Clade-specific forebrain cytoarchitectures of the extinct Tasmanian tiger.

The thylacine, or Tasmanian tiger, is the largest of modern-day carnivorous marsupials and was hunted to extinction by European settlers in Australia. Its physical resemblance to eutherian wolves is a striking example of evolutionary convergence to similar ecological niches. However, whether the neuroanatomical organization of the thylacine brain resembles that of canids and how it compares with other mammals remain unknown due to the scarcity of available samples. Here, we gained access to a century-old hematoxylin-stained histological series of a thylacine brain, digitalized it at high resolution, and compared its forebrain cellular architecture with 34 extant species of monotremes, marsupials, and eutherians. Phylogenetically informed comparisons of cortical folding, regional volumes, and cell sizes and densities across cortical areas and layers provide evidence against brain convergences with canids, instead demonstrating features typical of marsupials, and more specifically Dasyuridae, along with traits that scale similarly with brain size across mammals. Enlarged olfactory, limbic, and neocortical areas suggest a small-prey predator and/or scavenging lifestyle, similar to extant quolls and Tasmanian devils. These findings are consistent with a nonuniformity of trait convergences, with brain traits clustering more with phylogeny and head/body traits with lifestyle. By making this resource publicly available as rapid web-accessible, hierarchically organized, multiresolution images for perpetuity, we anticipate that additional comparative insights might arise from detailed studies of the thylacine brain and encourage researchers and curators to share, annotate, and preserve understudied material of outstanding biological relevance.

The topography of corticopontine projections is controlled by postmitotic expression of the area-mapping gene Nr2f1.

Axonal projections from layer V neurons of distinct neocortical areas are topographically organized into discrete clusters within the pontine nuclei during the establishment of voluntary movements. However, the molecular determinants controlling corticopontine connectivity are insufficiently understood. Here, we show that an intrinsic cortical genetic program driven by Nr2f1 graded expression is directly implicated in the organization of corticopontine topographic mapping. Transgenic mice lacking cortical expression of Nr2f1 and exhibiting areal organization defects were used as model systems to investigate the arrangement of corticopontine projections. By combining three-dimensional digital brain atlas tools, Cre-dependent mouse lines and axonal tracing, we show that Nr2f1 expression in postmitotic neurons spatially and temporally controls somatosensory topographic projections, whereas expression in progenitor cells influences the ratio between corticopontine and corticospinal fibres passing the pontine nuclei. We conclude that cortical gradients of area-patterning genes are directly implicated in the establishment of a topographic somatotopic mapping from the cortex onto pontine nuclei.

Waxholm Space atlas of the rat brain auditory system: Three-dimensional delineations based on structural and diffusion tensor magnetic resonance imaging.

The mammalian auditory system comprises a complex network of brain regions. Interpretations and comparisons of experimental results from this system depend on appropriate anatomical identification of auditory structures. The Waxholm Space (WHS) atlas of the Sprague Dawley rat brain (Papp et al., Neuroimage 97:374-86, 2014) is an open access, three-dimensional reference atlas defined in an ex-vivo magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) volume. Version 2.0 of the atlas (Kjonigsen et al., Neuroimage 108:441-9, 2015) includes detailed delineations of the hippocampus and several major subcortical regions, but only few auditory structures. To amend this, we have delineated the complete ascending auditory system from the cochlea to the cerebral cortex. 40 new brain structure delineations have been added, and the delineations of 10 regions have been revised based on the interpretation of image features in the WHS rat brain MRI/DTI volumes. We here describe and validate the new delineations in relation to corresponding cell- and myelin-stained histological sections and previous literature. We found it possible to delineate all main regions and the majority of subregions and fibre tracts of the ascending auditory pathway, apart from the auditory cortex, for which delineations were extrapolated from a conventional two-dimensional atlas. By contrast, only parts of the descending pathways were discernible in the template. Version 3.0 of the atlas, with altogether 118 anatomical delineations, is shared via the NeuroImaging Tools and Resources Collaboratory (www.nitrc.org).

Waxholm Space atlas of the rat brain hippocampal region: three-dimensional delineations based on magnetic resonance and diffusion tensor imaging.

Atlases of the rat brain are widely used as reference for orientation, planning of experiments, and as tools for assigning location to experimental data. Improved quality and use of magnetic resonance imaging (MRI) and other tomographical imaging techniques in rats have allowed the development of new three-dimensional (3-D) volumetric brain atlas templates. The rat hippocampal region is a commonly used model for basic research on memory and learning, and for preclinical investigations of brain disease. The region features a complex anatomical organization with multiple subdivisions that can be identified on the basis of specific cytoarchitectonic or chemoarchitectonic criteria. We here investigate the extent to which it is possible to identify boundaries of divisions of the hippocampal region on the basis of high-resolution MRI contrast. We present the boundaries of 13 divisions, identified and delineated based on multiple types of image contrast observed in the recently published Waxholm Space MRI/DTI template for the Sprague Dawley rat brain (Papp et al., Neuroimage 97:374-386, 2014). The new detailed delineations of the hippocampal formation and parahippocampal region (Waxholm Space atlas of the Sprague Dawley rat brain, v2.0) are shared via the INCF Software Center (http://software.incf.org/), where also the MRI/DTI reference template is available. The present update of the Waxholm Space atlas of the rat brain is intended to facilitate interpretation, analysis, and integration of experimental data from this anatomically complex region.

Waxholm Space atlas of the Sprague Dawley rat brain.

Three-dimensional digital brain atlases represent an important new generation of neuroinformatics tools for understanding complex brain anatomy, assigning location to experimental data, and planning of experiments. We have acquired a microscopic resolution isotropic MRI and DTI atlasing template for the Sprague Dawley rat brain with 39 µm isotropic voxels for the MRI volume and 78 µm isotropic voxels for the DTI. Building on this template, we have delineated 76 major anatomical structures in the brain. Delineation criteria are provided for each structure. We have applied a spatial reference system based on internal brain landmarks according to the Waxholm Space standard, previously developed for the mouse brain, and furthermore connected this spatial reference system to the widely used stereotaxic coordinate system by identifying cranial sutures and related stereotaxic landmarks in the template using contrast given by the active staining technique applied to the tissue. With the release of the present atlasing template and anatomical delineations, we provide a new tool for spatial orientation analysis of neuroanatomical location, and planning and guidance of experimental procedures in the rat brain. The use of Waxholm Space and related infrastructures will connect the atlas to interoperable resources and services for multi-level data integration and analysis across reference spaces.

Vascular synthesis based on hemodynamic efficiency principle recapitulates measured cerebral circulation properties in the human brain.

Quantifying anatomical and hemodynamical properties of the brain vasculature in vivo is difficult due to limited spatiotemporal resolution neuroimaging, variability between subjects, and bias between acquisition techniques. This work introduces a metabolically inspired vascular synthesis algorithm for creating a digital representation of the cortical blood supply in humans. Spatial organization and segment resistances of a cortical vascular network were generated. Cortical folding and macroscale arterial and venous vessels were reconstructed from anatomical MRI and MR angiography. The remaining network, including ensembles representing the parenchymal capillary bed, were synthesized following a mechanistic principle based on hydrodynamic efficiency of the cortical blood supply. We evaluated the digital model by comparing its simulated values with in vivo healthy human brain measurements of macrovessel blood velocity from phase contrast MRI and capillary bed transit times and bolus arrival times from dynamic susceptibility contrast. We find that measured and simulated values reasonably agree and that relevant neuroimaging observables can be recapitulated in silico. This work provides a basis for describing and testing quantitative aspects of the cerebrovascular circulation that are not directly observable. Future applications of such digital brains include the investigation of the organ-wide effects of simulated vascular and metabolic pathologies.

Noninvasive Electrical Stimulation Neuromodulation and Digital Brain Technology: A Review.

We review the research progress on noninvasive neural regulatory systems through system design and theoretical guidance. We provide an overview of the development history of noninvasive neuromodulation technology, focusing on system design. We also discuss typical cases of neuromodulation that use modern noninvasive electrical stimulation and the main limitations associated with this technology. In addition, we propose a closed-loop system design solution of the "time domain", "space domain", and "multi-electrode combination". For theoretical guidance, this paper provides an overview of the "digital brain" development process used for noninvasive electrical-stimulation-targeted modeling and the development of "digital human" programs in various countries. We also summarize the core problems of the existing "digital brain" used for noninvasive electrical-stimulation-targeted modeling according to the existing achievements and propose segmenting the tissue. For this, the tissue parameters of a multimodal image obtained from a fresh cadaver were considered as an index. The digital projection of the multimodal image of the brain of a living individual was implemented, following which the segmented tissues could be reconstructed to obtain a "digital twin brain" model with personalized tissue structure differences. The "closed-loop system" and "personalized digital twin brain" not only enable the noninvasive electrical stimulation of neuromodulation to achieve the visualization of the results and adaptive regulation of the stimulation parameters but also enable the system to have individual differences and more accurate stimulation.

A dynamic simulation framework for CT perfusion in stroke assessment built from first principles.

PURPOSE: Physicians utilize cerebral perfusion maps (e.g., cerebral blood flow, cerebral blood volume, transit time) to prescribe the plan of care for stroke patients. Variability in scanning techniques and post-processing software can result in differences between these perfusion maps. To determine which techniques are acceptable for clinical care, it is important to validate the accuracy and reproducibility of the perfusion maps. Validation using clinical data is challenging due to the lack of a gold standard to assess cerebral perfusion and the impracticality of scanning patients multiple times with different scanning techniques. In contrast, simulated data from a realistic digital phantom of the cerebral perfusion in acute stroke patients would enable studies to optimize and validate the scanning and post-processing techniques. METHODS: We describe a complete framework to simulate CT perfusion studies for stroke assessment. We begin by expanding the XCAT brain phantom to enable spatially varying contrast agent dynamics and incorporate a realistic model of the dynamics in the cerebral vasculature derived from first principles. A dynamic CT simulator utilizes the time-concentration curves to define the contrast agent concentration in the object at each time point and generates CT perfusion images compatible with commercially available post-processing software. We also generate ground truth perfusion maps to which the maps generated by post-processing software can be compared. RESULTS: We demonstrate a dynamic CT perfusion study of a simulated patient with an ischemic stroke and the resulting perfusion maps generated by post-processing software. We include a visual comparison between the computer-generated perfusion maps and the ground truth perfusion maps. The framework is highly tunable; users can modify the perfusion properties (e.g., occlusion location, CBF, CBV, and MTT), scanner specifications (e.g., focal spot size and detector configuration), scanning protocol (e.g., kVp and mAs), and reconstruction parameters (e.g., slice thickness and reconstruction filter). CONCLUSIONS: This framework provides realistic test data with the underlying ground truth that enables a robust assessment of CT perfusion techniques and post-processing methods for stroke assessment.

Changes of the Brain Causal Connectivity Networks in Patients With Long-Term Bilateral Hearing Loss.

It remains poorly understood how brain causal connectivity networks change following hearing loss and their effects on cognition. In the current study, we investigated this issue. Twelve patients with long-term bilateral sensorineural hearing loss [mean age, 55.7 ± 2.0; range, 39-63 years; threshold of hearing level (HL): left ear, 49.0 ± 4.1 dB HL, range, 31.25-76.25 dB HL; right ear, 55.1 ± 7.1 dB HL, range, 35-115 dB HL; the duration of hearing loss, 16.67 ± 4.5, range, 3-55 years] and 12 matched normally hearing controls (mean age, 52.3 ± 1.8; range, 42-63 years; threshold of hearing level: left ear, 17.6 ± 1.3 dB HL, range, 11.25-26.25 dB HL; right ear, 19.7 ± 1.3 dB HL, range, 8.75-26.25 dB HL) participated in this experiment. We constructed and analyzed the causal connectivity networks based on functional magnetic resonance imaging data of these participants. Two-sample t-tests revealed significant changes of causal connections and nodal degrees in the right secondary visual cortex, associative visual cortex, right dorsolateral prefrontal cortex, left subgenual cortex, and the left cingulate cortex, as well as the shortest causal connectivity paths from the right secondary visual cortex to Broca's area in hearing loss patients. Neuropsychological tests indicated that hearing loss patients presented significant cognitive decline. Pearson's correlation analysis indicated that changes of nodal degrees and the shortest causal connectivity paths were significantly related with poor cognitive performances. We also found a cross-modal reorganization between associative visual cortex and auditory cortex in patients with hearing loss. Additionally, we noted that visual and auditory signals had different effects on neural activities of Broca's area, respectively. These results suggest that changes in brain causal connectivity network are an important neuroimaging mark of cognitive decline. Our findings provide some implications for rehabilitation of hearing loss patients.

Multimodal cross-registration and quantification of metric distortions in marmoset whole brain histology using diffeomorphic mappings.

Whole brain neuroanatomy using tera-voxel light-microscopic data sets is of much current interest. A fundamental problem in this field is the mapping of individual brain data sets to a reference space. Previous work has not rigorously quantified in-vivo to ex-vivo distortions in brain geometry from tissue processing. Further, existing approaches focus on registering unimodal volumetric data; however, given the increasing interest in the marmoset model for neuroscience research and the importance of addressing individual brain architecture variations, new algorithms are necessary to cross-register multimodal data sets including MRIs and multiple histological series. Here we present a computational approach for same-subject multimodal MRI-guided reconstruction of a series of consecutive histological sections, jointly with diffeomorphic mapping to a reference atlas. We quantify the scale change during different stages of brain histological processing using the Jacobian determinant of the diffeomorphic transformations involved. By mapping the final image stacks to the ex-vivo post-fixation MRI, we show that (a) tape-transfer assisted histological sections can be reassembled accurately into 3D volumes with a local scale change of 2.0 ± 0.4% per axis dimension; in contrast, (b) tissue perfusion/fixation as assessed by mapping the in-vivo MRIs to the ex-vivo post fixation MRIs shows a larger median absolute scale change of 6.9 ± 2.1% per axis dimension. This is the first systematic quantification of local metric distortions associated with whole-brain histological processing, and we expect that the results will generalize to other species. These local scale changes will be important for computing local properties to create reference brain maps.

Investigation of the source-detector separation in near infrared spectroscopy for healthy and clinical applications.

Understanding near infrared light propagation in tissue is vital for designing next generation optical brain imaging devices. Monte Carlo (MC) simulations provide a controlled mechanism to characterize and evaluate contributions of diverse near infrared spectroscopy (NIRS) sensor configurations and parameters. In this study, we developed a multilayer adult digital head model under both healthy and clinical settings and assessed light-tissue interaction through MC simulations in terms of partial differential pathlength, mean total optical pathlength, diffuse reflectance, detector light intensity and spatial sensitivity profile of optical measurements. The model incorporated four layers: scalp, skull, cerebrospinal-fluid and cerebral cortex with and without a customizable lesion for modeling hematoma of different sizes and depths. The effect of source-detector separation (SDS) on optical measurements' sensitivity to brain tissue was investigated. Results from 1330 separate simulations [(4 lesion volumes × 4 lesion depths for clinical +3 healthy settings) × 7 SDS × 10 simulation = 1330)] each with 100 million photons indicated that selection of SDS is critical to acquire optimal measurements from the brain and recommended SDS to be 25 to 35 mm depending on the wavelengths to obtain optical monitoring of the adult brain function. The findings here can guide the design of future NIRS probes for functional neuroimaging and clinical diagnostic systems.

Brain-Wide Mapping of Axonal Connections: Workflow for Automated Detection and Spatial Analysis of Labeling in Microscopic Sections.

Axonal tracing techniques are powerful tools for exploring the structural organization of neuronal connections. Tracers such as biotinylated dextran amine (BDA) and Phaseolus vulgaris leucoagglutinin (Pha-L) allow brain-wide mapping of connections through analysis of large series of histological section images. We present a workflow for efficient collection and analysis of tract-tracing datasets with a focus on newly developed modules for image processing and assignment of anatomical location to tracing data. New functionality includes automatic detection of neuronal labeling in large image series, alignment of images to a volumetric brain atlas, and analytical tools for measuring the position and extent of labeling. To evaluate the workflow, we used high-resolution microscopic images from axonal tracing experiments in which different parts of the rat primary somatosensory cortex had been injected with BDA or Pha-L. Parameters from a set of representative images were used to automate detection of labeling in image series covering the entire brain, resulting in binary maps of the distribution of labeling. For high to medium labeling densities, automatic detection was found to provide reliable results when compared to manual analysis, whereas weak labeling required manual curation for optimal detection. To identify brain regions corresponding to labeled areas, section images were aligned to the Waxholm Space (WHS) atlas of the Sprague Dawley rat brain (v2) by custom-angle slicing of the MRI template to match individual sections. Based on the alignment, WHS coordinates were obtained for labeled elements and transformed to stereotaxic coordinates. The new workflow modules increase the efficiency and reliability of labeling detection in large series of images from histological sections, and enable anchoring to anatomical atlases for further spatial analysis and comparison with other data.

Brainwide distribution and variance of amyloid-beta deposits in tg-ArcSwe mice.

Transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid-ß precursor protein (AßPP) develop amyloid-beta (Aß) deposits in the brain that resemble Alzheimer's disease neuropathology. Earlier studies of this model have documented morphologic features in selected parts of the cerebral cortex and hippocampus, but the spatial distribution within the brain and variance of Aß deposits within a group of tg-ArcSwe mice is unknown. Using immunohistochemistry and brainwide microscopic analysis of 12-month-old tg-ArcSwe mice, we show that Aßx-40 plaque deposits are consistently present in the cerebral cortex, hippocampus, and thalamus and variably present in other regions. Using quantitative image analysis, we demonstrated that the average Aß burden in the cortex and hippocampus is similar across animals, with coefficients of variance of 22% and 25%, respectively. This indicates that interventional studies of tg-ArcSwe mice are feasible using region-of-interest comparisons and that interventional trials require larger group sizes than commonly used. We also present an online atlas providing access to images showing the detailed characteristics and spatial distribution patterns of Aßx-40 labeling.

Digital atlas of anatomical subdivisions and boundaries of the rat hippocampal region.

The rat hippocampal region is frequently studied in relation to learning and memory processes and brain diseases. The region is complex, consisting of multiple subdivisions that are challenging to delineate anatomically. Published atlases of the rat brain typically lack the underlying histological criteria necessary to identify boundaries, and textbooks descriptions of the region are often inadequately illustrated and thus difficult to relate to experimental data. An overview of both anatomical features and criteria used to delineate boundaries is required to assign location to experimental material from the hippocampal region. To address this issue, we have developed a web-based atlas application in which images of histological sections are integrated with new and up-to-date criteria for subdividing the rat hippocampus formation, fasciola, and associated parahippocampal regions. The atlas application consists of an interactive image viewer with high-resolution images of an extensive series of sections stained for NeuN, calbindin, and parvalbumin, and an index of structures with detailed descriptions of the criteria used to define the boundaries. Images can be inspected with a graphical overlay of selected subregions. Bi-directional links between images and the index of structures are provided. In summary, we provide a novel content-rich digital atlas resource facilitating identification of morphological features relevant for delineating the anatomical subdivisions of the rat hippocampal region. The atlas application is available at http://www.rbwb.org.