Issue 015

Brain Center Bulletin

This digital Brain Center Bulletin gives an overview of recent developments in the UMC Utrecht Brain Center. Our mission is to perform high-level research in clinical and experimental neuroscience, whilst delivering an exceptional standard of care.

May 2019, 15th edition

Editorial

During the establishment of the UMC Utrecht Brain Center several years ago, choices were made to focus on specific patient groups and associated research and education activities, but not on others. These choices were not easy to make as they bore the risk of exclusion. However, this selection and bundling clearly aided in establishing the identity of our center in the past years, both in the UMC Utrecht as well as (inter)nationally. We are now known for our excellent patient care and research on for example psychiatric disease, neuromuscular disorders and epilepsy.

This focus has also been instrumental in obtaining funding, for being selected as a European referral center, for attracting talented people and much more. Also it has guided our own investments in facilities and young (and old) talents; see for example the selection of Leonard van den Berg as a new member of the Royal Netherlands Academy of Arts and Sciences.

However, academic centers are dynamic. Colleagues find positions elsewhere and leave or are attracted to the UMC Utrecht, bringing along new expertise. Furthermore, developments locally, such as the bloom in stem cell/organoid-based research in Utrecht Science Park, and nationally, such as a stronger focus on keeping individuals healthy in addition to curing them, direct our activities. This has recently triggered us to evaluate our five focus areas. This evaluation revealed that restructuring some of these areas will help to better align them to outside developments and to increase their visibility.

Therefore, we are very grateful that Roger Adan and Hilgo Bruining have agreed to chair and shape the focus area ‘Precision Psychiatry’ (formerly ‘Psychosis’), while Freek Hoebeek and Jeroen Dudink will be responsible for ‘Developmental Disorders’.

In addition, after consulting with many different stakeholders, we have decided to develop a sixth focus area around the theme ‘Neuro-oncology’. This will be chaired and structured by Elly Hol and Tom Snijders. In the coming months these chairs will develop new strategies for their themes, also in light of the five-yearly evaluation of our research in October and the definition of a new UMC Utrecht strategy (2020-2025). Discussions regarding this new strategic period on the organization of biomedical research laboratories, the positioning of clinical scientists, talent management, data-science and our connections with stakeholders outside the UMC Utrecht will be important for our focus areas and for the UMC Utrecht Brain Center as a whole.

This issue of the UMC Utrecht Brain Center Bulletin again features many different and exciting topics, ranging from interviews with the newest awardees of our Rudolf Magnus Young Talent fellowships to a newly appointed professor of ‘Translational Research of Early Life Events’ and articles on different research projects and technologies. We hope that you enjoy reading the Brain Center Bulletin!

Jeroen Pasterkamp

Leonard van den Berg elected as a new member of the Royal Netherlands Academy of Arts and Sciences

The Royal Netherlands Academy of Arts and Sciences (KNAW) has announced that it has elected prof. dr. Leonard van den Berg as a new member. Members of the KNAW are leading scientists from all disciplines and are chosen based on their scientific achievements. The KNAW has about 550 members. A membership is for life. Together with prof. dr. Van den Berg, eighteen other new members have been elected. The new Academy members will be installed on Monday September 16th.

The KNAW is a society of excellent scientists as well as an institution organization that, with their research and collections, belong to the (inter)national top. From an independent position, the Academy brings people and resources together to contribute to the development of our society with knowledge and creativity. In addition to this, the organization promotes the quality and integrity of scientific practice.

“I am especially grateful for the immense support we receive
for our work from patients”

Regarding the motivation for his appointment, the jury writes: “The incurable disease ALS and related disorders are central in the work of Leonard van den Berg. With clinical and genetic research, lifestyle research and imaging techniques, his research group is looking for what exactly leads to motor nerve cell failure and muscle paralysis. Van den Berg uses powerful bio-informatics to interpret large amounts of data. Collaboration is also one of his assets. He is, for example, the founder and coordinator of ALS Center Netherlands and leads several international research projects. His work gives hope that in time there will be a treatment for ALS. “

“It is an enormous honor to be appointed by the jury as a member of the KNAW,” says Leonard. “I am especially grateful for the immense support we receive for our work from patients, who are always willing to participate in the research that we do. Furthermore, cooperation with partners such as the ALS Foundation, patients’ associations ALS Patients Connected and Muscular Diseases Netherlands is of crucial importance in the search for a solution to this disease. Without their support we could never have gotten as far as we are now. This appointment is an additional motivation to continue with the entire team of researchers and caregivers in the ALS Center in the search for a solution for ALS .”

Sitting less can prevent new stroke

Exercise is healthy. It will not only leave you feeling fitter, but will also reduce the chances of all kinds of health problem, such as a stroke. “Keeping moving after a stroke is just as important, however. This helps prevent new, serious strokes and will improve your recovery,” says Martijn Pisters, researcher in the Brain Center at University Medical Center Utrecht. He is studying what the right aftercare is for stroke patients. “People who are sedentary a lot of the time are 40% more likely to die within three years of their stroke.”

Some 43,000 people have a stroke each year. Of those who survive their stroke, one third will have another stroke or die within five years. Significant risk factors in this regard include high blood pressure and lifestyle factors (not enough exercise, smoking).

Harmful
Hence for people who have suffered a stroke it is extremely important to prevent a second stroke. Treatment geared towards reducing sedentary behavior is essential in this respect. Martijn Pisters, researcher in Physiotherapy Science: “The fact that sufficient levels of physical activity are important for people after a stroke is something that has been known for a long time and which has been widely integrated into healthcare. What isn’t yet well known is that people who are sedentary a lot of the time have a 40% higher probability of dying within three years of their stroke compared to people who are more active. “After all, being sedentary is harmful if it exceeds 10 hours a day, spans long, uninterrupted periods, and is combined with limited physical activity.”

Research
“Guidance to reduce such behavior and encourage an active lifestyle isn’t something everyone needs following a stroke,” adds physiotherapist and doctoral student Roderick Wondergem. This was shown by a study over the past few years, subsidized by the Netherlands Organisation for Scientific Research (NWO). “We spent two years following patients after they were discharged from a hospital or rehabilitation facility, recording their habits in terms of being sedentary and exercising. We saw that following a stroke around 30% of people spent nigh on 80% of the day in one stretch sitting and barely getting up. For this group, customized guidance during the first few months after a stroke will probably be extremely worthwhile.”

Personal approach
A healthcare program is needed in order to provide the right people with the right personalized aftercare following a stroke. After all, various factors play a role in terms of sedentary behavior and exercise habits. The physiotherapist will have a coaching role, with behavior-oriented principles, monitoring, and e-coaching technology being integrated into the new healthcare program. Moreover, good cooperation in the healthcare chain between physiatrist, general practitioner, and first-line physiotherapist is important. SIA RAAK (NWO) recently made 600,000 euros available to develop this healthcare program.

“It’s absolutely fantastic for us in the field of physiotherapy to be able to develop a solid approach with stroke patients, healthcare chain partners, and national and international experts,” says Wendy Hendrickx, physiotherapist and doctoral student within the so-called RISE study.

New professor: Freek Hoebeek


Since January 2018, Freek Hoebeek has been affiliated with the UMC Utrecht Brain Center. He is Professor of Translational Research of Early Life Events and together with Jeroen Dudink he is the leader of the developmental disorders field of expertise.

 Where does your interest in brains come from?
After some exploration of the study of astrophysics, which I still find a mighty interesting subject, I found out that this study was not ideal for me. I wanted to be work on something tangible and my study to have value for others. For me, the brain is as complex as the universe; full of unknown factors and connections. So since high school I have focused on neuroscience.

You are professor of Translational Research of Early Life Events’. How do you explain that at a birthday party?
I am involved in translational research, specifically into the abnormalities that often occur in the young child’s brain. That’s why I explain that, even though “we” already know a lot about how the brain works, it’s not yet known how and when the connections between the cerebellum and cerebrum are made. And hence that scientists and doctors by no means know immediately what could be wrong if you have had a difficult start in life, let alone what needs to be done to fix it.

An important question for your research is how we can best help children with early brain damage in their further development. What is your ultimate goal, what would you like to achieve?
A dot on my horizon is to continuously monitor the activity and structure of all areas of the brain, including the deeper structures, in children very early after birth. And to understand what this data means for the future, enabling the development of effective treatment.

How do you intend to work towards that goal?
By taking several leaps forward. In the field of bioelectronics and imaging techniques, improvements will have to be made in the data quality of (deeper) brain structures. It should also become possible to use neuromonitoring in the home situation, both in the most vulnerable neonatology patients and in the older children. To this end, close partnerships with universities of technology, universities of applied sciences and knowledge institutes are of great importance. It is also important to discover through translational models which areas and connections of the brain are important for the different stages of brain development. With this knowledge, neuromonitoring of patients can be carried out even more efficiently and in a more targeted manner.

Who do you want to do that with?
The developmental disorders that arise from early brain damage require a broad approach. The brain focus area of the UMC Utrecht brings together both researchers and healthcare professionals who make fundamental, translational and clinical research possible. Together with Jeroen Dudink of the Neonatology department and Sarah Durston of the Psychiatry department, I am going to work to focus the strengths of Utrecht research even better. One example of a successful line of research is the collaboration between the translational work of Dr. Cora Nijboer and the clinical work of Prof. Manon Benders on neuroprotection and neuroregeneration in the young brain. Together with these and other research teams of the UMC Utrecht Brain Center, we can gain more knowledge about the causes, consequences and treatments of developmental disorders ensuing from early brain damage.

Where do you see interesting challenges within your field of healthcare and research?
One of the great challenges is to involve the different patient populations and their families, as it is not just a question of short-term effects and treatments, but also and above all those in the long term. This makes it all the more important that our fundamental, translational and clinical research is in line with the questions, wishes and limitations of our target group.

Freek in a nutshell

41 years old, lives in Oud-Beijerland (south of Rotterdam). Married to Elza and father of Luca. He likes to spend his spare time on oenology and other culinary matters.

2000 – graduated in Medical Biology from University of Amsterdam
2001-2004 – trainee research assistant at Erasmus MC, plus postdoc
2005-2009 – Postdoc Erasmus MC
2018 – head of department and professor of UMC Utrecht

Impact of cerebral infarctions better predicted with vulnerability maps

At the moment, it is not yet possible to predict which patient will develop a cognitive disorder immediately after a stroke and which not. A clear prognosis is key to a successful rehabilitation process. In order to better predict the impact of a cerebral infarction, international research groups are working together on a vulnerability map of the brain. The consortium is coordinated by professor Geert Jan Biessels of the UMC Utrecht Brain Center. An article about the pilot study for this multicenter research has been published in Alzheimer’s & Dementia: Diagnosis, Assessment and Disease Monitoring.

weaver afb

A significant proportion of patients who have suffered a cerebral infarction develop cognitive impairments, including problems with memory, concentration, orientation or language. At the moment it is not yet possible to predict who will continue to suffer from a cognitive disorder immediately after the cerebral infarction. Researcher Nick Weaver explains: “It is known that the nature and severity of cognitive symptoms are related to the location of the cognitive infarction. By linking the location to cognitive measurements in the short and long term, we can develop “vulnerability maps” that indicate critical areas for damage and the potential cognitive outcomes. Until now, these vulnerability maps have been incomplete because brain areas with fewer infarctions could not be studied. In order to map all potential locations, data from thousands of patients is required. Such a large-scale study cannot be conducted from an individual research center, so we have set up a large international partnership.”

The pilot study was conducted with 6 international research centers, using data from 878 patients. This was coordinated by researchers from the group of Prof. Biessels: Drs. Nick Weaver, Dr. Matthijs Biesbroek And Dr. Hugo Kuijf. The data was successfully integrated into a uniform dataset. Nick Weaver says, “The largest individual study so far comprised 410 participants, so the number has more than doubled in the pilot study. We were able to map a much larger part of the brain. First we had charted 20% of the brain, now we have 46%. This confirms our idea that combining cohorts is feasible and clearly has added value. This allows us to create a more complete vulnerability map of the brain.” For the follow-up project, 43 research groups are already interested in taking part, which means data from more than 3,500 patients.

These are good developments for patients who suffer a cerebral infarction. Initiator and coordinator Prof. Geert Jan Biessels explains: “The vulnerability maps resulting from these international projects can be applied in clinical practice to better predict cognitive disorders after a cerebral infarction, giving patients more certainty about their prognosis. The sooner patients are given more certainty and if possible the right therapy, for example through cognitive rehabilitation, the better!”

Rudolf Magus Young Talent Fellowships for Matthijs Biesbroek and Anja van der Kolk

In order to support gifted junior group leaders implementing their own research line, the UMC Utrecht Brain Center awards one to two Rudolf Magnus Young Talent Fellowships each year. This year the Fellowships go to Matthijs Biesbroek and Anja van der Kolk. The Fellowship provides the recipients with the equivalent of 2 years of salary and €100.000 to be spent on research as the recipient sees fit.

Matthijs Biesbroek
Matthijs Biesbroek is fascinated by cognition and stroke and particularly interested in the cognitive impact of lesion location. During his PhD, he used ‘lesion-symptom mapping’ methods to show that the location of vascular damage in the brain determines the cognitive consequences for the patient. After his PhD research, he further developed this technique, together with researchers at UMC Utrecht and the Chinese University of Hong Kong. Matthijs: “With the Rudolf Magnus Young Talent fellowship I can take the next step. My goal is to develop clinical tools that predict, based on infarct location, whether patients with stroke will develop cognitive impairment so that we can provide an individualized cognitive prognosis. Over 3000 patients from multiple centers worldwide will be included through the META VCI Map consortium that we recently initiated”. First, a ‘vulnerability map’ of the brain will be developed that shows which areas of the brain are associated with dementia in the short and long term after ischemic stroke. The next step is to use machine learning to develop and validate a prediction model for post-stroke dementia.

Anja van der Kolk
Anja has always been intrigued by MR images of the human brain, a fascination that started during early med school. “Back then, it seemed to me these images would hold the ground truth: they could visualize the underlying neurological disease the patient was suffering from, and provided a diagnosis that could be used as the primary basis for treatment. However, not all that glitters is gold, and although conventional MR images are often helpful in diagnosing neurological diseases, they still have a relatively low sensitivity and specificity. Metabolic MRI – which has gained increasing attention with the advent of ultrahigh-field MRI scanners like 7.0 tesla (7T) MRI – has the potential to increase this sensitivity and specificity by visualizing those molecules that are characteristic for a certain disease. The Rudolf Magnus Fellowship allows me to examine how promising (or ‘gold’) metabolic MRI really is.” Anja will develop and optimize metabolic MRI sequences at 7T, and then validate these sequences in patients with epilepsy and primary brain tumors that are planned to undergo surgery. “Apart from enabling this clinical study, the Fellowship also allows me to set up my own research line, and enables me to further develop myself as a clinician-scientist.”

Research on brain disease given new impetus

Identifying the causes of brain disease has been highly complicated till now. The most significant reason being that researchers had virtually no living brain tissue at their disposal. Till now. At UMC Utrecht scientists are growing small chunks of brain tissue. Important cells have been found in these which will enable targeted research.

Coverfoto brainorganoids

Sometimes a bit of luck is required: Jeroen Pasterkamp, professor of Translational Neuroscience, lent a cerebral organoid from his MIND facility to a colleague, Elly Hol, and to her astonishment she found microglial cells in it. Elly, professor of Gliabiology of Brain Disease, explains what these are: “Microglial cells are immune cells that look like tiny spiders in the brain. We know that they play a key role in most brain diseases, such as ALS, Alzheimer’s disease, Parkinson’s disease, and schizophrenia.”

Jeroen: “Up till now we’ve been able to use human stem cells to grow brain organoids—mini brains that we use for research purposes—but they didn’t contain these important cells. Which is why researchers across the globe have been trying to get microglial cells in brain organoids. Nobody had managed to do so yet, and we’ve it handed to us on a plate. How great is that!”

Cause of diseases
This discovery will finally enable targeted research to be done into the role of microglial cells in human brain material in brain disease. Microglial cells are important for such functions as clearing up dead material. Jeroen: “In the case of a disease like ALS, for instance, you’ll see an accumulation of material that would suggest the microglial cells aren’t doing their job properly.” Furthermore, these cells are involved in regulating the contact points (synapses) between nerve cells. In conditions such as autism and schizophrenia, there are sometimes more or fewer synapses, which may in part be due to improper functioning on the part of the microglial cells. Jeroen: “Our model marks a giant leap forwards and will yield insights into brain disease processes that we haven’t been able to study previously.”

Differences
Growing mini brains with microglial cells makes it possible to chart the role of these immune cells. That will show how the microglial cells work and how they behave in normal as well as abnormal processes. Patients’ stem cells are used for the purposes of growing the mini brains, and these can be compared to mini brains grown from the stem cells of healthy people of the same sex, age, etc. This research is now well under way.

Grants and Awards

  • The CRUCIAL-TRIAL of the departments of children’s cardiology, children’s intensive care unit, obstetrics, psychology, and neonatology is honored with a ZonMw grant. The trial is designed to diminish the risk of brain damage after cardiac surgery in children.
  • Martijn Pisters received a grant of SIA RAAK (NWO) for the RISE intervention study to develop a specialized care program for patients with a stroke.
  • The division KNO will be part of the Horizon 2020 TIN-ACT consortium.
  • Wim Otte received an EU-ATTRACT grant to bridge the epilepsy diagnostic gap.
  • Tanja Nijboer received a grant to develop a virtual toy store for children.
  • The ERANET project MigBAN to study the interaction of the microbiome on behavior is rewarded.
  • Jeroen Pasterkamp received two EU grants from the ERA-Net for Research Programmes on Rare Diseases.
  • Leonard van den Berg has received four grants from the Netherlands ALS Foundation.
  • Maeike Zijlmans received an ERC starting to improve the measurement and signal analysis of high frequency electric signals during epileptic surgery.
  • Elly Hol and Jeroen Pasterkamp received a grant for their Nano+ project in which neurodegenerative disorders are modelled as stem cell-derived neurons on a chip.
  • Sharon Berendsen, aios neurology and PhD student neuro-oncology, was awarded with the STOPhersentumoren stimulatory price.
  • Henk-Jan Westeneng has received the “Jaarprijs Neuromusculaire Ziekten” from the Prinses Beatrix Spierfonds for his publication: “Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model, Lancet Neurol. (2018)”
  • Tanja Nijboer was rewarded with the Betto Deelmanprijs 2019 for her work as neuropsychologist and her contributions to this field.
  • Kevin Kenna has been awarded a Vidi grant (NWO) of 800.000 euro for ‘decoding genetic disease by decoding gene regulation’

Publications

Some highlights

  • Straathof M, Sinke MR, Dijkhuizen RM, Otte WM. A systematic review on the quantitative relationship between structural and functional network connectivity strength in mammalian brains. J Cereb Blood Flow Metab. 2019 Feb; 39(2):189-209. Pubmed
  • Berendsen S, Spliet WGM, Geurts M, Van Hecke W, Seute T, Snijders TJ, Bours V, Bell EH, Chakravarti A, Robe PA. Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma. Cancers (Basel). 2019 Jan 4; 11(1). Pubmed
  • Leemans A. Diffusion MRI of the brain: The naked truth. NMR Biomed. 2019 Apr; 32(4):e4084. Pubmed
  • Verharen JPH, van den Heuvel M, Luijendijk M, Vanderschuren LJMJ, Adan RAH. Corticolimbic mechanisms of behavioral inhibition under threat of punishment.  J Neurosci. 2019 Mar 22. pii: 2814-18. Pubmed.
  • Gooskens B, Bos DJ, Mensen VT, Shook DA, Bruchhage MMK, Naaijen J, Wolf I, Brandeis D, Williams SCR, Buitelaar JK, Oranje B, Durston S; TACTICS consortium. No evidence of differences in cognitive control in children with autism spectrum disorder or obsessive-compulsive disorder: An fMRI study. Dev Cogn Neurosci. 2018. Nov 29:100602. Pubmed
  • van Diessen E, Lamberink HJ, Otte WM, Doornebal N, Brouwer OF, Jansen FE, Braun KPJ. A Prediction Model to Determine Childhood Epilepsy After 1 or More Paroxysmal Events Pediatrics. 2018 Dec;142(6). Pubmed
  • Hortensius LM, Dijkshoorn ABC, Ecury-Goossen GM, Steggerda SJ, Hoebeek FE, Benders MJNL, Dudink J. Neurodevelopmental Consequences of Preterm Isolated Cerebellar Hemorrhage: A Systematic Review. Pediatrics. 2018 Nov;142(5). Pubmed
  • Böttcher C, Schlickeiser S, Sneeboer MAM, Kunkel D, Knop A, Paza E, Fidzinski P, Kraus L, Snijders GJL, Kahn RS, Schulz AR, Mei HE; NBB-Psy, Hol EM, Siegmund B, Glauben R, Spruth EJ, de Witte LD, Priller JHuman microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry. Nature Neuroscience. 2019 Jan;22(1):78-90. Pubmed

Cover story


What is the story behind the thesis cover?

This time: Emma van Bodegraven

Glioma is a collective name for brain tumors that originate from the uncontrolled division of a specific braincell, the glia cell. Gliomas are incurable to date and patients with the most malignant and aggressive form of glioma pass away within 15 months after diagnosis despite extensive treatment (e.g. surgery, chemo- and radiotherapy). The biggest challenge to glioma treatment is to reach and destroy the cancer cells as they extensively infiltrate (invasion) healthy brain tissue. To develop curative treatments it is essential to gain more knowledge on the underlying mechanism of glioma invasion.

In this thesis we studied a part of the tumor cell that is crucial for invasion, the cytoskeleton (figure 1). The cell’s cytoskeleton is comparable to the human skeleton and connects all components of a cell and enables the cell to move.

Fig. 1
fig. 2

The cytoskeleton is composed of multiple proteins and in this thesis we investigated if the cytoskeleton of aggressive and invasive tumor cells is composed of different proteins compared to the cytoskeleton of less aggressive tumor cells. At first sight, we did not observe a difference (figure 1, black and white). However, when we used a method to detect smaller changes between the cytoskeletal proteins (figure 1, different colors) we ound that the balance between cytoskeletal proteins in more aggressive and invasive tumor cells is different compared to less aggressive tumor cells (figure 2, left). We next aimed at making the tumor cells less aggressive by interfering with this balance. With CRISPR-Cas9, a technique used to modify genes, we were indeed able to change the protein balance within the cytoskeleton and modulate the invasiveness of the tumor cell. Unfortunately this is not possible in patients yet, but nevertheless forms an interesting target to the development of new therapies.

Do you want to tell your cover story at our next Bulletin? Contact us at braincenter@umcutrecht.nl.

Calendar

X-Talk Structure and Connections
June 7, 2019

The X-talks consist of a series of programs within the Brain Center. The X-talks attract both students and senior researchers and provide a forum for inspiring discussion, knowledge transfer, and by bridging boundaries drives novel combined research efforts for the future. X-talks are all held at 15.00-17.00 lecture hall David the Wied Stratenum 4th floor.

Neuroanatomy Championships
Utrecht, November 22, 2019

More information on hersenanatomie.nl.

Brain Center Research Day
November 29, 2019

Utrecht Brain Conference
December 10, 2019

On Tuesday December 10 we will have the 3rd Utrecht Brain Conference at the Utrecht Science Park. This full day meeting is an initiative of several research groups and companies at Utrecht Science Park that focus on brain functioning and brain diseases, and is hosted by the UMC Utrecht Brain Center. The Utrecht Brain Conference aims to build and maintain a campus-wide community around brain research, thereby fostering collaboration between academia and industry and increasing the visibility of Utrecht Neuroscience.

Colophon

Editors: Mariken de Krom, Marjolein Sneeboer, Vicki Kurapka, Joanne Karssenberg
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