Clonidine modulates the activity of the subthalamic‐supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients

摘要

Abstract Clonidine is an antihypertensive medication which acts as an alphaadrenergic receptor agonist. As the noradrenergic system is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attentiondeficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the noradrenergic system regulates the activity of subthalamomotor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebocontrolled study in combination with subthalamic nucleusdeep brain stimulation (STN DBS ) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (SMA ) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo,STN DBS reduced proactive alpha power in theSMA , a marker of local inhibitory activity. This effect was associated with the speedingup of movement initiation. Clonidine substantially increased proactive alpha power from theSMA source, and canceled out the benefits ofSTN DBS on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the noradrenergic system, and that this activity can be targeted by pharmacological agents acting on alphaadrenergic receptors.