Determining the microstructural basis of diffusion MRI

Several major national initiatives such as the NIH Human Connectome Project and the NIH Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) have recently highlighted how surprisingly little we understand about the human brain and the need for improved methods to probe its structure and function. Little is known about how the brain transmits information and integrates it across different processing areas (“brain connectivity”) and how this connectivity relates to behavior and disease. In order to enable accurate and reliable structural connectivity measurements in vivo we need to better understand the microstructural basis of diffusion MRI as one of the most important technologies for in vivo human structural connectivity measurements.

Diffusion magnetic resonance imaging (dMRI) is a means of non-invasively mapping structural connectivity in the human brain. dMRI measures the diffusion of water inside the brain, and, since water diffuses more rapidly along the length of a fiber pathway than perpendicular to it, the orientation of fiber pathways can be visualized. However, some fundamental questions about the relationship of water diffusivity and tissue structure are still unknown. How does the tissue structure or the number of nerve fibers at a given imaging location influence the measured diffusion patterns? What is the minimum size of a fiber tract that can be detected at a given imaging location in a dMRI experiment? Due to this ambiguity, 3D trajectories of pathways in the brain based on dMRI data are still prone to many false positives and false negatives.

The aim of this project is to improve the accuracy and reliability of dMRI fiber tracking through comparison with a gold standard that unambiguously relates the measured water diffusion patterns to the underlying tissue structure. Histological methods can deliver such a gold standard since directional diffusion properties are preserved in fixed specimens. Prior work has compared the inherently 3D dMRI results to thin 2D histological sections. However, the 3D fiber trajectories moving in and out of the imaging plane severely limit the significance of this type of validation.

Our approach is to validate dMRI fiber tracking methods using CLARITY. CLARITY is a new 3D histology method developed in 2013 at the Deisseroth lab at Stanford University. CLARITY renders intact tissue samples optically transparent. The 3D nature of CLARITY allows optical examination of tissue structures in intact samples and makes it a formidable tool for dMRI validation. By comparing dMRI measurements of tissue specimen with the fiber projections visible in the same cleared specimen we get a way to better relate water diffusivity to tissue structure. And we will be able to unambiguously determine false positive or false negative fiber tract reconstructions of existing dMRI models.

Unraveling the basic relationships between tissue microstructure and dMRI offers the potential that dMRI may finally become the long sought-after technique that allows us to map structural human brain connectivity in vivo with sufficient robustness to determine its relationship to behavior and disease.