How does Parkinson’s disease cause motor problems?

Disease and treatment 7. mar 2021 4 min Professor and Head Hartwig Siebner Written by Kristian Sjøgren

New Danish research is shedding light on how Parkinson’s disease causes problems in the brain. The results can be used to stimulate the brain more precisely to alleviate symptoms.

Parkinson’s disease is a disabling neurodegenerative disorder that severely impairs movement.

Over the years, research groups in many countries have tried to determine what exactly happens in the brains of people with Parkinson’s disease, but the results have been conflicting.

Danish researchers tried to rectify this through a meta-analysis that revisited many previous studies.

The meta-analysis elucidates brain regions that have abnormal motor-related activity and what exactly happens when people develop Parkinson’s diseases. The results also provide more information on potential treatment to alleviate symptoms and hint at why some people with Parkinson’s might develop side-effects, such as involuntary movements, when they take medication.

“The interesting thing about Parkinson’s disease is that brain cells die in one region of the brain, such as the substantia nigra, and the symptoms arise in another brain region, such as the motor network. We have learned a lot more about the region in which Parkinson’s disease emerges,” explains the lead researcher, Hartwig Siebner, Clinical Professor, Department of Clinical Medicine, University of Copenhagen and Head of the Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Denmark.

The results have been published in Movement Disorders.

The brain’s motor areas do not function optimally in Parkinson’s

Parkinson’s disease results from lack of communication between brain regions, especially regions that control our movements.

Normal communication in the motor network is facilitated by the substantia nigra, which sends dopamine towards the striatum. The striatum consists of nerve cells in the depth of the cerebral hemispheres and receives input from the cerebral cortex. Together with other brain structures, the cortex and striatum form a functional loop in which the cortical signals are filtered: relevant signals are amplified and sent back to the cortex while irrelevant signals are suppressed. This reinforcement critically depends on the dopamine signal from the substantia nigra to the striatum, making the dopamine signal a reinforcement and invigoration signal that provides drive to our actions. For example, a dopamine signal in the motor network helps you when you scroll down to read more of this article.

People with Parkinson’s disease, however, have an impaired dopamine signal, and this launches a negative loop in which the various regions of the brain do not obtain the activity required to make the movements quickly and purposefully.

“In Parkinson’s disease, the dopamine signal generated in the substantia nigra is much weaker. This results in a dysfunction of the motor network, and movements become slower and more cumbersome,” says Hartwig Siebner.

Collected data on 571 people

Researchers can use functional magnetic resonance imaging (MRI) or other advanced neuroimaging techniques to further characterize the dysfunctional motor networks in the brain.

To better understand the neural underpinning of this motor impairment, researchers can use these neuroimaging techniques while people with Parkinson’s disease perform a motor task, such as moving their fingers in a certain way. This enables researchers to determine which brain regions are active, underactive and overactive.

Hartwig Siebner and colleagues quantitatively meta-analysed 39 neuroimaging studies involving 571 individuals with Parkinson’s disease carried out by researchers in many countries.

“These studies have produced different results over the past 30 years, but the overall pattern looks consistent. We merged the results of these studies. This enabled us to use a very large data set, including several hundred patients, to determine which brain regions are active when they performed motor tasks,” explains Hartwig Siebner.

Insufficient dopamine for brain regions to communicate

The meta-analysis shows that Parkinson’s results in underactivity in the motor part of the striatum. According to Hartwig Siebner, this is because there is insufficient dopamine to activate it.

“Insufficient dopamine signalling from the substantia nigra to the striatum reduces the engagement of the motor striatum when people generate a movement,” says Hartwig Siebner.

This underactivity of the motor striatum was paralleled by a weaker activation of motor areas in the cortex during movements, while other cortical areas were overactivated.

Hartwig Siebner says that the underactivated regions are known to generate and execute movements, whereas the overactivated regions are more associated with cognitive aspects of movement control, monitoring the execution of movements.

Downregulation of executive activity in the motor area of the cerebral cortex makes good sense, because the substantia nigra and striatum are less active and fail to reinforce brain activity related to movement. The upregulation of cognitive monitoring areas most likely reflects an effort to compensate for the dopamine deficit and to maintain enough motor drive, but this requires further study.

“When the motor area of the brain becomes less active, the brain compensates by engaging cortical regions that control our movements based on information provided by our eyes and other senses. When someone drives a car, they need to both steer and keep looking at the road. If turning the steering wheel becomes more difficult, the driver automatically focuses more closely on the wheel and the road, and this leads to more sensory activity in areas of the brain that can use this sensory information to adjust our movements,” explains Hartwig Siebner.

Two systems active in the brain in Parkinson’s

According to Hartwig Siebner, this discovery has practical implications because it may help to explain some of the side-effects of treatment among people with Parkinson’s.

For example, some people taking dopamine for Parkinson’s experience motor impairment, such as abnormal involuntary movements, which often occur in advanced Parkinson’s disease as a side-effect of dopamine therapy.

“Our results indicate that this may result from dopamine treatment excessively stimulating the already overactive areas in the cerebral cortex,” says Hartwig Siebner.

Improving treatment

Hartwig Siebner treats people with Parkinson’s with combined advanced magnetic resonance imaging (MRI) of the brain and transcranial stimulation techniques. The study results indicate that therapists should be very careful about transcranial stimulation.

“This requires a more tailored approach to individuals to ensure that the brain regions that are already very active are not stimulated excessively,” explains Hartwig Siebner.

This is precisely what Hartwig Siebner is investigating further in a major research project to improve treatment for people with Parkinson’s disease.

“The research results are very relevant, because they provide a goal and a network to target with brain stimulation. We need to know which areas to stimulate, and we now know this. I am very excited about these results and look forward to determining whether we can translate this into improving treatment,” concludes Hartwig Siebner.

Brain motor network changes in Parkinson’s disease: evidence from meta-analytic modeling” has been published in Movement Disorders. In 2016, the Novo Nordisk Foundation awarded a grant to Hartwig Siebner for the project Unravelling Altered Dopaminergic Network Dynamics in the Midbrain and Striatum in Parkinson’s Disease with Ultra-high-field MRI.

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