Interaction of Noradrenergic Pharmacological Manipulation and Subthalamic Stimulation on Movement Initiation Control in Parkinson's Disease

• PD patients are locked into a control mode of inappropriate response inhibition.
• STN-DBS overcomes this dysfunctional executive setting.
• Clonidine impairs the positive action of STN-DBS.
• Suggesting a noradrenergic-dependent STN-DBS efficiency on akinesia.

BackgroundSlowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic).ObjectiveTo test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity.MethodsSixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (∝2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 μg oral dose of clonidine (ON- or OFF-DBS).ResultsIn the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state.ConclusionsOverall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic “tonus” may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency.