Courtesy of Fabrizio Benedetti
During a deep brain stimulation clinical trial, researchers detected elements of the placebo effect. The pre-placebo neuron was recorded from the left subthalamic nucleus as a control. The post-placebo neuron was recorded from the right subthalamic nucleus. Other neurons demonstrated a similiar decrease in activity.
Revealing the complexities of the pain experience may offer a window into the mind-body interaction. Several recent studies into the placebo effect, human empathy, and their apparent interconnectedness are providing insight into the human subjective experience.
Such investigations, says Jon-Kar Zubieta, associate professor in psychiatry and radiology at the University of Michigan, help scientists understand the intersection of physical and emotional states. "The placebo effect gets at the core of how individuals react and modulate environmental events, whether positive or negative in nature," he says. If harnessed, the regulatory mechanisms involved could point to better treatments for pain, depression, and stress.
In earlier work, University of Turin physiology professor Fabrizio Benedetti showed that administering an opioid-blocking drug could reverse the psychological placebo effect.1 "People started believing there was something real there," says Columbia University assistant professor Tor Wager, lead author of a recent placebo effect study on functional magnetic resonance imaging (fMRI) .
Wager's group took a different tack, uncovering regions of the brain that showed decreased activity during the placebo effect.2 In one trial, they told subjects that they were administering a powerful analgesic cream. In another, the subjects received the same cream but were told it has no effect. When subjects were experiencing the placebo effect, a subset of known pain-sensitive brain regions showed a signal reduction of 20% to 25%.
In a subsequent study, Benedetti's group observed patterns of neuronal firing, not visible via neuroimaging, that corresponded with Wager's findings.3 His group performed single-neuron recording in patients with Parkinson disease who had been administered a sham treatment.
Investigators took advantage of a legitimate therapy, deep-brain stimulation, which involves the chronic stimulation of the two subthalamic nuclei via electrodes implanted in the subject's brain. But when only a mock procedure was performed, and the patients were told that they'd have relief, scientists noted less muscle rigidity and decreased neuronal activity.
According to Benedetti, the placebo treatment interrupted the typical pattern of Parkinson neurons, namely bursts of activity. In both his study and the Wager study, placebos suppress activity in pain pathways and motor pathways. "Unfortunately we do not know why and how," says Benedetti.
EMPATHY AND ANTICIPATION
Wager's group also separated pain from the anticipation of pain. They compared brain images of subjects just after they'd been given a cue that pain was coming, to brain images after the experience of pain and with and without placebo. Two areas of the brain were more active with placebo: the dorsal lateral prefrontal cortex, an area integral to working memory, and the orbital frontal cortex, an area known to be involved in evaluating stimuli. "You see the cue, the pain is coming up, but [the subject thinks], 'It's not going to be so bad because I've had the placebo,"' says Wager. "So there's an active process there."
The brain areas involved in anticipation of pain relief have significant overlap with those involving empathy, according to a study that accompanied Wager's.4 "You can imagine that these areas code for your subjective experience of how unpleasant something is, and not for the objective input," says lead author Tania Singer, a research fellow in the functional imaging laboratory at University College London.
The empathy study compared the fMRI brain images of persons when they received a painful stimulus to when they observed a signal indicating that a loved one was receiving a painful stimulus. Thus, subjects empathized with the emotions of others in the total absence of any external emotional sensory stimuli. Singer found that only the anterior cingulate cortex and the anterior insula were activated for both the response to one's own pain and to that of another's pain. The suggestion: Only those parts of the pain experience associated with the affective and not the sensory evaluation are involved in empathy. "It's as though you have a central circuitry for pain processing," says Wager.
"These studies," says Zubieta, "more precisely get at how the brain is modulating different forms of experience, whether emotional in the case of empathy of pain, or things like placebo effects, which is also the expectation of a positive outcome. ... For the first time we're beginning to see the true mind-body kind of connection and integration."