PROJECT SUMMARY To understand complex neural pathways and networks and their remarkable ability to generate human behaviors, it is critical to precisely map brain connectomics in vivo. We propose to make significant advances in such brain mapping by founding the Center for Mesoscale Connectomics (CMC). We will first map the mesoscale connections between the frontal and parietal cortices. These connections likely subserve higher-order functions such as attention, decision-making, prospection, and executive control. One key, underappreciated feature of cortical connectivity is its specific variations within a given brain region, further supporting the critical need for descriptions of connectivity at a finer scale. Unfortunately, there has traditionally been a major gap in our pursuit of creating a human brain “wiring diagram” at high spatial resolution, especially since the gold standard for mesoscale brain connectivity, anatomical tract-tracing, cannot be performed in humans. Moreover, techniques that can be applied to humans, such as diffusion MRI tractography, may not recapitulate anatomical connectivity at this scale. Due to this gap, we are lacking an accurate wiring diagram of the human brain that can only be obtained through a multi-modal, cross-species, multi-scale approach. Here, we propose to combine advanced anatomical tract-tracing (Aim 1), polarization-sensitive optical coherence tomography (PS-OCT) (Aim 2), and ultra-high field diffusion tractography (Aim 3) to create such accurate wiring diagrams of human and macaque brains while bridging spatial resolutions and species. Importantly, we will computationally bridge species, methods, and spatial scales via state-of-the art registration and joint (multimodal) modeling of fiber orientations. Subsequently, the remarkable amount of information available in each dataset will be further enhanced using optimized tractography methods. At the end of the proposed funding period, we expect to have complete maps of the mesoscale organization of fronto-parietal connections. We will be poised to apply our multimodal, cross-species methods brain-wide, including both cortical and subcortical circuits. Importantly, the foundation will be laid for computing noninvasive, in vivo, accurate, mesoscale connectivity maps of whole human brains through dMRI tractography, which will allow researchers to link brain connectivity with cognition, behavior, and disease.

PROJECT NARRATIVE Brain function is built atop connections made between neurons. The proposed Center for Mesoscale Connectomics will use multiple imaging and neuroanatomical methods across nonhuman primates and humans to build an accurate, fine-grained wiring diagram of the brain. We will start with connections between the frontal and parietal lobes, with the eventual goal of mapping connections across the whole brain.