Paradoxical facilitation after depotentiation protocol can precede dyskinesia onset in early Parkinson’s disease
- 262 Downloads
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.
KeywordsSynaptic plasticity Potentiation Depotentiation Levodopa-induced dyskinesia Parkinson’s disease
We are grateful for the use of TMS equipment and lab facilities permitted by Prof. C. Miall in Birmingham (Behavioural Brain Sciences, School of Psychology, University of Birmingham) and Prof P. Brown in Oxford (NIHR Oxford Biomedical Research Centre and the NIHR Oxford Cognitive Health Clinical Research Facility, Oxford).
This study was funded by Parkinson’s UK (Grant INN-12B). ALR was funded during the course of this study by the Oxfordshire Health Services Research Committee (OHSRC), Grant: No. 1082; and by the Wellcome Trust, Grant WT087554. BC was supported by the NIHR Oxford Biomedical Research Centre and Parkinson’s UK (Grant INN-12B).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Huang YZ (2012) Plasticity induction and modulation of the human motor cortex in health and disease. In: 6th international conference on complex medical engineering, CME, Kobe, 2012. pp 131–133Google Scholar
- Manson A, Schrag A (2006) Levodopa-induced dyskinesias. The clinical problem, clinical features, incidence, risk factors, management and impact on Quality of Life. In: Bezard E (ed) Recent Breakthroughs in Basal Ganglia Research. Nova Science Publishers, New York, pp 369–380Google Scholar
- Warren N, Burn DJ (2004) The use of Amantadine in Parkinson’s Disease and other Akinetic-Rigid Disorders. Adv Clin Neurosci Rehabil (ACNR) 4:38–41Google Scholar