Proactive Inhibitory Control of Response as the Default State of Executive Control

Refraining from reacting does not only involve reactive inhibitory mechanisms. It was recently found that inhibitory control also relies strongly on proactive mechanisms. However, since most available studies have focused on reactive stopping, little is known about how proactive inhibition of response is implemented. Two behavioral experiments were conducted to identify the temporal dynamics of this executive function. They manipulated respectively the time during which inhibitory control must be sustained until a stimulus occurs, and the time limit allowed to set up inhibition before a stimulus occurs. The results show that inhibitory control is not set up after but before instruction, and is not transient and sporadic but sustained across time. Consistent with our previous neuroimaging findings, these results suggest that proactive inhibition of response is the default mode of executive control. This implies that top-down control of sensorimotor reactivity would consist of a temporary release (up to several seconds), when appropriate (when the environment becomes predictable), of the default locking state. This conclusion is discussed with regard to current anatomo-functional models of inhibitory control, and to methodological features of studies of attention and sensorimotor control

L'akinésie du patient parkinsonien (un modèle d'étude des processus d'initiation du mouvement)

POITIERS-BU Sciences (861942102) / SudocPOITIERS-MSHS (861942220) / SudocSudocFranceF

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

International audienceAkinesia 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

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

International audienceThe basal ganglia (BG) have long been known for contributing to the regulation of motor behaviour by means of a complex interplay between tonic and phasic inhibitory mechanisms. However, after having focused for a long time on phasic reactive mechanisms, it is only recently that psychological research in healthy humans has modelled tonic proactive mechanisms of control. Mutual calibration between anatomo-functional and psychological models is still needed to better understand the unclear role of the BG in the interplay between proactive and reactive mechanisms of control. Here, we implemented an event-related fMRI design allowing proper analysis of both the brain activity preceding the target-stimulus and the brain activity induced by the target-stimulus during a simple go/nogo task, with a particular interest in the ambiguous role of the basal ganglia. Post-stimulus activity was evoked in the left dorsal striatum, the subthalamus nucleus and internal globus pallidus by any stimulus when the situation was unpredictable, pinpointing its involvement in reactive, non-selective inhibitory mechanisms when action restraint is required. Pre-stimulus activity was detected in the ventral, not the dorsal, striatum, when the situation was unpredictable, and was associated with changes in functional connectivity with the early visual, not the motor, cortex. This suggests that the ventral striatum supports modulatory influence over sensory processing during proactive contro

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

International audienceSlowness 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 diseas

Inhibitory control dysfunction in parkinsonian impulse control disorders

International audienceImpulse control disorders (ICDs) in Parkinson's disease have been associated with dysfunctions in the control of value-or reward-based responding (choice impulsivity) and abnormalities in mesocorticolimbic circuits. The hypothesis that dysfunctions in the control of response inhibition (action impulsivity) also play a role in Parkinson's disease ICDs has recently been raised, but the underlying neural mechanisms have not been probed directly. We used high-resolution EEG recordings from 41 patients with Parkinson's disease with and without ICDs to track the spectral and dynamical signatures of different mechanisms involved in inhibitory control in a simple visuomotor task involving no selection between competing responses and no reward to avoid potential confounds with reward-based decision. Behaviourally, patients with Parkinson's disease with ICDs proved to be more impulsive than those without ICDs. This was associated with decreased beta activity in the precuneus and in a region of the medial frontal cortex centred on the supplementary motor area. The underlying dynamical patterns pinpointed dysfunction of proactive inhibitory control, an executive mechanism intended to gate motor responses in anticipation of stimulation in uncertain contexts. The alteration of the cortical drive of proactive response inhibition in Parkinson's disease ICDs pinpoints the neglected role the precuneus might play in higher order executive functions in coordination with the supplementary motor area, specifically for switching between executive settings. Clinical perspectives are discussed in the light of the non-dopaminergic basis of this function

Distribution of α 2 -Adrenergic Receptors in the Living Human Brain Using [ 11 C]yohimbine PET

International audienceThe neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [ 11 C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20-50) to perform direct quantification of regional alpha 2 adrenergic receptors' (α 2-ARs) availability in the living human brain. The global map shows the highest [ 11 C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [ 11 C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α 2-ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α 2-ARs is suspected

A functional magnetic resonance imaging study of pathophysiological changes responsible for mirror movements in Parkinson's disease.

Mirror movements correspond to involuntary movements observed in the limb contralateral to the one performing voluntary movement. They can be observed in Parkinson's disease (PD) but their pathophysiology remains unclear. The present study aims at identifying their neural correlates in PD using functional magnetic resonance imaging. Ten control subjects and 14-off drug patients with asymmetrical right-sided PD were included (8 with left-sided mirror movements during right-hand movements, and 6 without mirror movements). Between-group comparisons of BOLD signal were performed during right-hand movements and at rest (p<0.005 uncorrected). The comparison between PD patients with and without mirror movements showed that mirror movements were associated with an overactivation of the insula, precuneus/posterior cingulate cortex bilaterally and of the left inferior frontal cortex and with a deactivation of the right dorsolateral prefrontal cortex, medial prefrontal cortex, and pre-supplementary motor area and occipital cortex. These data suggest that mirror movements in Parkinson's disease are promoted by: 1- a deactivation of the non-mirroring inhibitory network (dorsolateral prefrontal cortex, pre-supplementary motor area); 2- an overactivation of prokinetic areas (notably the insula). The concomitant overactivation of a proactive inhibitory network (including the posterior cingulate cortex and precuneus) could reflect a compensatory inhibition of mirror movements