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Background and purpose Axonal injury is a key player of disability in persons with multiple sclerosis (pwMS). Yet, detecting and measuring it in vivo is challenging. The neurite orientation dispersion and density imaging (NODDI) proposes a novel framework for probing axonal integrity in vivo. NODDI at 3.0 Tesla was used to quantify tissue damage in pwMS and its relationship with disease progression. Methods Eighteen pwMS (4 clinically isolated syndrome, 11 relapsing remitting, and 3 secondary progressive MS) and nine age- and sex-matched healthy controls underwent a brain MRI, inclusive of clinical sequences and a multi-shell diffusion acquisition. Parametric maps of axial diffusivity (AD), neurite density index (ndi), apparent isotropic volume fraction (ivf), and orientation dispersion index (odi) were fitted. Anatomically matched regions of interest were used to quantify AD and NODDI-derived metrics and to assess the relations between these measures and those of disease progression. Results AD, ndi, ivf, and odi significantly differed between chronic black holes (cBHs) and T2-lesions, and between the latter and normal appearing white matter (NAWM). All metrics except ivf significantly differed between NAWM located next to a cBH and that situated contra-laterally. Only NAWM odi was significantly associated with T2-lesion volume, the timed 25-foot walk test and disease duration. Conclusions NODDI is sensitive to tissue injury but its relationship with clinical progression remains limited.

PURPOSE: To demonstrate the feasibility of 3D multi-shot magnetic resonance imaging acquisitions for stimulus-evoked blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in the human spinal cord in vivo. METHODS: Two fMRI studies were performed at 3 Tesla. The first study was a hypercapnic gas challenge where data were acquired from healthy volunteers using a multi-shot 3D fast field echo (FFE) sequence as well as single-shot multi-slice echo-planar imaging (EPI). In the second study, another cohort of healthy volunteers performed an upper extremity motor task while fMRI data were acquired using a 3D multi-shot acquisition. RESULTS: Both 2D-EPI and 3D-FFE were shown to be sensitive to BOLD signal changes in the cervical spinal cord, and had comparable contrast-to-noise ratios in gray matter. FFE exhibited much less signal drop-out and weaker geometric distortions compared to EPI. In the motor paradigm study, the mean number of active voxels was highest in the ventral gray matter horns ipsilateral to the side of the task and at the spinal level associated with innervation of finger extensors. CONCLUSION: Highly multi-shot acquisition sequences such as 3D-FFE are well suited for stimulus-evoked spinal cord BOLD fMRI.

Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) and scientists with expertise on clinical and imaging techniques convened in Dallas, TX, USA on February 27, 2019 at a North American Imaging in Multiple Sclerosis Cooperative workshop meeting. The aim of the workshop was to discuss cardinal pathobiological mechanisms implicated in the progression of MS and novel imaging techniques, beyond brain atrophy, to unravel these pathologies. Indeed, although brain volume assessment demonstrates changes linked to disease progression, identifying the biological mechanisms leading up to that volume loss are key for understanding disease mechanisms. To this end, the workshop focused on the application of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging techniques to assess and measure disease progression in both the brain and the spinal cord. Clinical translation of quantitative MRI was recognized as of vital importance, although the need to maintain a relatively short acquisition time mandated by most radiology departments remains the major obstacle toward this effort. Regarding PET, the panel agreed upon its utility to identify ongoing pathological processes. However, due to costs, required expertise, and the use of ionizing radiation, PET was not considered to be a viable option for ongoing care of persons with MS. Collaborative efforts fostering robust study designs and imaging technique standardization across scanners and centers are needed to unravel disease mechanisms leading to progression and discovering medications halting neurodegeneration and/or promoting repair.

Purpose: Chemical exchange saturation transfer (CEST) is an MRI technique sensitive to the presence of low‐concentration solute protons exchanging with water. However, magnetization transfer (MT) effects also arise when large semisolid molecules interact with water, which biases CEST parameter estimates if quantitative models do not account for macromolecular effects. This study establishes under what conditions this bias is significant and demonstrates how using an appropriate model provides more accurate quantitative CEST measurements. Methods: CEST and MT data were acquired in phantoms containing bovine serum albumin and agarose. Several quantitative CEST and MT models were used with the phantom data to demonstrate how underfitting can influence estimates of the CEST effect. CEST and MT data were acquired in healthy volunteers, and a two‐pool model was fit in vivo and in vitro, whereas removing increasing amounts of CEST data to show biases in the CEST analysis also corrupts MT parameter estimates. Results: When all significant CEST/MT effects were included, the derived parameter estimates for each CEST/MT pool significantly correlated (P < .05) with bovine serum albumin/agarose concentration; minimal or negative correlations were found with underfitted data. Additionally, a bootstrap analysis demonstrated that significant biases occur in MT parameter estimates (P < .001) when unmodeled CEST data are included in the analysis. Conclusions: These results indicate that current practices of simultaneously fitting both CEST and MT effects in model‐based analyses can lead to significant bias in all parameter estimates unless a sufficiently detailed model is utilized. Therefore, care must be taken when quantifying CEST and MT effects in vivo by properly modeling data to minimize these biases.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.

The locus coeruleus (LC) is the major origin of norepinephrine in the central nervous system, and is subject to age-related and neurodegenerative changes, especially in disorders such as Parkinson's disease and Alzheimer's disease. Previous studies have shown that neuromelanin (NM)-sensitive MRI can be used to visualize the LC, and it is hypothesized that magnetization transfer (MT) effects are the primary source of LC contrast. The aim of this study was to characterize the MT effects in LC imaging by applying high spatial resolution quantitative MT (qMT) imaging to create parametric maps of the macromolecular content of the LC and surrounding tissues. Healthy volunteers (n = 26; sex = 17 F/9M; age = 41.0 ± 19.1 years) underwent brain MRI on a 3.0 T scanner. qMT data were acquired using a 3D MT-prepared spoiled gradient echo sequence. A traditional NM scan consisting of a T1-weighted turbo spin echo sequence with MT preparation was also acquired. The pool-size ratio (PSR) was estimated for each voxel using a single-point qMT approach. The LC was semi-automatically segmented on the MT-weighted images. The MT-weighted images provided higher contrast-ratio between the LC and surrounding pontine tegmentum (PT) (0.215 ± 0.031) than the reference images without MT-preparation (−0.005 ± 0.026) and the traditional NM images (0.138 ± 0.044). The PSR maps showed significant differences between the LC (0.090 ± 0.009) and PT (0.188 ± 0.025). The largest difference between the PSR values in the LC and PT was observed in the central slices, which also correspond to those with the highest contrast-ratio. These results highlight the role of MT in generating NM-related contrast in the LC, and should serve as a foundation for future studies aiming to quantify pathological changes in the LC and surrounding structures in vivo.

Background:Assessing the degree of myelin injury in patients with multiple sclerosis (MS) is challenging due to the lack of magnetic resonance imaging (MRI) methods specific to myelin quantity. By measuring distinct tissue parameters from a two-pool model of the magnetization transfer (MT) effect, quantitative magnetization transfer (qMT) may yield these indices. However, due to long scan times, qMT has not been translated clinically.Objectives:We aim to assess the clinical feasibility of a recently optimized selective inversion recovery (SIR) qMT and to test the hypothesis that SIR-qMT-derived metrics are informative of radiological and clinical disease-related changes in MS.Methods:A total of 18 MS patients and 9 age- and sex-matched healthy controls (HCs) underwent a 3.0 Tesla (3 T) brain MRI, including clinical scans and an optimized SIR-qMT protocol. Four subjects were re-scanned at a 2-week interval to determine inter-scan variability.Results:SIR-qMT measures differed between lesional and non-lesional tissue ( p Conclusion:SIR-qMT at 3 T is clinically feasible and predicts both radiological and clinical disease severity in MS.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.

Diffusion magnetic resonance images may suffer from geometric distortions due to susceptibility induced off resonance fields, which cause geometric mismatch with anatomical images and ultimately affect subsequent quantification of microstructural or connectivity indices. State-of-the art diffusion distortion correction methods typically require data acquired with reverse phase encoding directions, resulting in varying magnitudes and orientations of distortion, which allow estimation of an undistorted volume. Alternatively, additional field maps acquisitions can be used along with sequence information to determine warping fields. However, not all imaging protocols include these additional scans and cannot take advantage of state-of-the art distortion correction. To avoid additional acquisitions, structural MRI (undistorted scans) can be used as registration targets for intensity driven correction. In this study, we aim to (1) enable susceptibility distortion correction with historical and/or limited diffusion datasets that do not include specific sequences for distortion correction and (2) avoid the computationally intensive registration procedure typically required for distortion correction using structural scans. To achieve these aims, we use deep learning (3D U-nets) to synthesize an undistorted b0 image that matches geometry of structural T1w images and intensity contrasts from diffusion images. Importantly, the training dataset is heterogenous, consisting of varying acquisitions of both structural and diffusion. We apply our approach to a withheld test set and show that distortions are successfully corrected after processing. We quantitatively evaluate the proposed distortion correction and intensity-based registration against state-of-the-art distortion correction (FSL topup). The results illustrate that the proposed pipeline results in b0 images that are geometrically similar to non-distorted structural images, and more closely match state-of-the-art correction with additional acquisitions. In addition, we show generalizability of the proposed approach to datasets that were not in the original training / validation / testing datasets. These datasets included varying populations, contrasts, resolutions, and magnitudes and orientations of distortion and show efficacious distortion correction. The method is available as a Singularity container, source code, and an executable trained model to facilitate evaluation.

Purpose The non-uniform fast Fourier transform (NUFFT) involves interpolation of non-uniformly sampled Fourier data onto a Cartesian grid, an interpolation that is slowed by complex, non-local data access patterns. A faster NUFFT would increase the clinical relevance of the plethora of advanced non-Cartesian acquisition methods. Methods Here we customize the NUFFT procedure for a radial trajectory and GPU architecture to eliminate the bottlenecks encountered when allowing for arbitrary trajectories and hardware. We call the result TRON, for TRajectory Optimized NUFFT. We benchmark the speed and accuracy TRON on a Shepp-Logan phantom and on whole-body continuous golden-angle radial MRI. Results TRON was 6-30× faster than the closest competitor, depending on test data set, and was the most accurate code tested. Conclusions Specialization of the NUFFT algorithm for a particular trajectory yielded significant speed gains. TRON can be easily extended to other trajectories, such as spiral and PROPELLER. TRON can be downloaded at http://github.com/davidssmith/TRON.

Background and purpose An imaging biomarker of myelin integrity is an unmet need in multiple sclerosis (MS). Selective inversion recovery (SIR) quantitative magnetization transfer imaging (qMT) provides assays of myelin content in the human brain. We previously translated the SIR method to 7T and incorporated a rapid turbo field echo (TFE) readout for whole-brain imaging within clinically acceptable scan times. We herein provide histological validation and test in vivo feasibility and applicability of the SIR-TFE protocol in MS. Methods Clinical (T1 - and T2 -weighted) and SIR-TFE MRI scans were performed at 7T in a postmortem MS brain and MRI data were acquired in 10 MS patients and 14 heathy volunteers in vivo. The following parameters were estimated from SIR data: the macromolecular-to-free water pool-size-ratio (PSR), the spin-lattice relaxation rate of water (R1f ), and the MT exchange rate (kmf ). Differences in SIR parameters across tissue types, eg, white matter lesions (WM-Ls) and normal appearing WM (NAWM) in patients, and normal white matter (NWM) in heathy volunteers were evaluated. Associations between SIR parameters and disability scores were assessed. Results For postmortem scans, correspondence was observed between WM-Ls and NAWM from histology and PSR/R1f values. In vivo differences were detected for PSR, R1f , and kmf between WM-Ls and NWM (P ≤ .041). Associations were seen between WM-Ls/ NAWM PSR and disability scores (r ≤ -.671, P ≤ .048). Conclusions SIR-qMT at 7T provides sensitive, quantitative measures of myelin integrity for clinical and research applications.

Purpose The ability to evaluate pathological changes in the spinal cord in multiple sclerosis (MS) is limited because T1- and T2-w MRI imaging are not sensitive to biochemical changes in vivo. Amide proton transfer (APT) chemical exchange saturation transfer (CEST) can indirectly detect amide protons associated with proteins and peptides, potentially providing more pathological specificity. Here, we implement APT CEST in the cervical spinal cord of healthy and MS cohorts at 3T. Methods APT CEST of the cervical spinal cord was obtained in a cohort of 10 controls and 10 MS patients using a novel respiratory correction methodology. APT was quantified using two methods: 1) APTw, based off the conventional magnetization transfer ratio asymmetry, and 2) ΔAPT, a spatial characterization of APT changes in MS patients relative to the controls. Results Respiratory correction yielded highly reproducible z-spectra in white matter (intraclass correlation coefficient = 0.82). APTw signals in normal-appearing white matter (NAWM) of MS patients were significantly different from healthy controls (P = 0.04), whereas ΔAPT of MS patients highlighted large APT differences in NAWM. Conclusion Respiration correction in the spinal cord is necessary to accurately quantify APT CEST, which can provide unique biochemical information regarding disease processes within the spinal cord. Magn Reson Med 79:806–814, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose To investigate the physical mechanisms associated with the contrast observed in neuromelanin MRI. Methods Phantoms having different concentrations of synthetic melanins with different degrees of iron loading were examined on a 3 Tesla scanner using relaxometry and quantitative magnetization transfer (MT). Results Concentration-dependent T1 and T2 shortening was most pronounced for the melanin pigment when combined with iron. Metal-free melanin had a negligible effect on the magnetization transfer spectra. On the contrary, the presence of iron-laden melanins resulted in a decreased magnetization transfer ratio. The presence of melanin or iron (or both) did not have a significant effect on the macromolecular content, represented by the pool size ratio. Conclusion The primary mechanism underlying contrast in neuromelanin-MRI appears to be the T1 reduction associated with melanin-iron complexes. The macromolecular content is not significantly influenced by the presence of melanin with or without iron, and thus the MT is not directly affected. However, as T1 plays a role in determining the MT-weighted signal, the magnetization transfer ratio is reduced in the presence of melanin-iron complexes. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Cognitive impairment (CI) is a major manifestation of multiple sclerosis (MS) and is responsible for extensively hindering patient quality of life. Cortical gray matter (cGM) damage is a significant contributor to CI, but is poorly characterized by conventional MRI let alone with quantitative MRI, such as quantitative magnetization transfer (qMT). Here we employed high-resolution qMT at 7T via the selective inversion recovery (SIR) method, which provides tissue-specific indices of tissue macromolecular content, such as the pool size ratio (PSR) and the rate of MT exchange (kmf). These indices could represent expected demyelination that occurs in the presence of gray matter damage. We utilized selective inversion recovery (SIR) qMT which provides a low SAR estimate of macromolecular-bulk water interactions using a tailored, B1 and B0 robust inversion recovery (IR) sequence acquired at multiple inversion times (TI) at 7T and fit to a two-pool model of magnetization exchange. Using this sequence, we evaluated qMT indices across relapsing-remitting multiple sclerosis patients (N = 19) and healthy volunteers (N = 37) and derived related associations with neuropsychological measures of cognitive impairment. We found a significant reduction in kmf in cGM of MS patients (15.5%, p = 0.002), unique association with EDSS (ρ = -0.922, p = 0.0001), and strong correlation with cognitive performance (ρ = -0.602, p = 0.0082). Together these findings indicate that the rate of MT exchange (kmf) may be a significant biomarker of cGM damage relating to CI in MS.

International audience; Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. The goal of this study was to develop a fully-automatic framework, robust to variability in both image parameters and clinical condition, for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data. Scans of 1,042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n=30). Data spanned three contrasts (T1-, T2-, and T2*-weighted) for a total of 1,943 volumes. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg, a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. The proposed framework is open-source and readily available in the Spinal Cord Toolbox., Comment: 38 pages, 7 figures, 2 tables

Objects The diffusion‐based spherical mean technique (SMT) provides a novel model to relate multi‐b‐value diffusion magnetic resonance imaging (MRI) data to features of tissue microstructure. We propose the first clinical application of SMT to image the brain of patients with multiple sclerosis (MS) and investigate clinical feasibility and translation. Methods Eighteen MS patients and nine age‐ and sex‐matched healthy controls (HCs) underwent a 3.0 Tesla scan inclusive of clinical sequences and SMT images (isotropic resolution of 2 mm). Axial diffusivity (AD), apparent axonal volume fraction (V ax), and effective neural diffusivity (D ax) parametric maps were fitted. Differences in AD, V ax, and D ax between anatomically matched regions reflecting different tissues types were estimated using generalized linear mixed models for binary outcomes. Results Differences were seen in all SMT‐derived parameters between chronic black holes (cBHs) and T2‐lesions (P ≤ 0.0016), in V ax and AD between T2‐lesions and normal appearing white matter (NAWM) (P

BACKGROUND: Axonal injury is the primary source of irreversible neurological decline in persons with multiple sclerosis (pwMS). Identifying and quantifying myelin and axonal loss in lesional and perilesional tissue in vivo is fundamental for a better understanding of multiple sclerosis (MS) outcomes and patient impairment. Using advanced magnetic resonance imaging (MRI) methods, consisting of selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment diffusion MRI with the spherical mean technique (SMT), we conducted a cross-sectional pilot study to assess myelin and axonal damage in the normal appearing white matter (NAWM) surrounding chronic black holes (cBHs) and how this pathology correlates with disability in vivo. We hypothesized that lesional axonal transection propagates tissue injury in the surrounding NAWM and that the degree of this injury is related to patient disability. METHODS: Eighteen pwMS underwent a 3.0 Tesla conventional clinical MRI, inclusive of T1 and T2 weighted protocols, as well as SIR-qMT and SMT. Regions of interests (ROIs) were manually delineated in cBHs, NAWM neighboring cBHs (perilesional NAWM), distant ipsilateral NAWM and contra-lateral distant NAWM. SIR-qMT-derived macromolecular-to-free pool size ratio (PSR) and SMT-derived apparent axonal volume fraction (V(ax)) were extracted to infer on myelin and axonal content, respectively. Group differences were assessed using mixed-effects regression models and correlation analyses were obtained by bootstrapping 95% confidence interval. RESULTS: In comparison to perilesional NAWM, both PSR and V(ax) values were reduced in cBHs (p < 0.0001) and increased in distant contra-lateral NAWM ROIs (p < 0.001 for PSR and p < 0.0001 for V(ax)) but not ipsilateral NAWM (p = 0.176 for PSR and p = 0.549 for V(ax)). V(ax) values measured in cBHs correlated with those in perilesional NAWM (Pearson rho = 0.63, p < 0.001). No statistically relevant associations were seen between PSR/V(ax) values and clinical and/or MRI metrics of the disease with the exception of cBH PSR values, which correlated with the Expanded Disability Status Scale (Pearson rho = −0.63, p = 0.03). CONCLUSIONS: Our results show that myelin and axonal content, detected by PSR and V(ax), are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This finding is indicative of an ongoing anterograde/retrograde degeneration and suggests that treatment prevention of cBH development is a key factor for preserving NAWM integrity in surrounding tissue. It also suggests that measuring changes in perilesional areas over time may be a useful measure of outcome for proof-of-concept clinical trials on neuroprotection and repair. PSR and V(ax) largely foiled to capture associations with clinical and MRI characteristics, likely as a result of the small sample size and cross-sectional design, however, longitudinal assessment of a larger cohort may unravel the impact of this pathology on disease progression.

High-magnetic-field (7 T) chemical exchange saturation transfer (CEST) MRI provides information on the tissue biochemical environment. Multiple sclerosis (MS) affects the entire central nervous system, including the spinal cord. Optimal CEST saturation parameters found via simulation were implemented for CEST MRI in 10 healthy controls and 10 patients with MS, and the results were examined using traditional asymmetry analysis and a Lorentzian fitting method. In addition, T1 - and T2 *-weighted images were acquired for lesion localization and the transmitted B1 (+) field was evaluated to guide imaging parameters. Distinct spectral features for all tissue types studied were found both up- and downfield from the water resonance. The z spectra in healthy subjects had the expected z spectral shape with CEST effects apparent from 2.0 to 4.5 ppm. The z spectra from patients with MS demonstrated deviations from this expected normal shape, indicating this method's sensitivity to known pathology as well as to tissues appearing normal on conventional MRI. Examination of the calculated CESTasym revealed increased asymmetry around the amide proton resonance (Δω = 3.5 ppm), but it was apparent that this measure is complicated by detail in the CEST spectrum upfield from water, which is expected to result from the nuclear Overhauser effect. The z spectra upfield (negative ppm range) were also distinct between healthy and diseased tissue, and could not be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1 ppm, the Lorentzian differences (and z spectra) for lesions and normal-appearing white matter were distinct from those for healthy white matter. The increased frequency separation and signal-to-noise ratio, in concert with prolonged T1 at 7 T, resulted in signal enhancements necessary to detect subtle tissue changes not possible at lower field strengths. This study presents CEST imaging metrics that may be sensitive to the extensive and temporally varying biochemical neuropathology of MS in the spinal cord. Copyright © 2016 John Wiley & Sons, Ltd.

PURPOSE To empirically characterize and quantify the impact of gradient weighting schemes on the appearance and fidelity of diffusion tensor imaging of the human spinal cord in vivo in clinically relevant scan time equivalents (STE). MATERIALS AND METHODS In five healthy controls at 3T, we evaluated test-retest reproducibility and performed voxelwise analysis of diffusion tensor imaging (DTI)-derived indices (fractional anisotropy [FA], mean [MD], axial [AD], and radial [RD] diffusivity) in the cervical spinal cord to assess spatial dependencies of measurement error and differences across three different sampling schemes (6, 15, and 32 directions) at STE of 4.5, 9, and 18 minutes. A subjective assessment was also performed. RESULTS With six directions, column-specific errors are highest (effect size = 2.9%, 4.4%, 7.2% for FA in dorsal column, lateral column, and gray matter) and different than the 15-direction scheme (P 0.05). For FA and AD, measurement errors are prevalent in gray matter, while partial volume effects with cerebrospinal fluid heavily influence RD. Measurement errors decreased with increasing scan time (P < 0.01), albeit with diminishing returns at scan times longer than 9 minutes (P < 0.05). CONCLUSION A 15-direction scheme of 9 minutes yields measurements of the cervical spinal cord with low error. J. Magn. Reson. Imaging 2016;44:1608-1618.

PURPOSE The optic nerve (ON) represents the sole pathway between the eyes and brain; consequently, diseases of the ON can have dramatic effects on vision. However, quantitative magnetization transfer (qMT) applications in the ON have been limited to ex vivo studies, in part because of the fatty connective tissue that surrounds the ON, confounding the magnetization transfer (MT) experiment. Therefore, the aim of this study was to implement a multi-echo Dixon fat-water separation approach to remove the fat component from MT images. METHODS MT measurements were taken in a single slice of the ON and frontal lobe using a three-echo Dixon readout, and the water and out-of-phase images were applied to a two-pool model in ON tissue and brain white matter to evaluate the effectiveness of using Dixon fat-water separation to remove fatty tissue from MT images. RESULTS White matter data showed no significant differences between image types; however, there was a significant increase (p

Resting state functional magnetic resonance imaging (fMRI) has been used to study human brain function for over two decades, but only recently has this technique been successfully translated to the human spinal cord. The spinal cord is structurally and functionally unique, so resting state fMRI methods developed and optimized for the brain may not be appropriate when applied to the cord. This report therefore investigates the relative impact of different acquisition and processing choices (including run length, echo time, and bandpass filter width) on the detectability of resting state spinal cord networks at 3T. Our results suggest that frequencies beyond 0.08 Hz should be included in resting state analyses, a run length of ~8–12 mins is appropriate for reliable detection of the ventral (motor) network, and longer echo times – yet still shorter than values typically used for fMRI in the brain – may increase the detectability of the dorsal (sensory) network. Further studies are required to more fully understand and interpret the nature of resting state spinal cord networks in health and in disease, and the protocols described in this report are designed to assist such studies.

Background: Cognitive impairment (CI) profoundly impacts quality of life for patients with multiple sclerosis (MS). Dysfunctional regulation of glutamate in gray matter (GM) has been implicated in the pathogenesis of MS by post-mortem pathological studies and in CI by in vivo magnetic resonance spectroscopy, yet GM pathology is subtle and difficult to detect using conventional T1- and T2-weighted magnetic resonance imaging (MRI). There is a need for high-resolution, clinically accessible imaging techniques that probe molecular changes in GM. Objective: To study cortical GM pathology related to CI in MS using glutamate-sensitive chemical exchange saturation transfer (GluCEST) MRI at 7.0 Tesla (7T). Methods: A total of 20 patients with relapsing-remitting MS and 20 healthy controls underwent cognitive testing, anatomical imaging, and GluCEST imaging. Glutamate-sensitive image contrast was quantified for cortical GM, compared between cohorts, and correlated with clinical measures of CI. Results and Conclusion: Glutamate-sensitive contrast was significantly increased in the prefrontal cortex of MS patients with accumulated disability ( p S = −0.814) and choice reaction time ( rS = 0.772) scores in patients ( p

Introduction To investigate tissue flow disturbance and hypoxia during migraine aura, we studied a case of familial hemiplegic migraine (FHM) using novel magnetic resonance imaging (MRI) techniques. Case results A 44-year-old male was admitted with suspected stroke because of confusion and aphasia. Initial gadolinium-based perfusion MRI showed a decrease in cerebral blood flow and an increase in capillary flow disturbances within the left hemisphere. Later during the prolonged aura phase, chemical exchange saturation transfer MRI indicated a drop in pH in the affected area. The patient was diagnosed with an R908Q mutation in the ATP1A2 gene causing FHM type 2. Discussion During prolonged aura in FHM, MRI shows reduced CBF, capillary flow disturbances and a possible pH drop that could indicate tissue hypoxia.

Purpose Our goal is to develop an accurate, automated tool to characterize the optic nerve (ON) and cerebrospinal fluid (CSF) to better understand ON changes in disease. Methods Multi-atlas segmentation is used to localize the ON and sheath on T2-weighted MRI (0.6 mm3 resolution). A sum of Gaussian distributions is fit to coronal slice-wise intensities to extract six descriptive parameters, and a regression forest is used to map the model space to radii. The model is validated for consistency using tenfold cross-validation and for accuracy using a high resolution (0.4 mm2 reconstructed to 0.15 mm2) in vivo sequence. We evaluated this model on 6 controls and 6 patients with multiple sclerosis (MS) and a history of optic neuritis. Results In simulation, the model was found to have an explanatory R-squared for both ON and sheath radii greater than 0.95. The accuracy of the method was within the measurement error on the highest possible in vivo resolution. Comparing healthy controls and patients with MS, significant structural differences were found near the ON head and the chiasm, and structural trends agreed with the literature. Conclusion This is a first demonstration that the ON can be exclusively, quantitatively measured and separated from the surrounding CSF using MRI. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

PURPOSE: To optimize a selective inversion recovery (SIR) sequence for macromolecular content mapping in the human brain at 3.0 T. METHODS: SIR is a quantitative method for measuring magnetization transfer (qMT) that employs a low-power, on-resonance inversion pulse. This results in a biexponential recovery of free water signal that can be sampled at various inversion/predelay times (t(I)/t(D)) to estimate a subset of qMT parameters, including the macromolecular-to-free pool-size-ratio (PSR), the R(1) of free water (R(1f)), and the rate of MT exchange (k(mf)). The adoption of SIR has been limited by long acquisition times (≈4 mins/slice). Here, we use Cramér-Rao Lower Bound theory and data reduction strategies to select optimal t(I)/t(D) combinations to reduce imaging times. The schemes were experimentally validated in phantoms, and tested in healthy volunteers (N=4) and a multiple sclerosis patient. RESULTS: Two optimal sampling schemes were determined: i) a 5-point scheme (k(mf) estimated) and ii) a 4-point scheme (k(mf) assumed). In phantoms, the 5/4-point schemes yielded parameter estimates with similar signal-to-noise ratios as our previous 16-point scheme, but with 4.1/6.1-fold shorter scan times. Pair-wise comparisons between schemes did not detect significant differences for any scheme/parameter. In humans, parameter values were consistent with published values, and similar levels of precision were obtained from all schemes. Furthermore, fixing k(mf) reduced the sensitivity of PSR to partial-volume averaging, yielding more consistent estimates throughout the brain. CONCLUSIONS: qMT parameters can be robustly estimated in ≤1 min/slice (without independent measures of ΔB(0), B(1)(+), and T(1)) when optimized t(I)−t(D) combinations are selected.

Background Optic neuritis (ON) is one of the most common presentations of multiple sclerosis (MS). Magnetic resonance imaging (MRI) of the optic nerves is challenging because of retrobulbar motion, orbital fat and susceptibility artifacts from maxillary sinuses; therefore, axonal loss is investigated with the surrogate measure of a single heuristically defined point along the nerve as opposed to volumetric investigation. Objective The objective of this paper is to derive optic nerve volumetrics along the entire nerve length in patients with MS and healthy controls in vivo using high-resolution, clinically viable MRI. Methods An advanced, isotropic T2-weighted turbo spin echo MRI was applied to 29 MS patients with (14 patients ON+) or without (15 patients ON–) history of ON and 42 healthy volunteers. An automated tool was used to estimate and compare whole optic nerve and surrounding cerebrospinal fluid radii along the length of the nerve. Results and conclusion Only ON+ MS patients had a significantly reduced optic nerve radius compared to healthy controls in the central segment of the optic nerve. Using clinically available MRI methods, we show and quantify ON volume loss for the first time in MS patients.

Patients with multiple sclerosis present with focal lesions throughout the spinal cord. There is a clinical need for non-invasive measurements of spinal cord activity and functional organization in multiple sclerosis, given the cord's critical role in the disease. Recent reports of spontaneous blood oxygenation level-dependent fluctuations in the spinal cord using functional MRI suggest that, like the brain, cord activity at rest is organized into distinct, synchronized functional networks among grey matter regions, likely related to motor and sensory systems. Previous studies looking at stimulus-evoked activity in the spinal cord of patients with multiple sclerosis have demonstrated increased levels of activation as well as a more bilateral distribution of activity compared to controls. Functional connectivity studies of brain networks in multiple sclerosis have revealed widespread alterations, which may take on a dynamic trajectory over the course of the disease, with compensatory increases in connectivity followed by decreases associated with structural damage. We build upon this literature by examining functional connectivity in the spinal cord of patients with multiple sclerosis. Using ultra-high field 7 T imaging along with processing strategies for robust spinal cord functional MRI and lesion identification, the present study assessed functional connectivity within cervical cord grey matter of patients with relapsing-remitting multiple sclerosis (n = 22) compared to a large sample of healthy controls (n = 56). Patient anatomical images were rated for lesions by three independent raters, with consensus ratings revealing 19 of 22 patients presented with lesions somewhere in the imaged volume. Linear mixed models were used to assess effects of lesion location on functional connectivity. Analysis in control subjects demonstrated a robust pattern of connectivity among ventral grey matter regions as well as a distinct network among dorsal regions. A gender effect was also observed in controls whereby females demonstrated higher ventral network connectivity. Wilcoxon rank-sum tests detected no differences in average connectivity or power of low frequency fluctuations in patients compared to controls. The presence of lesions was, however, associated with local alterations in connectivity with differential effects depending on columnar location. The patient results suggest that spinal cord functional networks are generally intact in relapsing-remitting multiple sclerosis but that lesions are associated with focal abnormalities in intrinsic connectivity. These findings are discussed in light of the current literature on spinal cord functional MRI and the potential neurological underpinnings.

The optic nerve (ON) is a vital structure in the human visual system and transports all visual information from the retina to the cortex for higher order processing. Due to the lack of redundancy in the visual pathway, measures of ON damage have been shown to correlate well with visual deficits. These measures are typically taken at an arbitrary anatomically defined point along the nerve and do not characterize changes along the length of the ON. We propose a fully automated, three-dimensionally consistent technique building upon a previous independent slice-wise technique to estimate the radius of the ON and surrounding cerebrospinal fluid (CSF) on high-resolution heavily T2-weighted isotropic MRI. We show that by constraining results to be three-dimensionally consistent this technique produces more anatomically viable results. We compare this technique with the previously published slice-wise technique using a short-term reproducibility data set, 10 subjects, follow-up

Magnetic resonance imaging (MRI) of the human spinal cord at 7 Tesla has been demonstrated by a handful of research sites worldwide, and the spinal cord remains one of the areas in which higher fields and resolution could have high impact. The small diameter of the cord (~1 cm) necessitates high spatial resolution to minimize partial volume effects between gray and white matter, and so MRI of the cord can greatly benefit from increased signal-to-noise ratio and contrasts at ultra-high field (UHF). Herein we review the current state of UHF spinal cord imaging. Technical challenges to successful UHF spinal cord MRI include radiofrequency (B(1)) nonuniformities and a general lack of optimized radiofrequency coils, amplified physiological noise, and an absence of methods for robust B(0) shimming along the cord to mitigate image distortions and signal losses. Numerous solutions to address these challenges have been and are continuing to be explored, and include novel approaches for signal excitation and acquisition, dynamic shimming and specialized shim coils, and acquisitions with increased coverage or optimal slice angulations.

Background: Breast cancer treatment-related lymphedema (BCRL) arises from a mechanical insufficiency following cancer therapies. Early BCRL detection and personalized intervention require an improved understanding of the physiological processes that initiate lymphatic impairment. Here, internal magnetic resonance imaging (MRI) measures of the tissue microenvironment were paired with clinical measures of tissue structure to test fundamental hypotheses regarding structural tissue and muscle changes after the commonly used therapeutic intervention of manual lymphatic drainage (MLD). Methods and Results: Measurements to identify lymphatic dysfunction in healthy volunteers (n = 29) and patients with BCRL (n = 16) consisted of (1) limb volume, tissue dielectric constant, and bioelectrical impedance (i.e., non-MRI measures); (2) qualitative 3 Tesla diffusion-weighted, T1-weighted and T2-weighted MRI; and (3) quantitative multi-echo T2 MRI of the axilla. Measurements were repeated in patients immediately...

We sought to measure quantitative magnetization transfer (qMT) properties of the substantia nigra pars compacta (SNc) in patients with Parkinson’s disease (PD) and healthy controls (HCs) using a full qMT analysis and determine whether a rapid single-point measurement yields equivalent results for pool size ratio (PSR). Sixteen different MT-prepared MRI scans were obtained at 3 T from 16 PD patients and eight HCs, along with B1, B0, and relaxation time maps. Maps of PSR, free and macromolecular pool transverse relaxation times ( $$ {T}_2^f $$ , $$ {T}_2^m $$ ) and rate of MT exchange between pools (k mf ) were generated using a full qMT model. PSR maps were also generated using a single-point qMT model requiring just two MT-prepared images. qMT parameter values of the SNc, red nucleus, cerebral crus, and gray matter were compared between groups and methods. PSR of the SNc was the only qMT parameter to differ significantly between groups (p

Objective: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases. Methods: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n = 10), CMT type 2A (CMT2A, n = 3), hereditary neuropathy with liability to pressure palsies (n = 3), and healthy controls (n = 21). Additional patients without a genetically confirmed subtype (n = 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated. Results: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 ± 3.3 percent units) and CMT2A (31.5 ± 1.9 percent units) relative to controls (37.2 ± 2.3 percent units). A significant relationship between MTR and disability scores was also detected ( p = 0.01 for genetically confirmed patients only, p = 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels. Conclusions: MTR measurements may be a viable biomarker of proximal nerve pathology in patients with CMT.

Quantitative magnetization transfer (qMT) imaging can provide indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular proton fraction (MPF), which has been shown to correlate with myelin content in white matter. Because of the long scan times required for high-resolution spinal cord imaging, qMT studies of the human spinal cord have not found wide-spread application. Herein, we investigated whether these limitations could be overcome by utilizing only a single MT-weighted acquisition and a reference measurement, as was recently proposed in the brain. High-resolution, in vivo qMT data were obtained at 3.0 tesla in the spinal cords of healthy volunteers and patients with relapsing remitting multiple sclerosis (MS). Low- and high-resolution acquisitions (low/high resolution = 1×1×5 mm3/0.65×0.65×5 mm3) with clinically acceptable scan times (12 min/7 min) were evaluated. We also evaluated the reliability over time and the sensitivity of the model to the assumptions made in the single-point method, both in disease and healthy tissue. Our findings suggest that the single point qMT technique can provide maps of the MPF in the spinal cord in vivo with excellent grey/white matter contrast, can be reliably obtained within reasonable scan times, and are sensitive to MS pathology. Consistent with previous qMT studies in the brain, the observed MPF values were higher in healthy white matter (0.16±0.01) than in grey matter (0.13±0.01) and in MS lesions (0.09±0.01). The single point qMT technique applied at high resolution provides an improved method for obtaining qMT in the human spinal cord and may offer a reliable outcome measure for evaluating spinal cord disease.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small crosssectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research. © 2013 Elsevier Inc.

Multi-compartment tissue modeling using diffusion magnetic resonance imaging has proven valuable in the brain, offering novel indices sensitive to the tissue microstructural environment in vivo on clinical MRI scanners. However, application, characterization, and validation of these models in the spinal cord remain relatively under-studied. In this study, we apply a diffusion "signal" model (diffusion tensor imaging, DTI) and two commonly implemented "microstructural" models (neurite orientation dispersion and density imaging, NODDI; spherical mean technique, SMT) in the human cervical spinal cord of twenty-one healthy controls. We first provide normative values of DTI, SMT, and NODDI indices in a number of white matter ascending and descending pathways, as well as various gray matter regions. We then aim to validate the sensitivity and specificity of these diffusion-derived contrasts by relating these measures to indices of the tissue microenvironment provided by a histological template. We find that DTI indices are sensitive to a number of microstructural features, but lack specificity. The microstructural models also show sensitivity to a number of microstructure features; however, they do not capture the specific microstructural features explicitly modelled. Although often regarded as a simple extension of the brain in the central nervous system, it may be necessary to re-envision, or specifically adapt, diffusion microstructural models for application to the human spinal cord with clinically feasible acquisitions - specifically, adjusting, adapting, and re-validating the modeling as it relates to both theory (i.e. relevant biology, assumptions, and signal regimes) and parameter estimation (for example challenges of acquisition, artifacts, and processing).

Chemical exchange saturation transfer (CEST) can offer information about protons associated with mobile proteins through the amide proton transfer (APT) effect, which has been shown to discriminate tumor from healthy tissue and, more recently, has been suggested as a prognosticator of response to therapy. Despite this promise, APT effects are small (only a few percent of the total signal); and APT imaging is often prone to artifacts resulting from system instability. Here we present a procedure that enables the detection of APT effects in the human breast at 7 T while mitigating these issues. Adequate signal-to-noise ratio (SNR) was achieved via an optimized quadrature RF breast coil and 3D acquisitions. To reduce the influence of fat, effective fat suppression schemes were developed that did not degrade SNR. To reduce the levels of ghosting artifacts, dummy scans have been integrated into the scanning protocol. Compared to results obtained at 3 T, the standard deviation of the measured APT effect was reduced by a factor of four at 7 T, allowing for the detection of APT effects with a standard deviation of 1% in the human breast at 7 T. Together, these results demonstrate that the APT effect can be reliably detected in the healthy human breast with a high level of precision at 7 T.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) indirectly images exchangeable solute protons resonating at frequencies different than bulk water. These solute protons are selectively saturated using low bandwidth RF irradiation and saturation is transferred to bulk water protons via chemical exchange, resulting in an attenuation of the measured water proton signal. CEST MRI is an advanced MRI technique with wide application potential due to the ability to examine complex molecular contributions. CEST MRI at high field (7 Tesla [7 T]) will improve the overall results due to increase in signal, T1 relaxation time, and chemical shift dispersion. Increased field strength translates to enhanced quantification of the metabolite of interest, allowing more fundamental studies on underlying pathophysiology. CEST contrast is affected by several tissue properties, such as the concentrations of exchange partners and their rate of proton exchange, whose effects have been examined and explored in this review. We have highlighted the background of CEST MRI, typical implementation strategy, and complications at 7 T.

In multiple sclerosis (MS), spinal cord imaging can help in diagnosis and follow-up evaluation. However, spinal cord magnetic resonance imaging (MRI) is technically challenging, and image quality, particularly in the axial plane, is typically poor compared to brain MRI. Because gradient-recalled echo (GRE) images might offer improved contrast resolution within the spinal cord at high magnetic field strength, both without and with a magnetization transfer prepulse, we compared them to T2-weighted fast-spin-echo (T2-FSE) images for the detection of MS lesions in the cervical cord at 3T.On a clinical 3T MRI scanner, we studied 62 MS cases and 19 healthy volunteers. Axial 3D GRE sequences were performed without and with off-resonance radiofrequency irradiation. To mimic clinical practice, all images were evaluated in conjunction with linked images from a sagittal short tau inversion recovery scan, which is considered the gold standard for lesion detection in MS. Two experienced observers recorded image quality, location and size of focal lesions, atrophy, swelling, and diffuse signal abnormality independently at first and then in consensus.The number and volume of lesions detected with high confidence was more than three times as high on both GRE sequences compared to T2-FSE (p0.0001). Approximately 5 % of GRE scans were affected by artifacts that interfered with image interpretation, not significantly different from T2W-FSE.Axial 3D GRE sequences are useful for MS lesion detection when compared to 2D T2-FSE sequences in the cervical spinal cord at 3T and should be considered when examining intramedullary spinal cord lesions.

The optic nerve (ON) plays a crucial role in human vision transporting all visual information from the retina to the brain for higher order processing. There are many diseases that affect the ON structure such as optic neuritis, anterior ischemic optic neuropathy and multiple sclerosis. Because the ON is the sole pathway for visual information from the retina to areas of higher level processing, measures of ON damage have been shown to correlate well with visual deficits. Increased intracranial pressure has been shown to correlate with the size of the cerebrospinal fluid (CSF) surrounding the ON. These measures are generally taken at an arbitrary point along the nerve and do not account for changes along the length of the ON. We propose a high contrast and high-resolution 3-D acquired isotropic imaging sequence optimized for ON imaging. We have acquired scan-rescan data using the optimized sequence and a current standard of care protocol for 10 subjects. We show that this sequence has superior contrast-to-noise ratio to the current standard of care while achieving a factor of 11 higher resolution. We apply a previously published automatic pipeline to segment the ON and CSF sheath and measure the size of each individually. We show that these measures of ON size have lower short-term reproducibility than the population variance and the variability along the length of the nerve. We find that the proposed imaging protocol is (1) useful in detecting population differences and local changes and (2) a promising tool for investigating biomarkers related to structural changes of the ON.

The purpose of this study was to develop and evaluate two spinal cord (SC) diffusion tensor imaging (DTI) protocols, implemented at multiple sites (using scanners from two different manufacturers), one available on any clinical scanner, and one using more advanced options currently available in the research setting, and to use an automated processing method for unbiased quantification. DTI parameters are sensitive to changes in the diseased SC. However, imaging the cord can be technically challenging due to various factors including its small size, patient-related and physiological motion, and field inhomogeneities. Rapid acquisition sequences such as Echo Planar Imaging (EPI) are desirable but may suffer from image distortions. We present a multi-centre comparison of two acquisition protocols implemented on scanners from two different vendors (Siemens and Philips), one using a reduced field-of-view (rFOV) EPI sequence, and one only using options available on standard clinical scanners such as outer volume suppression (OVS). Automatic analysis was performed with the Spinal Cord Toolbox for unbiased and reproducible quantification of DTI metrics in the white matter. Images acquired using the rFOV sequence appear less distorted than those acquired using OVS alone. SC DTI parameter values obtained using both sequences at all sites were consistent with previous measurements made at 3T. For the same scanner manufacturer, DTI parameter inter-site SDs were smaller for the rFOV sequence compared to the OVS sequence. The higher inter-site reproducibility (for the same manufacturer and acquisition details, i.e. ZOOM data acquired at the two Philips sites) of rFOV compared to the OVS sequence supports the idea that making research options such as rFOV more widely available would improve accuracy of measurements obtained in multi-centre clinical trials. Future multi-centre studies should also aim to match the rFOV technique and signal-to-noise ratios in all sequences from different manufacturers/sites in order to avoid any bias in measured DTI parameters and ensure similar sensitivity to pathological changes.

Background: Spinal cord (SC) pathology is a major contributor to clinical disability in multiple sclerosis (MS). Conventional magnetic resonance imaging (MRI), specifically SC-MRI lesion load measures that include lesion count and volume, demonstrate only a modest relationship with the clinical status of MS patients. Although SC cross-sectional area (CSA) correlates better with clinical dysfunction than MRI lesion count, SC atrophy likely signifies irreversible tissue loss. Using quantitative MRI indices sensitive to early and late microstructural changes in the spinal cord, we searched for the presence of better correlations between MRI measures and clinical status in MS. Objectives: We investigated whether diffusion-tensor imaging indices and the magnetization-transfer ratio (MTR) were better associated with the clinical status of MS patients than conventional SC-MRI measures. Methods: A total of 129 MS patients underwent 3-tesla cervical SC-MRI and quantitative sensorimotor function testing, using the Vibratron-II and dynamometer. Regions-of-interest circumscribed the SC on axial slices between C3-C4. We calculated SC-CSA, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (λ⊥), parallel diffusivity (λ||) and MTR. We used multivariable linear regression to determine if there were any associations between MRI indices and clinical measures of dysfunction. Results: All MRI indices were significantly different in subjects with MS versus healthy controls, and between the progressive versus relapsing MS subtypes, with the exception of λ||. In multivariable regression models that were adjusted for age, sex, brain parenchymal fraction, and SC-CSA, the MRI indices independently explained variability in hip flexion strength ( p-values: MD, λ⊥, λ|| < 0.001; FA = 0.07), vibration sensation threshold ( p-values: FA = 0.04; MTR = 0.05; λ⊥ = 0.06), and Expanded Disability Status Scale scores ( p-values: FA = 0.003; MD = 0.03; λ⊥ = 0.005; MTR = 0.02). Conclusions: In a large, heterogeneous MS sample, quantitative SC-MRI indices demonstrated independent associations with system-specific and global clinical dysfunction. Our findings suggest that the indices studied may provide important information about microstructural SC changes and the substrates of limb disability in MS. The identified structure-function relationships underpin the potential utility of these measures in assessments of therapeutic efficacy.

Quantitative magnetization transfer imaging yields indices describing the interactions between free water protons and immobile, macromolecular protons-including the macromolecular to free pool size ratio (PSR) and the rate of magnetization transfer between pools k(mf) . This study describes the first implementation of the selective inversion recovery quantitative magnetization transfer method on a clinical 3.0-T scanner in human brain in vivo. Selective inversion recovery data were acquired at 16 different inversion times in nine healthy subjects and two patients with relapsing remitting multiple sclerosis. Data were collected using a fast spin-echo readout and reduced repetition time, resulting in an acquisition time of 4 min for a single slice. In healthy subjects, excellent intersubject and intrasubject reproducibilities (assessed via repeated measures) were demonstrated. Furthermore, PSR values in white (mean ± SD = 11.4 ± 1.2%) and gray matter (7.5 ± 0.7%) were consistent with previously reported values, while k(mf) values were approximately 2-fold slower in both white (11 ± 2 s(-1) ) and gray matter (15 ± 6 s(-1) ). In relapsing remitting multiple sclerosis patients, quantitative magnetization transfer indices were sensitive to pathological changes in lesions and in normal appearing white matter.

Chemical exchange saturation transfer (CEST) MRI is a molecular imaging method that has previously been successful at reporting variations in tissue protein and glycogen contents and pH. We have implemented amide proton transfer (APT), a specific form of chemical exchange saturation transfer imaging, at high field (7 T) and used it to study healthy human subjects and patients with multiple sclerosis. The effects of static field inhomogeneities were mitigated using a water saturation shift referencing method to center each z-spectrum on a voxel-by-voxel basis. Contrary to results obtained at lower fields, APT imaging at 7 T revealed significant contrast between white and gray matters, with a higher APT signal apparent within the white matter. Preliminary studies of multiple sclerosis showed that the APT asymmetry varied with the type of lesion examined. An increase in APT asymmetry relative to healthy tissue was found in some lesions. These results indicate the potential utility of APT at high field as a noninvasive biomarker of white matter pathology, providing complementary information to other MRI methods in current clinical use.

Modern MRI image processing methods have yielded quantitative, morphometric, functional, and structural assessments of the human brain. These analyses typically exploit carefully optimized protocols for specific imaging targets. Algorithm investigators have several excellent public data resources to use to test, develop, and optimize their methods. Recently, there has been an increasing focus on combining MRI protocols in multi-parametric studies. Notably, these have included innovative approaches for fusing connectivity inferences with functional and/or anatomical characterizations. Yet, validation of the reproducibility of these interesting and novel methods has been severely hampered by the limited availability of appropriate multi-parametric data. We present an imaging protocol optimized to include state-of-the-art assessment of brain function, structure, micro-architecture, and quantitative parameters within a clinically feasible 60-min protocol on a 3-T MRI scanner. We present scan-rescan reproducibility of these imaging contrasts based on 21 healthy volunteers (11 M/10 F, 22-61 years old). The cortical gray matter, cortical white matter, ventricular cerebrospinal fluid, thalamus, putamen, caudate, cerebellar gray matter, cerebellar white matter, and brainstem were identified with mean volume-wise reproducibility of 3.5%. We tabulate the mean intensity, variability, and reproducibility of each contrast in a region of interest approach, which is essential for prospective study planning and retrospective power analysis considerations. Anatomy was highly consistent on structural acquisition (~1-5% variability), while variation on diffusion and several other quantitative scans was higher (~

T1 and T2 were measured for white matter (WM) and gray matter (GM) in the human cervical spinal cord at 3T. T1 values were calculated using an inversion-recovery (IR) and B1-corrected double flip angle gradient echo (GRE) and show significant differences (p = 0.002) between WM (IR = 876 ± 27 ms, GRE = 838 ± 54 ms) and GM (IR = 973 ± 33 ms, GRE = 994 ± 54 ms). IR showed significant difference between lateral and dorsal column WM (863 ± 23 ms and 899 ± 18 ms, respectively, p = 0.01) but GRE did not (p = 0.40). There was no significant difference (p = 0.31) in T2 between WM (73 ± 6 ms) and GM (76 ± 3 ms) or between lateral and dorsal columns (lateral: 73 ± 6 ms, dorsal: 72 ± 7 ms, p = 0.59). WM relaxation times were similar to brain structures with very dense fiber packing (e.g., corpus callosum), while GM values resembled deep GM in brain. Optimized sequence parameters for maximal contrast between WM and GM, and between WM and cerebrospinal fluid (CSF) were derived. Since the spinal cord has rostral-caudal symmetry, we expect these findings to be applicable to the whole cord. Magn Reson Med 60:213–219, 2008. © 2008 Wiley-Liss, Inc.

Optical coherence tomography (OCT) noninvasively quantifies retinal nerve fiber layer (RNFL) thickness. Studies show RNFL thinning in multiple sclerosis (MS), and we assessed its association with brain atrophy.RNFL thickness was measured in 40 patients with MS and 15 controls. Brain parenchymal fraction (BPF) and partial brain volumes were estimated from cranial MRI scans using SIENA-X. Multiple linear regression modeling assessed the association between OCT and MRI measures of atrophy.Minimum RNFL thickness and subject age together predict 21% (p = 0.005) of the variance in BPF in all patients with MS and 43% (p = 0.003) of the variance in BPF in the subgroup with relapsing remitting MS (RRMS; n = 20). The partial correlation coefficient between BPF and minimum RNFL thickness, controlling for age, is 0.46 (p = 0.003) in all patients with MS and 0.69 (p = 0.001) in patients with RRMS. These associations are driven by CSF volume but not by gray or white matter volume. There is no significant association of these variables among controls.In multiple sclerosis (MS), retinal nerve fiber layer thickness is associated with brain parenchymal fraction and CSF volume. These data suggest that quantification of axonal thickness in the retina by optical coherence tomography (OCT) provides concurrent information about MRI brain abnormality in MS. OCT should be examined in longitudinal studies to determine if it could be used as an outcome measure in clinical trials of neuroprotective drugs.

To determine the added value of amide proton transfer (APT) imaging to conventional and perfusion MRI for differentiating tumour progression (TP) from the treatment-related effect (TE) in patients with post-treatment glioblastomas. Sixty-five consecutive patients with enlarging contrast-enhancing lesions following concurrent chemoradiotherapy were assessed using contrast-enhanced T1-weighted MRI (CE-T1WI), 90th percentile histogram parameters of normalized cerebral blood volume (nCBV90) and APT asymmetry value (APT90). Diagnostic performance was determined using the area under the receiver operating characteristic curve (AUC) and cross validations. There were statistically significant differences in the mean APT90 between the TP and the TE groups (3.87–4.01 % vs. 1.38–1.41 %; P

Background: The clinical course of multiple sclerosis (MS) is mainly attributable to cervical and upper thoracic spinal cord dysfunction. High-resolution, 7T anatomical imaging of the cervical spinal cord is presented. Image contrast between gray/white matter and lesions surpasses conventional, clinical T1- and T2-weighted sequences at lower field strengths. Objective: To study the spinal cord of healthy controls and patients with MS using magnetic resonance imaging at 7T. Methods: Axial (C2–C5) T1- and T2*-weighted and sagittal T2*-/spin-density-weighted images were acquired at 7T in 13 healthy volunteers (age 22–40 years), and 15 clinically diagnosed MS patients (age 19–53 years, Extended Disability Status Scale, (EDSS) 0–3) in addition to clinical 3T scans. In healthy volunteers, a high-resolution multi-echo gradient echo scan was obtained over the same geometry at 3T. Evaluation included signal and contrast to noise ratios and lesion counts for healthy and patient volunteers, respectively. Results/conclusion: High-resolution images at 7T exceeded resolutions reported at lower field strengths. Gray and white matter were sharply demarcated and MS lesions were more readily visualized at 7T compared to clinical acquisitions, with lesions apparent at both fields. Nerve roots were clearly visualized. White matter lesion counts averaged 4.7 vs 3.1 (52% increase) per patient at 7T vs 3T, respectively ( p=0.05).

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage., Graphical abstract, Highlights • NAWM is investigated in NPSLE and SLE using MTI and DTI. • Differences in DTI and MTR between NPSLE and HC are widespread but only moderately co-localized. • Significant differences in MD between SLE and NPSLE suggest link to onset of NPSLE.