Serial neuroimaging of brain growth and development in very preterm infants receiving tailored neuropromotive support in the NICU. Protocol for a prospective cohort study

IntroductionChildren born very preterm (VP) remain at risk for long-term neurodevelopmental impairment. Patterns of brain growth and injury, and how early neuropromotive therapies might mitigate developmental risk in VP infants remain insufficiently understood.MethodsThis is a prospective cohort study of VP infants born at/before 32 weeks gestation. The study will enroll n = 75 consecutively-born VP infants in a level-III NICU. Exposed infants will be categorized into two groups (group 1: low-risk, n = 25 or group 2: high-risk, n = 25) based on the degree of neurological injury on early brain magnetic resonance imaging (MRI) at enrollment. Infants in the low-risk group (i.e., without significant injury defined as intraventricular hemorrhage with dilation, moderate or severe white matter injury, or cerebellar hemorrhage) will receive neurodevelopmental support utilizing the Supporting and Enhancing NICU Sensory Experiences (SENSE) program, while infants in the high-risk group (with neurological injury) will receive more intensive neurorehabilitative support (SENSE-plus). Age-specific, tailored sensory experiences will be facilitated contingently, preferentially by the infant's family with coaching from NICU staff. VP infants in exposure groups will undergo a brain MRI approximately every 2 weeks from enrollment until term-equivalent to monitor brain growth and evolution of injury. Exposed infants will be compared with a reference group (group 3: n = 25), i.e. VP infants whose families decline initial enrollment in SENSE, and subsequently undergo a term-equivalent brain MRI for other purposes. The primary aim of this study is characterization of term-equivalent brain growth and development among VP infants receiving NICU-based neuropromotive interventions compared to VP infants receiving the standard of care. Secondary aims include defining the timing and factors associated with total and regional brain growth on serial brain MRI among VP infants, (Aim 2), and using early imaging to tailor developmental intervention in the NICU while exploring associations with outcomes in VP infants at discharge and at two years corrected age (Aim 3).DiscussionThis study will address gaps in understanding patterns of brain growth and injury drawing on serial MRI of hospitalized VP infants. These data will also explore the impact of intensive, tailored neuropromotive support delivered prior to term-equivalent on child and family outcomes

Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study.

Polyphenol-rich pomegranate juice has been shown to have benefit as a neuroprotectant in animal models of neonatal hypoxic-ischemia. No published studies have investigated maternal polyphenol administration as a potential neuroprotectant in at-risk newborns, such as those with intrauterine growth restriction (IUGR). This was a randomized, placebo-controlled, double-blind pilot study to investigate the impact of maternal pomegranate juice intake in pregnancies with IUGR, on newborn brain structure and function at term-equivalent age (TEA). Mothers with IUGR at 24-34 weeks\u27 gestation were recruited from Barnes-Jewish Hospital obstetrical clinic. Consented mothers were randomized to treatment (8 oz. pomegranate juice) or placebo (8 oz. polyphenol-free juice) and continued to take juice daily from enrollment until delivery (mean 20.1 and 27.1 days, respectively). Infants underwent brain MRI at TEA (36-41 weeks\u27 gestation). Brain measures were compared between groups including: brain injury score, brain metrics, brain volumes, diffusion tensor imaging and resting state functional connectivity. Statistical analyses were undertaken as modified intention-to-treat (including randomized participants who received their allocated intervention and whose infants received brain MRI) and per-protocol (including participants who strictly adhered to the protocol, based on metabolite status). Seventy-seven mothers were randomized to treatment (n = 40) or placebo (n = 37). Of these, 28 and 27 infants, respectively, underwent term-equivalent MRI. There were no group differences in brain injury, metrics or volumes. However, treatment subjects displayed reduced diffusivity within the anterior and posterior limbs of the internal capsule compared with placebo. Resting state functional connectivity demonstrated increased correlation and covariance within several networks in treatment subjects, with alterations most apparent in the visual network in per-protocol analyses. Direct effects on health were not found. In conclusion, maternal pomegranate juice intake in pregnancies with known IUGR was associated with altered white matter organization and functional connectivity in the infant brain, suggesting differences in brain structure and function following in utero pomegranate juice exposure, warranting continued investigation. Clinical trial registration. NCT00788866, registered November 11, 2008, initial participant enrollment August 21, 2012

Should therapeutic hypothermia be offered to babies with mild neonatal encephalopathy in the first 6 h after birth?

Infants with moderate to severe neonatal encephalopathy (NE) benefit significantly from therapeutic hypothermia, with reduced risk of death or disability. However, the need for therapeutic hypothermia for infants with milder NE remains unclear. It has been suggested that these infants should not be offered therapeutic hypothermia as they may not be at risk for adverse neurodevelopmental outcome and that the balance of risk against potential benefit is unknown. Several key questions need to be answered including first, whether one can define NE in the first 6 h after birth so as to accurately distinguish infants with brain injury who may be at risk for adverse neurodevelopmental consequences. Second, will treatment of infants with mild NE with therapeutic hypothermia improve or even worsen neurological outcomes? Although alternate treatment protocols for mild NE may be feasible, the use of the current approach combined with rigorous avoidance of hyperthermia and initiation of hypothermia as early as possible after birth may promote optimal outcomes. Animal experimental data support the potential for greater benefit for mild HIE compared with moderate to severe HIE. This review will summarize current knowledge of mild NE and the challenges to a trial in this population

Developmental Changes and Injury Induced Disruption of the Radial Organization of the Cortex in the Immature Rat Brain Revealed by In Vivo Diffusion Tensor MRI

During brain development, morphological changes modify the cortex from its immature radial organization to its mature laminar appearance. Applying in vivo diffusion tensor imaging (DTI), the microstructural organization of the cortex in the immature rat was analyzed and correlated to neurohistopathology. Significant differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were detected between the external (I-III) and deep (IV-VI) cortical layers in postnatal day 3 (P3) and P6 pups. With cortical maturation, ADC was reduced in both cortical regions, whereas a decrease in FA was only seen in the deep layers. A distinct radial organization of the external cortical layers with the eigenvectors perpendicular to the pial surface was observed at both ages. Histology revealed maturational differences in the cortical architecture with increased neurodendritic density and reduction in the radial glia scaffolding. Early DTI after hypoxia-ischemia at P3 shows reduced ADC and FA in the ipsilateral cortex that persisted at P6. Cortical DTI eigenvector maps reveal microstructural disruption of the radial organization corresponding to regions of neuronal death, radial glial disruption, and astrocytosis. Thus, the combined use of in vivo DTI and histopathology can assist in delineating normal developmental changes and postinjury modifications in the immature rodent brai

An allometric scaling relationship in the brain of preterm infants

Allometry has been used to demonstrate a power–law scaling relationship in the brain of premature born infants. Forty-nine preterm infants underwent neonatal MRI scans and neurodevelopmental testing at age 2. Measures of cortical surface area and total cerebral volume demonstrated a power–law scaling relationship (α = 1.27). No associations were identified between these measures and investigated clinical variables. Term equivalent cortical surface area and total cerebral volume measures and scaling exponents were not related to outcome. These findings confirm a previously reported allometric scaling relationship in the preterm brain, and suggest that scaling is not a sensitive indicator of aberrant cortical maturation

Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial

Objective: To investigate the effects of hypothermia treatment on magnetic resonance imaging (MRI) patterns of brain injury in newborns with hypoxic-ischemic encephalopathy compared with normothermia, including the prognostic utility of MRI for death and/or disability at a postnatal age of 2 years

Neonatal brain tissue classification with morphological adaptation and unified segmentation

Measuring the distribution of brain tissue types (tissue classification) in neonates is necessary for studying typical and atypical brain development, such as that associated with preterm birth, and may provide biomarkers for neurodevelopmental outcomes. Compared with magnetic resonance images of adults, neonatal images present specific challenges that require the development of specialized, population-specific methods. This paper introduces MANTiS (Morphologically Adaptive Neonatal Tissue Segmentation), which extends the unified segmentation approach to tissue classification implemented in Statistical Parametric Mapping (SPM) software to neonates. MANTiS utilizes a combination of unified segmentation, template adaptation via morphological segmentation tools and topological filtering, to segment the neonatal brain into eight tissue classes: cortical gray matter, white matter, deep nuclear gray matter, cerebellum, brainstem, cerebrospinal fluid (CSF), hippocampus and amygdala. We evaluated the performance of MANTiS using two independent datasets. The first dataset, provided by the NeoBrainS12 challenge, consisted of coronal T2-weighted images of preterm infants (born ≤30 weeks’ gestation) acquired at 30 weeks’ corrected gestational age (n= 5), coronal T2-weighted images of preterm infants acquired at 40 weeks’ corrected gestational age (n= 5) and axial T2-weighted images of preterm infants acquired at 40 weeks’ corrected gestational age (n= 5). The second dataset, provided by the Washington University NeuroDevelopmental Research (WUNDeR) group, consisted of T2-weighted images of preterm infants (born <30 weeks’ gestation) acquired shortly after birth (n= 12), preterm infants acquired at term-equivalent age (n= 12), and healthy term-born infants (born ≥38 weeks’ gestation) acquired within the first nine days of life (n= 12). For the NeoBrainS12 dataset, mean Dice scores comparing MANTiS with manual segmentations were all above 0.7, except for the cortical gray matter for coronal images acquired at 30 weeks. This demonstrates that MANTiS’ performance is competitive with existing techniques. For the WUNDeR dataset, mean Dice scores comparing MANTiS with manually edited segmentations demonstrated good agreement, where all scores were above 0.75, except for the hippocampus and amygdala. The results show that MANTiS is able to segment neonatal brain tissues well, even in images that have brain abnormalities common in preterm infants. MANTiS is available for download as an SPM toolbox from http://developmentalimagingmcri.github.io/mantis

Why monitor the neonatal brain-that is the important question

A key goal of neonatal neurocritical care is improved outcomes, and brain monitoring plays an essential role. The recent NEST trial(1) reported no outcome benefits using aEEG monitoring compared to clinical seizure identification among neonates treated for seizures. However, the study failed to prove the effects of monitoring on seizure treatment in the first place.Non peer reviewe