Exercise is increasingly an important component of treating Parkinson’s disease. To supplement the effects of medication or surgery, Parkinson’s patients may undergo physical therapy or programs such as Tai Chi to improve motor symptoms including balance, gait, and tremor. Generally, the idea behind these exercises is to strengthen the body’s muscles to compensate for the neurological effects of the disorder. But a new study by University of Chicago Medicine researchers, building upon research originally conducted in mice, suggests that the combination of drug therapy and exercise at the right time may actually help a patient’s brain re-wire itself to offset the disease’s progressive damage.
In 2010, a collaboration between laboratory scientists and clinicians produced a paper that potentially solved one of the greatest mysteries of Parkinson’s therapy. When a Parkinson’s patient is started on levodopa — a drug that replaces the neurotransmitter dopamine — they experience both an immediate effect as well as benefits that slowly build up over the course of weeks. Even when the drug is discontinued, this “long duration response” persists — a useful therapeutic effect even if nobody is quite sure why it happens.
“It’s actually much more beneficial than this short duration pharmacokinetic response, which is fluctuating and problematic after many years,” said Un Jung Kang, professor of neurology and director of the University of Chicago Parkinson’s Disease and Movement Disorders Center. “If we can enhance this slow long duration response, that would be much more therapeutically beneficial.”
With a bit of serendipity, the mouse experiments published in 2010 stumbled into a potential mechanism for that long-duration response. When dopamine-deficient mice were given levodopa and run on a special kind of treadmill, their motor performance improved over mice who ran the treadmill without the dopamine drug, or mice who received the drug without exercise. Even after the drug was stopped, the benefits persisted in a manner similar to the long-duration response observed in Parkinson’s patients. That suggested the long duration response might be the result of motor learning and changes in the brain enhanced through the combination of dopamine replacement and exercise.
The next step was to test whether the combination of dopamine and exercise would be similarly beneficial in humans. Un Jung Kang, a co-author on the 2010 paper, considered designing a motor task for his patients in the that could test the hypothesis. But before launching a complicated and expensive trial, he went back to completed studies to see if they might yield a preliminary answer.
“I realized that there was probably some data available in the clinical trials done already, that could maybe give us some insight into whether this same phenomenon appears in patients,” Kang said.
Looking through data from the largest clinical trial of levodopa, published in 2004, Kang found a potentially useful measure: finger-tapping. Patients enrolled in the study were periodically tested for their performance on a simple task, where they are asked to tap two targets on the table in front of them as many times as possible in one minute. In the paper, published this spring in Neurology, Kang and co-author Peggy Auinger decided to compare how finger-tapping performance improved between patients’ dominant and non-dominant hands after starting levodopa treatment. The premise was that a patient’s dominant hand (i.e. their right hand if right-handed) would see more use during daily life, and thus would show more of the potential benefits of combining dopamine and exercise versus the less-often-used other hand.
The reanalysis of the data confirmed their hypothesis: during levodopa treatment, patients improved their performance on the finger-tapping task with both hands, but the dominant hand improved more than the non-dominant hand. For patients in the placebo group that were not given levodopa, finger-tapping performance was unchanged for both hands. The results supported the idea that dopamine and exercise worked together to boost motor learning and control.
“You need the dopamine to take advantage of more activity leading to better performance,” Kang said. “If you didn’t have dopamine, it didn’t happen, or if you didn’t move as much it didn’t happen. So it was clearly a synergistic effect of being more active and having dopamine.”
Kang and Auinger also wanted to look at how long this benefit lasted in the absence of drug. But here the clinical trial data was insufficient — though the levodopa-treated patients went through a two-week “washout” period without the drug, the finger-tapping improvements diminished only slightly for either hand. The sustained performance supports the theory that the combination of exercise and dopamine is producing long-lasting changes in the brain, rather than a shorter, transient effect of merely replacing dopamine.
“It’s not saving cells from degenerating,” Kang said. “In a way, it may not be a disease modification but it could be a brain modification to compensate for the disease. What this study tells us is that there is a positive reason to start early, rather than thinking about delaying them for the negative reasons of having other complications. There’s a clear benefit of allowing your basal ganglia to rewire and improve your performance.”
However, some of the mouse data also add a cautionary possibility about adding exercise into a standard treatment plan for Parkinson’s. When the dopamine-deficient mice were trained on the treadmill in the absence of levodopa, their performance actually worsened more than if they hadn’t been trained at all, suggesting that exercise in the absence of dopamine promotes improper motor learning. But again, the decline in performance during the clinical trial’s washout period was too small for Kang and Auinger to test whether this phenomenon applies to humans as well. To bring out the best aspects of the dopamine/exercise synergy while avoiding any unintentionally detrimental effects, prospective trials examining the role of different tasks and drug/exercise combinations will be necessary.
“If you take mouse data and apply it to humans, it suggests that if you exercise without medicine, you could actually get worse than without exercise,” Kang said. “That’s kind of counter-intuitive and offers a cautionary note. We don’t have the clinical data to firmly say how you should exercise; whether you should exercise with medicine all the time, or if it is okay to exercise without medicine. That’s really a big question that has yet to be addressed.”
Kang UJ, Auinger P, & Parkinson Study Group ELLDOPA Investigators (2012). Activity enhances dopaminergic long-duration response in Parkinson disease. Neurology, 78 (15), 1146-9 PMID: 22459675