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Parkinson's disease (PD) can be effectively treated with levodopa and dopamine agonists but leads to levodopa-induced dyskinesia (LID) in most patients in the long run. Various functional brain mapping techniques are used to explore alterations in motor networks associated with LID. This pre-registered review (PROSPERO: CRD42022320830) summarizes the motor network abnormalities reported in functional brain mapping studies of patients with LID. We included studies using functional MRI, EEG, PET, SPECT, or TMS and included at least 10 LID patients. For completeness, we included studies of 5-9 patients with LID in a table. Some of these were also incorporated into the review if other studies used the same method. Thirty studies met our pre-defined criteria. Patients with LID showed stronger motor-related activation and functional connectivity of motor and premotor cortical areas and the putamen after levodopa intake relative to PD patients without LID. Decreased activation was found in the right inferior frontal cortex. TMS studies showed increased cortical excitability and blunted cortical plasticity in patients with LID, while "inhibitory" repetitive TMS of prefrontal motor control areas and cerebellum produced transient anti-dyskinetic effects. Overall, sample sizes were small, the number of studies per mapping modality was limited, and most studies lacked independent replication. The alterations associated with LID encompass changes in functional activity, connectivity, cortical excitability, and plasticity in motor execution and motor control networks. A comprehensive understanding of how LID manifests at the motor network level will guide the future development of stimulation-based network therapies for LID., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Birgitte L. C. Thomsen: No disclosures. Mikkel C. Vinding: No disclosures. David Meder: No disclosures. Lisbeth Marner: No disclosures. Annemette Løkkegaard: Annemette Løkkegaard has attended a course sponsored by Boston Scientific and has received a fee for a lecture from Abbvie and Ipsen. Hartwig Roman Siebner: Hartwig R. Siebner has received honoraria as speaker and consultant from Lundbeck AS, Denmark, and as editor (Neuroimage Clinical) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as a book editor from Springer Publishers, Stuttgart, Germany, Oxford University Press, Oxford, UK, and from Gyldendal Publishers, Copenhagen, Denmark]., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Levodopa-induced dyskinesia (LID) represents a severe adverse effect of long-term treatment of Parkinson's disease with levodopa. Neuroimaging studies have contributed to our understanding of LID and may help to identify patients at risk of developing LID. Amantadine can be used for the treatment of LID, and novel drugs are under development. Deep brain stimulation of the subthalamic nucleus and globus pallidus internus alleviates LID, the former indirectly by reducing levodopa intake, the latter through direct effects. Repetitive transcranial magnetic stimulation has been shown to transiently improve LID.

Background: Levodopa-induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood., Objectives: This study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting-state cortico-striatal connectivity., Methods: Twelve PD patients with peak-of-dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast-acting soluble levodopa and then underwent resting-state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa-induced modulation of cortico-striatal resting-state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity., Results: Dopaminergic modulation of resting-state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P < .0001). Modulation of resting-state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R(2) = 0.627, P = .004). Resting-state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity., Conclusions: The results corroborate the notion that altered dopaminergic modulation of cortico-striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD., (© 2016 International Parkinson and Movement Disorder Society.)

Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51-84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: In Parkinson disease (PD), long-term treatment with the dopamine precursor levodopa gradually induces involuntary "dyskinesia" movements. The neural mechanisms underlying the emergence of levodopa-induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic resonance imaging (fMRI) to map the emergence of peak-of-dose dyskinesias in patients with PD., Methods: Thirteen PD patients with dyskinesias and 13 PD patients without dyskinesias received 200mg fast-acting oral levodopa following prolonged withdrawal from their normal dopaminergic medication. Immediately before and after levodopa intake, we performed fMRI, while patients produced a mouse click with the right or left hand or no action (No-Go) contingent on 3 arbitrary cues. The scan was continued for 45 minutes after levodopa intake or until dyskinesias emerged., Results: During No-Go trials, PD patients who would later develop dyskinesias showed an abnormal gradual increase of activity in the presupplementary motor area (preSMA) and the bilateral putamen. This hyperactivity emerged during the first 20 minutes after levodopa intake. At the individual level, the excessive No-Go activity in the predyskinesia period predicted whether an individual patient would subsequently develop dyskinesias (p < 0.001) as well as severity of their day-to-day symptomatic dyskinesias (p < 0.001)., Interpretation: PD patients with dyskinesias display an immediate hypersensitivity of preSMA and putamen to levodopa, which heralds the failure of neural networks to suppress involuntary dyskinetic movements., (© 2014 American Neurological Association.)