Multidimensional MRI Core Publications

Kikinis Z, Muehlmann M, Pasternak O, Peled S, Kulkarni P, Ferris C, Bouix S, Rathi Y, Koerte IK, Pieper S, et al. Diffusion Imaging of Mild Traumatic Brain Injury in the Impact Accelerated Rodent Model: A Pilot Study. Brain Inj. 2017;31 (10) :1376-81.Abstract
PRIMARY OBJECTIVE: There is a need to understand pathologic processes of the brain following mild traumatic brain injury (mTBI). Previous studies report axonal injury and oedema in the first week after injury in a rodent model. This study aims to investigate the processes occurring 1 week after injury at the time of regeneration and degeneration using diffusion tensor imaging (DTI) in the impact acceleration rat mTBI model. RESEARCH DESIGN: Eighteen rats were subjected to impact acceleration injury, and three rats served as sham controls. Seven days post injury, DTI was acquired from fixed rat brains using a 7T scanner. Group comparison of Fractional Anisotropy (FA) values between traumatized and sham animals was performed using Tract-Based Spatial Statistics (TBSS), a method that we adapted for rats. MAIN OUTCOMES AND RESULTS: TBSS revealed white matter regions of the brain with increased FA values in the traumatized versus sham rats, localized mainly to the contrecoup region. Regions of increased FA included the pyramidal tract, the cerebral peduncle, the superior cerebellar peduncle and to a lesser extent the fibre tracts of the corpus callosum, the anterior commissure, the fimbria of the hippocampus, the fornix, the medial forebrain bundle and the optic chiasm. CONCLUSION: Seven days post injury, during the period of tissue reparation in the impact acceleration rat model of mTBI, microstructural changes to white matter can be detected using DTI.
Ji F, Pasternak O, Liu S, Loke YM, Choo BL, Hilal S, Xu X, Ikram MK, Venketasubramanian N, Chen CL-H, et al. Distinct White Matter Microstructural Abnormalities and Extracellular Water Increases Relate to Cognitive Impairment in Alzheimer's Disease with And without Cerebrovascular Disease. Alzheimers Res Ther. 2017;9 (1) :63.Abstract
BACKGROUND: Mixed vascular and neurodegenerative dementia, such as Alzheimer's disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method. METHODS: We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects. RESULTS: The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance. CONCLUSIONS: Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.
Essayed WI, Zhang F, Unadkat P, Cosgrove RG, Golby AJ, O'Donnell LJ. White Matter Tractography for Neurosurgical Planning: A Topography-based Review of the Current State of the Art. Neuroimage Clin. 2017;15 :659-72.Abstract
We perform a review of the literature in the field of white matter tractography for neurosurgical planning, focusing on those works where tractography was correlated with clinical information such as patient outcome, clinical functional testing, or electro-cortical stimulation. We organize the review by anatomical location in the brain and by surgical procedure, including both supratentorial and infratentorial pathologies, and excluding spinal cord applications. Where possible, we discuss implications of tractography for clinical care, as well as clinically relevant technical considerations regarding the tractography methods. We find that tractography is a valuable tool in variable situations in modern neurosurgery. Our survey of recent reports demonstrates multiple potentially successful applications of white matter tractography in neurosurgery, with progress towards overcoming clinical challenges of standardization and interpretation.
Koppelmans V, Pasternak O, Bloomberg JJ, Dios YDE, Wood SJ, Riascos R, Reuter-Lorenz PA, Kofman IS, Mulavara AP, Seidler RD. Intracranial Fluid Redistribution but No White Matter Microstructural Changes During a Spaceflight Analog. Sci Rep. 2017;7 (1) :3154.Abstract
The neural correlates of spaceflight-induced sensorimotor impairments are unknown. Head down-tilt bed rest (HDBR) serves as a microgravity analog because it mimics the headward fluid shift and axial body unloading of spaceflight. We investigated focal brain white matter (WM) changes and fluid shifts during 70 days of 6° HDBR in 16 subjects who were assessed pre (2x), during (3x), and post-HDBR (2x). Changes over time were compared to those in control subjects (n = 12) assessed four times over 90 days. Diffusion MRI was used to assess WM microstructure and fluid shifts. Free-Water Imaging was used to quantify distribution of intracranial extracellular free water (FW). Additionally, we tested whether WM and FW changes correlated with changes in functional mobility and balance measures. HDBR resulted in FW increases in fronto-temporal regions and decreases in posterior-parietal regions that largely recovered by two weeks post-HDBR. WM microstructure was unaffected by HDBR. FW decreases in the post-central gyrus and precuneus correlated negatively with balance changes. We previously reported that gray matter increases in these regions were associated with less HDBR-induced balance impairment, suggesting adaptive structural neuroplasticity. Future studies are warranted to determine causality and underlying mechanisms.
Nilsson M, Lasič S, Drobnjak I, Topgaard D, Westin C-F. Resolution Limit of Cylinder Diameter Estimation by Diffusion MRI: The Impact of Gradient Waveform and Orientation Dispersion. NMR Biomed. 2017;30 (7).Abstract
Diffusion MRI has been proposed as a non-invasive technique for axonal diameter mapping. However, accurate estimation of small diameters requires strong gradients, which is a challenge for the transition of the technique from preclinical to clinical MRI scanners, since these have weaker gradients. In this work, we develop a framework to estimate the lower bound for accurate diameter estimation, which we refer to as the resolution limit. We analyse only the contribution from the intra-axonal space and assume that axons can be represented by impermeable cylinders. To address the growing interest in using techniques for diffusion encoding that go beyond the conventional single diffusion encoding (SDE) sequence, we present a generalised analysis capable of predicting the resolution limit regardless of the gradient waveform. Using this framework, waveforms were optimised to minimise the resolution limit. The results show that, for parallel cylinders, the SDE experiment is optimal in terms of yielding the lowest possible resolution limit. In the presence of orientation dispersion, diffusion encoding sequences with square-wave oscillating gradients were optimal. The resolution limit for standard clinical MRI scanners (maximum gradient strength 60-80 mT/m) was found to be between 4 and 8 μm, depending on the noise levels and the level of orientation dispersion. For scanners with a maximum gradient strength of 300 mT/m, the limit was reduced to between 2 and 5 μm.
Tax CMW, Westin C-F, Dela Haije T, Fuster A, Viergever MA, Calabrese E, Florack L, Leemans A. Quantifying the Brain's Sheet Structure with Normalized Convolution. Med Image Anal. 2017;39 :162-77.Abstract
The hypothesis that brain pathways form 2D sheet-like structures layered in 3D as "pages of a book" has been a topic of debate in the recent literature. This hypothesis was mainly supported by a qualitative evaluation of "path neighborhoods" reconstructed with diffusion MRI (dMRI) tractography. Notwithstanding the potentially important implications of the sheet structure hypothesis for our understanding of brain structure and development, it is still considered controversial by many for lack of quantitative analysis. A means to quantify sheet structure is therefore necessary to reliably investigate its occurrence in the brain. Previous work has proposed the Lie bracket as a quantitative indicator of sheet structure, which could be computed by reconstructing path neighborhoods from the peak orientations of dMRI orientation density functions. Robust estimation of the Lie bracket, however, is challenging due to high noise levels and missing peak orientations. We propose a novel method to estimate the Lie bracket that does not involve the reconstruction of path neighborhoods with tractography. This method requires the computation of derivatives of the fiber peak orientations, for which we adopt an approach called normalized convolution. With simulations and experimental data we show that the new approach is more robust with respect to missing peaks and noise. We also demonstrate that the method is able to quantify to what extent sheet structure is supported for dMRI data of different species, acquired with different scanners, diffusion weightings, dMRI sampling schemes, and spatial resolutions. The proposed method can also be used with directional data derived from other techniques than dMRI, which will facilitate further validation of the existence of sheet structure.
Rydhög AS, Szczepankiewicz F, Wirestam R, Ahlgren A, Westin C-F, Knutsson L, Pasternak O. Separating Blood and Water: Perfusion and Free Water Elimination from Diffusion MRI in the Human Brain. Neuroimage. 2017;156 :423-34.Abstract
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.
Herberthson M, Özarslan E, Knutsson H, Westin C-F. Dynamics of Local Magnetization in the Eigenbasis of the Bloch-Torrey Operator. J Chem Phys. 2017;146 (12) :124201.Abstract

We consider diffusion within pores with general shapes in the presence of spatially linear magnetic field profiles. The evolution of local magnetization of the spin bearing particles can be described by the Bloch-Torrey equation. We study the diffusive process in the eigenbasis of the non-Hermitian Bloch-Torrey operator. It is possible to find expressions for some special temporal gradient waveforms employed to sensitize the nuclear magnetic resonance (NMR) signal to diffusion. For more general gradient waveforms, we derive an efficient numerical solution by introducing a novel matrix formalism. Compared to previous methods, this new approach requires a fewer number of eigenfunctions to achieve the same accuracy. This shows that these basis functions are better suited to the problem studied. The new framework could provide new important insights into the fundamentals of diffusion sensitization, which could further the development of the field of NMR.

Albi A, Pasternak O, Minati L, Marizzoni M, Bartrés-Faz D, Bargalló N, Bosch B, Rossini PM, Marra C, Müller B, et al. Free Water Elimination Improves Test-Retest Reproducibility of Diffusion Tensor Imaging Indices in the Brain: A Longitudinal Multisite Study of Healthy Elderly Subjects. Hum Brain Mapp. 2017;38 (1) :12-26.Abstract

Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics, there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects. Hum Brain Mapp 38:12-26, 2017. © 2016 Wiley Periodicals, Inc.

Shaffer JJ, Ghayoor A, Long JD, Kim RE-Y, Lourens S, O'Donnell LJ, Westin C-F, Rathi Y, Magnotta V, Paulsen JS, et al. Longitudinal Diffusion Changes in Prodromal and Early HD: Evidence of White-matter Tract Deterioration. Hum Brain Mapp. 2017;38 (3) :1460-77.Abstract

INTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion-weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre-HD). METHODS: As part of the PREDICT-HD study, N = 191 pre-HD individuals and 70 healthy controls underwent two or more (baseline and 1-5 year follow-up) DWI, with n = 649 total sessions. Images were processed using cutting-edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato-sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre-HD participants were divided into three CAG-Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. RESULTS: Cross-sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. CONCLUSIONS: This is the largest longitudinal DWI study of pre-HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. 

Ning L, Setsompop K, Westin C-F, Rathi Y. New Insights about Time-varying Diffusivity and its Estimation from Diffusion MRI. Magn Reson Med. 2017;78 (2) :763-74.Abstract

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 Stepišnik 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. 

Ning L, Özarslan E, Westin C-F, Rathi Y. Precise Inference and Characterization of Structural Organization (PICASO) of Tissue from Molecular Diffusion. Neuroimage. 2017;146 :452-73.Abstract

Inferring the microstructure of complex media from the diffusive motion of molecules is a challenging problem in diffusion physics. In this paper, we introduce a novel representation of diffusion MRI (dMRI) signal from tissue with spatially-varying diffusivity using a diffusion disturbance function. This disturbance function contains information about the (intra-voxel) spatial fluctuations in diffusivity due to restrictions, hindrances and tissue heterogeneity of the underlying tissue substrate. We derive the short- and long-range disturbance coefficients from this disturbance function to characterize the tissue structure and organization. Moreover, we provide an exact relation between the disturbance coefficients and the time-varying moments of the diffusion propagator, as well as their relation to specific tissue microstructural information such as the intra-axonal volume fraction and the apparent axon radius. The proposed approach is quite general and can model dMRI signal for any type of gradient sequence (rectangular, oscillating, etc.) without using the Gaussian phase approximation. The relevance of the proposed PICASO model is explored using Monte-Carlo simulations and in-vivo dMRI data. The results show that the estimated disturbance coefficients can distinguish different types of microstructural organization of axons.

Fan Z, Peter S, Cai W, Song Y, Verma R, Carl-Fredrik W, O'Donnell LJ. Fiber Clustering Based White Matter Connectivity Analysis for Prediction of Autism Spectrum Disorder using Diffusion Tensor Imaging. IEEE Int Symp Biomed Imaging. 2016.Abstract
Autism Spectrum Disorder (ASD) has been suggested to associate with alterations in brain connectivity. In this study, we focus on a fiber clustering tractography segmentation strategy to observe white matter connectivity alterations in ASD. Compared to another popular parcellation-based approach for tractography segmentation based on cortical regions, we hypothesized that the clustering-based method could provide a more anatomically correspondent division of white matter. We applied this strategy to conduct a population-based group statistical analysis for the automated prediction of ASD. We obtained a maximum classification accuracy of 81.33% be- tween ASDs and controls, compared to the results of 78.00% from the parcellation-based method.
Zhang ISBI 2016
Mirzaalian H, Ning L, Savadjiev P, Pasternak O, Bouix S, Michailovich O, Grant G, Marx CE, Morey RA, Flashman LA, et al. Inter-site and Inter-scanner Diffusion MRI Data Harmonization. Neuroimage. 2016;135 :311-23.Abstract

We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method.

Tax CMW, Dela Haije T, Fuster A, Westin C-F, Viergever MA, Florack L, Leemans A. Sheet Probability Index (SPI): Characterizing the Geometrical Organization of the White Matter with Diffusion MRI. Neuroimage. 2016;142 :260-79.Abstract

The question whether our brain pathways adhere to a geometric grid structure has been a popular topic of debate in the diffusion imaging and neuroscience societies. Wedeen et al. (2012a, b) proposed that the brain's white matter is organized like parallel sheets of interwoven pathways. Catani et al. (2012) concluded that this grid pattern is most likely an artifact, resulting from methodological biases that cause the tractography pathways to cross in orthogonal angles. To date, ambiguities in the mathematical conditions for a sheet structure to exist (e.g. its relation to orthogonal angles) combined with the lack of extensive quantitative evidence have prevented wide acceptance of the hypothesis. In this work, we formalize the relevant terminology and recapitulate the condition for a sheet structure to exist. Note that this condition is not related to the presence or absence of orthogonal crossing fibers, and that sheet structure is defined formally as a surface formed by two sets of interwoven pathways intersecting at arbitrary angles within the surface. To quantify the existence of sheet structure, we present a novel framework to compute the sheet probability index (SPI), which reflects the presence of sheet structure in discrete orientation data (e.g. fiber peaks derived from diffusion MRI). With simulation experiments we investigate the effect of spatial resolution, curvature of the fiber pathways, and measurement noise on the ability to detect sheet structure. In real diffusion MRI data experiments we can identify various regions where the data supports sheet structure (high SPI values), but also areas where the data does not support sheet structure (low SPI values) or where no reliable conclusion can be drawn. Several areas with high SPI values were found to be consistent across subjects, across multiple data sets obtained with different scanners, resolutions, and degrees of diffusion weighting, and across various modeling techniques. Under the strong assumption that the diffusion MRI peaks reflect true axons, our results would therefore indicate that pathways do not form sheet structures at every crossing fiber region but instead at well-defined locations in the brain. With this framework, sheet structure location, extent, and orientation could potentially serve as new structural features of brain tissue. The proposed method can be extended to quantify sheet structure in directional data obtained with techniques other than diffusion MRI, which is essential for further validation.

Ning L, Westin C-F, Rathi Y. Estimation of Bounded and Unbounded Trajectories in Diffusion MRI. Front Neurosci. 2016;10 :129.Abstract

Disentangling the tissue microstructural information from the diffusion magnetic resonance imaging (dMRI) measurements is quite important for extracting brain tissue specific measures. The autocorrelation function of diffusing spins is key for understanding the relation between dMRI signals and the acquisition gradient sequences. In this paper, we demonstrate that the autocorrelation of diffusion in restricted or bounded spaces can be well approximated by exponential functions. To this end, we propose to use the multivariate Ornstein-Uhlenbeck (OU) process to model the matrix-valued exponential autocorrelation function of three-dimensional diffusion processes with bounded trajectories. We present detailed analysis on the relation between the model parameters and the time-dependent apparent axon radius and provide a general model for dMRI signals from the frequency domain perspective. For our experimental setup, we model the diffusion signal as a mixture of two compartments that correspond to diffusing spins with bounded and unbounded trajectories, and analyze the corpus-callosum in an ex-vivo data set of a monkey brain.

O'Donnell LJ, Suter Y, Rigolo L, Kahali P, Zhang F, Norton I, Albi A, Olubiyi O, Meola A, Essayed WI, et al. Automated White Matter Fiber Tract Identification in Patients with Brain Tumors. Neuroimage Clin. 2016;13 :138-53.Abstract

We propose a method for the automated identification of key white matter fiber tracts for neurosurgical planning, and we apply the method in a retrospective study of 18 consecutive neurosurgical patients with brain tumors. Our method is designed to be relatively robust to challenges in neurosurgical tractography, which include peritumoral edema, displacement, and mass effect caused by mass lesions. The proposed method has two parts. First, we learn a data-driven white matter parcellation or fiber cluster atlas using groupwise registration and spectral clustering of multi-fiber tractography from healthy controls. Key fiber tract clusters are identified in the atlas. Next, patient-specific fiber tracts are automatically identified using tractography-based registration to the atlas and spectral embedding of patient tractography. Results indicate good generalization of the data-driven atlas to patients: 80% of the 800 fiber clusters were identified in all 18 patients, and 94% of the 800 fiber clusters were found in 16 or more of the 18 patients. Automated subject-specific tract identification was evaluated by quantitative comparison to subject-specific motor and language functional MRI, focusing on the arcuate fasciculus (language) and corticospinal tracts (motor), which were identified in all patients. Results indicate good colocalization: 89 of 95, or 94%, of patient-specific language and motor activations were intersected by the corresponding identified tract. All patient-specific activations were within 3mm of the corresponding language or motor tract. Overall, our results indicate the potential of an automated method for identifying fiber tracts of interest for neurosurgical planning, even in patients with mass lesions.

Ning L, Setsompop K, Michailovich O, Makris N, Shenton ME, Westin C-F, Rathi Y. A Joint Compressed-sensing and Super-resolution Approach for Very High-resolution Diffusion Imaging. Neuroimage. 2016;125 :386-400.Abstract

Diffusion MRI (dMRI) can provide invaluable information about the structure of different tissue types in the brain. Standard dMRI acquisitions facilitate a proper analysis (e.g. tracing) of medium-to-large white matter bundles. However, smaller fiber bundles connecting very small cortical or sub-cortical regions cannot be traced accurately in images with large voxel sizes. Yet, the ability to trace such fiber bundles is critical for several applications such as deep brain stimulation and neurosurgery. In this work, we propose a novel acquisition and reconstruction scheme for obtaining high spatial resolution dMRI images using multiple low resolution (LR) images, which is effective in reducing acquisition time while improving the signal-to-noise ratio (SNR). The proposed method called compressed-sensing super resolution reconstruction (CS-SRR), uses multiple overlapping thick-slice dMRI volumes that are under-sampled in q-space to reconstruct diffusion signal with complex orientations. The proposed method combines the twin concepts of compressed sensing and super-resolution to model the diffusion signal (at a given b-value) in a basis of spherical ridgelets with total-variation (TV) regularization to account for signal correlation in neighboring voxels. A computationally efficient algorithm based on the alternating direction method of multipliers (ADMM) is introduced for solving the CS-SRR problem. The performance of the proposed method is quantitatively evaluated on several in-vivo human data sets including a true SRR scenario. Our experimental results demonstrate that the proposed method can be used for reconstructing sub-millimeter super resolution dMRI data with very good data fidelity in clinically feasible acquisition time.

Szczepankiewicz F, van Westen D, Englund E, Westin C-F, Ståhlberg F, Lätt J, Sundgren PC, Nilsson M. The Link between Diffusion MRI and Tumor Heterogeneity: Mapping Cell Eccentricity and Density by Diffusional Variance Decomposition (DIVIDE). Neuroimage. 2016;142 :522-32.Abstract

The structural heterogeneity of tumor tissue can be probed by diffusion MRI (dMRI) in terms of the variance of apparent diffusivities within a voxel. However, the link between the diffusional variance and the tissue heterogeneity is not well-established. To investigate this link we test the hypothesis that diffusional variance, caused by microscopic anisotropy and isotropic heterogeneity, is associated with variable cell eccentricity and cell density in brain tumors. We performed dMRI using a novel encoding scheme for diffusional variance decomposition (DIVIDE) in 7 meningiomas and 8 gliomas prior to surgery. The diffusional variance was quantified from dMRI in terms of the total mean kurtosis (MKT), and DIVIDE was used to decompose MKT into components caused by microscopic anisotropy (MKA) and isotropic heterogeneity (MKI). Diffusion anisotropy was evaluated in terms of the fractional anisotropy (FA) and microscopic fractional anisotropy (μFA). Quantitative microscopy was performed on the excised tumor tissue, where structural anisotropy and cell density were quantified by structure tensor analysis and cell nuclei segmentation, respectively. In order to validate the DIVIDE parameters they were correlated to the corresponding parameters derived from microscopy. We found an excellent agreement between the DIVIDE parameters and corresponding microscopy parameters; MKA correlated with cell eccentricity (r=0.95, p<10(-7)) and MKI with the cell density variance (r=0.83, p<10(-3)). The diffusion anisotropy correlated with structure tensor anisotropy on the voxel-scale (FA, r=0.80, p<10(-3)) and microscopic scale (μFA, r=0.93, p<10(-6)). A multiple regression analysis showed that the conventional MKT parameter reflects both variable cell eccentricity and cell density, and therefore lacks specificity in terms of microstructure characteristics. However, specificity was obtained by decomposing the two contributions; MKA was associated only to cell eccentricity, and MKI only to cell density variance. The variance in meningiomas was caused primarily by microscopic anisotropy (mean±s.d.) MKA=1.11±0.33 vs MKI=0.44±0.20 (p<10(-3)), whereas in the gliomas, it was mostly caused by isotropic heterogeneity MKI=0.57±0.30 vs MKA=0.26±0.11 (p<0.05). In conclusion, DIVIDE allows non-invasive mapping of parameters that reflect variable cell eccentricity and density. These results constitute convincing evidence that a link exists between specific aspects of tissue heterogeneity and parameters from dMRI. Decomposing effects of microscopic anisotropy and isotropic heterogeneity facilitates an improved interpretation of tumor heterogeneity as well as diffusion anisotropy on both the microscopic and macroscopic scale.

Westin C-F, Knutsson H, Pasternak O, Szczepankiewicz F, Özarslan E, van Westen D, Mattisson C, Bogren M, O'Donnell LJ, Kubicki M, et al. Q-space Trajectory Imaging for Multidimensional Diffusion MRI of the Human Brain. Neuroimage. 2016;135 :345-62.Abstract

This work describes a new diffusion MR framework for imaging and modeling of microstructure that we call q-space trajectory imaging (QTI). The QTI framework consists of two parts: encoding and modeling. First we propose q-space trajectory encoding, which uses time-varying gradients to probe a trajectory in q-space, in contrast to traditional pulsed field gradient sequences that attempt to probe a point in q-space. Then we propose a microstructure model, the diffusion tensor distribution (DTD) model, which takes advantage of additional information provided by QTI to estimate a distributional model over diffusion tensors. We show that the QTI framework enables microstructure modeling that is not possible with the traditional pulsed gradient encoding as introduced by Stejskal and Tanner. In our analysis of QTI, we find that the well-known scalar b-value naturally extends to a tensor-valued entity, i.e., a diffusion measurement tensor, which we call the b-tensor. We show that b-tensors of rank 2 or 3 enable estimation of the mean and covariance of the DTD model in terms of a second order tensor (the diffusion tensor) and a fourth order tensor. The QTI framework has been designed to improve discrimination of the sizes, shapes, and orientations of diffusion microenvironments within tissue. We derive rotationally invariant scalar quantities describing intuitive microstructural features including size, shape, and orientation coherence measures. To demonstrate the feasibility of QTI on a clinical scanner, we performed a small pilot study comparing a group of five healthy controls with five patients with schizophrenia. The parameter maps derived from QTI were compared between the groups, and 9 out of the 14 parameters investigated showed differences between groups. The ability to measure and model the distribution of diffusion tensors, rather than a quantity that has already been averaged within a voxel, has the potential to provide a powerful paradigm for the study of complex tissue architecture.