Boards, Advisory Committees, Professional Organizations
Annual Meeting Program Committee Member, International Society for Magnetic Resonance in Medicine (2015 - 2017)
Chair of the Diffusion Study Group, International Society for Magnetic Resonance in Medicine (2018 - Present)
Post-doc, Harvard Medical School, Massachusetts General Hospital, Radiology (2012)
PhD, University of Oxford, MRI Physics (2009)
MSc, University of Western Ontario, Medical Biophysics (2005)
BSc, University of British Columbia, Physics (2003)
Current Research and Scholarly Interests
My research is focused on developing magnetic resonance imaging (MRI) methods that probe brain tissue microstructure. This requires new MRI contrast mechanisms, strategic encoding and reconstruction schemes, physiological monitoring, brain tissue modeling and validation. Applications of these methods include neuronavigation, neurosurgical planning and the development of improved biomarkers for brain development, degeneration, disease and injury. Active projects include comparisons of MRI with CLARITY 3D histology, development of mixed-reality neuronavigation, leveraging 7T MRI for predicting healthy versus pathological aging, developing high-resolution diffusion MRI methods that can map the fiber patterns of the cerebral cortex, diffusion tractography-based targeting for deep brain stimulation and MRI-guided focused ultrasound and the development of double diffusion encoding and q-space trajectory imaging for improved microstructural sensitivity and specificity.
- Independent Studies (6)
Double diffusion encoding MRI for the clinic
MAGNETIC RESONANCE IN MEDICINE
2018; 80 (2): 507–20
The purpose of this study is to develop double diffusion encoding (DDE) MRI methods for clinical use. Microscopic diffusion anisotropy measurements from DDE promise greater specificity to changes in tissue microstructure compared with conventional diffusion tensor imaging, but implementation of DDE sequences on whole-body MRI scanners is challenging because of the limited gradient strengths and lengthy acquisition times.A custom single-refocused DDE sequence was implemented on a 3T whole-body scanner. The DDE gradient orientation scheme and sequence parameters were optimized based on a Gaussian diffusion assumption. Using an optimized 5-min DDE acquisition, microscopic fractional anisotropy (μFA) maps were acquired for the first time in multiple sclerosis patients.Based on simulations and in vivo human measurements, six parallel and six orthogonal diffusion gradient pairs were found to be the minimum number of diffusion gradient pairs necessary to produce a rotationally invariant measurement of μFA. Simulations showed that optimal precision and accuracy of μFA measurements were obtained using b-values between 1500 and 3000 s/mm2 . The μFA maps showed improved delineation of multiple sclerosis lesions compared with conventional fractional anisotropy and distinct contrast from T2 -weighted fluid attenuated inversion recovery and T1 -weighted imaging.The μFA maps can be measured using DDE in a clinical setting and may provide new opportunities for characterizing multiple sclerosis lesions and other types of tissue degeneration. Magn Reson Med 80:507-520, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
View details for DOI 10.1002/mrm.27043
View details for Web of Science ID 000430469300009
View details for PubMedID 29266375
View details for PubMedCentralID PMC5910247
The separate effects of lipids and proteins on brain MRI contrast revealed through tissue clearing.
Despite the widespread use of magnetic resonance imaging (MRI) of the brain, the relative contribution of different biological components (e.g. lipids and proteins) to structural MRI contrasts (e.g., T1, T2, T2*, proton density, diffusion) remains incompletely understood. This limitation can undermine the interpretation of clinical MRI and hinder the development of new contrast mechanisms. Here, we determine the respective contribution of lipids and proteins to MRI contrast by removing lipids and preserving proteins in mouse brains using CLARITY. We monitor the temporal dynamics of tissue clearance via NMR spectroscopy, protein assays and optical emission spectroscopy. MRI of cleared brain tissue showed: 1) minimal contrast on standard MRI sequences; 2) increased relaxation times; and 3) diffusion rates close to free water. We conclude that lipids, present in myelin and membranes, are a dominant source of MRI contrast in brain tissue.
View details for DOI 10.1016/j.neuroimage.2017.04.021
View details for PubMedID 28411157
Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences
2016; 165 (7): 1776-1788
A major challenge in understanding the cellular diversity of the brain has been linking activity during behavior with standard cellular typology. For example, it has not been possible to determine whether principal neurons in prefrontal cortex active during distinct experiences represent separable cell types, and it is not known whether these differentially active cells exert distinct causal influences on behavior. Here, we develop quantitative hydrogel-based technologies to connect activity in cells reporting on behavioral experience with measures for both brain-wide wiring and molecular phenotype. We find that positive and negative-valence experiences in prefrontal cortex are represented by cell populations that differ in their causal impact on behavior, long-range wiring, and gene expression profiles, with the major discriminant being expression of the adaptation-linked gene NPAS4. These findings illuminate cellular logic of prefrontal cortex information processing and natural adaptive behavior and may point the way to cell-type-specific understanding and treatment of disease-associated states.
View details for DOI 10.1016/j.cell.2016.05.010
View details for Web of Science ID 000378062000026
View details for PubMedID 27238022
Q-space truncation and sampling in diffusion spectrum imaging.
Magnetic resonance in medicine
To characterize the q-space truncation and sampling on the spin-displacement probability density function (PDF) in diffusion spectrum imaging (DSI).DSI data were acquired using the MGH-USC connectome scanner (Gmax = 300 mT/m) with bmax = 30,000 s/mm(2) , 17 × 17 × 17, 15 × 15 × 15 and 11 × 11 × 11 grids in ex vivo human brains and bmax = 10,000 s/mm(2) , 11 × 11 × 11 grid in vivo. An additional in vivo scan using bmax =7,000 s/mm(2) , 11 × 11 × 11 grid was performed with a derated gradient strength of 40 mT/m. PDFs and orientation distribution functions (ODFs) were reconstructed with different q-space filtering and PDF integration lengths, and from down-sampled data by factors of two and three.Both ex vivo and in vivo data showed Gibbs ringing in PDFs, which becomes the main source of artifact in the subsequently reconstructed ODFs. For down-sampled data, PDFs interfere with the first replicas or their ringing, leading to obscured orientations in ODFs.The minimum required q-space sampling density corresponds to a field-of-view approximately equal to twice the mean displacement distance (MDD) of the tissue. The 11 × 11 × 11 grid is suitable for both ex vivo and in vivo DSI experiments. To minimize the effects of Gibbs ringing, ODFs should be reconstructed from unfiltered q-space data with the integration length over the PDF constrained to around the MDD. Magn Reson Med, 2016. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/mrm.26071
View details for PubMedID 26762670
The impact of gradient strength on in vivo diffusion MRI estimates of axon diameter.
2015; 106: 464-472
Diffusion magnetic resonance imaging (MRI) methods for axon diameter mapping benefit from higher maximum gradient strengths than are currently available on commercial human scanners. Using a dedicated high-gradient 3T human MRI scanner with a maximum gradient strength of 300mT/m, we systematically studied the effect of gradient strength on in vivo axon diameter and density estimates in the human corpus callosum. Pulsed gradient spin echo experiments were performed in a single scan session lasting approximately 2h on each of three human subjects. The data were then divided into subsets with maximum gradient strengths of 77, 145, 212, and 293mT/m and diffusion times encompassing short (16 and 25ms) and long (60 and 94ms) diffusion time regimes. A three-compartment model of intra-axonal diffusion, extra-axonal diffusion, and free diffusion in cerebrospinal fluid was fitted to the data using a Markov chain Monte Carlo approach. For the acquisition parameters, model, and fitting routine used in our study, it was found that higher maximum gradient strengths decreased the mean axon diameter estimates by two to three fold and decreased the uncertainty in axon diameter estimates by more than half across the corpus callosum. The exclusive use of longer diffusion times resulted in axon diameter estimates that were up to two times larger than those obtained with shorter diffusion times. Axon diameter and density maps appeared less noisy and showed improved contrast between different regions of the corpus callosum with higher maximum gradient strength. Known differences in axon diameter and density between the genu, body, and splenium of the corpus callosum were preserved and became more reproducible at higher maximum gradient strengths. Our results suggest that an optimal q-space sampling scheme for estimating in vivo axon diameters should incorporate the highest possible gradient strength. The improvement in axon diameter and density estimates that we demonstrate from increasing maximum gradient strength will inform protocol development and encourage the adoption of higher maximum gradient strengths for use in commercial human scanners.
View details for DOI 10.1016/j.neuroimage.2014.12.008
View details for PubMedID 25498429
The Human Connectome Project and beyond: Initial applications of 300 mT/m gradients
2013; 80: 234-245
The engineering of a 3T human MRI scanner equipped with 300mT/m gradients - the strongest gradients ever built for an in vivo human MRI scanner - was a major component of the NIH Blueprint Human Connectome Project (HCP). This effort was motivated by the HCP's goal of mapping, as completely as possible, the macroscopic structural connections of the in vivo healthy, adult human brain using diffusion tractography. Yet, the 300mT/m gradient system is well suited to many additional types of diffusion measurements. Here, we present three initial applications of the 300mT/m gradients that fall outside the immediate scope of the HCP. These include: 1) diffusion tractography to study the anatomy of consciousness and the mechanisms of brain recovery following traumatic coma; 2) q-space measurements of axon diameter distributions in the in vivo human brain and 3) postmortem diffusion tractography as an adjunct to standard histopathological analysis. We show that the improved sensitivity and diffusion-resolution provided by the gradients are rapidly enabling human applications of techniques that were previously possible only for in vitro and animal models on small-bore scanners, thereby creating novel opportunities to map the microstructure of the human brain in health and disease.
View details for DOI 10.1016/j.neuroimage.2013.05.074
View details for Web of Science ID 000322416000018
View details for PubMedID 23711537
Surface based analysis of diffusion orientation for identifying architectonic domains in the in vivo human cortex
2013; 69: 87-100
Diffusion tensor MRI is sensitive to the coherent structure of brain tissue and is commonly used to study large-scale white matter structure. Diffusion in gray matter is more isotropic, however, several groups have observed coherent patterns of diffusion anisotropy within the cerebral cortical gray matter. We extend the study of cortical diffusion anisotropy by relating it to the local coordinate system of the folded cerebral cortex. We use 1mm and sub-millimeter isotropic resolution diffusion imaging to perform a laminar analysis of the principal diffusion orientation, fractional anisotropy, mean diffusivity and partial volume effects. Data from 6 in vivo human subjects, a fixed human brain specimen and an anesthetized macaque were examined. Large regions of cortex show a radial diffusion orientation. In vivo human and macaque data displayed a sharp transition from radial to tangential diffusion orientation at the border between primary motor and somatosensory cortex, and some evidence of tangential diffusion in secondary somatosensory cortex and primary auditory cortex. Ex vivo diffusion imaging in a human tissue sample showed some tangential diffusion orientation in S1 but mostly radial diffusion orientations in both M1 and S1.
View details for DOI 10.1016/j.neuroimage.2012.11.065
View details for Web of Science ID 000314627800010
View details for PubMedID 23247190
Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project
JOURNAL OF NEUROTRAUMA
Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole-mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study.
View details for DOI 10.1089/neu.2017.5457
View details for Web of Science ID 000431463900001
View details for PubMedID 29421973
Characterizing Signals within Lesions and Mapping Brain Network Connectivity After Traumatic Axonal Injury: A 7 Tesla Resting-State FMRI Study.
Resting-state functional magnetic resonance imaging (RS-FMRI) has been widely used to map brain functional connectivity, but it is unclear how to probe connectivity within and around lesions. Here we characterize RS-FMRI signal time-course properties and evaluate different seed placements within and around hemorrhagic traumatic axonal injury lesions. RS-FMRI was performed on a 7 Tesla scanner in a patient who recovered consciousness after traumatic coma and in three healthy controls. Eleven lesions in the patient were characterized in terms of: 1) temporal signal-to-noise ratio (tSNR); 2) physiological noise, through comparison of noise regressors derived from the white matter (WM), cerebrospinal fluid (CSF) and gray matter (GM); and 3) seed-based functional connectivity. Temporal SNR at the center of the lesions was 38.3% and 74.1% lower compared to the same region in the contralesional hemisphere of the patient and in the ipsilesional hemispheres of the controls, respectively. Within the lesions, WM noise was more prominent than CSF and GM noise. Lesional seeds did not produce discernable networks, but seeds in the contralesional hemisphere revealed networks whose nodes appeared to be shifted or obscured due to overlapping or nearby lesions. Single-voxel seed analysis demonstrated that placing a seed within a lesion's periphery was necessary to identify networks associated with the lesion region. These findings provide evidence of resting-state network changes in the human brain after recovery from traumatic coma. Further, we show that seed placement within a lesion's periphery or in the contralesional hemisphere may be necessary for network identification in patients with hemorrhagic traumatic axonal injury.
View details for DOI 10.1089/brain.2017.0499
View details for PubMedID 29665699
Accelerating Functional MRI Using Fixed-Rank Approximations and Radial-Cartesian Sampling
MAGNETIC RESONANCE IN MEDICINE
2016; 76 (6): 1825-1836
Recently, k-t FASTER (fMRI Accelerated in Space-time by means of Truncation of Effective Rank) was introduced for rank-constrained acceleration of fMRI data acquisition. Here we demonstrate improvements achieved through a hybrid three-dimensional radial-Cartesian sampling approach that allows posthoc selection of acceleration factors, as well as incorporation of coil sensitivity encoding in the reconstruction.The multicoil rank-constrained reconstruction used hard thresholding and shrinkage on matrix singular values of the space-time data matrix, using sensitivity encoding and the nonuniform Fast Fourier Transform to enforce data consistency in the multicoil non-Cartesian k-t domain. Variable acceleration factors were made possible using a radial increment based on the golden ratio. Both retrospective and prospectively under-sampled data were used to assess the fidelity of the enhancements to the k-t FASTER technique in resting and task-fMRI data.The improved k-t FASTER is capable of tailoring acceleration factors for recovery of different signal components, achieving up to R = 12.5 acceleration in visual-motor task data. The enhancements reduce data matrix reconstruction errors even at much higher acceleration factors when compared directly with the original k-t FASTER approach.We have shown that k-t FASTER can be used to significantly accelerate fMRI data acquisition with little penalty to data quality. Magn Reson Med, 2016. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.
View details for DOI 10.1002/mrm.26079
View details for Web of Science ID 000389127200017
View details for PubMedID 26777798
Motion correction for functional MRI with three-dimensional hybrid radial-Cartesian EPI.
Magnetic resonance in medicine
Subject motion is a major source of image degradation for functional MRI (fMRI), especially when using multishot sequences like three-dimensional (3D EPI). We present a hybrid radial-Cartesian 3D EPI trajectory enabling motion correction in k-space for functional MRI.The EPI "blades" of the 3D hybrid radial-Cartesian EPI sequence, called TURBINE, are rotated about the phase-encoding axis to fill out a cylinder in 3D k-space. Angular blades are acquired over time using a golden-angle rotation increment, allowing reconstruction at flexible temporal resolution. The self-navigating properties of the sequence are used to determine motion parameters from a high temporal-resolution navigator time series. The motion is corrected in k-space as part of the image reconstruction, and evaluated for experiments with both cued and natural motion.We demonstrate that the motion correction works robustly and that we can achieve substantial artifact reduction as well as improvement in temporal signal-to-noise ratio and fMRI activation in the presence of both severe and subtle motion.We show the potential for hybrid radial-Cartesian 3D EPI to substantially reduce artifacts for application in fMRI, especially for subject groups with significant head motion. The motion correction approach does not prolong the scan, and no extra hardware is required. Magn Reson Med, 2016. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
View details for DOI 10.1002/mrm.26390
View details for PubMedID 27604503
Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-GradientDiffusion MR Imaging
2016; 280 (1): 244-251
Purpose To evaluate the ability of high-gradient-diffusion magnetic resonance (MR) imaging by using gradient strengths of up to 300 mT/m to depict axonal disease in lesions and normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) and to compare high-gradient-diffusion MR findings in these patients with those in healthy control subjects. Materials and Methods In this HIPAA-compliant institutional review board-approved prospective study in which all subjects provided written informed consent, six patients with relapsing-remitting MS and six healthy control subjects underwent diffusion-weighted imaging with a range of diffusion weightings performed with a 3-T human MR imager by using gradient strengths of up to 300 mT/m. A model of intra-axonal, extra-axonal, and free water diffusion was fitted to obtain estimates of axon diameter and density. Differences in axon diameter and density between lesions and NAWM in patients with MS were assessed by using the nonparametric Wilcoxon matched-pairs signed rank test, and differences between NAWM in subjects with MS and white matter in healthy control subjects were assessed by using the Mann-Whitney U test. Results MS lesions showed increased mean axon diameter (10.3 vs 7.9 μm in the genu, 10.4 vs 9.3 μm in the body, and 10.6 vs 8.2 μm in the splenium; P < .05) and decreased axon density ([0.48 vs 1.1] × 10(10)/m(2) in the genu, [0.40 vs 0.70] × 10(10)/m(2) in the body, and [0.35 vs 1.1] × 10(10)/m(2) in the splenium; P < .05) compared with adjacent NAWM. No significant difference in mean axon diameter or axon density was detected between NAWM in subjects with MS and white matter in healthy control subjects. Conclusion High-gradient-diffusion MR imaging using gradient strengths of up to 300 mT/m can be used to characterize axonal disease in patients with MS, with results that agree with known trends from neuropathologic data showing increased axon diameter and decreased axon density in MS lesions when compared with NAWM. (©) RSNA, 2016 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.2016151582
View details for Web of Science ID 000378721900027
View details for PubMedID 26859256
The Structural Connectome of the Human Central Homeostatic Network.
2016; 6 (3): 187-200
Homeostatic adaptations to stress are regulated by interactions between the brainstem and regions of the forebrain, including limbic sites related to respiratory, autonomic, affective, and cognitive processing. Neuroanatomic connections between these homeostatic regions, however, have not been thoroughly identified in the human brain. In this study, we perform diffusion spectrum imaging tractography using the MGH-USC Connectome MRI scanner to visualize structural connections in the human brain linking autonomic and cardiorespiratory nuclei in the midbrain, pons, and medulla oblongata with forebrain sites critical to homeostatic control. Probabilistic tractography analyses in six healthy adults revealed connections between six brainstem nuclei and seven forebrain regions, several over long distances between the caudal medulla and cerebral cortex. The strongest evidence for brainstem-homeostatic forebrain connectivity in this study was between the brainstem midline raphe and the medial temporal lobe. The subiculum and amygdala were the sampled forebrain nodes with the most extensive brainstem connections. Within the human brainstem-homeostatic forebrain connectome, we observed that a lateral forebrain bundle, whose connectivity is distinct from that of rodents and nonhuman primates, is the primary conduit for connections between the brainstem and medial temporal lobe. This study supports the concept that interconnected brainstem and forebrain nodes form an integrated central homeostatic network (CHN) in the human brain. Our findings provide an initial foundation for elucidating the neuroanatomic basis of homeostasis in the normal human brain, as well as for mapping CHN disconnections in patients with disorders of homeostasis, including sudden and unexpected death, and epilepsy.
View details for DOI 10.1089/brain.2015.0378
View details for PubMedID 26530629
- In vivo mapping of human spinal cord microstructure at 300 mT/m NEUROIMAGE 2015; 118: 494-507
Targeting of White Matter Tracts with Transcranial Magnetic Stimulation
2014; 7 (1): 80-84
TMS activations of white matter depend not only on the distance from the coil, but also on the orientation of the axons relative to the TMS-induced electric field, and especially on axonal bends that create strong local field gradient maxima. Therefore, tractography contains potentially useful information for TMS targeting.Here, we utilized 1-mm resolution diffusion and structural T1-weighted MRI to construct large-scale tractography models, and localized TMS white matter activations in motor cortex using electromagnetic forward modeling in a boundary element model (BEM).As expected, in sulcal walls, pyramidal cell axonal bends created preferred sites of activation that were not found in gyral crowns. The model agreed with the well-known coil orientation sensitivity of motor cortex, and also suggested unexpected activation distributions emerging from the E-field and tract configurations. We further propose a novel method for computing the optimal coil location and orientation to maximally stimulate a pre-determined axonal bundle.Diffusion MRI tractography with electromagnetic modeling may improve spatial specificity and efficacy of TMS.
View details for DOI 10.1016/j.brs.2013.10.001
View details for Web of Science ID 000329947300012
View details for PubMedID 24220599
A 22-channel receive array with Helmholtz transmit coil for anesthetized macaque MRI at 3 T
NMR IN BIOMEDICINE
2013; 26 (11): 1431-1440
The macaque monkey is an important model for cognitive and sensory neuroscience that has been used extensively in behavioral, electrophysiological, molecular and, more recently, neuroimaging studies. However, macaque MRI has unique technical differences relative to human MRI, such as the geometry of highly parallel receive arrays, which must be addressed to optimize imaging performance. A 22-channel receive coil array was constructed specifically for rapid high-resolution anesthetized macaque monkey MRI at 3 T. A local Helmholtz transmit coil was used for excitation. Signal-to-noise ratios (SNRs) and noise amplification for parallel imaging were compared with those of single- and four-channel receive coils routinely used for macaque MRI. The 22-channel coil yielded significant improvements in SNR throughout the brain. Using this coil, the SNR in peripheral brain was 2.4 and 1.7 times greater than that obtained with single- or four-channel coils, respectively. In the central brain, the SNR gain was 1.5 times that of both the single- and four-channel coils. Finally, the performance of the array for functional, anatomical and diffusion-weighted imaging was evaluated. For all three modalities, the use of the 22-channel array allowed for high-resolution and accelerated image acquisition. Copyright © 2013 John Wiley & Sons, Ltd.
View details for DOI 10.1002/nbm.2970
View details for Web of Science ID 000329225200011
View details for PubMedID 23703859
Pushing the limits of in vivo diffusion MRI for the Human Connectome Project.
Perhaps more than any other "-omics" endeavor, the accuracy and level of detail obtained from mapping the major connection pathways in the living human brain with diffusion MRI depend on the capabilities of the imaging technology used. The current tools are remarkable; allowing the formation of an "image" of the water diffusion probability distribution in regions of complex crossing fibers at each of half a million voxels in the brain. Nonetheless our ability to map the connection pathways is limited by the image sensitivity and resolution, and also the contrast and resolution in encoding of the diffusion probability distribution. The goal of our Human Connectome Project (HCP) is to address these limiting factors by re-engineering the scanner from the ground up to optimize the high b-value, high angular resolution diffusion imaging needed for sensitive and accurate mapping of the brain's structural connections. Our efforts were directed based on the relative contributions of each scanner component. The gradient subsection was a major focus since gradient amplitude is central to determining the diffusion contrast, the amount of T2 signal loss, and the blurring of the water PDF over the course of the diffusion time. By implementing a novel 4-port drive geometry and optimizing size and linearity for the brain, we demonstrate a whole-body sized scanner with Gmax=300mT/m on each axis capable of the sustained duty cycle needed for diffusion imaging. The system is capable of slewing the gradient at a rate of 200T/m/s as needed for the EPI image encoding. In order to enhance the efficiency of the diffusion sequence we implemented a FOV shifting approach to Simultaneous MultiSlice (SMS) EPI capable of unaliasing 3 slices excited simultaneously with a modest g-factor penalty allowing us to diffusion encode whole brain volumes with low TR and TE. Finally we combine the multi-slice approach with a compressive sampling reconstruction to sufficiently undersample q-space to achieve a DSI scan in less than 5min. To augment this accelerated imaging approach we developed a 64-channel, tight-fitting brain array coil and show its performance benefit compared to a commercial 32-channel coils at all locations in the brain for these accelerated acquisitions. The technical challenges of developing the over-all system are discussed as well as results from SNR comparisons, ODF metrics and fiber tracking comparisons. The ultra-high gradients yielded substantial and immediate gains in the sensitivity through reduction of TE and improved signal detection and increased efficiency of the DSI or HARDI acquisition, accuracy and resolution of diffusion tractography, as defined by identification of known structure and fiber crossing.
View details for DOI 10.1016/j.neuroimage.2013.05.078
View details for PubMedID 23707579
A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology
2012; 135: 2938-2951
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a 'tract-specific' pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
View details for DOI 10.1093/brain/aws242
View details for Web of Science ID 000310156700005
View details for PubMedID 23065787
An implanted 8-channel array coil for high-resolution macaque MRI at 3 T
2012; 62 (3): 1529-1536
An 8-channel receive coil array was constructed and implanted adjacent to the skull in a male rhesus monkey in order to improve the sensitivity of (functional) brain imaging. The permanent implant was part of an acrylic headpost assembly and only the coil element loop wires were implanted. The tuning, matching, and preamplifier circuitry was connected via a removable external assembly. Signal-to-noise ratio (SNR) and noise amplification for parallel imaging were compared to single-, 4-, and 8-channel external receive-only coils routinely used for macaque fMRI. In vivo measurements showed significantly improved SNR within the brain for the implanted versus the external coils. Within a region-of-interest covering the cerebral cortex, we observed a 5.4-, 3.6-fold, and 3.4-fold increase in SNR compared to the external single-, 4-, and 8-channel coils, respectively. In the center of the brain, the implanted array maintained a 2.4×, 2.5×, and 2.1× higher SNR, respectively compared to the external coils. The array performance was evaluated for anatomical, diffusion tensor and functional brain imaging. This study suggests that a stable implanted phased-array coil can be used in macaque MRI to substantially increase the spatial resolution for anatomical, diffusion tensor, and functional imaging.
View details for DOI 10.1016/j.neuroimage.2012.05.028
View details for Web of Science ID 000307369000021
View details for PubMedID 22609793
T-2* mapping and B-o orientation-dependence at 7 T reveal cyto- and myeloarchitecture organization of the human cortex
2012; 60 (2): 1006-1014
Ultra-high field MRI (≥ 7 T) has recently shown great sensitivity to depict patterns of tissue microarchitecture. Moreover, recent studies have demonstrated a dependency between T₂* and orientation of white matter fibers with respect to the main magnetic field B₀. In this study we probed the potential of T₂* mapping at 7 T to provide new markers of cortical architecture. We acquired multi-echo measurements at 7 T and mapped T₂* over the entire cortex of eight healthy individuals using surface-based analysis. B₀ dependence was tested by computing the angle θ(z) between the normal of the surface and the direction of B₀, then fitting T₂*(θ(z)) using model from the literature. Average T₂* in the cortex was 32.20 +/- 1.35 ms. Patterns of lower T₂* were detected in the sensorimotor, visual and auditory cortices, likely reflecting higher myelin content. Significantly lower T₂* was detected in the left hemisphere of the auditory region (p<0.005), suggesting higher myelin content, in accordance with previous investigations. B₀ orientation dependence was detected in some areas of the cortex, the strongest being in the primary motor cortex (∆R₂*=4.10 Hz). This study demonstrates that quantitative T₂* measures at 7 T MRI can reveal patterns of cytoarchitectural organization of the human cortex in vivo and that B₀ orientation dependence can probe the coherency and orientation of gray matter fibers in the cortex, shedding light into the potential use of this type of contrast to characterize cyto-/myeloarchitecture and to understand the pathophysiology of diseases associated with changes in iron and/or myelin concentration.
View details for DOI 10.1016/j.neuroimage.2012.01.053
View details for Web of Science ID 000303272300018
View details for PubMedID 22270354
Diffusion tractography of post-mortem human brains: Optimization and comparison of spin echo and steady-state free precession techniques
2012; 59 (3): 2284-2297
Diffusion imaging of post-mortem brains could provide valuable data for validation of diffusion tractography of white matter pathways. Long scans (e.g., overnight) may also enable high-resolution diffusion images for visualization of fine structures. However, alterations to post-mortem tissue (T2 and diffusion coefficient) present significant challenges to diffusion imaging with conventional diffusion-weighted spin echo (DW-SE) acquisitions, particularly for imaging human brains on clinical scanners. Diffusion-weighted steady-state free precession (DW-SSFP) has been proposed as an alternative acquisition technique to ameliorate this tradeoff in large-bore clinical scanners. In this study, both DWSE and DW-SSFP are optimized for use in fixed white matter on a clinical 3-Tesla scanner. Signal calculations predict superior performance from DW-SSFP across a broad range of protocols and conditions. DW-SE and DW-SSFP data in a whole, post-mortem human brain are compared for 6- and 12-hour scan durations. Tractography is performed in major projection, commissural and association tracts (corticospinal tract, corpus callosum, superior longitudinal fasciculus and cingulum bundle). The results demonstrate superior tract-tracing from DW-SSFP data, with 6-hour DW-SSFP data performing as well as or better than 12-hour DW-SE scans. These results suggest that DW-SSFP may be a preferred method for diffusion imaging of post-mortem human brains. The ability to estimate multiple fibers in imaging voxels is also demonstrated, again with greater success in DW-SSFP data.
View details for DOI 10.1016/j.neuroimage.2011.09.054
View details for Web of Science ID 000299494000030
View details for PubMedID 22008372
Size-optimized 32-Channel Brain Arrays for 3 T Pediatric Imaging
MAGNETIC RESONANCE IN MEDICINE
2011; 66 (6): 1777-1787
Size-optimized 32-channel receive array coils were developed for five age groups, neonates, 6 months old, 1 year old, 4 years old, and 7 years old, and evaluated for pediatric brain imaging. The array consisted of overlapping circular surface coils laid out on a close-fitting coil-former. The two-section coil former design was obtained from surface contours of aligned three-dimensional MRI scans of each age group. Signal-to-noise ratio and noise amplification for parallel imaging were evaluated and compared to two coils routinely used for pediatric brain imaging; a commercially available 32-channel adult head coil and a pediatric-sized birdcage coil. Phantom measurements using the neonate, 6-month-old, 1-year-old, 4-year-old, and 7-year-old coils showed signal-to-noise ratio increases at all locations within the brain over the comparison coils. Within the brain cortex the five dedicated pediatric arrays increased signal-to-noise ratio by up to 3.6-, 3.0-, 2.6-, 2.3-, and 1.7-fold, respectively, compared to the 32-channel adult coil, as well as improved G-factor maps for accelerated imaging. This study suggests that a size-tailored approach can provide significant sensitivity gains for accelerated and unaccelerated pediatric brain imaging.
View details for DOI 10.1002/mrm.22961
View details for Web of Science ID 000297285000033
View details for PubMedID 21656548
Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner
2011; 57 (1): 167-181
Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and "gold standard" histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
View details for DOI 10.1016/j.neuroimage.2011.03.070
View details for Web of Science ID 000291624100020
View details for PubMedID 21473920
Steady-state diffusion-weighted imaging: theory, acquisition and analysis
NMR IN BIOMEDICINE
2010; 23 (7): 781-793
Steady-state diffusion-weighted imaging (DWI) has long been recognized to offer potential benefits over conventional spin-echo methods. This family of pulse sequences is highly efficient and compatible with three-dimensional acquisitions, which could enable high-resolution, low-distortion images. However, the same properties that lead to its efficiency make steady-state imaging highly susceptible to motion and create a complicated signal with dependence on T(1), T(2) and flip angle. Recent developments in gradient hardware, motion-mitigation techniques and signal analysis offer potential solutions to these problems, reviving interest in steady-state DWI. This review offers a description of steady-state DWI signal formation and provides an overview of the current methods for steady-state DWI acquisition and analysis.
View details for DOI 10.1002/nbm.1509
View details for Web of Science ID 000283014300010
View details for PubMedID 20886565
3D Steady-State Diffusion-Weighted Imaging With Trajectory Using Radially Batched Internal Navigator Echoes (TURBINE)
MAGNETIC RESONANCE IN MEDICINE
2010; 63 (1): 235-242
While most diffusion-weighted imaging (DWI) is acquired using single-shot diffusion-weighted spin-echo echo-planar imaging, steady-state DWI is an alternative method with the potential to achieve higher-resolution images with less distortion. Steady-state DWI is, however, best suited to a segmented three-dimensional acquisition and thus requires three-dimensional navigation to fully correct for motion artifacts. In this paper, a method for three-dimensional motion-corrected steady-state DWI is presented. The method uses a unique acquisition and reconstruction scheme named trajectory using radially batched internal navigator echoes (TURBINE). Steady-state DWI with TURBINE uses slab-selection and a short echo-planar imaging (EPI) readout each pulse repetition time. Successive EPI readouts are rotated about the phase-encode axis. For image reconstruction, batches of cardiac-synchronized readouts are used to form three-dimensional navigators from a fully sampled central k-space cylinder. In vivo steady-state DWI with TURBINE is demonstrated in human brain. Motion artifacts are corrected using refocusing reconstruction and TURBINE images prove less distorted compared to two-dimensional single-shot diffusion-weighted-spin-EPI.
View details for DOI 10.1002/mrm.22183
View details for Web of Science ID 000273578600026
View details for PubMedID 19859953
Reduced limbic connections may contraindicate subgenual cingulate deep brain stimulation for intractable depression Case report
JOURNAL OF NEUROSURGERY
2009; 111 (4): 780-784
In this study, the authors performed deep brain stimulation (DBS) of the subgenual anterior cingulate cortex (SACC) in a patient with a history of bipolar disorder. After a right thalamic stroke, intractable depression without mood elevation or a mixed state developed in this patient. He underwent bilateral SACC DBS and died 16 months afterwards. Anatomical connections were studied in this patient preoperatively and postmortem using diffusion tractography (DT). A comparison of in vivo and high resolution ex vivo connectivity patterns was performed as a measure of the utility of in vivo DT in presurgical planning for DBS. Diagnostic measures included neuropsychological testing, preoperative and ex vivo DT, and macroscopic neuropathological assessment. Post-DBS depression rating scores did not improve. In vivo and ex vivo DT revealed markedly reduced limbic projections from the thalamus and SACC to the amygdala in the right (stroke-affected) hemisphere. A highly selective right mediothalamic lesion was associated with the onset of refractory depression. Reduced amygdalar-thalamic and amygdalar-SACC connections could be a contraindication to DBS for depression. Correspondence between preoperative and higher resolution ex vivo DT supports the validity of DT as a presurgical planning tool for DBS.
View details for DOI 10.3171/2009.2.JNS081299
View details for Web of Science ID 000270550000022
View details for PubMedID 19284230
High resolution diffusion-weighted imaging in fixed human brain using diffusion-weighted steady state free precession
2009; 46 (3): 775-785
High resolution diffusion tensor imaging and tractography of ex vivo brain specimens has the potential to reveal detailed fibre architecture not visible on in vivo images. Previous ex vivo diffusion imaging experiments have focused on animal brains or small sections of human tissue since the unfavourable properties of fixed tissue (including short T(2) and low diffusion rates) demand the use of very powerful gradient coils that are too small to accommodate a whole, human brain. This study proposes the use of diffusion-weighted steady-state free precession (DW-SSFP) as a method of extending the benefits of ex vivo DTI and tractography to whole, human, fixed brains on a clinical 3 T scanner. DW-SSFP is a highly efficient pulse sequence; however, its complicated signal dependence precludes the use of standard diffusion tensor analysis and tractography. In this study, a method is presented for modelling anisotropy in the context of DW-SSFP. Markov Chain Monte Carlo sampling is used to estimate the posterior distributions of model parameters and it is shown that it is possible to estimate a tight distribution on the principal axis of diffusion at each voxel using DW-SSFP. Voxel-wise estimates are used to perform tractography in a whole, fixed human brain. A direct comparison between 3D diffusion-weighted spin echo EPI and 3D DW-SSFP-EPI reveals that the orientation of the principal diffusion axis can be inferred on with a higher degree of certainty using a 3D DW-SSFP-EPI even with a 68% shorter acquisition time.
View details for DOI 10.1016/j.neuroimage.2009.01.008
View details for Web of Science ID 000265938700024
View details for PubMedID 19344686
Cortical and subcortical connections within the pedunculopontine nucleus of the primate Macaca mulatta determined using probabilistic diffusion tractography
JOURNAL OF CLINICAL NEUROSCIENCE
2009; 16 (3): 413-420
The anatomical connections of the pedunculopontine nucleus (PPN), a brainstem structure associated with locomotion, have been determined recently in healthy humans using probabilistic diffusion tractography (PDT). In order to compare these with histologically demonstrated connections of the PPN in monkeys, and thus to support the use of PDT in humans, we have carried out PDT in a fixed rhesus monkey (Macaca mulatta) brain. Probabilistic diffusion tractography was carried out in a fixed post-mortem rhesus monkey brain using diffusion data acquired at 3T MRI (60 directions x 5 averages, b=3000 s/mm(2), matrix size=104 x 132 x 96, 720 x 720 x 720 microm voxels). We identified the major connections of the PPN from single seed voxels that could be confidently located within the nucleus on the diffusion images. The organisation of these connections within a 3 x 3 x 3 voxel ( approximately 10 mm(3)) region surrounding the initial seed voxel was then examined. PDT confirmed that the rhesus monkey PPN connections with the basal ganglia and motor cortical areas matched those previously demonstrated using conventional anatomical tracing techniques. Furthermore, although the organisation of subcortical connections within the PPN has not been extensively demonstrated in animals, we show here in a rhesus monkey that there are clearly separated connections of the PPN with the thalamus, substantia nigra, and subthalamic nucleus. Thus, in addition to increasing confidence in the accuracy of PDT for tracing PPN connections and determining the organisation of these connections within the PPN in vivo, our observations suggest that diffusion tractography will be a useful new technique to rapidly identify connections in animal brains pre-mortem and post-mortem.
View details for DOI 10.1016/j.jocn.2008.03.018
View details for Web of Science ID 000263762300011
View details for PubMedID 19167229
Sensitivity of diffusion weighted steady state free precession to anisotropic diffusion
MAGNETIC RESONANCE IN MEDICINE
2008; 60 (2): 405-413
Diffusion-weighted steady-state free precession (DW-SSFP) accumulates signal from multiple echoes over several TRs yielding a strong sensitivity to diffusion with short gradient durations and imaging times. Although the DW-SSFP signal is well characterized for isotropic, Gaussian diffusion, it is unclear how the DW-SSFP signal propagates in inhomogeneous media such as brain tissue. This article presents a more general analytical expression for the DW-SSFP signal which accommodates Gaussian and non-Gaussian spin displacement probability density functions. This new framework for calculating the DW-SSFP signal is used to investigate signal behavior for a single fiber, crossing fibers, and reflective barriers. DW-SSFP measurements in the corpus callosum of a fixed brain are shown to be in good agreement with theoretical predictions. Further measurements in fixed brain tissue also demonstrate that 3D DW-SSFP out-performs 3D diffusion weighted spin echo in both SNR and CNR efficiency providing a compelling example of its potential to be used for high resolution diffusion tensor imaging.
View details for DOI 10.1002/mrm.21668
View details for Web of Science ID 000258105800021
View details for PubMedID 18666106
Quantitative short echo-time H-1 LASER-CSI in human brain at 4T
NMR IN BIOMEDICINE
2006; 19 (8): 999-1009
A novel short echo-time (1)H chemical shift imaging (CSI) pulse sequence is presented that incorporates localization by adiabatic selective refocusing (LASER) for FOV-reduction, k-space weighted averaging and macromolecule subtraction, to obtain quantitative concentration measurements of N-acetyl-aspartate, glutamate, glucose, myo-inositol, creatine and choline using a nominal voxel size of 0.56 cm(3). A comparison of spectral quality and metabolite concentration measurements was made between LASER-CSI and LASER-single voxel spectroscopy (SVS) in a region of homogeneous parietal white matter (N = 8). No significant differences were found in linewidths, signal-to-noise ratios or the effectiveness of the macromolecule subtraction between SVS and CSI. Water suppression was 45% more effective in SVS than in CSI (p < 0.05). A linear regression of all paired metabolite measurements resulted in a slope = 1.01 +/- 0.03 (r(2) = 0.73). LASER-CSI concentration measurements of N-acetyl-aspartate, glutamate, glucose, myo-inositol, creatine and choline were in agreement (within standard deviations) with LASER-SVS measurements. LASER-CSI is, therefore, a viable and attractive option for future (1)H CSI investigations.
View details for DOI 10.1002/nbm.1053
View details for Web of Science ID 000243168700001
View details for PubMedID 16927396
Tissue oxygen tension measurements in the Shionogi model of prostate cancer using F-19 MRS and MRI
12th Annual Meeting of the ISMRM
SPRINGER. 2004: 288–95
To investigate changes in tumour tissue oxygenation throughout the tumour growth-regression-relapse cycle in an androgen-dependent animal tumour model.19F T1 relaxometry of Perfluoro-15-Crown-5-Ether was used to measure in vivo partial oxygen pressure (pO2) of Shionogi tumours on a 2.35-T MR scanner. Perfluoro-15-Crown-5-Ether was administered as an emulsion injected intravenously or as a neat compound injected directly into the tumour. Non-localized, tumour 19F T1 measurements, made at multiple time points throughout the tumour cycle, were translated into pO2 levels.No correlation between tumour size and pO2 values was found. Values of pO2 for growing tumours (50 +/- 30 torr) were significantly lower than for regressing and relapsing tumours after 9 days post-castration (70 +/- 10 torr, p<0.05). Maximum pO2 values (90 +/- 30 torr) were reached between fifth and eighth day post-castration, when tumour pO2 was significantly higher than both pre-castration (p<0.001) and after 9 days post-castration (p<0.05).We demonstrate that longitudinal pO2 measurements in vivo are feasible. Values of pO2 for growing androgen-dependent tumours were significantly lower than for regressing and relapsing androgen-independent tumours. These results have potential clinical importance in optimizing the timing of chemotherapy and/or radiotherapy of hormone dependent tumours.
View details for DOI 10.1007/s10334-004-0083-3
View details for Web of Science ID 000227620700024
View details for PubMedID 15605277