Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson's disease

Abstract

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Methods: Twelve PD patients with peak-of-dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication.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.

Keywords: Parkinson's disease; dyskinesias; fMRI; levodopa MRI.

Figure 1

Study design. Structural scans (sMRI) were acquired in the off state. Resting‐state fMRI (RS‐fMRI) was recorded in the off‐medication state and repeatedly after levodopa intake (first vertical dashed line) until dyskinesias emerged (second vertical dashed line). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Classifier analyses. A: List of classifiers. B: Classifier accuracy in distinguishing patients with and without levodopa‐induced dyskinesias (LID). C: Key parameters of the best classifier (SM₁‐putamen connectivity in most affected hemisphere). AUC, area under the curve; rIFG, right inferior frontal gyrus; ROC, receiver‐operating characteristic; RS, resting state; SM₁, primary sensorimotor cortex; S, structural. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

Dopaminergic modulation of resting‐state connectivity between the SMA and putamen predict dyskinesia severity (P = .004). This relationship was specific for the development of dyskinesias because dopaminergic modulation of SMA–putamen connectivity did not predict disease severity. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]