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We have for the first time reported 120 nm silver/iron oxide hybrid nano-popcorns with surface plasmon resonance tuned at near-infrared (NIR) range for imaging and therapeutic applications. The nano-popcorns displayed excellent photothermal thrombolytic effect and anticancer activity in a concentration-dependent manner upon NIR laser irradiation, benefiting the photothermal treatment of thrombosis and cancer. At low concentrations, the nano-popcorns exhibited relatively good reactive oxygen species (ROS) scavenging capability. Notably, the nano-popcorns exerted excellent magnetic resonance imaging (MRI) T2-signal after being sequestered within cells or binding on the surface of the thrombus, becoming a promising imaging agent for cell labeling and thrombus detection. Cytotoxicity, biodistribution studies, and histology analysis demonstrated no significant toxicity caused by the nano-popcorns. There was no long-term retention of the nano-popcorns in the mouse organs at the dose treated. These results give insight into the potential of using these nano-popcorns for diagnosis and treatment of diseases related to ROS, cancer, and thrombosis.

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

Reactive oxygen species (ROS) play an essential role in the progression of many chronic diseases like atherosclerosis and rheumatoid arthritis. For decades, antioxidant compounds have always been considered as potential treatments for these ROS-related diseases. Concomitantly, noninvasive imaging systems such as magnetic resonance imaging (MRI) have also been widely used in the diagnosis of diseases, especially atherosclerosis. In this study, we investigated the feasibility to develop chitosan nanococktails containing both nanoceria and superparamagnetic iron oxide nanoparticles for ROS-related theranostics. Nanoceria utilized as therapeutic modules capable of ROS scavenging and iron-oxide nanoparticles utilized as imaging agents for MRI have been synthesized separately. Subsequently, two versions of theranostic chitosan nanococktails containing both nanoceria and iron oxide nanoparticles (Chit-IOCO and Chit-TPP-IOCO) were successfully synthesized via two different mechanisms, electrostatic self-assembly, and ionic gelation. In vitro studies such as cytotoxicity, MRI, and ROS scavenging were performed. These theranostic nanococktails demonstrated effective ROS scavenging and MRI contrast as a potential platform for treatment and diagnosis of ROS-related diseases. Results indicated that both Chit-IOCO and Chit-TPP-IOCO can reduce the ROS level of the lipopolysaccharide-stimulated macrophage J774A.1 to the baseline level. Chit-IOCO was less toxic to the cells than Chit-TPP-IOCO. In addition, Chit-IOCO exhibited higher MRI relaxivity than Chi-TPP-IOCO (308 and 150 mM-1 s-1, respectively), indicating that Chi-IOCO was more effective than Chit-TPP-IOCO as an MRI contrast agent in macrophages. Taken together, Chit-IOCO nanococktail demonstrates outstanding potential for treatment and diagnosis of ROS-related diseases. Potentially, this nanococktail can be easily modified to include new modules, allowing future application of personalized medicine.

A series of terpolymers of styrene, oligoethylene glycol methyl ether methacrylate and 2,2,2-trifluoroethyl acrylate were synthesized by free radical polymerization. The lower critical solution temperature (LCST) of the polymers was tuned to close to physiological temperature by controlling the hydrophobic (styrene) content. The thermoresponsive properties of the polymers were studied by nuclear magnetic resonance spectroscopy, UV-vis spectroscopy and dynamic light scattering experiments. The effect of styrene content on 1H and 19F NMR, 19F T2 relaxation times and 19F magnetic resonance imaging (MRI) was examined in detail at various temperatures. It was observed that above the LCST the 19F MR imaging intensity drops, as a consequence of enhanced dipolar interactions involving 19F spins. These results aided the design of a thermo- and pH-responsive 19F MRI agent by incorporation of a hydrophobic model drug via an acid cleavable hydrazone linkage. It was demonstrated that with the release of the model hydrophobic drug, the LCST of the polymer was elevated due to reduced hydrophobicity, enhancing the 19F MRI signal at the given measurement temperature. The results provide the basis for the development of switchable 19F MR-guided theranostic platforms for targeted drug delivery of hydrophobic chemotherapeutic drugs as well as quantifying the amount of drug released at the target site.

Cuttlefishes, like their octopus cousins, are masters of camouflage by control of body pattern and skin texture to blend in with their surroundings for prey ambush and threat avoidance. Aside from significant progress on the cuttlefish visual perception and communication, a growing number of studies have focused on their behavioural neurobiology and the remarkably rapid and apparently cognitively complex reactions to novel challenges such as spatial learning to solve maze tasks and vertebrate-like cognitive capabilities (e.g. object recognition, number sense and episodic-like memory). Despite intense interest of cuttlefish, much of our knowledge of its neuroanatomy and links to behaviour and ecology comes from one temperate species, the European common cuttlefish, Sepia officinalis. Here we present the first detailed comparison of neuroanatomical features between the tropical cuttlefish and squid and describe differences in basic brain and wiring anatomy using MRI-based techniques and conventional histology. Furthermore, comparisons amongst nocturnal and diurnal cuttlefish species suggest that the characteristic neuroanatomical features infer interspecific variation in visual capabilities, the importance of vision relative to the less utilised chemosensory system and clear links with life modes (e.g. diurnal vs nocturnal), ecological factors (e.g. living depth and ambient light condition) as well as to an extent, phylogeny. These findings link brain heterogeneity to ecological niches and lifestyle, feeding hypotheses around evolutionary history and provide a timely, new technology update to older literature.

Introduction High‐resolution magnetic resonance imaging (MRI) of the cervical spinal cord is important to provide accurate diagnosis and pathological assessment of injuries. MEDIC (Multiple Echo Data Image Combination) sequences have been used in clinical MRI; however, a comparison of the performance of 2D and 3D MEDIC for cervical spinal cord imaging has not been reported. The aim of this study is to compare axial 2D and 3D MEDIC for the visualisation of the grey matter (GM) and white matter (WM) of the human cervical spinal cord. Methods Eight healthy participants were scanned using Siemens Prismafit 3T MRI. T2*‐weighted gradient spoiled 2D and 3D MEDIC sequences were acquired at 0.4 × 0.4 × 3.0 and 0.3 × 0.3 × 3.0 mm resolutions, with the acquisition times of 6 and 7 min, respectively. Quantitative analyses of the images were made based on the image signal‐to‐noise ratio (SNR), contrast‐to‐noise ratio (CNR) and non‐uniformity (NU). Two independent radiologists (CS and FN), each provided Likert scoring assessments of anatomical visibility of the GM and WM structures and image clarity for all samples. Results Quantitative evaluation showed that 3D MEDIC provided higher SNR, higher CNR and lower NU than 2D MEDIC. However, 2D MEDIC provided better anatomical visibility for the GM, WM and CSF, and higher image clarity (lower artefacts) compared to 3D MEDIC. Conclusions 2D MEDIC provides better information for depicting the internal structures of the cervical spinal cord compared to 3D MEDIC., 2D MEDIC provided better quality images for depicting the cervical spinal cord's white and grey matter structures with reduced artefacts and superior clarity compared to the 3D MEDIC. This paper showed that the 2D MEDIC can potentially be used to obtain reliable measurements of atrophy and lesions in the internal spinal cord structures, which is important for diagnosis in diseases such as multiple sclerosis and spinal cord injury.

Introduction Prenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABAa receptors (GABAaR), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABAaR, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABAaR density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation. It was hypothesized that early moderate PEE would cause alterations in brain GABAaR levels in the adult offspring. Methods C57BL/6J mice were given 10% v/v ethanol during the first 8 gestational days. Male offspring were studied using in-vivo Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), biodistribution, in-vitro autoradiography using [18F]AH114726, a novel flumazenil analogue with a high affinity for the benzodiazepine-binding site, and validated using immunohistochemistry. Results In vivo PET and biodistribution did not detect alteration in brain tracer uptake. In vitro radiotracer studies detected significantly reduced GABAaR in the olfactory bulbs. Immunohistochemistry detected reduced GABAaR in the cerebral cortex, cerebellum and hippocampus, while Nissl staining showed that cell density was significantly higher in the striatum following PEE. Conclusion Early moderate PEE may induce long-term alterations in the GABAaR system that persisted into adulthood.

Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of upper and lower motor neurons. There is a need for an imaging biomarker to track disease progression. Previously, magnetic resonance imaging (MRI) has shown loss of grey and white matter in the brain of patients with ALS compared to controls. We performed serial diffusion tractography imaging (DTI) study of patients with ALS looking for changes over time. Methods On all subjects (n = 15), we performed three MRI studies at 6 month intervals. DTI changes were assessed with tract-based spatial statistics (TBSS) and region of interest (ROI) studies. Cortic-spinal tract (CST) was selected for our ROI at the upper level; the posterior limb of internal capsule (PLIC), and a lower level in the pons. Results There was no significant change in DTI measures over 12 months of observation. Better correlation of manual and atlas-based ROI methods was found in the posterior limb of the internal capsule than the pons. Conclusion While previous DTI studies showed significant differences between ALS subjects and controls, within individual subjects there is little evidence of progression over 12 months. This suggests that DTI is not a suitable biomarker to assess disease progression in ALS.

Summary We have shown that the improvement in hippocampal-based learning in aged mice following physical exercise observed is dependent on neurogenesis in the dentate gyrus (DG) and is regulated by changes in growth hormone levels. The changes in neurocircuitry, however, which may underlie this improvement, remain unclear. Using in vivo multimodal magnetic resonance imaging to track changes in aged mice exposed to exercise, we show the improved spatial learning is due to enhanced DG connectivity, particularly the strengthening of the DG-Cornu Ammonis 3 and the DG-medial entorhinal cortex connections in the dorsal hippocampus. Moreover, we provide evidence that these changes in circuitry are dependent on neurogenesis since they were abrogated by ablation of newborn neurons following exercise. These findings identify the specific changes in hippocampal circuitry that underlie the cognitive improvements resulting from physical activity and show that they are dependent on the activation of neurogenesis in aged animals., Graphical abstract, Highlights • Exercise can enhance connectivity in the dorsal hippocampus to improve spatial learning • Circuitry changes depend on increased neurogenesis in the hippocampus of aged animals • Identification of the specific changes in circuitry underlying cognitive improvements • Enhanced connectivity occurs only after exercise of a specific duration: the sweet spot, Cognitive neuroscience, Behavioral neuroscience, Biological sciences

Summary Octopods are masters of camouflage and solve complex tasks, and their cognitive ability is said to approach that of some small mammals. Despite intense interest and some research progress, much of our knowledge of octopus neuroanatomy and its links to behavior and ecology comes from one coastal species, the European common octopus, Octopus vulgaris. Octopod species are found in habitats including complex coral reefs and the relatively featureless mid-water. There they encounter different selection pressures, may be nocturnal or diurnal, and are mostly solitary or partially social. How these different ecologies and behavioral differences influence the octopus central nervous system (CNS) remains largely unknown. Here we present a phylogenetically informed comparison between diurnal and nocturnal coastal and a deep-sea species using brain imaging techniques. This study shows that characteristic neuroanatomical changes are linked to their habits and habitats. Enlargement and division of the optic lobe as well as structural foldings and complexity in the underlying CNS are linked to behavioral adaptation (diurnal versus nocturnal; social versus solitary) and ecological niche (reef versus deep sea), but phylogeny may play a part also. The difference between solitary and social life is mirrored within the brain including the formation of multiple compartments (gyri) in the vertical lobe, which is likened to the vertebrate cortex. These findings continue the case for convergence between cephalopod and vertebrate brain structure and function. Notably, within the current push toward comparisons of cognitive abilities, often with unashamed anthropomorphism at their root, these findings provide a firm grounding from which to work.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/. The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord., Measurement(s)spinal cordTechnology Type(s)magnetic resonance imagingFactor Type(s)manufacturer • siteSample Characteristic - OrganismHomo sapiensSample Characteristic - LocationCanada • Switzerland • Australia • United States of America • United Kingdom • Germany • French Republic • Czech Republic • Italy • Japan • Kingdom of Spain • China Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14052269

Converging evidence from human and animal studies support an association between vitamin D deficiency and cognitive impairment. Previous studies have shown that hippocampal volume is reduced in adults with vitamin D deficiency as well as in a range of disorders, such as schizophrenia. The aim of the current study was to examine the effect of adult vitamin D (AVD) deficiency on hippocampal-dependent spatial learning, and hippocampal volume and connectivity in healthy adult mice. Ten-week-old male BALB/c mice were fed a control (vitamin D 1500 IU/kg) or vitamin D-depleted (vitamin D 0 IU/kg) diet for a minimum of 10 weeks. The mice were then tested for hippocampal-dependent spatial learning using active place avoidance (APA) and on tests of muscle and motor coordination (rotarod and grip strength). The mice were perfused and brains collected to acquire ex vivo structural and diffusion-weighted images using a 16.4 T MRI scanner. We also performed immunohistochemistry to quantify perineuronal nets (PNNs) and parvalbumin (PV) interneurons in various brain regions. AVD-deficient mice had a lower latency to enter the shock zone on APA, compared to control mice, suggesting impaired hippocampal-dependent spatial learning. There were no differences in rotarod or grip strength, indicating that AVD deficiency did not have an impact on muscle or motor coordination. AVD deficiency did not have an impact on hippocampal volume. However, AVD-deficient mice displayed a disrupted network centred on the right hippocampus with abnormal connectomes among 29 nodes. We found a reduction in PNN positive cells, but no change in PV, centred on the hippocampus. Our results provide compelling evidence to show that AVD deficiency in otherwise healthy adult mice may play a key role in hippocampal-dependent learning and memory formation. We suggest that the spatial learning deficits could be due to the disruption of right hippocampal structural connectivity.

Background This study was performed to assess changes in diffusion tensor imaging (DTI) over time in patients with amyotrophic lateral sclerosis (ALS). Methods We performed DTI in 23 ALS patients who had two magnetic resonance imaging (MRI) scans at 6 month intervals and to correlate results with clinical features. The revised ALS functional rating scale (ALSFRS–R) was administered at each clinical visit. Data analysis included voxel–based white matter tract–based spatial statistics (TBSS) and atlas–based region–of–interest (ROI) analysis of fractional anisotropy (FA) and mean diffusivity (MD). Results With TBSS, there were no significant changes between the two scans. The average change in FA and MD in the ROIs over 6 months was small and not significant after allowing for multiple comparisons. After allowing for multiple comparisons, there was no significant correlation of FA or MD with ALSFRS–R. Conclusion This study shows that there is little evidence of progressive changes in DTI over time in ALS. This could be because white matter is already substantially damaged by the time of onset of symptoms of ALS.

Background Nuclear Factor One X (NFIX) haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to the enlarged head circumference and intellectual disability in these patients remains undefined. Methods Here, we used Nfix heterozygous mice as a model to investigate these aspects of Malan syndrome. Volumetric magnetic resonance imaging (MRI) was used to calculate the volumes of 20 brain sub regions. Diffusion tensor MRI was used to perform tractography-based analyses of the corpus callosum, hippocampal commissure, and anterior commissure, as well as structural connectome mapping of the whole brain. Immunohistochemistry examined the neocortical cellular populations. Two behavioral assays were performed, including the active place avoidance task to assess spatial navigation and learning and memory function, and the 3-chambered sociability task to examine social behaviour. Findings Adult Nfix+/− mice exhibit significantly increased brain volume (megalencephaly) compared to wildtypes, with the cerebral cortex showing the highest increase. Moreover, all three forebrain commissures, in particular the anterior commissure, revealed significantly reduced fractional anisotropy, axial and radial diffusivity, and tract density intensity. Structural connectome analyses revealed aberrant connectivity between many crucial brain regions. Finally, Nfix+/− mice exhibit behavioral deficits that model intellectual disability. Interpretation Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit. Fund Australian Research Council (ARC) Discovery Project Grants, ARC Fellowship, NYSTEM and Australian Postgraduate Fellowships.

The subiculum is the major output component of the hippocampal formation and one of the major brain structures most affected by Alzheimer’s disease. Our previous work revealed a hidden laminar architecture within the mouse subiculum. However, the rotation of the hippocampal longitudinal axis across species makes it unclear how the laminar organization is represented in human subiculum. Using in situ hybridization data from the Allen Human Brain Atlas, we demonstrate that the human subiculum also contains complementary laminar gene expression patterns similar to the mouse. In addition, we provide evidence that the molecular domain boundaries in human subiculum correspond to microstructural differences observed in high resolution MRI and fiber density imaging. Finally, we show both similarities and differences in the gene expression profile of subiculum pyramidal cells within homologous lamina. Overall, we present a new 3D model of the anatomical organization of human subiculum and its evolution from the mouse.

Octopods are masters of camouflage, solving complex tasks, expressing emotion and their cognitive ability is said to approach that of some small mammals. Despite intense interest and some research progress, much of our knowledge of octopus neuroanatomy and its links to behaviour and ecology comes from one coastal species, the European common octopus, Octopus vulgaris a largely nocturnal coastal dweller. Octopod species are found in habitats including complex coral reefs to the relatively featureless deep mid-water. There they encounter different selection pressures, may be nocturnal or diurnal and mostly solitary or partially social. How these different ecologies and behavioural differences influence the octopus central nervous system (CNS) or brain remains largely unknown. Here we present a phylogenetically-informed comparison between diurnal and nocturnal coastal and a deep-sea species using brain imaging techniques. This study shows that characteristic neuroanatomical changes are linked to their life modes and ecological niches. Octopods are voracious visual predators and we demonstrate enlargement and division of the optic lobe as well as structural foldings and complexity in the underlying CNS. It appears these modifications are linked to behavioural adaptation (diurnal versus nocturnal; social versus solitary) and ecological niche (reef versus deep sea), but phylogeny may play a part also. The difference between solitary and social life is mirrored within the brain including the formation of multiple compartments, or gyri, in the vertical lobe. This brain region has previously been linked to cognitive capability and is likened to the vertebrate cortex. Some of the life-mode related modifications described here are convergent with similar progressions of complexity found within the vertebrates. These findings continue the case for convergence between cephalopod and vertebrate brain structure and function. Notably, within the current push towards comparisons of cognitive abilities, often with unashamed anthropomorphism at their root, these findings provide a firm grounding from which to work.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.

In this study we combined ultra-high field diffusion MRI fiber tracking and super-resolution track density imaging (TDI) to map the relay locations and connectivity of the somatosensory pathway in paraformaldehyde fixed, C57Bl/6J mouse brains. Super-resolution TDI was used to achieve 20 μm isotropic resolution to inform the 3D topography of the relay locations including thalamic barreloids and brainstem barrelettes, not described previously using MRI methodology. TDI-guided mapping results for thalamo-cortical connectivity were consistent with thalamo-cortical projections labeled using virus mediated fluorescent protein expression. Trigemino-thalamic TDI connectivity maps were concordant with results obtained using anterograde dye tracing from brainstem to thalamus. Importantly, TDI mapping overcame the constraint of tissue distortion observed in mechanically sectioned tissue, enabling 3D reconstruction and long-range connectivity data. In conclusion, our results showed that diffusion micro-imaging at ultra-high field MRI revealed the stereotypical pattern of somatosensory connectivity and is a valuable tool to complement histologic methods, achieving 3D spatial preservation of whole brain networks for characterization in mouse models of human disease.

Genetic association studies have identified many factors associated with neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the way these genes shape neuroanatomical structure and connectivity is poorly understood. Recent research has focused on proteins that act as points of convergence for multiple factors, as these may provide greater insight into understanding the biology of neurodevelopmental disorders. USP9X, a deubiquitylating enzyme that regulates the stability of many ASD-related proteins, is one such point of convergence. Loss of function variants in human USP9X lead to brain malformations, which manifest as a neurodevelopmental syndrome that frequently includes ASD, but the underlying structural and connectomic abnormalities giving rise to patient symptoms is unknown. Here, we analyzed forebrain-specific Usp9x knockout mice (Usp9x−/y) to address this knowledge gap. Usp9x−/y mice displayed abnormal communication and social interaction behaviors. Moreover, the absence of Usp9x culminated in reductions to the size of multiple brain regions. Diffusion tensor magnetic resonance imaging revealed deficits in all three major forebrain commissures, as well as long-range hypoconnectivity between cortical and subcortical regions. These data identify USP9X as a key regulator of brain formation and function, and provide insights into the neurodevelopmental syndrome arising as a consequence of USP9X mutations in patients.