Reinforcement Learning and Obsessive-compulsive Disorder: Exploring the Role of the Orbitofrontal Cortex

NCT06566781 | Recruiting DMC

• 1 other identifier: NEUROCOMP
• Study Type: observational
• Target: 230
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Obsessive-Compulsive Disorder

Keywords

Obsessive-Compulsive Disorder; Transcranial Magnetic Stimulation

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (5)

• Peripheral concentration of cytokines.

  Baseline

• Peripheral concentration of transforming growth factor (TGF)-β.

  Baseline

• Presence of auto-antibodies.

  Baseline

• Seropositivity for Toxoplasma gondii, Cytomegalovirus (CMV), Herpes simplex virus (HSV1 and HSV2).

  Baseline

• Measurement of Neurite Orientation Dispersion and Density Imaging (NODDI) in the brain white matter.

  Baseline and longitudinal (up to one week after finishing rTMS treatment protocol).

Other Outcomes (3)

• Gene expression of peripheral cytokines.

  Baseline

• Functional connectivity pattern supported in lesional OCD neuroanatomy.

  Baseline

• Measurement of Mean Kurtosis (MK) in the brain white matter.

  Baseline

Study Arms (2)

Obsessive-compulsive disorder group

Obsessive-compulsive disorder group: Adult patients (18 to 65 years-old) with obsessive-compulsive (OCD) disorder will be recruited both at Champalimaud Clinical Center and collaborating clinical centers, namely Centro Hospitalar Psiquiátrico de Lisboa, Centro Hospitalar de Lisboa Ocidental and Hospital Garcia de Orta.

Healthy subjects group

Control subjects group: Adult individuals (18 to 65 years-old) age- and sex-mateched without past or current diagnosis of major neuropsychiatric disorders, including OCD.

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Participants in this study will be adults, aged 18 to 65 years, that will be recruited either for the clinical or control group. The clinical population will include individuals with OCD diagnosis, according to the following inclusion criteria. The two groups will be matched by age and sex.

You may qualify if:

• Exclusively for the OCD group: established diagnosis of Obsessive-Compulsive Disorder according to DSM-5 criteria;
• Exclusively for the control group: does not meet DSM criteria for any of the psychiatric diagnoses screened by the Mini International Neuropsychiatric Interview;
• Age between 18 and 65 years-old;
• Fluent Portuguese or English speaker.

You may not qualify if:

• Any acute medical illness;
• Substance abuse or dependence;
• Pregnancy;
• Dementia;
• Developmental disorders with low intelligence quotient or any other form of cognitive impairment;
• Active neurological disease;
• Previously known structural lesion of the central nervous system;
• Illiteracy or otherwise not understanding the study's instructions;
• Inability to give informed consent;
• Individuals presenting with any psychotic or mood disorder condition requiring hospitalization at that moment;

Sponsors & Collaborators

• Fundacao Champalimaud: lead

Study Sites (1)

Champalimaud Foundation

Lisbon, 1400-038, Portugal

RECRUITING

Related Publications (34)

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Biospecimen

Retention: SAMPLES WITH DNA

Blood samples (30mL: corresponding to 2 tubes EDTA of 6mL each, 2 tubes with clot activator of 6mL each and 1 tube Li+ heparinate of 6mL) from all participants will be collected after clinical assessment.

MeSH Terms

Conditions

Obsessive-Compulsive Disorder

Condition Hierarchy (Ancestors)

Anxiety Disorders; Mental Disorders

Study Officials

• Albino J Oliveira-Maia, MD MPH PhD

  Director of Neuropsychiatry, Champalimaud Research & Clinical Centre, Champalimaud Foundation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sofia Marques

CONTACT

00351 210480048; sofia.marques@research.fchampalimaud.org

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2024
• First Posted: August 22, 2024
• Study Start: October 1, 2019
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: August 22, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

PT (1)