Merged magnetic resonance and light sheet microscopy of the whole mouse brain.

We have developed workflows to align 3D magnetic resonance histology (MRH) of the mouse brain with light sheet microscopy (LSM) and 3D delineations of the same specimen. We start with MRH of the brain in the skull with gradient echo and diffusion tensor imaging (DTI) at 15 µm isotropic resolution which is ~ 1,000 times higher than that of most preclinical MRI. Connectomes are generated with superresolution tract density images of ~5 µm. Brains are cleared, stained for selected proteins, and imaged by LSM at 1.8 µm/pixel. LSM data are registered into the reference MRH space with labels derived from the ABA common coordinate framework. The result is a high-dimensional integrated volume with registration (HiDiver) with alignment precision better than 50 µm. Throughput is sufficiently high that HiDiver is being used in quantitative studies of the impact of gene variants and aging on mouse brain cytoarchitecture and connectomics.

Transcriptome analysis identifies an ASD-Like phenotype in oligodendrocytes and microglia from C58/J amygdala that is dependent on sex and sociability.

BACKGROUND: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. METHODS: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. RESULTS: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. LIMITATIONS: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic. CONCLUSIONS: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

Prenatal heroin exposure alters brain morphology and connectivity in adolescent mice.

The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently, the number of individuals exposed to opioids in utero. Prenatal opioid exposure has both acute and long-lasting effects on health and wellbeing. Effects on the brain, often identified at school age, manifest as cognitive impairment, attention deficit, and reduced scholastic achievement. The neurobiological basis for these effects is poorly understood. Here, we examine how in utero exposure to heroin affects brain development into early adolescence in a mouse model. Pregnant C57BL/6J mice received escalating doses of heroin twice daily on gestational days 4-18. The brains of offspring were assessed on postnatal day 28 using 9.4 T diffusion MRI of postmortem specimens at 36 µm resolution. Whole-brain volumes and the volumes of 166 bilateral regions were compared between heroin-exposed and control offspring. We identified a reduction in whole-brain volume in heroin-exposed offspring and heroin-associated volume changes in 29 regions after standardizing for whole-brain volume. Regions with bilaterally reduced standardized volumes in heroin-exposed offspring relative to controls include the ectorhinal and insular cortices. Regions with bilaterally increased standardized volumes in heroin-exposed offspring relative to controls include the periaqueductal gray, septal region, striatum, and hypothalamus. Leveraging microscopic resolution diffusion tensor imaging and precise regional parcellation, we generated whole-brain structural MRI diffusion connectomes. Using a dimension reduction approach with multivariate analysis of variance to assess group differences in the connectome, we found that in utero heroin exposure altered structure-based connectivity of the left septal region and the region that acts as a hub for limbic regulatory actions. Consistent with clinical evidence, our findings suggest that prenatal opioid exposure may have effects on brain morphology, connectivity, and, consequently, function that persist into adolescence. This work expands our understanding of the risks associated with opioid misuse during pregnancy and identifies biomarkers that may facilitate diagnosis and treatment.

A new gelatinous host for pelagic fishes: First in situ record of an association between driftfishes (Stromateiformes, Ariommatidae) and nudibranchs (Mollusca, Phylliroidae).

We describe the first recorded association between fishes and nudibranchs in epipelagic waters. In situ observations and photographs of a juvenile spotted driftfish Ariomma regulus (Stromateiformes; Ariommatidae) swimming alongside the planktonic nudibranch Phylliroe lichtensteinii (Gastropoda; Phylliroidae) were made during blackwater scuba dives off Palm Beach, Florida, United States of America. In this paper, we describe this behavior, highlighting a previously undocumented zooplanktonic host used by fishes. This finding also demonstrates the importance of community science in advancing our understanding of the early life history of marine species.

Resolution and b value dependent structural connectome in ex vivo mouse brain.

Diffusion magnetic resonance imaging has been widely used in both clinical and preclinical studies to characterize tissue microstructure and structural connectivity. The diffusion MRI protocol for the Human Connectome Project (HCP) has been developed and optimized to obtain high-quality, high-resolution diffusion MRI (dMRI) datasets. However, such efforts have not been fully explored in preclinical studies, especially for rodents. In this study, high quality dMRI datasets of mouse brains were acquired at 9.4T system from two vendors. In particular, we acquired a high-spatial resolution dMRI dataset (25 µm isotropic with 126 diffusion encoding directions), which we believe to be the highest spatial resolution yet obtained; and a high-angular resolution dMRI dataset (50 µm isotropic with 384 diffusion encoding directions), which we believe to be the highest angular resolution compared to the dMRI datasets at the microscopic resolution. We systematically investigated the effects of three important parameters that affect the final outcome of the connectome: b value (1000s/mm2 to 8000 s/mm2), angular resolution (10 to 126), and spatial resolution (25 µm to 200 µm). The stability of tractography and connectome increase with the angular resolution, where more than 50 angles is necessary to achieve consistent results. The connectome and quantitative parameters derived from graph theory exhibit a linear relationship to the b value (R2 > 0.99); a single-shell acquisition with b value of 3000 s/mm2 shows comparable results to the multi-shell high angular resolution dataset. The dice coefficient decreases and both false positive rate and false negative rate gradually increase with coarser spatial resolution. Our study provides guidelines and foundations for exploration of tradeoffs among acquisition parameters for the structural connectome in ex vivo mouse brain.

A time-course study of actively stained mouse brains: Diffusion tensor imaging parameters and connectomic stability over 1 year.

While the application of diffusion tensor imaging (DTI), tractography, and connectomics to fixed tissue is a common practice today, there have been limited studies examining the effects of fixation on brain microstructure over extended periods. This mouse model time-course study reports the changes of regional brain volumes and diffusion scalar parameters, such as fractional anisotropy, across 12 representative brain regions as measures of brain structural stability. The scalar DTI parameters and regional volumes were highly variable over the first 2 weeks after fixation. The same parameters were consistent over a 2-8-week window after fixation, which means confounds from tissue stability over that scanning window were minimal. Quantitative connectomes were analyzed over the same time with extension out to 1 year. While there was some change in the scalar metrics at 1 year after fixation, these changes were sufficiently small, particularly in white matter, to support reproducible connectomes over a period ranging from 2-weeks to 1-year post-fixation. These findings delineate a scanning period, during which brain volumes, diffusion scalar metrics, and connectomes are remarkably consistent.

A multicontrast MR atlas of the Wistar rat brain.

We describe a multi-contrast, multi-dimensional atlas of the Wistar rat acquired at microscopic spatial resolution using magnetic resonance histology (MRH). Diffusion weighted images, and associated scalar images were acquired of a single specimen with a fully sampled Fourier reconstruction, 61 angles and b=3000 s/mm2 yielding 50 um isotropic spatial resolution. The higher angular sampling allows use of the GQI algorithm improving the angular invariance of the scalar images and yielding an orientation distribution function to assist in delineating subtle boundaries where there are crossing fibers  and track density images providing insight into local fiber architecture.  A multigradient echo image of the same specimen was acquired at 25 um isotropic spatial resolution. A quantitative susceptibility map enhances fiber architecture relative to the magnitude images.  An accompanying multi-specimen atlas (n=6) was acquired with compressed sensing with the same diffusion protocol as used for the single specimen atlas.  An average was created using diffeomorphic mapping. Scalar volumes from the diffusion data, a T2* weighted volume, a quantitative susceptibility map, and a track density volume, all registered to the same space provide multiple contrasts to assist in anatomic delineation. The new template  provides significantly increased contrast in the scalar DTI images when compared to previous atlases. A compact interactive viewer based on 3D Slicer is provided to facilitate comparison among the contrasts in the multiple volumes. The single volume and average atlas with multiple 3D volumes provide an improved template for anatomic interrogation of the Wistar rat brain. The improved contrast to noise in the scalar DTI images and the addition of other volumes (eg. QA,QSM,TDI ) will facilitate automated label registration for MR histology and preclinical imaging.

A high-resolution interactive atlas of the human brainstem using magnetic resonance imaging.

Conventional atlases of the human brainstem are limited by the inflexible, sparsely-sampled, two-dimensional nature of histology, or the low spatial resolution of conventional magnetic resonance imaging (MRI). Postmortem high-resolution MRI circumvents the challenges associated with both modalities. A single human brainstem specimen extending from the rostral diencephalon through the caudal medulla was prepared for imaging after the brain was removed from a 65-year-old male within 24 h of death. The specimen was formalin-fixed for two weeks, then rehydrated and placed in a custom-made MRI compatible tube and immersed in liquid fluorocarbon. MRI was performed in a 7-Tesla scanner with 120 unique diffusion directions. Acquisition time for anatomic and diffusion images were 14 h and 208 h, respectively. Segmentation was performed manually. Deterministic fiber tractography was done using strategically chosen regions of interest and avoidance, with manual editing using expert knowledge of human neuroanatomy. Anatomic and diffusion images were rendered with isotropic resolutions of 50 µm and 200 µm, respectively. Ninety different structures were segmented and labeled, and 11 different fiber bundles were rendered with tractography. The complete atlas is available online for interactive use at https://www.civmvoxport.vm.duke.edu/voxbase/login.php?return_url=%2Fvoxbase%2F. This atlas presents multiple contrasting datasets and selected tract reconstruction with unprecedented resolution for MR imaging of the human brainstem. There are immediate applications in neuroanatomical education, with the potential to serve future applications for neuroanatomical research and enhanced neurosurgical planning through "safe" zones of entry into the human brainstem.

Investigating surface binding effects: antibacterial efficacy of bound 8-hydroxyquinoline against Staphylococcus aureus and Escherichia coli.

AIMS: To investigate the binding of the antimicrobial compound 8-hydroxyquinoline (8HQ) to a material interface and to determine whether immobilization affects the antibacterial efficacy. METHODS AND RESULTS: The 8HQ derivative 5-carboxy-8-hydroxyquinoline (5C8HQ) was attached to silica beads through amide bond coupling at the carboxyl moiety of 5C8HQ. Attachment of 5C8HQ was confirmed using a combination of mass spectrometry, thermogravimetric analysis, colorimetric testing and Soxhlet extraction. Computational modelling results indicated that this substitution did not compromise the active sites on the molecule, whereas other positions on the ring system could potentially inhibit antimicrobial activity. The antibacterial effect of 8HQ and the 5C8HQ-modified silica complex against Escherichia coli 15597 (ATCC® 25922) and Staphylococcus aureus (ATCC 25923) was evaluated. CONCLUSIONS: The test results show that the immobilized 8HQ continues to exhibit antibacterial activity, however, quantifying the efficacy compared to free 8HQ bears further investigation. The expected antibacterial mechanism requires that the metal chelation site of 8HQ be retained and available after attachment to a surface. The retention of antibacterial activity after surface bonding represents a novel mechanism of action not previously reported. SIGNIFICANCE AND IMPACT OF THE STUDY: Recent changes in regulations due to environmental concerns prompted many companies and organizations to explore antimicrobial treatments that are chemically bound to the product. Chemically bonding biocidal compounds to a surface limits environmental release; however, molecular mechanisms that drive antibacterial activity when compounds are immobilized are limited. The results reported here demonstrate that the 8HQ reactive site retains antibacterial efficacy even after covalent attachment to a surface. This approach supersedes other antimicrobial treatments where the active component is gradually released from the material surface in order to elicit antimicrobial effects. This specific antibacterial activity of bound 8HQ represents a novel mechanism of action not previously reported, and a potential conduit to a new class of bound antimicrobial materials.

Cytoarchitecture of the mouse brain by high resolution diffusion magnetic resonance imaging.

MRI has been widely used to probe the neuroanatomy of the mouse brain, directly correlating MRI findings to histology is still challenging due to the limited spatial resolution and various image contrasts derived from water relaxation or diffusion properties. Magnetic resonance histology has the potential to become an indispensable research tool to mitigate such challenges. In the present study, we acquired high spatial resolution MRI datasets, including diffusion MRI (dMRI) at 25 â€‹µm isotropic resolution and quantitative susceptibility mapping (QSM) at 21.5 â€‹µm isotropic resolution to validate with conventional mouse brain histology. Diffusion weighted images (DWIs) show better delineation of cortical layers and glomeruli in the olfactory bulb than fractional anisotropy (FA) maps. However, among all the image contrasts, including quantitative susceptibility mapping (QSM), T1/T2∗ images and DTI metrics, FA maps highlight unique laminar architecture in sub-regions of the hippocampus, including the strata of the dentate gyrus and CA fields of the hippocampus. The mean diffusivity (MD) and axial diffusivity (AD) yield higher correlation with DAPI (0.62 and 0.71) and NeuN (0.78 and 0.74) than with NF-160 (-0.34 and -0.49). The correlations between FA and DAPI, NeuN, and NF-160 are 0.31, -0.01, and -0.49, respectively. Our findings demonstrate that MRI at microscopic resolution deliver a three-dimensional, non-invasive and non-destructive platform for characterization of fine structural detail in both gray matter and white matter of the mouse brain.

Variability and heritability of mouse brain structure: Microscopic MRI atlases and connectomes for diverse strains.

Genome-wide association studies have demonstrated significant links between human brain structure and common DNA variants. Similar studies with rodents have been challenging because of smaller brain volumes. Using high field MRI (9.4 T) and compressed sensing, we have achieved microscopic resolution and sufficiently high throughput for rodent population studies. We generated whole brain structural MRI and diffusion connectomes for four diverse isogenic lines of mice (C57BL/6J, DBA/2J, CAST/EiJ, and BTBR) at spatial resolution 20,000 times higher than human connectomes. We measured narrow sense heritability (h2) I.e. the fraction of variance explained by strains in a simple ANOVA model for volumes and scalar diffusion metrics, and estimates of residual technical error for 166 regions in each hemisphere and connectivity between the regions. Volumes of discrete brain regions had the highest mean heritability (0.71 ± 0.23 SD, n = 332), followed by fractional anisotropy (0.54 ± 0.26), radial diffusivity (0.34 ± 0.022), and axial diffusivity (0.28 ± 0.19). Connection profiles were statistically different in 280 of 322 nodes across all four strains. Nearly 150 of the connection profiles were statistically different between the C57BL/6J, DBA/2J, and CAST/EiJ lines. Microscopic whole brain MRI/DTI has allowed us to identify significant heritable phenotypes in brain volume, scalar DTI metrics, and quantitative connectomes.

Characterization complex collagen fiber architecture in knee joint using high-resolution diffusion imaging.

PURPOSE: To evaluate the complex fiber orientations and 3D collagen fiber network of knee joint connective tissues, including ligaments, muscle, articular cartilage, and meniscus using high spatial and angular resolution diffusion imaging. METHODS: Two rat knee joints were scanned using a modified 3D diffusion-weighted spin echo pulse sequence with the isotropic spatial resolution of 45 µm at 9.4T. The b values varied from 250 to 1250 s/mm2 with 31 diffusion encoding directions for 1 rat knee. The b value was fixed to 1000 s/mm2 with 147 diffusion encoding directions for the second knee. Both the diffusion tensor imaging (DTI) model and generalized Q-sampling imaging (GQI) method were used to investigate the fiber orientation distributions and tractography with the validation of polarized light microscopy. RESULTS: To better resolve the crossing fibers, the b value should be great than or equal to 1000 s/mm2 . The tractography results were comparable between the DTI model and GQI method in ligament and muscle. However, the tractography exhibited apparent difference between DTI and GQI in connective tissues with more complex collagen fibers network, such as cartilage and meniscus. In articular cartilage, there were numerous crossing fibers found in superficial zone and transitional zone. Tractography generated with GQI also resulted in more intact tracts in articular cartilage than DTI. CONCLUSION: High-resolution diffusion imaging with GQI method can trace the complex collagen fiber orientations and architectures of the knee joint at microscopic resolution.

Qualitative and Quantitative Neuropathology Approaches Using Magnetic Resonance Microscopy (Diffusion Tensor Imaging) and Stereology in a Hexachlorophene Model of Myelinopathy in Sprague-Dawley Rats.

It is well established that hexachlorophene, which is used as an antibacterial agent, causes intramyelinic edema in humans and animal models. The hexachlorophene myelinopathy model, in which male Sprague-Dawley rats received 25 to 30 mg/kg hexachlorophene by gavage for up to 5 days, provided an opportunity to compare traditional neuropathology evaluations with magnetic resonance microscopy (MRM) findings. In addition, stereology assessments of 3 neuroanatomical sites were compared to quantitative measurements of similar structures by MRM. There were positive correlations between hematoxylin and eosin and luxol fast blue stains and MRM for identifying intramyelinic edema in the cingulum of corpus callosum, optic chiasm, anterior commissure (aca), lateral olfactory tracts, pyramidal tracts (py), and white matter tracts in the cerebellum. Stereology assessments were focused on the aca, longitudinal fasciculus of the pons, and py and demonstrated differences between control and treated rats, as was observed using MRM. The added value of MRM assessments was the ability to acquire qualitative 3-dimensional (3-D) images and obtain quantitative measurements of intramyelinic edema in 26 neuroanatomical sites in the intact brain. Also, diffusion tensor imaging (fractional anisotropy [FA]) indicated that there were changes in the cytoarchitecture of the white matter as detected by decreases in the FA in the treated compared to the control rats. This study demonstrates creative strategies that are possible using qualitative and quantitative assessments of potential white matter neurotoxicants in nonclinical toxicity studies. Our results lead us to the conclusion that volumetric analysis by MRM and stereology adds significant value to the standard 2-D microscopic evaluations.

Structural mapping with fiber tractography of the human cuneate fasciculus at microscopic resolution in cervical region.

Human spinal white matter tract anatomy has been mapped using post mortem histological information with the help of molecular tracing studies in animal models. This study used 7 Tesla diffusion MR tractography on a human cadaver that was harvested 24 hours post mortem to evaluate cuneate fasciculus anatomy in cervical spinal cord. Based on this method, for the first time much more nuanced tractographic anatomy was used to investigate possible new routes for cuneate fasciculus in the posterior and lateral funiculus. Additionally, current molecular tracing studies were reviewed, and confirmatory data was presented along with our radiological results. Both studies confirm that upon entry to the spinal cord, upper cervical level tracts (C1-2-3) travel inside lateral funiculus and lower level tracts travel medially inside the posterior funiculus after entry at posterolateral sulcus which is different than traditional knowledge of having cuneate fasciculus tracts concentrated in the lateral part of posterior funiculus.

Dynamic contrast-enhanced MRI promotes early detection of toxin-induced acute kidney injury.

Acute kidney injury (AKI) is a common cause of morbidity and mortality in hospitalized patients. Nevertheless, there is limited ability to diagnose AKI in its earliest stages through the collection of structural and functional information. Magnetic resonance imaging (MRI) is increasingly being used to provide structural and functional data that characterize the injured kidney. Dynamic contrast-enhanced (DCE) MRI is an imaging modality with robust spatial and temporal resolution; however, its ability to detect changes in kidney function following AKI has not been determined. We hypothesized that DCE MRI would detect a prolongation in contrast transit time following toxin-induced AKI earlier than commonly used serum and tissue biomarkers. To test our hypothesis, we injected mice with either vehicle or cisplatin (30 mg/kg) and performed DCE MRI at multiple time points. We found that commonly used kidney injury biomarkers, including creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin, did not rise until day 2 following cisplatin. Tissue levels of the proinflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1ß, IL-1α, IL-6, C-C motif chemokine ligand 2, and C-X-C motif chemokine ligand 2 similarly did not upregulate until day 2 following cisplatin. However, the time to peak intensity of contrast in the renal collecting system was already prolonged at day 1 following cisplatin compared with vehicle-treated mice. This intensity change mirrored changes in kidney injury as measured by histological analysis and in transporter expression in the proximal tubule. Taken together, DCE MRI is a promising preclinical imaging modality that is useful for assessing functional capacity of the kidney in the earliest stages following AKI.

Diffusion tractography of the rat knee at microscopic resolution.

PURPOSE: To evaluate whole knee joint tractography, including articular cartilage, ligaments, meniscus, and growth plate using diffusion tensor imaging (DTI) at microscopic resolution. METHODS: Three rat knee joints were scanned using a modified 3D diffusion-weighted spin echo pulse sequence with 90- and 45-µm isotropic spatial resolution at 9.4T. The b values varied from 250 to 1250 s/mm2 with 4 times undersampling in phase directions. Fractional anisotropy (FA) and mean diffusivity (MD) were compared at different spatial resolution and b values. Tractography was evaluated at multiple b values and angular resolutions in different connective tissues, and compared with conventional histology. The mean tract length and tract volume in various types of tissues were also quantified. RESULTS: DTI metrics (FA and MD) showed consistent quantitative results at 90- and 45-µm isotropic spatial resolutions. Tractography of various connective tissues was found to be sensitive to the spatial resolution, angular resolution, and diffusion weightings. Higher spatial resolution (45 µm) supported tracking the cartilage collagen fiber tracts from the superficial zone to the deep zone, in a continuous and smooth progression in the transitional zone. Fiber length and fiber volume in the growth plate were strongly dependent on angular resolution and b values, whereas tractography in ligaments was found to be less dependent on spatial resolution. CONCLUSION: High spatial and angular resolution DTI and diffusion tractography can be valuable for knee joint research because of its visualization capacity for collagen fiber orientations and quantitative evaluation of tissue's microscopic properties.

Thermionic Cooling of the Target Plasma to a Sub-eV Temperature.

Contemporary models of bounded plasmas assume that the target plasma electron temperature far exceeds the temperature of the cold electrons emitted from the target, T_{emit}. We show that when the sheath facing a collisional plasma becomes inverted, the target plasma electron temperature has to equal T_{emit} even if the upstream plasma is hotter by orders of magnitude. This extreme cooling effect can alter the plasma properties and the heat transmission to thermionically emitting surfaces in many applications. It also opens a possibility of using thermionic divertor plates to induce detachment in tokamaks.

A homozygous ADAMTS2 nonsense mutation in a Doberman Pinscher dog with Ehlers Danlos syndrome and extreme skin fragility.

An eight-week old Doberman Pinscher was diagnosed with Ehlers Danlos syndrome based on the dog's hyper-mobile carpal, tarsal and stifle joints and abnormal skin. The skin was loose and hyper-elastic with several wounds and large atrophic scars. The dog was euthanized after a severe degloving injury from minimal trauma. A whole-genome sequence, generated with DNA from the dog's blood, contained a rare, homozygous C-to-T transition at position 2408978 on chromosome 11. This transition is predicted to alter the ADAMTS2 transcript (ADAMTS2:c.769C>T) and encode a nonsense mutation (p.Arg257Ter). Biallelic ADAMTS2 mutations have caused a type of Ehlers Danlos syndrome known as dermatosparaxis in other species.

Diffusion tensor imaging using multiple coils for mouse brain connectomics.

The correlation between brain connectivity and psychiatric or neurological diseases has intensified efforts to develop brain connectivity mapping techniques on mouse models of human disease. The neural architecture of mouse brain specimens can be shown non-destructively and three-dimensionally by diffusion tensor imaging, which enables tractography, the establishment of a connectivity matrix and connectomics. However, experiments on cohorts of animals can be prohibitively long. To improve throughput in a 7-T preclinical scanner, we present a novel two-coil system in which each coil is shielded, placed off-isocenter along the axis of the magnet and connected to a receiver circuit of the scanner. Preservation of the quality factor of each coil is essential to signal-to-noise ratio (SNR) performance and throughput, because mouse brain specimen imaging at 7 T takes place in the coil-dominated noise regime. In that regime, we show a shielding configuration causing no SNR degradation in the two-coil system. To acquire data from several coils simultaneously, the coils are placed in the magnet bore, around the isocenter, in which gradient field distortions can bias diffusion tensor imaging metrics, affect tractography and contaminate measurements of the connectivity matrix. We quantified the experimental alterations in fractional anisotropy and eigenvector direction occurring in each coil. We showed that, when the coils were placed 12 mm away from the isocenter, measurements of the brain connectivity matrix appeared to be minimally altered by gradient field distortions. Simultaneous measurements on two mouse brain specimens demonstrated a full doubling of the diffusion tensor imaging throughput in practice. Each coil produced images devoid of shading or artifact. To further improve the throughput of mouse brain connectomics, we suggested a future expansion of the system to four coils. To better understand acceptable trade-offs between imaging throughput and connectivity matrix integrity, studies may seek to clarify how measurement variability, post-processing techniques and biological variability impact mouse brain connectomics.