SUBTHALAMIC NUCLEUS IN UNCERTAINTY MONITORING VS. ACTION INHIBITION IN OBSESSIVE-COMPULSIVE DISORDER IN HUMANS AND RODENTS – TYMON

Obsessive-Compulsive Disorder (OCD) is a mental disorder featuring obsessions (intrusive ideas) and
compulsions (repetitive overt behaviors such as checking or washing, or mental actions) associated
with high levels of anxiety. With a prevalence of 2-3%, OCD is among the most common anxiety
disorders with most severe forms bearing a high cost for the individuals and the society, thus calling
for effective treatments. Current standards have validated pharmacological (serotonin-reuptake
inhibitors) and psychotherapeutical (cognitive-behavioral therapy) interventions to treat OCD, however
20-30% patients do not respond to these approaches. In patients with severe treatment resistant OCD
recent clinical trials have demonstrated the clinical efficacy of deep-brain stimulation of several
subcortical nuclei or fibers. In this project we focus on the subthalamic nucleus (STN), which has
proved to be a very potent target by the highest level of evidence. Current knowledge derived from
clinical studies is however very limited regarding the role of STN in the psychopathological processes
underlying OCD and the therapeutical mechanisms triggered by high-frequency stimulation of this
region. TYMON project will bring together three internationally renowned teams from France,
Germany and Portugal to assess the role of STN in OCD. In particular, this three-year translational
project will focus on two specific cognitive processes that, when dysfunctional, could lead to
compulsive checking: (i) Uncertainty-monitoring: Deficit in accumulating sensory evidence would
trigger repetitive checking behavior as an attempt to reduce uncertainty before making a choice and
(ii) Inhibitory control: Failing to put an end to a sequence of checking actions would result in repetitive
checking. Therefore, TYMON partners will perform experiments with mice models of OCD as well as
human OCD patients in order to: (a) understand the role of STN in uncertainty-monitoring, inhibition
and checking processes; (b) identify circuitry dysfunction in OCD; and (c) assess the mechanisms of
deep brain stimulation that may revert compulsive checking. In addition, TYMON’s outputs will also provide the research community with the bases for new powerful tools ranging across animal models
of pathology and interventions to human behavioral and electrophysiological biomarkers that may not
only apply to investigate other neural pathways with the OCD brain but also foster the development of
new therapeutic approaches and/or improvement of existing ones in other psychiatric conditions.