Objective/Rationale:
Many researchers believe that placebo treatments may have beneficial effects on symptom progression in Parkinson’s disease, but there is very little experimental evidence on whether placebo treatments actually affect the brain systems disrupted in PD. Understanding placebo effects on the neurobiology of PD is important for predicting and controlling placebo effects in clinical trials, and for being able to harness placebo-related expectations to augment existing treatments.
Project Description:
This project uses functional magnetic resonance imaging (fMRI) to study placebo effects on the functions of two brain systems related to function and quality of life in Parkinson’s patients, the motor system and the dopamine system. fMRI can measure the relationship between brain and behavior in a living, functioning human brain. In this project, we will study how Parkinson’s patients’ brain activity during a motor task and a dopaminergic reward-learning task changes with both active medication (levodopa) and placebo treatments. In this way, we will be able to establish whether placebo treatments affect biological markers of Parkinson’s disease. We will assess how these measures of brain function relate to placebo effects in clinical scales of Parkinson’s symptoms, and how they are shaped by individual differences in patients’ optimism and expectations.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Though many clinical researchers believe that placebo effects in PD are real and have a neurobiological basis, many see them as irrelevant to the actual disease progression. Establishing which brain systems are affected by placebo in PD will provide insight into whether clinical trials should be designed to enhance or eliminate placebo effects. If placebo treatments affect the same brain systems as active medications (such as levodopa), then designing a clinical trial to eliminate placebo effects may actually eliminate the effects of the drug as well. In addition, the existence of neurobiological placebo effects suggests that large-scale efforts to combine psychological interventions that enhance positive expectations with standard medical treatment should be pursued.
Anticipated Outcome:
Through this project, we expect to learn whether placebo treatments, which are manipulations of positive expectations, affect the brain’s motor and dopamine systems. This information will tell us whether placebo effects may enhance the effects of medication, or whether they are irrelevant for the neurobiological progression of the disease.
Final Outcome
Several studies suggest that a combination of the expectation of relief associated with taking a drug and conditioned drug responses can trigger endogenous dopamine release in the brain. Although, this placebo effect is a prominent source of variation in clinical trial outcomes, and has been shown to be a clinically significant effect, little experimental evidence exists about its functional role for symptoms of PD and under what conditions it might occur. Here we addressed this question by using functional magnetic resonance imaging (fMRI) to measure placebo effects on brain activation in PD patients. To disentangle psychological and pharmacological effects of drug treatment, patients were scanned under three conditions: no treatment (off drug), placebo, and levodopa (on drug). Compared to no treatment, placebo and levodopa both enhanced learning from reward. FMRI revealed that this finding was related to changes in several key targets of the mesolimbic dopamine pathway: Enhanced value representation in the medial orbitofrontal cortex (OFC) at the time of choice, reduced error-related activity in the ventral striatum, and enhanced OFC-striatal connectivity. These findings suggest that the psychological effects of a drug may be, in some cases, as powerful in improving learning as the pharmacological effects of a dopamine precursor, consistent with findings that placebo can lead to enhanced dopaminergic activity.