This post is a game of two halves.
The first half will explain the concept of a surgical procedure for Parkinson’s called ‘subthalamic deep brain stimulation‘, in which doctors permenantly implant electrodes into the brain to stimulate a region – the subthalamic nucleus. By stimulating this region with electrical impulses, doctors can provide a better quality of life (in most cases) to people with severe features of Parkinson’s.
In the second half of this post, we will look at an approach to doing the same thing,… but without the electrodes.
Rather, researchers are using gene therapy.
In today’s post, we will discuss what deep brain stimulation is, what gene therapy is, and how the gene therapy approach is having a different kind of impact on the brain to that of deep brain stimulation.
Welcome to the first half of today’s post.
It begins with you asking the question:
What is deep brain stimulation?
Deep brain stimulation (or DBS) is a treatment method that involves embedding electrodes into the brain to help modulate the brain activity involved in movement.
It is a prodcedure that is usually offered to people with Parkinson’s who have excessive tremor or debilitating dyskinesias.
First introduced in 1987, deep brain stimulation consists of three components: the pulse generator, an extension wire, and the leads (which the electrodes are attached to). All of these components are implanted inside the body. The system is turned on, programmed and turned off remotely.
Today’s post discusses some interesting new research that could potentially have ‘blue sky’ implications for the treatment of Parkinson’s (‘blue sky‘ meaning somewhere in the longer-term framework).
The research deals with the amazing activity of a newly discovered protein, isolated from tiny little fish. The protein responds to magnetic fields. And with a lot more work, the researchers behind this discovery think that this protein could be useful in the future for the treatment of Parkinson’s.
In today’s post, we will have a look at this new protein, review the research report, and explore how this novel discovery could possibly be used for treating Parkinson’s.
The two fish in the image above are called Kryptopterus bicirrhis (or more commonly “glass catfish”).
These wondrous little creatures are typically found in the river waters of Thailand and Indonesia, they grow to a final length of approximately 8-12 cm (4-5 inches), and they live for 6-8 years.
But immediately you notice their most striking feature: the semi-transparent-ness of their bodies:
Why am I starting this post by talking about these curious little fish?
Some researchers in Baltimore (Maryland) recently made an amazing discovery related to them.
It is one of the most frequent non-motor features of Parkinson’s and yet it is one of the least publicly discussed.
The word ‘constipation’ is generally used to describe bowel movements that are infrequent or difficult to pass. The stool is often dry, lumpy and hard, and problematic to expel. Other symptoms can include abdominal pain, bloating, and the feeling that one has not completely passed the bowel movement.
In today’s post we look at what can cause constipation, why it may be so common in Parkinson’s, discuss what can be done to alleviate it, and look at clinical trials focused on this issue.
As many as 1 in 5 people say they have suffered from chronic (long-term) constipation at some point in their lives.
It results in more than 2.5 million hospital and physicians visits per year in the USA.
And Americans spend more than $700 million on treatments for it annually (Source).
More importantly, constipation is considered by many researchers to be a risk factor for developing Parkinson’s, as many people in the affected community claim to have experienced constipation for long periods prior to diagnosis.
Why this is, what is being done to research it, and what can be done about constipation in Parkinson’s is the topic of today’s post. But first, let’s start with the obvious question:
What is constipation?
Many members of the Parkinson’s community will have heard of deep brain stimulation – a surgical procedure that is offered to individuals with particularly bad tremor or dyskinesias – but there is now another form of stimulation that is now being tested in people with PD.
Spinal cord stimulation has long been used as a therapy for back pain and research groups have recently been asking if this technique could be applied to Parkinson’s.
In today’s post we will discuss some recently published data that points towards certain aspects of the motor features of Parkinson’s that could benefit from spinal cord stimulation, particularly freezing of gait.
Deep brain stimulation electrodes implanted in the brain. Source: 2ndFriday
Deep brain stimulation (or DBS) has now become a routine treatment option for those in the Parkinson’s community with particularly debilitating motor features (such as severe tremor or dyskinesias).
First introduced in 1987, deep brain stimulation consists of three components: the pulse generator, an extension wire, and the leads (which the electrodes are attached to). All of these components are implanted inside the body. Similar to a pace maker for the heart, the DBS system is turned on, programmed and turned off remotely.
The electrodes that are implanted deep in the brain are tiny, and the very tip of the electrode has small metal plates (each less than a mm in width) which provide the pulses that will help mediate the activity in the brain.
DBS electrode tip. Source: Oxford
Interesting. How does it work?
Deep brain stimulation (DBS) has now become a standard treatment option for people with Parkinson’s (Click here to read more about DBS), but recently researchers have been investigating a whole new form of stimulation to further help alleviate the symptom of the condition.
Spinal cord stimulation – the electrical modulation of the spinal cord – has been tested in models of Parkinson’s in laboratories for the last decade, and this week we saw the publication of the results of a pilot clinical study testing this approach in humans with Parkinson’s.
In today’s post we will discuss what spinal cord stimulation is, review the results of this pilot study, and discuss what could happen next for this new treatment approach.
2017 was the 200th anniversary of the first report of Parkinson’s by one James Parkinson in 1817 (Click here to read a previous post on this), and the 20th anniversary of the discovery of the first genetic mutation associated with Parkinson’s (Click here to read more about this).
It was also the 50th anniversary of the first use of a technique called spinal cord stimulation.
What is spinal cord stimulation?
Spinal cord stimulation is a form of implantable neuromodulation. Similar to deep brain stimulation (or DBS), it involves using electrical signals to modulate neural activity. But rather than electrodes being placed into the brain (in the case of DBA), spinal cord stimulation involves – as the label on the can suggests – specific areas of the spinal cord being stimulated for the treatment of certain types of pain.
The treatment involves a column of stimulating electrodes that is surgically implanted in the epidural space of the spine. And before you ask: the epidural space is the area between the outer protective skin of the spinal cord (called the dura mater) and the surrounding vertebrae. So the device lies against the spinal cord, and is protected by the bones that make up the spine (as shown in the image below).
The stimulating electrodes within the epidural space. Source: SpineOne
An electrical pulse generator is implanted in the lower abdomen and conducting wires are connected between the electrodes to the generator. Much like deep brain stimulation, the system is entirely enclosed in the body and operated with a remote control.
An x-ray of the spine with a stimulator implanted (towards the top of the image, and cords leading off to the bottom left). Source:Wikipedia
How does spinal cord stimulation work?
Today’s (experimental) post provides something new – an overview of some of the major bits of Parkinson’s-related research that were made available in January 2018.
In January of 2018, the world was rocked by news that New Zealand had become the 11th country in the world to put a rocket into orbit (no really, I’m serious. Not kidding here – Click here to read more). Firmly cementing their place in the rankings of world superpowers. In addition, they became only the second country to have a prime minister get pregnant during their term in office (in this case just 3 months into her term in office – Click here to read more about this).
In major research news, NASA and NOAA announced that 2017 was the hottest year on record globally (without an El Niño), and among the top three hottest years overall (Click here for more on this), and scientists in China reported in the journal Cell that they had created the first monkey clones, named Zhong Zhong and Hua Hua (Click here for that news)
Zhong Zhong the cute little clone. Source: BBC
At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
In 2002, deep brain stimulation (or DBS) was granted approval for the treatment of Parkinson’s disease by the US Food and Drug Administration (FDA). The historical starting point for this technology, however, dates quite far back…
Further back than many of you may be thinking actually…
In his text “Compositiones medicamentorum” (46 AD), Scribonius Largo, head physician of the Roman emperor Claudius, first suggested using pulses of electricity to treat afflictions of the mind.
Roman emperor Claudius. Source: Travelwithme
He proposed that the application of the electric ray (Torpedo nobiliana) on to the cranium could be a beneficial remedy for headaches (and no, I’m not kidding here – this was high tech at the time!).
Torpedo nobiliana. Source: Wikipedia
These Atlantic fish are known to be very capable of producing an electric discharge (approximately 200 volts). The shock is quite severe and painful – the fish get their name from the Latin “torpere,” meaning to be stiffened or paralysed, referring specifically to the response of those who try to pick these fish up – but the shock is not fatal.
Now, whether Largo was ever actually allowed to apply this treatment to the august ruler is unknown, and beyond the point. What matters here is that physicians have been considering and using this approach for a long time. And more recently, the application of it has become more refined.
What is deep brain stimulation?
The modern version of deep brain stimulation is a surgical procedure in which electrodes are implanted into the brain. It is used to treat a variety of debilitating symptoms, particularly those associated with Parkinson’s disease, such as tremor, rigidity, and walking problems.
Researchers are using a powerful new tool to determine which parts of the brain are involved in movement.
The technology involves shining light on brain cells…and well, a bit of biological magic.
Today we will review some newly published research highlighting how this approach and discuss what it means for Parkinson’s disease.
The Vienna city hall. Source: EUtourists
Personal story: I was at the Dopamine 2016 conference in September last year in lovely Vienna (Austria). Wonderful city, beautiful weather, and an amazing collection of brilliant researchers focused on all things dopamine-related. The conference really highlighted all the new research being done on this chemical.
There was – of course – a lots of research being presented on Parkinson’s disease, given that dopamine plays such an important role in the condition.
And it was all really interesting.
Anyways, I was sitting in one of the lecture presentation session, listening to all these new results being discussed.
And then, a lady from Carnegie Mellon University stood up and (without exaggeration) completely – blew – my – mind!
Her name is Aryn H. Gittis:
She is an Assistant Professor in the Department of Biological Sciences at Carnegie Mellon University, where her group investigates the neural circuits underlying the regulation of movement, learning, motivation, and reward.
And the ‘mind blowing‘ research that she presented in Vienna has recently been published in the journal Nature Neuroscience:
Title: Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice
Authors: Mastro KJ, Zitelli KT, Willard AM, Leblanc KH, Kravitz AV & Gittis AH
Journal: Nature Neuroscience (2017) doi:10.1038/nn.4559
In this report, Dr Gittis and her colleagues demonstrated that elevating the activity of one type of cell in an area of the brain called the globus pallidus, could provide long lasting relief from Parkinson’s-like motor features.
Hang on a second. What is the globus pallidus?
The globus pallidus is a structure deep in the brain and before Dr Gittis and her colleagues published their research, we already knew it played an important role in our ability to move.
Movement is largely controlled by the activity in a specific group of brain regions, collectively known as the ‘Basal ganglia‘.
The basal ganglia structures (blue) in the human brain. Source: iKnowledge
But while the basal ganglia controls movement, it is not the starting point for the movement process.
The prefrontal cortex is where we do most of our ‘thinking’. It is the part of the brain that makes decisions with regards to many of our actions, particularly voluntary movement. It is involved in what we call ‘executive functions’. It is the green area in the image below.
Areas of the cortex. Source: Rasmussenanders
Now the prefrontal cortex might come up with an idea: ‘the left hand should start to play the piano’. The prefrontal cortex will communicate this idea with the premotor cortex and together they will send a very excited signal down into the basal ganglia for it to be considered. Now in this scenario it might help to think of the cortex as hyperactive, completely out of control toddlers, and the basal ganglia as the parental figure. All of the toddlers are making demands/proposals and sending mixed messages, and it is for the inhibiting basal ganglia to gain control and decide which is the best.
So the basal ganglia receives signals from the cortex, processes that information before sending a signal on to another important participant in the regulation of movement: the thalamus.
A brain scan illustrating the location of the thalamus in the human brain. Source: Wikipedia
The thalamus is a structure deep inside the brain that acts like the central control unit of the brain. Everything coming into the brain from the spinal cord, passes through the thalamus. And everything leaving the brain, passes through the thalamus. It is aware of most everything that is going on and it plays an important role in the regulation of movement. If the cortex is the toddler and the basal ganglia is the parent, then the thalamus is the ultimate policeman.
Now to complicate things for you, the processing of movement in the basal ganglia involves a direct pathway and an indirect pathway. In the simplest terms, the direct pathway encourages movement, while the indirect pathway does the opposite: inhibits it.
The thalamus will receive signals from the two pathways and then decide – based on those signals – whether to send an excitatory or inhibitory message to the primary motor cortex, telling it what to do (‘tell the muscles to play the piano’ or ‘don’t start playing the piano’, respectively). The primary motor cortex is the red stripe in the image below.
The primary motor cortex then sends this structured order down the spinal cord (via the corticospinal pathway) and all going well the muscles will do as instructed.
Source: adapted from Pinterest
Now, in Parkinson’s disease, the motor features (slowness of movement and resting tremor) are associated with a breakdown in the processing of those direct and an indirect pathways. This breakdown results in a stronger signal coming from the indirect pathway – thus inhibiting/slowing movement. This situation results from the loss of dopamine in the brain.
Excitatory signals (green) and inhibitory signals (red) in the basal ganglia, in both a normal brain and one with Parkinson’s disease. Source: Animal Physiology 3rd Edition
Under normal circumstances, dopamine neurons release dopamine in the basal ganglia that helps to mediate the local environment. It acts as a kind of lubricant for movement, the oil in the machine if you like. It helps to reduce the inhibitory bias of the basal ganglia.
Thus, with the loss of dopamine neurons in Parkinson’s disease, there is an increased amount of activity coming out of the indirect pathway.
And as a result, the thalamus is kept in an overly inhibited state. With the thalamus subdued, the signal to the motor cortex is unable to work properly. And this is the reason why people with Parkinson’s disease have trouble initiating movement.
Now, as you can see from the basic schematic above, the globus pallidus is one of the main conduits of information into the thalamus. Given this pivotal position in the regulation of movement, the globus pallidus has been a region of major research focus for a long time.
It is also one of the sites targeted in ‘deep brain stimulation’ therapy for Parkinson’s disease (the thalamus being another target). Deep brain stimulation (or DBS) involves placing electrodes deep into the brain to help regulate activity.
DBS in the globus pallidus. Source: APS
By regulating the level of activity in the globus pallidus, DBS can control the signal being sent to the thalamus, reducing the level of inhibition, and thus alleviating the motor related features of the Parkinson’s disease.
The dramatic effects (and benefits) of deep brain stimulation can be seen in this video (kindly provided by fellow kiwi Andrew Johnson):
Deep brain stimulation is not perfect, however.
The placing of the electrodes can sometimes be off target, resulting in limited beneficial effects. Plus the tuning of the device can be a bit fiddly in some cases.
A more precise method of controlling the globus pallidus would be ideal.
Ok, so the globus Pallidus region of the brain is important for movement. What did Dr Gittis and her colleagues find in their research?
They used an amazing piece of technology called ‘optogenetics‘ to specifically determine which group of cells in the globus pallidus are involved in the inhibitory signals going to the thalamus.
And their results are VERY interesting.
But what is optogenetics?
The short answer: ‘Magic’
The long answer: In 1979, Nobel laureate Francis Crick suggested that one of the major challenge facing the study of the brain was the need to control one type of cell in the brain while leaving others unaltered.
The DNA duo: Francis Crick (left) and James Watson. Source: CNN
Electrical stimulation cannot address this challenge because electrodes stimulate everything in the immediate vicinity without distinction. In addition the signals from electrodes lack precision; they cannot turn on/off neurons as dynamically as we require. The same problems (and more) apply to the use of drugs.
Crick later speculated that the answer might be light.
How on earth would you do that?
Well, in 1971 – eight years before Crick considered the problem – two researchers, Walther Stoeckenius and Dieter Oesterhelt, discovered a protein, bacteriorhodopsin, which acts as an ion pump on the surface of a cell membrane. Amazingly, this protein can briefly become activated by green light.
A rather remarkable property.
Later, other groups found similar proteins. One such protein, called ‘Channelrhodopsin’, was discovered in green algae (click here to read more on this). When stimulated by particular frequencies of light, these channels open up on the cell surface and allow ions to pass through. If enough channels open, this process can stimulate particular activity in the cell.
Channelrhodopsin. Source: Openoptogenetics
Interesting, but how do you get this into the brain?
This is Karl Diesseroff:
Looks like the mad scientist type, right? Well, remember his name, because this guy is fast heading for a Nobel prize.
He is the D. H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University. And he is one of the leading researchers in a field that he basically started.
Back in 2005, he and his collaborators published this research report:
Title: Millisecond-timescale, genetically targeted optical control of neural activity
Authors: Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K.
Journal: Nat Neurosci. 2005 Sep;8(9):1263-8. Epub 2005 Aug 14.
In this research report, Deisseroth and his colleagues (particularly Ed Boyden, lead author and now a professor of Biological Engineering at the McGovern Institute for Brain Research at MIT) took the short section of DNA that provides the instructions for making Channelrhodopsin from green algae and they put that piece of DNA into neurons.
And when they then shined blue light on the neurons, guess what happened? Yes, the neurons became activated – that is to say, they produced an ‘action potential’, which is one of the way information is passed from one neuron to another.
Like I said ‘Magic’!
And the best part of this biological manipulation was that Deisseroth and his colleagues could activate the neurons with absolutely amazing precision! By pulsing light on the cells for just millisecond periods, they could elicit instant action potentials:
Precise control of the firing of a neuron. Source: Frontiers
And of course any surrounding cells that do not have the Channelrhodopsin DNA were not affected by the light, but were activated by the signal coming from the Channelrhodopsin+ cells.
This original research report lead to a gold rush-like search for other proteins that are light activated, and we now have an ever increasing toolbox of new proteins with curious properties. For example, we can now not only turn on neurons, but we also have proteins that can shut their activity down, blocking any action potentials (with proteins called ‘Halorhodopsin’ – click here for more on this). And many of these proteins are activated by different frequencies of light. It is really remarkable biology.
Two years after the first report of optogenetics, the first research demonstrating the use of this technology in the brain of a live animal was published (Click here and here to read more on this). And these fantastic tools are not just being used in the brain, they are being applied to tissues all over the body (for example, optogenetics can be used to make heart cells beat – click here to read more on this).
This TED talk video of Ed Boyden’s description of optogenetics is worth watching if you want to better understand the technique and to learn more about it:
Ok, so Dr Gittis and her colleagues used optogenetics in their research. What did they find?
Well, from previous research they knew that there were two types of neurons in the globus pallidus that regulate a lot of the activity in this region. The two types were identifiable by two different proteins: Lim homeobox 6 (Lhx6) and Parvalbumin (PV).
The Lhx6 neurons, which do not have any PV protein, are generally concentrated in the medial portion of the globus pallidus (closer to the centre of the brain). These Lhx6 neurons also have strong connections with the striatum and substantia nigra parts of the brain. The PV neurons, on the other hand, are more concentrated in the lateral portions of the globus pallidus (closer to the side of the brain), and they have strong connections with the thalamus (Click here to read this previous research).
In their new research report, Dr Gittis and her colleagues have used optogenetics to determine the functions of these two types of cells in the globus pallidus.
Initially, they stimulated both Lhx6 and PV neurons at the same time to see if they could restore movement in mice that had been treated with a neurotoxin (6-OHDA) that killed all the dopamine neurons. Unfortunately, they saw no rescue of the motor abilities of the mice.
They next shifted their attention to activating the two groups of cells separately to see if one of them was inhibiting the other. And when they stimulated the PV neurons alone, something amazing happened: the mice basically got up and started moving.
But the really mind blowing part: even after they turned off the stimulating light – after the pulse of light stopped – the mice were still able to keep moving around.
And this effect lasted for several hours! (note that the red line – indicating a decrease in immobility – in the image below remains stable after the stimulation of light pulses – blue lines – has stopped. Even between light pulses the mouse doesn’t return to immobility).
Stimulation of the PV neurons. Source: Nature
The investigators then tested the reverse experiment: inhibiting the Lhx6 neurons.
And guess what?
They found that by inhibiting the Lhx6 neurons with pulses of light, they could restore movement in the dopamine-depleted mice (and again for hours beyond stimulation – note the blue line in the image below remains even after the light pulses – green lines – have stopped).
Inhibiting of the Lhx6 neurons. Source: Nature
This result blew my mind at the conference in Vienna. And even now as I write this, I am still….well, flabbergasted! (there’s a good word).
In addition to being a very elegant experiment and use of this new optogenetic technology, this study opens new doors for us in the Parkinson’s disease research field regarding our understanding of how movement works and how we can now potentially treat PD.
Is optogentics being tested in the clinic?
The incredible answer to this question is: Yes.
A company in Ann Arbor (Michigan) called RetroSense Therapeutics announced in March of 2016 that they had treated their first subject in a Phase I/IIa, open-label, dose-escalation clinical study of the safety and tolerability of their lead product, RST-001 in patients with retinitis pigmentosa (Click here for the press release).
Retinitis pigmentosa is an inherited eye disease that causes severe vision impairment due to the progressive degeneration of the rod photoreceptor cells in the retina. The condition starts with patients experiencing progressive “tunnel vision” and eventual leads to blindness.
RetroSense’s lead product, RST-001 is basically a virus that infects cells with the photosensitivity gene, channelrhodopsin-2, that we discussed above. Several studies have demonstrated the ability of this approach to restore the perception of light and even vision in experimental models of blindness (Click here to read more about this).
The therapy involves injecting RST-001 into the retinas of patients who are blind. The infected cells will then fire when stimulated with blue light coming into the eye, and this information will hopefully be passed on to the brain. All going well, RetroSense plans to enroll 15 blind subjects in its trial, and they will follow them for two years. They hope to release some preliminary data, however, later this year. And a lot of people will be watching this trial and waiting for the results.
So, yes, optogenetics is being tested in humans.
Obviously, however, these are the first tentative steps in this new field. And it may be sometime before the medical regulatory bodies allow researchers to start conducting optogentic trials in the brain, let alone on people with Parkinson’s disease.
What does it all mean?
It is always rather wondrous where new discoveries take us.
A little over 10 years ago, some scientists discovered that by inserting a photosensitivity gene into brain cells they could control the firing of those cells with rapid pulses of light. And now other researchers are using that technology not only to better understand the works of our brains and how we move, but also to help make blind people see again.
Whether this technology will be able to replace therapies like deep brain stimulation with a more precise method of controlling the firing of the globus pallidus, is yet yo be seen. But this amazing new technique in our research toolbox will most certainly help to enhance our understanding of Parkinson’s disease. Taking us one step closer to ridding ourselves of it entirely.
The banner for today’s post was sourced from Scientifica