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1.  Diffusion tractography of post-mortem human brains: Optimization and comparison of spin echo and steady-state free precession techniques 
Neuroimage  2012;59(3-2):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.
► Comparison of DW-SE and DW-SSFP for post-mortem imaging on clinical scanners. ► Optimization of protocols predicts 50-130% higher SNR efficiency in DW-SSFP. ► Comparison of tractography 6- and 12-hour DW-SE and DW-SSFP scans. ► Lower uncertainty on fibre direction in DW-SSFP produces superior tractography. ► Crossing fibres can be estimated from 12-hour DW-SSFP data.
PMCID: PMC3314951  PMID: 22008372
Diffusion; Tractography; Post mortem; Steady-state free precession; DTI
2.  Improving diffusion-weighted imaging of post-mortem human brains: SSFP at 7 T 
Neuroimage  2014;102:579-589.
Post-mortem diffusion imaging of whole, human brains has potential to provide data for validation or high-resolution anatomical investigations. Previous work has demonstrated improvements in data acquired with diffusion-weighted steady-state free precession (DW-SSFP) compared with conventional diffusion-weighted spin echo at 3 T. This is due to the ability of DW-SSFP to overcome signal-to-noise and diffusion contrast losses brought about by tissue fixation related decreases in T2 and ADC. In this work, data of four post-mortem human brains were acquired at 3 T and 7 T, using DW-SSFP with similar effective b-values (beff ~ 5150 s/mm2) for inter-field strength comparisons; in addition, DW-SSFP data were acquired at 7 T with higher beff (~ 8550 s/mm2) for intra-field strength comparisons. Results demonstrate that both datasets acquired at 7 T had higher SNR and diffusion contrast than data acquired at 3 T, and data acquired at higher beff had improved diffusion contrast than at lower beff at 7 T. These results translate to improved estimates of secondary fiber orientations leading to higher fidelity tractography results compared with data acquired at 3 T. Specifically, tractography streamlines of cortical projections originating from the corpus callosum, corticospinal tract, and superior longitudinal fasciculus were more successful at crossing the centrum semiovale and projected closer to the cortex. Results suggest that DW-SSFP at 7 T is a preferential method for acquiring diffusion-weighted data of post-mortem human brain, specifically where the primary region of interest involves crossing white matter tracts.
•Diffusion weighted SSFP imaging of post-mortem human brain at 7 T is compared to 3 T.•Both SNR and diffusion contrast are improved at 7 T.•7 T data show improved crossing fiber estimates and accompanying tractography.•Including B1 map in 7 T data analysis brings diffusion metrics in line with 3 T data.
PMCID: PMC4229505  PMID: 25128709
Post-mortem human brain; Diffusion-weighted steady-state free precession; 7 T; Tractography; Diffusion tensor imaging; MRI
3.  The effects of brain tissue decomposition on diffusion tensor imaging and tractography 
NeuroImage  2007;36(1):64-68.
There have been numerous high resolution diffusion tensor imaging studies in fixed animal brains, but relatively few studies in human brains. While animal tissues are generally fixed pre-mortem or directly postmortem, this is not possible for human tissue, therefore there is always some delay between death and tissue fixation. The elapsed time between death and tissue fixation, the postmortem interval (PMI), will most likely adversely affect the tissue's diffusion properties. We studied the effects of PMI on the diffusion properties of rodent brain. Eight mice were euthanized and the brains (kept in the skull) were placed in formalin at PMIs of 0, 1, 4 and 14 days. Post fixation they were placed in a solution of GdDTPA and phosphate buffered saline. Brains were scanned with a 3D EPI DTI sequence at 4.7T. DTI data were processed to generate apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps. DTI tractography was also performed. The temporal changes in regional ADC and FA values were analyzed statistically using a one-way ANOVA, followed by individual Student's T-tests. Regional FA and ADC of gray and white matter decreased significantly with time (p<0.05). DTI tractography showed a decrease in the number and coherence of reconstructed fiber pathways between PMIs 0 and 14. Elapsed time between death and tissue fixation has a major effect upon the brain's diffusion properties and should be born in mind when interpreting fixed brain DTI.
PMCID: PMC4039353  PMID: 17433879
4.  In vivo detection of microscopic anisotropy using quadruple pulsed-field gradient (qPFG) diffusion MRI on a clinical scanner 
NeuroImage  2012;64:229-239.
We report our design and implementation of a quadruple pulsed-field gradient (qPFG) diffusion MRI pulse sequence on a whole-body clinical scanner and demonstrate its ability to non-invasively detect restriction-induced microscopic anisotropy in human brain tissue. The microstructural information measured using qPFG diffusion MRI in white matter complements that provided by diffusion tensor imaging (DTI) and exclusively characterizes diffusion of water trapped in microscopic compartments with unique measures of average cell geometry. We describe the effect of white matter fiber orientation on the expected MR signal and highlight the importance of incorporating such information in the axon diameter measurement using a suitable mathematical framework. Integration of qPFG diffusion-weighted images (DWI) with fiber orientations measured using high-resolution DTI allows the estimation of average axon diameters in the corpus callosum of healthy human volunteers. Maps of inter-hemispheric average axon diameters reveal an anterior-posterior variation in good topographical agreement with anatomical measurements reported in previous post-mortem studies. With further technical refinements and additional clinical validation, qPFG diffusion MRI could provide a quantitative whole-brain histological assessment of white and gray matter, enabling a wide range of neuroimaging applications for improved diagnosis of neurodegenerative pathologies, monitoring neurodevelopmental processes, and mapping brain connectivity.
PMCID: PMC3520437  PMID: 22939872
multiple pulsed-field gradient; diffusion MRI; multiple-wave-vector; diffusion-weighted image; microscopic anisotropy; axon diameter
5.  Comparison of In Vivo and Ex Vivo Diffusion Tensor Imaging in Rhesus Macaques at Short and Long Diffusion Times 
Diffusion tensor imaging (DTI) is widely used to non-invasively study neural tissue micro-structure. While DTI tractography of large nerve fibers is well accepted, visualization of smaller fibers and resolution of branching fibers is challenging. Sensitivity of DTI to diffusion anisotropy can be further enhanced using long diffusion time that can provide a more accurate representation of the tissue micro-structure. We previously reported that ex vivo fixed brain DTI at long tdiff (192 ms) showed improved sensitivity to fiber tracking compared to short tdiff (48 ms) in 4% formalin-fixed non-human primate (NHP) brains. This study further tested the hypothesis that DTI at longer diffusion time improves DTI fiber tracking in the in vivo NHP brains on a clinical 3 Tesla MRI scanner. Compared to fixed brains, the in vivo ADC was larger by a factor of 5. Also, the white-matter FA was 28% higher in the in vivo study as compared to our ex vivo experiments. Compared to short tdiff, long tdiff increased white-matter FA by 6.0±0.5%, diffusion was more anisotropic, tensor orientations along major fiber tracts were more coherent, and tracked fibers were about 10.1±2.9% longer in the corpus callosum and 7.3±2.8% longer along the cortico-spinal tract. The overall improvements in tractography were, however, less pronounced in the in vivo brain than in fixed brains. Nonetheless, these in vivo findings reinforce that DTI tractography at long diffusion time improves tracking of smaller fibers in regions of low fractional anisotropy.
PMCID: PMC3258009  PMID: 22253659
DTI; Fiber tracking; MRI; Fractional anisotropy; Non-human primate; Fixed brain.
6.  Unraveling the multiscale structural organization and connectivity of the human brain: the role of diffusion MRI 
The structural architecture and the anatomical connectivity of the human brain show different organizational principles at distinct spatial scales. Histological staining and light microscopy techniques have been widely used in classical neuroanatomical studies to unravel brain organization. Using such techniques is a laborious task performed on 2-dimensional histological sections by skilled anatomists possibly aided by semi-automated algorithms. With the recent advent of modern magnetic resonance imaging (MRI) contrast mechanisms, cortical layers and columns can now be reliably identified and their structural properties quantified post-mortem. These developments are allowing the investigation of neuroanatomical features of the brain at a spatial resolution that could be interfaced with that of histology. Diffusion MRI and tractography techniques, in particular, have been used to probe the architecture of both white and gray matter in three dimensions. Combined with mathematical network analysis, these techniques are increasingly influential in the investigation of the macro-, meso-, and microscopic organization of brain connectivity and anatomy, both in vivo and ex vivo. Diffusion MRI-based techniques in combination with histology approaches can therefore support the endeavor of creating multimodal atlases that take into account the different spatial scales or levels on which the brain is organized. The aim of this review is to illustrate and discuss the structural architecture and the anatomical connectivity of the human brain at different spatial scales and how recently developed diffusion MRI techniques can help investigate these.
PMCID: PMC4460430  PMID: 26106304
diffusion MRI; cortical layers and areas; cytoarchitecture; myeloachtecture; structural connectivity
7.  Q-Ball of Inferior Fronto-Occipital Fasciculus and Beyond 
PLoS ONE  2014;9(6):e100274.
The inferior fronto-occipital fasciculus (IFOF) is historically described as the longest associative bundle in the human brain and it connects various parts of the occipital cortex, temporo-basal area and the superior parietal lobule to the frontal lobe through the external/extreme capsule complex. The exact functional role and the detailed anatomical definition of the IFOF are still under debate within the scientific community. In this study we present a fiber tracking dissection of the right and left IFOF by using a q-ball residual-bootstrap reconstruction of High-Angular Resolution Diffusion Imaging (HARDI) data sets in 20 healthy subjects. By defining a single seed region of interest on the coronal fractional anisotropy (FA) color map of each subject, we investigated all the pathways connecting the parietal, occipital and posterior temporal cortices to the frontal lobe through the external/extreme capsule. In line with recent post-mortem dissection studies we found more extended anterior-posterior association connections than the “classical” fronto-occipital representation of the IFOF. In particular the pathways we evidenced showed: a) diffuse projections in the frontal lobe, b) fronto-parietal lobes connections trough the external capsule in almost all the subjects and c) widespread connections in the posterior regions. Our study represents the first consistent in vivo demonstration across a large group of individuals of these novel anterior and posterior terminations of the IFOF detailed described only by post-mortem anatomical dissection. Furthermore our work establishes the feasibility of consistent in vivo mapping of this architecture with independent in vivo methodologies. In conclusion q-ball tractography dissection supports a more complex definition of IFOF, which includes several subcomponents likely underlying specific function.
PMCID: PMC4063757  PMID: 24945305
8.  Segmentation of the Canine Corpus Callosum using Diffusion Tensor Imaging Tractography 
We set out to determine functional white matter (WM) connections passing through the canine corpus callosum useful for subsequent studies of canine brains that serve as models for human WM pathway disease. Based on prior studies, we anticipated that the anterior corpus callosum would send projections to the anterior cerebral cortex while progressively posterior segments would send projections to more posterior cortex.
A post mortem canine brain was imaged using a 7T MRI producing 100 micron isotropic resolution DTI analyzed by tractography. Using ROIs within cortical locations, which were confirmed by a Nissl stain that identified distinct cortical architecture, we successfully identified 6 important WM pathways. We also compared fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD) in tracts passing through the genu and splenium.
Callosal fibers were organized based upon cortical destination, i.e. fibers from the genu project to the frontal cortex. Histologic results identified the motor cortex based on cytoarchitectonic criteria that allowed placement of ROIs to discriminate between frontal and parietal lobes. We also identified cytoarchitecture typical of the orbital frontal, anterior frontal, and occipital regions and placed ROIs accordingly. FA, ADC, RD and AD values were all higher in posterior corpus callosum fiber tracts.
Using 6 cortical ROIs, we identified 6 major white matter tracts that reflect major functional divisions of the cerebral hemispheres and we derived quantitative values that can be used for study of canine models of human WM pathological states.
PMCID: PMC3998204  PMID: 24370161
9.  Diffusion tensor imaging of post mortem multiple sclerosis brain 
Neuroimage  2007;35(2):467-477.
Magnetic resonance imaging (MRI) is being used to probe the central nervous system (CNS) of patients with multiple sclerosis (MS), a chronic demyelinating disease. Conventional T2-weighted MRI (cMRI) largely fails to predict the degree of patients' disability. This shortcoming may be due to poor specificity of cMRI for clinically relevant pathology. Diffusion tensor imaging (DTI) has shown promise to be more specific for MS pathology. In this study we investigated the association between histological indices of myelin content, axonal count and gliosis, and two measures of DTI (mean diffusivity [MD] and fractional anisotropy [FA]), in unfixed post mortem MS brain using a 1.5-T MR system. Both MD and FA were significantly lower in post mortem MS brain compared to published data acquired in vivo. However, the differences of MD and FA described in vivo between white matter lesions (WMLs) and normal-appearing white matter (NAWM) were retained in this study of post mortem brain: average MD in WMLs was 0.35 × 10− 3 mm2/s (SD, 0.09) versus 0.22 (0.04) in NAWM; FA was 0.22 (0.06) in WMLs versus 0.38 (0.13) in NAWM. Correlations were detected between myelin content (Trmyelin) and (i) FA (r = − 0.79, p < 0.001), (ii) MD (r = 0.68, p < 0.001), and (iii) axonal count (r = − 0.81, p < 0.001). Multiple regression suggested that these correlations largely explain the apparent association of axonal count with (i) FA (r = 0.70, p < 0.001) and (ii) MD (r = − 0.66, p < 0.001). In conclusion, this study suggests that FA and MD are affected by myelin content and – to a lesser degree – axonal count in post mortem MS brain.
PMCID: PMC1892244  PMID: 17258908
10.  Diffusion Tensor Imaging of Post Mortem Multiple Sclerosis Brain 
NeuroImage  2006;35(2):467-477.
Magnetic resonance imaging (MRI) is being used to probe the central nervous system (CNS) of patients with multiple sclerosis (MS), a chronic demyelinating disease. Conventional T2-weighted MRI (cMRI) largely fails to predict the degree of patients' disability. This shortcoming may be due to poor specificity of cMRI for clinically relevant pathology. Diffusion tensor imaging (DTI) has shown promise to be more specific for MS pathology. In this study we investigated the association between histological indices of myelin content, axonal count and gliosis, and two measures of DTI (mean diffusivity [MD] and fractional anisotropy [FA]), in unfixed post mortem MS brain using a 1.5-T MR system. Both MD and FA were significantly lower in post mortem MS brain compared to published data acquired in vivo. However, the differences of MD and FA described in vivo between white matter lesions (WMLs) and normal-appearing white matter (NAWM) were retained in this study of post mortem brain: average MD in WMLs was 0.35×10−3 mm2/s (SD, 0.09) versus 0.22 (0.04) in NAWM; FA was 0.22 (0.06) in WMLs versus 0.38 (0.13) in NAWM. Correlations were detected between myelin content (Trmyelin) and (i) FA (r=−0.79, p<0.001), (ii) MD (r=0.68, p<0.001), and (iii) axonal count (r=−0.81, p<0.001). Multiple regression suggested that these correlations largely explain the apparent association of axonal count with (i) FA (r=0.70, p<0.001) and (ii) MD (r=−0.66, p<0.001). In conclusion, this study suggests that FA and MD are affected by myelin content and – to a lesser degree – axonal count in post mortem MS brain.
PMCID: PMC1892244  PMID: 17258908
11.  Magnetic Resonance Field Strength Effects on Diffusion Measures and Brain Connectivity Networks 
Brain Connectivity  2013;3(1):72-86.
The quest to map brain connectivity is being pursued worldwide using diffusion imaging, among other techniques. Even so, we know little about how brain connectivity measures depend on the magnetic field strength of the scanner. To investigate this, we scanned 10 healthy subjects at 7 and 3 tesla—using 128-gradient high-angular resolution diffusion imaging. For each subject and scan, whole-brain tractography was used to estimate connectivity between 113 cortical and subcortical regions. We examined how scanner field strength affects (i) the signal-to-noise ratio (SNR) of the non-diffusion-sensitized reference images (b0); (ii) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), mean, radial, and axial diffusivity (MD/RD/AD), in atlas-defined regions; (iii) whole-brain tractography; (iv) the 113×113 brain connectivity maps; and (v) five commonly used network topology measures. We also assessed effects of the multi-channel reconstruction methods (sum-of-squares, SOS, at 7T; adaptive recombine, AC, at 3T). At 7T with SOS, the b0 images had 18.3% higher SNR than with 3T-AC. FA was similar for most regions of interest (ROIs) derived from an online DTI atlas (ICBM81), but higher at 7T in the cerebral peduncle and internal capsule. MD, AD, and RD were lower at 7T for most ROIs. The apparent fiber density between some subcortical regions was greater at 7T-SOS than 3T-AC, with a consistent connection pattern overall. Suggesting the need for caution, the recovered brain network was apparently more efficient at 7T, which cannot be biologically true as the same subjects were assessed. Care is needed when comparing network measures across studies, and when interpreting apparently discrepant findings.
PMCID: PMC3621300  PMID: 23205551
brain network analysis; DTI; fractional anisotropy; graph theory; high-field MRI; high angular resolution diffusion imaging (HARDI); signal-to-noise ratio; tractography
12.  Quantitative Assessment of a Framework for Creating Anatomical Brain Networks via Global Tractography 
NeuroImage  2012;61(4):1017-1030.
Interregional connections of the brain measured with diffusion tractography can be used to infer valuable information regarding both brain structure and function. However, different tractography algorithms can generate networks that exhibit different characteristics, resulting in poor reproducibility across studies. Therefore, it is important to benchmark different tractography algorithms to quantitatively assess their performance. Here we systematically evaluated a newly introduced tracking algorithm, global tractography, to derive anatomical brain networks in a fiber phantom, 2 post-mortem macaque brains, and 20 living humans, and compared the results with an established local tracking algorithm. Our results demonstrated that global tractography accurately characterized the phantom network in terms of graph-theoretic measures, and significantly outperformed the local tracking approach. Results in brain tissues (post-mortem macaques and in vivo humans), however, showed that although the performance of global tractography demonstrated a trend of improvement, the results were not vastly different than that of local tractography, possibly resulting from the increased fiber complexity of real tissues. When using macaque tracer-derived connections as the ground truth, we found that both global and local algorithms generated non-random patterns of false negative and false positive connections that were probably related to specific fiber systems and largely independent of the tractography algorithm or tissue type (post-mortem vs. in vivo) used in the current study. Moreover, a close examination of the transcallosal motor connections, reconstructed via either global or local tractography, demonstrated that the lateral transcallosal fibers in humans and macaques did not exhibit the denser homotopic connections found in primate tracer studies, indicating the need for more robust brain mapping techniques based on diffusion MRI data.
PMCID: PMC3407566  PMID: 22484406
connectivity; diffusion; macaque; phantom; transcallosal motor fibers
13.  Pushing the limits of in vivo diffusion MRI for the Human Connectome Project 
NeuroImage  2013;80:220-233.
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 depends 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 200 T/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 5 minutes. 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.
PMCID: PMC3725309  PMID: 23707579
MRI; structural connectivity; diffusion imaging; gradient hardware; HARDI; DSI
14.  Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging 
NeuroImage : Clinical  2014;5:349-358.
Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery.
Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application.
We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy.
Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities.
•We performed a whole brain connectivity study in patients with RTLE and LTLE.•Diffusion Spectrum Imaging (DSI) was used to achieve a better angular resolution.•DSI was also used to allow investigating the tracts microstructure.•Temporal changes where more related to the neurite density.•The extratemporal changes where related to the neurite orientation dispersion.
PMCID: PMC4519999
Diffusion MRI; Connectome; Tractography; Network measures; DSI; GFA; NODDI; Temporal lobe epilepsy
15.  Effects of image distortions originating from susceptibility variations and concomitant fields on diffusion MRI tractography results 
NeuroImage  2012;61(1):10.1016/j.neuroimage.2012.02.054.
In this work we investigate the effects of echo planar imaging (EPI) distortions on diffusion tensor imaging (DTI) based fiber tractography results. We propose a simple experimental framework that would enable assessing the effects of EPI distortions on the accuracy and reproducibility of fiber tractography from a pilot study on a few subjects. We compare trajectories computed from two diffusion datasets collected on each subject that are identical except for the orientation of phase encode direction, either right–left (RL) or anterior–posterior (AP). We define metrics to assess potential discrepancies between RL and AP trajectories in association, commissural, and projection pathways. Results from measurements on a 3 Tesla clinical scanner indicated that the effects of EPI distortions on computed fiber trajectories are statistically significant and large in magnitude, potentially leading to erroneous inferences about brain connectivity. The correction of EPI distortion using an image-based registration approach showed a significant improvement in tract consistency and accuracy. Although obtained in the context of a DTI experiment, our findings are generally applicable to all EPI-based diffusion MRI tractography investigations, including high angular resolution (HARDI) methods. On the basis of our findings, we recommend adding an EPI distortion correction step to the diffusion MRI processing pipeline if the output is to be used for fiber tractography.
PMCID: PMC3653420  PMID: 22401760
Echo planar imaging; Diffusion tensor imaging; Fiber tractography; Image distortions; Susceptibility
16.  Comparison of Magnetic Resonance Imaging in Live vs. Post Mortem Rat Brains 
PLoS ONE  2013;8(8):e71027.
Magnetic Resonance Imaging (MRI) is an increasingly popular technique for examining neurobiology in rodents because it is both noninvasive and nondestructive. MRI scans can be acquired from either live or post mortem specimens. In vivo scans have a key advantage in that subjects can be scanned at multiple time-points in longitudinal studies. However, repeated exposure to anesthesia and stress may confound studies. In contrast, post mortem scans offer improved image quality and increased signal-to-noise ratio (SNR) due to several key advantages: First, the images are not disrupted by motion and pulsation artifacts. Second, they allow the brain tissue to be perfused with contrast agents, enhancing tissue contrast. Third, they allow longer image acquisition times, yielding higher resolution and/or improved SNR. Fourth, they allow assessment of groups of animals at the same age without scheduling complications. Despite these advantages, researchers are often skeptical of post mortem MRI scans because of uncertainty about whether the fixation process alters the MRI measurements. To address these concerns, we present a thorough comparative study of in vivo and post mortem MRI scans in healthy male Wistar rats at three age points throughout adolescence (postnatal days 28 through 80). For each subject, an in vivo scan was acquired, followed by perfusion and two post mortem scans at two different MRI facilities. The goal was to assess robustness of measurements, to detect any changes in volumetric measurements after fixation, and to investigate any differential bias that may exist between image acquisition techniques. We present this volumetric analysis for comparison of 22 anatomical structures between in vivo and post mortem scans. No significant changes in volumetric measurements were detected; however, as hypothesized, the image quality is dramatically improved in post mortem scans. These findings illustrate the validity and utility of using post mortem scans in volumetric neurobiological studies.
PMCID: PMC3742751  PMID: 23967148
17.  Diffusion-Prepared Fast Imaging with Steady-State Free Precession (DP-FISP): A Rapid Diffusion MRI Technique at 7T 
Diffusion MRI is a useful imaging technique with many clinical applications. Many diffusion MRI studies have utilized Echo-Planar Imaging (EPI) acquisition techniques. In this study, we have developed a rapid Diffusion Prepared - Fast Imaging with Steady-State Free Precession (DP-FISP) MRI acquisition for a preclinical 7T scanner providing diffusion-weighted images in less than 500 ms and DTI assessments in approximately 1 minute with minimal image artifacts in comparison to EPI. Phantom Apparent Diffusion Coefficient (ADC) and Fractional Anisotropy (FA) assessments obtained from the DP-FISP acquisition resulted in good agreement with EPI and spin echo diffusion methods. The mean ADC was 2.0×10−3 mm2/s, 1.90 ×10−3 mm2/s and 1.97×10−3 mm2/s for DP-FISP, DW-SE and DW-EPI, respectively. The mean FA was 0.073, 0.072, and 0.070 for DP-FISP, DW-SE and DW-EPI, respectively. Initial in vivo studies show reasonable ADC values in a normal mouse brain and polycystic rat kidneys.
PMCID: PMC3297727  PMID: 22139974
diffusion; MRI; FISP; 7T
18.  Staging Alzheimer’s Disease Progression with Multimodality Neuroimaging 
Progress in neurobiology  2011;95(4):535-546.
Rapid developments in medical neuroimaging have made it possible to reconstruct the trajectory of Alzheimer’s disease (AD) as it spreads through the living brain. The current review focuses on the progressive signature of brain changes throughout the different stages of AD. We integrate recent findings on changes in cortical gray matter volume, white matter fiber tracts, neuropathological alterations, and brain metabolism assessed with molecular positron emission tomography (PET). Neurofibrillary tangles accumulate first in transentorhinal and cholinergic brain areas, and 4-D maps of cortical volume changes show early progressive temporo-parietal cortical thinning. Findings from diffusion tensor imaging (DTI) for assessment fiber tract integrity show cortical disconnection in corresponding brain networks. Importantly, the developmental trajectory of brain changes is not uniform and may be modulated by several factors such as onset of disease mechanisms, risk-associated and protective genes, converging comorbidity, and individual brain reserve. There is a general agreement between in vivo brain maps of cortical atrophy and amyloid pathology assessed through PET, reminiscent of post mortem histopathology studies that paved the way in the staging of AD. The association between in vivo and post mortem findings will clarify the temporal dynamics of pathophysiological alterations in the development of preclinical AD. This will be important in designing effective treatments that target specific underlying disease AD mechanisms.
PMCID: PMC3223355  PMID: 21718750
Alzheimer’s disease; AD; mild cognitive impairment; MCI; pre-dementia; pre-clinical; pre-symptomatic; biological markers; neuroimaging; multimodal; neuropathology; neuroanatomy; computational; MRI; fMRI; DTI; VBM; DBM; tractography; drug development; clinical trials; CSF; staging; progression; diagnosis; classification; early detection; prediction; biological activity; ADNI; EADNI; regulatory authorities; FDA; EMEA
19.  DTI at long diffusion time improves fiber tracking 
NMR in biomedicine  2010;23(5):459-465.
While diffusion-tensor-imaging tractography provides remarkable in vivo anatomical connectivity of the central nervous system, the majority of DTI studies to date are predominantly limited to tracking large white-matter fibers. This study investigated DTI tractography using long diffusion time (tdiff) to improve tracking of thinner fibers in fixed rhesus monkey brains. Stimulated Echo Acquisition Mode (STEAM) sequence on a 3T Siemens TRIO was modified to include a diffusion module. DTI was acquired using STEAM with tdiff of 48 and 192 ms with matched signal-to-noise ratios (SNR). Comparisons were also made with the conventional double-spin echo (DSE) at a short tdiff of 45 ms. Not only did the fractional anisotropy increase significantly with the use of long diffusion time, but directional entropy measures indicated that there was an increased coherence amongst neighboring tensors. Further, the magnitude of the major eigenvector was larger at the tdiff = 192 ms as compared to the short tdiff. Probabilistic connectivity maps at long tdiff showed larger areas of connectivity with the use of long diffusion time, which traversed deeper into areas of low anisotropy. With tractography, it was found that the length of the fibers, increased by almost 10% in the callosal fibers that branch into the paracentral gyrus, the precentral gyrus and the post central gyrus. A similar increase of about 20% was observed in the fibers of the internal capsule. These findings offer encouraging data that DTI at long diffusion time could improve tract tracing of small fibers in areas of low fractional anisotropy (FA), such as at the interfaces of white matter and grey matter.
PMCID: PMC2949954  PMID: 20175137
diffusion tensor imaging; STEAM sequence; rhesus macaques; cross-terms; formalin fixation; fractional anisotropy; white matter tracking
20.  Surface Based Analysis of Diffusion Orientation for Identifying Architectonic Domains in the In Vivo Human Cortex 
NeuroImage  2012;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 grey matter is more isotropic, however, several groups have observed coherent patterns of diffusion anisotropy within the cerebral cortical grey 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.
PMCID: PMC3557597  PMID: 23247190
cerebral cortex; diffusion tensor imaging; laminar analysis; human; brain
21.  Cortical Depth Dependence of the Diffusion Anisotropy in the Human Cortical Gray Matter In Vivo 
PLoS ONE  2014;9(3):e91424.
Diffusion tensor imaging (DTI) is typically used to study white matter fiber pathways, but may also be valuable to assess the microstructure of cortical gray matter. Although cortical diffusion anisotropy has previously been observed in vivo, its cortical depth dependence has mostly been examined in high-resolution ex vivo studies. This study thus aims to investigate the cortical depth dependence of the diffusion anisotropy in the human cortex in vivo on a clinical 3 T scanner. Specifically, a novel multishot constant-density spiral DTI technique with inherent correction of motion-induced phase errors was used to achieve a high spatial resolution (0.625×0.625×3 mm) and high spatial fidelity with no scan time penalty. The results show: (i) a diffusion anisotropy in the cortical gray matter, with a primarily radial diffusion orientation, as observed in previous ex vivo and in vivo studies, and (ii) a cortical depth dependence of the fractional anisotropy, with consistently higher values in the middle cortical lamina than in the deep and superficial cortical laminae, as observed in previous ex vivo studies. These results, which are consistent across subjects, demonstrate the feasibility of this technique for investigating the cortical depth dependence of the diffusion anisotropy in the human cortex in vivo.
PMCID: PMC3946789  PMID: 24608869
22.  7 Tesla Magnetic Resonance Imaging to Detect Cortical Pathology in Multiple Sclerosis 
PLoS ONE  2014;9(10):e108863.
Neocortical lesions (NLs) are an important pathological component of multiple sclerosis (MS), but their visualization by magnetic resonance imaging (MRI) remains challenging.
We aimed at assessing the sensitivity of multi echo gradient echo (ME-GRE) T2*-weighted MRI at 7.0 Tesla in depicting NLs compared to myelin and iron staining.
Samples from two MS patients were imaged post mortem using a whole body 7T MRI scanner with a 24-channel receive-only array. Isotropic 200 micron resolution images with varying T2* weighting were reconstructed from the ME-GRE data and converted into R2* maps. Immunohistochemical staining for myelin (proteolipid protein, PLP) and diaminobenzidine-enhanced Turnbull blue staining for iron were performed.
Prospective and retrospective sensitivities of MRI for the detection of NLs were 48% and 67% respectively. We observed MRI maps detecting only a small portion of 20 subpial NLs extending over large cortical areas on PLP stainings. No MRI signal changes suggestive of iron accumulation in NLs were observed. Conversely, R2* maps indicated iron loss in NLs, which was confirmed by histological quantification.
High-resolution post mortem imaging using R2* and magnitude maps permits detection of focal NLs. However, disclosing extensive subpial demyelination with MRI remains challenging.
PMCID: PMC4193749  PMID: 25303286
23.  Diffusion anisotropy indexes are sensitive to selecting the EPI readout-encoding bandwidth at high-field MRI 
Magnetic resonance imaging  2008;26(5):676-682.
Diffusion tensor magnetic resonance imaging (DT-MRI) is generally performed using an echo planar imaging (EPI) acquisition to map directional water diffusion. However, the oscillating magnetic field gradients of the EPI acquisition can result in considerable mechanical vibrations, which lead, in turn, to magnetic field fluctuations causing Nyquist ghosting in the EPI data. The objective of this study was to investigate effects of EPI readout gradient modulation frequency, which is directly associated with the EPI readout bandwidth (BW), on the accuracy of DT-MRI measurements in a high magnetic field system. A spherical water phantom was used to study the relationship between the EPI BW and the Nyquist ghost for a spin-echo EPI acquisition with a matrix size of 128×128, complemented by diffusion sensitization gradients of up to b=800 s/mm2 along six directions for DT-MRI. Nine volunteers (four males and five females) were studied using EPI at different BW acquisitions. Analysis of variance was used to investigate the EPI BW effects. The phantom studies demonstrated a systematic relationship between BWs and the intensities of Nyquist ghosts. In the human brain studies, EPI BW variations substantially corrupted diffusion anisotropy indexes (i.e., fractional anisotropy and relative anisotropy) (F=10.5, P=.0001) but were unrelated to diffusion-encoding directions (F=0.14, P=.98). It was possible to minimize BW dependence (F=1.48, P=.25) by tuning the modulation frequency of the EPI readout gradient. In conclusion, diffusion anisotropic indexes are sensitive to the readout BW of EPI due to associated Nyquist ghosting. However, the effect can be minimized by tuning the modulation frequency of the EPI readout gradient, that is, the EPI BW, to a range outside the harmonics of mechanical gradient vibrations.
PMCID: PMC2556209  PMID: 18420366
Echo planar imaging; Readout-encoding bandwidth; Diffusion tensor; High-field MRI
24.  Diffusion Tensor Tractography of the Human Brain Cortico-Ponto-Cerebellar Pathways: A Quantitative Preliminary Study 
To investigate the utility of diffusion tensor tractography at 1mm slice thickness to map and quantify the whole trajectory of different cortico-ponto-cerebellar pathways of the healthy adult human brain.
Materials and Methods
This work was approved by the local Institutional Review Board, and was Health Insurance Portability and Accountability Act (HIPAA) compliant. Five healthy right-handed men (age range, 24–37 years) were studied and written informed consent was obtained. Diffusion tensor imaging data acquired with 1-mm slice thickness at a 3.0 Tesla (T) clinical MRI scanner were prepared and analyzed using tractography methods to reconstruct the cortico-ponto-cerebellar pathways which included the fronto-ponto-cerebellar, parieto-ponto-cerebellar, occipitoponto- cerebellar, and temporo-ponto-cerebellar tracts.
We demonstrate the feasibility of tractographic mapping and quantification of the four cortico-ponto-cerebellar system components based on their cortical connections in the healthy human brain using DTI data with thin 1-mm sections.
In vivo quantification of different corticoponto-cerebellar pathways based on cortical connection is feasible, using 1-mm slices at 3.0T.
PMCID: PMC4492525  PMID: 20882611
diffusion tensor imaging; tractography; thin slices; cortico-ponto-cerebellar pathways
25.  Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene, CNTNAP2 
Brain Connectivity  2011;1(6):447-459.
Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here, we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 women, 119 men, age: 23.4±2.17 SD years) were scanned with 105-gradient high-angular-resolution diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual's co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole-brain analyses, and lower eccentricity (maximum path length) in 60 of the 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study that links graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of the circuits implicated in the risk for autism.
PMCID: PMC3420970  PMID: 22500773
autism; CNTNAP2; graph theory; HARDI; structural connectivity; twins

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