Researchers continue to push the boundaries of interventional psychiatry research by exploring how precision brain stimulation can target the neural circuits underlying complex psychiatric symptoms. A newly published randomized clinical trial suggests that personalized TMS for schizophrenia may successfully engage brain networks responsible for social cognition, an area where few effective treatments currently exist.
Social cognitive difficulties are among the most disabling features of schizophrenia spectrum disorders. Challenges interpreting emotions, understanding the intentions of others, and navigating social interactions often persist even when hallucinations or delusions improve. Despite their impact on quality of life, no approved medications specifically target these impairments.
Why Social Cognition Has Remained Difficult To Treat
Traditional treatments for schizophrenia primarily focus on reducing psychotic symptoms rather than restoring the brain networks involved in higher-order social functioning. Previous research has shown that the dorsomedial prefrontal cortex and temporoparietal junction play central roles in “mentalizing,” or understanding another person’s thoughts and intentions.
Standard repetitive transcranial magnetic stimulation (rTMS) has demonstrated benefits for several psychiatric conditions, but responses vary considerably between individuals. One reason is that conventional targeting methods often stimulate approximately the same scalp location for every patient, even though brain anatomy and functional connectivity differ substantially from person to person.
A Personalized Approach To Brain Stimulation
To address this challenge, investigators designed a double-blind, randomized, sham-controlled trial involving adults with schizophrenia spectrum disorders. Rather than relying on standard anatomical landmarks, researchers individualized stimulation targets using resting-state functional MRI, functional connectivity mapping, electric field modeling, and neuronavigation.
The study compared three groups over two weeks of treatment:
Personalized intermittent theta burst stimulation (iTBS)
Personalized 10 Hz rTMS
Sham stimulation
Each participant underwent functional MRI before and after treatment, allowing researchers to directly measure whether stimulation altered the intended social cognitive networks rather than relying solely on symptom questionnaires.
Personalized TMS For Schizophrenia Increased Targeted Brain Connectivity
The most important finding was that personalized iTBS significantly strengthened connectivity within the mentalizing network compared with sham treatment. Specifically, connectivity between the dorsomedial prefrontal cortex and the left temporoparietal junction increased with a large effect size.
By contrast, conventional 10 Hz rTMS did not produce significant improvements compared with sham.
Researchers also evaluated connectivity between the mentalizing and simulation networks but found only negligible or small changes regardless of stimulation protocol.
Importantly, the study was designed as a target engagement trial. Its primary objective was to determine whether personalized stimulation successfully modified the intended neural circuits rather than demonstrate immediate clinical improvement in social functioning.
Why Individualized Targeting May Matter
One of the most innovative aspects of the trial was the use of the BOONStim targeting pipeline, which combines personalized functional connectivity maps with electric field modeling to determine the optimal stimulation location and coil orientation for each individual.
This precision approach recognizes that two patients with schizophrenia may have substantially different brain network organization. Instead of assuming identical treatment targets, the protocol seeks to maximize stimulation of the specific neural circuits involved in social cognition for each participant.
This represents a broader movement within neuromodulation toward precision psychiatry, where imaging and computational modeling guide individualized treatment planning.
Understanding The Biological Mechanism
Intermittent theta burst stimulation may offer unique advantages because its stimulation pattern resembles naturally occurring theta rhythms involved in synaptic plasticity and learning.
The researchers suggest this rhythmic stimulation may more effectively enhance communication within the mentalizing network than traditional high-frequency stimulation. Previous neuroscience research has linked theta oscillations to perspective taking, empathy, and theory of mind, making iTBS a biologically plausible strategy for strengthening these circuits.
Although imaging changes were encouraging, exploratory analyses did not demonstrate statistically significant improvements in behavioral measures of social cognition or overall clinical symptoms during the brief two-week treatment period.
Safety And Future Clinical Implications
Safety outcomes were reassuring. While participants receiving iTBS reported somewhat higher pain scores than those receiving sham treatment, adverse event rates and treatment discontinuation were similar across all study groups. No serious adverse events were reported.
The investigators emphasize that this work should be viewed as an important proof of target engagement rather than definitive evidence of clinical effectiveness. A larger, longer clinical trial is already underway to determine whether strengthening these brain networks ultimately translates into meaningful improvements in everyday social functioning.
If confirmed, personalized TMS for schizophrenia could represent a significant advance in precision neuromodulation by demonstrating that individualized targeting can reliably influence neural circuits associated with some of the disorder’s most persistent and difficult-to-treat symptoms.
Citations
- Oliver LD, Blumberger DM, Deng ZD, et al. Effects of Personalized Transcranial Magnetic Stimulation on Social Cognitive Network Functional Connectivity in Schizophrenia Spectrum Disorders: A Double-Blind, Randomized, Sham-Controlled Target Engagement Trial. Brain Stimulation. 2026. https://doi.org/10.1016/j.brs.2026.103172
- Oliver LD, Jeyachandra J, Dickie EW, et al. Bayesian Optimization of NeuroStimulation (BOONStim). Brain Stimulation. 2025;18(1):112-115. https://doi.org/10.1016/j.brs.2024.10.013
Explore more at https://www.interventionalpsychiatry.org/
