The Acute Brain Response to Levodopa Heralds Dyskinesias in Parkinson Disease

OBJECTIVE: In Parkinson disease (PD), long‐term treatment with the dopamine precursor levodopa gradually induces involuntary “dyskinesia” movements. The neural mechanisms underlying the emergence of levodopa‐induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic resonance imaging (fMRI) to map the emergence of peak‐of‐dose dyskinesias in patients with PD. METHODS: Thirteen PD patients with dyskinesias and 13 PD patients without dyskinesias received 200mg fast‐acting oral levodopa following prolonged withdrawal from their normal dopaminergic medication. Immediately before and after levodopa intake, we performed fMRI, while patients produced a mouse click with the right or left hand or no action (No‐Go) contingent on 3 arbitrary cues. The scan was continued for 45 minutes after levodopa intake or until dyskinesias emerged. RESULTS: During No‐Go trials, PD patients who would later develop dyskinesias showed an abnormal gradual increase of activity in the presupplementary motor area (preSMA) and the bilateral putamen. This hyperactivity emerged during the first 20 minutes after levodopa intake. At the individual level, the excessive No‐Go activity in the predyskinesia period predicted whether an individual patient would subsequently develop dyskinesias (p < 0.001) as well as severity of their day‐to‐day symptomatic dyskinesias (p < 0.001). INTERPRETATION: PD patients with dyskinesias display an immediate hypersensitivity of preSMA and putamen to levodopa, which heralds the failure of neural networks to suppress involuntary dyskinetic movements. Ann Neurol 2014;75:829–83

Dynamic control of decision and movement speed in the human basal ganglia

To optimally adjust our behavior to changing environments we need to both adjust the speed of our decisions and movements. Yet little is known about the extent to which these processes are controlled by common or separate mechanisms. Furthermore, while previous evidence from computational models and empirical studies suggests that the basal ganglia play an important role during adjustments of decision-making, it remains unclear how this is implemented. Leveraging the opportunity to directly access the subthalamic nucleus of the basal ganglia in humans undergoing deep brain stimulation surgery, we here combine invasive electrophysiological recordings, electrical stimulation and computational modelling of perceptual decision-making. We demonstrate that, while similarities between subthalamic control of decision- and movement speed exist, the causal contribution of the subthalamic nucleus to these processes can be disentangled. Our results show that the basal ganglia independently control the speed of decisions and movement for each hemisphere during adaptive behavior

Subthalamic stimulation modulates context-dependent effects of beta bursts during fine motor control.

Increasing evidence suggests a considerable role of pre-movement beta bursts for motor control and its impairment in Parkinson's disease. However, whether beta bursts occur during precise and prolonged movements and if they affect fine motor control remains unclear. To investigate the role of within-movement beta bursts for fine motor control, we here combine invasive electrophysiological recordings and clinical deep brain stimulation in the subthalamic nucleus in 19 patients with Parkinson's disease performing a context-varying task that comprised template-guided and free spiral drawing. We determined beta bursts in narrow frequency bands around patient-specific peaks and assessed burst amplitude, duration, and their immediate impact on drawing speed. We reveal that beta bursts occur during the execution of drawing movements with reduced duration and amplitude in comparison to rest. Exclusively when drawing freely, they parallel reductions in acceleration. Deep brain stimulation increases the acceleration around beta bursts in addition to a general increase in drawing velocity and improvements of clinical function. These results provide evidence for a diverse and task-specific role of subthalamic beta bursts for fine motor control in Parkinson's disease; suggesting that pathological beta bursts act in a context dependent manner, which can be targeted by clinical deep brain stimulation

Subthalamic nucleus correlates of decision and movement speed.

This dataset is availabel to download from: https://data.mrc.ox.ac.uk/data-set/subthalamic-nucleus-correlates-decision-and-movement-speed This code analyses behavioural data from a group of 13 Parkinson patients and 15 healthy control participants performing a moving dots paradigm with Speed vs. Accuracy instructions. The main behavioural outcomes are reaction times, movement times, peak force and response accuracy (folder 1, used for figure 1 in the published article), as well as computational analysis of behaviour with hierarchical drift diffusion modelling (folder 2, used for figure 2). In patients local field potentials were recorded during the task and corresponding code is stored in folder 3-5 (figure 3). In 10 patients burst deep brain stimulation was applied during a second session. Its effects on behaviour and local field potentials are analysed with code from folder 6 and 7 (figures 4-6). The results have been published in a paper termed ‘Dynamic control of decision and movement speed in the human basal ganglia’ by Herz et al

Brain Motor Network Changes in Parkinson's Disease: Evidence from Meta‐Analytic Modeling

Background: Motor-related brain activity in Parkinson's disease has been investigated in a multitude of functional neuroimaging studies, which often yielded apparently conflicting results. Our previous meta-analysis did not resolve inconsistencies regarding cortical activation differences in Parkinson's disease, which might be related to the limited number of studies that could be included. Therefore, we conducted a revised meta-analysis including a larger number of studies. The objectives of this study were to elucidate brain areas that consistently show abnormal motor-related activation in Parkinson's disease and to reveal their functional connectivity profiles using meta-analytic approaches.Methods: We applied a quantitative meta-analysis of functional neuroimaging studies testing limb movements in Parkinson's disease comprising data from 39 studies, of which 15 studies (285 of 571 individual patients) were published after the previous meta-analysis. We also conducted meta-analytic connectivity modeling to elucidate the connectivity profiles of areas showing abnormal activation.Results: We found consistent motor-related underactivation of bilateral posterior putamen and cerebellum in Parkinson's disease. Primary motor cortex and the supplementary motor area also showed deficient activation, whereas cortical regions localized directly anterior to these areas expressed overactivation. Connectivity modeling revealed that areas showing decreased activation shared a common pathway through the posterior putamen, whereas areas showing increased activation were connected to the anterior putamen.Conclusions: Despite conflicting results in individual neuroimaging studies, this revised meta-analytic approach identified consistent patterns of abnormal motor-related activation in Parkinson's disease. The distinct patterns of decreased and increased activity might be determined by their connectivity with different subregions of the putamen. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Keywords: Parkinson's disease; functional neuroimaging; meta-analysis; motor