Subthalamic nucleus activity dynamics preceding clinical manifestations in a progressive Parkinson’s disease model

Abstract

ABSTRACTBackgroundParkinson’s disease (PD) diagnosis relies on motor symptoms such as akinesia, rigidity, and tremor, which manifest late in the disease course, contributing to delayed diagnosis. However, cognitive, and limbic manifestations may precede motor symptoms, offering an earlier diagnostic opportunity, but their early kinetics require further characterization. Although high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves motor symptoms, it does not specifically address non-motor symptoms. Here, we aimed to correlate STN activity with the onset of motor, cognitive, and limbic symptoms of PD and propose specific STN-DBS paradigm to address both motor and non-motor symptoms.MethodsLocal field potentials of the STN were recorded in two non-human primates (Macaca fascicularis) performing a behavioral task assessing motor, cognitive, and limbic reward-related behaviors. A progressive model of PD, consisting of small injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.2-0.5mg/kg), was used to characterize behavior for several months until the onset of motor symptoms. Finally, when a stable parkinsonian syndrome was established, the behavioral effects of high- (HFS, 130Hz) and low- (LFS, 4Hz) frequency stimulations were investigated.ResultsAfter the first MPTP injections, we observed a progressive parkinsonian syndrome from stage 1, asymptomatic, to stage 3 with limbic, cognitive, and motor symptoms. Each stage was associated with specific changes in STN electrophysiological activity. Stage 1 was characterized by a decrease in the power of reward-related gamma/theta oscillations. Stage 2 featured an early decline in motivation and decreased theta-band activity during decision-making. Later, an increase in error on Switch trials was observed, illustrating the stage 2’, along with a decrease in beta-gamma power following movement. Finally, stage 3 was defined by an increase in motor response time while maintaining all the STN neuronal changes. In stage 3, HFS applied in dorsal STN improved motor reaction time, while LFS applied in ventral STN improved motivation.ConclusionOur results highlight a progressive timeline in the onset of behavioral parkinsonian manifestations, with limbic symptoms followed by cognitive and then motor symptoms. We identified specific electrophysiological biomarkers in the STN correlating with and preceding the onset of each symptom, providing insights into their pathophysiology. Finally, our results suggest that combined stimulation of HFS in the dorsal STN and LFS in the ventral STN may optimize STN-DBS outcomes, reducing both motor and non-motor symptoms.