Dopamine exerts modulatory signals on cortex-basal ganglia circuits to enable flexible motor control. Parkinson's disease is characterized by a loss of dopaminergic innervation in the basal ganglia leading to complex motor and non-motor symptoms. Clinical symptom alleviation through dopaminergic medication and deep brain stimulation in the subthalamic nucleus likely depends on a complex interplay between converging basal ganglia pathways. As a unique translational research platform, deep brain stimulation allows instantaneous investigation of functional effects of subthalamic neuromodulation in human patients with Parkinson's disease. The present study aims at disentangling the role of the inhibitory basal ganglia pathways in cognitive and kinematic aspects of automatic and controlled movements in healthy and parkinsonian states by combining behavioural experiments, clinical observations, whole-brain deep brain stimulation fibre connectivity mapping and computational modelling. Twenty patients with Parkinson's disease undergoing subthalamic deep brain stimulation and 20 age-matched healthy controls participated in a visuomotor tracking task requiring normal (automatic) and inverted (controlled) reach movements. Parkinsonian patients on and off deep brain stimulation presented complex patterns of reaction time and kinematic changes, when compared to healthy controls. Stimulation of cortico-subthalamic fibres was correlated with reduced reaction time adaptation to task demand, but not kinematic aspects of motor control or alleviation of Parkinson's disease motor signs. By using clinically, behaviourally and fibre tracking informed computational models, our study reveals that loss of cognitive adaptation can be attributed to modulation of the hyperdirect pathway, while kinematic depends on suppression of indirect pathway activity. Our findings suggest that hyperdirect and indirect pathways, converging in the subthalamic nucleus, are differentially involved in cognitive aspects of cautious motor preparation and kinematic gain control during motor performance. Subthalamic deep brain stimulation modulates but does not restore these functions. Intelligent stimulation algorithms could re-enable flexible motor control in Parkinson's disease when adapted to instantaneous environmental demand. Our results may inspire new innovative pathway-specific approaches to reduce side effects and increase therapeutic efficacy of neuromodulation in patients with Parkinson's disease.
The basal ganglia and cerebellum are implicated in both motor learning and Parkinson’s disease. Deep brain stimulation (DBS) is an established treatment for advanced Parkinson’s disease that leads to motor and non-motor effects by modulating specific neural pathways. Recently, a disynaptic projection from the subthalamic nucleus (STN) to cerebellar hemispheres was discovered. To investigate the functional significance of this pathway in motor learning, short-term improvement in motor execution in 20 patients with Parkinson’s disease on and off STN-DBS and 20 age-matched healthy controls was studied in a visuomotor task combined with whole-brain connectomics. Motor learning was impaired in Parkinson’s disease off stimulation but was partially restored through DBS. Connectivity between active DBS contacts and a distributed network of brain regions correlated with improvement in motor learning. Region of interest analysis revealed connectivity from active contact to cerebellar hemisphere ipsilateral to hand movement as the strongest predictor for change in motor learning. Peak predictive voxels in the cerebellum localized to Crus II of lobule VII, which also showed higher STN than motor cortex connectivity, suggestive of a connection surpassing motor cortex. Our findings provide new insight into the circuit nature of Parkinson’s disease and the distributed network effects of DBS in motor learning.
Mutations in the ADCY5 gene can cause a complex hyperkinetic movement disorder. Episodic exacerbations of dyskinesia are a particularly disturbing symptom as they occur predominantly during night and interrupt sleep. We present the clinical short- and long-term effects of pallidal deep brain stimulation (DBS) in three patients with a confirmed pathogenic ADCY5 mutation. Patients were implanted with bilateral pallidal DBS at the age of 34, 20 and 13 years. Medical records were reviewed for clinical history. Pre- and postoperative video files were assessed using the “Abnormal Involuntary Movement Scale” (AIMS) as well as the motor part of the “Burke Fahn Marsden Dystonia Rating Scale” (BFMDRS). All patients reported subjective general improvement ranging from 40 to 60%, especially the reduction of nocturnal episodic dyskinesias (80–90%). Objective scales revealed only a mild decrease of involuntary movements in all and reduced dystonia in one patient. DBS-induced effects were sustained up to 13 years after implantation. We demonstrate that treatment with pallidal DBS was effective in reducing nocturnal dyskinetic exacerbations in patients with ADCY5-related movement disorder, which was sustained over the long term.
Every decision that we make involves a conflict between exploiting our current knowledge of an action's value or exploring alternative courses of action that might lead to a better, or worse outcome. The sub-cortical nuclei that make up the basal ganglia have been proposed as a neural circuit that may contribute to resolving this explore-exploit 'dilemma'. To test this hypothesis, we examined the effects of neuromodulating the basal ganglia's output nucleus, the globus pallidus interna, in patients who had undergone deep brain stimulation (DBS) for isolated dystonia. Neuromodulation enhanced the number of exploratory choices to the lower value option in a 2-armed bandit probabilistic reversal-learning task. Enhanced exploration was explained by a reduction in the rate of evidence accumulation (drift rate) in a reinforcement learning drift diffusion model. We estimated the functional connectivity profile between the stimulating DBS electrode and the rest of the brain using a normative functional connectome derived from heathy controls. Variation in the extent of neuromodulation induced exploration between patients was associated with functional connectivity from the stimulation electrode site to a distributed brain functional network. We conclude that the basal ganglia's output nucleus, the globus pallidus interna, can adaptively modify decision choice when faced with the dilemma to explore or exploit.
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