Deep brain stimulation of the subthalamic nucleus is an established treatment for the motor symptoms of Parkinson’s disease. Given the frequent occurrence of stimulation-induced affective and cognitive adverse effects, a better understanding about the role of the subthalamic nucleus in non-motor functions is needed. The main goal of this study is to characterize anatomical circuits modulated by subthalamic deep brain stimulation, and infer about the inner organization of the nucleus in terms of motor and non-motor areas. Given its small size and anatomical intersubject variability, functional organization of the subthalamic nucleus is difficult to investigate in vivo with current methods. Here, we used local field potential recordings obtained from 10 patients with Parkinson’s disease to identify a subthalamic area with an analogous electrophysiological signature, namely a predominant beta oscillatory activity. The spatial accuracy was improved by identifying a single contact per macroelectrode for its vicinity to the electrophysiological source of the beta oscillation. We then conducted whole brain probabilistic tractography seeding from the previously identified contacts, and further described connectivity modifications along the macroelectrode’s main axis. The designated subthalamic ‘beta’ area projected predominantly to motor and premotor cortical regions additional to connections to limbic and associative areas. More ventral subthalamic areas showed predominant connectivity to medial temporal regions including amygdala and hippocampus. We interpret our findings as evidence for the convergence of different functional circuits within subthalamic nucleus’ portions deemed to be appropriate as deep brain stimulation target to treat motor symptoms in Parkinson’s disease. Potential clinical implications of our study are illustrated by an index case where deep brain stimulation of estimated predominant non-motor subthalamic nucleus induced hypomanic behaviour. * Abbreviations : DBS : deep brain stimulation LFP : local field potential MNI : Montreal Neurological Institute STN : subthalamic nucleus UPDRS : Unified Parkinson’s Disease Rating Scale

Disruption of subthalamic nucleus dynamics in Parkinson’s disease leads to impairments during walking. Here, we aimed to uncover the principles through which the subthalamic nucleus encodes functional and dysfunctional walking in people with Parkinson’s disease. We conceived a neurorobotic platform embedding an isokinetic dynamometric chair that allowed us to deconstruct key components of walking under well-controlled conditions. We exploited this platform in 18 patients with Parkinson’s disease to demonstrate that the subthalamic nucleus encodes the initiation, termination, and amplitude of leg muscle activation. We found that the same fundamental principles determine the encoding of leg muscle synergies during standing and walking. We translated this understanding into a machine learning framework that decoded muscle activation, walking states, locomotor vigor, and freezing of gait. These results expose key principles through which subthalamic nucleus dynamics encode walking, opening the possibility to operate neuroprosthetic systems with these signals to improve walking in people with Parkinson’s disease.

Depression in Parkinson's Disease (PD) is a prevalent and invalidating symptom. Deep brain stimulation (DBS) allows for an improvement of PD motor features, but its effects on mood are difficult to predict. Here, we review the evidence regarding mood effects after DBS of either subthalamic nucleus (STN) or globus pallidus pars interna (GPi). Different influences of multiple factors contribute to impact the neuropsychiatric outcome after surgery. Psychosocial presurgical situation, postsurgical coping mechanisms, dopaminergic treatment modifications, and direct effects of the stimulation of either target are all playing a distinct role on the psychological well-being of patients undergoing DBS. No clear advantage of either target (STN vs. GPi) has been consistently found, both being effective and with a favorable profile on depression symptoms. However, specific patients' characteristics or anatomical considerations can guide the neurosurgeon in the target choice. Further research together with technological advances are expected to confine the stimulation area within dysfunctional circuits causing motor symptoms of PD.

In predictable contexts, motor inhibitory control can be deployed before the actual need for response suppression. The brain functional underpinnings of proactive inhibition, and notably the role of basal ganglia, are not entirely identified. We investigated the effects of deep brain stimulation of the subthalamic nucleus or internal globus pallidus on proactive inhibition in patients with Parkinson's disease. They completed a cued go/no‐go proactive inhibition task ON and (unilateral) OFF stimulation while EEG was recorded. We found no behavioural effect of either subthalamic nucleus or internal globus pallidus deep brain stimulation on proactive inhibition, despite a general improvement of motor performance with subthalamic nucleus stimulation. In the non‐operated and subthalamic nucleus group, we identified periods of topographic EEG modulation by the level of proactive inhibition. In the subthalamic nucleus group, source estimation analysis suggested the initial involvement of bilateral frontal and occipital areas, followed by a right lateralized fronto‐basal network, and finally of right premotor and left parietal regions. Our results confirm the overall preservation of proactive inhibition capacities in both subthalamic nucleus and internal globus pallidus deep brain stimulation, and suggest a partly segregated network for proactive inhibition, with a preferential recruitment of the indirect pathway.

Disruption of subthalamic nucleus dynamics in Parkinson’s disease leads to impairments during walking. Here, we aimed to uncover the principles through which the subthalamic nucleus encodes functional and dysfunctional walking in people with Parkinson’s disease. We conceived a neurorobotic platform that allowed us to deconstruct the key components of walking under well-controlled conditions. We exploited this platform in 18 patients with Parkinson’s disease, which allowed us to demonstrate that the subthalamic nucleus encodes the initiation, termination, and vigor of leg muscle activation. We found that the same fundamental principles determine the encoding of walking. We translated this understanding into a machine-learning framework that decoded muscle activation, walking states, locomotor vigor, and freezing of gait. These results expose key principles through which subthalamic nucleus dynamics encode walking, opening the possibility to operate neuroprosthetic systems with these signals to improve walking in people with Parkinson’s disease. One Sentence Summary The subthalamic nucleus encodes the initiation, termination, and vigor of muscle activity, which supports real-time decoding of gait in people with Parkinson’s disease.