A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Interplay of White Matter Hyperintensities, Cerebral Networks, and Cognitive Function in an Adult Population:Diffusion-Tensor Imaging in the Maastricht Study

Background: Lesions of cerebral small vessel disease, such as white matter hyperintensities (WMHs) in individuals with cardiometabolic risk factors, interfere with the trajectories of the white matter and eventually contribute to cognitive decline. However, there is no consensus yet about the precise underlying topological mechanism. Purpose: To examine whether WMH and cognitive function are associated and whether any such association is mediated or explained by structural connectivity measures in an adult population. In addition, to investigate underlying local abnormalities in white matter by assessing the tract-specific WMH volumes and their tract-specific association with cognitive function. Materials and Methods: In the prospective type 2 diabetes-enriched population-based Maastricht Study, structural and diffusion-tensor MRI was performed (December 2013 to February 2017). Total and tract-specific WMH volumes; network measures; cognition scores; and demographic, cardiovascular, and lifestyle characteristics were determined. Multivariable linear regression and mediation analyses were used to investigate the association of WMH volume, tract-specific WMH volumes, and network measures with cognitive function. Associations were adjusted for age, sex, education, diabetes status, and cardiovascular risk factors. Results: A total of 5083 participants (mean age, 59 years +/- 9 [standard deviation]; 2592 men; 1027 with diabetes) were evaluated. Larger WMH volumes were associated with stronger local (standardized beta coefficient, 0.065; P Conclusion: White matter hyperintensity volume, local network efficiency, and information processing speed scores are interrelated, and local network properties explain lower cognitive performance due to white matter network alterations. (C) RSNA, 202

BundleSeg: A versatile, reliable and reproducible approach to white matter bundle segmentation

This work presents BundleSeg, a reliable, reproducible, and fast method for extracting white matter pathways. The proposed method combines an iterative registration procedure with a recently developed precise streamline search algorithm that enables efficient segmentation of streamlines without the need for tractogram clustering or simplifying assumptions. We show that BundleSeg achieves improved repeatability and reproducibility than state-of-the-art segmentation methods, with significant speed improvements. The enhanced precision and reduced variability in extracting white matter connections offer a valuable tool for neuroinformatic studies, increasing the sensitivity and specificity of tractography-based studies of white matter pathways

SHEEP AS ANIMAL MODEL IN MINIMALLY INVASIVE NEUROSURGERY IN EDEN2020

Glioblastomas (GBMs) is a malignant type of central nervous system tumours and its presentation is almost 80% of all malignant primary brain neoplasia. This kind of tumour is highly invasive infiltrating the white matter area and is confined to the central nervous with a very poor patient outcome survival around 10 months. Of the existing treatment approaches, Convection Enhanced drug Delivery (CED) offers several advantages for the patient but still suffers from significant shortcomings. Enhanced Delivery Ecosystem for Neurosurgery in 2020 (EDEN2020) is a European project supported with a new catheter development as the key project point in an integrated technology platform for minimally invasive neurosurgery. Due to the particular anatomy and size, sheep (Ovis aries) have been selected as experimental large animal model and a new Head Frame system MRI/CT compatible has been made and validated ad hoc for the project. In order to understand experimentally the best target point for the catheter introduction a sheep brain DTI atlas has been created. Corticospinal tract (CST), corpus callosum (CC), fornix (FX), visual pathway (VP) and occipitofrontal fascicle (OF), have been identified bilaterally for all the animals. Three of these white matter tracts, the corpus callosum, the fornix and the corona radiata, have been selected to understand the drugs diffusion properties and create a computational model of diffusivity inside the white matter substance. The analysis have been conducted via Focused Ion Beam using scanning Electron Microscopy combined with focused ion beam milling and a 2D analysis and 3D reconstruction made. The results showed homogeneous myelination via detection of ~40% content of lipids in all the different fibre tracts and the fibrous organisation of the tissue described as composite material presenting elliptical tubular fibres with an average cross-sectional area of circa 0.52\u3bcm2 and an estimated mean diameter of 1.15\u3bcm. Finally, as the project is currently ongoing, we provided an overview on the future experimental steps focalised on the brain tissue damage after the rigid catheter introduction

A tract-specific approach to assessing white matter in preterm infants.

Diffusion-weighted imaging (DWI) is becoming an increasingly important tool for studying brain development. DWI analyses relying on manually-drawn regions of interest and tractography using manually-placed waypoints are considered to provide the most accurate characterisation of the underlying brain structure. However, these methods are labour-intensive and become impractical for studies with large cohorts and numerous white matter (WM) tracts. Tract-specific analysis (TSA) is an alternative WM analysis method applicable to large-scale studies that offers potential benefits. TSA produces a skeleton representation of WM tracts and projects the group's diffusion data onto the skeleton for statistical analysis. In this work we evaluate the performance of TSA in analysing preterm infant data against results obtained from native space tractography and tract-based spatial statistics. We evaluate TSA's registration accuracy of WM tracts and assess the agreement between native space data and template space data projected onto WM skeletons, in 12 tracts across 48 preterm neonates. We show that TSA registration provides better WM tract alignment than a previous protocol optimised for neonatal spatial normalisation, and that TSA projects FA values that match well with values derived from native space tractography. We apply TSA for the first time to a preterm neonatal population to study the effects of age at scan on WM tracts around term equivalent age. We demonstrate the effects of age at scan on DTI metrics in commissural, projection and association fibres. We demonstrate the potential of TSA for WM analysis and its suitability for infant studies involving multiple tracts

Imaging of Glial Cell Activation and White Matter Integrity in Brains of Active and Recently Retired National Football League Players

Importance: Microglia, the resident immune cells of the central nervous system, play an important role in the brain\u27s response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury. Objective: To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity. Design, Setting, and Participants: This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level-, and body mass index-matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016. Main Outcomes and Measures: Positron emission tomography-based regional measures of TSPO using [11C]DPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance. Results: The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using [11C]DPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P \u3c .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance. Conclusions and Relevance: The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms