The present task might be of special relevance for the quantitative assessment of checking behaviors and for determining relationships with cognitive processes.

Using an innovative and highly sensitive exposure paradigm in fMRI, we showed that clinical and haemodynamic phenotypes have similar time courses during CBT. Our results, which suggest that the initial CBT sessions are crucial, prompt us to investigate the anatomo-functional modifications underlying the very first weeks of the therapy.

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should be to find the most appropriate DBS target for a given refractory patient. This quest will benefit from further investigation and understanding of the individual functional connectivity of OCD patients.

Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.

Obsessive-Compulsive Disorder (OCD) is characterized by intrusive, anxious thoughts with repetitive, ritualized behaviors, and has negative impacts on family relationships and social life. Its lifetime prevalence is estimated to be 2-3% [1]. Cognitive and behavioral therapy and selective serotonin reuptake inhibitors are the standard treatments for OCD; nevertheless, despite these treatments, between 25 and 40% of patients display persistent symptoms leading to severe functional disability [2]. Neurosurgical treatment targeting different parts of the orbito-fronto-striato-thalamo-cortical circuit has been proposed for the most severe and refractory forms, including both gamma knife non-invasive stereotactic lesions and invasive deep brain stimulation (DBS) [3] (Supplementary Information). However, the longterm efficacy (> 3 years) and safety of DBS for OCD is not fully reported. We prospectively followed 14 OCD patients treated with subthalamic DBS (STN-DBS, STOC study) for 46 months [4] (ClinicalTrials.gov Number: NCT00169377) (Supplementary Information). The primary outcome was the change in the total Yale Brown Obsessive Compulsive Scale (Y-BOCS) score between inclusion (baseline) and month 46 with STN-DBS, or month 34 in the case of missing data at month 46 (Supplementary Figure 1). We also assessed others psychiatric symptoms, global functioning and tolerance (Supplementary Information) [4].Twelve patients completed the follow-up study ( Supplementary Figure 1). The Y-BOCS total score between inclusion (baseline) and the end of the follow up period showed a median decrease of 15.5 points (IQR=-31 to -6), with a median change of 50% (IQR=-86.1 to -19.4%, Table 1). At the final follow-up, 11 patients (92%) were considered at least partial responders (>25% of Y-BOCS decrease) and 9 (75%) full responders (>35% of Y-BOCS decrease) ( Table 1). The Y-BOCS score was also significantly improved at month 46 compared to month 16 (Table 1) and decreased by an average of 1 (SE=.04) point per year between month 16 and month 46 (Time effect p=0.027, Supplementary Figure 2). At the end 4 of the follow-up period (month 46), the compulsion, obsession, anxiety and depression scores, but also global functioning and social and family life subscores were significantly improved ( Supplementary Table 1). We found a significant positive relationship between the severity of OCD at month 46 and the age at onset (r=0.61, p=0.045, Supplementary Figure 3) with early onset patients having fewer OCD symptoms with STN stimulation. During the follow-up, the medication had not changed significantly (not shown) but stimulation voltage was significantly increased (p=0.042, Supplementary Table 2). Twenty-three serious adverse events occurred, 5 being transient and related to STN-DBS (hypomania, impulsivity, dysarthria or fall) and 18 related to the disease (increased anxiety and obsessive and compulsive symptoms, and major depressive episodes with suicide attempts, Supplementary Table 3). Our results show that STN-DBS can effectively treat OCD...

Increased checking in OCD checkers, being independent of memory abilities and primary obsession-related anxiety, would, therefore, be closer to an automated behaviour than a coping strategy.

These quantitative and qualitative differences of anatomical connections go beyond the current model of a reduced cortical control of automatic behaviour stored in the basal ganglia. The hyper-segregation in OCD could also impair the integration of cortical information in the thalamus and striatum and distort the subsequent behavioural selection process. This provides new working hypotheses for functional and behavioural studies on OCD.