Multidimensional MRI Core Publications

O'Donnell LJ, Daducci A, Wassermann D, Lenglet C. Advances in Computational and Statistical Diffusion MRI. NMR Biomed. 2019;32 (4) :e3805.Abstract
Computational methods are crucial for the analysis of diffusion magnetic resonance imaging (MRI) of the brain. Computational diffusion MRI can provide rich information at many size scales, including local microstructure measures such as diffusion anisotropies or apparent axon diameters, whole-brain connectivity information that describes the brain's wiring diagram and population-based studies in health and disease. Many of the diffusion MRI analyses performed today were not possible five, ten or twenty years ago, due to the requirements for large amounts of computer memory or processor time. In addition, mathematical frameworks had to be developed or adapted from other fields to create new ways to analyze diffusion MRI data. The purpose of this review is to highlight recent computational and statistical advances in diffusion MRI and to put these advances into context by comparison with the more traditional computational methods that are in popular clinical and scientific use. We aim to provide a high-level overview of interest to diffusion MRI researchers, with a more in-depth treatment to illustrate selected computational advances.
Wu Y, Zhang F, Makris N, Ning Y, Norton I, She S, Peng H, Rathi Y, Feng Y, Wu H, et al. Investigation into Local White Matter Abnormality in Emotional Processing and Sensorimotor Areas using an Automatically Annotated Fiber Clustering in Major Depressive Disorder. Neuroimage. 2018;181 :16-29.Abstract
This work presents an automatically annotated fiber cluster (AAFC) method to enable identification of anatomically meaningful white matter structures from the whole brain tractography. The proposed method consists of 1) a study-specific whole brain white matter parcellation using a well-established data-driven groupwise fiber clustering pipeline to segment tractography into multiple fiber clusters, and 2) a novel cluster annotation method to automatically assign an anatomical tract annotation to each fiber cluster by employing cortical parcellation information across multiple subjects. The novelty of the AAFC method is that it leverages group-wise information about the fiber clusters, including their fiber geometry and cortical terminations, to compute a tract anatomical label for each cluster in an automated fashion. We demonstrate the proposed AAFC method in an application of investigating white matter abnormality in emotional processing and sensorimotor areas in major depressive disorder (MDD). Seven tracts of interest related to emotional processing and sensorimotor functions are automatically identified using the proposed AAFC method as well as a comparable method that uses a cortical parcellation alone. Experimental results indicate that our proposed method is more consistent in identifying the tracts across subjects and across hemispheres in terms of the number of fibers. In addition, we perform a between-group statistical analysis in 31 MDD patients and 62 healthy subjects on the identified tracts using our AAFC method. We find statistical differences in diffusion measures in local regions within a fiber tract (e.g. 4 fiber clusters within the identified left hemisphere cingulum bundle (consisting of 14 clusters) are significantly different between the two groups), suggesting the ability of our method in identifying potential abnormality specific to subdivisions of a white matter structure.
Zhang F, Wu Y, Norton I, Rigolo L, Rathi Y, Makris N, O'Donnell LJ. An Anatomically Curated Fiber Clustering White Matter Atlas for Consistent White Matter Tract Parcellation across the Lifespan. Neuroimage. 2018;179 :429-47.Abstract
This work presents an anatomically curated white matter atlas to enable consistent white matter tract parcellation across different populations. Leveraging a well-established computational pipeline for fiber clustering, we create a tract-based white matter atlas including information from 100 subjects. A novel anatomical annotation method is proposed that leverages population-based brain anatomical information and expert neuroanatomical knowledge to annotate and categorize the fiber clusters. A total of 256 white matter structures are annotated in the proposed atlas, which provides one of the most comprehensive tract-based white matter atlases covering the entire brain to date. These structures are composed of 58 deep white matter tracts including major long range association and projection tracts, commissural tracts, and tracts related to the brainstem and cerebellar connections, plus 198 short and medium range superficial fiber clusters organized into 16 categories according to the brain lobes they connect. Potential false positive connections are annotated in the atlas to enable their exclusion from analysis or visualization. In addition, the proposed atlas allows for a whole brain white matter parcellation into 800 fiber clusters to enable whole brain connectivity analyses. The atlas and related computational tools are open-source and publicly available. We evaluate the proposed atlas using a testing dataset of 584 diffusion MRI scans from multiple independently acquired populations, across genders, the lifespan (1 day-82 years), and different health conditions (healthy control, neuropsychiatric disorders, and brain tumor patients). Experimental results show successful white matter parcellation across subjects from different populations acquired on multiple scanners, irrespective of age, gender or disease indications. Over 99% of the fiber tracts annotated in the atlas were detected in all subjects on average. One advantage in terms of robustness is that the tract-based pipeline does not require any cortical or subcortical segmentations, which can have limited success in young children and patients with brain tumors or other structural lesions. We believe this is the first demonstration of consistent automated white matter tract parcellation across the full lifespan from birth to advanced age.
Chad JA, Pasternak O, Salat DH, Chen JJ. Re-examining Age-related Differences in White Matter Microstructure with Free-water Corrected Diffusion Tensor Imaging. Neurobiol Aging. 2018;71 :161-70.Abstract
Diffusion tensor imaging (DTI) has been used extensively to investigate white matter (WM) microstructural changes during healthy adult aging. However, WM fibers are known to shrink throughout the lifespan, leading to larger interstitial spaces with age. This could allow more extracellular free water molecules to bias DTI metrics, which are relied upon to provide WM microstructural information. Using a cohort of 212 participants, we demonstrate that WM microstructural changes in aging are potentially less pronounced than previously reported once the free water compartment is eliminated. After free water elimination, DTI parameters show age-related differences that match histological evidence of myelin degradation and debris accumulation. The fraction of free water is further shown to associate better with age than any of the conventional DTI parameters. Our findings suggest that DTI analyses involving free water are likely to yield novel insight into retrospective re-analysis of data and to answer new questions in ongoing DTI studies of brain aging.
Hong Y, O'Donnell LJ, Savadjiev P, Zhang F, Wassermann D, Pasternak O, Johnson H, Paulsen J, Vonsattel J-P, Makris N, et al. Genetic Load Determines Atrophy in Hand Cortico-striatal Pathways in Presymptomatic Huntington's Disease. Hum Brain Mapp. 2018;39 (10) :3871-83.Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder that causes progressive breakdown of striatal neurons. Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal-HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal-HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT-HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi-tensor tractography algorithm with an isotropic volume fraction compartment allows estimating diffusion of fast-moving extra-cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico-striatal pathways as a function of CAG-repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG-repeats, which connects the genetic abnormality (CAG-repeats) to an imaging-based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico-striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation.
Gong S, Zhang F, Norton I, Essayed WI, Unadkat P, Rigolo L, Pasternak O, Rathi Y, Hou L, Golby AJ, et al. Free Water Modeling of Peritumoral Edema using Multi-fiber Tractography: Application to Tracking the Arcuate Fasciculus for Neurosurgical Planning. PLoS One. 2018;13 (5) :e0197056.Abstract
PURPOSE: Peritumoral edema impedes the full delineation of fiber tracts due to partial volume effects in image voxels that contain a mixture of cerebral parenchyma and extracellular water. The purpose of this study is to investigate the effect of incorporating a free water (FW) model of edema for white matter tractography in the presence of edema. MATERIALS AND METHODS: We retrospectively evaluated 26 consecutive brain tumor patients with diffusion MRI and T2-weighted images acquired presurgically. Tractography of the arcuate fasciculus (AF) was performed using the two-tensor unscented Kalman filter tractography (UKFt) method, the UKFt method with a reduced fiber tracking stopping fractional anisotropy (FA) threshold (UKFt+rFA), and the UKFt method with the addition of a FW compartment (UKFt+FW). An automated white matter fiber tract identification approach was applied to delineate the AF. Quantitative measurements included tract volume, edema volume, and mean FW fraction. Visual comparisons were performed by three experts to evaluate the quality of the detected AF tracts. RESULTS: The AF volume in edematous brain hemispheres was significantly larger using the UKFt+FW method (p<0.0001) compared to UKFt, but not significantly larger (p = 0.0996) in hemispheres without edema. The AF size increase depended on the volume of edema: a significant correlation was found between AF volume affected by (intersecting) edema and AF volume change with the FW model (Pearson r = 0.806, p<0.0001). The mean FW fraction was significantly larger in tracts intersecting edema (p = 0.0271). Compared to the UKFt+rFA method, there was a significant increase of the volume of the AF tract that intersected the edema using the UKFt+FW method, while the whole AF volumes were similar. Expert judgment results, based on the five patients with the smallest AF volumes, indicated that the expert readers generally preferred the AF tract obtained by using the FW model, according to their anatomical knowledge and considering the potential influence of the final results on the surgical route. CONCLUSION: Our results indicate that incorporating biophysical models of edema can increase the sensitivity of tractography in regions of peritumoral edema, allowing better tract visualization in patients with high grade gliomas and metastases.
Özarslan E, Yolcu C, Herberthson M, Knutsson H, Westin C-F. Influence of the Size and Curvedness of Neural Projections on the Orientationally Averaged Diffusion MR Signal . Front Phys. 2018;6.Abstract
Neuronal and glial projections can be envisioned to be tubes of infinitesimal diameter as far as diffusion magnetic resonance (MR) measurements via clinical scanners are concerned. Recent experimental studies indicate that the decay of the orientationally-averaged signal in white-matter may be characterized by the power-law, () ∝ , where is the wavenumber determined by the parameters of the pulsed field gradient measurements. One particular study by McKinnon . [1] reports a distinctively faster decay in gray-matter. Here, we assess the role of the size and curvature of the neurites and glial arborizations in these experimental findings. To this end, we studied the signal decay for diffusion along general curves at all three temporal regimes of the traditional pulsed field gradient measurements. We show that for curvy projections, employment of longer pulse durations leads to a disappearance of the decay, while such decay is robust when narrow gradient pulses are used. Thus, in clinical acquisitions, the lack of such a decay for a fibrous specimen can be seen as indicative of fibers that are curved. We note that the above discussion is valid for an intermediate range of -values as the true asymptotic behavior of the signal decay is () ∝ for narrow pulses (through Debye-Porod law) or steeper for longer pulses. This study is expected to provide insights for interpreting the diffusion-weighted images of the central nervous system and aid in the design of acquisition strategies.
Albi A, Meola A, Zhang F, Kahali P, Rigolo L, Tax CMW, Ciris PA, Essayed WI, Unadkat P, Norton I, et al. Image Registration to Compensate for EPI Distortion in Patients with Brain Tumors: An Evaluation of Tract-Specific Effects. J Neuroimaging. 2018;28 (2) :173-82.Abstract
BACKGROUND AND PURPOSE: Diffusion magnetic resonance imaging (dMRI) provides preoperative maps of neurosurgical patients' white matter tracts, but these maps suffer from echo-planar imaging (EPI) distortions caused by magnetic field inhomogeneities. In clinical neurosurgical planning, these distortions are generally not corrected and thus contribute to the uncertainty of fiber tracking. Multiple image processing pipelines have been proposed for image-registration-based EPI distortion correction in healthy subjects. In this article, we perform the first comparison of such pipelines in neurosurgical patient data. METHODS: Five pipelines were tested in a retrospective clinical dMRI dataset of 9 patients with brain tumors. Pipelines differed in the choice of fixed and moving images and the similarity metric for image registration. Distortions were measured in two important tracts for neurosurgery, the arcuate fasciculus and corticospinal tracts. RESULTS: Significant differences in distortion estimates were found across processing pipelines. The most successful pipeline used dMRI baseline and T2-weighted images as inputs for distortion correction. This pipeline gave the most consistent distortion estimates across image resolutions and brain hemispheres. CONCLUSIONS: Quantitative results of mean tract distortions on the order of 1-2 mm are in line with other recent studies, supporting the potential need for distortion correction in neurosurgical planning. Novel results include significantly higher distortion estimates in the tumor hemisphere and greater effect of image resolution choice on results in the tumor hemisphere. Overall, this study demonstrates possible pitfalls and indicates that care should be taken when implementing EPI distortion correction in clinical settings.
Zhang F, Wu W, Ning L, McAnulty G, Waber D, Gagoski B, Sarill K, Hamoda HM, Song Y, Cai W, et al. Suprathreshold Fiber Cluster Statistics: Leveraging White Matter Geometry to Enhance Tractography Statistical Analysis. Neuroimage. 2018;171 :341-54.Abstract
This work presents a suprathreshold fiber cluster (STFC) method that leverages the whole brain fiber geometry to enhance statistical group difference analyses. The proposed method consists of 1) a well-established study-specific data-driven tractography parcellation to obtain white matter tract parcels and 2) a newly proposed nonparametric, permutation-test-based STFC method to identify significant differences between study populations. The basic idea of our method is that a white matter parcel's neighborhood (nearby parcels with similar white matter anatomy) can support the parcel's statistical significance when correcting for multiple comparisons. We propose an adaptive parcel neighborhood strategy to allow suprathreshold fiber cluster formation that is robust to anatomically varying inter-parcel distances. The method is demonstrated by application to a multi-shell diffusion MRI dataset from 59 individuals, including 30 attention deficit hyperactivity disorder patients and 29 healthy controls. Evaluations are conducted using both synthetic and in-vivo data. The results indicate that the STFC method gives greater sensitivity in finding group differences in white matter tract parcels compared to several traditional multiple comparison correction methods.
Ning L, Nilsson M, Lasič S, Westin C-F, Rathi Y. Cumulant Expansions for Measuring Water Exchange using Diffusion MRI. J Chem Phys. 2018;148 (7) :074109.Abstract
The rate of water exchange across cell membranes is a parameter of biological interest and can be measured by diffusion magnetic resonance imaging (dMRI). In this work, we investigate a stochastic model for the diffusion-and-exchange of water molecules. This model provides a general solution for the temporal evolution of dMRI signal using any type of gradient waveform, thereby generalizing the signal expressions for the Kärger model. Moreover, we also derive a general nth order cumulant expansion of the dMRI signal accounting for water exchange, which has not been explored in earlier studies. Based on this analytical expression, we compute the cumulant expansion for dMRI signals for the special case of single diffusion encoding (SDE) and double diffusion encoding (DDE) sequences. Our results provide a theoretical guideline on optimizing experimental parameters for SDE and DDE sequences, respectively. Moreover, we show that DDE signals are more sensitive to water exchange at short-time scale but provide less attenuation at long-time scale than SDE signals. Our theoretical analysis is also validated using Monte Carlo simulations on synthetic structures.
Stefanik L, Erdman L, Ameis SH, Foussias G, Mulsant BH, Behdinan T, Goldenberg A, O'Donnell LJ, Voineskos AN. Brain-Behavior Participant Similarity Networks Among Youth and Emerging Adults with Schizophrenia Spectrum, Autism Spectrum, or Bipolar Disorder and Matched Controls. Neuropsychopharmacology. 2018;43 (5) :1180-8.Abstract
There is considerable heterogeneity in social cognitive and neurocognitive performance among people with schizophrenia spectrum disorders (SSD), autism spectrum disorders (ASD), bipolar disorder (BD), and healthy individuals. This study used Similarity Network Fusion (SNF), a novel data-driven approach, to identify participant similarity networks based on relationships among demographic, brain imaging, and behavioral data. T1-weighted and diffusion-weighted magnetic resonance images were obtained for 174 adolescents and young adults (aged 16-35 years) with an SSD (n=51), an ASD without intellectual disability (n=38), euthymic BD (n=34), and healthy controls (n=51). A battery of social cognitive and neurocognitive tasks were administered. Data integration, cluster determination, and biological group formation were then obtained using SNF. We identified four new groups of individuals, each with distinct neural circuit-cognitive profiles. The most influential variables driving the formation of the new groups were robustly reliable across embedded resampling techniques. The data-driven groups showed considerably greater differentiation on key social and neurocognitive circuit nodes than groups generated by diagnostic analyses or dimensional social cognitive analyses. The data-driven groups were validated through functional outcome and brain network property measures not included in the SNF model. Cutting across diagnostic boundaries, our approach can effectively identify new groups of people based on a profile of neuroimaging and behavioral data. Our findings bring us closer to disease subtyping that can be leveraged toward the targeting of specific neural circuitry among participant subgroups to ameliorate social cognitive and neurocognitive deficits.
Zhang F, Savadjiev P, Cai W, Song Y, Rathi Y, Tunç B, Parker D, Kapur T, Schultz RT, Makris N, et al. Whole Brain White Matter Connectivity Analysis using Machine Learning: An Application to Autism. Neuroimage. 2018;172 :826-37.Abstract
In this paper, we propose an automated white matter connectivity analysis method for machine learning classification and characterization of white matter abnormality via identification of discriminative fiber tracts. The proposed method uses diffusion MRI tractography and a data-driven approach to find fiber clusters corresponding to subdivisions of the white matter anatomy. Features extracted from each fiber cluster describe its diffusion properties and are used for machine learning. The method is demonstrated by application to a pediatric neuroimaging dataset from 149 individuals, including 70 children with autism spectrum disorder (ASD) and 79 typically developing controls (TDC). A classification accuracy of 78.33% is achieved in this cross-validation study. We investigate the discriminative diffusion features based on a two-tensor fiber tracking model. We observe that the mean fractional anisotropy from the second tensor (associated with crossing fibers) is most affected in ASD. We also find that local along-tract (central cores and endpoint regions) differences between ASD and TDC are helpful in differentiating the two groups. These altered diffusion properties in ASD are associated with multiple robustly discriminative fiber clusters, which belong to several major white matter tracts including the corpus callosum, arcuate fasciculus, uncinate fasciculus and aslant tract; and the white matter structures related to the cerebellum, brain stem, and ventral diencephalon. These discriminative fiber clusters, a small part of the whole brain tractography, represent the white matter connections that could be most affected in ASD. Our results indicate the potential of a machine learning pipeline based on white matter fiber clustering.
Seitz J, Rathi Y, Lyall A, Pasternak O, Del Re EC, Niznikiewicz M, Nestor P, Seidman LJ, Petryshen TL, Mesholam-Gately RI, et al. Alteration of Gray Matter Microstructure in Schizophrenia. Brain Imaging Behav. 2018;12 (1) :54-63.Abstract
Neuroimaging studies demonstrate gray matter (GM) macrostructural abnormalities in patients with schizophrenia (SCZ). While ex-vivo and genetic studies suggest cellular pathology associated with abnormal neurodevelopmental processes in SCZ, few in-vivo measures have been proposed to target microstructural GM organization. Here, we use diffusion heterogeneity- to study GM microstructure in SCZ. Structural and diffusion magnetic resonance imaging (MRI) were acquired on a 3 Tesla scanner in 46 patients with SCZ and 37 matched healthy controls (HC). After correction for free water, diffusion heterogeneity as well as commonly used diffusion measures FA and MD and volume were calculated for the four cortical lobes on each hemisphere, and compared between groups. Patients with early course SCZ exhibited higher diffusion heterogeneity in the GM of the frontal lobes compared to controls. Diffusion heterogeneity of the frontal lobe showed excellent discrimination between patients and HC, while none of the commonly used diffusion measures such as FA or MD did. Higher diffusion heterogeneity in the frontal lobes in early SCZ may be due to abnormal brain maturation (migration, pruning) before and during adolescence and early adulthood. Further studies are needed to investigate the role of heterogeneity as potential biomarker for SCZ risk.
Nilsson M, Larsson J, Lundberg D, Szczepankiewicz F, Witzel T, Westin C-F, Bryskhe K, Topgaard D. Liquid Crystal Phantom for Validation of Microscopic Diffusion Anisotropy Measurements on Clinical MRI Systems. Magn Reson Med. 2018;79 (3) :1817-28.Abstract
PURPOSE: To develop a phantom for validating MRI pulse sequences and data processing methods to quantify microscopic diffusion anisotropy in the human brain. METHODS: Using a liquid crystal consisting of water, detergent, and hydrocarbon, we designed a 0.5-L spherical phantom showing the theoretically highest possible degree of microscopic anisotropy. Data were acquired on the Connectome scanner using echo-planar imaging signal readout and diffusion encoding with axisymmetric b-tensors of varying magnitude, anisotropy, and orientation. The mean diffusivity, fractional anisotropy (FA), and microscopic FA (µFA) parameters were estimated. RESULTS: The phantom was observed to have values of mean diffusivity similar to brain tissue, and relaxation times compatible with echo-planar imaging echo times on the order of 100 ms. The estimated values of µFA were at the theoretical maximum of 1.0, whereas the values of FA spanned the interval from 0.0 to 0.8 as a result of varying orientational order of the anisotropic domains within each voxel. CONCLUSIONS: The proposed phantom can be manufactured by mixing three widely available chemicals in volumes comparable to a human head. The acquired data are in excellent agreement with theoretical predictions, showing that the phantom is ideal for validating methods for measuring microscopic diffusion anisotropy on clinical MRI systems. 
Ohtani T, Nestor PG, Bouix S, Newell D, Melonakos ED, McCarley RW, Shenton ME, Kubicki M. Exploring the Neural Substrates of Attentional Control and Human Intelligence: Diffusion Tensor Imaging of Prefrontal White Matter Tractography in Healthy Cognition. Neuroscience. 2017;341 :52-60.Abstract
We combined diffusion tension imaging (DTI) of prefrontal white matter integrity and neuropsychological measures to examine the functional neuroanatomy of human intelligence. Healthy participants completed the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) along with neuropsychological tests of attention and executive control, as measured by Trail Making Test (TMT) and Wisconsin Card Sorting Test (WCST). Stochastic tractography, considered the most effective DTI method, quantified white matter integrity of the medial orbital frontal cortex (mOFC) and rostral anterior cingulate cortex (rACC) circuitry. Based on prior studies, we hypothesized that posterior mOFC-rACC connections may play a key structural role linking attentional control processes and intelligence. Behavioral results provided strong support for this hypothesis, specifically linking attentional control processes, measured by Trails B and WCST perseverative errors, to intelligent quotient (IQ). Hierarchical regression results indicated left posterior mOFC-rACC fractional anisotropy (FA) and Trails B performance time, but not WCST perseverative errors, each contributed significantly to IQ, accounting for approximately 33.95-51.60% of the variance in IQ scores. These findings suggested that left posterior mOFC-rACC white matter connections may play a key role in supporting the relationship of executive functions of attentional control and general intelligence in healthy cognition.

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