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•We constructed a brain age model in childhood and adolescence.•Very preterm children had a higher brain age delta than controls, but this difference was small-moderate and non-significant.•Brain age delta was not related to perinatal risk factors or neurodevelopmental outcomes.•Similar brain features contributed to age predictions across very preterm and control groups. Very preterm (VP) birth is associated with an increased risk for later neurodevelopmental and behavioural challenges. Although the neurobiological underpinnings of such challenges continue to be explored, previous studies have reported brain volume and morphology alterations in children and adolescents born VP compared with full-term (FT)-born controls. How these alterations relate to the trajectory of brain maturation, with potential implications for later brain ageing, remains unclear. In this longitudinal study, we investigate the relationship between VP birth and brain development during childhood and adolescence. We construct a normative ‘brain age’ model to predict age over childhood and adolescence based on measures of brain cortical and subcortical volumes and cortical morphology from structural MRI of a dataset of typically developing children aged 3–21 years (n = 768). Using this model, we examined deviations from normative brain development in a separate dataset of children and adolescents born VP (<30 weeks’ gestation) at two timepoints (ages 7 and 13 years) compared with FT-born controls (120 VP and 29 FT children at age 7 years; 140 VP and 47 FT children at age 13 years). Brain age delta (brain-predicted age minus chronological age) was, on average, higher in the VP group at both timepoints compared with controls, however this difference had a small to medium effect size and was not statistically significant. Variance in brain age delta was higher in the VP group compared with controls; this difference was significant at the 13-year timepoint. Within the VP group, there was little evidence of associations between brain age delta and perinatal risk factors or cognitive and motor outcomes. Under the brain age framework, our results may suggest that children and adolescents born VP have similar brain structural developmental trajectories to term-born peers between 7 and 13 years of age.

Serial regional brain growth from the newborn period to adolescence has not been described. Here, we measured regional brain growth in 216 very preterm (VP) and 45 full-term (FT) children. Brain MRI was performed at term-equivalent age, 7 and 13 years in 82 regions. Brain volumes increased between term-equivalent and 7 years, with faster growth in the FT than VP group. Perinatal brain abnormality was associated with less increase in brain volume between term-equivalent and 7 years in the VP group. Between 7 and 13 years, volumes were relatively stable, with some subcortical and cortical regions increasing while others reduced. Notably, VP infants continued to lag, with overall brain size generally less than that of FT peers at 13 years. Parieto–frontal growth, mainly between 7 and 13 years in FT children, was associated with higher intelligence at 13 years. This study improves understanding of typical and atypical regional brain growth. In this longitudinal study, the authors tracked the course of brain development from birth to adolescence (age 13 years) and examined the effects of very preterm birth. Very preterm children showed slower brain growth from age 0 (term equivalent) to age 7.

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' 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' 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.

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24–34 weeks’ gestation. Ninety-nine mothers and their eligible fetuses ( n  = 103) were recruited from Brigham and Women’s Hospital and randomly assigned to 8 oz pomegranate ( n  = 56) or placebo ( n  = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants ( n  = 26 pomegranate, n  = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation. Clinical trial registration: NCT04394910, https://clinicaltrials.gov/ct2/show/NCT04394910 , Registered May 20, 2020, initial participant enrollment January 16, 2016.

Our recently published M-CRIB atlas comprises 100 neonatal brain regions including 68 compatible with the widely-used Desikan-Killiany adult cortical atlas. A successor to the Desikan-Killiany atlas is the Desikan-Killiany-Tourville atlas, in which some regions with unclear boundaries were removed, and many existing boundaries were revised to conform to clearer landmarks in sulcal fundi. Our first aim here was to modify cortical M-CRIB regions to comply with the Desikan-Killiany-Tourville protocol, in order to offer: (a) compatibility with this adult cortical atlas, (b) greater labeling accuracy due to clearer landmarks, and (c) optimisation of cortical regions for integration with surface-based infant parcellation pipelines. Secondly, we aimed to update subcortical regions in order to offer greater compatibility with subcortical segmentations produced in FreeSurfer. Data utilized were the T2-weighted MRI scans in our M-CRIB atlas, for 10 healthy neonates (post-menstrual age at MRI 40-43 weeks, four female), and corresponding parcellated images. Edits were performed on the parcellated images in volume space using ITK-SNAP. Cortical updates included deletion of frontal and temporal poles and 'Banks STS,' and modification of boundaries of many other regions. Changes to subcortical regions included the addition of 'ventral diencephalon,' and deletion of 'subcortical matter' labels. A detailed updated parcellation protocol was produced. The resulting whole-brain M-CRIB 2.0 atlas comprises 94 regions altogether. This atlas provides comparability with adult Desikan-Killiany-Tourville-labeled cortical data and FreeSurfer-labeed subcortical data, and is more readily adaptable for incorporation into surface-based neonatal parcellation pipelines. As such, it offers the ability to help facilitate a broad range of investigations into brain structure and function both at the neonatal time point and developmentally across the lifespan.

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 T 2-weighted images of preterm infants (born ≤30 weeks' gestation) acquired at 30 weeks' corrected gestational age (n = 5), coronal T 2-weighted images of preterm infants acquired at 40 weeks' corrected gestational age (n = 5) and axial T 2-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 T 2-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 9 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.

Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello‐thalamo‐cortical and basal ganglia‐thalamo‐cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T‐type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T‐type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T‐type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond.

Point-of-care human milk analysis is now feasible in the neonatal intensive care unit (NICU) and allows accurate measurement of macronutrient delivery. Higher macronutrient intakes over this period may promote brain growth and development. In a prospective, observational study of 55 infants born at <32 weeks’ gestation, we used a mid-infrared spectroscopy-based human milk analyzer to measure the macronutrient content in repeated samples of human milk over the NICU hospitalization. We calculated daily nutrient intakes from unfortified milk and assigned infants to quintiles based on median intakes over the hospitalization. Infants underwent brain magnetic resonance imaging at term equivalent age to quantify total and regional brain volumes and fractional anisotropy of white matter tracts. Infants in the highest quintile of energy intake from milk, as compared with the lower four quintiles, had larger total brain volume (31 cc, 95% confidence interval [CI]: 5, 56), cortical gray matter (15 cc, 95%CI: 1, 30), and white matter volume (23 cc, 95%CI: 12, 33). Higher protein intake was associated with larger total brain (36 cc, 95%CI: 7, 65), cortical gray matter (22 cc, 95%CI: 6, 38) and deep gray matter (1 cc, 95%CI: 0.1, 3) volumes. These findings suggest innovative strategies to close nutrient delivery gaps in the NICU may promote brain growth for preterm infants.

It is well established that preterm infants have altered brain development compared with full-term (FT; ≥37 weeks' gestational age [GA]) infants, however the perinatal factors associated with brain development in preterm infants have not been fully elucidated. In particular, perinatal predictors of brain development may differ between very preterm infants (VP; <32 weeks' GA) and infants born moderate (MP; 32–33 weeks' GA) and late (LP; 34–36 weeks' GA) preterm, but this has not been studied. This study aimed to investigate the effects of early life predictors on brain volume and microstructure at term-equivalent age (TEA; 38–44 weeks), and whether these effects differ for GA groups (VP, MP, LP or FT). Structural images from 328 infants (91 VP, 63 MP, 104 LP and 70 FT) were segmented into white matter, cortical grey matter, cerebrospinal fluid, subcortical grey matter, brainstem and cerebellum. Cortical grey matter and white matter images were analysed using voxel-based morphometry. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) images from 361 infants (92 VP, 69 MP, 120 LP and 80 FT) were analysed using Tract-Based Spatial Statistics. Relationships between early life predictors (birthweight standard deviation score [BWSDS], multiple birth, sex, postnatal growth and social risk) and global brain volumes were analysed using linear regressions. Relationships between early life predictors and regional brain volumes and diffusion measures were analysed using voxelwise non-parametric permutation testing. Male sex was associated with higher global volumes of all tissues and higher regional volumes throughout much of the cortical grey matter and white matter, particularly in the FT group. Male sex was also associated with lower FA and higher AD, RD and MD in the optic radiation, external and internal capsules and corona radiata, and these associations were generally similar between GA groups. Higher BWSDS was associated with higher global volumes of all tissues and higher regional volumes in much of the cortical grey matter and white matter in all GA groups, as well as higher FA and lower RD and MD in many major tracts (corpus callosum, optic radiation, internal and external capsules and corona radiata), particularly in the MP and LP groups. Multiple birth and social risk also showed associations with global and regional volumes and regional diffusion values which varied by GA group, but these associations were not independent of the other early life predictors. Postnatal growth was not associated with brain volumes or diffusion values. Early life predictors of brain volumes and microstructure at TEA include sex, BWSDS, multiple birth and social risk, which have different effects based on GA group at birth. This study improves knowledge of the perinatal factors associated with brain abnormalities in infants born across the prematurity spectrum. •Early life factors affect regional brain volume and microstructural development.•Effects of early life factors on brain development differ by gestational age.•Males have higher brain volumes but less organised microstructure than females.•Poor prenatal growth is associated with lower volume and less mature white matter.•Multiple birth and social risk may also affect brain development.

ObjectiveTo determine associations between body composition and concurrent measures of brain development including (1) Tissue-specific brain volumes and (2) White matter microstructure, among very preterm infants at term equivalent age.DesignProspective observational study.SettingSingle-centre academic level III neonatal intensive care unit.PatientsWe studied 85 infants born <33 weeks’ gestation.MethodsAt term equivalent age, infants underwent air displacement plethysmography to determine body composition, and brain MRI from which we quantified tissue-specific brain volumes and fractional anisotropy (FA) of white matter tracts. We estimated associations of fat and lean mass Z-scores with each brain outcome, using linear mixed models adjusted for intrafamilial correlation among twins and potential confounding variables.ResultsMedian gestational age was 29 weeks (range 23.4–32.9). One unit greater lean mass Z-score was associated with larger total brain volume (10.5 cc, 95% CI 3.8 to 17.2); larger volumes of the cerebellum (1.2 cc, 95% CI 0.5 to 1.9) and white matter (4.5 cc, 95% CI 0.7 to 8.3); and greater FA in the left cingulum (0.3%, 95% CI 0.1% to 0.6%), right uncinate fasciculus (0.2%, 95% CI 0.0% to 0.5%), and right posterior limb of the internal capsule (0.3%, 95% CI 0.03% to 0.6%). Fat Z-scores were not associated with any outcome.ConclusionsLean mass—but not fat—at term was associated with larger brain volume and white matter microstructure differences that suggest improved maturation. Lean mass accrual may index brain growth and development.