For the many adults living with treatment-resistant depression, the promise of personalized brain stimulation has been compelling — and expensive. Functional connectivity neuroimaging, which maps individualized neural circuits to guide transcranial magnetic stimulation (TMS), received FDA clearance partly on the strength of rapid antidepressant effects. This trial asks a deceptively simple question: does the sophisticated neuroimaging-based targeting actually drive those results, or does the stimulation itself do most of the work?
This randomized, blinded clinical trial enrolled 40 adults aged 22–80 with moderate-to-severe major depressive disorder and meaningful treatment resistance, as measured by the Maudsley Staging Method. Participants were assigned to either connectivity-guided accelerated TMS — using functional neuroimaging to individually target subgenual anterior cingulate cortex circuits — or conventional scalp-landmark-based targeting. The primary outcome was Montgomery-Åsberg Depression Rating Scale scores at one month post-treatment, with follow-up extending across one year. Both arms received the same accelerated TMS protocol, isolating targeting method as the sole variable.
The findings challenge an assumption embedded in the field's recent enthusiasm for precision psychiatry. Connectivity-based targeting did not produce meaningfully superior antidepressant outcomes compared to standard anatomical targeting, suggesting that the therapeutic signal in accelerated TMS may be less sensitive to precise circuit localization than the underlying theory implies. This is not a dismissal of TMS — both approaches showed clinical activity — but it raises important questions about whether neuroimaging adds sufficient clinical value to justify its cost and complexity in routine care. The trial is small at 40 participants, limiting statistical power to detect modest but potentially real differences, and the one-site, highly controlled design may not generalize to community settings. Still, coming from Harvard's Center for Brain Circuit Therapeutics in JAMA Psychiatry, this is a credible and practically important signal that precision targeting claims deserve more rigorous scrutiny before widespread implementation.