Following spinal cord injury, diffusion MRI (DWI) has been shown to detect injury and functionally significant neuroprotection following treatment that otherwise would go undetected with conventional MRI. The underlying histologic correlates to directional apparent diffusion coefficients (ADC) obtained with DWI have not been determined, however, and we address this issue by directly correlating ADC values with corresponding axon morphometry in the normal rat cervical spinal cord. ADC values transverse (perpendicular) and longitudinal (parallel) to axons both correlate with axon counts, however each directional ADC reflects distinct histologic parameters. DWI may therefore be capable of providing specific histologic data regarding the integrity of white matter.

During wakefulness and in absence of performing tasks or sensory processing, the default-mode network (DMN), an intrinsic central nervous system (CNS) network, is in an active state. Non-human primate and human CNS imaging studies have identified the DMN in these two species. Clinical imaging studies have shown that the pattern of activity within the DMN is often modulated in various disease states (e.g., Alzheimer's, schizophrenia or chronic pain). However, whether the DMN exists in awake rodents has not been characterized. The current data provides evidence that awake rodents also possess ‘DMN-like’ functional connectivity, but only subsequent to habituation to what is initially a novel magnetic resonance imaging (MRI) environment as well as physical restraint. Specifically, the habituation process spanned across four separate scanning sessions (Day 2, 4, 6 and 8). At Day 8, significant (p<0.05) functional connectivity was observed amongst structures such as the anterior cingulate (seed region), retrosplenial, parietal, and hippocampal cortices. Prior to habituation (Day 2), functional connectivity was only detected (p<0.05) amongst CNS structures known to mediate anxiety (i.e., anterior cingulate (seed region), posterior hypothalamic area, amygdala and parabracial nucleus). In relating functional connectivity between cingulate-default-mode and cingulate-anxiety structures across Days 2-8, a significant inverse relationship (r = −0.65, p = 0.0004) was observed between these two functional interactions such that increased cingulate-DMN connectivity corresponded to decreased cingulate anxiety network connectivity. This investigation demonstrates that the cingulate is an important component of both the rodent DMN-like and anxiety networks.

Water diffusion in tissues is generally restricted and often anisotropic. Neural tissue is of particular interest, since it is well known that injury alters diffusion in a characteristic manner. Both Monte Carlo simulations and approximate analytical models have previously been reported in attempts to predict water diffusion behavior in the central nervous system. These methods have relied on axonal models, which assume simple geometries (e.g., ellipsoids, cylinders, and square prisms) and ignore the thickness of the myelin sheath. The current work describes a method for generating models using synthetic images. The computations are based on a 3D finite difference (FD) approximation of the diffusion equation. The method was validated with known analytic solutions for diffusion in a cylindrical pore and in a hexagonal array of cylinders. Therefore, it is envisioned that, by exploiting histologic images of neuronal tissues as input model, current method allows investigating the water diffusion behavior inside biological tissues and potentially as- Diffusion-sensitized MRI provides a means of probing the architectural features of structures that are much smaller than a voxel. In the CNS the degree of diffusion anisotropy is sensitive to local differences in nerve fiber orientation (1-3). Various mechanisms have been proposed to explain changes in the apparent diffusion coefficient (ADC) during pathologic states. For example, in the study of cat brain, cellular swelling in the initial stages of ischemia may account for the decreased ADC since water protons originally in the faster-diffusing extracellular space migrate into the intracellular space (4) In addition, the cellular swelling reduces the extracellular space and, thus, increases the tortuosity of the diffusion paths (5). In the rat spinal cord diffusion was found to be anisotropic (6 -8). Spinal cord injury resulted in reduced diffusion anisotropy (9) which has also been attributed to axonal swelling or loss and inflammation (10,11). Changes in the myelin sheath may also affect the ADC. For example, the demyelination resulting from mechanical trauma (12) and the varying levels of remyelination during recovery (13) may cause changes in the permeability of the barrier between the intracellular and extracellular compartments. Furthermore, regenerating and sprouting axon fibers are typically tortuous, small, and unmyelinated (14). The effect of these tissue parameters on the ADC may potentially be exploited to assess the extent of neural damage and repair in vivo. Reduced diffusion anisotropy in multiple sclerosis lesions have also been attributed to loss of axons and myelin (15,16). Diffusion-weighted imaging may thus potentially provide insight into the pathophysiologic changes in MS lesions if the relationship between morphology and the diffusion-sensitized MR signal are better understood.Previous attempts to predict the effects of morphologic changes have relied on Monte Carlo (MC) simulations (11,17) or approximate analytic expressions (18). Exact solutions...

Non-alcoholic fatty liver disease (NAFLD) has been on a global rise. While animal models have rendered valuable insights to the pathogenesis of NAFLD, discrepancy with patient data still exists. Since non-alcoholic steatohepatitis (NASH) involves chronic inflammation, and CD4 + T cell infiltration of the liver is characteristic of NASH patients, we established and characterized a humanized mouse model to identify humanspecific immune response(s) associated with NAFLD progression. Immunodeficient mice engrafted with human immune cells (HIL mice) were fed with high fat and high calorie (HFHC) or chow diet for 20 weeks. Liver histology and immune profile of HIL mice were analyzed and compared with patient data. HIL mice on HFHC diet developed steatosis, inflammation and fibrosis of the liver. Human CD4 + central and effector memory T cells increased within the liver and in the peripheral blood of our HIL mice, accompanied by marked up-regulation of pro-inflammatory cytokines (IL-17A and IFNγ). In vivo depletion of human CD4 + T cells in HIL mice reduced liver inflammation and fibrosis, but not steatosis. Our results highlight CD4 + memory T cell subsets as important drivers of NAFLD progression from steatosis to fibrosis and provides a humanized mouse model for pre-clinical evaluation of potential therapeutics.

Studies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB 2 receptor activation have been largely derived from the use of receptor-selective ligands. Here, we report the identification of A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], a potent and selective CB 2 agonist as characterized in in vitro pharmacological assays and in in vivo models of pain and central nervous system (CNS) behavior models. In radioligand binding assays, A-836339 displays high affinities at CB 2 receptors and selectivity over CB 1 receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB 2 and selectivity over CB 1 receptors in recombinant fluorescence imaging plate reader and cyclase functional assays. In addition A-836339 exhibits a profile devoid of significant affinity at other G-protein-coupled receptors and ion channels. A-836339 was characterized extensively in various animal pain models. In the complete Freund's adjuvant model of inflammatory pain, A-836339 exhibits a potent CB 2 receptor-mediated antihyperalgesic effect that is independent of CB 1 or -opioid receptors.A-836339 has also demonstrated efficacies in the chronic constrain injury (CCI) model of neuropathic pain, skin incision, and capsaicin-induced secondary mechanical hyperalgesia models. Furthermore, no tolerance was developed in the CCI model after subchronic treatment with A-836339 for 5 days. In assessing CNS effects, A-836339 exhibited a CB 1 receptor-mediated decrease of spontaneous locomotor activities at a higher dose, a finding consistent with the CNS activation pattern observed by pharmacological magnetic resonance imaging. These data demonstrate that A-836339 is a useful tool for use of studying CB 2 receptor pharmacology and for investigation of the role of CB 2 receptor modulation for treatment of pain in preclinical animal models.It is estimated that as high as 50% of the population will experience chronic pain during their lifetime, and the prevalence is likely to rise with the continued aging of the population (Markman and Philip, 2007). As a consequence, there exists an ever-growing demand for new therapies to provide safe and effective pain management. Despite intensive research to identify novel therapeutic approaches, there have been few major advances in pain therapy over the past sev-

A simple method for birdcage coil design (high pass, low pass, and band pass) is presented. Rather than iteratively approaching the Larmor resonant frequency with known capacitances and calculated inductances, a more versatile approach to birdcage coil design is developed and validated, in which the necessary capacitances are calculated using a desired current pattern, a calculated inductance, and a predetermined resonant frequency. In order to expedite coil design for experienced and novice coil builders, a computer program (BirdcageBuilder) is also implemented based on this method. Experimental results show that the calculated capacitances and actual capacitances for several existing birdcage coils are in good agreement.

Background and purpose: Activation of cannabinoid CB 1 and/or CB 2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB 2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB 1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB 1 from CB 2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB 1 / CB 2 (A-834735) and selective CB 2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB 1 (rimonabant) or CB 2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB 1 /CB 2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB 1 receptor density binding maps. Pretreatment with a CB 1 antagonist but not with a CB 2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB 1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB 2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB 1 and CB 2

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