Catherine Lebel

Microstructural maturation of the human brain from childhood to adulthood.

Brain maturation is a complex process that continues well beyond infancy, and adolescence is thought to be a key period of brain rewiring. To assess structural brain maturation from childhood to adulthood, we charted brain development in subjects aged 5 to 30 years using diffusion tensor magnetic resonance imaging, a novel brain imaging technique that is sensitive to axonal packing and myelination and is particularly adept at virtually extracting white matter connections. Age-related changes were seen in major white matter tracts, deep gray matter, and subcortical white matter, in our large (n=202), age-distributed sample. These diffusion changes followed an exponential pattern of maturation with considerable regional variation. Differences observed in developmental timing suggest a pattern of maturation in which areas with fronto-temporal connections develop more slowly than other regions. These in vivo results expand upon previous postmortem and imaging studies and provide quantitative measures indicative of the progression and magnitude of regional human brain maturation.

Longitudinal Development of Human Brain Wiring Continues from Childhood into Adulthood

Healthy human brain development is a complex process that continues during childhood and adolescence, as demonstrated by many cross-sectional and several longitudinal studies. However, whether these changes end in adolescence is not clear. We examined longitudinal white matter maturation using diffusion tensor tractography in 103 healthy subjects aged 5–32 years; each volunteer was scanned at least twice, with 221 total scans. Fractional anisotropy (FA) and mean diffusivity (MD), parameters indicative of factors including myelination and axon density, were assessed in 10 major white matter tracts. All tracts showed significant nonlinear development trajectories for FA and MD. Significant within-subject changes occurred in the vast majority of children and early adolescents, and these changes were mostly complete by late adolescence for projection and commissural tracts. However, association tracts demonstrated postadolescent within-subject maturation of both FA and MD. Diffusion parameter changes were due primarily to decreasing perpendicular diffusivity, although increasing parallel diffusivity contributed to the prolonged increases of FA in association tracts. Volume increased significantly with age for most tracts, and longitudinal measures also demonstrated postadolescent volume increases in several association tracts. As volume increases were not directly associated with either elevated FA or reduced MD between scans, the observed diffusion parameter changes likely reflect microstructural maturation of brain white matter tracts rather than just gross anatomy.

Diffusion tensor imaging of white matter tract evolution over the lifespan.

Diffusion tensor imaging (DTI) has been used widely to show structural brain changes during both development and aging. Lifespan studies are valuable because they connect these two processes, yet few DTI studies have been conducted that include both children and elderly subjects. This study used DTI tractography to investigate 12 major white matter connections in 403 healthy subjects aged 5-83 years. Poisson fits were used to model changes of fractional anisotropy (FA) and mean diffusivity (MD) across the age span, and were highly significant for all tracts. FA increased during childhood and adolescence, reached a peak between 20 and 42 years of age, and then decreased. MD showed an opposite trend, decreasing first, reaching a minimum at 18-41 years, and then increasing later in life. These trajectories demonstrate rates and timing of development and degradation that vary regionally in the brain. The corpus callosum and fornix showed early reversals of development trends, while frontal-temporal connections (cingulum, uncinate, superior longitudinal) showed more prolonged maturation and delayed declines. FA changes were driven by perpendicular diffusivity, suggesting changes of myelination and/or axonal density. Tract volume changed significantly with age for most tracts, but did not greatly influence the FA and MD trajectories. This study demonstrates clear age-related microstructural changes throughout the brain white matter, and provides normative data that will be useful for studying white matter development in a variety of diseases and abnormal conditions.

Lateralization of the arcuate fasciculus from childhood to adulthood and its relation to cognitive abilities in children

The arcuate fasciculus is a major white matter tract involved in language processing that has also been repeatedly implicated in intelligence and reasoning tasks. Language in the human brain is lateralized in terms of both function and structure, and while the arcuate fasciculus reflects this asymmetry, its pattern of lateralization is poorly understood in children and adolescents. We used diffusion tensor imaging (DTI) and tractography to examine arcuate fasciculus lateralization in a large (n = 183) group of healthy right‐handed volunteers aged 5–30 years; a subset of 68 children aged 5–13 years also underwent cognitive assessments. Fractional anisotropy and number of streamlines of the arcuate fasciculus were both significantly higher in the left hemisphere than the right hemisphere in most subjects, although some subjects (10%) were right lateralized. Age and gender effects on lateralization were not significant. Children receiving cognitive assessments were divided into three groups: a “left‐only” group in whom only the left side of the arcuate fasciculus could be tracked, a left‐lateralized group, and a right‐lateralized group. Scores on the Peabody Picture Vocabulary Test (PPVT) and NEPSY Phonological Processing task differed significantly among groups, with left‐only subjects outperforming the right‐lateralized group on the PPVT, and the left‐lateralized children scoring significantly better than the right‐lateralized group on phonological processing. In summary, DTI tractography demonstrates leftward arcuate fasciculus lateralization in children, adolescents, and young adults, and reveals a relationship between structural white matter lateralization and specific cognitive abilities in children. Hum Brain Mapp, 2009.

Imaging the Impact of Prenatal Alcohol Exposure on the Structure of the Developing Human Brain

Prenatal alcohol exposure has numerous effects on the developing brain, including damage to selective brain structure. We review structural magnetic resonance imaging (MRI) studies of brain abnormalities in subjects prenatally exposed to alcohol. The most common findings include reduced brain volume and malformations of the corpus callosum. Advanced methods have been able to detect shape, thickness and displacement changes throughout multiple brain regions. The teratogenic effects of alcohol appear to be widespread, affecting almost the entire brain. The only region that appears to be relatively spared is the occipital lobe. More recent studies have linked cognition to the underlying brain structure in alcohol-exposed subjects, and several report patterns in the severity of brain damage as it relates to facial dysmorphology or to extent of alcohol exposure. Future studies exploring relationships between brain structure, cognitive measures, dysmorphology, age, and other variables will be valuable for further comprehending the vast effects of prenatal alcohol exposure and for evaluating possible interventions.

Brain Diffusion Abnormalities in Children With Fetal Alcohol Spectrum Disorder

BACKGROUND Children with fetal alcohol spectrum disorder (FASD) have a variety of cognitive, behavioral, and neurological impairments, including structural brain damage. Despite the importance of white matter connections for proper brain function, little is known about how these connections, and the deep gray matter structures that act as relay stations, are affected in children with FASD. The purpose of this study was to use diffusion tensor imaging, an advanced magnetic resonance imaging technique, to examine microstructural differences of white and deep gray matter in children with FASD. METHODS Subjects were 24 children aged 5-13 years previously diagnosed with FASD and 95 healthy children over the same age range. Diffusion tractography was used to delineate 10 major white matter tracts in each individual, and region-of-interest analysis was used to assess 4 deep gray matter structures. Fractional anisotropy, an indicator of white matter integrity, and mean diffusivity, a measure of the average water diffusion, were assessed in all 14 brain structures. RESULTS Diffusion tensor imaging revealed significant differences of diffusion parameters in several areas of the brain, including the genu and splenium of the corpus callosum, cingulum, corticospinal tracts, inferior fronto-occipital fasciculus, inferior and superior longitudinal fasciculi, globus pallidus, putamen, and thalamus. Reduced white and gray matter volumes, as well as total brain volume, were observed in the FASD group. CONCLUSIONS These results demonstrate diffusion abnormalities in FASD beyond the corpus callosum and suggest that several specific white matter regions, particularly commissural and temporal connections, and deep gray matter areas of the brain are sensitive to prenatal alcohol exposure.

A longitudinal study of the long-term consequences of drinking during pregnancy: heavy in utero alcohol exposure disrupts the normal processes of brain development

Exposure to alcohol in utero can cause birth defects, including face and brain abnormalities, and is the most common preventable cause of intellectual disabilities. Here we use structural magnetic resonance imaging to measure cortical volume change longitudinally in a cohort of human children and youth with prenatal alcohol exposure (PAE) and a group of unexposed control subjects, demonstrating that the normal processes of brain maturation are disrupted in individuals whose mothers drank heavily during pregnancy. Trajectories of cortical volume change within children and youth with PAE differed from those of unexposed control subjects in posterior brain regions, particularly in the parietal cortex. In these areas, control children appear to show a particularly plastic cortex with a prolonged pattern of cortical volume increases followed by equally vigorous volume loss during adolescence, while the alcohol-exposed participants showed primarily volume loss, demonstrating decreased plasticity. Furthermore, smaller volume changes between scans were associated with lower intelligence and worse facial morphology in both groups, and were related to the amount of PAE during each trimester of pregnancy in the exposed group. This demonstrates that measures of IQ and facial dysmorphology predict, to some degree, the structural brain development that occurs in subsequent years. These results are encouraging in that interventions aimed at altering “experience” over time may improve brain trajectories in individuals with heavy PAE and possibly other neurodevelopmental disorders.

Brain Microstructure Is Related to Math Ability in Children With Fetal Alcohol Spectrum Disorder

BACKGROUND Children with fetal alcohol spectrum disorder (FASD) often demonstrate a variety of cognitive deficits, but mathematical ability seems to be particularly affected by prenatal alcohol exposure. Parietal brain regions have been implicated in both functional and structural studies of mathematical ability in healthy individuals, but little is known about the brain structure underlying mathematical deficits in children with FASD. The goal of this study was to use diffusion tensor imaging (DTI) to investigate the relationship between mathematical skill and brain white matter structure in children with FASD. METHODS Twenty-one children aged 5 to 13 years diagnosed with FASD underwent DTI on a 1.5-T MRI scanner and cognitive assessments including the Woodcock-Johnson Quantitative Concepts test. Voxel-based analysis was conducted by normalizing subject images to a template and correlating fractional anisotropy (FA) values across the brain white matter with age-standardized math scores. RESULTS Voxel-based analysis revealed 4 clusters with significant correlations between FA and math scores: 2 positively-correlated clusters in the left parietal region, 1 positively-correlated cluster in the left cerebellum, and 1 negatively-correlated cluster in the bilateral brainstem. Diffusion tractography identified the specific white matter tracts passing through these clusters, namely the left superior longitudinal fasciculus, left corticospinal tract and body of the corpus callosum, middle cerebellar peduncle, and bilateral projection fibers including the anterior and posterior limbs of the internal capsule. CONCLUSIONS These results identify 4 key regions related to mathematical ability and provide a link between brain microstructure and cognitive skills in children with FASD. Given previous findings in typically developing children and those with other abnormal conditions, our results highlight the consistent importance of the left parietal area for mathematical tasks across various populations, and also demonstrate other regions that may be specific to mathematical processing in children with FASD.

Developmental cortical thinning in fetal alcohol spectrum disorders.

Regional cortical thickness was evaluated using CIVET processing of 3D T1-weighted images (i) to compare the variation in cortical thickness between 33 participants with fetal alcohol spectrum disorders (FASD) aged 6-30 years (mean age 12.3 years) versus 33 age/sex/hand-matched controls, and (ii) to examine developmental changes in cortical thickness with age from children to young adults in both groups. Significant cortical thinning was found in the participants with FASD in large areas of the bilateral middle frontal lobe, pre- and post- central areas, lateral and inferior temporal and occipital lobes compared to controls. No significant cortical thickness increases were observed for the FASD group. Cortical thinning with age in a linear model was observed in both groups, but the locations were different for each group. FASD participants showed thinning with age in the left middle frontal, bilateral precentral, bilateral precuneus and paracingulate, left inferior occipital and bilateral fusiform gyri; while controls showed decreases with age in the bilateral middle frontal gyrus, right inferior frontal gyrus, bilateral precuneus gyrus, and bilateral occipital gyrus. A battery of cognitive assessments of memory, attention, motor, and verbal abilities was conducted with many of the FASD participants, but no significant correlations were found between these cognitive scores and regional cortical thickness. Non-invasive measurements of cortical thickness in children to young adults with FASD have identified both key regions of cortex that may be more deleteriously affected by prenatal alcohol exposure as well as cortical changes with age that differ from normal developmental thinning.

Longitudinal MRI reveals altered trajectory of brain development during childhood and adolescence in fetal alcohol spectrum disorders.

Diffusion tensor imaging (DTI) of brain development in fetal alcohol spectrum disorders (FASD) has revealed structural abnormalities, but studies have been limited by the use of cross-sectional designs. Longitudinal scans can provide key insights into trajectories of neurodevelopment within individuals with this common developmental disorder. Here we evaluate serial DTI and T1-weighted volumetric MRI in a human sample of 17 participants with FASD and 27 controls aged 5–15 years who underwent 2–3 scans each, ∼2–4 years apart (92 scans total). Increases of fractional anisotropy and decreases of mean diffusivity (MD) were observed between scans for both groups, in keeping with changes expected of typical development, but mixed-models analysis revealed significant age-by-group interactions for three major white matter tracts: superior longitudinal fasciculus and superior and inferior fronto-occipital fasciculus. These findings indicate altered developmental progression in these frontal-association tracts, with the FASD group notably showing greater reduction of MD between scans. ΔMD is shown to correlate with reading and receptive vocabulary in the FASD group, with steeper decreases of MD in the superior fronto-occipital fasciculus and superior longitudinal fasciculus between scans correlating with greater improvement in language scores. Volumetric analysis revealed reduced total brain, white, cortical gray, and deep gray matter volumes and fewer significant age-related volume increases in the FASD group, although age-by-group interactions were not significant. Longitudinal DTI indicates delayed white matter development during childhood and adolescence in FASD, which may underlie persistent or worsening behavioral and cognitive deficits during this critical period.