Reinforcement Learning and Obsessive-compulsive Disorder: Exploring the Role of the Orbitofrontal Cortex
NCT Number: NCT06566781
Acronym: NEUROCOMP
Status: RECRUITING
Study Type: OBSERVATIONAL
Conditions: Obsessive-Compulsive Disorder
Sponsor: Fundacao Champalimaud
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 230
Study Design: Observational Model: |Time Perspective: p
Start Date: 2019-10-01
Completion Date: 2026-12-31
Locations: Champalimaud Foundation, Lisbon, 1400-038, Portugal

Summary:
Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition affecting 1-3% of the population. Typically, symptoms start in adolescence or early adulthood, are time-consuming, and have a significant impact on quality of life. However, first-line approved treatments, based on a combination of pharmacotherapy and psychotherapy, are ineffective in at least 50% of cases. Since the pathophysiology of OCD remains largely unknown, it is expected that a better understanding of the biological mechanisms of OCD would contribute to improved strategies for treatment of the disorder.

Current neurobiological models for OCD highlight the role of corticostriatal dysfunction and hyperactivity of the orbitofrontal cortex (OFC), a part of the prefrontal cortex. Indeed, the lateral OFC plays a crucial role in controlling transitions between automatic, repetitive stimulus-response driven behaviors, and behaviors that reflect the acquisition, by the agent, of a predictive model of the consequences of each action. Previous studies have suggested that the ability to operate this transition is compromised in OCD and may be objectively measured using specifically designed Reinforcement Learning (RL) tasks. Furthermore, growing evidence has suggested that OCD may be associated with systemic immune dysfunction, as has been shown in other common neuropsychiatric conditions, such as depressive disorders. Indeed, there is evidence to support OCD-like symptoms occurring acutely in children after streptococcal infection. These findings have raised the hypothesis that vulnerable individuals exposed to pro-inflammatory early-life environmental risk factors, such as infections and childhood adversity, may suffer neuroinflammatory-induced dysfunction in corticostriatal pathways, increasing the risk of OCD psychopathology.

In this case-control study, the investigators propose an integrative approach to address how structural, functional, and metabolic brain changes involving the corticostriatal circuit correlate with performance in an RL task, as well as with peripheral blood markers of immune dysfunction and associated environmental risk factors such as infection and childhood trauma. Furthermore, since neuromodulation of the prefrontal cortex, using repetitive transcranial magnetic stimulation (rTMS), has recently received FDA clearance for adjunctive treatment in patients with OCD, these associations will be further explored in patients treated with this method. Indeed, in patients with OCD enrolled in the study upon referral to the rTMS Programme for OCD at the Champalimaud Clinical Centre, a follow-up visit will be conducted after the end of treatment (30 sessions of excitatory rTMS over the medial prefrontal cortex). In this subgroup of participants with longitudinal assessment, we will measure change in study parameters and the associations between such change and the clinical effects of treatment, as well as prediction of treatment effects according to baseline assessments.

Primary Outcome Measures: Concentration of high sensitivity C Reactive Protein (hsCRP)., Serum concentration of hsCRP, expressed in mg/dL, as measured by enzyme-linked immunosorbent assay (ELISA)., Baseline.|Seropositivity for Group A Streptococcus (GAS)., Number of participants who are seropositive for GAS measured by anti-streptolysin O (ASO) antibodies (IgG)., Baseline.|Basal ganglia and orbito-frontal cortex (OFC) volume., Volume of basal ganglia structures (e.g. caudate, putamen and globus pallidus) and the OFC, in cubic milimeters., Baseline.|Exposure to childhood trauma as measured by the Childhood Trauma Questionnaire (CTQ)., Exposure to childhood trauma measured by the CTQ. The total score varies between 25 and 125, providing an overall measure of the exposure to childhood trauma, with higher scores representing exposure to more (and more severe) traumatic events., Baseline.|Obsessive-compulsive symptom severity., Obsessive-compulsive symptom severity as measured by Yale-Brown Obsessive-Compulsive Scale II (YBOCS-II). YBOCS-II total score ranges between 0 and 50, with higher scores relating to higher severity of obsessive-compulsive symptoms., Baseline and longitudinal (up to one week after finishing rTMS treatment protocol).|Measurement of fractional anisotropy (FA) in the brain white matter., Voxel-wise FA measures obtained from diffusion-weighted imaging (DWI)., Baseline and longitudinal (up to one week after finishing rTMS treatment protocol).|Functional connectivity of the orbitofrontal cortex (OFC)., Voxel-wise FA measures obtained from diffusion-weighted imaging (DWI)., Baseline and longitudinal (up to one week after finishing rTMS treatment protocol).|Concentration of N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG)., Concentration of NAA and NAAG measured by Magnetic Resonance Spectroscopy (MRS) in the left caudate and left subcortical OFC, expressed in mmol/L., Baseline and longitudinal (up to one week after finishing rTMS treatment protocol).|Model-free component in a computational model of a reinforcement learning behavioral task., Weight of the model-free component in a computational model of behavior where behavior is assumed to be controlled by a weighted sum of model-based and model-free components., Baseline and longitudinal (up to one week after finishing rTMS treatment protocol).
Secondary Outcome Measures: Peripheral concentration of cytokines., Plasmatic concentration of cytokines (interferon gamma (IFN-γ), tumor necrosis factor (TNF-α), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17 and IL-23), expressed In pg/mL, as measured by ELISA., Baseline|Peripheral concentration of transforming growth factor (TGF)-β., Plasmatic concentration of TGF-β, expressed in pM, as measured by ELISA., Baseline|Presence of auto-antibodies., Number of participants positive for auto-antibodies such as anti-basal ganglia (ABGA), anti-nuclear (ANA), and anti-thyroid antibodies., Baseline|Seropositivity for Toxoplasma gondii, Cytomegalovirus (CMV), Herpes simplex virus (HSV1 and HSV2)., Number of participants who are seropositive for IgG Toxoplasma gondii, CMV, HSV1 and HSV2 antibodies., Baseline|Measurement of Neurite Orientation Dispersion and Density Imaging (NODDI) in the brain white matter., Voxel-wise NODDI measures obtained from diffusion-weighted imaging (DWI)., Baseline and longitudinal (up to one week after finishing rTMS treatment protocol).
Other Outcome Measures: Gene expression of peripheral cytokines., Genetic expression of peripheral cytokines (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-23 and TGF-β), expressed in cycle thresholds (CT), as measured by quantitative Real-Time Polymerase Chain Reaction (RT-PCR)., Baseline|Functional connectivity pattern supported in lesional OCD neuroanatomy., Voxel-wise functional connectivity of the regions-of-interest extracted from lesional network mapping analyses of cases with secondary OCD., Baseline|Measurement of Mean Kurtosis (MK) in the brain white matter., Voxel-wise MK obtained from DWI., Baseline