Maternal trait anxiety symptoms, frontolimbic resting-state functional connectivity, and cognitive development in infancy.

Exposure to maternal anxiety symptoms during infancy has been associated with difficulties in development and greater risk for developing anxiety later in life. Although previous studies have examined associations between prenatal maternal distress, infant brain development, and developmental outcomes, it is still largely unclear if there are associations between postnatal anxiety, infant brain development, and cognitive development in infancy. In this study, we used resting-state functional magnetic resonance imaging to examine the association between maternal anxiety symptoms and resting-state functional connectivity in the first year of life. We also examine the association between frontolimbic functional connectivity and infant cognitive development. The sample consisted of 21 infants (mean age = 24.15 months, SD = 4.17) that were scanned during their natural sleep using. We test the associations between maternal trait anxiety symptoms and amygdala-anterior cingulate cortex (ACC) functional connectivity, a neural circuit implicated in early life stress exposure. We also test the associations between amygdala-ACC connectivity and cognitive development. We found a significant negative association between maternal trait anxiety symptoms and left amygdala-right ACC functional connectivity (p < .05, false discovery rate corrected). We found a significant negative association between left amygdala-right ACC functional connectivity and infant cognitive development (p < .05). These findings have potential implications for understanding the role of postpartum maternal anxiety symptoms in functional brain and cognitive development in infancy.

Gut microbiome and brain functional connectivity in infants-a preliminary study focusing on the amygdala.

Recently, there has been a surge of interest in the possibility that microbial communities inhabiting the human gut could affect cognitive development and increase risk for mental illness via the "microbiome-gut-brain axis." Infancy likely represents a critical period for the establishment of these relationships, as it is the most dynamic stage of postnatal brain development and a key period in the maturation of the microbiome. Indeed, recent reports indicate that characteristics of the infant gut microbiome are associated with both temperament and cognitive performance. The neural circuits underlying these relationships have not yet been delineated. To address this gap, resting-state fMRI scans were acquired from 39 1-year-old human infants who had provided fecal samples for identification and relative quantification of bacterial taxa. Measures of alpha diversity were generated and tested for associations with measures of functional connectivity. Primary analyses focused on the amygdala as manipulation of the gut microbiota in animal models alters the structure and neurochemistry of this brain region. Secondary analyses explored functional connectivity of nine canonical resting-state functional networks. Alpha diversity was significantly associated with functional connectivity between the amygdala and thalamus and between the anterior cingulate cortex and anterior insula. These regions play an important role in processing/responding to threat. Alpha diversity was also associated with functional connectivity between the supplementary motor area (SMA, representing the sensorimotor network) and the inferior parietal lobule (IPL). Importantly, SMA-IPL connectivity also related to cognitive outcomes at 2 years of age, suggesting a potential pathway linking gut microbiome diversity and cognitive outcomes during infancy. These results provide exciting new insights into the gut-brain axis during early human development and should stimulate further studies into whether microbiome-associated changes in brain circuitry influence later risk for psychopathology.

Development of Amygdala Functional Connectivity During Infancy and Its Relationship With 4-Year Behavioral Outcomes.

BACKGROUND: The amygdala represents a core node in the human brain's emotional signal processing circuitry. Given its critical role, both the typical and atypical functional connectivity patterns of the amygdala have been extensively studied in adults. However, the development of amygdala functional connectivity during infancy is less well studied; thus, our understanding of the normal growth trajectory of key emotion-related brain circuits during a critical period is limited. METHODS: In this study, we used resting-state functional magnetic resonance imaging (N = 233 subjects with 334 datasets) to delineate the spatiotemporal dynamics of amygdala functional connectivity development during the first 2 years of life. Their relationships with 4-year emotional (i.e., anxiety and inhibitory self-control parent report measures) and cognitive (i.e., IQ) behavioral outcomes were also assessed using multivariate modeling. RESULTS: Our results revealed nonlinear growth of amygdala functional connectivity during the first 2 years of life, featuring dramatic synchronization during the first year followed by moderate growth or fine tuning during the second year. Importantly, functional connectivity growth during the second year had significant behavioral implications exemplified by multiple significant predictions of 4-year emotional and cognitive developmental outcomes. CONCLUSIONS: The delineation of the spatiotemporal dynamics of amygdala functional connectivity development during infancy and their associations with 4-year behavioral outcomes may provide new references on the early emergence of both typical and atypical emotion processing capabilities.

Functional Brain Parcellations of the Infant Brain and the Associated Developmental Trends.

Resting-state functional connectivity studies have dramatically improved our understanding of the early human brain functional development during the past decade. However, one emerging problem that could potentially impede future progresses in the field is the definition of regions of interest (ROI), since it is well known that functional connectivity estimation can be seriously contaminated by within-ROI signal heterogeneity. In this study, based on a large-scale rsfMRI data set in human infants (230 neonates, 143 1-year olds, and 107 2-year olds), we aimed to derive a set of anatomically constrained, infant-specific functional brain parcellations using functional connectivity-based clustering. Our results revealed significantly higher levels of signal homogeneity within the newly defined functional parcellations compared with other schemes. Importantly, the global functional connectivity patterns associated with the newly defined functional subunits demonstrated significantly increasing levels of differentiation with age, confirming increasing levels of local specialization. Subsequent whole brain connectivity analysis revealed intriguing patterns of regional-level functional connectivity developments and system-level hub redistribution during infancy. Overall, the newly derived infant-specific functional brain parcellations and the associated novel developmental patterns will likely prove valuable for future early developmental studies using the functional connectivity technique.

Maternal Adiposity Influences Neonatal Brain Functional Connectivity.

The neural mechanisms associated with obesity have been extensively studied, but the impact of maternal obesity on fetal and neonatal brain development remains poorly understood. In this study of full-term neonates, we aimed to detect potential neonatal functional connectivity alterations associated with maternal adiposity, quantified via body-mass-index (BMI) and body-fat-mass (BFM) percentage, based on seed-based and graph theoretical analysis using resting-state fMRI data. Our results revealed significant neonatal functional connectivity alterations in all four functional domains that are implicated in adult obesity: sensory cue processing, reward processing, cognitive control, and motor control. Moreover, some of the detected areas showing regional functional connectivity alterations also showed global degree and efficiency differences. These findings provide important clues to the potential neural basis for cognitive and mental health development in offspring of obese mothers and may lead to the derivation of imaging-based biomarkers for the early identification of risks for timely intervention.

Using Functional Connectivity Magnetic Resonance Imaging to Measure Brain Connectivity in Preterm Infants.

BACKGROUND: The use of functional connectivity magnetic resonance imaging (fcMRI) in research involving preterm infants is relatively new, and its feasibility in this population is not fully established. However, fcMRI images reveal functional neural connections that may be useful in establishing the mechanisms of neuroprotective interventions in preterm infants. OBJECTIVE: The aim of this study was to determine the feasibility of using fcMRI to measure differences in functional neural connections in nursing intervention studies. METHODS: A pilot study was conducted as part of a longitudinal, randomized controlled trial (RCT) testing the effect of a feeding intervention on neurodevelopmental and clinical outcomes of preterm infants randomly assigned to one of two groups: a patterned feeding experience (PFE) group and a usual feeding care (UFC) group. The fcMRIs were done at term-equivalent age. Visual, motor, and default mode networks were analyzed. RESULTS: Seven infants were studied (four were in the PFE group, and three were in the UFC group). Participants were selected sequentially from the parent RCT. Clear images were obtained from all participants. Differences were noted among PFE and UFC infants: Infants receiving PFE were hyperconnective in the default mode (caudate, anterior cingulate cortex, and precuneus) and motor networks (middle temporal and middle occipital areas) and hypoconnective in others areas of the default mode (hippocampal and lingual regions) and motor networks (precentral and superior frontal cortices) relative to UFC infants. No differences were noted in visual networks. DISCUSSION: The feasibility of using fcMRI at term-equivalent age in preterm infants who participated in an RCT on the effect of a nursing intervention was shown. Differences in connectivity among infants by group were detected. Further research is needed to show the benefit of fcMRI in studies of preterm infants given the costs of the procedure as well as the uncertain relationship of this early outcome measure to long-term neurodevelopment.

Emergence of a hierarchical brain during infancy reflected by stepwise functional connectivity.

The hierarchical nature of the brain's functional organization has long been recognized, but when and how this architecture emerges during development remains largely unknown. Here the development of the brain's hierarchical organization was characterized using a modified stepwise functional connectivity approach based on resting-state fMRI in a fully longitudinal sample of infants (N = 28, with scans after birth, and at 1 and 2 years) and adults. Results obtained by placing seeds in early sensory cortices revealed novel hierarchical patterns of adult brain organization ultimately converging in limbic, paralimbic, basal ganglia, and frontoparietal brain regions. These findings are remarkably consistent with predictive coding accounts of neural processing that place these regions at the top of predictive coding hierarchies. Infants gradually developed toward this architecture in a region- and step-dependent manner, and displayed many of the same regions as adults in top hierarchical positions, starting from 1 year of age. The findings further revealed patterns of inter-sensory connectivity likely reflecting the emergence and development of multisensory processing strategies during infancy, the strengths of which were correlated with early cognitive development scores. Hum Brain Mapp 38:2666-2682, 2017. © 2017 Wiley Periodicals, Inc.

Resting state network topology of the ferret brain.

Resting state functional magnetic resonance imaging (rsfMRI) has emerged as a versatile tool for non-invasive measurement of functional connectivity patterns in the brain. RsfMRI brain dynamics in rodents, non-human primates, and humans share similar properties; however, little is known about the resting state functional connectivity patterns in the ferret, an animal model with high potential for developmental and cognitive translational study. To address this knowledge-gap, we performed rsfMRI on anesthetized ferrets using a 9.4T MRI scanner, and subsequently performed group-level independent component analysis (gICA) to identify functionally connected brain networks. Group-level ICA analysis revealed distributed sensory, motor, and higher-order networks in the ferret brain. Subsequent connectivity analysis showed interconnected higher-order networks that constituted a putative default mode network (DMN), a network that exhibits altered connectivity in neuropsychiatric disorders. Finally, we assessed ferret brain topological efficiency using graph theory analysis and found that the ferret brain exhibits small-world properties. Overall, these results provide additional evidence for pan-species resting-state networks, further supporting ferret-based studies of sensory and cognitive function.

Thalamocortical functional connectivity and behavioral disruptions in neonates with prenatal cocaine exposure.

Prenatal cocaine exposure (PCE) affects neurobehavioral development, however, disentangling direct drug-related mechanisms from contextual effects (e.g., socioeconomic status) has proven challenging in humans. The effects of environmental confounds are minimal immediately after birth thus we aimed to delineate neurobehavioral correlates of PCE in a large cohort of neonates (2-6weeks of age, N=152) with and without drug exposure using resting state functional magnetic resonance imaging (rsfMRI) and developmental assessments at 3months with the Bayley Scales of Infant & Toddler Development, 3rd edition. The cohort included healthy controls and neonates with similar poly-drug exposure±cocaine. We focused on the thalamus given its critical importance in early brain development and its unique positioning in the dopamine system. Our results revealed PCE-related hyper-connectivity between the thalamus and frontal regions and a drug-common hypo-connective signature between the thalamus and motor-related regions. PCE-specific neonatal thalamo-frontal connectivity was inversely related to cognitive and fine motor scores and thalamo-motor connectivity showed a positive relationship with composite (gross plus fine) motor scores. Finally, cocaine by selective-serotonin-reuptake-inhibitor (SSRI) interactions were detected, suggesting the combined use of these drugs during pregnancy could have additional consequences on fetal development. Overall, our findings provide the first delineation of PCE-related disruptions of thalamocortical functional connectivity, neurobehavioral correlations, and drug-drug interactions during infancy.

Functional Connectivity Disruption in Neonates with Prenatal Marijuana Exposure.

Prenatal marijuana exposure (PME) is linked to neurobehavioral and cognitive impairments; however, findings in childhood and adolescence are inconsistent. Type-1 cannabinoid receptors (CB1R) modulate fetal neurodevelopment, mediating PME effects on growth of functional circuitry sub-serving behaviors critical for academic and social success. The purpose of this study was to investigate the effects of prenatal marijuana on development of early brain functional circuitry prior to prolonged postnatal environmental influences. We measured resting state functional connectivity during unsedated sleep in infants at 2-6 weeks (+MJ: 20 with PME in combination with nicotine, alcohol, opiates, and/or selective serotonin reuptake inhibitors; -MJ: 23 exposed to the same other drugs without marijuana, CTR: 20 drug-free controls). Connectivity of subcortical seed regions with high fetal CB1R expression was examined. Marijuana-specific differences were observed in insula and three striatal connections: anterior insula-cerebellum, right caudate-cerebellum, right caudate-right fusiform gyrus/inferior occipital, left caudate-cerebellum. +MJ neonates had hypo-connectivity in all clusters compared with -MJ and CTR groups. Altered striatal connectivity to areas involved in visual spatial and motor learning, attention, and in fine-tuning of motor outputs involved in movement and language production may contribute to neurobehavioral deficits reported in this at-risk group. Disrupted anterior insula connectivity may contribute to altered integration of interoceptive signals with salience estimates, motivation, decision-making, and later drug use. Compared with CTRs, both +MJ and -MJ groups demonstrated hyper-connectivity of left amygdala seed with orbital frontal cortex and hypo-connectivity of posterior thalamus seed with hippocampus, suggesting vulnerability to multiple drugs in these circuits.

Prenatal drug exposure affects neonatal brain functional connectivity.

Prenatal drug exposure, particularly prenatal cocaine exposure (PCE), incurs great public and scientific interest because of its associated neurodevelopmental consequences. However, the neural underpinnings of PCE remain essentially uncharted, and existing studies in school-aged children and adolescents are confounded greatly by postnatal environmental factors. In this study, leveraging a large neonate sample (N = 152) and non-invasive resting-state functional magnetic resonance imaging, we compared human infants with PCE comorbid with other drugs (such as nicotine, alcohol, marijuana, and antidepressant) with infants with similar non-cocaine poly drug exposure and drug-free controls. We aimed to characterize the neural correlates of PCE based on functional connectivity measurements of the amygdala and insula at the earliest stage of development. Our results revealed common drug exposure-related connectivity disruptions within the amygdala-frontal, insula-frontal, and insula-sensorimotor circuits. Moreover, a cocaine-specific effect was detected within a subregion of the amygdala-frontal network. This pathway is thought to play an important role in arousal regulation, which has been shown to be irregular in PCE infants and adolescents. These novel results provide the earliest human-based functional delineations of the neural-developmental consequences of prenatal drug exposure and thus open a new window for the advancement of effective strategies aimed at early risk identification and intervention.