Abstract Background The zona incerta (ZI) is involved in mediating survival behaviors and is connected to a wide range of cortical and subcortical structures, including key basal ganglia nuclei. Based on these connections and their links to behavioral modulation, we propose the ZI is a connectional hub for in mediating between top-down and bottom-up control and a possible target for deep brain stimulation for obsessive compulsive disorder. Methods We analyzed the trajectory of cortical fibers to the ZI in nonhuman and human primates, based on tracer injections in monkeys and high-resolution diffusion MRI in humans. The organization of cortical and subcortical connections with the ZI were identified in the nonhuman primate studies. Results Monkey anatomic data and human dMRI data showed a similar trajectory of fibers/streamlines to the ZI. PFC/ACC terminals all converge within the rostral ZI (ZIr), with dorsal and lateral areas most prominent. Motor areas terminate caudally. Dense subcortical reciprocal connections included the thalamus, medial hypothalamus, substantia nigra/ventral tegmental area, reticular formation, and pedunculopontine nucleus and a dense nonreciprocal projection to the lateral habenula (LHb). Additional connections included amygdala, dorsal raphe nucleus, and periaqueductal grey. Conclusions Dense connections with dorsal and lateral PFC/ACC cognitive control areas and LHb and SN/VTA coupled with inputs from the amygdala, hypothalamus, and brainstem, suggests that the ZIr is a subcortical hub positioned to modulate between top-down and bottom-up control. A DBS electrode placed in the ZIr would involve both connections common to other DBS sites, but also would capture several critically distinctive connections.

The rostral zona incerta: a subcortical integrative hub and potential DBS target for OCD