FEELINGS OF HOPE CREATE STRIKING BRAIN EFFECTS THAT COULD HELP ALLEVIATE SERIOUS AFFLICTIONS LIKE PAIN, PARKINSON'S DISEASE, AND DEPRESSION, RESEARCHERS REPORT
For immediate release.
NR-11-05 (11/15/05). For more information, please contact Sara Harris at (202) 462-6688 orsharris@sfn.org.
FEELINGS OF HOPE CREATE STRIKING BRAIN EFFECTS THAT COULD HELP ALLEVIATE SERIOUS AFFLICTIONS LIKE PAIN, PARKINSON'S DISEASE, AND DEPRESSION, RESEARCHERS REPORT
WASHINGTON, DC, November 15, 2005 — Belief in the healing power of positive thinking has existed since the beginning of recorded human history. But only now are researchers finding scientific evidence that hope uses the same neurological pathways to heal, as does real medication. The latest research, based on studies of placebos in patients, reveals that hope can affect the brain to alleviate a range of serious afflictions, including pain, Parkinson’s disease, and depression.
“New findings revealed through the study of placebos’ effects on the brain are opening up a whole new area of brain research,” says Jon-Kar Zubieta, MD, PhD, of the University of Michigan and chair of a symposium on the placebo effect at this meeting. “These findings can have a tremendous impact on medicine as well as help us understand how the brain manipulates itself.”
The placebo effect—a phenomenon of healing through therapeutically inert substances—is often discounted as psychological and therefore not real. New insight into placebo effect comes from several studies that suggest otherwise.
“The placebo effect is an important phenomenon in the clinical practice of medicine, and a prime example of cognitive-emotional influences on a number of physical processes,” says Zubieta.
Zubieta and Christian Stohler, PhD, of the Universities of Michigan and Maryland, respectively, are part of a team that has found that placebo effect boosts our own capacity to suppress pain by employing the brain’s own “anti-pain” mechanisms—the endogenous opioids or endorphins, causing observable changes in the brain. Endorphins—the brain’s own (endogenous) morphine—are released during stress, or sustained pain to regulate those experiences. Scientists have known for some time that some of the most powerful painkillers, such as the opiates, relieve the patient from pain by activating the receptors that also mediate the effects of our endogenous opioids or endorphins. Both opiate pain killers and endorphins then regulate pain-responsive pathways in the brain and spinal cord, bringing relief. Analgesia or pain relief can also be observed after administration of a placebo with believed analgesic properties (placebo analgesic effect). If patients think they received medication with pain relieving or analgesic properties they may feel the lessening of pain.
In their study, Zubieta and Stohler treated 14 subjects experiencing moderate levels of experimental pain in the presence and absence of placebos, which in this case was an intravenous hydrating solution. The placebo rescued the patients from pain, reducing their pain reports and this improvement corresponded to the release of endorphins in some areas of the brain.
“The administration of the placebo was associated with the activation of the release of endogenous opioids in a number of brain regions,” says Stohler. “These results indicate that the placebo response, in other words hopes and expectations, use the same chemical pathways in the brain as chemically active analgesics to reduce pain, improve health and feeling of well being.”
The patients in Zubieta and Stohler’s study not only felt less pain, but the degree of relief corresponded with the degree of pain they had felt earlier, i.e., the more the pain experience the greater the placebo effect. “This information helps us understand the responses to positive expectations, and how these expectations can modulate physical processes,” says Stohler.
These results, he says, have great potential for benefiting clinical research. “Harnessing the underlying mechanisms will increase our capacity to both enhance therapeutic effects and reduce placebo effects in clinical trials, where the effects of active and inactive treatments often become indistinguishable,” says Stohler.
Other studies also show how the brain processes expectations in order to influence behavior and shed further light on the neurobiology of placebo response to pain, says Tor Wager, PhD, assistant professor of psychology at Columbia University.
“New research shows that placebo-induced reductions in pain engage regions of the frontal cortex that are involved in maintaining expectations and evaluating the personal significance of environmental stimuli,” says Wager. These frontal regions in the brain are activated during several kinds of emotion- and pain-regulation tasks. Wager used functional magnetic resonance imaging (fMRI) to study the brain as it responded to placebos in patients suffering from pain. The results show that placebos decrease activity in certain areas of the brain—namely the thalamus, insula and anterior cingulate cortex. These regions become active during pain and the anticipation of pain, and are also influenced by analgesic medications—thus providing further evidence that pharmacologically active drugs and placebo treatment-induced positive expectations activate the same pain-modulation networks.
Expectations are predictions about the nature and significance of upcoming stimuli, while analgesia is presumed to result from alteration of pain-processing dynamics in the brain. Therefore, these results provide an entree to studying how different pathways in the brain influence each other, and in particular how expectations can influence emotional and perceptual experience. “Studies of placebo and expectancy provide some first steps towards a neurobiological understanding of the brain’s internal self-regulatory capacities,” says Wager.
Another study by Fabrizio Benedetti, MD, of the University of Torino Medical School in Italy reveals that placebos induce strong positive responses in patients suffering from Parkinson’s disease. “Due to the effect of placebos on Parkinson’s disease patients, the disease is now emerging as an interesting model to understand the neurobiology of placebo effect,” says Benedetti.
Treating Parkinson’s patients with placebo has not only improved motor functioning in patients, but has also been shown to cause dopamine release in the basal ganglia, the brain region that is impaired in the disease. Another reason for the growing significance of Parkinson’s disease in studying the neural pathways of placebo response is the fact that one can directly record electrical activity of neurons in patients with electrodes implanted in their brains for the treatment, deep brain stimulation.
Benedetti and his colleagues recorded electrical activity from the brains of Parkinson’s disease patients after they received placebo treatment. Their results revealed that placebos cause neurons in the subthalamic nucleus (STN)—a region of the brain that is a target for surgical therapy for Parkinson’s disease—to have a decreased firing rate and bursting activity. These neuronal changes were also correlated with a measurable reduction in muscle rigidity, and this correlated with improvement in patients’ movements and overall health.
“The next steps of this research will be to better describe the biochemical and neuronal changes caused by placebos, to identify which diseases are affected by them, and to better understand the implications of these mechanisms in clinical trial design and in medical practice,” said Benedetti.
He has studied the interplay of expectations and healing for many years. In his most recent study, Benedetti’s team took a different approach to understand the social and psychological components of placebo response in Parkinson’s patients as well as in pain patients. They did not treat patients with placebo, instead they gave them hidden treatment—patients were unaware that they were receiving therapy—and followed their recovery.
The researchers found that a hidden therapy is less effective than an open, or expected one. Even though the patients did not receive placebos, the difference between the open and hidden conditions represents the placebo, or the social and psychological, component.
“This indicates that the psychological component of a therapy is fundamental and that placebo effects can be studied without the administration of any placebo. This latter aspect is particularly important for the ethical guidelines of the World Medical Association Declaration of Helsinki, which suggest that the use of placebos in clinical trials should be avoided,” says Benedetti.
The psychological and social aspects mentioned above are also important for patients with depression. “As with other medical treatments, the study of placebo antidepressant effects involves an examination of the psychosocial context,” says Helen Mayberg, MD, of Emory University School of Medicine.
Placebo responses are common in antidepressant trials including medication and psychotherapy. Mayberg studies the neurobiology of antidepressant treatments by imaging the brain to identify active areas of the brain. Her recent work reveals that antidepressants and placebos affect the same areas in the brain to reduce depression, but differ from the areas influenced by behavioral therapy.
“Our group has been primarily interested in understanding mechanisms of various antidepressant treatments,” says Mayberg. “We are trying to define the neural pathways involved in clinical responses and remission by using functional neuroimaging.”
Mayberg’s group used the antidepressant fluoxetine in an experiment where neither of Mayberg’s two experimental groups knew whether they were receiving the active drug or the placebo. Six weeks after treatment, the scientists imaged the patients’ brains using positron emission tomography. This technique measures changes in blood flow or glucose metabolism in the brain, which correlate with neural activity.
“The metabolic change pattern in the placebo group shared many of the same regions as in the fluoxetine group,” says Mayberg. Both groups show changes in various parts of the cingulate cortex, an area in the center of the cerebral cortex known to be important for emotional and cognitive functions. The frontal, parietal and posterior cingulate cortex show increased activity while the subgenual cingulate cortex shows decreased activity. According to Mayberg the results suggest that the activated areas of the brain common to both groups may be critical for depression response. “This may constitute a so-called final common pathway, regardless of treatment modality,” she adds. “These preliminary results suggest that such studies can provide important clues as to the mechanisms mediating placebo effects in trials of diverse antidepressant treatments.”
The fluoxetine group however, showed additional changes in the brainstem and hippocampus. “These additional changes in the fluoxetine group could be important in maintaining long term effect as opposed to the short term effects of placebos,” says Mayberg. “But, we need further investigation to test this hypothesis.”
A third group studied separately, received cognitive behavioral therapy. This form of antidepressant treatment affected completely different areas of the brain as compared to either placebo or fluoxetine.
“Thus, placebo response appears to resemble the recovery pathways of the active treatment to which it was paired, which in our study was medication,” says Mayberg. “It does not seem to be the result of uncontrolled, non-specific psychological treatment effects, although a formal placebo-cognitive therapy study is needed to verify this.”
