UMC Utrecht Brain Center Special

UMC Utrecht Brain Center English edition | 2018 - 2019 | NewScientist.nl

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CUTTING-EDGE SCIENCE FOR BETTER TREATMENT

Together we invest in the future Science has a key role in the pursuit of smart and sustainable solutions for societal issues.

Through the research themes Dynamics of Youth and Life Sciences, Utrecht University and UMC Utrecht make a valuable contribution to specific questions concerning child development and health. We aim to increase our impact by tackling these issues in a multidisciplinary fashion, together with our societal partners, patients, parents and children.

www.uu.nl/youth “Utrecht has a unique position within the field of brain and language research in the Netherlands. Together, we can unravel how the young brain develops, and discover what causes developmental disorders.”

Prof Jeroen Pasterkamp, principal investigator of the interdisciplinary theme The first 1001 days of a child’s life

www.uu.nl/lifesciences “Utrecht is leader in the development of miniature organs from human tissue, also called organoids. These models give us better insight into the treatment of diseases, and offer unique chances for the development of new personalised treatments.”

Prof Madelon Maurice, leader of the Utrecht Platform for Organoïd Research

introduction ht UMC Utrec r te n Brain Ce

More information about UMC Utrecht Brain Center can be found at www.umcutrecht.nl/en/Research/ Strategic-themes/Brain-Center

Focusing on the brain

Jeroen Pasterkamp

Frank Miedema

Chairman of UMC Utrecht Brain Center

Member of the Executive Board UMC Utrecht

UMC Utrecht Brain Center brings together all knowledge of and expertise in healthcare, education, and research relating to the brain within UMC Utrecht. All with the same goal: cutting-edge science for better treatment. What does this entail? Spending time with patients, like in Project MinE. But also collaborating, both at UMC Utrecht Brain Center and internationally. Encouraging talent. Using the most advanced technologies, like we see in the work done with imaging and brain organoids.

More examples? Read about them in this special edition.

UMC Utrecht Brain Center is one of the focal areas of UMC Utrecht. This means many years of focus and investment within the field.

It covers a broad range, from psychiatry and neurology to translation neuroscience.

UMC Utrecht Brain Center is supported in this by valuable partner institutions at the Utrecht Science Park.

Collaborating, on this broad basis of support, provides patients, research, and society with added value.

This special is full of excellent examples of this.

In the regular editions of New Scientist, we write about a wide variety of fields and subjects: from physics to the quantum computer and DNA to robotization. In this special, which came about in collaboration with UMC Utrecht, we have a specific focus: the brain. Sometimes it’s nice to have a focus, because it lets us address matters in depth.

In Utrecht, pioneering neurological research is being done and a range of scientists will explain how their ideas are changing the world. Read about brain organoids, the living mini-brains made of human cells. Together with colleague Marleen Hoebe, I visited Manon Benders, professor of neonatology at Wilhelmina Children’s Hospital and expert in this field.

The research she is doing involving premature babies is fascinating and could change the lives of vulnerable children in the future. Happy reading.

Jim Jansen

editor-in-chief jim@newscientist.nl @jimfjansen (Twitter)

Follow us on Twitter twitter.com/ U_BCRM UMC Utrecht Brain Center | New Scientist | 3

contents

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Interview 08 Ludo van der Pol Finally, there is a medicine for children with spinal muscular atrophy. It doesn’t mean a cure, but it does make life much more enjoyable.

Neurologist Ludo van der Pol on his work and his patients.

Commentary 26 Brain organoids Living mini-brains made of human cells offer an opportunity to learn more about conditions such as Alzheimer’s, ALS, and schizophrenia.

20 Manon Benders Neonatologist Manon Benders studies the brains of babies. Her goal? To understand how premature babies develop.

4 | New Scientist | UMC Utrecht Brain Center

Feature 14 Brain power People with locked-in-syndrome are trapped in their own brain.

Researchers develop brain-computer interfaces that allow them to commu­ nicate.

30 This is what they do Four enthusiastic scientists searching for the best answers to their questions.

32 Super scanner There are only a few of them in the world and UMC Utrecht has one: a 7-Tesla MRI scanner.

What can a super scanner like this do?

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COLOPHON

UMC Utrecht Brain Center English edition | 2018 - 2019 | NewScientist.nl

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publication

Editor-in-chief Jim Jansen Editors Jaap Augustinus (photo editor), Emmeke Bos, Yannick Fritschy, George van Hal, Marleen Hoebe, Joris Janssen, Wim de Jong (final editor), Aafke Kok Translation Cait Kennedy Tel +31-(0)88-700 2931 Email redactie@newscientist.nl (for press releases), info@newscientist.nl (for questions for the editors only), lezersservice@veenmedia.nl (for membership questions and changes) Postal address PO Box 13288, 3507 LG Utrecht, the Netherlands Address Herculesplein 96, 3584 AA Utrecht, the Netherlands Contributors to this issue Pepijn Barnard, Bram Belloni, Bart Braun, Bob Bronshoff, Marieke Buijs, Monique Kitzen, Maaike Putman, Jolein de Rooij Basic design Sanna Terpstra (Twin Media bv) Design Miranda de Groot (Twin Media bv) and Pascal Tieman Brand manager Martine Verheij (martine.verheij@veenmedia.nl) Marketing Milou Snelleman Sales Value Zipper (info@valuezipper.nl +31-(0)20-2105463) Sr. account manager B2B Alex Sieval (alex.sieval@veenmedia.nl) Production manager Sonja Bon Printing Habo DaCosta bv Distribution Alipress (NL), AMP (BE) ISSN 2214-7403 The publisher is not liable for damages as a result of printing and typesetting errors.

CUTTING-EDGE SCIENCE FOR BETTER TREATMENT COVER PHOTO: BRAM BELLONI

20 Interview ‘Ultimately, we want to use brain scans to predict how premature babies will develop’

Focus 06 Up close Visualizing soft tissue with diffusion MRI. 12 Insight Working on ALS. 18 Virtual shopping Going to the supermarket can be tricky for people with ALS or a psychosis. They have trouble with crowds. The virtual supermarket offers a helping hand.

CUSTOMER SERVICE 0031 88 - 700 2777 or from Belgium: 0031 88 700 2777 for contact concerning membership, orders, changes, and questions. Or email klantenservice@newscientist.nl or go to newscientist.nl/faq The Netherlands PO Box 11249, 3004 EE Rotterdam, attn Veen Media, Utrecht Belgium PO Box 102, 2910 Essen, attn Veen Media, Utrecht Pricing 11 issues per year, incl. postage Subscription € 92.85; young people €68.50; Europe €121.42; outside of Europe €141.22 Cover price €8.50 (excl. postage) Subscriptions are concluded until notice of termination, unless otherwise specified.

Column 35 Column Yes, we should be wary of big data, according to Jim van Os, but we should also benefit from it.

COPYRIGHT This Dutch edition of New Scientist is a monthly publication of Veen Media, under license from Reed Business Information Ltd. © 2018 Reed Business Information Ltd. All other copy © 2018 Veen Media. The logo and other trademarks of New Scientist are the property of Reed Business Information Ltd. Nothing in this publication may be copied or stored in a database or retrieval system in any way without the written permission of the publisher. The publisher has endeavored to fulfil all legal requirements relating to the copyright of the illustrations. Anyone who is of the opinion that other copyright regulations apply, may apply to the publisher. This edition came about in collaboration with Brain Center Rudolf Magnus.

UMC Utrecht Brain Center | New Scientist | 5

FOCUS

ILLUSTRATION: MAAIKE PUTMAN

‘We are developing new methods for improving the visualization of soft tissue, like that of the brain, using diffusion MRI,’ says Alexander Leemans, physicist and professor at UMC Utrecht.

‘The diffusion process offers information about the characteristics of the underlying tissue and can be used to study diseases, among other things. On the one hand, we are trying to measure the diffusion process more accurately using new MRI images. And on the other hand, we can use our new algorithms to improve the processing of the recorded diffusion information, which leads to improvements in the characterization of these tissues. The longterm goal of our research is, in addition to earlier diagnosis, to gain more insight into the causes and the course of specific diseases, so that we can improve the targeting of treatment.

‘I am conducting this research in the PROVIDI Lab at UMC Utrecht. I have been blessed with an excellent team of young researchers (PhD students and postdocs) who have a drive that is similar to mine. But I almost always collaborate with others outside of my own research group, both within UMC Utrecht (other divisions) and nationally and internationally.’

TEXT: JIM JANSEN

Imaging

Interview with Ludo van der Pol

‘For the first time, we are able to do something’

Ludo van der Pol has been working with SMA patients for eighteen years. They have a genetic disorder that causes their muscles to waste away and for which there is no cure.

Until now.

By Bart Braun Images: Bram Belloni

‘I

n severe cases of spinal muscular atrophy, or SMA, the mother knows something is wrong during the pregnancy. In the third trimester, the child’s movements decrease. Children with SMA are floppy babies: they are very weak. This is seen in combination with several neurological disorders, but SMA typically presents itself in a pattern: the babies are very much alert, combined with lack of movement. The child would appear to be normal at birth, and a few weeks later there would be no chance of survival. We doctors were unable to offer anything.

‘There are four different types of SMA. The earlier it presents itself, the more severe the symptoms. Type 1 is diagnosed in newborn babies. They will never be able to sit, and the majority will not live to see their third birthday. Children with type 2 will never learn to walk. Type 3 is considered the ‘mild’ form, but it is not really mild at all. Some patients can walk for dozens of years, others end up in wheelchairs at the age of twenty. Type 4, in which symptoms develop after the age of thirty, is relatively rare.

‘Patients with SMA lack the SMN1 gene that codes a protein known as SMN, which is needed in all sorts of cells. The classic story is that, without SMN, the nerve cells in your spinal cord that control your muscles, the so-called motor neurons, die off. Because your muscles are no longer being stimulated, they waste away. We now know that this protein also plays a role in the muscles themselves and that other tissue is also affected when there is no SMN. The cells of the heart, for example, UMC Utrecht Brain Center | New Scientist | 9

and the cells involved in your sugar metabolism. The cells in your motor nervous system are just the most sensitive, so their loss is the most noticeable.’

Course of the disease

A normal school Yuxia Jiang’s daughter Caroline has SMA. ‘A child with SMA demands a lot from you as a parent, both physically and mentally. Because of her muscle problems, Caroline isn’t able to do much by herself and I have to help her with everything. Mentally, it occupies your mind constantly.

The course of the disease is difficult to predict, which causes a lot of worry. The future is not always something to which we look forward. I am very happy and grateful for the help from the hospital.

The doctors and researchers show a great deal of compas-

sion and try their very best to help us, to ensure that our daughter can go to a normal school when she is older. That really touches me. Caroline is now receiving full-time treatment with nusinersen. It helps her to lift up her arms and head, and she can even stand a bit with my help. We are always prepared to collaborate when researchers need our input. New drugs are already being developed, so we hope they will be available here soon. Despite everything, we try to remain positive, with all these new scientific developments.’

10 | New Scientist | UMC Utrecht Brain Center

‘If you genetically modify test animals and remove the SMN1 gene, the animals all die before birth. You cannot live without this protein. The reason that SMA patients are able to survive, initially, is that humans have a similar gene, SMN2. Because not everyone has an equal number of copies of this gene and not every copy of the gene results in the same amount of protein, the course of the disease varies greatly between patients.

‘Since December 2017, we are permitted to proscribe the drug nusinersen to SMA patients with type 1 and 2 and to some type-3 patients. In practice, the drug is now given almost exclusively to children aged five and below.

‘The active substance is a small bit of DNA-like material that affects the reduction of the SMN2 gene. It ensures that more SMN2 protein is created.

‘This injection doesn’t mean that a sick patient is transformed into a perfectly healthy child; there are no drugs like that for congenital defects. For babies it means survival. And motor development also improves: they can reach motor development milestones, like sitting. Their further development is still uncertain. In older children, we see that they learn to improve movement, for example an increase in arm function, and that there is no more deterioration of the things they were already able to do. It’s not a cure, but it is a giant step in the right direction. We can really make life a lot more enjoyable for these children.’

A real difference ‘Even more important is that this drug is a proof of concept: this type of medicine can be developed, and it works. There has been an enzyme-replacement drug for Pompe disease for the past twelve years, but nusinersen is the first comparable drug since then to really make a difference. Now a diagnosis no longer means the end of the line; we are able to do something.

‘At the moment, this drug is still very expensive. Patients will need it their entire lives. The debate concerning the maximum

interview

‘It is extremely important to converse with people: what really matters to you?’ price of medication is about limits and cost efficiency. It concerns not only this disorder, but it is something we will encounter with increasing frequency, because this is 21st-century medicine. We as a society must determine what we want, and how we are going to inform each other.

‘Spinal muscular atrophy and cystic fibrosis are two genetic disorders that are relatively common – there are a few hundred SMA patients in the Netherlands and approximately 1500 people with cystic fibrosis. This means these two diseases will determine how we deal with the rest. On the bright side: because these are the two

most common genetic disorders, they also make up the largest cost item.’

Patients’ stories ‘The Spieren voor Spieren [Muscles for Muscles] Children’s Center / SMA expertise center here at UMC Utrecht, of which I am the chairman, was set up in 2010. The parents of patients were complaining that it took too long for them to be put in contact with the right doctor, and the Spieren voor Spieren Foundation wanted there to be a specialized location for these patients. So, they ended up here in Utrecht. How did we get started? By seeing our young patients.

That story about cells and genetics is very important and has now resulted in treatment, but to really understand the disease requires more of the patients’ stories. We were in a privileged position, because many people wanted to tell us their story.

We also heard many things that were new to us.

‘For example, specialist literature on SMA ends at the age of 18. The interviews that we conducted showed us that deterioration continues into adulthood, even dramatically so. People become more and more dependent on others. When you end documentation at such an early age, you see teenagers who have lost the ability to walk but are still able to move themselves about in a wheelchair. But when you come across those same people in middle age, it’s shocking how invalid they have become.

‘First of all, research like this maps out the need for new therapies. And it shed light on another issue: muscles are one thing, but endurance is another. The problem is often that SMA patients are still able to hold a fork, but that they have to stop after two bites. In our research, we focus on what precisely happens and what can be done about it. We have just completed a study of a drug – an inexpensive drug that you can take like a pill – that could improve endurance.’

Fear ‘Research like this, based on patients’ requests, really contributes to what they want.

It is extremely important to converse with people: what really matters to you? What problems do you come across? What could we do to make the sun shine a bit more for you? This dialogue takes place annually, with the help of the Princess Beatrix Fund for Muscle Disease. Many of our studies are set up this way. They cover chewing and food, but also psychological needs. How do people perceive you? How is your mood?

Do you have many feelings of fear?

‘We consult with psychologists, physical therapists, speech therapists, and other people that you might not speak too very often as a neurologist. Too often patients visit just to please the doctor. These are situations in which the doctor looks back at a conversation and is satisfied, while the patient has the idea that he is leaving empty-handed. We try our best to do it the other way around.’

UMC Utrecht Brain Center | New Scientist | 11

insight

ALS ALS (Amyotrophic Lateral Sclerosis) is a disease in which motor nerve cells die off. This causes people to lose control of their muscles. At the moment, there is no cure. Project MinE and its followup, Project TryMe, are devoted to discovering the genetic cause of ALS and to the development of drugs that can stop the disease.

People 1,500 people in the Netherlands have ALS. Every year, 500 people die of ALS, but there are also 500 new patients.

Life expectancy Life expectancy with ALS is 3 to 5 years after diagnosis. Most people are between 40 and 60 when they become ill.

Disease The disease affects the motor nerve cells, causing patients to become paralyzed.

Respiratory failure is the most common cause of death for people with ALS.

Group It has now been shown that ALS is not one disease, but a group of different diseases that all lead to the dying off of nerve cells.

12 | New Scientist | UMC Utrecht Brain Center

Hereditary The disease is hereditary in 10% of patients. But genes that play a role in the development of ALS can also be identified in the other 90% of patients. Twin studies have shown that 65% of the disease lies in the genes. The other 35% are environmental factors. What these are exactly is as yet unknown.

INFOGRAPHIC: PEPIJN BARNARD TEXT: EMMEKE BOS SOURCE: PROJECTTRYME.EU, PROJECTMINE.COM

Project MinE

10,000

22,500

The aim of Project MinE is to analyze the DNA of 22,500 people, to help track down the genetic causes of ALS. This will allow medication to be developed that tackles the root cause of ALS.

Currently, over 10,000 DNA profiles have been collected.

7,500 control subjects 15,000 ALS patients

Each DNA profile is 100 GB. To analyze all these profiles, the processing power of super computer SURFsara is being used at the Science Park in Amsterdam. So far, 20 ALS genes have been found. Thanks to Project MinE, more and more ALS genes are being added to this.

Project TryMe With Project TryMe, scientists hope to find drugs that can deactivate the ALS genes. Hopefully, this will make ALS a disease with which you can grow old.

2%

Patients are divided into groups on the basis of their DNA. This will make clear which treatment works for which genetic defect.

Participants monitor their own health with the help of wearables: wearable technology that, for example, counts their steps, records their breathing or notes their sleeping pattern.

25%

Project TryMe’s aim is for 25% of ALS patients to participate in drug research. This is currently only 2%.

The future Genes are copied into mRNA by means of transcription. Translation is the process in which mRNA is turned into protein. Potential drugs can stop this process in two places.

1 Drugs can ‘stick’ to the ALS gene in the DNA, so that it can no longer create harmful protein.

2 Drugs can take out the protein coded by the ALS genes.

Medicine

ALS gene

ALS gene Transcription

Transcription mRNA

mRNA Translation

Translation Protein

Protein

Symptoms ALS

Medicine

Symptoms ALS

UMC Utrecht Brain Center | New Scientist | 13

Freed from the brain Patients with locked-in syndrome often have excellent cognitive abilities but are locked in their brain due to paralysis. Researchers at Brain Center Rudolf Magnus are developing brain-computer interfaces that allow these people to communicate again.

By Jolein de Rooij Image: Bram Belloni

T

he late, great scientist Stephen Hawking was also the world’s most famous ALS patient. At the end of his life, the discoverer of Hawking rays used his cheek muscles to select sentences, words, and letters and have them spoken by a speech synthesizer. However, Hawking ran a great risk of becoming ‘completely locked-in’. In anticipation of this fate, he began working with researchers at Intel, at the beginning of this century, to develop a system that translates the brain activity patterns behind facial expressions into actions. This system would never see the light of day.

Hawking would, therefore, have been very interested in the achievements of a research team at Brain Center Rudolf Magnus. In 2016, this team, led by professor 14 | New Scientist | UMC Utrecht Brain Center

Nick Ramsey, made headlines worldwide with a system that patients with locked-in syndrome (LIS) can use autonomously, at home, day and night, to call a carer and to communicate. A 58-year-old ALS patient learned to use the system to make ‘brain clicks’ with which she can select letters on a screen attached to her electric wheelchair. She does this by trying to touch her ring finger with her thumb. Even though this doesn’t result in a real movement of the hand, the system catches the motor signal and generates a click on the screen.

‘The greatest thing is that I can go outside again and that I can communicate,’ the first user told New Scientist in 2016.

No bells and whistles Since then, the team has been hard at work on new and improved methods of translating brain activity into all types of useful actions for people who have lost control of their muscles. Patients with locked-in syn-

drome are so severely paralyzed that they can hardly move. Speaking is almost impossible. ‘Many people think that a life with such a severe disability is not worth living,’ says researcher Mariska van Steensel. ‘However, French and Swedish research has shown that the quality of life of these people is surprisingly high. But the ability to communicate is very important.’

BCI’s may make this possible. A BCI, or brain-computer interface, is a device that turns brainwaves into action. In the BCI created by Ramsey’s team, the electrodes are attached directly to the brain itself. This is done through a number of small holes in the skull, ensuring that the quality of the brainwaves and the reliability of the system are the highest. Two strips of four electrodes send signals to a transmitter that has been placed under the skin of the chest and sends signals wirelessly to a computer.

‘Ramsey’s research team is among the global pioneers in BCI,’ says Femke Nijboer, professor of health, medical, and neuropsychology at the University of Leiden. ‘The team combines fundamental research with practical research and has a strong methodological foundation. The great thing about the BCI system that they have developed is that the patient from the first experiment in 2016 is still using the system today. It also meets the most important user requirements for this type of system: no wires, no bells, and no whistles, just very practical.’

The ALS patient can use the BCI to call her carer, she can use it to communicate, and also to change the channel on her TV. All this is possible because, following an intense period of training, she was able to use the power of her brain to produce a ‘brain click’, which is reliable almost 90 percent of the time. Van Steensel: ‘She is currently averaging three letters per minute.’ A second person is now also training with the system.

fMRI as a predictor The success of the Utrecht research team is the result of over a decade of research into human brain mapping. Ramsey: ‘Brain functions are organized spatially within the brain. Different areas have different funcUMC Utrecht Brain Center | New Scientist | 15

brain-computer interface

tions.’ For example, individual body parts have their own ‘control center’ in the brain, which is responsible for controlling and feeling movement.

To find positions on the surface of the brain that are particularly suited for BCI, many different areas of the brain had to be studied, for which the team required a steady stream of volunteers. They found them thanks to the cooperation of epilepsy patients, who came to Brain Center Rudolf Magnus to have temporary electrodes implanted under their skulls, directly on the brain, for diagnostic purposes. ‘For many years, we asked epilepsy patients to have an MRI before getting their implants,’ says Van Steensel. ‘We asked them to perform a task, like a specific hand movement.’ Using special technology – the functional MRI (fMRI) – their brain activity was visualized in a three-dimensional image. ‘It shows specific spots on the surface of the brain lighting up.’

After the diagnostic measurement electrodes were implanted, the team asked the 16 | New Scientist | UMC Utrecht Brain Center

test subjects to repeat the task. ‘This is how we tested to see whether fMRI can be used as a reliable predictor of the location where the most substantial changes in electric brainwaves take place when performing a certain task. This proved to be the case. We also asked test subjects to play a kind of game, in which they used these brainwaves to move a ball on a computer screen. This allowed us to study the extent to which patients were able to control the signal that they could send from a specific area of the brain.’

Smart signal processing In order to develop the world’s first BCI that could be used at home, the team made a number of smart choices. The team concentrated on a number of areas on the outside of the brain, where activity is relatively easy to interpret. This includes, for example, the area that controls the hands.

In addition, the team was looking for brain functions that can be controlled by will. ‘You want to be able to detect a signal

with which you can help people with severe disabilities,’ says Ramsey. ‘This means that the patient has to be able to control the signal and that noise has to be suppressed as much as possible.’

The signal must also be extremely reliable. Ramsey: ‘Our greatest challenge is preventing false positives. You have to make sure that the system doesn’t detect a false click when someone isn’t trying to click.’ This can be rather difficult, because the brain is ‘very unruly’, according to Ramsey. ‘It responds to everything,’ he says. ‘For example, the motor cortex becomes active as soon as you see someone else move or even think about movement.

We’ve had to use quite a few tricks to filter out the activity that is generated on purpose.’ On top of that, the biofeedback that the user gets during the training period alters the signal. ‘This means we also have to refine the processing of the signal. So, the placement of a BCI really stimulates interaction between humans and machines.’

lyzed people to control their own muscles again,’ says Ramsey.

But in the short term, Ramsey also sees promising applications for BCIs on the horizon. ‘It is possible that, in the future, BCIs could offer practical treatment of strokes.

Usually, a brain hemorrhage only takes place in one hemisphere of the brain. You then lose certain functions on one side of your body, because the pathways or gray matter in the corresponding hemisphere are damaged. However, there are indications that you can read a lot of information on the healthy side of the brain relating to what the injured side of the brain is trying to, albeit unsuccessfully. There is a chance that, in the future, people will be able to recover part of their lost functions following a stroke, thanks to BCIs.’

The least effort Speech using brain power The team is now also working on other ways to help LIS patients communicate. ‘In future versions of the BCI, we want to offer people even more control options,’ says Van Steensel. ‘We want to do this by making optimum use of the bounteous way in which the brain is organized. The area that controls the hand lends itself to this because it is relatively large, which makes it easier to distinguish between different movements.’ Ramsey: ‘Think of the surface

– p,k,a, and u – from the brainwaves of three different epilepsy patients. This research may make it possible for paralyzed people to learn to speak through a computer using brain power. ‘I think it might take another ten years before we become so good at it that we can try it with paralyzed patients,’ says Ramsey. ‘What we would like most of all, is to send the brainwaves generated by speaking out loud within the mind to a speech synthesizer, one by one.’

The potential applications seem endless.

‘What we would like most of all, is to send the brainwaves generated by speaking out loud within the mind to a speech ­synthesizer, one by one.’ of the brain as a screen that shows what the person is doing at that moment.’ In 2016, Ramsey’s team succeeded in distinguishing between four different signs in American Sign Language, thanks to smart signal-processing methods and intricate brain implants – again, in epilepsy patients. In addition, the researchers are focusing on the areas of the brain that control the tongue, the lips, the jaws, and the vocal cords. In 2017, Ramsey described how he could recognize four different phonemes

For example, in 2016, a research team led

by Professor Robert Gaunt of the University of Pittsburgh succeeded in having a 28-year-old man not only move a robot arm using a BCI, but also feel sensations of touch in his artificial fingers. These types of systems are currently too heavy and impractical for daily use. ‘Far in the future – I think thirty years is being optimistic – it will probably become possible to attach small computers the size of grains of rice to nerve-muscle connections, enabling para-

At the moment, many people with lockedin syndrome shy away from the brain surgery that is required for placement of a BCI. ‘That fear is understandable,’ says Van Steensel. ‘The only thing these people have is their ability to think. That makes taking the step to having brain surgery a difficult one.’ Femke Nijboer: ‘The real risk is much smaller than people think. The placement of a BCI is comparable to that of a cochlear implant (a system that communicates directly with the acoustic nerve), which is considered to be far more normal.’

Meanwhile, Ramsey’s research team is working on more intricate implants and smaller and more powerful transmitters, in collaboration with engineers at the ­Italian Consiglio Nazionale delle Ricerche (CNR). ‘In the future, operations on all fronts will become even less invasive,’ says Ramsey. For example, there are plans to place the implants not directly onto the brain, but on the cerebral membrane.

That is the tough membrane between the skull and the brain. ‘That would mean it’s no longer brain surgery.’

At the same time, the team is continuing its research into the wishes of potential users. Van Steensel: ‘These types of aids can only be successful if they are ­actually of use to the target group. That is why an intrinsic part of all our research is to work with users to see what works best with the least amount of effort.’

UMC Utrecht Brain Center | New Scientist | 17

By measuring eye movements, researchers can map out what patients are looking at. Warm, red colors indicate that someone has been looking at this point for a long time. Blue means a shorter time spent looking.

18 | New Scientist | UMC Utrecht Brain Center

With the help of a VR headset, researcher Tanja Nijboer is testing the virtual environment.

To market Patients who have had a stroke, suffer from psychosis or have ALS often have difficulty coping in busy situations. A visit to the supermarket can be hard.

The virtual supermarket offers a helping hand.

By Aafke Kok

P

eople with one of these illnesses may, for example, experience difficulty finding products in a supermarket. In the virtual supermarket, researcher Tanja Nijboer slowly increases the busyness of the environment. How do patients adapt their strategies to a busier supermarket compared to the control group? The answer to this question may help in making diagnoses. Sometime in the future, Nijboer would like to use the virtual supermarket to adapt treatments to the specific problems that patients are dealing with.

UMC Utrecht Brain Center | New Scientist | 19

interview with Manon Benders

‘Life doesn’t begin at birth, it begins in the womb’ Wilhelmina Children’s Hospital at UMC Utrecht is home to the most expert knowledge relating to neonatal neurology in all of the Netherlands.

This children’s hospital is one of the nine Dutch specialized maternity centers. We spoke to professor Manon Benders about studying babies’ brains prior to birth and in premature babies, stem cell research, and the ‘soft’ side of research.

interview

Text: Marleen Hoebe and Jim Jansen Photography: Bob Bronshoff

Can you study babies’ brains?

‘I was in Geneva last year, where I learned about a special application of MRI technology from a neonatologist, whose experience was mostly with newborns. This technology allows you to measure the size and maturity of the brain directly after birth.

This knowledge has enabled me to put together a research group. We are now also studying the brains of babies prior to birth, in collaboration with gynecologists. Because life doesn’t begin at birth; the baby is alive and is developing in the womb. We place the coils of the MRI scanner on the mother’s abdomen. This gives us an image of the entire baby, and allows us to study the brain in detail.’

Are newborn babies affected by the MRI scanner?

‘There are no risks related to MRI research, because it uses magnetic fields and not radiation. The scanner does make a lot of noise, but newborns are given triple hearing protection. First, they are given yellow earplugs, then earmuffs over that, and, finally, an acoustic hat that blocks a third of all sound. The children just go on sleeping.’

What do you see on the brain scans?

‘In the final trimester of pregnancy, the brain develops from smooth to folded, just like the adult brain. This development takes place over the course of ten weeks.

22 | New Scientist | UMC Utrecht Brain Center

It’s incredibly fast, very bizarre.

‘The brains of premature babies, born from twenty-four weeks, are completely smooth.

Their brain development takes place in an incubator at the hospital. In the incubator, the conditions are very different, and the process can be disrupted by the medication they are given, or by the ventilator they are on.

‘The brains of premature babies are often a lot smaller than those of healthy babies. They are often surrounded by a lot of fluid and water. If you were to measure the circumference of the skull, it would seem they their brains are the same size as those of healthy babies, but that is not the case.

We see that many of these children have developmental problems, such as behavioral, learning or psychiatric disabilities, later in life. The brain lags behind. The question is whether they will, ultimately, catch up and whether we can influence this development. That is what we are currently studying.’

motor development and psychological development. And doctors also look at the number of hospitalizations and the quality of life. Sometimes these doctors build up such a good bond with the parents, that they are later invited to a patient’s graduation or wedding.’

How do you study whether premature babies are able to catch up?

‘In the Netherlands, we adhere to a limit for premature babies. Babies born at less than twenty-four weeks are not actively

‘For us, it is a must to see babies again after

Do you find that premature children experience severe problems in later life?

‘It depends on what you mean by severe.

Many children continue to have problems, such as ADHD. But many people with ADHD lead wonderful lives. A large percentage of these children also display characteristics of autism. These children are less likely to have a relationship or a job in later life. Sometimes, they have difficulty holding their own in society. Occasionally, there are distressing cases, such as children with multiple severe disabilities. Fortunately, that is a minority.’

Can these distressing cases be prevented?

‘The brains of premature babies are completely smooth.’ treatment, to see how they are doing. It is only when you know that, that such intense and radical treatment can be justified. We want to know how they develop. After they have been released from the hospital, we see the children periodically from the due date of forty weeks – at six months, fifteen months, three and a half years, five and a half years, and eight years. We monitor

cared for, because their chances of survival are so slim, and they are likely to experience severe problems in later life. Half of the babies born at around twenty-four weeks survive. After that, the chance of survival increases by 10 percent with each week of pregnancy. After twenty-five weeks, there is a greater chance that the baby will survive.

detailed explanation of what they can expect. As long as parents are well informed, we are usually able to come to a decision together.

‘Sometimes the decisions are very difficult. When I was expecting my second child, I got a call from Tilburg when I was around twenty-four weeks pregnant. They had a premature baby there that was born at twenty-three weeks and was very active, and they were asking if we would treat the child. Saying no, when you are carrying a baby of around the same age, is terrible.’

Where does this interest in premature children with developmental difficulties come from?

CV

‘Very early on, in the second year of my medical studies, I knew I wanted to be a neonatologist. I was attending the birth of twins at twenty-six weeks. I found it so fascinating that I thought: this is the work that I want to do. I was interested in cognitive development of babies born prematurely or with difficulties.’

Manon Benders Born 24 January 1969 in Hellevoetsluis 1999 PhD in medicine, University of Leiden 2003 – 2008 academic position in neonatology, Wilhelmina Children’s Hospital Utrecht 2006 – 2007 academic position, University of Geneva, Switzerland 2009 – 2015 neonatology staff member, University Medical Center Utrecht 2014 consultant and clinical researcher, King’s College London, UK 2015 – present professor of neonatology, University Medical Center Utrecht

‘Babies under twenty-four weeks are born, but not treated in intensive care. We always take into account whether the intensive care that the child requires, but that can do damage, bridges the situation to improvement. If you know that children may be severely handicapped, we believe we should not treat them. This is done from love, to prevent severe suffering.’

How do you decide to terminate treatment?

‘When expectations are that prospects will be grim, we always make the decision with a team of doctors, nurses, and, if necessary, other specialists. We take into account how many radical treatments would follow. The final decision is always taken in consultation with the parents. The parents receive a

What has been discovered within neonatology in recent years?

‘Neonatology is rather a recent development. In the past, it was practiced by gynecologists. It wasn’t until the 1970s and 80s that the field really took off. In the Netherlands, it is very well organized. Mothers who are about to give birth prematurely are transferred to one of nine specialized centers. This means that the appropriate support for child and mother is available.

‘A great deal of progress has been made.

The greatest breakthrough was right before the turn of the century, with surfactant, a drug that develops the lungs, ensuring a high chance of survival for babies with very immature, damaged lungs. Another important step is the drug that we give mothers prior to delivery for the development of the baby’s lungs. This means that babies have to spend less time on respirators and there is a less risk of cerebral hemorrhaging.

‘At first, we were preoccupied with the technical side of the field. Now we are going in the softer direction. We are more concerned with the babies’ comfort and UMC Utrecht Brain Center | New Scientist | 23

whether they are experiencing pain or stress. We also want to involve the parents much more in the care of these babies. At the Neonatal Intensive Care Unit (NICU) we are switching from eight beds in one large space to single rooms, so parents can stay with their babies. We believe this is better for the parents and the children. I think this is one way to make even more progress.’

‘We now have permission to give stem cells to newborn babies with cerebral ­infarctions.’

What would you like to accomplish with your research?

‘Ultimately, we want to use brain scans to predict how premature babies will develop.

That is why it is so important to see the children again further down the road, so that we know which factors and which brain structure will play a role early on.

This will enable us to begin treatment sooner. We can already predict cognition at early primary school age, because we can look at the network connections between the different areas of the brain. But life is 24 | New Scientist | UMC Utrecht Brain Center

more than just a high IQ. ‘I believe solutions are not only to be found in imaging. The children are hooked up to all kinds of measurement equipment.

Everything is monitored: brain activity, heart rate, breaths per minute, any disruption in oxygen levels, lab results, radiology results, every dirty diaper, when they are fed, how often they spit up, whether they experience stress, how often they are given attention by their parents, and many more

things observed by the nurses. We want to combine this (big) data with brain scans, readings taken using EEG, and long-term development. For this, we need smarter people than doctors. Physicists and mathematicians can use this data to create a prediction model. We would prefer a system that notifies us when a child is getting too much or too little of something.

‘Stem cells are also the future. They go to wherever there is damage, like magic. They

interview

repair damaged tissue. This applies to brain damage, damaged lungs, and maybe even to damaged intestines in children with severe intestinal problems. We now have permission from the ethics committee to give stem cells to newborn babies with cerebral infarctions.

‘As we speak, we are also working on a major European application. Together with other researchers, we want to treat various groups of newborns with stem cells, for example, premature babies with lung problems. Our share of this study will cover stem-cell therapy for babies with brain damage due to lack of oxygen before, during or after birth. It is not yet clear whether this application will be granted, but we do expect that stem cell therapy will improve the care of newborns within ten years.’

What does the future look like for neonatology expertise here at UMC Utrecht?

‘We have officially been recognized as ­h­aving the most expert knowledge of neo-

‘Every doctor should really work at a few different hospitals.’ natal neurology in all of the Netherlands.

This recognition is given on the basis of various criteria that you provide, such as care, education, and research. Doctors often come here from abroad to learn about the brains of newborns.

‘We also want to impart knowledge and to learn from others. That is why we want to work with other institutes in Edinburgh,

London, Munich, and Toronto to bring together various expertise. Collaboration also provides a larger and more varied patient population, which allows us to find answers to more problems. It will enable us to compare patient populations.’

Have you learned from foreign hospitals yourself?

‘Yes, I have travelled to various places around the world to increase my knowledge of neonatal neurology, which I was then able to apply here. Every doctor should really work at a few different hospitals. Otherwise you will only ever do things in the way you were taught at your own hospital. Other hospitals show you that there’s more than one way to get a job done, because every hospital does things just a little bit differently. But more importantly, things that are done better elsewhere can be applied at your own hospital. Everyone should work on cross-­pollination.’

UMC Utrecht Brain Center | New Scientist | 25

Home made Brain organoids are not real brains; they cannot be used as replacement organs in case of brain damage.

But these artificially grown, living mini-brains made of human cells do offer a unique opportunity to unravel the dynamics of brain cells.

By Marieke Buijs Images: Bram Belloni

N

euroscientist Paul Ormel puts on a white lab coat and squeezes his hands into purple latex gloves. Just to be sure, he spritzes them with alcohol. Now he is ready to fish out container ‘#2 22/11/18 ProLabb’ from a swinging rack in the incubator. The clear plastic dish looks deceptively ordinary as the casing of a creation that is everything but ordinary. There they are, floating in a thin layer of clear pink fluid. Four mini-brains. Dull, pale pink lumps, roughly half a centimeter in diameter, with random dents and bulges.

These are brain organoids. Tiny brain structures made of human cells. Thought of and created by humans. Developed thanks to ingenious molecular tricks in the high-tech equivalent of a human uterus: nutrient-rich fluid that is carefully kept at body temperature. These are the creations that should help scientists figure out how the brain develops and what goes wrong in conditions like Alzheimer’s, ALS, and schizophrenia.

From the lab In the summer of 2013, a shudder went through the world of brain research. Bioengineer Madeline Lancaster and her col26 | New Scientist | UMC Utrecht Brain Center

leagues described how they managed to grow mini-brains in the prestigious scientific journal Nature. To Professor of Translational Neurosciences Jeroen Pasterkamp of UMC Utrecht it was instantly clear that this was a breakthrough. He began setting up a lab to create and, in particular, to study brain organoids. After the start-up and development stages, the first experiments in schizophrenia and ALS are now under way, and soon an organoid study of Alzheimer’s will begin.

The human brain is a collection of some 90 billion nerve cells that each have an estimated 7,000 communication links to other cells. This inconceivably complex information network plays a role in everything we do; from walking to having a discussion in a café, and from falling asleep to daydreaming. A vital organ. And, therefore, well hidden, floating in shock-absorbing brain fluid and packaged in a thick layer of bone – the scull.

Both this complexity and thorough packaging put scientists in an awkward position. How do you discover where things are going wrong when someone develops amnesia or when speech becomes distorted?

Taking a peek, touching the tissue or put-

UMC Utrecht Brain Center | New Scientist | 27

brain organoids

ting it under a microscope is not something that is easily done.

Over the course of centuries, brain researchers have built up a repertory of work-around tactics to gain insight into this complex organ. For example, the brains of deceased people are put under the microscope, scientists use fMRI scanners to visualize the living brain in action, and the genetic makeup of mice and rats is altered to create and study rodents with Alzheimer-like symptoms.

All these methods offer valuable insights, but they also have shortcomings.

The resolution of the brain scanner is not high enough to see what is happening at a cellular level, and a disease model for ALS in mice is actually not the same as for ALS in humans. Medication that may seem promising in mice-models of ALS often doesn’t seem to work in human patients.

Smaller than the real thing PhD student Ormel is now holding a promising extension kit of the scientific toolbox between his fingers. ‘For the first time, we have a three-dimensional structure of living human brain tissue in a Petri dish, with which we can simulate the brain of a living patient and study it at a microscopic level,’ says the neuroscientist. Another bonus: the organoids were created using the building plan that the cells carry in their own DNA. So, to a certain extent, they are taking their natural shape.

Let there be no misunderstanding here: brain organoids are not real brains. They cannot be used as a replacement organ in case of brain damage – something that can be done with, for example, lab-cultured bladder tissue. Think of them like this.

Imagine you give a hundred toddlers each a Lego Duplo set of a castle and let the children get to work. The resulting structures relate to the intended castle in approximately the same way as the brain organoids relate to the human brain. One looks a bit more like the original than the other, but most structures contain the most important elements. The brain organoids, for example, display the structures of the hippocampus, an area of the brain involved in learning and navigation, and the cerebral cortex is also visible, the outer section of the brain that is responsible for, among other things, impulse control and planning. But the areas of the brain are not 28 | New Scientist | UMC Utrecht Brain Center

consistently in the same place and some parts are missing. Furthermore, the organoids are many times smaller than the real brain. There are no blood vessels running through them, and so the laborious circulation of fluids is a limiting factor for growth and preservation. Without the supply of nutrients to the inner cells of the organoid, the brains remain relatively small – even though they do contain millions of cells within a few millimeters. With daily care, they will survive approximately two hundred days in the lab.

A valuable window Despite their limited size, the mini-brains offer a unique opportunity to unravel the dynamics of brain cells. For example, in the case of ALS, which Pasterkamp is researching. This motor disorder causes the death of brain cells that are responsible for muscle control. The result: patients slowly lose the ability to walk, the power of speech, and the ability to breath, until they die a few years later. There are a number of genetic anomalies that mean that people have an increased chance of ALS. But the big question is: how does such a mutation lead to the death of control cells? And how can this process be stopped? Comparing brain organoids made of cells from ALS patients with organoids on the basis of healthy cells offers Pasterkamp a valuable window into the disease mechanism.

Part of this comparison takes place in a darkened room, a few doors down from the lab with the organoid incubators. In the semidarkness, there are two large microscopes connected to impressive-looking computer screens. Pasterkamp and his colleagues examine the mini-brains at various stages in the development of the ALS and control organoids. Step one in this process is decolorizing. By extracting the fats from the tissue, the dull pink matter changes into a transparent, gelatinous substance.

Within this transparent tissue, the researchers color only those cells that they are interested in, e.g. all microglia, the brain’s cleaning cells. Then they place the organoids under a microscope, which scans the tissue layer by layer, over the course of many hours. All these layers are then digitally reassembled to form an extremely high-resolution 3D image of the organoid. The researchers zoom in on these images: what happens to this tissue at a cellular level? What do, for example, the synapses, the contact points between brain cells, look like? Are they still intact or are they attacked by the cleaning cells in the brain, as seems to be the case in ALS? In parallel, the scientists analyze what happens within the brain cells. Are specific genes allocated for the production of protein when things go wrong in the ALS organoid? Genes that are not active in the healthy organoids? Pasterkamp: ‘If, on the

one hand, we see irregularities in the 3D imaging of the ALS organoids and, on the other hand, anomalies in protein production in those organoids, we are given an idea of the molecular mechanisms that underlie the disruption at the cellular level.’

Getting to work You have to have a bit of luck with the anomalous proteins that Pasterkamp identifies in this way, he says. ‘Sometimes these are proteins of which the function is known. And occasionally, it is a function that you already know how to manipulate.

If the anomalous proteins play a role in, say, controlling ion channels that determine whether a nerve is activated, you can manipulate this with anti-epileptic drugs.’

This brings the professor to the next miracle of the organoids. Instead of setting up expensive and risky medical studies with real patients, you could potentially test a new drug on the organoids in the Petri dish first. Do they behave more ‘normally’ when you put a few drops of an anti-epileptic drug in their bath? Pasterkamp: ‘You can see the effects of medication immediately.

That could show which drugs are worth further study on human subjects.’

Organoids also offer a solution for research into psychological disorders. Professor of Glia Biology Elly Hol focusses on a neglected part of the brain: the glial cells.

These cells are just as numerous as nerve cells but were originally less appealing to researchers because their activity is more difficult to measure. Their name alone is ominous: glia is ancient Greek for ‘glue’; they were long seen as the glue that supported the brain cells. We now know that they do play an active role. They participate in the chemical communication between cells, help to speed up signal transmission, and are responsible for cleaning up waste.

Hol suspects that the cells play a crucial role in Alzheimer’s, to which she has devoted the majority of her research, and in schizophrenia, to which she is taking a research excursion as the PhD supervisor of, among others, Paul Ormel.

When it comes to the complex developmental disorder schizophrenia, glial cells are under suspicion. Schizophrenia patients have episodes of severely disrupted

perception and thought; for example, they hear voices that comment on their actions.

This could be connected to a disruption of one of the curious developmental processes in the brain. During learning and development in childhood, countless connections are created between brain cells.

These connections are like experiments of the brain. Some prove useful – for example, they assist in the newly acquired skill of solving differential equations – are used more often, and take root. Other prove not very useful, fall into disuse, and are ultimately ‘pruned’ by the tidying microglia. In schizophrenia patients, many connections are missing. It is thought that this might be caused by overzealous cleaning cells that – perhaps as a result of miscommunication – prune too many connections and cause something similar to a short circuit. Analogous to unravelling the differences between brain organoids of ALS patients and healthy people, Hol and Ormel are exploring the differences between organoids of patients with schizophrenia and those of healthy people at the cellular, genetic, and protein levels.

UMC Utrecht Brain Center | New Scientist | 29

This is what they do From collaborating with patients to research at cellular level: Brain Center Rudolf Magnus has a wide variety of scientists. They are all searching for the best answers to their questions, as are these four motivated researchers.

By Aafke Kok Images: Bram Belloni

30 | New Scientist | UMC Utrecht Brain Center

Frank Meye Translational neurosciences

Brain changes and binge eating In response to stress, both people and animals consume a great deal of sugar and fat. ‘Binge eating is a problem for people with obesity, eating disorders or people with impulsive behavior such as ADHD,’ says Frank Meye. The need for ‘bad’ food is accompanied by changes in communication between different areas of the brain involved in the processing of rewards. This is what Meye is studying.

He is using mice that have been subjected to social stress and, therefore, display binge-eating behavior. Meye examines the mice’s brain tissue. Using electrodes, he measures the electrical signal with which nerve cells communicate. The more they communicate, the stronger the connection. Meye studies the differences in the strength of this connection between stressed mice and control mice. For example, he looks at connections with dopamine neurons, an important group of cells in the reward circuit of the brain.

Meye can then control specific nerve cells in living mice and study the mice’s eating behavior. He does this through optogenetics or chemogenetics, with which he can turn nerve cells ‘on’ or ‘off’ using light or special viruses, respectively. This is how he is trying to uncover the link between changes in the brain and binge-eating behavior. Ultimately, he hopes to understand how to prevent these changes in the brain, in order to reduce binge eating.

Natalia Petridou Imaging technology

Understanding fMRI

Marjolijn Ketelaar Rehabilitation medicine

True patient collaboration For the study of cerebral palsy (CP), a congenital disruption of the brain, Marjolijn Ketelaar invited twelve teenagers with CP to join her study as ambassadors. One example of their participation was thinking about research questions – patients often have a very different view of what is really important in the study of their disease. Among other things, Ketelaar and her team studied problems young people with CP have within the educational setting. In addition to scientific publications, this also led to products that she created with the teenagers, like a poster for teachers explaining CP, to eliminate misunderstandings about the disease.

This is true patient participation, not just a tick on researchers’ checklists.

‘True collaboration with patients, from beginning to end, leads to much better research,’ says Ketelaar. She also tries to help her colleagues understand the importance of patient participation. For example, she contributed to the development of a tool that researchers can use to discuss desired participation at every step during studies. She also organized a conference with not one, but two chairs at every session: a researcher or doctor, and a patient or the parent of a patient. This keeps the focus on the question ‘for whom are we doing this?’

In order to understand the functioning of the brain, many researchers use fMRI scanners. In the images that they create, the active areas of the brain light up. This technology is also frequently used in the clinic. ‘But fMRI measures brain activity in an indirect way,’ says Natalia Petridou. What you are really measuring are the characteristics of blood flow in parts of the brain. The idea is that this flow of blood is connected to activation of nerve cells.

After all, they need oxygen from the blood to do their job. ‘But we don’t know how the link between blood and nerve cells works exactly,’ says Petridou.

She hopes to find out.

She is building models to predict how certain parts of the brain work. She then tests these models. For this, she uses a 7-Tesla MRI scanner, a scanner with an extremely strong magnetic field. Petridou is developing methods to use this scanner to make highly detailed images of the brain. In addition, she uses special cameras to study minute changes in the bloodstream. She also takes measurements using electrodes in the brain. Ultimately, Petridou hopes to understand the link between blood and nerve cells, and to use her findings to improve fMRI use.

Jan Veldink Neurogenetics

Gene therapy As a doctor, Jan Veldink sees ALS patients every week. ‘Their life expectancy is currently three to five years, and with the medication we now have this can be extended up to six months,’ says Veldink. He hopes to change this with his research. The goal of Project MinE, set up through crowdfunding, is to map out the DNA of 22,500 patients.

The counter is currently at 10,000. By comparing DNA, researchers have already found five spots in the DNA that are involved in the occurrence of ALS. This may be a line of approach for new treatment, such as gene therapy. In gene therapy, drugs focus on the protein in a gene identified by the study, or they block these genes directly.

But ALS is not caused by genetic anomalies alone. That is why Veldink also studies the outer shell of DNA, which is affected by life style factors such as diet and stress. On the basis of the outer DNA shell, Veldink can divide ALS patients into new subgroups, incorporating the interaction with lifestyle.

The starting points for new therapies are promising, but because these therapies serve a small subgroup of patients, it is difficult to find companies for further development. Veldink remains hopeful, ‘mainly because the increasing interest in ALS in recent years.’

UMC Utrecht Brain Center | New Scientist | 31

The brain on screen The brain is our most complicated and least understood organ. This makes it almost surprising that it functions so well in most people. But there is a lot that can go wrong. Luckily, we now have MRI scanners with which we can examine the brain in detail.

MRI scans are essential when uncovering whether Alzheimer’s, capillary damage or a combination of the two is behind dementia symptoms.

BRAM BELLONI

By Joris Janssen

I

t is located in a special wing of UMC Utrecht: one of the most powerful MRI scanners in the world in a clinical environment – an environment in which it can help patients directly, as opposed to an environment focused solely on research.

For two neurologists, this machine is a blessing for their research. Geert Jan Biessels uses it to study patients with ­dementia due to damage to small blood vessels in the brain. Kees Braun uses the scanner to treat children and adults with epilepsy that is difficult to control. Two ­different disciplines with something in common: technological progress promises improved treatment by visualizing the brain.

Anyone thinking of dementia, often thinks of Alzheimer’s disease. This disease causes pathogenic protein to damage the brain, leading to memory problems, among other things. However, this is often only part of the story. Nine out of ten ­people who develop Alzheimer’s in later life have another problem: damage to small capillaries in the brain. Sometimes, this type of capillary damage is even the

32 | New Scientist | UMC Utrecht Brain Center

main culprit behind the dementia-like symptoms. In those cases, patients are ­diagnosed with vascular dementia. ­Overall, capillary damage is responsible for roughly one third of all dementia symptoms. Half is due to Alzheimer-like processes, and the rest is caused by a catchall of other conditions. So, although it is not the most common form, many people with dementia are faced with the vascular variety, to a greater of lesser ­extent.

Tiny capillaries ‘The study of dementia due to capillary damage is lagging behind the study of ­dementia due to Alzheimer’s,’ says Geert Jan Biessels, head of general neurology and leader of the Vascular Cognitive Impairment research group at UMC Utrecht.

‘It’s a shame, because there is a very real opportunity to do something about it.’

This disadvantage is, in part, caused by lagging investments, but there is also a practical cause. Until recently, it was ­impossible to obtain a good visual of the culprits behind the condition: the small

Damage to small capillaries in the brain is the cause of roughly one third of all dementia symptoms.

BRAM BELLONI

capillaries that supply the brain with blood. Damage to these capillaries affects the connections in the brain, causing the fiber-optic network of the brain to mal­ function. ‘Compare it to streaming a ­series or a movie on Netflix with a slow connection,’ Biessels explains. ‘It is not that people with this type of dementia make lots of mistakes or really forget things, it just takes a lot more time to ­retrieve the information.’

Scans made by the average MRI scanner are not detailed enough to show the tiny capillaries in the brain, let alone ­abnormalities or damage to these capillaries. The only thing these scans show is the result of the damage: blotches in the fiber-optic network caused by small ­hemorrhages or cerebral infarctions. This imposes two major limitations. The blotches can be cause by something ­other than damage to the small capil­ laries. The presence of blotches alone does not have to mean that someone actually has vascular dementia. In addition, it means that you can’t identify the condition until its final stage, when it has ­already caused a great deal of damage.

Visualizing the tiny capillaries in the brain can help to identify the problem sooner and can enable fundamental ­research into ways of dealing with the disease at an early stage.

UMC Utrecht is unique And that is where the powerful 7-Tesla MRI scanner comes into play. An MRI scanner creates images of structures in the body by setting hydrogen atoms in motion using strong magnetic fields and radiofrequency pulses. When the atoms settle down again, they give off a signal.

This signal can then be picked up and turned into an image. The different types of tissue in the body contain different quantities of hydrogen atoms. This creates a contrast, allowing you to see the ­difference between, for example, blood, fat, and organ tissue on the image.

The stronger the magnet, the higher the contrast that can be achieved. The

strength of a magnet is expressed in Tesla.

Most MRI scanners in hospitals have a 1.5 or a 3-Tesla magnet. The magnet in the MRI scanner at UMC Utrecht is a bit stronger.

As the name indicates, it has a strength of 7 Tesla. When UMC Utrecht got the scanner in 2007, there were only twenty of them worldwide. This number has gone up a bit since then, but most of these scanners are at research institutes. The MRI scanner in Utrecht is unique because of its strength and because it is in a clinical environment, where many patients have now been ­examined using the scanner.

With a magnet that is many times stronger, contrasts become visible that would ­otherwise have remained hidden. ‘We can

‘We can see the circulation of blood through capillaries as thin as eyebrow hairs’ now see the circulation of blood through capillaries as thin as eyebrow hairs,’ says Biessels. ‘We can see how circulation varies during the cardiac cycle, which shows us how hard the capillaries are.’ Thanks to this increased contrast, for the first time, Biessels and his colleagues are able to make a connection between the damage seen on other scans and underlying ­abnormalities in the tiny capillaries. ‘For the first time, we are now able to describe disease of the capillaries in terms of those capillaries themselves.’

Examining the brain at this level of detail is an outcome for many more brain ­diseases than vascular dementia alone.

For Professor of Pediatric Neurology Kees Braun, it is also a boon. He treats children with so-called refractory epilepsy, which is difficult to treat, and he researches how improved imaging of the brain can ­improve the efficiency of treatment.

Epilepsy is a condition in which electric UMC Utrecht Brain Center | New Scientist | 33

mri-scanner

The human eye alone is no longer enough to interpret brain scans. Smart software helps doctors and researchers with this difficult task.

discharge occurs involuntarily and fitfully in the nerve cells of the brain. The result resembles a short circuit that can lead to twitching, decreased consciousness, and speech or vision difficulties, depending on where in the brain the short circuit is ­located. In roughly two-thirds of the cases, medication can eliminate nearly all symptoms. For the remainder of patients, medication does not offer a solution. These ­patients are diagnosed with refractory ­epilepsy, the variety that Braun and his ­colleagues study.

Vulnerability An operation may be a possible solution for patients with refractory epilepsy. If the source of the attacks is known, that source can be removed or disconnected from the rest of the brain, provided that it is not in an area of the brain that is so important that the neurosurgeon best leave it alone.

In some severe cases, surgeons can even disconnect an entire side of the brain in young children. A condition for this type of operation is that the source of the epilepsy is local. A specific area of the brain has to be identified as the source of the problem.

If involuntary electric discharge occurs throughout the entire brain, for example due to a genetic predisposition, an ­operation will be of no use.

A local source of electric discharge can have various causes. ‘It could be a tumor, an infarction, a scar, inflammation or an abnormal development of the cerebral 34 | New Scientist | UMC Utrecht Brain Center

c­ ortex,’ says Braun. ‘In those cases, an operation could help. So being able to make a diagnosis is very important. Imaging using an MRI scanner is crucial in this process.’

The better the scans are at visualizing the problem area, the greater the chance of a successful operation. This is particularly true for abnormal developments of the cerebral cortex, a condition known in ­medical terms as focal cortical dysplasia.

‘The technology that visualizes these small, local abnormalities has been improved over the past decades,’ says Braun. ‘This has allowed us to improve the selection of people who qualify for an operation. We had already made good progress with the previous generation of scanners, but our research shows that the chance of detection using the 7-Tesla MRI scanner is ­increased by another 20 percent.’

However, more powerful scanners are only part of the equation, in both Kees Braun’s

‘A large part of the progress also lies in a smarter way of looking at the scans’ epilepsy research and Geert Jan Biessels’ dementia research. A large part of the ­progress also lies in a smarter way of looking at the scans. For example, in Braun’s research, new statistical techniques ensure that computers are getting better at identifying abnormalities in the brain. Braun: ‘A computer can compare the scan of a ­patient to the scans of a large group of healthy people and identify the areas of the patient’s brain that are significantly differ-

ent from those of the control group. In this way, the computer can show you an abnormality that you would have missed with the naked eye.’

The field of vascular dementia also benefits greatly from statistically combining large amounts of data. Biessels hopes that an international cooperation project that he helped start will soon produce the first ‘vulnerability map’ of the brain. This combines the data of around one thousand patients from Asia and Europe to form a map that shows the extent of impact of damage to specific parts of the brain. ‘In the past, we only looked at the total amount of damage, but that’s too simple. The consequences of damage at a critical point are much greater. This map will show us in what areas damage has the most impact.’

Developing a platform As crazy as it may sound, statistical techniques created by electricity companies are also contributing to a better view of the condition of a person’s brain. Biessels: ‘These companies are very interested in what happens when, for example, a truck hits an electricity pylon. Will it take out the entire network, or not? Many measurements have been developed to indicate how robust and efficient a network is. We can also apply them here to see the condition of brain networks.’

More and more disciplines are becoming involved in research using brain scans and more and more international partnerships are being set up. ‘We are really pushing the scanner to its limits,’ says Biessels.

‘This results in so much data that you can no longer assess it with the naked eye. The limit of human perception is so easily reached that you need computer technolo-

opinion column Jim van Os Chairman of the Neuroscience division UMC Utrecht

Beware, yes, but good can come from it

O gy to give the scans meaning. In addition to a clinical team that works with the patient, we are, therefore, also working with a team of physicists who really know their way around this machine, and with a team of computer scientists who help interpret the data. In addition, we are part of an international network in which a great deal of knowledge is shared.’

International collaboration is also important in the field of research into focal cortical dysplasia in children. Braun is proud of the coordinating role that UMC Utrecht plays in European Reference Network (ERN) EpiCARE, which focusses on complex and rare forms of epilepsy. ‘The activities of this network include developing a standard for epilepsy imaging and setting up an international panel of researchers that will assess complex scans online, and we also want to develop a platform through which other European centers will be able to use the best statistical methods for the interpretation of scans.’

The future of imaging in brain research is one of zooming out and zooming in. More and more different forms of expertise are coming together on a large scale and there is more and more opportunity for experts to share their knowledge on an international level. These experts can then show their small-scale progress, in which stronger magnets continue to improve the imaging of our brain. Small abnormalities in the brain are less and less likely to escape the attention of the many eyes that view each scan, directly or indirectly. This opens the door to personal treatment of each patient, based on the cause of his or her condition. ‘We will finally be able to focus on the root of the disease instead of the final stage,’ Biessels concludes.

n the basis of a study among a thousand subjects, using simple tabulation, an experienced epidemiologist can be pretty successful in the prediction of, for example, mortality in a cohort study among the elderly. This is a form of machine learning in which the relative human-to-machine decision-making effort relies rather heavily on the human element. It is different in the so-called neural network ‘deep learning’ algorithm, which, with minimal human input, has learned to discover diabetic retinopathy in ‘big data’ recordings of retina among approximately one million people. To say nothing of Google, which developed a neutral network that learned to play the game Go without human help. eHealth is an empowered form of electronic data collection that makes it possible for people to become their own doctors. A person can continually monitor their health parameters, including hart rate, muscle tone, brain waves, blood pressure, blood sugar, sanguinity, and intestinal peristalsis, for the diagnosis, treatment, and prognosis of disease. This will make eHealth a major source of big data within the healthcare industry, which can be found in the electronic medical files.

For example, in Israel, the electronic drug prescriptions of approximately 750,000 patients were brought together and examined with an algorithm that searches for irregularities.

Errors – possibly fatal ones – were discovered in the prescriptions of 15,000 patients. The next step: a national big data system that analyzes and checks the prescription behavior of doctors in real time. Large Ameri-

can health insurance companies like Geisinger and Kaiser Permanente are reinventing themselves as DNA stockholders that analyze the genetic diversity of millions of customers in relation to their electronic files. In five years, perhaps 250 million people worldwide will have deposited their DNA in a similar analyzable database. Does the thought of all this big data make you nervous? It should.

But good things can also come from it, if we work together to apply rules that make it safe to use.

Does the thought of all this big data make you nervous? It should

MARTIN OUDSHOORN

UMC Utrecht Brain Center | New Scientist | 35