Levodopa-induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa-to-dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine-releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in-development treatments for peak-dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. ANN NEUROL 2018;84:797-811 D yskinesia, often referred to as L-dopa-induced dyskinesia (LID) to recognize L-dopa as the major contributor, is a motor complication arising in patients with Parkinson disease (PD) on chronic L-dopa treatment, largely in a dose-dependent fashion-except when given as an infusion, such as in L-dopa/carbidopa intestinal gel. 1 LID is phenomenologically recognized as chorea/choreoathetoid movements appearing initially on the more affected body side. LID occurs in 40% of patients after 4 years on L-dopa treatment, with risk especially high in younger patients treated with higher doses of L-dopa. 2 This review focuses on aspects of phenomenology, pathophysiology, and therapeutics that have undergone revisions or updates in recent years, emphasizing those of most relevance for modern clinical care and future research. We highlight the under-recognized diphasic dyskinesia, which is often mischaracterized as a peak-dose phenomenon and therefore mismanaged. We review evidence that corrects the misinterpretation of prior clinical trial data surmising LID as a function of duration of Ldopa exposure rather than duration of disease, justifying the inappropriate but still lingering recommendation to postpone L-dopa treatment as long as possible to "delay" the appearance of LID. 3 We also review the latest pathophysiologic concepts at the molecular, synaptic, and network levels, to provide the rationale for currently available as well as emerging treatments. Peak-Dose versus Diphasic DyskinesiaPeak-Dose Dyskinesia. Chorea that may be generalized or affect the more affected side or upper body often occurs during the therapeutic window of a L-dopa dose cycle View this article online at wileyonlinelibrary.com.

Commonly used for Parkinson’s disease (PD), deep brain stimulation (DBS) produces marked clinical benefits when optimized. However, assessing the large number of possible stimulation settings (i.e., programming) requires numerous clinic visits. Here, we examine whether functional magnetic resonance imaging (fMRI) can be used to predict optimal stimulation settings for individual patients. We analyze 3 T fMRI data prospectively acquired as part of an observational trial in 67 PD patients using optimal and non-optimal stimulation settings. Clinically optimal stimulation produces a characteristic fMRI brain response pattern marked by preferential engagement of the motor circuit. Then, we build a machine learning model predicting optimal vs. non-optimal settings using the fMRI patterns of 39 PD patients with a priori clinically optimized DBS (88% accuracy). The model predicts optimal stimulation settings in unseen datasets: a priori clinically optimized and stimulation-naïve PD patients. We propose that fMRI brain responses to DBS stimulation in PD patients could represent an objective biomarker of clinical response. Upon further validation with additional studies, these findings may open the door to functional imaging-assisted DBS programming.