Functional Connectome of the Fetal Brain.

Large-scale functional connectome formation and reorganization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated before birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules, and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function.SIGNIFICANCE STATEMENT The fetal to neonatal period is well known as a critical stage in brain development. Rapid neurodevelopmental processes establish key functional neural circuits of the human brain. Prenatal risk factors may interfere with early trajectories of connectome formation and thereby shape future health outcomes. Recent advances in MRI have made it possible to examine fetal brain functional connectivity. In this study, we evaluate the network topography of normative functional network development during connectome genesis in utero Understanding the developmental trajectory of brain connectivity provides a basis for understanding how the prenatal period shapes future brain function and disease dysfunction.

Using the Actor-Partner Interdependence Model to assess maternal and infant contributions to mother-infant affective exchanges during the Still-Face Paradigm.

This study describes maternal and infant contributions to dyadic affective exchanges during the Still-Face Paradigm (SFP) in an understudied mostly low-income sample. One hundred eleven mothers and their 7-month-old infants were videotaped during the SFP to analyze how a social stressor affects mother-infant positive and negative affective exchanges during interaction. The SFP includes 3 episodes: baseline, maternal still-face, and reunion. Maternal and infant positive and negative affect were scored by masked reliable coders. Data were analyzed using the Actor-Partner Interdependence Model to test the hypotheses that each partner's affectivity during the baseline episode would predict their own affectivity during the reunion episode (actor effects). We also expected that each partner's affectivity during the baseline episode would influence the other partner's affectivity during the reunion episodes (partner effects). After controlling for infant sex and maternal education, results provided evidence for actor effects for maternal and infant positive affect, and for partner effects for maternal baseline positive affect to infant positive affect during the reunion. One significant partner effect was observed for negative affect: Infant negativity during baseline predicted greater maternal negativity during reunion. Findings confirm that both mothers and infants contribute to dyadic affective processes during the SFP but specific findings vary depending on the affective valence in question. Clinical implications and future research are discussed.

Prenatal neural origins of infant motor development: Associations between fetal brain and infant motor development.

Functional circuits of the human brain emerge and change dramatically over the second half of gestation. It is possible that variation in neural functional system connectivity in utero predicts individual differences in infant behavioral development, but this possibility has yet to be examined. The current study examines the association between fetal sensorimotor brain system functional connectivity and infant postnatal motor ability. Resting-state functional connectivity data was obtained in 96 healthy human fetuses during the second and third trimesters of pregnancy. Infant motor ability was measured 7 months after birth using the Bayley Scales of Infant Development. Increased connectivity between the emerging motor network and regions of the prefrontal cortex, temporal lobes, posterior cingulate, and supplementary motor regions was observed in infants that showed more mature motor functions. In addition, females demonstrated stronger fetal-brain to infant-behavior associations. These observations extend prior longitudinal research back into prenatal brain development and raise exciting new ideas about the advent of risk and the ontogeny of early sex differences.

Hubs in the human fetal brain network.

Advances in neuroimaging and network analyses have lead to discovery of highly connected regions, or hubs, in the connectional architecture of the human brain. Whether these hubs emerge in utero, has yet to be examined. The current study addresses this question and aims to determine the location of neural hubs in human fetuses. Fetal resting-state fMRI data (N = 105) was used to construct connectivity matrices for 197 discrete brain regions. We discovered that within the connectional functional organization of the human fetal brain key hubs are emerging. Consistent with prior reports in infants, visual and motor regions were identified as emerging hub areas, specifically in cerebellar areas. We also found evidence for network hubs in association cortex, including areas remarkably close to the adult fusiform facial and Wernicke areas. Functional significance of hub structure was confirmed by computationally deleting hub versus random nodes and observing that global efficiency decreased significantly more when hubs were removed (p < .001). Taken together, we conclude that both primary and association brain regions demonstrate centrality in network organization before birth. While fetal hubs may be important for facilitating network communication, they may also form potential points of vulnerability in fetal brain development.

Functional integrity in children with anoxic brain injury from drowning.

Drowning is a leading cause of accidental injury and death in young children. Anoxic brain injury (ABI) is a common consequence of drowning and can cause severe neurological morbidity in survivors. Assessment of functional status and prognostication in drowning victims can be extremely challenging, both acutely and chronically. Structural neuroimaging modalities (CT and MRI) have been of limited clinical value. Here, we tested the utility of resting-state functional MRI (rs-fMRI) for assessing brain functional integrity in this population. Eleven children with chronic, spastic quadriplegia due to drowning-induced ABI were investigated. All were comatose immediately after the injury and gradually regained consciousness, but with varying ability to communicate their cognitive state. Eleven neurotypical children matched for age and gender formed the control group. Resting-state fMRI and co-registered T1-weighted anatomical MRI were acquired at night during drug-aided sleep. Network integrity was quantified by independent components analysis (ICA), at both group- and per-subject levels. Functional-status assessments based on in-home observations were provided by families and caregivers. Motor ICNs were grossly compromised in ABI patients both group-wise and individually, concordant with their prominent motor deficits. Striking preservations of perceptual and cognitive ICNs were observed, and the degree of network preservation correlated (ρ = 0.74) with the per-subject functional status assessments. Collectively, our findings indicate that rs-fMRI has promise for assessing brain functional integrity in ABI and, potentially, in other disorders. Furthermore, our observations suggest that the severe motor deficits observed in this population can mask relatively intact perceptual and cognitive capabilities. Hum Brain Mapp 38:4813-4831, 2017. © 2017 Wiley Periodicals, Inc.

Weak functional connectivity in the human fetal brain prior to preterm birth.

It has been suggested that neurological problems more frequent in those born preterm are expressed prior to birth, but owing to technical limitations, this has been difficult to test in humans. We applied novel fetal resting-state functional MRI to measure brain function in 32 human fetuses in utero and found that systems-level neural functional connectivity was diminished in fetuses that would subsequently be born preterm. Neural connectivity was reduced in a left-hemisphere pre-language region, and the degree to which connectivity of this left language region extended to right-hemisphere homologs was positively associated with the time elapsed between fMRI assessment and delivery. These results provide the first evidence that altered functional connectivity in the preterm brain is identifiable before birth. They suggest that neurodevelopmental disorders associated with preterm birth may result from neurological insults that begin in utero.

Lenticulostriate arterial distribution pathology may underlie pediatric anoxic brain injury in drowning.

Drowning is a leading cause of neurological morbidity and mortality in young children. Anoxic brain injury (ABI) can result from nonfatal drowning and typically entails substantial neurological impairment. The neuropathology of drowning-induced pediatric ABI is not well established. Specifically, quantitative characterization of the spatial extent and tissue distribution of anoxic damage in pediatric nonfatal drowning has not previously been reported but could clarify the underlying pathophysiological processes and inform clinical management. To this end, we used voxel-based morphometric (VBM) analyses to quantify the extent and spatial distribution of consistent, between-subject alterations in gray and white matter volume. Whole-brain, high-resolution T1-weighted MRI datasets were acquired in 11 children with chronic ABI and 11 age- and gender-matched neurotypical controls (4-12 years). Group-wise VBM analyses demonstrated predominantly central subcortical pathology in the ABI group in both gray matter (bilateral basal ganglia nuclei) and white matter (bilateral external and posterior internal capsules) (P < 0.001); minimal damage was found outside of these deep subcortical regions. These highly spatially convergent gray and white matter findings reflect the vascular distribution of perforating lenticulostriate arteries, an end-arterial watershed zone, and suggest that vascular distribution may be a more important determinant of tissue loss than oxygen metabolic rate in pediatric ABI. Further, these results inform future directions for diagnostic and therapeutic modalities.

Age-related increases in long-range connectivity in fetal functional neural connectivity networks in utero.

Formation of operational neural networks is one of the most significant accomplishments of human fetal brain growth. Recent advances in functional magnetic resonance imaging (fMRI) have made it possible to obtain information about brain function during fetal development. Specifically, resting-state fMRI and novel signal covariation approaches have opened up a new avenue for non-invasive assessment of neural functional connectivity (FC) before birth. Early studies in this area have unearthed new insights about principles of prenatal brain function. However, very little is known about the emergence and maturation of neural networks during fetal life. Here, we obtained cross-sectional rs-fMRI data from 39 fetuses between 24 and 38 weeks postconceptual age to examine patterns of connectivity across ten neural FC networks. We identified primitive forms of motor, visual, default mode, thalamic, and temporal networks in the human fetal brain. We discovered the first evidence of increased long-range, cerebral-cerebellar, cortical-subcortical, and intra-hemispheric FC with advancing fetal age. Continued aggregation of data about fundamental neural connectivity systems in utero is essential to establishing principles of connectomics at the beginning of human life. Normative data provides a vital context against which to compare instances of abnormal neurobiological development.

Intrinsic connectivity network mapping in young children during natural sleep.

Structural and functional neuroimaging have substantively informed the pathophysiology of numerous adult neurological and psychiatric disorders. While structural neuroimaging is readily acquired in sedated young children, pediatric application of functional neuroimaging has been limited by the behavioral demands of in-scanner task performance. Here, we investigated whether functional magnetic resonance imaging (fMRI) acquired during natural sleep and without experimental stimulation offers a viable strategy for studying young children. We targeted the lengthy epoch of non-rapid eye movement, stage 3 (NREM3) sleep typically observed at sleep onset in sleep-deprived children. Seven healthy, preschool-aged children (24-58 months) were studied, acquiring fMRI measurements of cerebral blood flow (CBF) and of intrinsic connectivity networks (ICNs), with concurrent sleep-stage monitoring. ICN data (T2* fMRI) were reliably obtained during NREM3 sleep; CBF data (arterial spin labeled fMRI) were not reliably obtained, as scanner noises disrupted sleep. Applying independent component analysis (ICA) to T2* data, distinct ICNs were observed which corresponded closely with those reported in the adult literature. Notably, a network associated with orthography in adults was not observed, suggesting that ICNs exhibit a developmental trajectory. We conclude that resting-state fMRI obtained in sleep is a promising paradigm for neurophysiological investigations of young children.