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Total intracranial volume (TICV) and posterior fossa volume (PFV) are essential covariates for brain volumetric analyses with structural magnetic resonance imaging (MRI). Detailed whole brain segmentation provides a non-invasive way to measure brain regions. Furthermore, increasing neuroimaging data are distributed in a skull-stripped manner for privacy protection. Therefore, generalizing deep learning brain segmentation for skull removal and intracranial measurements is an appealing task. However, data availability is challenging due to a limited set of manually traced atlases with whole brain and TICV/PFV labels. In this paper, we employ U-Net tiles to achieve automatic TICV estimation and whole brain segmentation simultaneously on brains w/and w/o the skull. To overcome the scarcity of manually traced whole brain volumes, a transfer learning method is introduced to estimate additional TICV and PFV labels during whole brain segmentation in T1-weighted MRI. Specifically, U-Net tiles are first pre-trained using large-scale BrainCOLOR atlases without TICV and PFV labels, which are created by multi-atlas segmentation. Then the pre-trained models are refined by training the additional TICV and PFV labels using limited BrainCOLOR atlases. We also extend our method to handle skull-stripped brain MR images. From the results, our method provides promising whole brain segmentation and volume estimation results for both brains w/and w/o skull in terms of mean Dice similarity coefficients and mean surface distance and absolute volume similarity. This method has been made available in open source (https://github.com/MASILab/SLANTbrainSeg_skullstripped)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Our main goal is to study and quantify the evolution of multiple sclerosis lesions observed longitudinally over many years in multi-sequence structural magnetic resonance imaging (sMRI). To achieve that, we propose a class of functional models for capturing the temporal dynamics and spatial distribution of the voxel-specific intensity trajectories in all sMRI sequences. To accommodate the hierarchical data structure (observations nested within voxels, which are nested within lesions, which, in turn, are nested within study participants), we use structured functional principal component analysis. We propose and evaluate the finite sample properties of hypothesis tests of therapeutic intervention effects on lesion evolution while accounting for the multilevel structure of the data. Using this novel testing strategy, we found statistically significant differences in lesion evolution between treatment groups., (© The Author 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The central vein sign (CVS) and "paramagnetic rim lesions" (PRL) are emerging imaging biomarkers in multiple sclerosis (MS) reflecting perivenular demyelination and chronic, smoldering inflammation. The objective of this study was to assess relationships between cognitive impairment (CI) and the CVS and PRL in radiologically isolated syndrome (RIS)., Methods: Twenty-seven adults with RIS underwent 3.0 T MRI of the brain and cervical spinal cord (SC) and cognitive assessment using the minimal assessment of cognitive function in MS battery. The CVS and PRL were assessed in white-matter lesions (WMLs) on T2*-weighted segmented echo-planar magnitude and phase images. Multivariable linear regression evaluated relationships between CI and MRI measures., Results: Global CI was present in 9 (33%) participants with processing speed and visual memory most frequently affected. Most participants (93%) had ⩾ 40% CVS + WML (a threshold distinguishing MS from other WM disorders); 63% demonstrated PRL. Linear regression revealed that CVS + WML predicted performance on verbal memory( β  =-0.024, p  = 0.03) while PRL predicted performance on verbal memory ( β  = -0.040, p  = 0.04) and processing speed ( β  = -0.039, p  = 0.03)., Conclusions: CI is common in RIS and is associated with markers of perivenular demyelination and chronic inflammation in WML, such as CVS + WML and PRL. A prospective follow-up of this cohort will ascertain the importance of CI, CVS, and PRL as risk factors for conversion from RIS to MS.

Background: Lower respiratory tract infections are a leading cause of death in young children, but few studies have collected the specimens needed to define the role of specific causes. The Child Health and Mortality Prevention Surveillance (CHAMPS) platform aims to investigate causes of death in children aged <5 years in high-mortality rate settings, using postmortem minimally invasive tissue sampling and other advanced diagnostic techniques. We examined findings for deaths identified in CHAMPS sites in 7 countries in sub-Saharan Africa and south Asia to evaluate the role of respiratory syncytial virus (RSV)., Methods: We included deaths that occurred between December 2016 and December 2019. Panels determined causes of deaths by reviewing all available data including pathological results from minimally invasive tissue sampling, polymerase chain reaction screening for multiple infectious pathogens in lung tissue, nasopharyngeal swab, blood, and cerebrospinal fluid samples, clinical information from medical records, and verbal autopsies., Results: We evaluated 1213 deaths, including 695 in neonates (aged <28 days), 283 in infants (28 days to <12 months), and 235 in children (12-59 months). RSV was detected in postmortem specimens in 67 of 1213 deaths (5.5%); in 24 deaths (2.0% of total), RSV was determined to be a cause of death, and it contributed to 5 other deaths. Younger infants (28 days to <6 months of age) accounted for half of all deaths attributed to RSV; 6.5% of all deaths in younger infants were attributed to RSV. RSV was the underlying and only cause in 4 deaths; the remainder (n = 20) had a median of 2 (range, 1-5) other conditions in the causal chain. Birth defects (n = 8) and infections with other pathogens (n = 17) were common comorbid conditions., Conclusions: RSV is an important cause of child deaths, particularly in young infants. These findings add to the substantial body of literature calling for better treatment and prevention options for RSV in high-mortality rate settings., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background and Purpose: White matter lesions of presumed ischemic origin are associated with progressive cognitive impairment and impaired BBB function. Studying the longitudinal effects of white matter lesion biomarkers that measure changes in perfusion and BBB patency within white matter lesions is required for long-term studies of lesion progression. We studied perfusion and BBB disruption within white matter lesions in asymptomatic subjects., Materials and Methods: Anatomic imaging was followed by consecutive dynamic contrast-enhanced and DSC imaging. White matter lesions in 21 asymptomatic individuals were determined using a Subject-Specific Sparse Dictionary Learning algorithm with manual correction. Perfusion-related parameters including CBF, MTT, the BBB leakage parameter, and volume transfer constant were determined., Results: MTT was significantly prolonged (7.88 [SD, 1.03] seconds) within white matter lesions compared with normal-appearing white (7.29 [SD, 1.14] seconds) and gray matter (6.67 [SD, 1.35] seconds). The volume transfer constant, measured by dynamic contrast-enhanced imaging, was significantly elevated (0.013 [SD, 0.017] minutes -1 ) in white matter lesions compared with normal-appearing white matter (0.007 [SD, 0.011] minutes -1 ). BBB disruption within white matter lesions was detected relative to normal white and gray matter using the DSC-BBB leakage parameter method so that increasing BBB disruption correlated with increasing white matter lesion volume (Spearman correlation coefficient = 0.44; P < .046)., Conclusions: A dual-contrast-injection MR imaging protocol combined with a 3D automated segmentation analysis pipeline was used to assess BBB disruption in white matter lesions on the basis of quantitative perfusion measures including the volume transfer constant (dynamic contrast-enhanced imaging), the BBB leakage parameter (DSC), and MTT (DSC). This protocol was able to detect early pathologic changes in otherwise healthy individuals., (© 2021 by American Journal of Neuroradiology.)

Background: The spinal cord (SC) is highly relevant to disability in multiple sclerosis (MS), but few studies have evaluated longitudinal changes in quantitative spinal cord magnetic resonance imaging (SC-MRI)., Objectives: The aim of this study was to characterize the relationships between 5-year changes in SC-MRI with disability in MS., Methods: In total, 75 MS patients underwent 3 T SC-MRI and clinical assessment (expanded disability status scale (EDSS) and MS functional composite (MSFC)) at baseline, 2 and 5 years. SC-cross-sectional area (CSA) and diffusion-tensor indices (fractional anisotropy (FA), mean, perpendicular, parallel diffusivity (MD, λ ⊥ , λ || ) and magnetization transfer ratio (MTR)) were extracted at C3-C4. Mixed-effects regression incorporating subject-specific slopes assessed longitudinal change in SC-MRI measures., Results: SC-CSA and MTR decreased ( p  = 0.009, p  = 0.03) over 5.1 years. There were moderate correlations between 2- and 5-year subject-specific slopes of SC-MRI indices and follow-up EDSS scores (Pearson's r with FA = -0.23 ( p  < 0.001); MD = 0.31 ( p  < 0.001); λ ⊥  = 0.34 ( p  < 0.001); λ ||  = -0.12 ( p  = 0.05), MTR = -0.37 ( p  < 0.001); SC-CSA = -0.47 ( p  < 0.001) at 5 years); MSFC showed similar trends. The 2- and 5-year subject-specific slopes were robustly correlated ( r  = 0.93-0.97 for FA, λ ⊥ , SC-CSA and MTR, all p s < 0.001)., Conclusion: In MS, certain quantitative SC-MRI indices change over 5 years, reflecting ongoing tissue changes. Subject-specific trajectories of SC-MRI index change at 2 and 5 years are strongly correlated and highly relevant to follow-up disability. These findings suggest that individual dynamics of change should be accounted for when interpreting longitudinal SC-MRI measures and that measuring short-term change is predictive of long-term clinical disability.

Background and Purpose: The manganese ion is used as an intracellular MR imaging contrast agent to study neuronal function in animal models, but it remains unclear whether manganese-enhanced MR imaging can be similarly useful in humans. Using mangafodipir (Teslascan, a chelated manganese-based contrast agent that is FDA-approved), we evaluated the dynamics of manganese enhancement of the brain and glandular structures in the rostral head and neck in healthy volunteers., Materials and Methods: We administered mangafodipir intravenously at a rate of 1 mL/minute for a total dose of 5 μmol/kg body weight. Nine healthy adult volunteers (6 men/3 women; median age, 43 years) completed baseline history and physical examination, 3T MR imaging, and blood work. MR imaging also followed mangafodipir administration at various time points from immediate to 7 days, with delayed scans at 1-3 months., Results: The choroid plexus and anterior pituitary gland enhanced within 10 minutes of infusion, with enhancement persisting up to 7 and 30 days, respectively. Exocrine (parotid, submandibular, sublingual, and lacrimal) glands also enhanced avidly as early as 1 hour postadministration, generally resolving by 1 month; 3 volunteers had residual exocrine gland enhancement, which resolved by 2 months in 1 and by 3 months in the other 2. Mangafodipir did not affect clinical parameters, laboratory values, or T1-weighted signal in the basal ganglia., Conclusions: Manganese ions released from mangafodipir successfully enable noninvasive visualization of intra- and extracranial structures that lie outside the blood-brain barrier without adverse clinical effects, setting the stage for future neuroradiologic investigation in disease., (© 2019 by American Journal of Neuroradiology.)

Objective: To summarize current and emerging imaging techniques that can be used to assess neuroprotection and repair in multiple sclerosis (MS), and to provide a consensus opinion on the potential utility of each technique in clinical trial settings., Methods: Clinicians and scientists with expertise in the use of MRI in MS convened in Toronto, Canada, in November 2016 at a North American Imaging in Multiple Sclerosis (NAIMS) Cooperative workshop meeting. The discussion was compiled into a manuscript and circulated to all NAIMS members in attendance. Edits and feedback were incorporated until all authors were in agreement., Results: A wide spectrum of imaging techniques and analysis methods in the context of specific study designs were discussed, with a focus on the utility and limitations of applying each technique to assess neuroprotection and repair. Techniques were discussed under specific themes, and included conventional imaging, magnetization transfer ratio, diffusion tensor imaging, susceptibility-weighted imaging, imaging cortical lesions, magnetic resonance spectroscopy, PET, advanced diffusion imaging, sodium imaging, multimodal techniques, imaging of special regions, statistical considerations, and study design., Conclusions: Imaging biomarkers of neuroprotection and repair are an unmet need in MS. There are a number of promising techniques with different strengths and limitations, and selection of a specific technique will depend on a number of factors, notably the question the trial seeks to answer. Ongoing collaborative efforts will enable further refinement and improved methods to image the effect of novel therapeutic agents that exert benefit in MS predominately through neuroprotective and reparative mechanisms., (© 2019 American Academy of Neurology.)

Background and Purpose: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging., Materials and Methods: Brain MR imaging using T1-weighted MP2RAGE at 500-μm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry., Results: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical ( r = 0.86, P < .001) and leukocortical lesion volume ( r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage., Conclusions: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications., (© 2018 by American Journal of Neuroradiology.)

Under oxygenated conditions, sulfate is relatively non-toxic to aquatic plants. However, in water-saturated soils, which are usually anoxic, sulfate can be reduced to toxic sulfide. Although the direct effects of sulfate and sulfide on the physiology of a few plant species have been studied in some detail, their cumulative effects on a plant's life cycle through inhibition of seed germination, seedling survival, growth, and seed production have been less well studied. We investigated the effect of sulfate and sulfide on the life cycle of wild rice (Zizania palustris L.) in hydroponic solutions and in outdoor mesocosms with sediment from a wild rice lake. In hydroponic solutions, sulfate had no effect on seed germination or juvenile seedling growth and development, but sulfide greatly reduced juvenile seedling growth and development at concentrations greater than 320 μg/L. In outdoor mesocosms, sulfate additions to overlying water increased sulfide production in sediments. Wild rice seedling emergence, seedling survival, biomass growth, viable seed production, and seed mass all declined with sulfate additions and hence sulfide concentrations in sediment. These declines grew steeper during the course of the 5 yr of the mesocosm experiment and wild rice populations became extinct in most tanks with concentrations of 250 mg SO 4 /L or greater in the overlying water. Iron sulfide precipitated on the roots of wild rice plants, especially at high sulfate application rates. These precipitates, or the encroachment of reducing conditions that they indicate, may impede nutrient uptake and be partly responsible for the reduced seed production and viability., (© 2016 by the Ecological Society of America.)

Diffusion tensor imaging (DTI) has become the predominant modality for studying white matter integrity in multiple sclerosis (MS) and other neurological disorders. Unfortunately, the use of DTI-based biomarkers in large multi-center studies is hindered by systematic biases that confound the study of disease-related changes. Furthermore, the site-to-site variability in multi-center studies is significantly higher for DTI than that for conventional MRI-based markers. In our study, we apply the Quantitative MR Estimation Employing Normalization (QuEEN) model to estimate the four DTI measures: MD, FA, RD, and AD. QuEEN uses a voxel-wise generalized additive regression model to relate the normalized intensities of one or more conventional MRI modalities to a quantitative modality, such as DTI. We assess the accuracy of the models by comparing the prediction error of estimated DTI images to the scan-rescan error in subjects with two sets of scans. Across the four DTI measures, the performance of the models is not consistent: Both MD and RD estimations appear to be quite accurate, while AD estimation is less accurate than MD and RD; the accuracy of FA estimation is poor. Thus, in some cases when assessing white matter integrity, it may be sufficient to acquire conventional MRI sequences alone.

Quantitative T1 maps estimate T1 relaxation times and can be used to assess diffuse tissue abnormalities within normal-appearing tissue. T1 maps are popular for studying the progression and treatment of multiple sclerosis (MS). However, their inclusion in standard imaging protocols remains limited due to the additional scanning time and expert calibration required and susceptibility to bias and noise. Here, we propose a new method of estimating T1 maps using four conventional MR images, which are intensity-normalized using cerebellar gray matter as a reference tissue and related to T1 using a smooth regression model. Using cross-validation, we generate statistical T1 maps for 61 subjects with MS. The statistical maps are less noisy than the acquired maps and show similar reproducibility. Tests of group differences in normal-appearing white matter across MS subtypes give similar results using both methods., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Separating plastic from ontogenetic and growth-limiting responses of plants to changes in resource availability can be challenging because there are a total of eight combinations of these three types of responses. These can, however, be uniquely distinguished on plots of root:shoot ratios against total biomass through time. We used this approach to separate ontogenetic, plastic, and growth-limiting responses of wild rice (Zizania palustris L.) to changes in nitrogen, phosphorus, and light availabilities. Relative growth rate was limited primarily by nitrogen but responded to increased light and phosphorus after nitrogen limitations were alleviated. Nitrogen addition increased relative growth rate because it simultaneously increased unit leaf rate, specific leaf area, and leaf weight ratio. Increased light did not change relative growth rate because decreased specific leaf area and leaf weight ratio compensated the increased unit leaf rate. Phosphorus did not change either relative growth rate or its underlying components. Plants responded ontogenetically to increased nitrogen and light availabilities by accelerating their developmental rate, and plastically by decreasing or increasing their root:shoot ratios, respectively. Plants did not respond either ontogenetically or plastically to increased phosphorus availability. Ontogenetic changes in growth can be separated from plastic and growth-limiting responses by plotting root:shoot ratio against total biomass in the context of the eight possible responses identified above, and also by examining how the underlying components of relative growth rate respond.

Peatlands comprise a globally important carbon pool whose input-output budgets may be significantly altered by climate change. To experimentally determine the sensitivity of the carbon stored in peatlands to climate change, we constructed a mesocosm facility with 54 peat monoliths from a bog and fen in northern Minnesota, USA. These mesocosms were subjected to nine combinations of heat and water-table levels over eight years. Bog mesocosms initially accumulated soil carbon, with greater gains in wetter mesocosms, but after three years no further water-table effects occurred. In contrast, fen mesocosms lost or had no change in soil carbon, with the greatest losses in drier and warmer mesocosms. Changes in soil-carbon storage resulted in concomitant changes in water-table depth, so that water-table depths were similar to those in the natural source sites by the end of the experiment regardless of the initial treatment. These results were primarily due to water-table effects on Sphagnum moss production in the bog mesocosms and to a more complicated suite of warming and water-table effects on production and decomposition in the fen mesocosms. We show that different kinds of peatlands will rapidly gain or lose carbon following hydrological disturbance until they return to their characteristic ("equilibrium") water-table levels. Our results illustrate the potential for a rapid homeostatic response of these ecosystems to future climate change at small spatial scales. Climate change will likely also interact with other carbon cycle-hydrological feedbacks at the scale of the entire peatland over longer time frames and larger spatial scales., (© 2008 by the Ecological Society of America.)