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Apathy, depression, and anxiety represent the main neuropsychiatric symptoms of Parkinson’s disease (PD). How subthalamic nucleus deep brain stimulation (STN-DBS) influences these symptoms, especially apathy, is a controversial topic. The present translational study investigates and compares the effect of bilateral or unilateral STN-DBS on this neuropsychiatric triad, combining a pre-clinical approach in rodents and a clinical follow-up of patients with PD. While depression and anxiety related behaviors remain unchanged, bilateral but not unilateral STN-DBS consistently induces apathy in patients and a reward seeking deficit in rodents. Together, these data substantiate the claim that STN-DBS may induce apathy by itself and suggest that bilateral but not the unilateral stimulation might be a critical factor.