A multiparametric analysis of white matter maturation during late childhood and adolescence.

White matter development has been well described using diffusion tensor imaging (DTI), but the microstructural processes driving development remain unclear due to methodological limitations. Here, using neurite orientation dispersion and density imaging (NODDI), inhomogeneous magnetization transfer (ihMT), and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT), we describe white matter development at the microstructural level in a longitudinal cohort of healthy 6-15 year olds. We evaluated age and gender-related trends in fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), orientation dispersion index (ODI), quantitative ihMT (qihMT), myelin volume fraction (VFm ), and g-ratio. We found age-related increases of VFm in most regions, showing ongoing myelination in vivo during late childhood and adolescence for the first time. No relationship was observed between qihMT and age, suggesting myelin volume increases are driven by increased water content. Age-related increases were observed for NDI, suggesting axonal packing is also occurring during this time. g-ratio decreased with age in the uncinate fasciculus, implying changes in communication efficiency are ongoing in this region. FA increased and MD decreased with age in most regions. Gender effects were present in the left cingulum for FA, and an age-by-gender interaction was found for MD in the left uncinate fasciculus. These findings suggest that FA and MD remain useful markers of gender-related processes, and gender differences are likely driven by factors other than myelin. We conclude that white matter development during late childhood and adolescence is driven by a combination of axonal packing and myelin volume increases.

A comparison of inhomogeneous magnetization transfer, myelin volume fraction, and diffusion tensor imaging measures in healthy children.

Sensitive and specific biomarkers of myelin can help define baseline brain health and development, identify and monitor disease pathology, and evaluate response to treatment where myelin content is affected. Diffusion measures such as radial diffusivity (RD) are commonly used to assess myelin content, but are not specific to myelin. Inhomogeneous magnetization transfer (ihMT) and multicomponent driven equilibrium single-pulse observation of T1 and T2 (mcDESPOT) offer quantitative parameters (qihMT and myelin volume fraction/VFm, respectively) which are suggested to have improved sensitivity to myelin. We compared RD, qihMT, and VFm in a cohort of 23 healthy children aged 8-13 years to evaluate the similarities and differences across these measures. All 3 measures were significantly related across brain voxels, but VFm and qihMT were significantly more strongly correlated (qihMT-VFm r = 0.89) than either measure was with RD (RD-qihMT r = -0.66, RD-VFm r = -0.74; all p < 0.001). Mean parameters differed in several regions, especially in subcortical gray matter. These differences can likely be explained by unique sensitivities of each measure to non-myelin factors, such as crossing fiber geometry, axonal packing, fiber orientation, glial density, or magnetization transfer effects in a voxel. We also observed an orientation dependence of qihMT in white matter, such that qihMT decreased as fiber orientation went from parallel to perpendicular to B0. All measures appear to be sensitive to myelin content, though qihMT and VFm appear to be more specific to it than RD. Scan time, noise tolerance, and resolution requirements may inform researchers of the appropriate measure to choose for a specific application.

Participant factors that contribute to magnetic resonance imaging motion artifacts in children with mild traumatic brain injury or orthopedic injury.

Motion can compromise image quality and confound results, especially in pediatric research. This study evaluated qualitative and quantitative approaches to motion artifacts detection and correction, and whether motion artifacts relate to injury history, age, or sex in children with mild traumatic brain injury or orthopedic injury relative to typically developing children. The concordance between qualitative and quantitative motion ratings was also examined. Children aged 8-16 years with mild traumatic brain injury (n = 141) or orthopedic injury (n = 73) were recruited from the emergency department and completed an MRI scan roughly 2 weeks post-injury. Typically developing children (n = 41) completed a single MRI scan. T1- and diffusion-weighted images were visually inspected and rated for motion artifacts by trained examiners. Quantitative estimates of motion artifacts were derived from FreeSurfer and FSL. Age (younger > older) and sex (boys > girls) were significantly associated with motion artifacts on both T1- and diffusion-weighted images. Children with mild traumatic brain or orthopedic injury had significantly more motion-corrupted diffusion-weighted volumes than typically developing children, but mild traumatic brain injury and orthopedic injury groups did not differ from each other. The exclusion of motion-corrupted volumes did not significantly change diffusion tensor imaging metrics. Results indicate that automated quantitative estimates of motion artifacts, which are less labour-intensive than manual methods, are appropriate. Results have implications for the reliability of structural MRI research and highlight the importance of considering motion artifacts in studies of pediatric mild traumatic brain injury.

Brain structure and internalizing and externalizing behavior in typically developing children and adolescents.

Mental health problems often emerge in adolescence and are associated with reduced gray matter thickness or volume in the prefrontal cortex (PFC) and limbic system and reduced fractional anisotropy (FA) and increased mean diffusivity (MD) of white matter linking these regions. However, few studies have investigated whether internalizing and externalizing behavior are associated with brain structure in children and adolescents without mental health disorders, which is important for understanding the progression of symptoms. 67 T1-weighted and diffusion tensor imaging datasets were obtained from 48 typically developing participants aged 6-16 years (37M/30F; 19 participants had two visits). Volume was calculated in the prefrontal and limbic structures, and diffusion parameters were assessed in limbic white matter. Linear mixed effects models were used to compute associations between brain structure and internalizing and externalizing behavior, assessed using the Behavioral Assessment System for Children (BASC-2) Parent Rating Scale. Internalizing behavior was positively associated with MD of the bilateral cingulum. Gender interactions were found in the cingulum, with stronger positive relationships between MD and internalizing behavior in females. Externalizing behavior was negatively associated with FA of the left cingulum, and the left uncinate fasciculus showed an age-behavior interaction. No relationships between behavior and brain volumes survived multiple comparison correction. These results show altered limbic white matter FA and MD related to sub-clinical internalizing and externalizing behavior and further our understanding of neurological markers that may underlie risk for future mental health disorders.

Multimodal principal component analysis to identify major features of white matter structure and links to reading.

The role of white matter in reading has been established by diffusion tensor imaging (DTI), but DTI cannot identify specific microstructural features driving these relationships. Neurite orientation dispersion and density imaging (NODDI), inhomogeneous magnetization transfer (ihMT) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT) can be used to link more specific aspects of white matter microstructure and reading due to their sensitivity to axonal packing and fiber coherence (NODDI) and myelin (ihMT and mcDESPOT). We applied principal component analysis (PCA) to combine DTI, NODDI, ihMT and mcDESPOT measures (10 in total), identify major features of white matter structure, and link these features to both reading and age. Analysis was performed for nine reading-related tracts in 46 neurotypical 6-16 year olds. We identified three principal components (PCs) which explained 79.5% of variance in our dataset. PC1 probed tissue complexity, PC2 described myelin and axonal packing, while PC3 was related to axonal diameter. Mixed effects regression models did not identify any significant relationships between principal components and reading skill. Bayes factor analysis revealed that the absence of relationships was not due to low power. Increasing PC1 in the left arcuate fasciculus with age suggest increases in tissue complexity, while increases of PC2 in the bilateral arcuate, inferior longitudinal, inferior fronto-occipital fasciculi, and splenium suggest increases in myelin and axonal packing with age. Multimodal white matter imaging and PCA provide microstructurally informative, powerful principal components which can be used by future studies of development and cognition. Our findings suggest major features of white matter undergo development during childhood and adolescence, but changes are not linked to reading during this period in our typically-developing sample.

Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent.

Seizures are often followed by sensory, cognitive or motor impairments during the postictal phase that show striking similarity to transient hypoxic/ischemic attacks. Here we show that seizures result in a severe hypoxic attack confined to the postictal period. We measured brain oxygenation in localized areas from freely-moving rodents and discovered a severe hypoxic event (pO2 < 10 mmHg) after the termination of seizures. This event lasted over an hour, is mediated by hypoperfusion, generalizes to people with epilepsy, and is attenuated by inhibiting cyclooxygenase-2 or L-type calcium channels. Using inhibitors of these targets we separated the seizure from the resulting severe hypoxia and show that structure specific postictal memory and behavioral impairments are the consequence of this severe hypoperfusion/hypoxic event. Thus, epilepsy is much more than a disease hallmarked by seizures, since the occurrence of postictal hypoperfusion/hypoxia results in a separate set of neurological consequences that are currently not being treated and are preventable.