The next phase of interventional psychiatry research may depend not only on how the brain is stimulated, but on how precisely clinicians identify where stimulation should occur. A new Biological Psychiatry study suggests that personalized rTMS targeting based on an individual’s deviation from typical brain connectivity could provide a more biologically informed way to select treatment sites for major depressive disorder.
Why TMS Targeting Remains An Important Challenge
Repetitive transcranial magnetic stimulation, or rTMS, is an established noninvasive treatment for depression. Treatment commonly targets the dorsolateral prefrontal cortex, or DLPFC, a region involved in cognitive and emotional regulation.
Yet the DLPFC is not a single uniform treatment target. Its functional connections differ across individuals, and conventional targeting approaches may not fully account for these differences. Previous neuroimaging research has shown that antidepressant response can be related to how strongly a stimulated DLPFC location is functionally connected with deeper regions involved in depression, particularly the subgenual anterior cingulate cortex, or sgACC.
The challenge is determining which location within the DLPFC may be most relevant for a particular patient.
Personalized rTMS Targeting Through Normative Modeling
Researchers led by Zhanjie Luo developed a strategy based on normative modeling of sgACC-DLPFC functional connectivity. Instead of simply mapping a patient’s connectivity, the method asks a more specific question: where does that person’s connectivity differ most strongly from what would normally be expected?
The researchers first constructed a reference model using resting-state functional MRI data from 1,313 healthy participants in the Depression Imaging REsearch ConsorTium, or DIRECT.
They then applied the model to 1,583 people with major depressive disorder. For each patient, the researchers generated Z-score maps showing how the individual’s sgACC-DLPFC connectivity differed from the healthy reference distribution.
The DLPFC location showing the most negative deviation became that person’s functional connectivity normative deviation, or FCND-guided, target.
A Target Linked To Depression Severity
The analysis found that patients with depression showed more pronounced negative connectivity deviations than healthy participants. Importantly, greater abnormalities were also associated with more severe depressive symptoms measured using the 17-item Hamilton Depression Rating Scale.
This relationship provides an important foundation for the targeting model. The selected location was not simply an unusual point on a brain scan. The magnitude of the connectivity deviation also tracked with clinical symptom severity.
Testing Whether Target Proximity Matters
The investigators next examined whether stimulating closer to the personalized FCND target was associated with better outcomes.
In an independent active rTMS cohort, shorter distance between the actual stimulation site and the personalized target was associated with greater clinical improvement. The same relationship was not observed in the comparison condition.
The researchers then examined a separate accelerated intermittent theta burst stimulation cohort. Again, stimulation sites located closer to the FCND-guided target were associated with greater improvement.
Finding a similar relationship across two independently collected active-treatment datasets strengthens the possibility that the model is capturing clinically relevant information rather than a pattern unique to a single sample.
Why Normative Modeling Could Change Personalized rTMS Targeting
Personalized connectivity targeting is not entirely new. Neuroimaging researchers have previously proposed using functional connectivity to improve TMS localization, particularly by identifying DLPFC regions with favorable relationships to the sgACC.
Normative modeling adds another layer. Rather than identifying connectivity alone, it estimates how unusual an individual’s connectivity is relative to expected variation in healthy people while accounting for demographic variability.
In practical terms, the framework attempts to distinguish ordinary differences between brains from connectivity patterns that may be more closely related to depression.
The study’s exploratory mediation analysis also produced findings statistically consistent with the hypothesis that treatment response may be related to normalization of these connectivity deviations. This mechanistic interpretation remains preliminary, but it offers a testable direction for future studies.
From Standard Coordinates Toward Individual Brain Networks
The broader implication is a shift from treating the DLPFC as a fixed anatomical destination toward treating depression as a network-level disorder requiring individualized targeting.
Brain imaging has already made it possible to position TMS more precisely, but greater spatial accuracy only becomes clinically meaningful if the chosen target is biologically relevant. Previous reviews have emphasized that connectivity-guided targeting could help bridge that gap, while also noting the need for rigorous prospective validation.
The new FCND framework moves this concept further by defining a personalized target according to how each patient’s network organization departs from a normative reference.
The results do not establish that FCND-guided targeting should replace current clinical methods. Larger prospective trials will need to determine whether selecting the stimulation site with this model directly improves response or remission rates.
Still, the study points toward a more individualized future for neuromodulation. Instead of asking where TMS generally works for depression, precision psychiatry may increasingly ask where stimulation is most relevant for the brain of the person receiving it.
Citations
- Luo Z, Li W, Liu G, et al. Normative Modeling of sgACC-DLPFC Functional Connectivity Identifies a Personalized rTMS Target Associated with Clinical Response in Major Depressive Disorder. Biological Psychiatry. 2026. DOI: 10.1016/j.biopsych.2026.07.025. ScienceDirect Article
- Cash RFH, Weigand A, Zalesky A, et al. Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression. Biological Psychiatry. 2021;90(10):689-700. DOI: 10.1016/j.biopsych.2020.05.033. PubMed Article
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