Development of neonatal connectome dynamics and its prediction for cognitive and language outcomes at age 2.

The functional brain connectome is highly dynamic over time. However, how brain connectome dynamics evolves during the third trimester of pregnancy and is associated with later cognitive growth remains unknown. Here, we use resting-state functional Magnetic Resonance Imaging (MRI) data from 39 newborns aged 32 to 42 postmenstrual weeks to investigate the maturation process of connectome dynamics and its role in predicting neurocognitive outcomes at 2 years of age. Neonatal brain dynamics is assessed using a multilayer network model. Network dynamics decreases globally but increases in both modularity and diversity with development. Regionally, module switching decreases with development primarily in the lateral precentral gyrus, medial temporal lobe, and subcortical areas, with a higher growth rate in primary regions than in association regions. Support vector regression reveals that neonatal connectome dynamics is predictive of individual cognitive and language abilities at 2  years of age. Our findings highlight network-level neural substrates underlying early cognitive development.

Differential cortical microstructural maturation in the preterm human brain with diffusion kurtosis and tensor imaging.

During the third trimester, the human brain undergoes rapid cellular and molecular processes that reshape the structural architecture of the cerebral cortex. Knowledge of cortical differentiation obtained predominantly from histological studies is limited in localized and small cortical regions. How cortical microstructure is differentiated across cortical regions in this critical period is unknown. In this study, the cortical microstructural architecture across the entire cortex was delineated with non-Gaussian diffusion kurtosis imaging as well as conventional diffusion tensor imaging of 89 preterm neonates aged 31-42 postmenstrual weeks. The temporal changes of cortical mean kurtosis (MK) or fractional anisotropy (FA) were heterogeneous across the cortical regions. Cortical MK decreases were observed throughout the studied age period, while cortical FA decrease reached its plateau around 37 weeks. More rapid decreases in MK were found in the primary visual region, while faster FA declines were observed in the prefrontal cortex. We found that distinctive cortical microstructural changes were coupled with microstructural maturation of associated white matter tracts. Both cortical MK and FA measurements predicted the postmenstrual age of preterm infants accurately. This study revealed a differential 4D spatiotemporal cytoarchitectural signature inferred by non-Gaussian diffusion barriers inside the cortical plate during the third trimester. The cytoarchitectural processes, including dendritic arborization and neuronal density decreases, were inferred by regional cortical FA and MK measurements. The presented findings suggest that cortical MK and FA measurements could be used as effective imaging markers for cortical microstructural changes in typical and potentially atypical brain development.

Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial.

OBJECTIVE: To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours. STUDY DESIGN: Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age. RESULTS: Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively. CONCLUSIONS: MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00614744.

Dynamic compression in vertebral artery dissection in children: apropos of a new protocol.

PURPOSE: Our goals are (1) to report a consecutive prospective series of children who had posterior circulation stroke caused by vertebral artery dissection at the V3 segment; (2) to describe a configuration of the vertebral artery that may predispose to rotational compression; and (3) to recommend a new protocol for evaluation and treatment of vertebral artery dissection at V3. METHODS: All children diagnosed with vertebral artery dissection at the V3 segment from September 2014 to July 2020 at our institution were included in the study. Demographic, clinical, surgical, and radiological data were collected. RESULTS: Sixteen children were found to have dissection at a specific segment of the vertebral artery. Fourteen patients were male. Eleven were found to have compression on rotation during a provocative angiogram. All eleven underwent C1C2 posterior fusion as part of their treatment. Their mean age was 6.44 years (range 18 months-15 years). Mean blood loss was 57.7 mL. One minor complication occurred: a superficial wound infection treated with oral antibiotics only. There were no vascular or neurologic injuries. There have been no recurrent ischemic events after diagnosis and/or treatment. Mean follow-up was 33.3 months (range 2-59 months). We designed a new protocol to manage V3 dissections in children. CONCLUSION: Posterior C1C2 fusion is a safe and effective option for treatment of dynamic compression in vertebral artery dissection in children. Institution of and compliance with a strict diagnostic and treatment protocol for V3 segment dissections seem to prevent recurrent stroke.

Development and Emergence of Individual Variability in the Functional Connectivity Architecture of the Preterm Human Brain.

Individual variability in human brain networks underlies individual differences in cognition and behaviors. However, researchers have not conclusively determined when individual variability patterns of the brain networks emerge and how they develop in the early phase. Here, we employed resting-state functional MRI data and whole-brain functional connectivity analyses in 40 neonates aged around 31-42 postmenstrual weeks to characterize the spatial distribution and development modes of individual variability in the functional network architecture. We observed lower individual variability in primary sensorimotor and visual areas and higher variability in association regions at the third trimester, and these patterns are generally similar to those of adult brains. Different functional systems showed dramatic differences in the development of individual variability, with significant decreases in the sensorimotor network; decreasing trends in the visual, subcortical, and dorsal and ventral attention networks, and limited change in the default mode, frontoparietal and limbic networks. The patterns of individual variability were negatively correlated with the short- to middle-range connection strength/number and this distance constraint was significantly strengthened throughout development. Our findings highlight the development and emergence of individual variability in the functional architecture of the prenatal brain, which may lay network foundations for individual behavioral differences later in life.

Structural network maturation of the preterm human brain.

During the 3rd trimester, large-scale neural circuits are formed in the human brain, resulting in a highly efficient and segregated connectome at birth. Despite recent findings identifying important preterm human brain network properties such as rich-club organization, how the structural network develops differentially across brain regions and among different types of connections in this period is not yet known. Here, using high resolution diffusion MRI of 77 preterm-born and full-term neonates scanned at 31.9-41.7 postmenstrual weeks (PMW), we constructed structural connectivity matrices and performed graph-theory-based analyses. Faster increases of nodal efficiency were mainly located at the brain hubs distributed in primary sensorimotor regions, superior-middle frontal, and precuneus regions during 31.9-41.7PMW. Higher rates of edge strength increases were found in the rich-club and within-module connections, compared to other connections. The edge strength of short-range connections increased faster than that of long-range connections. Nodal efficiencies of the hubs predicted individual postmenstrual ages more accurately than those of non-hubs. Collectively, these findings revealed more rapid efficiency increases of the hub and rich-club connections as well as higher developmental rates of edge strength in short-range and within-module connections. These jointly underlie network segregation and differentiated emergence of brain functions.

Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months.

BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.

Early Development of Functional Network Segregation Revealed by Connectomic Analysis of the Preterm Human Brain.

Human brain functional networks are topologically organized with nontrivial connectivity characteristics such as small-worldness and densely linked hubs to support highly segregated and integrated information processing. However, how they emerge and change at very early developmental phases remains poorly understood. Here, we used resting-state functional MRI and voxel-based graph theory analysis to systematically investigate the topological organization of whole-brain networks in 40 infants aged around 31 to 42 postmenstrual weeks. The functional connectivity strength and heterogeneity increased significantly in primary motor, somatosensory, visual, and auditory regions, but much less in high-order default-mode and executive-control regions. The hub and rich-club structures in primary regions were already present at around 31 postmenstrual weeks and exhibited remarkable expansions with age, accompanied by increased local clustering and shortest path length, indicating a transition from a relatively random to a more organized configuration. Moreover, multivariate pattern analysis using support vector regression revealed that individual brain maturity of preterm babies could be predicted by the network connectivity patterns. Collectively, we highlighted a gradually enhanced functional network segregation manner in the third trimester, which is primarily driven by the rapid increases of functional connectivity of the primary regions, providing crucial insights into the topological development patterns prior to birth.

Dynamic Arterial Compression in Pediatric Vertebral Arterial Dissection.

BACKGROUND AND PURPOSE: The pathogenesis of spontaneous pediatric vertebral artery dissections (VAD) is poorly understood but most often involves the V3 segment where C1 rotates on C2. We studied children with VAD with provocative digital catheter angiography and found an association between VAD and rotational compression. METHODS: Seven boys (12 months to 9 years; median 4 years) presented over 38 consecutive months with V3 VAD and underwent digital catheter angiography with provocative passive bilateral neck rotation. RESULTS: VAD were bilateral in 2 patients and unilateral in 5. Provocative digital catheter angiography showed dynamic V3 compression in 6 of 9 dissections, most pronounced or seen only with head rotation to the contralateral side. Two patients had VAD without dynamic compression; both returned 4 months later with a new dissection in a previously normal VA and worsening VAD in 1 patient each. Dynamic compression was also seen in 2 nondissected VA. Surgical management was C1/2 posterior fusion in 5 of 7 patients; 1 underwent unilateral C2 decompression with recurrent VAD and was subsequently fused. CONCLUSIONS: The association of dynamic VA compression and VAD at the same level suggests that the compression may contribute to the VAD. However, as dynamic compression was observed in nondissected VA and some VAD were not associated with dynamic compression, VAD may be multifactorial.

Heterogeneous increases of regional cerebral blood flow during preterm brain development: Preliminary assessment with pseudo-continuous arterial spin labeled perfusion MRI.

The human brain develops rapidly during 32-45 postmenstrual weeks (PMW), a critical stage characterized by dramatic increases of metabolic demand. The increasing metabolic demand can be inferred through measurements of regional cerebral blood flow (CBF), which might be coupled to regional metabolism in preterm brains. Arterial spin labeled (ASL) perfusion MRI is one of the few viable approaches for imaging regional CBF of preterm brains, but must be optimized for the extremely slow blood velocity unique in preterm brains. In this study, we explored the spatiotemporal CBF distribution in newborns scanned at the age of 32-45PMW using a pseudo-continuous ASL (pCASL) protocol adapted to slow blood flow in neonates. A total of 89 neonates were recruited. PCASL MRI was acquired from 34 normal newborns and phase contrast (PC) images from 19 newborns. Diffusion tensor images (DTI) were acquired from all 89 neonates for measuring cortical fractional anisotropy (FA), which characterizes cortical microstructure. Reproducible CBF measurements were obtained with the adjusted pCASL sequence. Global CBF measurement based on PC MRI was found to double its value in the 3rd trimester. Regional CBF increases were heterogeneous across the brain with a significantly higher rate of CBF increase in the frontal lobe and a lower rate of CBF increase in the occipital lobe. A significant correlation was found between frontal cortical CBF and cortical FA measurements (p<0.01). Increasing CBF values observed in the frontal lobe corresponded to lower FA values, suggesting that dendritic arborization and synaptic formation might be associated with an elevated local CBF. These results offer a preliminary account of heterogeneous regional CBF increases in a vital early developmental period and may shed the light on underlying metabolic support for cortical microstructural changes during the developmental period of 32-45PMW. Preterm effects and limitations of pCASL techniques in newborns need to be carefully considered for interpretation these results.

Structural Development of Human Fetal and Preterm Brain Cortical Plate Based on Population-Averaged Templates.

We hypothesized that the distinct maturational processes take place across different cortical areas from middle fetal stage to normal time of birth and these maturational processes are altered in late third trimester. Fractional anisotropies (FA) from diffusion tensor imaging (DTI) infer the microstructures of the early developing cortical plate. High-resolution DTI of 11 fetal brain specimens at postmenstrual age of 20 weeks (or simplified as 20 weeks), 19 in vivo brains at 35 weeks, and 17 in vivo brains at normal time of birth at term (40 weeks) were acquired. Population-averaged age-specific DTI templates were established with large deformation diffeomorphic metric mapping for subject groups at 20, 35, and 40 weeks. To alleviate partial volume effects, skeletonized FA values were used for mapping averaged cortical FA to the cortical surface and measuring FA at 12 functionally distinctive cortical regions. Significant and heterogeneous FA decreases take place in distinct cortical areas from 20 to 35 weeks and from 35 to 40 weeks, suggesting differentiated cortical development patterns. Temporally nonuniform FA decrease patterns during 35-40 weeks compared with those during 20-35 weeks were observed in higher-order association cortex. Measured skeletonized FA suggested dissociated changes between cerebral cortex and white matter during 35-40 weeks.

Development of human brain structural networks through infancy and childhood.

During human brain development through infancy and childhood, microstructural and macrostructural changes take place to reshape the brain's structural networks and better adapt them to sophisticated functional and cognitive requirements. However, structural topological configuration of the human brain during this specific development period is not well understood. In this study, diffusion magnetic resonance image (dMRI) of 25 neonates, 13 toddlers, and 25 preadolescents were acquired to characterize network dynamics at these 3 landmark cross-sectional ages during early childhood. dMRI tractography was used to construct human brain structural networks, and the underlying topological properties were quantified by graph-theory approaches. Modular organization and small-world attributes are evident at birth with several important topological metrics increasing monotonically during development. Most significant increases of regional nodes occur in the posterior cingulate cortex, which plays a pivotal role in the functional default mode network. Positive correlations exist between nodal efficiencies and fractional anisotropy of the white matter traced from these nodes, while correlation slopes vary among the brain regions. These results reveal substantial topological reorganization of human brain structural networks through infancy and childhood, which is likely to be the outcome of both heterogeneous strengthening of the major white matter tracts and pruning of other axonal fibers.

Assessment of diffusion tensor image quality across sites and vendors using the American College of Radiology head phantom.

The purpose of this study was to explore the feasibility of assessing quality of diffusion tensor imaging (DTI) from multiple sites and vendors using American College of Radiology (ACR) phantom. Participating sites (Siemens (n = 2), GE (n= 2), and Philips (n = 4)) reached consensus on parameters for DTI and used the widely available ACR phantom. Tensor data were processed at one site. B0 and eddy current distortions were assessed using grid line displacement on phantom Slice 5; signal-to-noise ratio (SNR) was measured at the center and periphery of the b = 0 image; fractional anisotropy (FA) and mean diffusivity (MD) were assessed using phantom Slice 7. Variations of acquisition parameters and deviations from specified sequence parameters were recorded. Nonlinear grid line distortion was higher with linear shimming and could be corrected using the 2nd order shimming. Following image registration, eddy current distortion was consistently smaller than acquisi-tion voxel size. SNR was consistently higher in the image periphery than center by a factor of 1.3-2.0. ROI-based FA ranged from 0.007 to 0.024. ROI-based MD ranged from 1.90 × 10-3 to 2.33 × 10-3 mm2/s (median = 2.04 × 10-3 mm2/s). Two sites had image void artifacts. The ACR phantom can be used to compare key qual-ity measures of diffusion images acquired from multiple vendors at multiple sites.

Acute silent cerebral ischemia and infarction during acute anemia in children with and without sickle cell disease.

We hypothesized that the silent cerebral infarcts (SCI), which affect up to 40% of children with sickle cell disease (SCD), could occur in the setting of acute anemic events. In a prospective observational study of children with and without SCD hospitalized for an illness associated with acute anemia, we identified acute silent cerebral ischemic events (ASCIE) in 4 (18.2%) of 22 with SCD and in 2 (6.7%) of 30 without SCD, using diffusion-weighted magnetic resonance imaging. Children with ASCIE had lower hemoglobin concentration than those without (median 3.1 vs 4.4 g/dL, P = .003). The unique temporal features of stroke on diffusion-weighted magnetic resonance imaging permit estimation of incidence rates for ASCIE of 421 (95% confidence interval, 155-920) per 100 patient-years during acute anemic events for all patients. For children with SCD, the estimated incidence was 663 (95% confidence interval, 182-1707) which is much higher than previously reported. Acute anemic events are common in children with SCD and prevalence could partially account for the high SCI. Some ASCIE (1 of 4 in our study) may be reversible. Alterations in management may be warranted for children with severe anemia to identify unrecognized ischemic brain injury that may have permanent neurocognitive sequelae.

Quantitative assessment of global cerebral metabolic rate of oxygen (CMRO2) in neonates using MRI.

The cerebral metabolic rate of oxygen (CMRO2) is the rate of oxygen consumption by the brain, and is thought to be a direct index of energy homeostasis and brain health. However, in vivo measurement of CMRO2 is challenging, in particular for the neonatal population, in whom conventional radiotracer methods are not applicable because of safety concerns. In this study, we propose a method to quantify global CMRO2 in neonates based on arteriovenous differences in oxygen content, and employ separate measurements of oxygenation and cerebral blood flow (CBF) parameters. Specifically, arterial and venous oxygenation levels were determined with pulse oximetry and the novel T2 relaxation under spin tagging (TRUST) MRI, respectively. Global CBF was measured with phase contrast (PC) flow velocity MRI. The proposed method was implemented on a standard 3-T MRI scanner without the need for any exogenous tracers, and the total scan duration was less than 5 min. We demonstrated the feasibility of this method in 12 healthy neonates within an age range of 35-42 gestational weeks. CMRO2 values were successfully obtained from 10 neonates. It was found that the average CMRO2 in this age range was 38.3 ± 17.7 µmol/100 g/min and was positively correlated with age (p = 0.007; slope, 5.2 µmol/100 g/min per week), although the highest CMRO2 value in this age range was still less than half of the adult level. Test-retest studies showed a coefficient of variation of 5.8 ± 2.2% between repeated CMRO2 measurements. In addition, given the highly variable blood flow velocity within this age range, it is recommended that the TRUST labeling thickness and position should be determined on a subject-by-subject basis, and an automatic algorithm was developed for this purpose. Although this method provides a global CMRO2 measure only, the clinical significance of an energy consumption marker and the convenience of this technique may make it a useful tool in the functional assessment of the neonatal population.

Development of sensorimotor-visual connectome gradient at birth predicts neurocognitive outcomes at 2 years of age.

Functional connectome gradients represent fundamental organizing principles of the brain. Here, we report the development of the connectome gradients in preterm and term babies aged 31-42 postmenstrual weeks using task-free functional MRI and its association with postnatal cognitive growth. We show that the principal sensorimotor-to-visual gradient is present during the late preterm period and continuously evolves toward a term-like pattern. The global measurements of this gradient, characterized by explanation ratio, gradient range, and gradient variation, increased with age (p < 0.05, corrected). Focal gradient development mainly occurs in the sensorimotor, lateral, and medial parietal regions, and visual regions (p < 0.05, corrected). The connectome gradient at birth predicts cognitive and language outcomes at 2-year follow-up (p < 0.005). These results are replicated using an independent dataset from the Developing Human Connectome Project. Our findings highlight early emergent rules of the brain connectome gradient and their implications for later cognitive growth.