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OBJECTIVE Magnetization EXchange (MEX) sequence measures a signal linearly dependent on the myelin proton fraction by selective suppression of water magnetization and a recovery period. Varying the recovery period enables extraction of the percentile fraction of myelin bound protons. We aim to demonstrate the MEX sequence sensitivity to the fraction of protons associated with myelin in mice brain, in vivo. METHODS The cuprizone mouse model was used to manipulate the myelin content. Mice fed cuprizone (n = 15) and normal chow (n = 8) were imaged in vivo using MEX sequence. MR images were segmented into corpus callosum and internal capsule (white matter) and cortical gray matter, and fitted to the recovery equation. Results were analyzed with correlation to MWF and histopathology. RESULTS The extracted parameters show significant differences in the corpus callosum between the cuprizone and control groups. The cuprizone group exhibited reduced myelin fraction 26.5% (P

Cerebral small vessel disease (CSVD) is the second most common cause of stroke and a major contributor to dementia. Manifestations of CSVD include cerebral microbleeds, intracerebral hemorrhages (ICH), lacunar infarcts, white matter hyperintensities (WMH) and enlarged perivascular spaces. Chronic hypertensive models have been found to reproduce most key features of the disease. Nevertheless, no animal models have been identified to reflect all different aspects of the human disease. Here, we described a novel model for CSVD using salt-sensitive ‘Sabra’ hypertension-prone rats (SBH/y), which display chronic hypertension and enhanced peripheral oxidative stress. SBH/y rats were either administered deoxycorticosteroid acetate (DOCA) (referred to as SBH/y-DOCA rats) or sham-operated and provided with 1% NaCl in drinking water. Rats underwent neurological assessment and behavioral testing, followed by ex vivo MRI and biochemical and histological analyses. SBH/y-DOCA rats show a neurological decline and cognitive impairment and present multiple cerebrovascular pathologies associated with CSVD, such as ICH, lacunes, enlarged perivascular spaces, blood vessel stenosis, BBB permeability and inflammation. Remarkably, SBH/y-DOCA rats show severe white matter pathology as well as WMH, which are rarely reported in commonly used models. Our model may serve as a novel platform for further understanding the mechanisms underlying CSVD and for testing novel therapeutics.

Treatment response assessment in patients with high-grade gliomas (HGG) is heavily dependent on changes in lesion size on MRI. However, in conventional MRI, treatment-related changes can appear as enhancing tissue, with similar presentation to that of active tumor tissue. We propose a model-free data-driven method for differentiation between these tissues, based on dynamic contrast-enhanced (DCE) MRI.The study included a total of 66 scans of patients with glioblastoma. Of these, 48 were acquired from 1 MRI vendor and 18 scans were acquired from a different MRI vendor and used as test data. Of the 48, 24 scans had biopsy results. Analysis included semi-automatic arterial input function (AIF) extraction, direct DCE pharmacokinetic-like feature extraction, and unsupervised clustering of the two tissue types. Validation was performed via (a) comparison to biopsy result (b) correlation to literature-based DCE curves for each tissue type, and (c) comparison to clinical outcome.Consistency between the model prediction and biopsy results was found in 20/24 cases. An average correlation of 82% for active tumor and 90% for treatment-related changes was found between the predicted component and population-based templates. An agreement between the predicted results and radiologist's assessment, based on RANO criteria, was found in 11/12 cases.The proposed method could serve as a non-invasive method for differentiation between lesion tissue and treatment-related changes.

Quantitative MRI can elucidate the complex microstructural changes in liver disease. The Magnetization EXchange (MEX) method estimates macromolecular fraction, such as collagen, and can potentially aid in this task.MEX sequence, and its derived quantitative macromolecular fraction, should correlate with collagen deposition in rodents liver fibrosis model.Prospective.Sixteen adults Sprague-Dawley rats and 13 adults C57BL/6 strain mice given carbon tetrachloride (CClA 7 T scanner. MEX sequence (selective suppression and magnetization exchange), spin-echo and gradient-echo scans.Macromolecular fraction (F) and TComparing CClRats: F values were significantly different after 6 weeks of treatment (0.10 ± 0.02) compared to controls (0.080 ± 0.003). After 8 weeks, F significantly increased (0.11 ± 0.02) in treated animals, while controls are not significant (0.0814 ± 0.0008, P = 0.079). F correlated with quantitative histology (R = 0.87), and TMEX extracted parameters are sensitive to collagen deposition and inflammation and are correlated with histology results of mouse and rat liver fibrosis model.1 TECHNICAL EFFICACY: Stage 3.

Predictive modelling of complex biological systems and biophysical interactions requires the inclusion of multiple nano- and micro-scale events. In many scenarios, however, numerical solutions alone do not necessarily enhance the understanding of the system. Instead, this work explores the use of an agent-based model with visualization capabilities to elucidate interactions between single cells. We present a model of juxtacrine signalling, using Cell Studio, an agent-based modelling system, based on gaming and three-dimensional visualization tools. The main advantages of the system are its ability to apply any cell geometry and to dynamically visualize the diffusion and interactions of the molecules within the cells in real time. These provide an excellent tool for obtaining insight about different biological scenarios, as the user may view the dynamics of a system and observe its emergent behaviour as it unfolds. The agent-based model was validated against the results of a mean-field model of Notch receptors and ligands in two neighbouring cells. The conversion to an agent-based model is described in detail. To demonstrate the advantages of the model, we further created a filopodium-mediated signalling model. Our model revealed that diffusion and endocytosis alone are insufficient to produce significant signalling in a filopodia scenario. This is due to the bottleneck at the cell–filopodium contact region and the long distance to the end of the filopodium. However, allowing active transport of ligands into filopodia enhances the signalling significantly compared with a face-to-face scenario. We conclude that the agent-based approach can provide insights into mechanisms underlying cell signalling. The open-source model can be found in the Internet hosting service GitHub.

Purpose Osteoporosis is characterized by a decrease in bone mineral density (BMD). A preliminary stage of the disease is progressive bone marrow adiposity, caused by imbalance between osteogenesis and adipogenesis in the marrow. Detection of osteoporosis relies on the quantification of BMD with techniques such as dual-energy X-ray absorptiometry. This work aimed to detect bone marrow changes in an experimental model of osteopenia using a low-field tabletop NMR scanner. Methods An experiment was performed on 32 female rats, 3 months old, 16 of which were ovariectomized (OVX) and 16 were sham-operated (sham). The femur and tibia from both hind limbs were isolated and underwent ex vivo NMR scans at four time points after the OVX and sham operations. NMR scans were complemented by BMD measurements and histology. Results Significant changes in the bone marrow of ovariectomized rats, relative to sham operated rats, were observed after 3.5 and 4.5 months. Bone marrow adiposity was detected by significant changes in T1 and T2 relaxation times, and in the diffusion coefficient. Conclusions This study suggests a potential detection of changes to the bone marrow using a tabletop NMR device. Clinical translation may facilitate screening, early detection of bone weakening as a result of estrogen withdrawal, and monitoring of treatment efficacy. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose To provide a biophysical basis to estimate the effect of cytoplasmic flow in neurons, and assess their contribution to the drop in the Apparent Diffusion Coefficient (ADC) in a nerve tissue following extreme conditions, such as brain injury and epileptic seizures. Methods Three mechanisms are treated using the relevant physics of hydrodynamics and electrostatics: cargo induced streaming, electroosmosis, and membrane swelling. Results We begin by discussing the lack of experimental evidence on the necessary velocities required to influence the Magnetic Resonance (MR) experiments. This is followed by demonstrating that cargo induced streaming, a widely known phenomenon in plant cells, has a minor effect on the ADC in neurons. Subsequently, we suggest and analyze two additional mechanisms that may induce fluid displacement in neurons, and are related to the electrical activity: electroosmosis and membrane swelling. Conclusion Although these mechanisms may induce interesting fluid displacements, these cannot explain the significant drop in the ADC. We conclude by outlining the criteria that any future mechanism should meet to have an influence on standard diffusion-MR measurements. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine

Immune tolerance toward “self” is critical in multiple immune disorders. While there are several mechanisms to describe the involvement of immune cells in the process, the role of peripheral tissue cells in that context is not yet clear. The theory of ecoimmunity postulates that interactions between immune and tissue cells represent a predator–prey relationship. A lifelong interaction, shaped mainly during early ontogeny, leads to selection of nonimmune cell phenotypes. Normally, therefore, nonimmune cells that evolve alongside an intact immune system would be phenotypically capable of evading immune responses, and cells whose phenotype falls short of satisfying this steady state would expire under hostile immune responses. This view was supported until recently by experimental evidence showing an inferior endurance of severe combined immunodeficiency (SCID)-derived pancreatic islets when engrafted into syngeneic immune-intact wild-type (WT) mice, relative to islets from WT. Here we extend the experimental exploration of ecoimmunity by searching for the presence of the phenotypic changes suggested by the theory. Immune-related phenotypes of islets, spleen, and bone marrow immune cells were determined, as well as SCID and WT nonlymphocytic cells. Islet submass grafting was performed to depict syngeneic graft functionality. Islet cultures were examined under both resting and inflamed conditions for expression of CD40 and major histocompatibility complex (MHC) class I/II and release of interleukin-1α (IL-1α), IL-1β, IL-6, tumor necrosis factor-α (TNF-α), IL-10, and insulin. Results depict multiple pathways that appear to be related to the sculpting of nonimmune cells by immune cells; 59 SCID islet genes displayed relative expression changes compared with WT islets. SCID cells expressed lower tolerability to inflammation and higher levels of immune-related molecules, including MHC class I. Accordingly, islets exhibited a marked increase in insulin release upon immunocyte depletion, in effect resuming endocrine function that was otherwise suppressed by resident immunocytes. This work provides further support of the ecoimmunity theory and encourages subsequent studies to identify its role in the emergence and treatment of autoimmune pathologies, transplant rejection, and cancer.

We report the development of a double diffusion encoding (DDE) MRI method to estimate and map the axon diameter distribution (ADD) within an imaging volume. A variety of biological processes, ranging from development to disease and trauma, may lead to changes in the ADD in the central and peripheral nervous systems. Unlike previously proposed methods, this ADD experimental design and estimation framework employs a more general, nonparametric approach, without a priori assumptions about the underlying form of the ADD, making it suitable to analyze abnormal tissue. In the current study, this framework was used on an ex vivo ferret spinal cord, while emphasizing the way in which the ADD can be weighted by either the number or the volume of the axons. The different weightings, which result in different spatial contrasts, were considered throughout this work. DDE data were analyzed to derive spatially resolved maps of average axon diameter, ADD variance, and extra-axonal volume fraction, along with a novel sub-micron restricted structures map. The morphological information contained in these maps was then used to segment white matter into distinct domains by using a proposed k-means clustering algorithm with spatial contiguity and left–right symmetry constraints, resulting in identifiable white matter tracks. The method was validated by comparing histological measures to the estimated ADDs using a quantitative similarity metric, resulting in good agreement. With further acquisition acceleration and experimental parameters adjustments, this ADD estimation framework could be first used preclinically, and eventually clinically, enabling a wide range of neuroimaging applications for improved understanding of neurodegenerative pathologies and assessing microstructural changes resulting from trauma.

Recently, several new functional (f)MRI contrast mechanisms including diffusion, phase imaging, proton density, etc. have been proposed to measure neuronal activity more directly and accurately than blood-oxygen-level dependent (BOLD) fMRI. However, these approaches have proved difficult to reproduce, mainly because of the dearth of reliable and robust test systems to vet and validate them. Here we describe the development and testing of such a test bed for non-BOLD fMRI. Organotypic cortical cultures were used as a stable and reproducible biological model of neuronal activity that shows spontaneous activity similar to that of in vivo brain cortex without any hemodynamic confounds. An open-access, single-sided magnetic resonance (MR) “profiler” consisting of four permanent magnets with magnetic field of 0.32 T was used in this study to perform MR acquisition. A fluorescence microscope with long working distance objective was mounted on the top of a custom-designed chamber that keeps the organotypic culture vital, and the MR system was mounted on the bottom of the chamber to achieve real-time simultaneous calcium fluorescence optical imaging and MR acquisition on the same specimen. In this study, the reliability and performance of the proposed test bed were demonstrated by a conventional CPMG MR sequence acquired simultaneously with calcium imaging, which is a well-characterized measurement of neuronal activity. This experimental design will make it possible to correlate directly the other candidate functional MR signals to the optical indicia of neuronal activity in the future. Copyright © 2015 John Wiley & Sons, Ltd.

Synthetic and biological gels undergo a sharp volume phase transition when subjected to a variety of environmental changes. Water and ion dynamics within swollen and compact phases are critical for understanding fundamental concepts in cellular (specifically neuronal) biophysics, for models of bound, free, or ordered water in complex environments; and for practical applications such as the design of gels for drug release, biomimetics, sensors, or actuators. In this work, we find, for the first time, basic physical parameters that shed light on the interaction of gels with water and electrolytes, across a volume phase transition. Water within a gel can be separated into bound and free populations with high exchange rate. We show that free water dynamics in compact gels are the same as those in pure water. Bound water was found to comprise a single layer around the polymers in both phases, with a correlation time three orders of magnitude higher than that of free water. Most importantly, salt-induced phase transition was found to be different from a standard coil-globule transition (e.g., temperature-induced), with no rejection of bound water as the gel compacts. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 1620–1628

Single-sided nuclear magnetic resonance (NMR) scanners find increased use in applications where non-destructive measurements are needed. These single-sided scanners are characterized by a weak magnetic field and a large stray magnetic field gradient. These characteristics make these scanners suitable for determining a sample’s proton density profile, or for mapping NMR properties such as T 1, T 2 or diffusivity as a function of distance. The strong stray-field gradient generated by these magnets dictates a need for relatively high transmission/reception bandwidths, even when thin slices are involved. Consequently, scanning a large volume demands multiple separate measurements, associated with long scan times, potential inaccuracies associated with mechanical misplacements and limitations in tackling certain in vivo or dynamic systems. This work explores the consequences of replacing the hard pulses in the usual multi-echo sequence used in this kind of scanner, with frequency-swept (chirped) pulses. It was found that, under identical echo times and number of echoes, peak power-limited cases like the ones usually involved in these setups endow chirped-pulse sequences with a higher sensitivity than their square-pulse counterparts. Furthermore, data can be extracted in this manner faster; it can also be measured from larger slabs following a single excitation, thereby avoiding the need for multiple mechanical motions of the scanner/sample. Still, at least with the system hereby assayed, hardware limitations prevented us from utilizing equally short echo times for square- as well as chirped-pulse implementations. Given the shorter echo delays that could be used in the square-pulse versions, optimal acquisitions ended up endowing the latter with the best overall sensitivity defined as signal intensity per unit acquisition time. Potential bypasses of this limitation are briefly discussed.

Human skin undergoes morphological and biochemical changes as a result of chronological aging and exposure to solar ultraviolet irradiation (photoaging). Noninvasive detection of these changes may aid in the prevention and treatment of both types of aging. This article presents a noninvasive method for the evaluation of aging skin with a unilateral stray field NMR scanner. These portable and inexpensive scanners may be suitable for in-depth skin characterization. In vivo profiles of sun-protected and sun-exposed skin from the forearms of female subjects of different ages (n = 9) were measured. Skin biopsies for histopathological examination were used as reference. T2 analysis with a bi-exponential decay model was applied and the extracted parameters were examined as markers for dermal aging. In the upper reticular dermis, a significant increase in the fraction of the slow T2 component and in the T2 value itself was found to correlate with chronological aging. For most subjects, there was an additional increase in the values of the slow T2 component and the T2 values from the sun-exposed forearm, superimposed on that measured for the sun-protected forearm. These results are in agreement with the decline in collagen content and the increase in free water content with aging. The results suggest that such a technique can be used as a tool for the assessment of aging, and that bi-exponential fitting can produce sensitive fingerprint parameters for the dermal alterations that occur during aging. Copyright © 2015 John Wiley & Sons, Ltd.

The field of computer modeling and simulation of biological systems is rapidly advancing, backed by significant progress in the fields of experimentation techniques, computer hardware, and programming software. The result of a simulation may be delivered in several ways, from numerical results, through graphs of the simulated run, to a visualization of the simulation. The vision of an in-silico experiment mimicking an in-vitro or in-vivo experiment as it is viewed under a microscope is appealing but technically demanding and computationally intensive. Here, we report “Cell Studio,” a generic, hybrid platform to simulate an immune microenvironment with biological and biophysical rules. We use game engines—generic programs for game creation which offer ready-made assets and tools—to create a visualized, interactive 3D simulation. We also utilize a scalable architecture that delegates the computational load to a server. The user may view the simulation, move the “camera” around, stop, fast-forward, and rewind it and inject soluble molecules into the extracellular medium at any point in time. During simulation, graphs are created in real time for a broad view of system-wide processes. The model is parametrized using a user-friendly Graphical User Interface (GUI). We show a simple validation simulation and compare its results with those from a “classical” simulation, validated against a “wet” experiment. We believe that interactive, real-time 3D visualization may aid in generating insights from the model and encourage intuition about the immunological scenario.

Osteoporosis is characterized by reduction in trabecular bone in conjunction with increased marrow cell adiposity. While these changes occur within weeks, monitoring of treatment efficacy as performed by DEXA is sensitive only to long-term changes. MRI is sensitive to bone marrow changes but is less affordable. In a recent study, we have shown that a stray-field NMR can monitor bone marrow cellular changes that are related to osteoporosis. Objectives. To demonstrate sensitivity of a low-field tabletop NMR scanner to bone marrow dynamics following hormonal treatment in rats. Methods. Two-month-old female rats (n=36) were ovariectomized (OVX) and dosed for the ensuing 3 or 5 weeks with 20 mg/kg of PTH(1-34). Hind limbs femurs and tibiae were isolated and underwent ex vivo microradiography and histology and NMR relaxometry at 6 weeks (preventive experiment) and 11 weeks (therapeutic treatment experiment) after OVX. Results. OVX rats developed osteoporotic changes including adipogenic marrow compared to Sham and PTH treated rats. T2 and ADC NMR relaxation coefficients were found to correlate with marrow composition. Conclusions. This study suggests that stray-field NMR, an affordable method that is sensitive to the rapid cellular changes in bone marrow, may have a clinical value in monitoring hormonal treatment for osteoporosis.

Here we present the successful translation of a pore size distribution (PSD) estimation method from NMR to MRI. This approach is validated using a well-characterized MRI phantom consisting of stacked glass capillary arrays (GCA) having different diameters. By employing a double pulsed-field gradient (d-PFG) MRI sequence, this method overcomes several important theoretical and experimental limitations of previous single-PFG (s-PFG) based MRI methods by allowing the relative diffusion gradients’ direction to vary. This feature adds an essential second dimension in the parameters space, which can potentially improve the reliability and stability of the PSD estimation. To infer PSDs from the MRI data in each voxel an inverse linear problem is solved in conjunction with the multiple correlation function (MCF) framework, which can account for arbitrary experimental parameters (e.g., long diffusion pulses). This scheme makes no a priori assumptions about the functional form of the underlying PSD. Creative use of region of interest (ROI) analysis allows us to create different underlying PSDs using the same GCA MRI phantom. We show that an s-PFG experiment on the GCA phantom fails to accurately reconstruct the size distribution, thus demonstrating the superiority of the d-PFG experiment. In addition, signal simulations corrupted by different noise levels were used to generate continuous and complex PSDs, which were then successfully reconstructed. Finally, owing to the reduced q - or b - values required to measure microscopic PSDs via d-PFG MRI, this method will be better suited to biomedical and clinical applications, in which gradient strength of scanners is limited.

Unilateral NMR devices are valuable tools used to study non-invasively arbitrarily-sized objects. They have been utilized in various applications, including non-destructive testing and well logging. However, measurements with such scanners are characterized by a low sensitivity, which is mainly the result of the low and inhomogeneous magnetic field B0. The resulting poor signal to noise ratio (SNR) is a prominent limitation, as it deteriorates the accuracy of data analysis. Improving the SNR is typically done by the use of averaging repetitions that result in too long scan times. This work presents a statistical signal-processing method that can improve the sensitivity of a Carr–Purcell–Meiboom–Gill (CPMG)-like sequence for measurements of transverse-relaxation with unilateral scanners. The method improves the extraction of the decay curve from the noisy data. This is done by exploiting the redundancy in the acquired signal and by the use of the noise characteristics, which are both incorporated into a weighted least-squares estimation approach. This technique is especially effective in applications where RF shielding is not in use, and the measurements are corrupted by dominant non-white noise. The method performance was evaluated with a series of CPMG-like measurements applied on two samples. Decay curves were extracted from each measurement with the proposed method and were compared to a conventional extraction of the decay curve. All measurements showed a significant improvement in the accuracy of estimation of the decaying signal. Thus, the improvement in the sensitivity can be translated into a reduction in the acquisition times (by reducing the need in averaging repetitions) or to a more accurate fitting process of the traverse relaxation distribution.

It is biologically and clinically important to understand and explain the functional properties of cartilage, such as its load bearing and lubricating ability, in terms of the structure, organization, components and their interactions. Our approach tries to explain functional material properties of these tissues as arising from polymeric interactions between and among the different molecular constituents within the tissues at different hierarchical lengthscales. We treat the tissue effectively as a complex molecular composite containing highly charged polysaccharide microgels trapped within a fine collagen meshwork. We have been developing a multi-scale experimental and theoretical framework to explain key material properties of cartilage by studying those of its constituents and the interactions among them at a variety of length and time scales. We use this approach to address important biological questions. One novel application we highlight here is the use of non-invasive magnetic resonance imaging (MRI) methods to characterize different components and compartments within cartilage and the different water environments associated with each one, in an attempt to provide a comprehensive picture of the mechanical/chemical state of cartilage.

Unilateral NMR devices are used in various applications including non-destructive testing and well logging, but are not used routinely for imaging. This is mainly due to the inhomogeneous magnetic field (B0) in these scanners. This inhomogeneity results in low sensitivity and further forces the use of the slow single point imaging scan scheme. Improving the measurement sensitivity is therefore an important factor as it can improve image quality and reduce imaging times. Short imaging times can facilitate the use of this affordable and portable technology for various imaging applications. This work presents a statistical signal-processing method, designed to fit the unique characteristics of imaging with a unilateral device. The method improves the imaging capabilities by improving the extraction of image information from the noisy data. This is done by the use of redundancy in the acquired MR signal and by the use of the noise characteristics. Both types of data were incorporated into a Weighted Least Squares estimation approach. The method performance was evaluated with a series of imaging acquisitions applied on phantoms. Images were extracted from each measurement with the proposed method and were compared to the conventional image reconstruction. All measurements showed a significant improvement in image quality based on the MSE criterion – with respect to gold standard reference images. An integration of this method with further improvements may lead to a prominent reduction in imaging times aiding the use of such scanners in imaging application.

Changes in the diffusion weighted MRI (DWI) signal were observed to be correlated with neuronal activity during chemically induced brain activity, epileptic seizures, or visual stimulation. These changes suggest a possible reduction in water displacement that accompanies neuronal activity, but were possibly affected by other physiological mechanisms such as blood oxygenation level and blood flow. We developed an imaging experiment of an excised and vital newborn rat spinal cord to examine the effect of neuronal function on the displacement of water molecules as measured by DWI signal. This approach provides a DWI experiment of a vital mammalian CNS tissue in the absence of some of the systemic sources of noise. We detected a significant and reproducible drop with an average value of 19.5 ± 1.6% (mean ± SE) upon activation. The drop repeated itself in three orthogonal directions. ADC values corresponded to an oblate anisotropy. This result was validated by high resolution DWI of a fixed tissue, imaged with an ultra-high field MRI. The results support our working hypothesis that water displacement is affected by neuronal activation. These results further imply that water displacement might serve as a potential marker for brain function, and that, although commonly viewed as wholly electrochemical, neuronal activity includes a significant mechanical dimension that affects water displacement.

To provide a biophysical basis to estimate the effect of cytoplasmic flow in neurons, and assess their contribution to the drop in the Apparent Diffusion Coefficient (ADC) in a nerve tissue following extreme conditions, such as brain injury and epileptic seizures.Three mechanisms are treated using the relevant physics of hydrodynamics and electrostatics: cargo induced streaming, electroosmosis, and membrane swelling.We begin by discussing the lack of experimental evidence on the necessary velocities required to influence the Magnetic Resonance (MR) experiments. This is followed by demonstrating that cargo induced streaming, a widely known phenomenon in plant cells, has a minor effect on the ADC in neurons. Subsequently, we suggest and analyze two additional mechanisms that may induce fluid displacement in neurons, and are related to the electrical activity: electroosmosis and membrane swelling.Although these mechanisms may induce interesting fluid displacements, these cannot explain the significant drop in the ADC. We conclude by outlining the criteria that any future mechanism should meet to have an influence on standard diffusion-MR measurements. Magn Reson Med 78:746-753, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Osteoporosis is characterized by a decrease in bone mineral density (BMD). A preliminary stage of the disease is progressive bone marrow adiposity, caused by imbalance between osteogenesis and adipogenesis in the marrow. Detection of osteoporosis relies on the quantification of BMD with techniques such as dual-energy X-ray absorptiometry. This work aimed to detect bone marrow changes in an experimental model of osteopenia using a low-field tabletop NMR scanner.An experiment was performed on 32 female rats, 3 months old, 16 of which were ovariectomized (OVX) and 16 were sham-operated (sham). The femur and tibia from both hind limbs were isolated and underwent ex vivo NMR scans at four time points after the OVX and sham operations. NMR scans were complemented by BMD measurements and histology.Significant changes in the bone marrow of ovariectomized rats, relative to sham operated rats, were observed after 3.5 and 4.5 months. Bone marrow adiposity was detected by significant changes in TThis study suggests a potential detection of changes to the bone marrow using a tabletop NMR device. Clinical translation may facilitate screening, early detection of bone weakening as a result of estrogen withdrawal, and monitoring of treatment efficacy. Magn Reson Med 78:860-870, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

The pulsed-field gradient (PFG) MR experiment enables one to measure particle displacements, velocities, and even higher moments of complex fluid motions. In diffusion-weighted MRI (DWI) in living tissue, where the PFG MRI experiment is used to measure diffusion, Brownian motion is assumed to dominate the displacements causing the observed signal loss. However, motions of water molecules caused by various active biological processes occurring at different length and time scales may also cause additional dephasing of magnetization and signal loss. To help understand their relative effects on the DWI signal attenuation, we used an integrated experimental and theoretical framework: a Rheo-NMR, which served as an experimental model system to precisely prescribe a microscopic velocity distribution; and a mathematical model that relates the DW signal intensity in the Rheo-NMR to experimental parameters that characterize the impressed velocity field. A technical innovation reported here is our use of ‘natural’ (in this case, polar) coordinates both to simplify the description the fluid motion within the Couette cell of the Rheo-NMR, as well as to acquire and reconstruct magnitude and phase MR images obtained within it. We use this integrated model system to demonstrate how shear flows appears as pseudo-diffusion in magnitude DW MR signals obtained using PFG spin-echo (PGSE) NMR and MRI sequences. Our results lead us to reinterpret the possible causes of signal loss in DWI in vivo, in particular to revise and generalize the previous notion of intra-voxel incoherent motion (IVIM) in order to describe activity driven flows that appear as pseudo-diffusion over multiple length and time scales in living tissues.

Diffusion tensor magnetic resonance imaging (DT-MRI) is capable of providing quantitative insights into tissue microstructure in the brain. An important piece of information offered by DT-MRI is the directional preference of diffusing water molecules within a voxel. Building upon this local directional information, DT-MRI tractography attempts to construct global connectivity of white matter tracts. The interplay between local directional information and global structural information is crucial in understanding changes in tissue microstructure as well as in white matter tracts. To this end, the right circular cone of uncertainty was proposed by Basser as a local measure of tract dispersion. Recent experimental observations by Jeong et al. and Lazar et al. that the cones of uncertainty in the brain are mostly elliptical motivate the present study to investigate analytical approaches to quantify their findings. Two analytical approaches for constructing the elliptical cone of uncertainty, based on the first-order matrix perturbation and the error propagation method via diffusion tensor representations, are presented and their theoretical equivalence is established. We propose two normalized measures, circumferential and areal, to quantify the uncertainty of the major eigenvector of the diffusion tensor. We also describe a new technique of visualizing the cone of uncertainty in 3-D.

In MRI, macroscopic boundaries lead to a diffusion-related increase in signal intensity near them—an effect commonly referred to as edge-enhancement. In diffusion-weighted imaging protocols where the signal attenuation due to diffusion results predominantly from the application of magnetic field gradients, edge-enhancement will depend on the orientation of these diffusion gradients. The resulting diffusion anisotropy can be exploited to map the direction normal to the macroscopic boundary. Simulations suggest that the hypothesized anisotropy may be within observable limits even when the voxel contains no boundary itself—hence, the name remote-anisotropy. Moreover, for certain experimental parameters there may be significant phase cancellations within the voxel that may lead to an edge detraction effect. When this is avoided, the eigenvector corresponding to the smallest eigenvalue of the diffusion tensor obtained from diffusion-tensor imaging can be used to create surface-normal maps conveniently. Experiments performed on simple geometric constructs as well as real tissue demonstrate the feasibility of using the edge-enhancement mechanism to map orientations orthogonal to macroscopic surfaces, which may be used to assess the integrity of tissue and organ boundaries noninvasively.

A double Pulsed Gradient Spin Echo (d-PGSE) MR experiment was used to measure and assess the degree of local diffusion anisotropy in brain gray matter, and in a novel "gray matter" phantom that consists of randomly oriented tubes filled with water. In both samples, isotropic diffusion was observed at a macroscopic scale while anisotropic diffusion was observed at a microscopic scale, however, the nature of the resulting echo attenuation profiles were qualitatively different. Gray matter, which contains multiple cell types and fibers, exhibits a more complicated echo attenuation profile than the phantom. Since microscopic anisotropy was observed in both samples in the low q regime comparable to that achievable in clinical scanner, it may offer a new potential contrast mechanism for characterizing gray matter microstructure in medical and biological applications.

Understanding how immune tolerance is induced and maintained is critical for our approach to immune-related diseases. Ecoimmunity is a new theory that views the immune system-tissue interaction as a co-adapting predator-prey system. Ecoimmunity suggests that tissues adapt to the selective immune pressure during ontogeny and throughout life. Therefore, immune tolerance towards 'self' represents a symmetric. balance between the propensity of the immune system to prey on 'self' cells, and the tissue's specific capacity to undergo phenotypic adaptations in order to avoid destructive immune interaction. According to this theory, we hypothesized that tissues of adult immune-deficient mice, which are not exposed to selective immune pressure, will not withstand immune activity and will therefore display higher susceptibility to graft rejection. To test this prediction, C57B1/6 wild type female mice were rendered diabetic by streptozotocin and transplanted with syngeneic pancreatic islets isolated from either immune-deficient C57B1/6 SCID or wild type females. Remarkably, recipients of islet grafts from immune-deficient syngeneic donors displayed significantly impaired glucose homeostasis compared to mice transplanted with islets of wild type donors (p

mechanisms, and the capacity of adapted tissue cells to avoid predation. This balance evolves during ontogeny, in parallel to immune adaptations, embryonic tissue cells adapt their phenotype to the corresponding immune activity by developing the ability to escape or modulate damaging local immune responses. This phenotypic plasticity of tissue cells is directed by epigenetic selection of gene expression pattern and cellular phenotype amidst an ongoing immune pressure. Thus, whereas some immune cells prey predominantly on pathogens and infected cells, self-reactive cells continuously prey on incompetent tissue cells that fail to express the adapted phenotype and resist predation. This model uses ecological generalization to reconcile current contradictory observations as well as classical enigmas related to both autoimmunity and to tolerance toward foreign tissues. Finally, it provides empirical predictions and alternative strategies toward clinical challenges.

The epidemic nature of type 2 diabetes mellitus (T2DM), along with the downsides of current treatments, has raised the need for therapeutic alternatives.We studied normo-glycemic and high-fat diet (HFD), induced insulin-resistant Wistar Han rats for 2 to 3weeks. Rats received peripheral electrical stimulation (PES) treatment (2Hz/16Hz bursts, 10mA) in their hind limbs for 3min, 3 times per week. Glucose tolerance was evaluated by using a glucose tolerance test at the beginning and again at the end of the study. The effect of an acute PES treatment on metabolic rates of glucose appearance and turnover was measured by using the hyperinsulinemic-euglycemic clamp (HEGC) test.Repeated PES treatment significantly inhibited the progression of glucose intolerance in normal and insulin-resistant rats and prevented HFD-induced gains in body weight and fat mass. Acute treatment induced a prolonged effect on glucose turnover, as evaluated by the HEGC test. Increased hepatic glucose output was observed during the basal state (P0.005). Under hyperinsulinemic conditions, PES improved tissue sensitivity to insulin (41.1%, P0.01), improved suppression of hepatic glucose production (58.9±4.4% vs. 87.1±4.4%, P0.02) and significantly elevated the rate of glycogenesis (P0.01), compared with controls.The present study indicates that a noninvasive PES treatment of very short duration is sufficiently potent to stimulate glucose utilization and improve hepatic insulin sensitivity in rats. Repeated PES treatment may have a beneficial effect on HFD-induced adiposity and control of body weight.

Recently, several new functional (f)MRI contrast mechanisms including diffusion, phase imaging, proton density, etc. have been proposed to measure neuronal activity more directly and accurately than blood-oxygen-level dependent (BOLD) fMRI. However, these approaches have proved difficult to reproduce, mainly because of the dearth of reliable and robust test systems to vet and validate them. Here we describe the development and testing of such a test bed for non-BOLD fMRI. Organotypic cortical cultures were used as a stable and reproducible biological model of neuronal activity that shows spontaneous activity similar to that of in vivo brain cortex without any hemodynamic confounds. An open-access, single-sided magnetic resonance (MR) "profiler" consisting of four permanent magnets with magnetic field of 0.32 T was used in this study to perform MR acquisition. A fluorescence microscope with long working distance objective was mounted on the top of a custom-designed chamber that keeps the organotypic culture vital, and the MR system was mounted on the bottom of the chamber to achieve real-time simultaneous calcium fluorescence optical imaging and MR acquisition on the same specimen. In this study, the reliability and performance of the proposed test bed were demonstrated by a conventional CPMG MR sequence acquired simultaneously with calcium imaging, which is a well-characterized measurement of neuronal activity. This experimental design will make it possible to correlate directly the other candidate functional MR signals to the optical indicia of neuronal activity in the future.

The trigger that leads to the pathogenesis of type 1 diabetes is currently unknown. It is well established that the pathophysiology of the disease is biphasic. In the first stage, leukocytes infiltrate the pancreatic islets in a response that does not cause damage. In the second phase, which occurs only in diabetes-prone individuals and strains, autoreactive T cells acquire aggressive potential and destroy the majority of the pancreatic islets. Rodents and humans exhibit a physiological ripple of apoptotic beta-cell death shortly after birth, which induces an adaptive autoimmune response towards islet-antigens, both in diabetes-prone non-obese diabetic (NOD) mice and in mice that do not develop diabetes. Here, we propose that the early T cell-mediated autoimmune response towards islet-antigens is physiological, purposeful and beneficial.

Closed head injury often has a devastating outcome, partly because the insult, like other injuries to the central nervous system (CNS), triggers self-destructive processes. During studies of the response to other CNS insults, it was unexpectedly discovered that the immune system, if well controlled, provides protection against self-destructive activities. Here we show that in mice with closed head injury, the immune system plays a key role in the spontaneous recovery. Strain-related differences were observed in the ability to harness a T cell-dependent protective mechanism against the effects of the injury. We further show that the trauma-induced deficit could be reduced, both functionally and anatomically, by post-traumatic vaccination with Cop-1, a synthetic copolymer used to treat patients with multiple sclerosis and found (using a different treatment protocol) to effectively counteract the loss of neurons caused by axonal injury or glutamate-induced toxicity. We suggest that a compound such as Cop-1 can be safely developed as a therapeutic vaccine to boost the body's immune repair mechanisms, thereby providing multifactorial protection against the consequences of brain trauma.

The function of the adaptive immune response against exogenous (non-self) agents is to help the innate arm of the immune system (represented by phagocytic cells) to fight and eliminate these agents. We suggest that the body also protects itself against potentially harmful self components using mechanisms similar to those used for fighting and eliminating non-self agents, and that the protective immune activity against self-components competes with the activity of self-destructive compounds. Tolerance to self is thus not a lack of response to self, but the ability to tolerate an active defense response to self without developing an autoimmune disease.

Human skin undergoes morphological and biochemical changes as a result of chronological aging and exposure to solar ultraviolet irradiation (photoaging). Noninvasive detection of these changes may aid in the prevention and treatment of both types of aging. This article presents a noninvasive method for the evaluation of aging skin with a unilateral stray field NMR scanner. These portable and inexpensive scanners may be suitable for in-depth skin characterization. In vivo profiles of sun-protected and sun-exposed skin from the forearms of female subjects of different ages (n = 9) were measured. Skin biopsies for histopathological examination were used as reference. T2 analysis with a bi-exponential decay model was applied and the extracted parameters were examined as markers for dermal aging. In the upper reticular dermis, a significant increase in the fraction of the slow T2 component and in the T2 value itself was found to correlate with chronological aging. For most subjects, there was an additional increase in the values of the slow T2 component and the T2 values from the sun-exposed forearm, superimposed on that measured for the sun-protected forearm. These results are in agreement with the decline in collagen content and the increase in free water content with aging. The results suggest that such a technique can be used as a tool for the assessment of aging, and that bi-exponential fitting can produce sensitive fingerprint parameters for the dermal alterations that occur during aging.

Pulsed field gradient (PFG) diffusion NMR experiments are sensitive to restricted diffusion within porous media and can thus reveal essential microstructural information about the confining geometry. Optimal design methods of inverse problems are designed to select preferred experimental settings to improve parameter estimation quality. However, in pore size distribution (PSD) estimation using NMR methods as in other ill-posed problems, optimal design strategies and criteria are scarce. We formulate here a new optimization framework for ill-posed problems. This framework is suitable for optimizing PFG experiments for probing geometries that are solvable by the Multiple Correlation Function approach. The framework is based on a heuristic methodology designed to select experimental sets which balance between lowering the inherent ill-posedness and increasing the NMR signal intensity. This method also selects favorable discrete pore sizes used for PSD estimation. Numerical simulations performed demonstrate that using this framework greatly improves the sensitivity of PFG experimental sets to the pores’ sizes. The optimization also sheds light on significant features of the preferred experimental sets. Increasing the gradient strength and varying multiple experimental parameters is found to be preferable for reducing the ill-posedness. We further evaluate the amount of pore size information that can be obtained by wisely selecting the duration of the diffusion and mixing times. Finally, we discuss the ramification of using single PFG or double PFG sequences for PSD estimation. In conclusion, the above optimization method can serve as a useful tool for experimenters interested in quantifying PSDs of different specimens. Moreover, the applicability of the suggested optimization framework extends far beyond the field of PSD estimation in diffusion NMR, and reaches design of sampling schemes of other ill-posed problems.

The Future Scientists' and Inventors' Program at Tel Aviv University was initiated by the Israeli president, Mr. Shimon Peres, in response to the decline in the number of students applying to scientific and technological studies. The program is tailored for the proficient nourishment of gifted teenagers. Our vision is to create a scientific community whose members are committed, skillful and happy to collaborate and share. Our courses go beyond mere enrichment for leisure or acquisition of academic merits. We offer a worthwhile purpose for the so-far unchallenged youth. The program demands academic standards, hard work, and is designed to take young teenagers through a journey of revelation, following the historical process of scientific thought. Instead of formal lectures, our lessons assume the form of discussion, during which the students are encouraged to take part in the development of scientific discoveries. The students search for questions, experience the excitement of discovery as well as its difficulties and limitations, and deeply understand the basics of the material. After four years of running the program, we achieved great results: our young students have passed difficult undergraduate exams with exceptionally high grades, and our senior students have already started partaking in actual academic research. Our program demonstrates a method for maximizing gifted children's potential, and arousing their passion for scientific work. In addition, a young community of scientists is formed within the program, and its members develop the skills to work together, consult peers and are positively committed to high quality scientific research.

Spinal cord injury results in a massive loss of neurons, and thus of function. We recently reported that passive transfer of autoimmune T cells directed against myelin-associated antigens provides acutely damaged spinal cords with effective neuroprotection. The therapeutic time window for the passive transfer of T cells was found to be at least 1 week. Here we show that posttraumatic T cell–based active vaccination is also neuroprotective. Immunization with myelin-associated antigens such as myelin basic protein (MBP) significantly promoted recovery after spinal cord contusion injury in the rat model. To reduce the risk of autoimmune disease while retaining the benefit of the immunization, we vaccinated the rats immediately after severe incomplete spinal cord injury with MBP-derived altered peptide ligands. Immunization with these peptides resulted in significant protection from neuronal loss and thus in a reduced extent of paralysis, assessed by an open-field behavioral test. Retrograde labeling of the rubrospinal tracts and magnetic resonance imaging supported the behavioral results. Further optimization of nonpathogenic myelin-derived peptides can be expected to lead the way to the development of an effective therapeutic vaccination protocol as a strategy for the prevention of total paralysis after incomplete spinal cord injury.

Background Regulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM). Methods Twelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation. Results We found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded. Conclusions These results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation. Trial registration ClinicalTrials.gov NCT02727790

Spinal cord injury and its devastating consequences are the subject of intensive research aimed at reversing or at least minimizing functional loss. Research efforts focus on either attenuating the post-injury spread of damage (secondary degeneration) or inducing some regeneration. In most of these studies, as well as in clinical situations, evaluation of the state of the injured spinal cord poses a serious difficulty. To address this problem, we carried out a diffusion-weighted MRI experiment and developed an objective routine for quantifying anisotropy in injured rat spinal cords. Rats were subjected to a contusive injury of the spinal cord caused by a controlled weight drop. Untreated control rats were compared with rats treated with T cells specific to the central nervous system self-antigen myelin basic protein, a form of therapy recently shown to be neuroprotective. After the rats were killed their excised spinal cords were fixed in formalin and imaged by multislice spin echo MRI, using two orthogonal diffusion gradients. Apparent diffusion coefficient (ADC) values and anisotropy ratio (AI) maps were extracted on a pixel-by-pixel basis. The calculated sum of AI values (SAI) for each slice was defined as a parameter representing the total amount of anisotropy. The mean-AI and SAI values increased gradually with the distance from the site of the lesion. At the site itself, the mean-AI and SAI values were significantly higher in the spinal cords of the treated animals than in the controls (P = 0.047, P = 0.028, respectively). These values were consistent with the score of functional locomotion. The difference was also manifested in the AI maps, which revealed well-organized neural structure in the treated rats but not in the controls. The SAI values, AI histograms, and AI maps proved to be useful parameters for quantifying injury and recovery in an injured spinal cord. These results encourage the development of diffusion anisotropy MRI as a helpful approach for quantifying the extent of secondary degeneration and measuring recovery after spinal cord injury. Magn Reson Med 45:1-9, 2001.

Pore size distribution (PSD) within porous biomaterials is an important microstructural feature for assessing their biocompatibility, longevity and drug release kinetics. Scanning electron microscopy (SEM) is the most common method used to obtain the PSD of soft biomaterials. The method is highly invasive and user dependent, since it requires fracturing of the sample and then considers only the small portion that the user had acquired in the image. In the current study we present a novel nuclear magnetic resonance (NMR) method as an alternative method for estimation of PSD in soft porous materials. This noninvasive 3-D diffusion NMR method considers the entire volume of the specimen and eliminates the user's need to choose a specific field of view. Moreover, NMR does not involve exposure to ionizing radiation and can potentially have preclinical and clinical uses. The method was applied on four porous 50/50 poly(dl-lactic-co-glycolic acid) bioresorbable films with different porosities, which were created using the freeze-drying of inverted emulsions technique. We show that the proposed NMR method is able to address the main limitations associated with SEM-based PSD estimations by being non-destructive, depicting the full volume of the specimens and not being dependent on the magnification factor. Upon comparison, both methods yielded a similar PSD in the smaller pore size range (1-25μm), while the NMR-based method provided additional information on the larger pores (25-50μm).