Circuit-targeted modulation of anxiety symptoms in individuals with major depression: A randomized head-to-head TMS trial.

Transcranial magnetic stimulation (TMS) is effective for major depressive disorder (MDD) and anxious depression despite imprecise scalp-based targeting. Retrospective connectomics analyses suggest that targeting one brain circuit preferentially improves "dysphoric" symptoms, while targeting a different brain circuit preferentially improves "anxiosomatic" symptoms. Here, we tested this hypothesis prospectively by randomizing adults with MDD (n = 40, age 18-65) who had moderate-to-severe symptoms of depression (Beck Depression Inventory (BDI) ≥ 20) and anxiety (Beck Anxiety Inventory (BAI) ≥ 16) to a 30-treatment TMS course at the dysphoric circuit target (MNI coordinates [-32, 44, 34], close to the conventional left dorsolateral prefrontal cortex target for MDD), or at the anxiosomatic circuit target (MNI coordinates [0, 48, 46], a dorsomedial target not routinely used). As hypothesized, dysphoric circuit targeting (n = 16) improved BDI more than BAI (ratio 1.08, IQR 0.69-2.02), while anxiosomatic circuit targeting (n = 20) improved BAI more than BDI (ratio 0.70, IQR 0.01-1.01) (Wilcoxon rank-sum test p = 0.0195). Both targets improved BDI (55 vs 54%), but BAI improved significantly more with anxiosomatic circuit targeting (58 vs 36%, p = 0.0301), even when controlling for BDI (p < 0.001). Thus, TMS targeting different connectome-derived brain circuits differentially modulates anxiety that is comorbid with major depressive disorder. Future studies could target according to baseline symptom profile, a step toward precision psychiatry. Trial Registration Number NCT04604210.