by Daniel Pendick
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
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
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
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.
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.”
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
A frank discussion with a spouse or partner can help. Then
the medications can be changed to reduce or eliminate the
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
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
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.
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
“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
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.
"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:
“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
“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.
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