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Robert A. Brown

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8 papers

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YNIMG Journal 2020 Journal Article

Deep learning segmentation of orbital fat to calibrate conventional MRI for longitudinal studies

Robert A. Brown
Dumitru Fetco
Robert Fratila
Giulia Fadda
Shangge Jiang
Nuha M. Alkhawajah
E. Ann Yeh
Brenda Banwell

In conventional non-quantitative magnetic resonance imaging, image contrast is consistent within images, but absolute intensity can vary arbitrarily between scans. For quantitative analysis of intensity data, images are typically normalized to a consistent reference. The most convenient reference is a tissue that is always present in the image, and is unlikely to be affected by pathological processes. In multiple sclerosis neuroimaging, both the white and gray matter are affected, so normalization techniques that depend on brain tissue may introduce bias or remove biological changes of interest. We introduce a complementary procedure, image “calibration, ” the goal of which is to remove technical intensity artifacts while preserving biological differences. We demonstrate a deep learning approach to segmenting fat from within the orbit of the eyes on T1-weighted images at 1. 5 and 3 T to use as a reference tissue, and use it to calibrate 1018 scans from 256 participants in a study of pediatric-onset multiple sclerosis. The machine segmentations agreed with the adjudicating expert (DF) segmentations better than did those of other expert humans, and calibration resulted in better agreement with semi-quantitative magnetization transfer ratio imaging than did normalization with the WhiteStripe1 algorithm. We suggest that our method addresses two key priorities in the field: (1) it provides a robust option for serial calibration of conventional scans, allowing comparison of disease change in persons imaged at multiple time points in their disease; and (ii) the technique is fast, as the deep learning segmentation takes only 0. 5 s/scan, which is feasible for both large and small datasets.

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YNIMG Journal 2019 Journal Article

Estimating and accounting for the effect of MRI scanner changes on longitudinal whole-brain volume change measurements

Hyunwoo Lee
Kunio Nakamura
Sridar Narayanan
Robert A. Brown
Douglas L. Arnold

Objective Longitudinal MRI studies are often subjected to mid-study scanner changes, which may alter image characteristics such as contrast, signal-to-noise ratio, contrast-to-noise ratio, intensity non-uniformity and geometric distortion. Measuring brain volume loss under these conditions can render the results potentially unreliable across the timepoint of the change. Estimating and accounting for this effect may improve the reliability of estimates of brain atrophy rates. Methods We analyzed 237 subjects who were scanned at 1. 5 T for the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and were subject to intra-vendor or inter-vendor scanner changes during follow-up (up to 8 years). Sixty-three subjects scanned on GE Signa HDx and HDxt platforms were also subject to a T1-weighted sequence change from Magnetization Prepared Rapid Gradient Echo (MP-RAGE) to Fast Spoiled Gradient Echo with IR Preparation (IR-FSPGR), as part of the transition from ADNI-1 to ADNI-2/GO. Two-timepoint percentage brain volume changes (PBVCs) between the baseline “screening” and the follow-up scans were calculated using SIENA. A linear mixed-effects model with subject-specific random slopes and intercepts was applied to estimate the fixed effects of scanner hardware changes on the PBVC measures. The same model also included a term to estimate the fixed effects of the T1-weighted sequence change. Results Different hardware upgrade or change combinations led to different offsets in the PBVC (SE; p): Philips Intera to Siemens Avanto, −1. 81% (0. 30; p < 0. 0001); GE Genesis Signa to Philips Intera, 0. 99% (0. 47, p = 0. 042); GE Signa Excite to Signa HDx, 0. 33% (0. 095, p = 0. 0005); GE Signa Excite to Signa HDxt, −0. 023% (0. 23, p = 0. 92); GE Signa Excite to Signa HDx to Signa HDxt, 0. 25% (0. 095, p = 0. 010) and 0. 27% (0. 16, p = 0. 098), respectively; GE Signa HDx to Signa HDxt, −0. 24% (0. 25, p = 0. 34); Siemens Symphony to Symphony TIM, −0. 39% (0. 16; p = 0. 019). The sequence change from MP-RAGE to IR-SPGR was associated with an average −1. 63% (0. 12; p < 0. 0001) change. Conclusion Inter-vendor scanner changes generally led to greater effects on PBVC measurements than did intra-vendor scanner upgrades. The effect of T1-weighted sequence change was comparable to that of the inter-vendor scanner changes. Inclusion of the corrective fixed-effects terms for the scanner hardware and T1-weighted sequence changes yielded better model goodness-of-fits, and thus, potentially more reliable estimates of whole-brain atrophy rates.

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YNIMG Journal 2017 Journal Article

GABA and glutamate levels correlate with MTR and clinical disability: Insights from multiple sclerosis

Julia C. Nantes
Sébastien Proulx
Jidan Zhong
Scott A. Holmes
Sridar Narayanan
Robert A. Brown
Richard D. Hoge
Lisa Koski

Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains’ left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to account for confounding factors that could contaminate the measurement of neurometabolite levels due to disease, such as the macromolecule signal, partial volume effects, and relaxation effects. Glutamate levels in both regions of interest were lower in people with multiple sclerosis. In the sensorimotor (though not the parietal) region, GABA concentration was higher in the multiple sclerosis group compared to controls. Lower magnetization transfer ratio within grey and white matter regions from which spectroscopy data were acquired was linked to neurometabolite levels. When adjusting for age, normalized brain volume, MTR, total N-acetylaspartate level, and glutamate level, significant relationships were found between lower sensorimotor GABA level and worse performance on several tests, including one of upper limb motor function. This work highlights important methodological considerations relevant to analysis of spectroscopy data, particularly in the afflicted human brain. These findings support that regional neurotransmitter levels are linked to local microstructural integrity and specific behavioral abilities that can be affected in diseases such as multiple sclerosis.

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YNIMG Journal 2015 Journal Article

Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations

Kunio Nakamura
Robert A. Brown
Sridar Narayanan
D. Louis Collins
Douglas L. Arnold

We investigated fluctuations in brain volume throughout the day using statistical modeling of magnetic resonance imaging (MRI) from large populations. We applied fully automated image analysis software to measure the brain parenchymal fraction (BPF), defined as the ratio of the brain parenchymal volume and intracranial volume, thus accounting for variations in head size. The MRI data came from serial scans of multiple sclerosis (MS) patients in clinical trials (n=755, 3269 scans) and from subjects participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=834, 6114 scans). The percent change in BPF was modeled with a linear mixed effect (LME) model, and the model was applied separately to the MS and ADNI datasets. The LME model for the MS datasets included random subject effects (intercept and slope over time) and fixed effects for the time-of-day, time from the baseline scan, and trial, which accounted for trial-related effects (for example, different inclusion criteria and imaging protocol). The model for ADNI additionally included the demographics (baseline age, sex, subject type [normal, mild cognitive impairment, or Alzheimer's disease], and interaction between subject type and time from baseline). There was a statistically significant effect of time-of-day on the BPF change in MS clinical trial datasets (−0. 180 per day, that is, 0. 180% of intracranial volume, p =0. 019) as well as the ADNI dataset (−0. 438 per day, that is, 0. 438% of intracranial volume, p <0. 0001), showing that the brain volume is greater in the morning. Linearly correcting the BPF values with the time-of-day reduced the required sample size to detect a 25% treatment effect (80% power and 0. 05 significance level) on change in brain volume from 2 time-points over a period of 1year by 2. 6%. Our results have significant implications for future brain volumetric studies, suggesting that there is a potential acquisition time bias that should be randomized or statistically controlled to account for the day-to-day brain volume fluctuations.

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YNICL Journal 2014 Journal Article

Correlation between brain volume change and T2 relaxation time induced by dehydration and rehydration: Implications for monitoring atrophy in clinical studies

Kunio Nakamura
Robert A. Brown
David Araujo
Sridar Narayanan
Douglas L. Arnold

Brain volume change measured from magnetic resonance imaging (MRI) provides a widely used and useful in vivo measure of irreversible tissue loss. These measurements, however, can be influenced by reversible factors such as shifts in brain water content. Given the strong effect of water on T2 relaxation, we investigated whether an estimate of T2 relaxation time would correlate with brain volume changes induced by physiologically manipulating hydration status. We used a clinically feasible estimate of T2 ("pseudo-T2") computed from a dual turbo spin-echo MRI sequence and correlated pseudo-T2 changes to percent brain volume changes in 12 healthy subjects after dehydration overnight (16-hour thirsting) and rehydration (drinking 1.5 L of water). We found that the brain volume significantly increased between the dehydrated and rehydrated states (mean brain volume change = 0.36%, p = 0.0001) but did not change significantly during the dehydration interval (mean brain volume change = 0.04%, p = 0.57). The changes in brain volume and pseudo-T2 significantly correlated with each other, with marginal and conditional correlations (R (2)) of 0.44 and 0.65, respectively. Our results show that pseudo-T2 may be used in conjunction with the measures of brain volume to distinguish reversible water fluctuations and irreversible brain tissue loss (atrophy) and to investigate disease mechanisms related to neuro-inflammation, e.g., in multiple sclerosis, where edema-related water fluctuations may occur with disease activity and anti-inflammatory treatment.

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YNICL Journal 2014 Journal Article

Imaging of repeated episodes of demyelination and remyelination in multiple sclerosis

Robert A. Brown
Sridar Narayanan
Douglas L. Arnold

Multiple sclerosis (MS) is characterized by the formation of demyelinating lesions in the white matter (WM). However, the timecourse of the evolution of healthy white matter into fully demyelinated lesions in MS is not well understood. We use a recently proposed technique to examine magnetization transfer ratio (MTR) timecourses in lesions segmented from MTR images in patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). In both groups we found MTR lesions forming both in previously normal appearing WM (de novo lesions) as well as in previously lesional tissue that appears to be experiencing a second round of inflammatory demyelination (repeat lesions). Both de novo and repeat lesions exhibited significant, but incomplete MTR recovery, suggesting partial remyelination; post-lesion MTR values in de novo lesions were similar to pre-lesion values in repeat lesions. Both de novo and repeat lesions were found in subjects in relapsing-remitting and secondary progressive stages of MS, and repeat lesions appeared relatively more common in the secondary progressive phase. These observations support the hypothesis that entirely demyelinated lesions found on histopathology are the result of multiple episodes of demyelination and incomplete remyelination, and may have implications for MS treatment development efforts aimed at neuroprotection and enhancing remyelination.

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YNICL Journal 2014 Journal Article

Magnetization transfer ratio recovery in new lesions decreases during adolescence in pediatric-onset multiple sclerosis patients

Robert A. Brown
Sridar Narayanan
Brenda Banwell
Douglas L. Arnold

Children and adolescents diagnosed with multiple sclerosis rarely accrue physical disability early in their disease. This could be explained by greater remyelination in children, a capacity that may be lost in adolescence or early adulthood. Magnetization transfer ratio (MTR) MRI can be used to quantify changes in myelin in MS. We used serial MTR imaging and longitudinal random effects analysis to quantify recovery of MTR in acute lesions and to evaluate MTR changes in normal-appearing tissue in 19 adolescent MS patients. Our objective was to determine whether younger adolescents have a greater capacity for remyelination and whether this decreases as patients approach adulthood. We detected a significant decrease in MTR recovery between ages 16 and 20 years (p = 0. 023), with older subjects approaching typical recovery levels for adult-onset MS. MTR recovery in acute MS lesions decreases with age in adolescents, suggesting loss of remyelination capacity. This may be related to the conclusion of primary myelination or other developmental factors.

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YNIMG Journal 2013 Journal Article

Segmentation of magnetization transfer ratio lesions for longitudinal analysis of demyelination and remyelination in multiple sclerosis

Robert A. Brown
Sridar Narayanan
Douglas L. Arnold

We demonstrate a new technique to quantify longitudinal changes in magnetization transfer ratio (MTR) magnetic resonance imaging (MRI). These changes are indicative of demyelination and remyelination. This technique comprises a definition of ΔMTR lesions, which are identified directly from the MTR images, and an automatic procedure for segmenting these lesions. We used this technique to analyze MTR changes in lesions of subjects with rapidly progressing multiple sclerosis before and after treatment with immunoablation and autologous stem cell transplant. Subjects who experienced clinical improvement after treatment showed significantly improved MTR recovery in lesions that were recovering during treatment (p <0. 0001) while those who were clinically stable after treatment showed significantly poorer MTR recovery (p =0. 002). The statistical power of this technique to detect treatment effects on MTR recovery was shown to be considerably better than previous methods. These results suggest that longitudinal measurements of MTR in ΔMTR lesions may be an important technique for the assessment of treatment effects on remyelination in clinical trials.

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