Anatomical Analysis of the Organization of the Human and Non-Human Primate Brain

Anatomical Analysis of the Organization of the Human and Non-Human Primate Brain

Microstructural Analysis of Brain Organization: the Ambitious Goal of Magnetic Resonance Imaging-Based in Vivo Histology (hMRI)

With high-field strength (7 tesla or more) structural MRI, scientists can today map the human brain with sub-millimeter resolution. This stands in sharp contrast to our remarkable ignorance of the underlying microstructural basis of the MRI signal. Which cellular components of the brain gray and white matter are involved? Neurons with their processes, glia cells, myelin sheaths? Does iron play a role? These pressing but largely unanswered questions are of great relevance both to basic research (e.g., non-invasive microanatomical parcellation of the human cortex into structural modules, so-called "In Vivo Brodmann Mapping") and to clinical research topics of neurology and psychiatry (e.g., non-invasive histological diagnosis of pathological changes in the brain).

To answer these questions we validate structural MRI data with histological techniques. We scan post-mortem brains with MRI and either embed them in paraffin and section them with a conventional microtome, or freeze and cut them with a freezing microtome or cryostat. On these sections we study various aspects of brain microanatomy, e.g., the structure and arrangement of cells (cytoarchitecture) with the "classical" Nissl stain, or the structure of myelin sheaths (myeloarchitecture) with myelin stains. In addition, we analyze the spatial distribution of chemical elements in brain tissue (e.g., iron, phosphorus and sulfur) with proton-induced X-ray emission (PIXE) in cooperation with the Physics Faculty and the Paul Flechsig Brain Research Institute of the Medical Faculty of the University of Leipzig. This combination of techniques allows us to directly compare MRI-based anatomy with histological anatomy.

We also employ revolutionary technological advances in the field of histology, e.g., a recently published technique called CLARITY. By extracting the lipids CLARITY transforms brain tissue into an optically transparent hydrogel polymer. This polymer can be incubated "en bloc" with fluorescent markers for specific components of neurons or glia cells (e.g., proteins of the myelin sheath) and then optically sectioned layer by layer with a laser scanning microscope. This obviates the need for tedious cutting of the blocks with a microtome, correcting the sections for artifacts, and assembling them into a 3-D volume.

With these transdisciplinary approaches – together with biophysical modeling – we expect to gain new insights into the histological and histochemical basis of the various MRI contrasts. We are convinced that in the future the "typical" tools for anatomical brain research such as a saw, hammer, knife or drill will become partly obsolete – an MRI scanner will do the job!



<p>DFG-gefördertes Projekt SPP 2041</p>
Human Microstructural Connectomics: Computational modeling and validation with histology and CLARITY

The arrangement, length, and microstructural properties of long-range connections in the central nervous system are of utmost importance for its functional organization because they determine how information is distributed across the brain. To date, diffusion magnetic resonance imaging (dMRI)-based tractography is the only in vivo technique for mapping  long-range structural connections in the human brain. However, mapping from diffusion to fiber pathways is still ill-posed and has several major limitations. As a result, tractography algorithms can take "wrong turns" and produce false positive and false negative connections.

To address this problem, microstructure-informed tractography has been suggested. It is an emerging computational framework that associates each computed fiber tract with microstructural properties, e.g., metrics for axon diameter or density, using the dMRI technique.

In this highly inter-disciplinary project, we will develop a computational framework for microstructure-informed tractography that addresses these limitations using multi-modal quantitative MRI at ultra-high spatial resolution. Moreover, we will develop an advanced ex vivo histological analysis strategy based on complementary 2D (high-resolution semithin and ultrathin sectioning) and 3D (CLARITY) techniques. We will combine ex vivo histology, the gold standard, with MRI to validate the proposed model at central junctions of long-range fiber pathways within the well characterized human voluntary motor control network. By emphasizing the close integration of multi-modal, computational, biophysical models, advanced MRI technology (the German-wide unique combination of a Siemens CONNECTOM & 7T MRI system), and advanced histological approaches (CLARITY in human tissue), this project aims to provide innovative new insights into MRI-based computational models for in vivo tractography.

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