Placebo-induced BOLD responses in a priori-defined emotion appraisal neurocircuitry. (A) The group contrast (placebo > control) revealed overlapping placebo-induced BOLD increases in the NAc during stroking, warm, and painful touch (as revealed by conjunction analysis), and in the PAG during stroking and warm touch. (B) Regions where individual placebo response (placebo > control) correlated with placebo-induced (placebo > control) BOLD increase. High placebo responses correlated with high placebo- induced increases in these regions. (C) Magnitude of stroking touch hyperhedonia correlated with increased functional coupling between the mOFC, left NAc, left amygdala, and the PAG. Magnitude of placebo analgesia correlated with increased functional coupling between pgACC and mOFC, and bilateral amygdalae as well as mesolimbic reward regions (right NAc and VTA). Green represents stroking touch; yellow represents warm touch; red represents painful touch. Averaged activation maps (Z > 2, uncorrected for illustration purposes) were superimposed on the MNI standard template brain. Copyright © PNAS, doi:10.1073/pnas.1305050110
The human brain’s exquisite complexity and power make it a unique evolutionary marvel. One of the brain’s more interesting abilities is known as the placebo effect, in which no more than the expectation of relief can lead to analgesia – the relief of pain, anxiety, depression, nausea, and many other aversive states. However, scientists at University of Gothenburg and University of Oslo recently showed that the placebo effect may not be limited to pain reduction, but may also enhance pleasure, or hyperhedonia. The researchers used the placebo effect to improve both painful and pleasant touch sensations in healthy humans – and by comparing brain processing using functional magnetic resonance imaging (fMRI), found that, depending on whether the starting point was painful or pleasant, neurocircuitry associated with emotion and reward underpinned improvement of both pain and pleasant touch by dampening pain but increasing touch pleasantness.
In an interview with Medical Xpress, PhD candidate Dan-Mikael Ellingsen discussed the paper he and his colleagues published in Proceedings of the National Academy of Sciences. “In recent years, functional brain imaging studies have shown that expecting a treatment to relieve negative symptoms – like pain, anxiety or unpleasant taste – leads to not only subjective reports of relief, but also suppressed brain activity in sensory circuitry during aversive stimuli, such as noxious heat or touch, threatening images, and unpleasant taste,” Ellingsen tells Medical Xpress. “However, both aversive and appetitive experiences – for example, tasty food or a pleasant touch – are affected by context and expectation.” Therefore, Ellingsen explains, in forming their hypothesis for this study, the researchers asked whether improvement of good experiences is encoded entirely in higher-level valuation processing, or whether it would mirror the modulation of early stages of sensory processing that is seen for aversive stimuli. “If so, we’d expect such positive sensory signals to be up-regulated, in contrast to the down-regulation of sensory signals we see during placebo-induced reduction of aversive experiences.”
In the placebo manipulation procedure, participants were shown a short video documentary convincing them that a nasal spray containing the neuropeptide oxytocin would reduce pain and enhance the pleasantness of pleasant touch. Following this video, they self-administered 10 puffs of a placebo nasal that they were told could contain oxytocin. The pleasant touch stimuli consisted of caress-like light strokes with a soft brush, or a hot/cold pack (resembling a warm hand, applied to the subject’s forearm. The pain stimulus was a thermode (~47 degrees Celsius) on the hand.
Ellingsen notes that by comparing brain activation during painful or pleasant touch stimuli after placebo treatment versus no-placebo, the scientists were able to assess differences in activation that was specifically related to having received placebo treatment. “Importantly, the subjective reports showed that, after receiving placebo relative to no-placebo, touch pleasantness was increased while pain unpleasantness was decreased,” he adds. “When contrasting placebo and no-placebo on brain activation, we found that sensory activation was increased during pleasant touch stimuli and decreased during painful touch stimuli. In other words, the placebo-induced change in sensory processing reflected the placebo-induced change in subjective reports.”
The team also hypothesized that placebo improvement of pleasant touch would recruit the same emotion appraisal neurocircuitry that underpins placebo analgesia. “Neural systems mediating pain and pleasure interact extensively, with pain and pleasure often being mutually inhibitory,” Ellingsen says. “For instance,” he illustrates, “pleasant stimuli such as music, food, odors, and touch can have analgesic effects – and pain can inhibit pleasure and positive feelings. Further, opioids can induce both potent analgesia and feelings of pleasure.” (An opioid is any psychoactive chemical that resembles morphine or other opiate in its pharmacological effects.) Ellingsen points out that previous findings show that relief from pain induces pleasant feelings1,2, and when a normally painful stimulus represents the best possible outcome – that is, when the alternative is even more intense pain3 – it can even become pleasant.
Ellingsen explains that a central element in all placebo effects is that there is an expectation or desire for an improvement, for example, a relief of pain or unpleasantness – and placebo effects have been theorized to arise from a generalized mechanism of reward prediction. This reasoning, he notes, is supported by evidence that placebo responses across modalities – analgesia6, anxiety relief7, and so on – rely on activation of similar neural systems involved in reward and emotion. “In line with this strong link between pleasure and the relief from negative feelings, we hypothesized that improving the pleasantness of an appetitive stimulus would rely on modulatory mechanisms similar to those involved in the improvement of aversive feelings.”
A key aspect of the team’s research was devising and applying an fMRI crossover study to compare neural processing of placebo hyperhedonia and analgesia. “In order to compare the brain mechanisms of placebo hyperhedonia and analgesia, we assessed the effect of placebo treatment on subjective experiences within the same sensory modality – namely, touch, both pleasant and painful.”
A key aspect of the study’s analytic design was based on the researchers’ knowledge that all dermal information is processed in the same neural pathways – specifically, the sensory thalamus, primary and secondary somatosensory areas, and the posterior insula. “As a result,” Ellingsen points out, “we were able to perform two important measurements: we directly compared how expectation of improvement affected the processing of positive and negative somatosensory signals in these pathways, and investigated the effect of higher-level modulatory circuitry on sensory processing of pleasant or painful touch.”