title: Acute dopamine boost has a negative effect on plasticity of the primary motor cortex in advanced Parkinson's disease.
abstract: Plasticity of primary motor cortex is severely impaired in Parkinson's disease and chronic dopaminergic treatment is reported not to rescue it. The effect of an acute dose of levodopa on cortical plasticity reported so far is variable. In this study, it was hypothesized that cortical plasticity would be restored in Parkinson's disease as a long duration response to treatment in stable responders while those with motor complications would have a reduction or loss of plasticity similar to the decay of long duration response of motor signs. Patients were carefully stratified based on their motor response to levodopa into stable responders (n=17), fluctuating non-dyskinetics (n=18) and fluctuating dyskinetics (n=20). Theta burst stimulation was applied to the motor cortex to induce long-term potentiation and long-term depression-like plasticity in both OFF and ON conditions. In OFF, stable responders could express both types of plasticity, fluctuating non-dyskinetics had long-term potentiation, but no long-term depression and both types of plasticity were lost in fluctuating dyskinetics. This suggests the presence of a long duration response in early stages of levodopa treatment and a gradual loss of chronic treatment benefit on plasticity, particularly for long-term depression, when motor complications develop. An acute dose of levodopa led to a worsening of long-term potentiation in fluctuating non-dyskinetic patients, and it did not have any effect on the plasticity that was absent in OFF in the fluctuating dyskinetic patients. Acute dosing led to a worsening of long-term depression in all the groups. In the fluctuating dyskinetic patients, there was a paradoxical potentiation instead of depression. Our results suggest that an acute non-physiological dopamine boost has a negative effect on cortical plasticity as disease advances. We propose that the loss of long duration response and the negative effect of acute doses on cortical plasticity with progression of disease may contribute to the pathophysiology of motor complications. Repeated non-physiological surges in synaptic dopamine during acute levodopa dosing could potentially lead to persistent dysfunction of key enzymes of the intracellular signalling cascade that are involved in the induction and maintenance of both forms of plasticity.
authors.affiliation: Department of Neurology, Comprehensive Care Centre for Movement Disorders, Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Thiruvanathapuram, Kerala 695011, India. asha@sctimst.ac.in
authors.forename: Asha
authors.initials: A
authors.lastname: Kishore
authors.forename: Traian
authors.initials: T
authors.lastname: Popa
authors.forename: Balu
authors.initials: B
authors.lastname: Velayudhan
authors.forename: Thomas
authors.initials: T
authors.lastname: Joseph
authors.forename: Ammu
authors.initials: A
authors.lastname: Balachandran
authors.forename: Sabine
authors.initials: S
authors.lastname: Meunier
mesh_terms: D000328:Adult; D000368:Aged; D004298:Dopamine / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000150:complications / Q000503:physiopathology; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology*; D050781:Transcranial Magnetic Stimulation / Q000379:methods
chemical_list: D007980:Levodopa; D004298:Dopamine