Parkinson’s disease is notorious for so-called motor symptoms like muscle rigidity, tremor, slowed movement, and unsteady posture and gait. Less well known -- even to some doctors who treat the disease -- are the effects of Parkinson’s on thinking. These “cognitive” signs include a general slowness of thought, “tip of the tongue” forgetfulness of words, and difficulty juggling multiple mental tasks.

Parkinson’s disease and the medications used to treat it may also affect how the brain learns. And even stranger, certain Parkinson's drugs can trigger compulsive behaviors such as pathological gambling or uncontrolled shopping. Understanding these and other aspects of how Parkinson's disease affects the mind offers hope of a better life for people with a disease estimated to affect more than a half million Americans.

The death of dopamine

Parkinson's is caused by the death of brain cells that produce dopamine, one of the chemicals that carry messages between neurons. Low dopamine impairs the basal ganglia, which are brain regions that control movement and coordination.

Drug treatments try to shore up dopamine levels. For example, medications containing the chemical L-dopa provide extra raw materials to produce natural dopamine. Another, newer class of drugs, dopamine “agonists,” mimic the action of natural dopamine on motor-control brain cells.

Dopamine-boosting drugs address motor symptoms, and this allows people to function better. But realization is growing that some patients need help with non-motor symptoms. These include depression, anxiety, daytime sleepiness, insomnia, lightheadedness, urinary incontinence, nerve pain and loss of smell. Some patients develop memory loss and dementia, generally late in the disease’s progression.

Research priorities

In 2001 and again in 2006, the National Institute of Neurological Disorders and Stroke (NINDS) held meetings at which scientists, doctors, and patients discussed priorities in Parkinson’s disease research. Non-motor symptoms emerged as a major concern.

“In both summits, patient advocates and the clinical community identified it as one of the most important under-addressed areas for patients with Parkinson’s disease,” notes neurologist Debra Babcock, MD. She heads the NINDS program on Cognitive Neuroscience that funds research on non-motor Parkinson’s symptoms. “What's worse is that some non-motor symptoms are actually aggravated by the treatments used for the motor symptoms.”

What is needed, Babcock says, is more research. “It's understudied,” she says. “Less than 5 percent of our Parkinson's disease grants are looking at cognitive dysfunction. This is an improvement over prior years though, and we continue to actively encourage the research community to focus on this issue.”

Impulse-control disorders

The latest non-motor symptoms to come to light are impulse-control disorders. These occur in at least 14 to 17 percent of people who take dopamine agonists, says neurologist Melissa J. Nirenberg, MD, of Weill Cornell Medical College in New York. The most common are compulsions for gambling, sex, shopping, food, eating, or even hobbies. Some people exhibit “punding,” or repetitive, purposeless behaviors such as sorting objects. Frequently the compulsion involves a behavior the person "previously enjoyed in moderation,” Nirenberg notes.

Nirenberg is an expert in impulse-control disorders associated with Parkinson’s medications. One factor that still obscures this problem even from experienced neurologists is the sensitive nature of the behaviors.

Some patients might be willing to bring up the fact that they have been eating uncontrollably. But it’s harder to uncover repeated and financially disastrous trips to the casino, or all-night Internet pornography-viewing sessions and visits to prostitutes.

A frank discussion with a spouse or partner can help. Then the medications can be changed to reduce or eliminate the problem.

Changes in learning

In recent years, researchers have uncovered another odd and unexpected effect of Parkinson's disease on the mind. Depending on whether people are taking dopamine-boosting medications or not, their mode of learning changes.

Normally we learn from both "rewards" and "punishment." In reward learning, we receive positive feedback (a reward) for doing the right thing. In punishment learning, we receive negative feedback for doing the wrong thing. For example, studying for an exam brings the reward of a high grade, but not studying brings a failing mark.

Remarkably, people with PD who are not taking dopamine-boosting medication learn better when they are punished for making the wrong choices rather than being rewarded for making the right choices. But on medication, the scales tip completely the opposite way, and rewards have more of an effect.

In a study published online May 4, 2009, in the journal Brain, researchers led by Hungarian psychiatrist Szabolcs Kéri and U.S. neuroscientist Mark Gluck probed this reversible learning bias in a special group of test subjects: relatively young patients (in their 40s) recently diagnosed with Parkinson's, but who were not yet on medication. This unique group of patients allowed the scientists to explore the effects of dopamine agonist medication on learning and improve on previous research in several ways.

In previous studies, patients were commonly older and farther along in the disease. They were more likely to suffer from memory problems and mood disorders, such as depression, that could affect the study outcomes. In contrast, the younger and healthier Hungarian group provided a way to study the effects of Parkinson's on learning with fewer potentially confounding factors — both before and after the patients started on medications.


New learning test

Gluck, professor of neuroscience at the Center for Molecular and Behavioral Neuroscience at Rutgers University, Newark, worked with researchers at Rutgers and New York University to develop a new testing technique for the study. Compared to previous methods, the new test more directly assessed the degree to which the patients learned from punishment or reward. It takes just 20 minutes to complete and runs on any laptop computer.

Nikoletta Bódi, a graduate student in Kéri's lab, performed most of the testing on the Hungarian patients for the study. The results were consistent with previous research. "We demonstrated that these newly diagnosed patients have a very specific deficit in learning from reward but are normal at learning from punishment," Gluck explains. "In contrast, when they are placed on medication this learning sensitivity reverses: They become impaired at learning from punishment, but are normal in their ability to learn from reward."

The results confirmed the reversible learning bias on and off medication. The study also extended previous research by examining the effect of medication on certain personality traits associated with Parkinson's disease.

One trait is "novelty seeking," or a preference for things that are new and different, rather than comfort with the familiar. In the study, never-medicated patients with Parkinson’s disease show much less novelty seeking behavior. But once they started taking the dopamine-boosting drugs, novelty seeking increased.

Impulsivity insights

Gluck says the study findings help to make sense of the gambling and other impulse-control disorders seen in some Parkinson's patients. It suggests these problems are simply reward-seeking behaviors unchecked by a normal sensitivity to their possible negative consequences.

“If your ability to learn from negative outcomes is reduced and you play the slot machines and win $10 for a few rounds but lose many more times in between, what you may recall best is the thrill of winning," Gluck says. "As such, you will be hampered in your ability to learn that gambling can also have negative consequences.”

This and other research on the interactions of Parkinson's, dopamine medication, and learning could help have some practical benefits for patients. “The research should motivate neurologists to keep an eye on these cognitive effects and impulse control disorders that until recently were largely ignored because the doctors were trying to treat the motor dysfunction,” says Michael Frank, a cognitive neuroscientist at Brown University and one of the first to document the affect of dopamine medications on learning in people with Parkinson's. “But it’s becoming more clear that these cognitive effects significantly impact the quality of life.”

Effects on behavior and thinking are just “another factor they could use to determine which patient should be on which drug and at what dose,” Frank says. Genes may someday come into play, too. Frank and his colleagues have studied gene variations associated with the sites on neurons that interact with dopamine. Certain dopamine gene variants are associated with whether a person learns better from positive or negative experience. In the coming age of “genomic medicine,” genetic testing could identify people at risk of impulsive behavior when taking a given medication.

So could tests for changes in personality and learning, Gluck adds. "It is generally believed that at the time of initial diagnosis, most Parkinson's patients have already lost up to 70 percent of their dopamine cells. Thus, there is surely a long period in which the loss of dopamine cells may cause cognitive and personality changes before the motor symptoms are apparent."

Developing genetic or neuropsychological early warning tests for Parkinson's is going to take a lot more time and research. In the meantime, what researchers have already revealed is laying the groundwork for treatments that provide a better quality of life.

RESOURCES

"Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson’s patients," by Nikoletta Bodi, Szabolcs Keri, Helga Nagy, Ahmed Moustafa, Catherine E. Myers, Nathaniel Daw, Gyorgy Dibo, Annamaria Takats, Daniel Bereczki, and Mark A. Gluck. Published online in Brain May 4, 2009.

Read an interview with Mark Gluck about the new research at PD Online Research:
http://www.pdonlineresearch.org/news/2009-08/05/laptop-test-reveals-parkinsons-related-differences-reward-and-harm-avoidance-learning

“By carrot or stick: cognitive reinforcement learning in Parkinsonism,” by Michael Frank and others. (Science, 2004, Vol. 306, pp. 1940-1943.) Abstract available via PubMed.

National Institute of Neurological Disorders and Stroke
http://www.ninds.nih.gov

“Compulsive eating and weight gain related to dopamine agonist use,” by M.J. Nirenberg & C. Waters. (Movement Disorders, 2005, Vol. 21, pp. 524-529) Abstract available via PubMed.

                        -- Copyright © 2010 Memory Loss and the Brain