Intermittent Theta Burst Stimulation of the Dorsomedial PFC and Expectancy-Driven Placebo Mood Effects: A Randomized...

Default mode network (DMN) activity has been implicated in mechanisms of antidepressant treatment response, particularly expectancy processes that contribute to placebo effects. However, causal evidence is limited.

To test whether modulating DMN function via theta burst stimulation (TBS) over the dorsomedial prefrontal cortex (PFC) alters placebo-related neural activity and expectancy-driven mood responses.

This randomized clinical trial was conducted from October 2020 to March 2025 and represented a within-person, counterbalanced design. Adults with depressive symptoms aged 18 to 53 years not taking psychotropic medication were included in the analysis. Participants were recruited from the University of Pittsburgh Medical Center. Trial × trial expectancy and mood ratings were recorded. Data analysis was performed on a rolling basis from October 2021 to March 2025.

Three TBS sessions over the dorsomedial PFC (electroencephalogram coordinate F2; 80% resting motor threshold, 1 week apart): intermittent (iTBS), continuous (cTBS), and sham (sTBS). One hour later, they completed the antidepressant placebo functional magnetic resonance imaging (MRI) task, which manipulated anticipatory beliefs using expectancy cues and sham neurofeedback.

Outcomes included expectancy and mood ratings during the antidepressant placebo functional MRI task and placebo-related neural activation in the DMN.

A total of 103 individuals were enrolled in the study. Of those enrolled, 67 completed at least 1 session, and 50 (mean [SD] age, 28.3 [9.5] years; 26 male [52.0%]) composed the final analytic sample. Voxelwise analyses showed that iTBS increased dorsomedial PFC activity relative to cTBS in the DMN (threshold-free cluster enhancement corrected P = .98). Cluster-based analyses confirmed a main effect of stimulation, with a significant monotonic pattern (iTBS > sTBS > cTBS, F2,144 = 4.55; P = .01; η2 = 0.06). In models predicting mood, greater DMN activation predicted stronger expectancy-related mood responses under iTBS compared with sTBS (β = 0.30; 95% credible interval [CrI], 0.07-0.52). In contrast, in models predicting expectancies, greater DMN activation predicted higher expectancy ratings in response to the treatment cue (β = 0.38; 95% CrI, 0.22-0.55), but this coupling was strongest under cTBS (β = -0.22; 95% CrI, -0.44 to 0), likely reflecting engagement of upstream regions. Behaviorally, cTBS increased expectancy ratings relative to the other conditions.

Results of this randomized clinical trial show that a single session of iTBS targeting the dorsomedial PFC enhanced expectancy-related modulation of the DMN and amplified placebo-induced mood improvement. These findings implicate DMN plasticity in the rapid shaping of antidepressant expectancy effects and highlight a potential circuit-based mechanism for augmenting treatment response in depression.

ClinicalTrials.gov Identifier: NCT04276259.