title: Dopaminergic modulation of motor network dynamics in Parkinson's disease.
abstract: Although characteristic motor symptoms of Parkinson's disease such as bradykinesia typically improve under dopaminergic medication, deficits in higher motor control are less responsive. We here investigated the dopaminergic modulation of network dynamics underlying basic motor performance, i.e. finger tapping, and higher motor control, i.e. internally and externally cued movement preparation and selection. Twelve patients, assessed ON and OFF medication, and 12 age-matched healthy subjects underwent functional magnetic resonance imaging. Dynamic causal modelling was used to assess effective connectivity in a motor network comprising cortical and subcortical regions. In particular, we investigated whether impairments in basic and higher motor control, and the effects induced by dopaminergic treatment are due to connectivity changes in (i) the mesial premotor loop comprising the supplementary motor area; (ii) the lateral premotor loop comprising lateral premotor cortex; and (iii) cortico-subcortical interactions. At the behavioural level, we observed a marked slowing of movement preparation and selection when patients were internally as opposed to externally cued. Preserved performance during external cueing was associated with enhanced connectivity between prefrontal cortex and lateral premotor cortex OFF medication, compatible with a context-dependent compensatory role of the lateral premotor loop in the hypodopaminergic state. Dopaminergic medication significantly improved finger tapping speed in patients, which correlated with a drug-induced coupling increase of prefrontal cortex with the supplementary motor area, i.e. the mesial premotor loop. In addition, only in the finger tapping condition, patients ON medication showed enhanced excitatory influences exerted by cortical premotor regions and the thalamus upon the putamen. In conclusion, the amelioration of bradykinesia by dopaminergic medication seems to be driven by enhanced connectivity within the mesial premotor loop and cortico-striatal interactions. In contrast, medication did not improve internal motor control deficits concurrent to missing effects at the connectivity level. This differential effect of dopaminergic medication on the network dynamics underlying motor control provides new insights into the clinical finding that in Parkinson's disease dopaminergic drugs especially impact on bradykinesia but less on executive functions.
authors.affiliation: 1 Department of Neurology, Cologne University Hospital, Kerpener Str. 62, 50937 Cologne, Germany 2 Max Planck Institute for Neurological Research, Gleueler Str. 50, 50931 Cologne, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Michely
authors.affiliation: 1 Department of Neurology, Cologne University Hospital, Kerpener Str. 62, 50937 Cologne, Germany 2 Max Planck Institute for Neurological Research, Gleueler Str. 50, 50931 Cologne, Germany.
authors.forename: Lukas J
authors.initials: LJ
authors.lastname: Volz
authors.affiliation: 1 Department of Neurology, Cologne University Hospital, Kerpener Str. 62, 50937 Cologne, Germany 3 Institute of Neuroscience and Medicine (INM-1, INM-3), Research Centre Jülich, 52425 Jülich, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Barbe
authors.affiliation: 3 Institute of Neuroscience and Medicine (INM-1, INM-3), Research Centre Jülich, 52425 Jülich, Germany 4 Department of Clinical Neuroscience and Medical Psychology, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Hoffstaedter
authors.affiliation: 1 Department of Neurology, Cologne University Hospital, Kerpener Str. 62, 50937 Cologne, Germany 3 Institute of Neuroscience and Medicine (INM-1, INM-3), Research Centre Jülich, 52425 Jülich, Germany.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Viswanathan
authors.affiliation: 1 Department of Neurology, Cologne University Hospital, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Timmermann
authors.affiliation: 3 Institute of Neuroscience and Medicine (INM-1, INM-3), Research Centre Jülich, 52425 Jülich, Germany 4 Department of Clinical Neuroscience and Medical Psychology, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Simon B
authors.initials: SB
authors.lastname: Eickhoff
authors.affiliation: 1 Department of Neurology, Cologne University Hospital, Kerpener Str. 62, 50937 Cologne, Germany 3 Institute of Neuroscience and Medicine (INM-1, INM-3), Research Centre Jülich, 52425 Jülich, Germany.
authors.forename: Gereon R
authors.initials: GR
authors.lastname: Fink
authors.affiliation: 1 Department of Neurology, Cologne University Hospital, Kerpener Str. 62, 50937 Cologne, Germany 2 Max Planck Institute for Neurological Research, Gleueler Str. 50, 50931 Cologne, Germany 3 Institute of Neuroscience and Medicine (INM-1, INM-3), Research Centre Jülich, 52425 Jülich, Germany Christian.Grefkes@uk-koeln.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Grefkes
mesh_terms: D000368:Aged; D001499:Bayes Theorem; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology*; D001931:Brain Mapping; D003198:Computer Simulation; D004185:Disability Evaluation; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009434:Neural Pathways / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology*; D017711:Nonlinear Dynamics; D010100:Oxygen / Q000097:blood; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects; D012720:Severity of Illness Index
chemical_list: D015259:Dopamine Agents; D010100:Oxygen
keywords: bradykinesia; dopaminergic medication; effective connectivity; higher motor control; premotor loops