The acute brain response to levodopa heralds dyskinesias in Parkinson disease

Abstract

ObjectiveIn 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.MethodsThirteen 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.ResultsDuring 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).InterpretationPD 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;75:829–836

Behavioural and neuroimaging correlates of impaired self-awareness of hypo- and hyperkinesia in Parkinson's disease

“…These findings are consistent with previous studies showing that the putamen, the SMA, and the pre-SMA are involved in the development of LID in PD (Cerasa et al, 2012;Herz et al, 2014Herz et al, , 2015.…”

Grey Matter Microstructural Integrity Alterations in Blepharospasm Are Partially Reversed by Botulinum Neurotoxin Therapy

“…In this region, the rate of cortical thinning was also much higher and to a greater extent after BoNT than in the HFS group. Pre-SMA is directly involved in the control of involuntary actions [31] and shows over-activity during dyskinesia’s in PD patients [32]. Direct electrical stimulation of pre-SMA can elicit an ‘urge’ to move a specific body part [33].…”

The motor inhibition system in Parkinson's disease with levodopa‐induced dyskinesias

“…An Family‐Wise Error (FWE) threshold within regions of interest (ROIs) was used to correct second‐level SPM maps. Based on previous findings, we decided to use the IFC, MFC, primary motor cortex (M1), subthalamic nucleus and putamen (including globus pallidum) as ROIs given their critical involvement in the pathophysiology of LIDs and in motor inhibition processing . To further control for multiple comparisons, we set the threshold at P ≤ 0.01 instead of at P < 0.05 (0.05/5 [no.…”

“…In the last few years, evidence coming from neuroimaging has shed new light on LIDs, proposing that the pathophysiological mechanisms underlying this disorder may extend beyond the primary motor circuit, involving other regions with a pronounced cognitive profile: the medial frontal cortex (MFC, including the supplementary motor areas) and the right inferior frontal cortex (IFC) . Although several neuroimaging and neurophysiological studies demonstrate the key role of the MFC in pathophysiological mechanisms of LIDs, the involvement of the IFC is new information that has stimulated very challenging debate on where LID‐related symptoms may originate .…”