Behavioral changes preceded by subthalamic nucleus activity alterations in a progressive macaque model of Parkinson’s disease

Abstract Parkinson’s disease (PD) is diagnosed after motor symptoms appear, although non-motor symptoms emerge years earlier. Following years of pharmacological treatment, high-frequency stimulation (HFS) of the subthalamic nucleus (STN), a key hub in goal-directed behaviors, can be proposed. While HFS-STN reliably improves motor symptoms, it does not specifically address non-motor symptoms. Clarifying how STN dysfunction contributes to these symptoms could improve stimulation strategies. Here, we longitudinally recorded STN local field potentials in two macaques performing a demanding task during chronic low-dose MPTP treatment. This progressive model, evolving from an asymptomatic stage to motivational, cognitive, and motor deficits, enabled detailed characterization of non-motor stages preceding motor impairment. Each stage was associated with distinct electrophysiological alterations, including early loss of reward-related theta activity, followed by disappearance of decision-related theta oscillations and later reduction of movement-related beta rebound. In the stable parkinsonian stage, stimulation of different STN territories produced complementary behavioral effects: dorsal HFS improved motor performance, whereas ventral low-frequency stimulation alleviated motivational deficits. These findings reveal a temporal relationship between STN dysfunction and symptom onset and support site- and frequency-specific stimulation strategies to address motor and non-motor symptoms in PD.