Subthalamic nucleus activity modifications prior to clinical impairment in a progressive model of Parkinson's disease

Background: Parkinson's disease (PD) is clinically diagnosed based on motor impairments related to akinesia, rigidity, and tremor. These symptoms are delayed in the course of the disease and that contributes strongly to its late diagnosis. Cognitive and limbic symptoms may precede motor symptoms, thus opening an earlier diagnostic window, but their early kinetics need to be better characterized. Furthermore, despite adapted medications, these non-motor symptoms evolve and worsen over time. Surgical treatment with high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN), whereas significantly improves motor symptoms, does not address specifically the non-motor symptoms. A better temporal characterization of the onset of non-motor symptoms combined with adapted parameters of stimulation of DBS could potentially optimize the surgical treatment. Objective: We aimed to correlate STN activity with the early phase of motor, cognitive, and limbic symptoms of PD and to propose specific STN-DBS paradigm of stimulation to take over all symptoms. Methods: Local field potentials of the STN were recorded in two non-human primates (Macaca fascicularis) while performing a behavioral task allowing the assessment of motor, cognitive, and limbic reward-related behavioral components. In parallel, a progressive model of PD, consisting in small injections of 1-methyl-4-phenyl-1,2,3,6-tetrhydropyridine (MPTP, 0.2-0.5mg/kg), was used to characterize behavior for several months until the appearance of motor symptoms. Finally, when a parkinsonian syndrome was well established and stable, behavioral effects of high- (HFS, 130Hz) and low- (LFS, 4Hz) frequency stimulations were investigated. Results After the first MPTP injections, we observed a gradual progression of the parkinsonian syndrome from stage 1 without any symptoms, to stage 3 with limbic, cognitive, and motor symptoms. In addition, each stage was associated with specific changes in STN electrophysiological activities. Stage 1, with no significant symptoms although MPTP intoxication has begun, was marked by a decrease in the power of reward-related gamma/theta oscillations. Stage 2 was characterized by an early decline in motivation and the appearance of decreased theta-band activity during decision-making. Later, an increase in error on Switch trials was reported, illustrating the stage 2', and a decrease in beta-gamma power after motor movement occurred. Finally, stage 3 was characterized by an increase in motor response time, while retaining all the STN neuronal changes. Conclusion: Our results suggest a progressive timeline in the onset of behavioral impairments with first limbic symptoms, followed by cognitive and then motor symptoms. Furthermore, specific electrophysiological biomarkers of each symptom are found early in the STN and can predict their onset and help to better understand their pathophysiology. Finally, we propose a combined stimulation with HFS in dorsal STN and LFS in ventral STN to optimize STN-DBS and reduce both motor and non-motor symptoms. ### Competing Interest Statement The authors have declared no competing interest.