PROJECT SUMMARY/ABSTRACT Diffusion MRI (dMRI), with its sensitivity to neurological changes, has contributed immensely to our understanding of the white matter structure at large-to-medium spatial scales, and more recently towards smaller structures, particularly in the cortical and subcortical regions, as submillimeter dMRI is starting to become more feasible. Nonetheless, further increase in resolution is required to move dMRI to the mesoscopic scale (100- 500µm), to improve sensitivity to small but important brain microstructural features and improve capability to e.g. detect highly-localized tissue abnormalities such as focal cortical dysplasia and silent acute microinfarcts, as well as enable study of brain connectivity across laminar structures and delineate functionally important small sub-cortical gray matter structures. In this proposal, we aim to develop imaging technologies to allow mesoscale dMRI and extend our development to enable mesoscale joint diffusion-relaxometry MRI with rich information, to improve tractography’s robustness and enhance capability to extract detailed microstructural information. Mesoscale dMRI and diffusion-relaxometry MRI will enhance the capability of many current clinical and neuroscientific investigations and open doors to entirely new ones, facilitating new discoveries to deepen our understanding of the human brain in both its healthy and diseased states. In the previous funding cycle, we developed the gSlider-SMS technology to allow 700-800µm dMRI to be acquired in a short 20-minute timeframe and shared it across 26 research institutes world-wide, where it is being used to investigate numerous neuroscientific questions and neurological disorders, including aging, epilepsy, acute micro-infarcts, and deep-brain stimulation planning. For this renewal, we propose to create technologies to allow 300-500µm whole-brain dMRI in 20-30 minutes, with fast reconstruction, suitable for wide-adoption. We will then expand our development to create a joint T2-dMRI acquisition for fiber-specific microstructure imaging and improved fiber tracking capability at the mesoscopic scale. Lastly, we will also create a highly efficient joint T1-T2-dMRI acquisition, to rapidly collect large multidimensional data and provide diffusion-relaxation correlation spectroscopic map per imaging voxel for detailed microstructural investigation. The multitude of imaging technologies that we will develop will enable creation of new richer datasets that will have a significant and lasting impact on the neuroscientific study of the human brain and many clinical applications. Optimized protocols will be developed for high-end clinical 3T MRIs for wide deployment, and on high-performance head-only 3T MRIs to enable neuroscientific explorations at the limit.