Brain age prediction and deviations from normative trajectories in the neonatal connectome.

Structural and functional connectomes undergo rapid changes during the third trimester and the first month of postnatal life. Despite progress, our understanding of the developmental trajectories of the connectome in the perinatal period remains incomplete. Brain age prediction uses machine learning to estimate the brain's maturity relative to normative data. The difference between the individual's predicted and chronological age-or brain age gap (BAG)-represents the deviation from these normative trajectories. Here, we assess brain age prediction and BAGs using structural and functional connectomes for infants in the first month of life. We used resting-state fMRI and DTI data from 611 infants (174 preterm; 437 term) from the Developing Human Connectome Project (dHCP) and connectome-based predictive modeling to predict postmenstrual age (PMA). Structural and functional connectomes accurately predicted PMA for term and preterm infants. Predicted ages from each modality were correlated. At the network level, nearly all canonical brain networks-even putatively later developing ones-generated accurate PMA prediction. Additionally, BAGs were associated with perinatal exposures and toddler behavioral outcomes. Overall, our results underscore the importance of normative modeling and deviations from these models during the perinatal period.

Mapping Early Brain-Body Interactions: Associations of Fetal Heart Rate Variation with Newborn Brainstem, Hypothalamic, and Dorsal Anterior Cingulate Cortex Functional Connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.

The effects of experience of discrimination and acculturation during pregnancy on the developing offspring brain.

The experience of ethnic, racial, and structural inequalities is increasingly recognized as detrimental to health, and early studies suggest that its experience in pregnant mothers may affect the developing fetus. We characterized discrimination and acculturation experiences in a predominantly Hispanic sample of pregnant adolescent women and assessed their association with functional connectivity in their neonate's brain. We collected self-report measures of acculturation, discrimination, maternal distress (i.e., perceived stress, childhood trauma, and depressive symptoms), and socioeconomic status in 165 women. Then, we performed a data-driven clustering of acculturation, discrimination, perceived stress, depressive symptoms, trauma, and socioeconomic status variables during pregnancy to determine whether discrimination or acculturation clustered into distinct factors. Discrimination and acculturation styles loaded onto different factors from perceived stress, depressive symptoms, trauma, and socioeconomic status, suggesting that they were distinct from other factors in our sample. We associated these data-driven maternal phenotypes (discrimination and acculturation styles) with measures of resting-state functional MRI connectivity of the infant amygdala (n = 38). Higher maternal report of assimilation was associated with weaker connectivity between their neonate's amygdala and bilateral fusiform gyrus. Maternal experience of discrimination was associated with weaker connectivity between the amygdala and prefrontal cortex and stronger connectivity between the amygdala and fusiform of their neonate. Cautiously, the results may suggest a similarity to self-contained studies with adults, noting that the experience of discrimination and acculturation may influence amygdala circuitry across generations. Further prospective studies are essential that consider a more diverse population of minoritized individuals and with a comprehensive assessment of ethnic, racial, and structural factors.

Maternal childhood maltreatment: associations to offspring brain volume and white matter connectivity.

The deleterious effects of adversity are likely intergenerational, such that one generation's adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children's behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

Network controllability of structural connectomes in the neonatal brain.

White matter connectivity supports diverse cognitive demands by efficiently constraining dynamic brain activity. This efficiency can be inferred from network controllability, which represents the ease with which the brain moves between distinct mental states based on white matter connectivity. However, it remains unclear how brain networks support diverse functions at birth, a time of rapid changes in connectivity. Here, we investigate the development of network controllability during the perinatal period and the effect of preterm birth in 521 neonates. We provide evidence that elements of controllability are exhibited in the infant's brain as early as the third trimester and develop rapidly across the perinatal period. Preterm birth disrupts the development of brain networks and altered the energy required to drive state transitions at different levels. In addition, controllability at birth is associated with cognitive ability at 18 months. Our results suggest network controllability develops rapidly during the perinatal period to support cognitive demands but could be altered by environmental impacts like preterm birth.

Intergenerational transmission of cognitive control capacity among children at risk for depression.

A maternal history of major depressive disorder (MDD) is a well-known risk factor for depression in offspring. However, the mechanism through which familial risk is transmitted remains unclear. Cognitive control alterations are common in MDD, and thus, the current study investigated whether altered control capacity is transmitted intergenerationally, and whether it then contributes to the developmental pathways through which depression is passed from mothers to children. We recruited children (N = 65) ages 4-10-years-old, of which 47.7 % (n = 31) reported a maternal history of MDD, and their biological mother (N = 65). Children performed a child-friendly Go/NoGo task while electroencephalography (EEG) data were recorded, and mothers performed a Flanker task. Children exhibited heightened sensitivity to error versus correct responses, which was characterized by an error-related negativity (ERN), error positivity (Pe) as well as prominent delta and frontal midline theta (FMT) oscillations. Interestingly, worse maternal performance on the Flanker task associated with an increased Go/NoGo error rate and a smaller ERN and Pe in children. However, there was no association between maternal or child control indices with child depression symptoms. Our results suggest a familial influence of cognitive control capacity in mother-child dyads, but it remains unclear whether this confers risk for depressive symptoms in children. Further research is necessary to determine whether alterations in cognitive control over time may influence symptom development in at-risk children.

Utilizing maternal prenatal cognition as a predictor of newborn brain measures of intellectual development.

Identifying reliable indicators of cognitive functioning prior to age five has been challenging. Prior studies have shown that maternal cognition, as indexed by intellectual quotient (IQ) and years of education, predict child intelligence at school age. We examined whether maternal full scale IQ, education, and inhibitory control (index of executive function) are associated with newborn brain measures and toddler language outcomes to assess potential indicators of early cognition. We hypothesized that maternal indices of cognition would be associated with brain areas implicated in intelligence in school-age children and adults in the newborn period. Thirty-seven pregnant women and their newborns underwent an MRI scan. T2-weighted images and surface-based morphometric analysis were used to compute local brain volumes in newborn infants. Maternal cognition indices were associated with local brain volumes for infants in the anterior and posterior cingulate, occipital lobe, and pre/postcentral gyrus - regions associated with IQ, executive function, or sensori-motor functions in children and adults. Maternal education and executive function, but not maternal intelligence, were associated with toddler language scores at 12 and 24 months. Newborn brain volumes did not predict language scores. Overall, the pre/postcentral gyrus and occipital lobe may be unique indicators of early intellectual development in the newborn period. Given that maternal executive function as measured by inhibitory control has robust associations with the newborn brain and is objective, brief, and easy to administer, it may be a useful predictor of early developmental and cognitive capacity for young children.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Importance: Few translational human studies have assessed the association of prenatal maternal immune activation with altered brain development and psychiatric risk in newborn offspring. Objective: To identify the effects of maternal immune activation during the 2nd and 3rd trimesters of pregnancy on newborn brain metabolite concentrations, tissue microstructure, and longitudinal motor development. Design: Prospective longitudinal cohort study conducted from 2012 - 2017. Setting: Columbia University Irving Medical Center and Weill Cornell Medical College. Participants: 76 nulliparous pregnant women, aged 14 to 19 years, were recruited in their 2nd trimester, and their children were followed through 14 months of age. Exposure: Maternal immune activation indexed by maternal interleukin-6 and C-reactive protein in the 2nd and 3rd trimesters of pregnancy. Main Outcomes and Measures: The main outcomes included (1) newborn metabolite concentrations, measured as N-acetylaspartate, creatine, and choline using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity measured using Diffusion Tensor Imaging; and (3) indices of motor development assessed prenatally and postnatally at ages 4- and 14-months. Results: Maternal interleukin-6 and C-reactive protein levels in the 2nd or 3rd trimester were significantly positively associated with the N-acetylaspartate, creatine, and choline concentrations in the putamen, thalamus, insula, and anterior limb of the internal capsule. Maternal interleukin-6 was associated with fractional anisotropy in the putamen, insula, thalamus, precuneus, and caudate, and with mean diffusivity in the inferior parietal and middle temporal gyrus. C-reactive protein was associated with fractional anisotropy in the thalamus, insula, and putamen. Regional commonalities were found across imaging modalities, though the direction of the associations differed by immune marker. In addition, a significant positive association was observed between offspring motor development and both maternal interleukin-6 and C-reactive protein (in both trimesters) prenatally and 4- and 14-months of age. Conclusions and Relevance: Using a healthy sample, these findings demonstrate that levels of maternal immune activation in mid- to late pregnancy associate with tissue characteristics in newborn brain regions primarily supporting motor integration/coordination and behavioral regulation and may lead to alterations in motor development.

Machine Learning and Prediction in Fetal, Infant, and Toddler Neuroimaging: A Review and Primer.

Predictive models in neuroimaging are increasingly designed with the intent to improve risk stratification and support interventional efforts in psychiatry. Many of these models have been developed in samples of children school-aged or older. Nevertheless, despite growing evidence that altered brain maturation during the fetal, infant, and toddler (FIT) period modulates risk for poor mental health outcomes in childhood, these models are rarely implemented in FIT samples. Applications of predictive modeling in children of these ages provide an opportunity to develop powerful tools for improved characterization of the neural mechanisms underlying development. To facilitate the broader use of predictive models in FIT neuroimaging, we present a brief primer and systematic review on the methods used in current predictive modeling FIT studies. Reflecting on current practices in more than 100 studies conducted over the past decade, we provide an overview of topics, modalities, and methods commonly used in the field and under-researched areas. We then outline ethical and future considerations for neuroimaging researchers interested in predicting health outcomes in early life, including researchers who may be relatively new to either advanced machine learning methods or using FIT data. Altogether, the last decade of FIT research in machine learning has provided a foundation for accelerating the prediction of early-life trajectories across the full spectrum of illness and health.

Third Trimester Fetuses Demonstrate Priming, a Form of Implicit Memory, In Utero.

Research examinations of changes in fetal heart rate (HR) to operationalize fetal memory suggests that human memory capacities emerge in utero. However, there is little evidence for a form of implicit memory or priming. The present aim was to determine if priming is evident in utero. Fetal HR, maternal HR and maternal respiratory rate (RR) were examined in 105 women during the third trimester of pregnancy. Women experienced two counterbalanced laboratory tasks, the Stroop task and the paced breathing task, and their cardiorespiratory activity functioned as a stimulus for fetuses. Repeated measures ANOVAs revealed maternal HR increased during the Stroop task but only when the Stroop task was presented first (89.64 bpm to 92.39 bpm) (p = 0.04). Maternal RR increased during the Stroop task, regardless of task order (17.72 bpm to 21.11 bpm; 18.50 bpm to 22.60 bpm) (p < 0.01). Fetal HR increased during the paced breathing task, but only when it followed maternal exposure to the Stroop task (141.13 bpm to 143.97 bpm) (p < 0.01). Fetuses registered maternal HR and RR reactivity to the Stroop task, which influenced their response during maternal engagement with a related task, suggesting priming. Further study of fetal memory may suggest another pathway by which prenatal exposures impact future development.

Brain-phenotype models fail for individuals who defy sample stereotypes.

Individual differences in brain functional organization track a range of traits, symptoms and behaviours1-12. So far, work modelling linear brain-phenotype relationships has assumed that a single such relationship generalizes across all individuals, but models do not work equally well in all participants13,14. A better understanding of in whom models fail and why is crucial to revealing robust, useful and unbiased brain-phenotype relationships. To this end, here we related brain activity to phenotype using predictive models-trained and tested on independent data to ensure generalizability15-and examined model failure. We applied this data-driven approach to a range of neurocognitive measures in a new, clinically and demographically heterogeneous dataset, with the results replicated in two independent, publicly available datasets16,17. Across all three datasets, we find that models reflect not unitary cognitive constructs, but rather neurocognitive scores intertwined with sociodemographic and clinical covariates; that is, models reflect stereotypical profiles, and fail when applied to individuals who defy them. Model failure is reliable, phenotype specific and generalizable across datasets. Together, these results highlight the pitfalls of a one-size-fits-all modelling approach and the effect of biased phenotypic measures18-20 on the interpretation and utility of resulting brain-phenotype models. We present a framework to address these issues so that such models may reveal the neural circuits that underlie specific phenotypes and ultimately identify individualized neural targets for clinical intervention.

An ode to fetal, infant, and toddler neuroimaging: Chronicling early clinical to research applications with MRI, and an introduction to an academic society connecting the field.

Fetal, infant, and toddler neuroimaging is commonly thought of as a development of modern times (last two decades). Yet, this field mobilized shortly after the discovery and implementation of MRI technology. Here, we provide a review of the parallel advancements in the fields of fetal, infant, and toddler neuroimaging, noting the shifts from clinical to research use, and the ongoing challenges in this fast-growing field. We chronicle the pioneering science of fetal, infant, and toddler neuroimaging, highlighting the early studies that set the stage for modern advances in imaging during this developmental period, and the large-scale multi-site efforts which ultimately led to the explosion of interest in the field today. Lastly, we consider the growing pains of the community and the need for an academic society that bridges expertise in developmental neuroscience, clinical science, as well as computational and biomedical engineering, to ensure special consideration of the vulnerable mother-offspring dyad (especially during pregnancy), data quality, and image processing tools that are created, rather than adapted, for the young brain.

Dear reviewers: Responses to common reviewer critiques about infant neuroimaging studies.

The field of adult neuroimaging relies on well-established principles in research design, imaging sequences, processing pipelines, as well as safety and data collection protocols. The field of infant magnetic resonance imaging, by comparison, is a young field with tremendous scientific potential but continuously evolving standards. The present article aims to initiate a constructive dialog between researchers who grapple with the challenges and inherent limitations of a nascent field and reviewers who evaluate their work. We address 20 questions that researchers commonly receive from research ethics boards, grant, and manuscript reviewers related to infant neuroimaging data collection, safety protocols, study planning, imaging sequences, decisions related to software and hardware, and data processing and sharing, while acknowledging both the accomplishments of the field and areas of much needed future advancements. This article reflects the cumulative knowledge of experts in the FIT'NG community and can act as a resource for both researchers and reviewers alike seeking a deeper understanding of the standards and tradeoffs involved in infant neuroimaging.

Atypical Intrinsic Hemispheric Interaction Associated with Autism Spectrum Disorder Is Present within the First Year of Life.

Autism spectrum disorder (ASD) is characterized by atypical connectivity lateralization of functional networks. However, previous studies have not directly investigated if differences in specialization between ASD and typically developing (TD) peers are present in infancy, leaving the timing of onset of these differences relatively unknown. We studied the hemispheric asymmetries of connectivity in children with ASD and infants later meeting the diagnostic criteria for ASD. Analyses were performed in 733 children with ASD and TD peers and in 71 infants at high risk (HR) or normal risk (NR) for ASD, with data collected at 1 month and 9 months of age. Comparing children with ASD (n = 301) to TDs (n = 432), four regions demonstrated group differences in connectivity: posterior cingulate cortex (PCC), posterior superior temporal gyrus, extrastriate cortex, and anterior prefrontal cortex. At 1 month, none of these regions exhibited group differences between ASD (n = 10), HR-nonASD (n = 15), or NR (n = 18) infants. However, by 9 months, the PCC and extrastriate exhibited atypical connectivity in ASD (n = 11) and HR-nonASD infants (n = 24) compared to NR infants (n = 22). Connectivity did not correlate with symptoms in either sample. Our results demonstrate that differences in network asymmetries associated with ASD risk are observable prior to the age of a reliable clinical diagnosis.

How prenatal exposures shape the infant brain: Insights from infant neuroimaging studies.

Brain development during the prenatal period is rapid and unparalleled by any other time during development. Biological systems undergoing rapid development are at higher risk for disorganizing influences. Therefore, certain prenatal exposures impact brain development, increasing risk for negative neurodevelopmental outcome. While prenatal exposures have been associated with cognitive and behavioral outcomes later in life, the underlying macroscopic brain pathways remain unclear. Here, we review magnetic resonance imaging (MRI) studies investigating the association between prenatal exposures and infant brain development focusing on prenatal exposures via maternal physical health factors, maternal mental health factors, and maternal drug and medication use. Further, we discuss the need for studies to consider multiple prenatal exposures in parallel and suggest future directions for this body of research.

Pregnancy-specific stress and sensitive caregiving during the transition to motherhood in adolescents.

BACKGROUND: Maternal prenatal stress is associated with worse socio-emotional outcomes in offspring throughout childhood. However, the association between prenatal stress and later caregiving sensitivity is not well understood, despite the significant role that caregiving quality plays in child socio-emotional development. The goal of this study was to examine whether dimensions of pregnancy-specific stress are correlated with observer-based postnatal maternal caregiving sensitivity in pregnant adolescents. METHODS: Healthy, nulliparous pregnant adolescents (n = 244; 90 % LatinX) reported on their pregnancy-specific stress using the Revised Prenatal Distress Questionnaire (NuPDQ). Of these 244, 71 participated in a follow-up visit at 14 months postpartum. Videotaped observations of mother-child free play interactions at 14 months postpartum were coded for maternal warmth and contingent responsiveness. Confirmatory factor analysis of the NuPDQ supported a three-factor model of pregnancy-specific stress, with factors including stress about the social and economic context, baby's health, and physical symptoms of pregnancy. RESULTS: Greater pregnancy-specific stress about social and economic context and physical symptoms of pregnancy was associated with reduced maternal warmth but not contingent responsiveness. CONCLUSIONS: Heightened maternal stress about the social and economic context of the perinatal period and physical symptoms of pregnancy may already signal future difficulties in caregiving and provide an optimal opening for early parenting interventions.