Quantitative Susceptibility Atlas Construction in Montreal Neurological Institute Space: Towards Histological-consistent Iron-rich Deep Brain Nucleus Sub-region Identification

Iron-rich deep brain nuclei (DBN) of the human brain are involved in various motoric, emotional and cognitive brain functions. The abnormal iron alterations in the DBN are closely associated with multiple neurological and psychiatric diseases. Quantitative susceptibility mapping (QSM) provides the spatial distribution of tissue magnetic susceptibility in the human brain. Compared to traditional structural imaging, QSM has superiority for imaging the iron-rich DBN owing to the susceptibility difference existing between brain tissues. In this study, we construct a Montreal Neurological Institute (MNI) space unbiased QSM human brain atlas via group-wise registration from 100 healthy subjects aged 19-29 years. The atlas construction process is guided by hybrid images that fused from multi-modal Magnetic Resonance Images (MRI), thus named as Multi-modal-fused magnetic Susceptibility (MuSus-100) atlas. The high-quality susceptibility atlas provides extraordinary image contrast between iron-rich DBN with their surroundings. Parcellation maps of DBN and their sub-regions that are highly related to neurological and psychiatric pathology are then manually labeled based on the atlas set with the assistance of an image border-enhancement process. Especially, the bilateral thalamus is delineated into 64 detailed sub-regions referring to the Schaltenbrand and Wahren stereotactic atlas. To our best knowledge, the histological-consistent thalamic nucleus parcellation map is well defined for the first time in MNI space. Comparing with existing atlases emphasized on DBN parcellation, the newly proposed atlas outperforms on atlas-guided individual brain image DBN segmentation accuracy and robustness. Moreover, we apply the proposed DBN parcellation map to conduct detailed identification of the pathology-related iron content alterations in subcortical nuclei for Parkinson Disease (PD) patients. We envision that the MuSus-100 atlas could play a crucial role in improving the accuracy of DBN segmentation for the research of neurological and psychiatric disease progress and also be helpful for target planning in deep brain stimulation surgery

A Cellular Reference Resource for the Mouse Urinary Bladder

The urinary bladder functions as a reservoir to store and extrude liquid bodily waste. Significant debate exists as to this tissue's cellular composition and genes associated with their functions. We use a repertoire of cell profiling tools to comprehensively define and spatial resolve cell types. We characterize spatially validated, basal-to-luminal gene expression dynamics within the urothelium, the cellular source of most bladder cancers. We define three distinct populations of fibroblasts that spatially organize from the sub-urothelial layer through to the detrusor muscle, clarifying knowledge around these controversial interstitial cells, and associate increased fibroblasts with aging. We overcome challenges of profiling the detrusor muscle, absence from earlier single cell studies, to report on its transcriptome with many novel and neuronal-like features presumably associated with neuromuscular junctions. Our approach provides a blueprint for tissue atlas construction and the data provides the foundation for future studies of bladder function in health and disease.

Multi-omics integration and regulatory inference for unpaired single-cell data with a graph-linked unified embedding framework

With the ever-increasing amount of single-cell multi-omics data accumulated during the past years, effective and efficient computational integration is becoming a serious challenge. One major obstacle of unpaired multi-omics integration is the feature discrepancies among omics layers. Here, we propose a computational framework called GLUE (graph-linked unified embedding), which utilizes accessible prior knowledge about regulatory interactions to bridge the gaps between feature spaces. Systematic benchmarks demonstrated that GLUE is accurate, robust and scalable. We further employed GLUE for various challenging tasks, including triple-omics integration, model-based regulatory inference and multi-omics human cell atlas construction (over millions of cells) and found that GLUE achieved superior performance for each task. As a generalizable framework, GLUE features a modular design that can be flexibly extended and enhanced for new analysis tasks. The full package is available online at https://github.com/gao-lab/GLUE for the community.

A Probabilistic Atlas of the Pineal Gland in the Standard Space

Pineal gland (PG) is a structure located in the midline of the brain, and is considered as a main part of the epithalamus. There are numerous reports on the facilitatory role of this area for brain function; hormone secretion and its role in sleep cycle are the major reports. However, reports are rarely available on the direct role of this structure in brain cognition and in information processing. A suggestion for the limited number of such studies is the lack of a standard atlas for the PG; none of the available MRI templates and atlases has provided parcellations for this structure. In this study, we used the three-dimensional (3D) T1-weighted MRI data of 152 healthy young volunteers, and provided a probabilistic map of the PG in the standard Montreal Neurologic Institute (MNI) space. The methods included collecting the data using a 64-channel head coil on a 3-Tesla Prisma MRI Scanner, manual delineation of the PG by two experts, and robust template and atlas construction algorithms. This atlas is freely accessible, and we hope importing this atlas in the well-known neuroimaging software packages would help to identify other probable roles of the PG in brain function. It could also be used to study pineal cysts, for volumetric analyses, and to test any associations between the cognitive abilities of the human and the structure of the PG.

The 3D-atlas builder: a dynamic and expandable 3D-tool for monitoring the changes in the neuronal differentiation domain during hindbrain morphogenesis

Reconstruction of prototypic three-dimensional (3D) atlases at the scale of whole tissues or organs requires specific methods to be developed. We have established a protocol and provide experimental proof for building a digital 3D-atlas (here, for zebrafish hindbrain) that integrates spatial and temporal data for neuronal differentiation and brain morphogenesis, through a combination of in vivo imaging techniques paired with image analyses and segmentation tools. First, we generated a reference 3D hindbrain from several imaged specimens and segmented them using a trainable tool; these were aligned using rigid registration, revealing distribution of neuronal differentiation patterns along the axes. Second, we quantified the dynamic growth of the neuronal differentiation domain vs. the progenitor domain in the whole hindbrain. Third, we used in vivo Kaede-photoconversion experiments to generate a temporal heatmap of the neuronal growth in the whole hindbrain, revealing the spatiotemporal dynamics of neuronal differentiation upon morphogenesis. Last, as proof-of-concept, we assessed the birthdate order of GABAergic-neurons using our temporal registration map. As this protocol uses open-access tools and algorithms, it can be shared for standardized and accessible tissue-wide cell population atlas construction.

Constructing and optimizing 3D atlases from 2D data with application to the developing mouse brain

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from 15 whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.