title: Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus.
abstract: Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic medication reduces tremor in some patients, but many patients have a dopamine-resistant tremor. Using pharmacological functional magnetic resonance imaging, we test how a dopaminergic intervention influences the cerebral circuit involved in Parkinson's tremor. From a sample of 40 patients with Parkinson's disease, we selected 15 patients with a clearly tremor-dominant phenotype. We compared tremor-related activity and effective connectivity (using combined electromyography-functional magnetic resonance imaging) on two occasions: ON and OFF dopaminergic medication. Building on a recently developed cerebral model of Parkinson's tremor, we tested the effect of dopamine on cerebral activity associated with the onset of tremor episodes (in the basal ganglia) and with tremor amplitude (in the cerebello-thalamo-cortical circuit). Dopaminergic medication reduced clinical resting tremor scores (mean 28%, range -12 to 68%). Furthermore, dopaminergic medication reduced tremor onset-related activity in the globus pallidus and tremor amplitude-related activity in the thalamic ventral intermediate nucleus. Network analyses using dynamic causal modelling showed that dopamine directly increased self-inhibition of the ventral intermediate nucleus, rather than indirectly influencing the cerebello-thalamo-cortical circuit through the basal ganglia. Crucially, the magnitude of thalamic self-inhibition predicted the clinical dopamine response of tremor. Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus (ventral intermediate nucleus). This suggests that altered dopaminergic projections to the cerebello-thalamo-cortical circuit have a role in Parkinson's tremor.aww331media15307619934001.
authors.affiliation: Donders Institute for Brain, Cognition and Behavior, Radboud University, 6500 HB Nijmegen, The Netherlands.|Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Parkinson Centre Nijmegen (ParC), 6500 HB Nijmegen, The Netherlands.
authors.forename: Michiel F
authors.initials: MF
authors.lastname: Dirkx
authors.affiliation: Donders Institute for Brain, Cognition and Behavior, Radboud University, 6500 HB Nijmegen, The Netherlands.
authors.forename: Hanneke E M
authors.initials: HE
authors.lastname: den Ouden
authors.affiliation: Donders Institute for Brain, Cognition and Behavior, Radboud University, 6500 HB Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Aarts
authors.affiliation: Donders Institute for Brain, Cognition and Behavior, Radboud University, 6500 HB Nijmegen, The Netherlands.|Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Parkinson Centre Nijmegen (ParC), 6500 HB Nijmegen, The Netherlands.
authors.forename: Monique H M
authors.initials: MH
authors.lastname: Timmer
authors.affiliation: Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Parkinson Centre Nijmegen (ParC), 6500 HB Nijmegen, The Netherlands.
authors.forename: Bastiaan R
authors.initials: BR
authors.lastname: Bloem
authors.affiliation: Donders Institute for Brain, Cognition and Behavior, Radboud University, 6500 HB Nijmegen, The Netherlands.
authors.forename: Ivan
authors.initials: I
authors.lastname: Toni
authors.affiliation: Donders Institute for Brain, Cognition and Behavior, Radboud University, 6500 HB Nijmegen, The Netherlands.|Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Parkinson Centre Nijmegen (ParC), 6500 HB Nijmegen, The Netherlands.
authors.forename: Rick C
authors.initials: RC
authors.lastname: Helmich
mesh_terms: D001499:Bayes Theorem; D001931:Brain Mapping; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004576:Electromyography; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000187:drug effects*; D017711:Nonlinear Dynamics; D010100:Oxygen / Q000097:blood; D010300:Parkinson Disease / Q000150:complications* / Q000000981:diagnostic imaging; D012720:Severity of Illness Index; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects*; D014202:Tremor / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy*
chemical_list: D015259:Dopamine Agents; D010100:Oxygen
keywords: Parkinson’s disease; dopamine; dynamic causal modelling; resting state functional MRI; resting tremor