Timing may be key to understanding cognitive problems in Parkinson’s disease

When a cheetah chases a gazelle, it’s not raw speed that predicts the outcome of the contest. Instead, it’s the animal that times its movements better that has the advantage. That ability to consciously guide movements over a timeframe of a few seconds is a simple but universal skill in mammals. It also is an ability that is consistently impaired in patients with Parkinson’s disease (PD), and for University of Iowa neurologist Nandakumar Narayanan, that makes “timing” an ideal tool to study cognitive problems in PD.

PD is caused by loss of the brain-signaling chemical dopamine and affects about 1 million people in the United States. It is most commonly thought of as a disease that causes movement problems, but neurologists now know that PD can significantly affect patients’ thinking, or cognitive abilities, too.

Nandakumar Narayanan

“The cognitive problems associated with PD are very debilitating,” says Narayanan, assistant professor of neurology in the UI Carver College of Medicine. “They affect quality of life by causing loss of the ability to work, nursing home placement, falls, and increased health care costs. We have a lot of great treatments for the motor symptoms of Parkinson’s disease, but there is very little I can do to treat the cognitive symptoms, and that is very frustrating for me.”

Working in the lab and the clinic, Narayanan and his team record brain activity in mice and humans as they perform simple timing tasks. The scientists also use various genetic technologies to manipulate and study brain activity in the mice. These experiments help to reveal the neurocircuitry that controls timing ability, and explain how this simple cognitive process is disrupted by a lack of dopamine.

In a new study, published online Dec. 15 in the journal Current Biology, the researchers show for the first time that brain stimulation of specific neurons at a specific frequency can improve timing in mice that lack dopamine. The findings imply that, at least in theory, it might be possible to use brain stimulation to improve cognitive problems caused by PD—and possibly other cognitive disorders too.

The team studied 12 patients with PD and showed that their ability to judge a period of time (12 seconds) was much poorer than people without PD. Measurements of brain activity from the frontal cortex using electroencephalography (EEG) showed that PD patients were also missing a specific brain wave known as the delta wave, which cycles at a frequency of about one to four times per second (one to four Hertz), while they were performing the timing task.

As expected, mice that lacked dopamine in their frontal cortex also performed poorly on a timing task. However, the team was excited to discover that the animals were also missing the delta wave, suggesting that this specific, dopamine-dependent neural signal might be important for timing abilities.

In the frontal cortex, dopamine normally activates neurons with D1 dopamine receptors. The UI team, including Young-Cho Kim, first author on the study and a postdoctoral fellow in Narayanan’s lab, genetically altered the mice so that their D1 neurons could be artificially activated using pulses of light. When the researchers pulsed the light at the same frequency as the missing delta wave signal—two Hertz—the mice recovered their ability to perform the timing task.

“This was jaw-dropping,” Narayanan says. “For the first time we are able to deliver brain stimulation to improve a cognitive behavior.

“When we stimulated D1 neurons in normal mice, we did not improve their timing,” he adds. “But in mice that have cognitive (timing) impairment due to loss of dopamine, we can make those mice better. The results suggest that, theoretically, delivering targeted, selective, and specific brain stimulation might improve some of the cognitive aspects of losing dopamine in Parkinson’s disease.”

Brain stimulation is already used to treat some patients with PD, but the therapy targets specific areas of the brain that are important for motor control (not the frontal cortex) and only improves the movement problems of PD. The new findings suggest precise stimulation of specific neural networks in the cortex might also form the basis of new therapies that improve cognitive processes that depend on dopamine.

In addition to Narayanan and Kim, the team included Sang-Woo Han, Stephanie Alberico, Rafael Ruggiero, and Benjamin De Corte from the Department of Neurology at the UI Carver College of Medicine, and Kuan-Hua Chen at University of California Berkeley. Narayanan is a member of the UI Pappajohn Biomedical Institute and the Aging Mind and Brain Initiative at the UI.

The research was funded in part by grants from the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Brain and Behavior Foundation, and the Sao Paulo Research Foundation.