Associations between neighborhood characteristics and child well-being before and during the COVID-19 pandemic: A repeated cross-sectional study in the Environmental influences on Child Health Outcomes (ECHO) program.

The corona virus disease (COVID-19) pandemic disrupted daily life worldwide, and its impact on child well-being remains a major concern. Neighborhood characteristics affect child well-being, but how these associations were affected by the pandemic is not well understood. We analyzed data from 1039 children enrolled in the Environmental influences on Child Health Outcomes Program whose well-being was assessed using the Patient-Reported Outcomes Measurement Information System Global Health questionnaire and linked these data to American Community Survey (ACS) data to evaluate the impacts of neighborhood characteristics on child well-being before and during the pandemic. We estimated the associations between more than 400 ACS variables and child well-being t-scores stratified by race/ethnicity (non-Hispanic white vs. all other races and ethnicities) and the timing of outcome data assessment (pre-vs. during the pandemic). Network graphs were used to visualize the associations between ACS variables and child well-being t-scores. The number of ACS variables associated with well-being t-scores decreased during the pandemic period. Comparing non-Hispanic white with other racial/ethnic groups during the pandemic, different ACS variables were associated with child well-being. Multiple ACS variables representing census tract-level housing conditions and neighborhood racial composition were associated with lower well-being t-scores among non-Hispanic white children during the pandemic, while higher percentage of Hispanic residents and higher percentage of adults working as essential workers in census tracts were associated with lower well-being t-scores among non-white children during the same study period. Our study provides insights into the associations between neighborhood characteristics and child well-being, and how the COVID-19 pandemic affected this relationship.

In vivo T1 mapping of neonatal brain tissue at 64 mT.

PURPOSE: Ultralow-field (ULF) point-of-care MRI systems allow image acquisition without interrupting medical provision, with neonatal clinical care being an important potential application. The ability to measure neonatal brain tissue T1 is a key enabling technology for subsequent structural image contrast optimization, as well as being a potential biomarker for brain development. Here we describe an optimized strategy for neonatal T1 mapping at ULF. METHODS: Examinations were performed on a 64-mT portable MRI system. A phantom validation experiment was performed, and a total of 33 in vivo exams were acquired from 28 neonates with postmenstrual age ranging from 31+4 to 49+0  weeks. Multiple inversion-recovery turbo spin-echo sequences were acquired with differing inversion and repetition times. An analysis pipeline incorporating inter-sequence motion correction generated proton density and T1 maps. Regions of interest were placed in the cerebral deep gray matter, frontal white matter, and cerebellum. Weighted linear regression was used to predict T1 as a function of postmenstrual age. RESULTS: Reduction of T1 with postmenstrual age is observed in all measured brain tissue; the change in T1 per week and 95% confidence intervals is given by dT1  = -21 ms/week [-25, -16] (cerebellum), dT1  = -14 ms/week [-18, -10] (deep gray matter), and dT1  = -35 ms/week [-45, -25] (white matter). CONCLUSION: Neonatal T1 values at ULF are shorter than those previously described at standard clinical field strengths, but longer than those of adults at ULF. T1 reduces with postmenstrual age and is therefore a candidate biomarker for perinatal brain development.

Altered myelination in youth born with congenital heart disease.

Brain injury and dysmaturation is common in fetuses and neonates with congenital heart disease (CHD) and is hypothesized to result in persistent myelination deficits. This study aimed to quantify and compare myelin content in vivo between youth born with CHD and healthy controls. Youth aged 16 to 24 years born with CHD and healthy age- and sex-matched controls underwent brain magnetic resonance imaging including multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). Average myelin water fraction (MWF) values for 33 white matter tracts, as well as a summary measure of average white matter MWF, the White Matter Myelination Index, were calculated and compared between groups. Tract-average MWF was lower throughout the corpus callosum and in many bilateral association tracts and left hemispheric projection tracts in youth with CHD (N = 44) as compared to controls (N = 45). The White Matter Myelination Index was also lower in the CHD group. As such, this study provides specific evidence of widespread myelination deficits in youth with CHD, likely representing a long-lasting consequence of early-life brain dysmaturation in this population. This deficient myelination may underlie the frequent neurodevelopmental impairments experienced by CHD survivors and could eventually serve as a biomarker of neuropsychological function.

Simultaneous high-resolution T2 -weighted imaging and quantitative T2 mapping at low magnetic field strengths using a multiple TE and multi-orientation acquisition approach.

PURPOSE: Low magnetic field systems provide an important opportunity to expand MRI to new and diverse clinical and research study populations. However, a fundamental limitation of low field strength systems is the reduced SNR compared to 1.5 or 3T, necessitating compromises in spatial resolution and imaging time. Most often, images are acquired with anisotropic voxels with low through-plane resolution, which provide acceptable image quality with reasonable scan times, but can impair visualization of subtle pathology. METHODS: Here, we describe a super-resolution approach to reconstruct high-resolution isotropic T2 -weighted images from a series of low-resolution anisotropic images acquired in orthogonal orientations. Furthermore, acquiring each image with an incremented TE allows calculations of quantitative T2 images without time penalty. RESULTS: Our approach is demonstrated via phantom and in vivo human brain imaging, with simultaneous 1.5 × 1.5 × 1.5 mm3 T2 -weighted and quantitative T2 maps acquired using a clinically feasible approach that combines three acquisition that require approximately 4-min each to collect. Calculated T2 values agree with reference multiple TE measures with intraclass correlation values of 0.96 and 0.85 in phantom and in vivo measures, respectively, in line with previously reported brain T2 values at 150 mT, 1.5T, and 3T. CONCLUSION: Our multi-orientation and multi-TE approach is a time-efficient method for high-resolution T2 -weighted images for anatomical visualization with simultaneous quantitative T2 imaging for increased sensitivity to tissue microstructure and chemical composition.

Connecting inside out: Development of the social brain in infants and toddlers with a focus on myelination as a marker of brain maturation.

Early childhood is a sensitive period for learning and social skill development. The maturation of cerebral regions underlying social processing lays the foundation for later social-emotional competence. This study explored myelin changes in social brain regions and their association with changes in parent-rated social-emotional development in a cohort of 129 children (64 females, 0-36 months, 77 White). Results reveal a steep increase in myelination throughout the social brain in the first 3 years of life that is significantly associated with social-emotional development scores. These findings add knowledge to the emerging picture of social brain development by describing neural underpinnings of human social behavior. They can contribute to identifying age-/stage-appropriate early life factors in this developmental domain.

The Effects of Delayed Cord Clamping on 12-Month Brain Myelin Content and Neurodevelopment: A Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine if delayed cord clamping (DCC) affected brain myelin water volume fraction (VFm) and neurodevelopment in term infants. STUDY DESIGN: This was a single-blinded randomized controlled trial of healthy pregnant women with term singleton fetuses randomized at birth to either immediate cord clamping (ICC) (≤ 20 seconds) or DCC (≥ 5 minutes). Follow-up at 12 months of age consisted of blood work for serum iron indices and lead levels, a nonsedated magnetic resonance imaging (MRI), followed within the week by neurodevelopmental testing. RESULTS: At birth, 73 women were randomized into one of two groups: ICC (the usual practice) or DCC (the intervention). At 12 months, among 58 active participants, 41 (80%) had usable MRIs. There were no differences between the two groups on maternal or infant demographic variables. At 12 months, infants who had DCC had increased white matter brain growth in regions localized within the right and left internal capsules, the right parietal, occipital, and prefrontal cortex. Gender exerted no difference on any variables. Developmental testing (Mullen Scales of Early Learning, nonverbal, and verbal composite scores) was not significantly different between the two groups. CONCLUSION: At 12 months of age, infants who received DCC had greater myelin content in important brain regions involved in motor function, visual/spatial, and sensory processing. A placental transfusion at birth appeared to increase myelin content in the early developing brain. KEY POINTS: · DCC resulted in higher hematocrits in newborn period.. · DCC appears to increase myelin at 12 months.. · Gender did not influence study outcomes..

Accessible pediatric neuroimaging using a low field strength MRI scanner.

Magnetic resonance imaging (MRI) has played an increasingly relevant role in understanding infant, child, and adolescent neurodevelopment, providing new insight into developmental patterns in neurotypical development, as well as those associated with potential psychopathology, learning disorders, and other neurological conditions. In addition, studies have shown the impact of a child's physical and psychosocial environment on developing brain structure and function. A rate-limiting complication in these studies, however, is the high cost and infrastructural requirements of modern MRI systems. High costs mean many neuroimaging studies typically include fewer than 100 individuals and are performed predominately in high resource hospitals and university settings within high income countries (HICs). As a result, our knowledge of brain development, particularly in children who live in lower and middle income countries (LMICs) is relatively limited. Low field systems, with magnetic fields less than 100mT offer the promise of lower scanning costs and wide-spread global adoption, but routine low field pediatric neuroimaging has yet to be demonstrated. Here we present the first pediatric MRI data collected on a low cost and assessable 64mT scanner in children 6 weeks to 16 years of age and replicate brain volumes estimates and developmental trajectories derived from 3T MRI data. While preliminary, these results illustrate the potential of low field imaging as a viable complement to more conventional high field imaging systems, and one that may further enhance our knowledge of neurodevelopment in LMICs where malnutrition, psychosocial adversities, and other environmental exposures may profoundly affect brain maturation.

Longitudinal white matter and cognitive development in pediatric carriers of the apolipoprotein ε4 allele.

We have previously demonstrated cross-sectional differences in magnetic resonance imaging (MRI) measurements of white matter myelin and gray matter in infants with or without the apolipoprotein ε4 allele, a major genetic risk factor for late-onset Alzheimer's disease (AD). In this study, we sought to compare longitudinal MRI white matter myelin and cognitive-behavioral changes in infants and young children with and without this allele. Serial MRI and cognitive tests were obtained on 223 infants and young children, including 74 ε4 carriers and 149 non-carriers, 2-68 months of age, matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated brain mapping algorithms and non-linear mixed models were used to characterize and compare trajectories of white matter myelin and cognitive-behavioral test scores. The APOE ε4 carriers had statistically significant differences in white matter myelin development, in the uncinate fasciculus, temporal lobe, internal capsule and occipital lobe. Additionally, ε4 carriers had a slightly greater rate of development in early learning composite a surrogate measure of IQ representative of expressive language, receptive language, fine motor, and visual skills, but displayed slightly lower non verbal development quotient scores a composite measure of fine motor and visual skills across the entire age range. This study supports the possibility that ε4 carriers have slightly altered rates of white matter and cognitive development in childhood. It continues to raise questions about the role of APOE in human brain development and the relevance of these developmental differences to the predisposition to AD.

A simple sleep EEG marker in childhood predicts brain myelin 3.5 years later.

Epidemiological research reveals that insufficient sleep in children has negative cognitive and emotional consequences; however, the physiological underpinnings of these observations remain understudied. We tested the hypothesis that the topographical distribution of deep sleep slow wave activity during the childhood predicts brain white matter microstructure (myelin) 3.5 y later. Healthy children underwent sleep high-density EEG at baseline (n = 13; ages 2.4-8.0 y) and follow-up (n = 14; ages 5.5-12.2 y). At follow-up, myelin (myelin water fraction) and cortical morphology were also quantified. Our investigation revealed 3 main findings. (1) The Frontal/Occipital (F/O)-ratio at baseline strongly predicted whole brain myelin at follow-up. (2) At follow-up, the F/O-ratio was only minimally (negatively) linked to brain myelin. (3) Cortical morphology was not related to the F/O-ratio, neither at baseline nor at follow-up. Our results support the hypothesis that during child development EEG markers during sleep longitudinally predict brain myelin content. Data extend previous findings reporting a link between EEG markers of sleep need and cortical morphology, by supporting the hypothesis that sleep is a necessary component to underlying processes of brain, and specifically myelin, maturation. In line with the overarching theory that sleep contributes to neurodevelopmental processes, it remains to be investigated whether chronic sleep loss negatively affects white matter myelin microstructure growth during sensitive periods of development.

Longitudinal associations between white matter maturation and cognitive development across early childhood.

From birth to 5 years of age, brain structure matures and evolves alongside emerging cognitive and behavioral abilities. In relating concurrent cognitive functioning and measures of brain structure, a major challenge that has impeded prior investigation of their time-dynamic relationships is the sparse and irregular nature of most longitudinal neuroimaging data. We demonstrate how this problem can be addressed by applying functional concurrent regression models (FCRMs) to longitudinal cognitive and neuroimaging data. The application of FCRM in neuroimaging is illustrated with longitudinal neuroimaging and cognitive data acquired from a large cohort (n = 210) of healthy children, 2-48 months of age. Quantifying white matter myelination by using myelin water fraction (MWF) as imaging metric derived from MRI scans, application of this methodology reveals an early period (200-500 days) during which whole brain and regional white matter structure, as quantified by MWF, is positively associated with cognitive ability, while we found no such association for whole brain white matter volume. Adjusting for baseline covariates including socioeconomic status as measured by maternal education (SES-ME), infant feeding practice, gender, and birth weight further reveals an increasing association between SES-ME and cognitive development with child age. These results shed new light on the emerging patterns of brain and cognitive development, indicating that FCRM provides a useful tool for investigating these evolving relationships.

Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether placental transfusion influences brain myelination at 4 months of age. STUDY DESIGN: A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. RESULTS: In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. CONCLUSION: At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01620008.

Quantifying cortical development in typically developing toddlers and young children, 1-6 years of age.

Cortical maturation, including age-related changes in thickness, volume, surface area, and folding (gyrification), play a central role in developing brain function and plasticity. Further, abnormal cortical maturation is a suspected substrate in various behavioral, intellectual, and psychiatric disorders. However, in order to characterize the altered development associated with these disorders, appreciation of the normative patterns of cortical development in neurotypical children between 1 and 6 years of age, a period of peak brain development during which many behavioral and developmental disorders emerge, is necessary. To this end, we examined measures of cortical thickness, surface area, mean curvature, and gray matter volume across 34 bilateral regions in a cohort of 140 healthy children devoid of major risk factors for abnormal development. From these data, we observed linear, logarithmic, and quadratic patterns of change with age depending on brain region. Cortical thinning, ranging from 10% to 20%, was observed throughout most of the brain, with the exception of posterior brain structures, which showed initial cortical thinning from 1 to 5 years, followed by thickening. Cortical surface area expansion ranged from 20% to 108%, and cortical curvature varied by 1-20% across the investigated age range. Right-left hemisphere asymmetry was observed across development for each of the 4 cortical measures. Our results present new insight into the normative patterns of cortical development across an important but under studied developmental window, and provide a valuable reference to which trajectories observed in neurodevelopmental disorders may be compared.

On the brain structure heterogeneity of autism: Parsing out acquisition site effects with significance-weighted principal component analysis.

Neuroimaging studies have reported structural and physiological differences that could help understand the causes and development of Autism Spectrum Disorder (ASD). Many of them rely on multisite designs, with the recruitment of larger samples increasing statistical power. However, recent large-scale studies have put some findings into question, considering the results to be strongly dependent on the database used, and demonstrating the substantial heterogeneity within this clinically defined category. One major source of variance may be the acquisition of the data in multiple centres. In this work we analysed the differences found in the multisite, multi-modal neuroimaging database from the UK Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) in terms of both diagnosis and acquisition sites. Since the dissimilarities between sites were higher than between diagnostic groups, we developed a technique called Significance Weighted Principal Component Analysis (SWPCA) to reduce the undesired intensity variance due to acquisition site and to increase the statistical power in detecting group differences. After eliminating site-related variance, statistically significant group differences were found, including Broca's area and the temporo-parietal junction. However, discriminative power was not sufficient to classify diagnostic groups, yielding accuracies results close to random. Our work supports recent claims that ASD is a highly heterogeneous condition that is difficult to globally characterize by neuroimaging, and therefore different (and more homogenous) subgroups should be defined to obtain a deeper understanding of ASD. Hum Brain Mapp 38:1208-1223, 2017. © 2016 Wiley Periodicals, Inc.

Examining the relationships between cortical maturation and white matter myelination throughout early childhood.

Cortical development and white matter myelination are hallmark processes of infant and child neurodevelopment, and play a central role in the evolution of cognitive and behavioral functioning. Non-invasive magnetic resonance imaging (MRI) has been used to independently track these microstructural and morphological changes in vivo, however few studies have investigated the relationship between them despite their concurrency in the developing brain. Further, because measures of cortical morphology rely on underlying gray-white matter tissue contrast, which itself is a function of white matter myelination, it is unclear if contrast-based measures of cortical development accurately reflect cortical architecture, or if they merely represent adjacent white matter maturation. This may be particularly true in young children, in whom brain structure is rapidly maturing. Here for the first time, we investigate the dynamic relationship between cortical and white matter development across early childhood, from 1 to 6years. We present measurements of cortical thickness with respect to cortical and adjacent myelin water fraction (MWF) in 33 bilateral cortical regions. Significant results in only 14 of 66 (21%) cortical regions suggest that cortical thickness measures are not heavily driven by changes in adjacent white matter, and that brain imaging studies of cortical and white matter maturation reflect distinct, but complimentary, neurodevelopmental processes.

Mapping an index of the myelin g-ratio in infants using magnetic resonance imaging.

Optimal myelination of neuronal axons is essential for effective brain and cognitive function. The ratio of the axon diameter to the outer fiber diameter, known as the g-ratio, is a reliable measure to assess axonal myelination and is an important index reflecting the efficiency and maximal conduction velocity of white matter pathways. Although advanced neuroimaging techniques including multicomponent relaxometry (MCR) and diffusion tensor imaging afford insight into the microstructural characteristics of brain tissue, by themselves they do not allow direct analysis of the myelin g-ratio. Here, we show that by combining myelin content information (obtained with mcDESPOT MCR) with neurite density information (obtained through NODDI diffusion imaging) an index of the myelin g-ratio may be estimated. Using this framework, we present the first quantitative study of myelin g-ratio index changes across childhood, examining 18 typically developing children 3months to 7.5years of age. We report a spatio-temporal pattern of maturation that is consistent with histological and developmental MRI studies, as well as theoretical studies of the myelin g-ratio. This work represents the first ever in vivo visualization of the evolution of white matter g-ratio indices throughout early childhood.

Paradoxical centrally increased diffusivity in perinatal arterial ischemic stroke.

BACKGROUND: Restricted diffusion on acute MRI is the diagnostic standard for perinatal arterial ischemic stroke. In a subset of children with perinatal arterial ischemic stroke, primarily those with large infarct volumes, we noted a core of centrally increased diffusivity with a periphery of restricted diffusion. OBJECTIVE: Given the paradoxical diffusion-weighted imaging (DWI) appearance observed in some children with perinatal arterial ischemic stroke, we sought to determine its significance and hypothesized that: (1) centrally increased diffusivity is associated with larger infarcts in perinatal arterial ischemic stroke and (2) this tissue is irreversibly injured (infarcted). MATERIALS AND METHODS: We reviewed all perinatal arterial ischemic stroke cases in a prospective cohort study from Aug. 1, 2000, to Jan. 1, 2012. Infarct volumes were measured by drawing regions of interest around the periphery of the area of restricted diffusion on DWI. The Mann-Whitney U test was used to compare means between groups. RESULTS: Of 25 eligible cases, centrally increased diffusivity was seen in 4 (16%). Cases with centrally increased diffusivity had larger average infarct volumes (mean 117,182 mm(3) vs. 36,995 mm(3); P = 0.008), higher average apparent diffusion coefficient (ADC) values in the infarct core (1,679 × 10(-6) mm(2)/s vs. 611 × 10(-6) mm(2)/s, P < 0.0001), and higher ADC ratio (1.2 vs. 0.5, P < 0.0001). At last clinical follow-up, children with perinatal arterial ischemic stroke and centrally increased diffusivity were more often treated for ongoing seizures (75% vs. 0%; P < 0.001) than those without. CONCLUSION: Centrally increased diffusivity was associated with larger stroke volume and the involved tissue was confirmed to be infarcted on follow-up imaging. Radiologists should be aware of this unusual appearance of perinatal arterial ischemic stroke in order to avoid underestimating infarct volume or making an incorrect early diagnosis.

Cortical maturation and myelination in healthy toddlers and young children.

The maturation of cortical structures, and the establishment of their connectivity, are critical neurodevelopmental processes that support and enable cognitive and behavioral functioning. Measures of cortical development, including thickness, curvature, and gyrification have been extensively studied in older children, adolescents, and adults, revealing regional associations with cognitive performance, and alterations with disease or pathology. In addition to these gross morphometric measures, increased attention has recently focused on quantifying more specific indices of cortical structure, in particular intracortical myelination, and their relationship to cognitive skills, including IQ, executive functioning, and language performance. Here we analyze the progression of cortical myelination across early childhood, from 1 to 6 years of age, in vivo for the first time. Using two quantitative imaging techniques, namely T1 relaxation time and myelin water fraction (MWF) imaging, we characterize myelination throughout the cortex, examine developmental trends, and investigate hemispheric and gender-based differences. We present a pattern of cortical myelination that broadly mirrors established histological timelines, with somatosensory, motor and visual cortices myelinating by 1 year of age; and frontal and temporal cortices exhibiting more protracted myelination. Developmental trajectories, defined by logarithmic functions (increasing for MWF, decreasing for T1), were characterized for each of 68 cortical regions. Comparisons of trajectories between hemispheres and gender revealed no significant differences. Results illustrate the ability to quantitatively map cortical myelination throughout early neurodevelopment, and may provide an important new tool for investigating typical and atypical development.

Estimating the age of healthy infants from quantitative myelin water fraction maps.

The trajectory of the developing brain is characterized by a sequence of complex, nonlinear patterns that occur at systematic stages of maturation. Although significant prior neuroimaging research has shed light on these patterns, the challenge of accurately characterizing brain maturation, and identifying areas of accelerated or delayed development, remains. Altered brain development, particularly during the earliest stages of life, is believed to be associated with many neurological and neuropsychiatric disorders. In this work, we develop a framework to construct voxel-wise estimates of brain age based on magnetic resonance imaging measures sensitive to myelin content. 198 myelin water fraction (VF(M) ) maps were acquired from healthy male and female infants and toddlers, 3 to 48 months of age, and used to train a sigmoidal-based maturational model. The validity of the approach was then established by testing the model on 129 different VF(M) datasets. Results revealed the approach to have high accuracy, with a mean absolute percent error of 13% in males and 14% in females, and high predictive ability, with correlation coefficients between estimated and true ages of 0.945 in males and 0.94 in females. This work represents a new approach toward mapping brain maturity, and may provide a more faithful staging of brain maturation in infants beyond chronological or gestation-corrected age, allowing earlier identification of atypical regional brain development.

Investigating the stability of mcDESPOT myelin water fraction values derived using a stochastic region contraction approach.

PURPOSE: Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) is an alternative to established multiecho T2 -based approaches for quantifying myelin water fraction, affording increased volumetric coverage and spatial resolution. A concern with mcDESPOT, however, is the large number of model parameters that must be estimated, which may lead to nonunique solutions and sensitivity to fitting constraints. Here we explore mcDESPOT performance under different experimental conditions to better understand the method's sensitivity and reliability. METHODS: To obtain parameter estimates, mcDESPOT uses a stochastic region contraction (SRC) approach to iteratively contract a predefined solution search-space around a global optimum. The sensitivity of mcDESPOT estimates to SRC boundary conditions, and tissue parameters, was examined using numerical phantoms and acquired in vivo human data. RESULTS: The SRC approach is described and shown to return robust myelin water estimates in both numerical phantoms and in vivo data under a range of experimental conditions. However, care must be taken in choosing the initial SRC boundary conditions, ensuring they are broad enough to encompass the "true" solution. CONCLUSION: Results suggest that under the range of conditions examined, mcDESPOT can provide stabile and precise values.

Hypomyelinating leukodystrophies: translational research progress and prospects.

Hypomyelinating leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials.