Garance Meyer Defense Thesis - Neuro-functional bases of impulsivity disorders in Parkinson’s Disease

Dear all,

It is my pleasure to invite you to my PhD thesis defense, entitled « Neuro-functional bases of impulsivity disorders in Parkinson’s Disease », and directed by Philippe Boulinguez and Guillaume Sescousse.

The defense will take place on Wenesday 30 March at 2p.m., in the Neurocampus amphitheater. The presentation will be in English. The jury will be composed of Nathalie George (Referee; Paris), Thilo Van Eimeren (Referee; Cologne, Germany), Christelle Baunez (Examiner; Marseille), Ana Marques (Examiner; Clermont-Ferrand), Stéphane Thobois (Examiner; Lyon) and Roberto Cilia (Invited member; Milano, Italy).

Garance Meyer

Abstract

Neuro-functional bases of impulsivity disorders in Parkinson’s Disease Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, and has

dramatic consequences on patients' life. Nowadays, motor symptoms can be reasonably well-controlled thanks to dopaminergic medication and deep brain stimulation. But other symptoms, as well as side-effects associated with the treatments, still have no satisfactory therapeutic option. This work focuses on one of these side-effects, impulsivity, which can be manifest in the form of Impulse Control Disorders (ICDs; pathological gambling, hypersexuality, compulsive eating and compulsive shopping) induced by dopaminergic medication, or in the form of inhibitory control dysfunctions following subthalamic nucleus deep brain stimulation (STN-DBS).

A thorough assessment of the state of the art returns that the nature and neuro-functional bases of the dysfunctions contributing to these forms of impulsivity are unclear, which limits therapeutic progress. To tackle this issue, we rely on 1) the psychological modeling of the cognitive processes of interest (in particular, response inhibition mechanisms), 2) behavioral tasks designed to target precisely these processes, and 3) electroencephalography (EEG) and advanced signal processing

techniques (time-frequency analyses performed directly in the source space). Indeed, combining these tools can substantially increase our discriminative power regarding the neurocognitive mechanisms involved.

In the first Chapter, we provide evidence against the leading hypothesis in the field, which posits that ICDs only imply dysfunctions of motivation, decision-making and reward processing.

Indeed, in a systematic review of neuroimaging studies, we demonstrate various abnormalities beyond the mesocorticolimbic reward circuit. We also argue that the field needs a stronger neurocognitive footing. Then, we test the neglected hypothesis of inhibitory control dysfunctions in PD-ICDs. In a first experimental study, we show that ICDs are associated with abnormal resting-state activity within frequency bands and cortical regions supporting response inhibition. In a second study, we show that patients with ICDs are more impulsive in a Go/NoGo task, and show decreased pre-stimulus beta oscillatory activity in the precuneus and the supplementary motor area, pinpointing dysfunction of proactive inhibitory control.

In the second Chapter, we explore the neurophysiological mechanisms that contribute to STN-DBS effects on inhibitory control. Indeed, these effects are relevant for clinical outcome, as they can contribute to akinesia improvement, but also to increased impulsivity. The third experimental study tests the hypothesis that STN-DBS effects on inhibitory control may entail a direct modulation of thesupplementary motor cortex activity due to antidromic activation. We show that STN-DBS has a clear

effect on inhibitory control, which is visible at both the level of behavior and electrophysiological activity of the supplementary motor cortex in a Go/NoGo task. Importantly, we show that this effect depends on the strength of the structural connectivity between the stimulated area of the STN and the supplementary motor cortex. We propose that STN-DBS impacts inhibitory performance by directly disrupting inhibitory control at the cortical level, rather than the relay of inhibitory signals through the STN.

In sum, this work unravels the diverse neuro-functional bases contributing to impulsivity disorders in PD. Their identification paves the way for exploring targeted therapeutic options.

[Google scholar profile: Garance Meyer]