In this paper, we present a transdisciplinary framework and testable hypotheses regarding the process of fetal programming of energy homeostasis brain circuitry. Our model proposes that key aspects of energy homeostasis brain circuitry already are functional by the time of birth (with substantial interindividual variation); that this phenotypic variation at birth is an important determinant of subsequent susceptibility for energy imbalance and childhood obesity risk; and that this brain circuitry exhibits developmental plasticity, in that it is influenced by conditions during intrauterine life, particularly maternal-placental-fetal endocrine, immune/inflammatory, and metabolic processes and their upstream determinants. We review evidence that supports the scientific premise for each element of this formulation, identify future research directions, particularly recent advances that may facilitate a better quantification of the ontogeny of energy homeostasis brain networks, highlight animal and in vitro-based approaches that may better address the determinants of interindividual variation in energy homeostasis brain networks, and discuss the implications of this formulation for the development of strategies targeted towards the primary prevention of childhood obesity.

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.

Environmental enrichment, particularly during the early life phases of enhanced neuroplasticity, can stimulate cognitive development. However, individuals exhibit considerable variation in their response to environmental enrichment. Recent evidence suggests that certain neurophenotypes such as hippocampal size may index inter-individual differences in sensitivity to environmental conditions. We conducted a prospective, longitudinal investigation in a cohort of 75 mother-child dyads to investigate whether neonatal hippocampal volume moderates the effects of the postnatal environment on cognitive development. Newborn hippocampal volume was quantified shortly after birth (26.2 ± 12.5 days) by structural MRI. Measures of infant environmental enrichment (assessed by the IT-HOME) and cognitive state (assessed by the Bayley-III) were obtained at 6 months of age (6.09 ± 1.43 months). The interaction between neonatal hippocampal volume and enrichment predicted infant cognitive development (b = 0.01, 95 % CI [0.00, 0.02], t = 2.08, p = .04), suggesting that exposure to a stimulating environment had a larger beneficial effect on cognitive outcomes among infants with a larger hippocampus as neonates. Our findings suggest that the effects of the postnatal environment on infant cognitive development are conditioned, in part, upon characteristics of the newborn brain, and that newborn hippocampal volume is a candidate neurophenotype in this context.

Background

While neonates have no sophisticated language skills, the neural basis for acquiring this function is assumed to already be present at birth. Receptive language is measurable by 6 months of age and meaningful speech production by 10-18 months of age. Fiber tracts supporting language processing include the corpus callosum (CC), which plays a key role in the hemispheric lateralization of language; the left arcuate fasciculus (AF), which is associated with syntactic processing; and the right AF, which plays a role in prosody and semantics. We examined if neonatal maturation of these fiber tracts is associated with receptive language development at 12 months of age.

Methods

Diffusion-weighted imaging (DWI) was performed in 86 infants at 26.6 ± 12.2 days post-birth. Receptive language was assessed via the MacArthur-Bates Communicative Development Inventory at 12 months of age. Tract-based fractional anisotropy (FA) was determined using the NA-MIC atlas-based fiber analysis toolkit. Associations between neonatal regional FA, adjusted for gestational age at birth and age at scan, and language development at 12 months of age were tested using ANOVA models.

Results

After multiple comparisons correction, higher neonatal FA was positively associated with receptive language at 12 months of age within the genu (p < 0.001), rostrum (p < 0.001), and tapetum (p < 0.001) of the CC and the left fronto-parietal AF (p = 0.008). No significant clusters were found in the right AF.

Conclusion

Microstructural development of the CC and the AF in the newborn is associated with receptive language at 12 months of age, demonstrating that interindividual variation in white matter microstructure is relevant for later language development, and indicating that the neural foundation for language processing is laid well ahead of the majority of language acquisition. This suggests that some origins of impaired language development may lie in the intrauterine and potentially neonatal period of life. Understanding how interindividual differences in neonatal brain maturity relate to the acquisition of function, particularly during early development when the brain is in an unparalleled window of plasticity, is key to identifying opportunities for harnessing neuroplasticity in health and disease.

The association between maternal immune activation (MIA) during pregnancy and risk for offspring neuropsychiatric disorders has been increasingly recognized over the past several years. Among the mechanistic pathways that have been described through which maternal inflammation during pregnancy may affect fetal brain development, the role of mitochondria has received little attention. In this review, the role of mitochondria as a potential mediator of the association between MIA during pregnancy and offspring brain development and risk for psychiatric disorders will be proposed. As a basis for this postulation, convergent evidence is presented supporting the obligatory role of mitochondria in brain development, the role of mitochondria as mediators and initiators of inflammatory processes, and evidence of mitochondrial dysfunction in preclinical MIA exposure models and human neurodevelopmental disorders. Elucidating the role of mitochondria as a potential mediator of MIA-induced alterations in brain development and neurodevelopmental disease risk may not only provide new insight into the pathophysiology of mental health disorders that have their origins in exposure to infection/immune activation during pregnancy but also offer new therapeutic targets.

Context

Glucocorticoids play a key role during intrauterine development in cellular growth and differentiation. Evidence suggests that exposure to inappropriate concentrations of glucocorticoids during sensitive developmental periods may produce alterations in physiological systems that impact obesity risk.

Objective

To elucidate the magnitude and stage-of-gestation-specific association of maternal cortisol concentrations during pregnancy with infant adiposity.

Design, participants, and setting

Sixty-seven mother-child dyads recruited in early pregnancy at university-based obstetric clinics in Southern California were followed with serial assessments from early gestation through birth until 6 months postnatal age. Maternal cumulative cortisol production was assessed over each of 4 consecutive days in early (≅13 weeks), mid (≅24 weeks), and late pregnancy (≅30 weeks) (5 saliva samples/d × 4 days × 3 trimesters = 60 saliva samples/subject). Infant body composition was serially assessed in newborns (at ∼25 days postnatal age) and at ∼6 months age with dual-energy X-ray absorptiometry imaging.

Results

After adjusting for key prenatal, birth, and postnatal covariates, higher maternal cortisol during the early third trimester (conditioned on prior early and midgestation cortisol concentrations) was significantly associated with a greater change in infant percent body fat from 1 to 6 months of age [partial r (adjusted for covariates) = 0.379, P = 0.007], accounting for ∼14% of the variance in this measure of childhood obesity risk.

Conclusion

The present findings suggest a stage-of-gestation-specific effect of maternal cortisol on infant adiposity gain in early postnatal life and provide evidence in humans to support the role of glucocorticoids in fetal programming of childhood obesity risk.

There is a major resurgence of interest in brown adipose tissue (BAT) biology, particularly regarding its determinants and consequences in newborns and infants. Reliable methods for non-invasive BAT measurement in human infants have yet to be demonstrated. The current study first validates methods for quantitative BAT imaging of rodents post mortem followed by BAT excision and re-imaging of excised tissues. Identical methods are then employed in a cohort of in vivo infants to establish the reliability of these measures and provide normative statistics for BAT depot volume and fat fraction. Using multi-echo water-fat MRI, fat- and water-based images of rodents and neonates were acquired and ratios of fat to the combined signal from fat and water (fat signal fraction) were calculated. Neonatal scans (n = 22) were acquired during natural sleep to quantify BAT and WAT deposits for depot volume and fat fraction. Acquisition repeatability was assessed based on multiple scans from the same neonate. Intra- and inter-rater measures of reliability in regional BAT depot volume and fat fraction quantification were determined based on multiple segmentations by two raters. Rodent BAT was characterized as having significantly higher water content than WAT in both in situ as well as ex vivo imaging assessments. Human neonate deposits indicative of bilateral BAT in spinal, supraclavicular and axillary regions were observed. Pairwise, WAT fat fraction was significantly greater than BAT fat fraction throughout the sample (Δ_WAT-BAT = 38%, p<10⁻⁴). Repeated scans demonstrated a high voxelwise correlation for fat fraction (R_all = 0.99). BAT depot volume and fat fraction measurements showed high intra-rater (ICC_BAT,VOL = 0.93, ICC_BAT,FF = 0.93) and inter-rater reliability (ICC_BAT,VOL = 0.86, ICC_BAT,FF = 0.93). This study demonstrates the reliability of using multi-echo water-fat MRI in human neonates for quantification throughout the torso of BAT depot volume and fat fraction measurements.

Background

Maternal inflammation during pregnancy can alter offspring brain development and influence risk for disorders commonly accompanied by deficits in cognitive functioning. We therefore examined associations between maternal interleukin 6 (IL-6) concentrations during pregnancy and offspring cognitive ability and concurrent magnetic resonance imaging-based measures of brain anatomy in early childhood. We further examined newborn brain anatomy in secondary analyses to consider whether effects are evident soon after birth and to increase capacity to differentiate effects of pre- versus postnatal exposures.

Methods

IL-6 concentrations were quantified in early (12.6 ± 2.8 weeks), mid (20.4 ± 1.5 weeks), and late (30.3 ± 1.3 weeks) pregnancy. Offspring nonverbal fluid intelligence (Gf) was assessed at 5.2 ± 0.6 years using a spatial reasoning task (Wechsler Preschool and Primary Scale of Intelligence-Matrix) (n = 49). T1-weighted magnetic resonance imaging scans were acquired at birth (n = 89, postmenstrual age = 42.9 ± 2.0 weeks) and in early childhood (n = 42, scan age = 5.1 ± 1.0 years). Regional cortical volumes were examined for a joint association between maternal IL-6 and offspring Gf performance.

Results

Average maternal IL-6 concentration during pregnancy was inversely associated with offspring Gf performance after adjusting for socioeconomic status and the quality of the caregiving and learning environment (R² = 13%; p = .02). Early-childhood pars triangularis volume was jointly associated with maternal IL-6 and childhood Gf (p_corrected < .001). An association also was observed between maternal IL-6 and newborn pars triangularis volume (R² = 6%; p = .02).

Conclusions

These findings suggest that the origins of variation in child cognitive ability can, in part, trace back to maternal conditions during the intrauterine period of life and support the role of inflammation as an important component of this putative biological pathway.

BACKGROUND:Maternal cortisol during pregnancy has the potential to influence rapidly developing fetal brain systems that are commonly altered in neurodevelopmental and psychiatric disorders. Research examining maternal cortisol concentrations across pregnancy and offspring neurodevelopment proximal to birth is needed to advance understanding in this area and lead to insight into the etiology of these disorders. METHODS:Participants were 70 adult women recruited during early pregnancy and their infants born after 34 weeks gestation. Maternal cortisol concentrations were assessed serially over 4 days in early, mid, and late gestation. Resting state functional connectivity magnetic resonance imaging of the neonatal amygdala was examined. Mothers reported on children's internalizing behavior problems at 24 months of age. RESULTS:Maternal cortisol concentrations during pregnancy were significantly associated with neonatal amygdala connectivity in a sex-specific manner. Elevated maternal cortisol was associated with stronger amygdala connectivity to brain regions involved in sensory processing and integration, as well as the default mode network in girls, and with weaker connectivity to these brain regions in boys. Elevated maternal cortisol was associated with higher internalizing symptoms in girls only, and this association was mediated by stronger neonatal amygdala connectivity. CONCLUSIONS:Normative variation in maternal cortisol during pregnancy is associated with the coordinated functioning of the amygdala soon after birth in a sex-specific manner. The identified pathway from maternal cortisol to higher internalizing symptoms in girls via alterations in neonatal amygdala connectivity may be relevant for the etiology of sex differences in internalizing psychiatric disorders, which are more prevalent in women.