Noradrenaline and Movement Initiation Disorders in Parkinson's Disease: A Pharmacological Functional MRI Study with Clonidine

Abstract

Slowness of movement initiation is a cardinal motor feature of Parkinson's disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols. For that purpose, we administered 150 μg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson's disease.

Keywords: Parkinson’s disease; akinesia; clonidine; functional MRI; inhibitory control; movement initiation; noradrenaline; α2-adrenoceptor.

Figure 1

Issues and Hypotheses. (A) Nondopaminergic neurotransmitter systems involved in the motor features of PD. Taken from [1] and reproduced with permission. (B) We hypothesize that the impairment in initiating movements in PD patients might be related to the NA system. Indeed, the NA system likely plays a substantial role in proactive response inhibition: a cortico–ganglio–thalamo–cortical function is intended to inhibit movement triggering mechanisms by anticipation to prevent erroneous responses when the context is uncertain. When proactive inhibition is ON, motor responses are delayed with respect to a condition that does not require inhibition (fast automatic responses) because it takes additional time to release inhibition after the stimulus has been identified. PD patients are known to have enhanced difficulties to trigger automatic responses when the context does not require action restraint. This might be due to the fact that PD patients are often locked into a mode of control, maintaining inappropriate proactive inhibition over willed movements (i.e., troubles to switch from controlled to automatic behavior). If this disorder is associated with the NA system, manipulating noradrenergic tonus by means of clonidine, an α2-AR agonist, should induce brain activation differences in the proactive inhibition network associated with the lengthening of reaction time in PD patients with respect to healthy controls. GPe, globus pallidus externa; GPi, globus pallidus interna; LC, locus coeruleus; SN, substantia nigra; Str, striatum; STN, subthalamic nucleus; Th, thalamus.

Figure 2

Overview of the experimental setup. Subjects were instructed to react to the presentation of a go signal (diamond) by pressing a button. At the beginning of a trial, the central fixation point (cue) could turn either red or green, indicating, respectively, that NoGo stimuli (X) could or could not be presented. In the former condition (uncertainty condition), proactive inhibition was required during the pre-stimulus period to avoid erroneous automatic responses to NoGo stimuli. In the latter condition, proactive inhibition was not required during the pre-stimulus period. Subjects could react automatically to any upcoming target (no uncertainty condition).

Figure 3

Reaction times (means and standard deviations) for PD patients versus healthy matched controls.

Figure 4

Percentages of omissions (means and standard deviations) for PD patients versus healthy matched controls. * p < 0.05.

Figure 5

Interaction between drug and disease effects during the pre-stimulus period assessed by means of the [(green cue_(clonidine-placebo)_Patients)-(green cue_(clonidine-placebo)_Controls)] contrast. The differential increase in BOLD signal under clonidine between PD patients and healthy controls is overlaid on the Colin 27 brain template in the MNI space visualized with the Mango software [43]. This overactivation of the anterior node of the proactive inhibition network (mPFC/ACC) is associated with the enhanced difficulty of PD patients to initiate movements when action restraint is not required (control condition with no uncertainty) under the effect of clonidine. L = Left. A = Anterior. S = Superior. X, Y, Z are coordinates in mm in the MNI space.