Diffusion Magnetic Resonance Imaging Tractography Guides Investigation of the Zona Incerta: A Novel Target for Deep Brain Stimulation

The zona incerta (ZI) is a subcortical structure primarily investigated in rodents, that is implicated in various behaviors from motor control to survival-associated activities, partly due to its integration in multiple neural circuits. In our study, we used diffusion MRI tractography to segment the ZI and gain insight into its connectivity in various circuits in humans.We performed probabilistic tractography in 7T on 178 subjects from the Human Connectome Project to validate the ZI's anatomical subdivisions and their respective tracts. K-means clustering segmented the ZI based on each voxel's connectivity profile. We further characterized the connections of each ZI subregion using probabilistic tractography with each subregion as a seed.We identified two dominant clusters that delineated the whole ZI into rostral (ZIr) and caudal (ZIc) subregions. ZIc primarily connected with motor regions, while ZIr received a topographic distribution of projections from prefrontal areas, notably the anterior cingulate and medial prefrontal cortices. We generated a probabilistic ZI atlas that was registered to a patient-participant's MRI for placement of stereoencephalographic leads for electrophysiology-guided DBS for treating their obsessive-compulsive disorder. ZIr stimulation improved the patient's core symptoms (mean improvement: 21%).We present a tractography-based atlas of the rostral and caudal ZI subregions, constructed using high resolution diffusion MRI from 178 healthy subjects. Our work provides an anatomic foundation to explore the ZIr as a novel target for deep brain stimulation to treat refractory obsessive-compulsive disorder and other disorders associated with dysfunctional reward circuitry.