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A recently published randomized clinical trial in JAMA Psychiatry examined whether brain imaging can improve outcomes of accelerated transcranial magnetic stimulation (aTMS) for people with treatment resistant depression. The study compared two ways of choosing where to stimulate the brain.
One approach used standard scalp based targeting, which relies on external head measurements. The other used individualized functional connectivity brain imaging to guide targeting of a depression related brain circuit.
The key question was simple but important: does imaging guided targeting lead to better antidepressant outcomes than traditional scalp based methods when all other treatment factors are the same?
This was a randomized clinical trial conducted between 2023 and 2025 at Mass General Brigham and Harvard Medical School. A total of 40 adults aged between 22 and 80 years participated. All participants had moderate to severe major depressive disorder and had not responded adequately to multiple prior antidepressant treatments.
Participants were randomly assigned into two groups:
Both groups received identical stimulation protocols. This included high dose accelerated treatment delivered as 10 sessions per day for 5 consecutive days, using intermittent theta burst stimulation.
The only difference between groups was how the brain stimulation target was selected.
Connectivity based targeting uses resting state functional MRI scans to map how different brain regions communicate. In this study, researchers focused on a previously defined “convergent depression circuit.” This circuit includes brain regions linked to mood regulation, especially connections involving the dorsolateral prefrontal cortex and subgenual cingulate cortex.
For each participant, researchers identified the exact spot in the left dorsolateral prefrontal cortex that was most strongly connected to this depression circuit. That individualized point became the stimulation target.
In contrast, scalp based targeting used a standardized anatomical method that does not rely on brain imaging.
The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) at one month after treatment.
Results showed:
This indicates that both groups improved, but the imaging guided group improved more.
The effect size for connectivity guided targeting was reported as approximately 0.8, which is considered a large effect in clinical research.
The study also measured clinical response and remission.
Results:
This suggests that individualized targeting may increase the likelihood of meaningful clinical improvement.
Interestingly, both groups showed similar improvement during treatment and shortly after. Differences became more noticeable at one month follow up.
This suggests that connectivity guided targeting may not change immediate response but could influence longer term consolidation of antidepressant effects.
One important part of the study was whether individualized brain targets are stable and reliable.
Researchers found:
This is important because it shows the method is both personalized and consistent within a person.
The treatment was generally well tolerated. No seizures or serious adverse events were reported.
Blinding was also tested. Study psychiatrists and participants were largely unable to correctly guess group assignment beyond chance levels, suggesting that expectancy bias was limited.
The study suggests that using brain imaging to guide TMS targeting may improve outcomes in treatment resistant depression compared to standard scalp based methods.
Several possible explanations were discussed:
However, the authors emphasize that this was a relatively small pilot trial and should be interpreted carefully.
The study had several limitations:
Because of these limitations, the results should be considered preliminary and hypothesis generating rather than definitive.
Despite limitations, the findings are important for several reasons.
First, this is one of the first randomized trials to directly compare imaging guided and non imaging guided TMS targeting in a controlled design. Most prior evidence has been observational or retrospective.
Second, the results suggest that brain connectivity mapping may enhance the effectiveness of already established neuromodulation treatments.
Third, the concept of a “depression circuit” provides a more unified biological model of depression that goes beyond traditional region based thinking.
This randomized clinical trial found that connectivity based targeting of accelerated TMS produced greater improvements in depression symptoms than standard scalp based targeting in adults with treatment resistant depression.
While both approaches were effective, the imaging guided method showed a larger clinical benefit and higher response rates at one month.
The study supports the idea that personalized brain circuit mapping could improve neuromodulation therapies for psychiatric conditions. However, larger multi site trials are needed before widespread clinical adoption.
Source: Taylor JJ, Kare MR, Haj-Darwish D, et al. Connectivity- vs Scalp-Based Targeting of Accelerated Transcranial Magnetic Stimulation for Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online June 24, 2026. doi:10.1001/jamapsychiatry.2026.1100