Decision, confidence, and compulsive actions: the neural bases of metacognition and its dysfunctions in obsessive-compulsive disorder – DECCA

Our reseatch project employs a transversal explorative approach in halthy volunteers, OCD patients and macaques to study complex behaviours of a metacognitive type (decision confidence and related verification). The first phase is to validate our protocol, including its capacity to produce adequate checking behaviour. To this purpose, we will use a perceptual categorisation task: manipulating difficulty levels in a parametric manner should give us a quantification of checking with regard to performance. Despite adaptation constraints (longer training in animal, different rewards), we will use protocols as similar as possible in both species. Functional exploration tools (fMRI in humans, electrophysiology in macaques) will bring complementary vues of cerebral activity associated to this behaviour, especially in regions such as the cingulate and orbitofrontal cortices, thought to be involved in OCD. Electrophysiological recordings in OCd patients operated for DBS (associated but distinct clinical trial), we will be able to confront human and animal data and test their influence on behaviour at the behavioural task

Because of major administrative difficulties, the project has accumulated delays in the construction of behavioural paradigm in humans. To compensate, pilote studies have beens tarted by the partner. 2. Despite difficulties to obtain a great number of verifications in healthy volunteers, data from pilot studies show a relation a non trivial relation between task difficulty, decision to check and accuracy. This intriguing result will continue to be explored by other behavioural studies, including manipulation of incentives (speed accuracy tradeoff) and modelling methods derived from signal detection theory. Also, the first results undeline the influence of a dynamical vs static sensory stimulus on verification behaviour. this aspect will also be investigated further with regard to metacognition.

Human electrophysiuological data have been obtained in the contect of a clinical trial in 6 OCD patients operated for DBS (prestoc2) in the subthalamic nucleus and the caudate nucleus. The first analyses of local field potentials in the STN show differential response to positive vs negative feedback. This preliminary result suggests that information concerning behavioural monitoring is available at this level of basal ganglia, thus reinforcing our hypothesis of the STN's involvement in metacognitive control.

These still prelimlinary results suggest a number of directions for the remainder of the project. First, they call for a refining of the checking task so that it takes better account of the variables leading to checking in healthy and OCD subjects. Second, the STN's response to limbic information (reward) asks us to take into account the role of emotional context in metacognitive control, at the STN level, and thus in neurobehavioural models of OCD. Our access to a behavioural model of symptomatology transferable to animal models is a unique explorative approach of pathophysiology an therapeutic mechanisms of DBS in the basal ganglia.

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SScientific background
Obsessive-compulsive disorder (OCD) is a pervasive psychiatric condition under which patients exhibit compulsive behaviour and complain from obsessional ideas. Recent psychopathological models of OCD have proposed that deficits in metacognition (the ability to evaluate one’s own cognitive functioning, for example how much one trust one’s perception or one’s memory) may be central to the emergence of compulsive behaviour seen in most OCD patients, in particular compulsive checking. Indeed, OCD patients often express pathological doubt that translate into memory distrust or exacerbated feeling of uncertainty regarding the consequences of their decision. Most recently, animal neuroscience data have suggested that an electrophysiological correlate of decision uncertainty can be found in the orbitofrontal cortex (OFC) which entertains functional link with the limbic portion of the basal ganglia (BG). One major hypothesis is that such processes also concern the anterior cingulate cortex (ACC) which we have shown in non-human primates to be central in action-monitoring beyond mere error-detection. In addition, preliminary results from our group show that within the BG, the neuronal activity of the subthalamic nucleus (STN) predicts the checking behaviour of OCD patients. This is in line with the theoretical proposal that the STN contributes to decision-making by withholding decision and response initiation and with recent clinical results suggesting that deep-brain stimulation (DBS) of the STN might be effective in OCD patients.

Project Methodology
The present project will aim at exploring the neural correlates of metacognitive processes in a behavioural task designed to induce uncertainty monitoring and checking behaviour in healthy humans, OCD and PD patients and non-humans primates. Major specific aims are:
1) Refine the understanding of the specific role of ACC and OFC in metacognition. We will perform neurophysiological recordings in monkeys and confront the results to cortical and BG metabolic signals in humans performing the exact same task.
2) Analyse the specific contribution of OFC and ACC to metacognitive processes. We will measure the behavioural consequences of temporarily inactivating each area separately with a pharmacological inhibitor.
3) Understand the role of the STN in metacognition and the effect of its modulation by DBS. We will assess the effect of DBS on the performance of OCD patients (and PD patients) in our task to evidence modifications of metacognitive functioning induced by the STN modulation. This part of the project will also benefit from the results of a connected but separate research program aimed at recording single-neuron electrophysiological activity in the BG during the DBS-implantation surgery of OCD and PD patients while they perform our behavioural task.

Expected Results
These data will be critical to validate the involvement of BG in metacognitive processes and compulsive actions. The central hypothesis underlying the current project and this parallel program will finally be assessed in the light of the scientific outcomes to decide on the development of a research program dedicated at elaborating a primate neuro-behavioural model of compulsive disorders and their treatment through DBS. If successful, this outcome will serve to decide on the feasibility and scheduling of a subsequent program, referred to as Task 4 in this proposal, and which will aim to develop an animal model of compulsive behaviour and its treatment by STN stimulation. This model will easily emerge as a competence transfer between the partners of this project.