To this day, critical procedures in neurosurgery and neuromodulation for patients with devastating diseases are guided by knowledge on how the brain is wired that derives largely from animal studies. Such studies rely on the precision of techniques, like tracer injections, that are not feasible in human subjects. Inter-species homologies, particularly between non-human primates and humans, are then used to extrapolate information from the former to the latter. This approach has afforded us an understanding of broad organizational principles in the wiring of the human brain, but crucial details are missing. Recent advances in ex vivo tissue processing and microscopy show great promise for imaging the wiring of the human brain down to the scale of single axonal projections. Much work is needed, however, to turn these breakthroughs into tools in the hands of anatomists. Doing so will allow us to map precisely, for the first time, clinically relevant brain circuits and to design better therapeutic interventions. It will also provide the ground truth that we need to harness recent advances in artificial intelligence and improve noninvasive imaging of the wiring of the brain with diffusion MRI. In this talk, I will present our efforts within the NIH BRAIN Initiative CONNECTS program to lay the technological groundwork for imaging the wiring of the human and non-human primate brain across scales, from the large highways to the small fascicles and down to the single axon level. I will discuss why there is currently no single imaging modality that can give us the complete wiring diagram of the primate brain, and why combining the complementary strengths of multiple techniques at different scales is our best chance to make this previously unattainable goal a reality.

Learning Objectives:

1. Discuss the technologies being used to understand human and non-human primate fiber tracts.

2. Explain why multiple imaging modalities are necessary for a complete wiring diagram of primate brains.

3. Describe how AI is used to improve non-invasive imaging of the brain's wiring.