title: Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans.
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.
authors.affiliation: 1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark 2 Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark damianh@drcmr.dk.
authors.forename: Damian M
authors.initials: DM
authors.lastname: Herz
authors.affiliation: 1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Haagensen
authors.affiliation: 1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark 3 Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark 4 Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Christensen
authors.affiliation: 1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark 5 DTU Compute, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Kristoffer H
authors.initials: KH
authors.lastname: Madsen
authors.affiliation: 6 Department of Clinical Neurosciences, Cambridge University, Cambridge, UK 7 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK 8 Behavioural and Clinical Neuroscience Institute, Cambridge, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
authors.affiliation: 2 Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.
authors.forename: Annemette
authors.initials: A
authors.lastname: Løkkegaard
authors.affiliation: 1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark 2 Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark 9 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hartwig R
authors.initials: HR
authors.lastname: Siebner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000009:adverse effects; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000187:drug effects* / Q000503:physiopathology*; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011699:Putamen / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa
keywords: Parkinson's disease; connectivity; dynamic causal modelling; functional MRI; levodopa-induced dyskinesia