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Placebo responses are common in clinical trials of depression treatments. However, how the expectation of treatment benefits patients is not well understood, in part because it is challenging to simulate these expectations in experimental designs. In an article appearing in Translational Psychiatry, Department of Psychiatry researchers Assistant Professor Marta Peciña, MD, PhD, and Associate Professor Alexandre Dombrovski, MD, and their colleagues describe an experimental design in which participants received a placebo infusion said to be a fast-acting antidepressant that was coupled with artificial neurofeedback. The researchers then measured participants’ expectations for mood improvement, actual mood improvement, and related neuronal activity.
 
The investigators found that participants had greater expectations for mood improvement and actual mood improvement when given the placebo infusion than when not. Moreover, greater expectancy ratings were associated with reports of greater mood improvement. These changes in mood were reinforced by the neurofeedback displays, which also enhanced expectations. 
 
The research team also collected real physiological data on the participants during the experiments. The team monitored changes in blood-oxygen levels in the brain indicative of neural activity. Strong positive neurofeedback signals were associated with greater changes in blood-oxygen levels in parts of the lateral prefrontal cortex. Participants with greater prefrontal cortex responses to the artificial neurofeedback likewise had greater mood improvements in response to the neurofeedback. 
 
The investigators took blood samples before and after the experiment to measure β-endorphin levels as a proxy for changes in opioid neurotransmission. Prior work by Dr. Peciña and other researchers have found that opioid signaling in the brain is associated with placebo responses. In this study, increases in β-endorphin levels were associated with greater expectations for mood improvements as well as mood improvements themselves in response to positive neurofeedback. However, the β-endorphin changes did not correlate with lateral prefrontal cortex activity, suggesting that opioid signaling and the lateral prefrontal cortex use different brain mechanisms to influence the placebo response. 

Overall, the researchers showed that a placebo drug treatment reinforced by artificial neurofeedback led to real changes in mood associated with lateral prefrontal cortex activity. These findings underscore that placebos can be a powerful source of treatment. The findings could also potentially guide development of critically needed fast-acting antidepressants by helping to differentiate between placebo and drug effects in clinical trials. 
 
Prefrontal expectancy and reinforcement-driven antidepressant placebo effects
Peciña M, Heffernan J, Wilson J, Zubieta JK and Dombrovski AY
Translational Psychiatry (2018) Oct 15;8(1):222. https://doi: 10.1038/s41398-018-0263-y