Experimental Brain Research

, Volume 234, Issue 12, pp 3659–3667 | Cite as

Paradoxical facilitation after depotentiation protocol can precede dyskinesia onset in early Parkinson’s disease

  • Angel Lago-Rodriguez
  • Viviana Ponzo
  • Ned Jenkinson
  • Sonia Benitez-Rivero
  • Miguel Fernandez Del-Olmo
  • Michele Hu
  • Giacomo Koch
  • Binith CheeranEmail author
Research Article


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.


Synaptic 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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordUK
  2. 2.School of PsychologyUniversity of BirminghamBirminghamUK
  3. 3.Laboratorio di Neurologia Clinica e ComportamentaleFondazione Santa Lucia IRCCSRomeItaly
  4. 4.Department of Physical Education, Faculty of Sciences of Sport and Physical EducationUniversity of A CoruñaA CoruñaSpain
  5. 5.Stroke Unit, Dipartimento di NeuroscienzeUniversità di Roma Tor VergataRomeItaly

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