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Selecting the Best Target for Deep Brain Stimulation in Parkinson’s Disease

Stimulating excitatory neurons in the caudal pedunculopontine nucleus of the brain improved the walking abilities of mice that showed Parkinson’s Disease symptoms.

In 2016, there were 6.1 million Parkinson’s Disease (PD) patients globally. With the rising prevalence of PD, studies predict that the burden of PD would grow substantially in the future decades. By 2030, it is estimated that there would be 4.94 million patients in China alone. PD is a neurodegenerative disease characterised by the progressive death of dopaminergic neurons in the brainstem. Bradykinesia or slowness, rigidity, resting tremors, and walking difficulties are among the recognisable motor symptoms of PD. Over time, patients may experience such great trouble walking that they often freeze on the spot and fall, rendering many of these patients housebound.

As treatment, patients are prescribed certain medications to relieve their motor symptoms. In some cases, doctors may recommend Deep Brain Stimulation (DBS), where surgeons place a thin metal wire in the brain that can be used to send electrical pulses. However, although DBS is effective in treating tremors, it cannot completely alleviate the walking difficulties and freezing. Now, scientists at the University of Copenhagen have demonstrated that treating walking problems in PD using DBS may be improved by targeting specific neurons in the brainstem of mice.

Previous animal studies of motor circuits, which regulate planning, control, and execution of voluntary movements, have led scientists to hypothesise that freezing of walking in PD could be reduced. To achieve this, surgeons would need to apply DBS to stimulate neurons in the pedunculopontine nucleus (PPN), which is located in the brainstem, of patients. PPN was believed to send signals from the brain to the spinal cord to initiate body movements.

“We believe that clinical trials with brainstem DBS are the right strategy to facilitate patients to walk properly again. But the variable clinical results occur, because DBS would require higher precision to target the particular group of neurons in the caudal PPN. It is a very delicate area, because if we were to stimulate excitatory neurons in other areas than the caudal PPN, it would cause complete immobilisation instead,” said corresponding author Professor Ole Kiehn at the Department of Neuroscience.

However, Prof. Ole Kiehn further explained that the initial results from clinical trials with DBS of the PPN had very variable effect on movement recovery, particularly in patients who experience freezing of walking. Therefore, the optimal location for stimulation within the brainstem has remained uncertain. Fortunately, their novel study has brought new knowledge to the table regarding the best area for DBS to help alleviate this symptom.

In a prior study, the researchers showed that stimulation of so-called excitatory neurons in the PPN could initiate locomotion in normal mice. This suggests that these nerve cells could indeed be used to treat movement symptoms in mice with features of PD.

“We use[d] a technology to target [a] specific group of cells in the PPN in order to close in on what areas are the best to stimulate if we want to alleviate these particular symptoms. The result shows that the motor improvement is optimal if we stimulate what we call excitatory neurons in the caudal area of the PPN,” explained Ole Kiehn.

“When we stimulated these specific neurons in the caudal area of the PPN, the animals were able to walk normally, across longer distances and with normal walking speed, as opposed to before the stimulation, where they would display symptoms of Parkinson’s Disease,” said Postdoc Debora Masini, first author of the study. “We systematically compared stimulation of different locations and cell types in a series of complementary experiments. And they all pointed towards the same conclusion. It strongly indicates these excitatory neurons in the caudal PPN are an ideal target for recovery of movement loss.”

The researchers are excited about the potential implications of their findings and hope that the new study could aid clinicians in choosing the exact location for DBS in the brainstem.

“The mice in our study only partially represent the complexity of this disease, but the results have been very telling. Nearly everything we have learned in the beginning on how to treat Parkinson’s Disease comes from animal models, including the medication we use nowadays for patients. In this sense, it is a valid approach, and we hope our study can help provide better treatment for human patients,” said Masini. [APBN]

Source: Masini, D., Kiehn, O. (2022). Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism. Nature Communications, 13, 504.