Scientists delve into Parkinson’s timing

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University of Iowa researchers show that timing deficits in Parkinson’s disease can potentially be restored through brain stimulation.

By Kasra Zarei

kasra-zarei@uiowa.edu

A study recently published by University of Iowa researchers reveals how brain stimulation can potentially be used to rescue timing deficits in Parkinson’s disease.

Parkinson’s disease is a condition commonly thought of as a movement disorder, but most individuals affected by Parkinson’s also develop cognitive deficits.

“About one-third of Parkinson’s patients have cognitive deficits at their first clinic visit, and 80 percent of patients will have cognitive complaints at some point in their disease course,” said UI neurology Assistant Professor Nandakumar Narayanan.

Some of the cognitive dysfunctions in Parkinson’s consist of deficits in awareness of time and tempo. For instance, people with Parkinson’s may exhibit difficulties in clapping hands steadily.

“Patients with Parkinson’s disease are quite diverse, but all patients have timing deficits,” Narayanan said. “Not only do they experience slowness in movement, but they make errors in estimating exactly when to move.”

Timing provides a valuable approach to study cognitive deficits in Parkinson’s through mapping the underlying neurocircuitry that becomes abnormal in the disorder.

“We believe we can use timing to map the circuitry of cognitive dysfunction in Parkinson’s disease and identify new treatments,” Narayanan said.

In a study published in Current Biology, Narayanan and his team collected measurements of brain activity, using electroencephalography, on patients with Parkinson’s while completing a timing task.

In humans, the timing task consists of pressing a button after they have estimated a three- or 12-second interval to have elapsed,” said Young-cho Kim, UI postdoctoral research scholar and lead author on the study.

The same approach was used on a mouse model of Parkinson’s — specifically, mice that lack dopamine in the frontal cortex. Dopamine is a chemical substance that normally propagates neural signals in the brain, but when it is deficient, results in Parkinson’s. The frontal cortex is the part of the brain that controls flexible behavior and cognitive processing.

The multifaceted study demonstrated that both Parkinson’s patients and the corresponding mouse model not only performed poorly on the timing task but also lacked a brain rhythm, called delta waves, when completing the task.

“The brain rhythms that we measure using EEG recordings are composed of different types of brain waves,” Kim said. “Delta waves are the 1 to 4 Hertz waves that we have now shown to be missing in Parkinson’s patients and mice that lack dopaminergic signaling to the cortex.”

Narayanan and his team believe that the delta waves are likely to be caused by dopamine-dependent signaling to the brain’s cortex. However, the key finding the team discovered was the frequency-specific rescue of timing behavior in mice.

“We used genetically altered mice with specific dopamine-dependent neurons that could be artificially activated with pulses of light,” Kim said. “When we stimulated these timing-impaired mice at the delta-wave frequency, we restored their performance on the timing task to normal.”

The unique finding of the study was that the rescue stimulation only worked at the delta wave frequency.

“Other researchers mainly use high frequency stimulation, but trying this in our study did not produce the same cognitive improvement we showed at the lower, delta-wave frequency,” Kim said.

Deep brain stimulation is already used to treat movement problems in Parkinson’s patients, but to date, it has not been used to provide precise, frequency-specific treatments or rectify the cognitive symptoms of Parkinson’s patients.

“Typically humans with Parkinson’s receive ‘high-frequency’ deep brain stimulation, in the 130 to 180 Hertz range,” said Jeremy Greenlee, a UI associate professor of neurosurgery. “It is tailored by the programming neurologist to best improve motor function and minimize any potential stimulation-related side effects.”

For Greenlee, the results of Narayanan’s study are exciting in the field of deep-brain stimulation in providing new, specific treatments that target neurocircuits of the cortex in Parkinson’s patients.

“It is exciting to see possible ways of improving cognitive function, as many Parkinson’s patients have impaired cognitive function due to the disease,” Greenlee said.

The work of Narayanan, Kim, and colleagues provides a foundation for future research and clinical applications to rectify abnormal cognitive processes, including timing deficits, in Parkinson’s and potentially other cognitive disorders including schizophrenia.

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