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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.
Highlights
► 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.
doi:10.1016/j.neuroimage.2011.09.054
PMCID: PMC3314951  PMID: 22008372
Diffusion; Tractography; Post mortem; Steady-state free precession; DTI
2.  Ultrafast bold fMRI using single-shot spin-echo echo planar imaging 
The choice of imaging parameters for functional MRI can have an impact on the accuracy of functional localization by affecting the image quality and the degree of blood oxygenation-dependent (BOLD) contrast achieved. By improving sampling efficiency, parallel acquisition techniques such as sensitivity encoding (SENSE) have been used to shorten readout trains in single-shot (SS) echo planar imaging (EPI). This has been applied to susceptibility artifact reduction and improving spatial resolution. SENSE together with single-shot spin-echo (SS-SE) imaging may also reduce off-resonance artifacts. The goal of this work was to investigate the BOLD response of a SENSE-adapted SE-EPI on a three Tesla scanner. Whole-brain fMRI studies of seven healthy right hand-dominant volunteers were carried out in a three Tesla scanner. fMRI was performed using an SS-SE EPI sequence with SENSE. The data was processed using statistical parametric mapping. Both, group and individual subject data analyses were performed. Individual average percentage and maximal percentage signal changes attributed to the BOLD effect in M1 were calculated for all the subjects as a function of echo time. Corresponding activation maps and the sizes of the activated clusters were also calculated. Our results show that susceptibility artifacts were reduced with the use of SENSE; and the acquired BOLD images were free of the typical quadrature artifacts of SS-EPI. Such measures are crucial at high field strengths. SS SE-EPI with SENSE offers further benefits in this regard and is more specific for oxygenation changes in the microvasculature bed. Functional brain activity can be investigated with the help of single-shot spin echo EPI using SENSE at high magnetic fields.
doi:10.4103/0971-6203.48719
PMCID: PMC2804146  PMID: 20126564
Bold-fMRI; parallel imaging; sense; spin-echo echo planar imaging; Tesla
3.  Three Dimensional Diffusion Tensor Microimaging for Anatomical Characterization of the Mouse Brain 
Diffusion tensor imaging (DTI) is gaining increasing importance for anatomical imaging of the developing mouse brain. However, the application of DTI to mouse brain imaging at microscopic levels is hindered by the limitation on achievable spatial resolution. In this study, fast diffusion tensor microimaging (DTMI) of the mouse brain based on a diffusion-weighted gradient and spin echo (DW-GRASE) technique with twin-navigator echo phase correction is presented. Compared to echo planar and spin echo acquisition, the DW-GRASE acquisition resulted in significant reduction in scan time and had minimal image distortion, thereby allowing acquisition at higher spatial resolution. In this study, three dimensional DTMI of the mouse brains at spatial resolutions of 50 – 60 µm revealed unprecedented anatomical details. Thin fiber bundles in the adult striatum and white matter tracts in the embryonic day 12 mouse brains were visualized for the first time. The study demonstrated that data acquired using the DTMI technique allow three dimensional mapping of gene expression data and can serve as a platform to study gene expression patterns in the context of neuroanatomy in the developing mouse brain.
doi:10.1002/mrm.22426
PMCID: PMC2915547  PMID: 20577980
diffusion tensor imaging; mouse; brain; gene expression mapping
4.  Magnetic Resonance Field Strength Effects on Diffusion Measures and Brain Connectivity Networks 
Brain Connectivity  2013;3(1):72-86.
Abstract
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.
doi:10.1089/brain.2012.0114
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
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.
doi:10.2174/1874440001105010172
PMCID: PMC3258009  PMID: 22253659
DTI; Fiber tracking; MRI; Fractional anisotropy; Non-human primate; Fixed brain.
6.  Multiplexed Echo Planar Imaging for Sub-Second Whole Brain FMRI and Fast Diffusion Imaging 
PLoS ONE  2010;5(12):e15710.
Echo planar imaging (EPI) is an MRI technique of particular value to neuroscience, with its use for virtually all functional MRI (fMRI) and diffusion imaging of fiber connections in the human brain. EPI generates a single 2D image in a fraction of a second; however, it requires 2–3 seconds to acquire multi-slice whole brain coverage for fMRI and even longer for diffusion imaging. Here we report on a large reduction in EPI whole brain scan time at 3 and 7 Tesla, without significantly sacrificing spatial resolution, and while gaining functional sensitivity. The multiplexed-EPI (M-EPI) pulse sequence combines two forms of multiplexing: temporal multiplexing (m) utilizing simultaneous echo refocused (SIR) EPI and spatial multiplexing (n) with multibanded RF pulses (MB) to achieve m×n images in an EPI echo train instead of the normal single image. This resulted in an unprecedented reduction in EPI scan time for whole brain fMRI performed at 3 Tesla, permitting TRs of 400 ms and 800 ms compared to a more conventional 2.5 sec TR, and 2–4 times reductions in scan time for HARDI imaging of neuronal fibertracks. The simultaneous SE refocusing of SIR imaging at 7 Tesla advantageously reduced SAR by using fewer RF refocusing pulses and by shifting fat signal out of the image plane so that fat suppression pulses were not required. In preliminary studies of resting state functional networks identified through independent component analysis, the 6-fold higher sampling rate increased the peak functional sensitivity by 60%. The novel M-EPI pulse sequence resulted in a significantly increased temporal resolution for whole brain fMRI, and as such, this new methodology can be used for studying non-stationarity in networks and generally for expanding and enriching the functional information.
doi:10.1371/journal.pone.0015710
PMCID: PMC3004955  PMID: 21187930
7.  Mapping Spatio-Temporal Diffusion inside the Human Brain Using a Numerical Solution of the Diffusion Equation 
Magnetic resonance imaging  2008;26(5):694-702.
Diffusion is an important mechanism for molecular transport in living biological tissues. Diffusion magnetic resonance imaging (dMRI) provides a unique probe to examine microscopic structures of the tissues in vivo, but current dMRI techniques usually ignore the spatio-temporal evolution process of the diffusive medium. In the present study, we demonstrate the feasibility to reveal the spatio-temporal diffusion process inside the human brain based on a numerical solution of the diffusion equation. Normal human subjects were scanned with a diffusion tensor imaging (DTI) technique on a 3-Tesla MRI scanner, and the diffusion tensor in each voxel was calculated from the DTI data. The diffusion equation, a partial-derivative description of Fick’s Law for the diffusion process, was discretized into equivalent algebraic equations. A finite-difference method was employed to obtain the numerical solution of the diffusion equation with a Crank-Nicholson iteration scheme to enhance the numerical stability. By specifying boundary and initial conditions, the spatio-temporal evolution of the diffusion process inside the brain can be virtually reconstructed. Our results exhibit similar medium profiles and diffusion coefficients as those of light fluorescence dextrans measured in integrative optical imaging experiments. The proposed method highlights the feasibility to non-invasively estimate the macroscopic diffusive transport time for a molecule in a given region of the brain.
doi:10.1016/j.mri.2008.01.025
PMCID: PMC2587395  PMID: 18440744
diffusion equation; diffusion tensor imaging (DTI); numerical solution; spatio-temporal process
8.  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.
doi:10.1016/j.neuroimage.2012.02.054
PMCID: PMC3653420  PMID: 22401760
Echo planar imaging; Diffusion tensor imaging; Fiber tractography; Image distortions; Susceptibility
9.  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.
doi:10.1002/mrm.23287
PMCID: PMC3297727  PMID: 22139974
diffusion; MRI; FISP; 7T
10.  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.
doi:10.1016/j.neuroimage.2012.08.048
PMCID: PMC3520437  PMID: 22939872
multiple pulsed-field gradient; diffusion MRI; multiple-wave-vector; diffusion-weighted image; microscopic anisotropy; axon diameter
11.  Selective frontal neurodegeneration of the inferior fronto-occipital fasciculus in progressive supranuclear palsy (PSP) demonstrated by diffusion tensor tractography 
BMC Neurology  2011;11:13.
Background
The clinical presentation in progressive supranuclear palsy (PSP), an atypical parkinsonian disorder, includes varying degrees of frontal dysexecutive symptoms. Using diffusion tensor imaging (DTI) and tractography (DTT), we investigated whether diffusion changes and atrophy of the inferior fronto-occipital fasciculus (IFO) occurs in PSP and if these changes correlate with disease stage and clinical phenotype. The corticospinal tract (CST), which is often involved in PSP, was investigated for comparison.
Methods
DTI of the whole brain was performed with a 3 T MR scanner using a single shot-EPI sequence with diffusion encoding in 48 directions. Scans were obtained in patients with PSP (n = 13) and healthy age-matched controls (n = 12). DTT of the IFO and CST was performed with the PRIDE fibre tracking tool (Philips Medical System). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated and correlated with disease stage and clinical phenotype.
Results
In patients with PSP, significantly decreased FA and increased ADC was found in the frontal part of IFO compared with the medial and occipital parts of IFO, as well as compared to controls. Four of the thirteen patients with PSP showed a marked decrease in the number of tracked voxels in the frontal part of IFO. These findings were most pronounced in patients with severe frontal cognitive symptoms, such as dysexecutive problems, apathy and personality change. There was a strong correlation (r2 = -0.84; p < 0,001) between disease stage and FA and ADC values in the CST.
Conclusions
DTT for identification of neuronal tracts with subsequent measurement of FA and ADC is a useful diagnostic tool for demonstrating patterns of neuronal tract involvement in neurodegenerative disease. In selected tracts, FA and ADC values might act as surrogate markers for disease stage.
doi:10.1186/1471-2377-11-13
PMCID: PMC3041656  PMID: 21269463
12.  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.
doi:10.1016/j.neuroimage.2006.12.010
PMCID: PMC1892244  PMID: 17258908
13.  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.
doi:10.1016/j.neuroimage.2006.12.010
PMCID: PMC1892244  PMID: 17258908
14.  MRI Quantification of Non-Gaussian Water Diffusion by Kurtosis Analysis 
NMR in biomedicine  2010;23(7):698-710.
Quantification of non-Gaussianity for water diffusion in brain by means of diffusional kurtosis imaging (DKI) is reviewed. Diffusional non-Gaussianity is a consequence of tissue structure that creates diffusion barriers and compartments. The degree of non-Gaussianity is conveniently quantified by the diffusional kurtosis and derivative metrics, such as the mean, axial, and radial kurtoses. DKI is a diffusion-weighted MRI technique that allows the diffusional kurtosis to be estimated with clinical scanners using standard diffusion-weighted pulse sequences and relatively modest acquisition times. DKI is an extension of the widely used diffusion tensor imaging method, but requires the use of at least 3 b-values and 15 diffusion directions. This review discusses the underlying theory of DKI as well as practical considerations related to data acquisition and post-processing. It is argued that the diffusional kurtosis is sensitive to diffusional heterogeneity and suggested that DKI may be useful for investigating ischemic stroke and neuropathologies, such as Alzheimer’s disease and schizophrenia.
doi:10.1002/nbm.1518
PMCID: PMC2997680  PMID: 20632416
diffusion; non-Gaussian; brain; MRI; kurtosis; DKI; DTI
15.  Evaluation of pressure-driven brain infusions in non-human primates by intra-operative 7 Tesla MRI 
PURPOSE
The goal of this study was to characterize the effects of pressure-driven brain infusions using high field intra-operative MRI. Understanding these effects is critical for upcoming neurodegeneration and oncology trials using convection-enhanced delivery (CED) to achieve large drug distributions with minimal off-target exposure.
MATERIALS AND METHODS
High-resolution T2-weighted and diffusion-tensor images were acquired serially on a 7 Tesla MRI scanner during six CED infusions in non-human primates. The images were used to evaluate the size, distribution, diffusivity and temporal dynamics of the infusions.
RESULTS
The infusion distribution had high contrast in the T2-weighted images. Diffusion tensor images showed the infusion increased diffusivity, reduced tortuosity and reduced anisotropy. These results suggested CED caused an increase in the extracellular space.
CONCLUSIONS
High-field intra-operative MRI can be used to monitor the distribution of infusate and changes in the geometry of the brain’s porous matrix. These techniques could be used to optimize the effectiveness of pressure-driven drug delivery to the brain.
doi:10.1002/jmri.23771
PMCID: PMC3509951  PMID: 22887937
7T MRI; convection-enhanced drug delivery; diffusion; extracellular space; non-human primate
16.  In Vivo Fiber Tracking in the Rat Brain on a Clinical 3T MRI System Using a High Strength Insert Gradient Coil 
NeuroImage  2007;35(3):1077-1085.
In vivo neuroimaging methods permit longitudinal quantitative examination of the dynamic course of neurodegenerative conditions in humans and animal models and enable assessment of therapeutic efforts in mitigating disease effects on brain systems. The study of conditions affecting white matter, such as multiple sclerosis, demyelinating conditions, and drug and alcohol dependence, can be accomplished with diffusion tensor imaging (DTI), a technique uniquely capable of probing the microstructural integrity of white matter fibers in the living brain. We used a 3T clinical MR scanner equipped with an insert gradient coil that yields an order of magnitude increase in performance over the whole-body hardware to acquire in vivo DTI images of rat brain. The resolution allowed for fiber tracking evaluation of fractional anisotropy (FA) and apparent diffusion coefficients in the genu and splenium of the corpus callosum. A comparison of short (46 min) and long (92 min) acquisition time DTI protocols indicated low but adequate signal-to-noise ratio (SNR=6.2) of the shorter protocol to conduct quantitative fiber tracking enhanced by multiple acquisitions. As observed in human studies, FA in the rat splenium was higher than in the genu. Advantages of this technology include the use of similar user interface, pulse sequences, and field strength for preclinical animal and clinical human research, enhancing translational capabilities. An additional benefit of scanning at lower field strength, such as 3T, is the reduction of artifacts due to main field inhomogeneity relative to higher field animal systems.
doi:10.1016/j.neuroimage.2007.01.006
PMCID: PMC1868575  PMID: 17331742
17.  Towards Ultra-High Resolution Fibre Tract Mapping of the Human Brain – Registration of Polarised Light Images and Reorientation of Fibre Vectors 
Polarised light imaging (PLI) utilises the birefringence of the myelin sheaths in order to visualise the orientation of nerve fibres in microtome sections of adult human post-mortem brains at ultra-high spatial resolution. The preparation of post-mortem brains for PLI involves fixation, freezing and cutting into 100-μm-thick sections. Hence, geometrical distortions of histological sections are inevitable and have to be removed for 3D reconstruction and subsequent fibre tracking. We here present a processing pipeline for 3D reconstruction of these sections using PLI derived multimodal images of post-mortem brains. Blockface images of the brains were obtained during cutting; they serve as reference data for alignment and elimination of distortion artefacts. In addition to the spatial image transformation, fibre orientation vectors were reoriented using the transformation fields, which consider both affine and subsequent non-linear registration. The application of this registration and reorientation approach results in a smooth fibre vector field, which reflects brain morphology. PLI combined with 3D reconstruction and fibre tracking is a powerful tool for human brain mapping. It can also serve as an independent method for evaluating in vivo fibre tractography.
doi:10.3389/neuro.09.009.2010
PMCID: PMC2866503  PMID: 20461231
human brain atlas; polarised light imaging; image registration; fibre orientation map; vector reorientation
18.  Comparison of Single-Shot Echo-Planar and Line Scan Protocols for Diffusion Tensor Imaging1 
Academic radiology  2004;11(2):224-232.
Rationale and Objectives
Both single-shot diffusion-weighted echo-planar imaging (EPI) and line scan diffusion imaging (LSDI) can be used to obtain magnetic resonance diffusion tensor data and to calculate directionally invariant diffusion anisotropy indices, ie, indirect measures of the organization and coherence of white matter fibers in the brain. To date, there has been no comparison of EPI and LSDI. Because EPI is the most commonly used technique for acquiring diffusion tensor data, it is important to understand the limitations and advantages of LSDI relative to EPI.
Materials and Methods
Five healthy volunteers underwent EPI and LSDI diffusion on a 1.5 Tesla magnet (General Electric Medical Systems, Milwaukee, WI). Four-mm thick coronal sections, covering the entire brain, were obtained. In addition, one subject was tested with both sequences over four sessions. For each image voxel, eigenvectors and eigenvalues of the diffusion tensor were calculated, and fractional anisotropy (FA) was derived. Several regions of interest were delineated, and for each, mean FA and estimated mean standard deviation were calculated and compared.
Results
Results showed no significant differences between EPI and LSDI for mean FA for the five subjects. When inter-session reproducibility for one subject was evaluated, there was a significant difference between EPI and LSDI in FA for the corpus callosum and the right uncinate fasciculus. Moreover, errors associated with each FA measure were larger for EPI than for LSDI.
Conclusion
Results indicate that both EPI- and LSDI-derived FA measures are sufficiently robust. However, when higher accuracy is needed, LSDI provides smaller error and smaller inter-subject and inter-session variability than EPI.
PMCID: PMC2793336  PMID: 14974598
Diffusion; single-shot EPI; LSDI; anisotropy
19.  Diffusion Tensor Imaging of Frontal White Matter and Executive Functioning in Cocaine-Exposed Children 
Pediatrics  2006;118(5):2014-2024.
BACKGROUND
Although animal studies have demonstrated frontal white matter and behavioral changes resulting from prenatal cocaine exposure, no human studies have associated neuropsychological deficits in attention and inhibition with brain structure. We used diffusion tensor imaging to investigate frontal white matter integrity and executive functioning in cocaine-exposed children.
METHODS
Six direction diffusion tensor images were acquired using a Siemens 3T scanner with a spin-echo echo-planar imaging pulse sequence on right-handed cocaine-exposed (n = 28) and sociodemographically similar non-exposed children (n = 25; mean age: 10.6 years) drawn from a prospective, longitudinal study. Average diffusion and fractional anisotropy were measured in the left and right frontal callosal and frontal projection fibers. Executive functioning was assessed using two well-validated neuropsychological tests (Stroop color-word test and Trail Making Test).
RESULTS
Cocaine-exposed children showed significantly higher average diffusion in the left frontal callosal and right frontal projection fibers. Cocaine-exposed children were also significantly slower on a visual-motor set-shifting task with a trend toward lower scores on a verbal inhibition task. Controlling for gender and intelligence, average diffusion in the left frontal callosal fibers was related to prenatal exposure to alcohol and marijuana and an interaction between cocaine and marijuana exposure. Performance on the visual-motor set-shifting task was related to prenatal cocaine exposure and an interaction between cocaine and tobacco exposure. Significant correlations were found between test performance and fractional anisotropy in areas of the frontal white matter.
CONCLUSIONS
Prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and subtle microstructural changes suggesting less mature development of frontal white matter pathways. The relative contribution of postnatal environmental factors, including characteristics of the caregiving environment and stressors associated with poverty and out-of-home placement, on brain development and behavioral functioning in polydrug-exposed children awaits further research.
doi:10.1542/peds.2006-0003
PMCID: PMC3166953  PMID: 17079574
prenatal exposure; cocaine infants; neuroimaging; cognitive function; neuropsychology
20.  Enhancement of Temporal Resolution and BOLD Sensitivity in Real-Time fMRI using Multi-Slab Echo-Volumar Imaging 
Neuroimage  2012;61(1):115-130.
In this study, a new approach to high-speed fMRI using multi-slab echo-volumar imaging (EVI) is developed that minimizes geometrical image distortion and spatial blurring, and enables nonaliased sampling of physiological signal fluctuation to increase BOLD sensitivity compared to conventional echo-planar imaging (EPI). Real-time fMRI using whole brain 4-slab EVI with 286 ms temporal resolution (4 mm isotropic voxel size) and partial brain 2-slab EVI with 136 ms temporal resolution (4×4×6 mm3 voxel size) was performed on a clinical 3 Tesla MRI scanner equipped with 12-channel head coil. Four-slab EVI of visual and motor tasks significantly increased mean (visual: 96%, motor: 66%) and maximum t-score (visual: 263%, motor: 124%) and mean (visual: 59%, motor: 131%) and maximum (visual: 29%, motor: 67%) BOLD signal amplitude compared with EPI. Time domain moving average filtering (2 s width) to suppress physiological noise from cardiac and respiratory fluctuations further improved mean (visual: 196%, motor: 140%) and maximum (visual: 384%, motor: 200%) t-scores and increased extents of activation (visual: 73%, motor: 70%) compared to EPI. Similar sensitivity enhancement, which is attributed to high sampling rate at only moderately reduced temporal signal-to-noise ratio (mean: − 52%) and longer sampling of the BOLD effect in the echo-time domain compared to EPI, was measured in auditory cortex. Two-slab EVI further improved temporal resolution for measuring task-related activation and enabled mapping of five major resting state networks (RSNs) in individual subjects in 5 min scans. The bilateral sensorimotor, the default mode and the occipital RSNs were detectable in time frames as short as 75 s. In conclusion, the high sampling rate of real-time multi-slab EVI significantly improves sensitivity for studying the temporal dynamics of hemodynamic responses and for characterizing functional networks at high field strength in short measurement times.
doi:10.1016/j.neuroimage.2012.02.059
PMCID: PMC3342442  PMID: 22398395
fMRI; echo-volumar imaging; real-time; temporal resolution; BOLD sensitivity; physiological noise; event related; resting state networks
21.  High Efficiency, Low Distortion 3D Diffusion Tensor Imaging with Variable Density Spiral Fast Spin Echoes (3D DW VDS RARE) 
NeuroImage  2009;49(2):1510-1523.
We present an acquisition and reconstruction method designed to acquire high resolution 3D fast spin echo diffusion tensor images while mitigating the major sources of artifacts in DTI - field distortions, eddy currents and motion. The resulting images, being 3D, are of high SNR, and being fast spin echoes, exhibit greatly reduced field distortions. This sequence utilizes variable density spiral acquisition gradients, which allow for the implementation of a self-navigation scheme by which both eddy current and motion artifacts are removed. The result is that high resolution 3D DTI images are produced without the need for eddy current compensating gradients or B0 field correction. In addition, a novel method for fast and accurate reconstruction of the non-Cartesian data is employed. Results are demonstrated in the brains of normal human volunteers.
doi:10.1016/j.neuroimage.2009.09.010
PMCID: PMC2791091  PMID: 19778618
diffusion; three-dimensional; diffusion tensor imaging; diffusion anisotropy; high angular resolution diffusion; 3D fast spin echo; 3D RARE; spiral; self-navigation
22.  Diffusion Tensor Imaging Based Tissue Segmentation: Validation and Application to the Developing Child and Adolescent Brain 
NeuroImage  2006;34(4):1497-1505.
We present and validate a novel diffusion tensor imaging (DTI) approach for segmenting the human whole-brain into partitions representing grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF). The approach utilizes the contrast among tissue types in the DTI anisotropy vs. diffusivity rotational invariant space. The DTI-based whole-brain GM and WM fractions (GMf and WMf) are contrasted with the fractions obtained from conventional magnetic resonance imaging (cMRI) tissue segmentation (or clustering) methods that utilized dual echo (proton density-weighted (PDw), and spin-spin relaxation-weighted (T2w) contrast, in addition to spin-lattice relaxation weighted (T1w) contrasts acquired in the same imaging session and covering the same volume. In addition to good correspondence with cMRI estimates of brain volume, the DTI-based accurately depicts expected age vs. WM and GM volume-to-total intracranial brain volume percentage trends on the rapidly developing brains of a cohort of 29 children (6–18 years). This approach promises to extend DTI utility to both micro and macrostructural aspects of tissue organization.
doi:10.1016/j.neuroimage.2006.10.029
PMCID: PMC1995007  PMID: 17166746
DTI; Segmentation; Icosa21; Child Brain Development; Meta Analysis
23.  Murine diffusion imaging using snapshot interleaved EPI acquisition at 7 Tesla 
Journal of neuroscience methods  2011;199(1):10-14.
Diffusion Tensor Imaging (DTI) is a powerful magnetic resonance imaging tool for quantitative assessment of white matter micro structure. The majority of DTI methods employ Echo Planar Imaging (EPI) because it is insensitive to motion. However, EPI suffers from distortions and signal losses induced by inhomogeneities in magnetic field susceptibility. This is particularly accentuated in murine imaging at very high magnetic fields. The purpose of this study is to demonstrate that a Snapshot Interleaved EPI acquisition block combined with a stimulated echo module for diffusion sensitization can be successfully used to obtain high quality DTI of a mouse brain at 7 Tesla. This technique preserves the EPI speed but reduces its susceptibility artifacts and signal losses. Signal to noise ratio is also reduced but remains higher than in the DTI acquisitions based on a fast low angle shot technique. In vivo results using this new approach are presented along with a full description of the methodology.
doi:10.1016/j.jneumeth.2011.04.011
PMCID: PMC3112266  PMID: 21557967
Diffusion Tensor Imaging; fractional anisotropy; white matter; mouse brain
24.  Magnetic Resonance Imaging And Brain Histopathology In Neuropsychiatric Systemic Lupus Erythematosus 
Objective
Magnetic resonance imaging (MRI) often demonstrates brain lesions in neuropsychiatric systemic lupus erythematosus (NPSL). The present study compared post-mortem histopathology with pre-mortem MRI in NPSL.
Methods
200 subjects with NPSLE were studied prospectively with MRI over a 10-year period during which 22 subjects died. In 14 subjects, a brain autopsy with histopathology that permitted direct comparison with pre mortem MRI was successfully obtained. Surface anatomy was used to determine the approximate location of individual lesions.
Results
Pre mortem MRI findings in fatal NPSLE were small focal white matter lesions (100%), cortical atrophy (64%), ventricular dilation (57%), cerebral edema (50%), diffuse white matter abnormalities (43%), focal atrophy (36%), cerebral infarction (29%), acute leukoencephalopathy (25%), intracranial hemorrhage (21%), and calcifications (7%). Microscopic findings in fatal NPSLE included global ischemic changes (57%), parenchymal edema (50%), microhemorrhages (43%), glial hyperplasia (43%), diffuse neuronal/axonal loss (36%), resolved cerebral infarction (33%), microthomboemboli (29%), blood vessel remodeling (29%), acute cerebral infarction (14%), acute macrohemorrhages (14%), and resolved intracranial hemorrhages (7%). Cortical atrophy and ventricular dilation seen by MRI predicted brain mass at autopsy (r = -0.72, p = 0.01, and r = -0.77, p =0.01, respectively). Cerebral autopsy findings, including infarction, cerebral edema, intracranial hemorrhage, calcifications, cysts, and focal atrophy were also predicted accurately by pre mortem MRI.
Conclusion
Brain lesions in NPSLE detected by MRI accurately represent serious underlying cerebrovascular and parenchymal brain injury on pathology.
doi:10.1016/j.semarthrit.2009.08.005
PMCID: PMC3586567  PMID: 19880162
SLE; Neuropsychiatric; Magnetic Resonance; NPSLE; MRI; Autopsy
25.  Diffusion tensor magnetic resonance imaging at 3.0 tesla shows subtle cerebral grey matter abnormalities in patients with migraine 
Background and objective
Diffusion tensor (DT) magnetic resonance imaging (MRI) has the potential to disclose subtle abnormalities in the brain of migraine patients. This ability may be increased by the use of high field magnets. A DT MRI on a 3.0 tesla scanner was used to measure the extent of tissue damage of the brain normal appearing white (NAWM) and grey matter in migraine patients with T2 visible abnormalities.
Methods
Dual echo, T1 weighted and DT MRI with diffusion gradients applied in 32 non‐collinear directions were acquired from 16 patients with migraine and 15 sex and age matched controls. Lesion load on T2 weighted images was measured using a local thresholding segmentation technique, and brain atrophy assessed on T1 weighted images using SIENAx. Mean diffusivity and fractional anisotropy histograms of the NAWM and mean diffusivity histograms of the grey matter were also derived.
Results
Brain atrophy did not differ between controls and patients. Compared with healthy subjects, migraine patients had significantly reduced mean diffusivity histogram peak height of the grey matter (p = 0.04). No diffusion changes were detected in patients' NAWM. In migraine patients, no correlation was found between T2 weighted lesion load and brain DT histogram derived metrics, whereas age was significantly correlated with grey matter mean diffusivity histogram peak height (p = 0.05, r = −0.52).
Conclusions
DT MRI at high field strength discloses subtle grey matter damage in migraine patients, which might be associated with cognitive changes in these patients.
doi:10.1136/jnnp.2005.080002
PMCID: PMC2117460  PMID: 16614037
migraine; grey matter; magnetic resonance imaging; diffusion tensor imaging

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