While in most cases of obsessive-compulsive disorder (OCD) a cause cannot be identified, this syndrome may develop as a consequence of focal brain lesions. Neuropsychiatric disorders secondary to brain insults are open windows to understand their underlying neurobiology. Different neuroimaging analysis methods, including pooled lesion topography and lesion network mapping, can be used to study lesional neuropsychiatric syndromes, including OCD. If successful, these strategies can also reveal new neuromodulation treatment targets, including for transcranial magnetic stimulation (TMS). Indeed, TMS targets to treat depression evolved from evidence extracted from lesional studies that were then refined and validated. For OCD treatment with TMS, already approved by the FDA and European Commission, targets were defined using a distinct approach, not involving causal brain lesions, which may contribute to lower than desirable remission rates. Lesional OCD is characterized by specific dysfunctional brain circuits. These circuits may be effectively targeted by TMS, which may optimize treatment of OCD. To address these hypotheses, we will test the therapeutic benefits of optimizing brain targets for the currently used TMS treatment of OCD, using information from the lesional-OCD brain network namely refining the target in the medial orbitofrontal cortex, bilaterally. Specifically, we will conduct a randomized clinical interventional study, using TMS to treat patients with OCD with inadequate response to other treatments, comparing, within the approved protocol for OCD treatment, the most frequently used stimulation site with a new target, adjusted according to the connectivity of lesions associated with the occurrence of OCD. If successful, our results may have immediate clinical implications in OCD treatment, as it will contribute to refine current therapeutic TMS strategies for OCD and defining new clinical research strategies in this domain.

In this study, we hypothesize that the cortical region identified from connectivity networks associated with lesional OCD may be a more effective TMS stimulation site than the one currently used in OCD treatment. Thus, we intend to compare the efficacy of the TMS protocol as approved for OCD, between its application at the currently used stimulation site (bilateral dorsomedial prefrontal cortex) and its application at an adjusted stimulation site, according to the more specific cortical areas of dysfunctional circuits associated with lesional OCD, namely the bilateral medial orbitofrontal cortex (OFC) region.

The participants in this study will be recruited at the Champalimaud Foundation. The physicians on the research team will identify patients who are being treated for OCD in the Neuropsychiatry Unit, or who are referred to the unit for this purpose. In this study, we aim to prospectively recruit 32 individuals according to the eligibility criteria specified in the respective section.

We propose to conduct a randomized, double-blinded interventional study, open only to the technician administering the treatment. After agreeing to participate in the study, the participant will be invited to attend the first study visit. There, participants will be assigned a unique identification number to maintain their anonymity in the study. Then, a qualified team member will ask the participant to complete the sociodemographic and clinical questionnaire to confirm the conditions for TMS and MRI, including an appropriate screening tool for the occurrence of seizures and/or epilepsy. The Mini International Neuropsychiatric Interview (MINI) and he Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (SCID) will serve the purpose of verifying the eligibility criteria of the study participant, including confirmation of the OCD diagnosis, using SCID. After confirming their eligibility, the participant will be invited to complete the remaining psychometric assessment, which will reflect the baseline values of each instrument. The following will be assessed: YBOCS-II (primary outcome), BDI-II, OCI-R, STAI, World Health Organization Five Well-Being Index (WHO-5), and YMRS (secondary outcomes), and Edinburgh Handedness Inventory (EHI).

In this study, to ensure that the TMS target site used is precisely located, we will use neuronavigation in each TMS session performed. Thus, in the next step of the first visit, the participant will be invited to undergo an MRI scan. This procedure cannot be waived, as without the MRI scan of each individual, the appropriate use of neuronavigation is compromised. If the participant cannot or does not want to undergo this procedure, they will be excluded from the study. The MRI protocol will include the collection of structural and functional neuroimaging data. The duration of this neuroimaging exam will be approximately 20-30 minutes.

After completing this step, the participant will be randomized to one of the two study arms. Please see details of each study arm in the respective section. The first visit of the TMS treatment cycle will be scheduled later. During this first visit of the TMS treatment cycle, the motor hotspot and the motor excitability threshold will be determined, which will be subsequently used to define the appropriate treatment intensity for each individual. Finally, the stimulation site will be determined using the neuronavigation system utilizing each individual's MRI scan. It is emphasized that the stimulation site will be mandatory determined at all TMS treatment visits. The TMS protocol will then commence, characterized by 20 Hz frequency irrespective of study arm. At the beginning of each TMS treatment cycle visit, the presence of potential side effects since the last TMS session will be screened. Every 5 TMS treatment cycle visits (1st, 6th, 11th, 16th, 21st, and 26th visits), the following psychometric scales will be repeated at the beginning of each visit: BDI-II, WHO-5, OCI-R, and YMRS (secondary outcomes). Every 5 TMS treatment cycle visits (1st, 6th, 11th, 16th, 21st, and 26th visits), the motor hotspot and the motor excitability threshold will be redefined, and consequently, the treatment stimulation intensity will be adjusted. At the end of each TMS treatment cycle visit, the next visit will be scheduled to occur on a daily basis, on business days, for a total of 30 visits. After the end of the TMS treatment cycle, the last study visit will be scheduled (primary endpoint, end-of-study visit), which should preferably occur between 2-3 weeks after the 30th TMS treatment cycle visit. During this visit, the YBOCS-II (primary outcome) will be applied. Participants will also be invited to undergo a new MRI scan, with the same characteristics as identified above.

Clinical efficacy will be assessed by changes in the severity of OCD symptoms compared to baseline, evaluated (using YBOCS-II; primary outcome) after 30 daily sessions of TMS, comparing the two study arms.

Inclusion Criteria:

• Age between 18 and 75 years;
• Established diagnosis of Obsessive-Compulsive Disorder according to Diagnostic and statistical manual of mental disorders 5 (DSM5) criteria;
• Capacity to give consent;
• Fluent in Portuguese and/or English;
• If potential for pregnancy, agrees to use an effective method of contraception throughout the study period.

Exclusion Criteria:

• Obsessive-compulsive symptoms severity assessed at baseline visit with the instrument Yale-Brown Obsessive Compulsive Scale - II (YBOCS-II) ≤ 24;
• Presence of uncontrolled active medical illness;
• Known structural lesion of the central nervous system;
• Electric or metallic implants in the body not compatible with electromagnetic radiation;
• Electric or metallic brain implants;
• Cardiac implants;
• Epilepsy;
• Pregnant, breastfeeding, or planning pregnancy women;
• Alcohol or substance abuse and/or dependence;
• Major Neurocognitive Disorder;
• Developmental disorders with low intelligence quotient or any other form of cognitive deficit;
• Active neurological disease;
• Individuals presenting with any psychotic or mood disorder requiring hospitalization at the time of eligibility criteria assessment;
• Contraindication for performing MRI;
• Individuals who have already been treated for OCD with TMS;
• Any other reason that renders the individual unable to provide informed consent.

To date there is no plan to make individual participant data (IPD) available to other researchers.