MICA: How does the pedunculopone nucleus influence treatment responses in Parkinson's disease, and can it be targeted for new treatment strategies

Parkinson's disease (PD) is the second most common neurodegenerative disorder (second only to Alzheimer's disease). It is characterized by a progressive loss of motor ability over time. Partly due to the world's ageing population, PD is now one of the leading causes of disability worldwide.

We know that PD is associated with a loss of dopamine cells in the brain. Treatment with dopamine replacement medications is highly effective in the early stages of the disease. Unfortunately however, over time, people become resistant to this medication, and develop new motor symptoms as a result. The symptoms that are particularly resistant to dopamine medications include balance impairment, and changes to the way people walk. As these complications progress, they impair quality of life, and eventually lead to falls and a loss of independence.

We know that a small region of the brainstem, called the pedunculopontine nucleus (PPN), is involved in the control of balance and walking. We also know, primarily from work in animals, that the PPN can influence dopamine levels in the brain regions from which dopamine is lost in PD. However, we understand very little about the PPN and how it is connected with the rest of the brain in humans. As a result, therapies that have been developed to target the PPN have so far failed to meet our clinical expectations for improving balance and walking impairments.

There are two recent technological advances that will help us to address this problem.

First, new advances in how we image the brain have recently made it possible to examine the structure of the brain in more detail. Our study will apply these advances to investigate how the PPN might be targeted for new treatment strategies in PD.

Second, we will take advantage of a new development in deep brain stimulation technology. Deep brain stimulation is a treatment for PD that applies electrical stimulation to the regions of brain that become disrupted by the disease. This is a highly effective treatment, but it does not work for everyone, and is extremely costly and invasive. When the deep brain stimulation electrodes are implanted in the brain however, researchers can record from the electrodes to understand more about how PD effects the brain. This approach has lead to the understanding that activity in the brain regions targeted by deep brain stimulation is aberrant in PD, and that this activity can be 'normalised' by dopamine medication.

Until very recently these recordings could only be made around the time of the brain surgery, when people are generally immobile and fatigued. Now however, it is possible to record from the electrodes wirelessly, meaning people can fully recover from the surgery before taking part in research. As a result, we can now ask people to carry out some of the motor tasks that we know depend on the PPN, and record brain activity at the same time.

By combining the information we can get about the brain from these two technologies when people are on and off their dopamine medications, we have the opportunity to examine how the PPN modifies how the brain uses dopamine to perform motor functions in the human for the first time. We can also examine how the PPN might participate in treatment responses to both dopamine replacement and deep brain stimulation.

These findings will guide the development of new therapies that can target the PPN, and will enable us to personalise current treatment approaches to improve their effectiveness

Loss of dopamine neurons in the substantia nigra (SN) is a hallmark of Parkinson's disease (PD). A solid body of literature in animals has established that the pedunculopontine nucleus (PPN) can modify dopamine signalling in this region. Very recently it was revealed that stimulating the PPN can restore dopamine and motor function in Parkinson's rats. These findings implicate the PPN as a target for new therapy, or for improving the current dopamine-replacement treatment approaches. However, we understand very little about how the PPN influences dopamine in the human, limiting our ability to target it effectively.

To address this, we will take advantage of two recent advances in neuroimaging and deep brain stimulation (DBS) technology to identify the PPN's role in dopamine signalling in the human for the first time:

- We have developed an advanced neuroimaging pipeline that can index the structural integrity of the PPN and its connections with the basal ganglia, including the PPN-SN pathway. Importantly, we have demonstrated the relevance of these structural metrics for PD-related degeneration.

- DBS technology now allows wireless recording directly from the basal ganglia in humans. This means we can examine how activity in this region changes following dopamine replacement during mobile performance of the motor skills that are most relevant for PD.

Thus, we will perform imaging of the PPN and its connectivity in people with PD who are scheduled to receive DBS. Following surgery, basal ganglia activity will be recorded while participants are on and off dopamine replacement during motor learning and mobile motor tasks.

Whether PPN structure and connectivity influences dopamine-induced activity in the basal ganglia, and how this influence contributes to PD symptoms will be investigated. This will lead to new opportunities to translate our findings into new pharmacological strategies to exploit the PPN's influence over basal ganglia dopamine.