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The diversity of the diprotodontids provides an excellent opportunity to study how a basic marsupial cortical plan has been modified for the needs of the mammals living in different habitats. Very little is known about the connections of the cerebral cortex with the deep brain structures (basal ganglia and thalamus) in this evolutionarily significant group of mammals. In this study, we performed mapping of brain regions and connections in a diprotodontid marsupial from data obtained from an excised brain scanned in high-field (9.4 T) microstructural magnetic resonance imaging (MRI) instrument. The analysis was based on two MRI methodologies. First, high-resolution structural scans were used to map MRI visible brain regions from T1w and T2w images. Second, extensive diffusion tensor imaging (DTI) data were obtained to elucidate connectivity between brain areas using deterministic diffusion tracking of neuronal brain fibers. From the data, we were able to identify corticostriate connections between the frontal association and dorsomedial isocortex and the head of the caudate, and between the lateral somatosensory cortex and the putamen. We were also able to follow the olfactory and limbic connections by tracing fibers in the fornix, cingulum, intrabulbar part of the anterior commissure, and lateral olfactory tract. There was segregation of fibers in the anterior commissure such that olfactory connections passed through the rostroventral part and successively more dorsal cortical areas connected through more dorsal parts of the commissure. Our findings confirm a common pattern of cortical connectivity in therian mammals, even where brain expansion has occurred independently in diverse groups.

The leukodystrophy Hypomyelination with Brainstem and Spinal cord involvement and Leg spasticity (HBSL) is caused by recessive mutations of the DARS1 gene, which encodes the cytoplasmic aspartyl-tRNA synthetase. HBSL is a spectrum disorder with disease onset usually during early childhood and no available treatment options. Patients display regression of previously acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Gene-function studies in mice revealed that homozygous Dars1 deletion is embryonically lethal, suggesting that successful modelling of HBSL requires the generation of disease-causing genocopies in mice. In this study, we introduced the pathogenic DARS1M256L mutation located on exon nine of the murine Dars1 locus. Despite causing severe illness in humans, homozygous Dars1M256L mice were only mildly affected. To exacerbate HBSL symptoms, we bred Dars1M256L mice with Dars1-null ‘enhancer’ mice. The Dars1M256L/− offspring displayed increased embryonic lethality, severe developmental delay, reduced body weight and size, hydrocephalus, anophthalmia, and vacuolization of the white matter. Remarkably, the Dars1M256L/− genotype affected energy metabolism and peripheral organs more profoundly than the nervous system and resulted in reduced body fat, increased respiratory exchange ratio, reduced liver steatosis, and reduced hypocellularity of the bone marrow. In summary, homozygous Dars1M256L and compound heterozygous Dars1M256L/− mutation genotypes recapitulate some aspects of HBSL and primarily manifest in developmental delay as well as metabolic and peripheral changes. These aspects of the disease might have been overlooked in HBSL patients with severe neurological deficits but could be included in the differential diagnosis of HBSL in the future.

Functional integration of implanted biomaterials and bioengineered tissues in vivo requires effective and timely vascular ingrowth. While many vascularization strategies rely on delivery of angiogenic growth factors or endothelial cells to promote vascular ingrowth, the effect of physical and architectural features of biomaterials on the vascularization process is less well understood. Microchannels are a simple, accessible architectural feature frequently engineered into 3D biomaterials to promote mass transfer. In this study, the effect of microchannels on the integration and vascularization of 3D porous silk scaffolds was explored over a 14 week period. An array of 508 μm diameter microchannels spanning the length of critically sized, porous silk scaffolds significantly improved tissue ingrowth into the constructs. At week 6, all silk scaffolds (n = 8) with microchannels showed complete tissue infiltration throughout the construct, while only one of eight (12.5%) did so in the absence of microchannels. The presence of microchannels improved silk scaffold vascularization with significantly more vessels per unit area in the presence of microchannels. The vessel size distribution was similar in both scaffold types, but a shift in distribution toward smaller vessels was observed in the presence of microchannels. The blood vessels in silk scaffolds were perfused, functional and connected to the animal's cardiovascular system, as demonstrated by the presence of red blood cells in the vessel lumens, and effective delivery of a contrast agent the vessels inside the scaffold. This study demonstrates the utility of microchannels as a simple architectural feature that significantly improves vascularization and integration of implanted biomaterials.

The leukodystrophy Hypomyelination with Brainstem and Spinal cord involvement and Leg spasticity (HBSL) is caused by recessive mutations of the DARS1 gene, which encodes the cytoplasmic aspartyl-tRNA synthetase. HBSL is a spectrum disorder with disease onset usually during early childhood and no available treatment options. Patients display regression of previously acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Gene-function studies in mice revealed that homozygous Dars1 deletion is embryonically lethal, suggesting that successful modelling of HBSL requires the generation of disease-causing genocopies in mice. In this study, we introduced the pathogenic DARS1

Purpose of review This review discusses recent developments in the application of magnetic particle imaging (MPI) to dementia research. Recent findings MPI is a tracer method that is currently in the preclinical development stage. It provides high sensitivity for the detection and localization of magnetic nanoparticles with very high spatial and temporal resolution and a similar application spectrum as PET. Unlike MRI, the MPI signal is not contaminated by background signal from tissues and is highly quantifiable in terms of local tracer concentrations. These properties make the technology ideally suited for localization of specific targets or quantification of vascular parameters. MPI uses magnetic nanoparticles which can be modified by various coatings, and by adding ligands (i.e. peptides or antibodies) for specific targeting. This makes MPI an attractive tool for the potential detection of abnormal protein deposits, such as Aβ plaques, with greater specificity than MRI. Neural stem cells can also be labelled with these nanoparticles ex vivo to monitor their migration in vivo. Summary The capabilities of MPI opens the potential for several applications of MPI in neurocognitive disorders, including vascular imaging, detection of amyloid plaques and potentially other pathological hallmarks of Alzheimer's disease and stem-cell tracking.

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene DARS1. The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking. Dars1 knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing Dars1D367Y point mutation into the mouse genome. Surprisingly, mice carrying this mutation homozygously were phenotypically normal. As hypomorphic mutations are more severe in trans to a deletion, we crossed Dars1D367Y/D367Y mice with Dars1-null carriers. The resulting Dars1D367Y/− offspring displayed a strong developmental delay compared to control Dars1D367Y/+ littermates, starting during embryogenesis. Only a small fraction of Dars1D367Y/− mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few Dars1D367Y/− mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, Dars1D367Y/− mice remained smaller and lighter than their Dars1D367Y/+ littermates. Despite this early developmental deficit, once they made it through early adolescence Dars1D367Y/− mice were phenotypically inconspicuous for most of their adult life, until they developed late onset motor deficits as well as vacuolization and demyelination of the spinal cord white matter. Expression levels of the major myelin proteins were reduced in Dars1D367Y/− mice compared to controls. Taken together, Dars1D367Y/− mice model aspects of the clinical picture of the corresponding missense mutation in HBSL. This model will enable studies of late onset deficits, which is precluded in Dars1 knockout mice, and can be leveraged to test potential HBSL therapeutics including DARS1 gene replacement therapy.

Aims As the inflammatory enzyme myeloperoxidase (MPO) is abundant in ruptured human atherosclerotic plaques, we aimed to investigate the role of MPO as a potential diagnostic and therapeutic target for high-risk plaque. Methods and results We employed the tandem stenosis model of atherosclerotic plaque instability in apolipoprotein E gene knockout (Apoe-/-) mice. To test the role of MPO, we used Mpo-/-Apoe-/- mice and the 2-thioxanthine MPO inhibitor AZM198. In vivo MPO activity was assessed by liquid chromatography-tandem mass spectrometry detection of 2-chloroethidium generation from hydroethidine and by bis-5HT-DTPA-Gd (MPO-Gd) molecular magnetic resonance imaging (MRI), while plaque phenotype was verified histologically. Myeloperoxidase activity was two-fold greater in plaque with unstable compared with stable phenotype. Genetic deletion of MPO significantly increased fibrous cap thickness, and decreased plaque fibrin and haemosiderin content in plaque with unstable phenotype. AZM198 inhibited MPO activity and it also increased fibrous cap thickness and decreased fibrin and haemosiderin in plaque with unstable phenotype, without affecting lesion monocytes and red blood cell markers or circulating leukocytes and lipids. MPO-Gd MRI demonstrated sustained enhancement of plaque with unstable phenotype on T1-weighted imaging that was two-fold greater than stable plaque and was significantly attenuated by both AZM198 treatment and deletion of the Mpo gene. Conclusion Our data implicate MPO in atherosclerotic plaque instability and suggest that non-invasive imaging and pharmacological inhibition of plaque MPO activity hold promise for clinical translation in the management of high-risk coronary artery disease.

N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease—a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CNS pathology and lasting neurological benefits. This finding signifies the first successful post-symptomatic treatment of a white matter disorder using an adeno-associated virus vector tailored towards oligodendroglial-restricted transgene expression. Electronic supplementary material The online version of this article (10.1007/s00401-017-1784-9) contains supplementary material, which is available to authorized users.

We used magnetic resonance imaging to study the anatomy of cortical regions, nuclear groups, and major tracts in the brain of a monotreme, i.e., the short-beaked echidna (Tachyglossus aculeatus). Our specimens were from a collection held at the Australian Museum in Sydney and had been stored in formaldehyde solution for at least 70 years. Despite this, we were able to detect fine detail in the nuclear divisions of structures as well as in fiber tracts. In particular, we could detect the medial lemniscus as it approached the ventral posterior thalamic nucleus, subdivisions within the ventral posterior thalamic nucleus, lamination and subdivisions within the hippocampal formation, components of the olfactory pathways, and nuclei within the temporal amygdala. We were able to map the topography of subcortical white matter and relate it to cortical regions determined on the basis of physiology, as well as chemical and cytoarchitecture. As expected, dense aggregations of fibers were noted in association with the primary sensory areas of the isocortex (somatosensory, visual, and auditory) and connecting primary olfactory regions (intrabulbar anterior commissure and associated fibers). We found longitudinal fibers in the basal forebrain (medial forebrain bundle) and brainstem (corticopontine and corticospinal tracts), as well as a dense array of fibers associated with the vermal and paravermal zones of the anterior lobe of the cerebellum. We also observed previously unrecognized fiber systems, i.e., commissural connections between the paired frontal isocortical fields (dorsal Fr1), dense fibers to the retrosplenial association cortex, and prominent, paired longitudinal fiber bundles in the dorsal forebrain (longitudinal fasciculus) that intersected the dorsal anterior commissure. The connectome results are consistent with the known neuroanatomy of this monotreme and they extend our knowledge of the fiber topography within this unusual brain. Our findings demonstrate the feasibility of using this sort of imaging of archived brains to analyze the neuroanatomy of rare, endangered, and evolutionarily significant species.

Peramelemorphians (bandicoots and bilbies) are a unique and diverse group of digging Australasian marsupials, but their behavioral neurology and neuroanatomy is poorly known. Here, we have used Magnetic Resonance Imaging (MRI) to study the brains of three peramelemorphians: two bandicoots (Perameles nasuta and Isoodon obesulus) and the bilby (Macrotis lagotis), which is endangered. These brains had been stored in formaldehyde solution for more than 80 years and one of our goals was to demonstrate the feasibilty of extracting detailed comparative neuroanatomical information from the long-term preserved brains of rare, endangered, and extinct animals. High resolution anatomical and Diffusion Tensor Imaging was performed using a 9.4-T Bruker BioSpec 94/20 Avance III MRI system (Bruker, Ettlingen, Germany) located at the UNSW in Sydney. We were able to differentiate areal and laminar topography within isocortical areas (primary somatosensory – S1; and visual - V1, V2), as well as subdivisions within olfactory and limbic allocortical regions (cingulate, hippocampal). Resolution of subcortical structures was sufficient to differentiate α and β segments within the visual nucleus of the thalamus. We identified several previously unrecognized longitudinal association fiber systems as well as a rich array of sensory thalamocortical connections. Dense fiber pathways were observed to S1 and in the midbrain auditory pathways (mainly the lateral lemniscus, but also the brachium of the inferior colliculus). Our findings demonstrate the feasibility of using this sort of imaging of archived brains to analyze the neuroanatomy of rare and evolutionarily significant species and to relate these findings to the behavioral neurology of those species. Fil: Gurovich, Yamila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina. University of New South Wales; Australia Fil: Bongers, Andre. University of New South Wales; Australia Fil: Ashwell, Ken W. S.. University of New South Wales; Australia

OBJECTIVE Syringomyelia pathophysiology is commonly studied using rodent models. However, in vivo studies of posttraumatic syringomyelia have been limited by the size of animals and lack of reliable noninvasive evaluation techniques. Imaging the rat spinal cord is particularly challenging because the spinal cord diameter is approximately 1–3 mm, and pathological lesions within the spinal cord parenchyma are even smaller. The standard technique has been histological evaluation, but this has its limitations. The aim of the present study was to determine whether syrinx size could be reliably measured using a preclinical high-field MRI animal system in a rat model of posttraumatic syringomyelia. METHODS The authors used an existing rat model of posttraumatic syringomyelia, which was created using a controlled pneumatic compression device to produce the initial spinal cord injury, followed by a subarachnoid injection of kaolin to produce arachnoiditis. T2-weighted MRI was performed on each animal using a 9.4-T scanner at 7, 10, and 13 weeks after injury. Animals were killed and syrinx sizes were calculated from in vivo MRI and histological studies. RESULTS MRI measurements of syrinx volume and length were closely correlated to histological measurements across all time points (Pearson product moment correlation coefficient r = ± 0.93 and 0.79, respectively). CONCLUSIONS This study demonstrates that high-field T2-weighted MRI can be used to measure syrinx size, and data correlate well with syrinx size measured using histological methods. Preclinical MRI may be a valuable noninvasive technique for tracking syrinx formation and enlargement in animal models of syringomyelia.

This study compares the theoretical information content of single- and multi-compartment models of diffusion-weighted signal attenuation in prostate tissue. Diffusion-weighted imaging (DWI) was performed at 9.4 T with multiple diffusion times and an extended range of b values in four whole formalin-fixed prostates. Ten models, including different combinations of isotropic, anisotropic and restricted components, were tested. Models were ranked using the Akaike information criterion. In all four prostates, two-component models, comprising an anisotropic Gaussian component and an isotropic restricted component, ranked highest in the majority of voxels. Single-component models, whether isotropic (apparent diffusion coefficient, ADC) or anisotropic (diffusion tensor imaging, DTI), consistently ranked lower than multi-component models. Model ranking trends were independent of voxel size and maximum b value in the range tested (1.6-16 mm(3) and 3000-10,000 s/mm(2)). This study characterizes the two major water components previously identified by biexponential models and shows that models incorporating both anisotropic and restricted components provide more information-rich descriptions of DWI signals in prostate tissue than single- or multi-component anisotropic models and models that do not account for restricted diffusion.

Facile preparation of well-defined and multifunctional polymers is of great importance for the development of polymer-based drug carriers. By performing enzymatic transacylation during RAFT polymerization, diverse monomers with different functions were generated in situ and simultaneously copolymerized via the RAFT process to form a well-defined multifunctional copolymer precursor which contains fluorine, polyethylene glycol (PEG), benzaldehyde and azido groups. The glucose moiety (which represents a possible targeting group for tumor treatment) was conjugated to this precursor via a copper-catalyzed azide alkyne cycloaddition (CuAAc) reaction to generate the polymer drug carrier. A 19F MRI phantom was performed for the polymer drug carrier, indicating its potential as a possible 19F MRI tracer. The polymer drug carrier has been shown to specifically bind to lectin due to the contained glucose moiety, demonstrating its potential targeting effect. Then, doxorubicin (dox, an anticancer drug) was conjugated with the polymer drug carrier through imine chemistry to generate a target polymer–dox complex. This polymer–dox complex possesses amphiphilic character and self-assembles in aqueous solution into spherical micelles with a size of ∼30 nm, which exhibit much faster release of dox at pH 5.5 than at pH 7.4. Subsequent cell experiments showed that the polymer–dox complex is less toxic than native dox to normal cells while retaining similar cytotoxicity against cancer cells, suggesting that the polymer drug carrier is potentially a safe and effective drug delivery system. We believe that as several reactive moieties can be implanted into the polymer structure in a one-pot manner to achieve a multifunctional polymer precursor for efficient post-modification, this concurrent tandem polymerization (CTP) system might be useful for the development of novel anticancer theranostic nanomedicines.

Purpose To investigate diffusion anisotropy in whole human prostate specimens Methods Seven whole radical prostatectomy specimens were obtained with informed patient consent and institutional ethics approval. Diffusion tensor imaging was performed at 9.4 Tesla. Diffusion tensors were calculated from the native acquired data and after progressive downsampling Results Fractional anisotropy (FA) decreased as voxel volume increased, and differed widely between prostates. Fixation decreased mean FA by ∼0.05–0.08 at all voxel volumes but did not alter principle eigenvector orientation. In unfixed tissue high FA (> 0.6) was found only in voxels of volume 0.25. FA decreased at longer diffusion times (Δ = 60 or 80 ms compared with 20 ms), but only by ∼0.02 at typical clinical voxel volume. Peripheral zone FA was significantly lower than transition zone FA in five of the seven prostates Conclusion FA varies widely between prostates. The very small proportion of clinical size voxels with high FA suggests that in clinical DWI studies ADC based on three-direction measurements will be minimally affected by anisotropy. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.

Non-Gaussian diffusion dynamics was investigated in the two distinct water populations identified by a biexponential model of diffusion in prostate tissue. Diffusion-weighted MRI (DWI) signal attenuation was measured ex vivo in two formalin-fixed prostates at 9.4 T with diffusion times Δ = 10, 20 and 40 ms, and b values in the range 0.017–8.2 ms/µm2. A conventional biexponential model was compared with models in which either the lower diffusivity component or both of the components of the biexponential were stretched. Models were compared using Akaike's Information Criterion (AIC) and a leave-one-out (LOO) test of model prediction accuracy. The doubly stretched (SS) model had the highest LOO prediction accuracy and lowest AIC (highest information content) in the majority of voxels at Δ = 10 and 20 ms. The lower diffusivity stretching factor (α2) of the SS model was consistently lower (range ~0.3–0.9) than the higher diffusivity stretching factor (α1, range ~0.7–1.1), indicating a high degree of diffusion heterogeneity in the lower diffusivity environment, and nearly Gaussian diffusion in the higher diffusivity environment. Stretched biexponential models demonstrate that, in prostate tissue, the two distinct water populations identified by the simple biexponential model individually exhibit non-Gaussian diffusion dynamics. Copyright © 2015 John Wiley & Sons, Ltd.

Purpose To investigate a novel alternative diffusion-weighted imaging (DWI) approach using oscillating gradients preparation (OGSE) to obtain much shorter effective diffusion times (Δeff) for tumor response monitoring by apparent diffusion coefficient (ADC) mapping in a glioblastoma mouse model. Methods and Materials Twenty-four BALB/c nude mice inoculated with U87 glioblastoma cells were randomized into a control group and an irradiation group, which underwent a 15-day fractioned radiation therapy (RT) course with 2 Gy/d. Therapy response was assessed by mapping of ADCs at 6 time points using an in-house implementation of a cos-OGSE DWI sequence with Δeff = 1.25 ms and compared with a standard pulsed gradient DWI protocol (PGSE) with typical clinical diffusion time Δeff = 18 ms. Longitudinal ADC changes in tumor and contralateral white matter (WM) were statistically assessed using repeated-measures analysis of variance and post hoc (Sidak) testing. Results On short Δeff OGSE maps tumor ADC was generally 30%-50% higher than in surrounding WM. Areas correlated well with histology. Tumor identification was generally more difficult on PGSE maps owing to nonsignificant WM/tumor contrast. During RT, OGSE maps also showed significant tumor ADC increase (approximately 15%) in response to radiation, consistently seen after 14-Gy RT dose. The clinical reference (PGSE) showed lower sensitivity to radiation changes, and no significant response across the radiation group and time course could be detected. Conclusion Our short Δeff DWI method using OGSE better reflected histologically defined tumor areas and enabled more consistent and earlier detection of microstructural radiation changes than conventional methods. Oscillating gradients preparation offers significant potential as a robust microstructural RT response biomarker, potentially helping to shift important therapy decisions to earlier stages in the RT time course.

We used magnetic resonance imaging to study the anatomy of cortical regions, nuclear groups, and major tracts in the brain of a monotreme, i.e., the short-beaked echidna (Tachyglossus aculeatus). Our specimens were from a collection held at the Australian Museum in Sydney and had been stored in formaldehyde solution for at least 70 years. Despite this, we were able to detect fine detail in the nuclear divisions of structures as well as in fiber tracts. In particular, we could detect the medial lemniscus as it approached the ventral posterior thalamic nucleus, subdivisions within the ventral posterior thalamic nucleus, lamination and subdivisions within the hippocampal formation, components of the olfactory pathways, and nuclei within the temporal amygdala. We were able to map the topography of subcortical white matter and relate it to cortical regions determined on the basis of physiology, as well as chemical and cytoarchitecture. As expected, dense aggregations of fibers were noted in association with the primary sensory areas of the isocortex (somatosensory, visual, and auditory) and connecting primary olfactory regions (intrabulbar anterior commissure and associated fibers). We found longitudinal fibers in the basal forebrain (medial forebrain bundle) and brainstem (corticopontine and corticospinal tracts), as well as a dense array of fibers associated with the vermal and paravermal zones of the anterior lobe of the cerebellum. We also observed previously unrecognized fiber systems, i.e., commissural connections between the paired frontal isocortical fields (dorsal Fr1), dense fibers to the retrosplenial association cortex, and prominent, paired longitudinal fiber bundles in the dorsal forebrain (longitudinal fasciculus) that intersected the dorsal anterior commissure. The connectome results are consistent with the known neuroanatomy of this monotreme and they extend our knowledge of the fiber topography within this unusual brain. Our findings demonstrate the feasibility of using this sort of imaging of archived brains to analyze the neuroanatomy of rare, endangered, and evolutionarily significant species.

Non-invasive treatment of moving organs like liver and kidney with high intensity focused ultrasound (HIFU/FUS) is challenging. The highly precise HIFU ablation requires real-time knowledge of tumor position with mm precision. The aim of this work was to build up a magnetic resonance imaging compatible tracking device using diagnostic ultrasound imaging for MR guided FUS (MRgFUS).The hardware of the developed US-tracking system comprises the ultrasound beam former with a screen directly placed in front of the MR-magnet, a linear and a special ultrasound tracking probe. The tracking probe (2x64 element phased array) can acquire two perpendicularly oriented US-image planes for quasi 3D tracking. The US-data are sent to a workstation in the console room of the MRI scanner which controls the whole tracking device. The tracking software (Sonoplan II) analyzes the ultrasound image stream and calculates the actual position of pre-defined contours. Beside the 2D-translation, the tracking algorithm analyzes the ro...

© The Author(s) 2019. Prostate cancer (CaP) is the most commonly diagnosed cancer in males in western countries. Orthotopic implantation is considered as an ideal xenograft model for CaP study, and noninvasive measurement of tumor volume changes is important for monitoring responses to anticancer therapies. In this study, the T2-weighted fast spin echo sequence magnetic resonance imaging (MRI) was performed on a CaP orthotopic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model weekly for 6 weeks post PC-3 CaP cell inoculation, and the fat signal was suppressed using a chemical shift-selective pulse. Subsequently, the MRI data were imported into the image processing software Avizo Standard and stacked into three-dimensional (3D) volumes. Our results demonstrate that MRI, combined with 3D reconstruction, is a feasible and sensitive method to assess tumor growth in a PC-3 orthotopic CaP mouse model and this established monitoring approach is promising for longitudinal observation of CaP xenograft development after anticancer therapy in vivo. Further investigation is needed to validate this protocol in a larger cohort of mice to generate enough statistical power.

Purpose To compare the theoretical information content of four popular models of diffusion-weighted signal attenuation. Method Four whole prostates were imaged fresh unfixed and fixed at 9.4T. Biexponential, kurtosis, stretched exponential, and monoexponential models were ranked using Akaike's Information Criterion (AIC) with validation by a leave-one-out test of model prediction error. Results For unfixed tissue measurements (b-value range: 17–2104 s/mm2) the biexponential and kurtosis models had similar information content to each other and this was distinctly higher than for the stretched and monoexponential models. In fixed-tissue measurements (b-value range: 17–8252 s/mm2), the biexponential model had much higher information content than the three other models. Conclusion AIC-based model ranking is consistent with an independent prediction accuracy test. Biexponential and kurtosis models consistently perform better than stretched and monoexponential models. The biexponential model has increasing superiority over all three other models as maximum b-value increases above ∼2000 s/mm2. Magn Reson Med 72:1418–1426, 2014. © 2013 Wiley Periodicals, Inc.

Several mouse lines with knockout of the tau-encoding MAPT gene have been reported in the past; they received recent attention due to reports that tau reduction prevented Aβ-induced deficits in mouse models of Alzheimer's disease. However, the effects of long-term depletion of tau in vivo remained controversial. Here, we used the tau-deficient GFP knockin line Mapttm1(EGFP)kit on a pure C57Bl/6 background and subjected a large cohort of males and females to a range of motor, memory and behavior tests and imaging analysis, at the advanced age of over 16 months. Neither heterozygous nor homozygous Mapttm1(EGFP)kit mice presented with deficits or abnormalities compared to wild-type littermates. Differences to reports using other tau knockout models may be due to different genetic backgrounds, respective gene targeting strategies or other confounding factors, such as nutrition. To this end, we report no functional or morphological deficits upon tau reduction or depletion in aged mice.

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.

Understanding neural injury in hydrocephalus and how the brain changes during the course of the disease in-vivo remain unclear. This study describes brain deformation, microstructural and mechanical properties changes during obstructive hydrocephalus development in a rat model using multimodal magnetic resonance (MR) imaging. Hydrocephalus was induced in eight Sprague-Dawley rats (4 weeks old) by injecting a kaolin suspension into the cisterna magna. Six sham-injected rats were used as controls. MR imaging (9.4T, Bruker) was performed 1 day before, and at 3, 7 and 16 days post injection. T2-weighted MR images were collected to quantify brain deformation. MR elastography was used to measure brain stiffness, and diffusion tensor imaging (DTI) was conducted to observe brain tissue microstructure. Results showed that the enlargement of the ventricular system was associated with a decrease in the cortical gray matter thickness and caudate-putamen cross-sectional area (P < 0.001, for both), an alteration of the corpus callosum and periventricular white matter microstructure (CC+PVWM) and rearrangement of the cortical gray matter microstructure (P < 0.001, for both), while compression without gross microstructural alteration was evident in the caudate-putamen and ventral internal capsule (P < 0.001, for both). During hydrocephalus development, increased space between the white matter tracts was observed in the CC+PVWM (P < 0.001), while a decrease in space was observed for the ventral internal capsule (P < 0.001). For the cortical gray matter, an increase in extracellular tissue water was significantly associated with a decrease in tissue stiffness (P = 0.001). To conclude, this study characterizes the temporal changes in tissue microstructure, water content and stiffness in different brain regions and their association with ventricular enlargement. In summary, whilst diffusion changes were larger and statistically significant for majority of the brain regions studied, the changes in mechanical properties were modest. Moreover, the effect of ventricular enlargement is not limited to the CC+PVWM and ventral internal capsule, the extent of microstructural changes vary between brain regions, and there is regional and temporal variation in brain tissue stiffness during hydrocephalus development.

Purpose To evaluate the effect of formalin fixation on biexponential modeling of diffusion decay in prostate tissue. Methods Three whole prostate specimens were imaged unfixed immediately postsurgery, and again after formalin fixation. Diffusion-weighted imaging was performed over an extended range of b-values and a biexponential model fitted to the signal decay curves. Results Tissue fixation resulted in a 35%, 20%, and 20% reduction in mean apparent diffusion coefficient of the higher diffusivity fit component for the three organs, respectively, and a 64%, 57%, and 45% reduction in mean apparent diffusion coefficient of the lower diffusivity component. The mean signal fraction of the higher diffusivity component was increased by 23%, 5%, and 1%, respectively. The effect of fixation did not appear to vary according to tissue type or glandular zone. Conclusion Formalin fixed tissue appears to provide a stable model for detailed investigation of the microscopic biophysical basis of diffusion phenomena observed in vivo. Diffusivity changes that result from fixation may provide information about the microscopic environments of the biexponential components. Magn Reson Med, 70:1160–1166, 2013. © 2012 Wiley Periodicals, Inc.

The regulation of emotion is vital for adaptive behavior in a social environment. Different strategies may be adopted to achieve successful emotion regulation, ranging from attentional control (e.g., distraction) to cognitive change (e.g., reappraisal). However, there is only scarce evidence comparing the different regulation strategies with respect to their neural mechanisms and their effects on emotional experience. We, therefore, directly compared reappraisal and distraction in a functional magnetic resonance imaging study with emotional pictures. In the distraction condition participants performed an arithmetic task, while they reinterpreted the emotional situation during reappraisal to downregulate emotional intensity. Both strategies were successful in reducing subjective emotional state ratings and lowered activity in the bilateral amygdala. Direct contrasts, however, showed a stronger decrease in amygdala activity for distraction when compared with reappraisal. While both strategies relied on common control areas in the medial and dorsolateral prefrontal and inferior parietal cortex, the orbitofrontal cortex was selectively activated for reappraisal. In contrast, the dorsal anterior cingulate and large clusters in the parietal cortex were active in the distraction condition. Functional connectivity patterns of the amygdala activation confirmed the roles of these specific activations for the 2 emotion regulation strategies.

Motivational orientation defines the source of motivation for an individual to perform a particular action and can either originate from internal desires (e.g., interest) or external compensation (e.g., money). To this end, motivational orientation should influence the way positive or negative feedback is processed during learning situations and this might in turn have an impact on the learning process. In the present study, we thus investigated whether motivational orientation, i.e., extrinsic and intrinsic motivation modulates the neural response to reward and punishment as well as learning from reward and punishment in 33 healthy individuals. To assess neural responses to reward, punishment and learning of reward contingencies we employed a probabilistic reversal learning task during functional magnetic resonance imaging. Extrinsic and intrinsic motivation were assessed with a self-report questionnaire. Rewarding trials fostered activation in the medial orbitofrontal cortex and anterior cingulate gyrus (ACC) as well as the amygdala and nucleus accumbens, whereas for punishment an increased neural response was observed in the medial and inferior prefrontal cortex, the superior parietal cortex and the insula. High extrinsic motivation was positively correlated to increased neural responses to reward in the ACC, amygdala and putamen, whereas a negative relationship between intrinsic motivation and brain activation in these brain regions was observed. These findings show that motivational orientation indeed modulates the responsiveness to reward delivery in major components of the human reward system and therefore extends previous results showing a significant influence of individual differences in reward-related personality traits on the neural processing of reward.

A hybridized dual-imaging system combining real-time ultrasound imaging and MRI was utilized for cardiac imaging at 1.5 T and 3 T. The ultrasound scanner with a programmable software interface was connected via computer to the MRI scanner. Electronic noise was eliminated with electromagnetic shielding and grounding to the screen room. At 3 T, real-time prospective motion compensation in dynamic cine cardiac imaging was implemented using B-mode ultrasound imaging. The ultrasound technique avoided drawbacks such as signal saturation or steady-state interruption of the MR navigator gating. At 1.5 T, a low-latency real-time feedback to balanced steady state free precision MR imaging was performed in three normal volunteers. Results showed active tracking of the heart during respiratory motion and improvement in time-averaged cardiovascular images. Future studies can fully exploit the potential of the high-frequency position information provided by the ultrasound system for more advanced applications in real-time organ tracking.

This study compares the theoretical information content of single- and multi-compartment models of diffusion-weighted signal attenuation in prostate tissue. Diffusion-weighted imaging (DWI) was performed at 9.4 T with multiple diffusion times and an extended range of b values in four whole formalin-fixed prostates. Ten models, including different combinations of isotropic, anisotropic and restricted components, were tested. Models were ranked using the Akaike information criterion. In all four prostates, two-component models, comprising an anisotropic Gaussian component and an isotropic restricted component, ranked highest in the majority of voxels. Single-component models, whether isotropic (apparent diffusion coefficient, ADC) or anisotropic (diffusion tensor imaging, DTI), consistently ranked lower than multi-component models. Model ranking trends were independent of voxel size and maximum b value in the range tested (1.6-16 mm(3) and 3000-10,000 s/mm(2)). This study characterizes the two major water components previously identified by biexponential models and shows that models incorporating both anisotropic and restricted components provide more information-rich descriptions of DWI signals in prostate tissue than single- or multi-component anisotropic models and models that do not account for restricted diffusion.

To investigate diffusion anisotropy in whole human prostate specimensSeven whole radical prostatectomy specimens were obtained with informed patient consent and institutional ethics approval. Diffusion tensor imaging was performed at 9.4 Tesla. Diffusion tensors were calculated from the native acquired data and after progressive downsamplingFractional anisotropy (FA) decreased as voxel volume increased, and differed widely between prostates. Fixation decreased mean FA by ∼0.05-0.08 at all voxel volumes but did not alter principle eigenvector orientation. In unfixed tissue high FA (0.6) was found only in voxels of volume0.5 mm(3) , and then only in a small fraction of all voxels. At typical clinical voxel volumes (4-16 mm(3) ) less than 50% of voxels had FA 0.25. FA decreased at longer diffusion times (Δ = 60 or 80 ms compared with 20 ms), but only by ∼0.02 at typical clinical voxel volume. Peripheral zone FA was significantly lower than transition zone FA in five of the seven prostatesFA varies widely between prostates. The very small proportion of clinical size voxels with high FA suggests that in clinical DWI studies ADC based on three-direction measurements will be minimally affected by anisotropy. Magn Reson Med 76:626-634, 2016. © 2015 Wiley Periodicals, Inc.

Half pulse excitation plays an important role in imaging with ultra-short echo times (UTE imaging) of the order of TE < 100 micros. Based on half RF-pulses this method was theoretically modeled and experimentally applied in 1991 for the first time. Following this work, measurements of slice profiles produced by half pulses were performed and results were compared to the slice profiles produced by the original full pulse. Furthermore, the hypothesis was tested that short RF pulses may be of advantage in minimizing the relaxation effects during the pulse. Within the scope of these measurements no dependency of slice profile on the pulse duration could be found.

(23)Na MRI has the potential to noninvasively detect sodium (Na) content changes in vivo. The goal of this study was to implement (23)Na MRI in a clinical setting for neurooncological and muscular imaging. Due to the biexponential T(2) decay of the tissue Na signal with a short component, which ranges between 0.5-8 ms, the measurement of total Na content requires imaging techniques with echo times (TEs) below 0.5 ms. A 3D radial pulse sequence with a TE of 0.2 ms at a spatial resolution of 4 x 4 x 4 mm(3) was developed that allows the acquisition and presentation of Na images on the scanner. This sequence was evaluated in patients with low- and high-grade gliomas, and higher (23)Na MR signals corresponding to an increased Na content were found in the tumor regions. The contrast-to-noise ratio (CNR) between tumor and white matter increased from 0.8 +/- 0.2 to 1.3 +/- 0.3 with tumor grade. In patients with an identified muscular (23)Na channelopathy (Paramyotonia congenita (PC)), induced muscle weakness led to a signal increase of approximately 18% in the (23)Na MR images, which was attributed to intracellular Na(+) accumulation in this region.

Zusammenfassung Eine detaillierte Kenntnis der Sauerstoffversorgung ist aufgrund ihrer grosen Bedeutung fur die Funktionalitat des Gewebes in der Krebsdiagnostik und -therapie von hohem Interesse. Eine Moglichkeit hieruber Informationen zu gewinnen stellt die Bestimmung der Blutsauerstoffsattigung mit Hilfe des BOLD-Effektes dar. In dieser Arbeit wird ein einfaches Gewebemodell untersucht, das eine Beziehung zwischen gemessenen Relaxationsraten und der Suszeptibilitatsdifferenz Δχ von Gewebe und venosem Blut herstellt und damit indirekt die Berechnung der Sauerstoffextraktionsfraktion ermoglicht. Zur Uberprufung der Validitat zur Bestimmung der Sauerstoffversorgung wurden zwei Vorhersagen bzw. Voraussetzungen dieses Modells untersucht: die Abhangigkeit der Ergebnisse von der Kapillarstarke d und von dem relativen Blutvolumen λ. Dazu wurde ein Messphantom entwickelt, mit dem Δχ in Abhangigkeit von d (27 m–238 m) und λ (3%–12%) bestimmt werden konnte. In mit diesem Phantom durchgefuhrten Messungen zeigt Δχ(λ) modellkonform eine weitgehende Unabhangigkeit vom relativen Volumenanteil der Kapillaren. Fur Δχ(d) hingegen ergibt sich abweichend von den Modellannahmen eine deutlich positive Abhangigkeit vom Radius der Kapillaren (Δχ-Bereich: 0,35–0,57 ppm). Unsere Messungen legen den Schluss nahe, dass das Modell aufgrund unzureichender Modellannahmen Defizite in der quantitativen Vorhersage der Gewebeoxygenierung hat.

This review presents the basic principles of functional imaging of the central nervous system utilizing magnetic resonance imaging. The focus is set on visualization of different functional aspects of the brain and related pathologies. Additionally, clinical cases are presented to illustrate the applications of functional imaging techniques in the clinical setting. The relevant physics and physiology of contrast-enhanced and non-contrast-enhanced methods are discussed. The two main functional MR techniques requiring contrast-enhancement are dynamic T1- and T2*-MRI to image perfusion. Based on different pharmacokinetic models of contrast enhancement diagnostic applications for neurology and radio-oncology are discussed. The functional non-contrast enhanced imaging techniques are based on "blood oxygenation level dependent (BOLD)-fMRI and arterial spin labeling (ASL) technique. They have gained clinical impact particularly in the fields of psychiatry and neurosurgery.

Rationale and Objectives: To assess if preradiation and early follow-up measurements of relative regional cerebral blood flow (rrCBF) can predict treatment outcome in patients with cerebral metastases and to evaluate rrCBF changes in tumor and normal tissue after stereotactic radiosurgery using arterial spin-labeling (ASL) and first-pass dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MRI. Methods: In 25 patients with a total of 28 brain metastases, DSC MRI and ASL perfusion MRI using the Q2TIPS sequence were performed with a 1.5-T unit. Measurements were performed prior to and at 6 weeks, 12 weeks, and 24 weeks after stereotactic radiosurgery. Follow-up examinations were completely available in 25 patients for Q2TIPS and 17 patients with 18 metastases for DSC MRI. The rrCBF of the metastases and the normal brain tissue was determined by a region-of-interest analysis. rrCBF values were correlated with the treatment outcome that was classified according to tumor volume changes at 6 months. Results: The alteration of the rrCBF at the 6-week follow-up was highly predictive for treatment outcome. A decrease of the rrCBF value predicted tumor response correctly in all metastases for Q2TIPS and in 13 of 16 metastases for DSC MRI. The pretherapeutic rrCBF was not able to predict treatment outcome. The rrCBF values in normal brain tissue affected by radiation doses less than 0.5 Gy remained unchanged after therapy. Conclusion: These preliminary results suggest that ASL and DSC MRI techniques determining rrCBF changes in brain metastases after stereotactic radiosurgery allow the prediction of treatment outcome.

For decades the respiratory protein keyhole limpet hemocyanin (KLH1) from the marine gastropod Megathura crenulata has been used widely as a potent immunostimulant, useful hapten carrier, and valuable agent in the treatment of bladder carcinoma. Although much information on the immunological properties of KLH1 is available, biochemical and structural data are still incomplete. Small-angle x-ray scattering revealed the existence of two conformations, an oxy state being slightly more compact than the deoxy state. Based on small-angle scattering curves, a newly developed Monte Carlo algorithm delivered a surface representation of proteins. The massive changes of the surfaces of reconstructed didecameric KLH1 molecules are explained as a twist of the two non-covalently associated decameric half-molecules. Upon oxygenation, the KLH1 molecule becomes longer and skinnier. This study provides the first real evidence how a molluscan hemocyanin changes conformation during an allosteric transition.

The purpose of this study was to measure and model the diffusion time dependence of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) derived from conventional prostate diffusion-weighted imaging methods as used in recommended multiparametric MRI protocols. Diffusion tensor imaging (DTI) was performed at 9.4 T with three radical prostatectomy specimens, with diffusion times in the range 10–120 ms and b-values 0–3000 s/mm2. ADC and FA were calculated from DTI measurements at b-values of 800 and 1600 s/mm2. Independently, a two-component model (restricted isotropic plus Gaussian anisotropic) was used to synthesize DTI data, from which ADC and FA were predicted and compared with the measured values. Measured ADC and FA exhibited a diffusion time dependence, which was closely predicted by the two-component model. ADC decreased by about 0.10–0.15 μm2/ms as diffusion time increased from 10 to 120 ms. FA increased with diffusion time at b-values of 800 and 1600 s/mm2 but was predicted to be independent of diffusion time at b = 3000 s/mm2. Both ADC and FA exhibited diffusion time dependence that could be modeled as two unmixed water pools — one having isotropic restricted dynamics, and the other unrestricted anisotropic dynamics. These results highlight the importance of considering and reporting diffusion times in conventional ADC and FA calculations and protocol recommendations, and inform the development of improved diffusion methods for prostate cancer imaging.

Non-Gaussian diffusion dynamics was investigated in the two distinct water populations identified by a biexponential model of diffusion in prostate tissue. Diffusion-weighted MRI (DWI) signal attenuation was measured ex vivo in two formalin-fixed prostates at 9.4 T with diffusion times Δ = 10, 20 and 40 ms, and b values in the range 0.017-8.2 ms/µm(2) . A conventional biexponential model was compared with models in which either the lower diffusivity component or both of the components of the biexponential were stretched. Models were compared using Akaike's Information Criterion (AIC) and a leave-one-out (LOO) test of model prediction accuracy. The doubly stretched (SS) model had the highest LOO prediction accuracy and lowest AIC (highest information content) in the majority of voxels at Δ = 10 and 20 ms. The lower diffusivity stretching factor (α2 ) of the SS model was consistently lower (range ~0.3-0.9) than the higher diffusivity stretching factor (α1 , range ~0.7-1.1), indicating a high degree of diffusion heterogeneity in the lower diffusivity environment, and nearly Gaussian diffusion in the higher diffusivity environment. Stretched biexponential models demonstrate that, in prostate tissue, the two distinct water populations identified by the simple biexponential model individually exhibit non-Gaussian diffusion dynamics.