Podcast

When will we be able to cure Parkinson’s disease?

Intro: The reason the brain is so difficult and so fascinating to study is because when you change one little thing, huge amounts of things change. So, the brain is highly homeostatic, the fancy word a biologist would use to say that when you change something, there are lots of mechanisms to adapt and compensate for that change. AskDifferent, the podcast by the Einstein Foundation. 

Marie Röder: Welcome to the podcast. My name is Marie Röder, and I'm your host today. Slowness in movement, a tremor, or stiffness and inflexibility. Those are some of the symptoms that people with Parkinson's disease can experience. With our aging society, Parkinson's disease is becoming more and more common. Millions of people worldwide are affected. Parkinson's disease is a multifaceted condition that demands innovative treatment approaches, which is why I'm happy to have Prof Dr Andrew Sharott here with me in the studio whose area of research is exactly that: the treatment of Parkinson's with so called deep brain stimulation. Andrew Sharott is a professor at the University of Oxford and an Einstein-Berlin University Alliance Oxford-visiting fellow. Welcome, Mr. Sharott. 

Andrew Sharott: Thanks, Marie. It's great to be here. 

Röder: Mr. Sharott, today we want to understand what your research is all about and whether and when Parkinson's disease may be curable one day. But first, before we dive into all of that, can you give us some background on Parkinson's disease? What happens in the brain that causes those typical symptoms that I just talked about?

Sharott: So, as you said, Parkinson's disease is, you know, quite a common disorder, particularly in the older age groups plus 60. And so, the disease is quite a slow, ongoing process over a long period of time. So, before somebody notices they've got the symptoms of Parkinson's disease, there's already a degenerative process where neurons, so that's the cells in the brain that process and carry information, in various different parts of the older parts of the brain start to degenerate. And so, there are some symptoms while this is occurring.

So particularly the neurons in the areas of the brain which deal with smell are some of the first to degenerate. And one of the things that can happen is people start to lose their sense of smell, but, of course, they don't put it down to the disease necessarily. But then when people typically notice that something might be wrong is when the disease reaches a small group of neurons in a brain structure called the substantia nigra, which are particularly vulnerable to the disease process. And then what happens is once you lose around 80% of these neurons, the person will start to notice that they're having trouble moving, they're having trouble initiating movement, that their movement is slower, or in some cases that they develop the classic tremor, which most people will have seen. 

I guess what you're also asking is then what happens when this small group of neurons die. Well, these neurons are quite special. They release a neurotransmitter called dopamine. So, a neurotransmitter is something released by a neuron to other neurons which changes the way that those neurons carry their messages. And the loss of these neurons basically changes the activity across large, large areas of the brain, and that is what ultimately leads to the disease. 

Röder: So, if I could sum this up, Parkinson's disease causes a degeneration of the neurons that transmit dopamine. And dopamine is what helps our bodies move smoothly. 

Sharott: Well, that in itself is a complicated question. What do these neurons do? They certainly regulate those processes, except the motivation to move and how fast we move. And they play a particular role in this larger network of brain activities called the basal ganglia, which was really my, you know, area of expertise that I've spent my career studying. What you get when you lose this small group of neurons that release dopamine into a key bit of the basal ganglia called the striatum is really huge changes in the way that this network of neurons works. The reason the brain is so difficult and so fascinating to study is because when you change one little thing, huge amounts of things change. So, the brain is highly homeostatic, the fancy word a biologist would use to say that when you change something, there are lots of mechanisms to adapt and compensate for that change. 

And so, when you move this crucial group of neurons, the network tries to adapt and compensate. Another one of the reasons that it takes so long for people to realize they have the disease is that the brain is very clever and it compensates, carries on working as well as it can, and then it reaches a critical period. And then these brain areas are no longer able to do their job properly. 

Röder: Let me ask you, what was it that sparked your interest in the study of Parkinson's and deep brain stimulation in the first place? 

Sharott: I actually came to Parkinson's from a kind of tangent. So, what I was really interested in was two things. One was this network of brain areas called the basal ganglia, which I was just describing in the context of Parkinson's, but in the context of the healthy brain, the basal ganglia are crucial for both controlling movement and for learning which behaviors lead to good things and bad things, so rewards and punishments. And then on top of that, my other main interest was how the brain has these large electrical activities what we would call oscillations, but you might call brainwaves. So, if you've ever seen somebody with an EEG recording, so when we put electrodes on the top of the head and you can see the electrical activity that's happening under the skull. And one of the things that fascinated me was: what is it that these activities do? And when I started my PhD, there was a lot of controversy about whether they do anything, whether they're crucially important for organizing brain activity, and there was every opinion in between. 

Röder: So now let's look at the possible treatment, which one of them is deep brain stimulation, so called DBS. Can you give us a very brief overlook of what DBS is? 

Sharott: The key method in DBS is that electrodes are implanted deep into the brain, and they are connected to a pacemaker-like device, a stimulator, which is implanted in the patient's chest, and that stimulator then delivers pulses at very high frequency, so 100 of times a second to that deep brain structure. 

Röder: How does this help a patient that suffers from Parkinson's disease?

Sharott: Well, that is a very big question in my field, so I can tell you some of the ways we think it helps. So what it might do is it might decrease the neuronal activity at the stimulation site. So almost act like a lesion of the structure or destroying the structure without actually doing so. The other thing that it might do is I've been talking about these large oscillations that are associated with Parkinson's disease. By putting in these high frequency pulses, we might break those up and return the brain to its normal function. Or, indeed, there might be a pacemaker-like function where actually these high-frequency pulses help that structure and targets around it to function normally by putting in the high frequency itself. And it might be that all of these things play a role in some way. But in some way, that in the Parkinsonian brain, what DBS does is it help those brain areas to function normally again. 

Röder: And what role does AI play in the technology of DBS? 

Sharott: Well, perhaps I could go back one step to the concept of closed-loop DBS, which is one of my own main interests. So, the standard practice of DBS involves, as I said, you attach the electrodes in the brain to this pacemaker-like device, and you deliver high-frequency pulses at a 130 times a second, and it works remarkably well. It's been used to treat 100 of thousands of people. And at its best, it's completely transformative. However, what people started to ask in the last kind of 5 or 10 years is, well, can you do this better? And so, this is where we go back to this idea that you have these big oscillations or brainwaves that you can detect, which tell you when they're present, when they're really big, that the disease symptoms are strong or that the brain is in its diseased state.

The idea of closed loop stimulation in this context is that if you can record the strength of those big brainwaves in real time, you could use them to just deliver stimulation at those times. So, you can basically use electrical circuits in the device to detect when those oscillations are strong in real time and use that just to switch on the stimulation and then switch it off when they go down again. So, the idea of this is that you have a more precise intervention where you're only stimulating when you need to and that you're gonna have less side effects. So that kind of closed-loop stimulation is already being done and carried out in clinical trials, particularly in some groups in California and has shown promising early results. But what those systems use at the moment is a kind of relatively sim simple engineering approach, a bit like a thermostat in your house. Like, when it's too hot, make it cooler. If it's too cold, make it hotter. It's a bit like that. So, it's like a kind of fundamental engineering kind of control loop. And so where a lot of people are interested in AI is that you could do much more potentially complicated control where you can really take electrophysiological activity for the brain, those electrical signals, put them into an artificial network, and say, tell me how to reduce this signal based on the input and based on the stimulation that we are going to give. And so this is quite a long way off at the moment. There are lots of people that are interested in it but it is a very exciting potential path forward to use these developments in AI, things like reinforcement learning, to have a more automated way of working out how to pair the recordings of electrophysiological signals with the stimulation pattern in in the way that reduces disease symptoms with the least side effects.

Röder: And how does DBS compare to other treatments of Parkinson's disease, like just medication? 

Sharott: It's a very important relationship between medication and DBS. So, another really important part of Parkinson's disease was the discovery of a drug called L Dopa. So, L Dopa takes a completely different effect of therapy. It is basically allowing the remaining dopamine neurons to release more dopamine. So, it's replacing the lost dopamine in the striatum. And so, this is an absolutely crucial first treatment in Parkinson's disease. So, when someone is diagnosed with the disease, the first thing that they will do is work out the first thing that will they will do is work out drugs to put them on which either replace the lost dopamine or they stimulate the dopamine receptors on neurons. So, where that dopamine would act, they activate those receptors.

And how effective this is, varies from patient to patient. So, for some patients, they'll have quite really quite good quality of life on these drugs for 5 to 10 years. Others, they'll work well for less time. And the reason that they start not to work so well is that you get what's called drug related fluctuations. So, essentially, you start to get side effects where the patient has uncontrollable movements, which we call dyskinesia.

And what happens is over time, the dose of the drug, which relieves their movement symptoms, so helps them move, as compared to causes these dyskinetic symptoms get smaller and smaller, and they fluctuate quickly between not being able to move and moving too much. And actually, this is often the point at which DBS is used because DBS is independent of this process, and so it allows much less medication to be used and the patient to going back to having a higher quality of life. 

Röder: So, patients should consider getting DBS treatment when they're when they feel the medication just isn't enough for to treat their symptoms anymore? 

Sharott: Exactly. So, this is the decision a urologist might make if they have you know, DBS is a is a complicated expensive process. You have to have neurosurgery. You have to have a big team. It costs money for the device. So, unfortunately, it's not available to every patient. But if it's an option for that neurologist, they might say, okay, the drugs aren't working well enough, I recommend that we do this. And, of course, you know, this is a big decision for the patient because they are then undergoing neurosurgery where they're having something put into their brain. And not all patients will want to do this, but many do. 

Röder: And what improvements do patients experience once they did have DBS treatment?

Sharott: he yeah. Their main improvements will be in their ability to initiate movement and to move at a more normal speed. So, the two main symptoms of Parkinson's disease are akinesia, not being able to move, and bradykinesia, moving too slowly. And so, DBS in the subthalamic nucleus is really good at addressing these two symptoms. The third main symptom is tremor, and sometimes for tremor, a different part of the brain called the thalamus is implanted.

And so, one of the remarkable things about DBS is that the relief of these symptoms is immediate. So, in fact, when the DBS operation happens, a lot of groups - I mean, one of the remarkable things about the operation is that often the patients are awake while they're having the electrodes implanted either through the operation or they have anesthesia, and then that anesthesia is allowed to go and they wake up. And so why would you do this, you know, while somebody is having electrodes put into their brain? Well, the main reason is you can then turn the electric current on, and you can see there in the operating room whether they start to move more easily, whether their tremor stops, and that can tell you whether you're in the right place. 

Röder: What are challenges associated with DBS?

Sharott: I think for DBS, we have multiple challenges, and one of those challenges is to make it cheaper and more accessible for more people because we do know that it works. And so one of the big challenges is to make the technology cheaper to make surgery more efficient and to be able to offer this to more people. And then, obviously, we're always trying to make it better, better at treating the symptoms, better at not causing side effects, and this is where these kind of ideas of closed loop stimulation where you use the brain activity might really be able to help. I mean, I think another important thing to say is there's another massive branch of Parkinson's research, which is really aimed at a more curative approach. 

Röder: I wanted to get to that. Do you think that there can be a cure for Parkinson's one day? 

Sharott: Of course, there can. It's a very hard problem, and there's a lot of brilliant people that work on that problem. I think, you know, there are many promising approaches. I mean, one of the most promising approaches is, as I say, this is a disease that takes a long, long time to manifest. And so I think one of the most promising approaches is to look for ways of detecting that people have started that process early and then finding drugs or antibodies or other strategies that will protect particularly those dopamine neurons that cause the most prominent symptoms of the disease. And there are there's a huge amount of work on that. And I think, you know, in Alzheimer's disease, there have been these recent breakthrough treatments that do seem to slow the progression of the disease. And so, you know, I personally see no problem with these two things going on in parallel. We don't know how long that's going to take something that protects the neurons. So, in the meantime, we can build up these surgical techniques which can offer immediate relief of symptoms. I think another thing that is worth mentioning is that many people are interested in whether you can also use brain stimulation to slow the progression of the disease. And this is at a very early stage, but an example of how one might do this is to use brain stimulation to modulate sleep. So, sleep is considerably affected in Parkinson's disease. So, it becomes fragmented and broken up. People don't sleep as well. And we think that, in various ways, sleep is important for the health of neurons. So one way that you could possibly use stimulation to affect the disease process itself is to improve sleep and therefore, somewhat indirectly, help to protect the brain from disease processes. 

Röder: We talked a lot about Parkinson's disease today. Are there other neurological conditions that could potentially benefit from DBS? 

Sharott: I mean, I think the first thing to say is there already are other conditions benefit from DBS. So there's a disease called essential tremor where the really dominant symptom is a tremor. So that's treated quite well with DBS as is another movement disease of movement called dystonia. So it's I think the first thing to say is it's already not just.

Then when we talk about kind of future directions, there are two that I'm particularly interested in as many other people are. One is diseases that would traditionally be called psychiatric. There are already quite a few teams around the world that use DBS to treat obsessive compulsive disorder. So these tend to be people who have really quite severe obsessive compulsive disorder where they spend, you know, half their day or more acting out their compulsions. And so that is already a successful treatment for many of these patients and also in a major depressive disorder, depression. It's a relatively small amount of patients that get treated worldwide, but I think there's enough evidence to suggest that DBS can have a real impact on severely depressed patients. So in psychiatry, there's certainly opportunities and things that are developing. Secondly, one of my own interests, which I think is in in quite an early stage of development, is Alzheimer's disease. And so, if we go back to oscillations, the areas of the brain, that are particularly responsible for memory, which are kind of at the side of your brain or the temporal lobe or you may have called of a structure heard of a structure called the hippocampus, which is kind of the center of memory circuits. So, there's much, much work over many years showing that these circuits really use big oscillations to organize the formation and retrieval of memories.

And so for me, I've already looked at how you manipulate these big brainwaves, these big oscillations. This seems like a big opportunity where if you can really interact with these big oscillations, you might be able to enhance the way that people with Alzheimer's disease or dementia lay down and retrieve their memories. 

Röder: That's a really interesting outlook. Let me ask you my final question, which is, what is the point for you personally when you say in your research, okay, now I have reached my goal? 

Sharott: I mean, I think as a neuroscientist, I have two main goals, which I don't think I'd ever say I'll reach the end of. I think one is to try and find a fundamental understanding of a given brain process or at least a large advance in the understanding of how the brain does something. I think many neuroscientists would probably say that's a real goal. And that's hard because the brain is, you know, is a very complicated, highly dimensional system. And the other would really be to play a big role in bringing a new technology to the clinic, which is also a many-step process which involves, you know, not just this really interesting neuroscience that I've been talking about, but also it involves brilliant engineering. It involves how you design trials to show that your treatment is going to work or not and all the regulation that comes with that.

And so it's really to achieve that, that kind of clinical impact involves a lot of people doing a lot of different things. And neuroscience and particularly clinical neuroscience is definitely a team sport. It needs multiple people with many disciplines to try and achieve something. 

Röder: I wish you best of luck for that. Thank you so much for taking the time and giving us those interesting insights.

Sharott: Well, thanks a lot for having me. It's been great to talk. Thank you. 

Röder: And thank you for listening. Feel free to follow and rate our podcast. My name is Marie Röder, and we will be back soon with another episode. 

Ask different, the podcast by the Einstein Foundation.