title: Paradoxical facilitation after depotentiation protocol can precede dyskinesia onset in early Parkinson's disease.
abstract: Loss of dopamine, a key modulator of synaptic signalling, and subsequent pulsatile non-physiological levodopa replacement is believed to underlie altered neuroplasticity in Parkinson's disease (PD). Animal models suggest that maladaptive plasticity (e.g. deficient depotentiation at corticostriatal synapses) is key in the development of levodopa-induced dyskinesia (LID), a common complication following levodopa replacement in PD. Human studies using transcranial magnetic stimulation protocols have shown similar depotentiation deficit in patients with LID. We hypothesized that subtle depotentiation deficits should precede LID if these deficits are mechanistically linked to LID onset. Moreover, patients on pulsatile levodopa-based therapy may show these changes earlier than those treated with levodopa-sparing strategies. We recruited 22 early non-dyskinetic PD patients (<5 years since diagnosis) and 12 age-matched healthy controls. We grouped patients into those on Levodopa-Based (n = 11) and Levodopa-Sparing therapies (n = 11). Patients were selected to obtain groups matched for age and disease severity. We used a theta-burst stimulation protocol to investigate potentiation and depotentiation in a single session. We report significant depotentiation deficits in the Levodopa-Based group, compared to both Levodopa-Sparing and Healthy Control groups. Potentiation and Depotentiation responses were similar between Levodopa-Sparing and Healthy Control groups. Although differences persist after accounting for potential confounds (e.g. levodopa-equivalent dose), these results may yet be caused by differences in disease severity and cumulative levodopa-equivalent dose as discussed in the text. In conclusion, we show for the first time that paradoxical facilitation in response to depotentiation protocols can occur in PD even prior to LID onset.
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK.|School of Psychology, University of Birmingham, Birmingham, UK.
authors: Angel
authors: 0000-0002-2942-5462
authors: A
authors: Lago-Rodriguez
authors: Laboratorio di Neurologia Clinica e Comportamentale, Fondazione Santa Lucia IRCCS, Rome, Italy.
authors: Viviana
authors: V
authors: Ponzo
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK.
authors: Ned
authors: N
authors: Jenkinson
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK.
authors: Sonia
authors: S
authors: Benitez-Rivero
authors: Department of Physical Education, Faculty of Sciences of Sport and Physical Education, University of A Coruña, A Coruña, Spain.
authors: Miguel Fernandez
authors: MF
authors: Del-Olmo
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK.
authors: Michele
authors: M
authors: Hu
authors: Laboratorio di Neurologia Clinica e Comportamentale, Fondazione Santa Lucia IRCCS, Rome, Italy.|Stroke Unit, Dipartimento di Neuroscienze, Università di Roma Tor Vergata, Rome, Italy.
authors: Giacomo
authors: G
authors: Koch
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK. Binith.cheeran@ndncn.ox.ac.uk.
authors: Binith
authors: B
authors: Cheeran
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000978:Antiparkinson Agents / Q000009:adverse effects; D001703:Biophysics; D016022:Case-Control Studies; D004409:Dyskinesia, Drug-Induced / Q000473:pathology*; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000187:drug effects / Q000503:physiopathology*; D010300:Parkinson Disease / Q000188:drug therapy; D013826:Theta Rhythm; D050781:Transcranial Magnetic Stimulation
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa
keywords: Depotentiation; Levodopa-induced dyskinesia; Parkinson’s disease; Potentiation; Synaptic plasticity