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

Marion Albares (1) , Stéphane Thobois (1, 2) , Emilie Favre (1, 2) , Emmanuel Broussolle (1, 2) , Gustavo Polo (2) , Philippe Domenech (3, 4) , Philippe Boulinguez (1) , Benedicte Ballanger (1)

1 ISC-MJ - Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229
2 Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]
3 L2C2 - Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition
4 CHU Henri Mondor [Créteil]

Background: Slowness 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). Objective: To 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. Methods: Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (f2-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 mg oral dose of clonidine (ON-or OFF-DBS). Results: In 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. Conclusions: Overall 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.

Mots clés: Akinesia; Executive control; Noradrenaline; Reaction time; STN-DBS

Domaines: Neurosciences [q-bio.NC]

Marion Albares, Stéphane Thobois, Emilie Favre, Emmanuel Broussolle, Gustavo Polo, et al.. Interaction of Noradrenergic Pharmacological Manipulation and Subthalamic Stimulation on Movement Initiation Control in Parkinson's Disease. Brain Stimulation, 2015, 8 (1), pp.27-35. ⟨10.1016/j.brs.2014.09.002⟩. ⟨hal-02115089⟩