Naked Neuroscience news roundup!

20 May 2019
Presented by Katie Haylor.

BRAIN

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This month - from digging into dementia, to asking "are bigger brains always better?", we’ve had a glut of neuroscience news harvested in the naked scientists office, so prepare for a neuroscience news round up...

In this episode

Close up of a doctor's coat, with a stethoscope and a pocket full of pens

01:03 - Reflections on treating dementia

How do doctors go about helping people who suffer from dementia?

Reflections on treating dementia
with Isabelle Cochrane, trainee doctor

Dementia is an umbrella term for a number of conditions, and worldwide, around 50 million people have it. To sift through the science of this group of conditions and to reflect on her experiences caring for dementia patients, here’s trainee doctor Isabelle Cochrane.

Something is happening to Mrs Jones. She loses her train of thought and her daughter tells her that she keeps asking the same questions over and over. Cooking dinner has become a nightmare. She gets muddled when the recipe involves more than a couple of steps. Yesterday, she got lost on her way to the bakery despite living in the same neighbourhood for the past 40 years. But this is just the beginning.

These subtle changes will gradually evolve meaning that eventually she won't know the time of day or the day of the year. Her home will feel unfamiliar, unsafe, and confusing and her family may notice her become more aggressive or even violent. Losing her mild manner, she may start saying and doing alarming things that she never previously would. By now, you may have guessed that Mrs Jones is suffering from dementia.

This is a term we hear a lot, but it can be tricky to put a finger on exactly what dementia is. One thing that is important to understand is that dementia is not a single disease but rather something called a clinical syndrome. In other words, it is a collection of symptoms that tend to appear together in an identifiable pattern. So, along with a memory loss that most people would associate with dementia, we also get other characteristic changes. People lose the ability to plan ahead effectively and may find it hard to concentrate. Decreased spatial awareness makes it hard to navigate even familiar environments and there is often also a decrease in verbal fluency.

People suffering from dementia may also have changes in their personality. Showing what we call this inhibition they find it difficult to control their behaviour and may act in ways that most of us would consider socially unacceptable. So, what does these processes can lead to these cognitive changes that we call dementia. By far the most common cause is Alzheimer's disease. It is not entirely clear how the disease comes about. But what we do know is that when the brains of people with Alzheimer's are examined at post-mortem, abnormal protein fragments called amyloid plaques are seen. As these plaques are deposited in the brain, it is believed that they cause inflammation. Inflammation is a generic term which describes the response of the immune system to entities that are recognized as being foreign or harmful to the body. This process of inflammation leads to the neurons in the brain behaving abnormally which, in turn, is thought to result in the characteristic changes in brain function that we see.

Alzheimer's disease accounts for over half of all dementia cases. Another very common cause is vascular dementia which accounts for about another quarter of cases. Here blood is unable to reach all areas of the brain normally. This is usually due to changes in the blood vessels which may occur when factors such as blood pressure, cholesterol, and blood sugar are poorly controlled. Over time, this abnormal blood supply causes multiple small strokes. This results in neurons dying, once again causing changes in cognitive function.

Aside from vascular dementia and Alzheimer's several other types of dementia also exist but these are generally much more uncommon. Sometimes several different types of dementia may coexist. It can be difficult to differentiate between the different forms of dementia, although often the exact pattern of cognitive changes is subtly different in each type. In order to arrive at a diagnosis, doctors will initially perform a cognitive test, a little like a long questionnaire which allows the various functions of the brain to be measured in a reasonably objective way. This will sometimes then be followed by a scan of the brain which may reveal which areas are most severely affected. The cognitive test and the results of any scans are used in combination to make a diagnosis of dementia and to work out which disease is underlying the process. If Alzheimer's disease is thought to be the cause, certain drugs can be given. In other cases, there is very little to be gained from giving medications.

In all types of dementia focus is given on trying to keep the brain active through programs run by specialist therapists. Unfortunately, however, the outlook for people with dementia is still quite poor with little that can be done to slow its progression. The average life expectancy is around seven years but of this time much will be lived with severe disability and dependence on the care of others. With the number of cases of dementia set to increase to over 2 million by 2050 in the UK alone, learning to manage this condition effectively is rapidly becoming a priority for doctors and healthcare systems alike.

DEMENTIA

07:15 - LATE dementia discovered

How many different types of dementia are there?

LATE dementia discovered
with Duncan Astle, Cambridge University

It’s been described by some as one of the biggest dementia breakthroughs in the last decade. Scientists have categorised a new form of the condition. Katie Haylor spoke with cognitive neuroscientist Duncan Astle from  Cambridge University, who's been purusing the paper...

Duncan - To give it its long title: Limbic predominant age related TPD 43 Encephalopathy or LATE for short.

Katie - It's not the catchiest.

Duncan - No but it's got the good acronym - LATE. When I say new, I'm not suggesting this is something new that has just started occurring, it's been occurring for a long time. It's new in the sense that we have been able to identify it and classify it and separate it out from other forms of dementia. So, in this paper they studied the brains of individuals post-mortem from people who have donated their brains, and they found about 25 percent of their sample had a build-up of a particular type of protein which is called TPD 23 protein. And it is in the limbic areas, that's areas of the brain like the hippocampus which we know is really important for memory and amygdala which is really important for emotional processing. The symptoms include things like memory loss and they're very similar to the symptoms of Alzheimer's disease, but really crucially the underlying cause is different.

So, Alzheimer's disease is driven by a build-up of different types of protein like amyloid B plaque proteins and tau proteins. And they’re sort of tangly proteins that build up inside cells in the brain to the point that they impair the cells functioning and ultimately, they die. So that's one particular cause and that gives rise to Alzheimer's, but these are different proteins and they give rise to this new late form of dementia.

Katie - This is very interesting but what is the relevance of understanding that this is a different type of dementia?

Duncan - Treatments for dementia are few and far between at the minute, and it's been incredibly difficult to develop new drugs that will translate to a kind of prescription that you could be given by your GP. So pharmaceutical companies have been very good at finding compounds that work in the test tube or in an animal model of the disease, but when you get to what's called Phase 1 randomized controlled trial, that's the first point at which that compound will come into contact with human subjects. The vast majority of those compounds fail.

Now one potential crucial reason why they might not work in practice is because when we identify the patients that we want to try the new drug out on, what we're doing is accidentally including lots of patients who have superficially similar symptoms, but a very different underlying pathology. So, for instance, let's say we gather a group of subjects for our new drug and we think they've all the Alzheimer’s and a good proportion of them do, but let's say a third of them actually have LATE. Now there's no reason that your drug would be effective with them because they don't have the same pathology.

Now when you run your trial, of course, your medication only stands a chance of working in a reduced proportion of your sample. And so, the overall efficacy of the drug will always look like it's reduced by comparison than relative to what is required for a trial. And so, the very process of being able to demarcate out different types of dementia with different types of underlying pathology is crucial. The experts in dementia said this is one of the biggest breakthroughs in dementia for the last decade. And that's because until we can understand the different pathways to having dementia we don't really stand a chance of developing proper treatments for it.

Katie - Do we know how many people may have this LATE form of dementia compared to people who might have Alzheimer’s?

Duncan – Not as yet and that's because the next step, having identified that it exists and what the underlying cause is, is to find ways of producing what's called biomarkers. So that's a way of you knowing whether or not a person has a particular specific disorder relative to say Alzheimer’s. And so that requires lots more work in test tubes and in animal models and hopefully, ultimately, with new imaging so that we can do it with human subjects.

Katie - Oh I see. Because crucially this is whilst they're alive rather than post-mortem when they’ve died?

Duncan – Exactly. So, to be able to distinguish them from our Alzheimer’s patients to kind of tease them out for the purpose of doing Alzheimer's trials, but then also to study their condition as well and identify treatments requires that we have ways of detecting it in people who are alive so that we can trial treatments on them. And that's the next step.

OLDER PEOPLE

11:45 - Boosting working memory

Scientists have managed to temporarily boost the working memory of older people...

Boosting working memory
with Rob Reinhart, Boston University

Unfortunately, working memory declines with age, and the consequences can be debilitating. But now, by using electrical signals to artificially manipulate the brain waves of a group of older people, researchers from Boston University have succeeded in temporarily improving working memory. Katie Haylor heard how, from study author Rob Reinhart...

Rob - We're looking at fast and slow waves in the temporal region of the brain and that relationship is thought to index how information is combined across time. And then we're also looking at relationships between a slow wave in the front part of the brain and a slow wave in the temporal region, and that's thought to index communication across long distances in the brain. And this relationship between frontal cortex and temporal cortex during working memory, we think is special and important. And we targeted it with an external alternating current delivering extremely weak and safe levels of electrical alternating current to these brain areas simultaneously to try to synchronize or make better connected these two brain areas. We did indeed find after 25 minutes of stimulation that we can enhance the synchrony or communication between these two brain areas, and as a result, boost working memory performance in older individuals to levels that were comparable to those of 20 year olds.

Katie - This lasts for up to fifty, 50 minutes after about a half an hour period of treatment. Is that right?

Rob - That's right. We were really shocked with that. Typically, we find stimulation that is of this sort, incredibly weak. We see changes in brain and behaviour but only while the stimulator is on, and we turn it off the effects go away. In this case it was quite different. We could turn the stimulator off and we could still see these benefits in terms of brain and behavioural changes. And so we're very keen on next step, follow up experiments to determine the duration of the effects empirically with more research.

Katie - If we imagine a sine wave or even a wave on the ocean, are we literally talking about making sure the peak lines up with the peak, the trough lines up at the trough?

Rob - It could look that way for sure. It doesn't have to be peak to peak as long as it's systematic and regularly related in time. Lots of people have perhaps heard of the snappy phrase “cells that fire together wire together.” Well in our case these big populations of cells that rhythmically synchronize we think are then communicating with each other.

Katie - How did you actually do this then? Is it a kind of thinking cap?

Rob - There are electrodes that we have embedded into it like a swimmer's cap that are delivering extremely weak electrical current in a number of different, important ways. One is a high definition manner, which means we're just taking advantage of some innovations that allow us better spatial targeting, better spatial resolution so we can target brain areas with finer spatial precision. A second feature is it's an alternating current. So, it alternates at a certain frequency that we decide, it's frequency-tuned to the individuals. We find the ‘sweet spot’ in your rhythmic brain network and then we tune our stimulator to that precise frequency, in addition to aiming the current with greater spatial targeting.

Katie - Okay. So, you have this kit that noninvasively and safely can target very specific waves, tweak them to make sure they're in sync with others. Tell us about how many people you did this in and what kind of test were you using of working memory to check this was actually making a difference?

Rob - The study overall involved 154 participants across a series of different experiments. The first was with 42 healthy young adults in their 20s and 42 older individuals between 60 and 76 years old.

The task we used as a classic working memory task -  presenting someone with an image of a natural or real world object like a landscape, scene, picture of someone's face for example. And then a brief delay period where nothing is appearing on the computer screen. And then I present you that same image or slightly different image, and you have to indicate with a button press whether it's same or different. And it allows us to investigate what's happening during that delay period, when nothing is being shown on the computer screen, but you need to maintain in your mind's eye a high fidelity, a highly resolved and detailed picture of that image.

Katie - So where does the novelty lie in this study?

Rob - One is that we're providing new insights into the brain basis of working memory decline in the elderly. And the second is we're showing that with this new technique, that we can push these brain circuits around noninvasively, safely and rapidly induce better connected brain circuits and, as a result, boost working memory in the elderly.

Katie - Are you hoping this could be a cap that people can wear every day?

Rob - Much more research needs to be done to better establish these findings in terms of the technology development as well as basic research. And certainly, also porting this over to clinical studies and patient populations to see if it can really help people suffering from memory and other cognitive disabilities.

Katie - Okay. I appreciate this is a long way off, but if you can put in phase these brainwaves which you're saying will help people with their working memory, can you do the opposite? Can you pull out of sync brainwaves and would you want to do that?

Rob - That's a great question. So just as, like you were saying, we can sync up brain circuits and boost behaviour, we also found that we can change the orientation of the electrical field that we pass through the brain and desynchronize those same brain networks and make people slightly worse at performing this task. And what's really interesting about that, for us, is that there are brain disorders that are characterized by hyper-functional brain connectivity. And so, we're excited about the potential for future research using this stimulation protocol we've developed to desynchronize connectivity in these patient populations such as Parkinson's and epilepsy.

A pyramidal neurone in the human cerebral cortex

19:54 - Building brains - is bigger always better?

Because chemical connections between neurons are slightly unreliable, it doesn’t always help to have more...

Building brains - is bigger always better?
with Timothy O'Leary, Cambridge University

This month, Cambridge University scientists have discovered that having a bigger brain doesn’t necessarily make you smarter. Engineers used a mathematical model to show that, because the chemical connections between neurons are slightly unreliable, it doesn’t always help to have more of them. They also say that having redundant connections in the brain can make you learn faster. Timothy O’Leary is one of the authors of this study, and he took Phil Sansom out for a stroll on Coe Fen in Cambridge, to explain more.

Tim - Like lots of discoveries in science, you set out looking at one particular question, and then as you dig deeper you find that there's a related question that ends up being more interesting. The question we set out to address was to understand how the brain rewires is itself to learn new information.

So what we wanted to do is find a learning rule that was sufficiently simple that a bag of chemicals, like the connection between two neurons or a synapses as it’s called could actually carry out this rule. Of course there's this fancy clever learning algorithms that are used in artificial intelligence, for example, but currently the field doesn't really believe that these can be implemented in the brain because it requires all of the connections essentially to know what all of the other connections are doing at any point in time. And that just didn't seem realistic.

Phil - Simple learning rules and algorithms have been tested on models of the brain neural networks before. But what Tim and his colleagues did is have one neural network learning from another. That way the teacher network could use a completely random rule that the learner would have to figure out.

Tim - So what we found was that almost independent of the actual learning rule that any neural circuit uses, if you simply add redundant connections, the network will learn faster. So, to take an example, I could think of a map of the country and I could think of all of the roads between two points. And we could have a connection between neuron a and neuron B and instead of just being a single connection there'd be multiple alternative routes just like there'd been multiple possible roads you could take from one city to another.

Phil - Scientists have known about these redundant connections in our brains for a while but this result might finally explain them. They actually seem to help us learn quicker, but that's a confusing idea. How can redundant connections be useful? Well funnily enough Tim says it's a little bit like hiking.

Tim - So if you imagine you're out here and it's very very foggy, and that does happen, and all you can see is the few square feet around your feet and you're standing on a slope but you'd like to get to the bottom of that slope. What do you do? You follow the steepest.

Phil – Yeah. You go down where you can see it goes down.

Tim - Exactly. But then if you think about the wider landscape, what you might be doing is following the slope down into a local gully.

Phil - Right. You might end up in like a force like dip.

Tim – Exactly. And up in some kind of gully.

Phil - What does this have to do with learning?

Tim - The way learning works is you can think of the height of the hill as a measure of how badly you're doing a task. The higher up the hill the worse you're doing so what you want to do is get to the bottom. This is essentially how all learning rules work. And what we found was that adding these redundant connections to the brain actually smooths out the area landscape, so it makes the crinklyness smaller relative to the immediate slope underfoot.

Phil - It would be like it is here, a very simple slope down to the bottom.

Tim – It’s a very simple slope and the slope doesn't change much as you move around.

Phil - This idea that redundant connections help us learn. That is result number one. Number two has to do with another part of Tim's model and that's the noise. In real life, the chemical transmissions between our neurons aren't perfect and sometimes they mess up. That's what's called intrinsic synaptic noise. People don't include this noise when they programmed neural networks and with those networks the bigger they are the better they do. But Tim and his colleagues did include it. And when they did, they got to a point where bigger stopped equalling better. And that is where the noise started to drown out the signal, the signal being how we learn. What they found is that there's actually an optimal size for a neural network that's trying to learn something

So, what does that mean? Say I'm God. I want to create a brain to learn a task. Here is how I do it. I'm making neurons and adding brand new connections to those neurons until the brain is physically able to learn this rule. Then I start adding redundant connections between neurons that are already connected, and this makes the learning quicker. But I only add them up to the point where this synaptic noise becomes too great. And there you go. This is only for one learning task but I've made the perfect brain.

DRUG DISCOVERY

25:32 - New drugs for mental illness

Why is there a paucity of new drugs for mental illness?

New drugs for mental illness
with Santiago Lago, Cambridge University

Mental illness is, unfortunately, very common. And although there are drug treatments for many psychiatric conditions, they all have side effects and very few genuinely new drugs have been discovered in decades. But now that might be about to change. Using blood cells from patients with mental health disorders, scientists at Cambridge University have found a way to identify potential new targets for drug discovery. Katie Haylor spoke to Santiago Lago, who worked on the study. Firstly, Katie asked, why the paucity of new drugs for mental illness?

Santiago – It turns out actually that up to 75 percent of patients do not respond fully to the drugs that exist and this is because we don't really understand what causes the diseases. We don't have very good ways of testing new drugs in the labs. So, for example, you can't really ask a laboratory mouse whether it's depressed. It's not easy to access live brain tissue from patients and also actually when we talk about diseases like schizophrenia we're not talking about a single disease, there are actually many different types of schizophrenia.

Katie - Okay. So, what are you doing differently then? How does your approach work?

Santiago - What we're doing differently is actually using patient blood cells as an accessible way to test new drugs. So, I mentioned that it's difficult to take live brain tissue but it's obviously much easier to take a blood sample and use live blood cells. Blood cells actually share many of the pathways which brain cells use to function. What we're doing here is we're testing those shared pathways to see if they can reveal new drugs. And another thing that we're doing differently is instead of simply counting genes and proteins we're actually focusing on cellular behaviour.

Katie - Can you tell us about what you did in this study, specifically how many people's blood we looking at?

Santiago - So initially we took a cohort of patients with schizophrenia and healthy controls, although that's a very relative term. Who is who is healthy, who is normal? But for the purpose of argument we took a group of 12 patients with schizophrenia and 12 healthy individuals. Then we used robots in the lab to culture their blood cells with a range of chemical compounds. We then painted the cells with fluorescent dyes which allow us to look inside the cell and see how the proteins are behaving differently. And then we measured each individual cell using a laser based technology called flow cytometry. So, this actually allowed us to examine how the blood cells from patients were behaving differently than healthy controls.

Katie - Okay and how are they behaving differently thn?

Santiago – Actually, in a number of ways for the purpose of this study we focused on the most important response, or the one that we saw that was most drastically different in the patients. The cells from schizophrenia patients used calcium in a different way within the cell. So calcium in the cells in our body, it’s a way that the cell communicates inside, and it turns out that when we administered a certain drug to these schizophrenia cells they used calcium differently within the cell.

Katie - And is this new information this calcium response?

Santiago - This particular response is. I mean calcium has been known to be involved in these disorders, but we have discovered a new protein which responds to the calcium differently in patient cells.

Katie - So how could this translate then to finding drugs to treat schizophrenia? What's the next step I guess?

Santiago - So that's really what it's all about. Then what we did was to see which drugs could actually fix this abnormal calcium response. And we looked at a large library of existing drugs, so ones used to treat other diseases and many of which you'd actually find in the pharmacy. It turns out that drugs that are used to treat diseases like hypertension or anti-arrhythmias or. anti-inflammatory drugs actually are able to fix this calcium response in schizophrenia.

Chris - How do know though, Santiago, that if you give that drug and it fixes it in a blood cell it's going to fix a brain cell?

Santiago - That's a very good question. In this study what we did was to compare the activity of the drugs in the blood cells with their activity in human nerve cells, so we see that the drugs actually work in nerve cells as well. As a follow up as well, we tested whether the cellular response was able to predict the response to clinical treatment in an independent patient cohort. So this this really opens up the way for using it for personalized medicine.

Katie - It sounds like the logic of using pre-existing drugs is that you're not having to make an entirely new drug which costs a lot of money and takes a lot of time?

Santiago - Absolutely. It's about using drugs which we know are safe in humans and it provides a means to bring them to the clinic in less time and at a lower cost.

ADULT ASLEEP

30:56 - Rock-a-bye adults

We rock babies to sleep, why not adults?

Rock-a-bye adults
with Helen Keyes, Anglia Ruskin University

Perceptual psychologist Helen Keyes from Anglia Ruskin University has stumbled upon a slumbering story on sleep, and she spoke to Katie Haylor...

Helen - This paper was looking at the best way to get a good night's sleep. And specifically, the best type of sleep environment and whether sleep can improve our memory performance also.

Katie – Right then. So, what did they do and what did they find?

Helen - Well contrary to what we might naturally assume that a quiet environment with a lack of any sort of stimulation might be the best way to get a good night's sleep. These authors thought that maybe a rhythmic rocking motion might induce a deeper sleep and they hypothesized that this might be because rocking can tune in to the particular neural patterns that are happening when you're going to sleep and perhaps regulate those.

Katie - So we rock babies stereotypically to sleep. Is this suggesting that we potentially should be rocking ourselves as adult, is not too farfetched really.

Helen - I love that idea. So, we do rock babies and I think it's really nice because it's something everybody naturally does when they have a child in their arms or a baby in their arms. And it suggests that it really might directly help people to go to sleep and enter that deep sleep more quickly.

Katie – Okay. So, let's dig into the science. How did they do this and what did they find out?

Katie - Okay. So, they took 18 healthy participants and there was quite a bigtime investment from participants here they had to sleep in the sleep lab for three nights in a row. So, the first night was just to get used to being in the lab environment and settling into sleeping there. The second two nights were experimental nights. So, on one of those nights you would be asleep on a bed with a motor beside you that could rock the bed. And that motor was on but not rocking the bed, so you could hear the noise of the motor, but it wasn't rocking you, that was a control. The second night you would be in the same bed but the motor this time would be attached to the bed and very gently rocking you in a consistent pattern all night. And those nights were alternated between participants, some had rocking first and then no rocking and vice versa. And while they were doing this people's neural activity was recorded while they were asleep. And participants also performed a memory task prior to falling asleep each night and when they woke up the next morning, which was a word pair association task. So we were able to see whether their memory was improved by the rocking.

Katie – Okay. This sounds like a very nice experiment to partake in. I personally would quite enjoy that I think. What did they find out?

Helen - So they found really interestingly by looking at your EEG patterns we can look at what's called your sleep architecture and that's really just how deeply asleep you are. You can you can record this, there's patterns of activity in the brain that show how deeply asleep you are and they're called Sleep oscillations. And they found that when participants were in the rocking bed their sleep oscillations showed that it sped up your entrance into a deep sleep. So you fell into a deeper sleep more quickly and also the length of time you spent in that deep sleep was lengthened when you were rocking. And they could correlate this with the EEG activity and it showed that the rocking motion seemed to be synchronizing your neural activity, those sleep oscillations, and synchronizing them together to get you into that deeper sleep and keep you in that deeper sleep for longer.

Katie - This sounds great considering how many people struggle with sleep. Do you think people, companies should be making adult sized rocking beds?

Helen - Well they absolutely should. This sounds like a lovely potential clinical tool for treating insomnia. Even on a population level, if we look at for example our ageing population which is a population that has particular trouble with falling asleep and staying in deep sleeps, this sounds like it could be a really nice mechanical, direct intervention into people's sleep without relying on drugs or other therapies.

Katie – Or, of course, you just go out and buy a hammock.

Helen - Absolutely that'll be fantastic.

Katie - So what else did they find? Because you said before that they were testing memory.

Helen - They also found that participants who had been in the rocking condition that night, the next morning their memory was improved. So this is lovely, this suggests to us that entrance into that deep sleep caused by rocking can improve your memory and it does suggest to us that maybe if you want to improve your memory for a big exam the next day you should sleep in a hammock. The patterns that they were looking at where these sleep oscillations are occurring happen in a part of the brain called the thalamal cortical network. And this part of the brain is really important for consciousness and wakefulness, as we'd expect with sleep, but it's also largely responsible for your memory attention things like that. So it makes sense that this would be linked.

Katie – And, of course, if you get a bad night's sleep most of us have probably witnessed that memory does decline?

Helen – Yes, this is absolutely well documented. So this is a nice route to improving your memory as well as loads of other benefits from getting a good night's sleep.

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