ANN ARBOR, MI -Researchers have produced the strongest evidence yet that placebo--or the mere expectation of relief, with no real treatment--causes physical changes in how the brain responds to pain. Their report appears in the Feb. 20 issue of Science.

In two related studies at the Ann Arbor Veterans Affairs (VA) Health Care System, University of Michigan and Princeton University, researchers used functional magnetic resonance imaging (fMRI) to map changes in blood flow in the brains of volunteers. The volunteers were subjected to harmless but occasionally painful electric shocks or heat. When they believed an anti-pain cream had been applied to their arm, they rated the pain as less intense--and the pain circuits in their brain showed less activity.

Doctors have long recognized the power of placebo to make patients feel better. But scientists are unsure why it works, and whether nerve pathways are actually affected. The new studies provide the first scans documenting the changes induced by placebo in the brain's pain pathways.

"We've shown what the old family doctor knew very well--that his interaction with the patient made a great difference in the effectiveness of whatever treatment he was giving," said one of the researchers, Kenneth L. Casey, MD, who has studied pain for three decades. Casey is a neurology consultant for VA and a professor at the University of Michigan. Lead author was Tor D. Wager, MD, a graduate student at the University of Michigan when the research was conducted.

Researchers have performed brain experiments with fMRI since the early 1990s. It uses the technology of MRI--radio waves and a strong magnetic field--to show regions of the brain where blood vessels are widening, extra oxygen is being delivered, or other chemical changes are occurring. These are signs that an area of the brain is busy at work. By taking fMRI images as patients perform different tasks, researchers learn which areas of the brain control which functions.

The Michigan and Princeton pain studies, each involving about two dozen volunteers, show the prefrontal cortex as the area of the brain active in the placebo response. Scientists have developed intriguing models of how this area of the brain guides thought and action based on internal goals and expectations. In support of those theories, the new research by Casey and Wager's group provides the first images of how the prefrontal cortex is activated by the expectation of pain relief, and how this in turn triggers a reduction of activity in pain-sensing areas of the brain: the thalamus, somatosensory cortex, and other parts of the cerebral cortex.

According to Casey, this clearer knowledge of the brain's pain pathways may lead to new therapies for those with chronic or acute pain. "One could imagine compounds that would activate these control systems specifically," he said.

Casey also said the research sheds new light on the tangible benefits of the placebo effect in medicine. "If you're providing a treatment to a patient, it's important that you realistically provide them with the expectation that it would work, so you enhance the effect. If you gave them a drug or any kind of treatment with the attitude, either explicit or implicit, that this might not be effective, it would be much less likely to be effective."

Working with Wager and Casey on the study were James K. Rilling and Jonathan D. Cohen of Princeton University; Edward E. Smith and Alex Sokolik, University of Michigan; Richard J. Davidson, University of Wisconsin; Stephen M. Kosslyn, Harvard University; and Robert M. Rose, University of Texas Medical Branch.

Members of the media who wish to reach Dr. Casey for an interview may contact: Bonnie Johnson, bonnie.johnson3@med.va.gov , 734-761-7910

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