Mapping the topographic organization of the human zona incerta using diffusion MRI

The zona incerta (ZI) is a deep brain region originally described by Auguste Forel as an 'immensely confusing area about which nothing can be said'. Despite the elusive nature of this structure, mounting evidence supports the role of the ZI and surrounding regions across a diverse range of brain functions and as a candidate target for neuromodulatory therapies. Using in vivo diffusion magnetic resonance imaging and data-driven connectivity, we identify a topographic organization between the ZI and neocortex. Specifically, our methods identify a rostral-caudal gradient predominantly connecting the frontopolar and ventral prefrontal cortices with the rostral ZI, and the primary sensorimotor cortices with the caudal ZI. Moreover, we demonstrate how clustering and gradient approaches build complementary evidence including facilitating the mapping of a central region of the ZI, connected with the dorsal prefrontal cortex. These results were shown to be replicable across multiple datasets and at the individual subject level, building evidence for the important role of the ZI in mediating frontal lobe-associated tasks, ranging from motor to cognitive to emotional control. Finally, we consider the impact of this topographic organization on the refinement of neuromodulatory targets. These results pave the way for an increasingly detailed understanding of ZI substructures, and considerations for in vivo targeting of the ZI for neuromodulation.