Identifying brain circuits causally related to OCD

by Champalimaud Centre for the Unknown

edited by Sadie Harley, reviewed by Andrew Zinin

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Obsessive-compulsive disorder (OCD) can be an extremely incapacitating neuropsychiatric condition. The symptoms of people who suffer from OCD can entail washing their hands or showering over and over again, repeatedly checking whether they switched off the gas in the kitchen or locked their front door. In the most extreme cases, this takes up so much of their time and energy that they become unable to leave their house, work, develop meaningful relationships or interact with other people.

At the Champalimaud Foundation, Gonçalo Cotovio and his colleagues in the Neuropsychiatry Unit, led by Albino J. Oliveira-Maia, have been treating OCD with a type of brain stimulation technique called rTMS (repetitive transcranial magnetic stimulation).

Repetitive TMS has been approved for use in OCD by the FDA and also in Europe, and while it has allowed successful treatment of many patients who didn't respond to medication and psychotherapy, there are also many others for whom this strategy is insufficient and who are left with very few options.

Repetitive TMS is a noninvasive, painless technique that has proven its efficacy for the treatment of not only OCD, but also other neuropsychiatric disorders such as treatment-resistant depression.

In rTMS treatments, an electromagnetic coil is applied to a precise location on the patient's head, delivering electromagnetic pulses that are capable of modifying the neuronal activity of a target brain area. The rationale is that if that brain area's neural activity is causing the condition, changing it will alleviate the symptoms.

However, when treating OCD with rTMS, it is uncertain whether the stimulated target brain area is causally linked to the OCD symptoms patients experience. Standard neuroimaging—with functional MRI (magnetic resonance imaging)—of OCD patients' brains shows associations between the presence of symptoms and abnormal patterns of activity.

However, this approach cannot distinguish cause from consequence: Does the symptom result from the altered activity, or does the changed brain activity result from the symptom or the responses to the symptom?

On the other hand, if someone with no prior OCD develops the same symptoms after a focal brain injury, that lesion is causally implicated in the disorder.

Indeed, there are rare cases of OCD that appear after a lesion (e.g. stroke or tumor). Using these "lesional OCD" cases, Cotovio and the team at the Champalimaud Foundation, in collaboration with colleagues at Massachusetts General Hospital in the U.S., have, for the first time, identified the brain circuits where the cause of OCD symptoms most likely resides.

The final results were published in the journal Biological Psychiatry.

To look for such lesional cases, the researchers performed an extensive search through a group of brain lesion images in the published literature. They found information from 40 patients with OCD developing after a brain lesion that could be used for their study.

The lesions were drawn and their overlap was assessed in a common "brain space," corresponding to an average human brain. But they did not converge on a single brain region: Strokes and tumors were not in the same place, and even regions of the same type were widely distributed across the brain. The researchers then reasoned that the shared outcome of these lesions (i.e., OCD) could lie not in their location, but in the underlying neural circuits connecting them.

To address this hypothesis, they used a method they had already applied to mania in the past, with positive results. Nowadays, this method is known as "causal network mapping," and the advantages of its use in psychiatry cases are clear, as was recently argued by Cotovio and Oliveira-Maia in a publication in Brain Health by the two clinicians and researchers.

Using the human connectome (that is, the average resting-state functional brain connectivity extracted from fMRI of 1,000 healthy individuals), each lesion's functional "neural map" was computed, and the maps of OCD lesions were compared against control lesions to extract OCD-specific circuitry.

This led the team to pinpoint four brain regions as "core hubs" for OCD: the orbitofrontal cortex (OFC) and the basal ganglia on both sides of the brain. These hubs are all positively connected to the lesion sites, suggesting that they become disconnected after lesions that caused OCD symptoms, but not after lesions that are not associated with the syndrome.

"The OFC has been associated with judgment," says Cotovio. "That is, the way we judge what we should do. And there are deficits in judgment in OCD. Others have proposed, and this work supports this hypothesis, that when patients have OCD symptoms, what is happening is that this region is signaling 'you need to do this, it's very important to you,' even in the presence of competing information suggesting that it is not."

He adds, "As to the basal ganglia, we also have evidence showing a relationship to compulsions. Once you engage in a certain act, it's very difficult to stop because this circuit is reinforced to do this act again, and again, and again, surely also because of connections to the OFC."

The team was also interested in understanding how this causal circuit was involved in OCD in patients without brain lesions. Using a software tool called NeuroSynth to analyze existing brain fMRI data from nonlesional OCD, they confirmed that hot spots from those nonlesional OCD studies overlapped the same core hubs as those of lesional OCD.

On the other hand, hot spots identified in other syndromes that in some cases may accompany OCD—such as depression or anxiety—did not overlap with the lesional OCD circuit. This and other validations, including brain imaging data from patients with OCD collected at the Champalimaud Foundation, established that those core hubs were meaningful for nonlesional OCD, even though they were derived from lesional OCD.

The results could have implications for improving the treatment of OCD with rTMS. The researchers are currently performing a clinical trial to compare the efficacy in improving OCD clinical symptoms of stimulating the standard rTMS target regions versus stimulating the newly identified lesional OCD network.

"That means that ultimately, and that's the next step of the project, we may use our lesional OCD network as a tool to guide neuromodulation treatment, instead of relying on average places," says Oliveira-Maia, senior author of the study. "This could also allow for more individualized targeting, picking the cortical spot that, in each individual patient, best matches the OCD circuit we describe here."

Publication details

Biological Psychiatry (2026).

Gonçalo Cotovio et al, From lesions to brain health: Causal circuits in psychiatry, Brain Health (2026). DOI: 10.61373/bh026v.0012

Journal information: Biological Psychiatry

Key medical concepts

Obsessive-Compulsive DisorderArea, Orbital

Clinical categories

PsychiatryPsychology & Mental healthNeurology Provided by Champalimaud Centre for the Unknown Who's behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Andrew Zinin

Master's in physics with research experience. Long-time science news enthusiast. Plays key role in Science X's editorial success. Full profile →

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