EEG and Pharmacological Exploration of Executive Dysfunctions Induced by STN-DBS in PD

Summary

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) remarkably improves motor functions in patients with Parkinson disease (PD). However, growing evidence suggests that STN-DBS also causes executive inhibitory deficits and impulsive behaviour (Jahanshahi et al 2000; Schroeder et al 2002; Hershey et al 2004; Thobois et al 2007; Frank et al 2007; Ballanger et al., 2009). Despite a widespread use, the mechanisms of action of STN-DBS are still unclear. Two reasons might explain this. 1) From a theoretical point of view, cognitive models of executive control mechanisms are incomplete. 2) From a methodological point of view, investigating cerebral activity during STN-DBS is very limited because most techniques are incompatible with locally implanted electrodes.

This project relies on a double opportunity to answer these questions offered by recent theoretical and methodological advances. First, investigations in healthy subjects (Jaffard et al 2007, 2008, Boulinguez et al 2009) revealed an essential function of inhibitory control, so far ignored, consisting in locking in advance movement triggering processes to prevent undesired automatic or anticipated responses to unattended stimuli. In other words, key processes of executive control may act tonically before stimulation occurs, calling brain imaging studies to look at proactive and not only reactive activations. Second, recent advances in EEG signal processing now allow suppressing from the electroencephalogram DBS-related artifacts (Allen et al. 2010), providing a tremendous opportunity to use a non-invasive technique with the high temporal resolution necessary to disentangle proactive from reactive brain activity. To our knowledge, up to date no study has been published using EEG with STN-DBS patients since Allen et al.'s paper. The first operational purpose of this project is to identify the anatomo-functional origin of STN-DBS-induced executive dysfunction using EEG recordings in classical stimulus-response tasks. Results expected from this first part of the project may help resolving other long-lasting issues. Indeed, reactivity as assessed by simple reaction time in non-implanted patients as well as impulsivity in STN-DBS patients are known to remain insensitive to dopaminergic medication. Since the proactive activity related to executive, inhibitory, control may be supported by the noradrenergic (NA) system, the second purpose of this project is to test the original hypothesis according to which NA plays a central role in both akinesia and STN-DBS side effects.

Conditions

• Parkinson Disease

Interventions

DEVICE

Clonidine (Catapressan)

Clonidine (Catapressan) : Oral administration - Single dose (150 µg) - 90 minutes before EEG

DEVICE

Placebo 90 minutes before EEG

Placebo : Oral administration - Single dose (lactose) - 90 minutes before EEG

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

40 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2012-10-31

Primary Completion

2013-06-30

Completion

2016-06-30

Countries

• France

Study Locations