Publications by Year: 2017

PURPOSE: Characterizing the relation between the applied gradient sequences and the measured diffusion MRI signal is important for estimating the time-dependent diffusivity, which provides important information about the microscopic tissue structure. THEORY AND METHODS: In this article, we extend the classical theory of Stepi\v snik for measuring time-dependent diffusivity under the Gaussian phase approximation. In particular, we derive three novel expressions which represent the diffusion MRI signal in terms of the mean-squared displacement, the instantaneous diffusivity, and the velocity autocorrelation function. We present the explicit signal expressions for the case of single diffusion encoding and oscillating gradient spin-echo sequences. Additionally, we also propose three different models to represent time-varying diffusivity and test them using Monte-Carlo simulations and in vivo human brain data. RESULTS: The time-varying diffusivities are able to distinguish the synthetic structures in the Monte-Carlo simulations. There is also strong statistical evidence about time-varying diffusivity from the in vivo human data set. CONCLUSION: The proposed theory provides new insights into our understanding of the time-varying diffusivity using different gradient sequences. The proposed models for representing time-varying diffusivity can be utilized to study time-varying diffusivity using in vivo human brain diffusion MRI data. Magn Reson Med 78:763-774, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is considered to be a promising cohort to explore biomarkers of schizophrenia risk based on a 30 % probability of developing schizophrenia in adulthood. In this study, we investigated abnormalities in the microstructure of white matter in adolescents with 22q11DS and their specificity to prodromal symptoms of schizophrenia. METHODS: Diffusion Magnetic Resonance Imaging (dMRI) data were acquired from 50 subjects with 22q11DS (9 with and 41 without prodromal psychotic symptoms), and 47 matched healthy controls (mean age 18 +/-2 years). DMRI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and compared between groups using the Tract Based Spatial Statistics (TBSS) method. Additionally, correlations between dMRI measures and scores on positive symptoms were performed. RESULTS: Reductions in MD, AD and RD (but not FA) were found in the corpus callosum (CC), left and right superior longitudinal fasciculus (SLF), and left and right corona radiata in the entire 22q11DS group. In addition, the 22q11DS subgroup with prodromal symptoms showed reductions in AD and MD, but no changes in RD when compared to the non-prodromal subgroup, in CC, right SLF, right corona radiata and right internal capsule. Finally, AD values in these tracts correlated with the scores on the psychosis subscale. CONCLUSION: Microstructural abnormalities in brain white matter are present in adolescent subjects with prodromal psychotic symptoms.

Recent studies of long-term anabolic-androgenic steroid (AAS) users reported amygdala structural and functional connectivity abnormalities. We assessed white matter microstructure in the inferior-fronto-occipital fasciculus (IFOF), a major associative bundle of the amygdala network. Diffusion weighted images acquired from 9 male long-term AAS users and 8 matched controls aged 36-51 years old were processed using a standardized pipeline (Tract-Based Spatial Statistics). Group differences were examined using linear regression with adjustment for age and current testosterone level. Compared to nonusers, AAS users exhibited significantly higher fractional anisotropy (FA) in the IFOF. Users showed markedly greater FA than nonusers on the left IFOF but only a modest, nonsignificant difference on the right IFOF. Moreover, FA was positively associated with lifetime cumulative AAS dose. Our results suggest that long-term AAS use alters IFOF white matter organization and integrity, which in turn might affect amygdala-related processes such as reward system function. Accordingly, further studies are needed to replicate findings in larger subject groups to determine the functional significance of the FA abnormality.

Alcoholism can lead to a complex mixture of cognitive and emotional deficits associated with abnormalities in fronto-cortico-striatal-limbic brain circuitries. Given the broad variety of neurobehavioral symptoms, one would also expect alterations of postrolandic neocortical systems. Thus, we used diffusion tensor imaging (DTI) to study the integrity of the middle longitudinal fascicle (MdLF), a major postrolandic association white matter tract that extends from the superior temporal gyrus to the parietal and occipital lobes, in individuals with a history of chronic alcohol abuse. DTI data were acquired on a 3 Tesla scanner in 30 abstinent alcoholics (AL; 9 men) and 25 nonalcoholic controls (NC; 8 men). The MdLF was determined using DTI-based tractography. Volume of the tract, fractional anisotropy (FA), radial (RD), and axial (AD) diffusivity, were compared between AL and NC, with sex and hemispheric laterality as independent variables. The association of DTI measures with neuropsychological performance was evaluated. Men showed bilateral reduction of MdLF volume and abnormal diffusion measurements of the left MdLF. Analyses also indicated that the left MdLF diffusion measurements in AL men were negatively associated with Verbal IQ and verbal fluency test scores. Abstinent alcoholic men display macrostructural abnormalities in the MdLF bilaterally, indicating an overall white matter deficit. Additionally, microstructural deficits of the left MdLF suggest more specific alterations associated with verbal skills in men.

Thepromoter polymorphism (rs35705950) has been associated with interstitial lung abnormalities (ILA) in white participants from the general population; whether these findings are replicated and influenced by the ILA subtype is not known. We evaluated the associations between thegenotype and ILA in cohorts with extensive imaging characterisation.We performed ILA phenotyping andpromoter genotyping in 5308 and 9292 participants from the AGES-Reykjavik and COPDGene cohorts, respectively.We found that ILA was present in 7% of participants from the AGES-Reykjavik, 8% of non-Hispanic white participants from COPDGene and 7% of African-American participants from COPDGene. Although thegenotype was strongly associated (after correction for multiple testing) with ILA (OR 2.1, 95% CI 1.8-2.4, p=1×10), there was evidence of significant heterogeneity between cohorts (I=81%). When narrowed to specific radiologic subtypes, (subpleural ILA), thegenotype remained strongly associated (OR 2.6, 95% CI 2.2-3.1, p=1×10) with minimal heterogeneity (I=0%). Although there was no evidence that thegenotype influenced survival, there was evidence thatgenotype improved risk prediction for possible usual interstitial pneumonia (UIP) or a UIP pattern in non-Hispanic white populations.Thepromoter polymorphism is strongly associated with ILA and specific radiologic subtypes of ILA, with varying degrees of heterogeneity in the underlying populations.

Solvents are commonly used in pharmaceutical and cosmetic formulations and sanitary products and cleansers. The uptake of solvent into the skin may change the molecular organization of skin lipids and proteins, which may in turn alter the protective skin barrier function. We herein examine the molecular effects of 10 different solvents on the outermost layer of skin, the stratum corneum (SC), using polarization transfer solid-state NMR on natural abundance (13)C in intact SC. With this approach it is possible to characterize the molecular dynamics of solvent molecules when present inside intact SC and to simultaneously monitor the effects caused by the added solvent on SC lipids and protein components. All solvents investigated cause an increased fluidity of SC lipids, with the most prominent effects shown for the apolar hydrocarbon solvents and 2-propanol. However, no solvent other than water shows the ability to fluidize amino acids in the keratin filaments. The solvent molecules themselves show reduced molecular mobility when incorporated in the SC matrix. Changes in the molecular properties of the SC, and in particular alternation in the balance between solid and fluid SC components, may have significant influences on the macroscopic SC barrier properties as well as mechanical properties of the skin. Deepened understanding of molecular effects of foreign compounds in SC fluidity can therefore have strong impact on the development of skin products in pharmaceutical, cosmetic, and sanitary applications.

RATIONALE AND OBJECTIVES: Imaging-based assessment of cardiovascular structure and function provides clinically relevant information in smokers. Non-cardiac-gated thoracic computed tomographic (CT) scanning is increasingly leveraged for clinical care and lung cancer screening. We sought to determine if more comprehensive measures of ventricular geometry could be obtained from CT using an atlas-based surface model of the heart. MATERIALS AND METHODS: Subcohorts of 24 subjects with cardiac magnetic resonance imaging (MRI) and 262 subjects with echocardiography were identified from COPDGene, a longitudinal observational study of smokers. A surface model of the heart was manually initialized, and then automatically optimized to fit the epicardium for each CT. Estimates of right and left ventricular (RV and LV) volume and free-wall curvature were then calculated and compared to structural and functional metrics obtained from MRI and echocardiograms. RESULTS: CT measures of RV dimension and curvature correlated with similar measures obtained using MRI. RV and LV volume obtained from CT inversely correlated with echocardiogram-based estimates of RV systolic pressure using tricuspid regurgitation jet velocity and LV ejection fraction respectively. Patients with evidence of RV or LV dysfunction on echocardiogram had larger RV and LV dimensions on CT. Logistic regression models based on demographics and ventricular measures from CT had an area under the curve of >0.7 for the prediction of elevated right ventricular systolic pressure and ventricular failure. CONCLUSIONS: These data suggest that non-cardiac-gated, non-contrast-enhanced thoracic CT scanning may provide insight into cardiac structure and function in smokers.

Computerized tomography (CT) is a widely adopted modality for analyzing directly or indirectly functional, biological and morphological processes by means of the image characteristics. However, the potential utilization of the information obtained from CT images is often limited when considering the analysis of quantitative information involving different devices, acquisition protocols or reconstruction algorithms. Although CT scanners are calibrated as a part of the imaging workflow, the calibration is circumscribed to global reference values and does not circumvent problems that are inherent to the imaging modality. One of them is the lack of noise stationarity, which makes quantitative biomarkers extracted from the images less robust and stable. Some methodologies have been proposed for the assessment of non-stationary noise in reconstructed CT scans. However, those methods focused on the non-stationarity only due to the reconstruction geometry and are mainly based on the propagation of the variance of noise throughout the whole reconstruction process. Additionally, the philosophy followed in the state-of-the-art methods is based on the reduction of noise, but not in the standardization of it. This means that, even if the noise is reduced, the statistics of the signal remain non-stationary, which is insufficient to enable comparisons between different acquisitions with different statistical characteristics. In this work, we propose a statistical characterization of noise in reconstructed CT scans that leads to a versatile statistical model that effectively characterizes different doses, reconstruction kernels, and devices. The statistical model is generalized to deal with the partial volume effect via a localized mixture model that also describes the non-stationarity of noise. Finally, we propose a stabilization scheme to achieve stationary variance. The validation of the proposed methodology was performed with a physical phantom and clinical CT scans acquired with different configurations (kernels, doses, algorithms including iterative reconstruction). The results confirmed its suitability to enable comparisons with different doses, and acquisition protocols.

We present a method to estimate a multivariate Gaussian distribution of diffusion tensor features in a set of brain regions based on a small sample of healthy individuals, and use this distribution to identify imaging abnormalities in subjects with mild traumatic brain injury. The multivariate model receives apriori knowledge in the form of a neighborhood graph imposed on the precision matrix, which models brain region interactions, and an additional Lsparsity constraint. The model is then estimated using the graphical LASSO algorithm and the Mahalanobis distance of healthy and TBI subjects to the distribution mean is used to evaluate the discriminatory power of the model. Our experiments show that the addition of the apriori neighborhood graph results in significant improvements in classification performance compared to a model which does not take into account the brain region interactions or one which uses a fully connected prior graph. In addition, we describe a method, using our model, to detect the regions that contribute the most to the overall abnormality of the DTI profile of a subject’s brain.

The assessment of the free water fraction in the brain provides important information about extracellular processes such as atrophy and neuroinflammation in various clinical conditions as well as in normal development and aging. Free water estimates from diffusion MRI are assumed to account for freely diffusing water molecules in the extracellular space, but may be biased by other pools of molecules in rapid random motion, such as the intravoxel incoherent motion (IVIM) of blood, where water molecules perfuse in the randomly oriented capillary network. The goal of this work was to separate the signal contribution of the perfusing blood from that of free-water and of other brain diffusivities. The influence of the vascular compartment on the estimation of the free water fraction and other diffusivities was investigated by simulating perfusion in diffusion MRI data. The perfusion effect in the simulations was significant, especially for the estimation of the free water fraction, and was maintained as long as low b-value data were included in the analysis. Two approaches to reduce the perfusion effect were explored in this study: (i) increasing the minimal b-value used in the fitting, and (ii) using a three-compartment model that explicitly accounts for water molecules in the capillary blood. Estimation of the model parameters while excluding low b-values reduced the perfusion effect but was highly sensitive to noise. The three-compartment model fit was more stable and additionally, provided an estimation of the volume fraction of the capillary blood compartment. The three-compartment model thus disentangles the effects of free water diffusion and perfusion, which is of major clinical importance since changes in these components in the brain may indicate different pathologies, i.e., those originating from the extracellular space, such as neuroinflammation and atrophy, and those related to the vascular space, such as vasodilation, vasoconstriction and capillary density. Diffusion MRI data acquired from a healthy volunteer, using multiple b-shells, demonstrated an expected non-zero contribution from the blood fraction, and indicated that not accounting for the perfusion effect may explain the overestimation of the free water fraction evinced in previous studies. Finally, the applicability of the method was demonstrated with a dataset acquired using a clinically feasible protocol with shorter acquisition time and fewer b-shells.