Fatigue in Parkinson's Disease: Exploring the Unexplored

Fatigue in Parkinson’s Disease: Exploring the Unexplored

By Ann Freestone, BA’89

Michael J. Fox has long been the face of Parkinson’s disease, which affects at least 1 million people in the United States and 5 million worldwide, making it the leading movement-disorder disease. Other well-known people who are battling or have battled Parkinson’s include Muhammad Ali, Janet Reno, Billy Graham, Linda Ronstadt and Pope John Paul II.

Now 55, Fox was diagnosed with Parkinson’s in his 20s, which is considered early onset, and has fought for a cure for many years. As Fox has continued acting since being diagnosed, viewers would notice physical symptoms; however, one of the most debilitating symptoms is not noticeable in movements. It’s fatigue.

Creighton researchers are collaborating with colleagues from other institutions to explore this unexplored aspect of the disease, through the wide lens of physical therapy, exercise science, pharmacy, neurology and biomechanics.

What they’ve found has shed light on mobility issues experienced by people with Parkinson’s disease, and has opened doors to future research and possible novel treatment options.

Parkinson’s is a lot more than a tremor. It’s a movement disorder that’s degenerative and chronic. Parkinson’s afflicts more people than multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined.

The hallmarks of the disease in terms of motor symptoms are slowness, rigidity and tremor; however, other symptoms are often present as well, such as fatigue, dementia, depression and psychosis.

Although people think of Parkinson’s as a disease of the central nervous system, it is also a disease of the autonomic nervous system, which controls bodily functions that are not consciously directed, such as the heart beating, digestive process and breathing.

Because Parkinson’s affects the autonomic system, people with Parkinson’s may experience dizziness, constipation and a drop in blood pressure. Later in the disease, the symptoms contribute to difficulties in daily living.  

The neurotransmitter dopamine, a substance produced in the brain, helps control movement. Dopamine decreases in people with Parkinson’s. As dopamine decreases, it affects movement, the body and emotions as well.

“A cornerstone of Parkinson’s, regardless of the cause, is a deficiency in this neurotransmitter,” says Michele Faulkner, PharmD, professor of pharmacy practice and professor of medicine in the Department of Neurology.

“The role of dopamine in the body — when you perform any deliberate movement — is to release the inhibition of movement to allow you to execute it accurately and smoothly,” Faulkner continues. “When you don’t have enough dopamine, you have to fight to perform normal movements, so movements are slowed, and muscles feel stiff. Additionally, there’s an imbalance between a couple of different neurotransmitters, dopamine and acetylcholine specifically. This allows acetylcholine to exert its effects unchecked which causes the tremor.”

Dopamine also affects motivation.

“Dopamine does two major things — it moves and motivates us,” says John Bertoni, MD, PhD, director of the Parkinson’s clinic at the University of Nebraska Medical Center (UNMC) who spent 20 years at Creighton. Its effect can be seen in cocaine and other illicit drug use, which stimulate a rush of dopamine to the brain. When the person stops taking the drugs, they often show very little motivation and are withdrawn. “That’s how people with Parkinson’s feel. It takes away their gumption.”  

According to Faulkner, “The medications in the current arsenal, with few exceptions, are created for the replacement of dopamine or to keep enzymes in the body from breaking dopamine down.” In fact, prescribing dopamine-enhancing drugs is part of the diagnostic process: If a person improves while on the medication, then the diagnosis is typically Parkinson’s.  

A major limitation is the disease progresses despite medication.

“We don’t have any medications that stop Parkinson’s, and we don’t have any medications proven to slow it down,” says Faulkner. “As the disease progresses, we continue to add medication after medication and escalate doses, which can result in complicated medication regimens.”

In the advanced stages of the disease, patients have to medicate every couple of hours.

“We’re looking for that magic pill that will stop Parkinson’s in its tracks,” Faulkner says. “Until we find a way to prevent the disease, or stop or slow progression, we haven’t really found success.”

Beyond pharmacological interventions are other therapies such as physical therapy, occupational therapy and exercise.  

“Physical therapy and occupational therapy components include alternative ways to perform tasks and strengthen muscles in people not moving to their full range,” says Joseph Threlkeld, a physical therapist with a PhD in anatomy. “All are classic approaches.”

Threlkeld, the lead investigator in the fatigue study, has researched Parkinson’s disease and movement disorders since 2002. “As a practicing physical therapist as well as an educator, I became interested in how the neurological system controlled movement and how movement controlled the brain,” says Threlkeld.  

Over the years, he investigated whether physical intervention could change the nervous system to alter or improve movement characteristics to maintain functionality of the person with Parkinson’s.

One study analyzed how people with Parkinson’s walked on a treadmill when changing the amount of weight on their legs, which ultimately changed movement patterns. Then he looked closer at how the brain and muscles work together to form movement patterns. Following that research, he spent time studying deep brain stimulators — a treatment that helps a very small percentage of people with Parkinson’s.  

“To wrap all that up, it taught me that normal movement patterns necessary for functions were still present in people with Parkinson’s, but were merely suppressed,” says Threlkeld. “There are better ways to allow patterns to be expressed to gain motion and functionality. It got us started, but there are limitations to functionality and how we could intervene.”  

Exercise is key. The more a person with Parkinson’s does, the slower the disease symptoms progress and the less fatigue a person will experience.

“Exercise decreases fatigue. If you are fit and are moving the muscles, you are more capable of using them and can do more,” says Bertoni. He cites an example of going up a set of stairs; with practice, it gets easier. “If we don’t use it, we lose it. It’s like making a path in the forest. If you stop making the path, the forest grows and covers the path. This works for the brain and muscles. If you use them enough, the path gets stronger.”

“In my view, inactivity is a major cause of disability in Parkinson’s patients,” says Bertoni.    

According to Threlkeld, “The newest approach is to change the brain itself by rebuilding it, which is called neuroplasticity. We’re looking at a renaissance and asking what activity will help rewire the brain.”

One approach uses highly repetitive, high-effort activities that require attention such as boxing, ballroom dancing, tai chi and high-intensity treadmill training. “These three elements help us to rebuild neurocircuitry, but how effective it is in Parkinson’s remains to be seen.”    

Unfortunately, current therapies are limited.  

“The pharmacological approach is less effective as Parkinson’s progresses,” says Threlkeld. “It’s very effective in the early and middle stages. The medication is primarily focused on controlling the motor symptoms. In people with very advanced Parkinson’s, dopamine becomes less and less effective at controlling the symptoms. The same can be said about the limitations of physical therapy and exercise interventions. Parkinson’s can become so severe that you can’t stand or walk. The advanced disease makes interventions hard to deliver and less successful. If we wanted to hit a home run, we’d deliver successful interventions to people in much later stages of Parkinson’s.

A Closer Look at Fatigue

For the past seven years, Threlkeld has been performing research related to one of the most debilitating symptoms of the disease — fatigue. This insidious symptom can make it daunting to pour a glass of milk, wash the dishes and take a shower. “People with Parkinson’s find fatigue very difficult,” says Bertoni.   

“If it takes 10 units of effort to lift 10 pounds, then with Parkinson’s it takes 20 to 30 units of effort,” he says. “It’s harder because messages are not getting through. It’s like the middleman in the brain is asleep at the wheel and doesn’t send the messages, so people with Parkinson’s have to try and try to do something, which equals effort — physical and psychological.” That work is fatiguing.    

The broad definition of fatigue is an overall sense of tiredness, according to Threlkeld. Fatigue for a healthy person is caused by exercising or being sleep deprived; however, for a person with Parkinson’s, there can be multiple causes. “It’s hard to identify the actual cause of the fatigue,” says Dimitrios Katsavelis, PhD, assistant professor in the Department of Exercise Science and Pre-Health Professions. “It’s multifactorial.”    

Threlkeld brought together an interprofessional team, with each of the members bringing something different to the research. In addition to Threlkeld, two other physical therapists are on the team, Terry Grindstaff, PhD, and Jenny Bagwell, PhD.

Faulkner, a doctor of pharmacy with a neurology specialty and a focus on Parkinson’s, handled the medication component of the research. She reviewed the medication profiles of each participant to determine if any medications or pre-existing conditions could cause fatigue and complicate the findings.

Katsavelis, an exercise scientist, looked at the biomechanical aspects of movement and used his background in software engineering and data analysis. Bertoni, who lauded the cooperation between Creighton and UNMC, provided and screened the participants.  

The study looked at how exercise fatigues people with Parkinson’s, healthy older adults and healthy young adults. The participants with Parkinson’s were in the early stages of the disease and had the ability to walk; however, they were dealing with “serious fatigue.”  

The study included three research groups:

  • Subjects with Parkinson’s disease between 40 and 75 years of age who had leg fatigue after walking
  • Subjects without Parkinson’s disease between 40 and 75 years of age
  • Subjects without Parkinson’s disease between 21 and 30 years of age

“We asked the question about how rapidly someone fatigues as a young person versus older, and healthy older adults versus people with Parkinson’s,” says Threlkeld. “We had two control groups — older adults who were age, sex and body-mass-indexed matched — and a group of healthy young adults.”  

The team brought the participants with Parkinson’s into the lab twice — one day the participants took their dopamine-enhancing medication and another day they came in not taking their medication in the morning. When they were done testing, they took their medication. Seventy people initially took part in the study and the data ultimately included 58 participants.      

The research involved testing leg muscle strength through various exercises. Participants sat on a chair and pushed against resistance with their legs. “They are pushing against resistance so no motion is involved. It’s isometric,” says Katsavelis. “Because of tremors, we wanted them to be stable and push against resistance.” The team measured the amount of exercise they did and the amount of fatigue by looking at the strength of the quadriceps, the muscle in the front of the thigh that helps a person stand up straight.   

“The major finding and the thing that surprised us,” says Threlkeld, “was their performance when on the medication was not different from healthy older adults.”

When off the medication, the baseline muscle strength of the people with Parkinson’s dropped dramatically — a 20 percent reduction compared to on medication.

“The dopamine had decreased. The central pattern of decreased muscle force generation was related to the availability of dopamine. The brain dysfunction in a person with Parkinson’s causes muscle contractions to become weak compared to another adult.”    

According to Bertoni, “This research helps explain why moving is so difficult for patients with Parkinson’s disease. Although to others it appears Parkinson’s patients are not trying, in fact they are trying very hard but getting little results.”

The Next Phase

“We are testing affordable and usable treatments that will diminish the fatigue and improve motor performance,” says Threlkeld. These treatments include brain stimulation and virtual reality applications.

“Our goal is to apply treatments patients can take home and apply themselves,” says Threlkeld. “There may be drugs that can supplement our take-home treatments.

“Exercise is effective. People who can engage in intensive exercise that also requires focus and attention are able to improve their function because we think it’s rewiring the brain. We also want to supplement that exercise component with brain electrical and visual stimulation. Those are experimental.” Transcranial stimulation, a safe form of electrical stimulation to the brain, is noninvasive and could potentially reduce fatigue symptoms.   

Katsavelis will be conducting research using virtual reality. Cues, whether auditory or visual, help people with Parkinson’s. “If you tell them ‘take longer steps, take longer steps,’ they will do it and follow the auditory cues,” says Katsavelis. “In Parkinson’s, the brain is not doing things automatically. They have to think for every step they take, so we have to retrain the brain to send the appropriate messages.” The research is interrelated to fatigue.     

The team is now in the process of preparing to publish two to three manuscripts on the study and more research related to fatigue is on the horizon. “The next step is to get a better picture of what regions of the brain are involved,” says Threlkeld. “The research will involve neuroimaging of the brain. We can now produce fatigue in a reliable way. Now we have to observe the fatigue by imaging the brain.”

For the Creighton scientists — and for people suffering from Parkinson’s — the future of this line of research is nothing short of energizing.