Additional whole-brain analyses were conducted and the results of these analyses were examined for potential relationships with depression severity. RESULTS Findings indicated that depressed preschoolers exhibited a significant positive relationship between depression severity and right amygdala activity when viewing facial expressions of negative affect. In addition, we found a significant positive relationship between degree of functional activation in the occipital cortex while viewing faces and level of depression severity. LIMITATIONS Additional research including a larger sample of depressed preschoolers, as well as a healthy comparison group, is needed to replicate the current findings and examine their specificity at this age. CONCLUSIONS This is the first study directly examining brain function in depressed preschoolers. The results suggest that, similar to older children and adults with depression, amygdala responsivity and degree of depression severity are related as early as age 3.

Subgenual cingulate connectivity in children with a history of preschool-depression

The subgenual anterior cingulate cortex (sgACC) presents altered functional connections with other regions of the brain in individuals with depression. However, the developmental nature of this phenomenon remains largely unexplored. Functional connections of the sgACC were examined in 36 school age children, 17 with a history of preschool onset major depressive disorder (PO-MDD). The sgACC exhibited increased connections with cognitive control regions in healthy children and increased connections with thalamic and parietal regions in the PO-MDD group. A significant correlation between dysregulated emotional behavior and connectivity of the sgACC and dorsal medial prefrontal cortex was also found. These findings demonstrate that atypical sgACC functional connections are evident as early as school age in children with a history of PO-MDD and suggest an association with a very early episode of depression.

The 2-week duration criterion and severity and course of early childhood depression: Implications for nosology

BACKGROUND Although validity for DSM-IV MDD symptom criteria in preschoolers has been demonstrated, whether the 2-week duration criterion is an appropriate threshold of clinical significance at this age remains unclear. The current study aimed to begin addressing this question. METHOD Three hundred and six preschoolers were recruited from community sites and followed longitudinally for 2 years. A subsample including healthy preschoolers (N=77) and those with MDD (N=74) were examined. The MDD group was further divided based upon meeting (DSM, N=24) or failing to meet (<DSM, N=50) the DSM-IV 2-week duration criterion. Groups were compared on parent and teacher report measures of symptom severity and functional impairment at baseline and 2-year follow-up. LIMITATIONS A larger sample of depressed preschoolers and refined measures of duration are needed to replicate the current study. RESULTS Preschoolers with MDD differed significantly from controls on the majority of measures examined regardless of duration status and time of assessment. Further, the DSM group significantly differed from the<DSM group at baseline on measures of MDD symptom severity and impairment. No differences in the risk of a MDD diagnosis at follow-up were found on the basis of duration group status. CONCLUSIONS DSM-IV duration criterion failed to capture all clinically affected preschoolers at baseline or confer greater predictive validity for a depression diagnosis 2 years later. Findings suggest that preschoolers meeting all DSM-IV MDD criteria except for episode duration exhibit a clinically significant form of depression and experience a 2-year MDD outcome similar to those meeting full criterion.

Functional Brain Activation to Emotionally Valenced Faces in School-Aged Children with a History of Preschool-Onset Major Depression

BACKGROUND Recent research has demonstrated that clinical depression can emerge as early as the preschool period. Here, we examine brain function in children with a history of preschool-onset depression (PO-MDD) in comparison with healthy children. METHODS Participants were medication naïve school-aged children (ages 7-11) with PO-MDD (n = 22) or no psychiatric history (n = 16) followed longitudinally as part of the Preschool Depression Study. We used functional magnetic resonance imaging measures of blood oxygen level-dependent signal to examine functional brain activity in response to emotionally valenced faces (sad, fearful, angry, happy, neutral) following a negative mood induction provided to all children. RESULTS In categorical group comparisons, children with PO-MDD demonstrated increased activity in parietal cortex in response to sad faces but no differences in brain activity in a priori regions of interest (e.g., amygdala). However, in dimensional analyses, the severity of depression symptoms at the baseline preschool assessment predicted increased responses to sad faces in amygdala, hippocampal, parietal, and orbital frontal regions. CONCLUSIONS School-aged children with a history of PO-MDD showed patterns of functional brain responses to emotionally evocative stimuli similar to patterns found in adults and adolescents with major depression. These patterns were most strongly related to the severity of depression during the preschool period, suggesting that the magnitude of early symptoms may be particularly important for understanding altered brain function. These findings suggest that an early episode of depression before age 6 may be associated with enduring brain change or may represent a biomarker that was present even before the preschool episode.

Social cognition in Williams syndrome: Relations between performance on the social attribution task and cognitive and behavioral characteristics

Williams syndrome (WS) is a developmental disorder of genetic origin, with characteristic cognitive and personality profiles. Studies of WS point to an outgoing and gregarious personality style, often contrasted with autism spectrum disorders; however, recent research has uncovered underlying social reciprocity difficulties in people with WS. Social information processing difficulties that underlie these social reciprocity difficulties have been sparsely examined. Participants in the current study included 24 children with WS ages 8 through 15. A lab-based measure of social perception and social cognition was administered (Social Attribution Test), as well as an intellectual functioning measure (KBIT-II) and parent reports of communication and reciprocal social skills (Social Communication Questionnaire, Social Responsiveness Scale). Relations between social cognition, cognitive abilities, and social-communication were examined. Results demonstrated relations between parent-reported social reciprocity and the typicality of the responses provided in the lab-based measure, even once variability in intellectual functioning was taken into account. Specifically, those individuals who produced narratives in response to the social attribution task (SAT) that were more similar to those described in previous studies of typically developing individuals were also reported to have fewer social reciprocity difficulties in the real world setting as reported by parents. In addition, a significant improvement in performance on the SAT was seen with added scaffolding, particularly for participants with stronger intellectual functioning. These findings indicate that difficulties interpreting the social dynamics between others in ambiguous situations may contribute to the social relationship difficulties observed in people with WS, above and beyond the role of intellectual functioning. Exploratory analyses indicated that performance by individuals with stronger intellectual functioning is improved with additional structure to a greater degree than for those with weaker intellectual functioning. Interventions that specifically target these social information processing of individuals with WS would likely be beneficial.

Disrupted Amygdala Reactivity in Depressed 4- to 6-Year-Old Children

OBJECTIVE Disrupted amygdala activity in depressed adolescents and adults while viewing facial expressions of emotion has been reported. However, few data are available to inform the developmental nature of this phenomenon, an issue that studies of the earliest known forms of depression might elucidate. The current study addressed this question by examining functional brain activity and its relationships to emotion regulation in depressed 4- to 6-year-old children and their healthy peers. METHOD A total of 54 medication-naive 4- to 6-year-olds (23 depressed and 31 healthy) participated in a case-control study using functional magnetic resonance imaging (fMRI). Imaging data were used to compare functional brain activity in children with and without depression during emotion face processing. RESULTS A right-lateralized pattern of elevated amygdala, thalamus, inferior frontal gyrus, and angular gyrus activity during face processing was found in depressed 4- to 6-year-olds. In addition, relationships between increased amygdala activity during face processing and disruptions in parent-reported emotion regulation and negative affect were found. No between-group differences specific to emotion face type were identified. CONCLUSION To our knowledge, this is the earliest evidence of alterations in functional brain activity in depression using fMRI. Results suggest that, similar to findings in older depressed groups, depression at this age is associated with disrupted amygdala functioning during face processing. The findings also raise the intriguing possibility that disrupted amygdala function is a depression-related biomarker that spans development. Additional studies will be needed to clarify whether the current findings are a precursor to or a consequence of very early childhood depression.