Video: Shining a light on Parkinson's disease and dementia

Hear from experts funded by generous donors to the Auckland Medical Research Foundation who talk about the latest advancements in brain research and where neuroscience is headed in the future.

Summary transcript from Dr Peter Freestone

I really love the research that I do and I'm delighted to be able to share some of it with you. This may get a little bit sci-fi, maybe a little bit like an episode of Black Mirror, but ultimately the goal is to understand Parkinson's disease and work towards better treatments for the disease.

As we all know, many people suffer from Parkinson's disease. Most recently, the guy from The Chase has been diagnosed with Parkinson's disease. I've deliberately left a space there empty because chances are you probably know someone with Parkinson's disease or you experience it yourself. It affects about 10,000 New Zealanders, so it's not something that is incredibly rare. In fact, it's common and families are coping with it all the time.

Parkinson's disease was first described in 1817 by James Parkinson and is described as the saddest disease. It typically affects people about 1 to 2 percent of the population over 60. This is the normal or idiopathic form of the disease that arises for no known reason. There is also a genetic form of Parkinson's disease, familial or generational Parkinson's disease, that affects a small population and tends to affect people earlier, in their 30s or 40s. Michael J. Fox has experienced Parkinson's disease from a very young age.

The three main symptoms of Parkinson's disease are tremor or shaking at rest, slowness of movement (bradykinesia), and rigidity. There is also an associated stooped posture. These primary symptoms of Parkinson's disease are described as affecting the motor system, but there are also other effects of the disease, such as loss of sense of smell, etc.

We already know quite a lot about what is happening within the brain. Parkinson's disease is a neurodegenerative disorder that affects the brain. There is actually a part of the brain that is dying off.

There is an area of the brain located in the midbrain region called the substantia pars compacta (the black substantial nigra). In normal individuals, these cells produce dopamine, a chemical neurotransmitter that is essential for reward, learning, and normal movement behaviours. However, in Parkinson's disease, the dopamine-producing neurons in this region die off, causing an imbalance in the direct and indirect pathways in the brain.

This leads to the rigidity and slowness of movement seen in Parkinson's disease. There are two main treatment strategies for Parkinson's disease: L-Dopa and subthalamic nucleus stimulation. L-Dopa is a commonly prescribed drug that serves as a precursor to dopamine, but its effectiveness decreases over time and can lead to complications.

On the other hand, subthalamic nucleus stimulation involves the implantation of electrodes that deliver an electrical pulse continuously, bringing back the balance in the pathways and allowing for normal motor function. This treatment has been around for over 30-40 years and has been highly effective in treating Parkinson's disease.

Surprisingly, the mechanisms behind deep brain stimulation are still not well understood, but it works. A man named Andrew Johnson in New Zealand posted a video on YouTube showcasing his experience with deep brain stimulation. In the video, he demonstrates the effects of the stimulation by turning it on and off using a remote control. When the stimulation is on, his tremors decrease and he experiences less discomfort. However, when the stimulation is turned off, his tremors increase.

So you can see that it’s a really transformative therapy. I’m not a medically trained doctor, so not able to comment on all the nuances of deep brain stimulation that neurologists can.

So I’m interested in the subthalamic nucleus, which is the target for deep brain stimulation in Parkinson's disease. However, there are many unknown aspects of this nucleus, such as how it regulates dopamine release and its involvement in cannabinoid modulation. I’m also interested in understanding how brain cells communicate with each other in the subthalamic nucleus.

The complexity of the human brain presents a challenge to neuroscientists. The human brain has 86 billion brain cells and around ten trillion synapses, making it a complex network of neurons. The renowned neuroscientist Ramon y Cajal tried to capture this complexity in his drawings of individual brain cells back in 1888. The problem with studying the brain is its overwhelming complexity, with different shapes of neurons and different cell types densely packed together.

Francis Crick, one of the discoverers of the structure of DNA, predicted that light would be the perfect tool for studying the brain. The solution to the complexity of the brain lies in light, as was discovered with single-cell algae that can move towards light to photosynthesize. In the early 2000s, it was discovered that a molecule called channelrhodopsin could be used to control brain cell activity by shining light on it. This discovery has sparked a new field of optogenetics, which combines light and genetics to control the activity of brain cells.

So, if we come back to our complex challenge, the brain being densely packed with all sorts of brain cells, what we can do now is through blue light. We can shine it at the brain and activate just the particular cell type that we're interested in. It's important because it helps us to dissect pathways and work out behaviours that are associated with those pathways. There has been huge progress in understanding using this approach. Also, you can actually focus the light very well and make a pinpoint of light (photo stimulation) to activate just one single brain cell. Then, you can observe how it is connected and what its function is.

We can use this approach to dissect micro-circuits and work out how brain cells are communicating with each other. I should acknowledge the Auckland Medical Research Foundation at this point, because they saw the potential a few years ago and were keen on developing and establishing this approach here at the University of Auckland. They provided funding for me to learn this technique from a world leader in Singapore, and buy the equipment required to establish it here. The project has been going very well.

The question that we're asking is: "How do these cells communicate?" We play battleships of course, but when you play battleships, you fire torpedoes and try to sink your opponent's ships. In this case, we fire a torpedo to a location, hoping for a hit. What I do is I record from a brain cell and shine light at a particular location. If there's a cell there, then I get a hit, and if there isn't, I get a miss. I can work out where all the cells are and how they communicate to me. There's a lot of hardware to do this, but essentially we have a slice of brain tissue and then stimulate it. We shine light at all these different locations and all the animation you're going to see in my presentation is complicated, but hopefully, it will just show you how we can build up a map of the micro-circuitry within the sub-thalamic nucleus.

Here, we're shining light at a brain slice. This is the response that we're looking for and this is the amplitude of that response. We then do some processing and decide if there is a good connection. Eventually, we build up a diagram which shows how those cells are connected. This isn't in real-time, it's actually at two times speed, but regardless, this is a very fast approach, and we can do this with relative ease now that it's all going. You can see the light jumping around different locations, recording responses, building up maps of connections, and eventually, that allows us to draw a diagram of what that micro-circuit looks like. Then, we interrogate it to find out how those cells communicate in more detail.

This is where my master's student comes in, Si Yin Lui. She just submitted her bound thesis to me yesterday. This is just some of the highlights of the work that she's done in understanding what's in this sub-thalamic nucleus. We've already made some progress in trying to work out how these cells are communicating.

Next, we'll look at how the situation changes in Parkinson's disease and what has changed in the Sun Network. Lastly, I'd like to present a small aspect of my research where we're using light therapy for Parkinson's disease. Can we take optogenetics into the clinic? Currently, electrical stimulation for deep brain stimulation is very effective, but could it be replaced with light? There are a few benefits to this change. Firstly, light is more efficient than electrical stimulation, so the battery doesn't need to be changed as often. Secondly, by using light, we can better understand the mechanism and produce a more specific response.

We have developed a new version of the device that is implantable and compatible with rodents. It's already helping us understand the subthalamic nucleus in more detail. This new version is much smaller and we're hoping to implant it in humans in collaboration with bioengineers who have years of experience putting things inside bodies.

An optogenetics device

I'd like to acknowledge the funders, AMRF, and the Davis & Carr Senior Fellowship, as well as Katherine, a PhD student whose work I didn't present today, but is also looking at the subthalamic nucleus and treatments for Parkinson's disease.

My research work is collaborative, and I confer with other researchers internationally. For example, Katherine presented her work at an international conference in Berlin last year, which was attended by many international investigators who were interested in her findings. This leads to new ideas, questions, and refinements in the methodology.