Advancement In Dyskinesia Research
Dopamine replacement therapy with L-DOPA (levodopa) is a cornerstone in the management of Parkinson's disease (PD), providing essential support to patients in maintaining function and independence. This therapy is quite effective in reducing the typical motor symptoms of PD (stiffness, slowness of movement, tremors) and significantly improves patients´ quality of life. Notwithstanding these benefits, treatment with L-DOPA can lead to the development of abnormal involuntary movements (dyskinesia) that often interfere with the execution of normal motor actions and can cause social stigma. Dyskinesia has been reported to affect up to 40% of PD patients within 4–6 years of L-DOPA treatment, and up to 80% within 10 years [1]. The risk of LID is particularly high in people with early-onset PD (those diagnosed before the age of 50). Dyskinesia can negatively impact activities of daily living, resulting in a diminished quality of life. Moreover, it is strongly linked with both motor fluctuations and non-motor symptoms. For example, the expression of these abnormal involuntary movements can be associated with excessive sweating, altered sensory perception, and mood dysregulation [2].
Dyskinesia stems from dysfunctions in cortico-basal ganglia circuits that control our movements and actions. Upon severe dopamine depletion, these neuronal circuits undergo multiple layers of alterations and respond to dopaminergic therapies in a pathological manner [3]. The complexity and medical importance of dyskinesia continue to inspire many researchers aiming to unravel the underlying mechanisms and identify new therapeutic targets. This is a particularly fruitful area of translational research where many basic discoveries have been successfully verified in human studies. Several advances have been made possible by the availability of animal models that effectively mimic the biological and behavioral characteristics of human LID. For example, some small-molecule drugs with proven antidyskinetic action in animal models were found effective in phase-2 clinical trials just last year. Two such drugs are befiradol (a selective serotonin receptor 1A agonist) and mesdopetam (a D2-class dopamine receptor modulator) [4, 5]. In the phase-2 trials, these drugs were found to significantly reduce dyskinesia severity without interfering with the good motor effects of L-DOPA; moreover befiradol reduced parkinsonian symptoms [5]. However, to introduce these compounds in the clinical practice it is necessary to verify their beneficial effects in large clinical trials, which are costly. A further development of these drugs as actual treatment options is therefore conditional on successful fundraising by the companies involved.
In addition to informing drug interventions, animal models of LID are instrumental in devising novel methods of brain stimulation that target dysfunctional neuronal circuits. In this area, there is a rapid development of technologies that allow for dynamic adjustments of the stimulation parameters based on continuously recorded neural activity signals. These adaptive methods of brain stimulation promise to provide a more tailored and personalized approach to managing PD motor symptoms while minimizing dyskinesia and other complications of conventional treatments. A successful development of these methods is dependent on our ability to distinguish the “good” patterns of neural activity from the dysfunctional ones. Interestingly, rat models of LID exhibit patterns of cortico-basal ganglia activities similar to those observed in human patients. In particular, dyskinetic rats exhibit excessive oscillatory neural activity within a narrowband gamma frequency in the motor cortex and other nodes of the cortico-basal ganglia network [6, 7]. This oscillatory rhythm has been recently found to correlate with the expression of dyskinesia also in people with PD [8], and it is now being used to develop control signals for adaptive deep brain stimulation (DBS) [9, 10].
Additional areas of rapid translational progress include the development of drug formulations that allow for a continuous and minimally invasive delivery of L-DOPA, as well as the application of machine learning (ML) to enable objective monitoring of dyskinesia severity [11, 12]. We can be (almost) certain that ML-based assessment methods will become essential assets in intervention trials for PD and LID in the future.
It is invigorating to realize that a complex and often under-recognized condition such as dyskinesia has spurred such tangible scientific and translational development over the past few years. As a researcher, I feel really privileged to contribute to this development through my daily work. In closing, I would like to express my gratitude to the people with PD who participate in this research. By sharing your experience and questions, you provide a great source of inspiration and motivation for us in the lab to continue the good work.
Literature citations
[1]. Tran TN, Vo TNN, Frei K, Truong DD. Levodopa-induced dyskinesia: clinical features, incidence, and risk factors. J Neural Transm (Vienna) 2018;125(8):1109-1117.
[2]. Cenci MA, Riggare S, Pahwa R, Eidelberg D, Hauser RA. Dyskinesia matters. Mov Disord 2020;35(3):392-396.
[3]. Cenci MA, Kumar A. Cells, pathways, and models in dyskinesia research. Curr Opin Neurobiol 2024;84:102833.
[4]. Antonini A, O'Suilleabhain P, Stocchi F, et al. Mesdopetam for the Treatment of Levodopa Induced Dyskinesia in Parkinson's Disease: A Randomized Phase 2b Trial. Mov Disord Clin Pract 2025;12(6):796-806.
[5]. Svenningsson P, Odin P, Bergquist F, et al. NLX-112 Randomized Phase 2A Trial: Safety, Tolerability, Anti-Dyskinetic, and Anti-Parkinsonian Efficacy. Mov Disord 2025;40(6):1134-1142.
[6]. Halje P, Tamte M, Richter U, Mohammed M, Cenci MA, Petersson P. Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations. J Neurosci 2012;32(47):16541-16551.
[7]. Skovgard K, Barrientos SA, Petersson P, Halje P, Cenci MA. Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia. Neurotherapeutics 2023;20(1):304-324.
[8]. Olaru M, Cernera S, Hahn A, et al. Motor network gamma oscillations in chronic home recordings predict dyskinesia in Parkinson's disease. Brain 2024;147(6):2038-2052.
[9]. Mathiopoulou V, Habets J, Feldmann LK, et al. Gamma entrainment induced by deep brain stimulation as a biomarker for motor improvement with neuromodulation. Nat Commun 2025;16(1):2956.
[10]. Oehrn CR, Cernera S, Hammer LH, et al. Chronic adaptive deep brain stimulation versus conventional stimulation in Parkinson's disease: a blinded randomized feasibility trial. Nat Med 2024;30(11):3345-3356.
[11]. Loo RTJ, Tsurkalenko O, Klucken J, et al. Levodopa-induced dyskinesia in Parkinson's disease: Insights from cross-cohort prognostic analysis using machine learning. Parkinsonism Relat Disord 2024;126:107054.
[12]. Twala B. AI-driven precision diagnosis and treatment in Parkinson's disease: a comprehensive review and experimental analysis. Front Aging Neurosci 2025;17:1638340.
Angela Cenci Nilsson, MD, PhD. Professor Cenci Nilsson has been involved with the WPC for many years, both as a speaker and committee member. Her Research Spotlight interview will take place on Tuesday, March 10, 2026 Register here.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®