Deep Brain Stimulation of the Subthalamic Nucleus, but not Dopaminergic Medication, Improves Proactive Inhibitory Control of Movement Initiation in Parkinson's Disease

Abstract

Slowness in movement initiation is a cardinal feature of Parkinson's disease (PD) that is still poorly understood and unsuccessfully alleviated by standard therapies. Here, we raise this major clinical issue within the framework of a novel theoretical model that allows a better understanding of the basic mechanisms involved in movement initiation. This model assumes that movement triggering is inhibited by default to prevent automatic responses to unpredictable events. We investigated to which extent the top-down control necessary to release this locking state before initiating actions is impaired in PD and restored by standard therapies. We used a cue-target reaction time task to test both the ability to initiate fast responses to targets and the ability to refrain from reacting to cues. Fourteen patients with dopaminergic (DA) medication and 11 with subthalamic nucleus (STN) stimulation were tested on and off treatment, and compared with 14 healthy controls. We found evidence that patients withdrawn from treatment have trouble voluntarily releasing proactive inhibitory control; while DA medication broadly reduces movement initiation latency, it does not reinstate a normal pattern of movement initiation; and stimulation of the STN specifically re-establishes the efficiency of the top-down control of proactive inhibition. These results suggest that movement initiation disorders that resist DA medication are due to executive, not motor, dysfunctions. This conclusion is discussed with regard to the role the STN may play as an interface between non-DA executive and DA motor systems in cortico-basal ganglia loops.

The dorsal medial frontal cortex mediates automatic motor inhibition in uncertain contexts: Evidence from combined fMRI and EEG studies

“…We suggest that an early, automatic, nonselective self-inhibitory mechanism of the SMC is involved in response control when the context is uncertain, and is released when the situation becomes predictable. Such executive dysfunctions may account for various motor and cognitive disorders, as might obviously be the case for impulsivity but also for opposing symptoms like akinesia [e.g., Favre et al, 2013]. These results open-up new clinical perspectives since impairments in the ability to implement or release this form of inhibitory setting would be devastating in different psychiatric and neurologic conditions.…”

“…These results open-up new clinical perspectives since impairments in the ability to implement or release this form of inhibitory setting would be devastating in different psychiatric and neurologic conditions. Such executive dysfunctions may account for various motor and cognitive disorders, as might obviously be the case for impulsivity but also for opposing symptoms like akinesia [e.g., Favre et al, 2013].…”

Parkinson's Disease, the Subthalamic Nucleus, Inhibition, and Impulsivity

“…To date, the main focus has been on the role of the STN in reactive and global inhibition, and few studies have investigated proactive or selective inhibition, with exceptions . Certainly, this is an imbalance that needs to be addressed in the future.…”

The frontal aslant tract (FAT) and its role in speech, language and executive function

“…In several models of inhibitory control (Aron & Poldrack, 2006;Wiecki & Frank, 2013), the right IFG directly activates neurons of the subthalamic nucleus through a direct pathway, which plays an explicit role in stopping motor behavior (Cai & Leung, 2009;Favre, Ballanger, Thobois, Broussolle, & Boulinguez, 2013;Frank, 2006;Jahanshahi, 2013;Obeso et al, 2014;van Wouwe et al, 2017). Thus, the early suggestion has been that suppression occurs through a direct interaction with right IFG and subthalamic nucleus.…”