Akinesia is a major manifestation of Parkinson's disease (PD) related to difficulties or failures of willed movement to occur. Akinesia is still poorly understood and is not fully alleviated by standard therapeutic strategies. One reason is that the area of the clinical concept has blurred boundaries referring to confounded motor symptoms. Here, we review neuroimaging studies which, by providing access to finer-grained mechanisms, have the potential to reveal the dysfunctional brain processes that account for akinesia. It comes out that no clear common denominator could be identified across studies that are too heterogeneous with respect to the clinical/theoretical concepts and methods used. Results reveal, however, that various abnormalities within but also outside the motor and dopaminergic pathways might be associated with akinesia in PD patients. Notably, numerous yet poorly reproducible neural correlates were found in different brain regions supporting executive control by means of resting-state or task-based studies. This includes for instance the dorsolateral prefrontal cortex, the inferior frontal cortex, the supplementary motor area, the medial prefrontal cortex, the anterior cingulate cortex or the precuneus. This observation raises the issue of the multidimensional nature of akinesia. Yet, other open issues should be considered conjointly to drive future investigations. Above all, a unified terminology is needed to allow appropriate association of behavioral symptoms with brain mechanisms across studies. We adhere to a use of the term akinesia restricted to dysfunctions of movement initiation, ranging from delayed response to freezing or even total abolition of movement. We also call for targeting more specific neural mechanisms of movement preparation and action triggering with more sophisticated behavioral designs/event-related neurofunctional analyses. More work is needed to provide reliable evidence, but answering these still open issues might open up new prospects, beyond dopaminergic therapy, for managing this disabling symptom.

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.