Early motor outcomes in infants with critical congenital heart disease are related to neonatal brain development and brain injury.

AIM: To assess the relationship between neonatal brain development and injury with early motor outcomes in infants with critical congenital heart disease (CCHD). METHOD: Neonatal brain magnetic resonance imaging was performed after open-heart surgery with cardiopulmonary bypass. Cortical grey matter (CGM), unmyelinated white matter, and cerebellar volumes, as well as white matter motor tract fractional anisotropy and mean diffusivity were assessed. White matter injury (WMI) and arterial ischaemic stroke (AIS) with corticospinal tract (CST) involvement were scored. Associations with motor outcomes at 3, 9, and 18 months were corrected for repeated cardiac surgery. RESULTS: Fifty-one infants (31 males, 20 females) were included prospectively. Median age at neonatal surgery and postoperative brain magnetic resonance imaging was 7 days (interquartile range [IQR] 5-11d) and 15 days (IQR 12-21d) respectively. Smaller CGM and cerebellar volumes were associated with lower fine motor scores at 9 months (CGM regression coefficient=0.51, 95% confidence interval [CI]=0.15-0.86; cerebellum regression coefficient=3.08, 95% CI=1.07-5.09) and 18 months (cerebellum regression coefficient=2.08, 95% CI=0.47-5.12). The fractional anisotropy and mean diffusivity of white matter motor tracts were not related with motor scores. WMI was related to lower gross motor scores at 9 months (mean difference -0.8SD, 95% CI=-1.5 to -0.2). AIS with CST involvement increased the risk of gross motor problems and muscle tone abnormalities. Cerebral palsy (n=3) was preceded by severe ischaemic brain injury. INTERPRETATION: Neonatal brain development and injury are associated with fewer favourable early motor outcomes in infants with CCHD.

Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5'UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH2-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH2-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings-and the lack of correlations with FXTAS diagnosis/stages-may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.

Wiring and plumbing: Oligodendrocyte precursors and angiogenesis in the oligovascular niche.

For efficient stroke recovery, the entire neurovascular unit must be repaired. A recent study underscores this concept by highlighting the importance of cellular crosstalk for white mater remodeling. In developing brains and in brains injured by hypoxia, interactions between oligodendrocyte precursors and endothelium play an essential role for physiological and compensatory angiogenesis. Further studies are warranted to build on these emerging findings in the oligovascular niche in order to identify novel therapeutic targets for stroke and other CNS diseases.

Preliminary evaluation of pre-speech and neurodevelopmental measures in 7-11-week-old infants with isolated oral clefts.

BACKGROUND: The purpose of this research study was to evaluate the earliest markers of vocal functioning and neurological development in infants with isolated oral cleft of the lip and/or palate (iCL/P). METHODS: Participants were recruited through advertisements and clinic visits at a local mid-western university. A total of eight participants (four unaffected and four with iCL/P), ranging in age from 7.29 to 11.57 weeks, were enrolled and completed demographic and pre-speech measures. A subset of six males (four unaffected and two with iCL/P) successfully completed a structural magnetic resonance imaging scan. RESULTS: Patterns of disrupted vocal control and reduced myelinated white matter were found in participants with iCL/P. CONCLUSIONS: The findings of this study provide a foundation from which to build further research on the neuronal development of infants with oral clefts: the need to evaluate measures of cortical development, inclusion of information on anesthesia exposure and airway obstruction, and suggestions for avoiding identified pitfalls/blocks to obtaining data are discussed. IMPACT: Research in children with isolated oral clefts has demonstrated higher rates of learning disorders connected to subtle differences in brain structure. There is no work evaluating the potential impact of exposure to anesthesia on development. This is the first known attempt to evaluate brain structure and function in infants with isolated oral clefts before exposure to anesthesia. Potential trends of early vocal issues and structural brain differences (less myelinated white matter) were identified in infants with isolated oral clefts compared to unaffected controls. Differences in brain structure and function in infants with isolated oral clefts may be present before surgery.

Surgery requiring general anesthesia in preterm infants is associated with altered brain volumes at term equivalent age and neurodevelopmental impairment.

BACKGROUND: The aim of the study was to describe and contrast the brain development and outcome among very preterm infants that were and were not exposed to surgery requiring general anesthesia prior to term equivalent age (TEA). METHODS: Preterm infants born ≤30 weeks' gestation who did (n = 25) and did not (n = 59) have surgery requiring general anesthesia during the preterm period were studied. At TEA, infants had MRI scans performed with measures of brain tissue volumes, cortical surface area, Gyrification Index, and white matter microstructure. Neurodevelopmental follow-up with the Bayley Scales of Infant and Toddler Development, Third Edition was undertaken at 2 years of corrected age. Multivariate models, adjusted for clinical and social risk factors, were used to compare the groups. RESULTS: After controlling for clinical and social variables, preterm infants exposed to surgical anesthesia demonstrated decreased relative white matter volumes at TEA and lower cognitive and motor composite scores at 2-year follow-up. Those with longer surgical exposure demonstrated the greatest decrease in white matter volumes and lower cognitive and motor outcomes at age 2 years. CONCLUSIONS: Very preterm infants who required surgery during the preterm period had lower white mater volumes at TEA and worse neurodevelopmental outcome at age 2 years. IMPACT: In very preterm infants, there is an association between surgery requiring general anesthesia during the preterm period and reduced white mater volume on MRI at TEA and lower cognitive and motor composite scores at age 2 years. It is known that the very preterm infant's brain undergoes rapid growth during the period corresponding to the third trimester. The current study suggests an association between surgery requiring general anesthesia during this period and worse outcomes.

Neuroactive Peptide Nanofibers for Regeneration of Spinal Cord after Injury.

The highly complex nature of spinal cord injuries (SCIs) requires design of novel biomaterials that can stimulate cellular regeneration and functional recovery. Promising SCI treatments use biomaterial scaffolds, which provide bioactive cues to the cells in order to trigger neural regeneration in the spinal cord. In this work, the use of peptide nanofibers is demonstrated, presenting protein binding and cellular adhesion epitopes in a rat model of SCI. The self-assembling peptide molecules are designed to form nanofibers, which display heparan sulfate mimetic and laminin mimetic epitopes to the cells in the spinal cord. These neuroactive nanofibers are found to support adhesion and viability of dorsal root ganglion neurons as well as neurite outgrowth in vitro and enhance tissue integrity after 6 weeks of injury in vivo. Treatment with the peptide nanofiber scaffolds also show significant behavioral improvement. These results demonstrate that it is possible to facilitate regeneration especially in the white matter of the spinal cord, which is usually damaged during the accidents using bioactive 3D nanostructures displaying high densities of laminin and heparan sulfate-mimetic epitopes on their surfaces.

Mechanical Ventilation Duration, Brainstem Development, and Neurodevelopment in Children Born Preterm: A Prospective Cohort Study.

OBJECTIVES: To determine, in children born preterm, the association of mechanical ventilation duration with brainstem development, white matter maturation, and neurodevelopmental outcomes at preschool age. STUDY DESIGN: This prospective cohort study included 144 neonates born at <30 weeks of gestation (75 male, mean gestational age 27.1 weeks, SD 1.6) with regional brainstem volumes automatically segmented on magnetic resonance imaging at term-equivalent age (TEA). The white matter maturation was assessed by diffusion tensor imaging and tract-based spatial statistics. Neurodevelopmental outcomes were assessed at 4.5 years of age using the Movement Assessment Battery for Children, 2nd Edition, and the Wechsler Primary and Preschool Scale of Intelligence, 4th Edition, full-scale IQ. The association between the duration of mechanical ventilation and brainstem development was validated in an independent cohort of children born very preterm. RESULTS: Each additional day of mechanical ventilation predicted lower motor scores (0.5-point decrease in the Movement Assessment Battery for Children, 2nd Edition, score by day of mechanical ventilation, 95% CI -0.6 to -0.3, P < .0001). Prolonged exposure to mechanical ventilation was associated with smaller pons and medulla volumes at TEA in 2 independent cohorts, along with widespread abnormalities in white matter maturation. Pons and medulla volumes at TEA predicted motor outcomes at 4.5 years of age. CONCLUSIONS: In neonates born very preterm, prolonged mechanical ventilation is associated with impaired brainstem development, abnormal white matter maturation, and lower motor scores at preschool age. Further research is needed to better understand the neural pathological mechanisms involved.

Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is prevalent in tuberous sclerosis complex (TSC), occurring in approximately 50% of patients, and is hypothesized to be caused by disruption of neural circuits early in life. Tubers, or benign hamartomas distributed stochastically throughout the brain, are the most conspicuous of TSC neuropathology, but have not been consistently associated with ASD. Widespread neuropathology of the white matter, including deficits in myelination, neuronal migration, and axon formation, exist and may underlie ASD in TSC. We sought to identify the neural circuits associated with ASD in TSC by identifying white matter microstructural deficits in a prospectively recruited, longitudinally studied cohort of TSC infants. METHODS: TSC infants were recruited within their first year of life and longitudinally imaged at time of recruitment, 12 months of age, and at 24 months of age. Autism was diagnosed at 24 months of age with the ADOS-2. There were 108 subjects (62 TSC-ASD, 55% male; 46 TSC+ASD, 52% male) with at least one MRI and a 24-month ADOS, for a total of 187 MRI scans analyzed (109 TSC-ASD; 78 TSC+ASD). Diffusion tensor imaging properties of multiple white matter fiber bundles were sampled using a region of interest approach. Linear mixed effects modeling was performed to test the hypothesis that infants who develop ASD exhibit poor white matter microstructural integrity over the first 2 years of life compared to those who do not develop ASD. RESULTS: Subjects with TSC and ASD exhibited reduced fractional anisotropy in 9 of 17 white matter regions, sampled from the arcuate fasciculus, cingulum, corpus callosum, anterior limbs of the internal capsule, and the sagittal stratum, over the first 2 years of life compared to TSC subjects without ASD. Mean diffusivity trajectories did not differ between groups. CONCLUSIONS: Underconnectivity across multiple white matter fiber bundles develops over the first 2 years of life in subjects with TSC and ASD. Future studies examining brain-behavior relationships are needed to determine how variation in the brain structure is associated with ASD symptoms.

Pten haploinsufficiency disrupts scaling across brain areas during development in mice.

Haploinsufficiency for PTEN is a cause of autism spectrum disorder and brain overgrowth; however, it is not known if PTEN mutations disrupt scaling across brain areas during development. To address this question, we used magnetic resonance imaging to analyze brains of male Pten haploinsufficient (Pten+/-) mice and wild-type littermates during early postnatal development and adulthood. Adult Pten+/- mice display a consistent pattern of abnormal scaling across brain areas, with white matter (WM) areas being particularly affected. This regional and WM enlargement recapitulates structural abnormalities found in individuals with PTEN haploinsufficiency and autism. Early postnatal Pten+/- mice do not display the same pattern, instead exhibiting greater variability across mice and brain regions than controls. This suggests that Pten haploinsufficiency may desynchronize growth across brain regions during early development before stabilizing by maturity. Pten+/- cortical cultures display increased proliferation of glial cell populations, indicating a potential substrate of WM enlargement, and provide a platform for testing candidate therapeutics. Pten haploinsufficiency dysregulates coordinated growth across brain regions during development. This results in abnormally scaled brain areas and associated behavioral deficits, potentially explaining the relationship between PTEN mutations and neurodevelopmental disorders.

Effects of hypogonadism on brain development during adolescence in girls with Turner syndrome.

Gonadal steroids play an important role in brain development, particularly during puberty. Girls with Turner syndrome (TS), a genetic disorder characterized by the absence of all or part of the second X chromosome, mostly present a loss of ovarian function and estrogen deficiency, as well as neuroanatomical abnormalities. However, few studies have attempted to isolate the indirect effects of hormones from the direct genetic effects of X chromosome insufficiency. Brain structural (i.e., gray matter [GM] morphology and white matter [WM] connectivity) and functional phenotypes (i.e., resting-state functional measures) were investigated in 23 adolescent girls with TS using multimodal MRI to assess the role of hypogonadism in brain development in TS. Specifically, all girls with TS were divided into a hormonally subnormal group and an abnormal subgroup according to their serum follicle-stimulating hormone (FSH) levels, with the karyotypes approximately matched between the two groups. Statistical analyses revealed significant effects of the "group-by-age" interaction on GM volume around the left medial orbitofrontal cortex and WM diffusion parameters around the bilateral corticospinal tract, anterior thalamic radiation, left superior longitudinal fasciculus, and cingulum bundle, but no significant "group-by-age" or group differences were observed in resting-state functional measures. Based on these findings, estrogen deficiency has a nontrivial impact on the development of the brain structure during adolescence in girls with TS. Our present study provides novel insights into the mechanism by which hypogonadism influences brain development during adolescence in girls with TS, and highlights the important role of estrogen replacement therapy in treating TS.

Predicting developmental outcomes in preterm infants: A simple white matter injury imaging rule.

OBJECTIVE: To develop a simple imaging rule to predict neurodevelopmental outcomes at 4.5 years in a cohort of preterm neonates with white matter injury (WMI) based on lesion location and examine whether clinical variables enhance prediction. METHODS: Sixty-eight preterm neonates born 24-32 weeks' gestation (median 27.7 weeks) were diagnosed with WMI on early brain MRI scans (median 32.3 weeks). 3D T1-weighted images of 60 neonates with 4.5-year outcomes were reformatted and aligned to the posterior commissure-eye plane and WMI was classified by location: anterior or posterior-only to the midventricle line on the reformatted axial plane. Adverse outcomes at 4.5 years were defined as Wechsler Preschool and Primary Scale of Intelligence full-scale IQ <85, cerebral palsy, or Movement Assessment Battery for Children, second edition percentile <5. The prediction of adverse outcome by WMI location, intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP) was assessed using multivariable logistic regression. RESULTS: Six children had adverse cognitive outcomes and 17 had adverse motor outcomes. WMI location predicted cognitive outcomes in 90% (area under receiver operating characteristic curve [AUC] 0.80) and motor outcomes in 85% (AUC 0.75). Adding IVH, BPD, and ROP to the model enhances the predictive strength for cognitive and motor outcomes (AUC 0.83 and 0.88, respectively). Rule performance was confirmed in an independent cohort of children with WMI. CONCLUSIONS: WMI on early MRI can be classified by location to predict preschool age outcomes in children born preterm. The predictive value of this WMI classification is enhanced by considering clinical factors apparent by term-equivalent age.

Neurodevelopmental Outcomes in Preterm Infants with White Matter Injury Using a New MRI Classification.

OBJECTIVE: The aim of this study was to evaluate whether a new MRI scoring system for preterm non-haemorrhagic white matter injury (WMI), derived from the analysis of the natural evolution of WMI throughout the neonatal period until term-equivalent age, can be used for outcome prediction. METHODS: Eighty-two infants <36 weeks gestation with WMI diagnosed from sequential cranial ultrasound and confirmed on neonatal MRI were retrospectively included. WMI was classified in four grades of severity. Neurodevelopmental data at a median age of 24 months were analysed. RESULTS: In 74 surviving children WMI severity was strongly associated with the presence and severity of cerebral palsy (CP) and other neurodevelopmental impairments (Spearman's rank correlation 0.88, p < 0.001). Only 3 children with grade I WMI (9%) developed CP (all ambulant) and their developmental scores were not different to those from the controls, although they started walking significantly later (p = 0.036). Of the 6 children with grade II, 83% developed CP (mild in most), whereas 91% of the 34 children with grade III had CP (moderate-severe in 76%) and all had some degree of neurodevelopmental impairment. Three children with grade III WMI did not develop CP; their imaging showed, in contrast to children who developed CP, that the cysts did not affect the corticospinal tracts; also, myelin in the posterior limb of the internal capsule appeared normal in 2 children and suboptimal in 1. CONCLUSIONS: This MRI scoring system for preterm WMI can be used to predict neurodevelopmental outcomes. Individualized assessment of the site of lesions and the progression of myelination improves prognostic accuracy.

Hypoxic preconditioning improves long-term functional outcomes after neonatal hypoxia-ischemic injury by restoring white matter integrity and brain development.

AIMS: Neonatal hypoxia-ischemia (H/I) results in gray and white matter injury, characterized by neuronal loss, failure of neural network formation, retarded myelin formation, and abnormal accumulation of oligodendrocyte progenitor cells (OPCs). These changes lead to severe neurological deficits and mortality. Sublethal hypoxic preconditioning (HPC) can protect the developing brain against H/I. However, limited evidence is available concerning its effect on white matter injury. METHODS: In this study, P6 neonatal Sprague-Dawley rats were subjected to normoxic (21% O2 ) or HPC (7.8% O2 ) for 3 hours followed 24 hours later by H/I brain injury. Neurological deficits were assessed by gait, righting reflex, foot fault, and Morris water maze tests. Compound action potential of the corpus callosum was recorded 35 days after surgery, and the correlation between axon myelination and neurological function was determined. RESULTS: Hypoxic preconditioning significantly attenuated H/I brain injury at 7 days and remarkably improved both sensorimotor and cognitive functional performances up to 35 days after H/I. HPC-afforded improvement in long-term neurological outcomes was attributable, at least in part, to restoration of the differentiation and maturation capacity in oligodendrocyte progenitor cells, amelioration of microglia/macrophage activation and neuroinflammation, and continuation of brain development after H/I. CONCLUSIONS: Hypoxic preconditioning restores white matter repair, development, and functional integrity in developing brain after H/I brain injury.

Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life.

Maternal inflammation during pregnancy can alter the trajectory of fetal brain development and increase risk for offspring psychiatric disorders. However, the majority of relevant research to date has been conducted in animal models. Here, in humans, we focus on the structural connectivity of frontolimbic circuitry as it is both critical for socioemotional and cognitive development, and commonly altered in a range of psychiatric disorders associated with intrauterine inflammation. Specifically, we test the hypothesis that elevated maternal concentration of the proinflammatory cytokine interleukin-6 (IL-6) during pregnancy will be associated with variation in microstructural properties of this circuitry in the neonatal period and across the first year of life. Pregnant mothers were recruited in early pregnancy and maternal blood samples were obtained for assessment of maternal IL-6 concentrations in early (12.6 ±â€¯2.8 weeks [S.D.]), mid (20.4 ±â€¯1.5 weeks [S.D.]) and late (30.3 ±â€¯1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ±â€¯1.7 weeks [S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ±â€¯3.1 weeks [S.D.]). Diffusion Tensor Imaging (DTI) was used to characterize fractional anisotropy (FA) along the left and right uncinate fasciculus (UF), representing the main frontolimbic fiber tract. In N = 30 of the infants with serial MRI data at birth and 12-mo age, cognitive and socioemotional developmental status was characterized using the Bayley Scales of Infant Development. All analyses tested for potentially confounding influences of household income, prepregnancy Body-Mass-Index, obstetric risk, smoking during pregnancy, and infant sex, and outcomes at 12-mo age were additionally adjusted for the quality of the postnatal caregiving environment. Maternal IL-6 concentration (averaged across pregnancy) was prospectively and inversely associated with FA (suggestive of reduced integrity under high inflammatory conditions) in the newborn offspring (bi-lateral, p < 0.01) in the central portion of the UF proximal to the amygdala. Furthermore, maternal IL-6 concentration was positively associated with rate of FA increase across the first year of life (bi-lateral, p < 0.05), resulting in a null association between maternal IL-6 and UF FA at 12-mo age. Maternal IL-6 was also inversely associated with offspring cognition at 12-mo age, and this association was mediated by FA growth across the first year of postnatal life. Findings from the current study support the premise that susceptibility for cognitive impairment and potentially psychiatric disorders may be affected in utero, and that maternal inflammation may constitute an intrauterine condition of particular importance in this context.

Early breast milk exposure modifies brain connectivity in preterm infants.

Preterm infants are at increased risk of alterations in brain structure and connectivity, and subsequent neurocognitive impairment. Breast milk may be more advantageous than formula feed for promoting brain development in infants born at term, but uncertainties remain about its effect on preterm brain development and the optimal nutritional regimen for preterm infants. We test the hypothesis that breast milk exposure is associated with improved markers of brain development and connectivity in preterm infants at term equivalent age. We collected information about neonatal breast milk exposure and brain MRI at term equivalent age from 47 preterm infants (mean postmenstrual age [PMA] 29.43 weeks, range 23.28-33.0). Network-Based Statistics (NBS), Tract-based Spatial Statistics (TBSS) and volumetric analysis were used to investigate the effect of breast milk exposure on white matter water diffusion parameters, tissue volumes, and the structural connectome. Twenty-seven infants received exclusive breast milk feeds for ≥75% of days of in-patient care and this was associated with higher connectivity in the fractional anisotropy (FA)-weighted connectome compared with the group who had < 75% of days receiving exclusive breast milk feeds (NBS, p = 0.04). Within the TBSS white matter skeleton, the group that received ≥75% exclusive breast milk days exhibited higher FA within the corpus callosum, cingulum cingulate gyri, centrum semiovale, corticospinal tracts, arcuate fasciculi and posterior limbs of the internal capsule compared with the low exposure group after adjustment for PMA at birth, PMA at image acquisition, bronchopulmonary dysplasia, and chorioamnionitis (p < 0.05). The effect on structural connectivity and tract water diffusion parameters was greater with ≥90% exposure, suggesting a dose effect. There were no significant groupwise differences in brain volumes. Breast milk feeding in the weeks after preterm birth is associated with improved structural connectivity of developing networks and greater FA in major white matter fasciculi.

Altered white matter structure in the visual system following early monocular enucleation.

Partial visual deprivation from early monocular enucleation (the surgical removal of one eye within the first few years of life) results in a number of long-term morphological adaptations in adult cortical and subcortical visual, auditory, and multisensory brain regions. In this study, we investigated whether early monocular enucleation also results in the altered development of white matter structure. Diffusion tensor imaging and probabilistic tractography were performed to assess potential differences in visual system white matter in adult participants who had undergone early monocular enucleation compared to binocularly intact controls. To examine the microstructural properties of these tracts, mean diffusion parameters including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were extracted bilaterally. Asymmetries opposite to those observed in controls were found for FA, MD, and RD in the optic radiations, the projections from primary visual cortex (V1) to the lateral geniculate nucleus (LGN), and the interhemispheric V1 projections of early monocular enucleation participants. Early monocular enucleation was also associated with significantly lower FA bidirectionally in the interhemispheric V1 projections. These differences were consistently greater for the tracts contralateral to the enucleated eye, and are consistent with the asymmetric LGN volumes and optic tract diameters previously demonstrated in this group of participants. Overall, these results indicate that early monocular enucleation has long-term effects on white matter structure in the visual pathway that results in reduced fiber organization in tracts contralateral to the enucleated eye. Hum Brain Mapp 39:133-144, 2018. © 2017 Wiley Periodicals, Inc.

Cannabis and alcohol use, and the developing brain.

Sex hormones and white (and grey) matter in the limbic system, cortex and other brain regions undergo changes during adolescence. Some of these changes include ongoing white matter myelination and sexually dimorphic features in grey and white matter. Adolescence is also a period of vulnerability when many are first exposed to alcohol and cannabis, which appear to influence the developing brain. Neuropsychological studies have provided considerable understanding of the effects of alcohol and cannabis on the brain. Advances in neuroimaging have allowed examination of neuroanatomic changes, metabolic and neurotransmitter activity, and neuronal activation during adolescent brain development and substance use. In this review, we examine major differences in brain development between users and non-users, and recent findings on the influence of cannabis and alcohol on the adolescent brain. We also discuss associations that appear to resolve following short-term abstinence, and attentional deficits that appear to persist. These findings can be useful in guiding earlier educational interventions for adolescents, and clarifying the neural sequelae of early alcohol and cannabis use to the general public.

White Matter Volume Predicts Language Development in Congenital Heart Disease.

OBJECTIVE: To determine whether brain volume is reduced at 1 year of age and whether these volumes are associated with neurodevelopment in biventricular congenital heart disease (CHD) repaired in infancy. STUDY DESIGN: Infants with biventricular CHD (n = 48) underwent brain magnetic resonance imaging (MRI) and neurodevelopmental testing with the Bayley Scales of Infant Development-II and the MacArthur-Bates Communicative Development Inventories at 1 year of age. A multitemplate based probabilistic segmentation algorithm was applied to volumetric MRI data. We compared volumes with those of 13 healthy control infants of comparable ages. In the group with CHD, we measured Spearman correlations between neurodevelopmental outcomes and the residuals from linear regression of the volumes on corrected chronological age at MRI and sex. RESULTS: Compared with controls, infants with CHD had reductions of 54 mL in total brain (P = .009), 40 mL in cerebral white matter (P <.001), and 1.2 mL in brainstem (P = .003) volumes. Within the group with CHD, brain volumes were not correlated with Bayley Scales of Infant Development-II scores but did correlate positively with MacArthur-Bates Communicative Development Inventory language development. CONCLUSIONS: Infants with biventricular CHD show total brain volume reductions at 1 year of age, driven by differences in cerebral white matter. White matter volume correlates with language development, but not broader developmental indices. These findings suggest that abnormalities in white matter development detected months after corrective heart surgery may contribute to language impairment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00006183.

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants.

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units-alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise.

White matter development and tobacco smoking in young adults: A systematic review with recommendations for future research.

BACKGROUND: Adolescence and young adulthood are critical vulnerability periods for initiation of tobacco smoking. White matter development is ongoing during this time and may be influenced by exposure to nicotine. Synthesis of findings from diffusion tensor imaging (DTI) studies of adolescent and young adult smokers may be helpful in understanding the relationship between neurodevelopment and initiation and progression of tobacco-use behaviors and in guiding further research. METHODS: A systematic literature review was conducted to identify DTI studies comparing adolescent and young adult (mean age <30 years) smokers versus nonsmokers. A total of 5 studies meeting inclusion criteria were identified. Primary study findings are reviewed and discussed within the context of neurodevelopment and in relation to findings from adult studies. Directions for further research are also discussed. RESULTS: All identified studies reported increases in fractional anisotropy (FA) among adolescent/young adult smokers in comparison to non-smokers. Increased FA was most frequently reported in regions of the corpus callosum (genu, body and spenium), internal capsule and superior longitudinal fasciculus. CONCLUSIONS: Findings of increased FA among adolescent/young adult smokers are contrary to those from most adult studies and thus raise the possibility of differential effects of nicotine on white matter across the lifespan. Further research including multiple time points is needed to test this hypothesis. Other areas warranting further research include DTI studies of e-cigarette use and studies incorporating measures of pubertal stage.