title: The acute brain response to levodopa heralds dyskinesias in Parkinson disease.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Danish Research Center for Magnetic Resonance, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.
authors.forename: Damian M
authors.initials: DM
authors.lastname: Herz
authors.forename: Brian N
authors.initials: BN
authors.lastname: Haagensen
authors.forename: Mark S
authors.initials: MS
authors.lastname: Christensen
authors.forename: Kristoffer H
authors.initials: KH
authors.lastname: Madsen
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
authors.forename: Annemette
authors.initials: A
authors.lastname: Løkkegaard
authors.forename: Hartwig R
authors.initials: HR
authors.lastname: Siebner
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D001931:Brain Mapping; D003657:Decision Making; D004409:Dyskinesia, Drug-Induced / Q000473:pathology*; D005260:Female; D019416:Head Movements / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D010300:Parkinson Disease / Q000188:drug therapy; D011597:Psychomotor Performance; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D010100:Oxygen