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Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans.


Type

Article

Change log

Authors

Herz, Damian M 
Haagensen, Brian N 
Christensen, Mark S 
Madsen, Kristoffer H 
Rowe, James B 

Abstract

Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51-84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements.

Description

Keywords

Parkinson's disease, connectivity, dynamic causal modelling, functional MRI, levodopa-induced dyskinesia, Aged, Aged, 80 and over, Antiparkinson Agents, Dopaminergic Neurons, Dyskinesia, Drug-Induced, Female, Functional Neuroimaging, Humans, Levodopa, Magnetic Resonance Imaging, Male, Middle Aged, Motor Cortex, Neural Pathways, Psychomotor Performance, Putamen

Journal Title

Brain

Conference Name

Journal ISSN

0006-8950
1460-2156

Volume Title

138

Publisher

Oxford University Press (OUP)
Sponsorship
Medical Research Council (G0001354)
Wellcome Trust (088324/Z/09/Z)
Medical Research Council (MC_U105597119)
Medical Research Council (G1000183)
This work was supported by the Danish Medical Research Council (FSS 09-072163), a Grant of Excellence sponsored by The Lundbeck Foundation Mapping, Modulation & Modeling the Control of Actions (ContAct) (R59-A5399 to H.R.S.), the Wellcome Trust (088324 to J.B.R.) and the Medical Research Council (MC-A060-5PQ30 to J.B.R.). The funding sources had no involvement in the undertaking of the study.