September 2020, 18th edition

Here is a new edition of the Brain Center Bulletin after an impactful period. The past few months were characterized by major challenges for all of us, and some things are not back to normal still. We are grateful that research is (partly) resumed, new plans are made for the upcoming academic year with respect to teaching, and that COVID-19 care is intervening less with daily activities in the clinic. Despite these harsh times there’s lot of news to share, of which I am very proud. Also there are events to look forward to, such as the annual Research Day, which will be a virtual meeting accessible for all of you. The X-talks are also resuming in an online format and we are planning another event with the New Scientist early 2021. Take care and I hope to see you online!

Jeroen Pasterkamp  


Outcome of European study: the sooner epilepsy surgery, the better the result

A large-scale European study into the effectiveness of epilepsy surgery, led by the UMC Utrecht and the University Hospitals of Erlangen, convincingly shows its success. One year after surgery, 72% of patients with epilepsy are seizure-free. After two years, that percentage is still 68% and after five years 66%. The results help in deciding whether surgery to treat epilepsy is effective. The findings also support the idea that operating as quickly as possible improves the outcome. This study was published in the Lancet Neurology on August 18.
 

The European Epilepsy Brain Bank study examined 9,147 patients who underwent surgery between 2000 and 2012. The study looked at whether and how long the patients are seizure-free after the operation, as well as at the difference in outcome between the different causes of epilepsy. For example, 78% of patients who had epilepsy as a result of a tumor were seizure-free after surgery. For epilepsy patients with certain predispositions of the cerebral cortex, this percentage was considerably lower at 50%.

Earlier surgery
Professor of pediatric neurology at the UMC Utrecht and research leader Kees Braun says, “The study clearly shows that the sooner you operate, the greater the chances of success. For a patient with epilepsy caused by a vascular lesion, for example, the chance of becoming seizure-free after surgery within one year is 85%. However, if you do not operate until after twenty years, that chance is reduced to 70%. That is another argument to operate at an early stage. Yet another argument for early surgery is that patients need medication for a smaller period of time. The study also shows that in children the medication is much more often phased out after five years than in adults, which benefits their development.”

The results can be taken into account when considering treatment for epilepsy. Kees says, “Epilepsy surgery removes the source of epilepsy from the brain. This is only possible if no important brain functions are lost in the process. In practice, a multidisciplinary team investigates which treatment works best for which patient. These study results can be taken into account in that decision.”

Third publication
This is the third publication on applied epilepsy research of the research group in the Lancet Neurology . The first showed that after epilepsy surgery, children could safely reduce their medication at an early stage. The second describes an online prediction model that can be used to calculate the risk of reducing medication for each individual. Kees is particularly pleased with these publications because they can improve the care for epilepsy patients worldwide. “These types of results are only possible because we receive the data from a great many hospitals. Close European cooperation forms the basis for this study.” The European Epilepsy Brain Bank study is a European collaboration and part of the European Reference Network Epicare. The UMC Utrecht and the Erlangen University Hospitals have studied the outcomes of more than 9,000 epilepsy patients from 37 centers in 18 countries.


Multimillion grant for research into brain damage

A European consortium of scientists will receive a total of 9 million euros for research into the treatment of brain damage in premature babies. Of these 9 million euros, 1.2 million will go to researchers of UMC Utrecht. “This European grant will help us develop a new therapy to reduce brain damage in premature babies,” says Dr. Cora Nijboer.

In the Netherlands, eight percent of babies are born prematurely every year, before the 37th week of pregnancy. One percent is even born before the 28th week of pregnancy. The brain of premature babies is not fully grown yet and may be damaged. Such brain damage may have far-reaching consequences later in life, such as motor or mental disorders and behavioral and emotional problems.

New therapy

“This European grant will help us develop a new therapy to reduce brain damage in premature babies,” says Dr. Cora Nijboer. Cora is the leading researcher of the Utrecht research group. “This therapy is based on stem cells that we administer through, among others, nasal drops, a method that we developed in Utrecht in recent years to treat brain damage in newborns.” Nijboer is assisted by Dr. Caroline de Theije and the team of the ‘Department of Developmental Origins of Disease’ (DDOD) of UMC Utrecht. They work closely together with Prof. Manon Benders (neonatology) and Dr. Titia Lely (Obstetrics).

Early treatment

“The survival rate of babies who are born extremely prematurely is increasing,” says Benders. “Yet the long-term effects of brain damage and disturbed brain development do not decrease.” There currently is no treatment for brain damage. Benders: “Because of this, we cannot prevent disturbed development. It is important for the rest of the babies’ lives to tackle the problem as early as possible. If we can make a difference in the first phase of life treating brain damage and therefore support brain development, these children will benefit for the rest of their lives.”

Development of brain damage

To treat children as early as possible in life, it is important to know what causes the damage in the immature brain. This is what the Utrecht research group is studying. They also study how stem cells can reduce this damage and support brain development and for whom this stem cell therapy is most effective. Nijboer explains: “Because premature birth may have different causes, the group of patients has a fairly diverse composition. That is why this study will look at which group of premature babies can benefit most from stem cell therapy.”

International collaboration The European grant for the study, called PREMSTEM, is coordinated by the Parisian Institut National de la Santé et de la Recherche Médicale (INSERM). They will receive over 1.7 million. The other partners in the research consortium are MUMC+, Radboudumc, Universitätsklinikum Essen, Göteborgs Universitet, Consiglio Nazionale delle Ricerche (Milan), Université de Genève, Royal Melbourne Institute of Technology (RMIT) University (Australia and Spain), Iconeus (France) and CHIESI Farmaceutici SPA (Italy), the European Foundation for the Care of Newborn Infants (EFCNI) in Germany and the Cerebral Palsy Alliance (Australia). The PREMSTEM project is a study as part of the EU Horizon 2020 research and innovation program with grant number 874721.


Looking for new anti-epileptics

Certain molecules, tRNAs, or fragments thereof, tRFs, appear to play a role in the brain in the development of temporal lobe epilepsy (TLE). Jeroen Pasterkamp has received a grant from the Epilepsy Fund to conduct research into this. “If we can manipulate them the right way, it will provide leads for a new generation of antiepileptic drugs.”

Epilepsy is a serious chronic disorder of the nervous system that affects 60 million people worldwide. The condition manifests itself in the form of seizures, which are caused by a sudden disturbance of the electrical stimulus transmission in the brain. Depending on where this happens, patients may fall, make shocking movements, smell something strange, be absent for a while or lose consciousness. The unpredictability of these seizures limits the freedom of movement of epilepsy patients and has a major impact on their safety and social well-being. Moreover, ongoing epileptic activity can lead to damage to the brain and loss of mental faculties. According to the Epilepsy Fund, about 14,000 people in the Netherlands are diagnosed with epilepsy every year. 

Temporal lobe epilepsy 
Temporal lobe epilepsy (TLE) is one of the most common and severe forms of epilepsy. It affects a brain area that is involved in learning and memory (hippocampus). Nearly one third of TLE patients have severe seizures despite treatment with various medications. For these patients, the surgical removal of the hippocampus is often the only remedy, although not all TLE patients qualify for it and the procedure is not without risk and not always effective. 

Brain tissue
The development of new therapies, which work fundamentally differently from the existing antiepileptics (and which also go beyond symptom control), requires more knowledge of the etiology of epilepsy. Jeroen Pasterkamp, professor of translational neuroscience, is researching this and has been concerned with temporal lobe epilepsy for almost ten years. He studies such things as the brain tissue of TLE patients, where the epileptic focus has been removed by the neurosurgeon. “We collect that material directly from the operating room,” he says, “with the patient’s consent, of course. We know from previous studies that changes occur in the brains of TLE patients long before the first seizure starts. There are inexplicable differences in the amount of protein, but how they originate is unknown.” 



Transfer RNAs
With a grant from the Epilepsy Fund, Jeroen will now investigate the role of so-called transfer RNAs (tRNAs) for the next three years. These are molecules in the brain, which he expects to be at the root of temporal lobe epilepsy. TRNAs are RNAs that do not code for a protein but play an important role in protein synthesis, the process whereby proteins are made with information from DNA. Jeroen says, “tRNAs bring amino acids to the right place to produce proteins and they play a role in regulating the amount of proteins. Remarkably, these large molecules can disintegrate into fragments. We call those fragments tRFs (see picture). What those tRFs do is still unclear, but they aren’t waste. They’re bioactive molecules with a new, as yet unknown function.” 

RNA sequencing
Earlier research by Jeroen into microRNAs (which include the tRFs) in mice showed that if you eliminate them, the mice’s epileptic seizures disappear completely . “Now, in traditional mouse research, you trigger a seizure in and treat the mice immediately after,” he explains. “That’s not completely comparable to people: they are treated at a later stage after a seizure. But if we wait as long with the treatment of mice as of humans, it proves to work.” He recently also discovered that tRNAs in the brains of TLE patients display abnormalities, but the intricacies of them are still unclear.

As a first step, Jeroen will use RNA sequencing to investigate which tRNAs/tRFs are abnormal in the brain tissue of TLE patients and in which type of nerve cell these tRNAs/tRFs occur. He will then manipulate a number of specific tRFs in human nerve cell cultures to determine exactly how they work and why they deviate in TLE. Finally, he will investigate whether manipulation of these specific tRFs can lead to a reduction in epileptic activity. 

Therapeutic targets
Jeroen says, “I’m really curious about how those tRFs originate. And once we have been able to detect the abnormal tRNAs, I wonder how they work and which processes will be disrupted if you manipulate them. And what consequences that has for epilepsy patients: are there any defects in the synapse communication, an overactive brain or on the contrary?” He expects that the study will provide the first direct evidence that tRFs are related to epileptic activity in the nerve networks of patients with TLE. And that it will provide the necessary tools with which to manipulate tRNAs and tRFs. And that this makes it an important starting point for finding a new, more effective treatment for TLE. “We see non-coding RNAs, including tRNAs, as the therapeutic targets of the future in the treatment of brain diseases.”


PhD ceremony in sneakers – Gijsje Snijders

Actually, she would obtain her PhD on March 20, 2020 in the beautiful Utrecht University Building. But the coronary measures threw a wrench in the works. Eventually, she became the first PhD student at the Brain Center to obtain her PhD during an online ceremony on April 21. Five questions to Dr. Gijsje Snijders.

What was your PhD research about? An activated immune system, as you also see during an inflammatory reaction, may be the driving force behind the development of mood disorders. Genetic, epidemiological, and laboratory studies show a relationship between mood disorders and the immune system. Inflammatory substances in the blood can cross the blood-brain barrier and influence important signaling substances in the brain. But the exact involvement of the immune system in bipolar and depressive disorder has yet to be clarified. That is why I did studied three things in my doctoral research:

  • Key immune markers in the blood of patients with an increased risk of developing mood pathology
  • Various antibodies in the blood of patients with bipolar disorder or post-partum psychosis
  • Immune cells of the brain (microglia) in post-mortem brain tissue of patients with bipolar or depressive disorder

Based on these findings, I explained in the discussion how the observed immune changes in the blood are related to (immune) abnormalities in the brain and could possibly explain mood pathology. 

What did you think when all the strict measures relating to the coronavirus came into effect?
It was a stressful period. I currently live and work in New York as a postdoc. On the day that I would fly to the Netherlands for my PhD defense, President Trump announced a travel ban, which meant that I would not be able to return to the United States after defending my thesis in Utrecht. At that time it was still uncertain whether my PhD ceremony would be held in the Netherlands. Eventually I decided not to travel to the Netherlands and to find out whether it would be possible to obtain my PhD electronically on that day. I had to cancel the reception, dinner and party. Two days later it turned out that everything in the Netherlands was put “on hold” as well, so luckily I had made a good choice.

How did it go, that digital ceremony?
Utrecht University had done its best to make the digital PhD ceremony look as similar as possible to the “normal” PhD ceremony. For example, there was a “virtual sweatbox” where I as a PhD student, together with my assistants and the registrar, discussed the ceremony, after which I was led to the “virtual senate room.” The ceremony was opened by the chair and after 45 minutes of questions from the opponents, the registrar rang a bell and “Hora Est’’ was announced. The opponents, supervisors and co-supervisors left for a “virtual consultation room.” Then the verdict was given and I was allowed to take the oath. The laudatio was pronounced by my supervisor, and the opponents were given the opportunity to address me briefly. The congratulations from the opponents were very personal, something I have not noticed before during “normal” PhD ceremonies. Perhaps this was because of the intimate setting created by the “digital environment.” Family, friends and colleagues could watch via a video connection that had been established. As a PhD student, I had no idea who “digitally attended” my PhD ceremony. Afterwards I had a quick digital drink with colleagues and family. An advantage of holding a PhD ceremony through a video connection is that only the upper part of your body needs to be formally dressed. I was still in doubt about putting on a pair of sweat pants in addition to sneakers…

Are you going to catch up with the party later?
I hope to be able to throw a big party in the Netherlands in November for colleagues, family and friends. I’m having a baby in August, so that can be celebrated at the same time. The advantage is that I can have a drink again then. 

What does your future look like? What is the next step in your career?
I will stay in the United States for a while to continue my work as a postdoc in the laboratory of Dr. L. de Witte (psychiatry) and Dr. T. Raj (neurogenetics) that is affiliated with the Icahn School of Medicine Mount Sinai Hospital. Then I will return to the Netherlands to complete the remainder of my training as a child and adolescent psychiatrist. In the future I hope to be able to combine my clinical work as a child and adolescent psychiatrist with research in biological psychiatry at the academy. 


Two ZonMW grants for Matthijs Biesbroek

Matthijs Biesbroek is a neurologist and researcher in the VCI group of Geert Jan Biessels. He recently received two grants from ZonMw for his research on the diagnostic and prognostic value of the location of vascular brain injury in vascular cognitive impairment: the VIMP grant (€50.000) and the Off Road grant (€100.000).

Cerebrovascular disease is a major cause of cognitive decline and dementia. A common observation in clinical practice is that some patients with vascular brain injury develop cognitive impairment, whereas others do not. This hampers an accurate cognitive prognosis in patients with stroke and can cause diagnostic uncertainty in memory clinic patients. The impact of vascular brain lesions on cognitive functioning depends on location, which means that information on lesion location can help to provide patients with a more accurate diagnosis and prognosis.

Biesbroek: “My aim is to develop diagnostic and prognostic models for vascular cognitive impairment based on vascular lesion location. The VIMP grant from ZonMw enables me to validate and implement the previously developed lesion impact score, which integrates infarct location with  information on brain networks to provide an individualized cognitive prognosis.

Because the information on brain networks is extracted from a previously developed atlas, the patient only has to undergo standard CT or MR to enable infarct detection and segmentation. As part of this project, a fully automated open source tool to calculate the lesion impact score will be published in order to facilitate implementation. My Off Road project focuses on improving the diagnostic workup of patients attending a memory clinic by analyzing patterns of vascular lesion location, as opposed to the visual global grading methods that are currently used in clinical practice.”

Both projects will involve thousands of individuals, which is made possible by collaboration with international partner through the META VCI Map consortium.


New, international partnership: an important step for SMA research

As part of the Marie Skłodowska-Curie Actions, the European Union has recently awarded funding to a large, international partnership between the SMA Center of Expertise of the UMC Utrecht and researchers from other European countries. This is the first time that a large SMA consortium is sponsored by the European Union. An important step for SMA research.

SMA is a neuromuscular disease caused by the loss of motor nerve cells (motor neurons) in the spinal cord. In addition to the loss of motor neurons, it has recently become clear that other cells and tissues in the body may also be affected by the disease. However, research into this has so far been limited to small groups of patients. It is therefore still unclear to what extent certain problems occur in all or only in limited groups of patients. It is also unknown whether these problems arise through the same molecular mechanisms that underlie the loss of motor neurons.

The appropriate treatment for the individual patient
Earlier this year, Dr. Ewout Groen and Professor Ludo van der Pol on behalf of the SMA Center of Expertise and in collaboration with researchers from Germany and a number of other European countries, applied to the European Union, to obtain funding for an international research consortium. It has recently been announced that this application has been awarded. Ewout says: “With this consortium, called SMABEYOND, we want to jointly and systematically map the non-motor neuron problems associated with SMA in order to gain more insight into SMA as a disease not only of the nervous system, but of the entire body. We also want to find out whether different non-motor neuron problems occur in different patients. Current and future treatments such as Spinraza, Zolgensma and Risdiplam are administered in different ways and, consequently, reach different places in the body. By investigating whether all patients experience symptoms outside the nervous system and to what extent, we will be able to better choose which medication is necessary and effective for each individual patient in the future.”

Exchange of knowledge for better SMA research
International collaboration makes it possible to achieve results quickly. In addition to important insights into non-motor neuron problems associated with SMA, the consortium offers many opportunities for the exchange of knowledge and research techniques between the various laboratories. Moreover, because each research group has expertise in its own field, the consortium offers young researchers extensive training opportunities. This collaboration is therefore also an important next step to further improve future research into SMA.

SMABEYOND
The SMABEYOND consortium is led by the University Medical Center in Hanover (Germany) and consists of research groups in Italy (Trento), Great Britain (Edinburgh and London), Spain (Barcelona), Germany (Cologne) and a second group from Hanover, in addition to the SMA Center of Expertise of the UMC Utrecht. The consortium will start later this year.


Cover Story

What is the story behind the thesis cover?

This time: Kim Annink

“My thesis focusses on neuroimaging, neuroprotection and follow-up in neonates with hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia.

On the cover, created by Evelien Jagtman, you see an empty head that is “flipped open”. The emptiness of the head represents the missing knowledge on this subject. The aim of our research is to adequately predict neurodevelopmental outcome of infants with HIE by using MRI, so by looking into the head. 

To predict and improve neurodevelopmental outcome of an individual neonate, we have to investigate a population of infants with HIE, this population is visualized by the blue and pink faces on the cover. On the other hand, the faces represent all the pieces (research) that are needed to solve the puzzle (improve outcome of infants with HIE).

A nice personal detail: all the faces in blue and pink are inspired on African masks in my living room and represent my passion for Africa and travelling.”


MSCA-IF grant for Rogier Poorthuis

Rogier Poorthuis received a European MSCA-IF grant of 200,000 euros. These grants, named after Nobel Prize winner Marie Curie, are awarded to excellent post-doctoral researchers. Rogier studies the neural mechanisms of stress eating.

When stressed, many people tend to eat more and less healthy. Because stress and food stimuli are present everywhere in our society, this feeds the development of obesity, especially in people who are sensitive to it. So-called interneurons in the prefrontal cortex of our brain are expected to play a role in this. These switch cells regulate the transfer of information between brain cells of the prefrontal cortex and other parts of the brain that are involved in our eating behavior. Rogier: “I expect that the activity of these interneurons in particular is sensitive to stress and that this leads to permanent activity changes in the brain connections that regulate eating behavior.”

He will investigate this in mice by using modern techniques to perform electrophysiological measurements of the activity patterns of the neurons in the prefrontal cortex during stress eating. Rogier: “Then I will simulate the altered activity patterns of these neurons in non-stressed mice to see if they are actually the underlying cause of the increased food intake after stress. By uncovering the neuronal mechanisms of stress eating, I hope to find a targeted approach to intervention.”


Research Day 2020 widely accessible

This year our annual Research Day will take place on Friday November 27. Due to corona, this edition will be a virtual one, which means that it will be accessible for all of you! So not only for the researchers who are actually working in the UMC Utrecht, but for anyone who is interested in the program and its speakers.

The Research Day 2020 is composed of  both fundamental and clinical talks. Furthermore,  the winners of the Rudolf Magnus Young Talent Fellowship and other prizes will be announced.

For the program and signing up, keep following us on Twitter (@UMCUBrainCenter)


Publications

Luykx JJ, Stam N, Tanskanen A, Tiihonen J, Taipale H. In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine. Br J Psychiatry. 2020 Jan 8:1-8. Pubmed

Slooter AJC, Otte WM, Devlin JW, Arora RC, Bleck TP, et al. Updated nomenclature of delirium and acute encephalopathy: statement of ten Societies. Intensive Care Med. 2020 Feb 13. Pubmed

Resch C, Van Kruijsbergen M, Ketelaar M, Hurks P, Adair B, et al. Assessing participation of children with acquired brain injury and cerebral palsy: a systematic review of measurement properties. Dev Med Child Neurol. 2020 Apr;62(4):434-444. Pubmed

De Wit J, Beelen A, Drossaert CHC, Kolijn R, Van Den Berg LH, Schröder CD, Visser-Meily JMA.Blended psychosocial support for partners of patients with ALS and PMA: results of a randomized controlled trial.Amyotroph Lateral Scler Frontotemporal Degener. 2020 May 2:1-11. Pubmed

Dubois J, Alison M, Counsell SJ, Hertz-Pannier L, Hüppi PS, Benders MJNL. MRI of the Neonatal Brain: A Review of Methodological Challenges and Neuroscientific Advances. J Magn Reson Imaging. 2020 May 18. doi: 10.1002/jmri.27192. Pubmed

Annink KV, van der Aa NE, Dudink J, Alderliesten T, Groenendaal F, Lequin M, Jansen FE, Rhebergen KS, Luijten P, Hendrikse J, Hoogduin HJM, Huijing ER, Versteeg E, Visser F, Raaijmakers AJE, Wiegers EC, Klomp DWJ, Wijnen JP, Benders MJNL. Introduction of Ultra-High-Field MR Imaging in Infants: Preparations and Feasibility. AJNR Am J Neuroradiol. 2020 Aug;41(8):1532-1537. Pubmed

Schijven D, Stevelink R, McCormack M, van Rheenen W, Luykx JJ, Koeleman BPC, Veldink JH; Project MinE ALS GWAS Consortium; International League Against Epilepsy Consortium on Complex Epilepsies. Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy. Neurobiol Aging. 2020 Aug;92:153.e1-153.e5. Pubmed


Grants and awards

Rogier Poorthuis was granted with an individual Marie Curie Individual Fellowship

The MING-fund received a donation of 2 million euro from two parents of a child with epilepsy. The MING fund finances the research program under supervision of Kees Braun and Bobby Koeleman to study genetic risk factors, epilepsy surgery, and the development of individual prediction models in epilepsy. https://vriendenumcutrecht-wkz.nl/mingfonds/

Matthijs Biesbroek and Vanessa Donega were awarded with a ZonMw Off Road grant. The grant allows young researchers to work on unconventional research ideas. With the grant, Matthijs will work on a road map of the brain to define and recognize critical patterns of vascular damage. Vanessa will study if human neural stem cells can be activated and are capable of transforming in functional neurons after brain damage.

Jeroen Pasterkamp received a grant from the Epilepsy Fund to conduct research into the role of transfer RNAs in the development of temporal lobe epilepsy (TLE). https://www.umcutrecht.nl/nieuws/op-zoek-naar-nieuwe-anti-epileptica; https://www.epilepsie.nl/nieuws/detail/onderzoek-van-start-dankzij-online-collectanten/154

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