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A growing body of evidence demonstrates that antidepressant placebo medications are not merely control conditions in clinical trials. Rather, the expectations and learning processes engaged with use of placebo actively shape mood outcomes through neural and molecular mechanisms. These effects recruit circuits involved in valuation, interoception, and affective regulation, and engage neurochemical pathways known to underlie antidepressant treatment response mechanisms. Yet, the causal role of expectancy-driven processes in shaping perception remains largely untested. 

Investigators from the University of Pittsburgh including Ian Snyder, BS (Systems Programmer/Analyst II); Helmet Karim, PhD (Assistant Professor of Psychiatry and Bioengineering); Rebecca Price, PhD (Professor of Psychiatry and Psychology, and Associate Professor of Clinical and Translational Science); Fabio Ferrarelli, MD, PhD (Professor of Psychiatry); Alex Dombrovski, MD (Pittsburgh Foundation Endowed Professor in Brain and Mind Research and Professor of Psychiatry and Psychology); and Marta Peciña, MD, PhD (Associate Professor of Psychiatry and Bioengineering), used neuromodulation to directly manipulate the neural targets of placebo-induced expectancies, to learn how these mechanisms contribute to mood improvement. The team theorized that reinforcement learning–predicted expectancies, arising from greater attention to contextual treatment cues in the dorsal attention network, are encoded in the salience network and trigger mood regulation through enhanced connections with the default mode network, a robust predictor of antidepressant and placebo response.

To test whether modulation of default mode network engagement alters the influence of expectancy on mood, the investigators, led by Dr. Peciña, conducted a mechanistic antidepressant placebo trial in a cohort of 50 adults with depressive symptoms. Each participant completed three sessions of theta burst stimulation (TBS; a powerful transcranial magnetic stimulation variant) one week apart. In each session, a single application of TBS—intermittent, continuous, or sham—was delivered to the dorsomedial prefrontal cortex (the cortical target of the default mode network), approximately one hour before an antidepressant placebo functional magnetic resonance imaging task.

In a paper published in JAMA Psychiatry, the investigators reported that the randomized clinical trial provided causal evidence that intermittent TBS over the dorsomedial prefrontal cortex enhanced the translation of expectancies into mood.

“Beyond observing placebo effect, our findings demonstrate that we can now actively harness expectancy-driven recovery through targeted neuroplasticity, offering a new therapeutic frontier for depression,” said Dr. Peciña, senior author of the study.

Intermittent Theta Burst Stimulation of the Dorsomedial PFC and Expectancy-Driven Placebo Mood Effects - A Randomized Clinical Trial
Snyder I, Handoko K, Neppach A, Badhan G, Karim HT, Price RB, Ferrarelli F, Dombrovski AY, Peciña M. 
JAMA Psychiatry. Published online May 06, 2026. doi:10.1001/jamapsychiatry.2026.0647