Reinforcement Learning and Obsessive-compulsive Disorder: Exploring the Role of the Orbitofrontal Cortex
Reinforcement Learning and Obsessive-compulsive Disorder: Exploring the Role of the Orbitofrontal Cortex
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.
INTRODUCTION:
Obsessive-compulsive disorder (OCD) is the fourth most common psychiatric disorder, characterized by recurrent and intrusive obsessive thoughts and/or compulsions that are distressing, time-consuming , and a cause of significant impairment. OCD has a lifetime prevalence of 1-3%, and is associated with a reduced life expectancy due to natural and unnatural causes. Current treatments, based on a combination of pharmacotherapy and psychotherapy, are ineffective in at least 50% of cases, with rTMS of the prefrontal cortex having recently received FDA clearance as an adjunctive treatment. Yet, OCD pathophysiology remains largely unknown , and it is expected that a better understanding of OCD 's biological mechanisms would contribute to a better prevention and treatment of the disorder.
Current neurobiological models for the disorder highlight the role of cortico-striatal-thalamo-cortical (CSTC) loops and hyperactivity of the orbitofrontal cortex (OFC), and it has been hypothesized that corticostriatal dysfunction in OCD may occur as an end-consequence of immune and inflammatory dysregulation that leads to structural and functional changes in these circuits. This pathophysiological mechanism was first proposed based on the association between group A β-hemolytic streptococcal (GAS) infection and the abrupt onset of OCD in children, described by Swedo and colleagues (1998) as a distinctive nosologic entity named Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS). This post-infectious neuropsychiatric syndrome was hypothesized to occur due to a cross-reaction between anti-streptococcal antibodies and the basal ganglia, causing CSTC circuit dysfunction. In addition to GAS, other pathogens have since been suggested as contributing to the development of OCD, albeit no definitive causal associations have been established. Interestingly, childhood adversity, an environmental risk factor for OCD, has also been associated with chronic immune dysfunction in adulthood, namely with increased C-reactive protein, interleukin-6, and tumor necrosis factor (TNF)-α, as well as with increased volume of the right OFC in adult patients with OCD.
While the specific psychopathological consequences of OFC dysfunction in OCD remain unclear, in recent years research in rodents has shown that the OFC, particularly the lateral OFC, is crucial in controlling transitions between automatic, repetitive stimulus-response behaviors (such as habitual behavior in operant-learning tasks, or model-free RL), and behaviors that reflect the acquisition, by the agent, of a predictive model of the consequences of each action (such as goal-directed behavior, or model-based RL). Evidence suggests that patients with OCD may have an abnormal bias towards habitual behavior during operant learning tasks, with subjects having a higher difficulty in developing model-based reinforcement learning strategies. This bias has been proposed to favor the emergence of ritualized compulsive behaviors typical of OCD, and is regarded as a marker of corticostriatal dysfunction that is central to the disorder's pathophysiology.
In this case-control study, the investigators propose an integrative experimental approach to test if structural, functional , and metabolic changes in corticostriatal circuits of patients with OCD correlate with performance in an RL task, as well as with peripheral blood markers of immune dysfunction and early-life environmental risk factors previously implicated in the disorder (e.g., infectious insults and childhood adversities).
STUDY OBJECTIVES:
In this study, the investigators aim to compare patients with OCD and healthy volunteers to assess the association between OCD and:
The investigators also intend to explore associations of the outcome variables with clinical variables such as obsessive-compulsive symptom severity and age of onset.
Additionally, for patients enrolled in this study who will undergo rTMS for clinical purposes at our clinical center, the investigators aim to assess if there is an association between the behavioral, neuroimaging, and immunological variables and treatment response. Specifically, the investigators will test 1) if post-treatment changes in behavioral and neuroimaging measures correlate with treatment response, and 2) if baseline behavioral, neuroimaging, and immune measures predict response to treatment. Specifically, the investigators will test:
PROCEDURES:
For this study, the investigators will recruit 115 age- and sex-matched subjects with OCD and 115 control volunteers. After signing informed consents, participants will complete a thorough clinical assessment, including confirmation of psychiatric diagnoses using the appropriate modules of the Structured Clinical Interview for DSM-5, and rating of obsessive-compulsive symptoms using the Yale-Brown Obsessive-Compulsive Scale II, the gold-standard structured clinical interview for OCD assessment. Other clinical variables of interest will be assessed using the following instruments:
For the subgroup of patients enrolled in the study that will undergo rTMS for clinical purposes at our Champalimaud Clinical Programme, the investigators will propose a follow-up visit after completion of the treatment. In this visit, participants will be asked to repeat the clinical assessment, RL task , and the MRI protocol as described before. The clinical TMS protocol comprises 30 sessions of excitatory rTMS (20 Hz) over the medial prefrontal cortex, as defined by international guidelines, using a protocol that includes individualized symptom provocation before each stimulation session, to elicit a moderate level of obsessional distress, as reported by patients. This subgroup will also complete all the procedures of experiment 1 prior to initiating the rTMS treatment protocol. After the last session of rTMS treatment, up to one week after the treatment has ended, these participants will repeat the RL task and the MRI protocol as described for baseline.
DATA COLLECTION:
Inclusion Criteria:
Exclusion Criteria:
sofia.marques@research.fchampalimaud.org00351 210480048 ext. 4153
Lisbon, 1400-038, Portugal
sofia.marques@research.fchampalimaud.org