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

Abstract

Clonidine is an anti-hypertensive medication which acts as an alpha-adrenergic 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 attention-deficit 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 subthalamo-motor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebo-controlled study in combination with subthalamic nucleus-deep 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 the SMA, a marker of local inhibitory activity. This effect was associated with the speeding-up of movement initiation. Clonidine substantially increased proactive alpha power from the SMA source, and canceled out the benefits of STN-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 alpha-adrenergic receptors.

The Human Basal Ganglia Mediate the Interplay between Reactive and Proactive Control of Response through Both Motor Inhibition and Sensory Modulation

“…The dominant view is that, while reactive control is exerted through the hyperdirect pathway, proactive control is exerted through a competition of facilitation and suppression signals within the direct and indirect pathways. Yet, there are converging clues from human studies using direct electrophysiological recordings [ 57 , 58 , 71 ] or studies combining DBS and cortical activity recordings [ 91 , 101 ] that the STN mediates proactive control and the switch between control states, possibly via the indirect and hyperdirect pathways, respectively [ 64 ]. Although the present data provide null results, we do not reject this hypothesis.…”

“…Finally, the STN may also play a substantial role in proactive inhibition [ 57 , 58 ], either indirectly through the indirect pathway or more directly by relaying a fast signal switching the executive state (i.e., the balance between facilitation and suppression states from direct and indirect pathways) as a function of perceived contextual changes. By establishing a causal link between the experimental manipulation and the behavioral outcomes, studies using deep brain stimulation (DBS) of the STN have been very useful to pinpoint the involvement of the STN in both reactive [ 59 , 60 , 61 , 62 ] and proactive [ 63 , 64 , 65 , 66 , 67 ] inhibition of upper limb movements. However, understanding what precisely is modulated in reactive and proactive control of response needs a stronger neurocognitive footing, with particular concern about the various processes possibly involved and intermixed in the two multifaceted functions [ 3 , 11 , 21 , 68 ].…”

Functional imaging correlates of akinesia in Parkinson's disease: Still open issues

“…3 ). In other words, it is likely that there are other, non-DA dysfunctional neural mechanisms that contribute to akinesia ( Albares et al, 2015b ; Spay et al, 2018 ). Much more pharmacological neuroimaging investigations of resting states modulations building on the papers identified here are required to clarify this point, in particular studies testing directly the effect of DA medication.…”

“…Indeed, results pinpoint brain regions which are known to support executive control of movement initiation, including notably the PCC/Precuneus ( Chikazoe et al, 2009 ; Criaud et al, 2017 ), the IPC ( Criaud et al, 2017 ; Jaffard et al, 2008 ; Zandbelt et al, 2013 ), the insula ( Chikazoe et al, 2009 ; Criaud et al, 2017 ), the mPFC ( Jaffard et al, 2008 ) and the iFG ( Aron, 2011 ; Aron et al, 2003 ; Jahfari et al, 2012 ; Zandbelt et al, 2013 ). Interestingly, most of these regions are also known to involve non-DA systems when engaged in these functions ( Borchert et al, 2016 ; Buddhala et al, 2015 ; Chamberlain et al, 2009 ; Fox, 2013 ; Spay et al, 2018 ; Ye et al, 2015 ). This tentative explanation is consistent with previous studies on the neural bases of executive deficits in PD ( Huang et al, 2007 ; Mattis et al, 2016 ; Pereira et al, 2014 ; van Eimeren et al, 2009 ).…”

“…It is likely that the lack of neurocognitive footing in clinical neuroimaging studies does not help for distinguishing the neural mechanisms that rely on DA neurotransmission from those that rely on other systems. We especially think about the noradrenergic system, which might be involved in the functioning of BG-thalamo-cortical loops and executive functions ( Albares et al, 2015b ; Chamberlain et al, 2009 ; Faggiani and Benazzouz, 2017 ; Spay et al, 2018 ), but also about the serotoninergic ( Carli and Invernizzi, 2014 ; Miguelez et al, 2014 ) and the cholinergic ( Bohnen and Albin, 2011 ) systems. Here, we suggest that future pharmacological neuroimaging designs, whatever goal they are intended for –e.g., testing dose-dependent effects in DA-medicated patients or non-DA pharmacological agents in healthy subjects-, should comply with the general recommendations described above to reveal the neurochemical bases of movement initiation and related disorders.…”