Assessment of MRI to estimate metastatic dissemination risk and prometastatic effects of chemotherapy.

Metastatic dissemination in breast cancer is regulated by specialized intravasation sites called "tumor microenvironment of metastasis" (TMEM) doorways, composed of a tumor cell expressing the actin-regulatory protein Mena, a perivascular macrophage, and an endothelial cell, all in stable physical contact. High TMEM doorway number is associated with an increased risk of distant metastasis in human breast cancer and mouse models of breast carcinoma. Here, we developed a novel magnetic resonance imaging (MRI) methodology, called TMEM Activity-MRI, to detect TMEM-associated vascular openings that serve as the portal of entry for cancer cell intravasation and metastatic dissemination. We demonstrate that TMEM Activity-MRI correlates with primary tumor TMEM doorway counts in both breast cancer patients and mouse models, including MMTV-PyMT and patient-derived xenograft models. In addition, TMEM Activity-MRI is reduced in mouse models upon treatment with rebastinib, a specific and potent TMEM doorway inhibitor. TMEM Activity-MRI is an assay that specifically measures TMEM-associated vascular opening (TAVO) events in the tumor microenvironment, and as such, can be utilized in mechanistic studies investigating molecular pathways of cancer cell dissemination and metastasis. Finally, we demonstrate that TMEM Activity-MRI increases upon treatment with paclitaxel in mouse models, consistent with prior observations that chemotherapy enhances TMEM doorway assembly and activity in human breast cancer. Our findings suggest that TMEM Activity-MRI is a promising precision medicine tool for localized breast cancer that could be used as a non-invasive test to determine metastatic risk and serve as an intermediate pharmacodynamic biomarker to monitor therapeutic response to agents that block TMEM doorway-mediated dissemination.

Three-Dimensional Printed Anatomic Models Derived From Magnetic Resonance Imaging Data: Current State and Image Acquisition Recommendations for Appropriate Clinical Scenarios.

Three-dimensional (3D) printing technologies have been increasingly utilized in medicine over the past several years and can greatly facilitate surgical planning thereby improving patient outcomes. Although still much less utilized compared to computed tomography (CT), magnetic resonance imaging (MRI) is gaining traction in medical 3D printing. The purpose of this study was two-fold: 1) to determine the prevalence in the existing literature of using MRI to create 3D printed anatomic models for surgical planning and 2) to provide image acquisition recommendations for appropriate clinical scenarios where MRI is the most suitable imaging modality. The workflow for creating 3D printed anatomic models from medical imaging data is complex and involves image segmentation of the regions of interest and conversion of that data into 3D surface meshes, which are compatible with printing technologies. CT is most commonly used to create 3D printed anatomic models due to the high image quality and relative ease of performing image segmentation from CT data. As compared to CT datasets, 3D printing using MRI data offers advantages since it provides exquisite soft tissue contrast needed for accurate organ segmentation and it does not expose patients to unnecessary ionizing radiation. MRI, however, often requires complicated imaging techniques and time-consuming postprocessing procedures to generate high-resolution 3D anatomic models needed for 3D printing. Despite these challenges, 3D modeling and printing from MRI data holds great clinical promises thanks to emerging innovations in both advanced MRI imaging and postprocessing techniques. EVIDENCE LEVEL: 2 TECHNICAL EFFICATCY: 5.

Anatomical brain MRI study of pediatric cancer survivors treated with chemotherapy: Correlation with behavioral measures.

The negative impacts of chemotherapy on pediatric patients treated with chemotherapy during the formative years of brain development are understudied compared to adult chemotherapy cancer patients. This work investigated the morphometry, cortical thickness, and subcortical volumes using MRI and their correlations with behavioral measures in pediatric oncology survivors treated with chemotherapy. Chemotherapy-treated childhood cancer survivors (N = 15, 15.12 ± 5.98 years old) diagnosed with a non-central nervous system malignancy and healthy age-matched controls (N = 15, 15.13 ± 4.21 years old) were studied. MRI was acquired at 3 Tesla. Behavioral Rating Inventory of Executive Functioning (BRIEF) Parental Rating, Purdue Pegboard manual dexterity and n-back working memory measures were administered. Structural MRI scans at 3 Tesla were acquired. Voxel-based morphometry, cortical thickness and subcortical volumes were analyzed and correlated with behavioral scores. Parametric statistics with a p < .05 and adjusted for multiple comparison corrections were performed. Patients exhibited significantly smaller gray-matter volumes in the left globus pallidum, bilateral thalami, left caudate and left nucleus accumbens (p < .05) and thinner cortex in the right parahippocampal gyrus (p < .05) compared to controls. BRIEF scores were similar to normative values. Purdue Pegboard revealed manual dexterity deficits compared to normative values, and the n-back task showed working-memory deficits in patients compared to controls. Left thalamus volume positively correlated with dexterity performance (p = .029). The number of correct answers positively correlated and the number of incorrect answers negatively correlated with total-brain and white-matter volume (p < .05), but not gray-matter volume (p > .05). Our results support the hypothesis that the neurotoxicity of systemic chemotherapy has widespread negative effects on brain development in pediatric oncology patients with relatively mild cognitive deficits. MRI identified neuroanatomical changes have the potential to provide neural correlates of the sequelae associated with pediatric chemotherapy.

Neural correlates of working memory function in pediatric cancer survivors treated with chemotherapy: an fMRI study.

The goal of this study is to investigate the neural correlates of working memory function associated with chemotherapy in pediatric cancer survivors using event-related functional MRI (fMRI) analysis. Fifteen pediatric cancer survivors treated with chemotherapy and 15 healthy controls were studied. Blood oxygenation level dependent (BOLD) fMRI was acquired. A visual n-back task was used to test working memory function during the fMRI scan. Responses were recorded via an MRI compatible button box for analysis. fMRI scans were analyzed using statistical parametric mapping software. All statistics were corrected for multiple comparisons by false discovery rate, with p < 0.05 as significance. Patients however gave more incorrect responses (p < 0.05), more no responses (p < 0.05), and longer response times (p < 0.05) compared with healthy controls. Correct responses generated significantly lower BOLD responses in the posterior cingulate for pediatric cancer survivors compared with controls (p < 0.05). Incorrect responses generated significantly greater BOLD responses in the angular gyrus in survivors (p < 0.05), and no response trials generated greater BOLD responses within the superior parietal lobule (p < 0.05) compared with controls. Working memory impairment appears to be due to an inability to manipulate information and to retrieve information from memory. The ability to delineate the affected neural circuits associated with chemotherapy-induced cognitive impairment could inform treatment strategies, identify patients at high risk of developing cognitive deficits, and pre-emptively tailor behavioral enrichment to overcome specific cognitive deficits.

Convolutional Neural Network Detection of Axillary Lymph Node Metastasis Using Standard Clinical Breast MRI.

BACKGROUND: Axillary lymph node status is important for breast cancer staging and treatment planning as the majority of breast cancer metastasis spreads through the axillary lymph nodes. There is currently no reliable noninvasive imaging method to detect nodal metastasis associated with breast cancer. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) data were those from the peak contrast dynamic image from 1.5 Tesla MRI scanners at the pre-neoadjuvant chemotherapy stage. Data consisted of 66 abnormal nodes from 38 patients and 193 normal nodes from 61 patients. Abnormal nodes were those determined by expert radiologist based on 18Fluorodeoxyglucose positron emission tomography images. Normal nodes were those with negative diagnosis of breast cancer. The convolutional neural network consisted of 5 convolutional layers with filters from 16 to 128. Receiver operating characteristic analysis was performed to evaluate prediction performance. For comparison, an expert radiologist also scored the same nodes as normal or abnormal. RESULTS: The convolutional neural network model yielded a specificity of 79.3% ± 5.1%, sensitivity of 92.1% ± 2.9%, positive predictive value of 76.9% ± 4.0%, negative predictive value of 93.3% ± 1.9%, accuracy of 84.8% ± 2.4%, and receiver operating characteristic area under the curve of 0.91 ± 0.02 for the validation data set. These results compared favorably with scoring by radiologists (accuracy of 78%). CONCLUSION: The results are encouraging and suggest that this approach may prove useful for classifying lymph node status on MRI in clinical settings in patients with breast cancer, although additional studies are needed before routine clinical use can be realized. This approach has the potential to ultimately be a noninvasive alternative to lymph node biopsy.

Repolarized macrophages, induced by intermediate stereotactic dose radiotherapy and immune checkpoint blockade, contribute to long-term survival in glioma-bearing mice.

INTRODUCTION: Glioblastoma multiforme (GBM) is a deadly brain tumor with a short expected median survival, despite current standard-of-care treatment. We explored the combination of intermediate stereotactic dose radiation therapy and immune checkpoint inhibitor therapy as a novel treatment strategy for GBM. METHODS: Glioma xenograft-bearing mice were exposed to high dose brain-directed radiation (10 Gy single exposure) as well as mouse anti-PD-1 antibody. The tumor-bearing animals were randomized to four groups: no treatment, radiation alone, anti-PD-1 alone, and radiation + anti-PD-1. Survival was followed, and tumor growth was monitored using MRI. Immunohistochemistry, gene expression arrays, and flow cytometry were used to characterize the treatment-induced effects. Pharmacologic inhibitors of T-lymphocytes, bone marrow derived macrophages, and microglia were used to assess the respective roles of different immune populations in observed treatment effects. RESULTS: We found the combined treatment with high dose radiation and immunotherapy to be highly effective with a 75% complete pathologic response and dramatically improved survival outcomes. We found both CD8+ T-cells and macrophages to be necessary for the full effect of combined therapy, with T lymphocytes appearing to play a role early on and macrophages mediating a later phase of the combined treatment effect. Radiation treatment appeared to trigger macrophage repolarization, increasing M1/M2 ratio. CONCLUSIONS: These findings point to a novel immunologic mechanism underlying the interaction between radiotherapy and immunotherapy. They also provide the basis for clinical investigation of immunogenic dose radiation in combination with immune checkpoint blockade as a potential treatment approach for newly diagnosed high grade gliomas.

Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function.

BACKGROUND: Human umbilical cord blood (hUCB) cell therapy is a promising treatment for ischemic stroke. The effects of hyperacute stem cell transplantation on cerebrovascular function in ischemic stroke are, however, not well understood. This study evaluated the effects of hyperacute intraarterial transplantation of hUCB mononuclear cells (MNCs) on cerebrovascular function in stroke rats using serial magnetic resonance imaging (MRI). METHODS: HUCB MNCs or vehicle were administered to stroke rats via the internal carotid artery immediately after reperfusion at 60 min following ischemia onset. Lesion volumes were longitudinally evaluated by MRI on days 0, 2, 14, and 28 after stroke, accompanied by behavioral tests. Cerebral blood flow (CBF) and cerebrovascular reactivity were measured by perfusion MRI and CO2 functional MRI (fMRI) at 28 days post-stroke; corresponding vascular morphological changes were also detected by immunohistology in the same animals. RESULTS: We found that CBF to the stroke-affected region at 28 days was improved (normalized CBF value: 1.41 ± 0.30 versus 0.49 ± 0.07) by intraarterial transplantation of hUCB MNCs in the hyperacute stroke phase, compared to vehicle control. Cerebrovascular reactivity within the stroke-affected area, measured by CBF fMRI, was also increased (35.2 ± 3.5% versus 12.8 ± 4.3%), as well as the corresponding cerebrovascular density. Some engrafted cells appeared with microvascular-like morphology and stained positive for von Willebrand Factor (an endothelial cell marker), suggesting they differentiated into endothelial cells. Some engrafted cells also connected to host endothelial cells, suggesting they interacted with the host vasculature. Compared to the vehicle group, infarct volume at 28 days in the stem cell treated group was significantly smaller (160.9 ± 15.7 versus 231.2 ± 16.0 mm3); behavioral deficits were also markedly reduced by stem cell treatment at day 28 (19.5 ± 1.0% versus 30.7 ± 4.7% on the foot fault test; 68.2 ± 4.6% versus 86.6 ± 5.8% on the cylinder test). More tissue within initial perfusion-diffusion mismatch was rescued in the treatment group. CONCLUSIONS: Intraarterial hUCB MNC transplantation during the hyperacute phase of ischemic stroke improved cerebrovascular function and reduced behavioral deficits and infarct volume.

The Effects of Methylene Blue on Autophagy and Apoptosis in MRI-Defined Normal Tissue, Ischemic Penumbra and Ischemic Core.

Methylene blue (MB) USP, which has energy-enhancing and antioxidant properties, is currently used to treat methemoglobinemia and cyanide poisoning in humans. We recently showed that MB administration reduces infarct volume and behavioral deficits in rat models of ischemic stroke and traumatic brain injury. This study reports the underlying molecular mechanisms of MB neuroprotection following transient ischemic stroke in rats. Rats were subjected to transient (60-mins) ischemic stroke. Multimodal MRI during the acute phase and at 24 hrs were used to define three regions of interest (ROIs): i) the perfusion-diffusion mismatch salvaged by reperfusion, ii) the perfusion-diffusion mismatch not salvaged by reperfusion, and iii) the ischemic core. The tissues from these ROIs were extracted for western blot analyses of autophagic and apoptotic markers. The major findings were: 1) MB treatment reduced infarct volume and behavioral deficits, 2) MB improved cerebral blood flow to the perfusion-diffusion mismatch tissue after reperfusion and minimized harmful hyperperfusion 24 hrs after stroke, 3) MB inhibited apoptosis and enhanced autophagy in the perfusion-diffusion mismatch, 4) MB inhibited apoptotic signaling cascades (p53-Bax-Bcl2-Caspase3), and 5) MB enhanced autophagic signaling cascades (p53-AMPK-TSC2-mTOR). MB induced neuroprotection, at least in part, by enhancing autophagy and reducing apoptosis in the perfusion-diffusion mismatch tissue following ischemic stroke.

Brain high-energy phosphates and creatine kinase synthesis rate under graded isoflurane anesthesia: An in vivo (31) P magnetization transfer study at 11.7 tesla.

PURPOSE: The creatine kinase rate of metabolic adenosine triphosphate (ATP) synthesis is an important metabolic parameter but is challenging to measure in vivo due to limited signal-to-noise ratio and long measurement time. THEORY AND METHODS: This study reports the implementation of an accelerated (31) P Four Angle Saturation Transfer (FAST) method to measure the forward creatine kinase (CK) rate of ATP synthesis. Along with a high-field scanner (11.7 Tesla) and a small sensitive surface coil, the forward CK rate in the rat brain was measured in ∼5 min. RESULTS: Under 1.2% isoflurane, the forward CK rate constant and metabolic flux were, respectively, kf , CK =0.26 ± 0.02 s(-1) and Ff,CK =70.8 ± 4.6 µmol/g/min. As a demonstration of utility and sensitivity, measurements were made under graded isoflurane. Under 2.0% isoflurane, kf , CK =0.16 ± 0.02 s(-1) and Ff,CK =410.0 ± 4.2 µmol/g/min, corresponding to a 38% and 42% reduction, respectively, relative to 1.2% isoflurane. By contrast, the ATP and phosphocreatine concentrations were unaltered. CONCLUSION: This study demonstrated the (31) P FAST measurement of creatine kinase rate of ATP synthesis in rat brain with reasonable temporal resolution. Different isoflurane levels commonly used in animal models significantly alter the CK reaction rate but not ATP and phosphocreatine concentrations.

Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice.

Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults. In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation. These findings suggest that Surf1 deficiency-induced metabolic alterations may have positive effects on brain function. Exploring the relationship between mitochondrial activity, oxidative stress, and brain function will enhance our understanding of cognitive aging and of age-related neurologic disorders.

Pharmacological MRI of the choroid and retina: blood flow and BOLD responses during nitroprusside infusion.

Nitroprusside, a vasodilatory nitric oxide donor, is clinically used during vascular surgery and to lower blood pressure in acute hypertension. This article reports a novel application of blood flow (BF) and blood oxygenation level dependent (BOLD) MRI on an 11.7T scanner to image the rat chorioretinal BF and BOLD changes associated with graded nitroprusside infusion. At low doses (1 or 2 µg/kg/min), nitroprusside increased BF as expected but decreased BOLD signals, showing an intriguing BF-BOLD uncoupling. At high doses (3-5 µg/kg/min), nitroprusside decreased BF and markedly decreased BOLD signals. To our knowledge, this is the first pharmacological MRI application of the retina. This approach has potential to open up new avenues to study the drug-related hemodynamic functions and to evaluate the effects of novel therapeutic interventions on BOLD and BF in the normal and diseased retinas.

Longitudinal study of tumor-associated macrophages during tumor expansion using MRI.

MRI is being used increasingly for the noninvasive longitudinal monitoring of cellular processes in various pathophysiological conditions. Macrophages are the main stromal cells in neoplasms and have been suggested to be the major cell type ingesting superparamagnetic iron oxide (SPIO) nanoparticles. However, no MRI study has described longitudinally the presence of tumor-associated macrophages (TAMs) during tumorigenesis with histological confirmation. To address this, we injected SPIO nanoparticles into the circulation of tumor-bearing mice and used MRI and post-mortem histology to monitor TAMs at different time points. The MRI results demonstrated that TAMs, as hypointense signals, appeared continually with the expansion of the tumor. The histological findings also revealed that SPIO-labeled TAMs tended to deposit closer to the vessel lumen with time prior to rapid tumor growth. The present study demonstrates the potential of using MRI to assess longitudinally TAM accumulation during tumorigenesis, and provides the first in vivo insight into the topographical arrangement of TAMs in relation to the progression of tumors. In vivo monitoring of the presence of TAMs could be useful for the development of tumor treatments that target TAM functions.

Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex.

The purpose of this study was to investigate activation-induced hypermetabolism and hyperemia by using a multifrequency (4, 8, and 16 Hz) reversing-checkerboard visual stimulation paradigm. Specifically, we sought to (i) quantify the relative contributions of the oxidative and nonoxidative metabolic pathways in meeting the increased energy demands [i.e., ATP production (J(ATP))] of task-induced neuronal activation and (ii) determine whether task-induced cerebral blood flow (CBF) augmentation was driven by oxidative or nonoxidative metabolic pathways. Focal increases in CBF, cerebral metabolic rate of oxygen (CMRO(2); i.e., index of aerobic metabolism), and lactate production (J(Lac); i.e., index of anaerobic metabolism) were measured by using physiologically quantitative MRI and spectroscopy methods. Task-induced increases in J(ATP) were small (12.2-16.7%) at all stimulation frequencies and were generated by aerobic metabolism (approximately 98%), with %DeltaJ(ATP) being linearly correlated with the percentage change in CMRO(2) (r = 1.00, P < 0.001). In contrast, task-induced increases in CBF were large (51.7-65.1%) and negatively correlated with the percentage change in CMRO(2) (r = -0.64, P = 0.024), but positively correlated with %DeltaJ(Lac) (r = 0.91, P < 0.001). These results indicate that (i) the energy demand of task-induced brain activation is small (approximately 15%) relative to the hyperemic response (approximately 60%), (ii) this energy demand is met through oxidative metabolism, and (iii) the CBF response is mediated by factors other than oxygen demand.

Functional evaluation of therapeutic response for a mouse model of medulloblastoma.

Medulloblastoma is an aggressive childhood cerebellar tumor. We recently reported a mouse model with conditional deletion of Patched1 gene that recapitulates many characteristics of the human medulloblastoma. Qualitative symptoms observed in the mouse model include irregular stride length, impaired cranial nerve function and decreased motor coordination and performance. In our current study, several quantitative behavioral assays including a mouse rotarod, a forced air challenge, a screen inversion test, a horizontal wire test, and stride length analysis were evaluated to determine the most sensitive and cost-effective functional assay for impaired neuromotor behavior associated with disease progression. Magnetic resonance imaging (MRI) was used to confirm and monitor tumor growth and as an anatomical biomarker for therapeutic response. Wild type mice or medulloblastoma-prone, conditional Patched1 knockout mice were observed by behavioral assays and MRI from postnatal weeks 3-6. Bortezomib treatment was administered during this period and therapeutic response was assessed using cerebellar volumes at the end of treatment. Of the behavioral tests assessed in this study, stride length analysis was best able to detect differences between tumor-prone mice and wild type mice as early as postnatal day 37 (P=0.003). Significant differences between stride lengths of bortezomib treated and control tumor-bearing mice could be detected as early as postnatal day 42 (P=0.020). Cerebellar volumes measured by MRI at the end of treatment validated the therapeutic effects seen by behavioral tests (P=0.03). These findings suggest that stride length analysis may serve as one of the more sensitive and cost-effective method for assessing new therapeutic compounds in this and other preclinical model of brain tumors.

Tauopathy with paired helical filaments in an aged chimpanzee.

An enigmatic feature of age-related neurodegenerative diseases is that they seldom, if ever, are fully manifested in nonhuman species under natural conditions. The neurodegenerative tauopathies are typified by the intracellular aggregation of hyperphosphorylated microtubule-associated protein tau (MAPT) and the dysfunction and death of affected neurons. We document the first case of tauopathy with paired helical filaments in an aged chimpanzee (Pan troglodytes). Pathologic forms of tau in neuronal somata, neuropil threads, and plaque-like clusters of neurites were histologically identified throughout the neocortex and, to a lesser degree, in allocortical and subcortical structures. Ultrastructurally, the neurofibrillary tangles consisted of tau-immunoreactive paired helical filaments with a diameter and helical periodicity indistinguishable from those seen in Alzheimer's disease. A moderate degree of Abeta deposition was present in the cerebral vasculature and, less frequently, in senile plaques. Sequencing of the exons and flanking intronic regions in the genomic MAPT locus disclosed no mutations that are associated with the known human hereditary tauopathies, nor any polymorphisms of obvious functional significance. Although the lesion profile in this chimpanzee differed somewhat from that in Alzheimer's disease, the copresence of paired helical filaments and Abeta-amyloidosis indicates that the molecular mechanisms for the pathogenesis of the two canonical Alzheimer lesions--neurofibrillary tangles and senile plaques--are present in aged chimpanzees.

Myelination and long diffusion times alter diffusion-tensor-imaging contrast in myelin-deficient shiverer mice.

Diffusion tensor imaging (DTI) using variable diffusion times (t(diff)) was performed to investigate wild-type (wt) mice, myelin-deficient shiverer (shi) mutant mice and shi mice transplanted with wt neural precursor cells that differentiate and function as oligodendrocytes. At t(diff) = 30 ms, the diffusion anisotropy "volume ratio" (VR), diffusion perpendicular to the fibers (lambda( perpendicular)), and mean apparent diffusion coefficient () of the corpus callosum of shi mice were significantly higher than those of wt mice by 12 +/- 2%, 13 +/- 2%, and 10 +/- 1%, respectively; fractional anisotropy (FA) and relative anisotropy (RA) were lower by 10 +/- 1% and 11 +/- 3%, respectively. Diffusion parallel to the fibers (lambda(//)) was not statistically different between shi and wt mice. Normalized T(2)-weighted signal intensities showed obvious differences (27 +/- 4%) between wt and shi mice in the corpus callosum but surprisingly did not detect transplant-derived myelination. In contrast, diffusion anisotropy maps detected transplant-derived myelination in the corpus callosum and its spatial distribution was consistent with the donor-derived myelination determined by immunohistochemical staining. Anisotropy indices (except lambda(//)) in the corpus callosum showed strong t(diff) dependence (30-280 ms), and the differences in lambda( perpendicular) and VR between wt and shi mice became significantly larger at longer t(diff), indicative of improved DTI sensitivity at long t(diff). In contrast, anisotropy indices in the hippocampus showed very weak t(diff) dependence and were not significantly different between wt and shi mice across different t(diff). This study provides insights into the biological signal sources and measurement parameters influencing DTI contrast, which could lead to developing more sensitive techniques for detection of demyelinating diseases.