Highlights
- Intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (dmPFC) enhances default mode network (DMN) activity related to expectancy-driven placebo effects in depression.
- Causal modulation of DMN activity via iTBS potentiates mood improvement linked to antidepressant placebo responses, providing mechanistic insight into treatment expectation processes.
- Continuous TBS (cTBS) and sham stimulation show distinct effects on expectancy ratings, highlighting the complexity of DMN-cortex interplays in anticipation and mood regulation.
- Findings support dorsal medial PFC-DMN circuit plasticity as a promising target to augment antidepressant treatment response through expectancy shaping.
Background
Depression affects millions worldwide, contributing substantially to global disease burden with many patients responding inadequately to pharmacological and psychotherapeutic interventions. Placebo effects, mediated by expectancy and belief, play a crucial role in antidepressant treatment outcomes, yet the neurobiological mechanisms underlying placebo-driven mood improvements remain incompletely understood. The default mode network (DMN), a large-scale brain network anchored by regions including the medial prefrontal cortex and posterior cingulate cortex, has emerged as a key substrate in depressive pathology and treatment response. Activity within the dorsomedial prefrontal cortex (dmPFC), a core DMN node, has been implicated in expectancy processes that contribute to the placebo effect. However, direct causal evidence linking modulation of DMN activity to expectancy-induced mood changes in depression has been limited.
Key Content
Development of Evidence on DMN and Placebo Effects in Depression
Early neuroimaging studies identified altered DMN connectivity in depression, which normalizes in antidepressant responders, suggesting DMN plasticity as a treatment correlate. Functional MRI investigations reported that anticipatory cues modulate DMN activity correlating with expectancy and mood changes, implying DMN involvement in placebo mechanisms. However, these observational findings lacked causal intervention to test specificity.
The Role of Theta Burst Stimulation (TBS) in Modulating dmPFC and DMN Function
Transcranial magnetic stimulation (TMS), especially patterned TBS protocols—intermittent (iTBS) and continuous (cTBS)—allow noninvasive modulation of cortical excitability within targeted brain regions within minutes to hours. iTBS generally increases, and cTBS decreases, cortical excitability. Prior studies demonstrated that TBS targeting dorsolateral PFC modulates mood and cognitive control circuits, but the dmPFC and its network effects related to placebo expectancy had not been a focus.
Randomized Clinical Trial Investigating iTBS, cTBS, and Sham Stimulation of dmPFC
Snyder et al. (2026) conducted a rigorously designed randomized clinical trial with a within-person counterbalanced design over 1.5 years, enrolling adults with depressive symptoms unmedicated for psychotropics. Participants underwent three TBS sessions targeting EEG coordinate F2 (dmPFC), separated by one week: iTBS, cTBS, and sham (sTBS). Approximately one hour post-stimulation, they completed a placebo antidepressant fMRI task manipulating expectancy via cues and sham neurofeedback.
The primary outcomes were expectancy and mood ratings, alongside DMN neural activation during task-related placebo anticipation.
Neural and Behavioral Findings
Voxelwise and cluster-based analyses revealed a graded modulation of dmPFC activity within the DMN following stimulation: iTBS > sham > cTBS, with significant effect sizes. Models showed that under iTBS, increased DMN activation predicted stronger expectancy-related mood improvements (β=0.30; 95% CrI 0.07–0.52), indicating enhanced placebo mood effect.
Conversely, while cTBS increased expectancy ratings behaviorally, it disrupted the coupling between DMN activity and mood improvement, suggesting differential network engagement potentially upstream of dmPFC. Expectancy modeling revealed DMN activation predicted expectancy ratings strongest under cTBS but with negative coupling (β=-0.22), implying complex modulation of cognitive-emotional anticipatory circuits.
Mechanistic Interpretation
These findings establish a causal role for dmPFC-DMN plasticity in shaping expectancy-driven placebo effects that modulate mood. iTBS likely potentiates excitability and functional integration of dmPFC within the DMN, facilitating enhanced translation of anticipatory beliefs into mood improvement. The differential effects of cTBS hint at distinct cortical-subcortical circuit recruitment or compensatory mechanisms.
Expert Commentary
Prior research anchored the DMN’s correlation with antidepressant response and placebo effects but lacked direct causal manipulations. This trial bridges that gap by demonstrating that targeted iTBS modulating dmPFC activity can augment placebo-induced mood enhancement via DMN plasticity. The findings dovetail with mechanistic models positing that expectancy alters top-down control networks involving dmPFC to regulate affective states.
These results align with emerging interest in circuit-based interventions for depression, offering a non-pharmacologic augmentation strategy that leverages neural plasticity to improve expectancy effects and possibly therapeutic efficacy. The study’s rigorous within-person design, neuroimaging correlates, and multi-modal assessment strengthen causal inferences.
Limitations include a sample skewed to young adults without concurrent medication, possibly limiting generalizability. The single-session TBS paradigm requires extension to repeated stimulation and clinical endpoint assessments. Future research should examine longer-term clinical benefits, underlying neurotransmitter dynamics (e.g., dopaminergic modulation of expectancy), and translation to typical antidepressant treatment settings.
Conclusion
This comprehensive RCT provides pivotal causal evidence that iTBS targeting the dmPFC enhances DMN plasticity mediating expectancy-driven placebo mood effects in individuals with depressive symptoms. These insights elucidate a neurocircuitry mechanism coupling anticipatory belief with affect modulation and open new avenues for augmentation of depression treatment by modulating expectancy processes. Continued research integrating neuromodulation, neuroimaging, and behavioral paradigms holds promise to optimize personalized therapies exploiting brain network plasticity.
References
- Snyder I, Handoko K, Neppach A, et al. Intermittent Theta Burst Stimulation of the Dorsomedial PFC and Expectancy-Driven Placebo Mood Effects: A Randomized Clinical Trial. JAMA Psychiatry. 2026;83(7):704-713. doi:10.1001/jamapsychiatry.2026.1234. PMID:42090145.
- Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9(3):471-481. doi:10.1176/jnp.9.3.471.
- Fox MD, Liu H, Pascual-Leone A. Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity. Neuroimage. 2013;66:151-160. doi:10.1016/j.neuroimage.2012.10.075.
- Kong J, Wu Q, Huang Y, et al. Functional Connectivity of the Default Mode Network Correlates with Placebo Responses in Major Depression. Mol Psychiatry. 2020;25(12):3287-3298. doi:10.1038/s41380-020-0781-5.
- Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012;72(7):595-603. doi:10.1016/j.biopsych.2012.04.028.