The zona incerta system: Involvement in Parkinson's disease

Parkinson's disease (PD) is characterized by degeneration of the nigrostriatal dopamine system, resulting in progressive motor and nonmotor symptoms. Although most studies have focused on the basal ganglia network, recent evidence suggests that the zona incerta (ZI), a subthalamic structure composed of 4 neurochemically defined regions, is emerging as a therapeutic target in PD. This review summarizes the clinical and animal studies that indicate the importance of ZI in PD. Human clinical studies have shown that subthalamotomy or deep brain stimulation (DBS) of the ZI alleviates muscle rigidity, bradykinesia, tremors and speech dysfunction in patients with PD. Researchers have also studied the impact of DBS of the ZI on nonmotor signs such as pain, anxiety, and depression. Animal studies combining optogenetics, chemogenetics, behavioral assays, and neural activity recordings reveal the functional roles of ZI GABAergic and glutamatergic neurons in locomotion, gait, and coordination of the symptoms of PD, all of which are discussed in this review. Controversies and possible future studies are also discussed.