Neurocircuit Mechanisms of OCD Across the Lifespan

Obsessive-compulsive disorder (OCD), characterized by intrusive thoughts (obsessions) and related behavioral rituals (compulsions), is a common psychiatric illness that often emerges in childhood and causes life-long disability in over 50% of patients. Psychological theory suggests that OCD symptoms are driven by a person's difficulty disengaging their feelings from simple tasks (e.g. washing hands, locking a door) due to excessive anxiety about performance errors. Cognitive behavioral therapy (CBT), the gold standard treatment for OCD, repeatedly exposes patients to their OCD-stressor until this anxiety is reduced. While CBT is typically more effective in teenagers than adults, patients from both age groups are usually left with residual symptoms, highlighting the need for better treatments. In this study, CBT will be studied in both teen-aged and adult patients. Two groups, both with childhood onset OCD, will be randomized to either CBT for OCD or stress management training (SMT), an active therapy but with minimal effects on OCD symptoms. The investigators will also study age-matched, healthy controls as comparison subjects. Before and after 12 weeks of CBT, all subjects will undergo functional Magnetic Resonance Imaging (fMRI) scans to see what regions of the brain become active when a concentration task is performed and how that activation is changed after CBT. The purpose of this study is to demonstrate the brain changes associated with CBT treatment and how differences in these changes in teenage compared to adult patients may drive differences in CBT response.

While the study itself is of parallel design for its data-collection and measurement purpose, it is listed as a partial-crossover design in the IRB-approved protocol because subjects randomized to the SMT group are given the option of entering 12-weeks of CBT sessions after all of their SMT data collection. To understand brain changes that occur with CBT compared to SMT in both age groups, the investigators will collect fMRI data before and after therapy. Some limited data will be collected in patients who are initially randomized to SMT but then opt to crossover to CBT. fMRI data will also be collected in healthy teens and adults before and after 12 weeks (but without intervening therapy) to allow the investigators to control for the simple effects of time that may cause brain changes that are not related to therapy.

12 SMT sessions scheduled weekly over a 12-week period. After study completion, the OCD subjects who received SMT may derive benefit for non-OCD anxiety symptoms. They will be offered a 12-week course of CBT with a study therapist to directly target OCD symptoms (i.e., a partial cross-over).

12 SMT sessions scheduled weekly over a 12-week period. After study completion, the OCD subjects who received SMT may derive benefit for non-OCD anxiety symptoms. They will be offered a 12-week course of CBT with a study therapist to directly target OCD symptoms (i.e., a partial cross-over).

Healthy control adolescents matched to gender, race and socioeconomic status (SES) with adolescent patients with OCD will be enrolled. These healthy adolescents will be scanned with fMRI before and after 12 weeks, but without any intervention (i.e., no therapy).

Healthy control adults matched to gender, race and socioeconomic status (SES) with adult patients with OCD will be enrolled. These healthy adults will be scanned with fMRI before and after 12 weeks, but without any intervention (i.e., no therapy).

OCD adolescent participants who were randomized to the SMT and have completed all study procedures will be offered an additional 12 weeks of Optional Cognitive-Behavioral Therapy.

OCD adult participants who were randomized to the SMT and have completed all study procedures will be offered an additional 12 weeks of Optional Cognitive-Behavioral Therapy.

A therapy which gradually yet repeatedly exposes adolescent patients to their obsessive compulsive-relevant "error" cues during a task performance until their anxiety habituates.

This is the cross-over element for those that completed the SMT treatment group and opt to have the OCD treatment.

A therapy which gradually yet repeatedly exposes adult patients to their obsessive compulsive-relevant "error" cues during a task performance until their anxiety habituates.

This is the cross-over element for those that completed the SMT treatment group and opt to have the OCD treatment.

Two fMRI's only, scheduled at 12-weeks apart. This is for Healthy Control Adults and is used only as a means for observation, NOT as an intervention to be studied.

Two fMRI's only, scheduled at 12-weeks apart. This is for Healthy Control Adolescents and is used only as a means for observation, NOT as an intervention to be studied.

fMRI BOLD signal response of posterior medial frontal cortex (pMFC), ventral medial prefrontal cortex (vmPFC) and anterior insula (aIns) during performance monitoring. This signal will be measured as BOLD contrast estimates for errors compared to correct trials based on average signal in a priori defined regions of interest for pMFC, vmPFC and aIns. The investigators are looking for increases in pMFC activation in adolescents from pre- to post-treatment. In contrast, the investigators are looking for increases in inverse connectivity (resting state and during task) between vmPFC and aIns in adults from pre- to post-treatment.

OCD symptom severity measured by the Yale Brown Obsessive Compulsive Scale for adults or the Child Yale Brown Obsessive Compulsive Scale for adolescents.

OCD symptom severity measured by the Yale Brown Obsessive Compulsive Scale for adults and the Child Yale Brown Obsessive Compulsive Scale for adolescents. This scale is administered by an independent assessor to rate OCD symptom severity on a scale of 0 to 40, with 40 being most severe. The investigators are looking for decreases in OCD severity ratings from pre- to post-treatment.

Inclusion Criteria for all OCD Subjects & Healthy Volunteers: Male or female Age 13-17 (inclusive) subjects diagnosed with OCD, age of onset before 15 years Age 25-45 (inclusive) subjects diagnosed with OCD, age of onset before 15 years Age 13-17 (inclusive) year old healthy volunteers Age 25-45 (inclusive) year old healthy volunteers OCD adolescent and adult subjects can be on medications but will have to be on a stable medication regimen for at least 4 weeks prior to enrolling. Able and willing to give informed consent Ability to tolerate small, enclosed spaces without anxiety Exclusion Criteria for OCD Subjects: Anyone between the ages of 18-24 (inclusive range) No lifetime diagnosis of bipolar or psychosis disorders Age of OCD onset after 15 years old No substance/alcohol abuse in the past 6 months No lifetime history of substance/alcohol dependence No evidence of suicidal intentions or behaviors in the past 6 months No history of serious medical or neurological illness No history of closed head injury (e.g. loss of consciousness) Pregnant or trying to become pregnant Additional Exclusion Criteria for Healthy Volunteers: No history of past or current mental illness Not taking any medication, prescription or non-prescription, with psychotropic effects First-degree family members with OCD or tic disorders

Rueppel M, Mannella KA, Fitzgerald KD, Schroder HS. Post-error slowing in anxiety and obsessive-compulsive disorders. Cogn Affect Behav Neurosci. 2022 Jun;22(3):610-624. doi: 10.3758/s13415-021-00976-9. Epub 2021 Dec 29.

Norman LJ, Mannella KA, Yang H, Angstadt M, Abelson JL, Himle JA, Fitzgerald KD, Taylor SF. Treatment-Specific Associations Between Brain Activation and Symptom Reduction in OCD Following CBT: A Randomized fMRI Trial. Am J Psychiatry. 2021 Jan 1;178(1):39-47. doi: 10.1176/appi.ajp.2020.19080886. Epub 2020 Aug 28.