Circuit-Specific TMS Targeting for Depression and Anxiety: What a Head-to-Head Trial and Its Mechanistic Follow-Up Reveal

Major depressive disorder (MDD) and anxiety symptoms frequently co-occur, yet most TMS protocols still target depression using a single, conventional left dorsolateral prefrontal cortex (DLPFC) approach regardless of a patient’s anxiety burden. Prior retrospective connectomics work suggested that two distinct, functionally connected brain circuits might map onto distinct symptom clusters within depression: a “dysphoric” circuit, centered near the conventional left DLPFC target and associated with sadness, anhedonia, and suicidality, and an “anxiosomatic” circuit, centered in the dorsomedial prefrontal cortex (dmPFC), a target not routinely used in clinical practice, associated with worry, irritability, and sleep disturbance. The trial described below prospectively tested whether stimulating these two circuits would differentially affect depressive versus anxiety symptoms in patients with MDD and comorbid anxiety, and a follow-up study then examined the neural mechanism behind the result.

This was a phase 2, double-blind, parallel-group randomized trial. Adults aged 18–65 with MDD, moderate-to-severe depression (BDI ≥20), and moderate-to-severe anxiety (BAI ≥16) were randomized to TMS at the dysphoric circuit target (MNI coordinates [-32, 44, 34]) or the anxiosomatic circuit target (MNI coordinates [0, 48, 46]), each delivered across 30 weekday sessions at 10 Hz, 3,000 pulses per session, and 120% resting motor threshold. Forty participants were randomized; after early discontinuations before assessment, 16 were analyzed in the dysphoric group and 20 in the anxiosomatic group. Both groups entered the trial with severe baseline symptoms and substantial treatment resistance.

The primary outcome was the rank-transformed ratio of percentage change in BDI relative to BAI scores. Dysphoric targeting produced a BDI:BAI improvement ratio of 1.08 (IQR 0.69–2.02), while anxiosomatic targeting produced a ratio of 0.70 (IQR 0.01–1.01), a significant between-group difference (Wilcoxon rank-sum p = 0.0195) that confirmed the study’s central hypothesis: target selection differentially shapes which symptom domain improves most. On secondary outcomes, depression improvement was similar between groups (roughly 55% with dysphoric targeting versus 54% with anxiosomatic targeting; p = 0.12), while anxiety improvement was significantly greater with anxiosomatic targeting than with dysphoric targeting, in a group-by-time interaction that remained significant even after controlling for depression severity.

This study  was conducted at a single site, with a modest sample size, no sham control arm, and non-individualized (group-level rather than patient-specific) targeting. Importantly, the dmPFC anxiosomatic target used here is investigational and not a standard, FDA-cleared clinical target.

The Mechanistic Follow-Up: Did TMS Actually Engage the Intended Circuit?

A natural question left open by the original trial was why the two targets diverged in their effects, and whether the stimulation was truly engaging the circuits it was designed to hit. A follow-up study by Baldi and colleagues addressed this using pre- and post-treatment resting-state fMRI in 29 of the original participants, asking three things: whether TMS selectively engaged the targeted circuit, whether a participant’s baseline connectivity between their individual stimulation site and the targeted circuit predicted how much that circuit’s connectivity changed, and whether either measure , engagement or baseline connectivity, correlated with clinical improvement on the BDI or BAI.

Connectivity decreased within both circuits after treatment, but this change was not clearly target-specific, and it did not predict clinical improvement, meaning that simply observing whether connectivity changed after treatment turned out not to be a useful biomarker on its own. What did matter was baseline connectivity: participants whose individual TMS site was more strongly connected to the targeted circuit before treatment began showed both greater connectivity change (r = −0.61, p < 0.001) and greater anxiety improvement (rw = 0.47, p = 0.004). Notably, this baseline-connectivity effect was driven almost entirely by the anxiosomatic group; the dysphoric group showed no comparable relationship, a pattern the authors suggest may reflect greater person-to-person variability in the anatomy of the dysphoric circuit, which would make a single fixed group-level target less reliable for that circuit specifically.

The clinical implication is that post-treatment connectivity change,  a common way of measuring whether a treatment “engaged” its target, may be less useful than expected as a biomarker. Instead, a patient’s baseline connectivity between their planned stimulation site and their target circuit may better predict who is likely to benefit, particularly for anxiety-focused, anxiosomatic-circuit protocols. The dysphoric circuit’s greater anatomical variability across individuals also suggests that individualized targeting may matter more there than a fixed scalp-based approach currently allows.

Putting the Two Studies Together

These studies suggest two things. First, where TMS is targeted within the prefrontal cortex may shape which symptom domain, depressive or anxious, responds most: the original trial’s ratio-based primary outcome showed dysphoric targeting relatively favoring depression improvement and anxiosomatic targeting favoring anxiety improvement, even though absolute depression improvement was similar across groups. Second, a patient’s individual brain connectivity measured before treatment appears to be a more informative predictor of who benefits than watching how connectivity changes during treatment , an effect that was clear for the anxiosomatic target but not yet demonstrated for the dysphoric target.

*Educational summary for healthcare professionals. Source studies: Taylor JJ, Li J, Lin C, et al. Circuit-targeted modulation of anxiety symptoms in individuals with major depression: a randomized head-to-head TMS trial. Mol Psychiatry. 2026:1–10. https://doi.org/10.1038/s41380-026-03535-1; and Baldi S, Lin C, Li J, et al. Target engagement in a head-to-head clinical trial of dysphoric versus anxiosomatic TMS targets. Neuropsychopharmacology. 2026;51(10):1790–1797. https://doi.org/10.1038/s41386-026-02416-z*