Summary: Researchers report the adverse cognitive effects associated with DBS in Pakinson’s patients are linked to a different neural pathway than the one responsible for the motor effects generated by the treatment.
Researchers from Charité – Universitätsmedizin Berlin have studied motor and cognitive effects of deep brain stimulation in patients with Parkinson’s disease. Their results show that the adverse cognitive effects of deep brain stimulation are linked to a different neural pathway than that responsible for the treatment’s desired motor effects. This finding will help optimize treatments for patients with Parkinson’s disease. Results from this research have been published in Brain.
Deep brain stimulation (DBS) is an effective treatment alternative for Parkinson’s disease patients with an inadequate response to drug treatments. DBS targets the subthalamic nucleus, which forms part of the diencephalon, a division of the forebrain. The subthalamic nucleus integrates information from different neurons and is primarily responsible for motor processes, but also plays an important role in cognitive processes, such as decision-making and response modulation.
Researchers from Charité’s Department of Neurology on Campus Charité Mitte have studied the effect of DBS on both cognitive and motor pathways. By combining behavioral experiments with brain mapping and computational modeling, the researchers were able to show that effects on motor function – such as improvements in motor control – are mediated by different neural pathways to those responsible for unwanted cognitive effects, such as premature actions in situations involving a decision-making process.
These findings enhance our understanding of the neuronal networks affected by Parkinson’s disease, deliver insights into the pathophysiology of Parkinson’s disease, and enable us to draw conclusions regarding the mechanism of action of DBS. “Only an improved understanding of the treatment’s mechanism of action will allow us to make deep brain stimulation more effective, thus enabling us to improve the quality of life of patients with Parkinson’s disease through a reduction in the side effects of treatment,” explains the study’s first author, Dr. Wolf-Julian Neumann, a researcher at the Department of Neurology.
As a next step, the researchers from the Movement Disorders Working Group are hoping to use measurements of neural activity to differentiate between disease-specific patterns of neural activity and patterns found in healthy individuals. “This will allow us to adapt brain stimulation treatments according to the needs of the individual patient and in real time. “It is an important step on the way to developing an intelligent, personalized and demand-adapted treatment,” says Working Group Leader Prof. Dr. Andrea A. Kühn of the Department of Neurology.
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Image Source: NeuroscienceNews.com image is credited to Neumann/Charité.
Original Research: Open access research for “Functional segregation of basal ganglia pathways in Parkinson’s disease” by Wolf-Julian Neumann, Henning Schroll, Ana Luisa de Almeida, Marcelino Andreas Horn, Siobhan Ewert, Friederike Irmen, Patricia Krause, Gerd-Helge Schneider, Fred Hamker, and Andrea A Kühn in PNAS. Published August 6 2018.
Functional segregation of basal ganglia pathways in Parkinson’s disease
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.