Summary: A randomized clinical trial from Mass General Brigham indicates that using each patient’s resting-state functional MRI (fMRI) to select targets for transcranial magnetic stimulation (TMS) can meaningfully improve outcomes for treatment-resistant major depressive disorder. The study found that connectivity-based targeting — selecting stimulation sites based on individualized functional connectivity maps — produced larger antidepressant effects than standard scalp-based targeting when paired with accelerated TMS (aTMS).
The trial used accelerated TMS, a protocol that delivers multiple stimulation sessions per day to compress what is normally a multi-week course into a single week. Investigators mapped resting-state functional connectivity to identify the left dorsolateral prefrontal cortex region most strongly linked to a convergent depression circuit in each participant. One month after treatment, the connectivity-guided group showed greater symptom reduction and higher response rates than the group whose targets were determined by traditional scalp measurements.
Key Facts
- Personalized targeting advantage: Choosing aTMS targets based on an individual’s fMRI-derived functional connectivity provides a measurable clinical benefit compared with standard scalp-based methods that do not account for individual circuit differences.
- Condensed treatment schedule: Accelerated TMS delivers multiple daily sessions, reducing a multi-week course to one intensive week.
- Improved remission and response: At one month post-treatment, the connectivity-targeted group exhibited an 80% response rate versus 60% in the scalp-targeted group.
- Objective outcomes: Results were assessed with the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS), and both participants and clinical raters were blinded to targeting assignment.
- Prospective evidence: This randomized trial provides prospective support that functional neuroimaging can be translated into scalable clinical improvements for aTMS in depression.
Source: Mass General
Overview
Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation technique that uses magnetic pulses to alter brain activity. Since 2008, TMS has been FDA-cleared for adults with major depressive disorder, particularly for cases that have not responded to medication or psychotherapy. Traditional clinical practice typically identifies stimulation sites using scalp-based measurements such as the Beam F3 method. These approaches are practical and widely used, but they do not take into account individual differences in brain network organization.
This trial tested whether choosing targets with an individual’s resting-state fMRI connectivity would enhance the antidepressant effects of accelerated TMS. Resting-state functional connectivity measures how brain regions co-activate at rest, revealing personalized network relationships that can guide where stimulation will most effectively modulate depression-related circuits.
Joseph J. Taylor, MD, PhD, the study’s corresponding author, noted the importance of translating neuroimaging advances into direct patient benefit. Imaging adds cost and logistical complexity to TMS; the trial was designed to determine how much clinical advantage imaging-based targeting might add over conventional scalp-based targeting.
Forty adults, aged 22–80, with major depressive disorder and moderate-to-severe treatment resistance were enrolled. Each participant received a multiecho resting-state fMRI before treatment and was randomized to receive a week of aTMS targeted either by their individualized connectivity map or by standard scalp-based placement. Participants, TMS technicians, and study clinicians were blinded to assignment.
At one month after treatment, the connectivity-targeted group demonstrated significantly greater improvement on the MADRS than the scalp-targeted group. Median MADRS score reductions were larger with connectivity-based targeting (median reduction 24 points) than with scalp-based targeting (median reduction 18 points). The study reported an effect size corresponding to Cohen’s d analog of 0.8 and calculated a number needed to scan of five individuals to gain one additional responder by using connectivity-based targeting.
The study also evaluated the reproducibility of individualized targets, finding that targets were consistent within individuals and distinct between different participants. The investigators emphasize that these findings advance prior retrospective analyses by providing prospective randomized evidence that individualized functional imaging can meaningfully change clinical outcomes in aTMS treatment for depression.
Limitations and next steps
The authors acknowledge limitations including the relatively small sample size and the single-site design. Planned next steps include larger, multi-site trials to validate efficacy across more diverse populations and to assess longer-term durability of benefit. Such trials will also help determine cost-effectiveness and guide decisions about wider clinical implementation of connectivity-guided aTMS.
Authorship
The study team includes Joseph J. Taylor and colleagues at Mass General Brigham and Harvard Medical School, as well as additional contributors. Full author names are listed in the original publication.
Disclosures and funding
Dr. Taylor reported grants from the Brain and Behavior Research Foundation during the study. Drs. Taylor, Fox, and Siddiqi are coinventors on a provisional patent application related to methods described in this work. Additional authors reported consulting fees and other disclosures as noted in the paper. Funding sources include the Brain and Behavior Research Foundation and several institutional and federal awards supporting the investigators’ work.
Frequently asked questions
A: Standard TMS is delivered over several weeks in single daily sessions. Accelerated TMS compresses therapy into one week with multiple daily sessions. Because aTMS delivers a higher density of stimulation in a short time, tailoring the stimulation site using each patient’s functional connectivity helps ensure the rapid, high-dose therapy targets the most relevant depression-related circuit for that individual.
A: The primary outcome was the clinician-rated MADRS score one month after treatment. The connectivity-based group had greater median reductions in MADRS and an 80% response rate versus 60% in the scalp-targeted group, indicating a clinically meaningful advantage.
A: Limitations include the sample size (40 participants) and single-site design. The team plans larger, multi-site trials to confirm effectiveness in broader populations and to evaluate longer-term outcomes and cost-effectiveness.
Editorial notes
- This article was edited by a Neuroscience News editor.
- The full journal paper was reviewed for accuracy.
- Additional explanatory context was added by editorial staff.
About this research
Author: Cassandra Falone
Source: Mass General
Contact: Cassandra Falone – Mass General
Image credit: Neuroscience News
Original research: The study appears as an open-access article in JAMA Psychiatry under the title “Connectivity- versus scalp-based targeting of accelerated TMS for depression: A randomized trial.” DOI: 10.1001/jamapsychiatry.2026.1100
Clinical trial registration: ClinicalTrials.gov identifier: NCT05680727
Abstract (condensed)
Importance: Functional neuroimaging is widely used in psychiatric research, but prospective evidence that it improves clinical outcomes is limited. This study evaluates whether individualized connectivity-based targets improve outcomes for accelerated TMS in treatment-resistant depression.
Objective: To estimate the effect size of connectivity-based versus scalp-based targeting of aTMS.
Design and participants: A randomized trial of 40 adults with treatment-resistant major depressive disorder conducted at Mass General Brigham with primary outcome at one month post-treatment. Participants, clinicians, and technicians were blinded.
Intervention: All participants underwent a multiecho resting-state fMRI. Half received aTMS targeted to individualized connectivity-defined left dorsolateral prefrontal cortex sites linked to a convergent depression circuit; the other half received aTMS targeted using the Beam F3 scalp method.
Main outcome: MADRS score one month after treatment, adjusted for baseline.
Results: Connectivity-based targeting produced larger median MADRS reductions (24 points) than scalp-based targeting (18 points), with an effect size analog of 0.8 and a number needed to scan of five. Individual targets were reproducible within individuals and varied between individuals.
Conclusions: Individualized connectivity-guided targeting enhanced the antidepressant effect of high-dose accelerated TMS in this randomized trial. These findings support further large-scale studies to confirm clinical utility, assess long-term outcomes, and inform implementation strategies.