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Despite decades of progress in neuroimaging and systems neuroscience, we still lack a wiring diagram of the human brain. This gap reflects fundamental constraints of species and scale: invasive tract-tracing methods cannot be applied in humans, while whole-brain reconstruction in large nonhuman primates remains technically and computationally challenging. As a result, diffusion MRI-based tractography, our primary tool for mapping human white matter, remains only loosely anchored to ground-truth axonal anatomy.

In this talk, I outline an axon-centric strategy for building a biologically informed wiring diagram of the human brain through a coordinated, multimodal and multispecies approach. Leveraging recent advances from the Center for Mesoscale Connectomics, this framework integrates novel types of tract-tracing, polarization-sensitive optical coherence tomography (PS OCT), and diffusion MRI across nonhuman primates and humans. By aligning these complementary modalities, we can quantitatively evaluate tractography accuracy, test assumptions about streamline behavior, and identify representations shared across anatomical scales. Rather than relying solely on qualitative anatomical constraints, this approach enables systematic, data-driven refinement of diffusion MRI models informed by true axonal organization.

Finally, I argue that constructing an accurate wiring diagram of the human brain is not merely a technical exercise, but a prerequisite for progress in human circuit neuroscience and neuromodulation. Precise knowledge of anatomical connectivity is essential for interpreting function and for improving outcomes in circuit-based interventions such as deep brain stimulation (DBS). Emerging evidence shows that therapeutic efficacy and side effects of DBS depend on capturing specific fiber pathways and that tract-informed metrics can predict clinical response. Together, these findings motivate a new generation of connectomic tools that bridge basic neuroanatomy and human brain intervention, advancing both mechanistic understanding and clinical translation.