Mere Expectation of Treatment Can Improve Brain Activity in Parkinson’s Disease Patients

Researchers at Columbia University and the University of Colorado at Boulder have found that expectations can drive changes in the brain, highlighting an important link between psychology and medicine. It is a finding that could improve the quality of life and presence of symptoms in patients with Parkinson’s disease and change how clinical trials operate.

Previous studies have shown that patients with Parkinson’s are vulnerable to expectations of treatment. Placebo treatment – in which patients believe they receive medication when in fact they do not – can sometimes help almost as much as real medication. It has already been proven that Parkinson’s patients who receive a placebo (in this case, a starch pill) instead of real medication can sometimes show improvement in motor function. So far, however, no studies have looked at the effect of placebo on cognitive and learning impairments that develop in Parkinson’s or on how they work in the brain. The current study, published online in Nature Neuroscience on October 19, examines this effect and reveals the mechanism behind the phenomenon.

"What’s really exciting about this study is that it links the neurobiology and psychology of expectations - such an abstract concept - with a concrete improvement in patients' behavior,” said one of the study’s two senior investigators, Daphna Shohamy, associate professor of psychology at Columbia University and a member of the both the University’s Kavli Center for Brain Science and Mortimer B. Zuckerman Mind Brain Behavior Institute. “For those of us who do research in cognitive neuroscience, this is really the grand hope - that by understanding more about the basic mechanisms behind how the mind and brain work, we will be able to better help people suffering from neurological and psychiatric disorders."

Funded by the Michael J. Fox Foundation for Parkinson’s Research, Shohamy, with help from her Columbia co-researchers Liane Schmidt and Erin Kendall Braun, as well as the other senior investigator for the study, Tor Wager, from University of Colorado, set out to uncover the effect of placebo on the brain using functional magnetic resonance imaging (fMRI) to visualize how a placebo enhances learning-related brain responses in patients by utilizing a game designed to measure activity in brain areas disrupted in Parkinson’s. In healthy patients, these areas respond when the individual receives an unexpected reward, such as discovering a $20 bill while walking down the street. In Parkinson’s, however, these areas lose their inputs and do not respond as strongly to rewards.

Reward learning requires specialized neurons that signal using the neurotransmitter dopamine. Parkinson’s causes these neurons to die, so in addition to the motor symptoms commonly associated with the disease, Parkinson’s patients are also impaired at reward learning. Once treated with medication that increases the amount of dopamine these neurons release, Parkinson’s patients’ motor impairment is improved.

The researchers asked Parkinson’s patients to play a computer game in which they learned through trial-and-error which of two symbols was more likely to lead to a better outcome - either a reward of $10 or not losing money. While the patients played the game, their brain activity was monitored via fMRI. This was repeated many times under three different conditions – without medication, on medication and, critically, while the patients thought they were on medication but had received a placebo.

The findings reveal that improved reward learning on placebo was no different than the degree of improved reward learning while on medication. The associated activity in brain regions that are known to support this type of learning was indistinguishable between the placebo and medication conditions, demonstrating the power of expectations to elicit changes in the brain. It also suggests that the improvements patients see with their medications in standard clinical settings may be partly due to the expectations of the patient that the medicine will work.This placebo effect in the cognitive domain correlated with improvements in motor impairments.

The study also revealed a limitation that could affect the majority of clinical trials that use placebo to evaluate the efficacy of an experimental therapy. (Placebo conditions and effects typically serve as the baseline by which experimental drugs and efficacy are evaluated in a clinical trial setting.) This presents a limitation that should be considered in any clinical trial that employs the use of placebo as a tool to compare against experimental treatment, Shohamy advised.

With these findings, investigators believe that the learned association between a drug and its outcome could potentially be reinforced by expectations created by verbal suggestions and other elements of treatment. If true, it is feasible that medical professionals may be able to influence treatment efficacy – in a variety of disease states – by expressing optimism, having positive conversations about treatment with patients, adapting the physical location of treatment and generally conveying a belief that the medicine will make the patient’s condition better. Such synergy between expectations, pharmacology and behavior could have a positive cumulative effect on patients’ motivation, response to treatment and quality of life.

This new study illustrates the power of applying a sophisticated cognitive perspective on motivation and reward, judiciously, to problems of neurodegeneration,” said Thomas Jessell, co-director of the Zuckerman Institute. “Appreciation of behavioral deficits in Parkinsonian patients should, in the long term, lead to a more nuanced and effective approach to therapy."