Many psychiatric disorders are what doctors call “comorbid”—they co-occur with other disorders, whether other brain-based disorders or those affecting other parts of the body. Depression, for example, is often comorbid with anxiety. In such cases, one question that intrigues researchers is how treatment for one set of symptoms affects symptoms of the comorbid condition, if at all.

A research team co-led by BBRF grantees has published findings of a clinical study that measured how transcranial magnetic stimulation (TMS), a now-standard non-invasive treatment for depression, affects levels of depression and anxiety symptoms in individuals who have moderate to severe levels of both depressive and anxiety symptoms.

The study took a novel approach. It divided a cohort of similar patients with both depression and anxiety into two groups, and administered TMS targeted at two distinct places in the brain. In one group, TMS’s magnetic pulses were focused on a site in the cortex where stimulation is associated with reduction in depression symptoms. In the other group, TMS pulses were focused on an alternate cortical site that the researchers had reason to think might be more effective in reducing anxiety symptoms.

The study was led by Shan H. Siddiqi, M.D., winner of the 2022 BBRF Klerman Prize for Exceptional Clinical Research and a 2019 BBRF Young Investigator, Michael D. Fox, M.D., Ph.D., and Joseph J. Taylor M.D., Ph.D., the BBRF Klerman Prize winner in 2025 and a 2022 BBRF Young Investigator. All are affiliated with Harvard Medical School and Mass General Brigham; Dr. Siddiqi is the new Stahl Professor at Northwestern University. Dr. Taylor was first author on the team’s paper, which appeared in Molecular Psychiatry.

In recent years, Drs. Siddiqi and Fox have conducted influential research that has sought to find causal relationships between damage (“lesions”) or dysfunction in specific brain circuits and causation in a variety of brain-based illnesses, including depression and anxiety. In addition to finding a “causal circuit” implicated in depression and other disorders, they have used human whole-brain wiring maps (called “connectome maps”) to retrospectively map circuits in the brain that are functionally connected to cortical locations targeted in successful TMS treatments.

This research enabled them to make a number of interesting observations, one of which is that distinct TMS focal sites, while generally overlapping in terms of their apparent therapeutic effects, do not always stimulate the same circuits. This is not surprising, since most TMS clinics use physical scalp measurements in each patient to mark their target in a part of the cortex called the dorsolateral prefrontal cortex (DLPFC). The target site thus varies between patients—sometimes markedly so—meaning different circuits are stimulated. (In general, magnetic stimulation can either increase or decrease neural excitation at the targeted site and in circuits deeper in the brain that they connect to, with therapeutic effects.)

It has been noted in the clinic that TMS, when it does help reduce depression symptoms, often also has at least some impact in relieving comorbid anxiety symptoms. The question driving the new research by Drs. Siddiqi, Fox, Taylor, and colleagues is whether there might be alternate stimulation targets in the cortex that would reduce anxiety symptoms more specifically or dramatically. If such a site could be identified, it would also be important to know if stimulating at such an “anxiety target” would affect comorbid depression symptoms. Might a single target be optimal in reducing both depression and anxiety in comorbid patients, or would there be an advantage in targeting two different locations over the course of TMS therapy?

The team recruited 40 individuals with comorbid depression and anxiety for what is called a “head-to-head” trial, which was randomized and blinded, but did not include a placebo group. Data on 36 participants were used for the analysis. They were typically in their early 30s; two-thirds were female; three-fourths were White. All had moderate to severe depression and anxiety symptoms, measured on separate symptom scales designed to capture each. And many had taken multiple courses of antidepressants over a period of years.

Both groups received 30 weekday TMS sessions given over 6 weeks. Sixteen received TMS targeted at a spot in the DLPFC connected to a brain circuit causally linked with “dysphoric” symptoms (i.e. depressive symptoms including sadness, decreased interest, suicidal thoughts). Twenty received TMS targeting a spot above the dorsomedial prefrontal cortex (DMPFC), a different location that wiring maps suggested would be more effective in altering a circuit causally implicated in anxiety symptoms (changes in sleep, decreased sexual drive, worry and irritability).

TMS therapy at both of these targets had virtually the same impact in reducing depression symptoms—reductions in symptoms of about 55%, on average. But those receiving TMS at the “anxiety” target in the DMPFC had a significantly larger reduction in anxiety symptoms: 58% vs. 36% for those treated at the “depression” target.

This result raises the question of whether the “anxiety” target in the DMPFC might be superior to the traditional site used in TMS therapy for depression. Perhaps, the team thinks, but only for certain patients. The alternate target in the DMPFC might indeed be superior for patients with both significant depression and anxiety, but because the trial only included people with this combination of symptoms, it cannot be assumed that this would apply to other patient populations. Dr. Siddiqi explained that the results of this trial “may not apply to patients who have primary major depressive disorder without heavy anxiety, so we recommend continuing to follow the existing evidence,” which favors treatment at the traditional target in the DLPFC.

Is the “anxiety” target superior to the traditional “depression” target for everyone with depression symptoms? Or does the optimal target vary according to the patient or groups of patients sorted by symptoms, including comorbid ones? “Our exploratory analyses suggest the latter” the team wrote, “as relatively severe depression was more responsive” to the depression target, while relatively severe anxiety was more responsive to stimulation of the anxiety circuit. “The most direct clinical conclusion from this paper,” Dr. Siddiqi summed up, “is that patients with both significant anxiety and depression do best with the DMPFC target. Conclusions beyond that for now, would be more speculative.”

More broadly, the team said, the current results suggest “it may be possible to stratify individuals to different [TMS] targets based on their symptom profiles” when treatment begins. This would not only be a major step forward in precision psychiatry; it also, the team says, suggests the promise of using “connectome-based brain circuit” data in optimizing treatments patient by patient.

Among their recommendations for future studies, in addition to replicating their results, is to explore the possibility of simultaneous or sequential targeting of the brain within a single course of TMS therapy to address different targets for different symptom clusters. Another useful approach, they said, would be to study whether accelerated forms of TMS, in which more total stimulation is delivered in the span of just a few days as opposed to 6 weeks, might accentuate the advantages of targeting TMS at different cortical sites to address different symptoms.