New knowledge on treating walking problems in Parkinson’s

Disease and treatment 5. apr 2022 2 min Professor Ole Kiehn Written by Morten Busch

Stimulating an area in the midbrain can start locomotion. Unfortunately, attempts to treat people with Parkinson’s disease for walking problems through electrical deep brain stimulation have had varying success. However, a new study in mice now indicates that precise stimulation targeting one area of the brainstem may improve locomotion considerably. The researchers suggest that the results may lead to new attempts to use deep brain stimulation to improve how people with Parkinson’s disease walk.

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Mobility through being able to walk is crucial to most people’s quality of life. The brain’s dopamine-producing neurons gradually die among people with Parkinson’s, leading to such symptoms as uncontrollable tremors. Additionally, nearly one quarter of people with Parkinson’s have so much difficulty walking that they end up with a freezing gait and falling. This has been difficult to treat.

“Electrical deep brain stimulation has been relatively effective in treating people with tremors, but it has had variable effectiveness in restoring the ability to walk. Our recent results show that the lack of consistent results probably results from the fact that the stimulation must target a very specific area of the brain’s locomotor command area, the pedunculopontine nucleus. We therefore believe that clinical experiments targeting this might be the right strategy to help people walk properly again,” explains Ole Kiehn, Professor, Department of Neuroscience, University of Copenhagen and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Stopped walking almost immediately

The background for the new study was the previous groundbreaking results from a Danish-Swedish research group published in Nature in 2018. They found two areas in the midbrain that set locomotor speed and gait selection: the pedunculopontine nucleus, which is crucial in initiating slow and exploratory walking and the cunieform nucleus, involved in initiating high-speed running. The results led them to test the possibility of alleviating gait disorders in Parkinson’s disease by specifically stimulating these areas.

“Parkinson’s affects people’s dopamine-producing cells and thus the function of the neurons in the basal ganglia, which forward the signals to the pedunculopontine nucleus. We therefore thought we could improve the gait disorders among people with Parkinson’s if we could specifically activate the pedunculopontine nucleus neurons by using targeted deep brain stimulation,” says Ole Kiehn.

In the new experiment in mice, the researchers blocked dopamine transmission with drugs. They then used chemo- and optogenetic approaches in which specific cells are turned on and off using chemical substances or light to determine how activating these cells in different brain regions affected the cells.

“The results show that the optimal way to improve locomotion is to stimulate neurons in the caudal pedunculopontine nucleus region, the region of the pedunculopontine nucleus that is closest to the spinal cord. Signals are sent from the pedunculopontine nucleus region to the lower brainstem and then to the spinal cord, where they trigger locomotion. The remarkable thing is that stimulating the neurons at the opposite end of the pedunculopontine nucleus had the opposite effect. The animals stop walking almost immediately,” explains first author Debora Masini, Postdoctoral Fellow, Department of Neuroscience, University of Copenhagen.

Reasons for optimism

The neurons that are activated to stimulate locomotion have to be in a specific area of the pedunculopontine nucleus – the caudal area – but excitatory neurons must also be activated. Excitatory neurons trigger action potential through an impulse in the neurons to which they send signals. Restoring the impulse can apparently make the animals walk normally again.

The nerve cells that produce dopamine gradually die among people with Parkinson’s disease. Treatment previously depended on drugs that can compensate for the lack of dopamine. In deep brain stimulation, however, the surgeon implants tiny electrodes in the brain to electrically stimulate various regions.

Deep brain stimulation is already being used to treat motor dysfunction among people with Parkinson’s but has worked best to alleviate tremors.

“So far, the results from clinical trials of the pedunculopontine nucleus have had quite varying effects, especially in unlocking freezing gait. There have therefore been discussions as to where in the brainstem to optimally target stimulation,” says Debora Masini.

The new experiments indicate that brainstem stimulation requires targeting specific pedunculopontine nucleus neurons to improve gait and thus restore the ability to walk.

“Our results suggest that deep brain stimulation may help people with Parkinson’s to fully or partly regain mobility. The trials were carried out in mice, so clinical testing with people is needed. However, almost everything we have learned about how to treat people with Parkinson’s originated from animal models, including the drugs we use today. There are therefore reasons for optimism,” concludes Ole Kiehn.

Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism” has been published in Nature Communications. The Novo Nordisk Foundation awarded the main author, Ole Kiehn, a Laureate Research Grant in 2016 for the project Functional Organization of Large-scale Integrated Neuronal Networks Controlling Locomotion in Mammals and Mechanisms for Development of Impaired Motor Function in the Diseased Brain. The research has also been supported by the European Research Council Horizon 2020 research and innovation programme grant and by the Lundbeck Foundation. Ole Kiehn recently shared the 2022 Brain Prize with Silvia Arber and Martyn Goulding for revolutionising understanding of the neuronal cell types and circuits underlying movement.

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