Alice M. Graham

What Sleeping Babies Hear: A Functional MRI Study of Interparental Conflict and Infants’ Emotion Processing

Experiences of adversity in the early years of life alter the developing brain. However, evidence documenting this relationship often focuses on severe stressors and relies on peripheral measures of neurobiological functioning during infancy. In the present study, we employed functional MRI during natural sleep to examine associations between a more moderate environmental stressor (nonphysical interparental conflict) and 6- to 12-month-old infants’ neural processing of emotional tone of voice. The primary question was whether interparental conflict experienced by infants is associated with neural responses to emotional tone of voice, particularly very angry speech. Results indicated that maternal report of higher interparental conflict was associated with infants’ greater neural responses to very angry relative to neutral speech across several brain regions implicated in emotion and stress reactivity and regulation (including rostral anterior cingulate cortex, caudate, thalamus, and hypothalamus). These findings suggest that even moderate environmental stress may be associated with brain functioning during infancy.

The potential of infant fMRI research and the study of early life stress as a promising exemplar

Highlights • fMRI research with infants and toddlers has increased rapidly over the past decade.• Infant fMRI has provided unique insight into early functional brain development.• Complex methodological challenges associated with infant fMRI warrant careful consideration and ongoing research.• Infant fMRI has potential to contribute to multiple fields of study.• The study of early life stress is a prime example of a field that is ripe to benefit from this technique.

What Sleeping Babies Hear

Experiences of adversity in the early years of life alter the developing brain. However, evidence documenting this relationship often focuses on severe stressors and relies on peripheral measures of neurobiological functioning during infancy. In the present study, we employed functional MRI during natural sleep to examine associations between a more moderate environmental stressor (nonphysical interparental conflict) and 6- to 12-month-old infants’ neural processing of emotional tone of voice. The primary question was whether interparental conflict experienced by infants is associated with neural responses to emotional tone of voice, particularly very angry speech. Results indicated that maternal report of higher interparental conflict was associated with infants’ greater neural responses to very angry relative to neutral speech across several brain regions implicated in emotion and stress reactivity and regulation (including rostral anterior cingulate cortex, caudate, thalamus, and hypothalamus). These findings suggest that even moderate environmental stress may be associated with brain functioning during infancy.

Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age

The first year of life is an important period for emergence of fear in humans. While animal models have revealed developmental changes in amygdala circuitry accompanying emerging fear, human neural systems involved in early fear development remain poorly understood. To increase understanding of the neural foundations of human fear, it is important to consider parallel cognitive development, which may modulate associations between typical development of early fear and subsequent risk for fear-related psychopathology. We, therefore, examined amygdala functional connectivity with rs-fcMRI in 48 neonates (M = 3.65 weeks, SD = 1.72), and measured fear and cognitive development at 6-months-of-age. Stronger, positive neonatal amygdala connectivity to several regions, including bilateral anterior insula and ventral striatum, was prospectively associated with higher fear at 6-months. Stronger amygdala connectivity to ventral anterior cingulate/anterior medial prefrontal cortex predicted a specific phenotype of higher fear combined with more advanced cognitive development. Overall, findings demonstrate unique profiles of neonatal amygdala functional connectivity related to emerging fear and cognitive development, which may have implications for normative and pathological fear in later years. Consideration of infant fear in the context of cognitive development will likely contribute to a more nuanced understanding of fear, its neural bases, and its implications for future mental health.

Patterns of brain activation in foster children and nonmaltreated children during an inhibitory control task

Children in foster care have often encountered a range of adverse experiences, including neglectful and/or abusive care and multiple caregiver transitions. Prior research findings suggest that such experiences negatively affect inhibitory control and the underlying neural circuitry. In the current study, event-related functional magnetic resonance imaging was employed during a go/no go task that assesses inhibitory control to compare the behavioral performance and brain activation of foster children and nonmaltreated children. The sample included two groups of 9- to 12-year-old children: 11 maltreated foster children and 11 nonmaltreated children living with their biological parents. There were no significant group differences on behavioral performance on the task. In contrast, patterns of brain activation differed by group. The nonmaltreated children demonstrated stronger activation than did the foster children across several regions, including the right anterior cingulate cortex, the middle frontal gyrus, and the right lingual gyrus, during correct no go trials, whereas the foster children displayed stronger activation than the nonmaltreated children in the left inferior parietal lobule and the right superior occipital cortex, including the lingual gyrus and cuneus, during incorrect no go trials. These results provide preliminary evidence that the early adversity experienced by foster children impacts the neural substrates of inhibitory control.

Effects of maltreatment and early intervention on diurnal cortisol slope across the start of school: A pilot study ☆

Maltreated foster children have a high prevalence of developmental delays, psychosocial maladjustment, and psychiatric symptoms (Klee, Kronstadt, & Zlotnick, 1997; Landsverk, Garland, & Leslie, 2002). Recent work has focused on understanding effects of maltreatment and caregiver transitions on neurobiological systems involved in the stress response, specifically the hypothalamic-pituitary-adrenal (HPA) axis (Bruce, Fisher, Pears, & Levine, 2009; Dozier et al., 2006). The HPA axis—indexed by cortisol levels—displays a diurnal rhythm, typically characterized by relatively high morning levels that decline to near-zero by bedtime (Kirschbaum et al., 1990). This change across the day is referred to as the diurnal cortisol slope. Previous work indicates that young foster children are more likely than their nonmaltreated peers to evidence a flattened diurnal cortisol slope (or less change across the day), resulting from low morning cortisol levels, which may indicate a poorly regulated system (Dozier et al., 2006; Fisher et al., 2006). However, despite the high prevalence of socioemotional difficulties in this population, only a minority of foster children display low morning cortisol levels (Bruce et al., 2009). Because the HPA axis is also designed to respond to physical and psychological challenges in the environment (Kirschbaum et al., 1990), examining the responsiveness of the system to stressors may provide further insight into potential effects of maltreatment and caregiver transitions. Although research with older children and adults has often employed laboratory stressors to measure immediate changes in cortisol levels, research with normative samples of young children has focused on changes in the diurnal cortisol rhythm in response to naturally occurring stressors, such as the start of school (Bruce, Davis, & Gunnar, 2002; Davis, Donzella, Krueger, & Gunnar, 1999; Quas, Murowchick, Bensadoun, & Boyce, 2002; Turner-Cobb, Rixon, & Jessop, 2008). This work provides evidence for a transient perturbation in the diurnal cortisol rhythm in response to the start of school, characterized by a steeper slope on the 1st day of school compared to weekend days later in the year (Bruce et al., 2002). This steeper slope, which has been viewed as a healthy adaptation to a novel, significant event, resulted from higher morning and lower evening cortisol levels on the 1st day of school. However, individual differences appear to play a large role, such that higher temperamental surgency (Bruce et al., 2002; Davis et al., 1999) and lower effortful control (Turner-Cobb et al., 2008) predict a steeper slope beyond the 1st day of school, potentially indicative of greater reactivity or less recovery of the system. Although Gutteling, de Weerth, and Buitelaar (2008) documented effects of prenatal stress on the diurnal cortisol rhythm across the start of school, the effects of severe early life stress, such as maltreatment and caregiver transitions, remain unknown. Moreover, it is unclear whether comprehensive early preventive intervention programs such as Multidimensional Treatment Foster Care for Preschoolers (MTFC-P; Fisher, Ellis, & Chamberlain, 1999) affect changes in the diurnal cortisol rhythm in response to a naturally occurring stressor. MTFC-P supports foster parents in providing consistent and contingent responses to positive and negative child behaviors. The child’s environment thus becomes more predictable, responsive and reinforcing, which has been shown to prevent the development of an increasingly flattened diurnal cortisol rhythm in foster children (Fisher, Stoolmiller, Gunnar, & Burraston, 2007). However, the impact of MTFC-P on the responsiveness of the HPA axis to important life events, such as the start of school, remains untested. Foster children often experience difficulties in school (Pears, Fisher, Bruce, Kim & Yoerger, 2010), and preventive interventions that influence the capacity of the HPA axis to respond to the challenge of the start of school may support a more adaptive transition. This pilot study examines changes in diurnal cortisol in response to the start of school for three groups of children: foster children who received regular foster care (RFC); foster children who received MTFC-P; and low-income, nonmaltreated children living with their biological parents (community comparison [CC]). We hypothesized that RFC children would show an extended cortisol response, characterized by a steeper slope on the 1st and 5th days compared to the week before school, and that MTFC-P and CC children would show a transient cortisol response, characterized by a steeper slope only on the 1st day of school.

Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring

Several lines of evidence support the link between maternal inflammation during pregnancy and increased likelihood of neurodevelopmental and psychiatric disorders in offspring. This longitudinal study seeks to advance understanding regarding implications of systemic maternal inflammation during pregnancy, indexed by plasma interleukin-6 (IL-6) concentrations, for large-scale brain system development and emerging executive function skills in offspring. We assessed maternal IL-6 during pregnancy, functional magnetic resonance imaging acquired in neonates, and working memory (an important component of executive function) at 2 years of age. Functional connectivity within and between multiple neonatal brain networks can be modeled to estimate maternal IL-6 concentrations during pregnancy. Brain regions heavily weighted in these models overlap substantially with those supporting working memory in a large meta-analysis. Maternal IL-6 also directly accounts for a portion of the variance of working memory at 2 years of age. Findings highlight the association of maternal inflammation during pregnancy with the developing functional architecture of the brain and emerging executive function.The authors show that maternal inflammation during pregnancy, indexed by IL-6, can be estimated from the newborn brain connectome and predicts future working memory performance in offspring at two years of age.

Effects of a school readiness intervention on hypothalamus-pituitary-adrenal axis functioning and school adjustment for children in foster care

Maltreated children in foster care are at high risk for dysregulated hypothalamus-pituitary-adrenal (HPA) axis functioning and educational difficulties. The present study examined the effects of a short-term school readiness intervention on HPA axis functioning in response to the start of kindergarten, a critical transition marking entry to formal schooling, and whether altered HPA axis functioning influenced childrens school adjustment. Compared to a foster care comparison group, children in the intervention group showed a steeper diurnal cortisol slope on the first day of school, a pattern previously observed among nonmaltreated children. A steeper first day of school diurnal cortisol slope predicted teacher ratings of better school adjustment (i.e., academic performance, appropriate classroom behaviors, and engagement in learning) in the fall of kindergarten. Furthermore, the childrens HPA axis response to the start of school mediated the effect of the intervention on school adjustment. These findings support the potential for ameliorative effects of interventions targeting critical transitional periods, such as the transition of formal schooling. This school readiness intervention appears to influence stress neurobiology, which in turn facilitates positive engagement with the school environment and better school adjustment in children who have experienced significant early adversity.

Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life

&NA; Maternal inflammation during pregnancy can alter the trajectory of fetal brain development and increase risk for offspring psychiatric disorders. However, the majority of relevant research to date has been conducted in animal models. Here, in humans, we focus on the structural connectivity of frontolimbic circuitry as it is both critical for socioemotional and cognitive development, and commonly altered in a range of psychiatric disorders associated with intrauterine inflammation. Specifically, we test the hypothesis that elevated maternal concentration of the proinflammatory cytokine interleukin‐6 (IL‐6) during pregnancy will be associated with variation in microstructural properties of this circuitry in the neonatal period and across the first year of life. Pregnant mothers were recruited in early pregnancy and maternal blood samples were obtained for assessment of maternal IL‐6 concentrations in early (12.6 ± 2.8 weeks [S.D.]), mid (20.4 ± 1.5 weeks [S.D.]) and late (30.3 ± 1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ± 1.7 weeks [S.D.]) and again at 12‐mo age (N = 32, scan age = 54.0 ± 3.1 weeks [S.D.]). Diffusion Tensor Imaging (DTI) was used to characterize fractional anisotropy (FA) along the left and right uncinate fasciculus (UF), representing the main frontolimbic fiber tract. In N = 30 of the infants with serial MRI data at birth and 12‐mo age, cognitive and socioemotional developmental status was characterized using the Bayley Scales of Infant Development. All analyses tested for potentially confounding influences of household income, prepregnancy Body‐Mass‐Index, obstetric risk, smoking during pregnancy, and infant sex, and outcomes at 12‐mo age were additionally adjusted for the quality of the postnatal caregiving environment. Maternal IL‐6 concentration (averaged across pregnancy) was prospectively and inversely associated with FA (suggestive of reduced integrity under high inflammatory conditions) in the newborn offspring (bi‐lateral, p < 0.01) in the central portion of the UF proximal to the amygdala. Furthermore, maternal IL‐6 concentration was positively associated with rate of FA increase across the first year of life (bi‐lateral, p < 0.05), resulting in a null association between maternal IL‐6 and UF FA at 12‐mo age. Maternal IL‐6 was also inversely associated with offspring cognition at 12‐mo age, and this association was mediated by FA growth across the first year of postnatal life. Findings from the current study support the premise that susceptibility for cognitive impairment and potentially psychiatric disorders may be affected in utero, and that maternal inflammation may constitute an intrauterine condition of particular importance in this context. Graphical abstract Figure. No caption available.

Commentary: Developmental connectomics to advance our understanding of typical and atypical brain development – a commentary on Vértes and Bullmore (2015)

Vertes and Bullmores article lays a framework for applying connectomics, the study of brain function from the perspective of underlying network organization, to advance understanding of healthy and maladaptive brain development. They elucidate the power of connectomics for bridging both different levels of analysis (e.g. from synapses to brain regions) and multiple academic fields. In this commentary, we highlight important themes and remaining questions stemming from Vertes and Bullmores work, including: (1) the application of connectomics in the context of integrating analyses across multiple spatial and temporal dimensions, (2) the extent to which connectomics might be applied in translational and clinical studies of development, (3) growth connectomics and the Developmental Origins of Health and Disease (DOHaD) hypothesis, and (4) the importance and complexity of sound methodological practices in applying connectomics to developmental and clinical science. Ongoing work in these areas will be important for fulfilling the promise of connectomics as a bridge between neuroscience, developmental science, and translational and clinical research.