Bloggers: Anne Line Stensjøen, PhD Candidate, Department of Neuromedicine and Movement Science (INB), and Asta Håberg, Professor and Centre Director, Centre of Innovative Ultrasound Solutions (CIUS)

Glioblastomas are tumours that originate from brain tissue. It is both the most common and most aggressive type of brain tumour. The median survival at group level is only 10 months for glioblastoma patients in Norway, but it is difficult to predict how long an individual long patient will survive.

How fast brain tumours grow is important to know to make the best decisions with regard to treatment. Tumour growth can also tell us something about how aggressive the tumour is, and perhaps be used as a marker of prognosis. It has been difficult to assess tumour growth because it requires at least two magnetic resonance images (MRIs) of the brain before treatment is started.

Anne Line Stensjøen has in her recent PhD at NTNU, performed the first large study measuring brain tumour growth, showing that glioblastomas grow rapidly when they are small and then more slowly as they get bigger. The growth rate was very fast with about 1.4% per day, which is equivalent to a doubling of the tumour size every 50 days across all the 106 glioblastomas investigated. This demonstrates the need for swift treatment of glioblastomas to prevent unnecessary growth.

Importantly, tumour growth is associated with survival. Patients with slower growing tumours had a 4.4 higher chance of surviving for more than two years compared to patients with faster growing tumours. Measuring glioblastoma growth using MRI could therefore help estimating the prognosis for each patient.

Stensjøen had to perform all tumour segmentations manually to find the tumour size. Manual segmentation is very labour intensive. Developing automated methods, for instance based on machine learning will make it possible to obtain growth measure in a more efficient manner suitable for clinical practice.

This work will be continued at the Centre for Innovative Ultrasound Solutions (CIUS) in the work package “Multimodal imaging and intervention” (WP5).

Dr. Christian Doeller is head of the Doeller research group at the Kavli Institute for Systems Neuroscience

Christian Doeller at the Kavli Institute for Systems Neuroscience has been awarded the Radboud Science Award for his research on how the brain links memories of different events to form one coherent memory. To answer this question, he and his team used pictures and videos of the computer game “The Sims” to create stories. They then showed these stories to participants lying in an MRI scanner and recorded brain activity while people remembered events. They found that the brain forms memory networks of related events which are encoded hierarchically in a brain structure called the hippocampus. How these memory hierarchies are organized resembles what is known about how space is encoded in the brain. “Our findings might point towards a more general code for cognition” says Christian Doeller. “Our memories are what defines our personality and improving our understanding of these mechanisms will be crucial in understanding cognition and neural breakdown in neurodegenerative diseases”.

Screenshots from the computer game showed to participants while recording their brain activity in an MRI scanner

The Kavli Prize in Neuroscience is shared between Eve Marder, Brandeis University, USA, Michael Merzenich, University of California San Francisco, USA, and Carla Shatz, Stanford University, USA. They receive the prize “for the discovery of mechanisms that allow experience and neural activity to remodel brain function”.

From left: Eve Marder, Brandeis University, USA; Michael Merzenich, University of California San Francisco, USA; Carla Shatz, Stanford University, USA.

Keeping the old tricks and learning new ones: how the brain remains stable yet flexible
Until the 1970s, neuroscientists largely believed that by the time we reach adulthood the architecture of the brain is hard-wired and relatively inflexible. The ability of nerves to grow and form abundant new connections was thought mainly to occur during infancy and childhood. This view supported the notion that it is easier for children to learn new skills such as a language or musical instrument than it is for adults. Over the past 40 years, however, the three Kavli neuroscience prize-winners have challenged these assumptions and provided a convincing view of a far more flexible adult brain than previously thought possible — one that is ‘plastic’, or capable of remodeling. Working in different model systems, each researcher has focused on how experience can alter both the architecture and functioning of nerve circuits throughout life, given the right stimulus and context. They have provided a physical and biochemical understanding of the idea of ‘use it, or lose it’. This new picture of a more adaptable brain offers hope for developing new ways to treat neurological conditions that were once considered untreatable.

Michael Merzenich demonstrated that sensory circuits in the cerebral cortex can be reorganized by experience in adulthood. Different parts of the body are represented in a continuous map in the somatosensory cortex. After demonstrating reorganization of this map after injury, Merzenich showed that simply expanding or limiting the use of different fingers leads to a corresponding change in the representation of the hand in the brain. Similarly, he showed that the auditory cortex can change its map of sound frequencies after individuals are trained to detect fine differences in pitch. This discovery helps explain how humans can recover their perception of speech with electronic cochlear implants, which generate signals much simpler than normal auditory inputs. Merzenich showed that neuromodulators as well as cognitive factors including attention determine whether adult plasticity takes place. This work is being extended in humans to maximize learning and recovery from brain injury and disease.

Carla Shatz showed how patterns of activity in the developing brain instruct and refine the arrangement of synapses between neurons. She demonstrated that the formation of appropriate connections between the eye and the brain of mammals depends on neuronal activity before birth. She discovered that spontaneous waves of activity sweep across the retina early in development, and showed that these organized activity patterns select the final set of connections from a coarse, genetically-determined map. Her demonstration that “neurons that fire together, wire together” links the mechanisms of brain wiring during development to those underlying adult learning and memory.

Eve Marder used the simple circuits of crustaceans to elucidate the dynamic interplay between flexibility and stability in the nervous system. She showed that numerous neuromodulators reconfigure the output of adult neural circuits without altering their underlying anatomy. At the same time, she found that circuits can generate similar neuronal and network outputs from many different configurations of intrinsic neuronal excitability and synaptic strength. This apparent paradox was solved by her recognition that neurons have a self-regulating homeostatic programme that drives them to a stable target activity level. With the other two Kavli Prize laureates, Marder defined the mechanisms by which brains remain stable while allowing for change during development and learning.

Illustration showing the action of neurotransmitters such as serotonin and noradrenaline in the synaptic cleft. Vesicles containing the neurotransmitter (green) move towards the pre-synaptic membrane where they fuse with the cell membrane, releasing their contents into the synaptic cleft. The neurotransmitter molecules act on the post-synaptic cell by binding to specific receptors on the cell surface (purple). They can also be taken back up by the presynaptic cell via other receptors (orange) for re-use. (Credit: Arran Lewis, Wellcome Images)

About the Kavli Prizes
The Kavli Prize is a partnership between the Norwegian Academy of Science and Letters, The Kavli Foundation (USA) and the Norwegian Ministry of Education and Research. The Kavli Prizes were initiated by and named after Fred Kavli (1927-2013), founder of The Kavli Foundation, which is dedicated to advancing science for the benefit of humanity, promoting public understanding of scientific research, and supporting scientists and their work. Kavli Prize recipients are chosen biennially by three prize committees comprised of distinguished international scientists recommended by the Chinese Academy of Sciences, the French Academy of Sciences, the Max Planck Society, the U.S. National Academy of Sciences and the Royal Society. After the prize committees have selected the award recipients, their recommendations are confirmed by the Norwegian Academy of Science and Letters.

The 2016 Kavli Prizes will be awarded in Oslo, Norway, on 6 September. His Royal Highness Crown Prince Haakon will present the prizes to the laureates. This year’s ceremony will be hosted by Alan Alda and Lena Kristin Ellingsen. Prime Minister Erna Solberg will host a banquet at Oslo City Hall in honour of the laureates. The ceremony is part of Kavli Prize Week – a week of special programmes to celebrate extraordinary achievements in science. Prize lectures and symposia in neuroscience and nanoscience will be held in Trondheim on 8 September.

This time Debora Ledergerber, Researcher at the Kavli Institute for Systems Neuroscience/Centre for Neural Computation/Egil and Pauline and Fred Kavli Centre for Cortical Microcircuits, will answer questions from one of our readers.

Q:

My husband has close to no spatial memory (hand-eye coordination is far above average and making maps is part of his job). He gets lost moving around the small town we live in and has no internal map to help him navigate. This has been a problem all his life – as a teenager his dog almost died from exhaustion after walking around with him in his home town for hours, being lost.

Could this be something like dyslexia?

A:

It could be compared to dyslexia in as much as both disorders are characterized by trouble doing something (reading or navigating) despite normal intelligence. However, most likely very different brain areas underlie those two symptoms.

Q:

Has this lack of spatial memory been observed in rats?

A:

The hippocampus is a brain area involved in memory and spatial navigation. Humans and rats with lesions in the hippocampus are impaired to build new memories and have troubles finding their ways. Rats have been extensively tested in the Morris watermaze for example. This is a waterpool where rats have to swim to find a hidden platform they can step on. Rats with lesions in the hippocampus or in the connection between the hippocampus and the entorhinal cortex have problems remembering where the platform is located.

Q:

What could be the cause of this?
A:

The brain areas underlying the formation of an internal map are certainly Hippocampus and Entorhinal Cortex, but also other brain areas like the Retrosplenial Cortex have been shown to be important for human navigation. However, it is important to remember that during a walk in the city many more brain areas are active, and if a person is strongly drawn towards other intellectual activities while walking they will not focus on building an internal memory of the path they have been taking.

Bloggers:
Marianne Bjordal Havnes, Post Doc
Andreas Møllerløkken, Researcher,
The Barophysiology group at the Department of circulation and medical imaging

Researchers are trying to find out why U-2 pilots operating in high altitude have  central nervous system changes in a NATO-led project involving researchers from the Barophysiology group at NTNU, researchers from the U.S. Air Force in Texas and from the Institute of Aviation Medicine in Oslo.

You have probably been in a passenger jet, and as you get ready for take-off, you register the cabin attendants going through the safety instructions, mentioning something about loss of cabin pressure and oxygen masks, but you don’t worry about it. 15 minutes later the captain announces that the airplane has reached its cruising altitude of 38,000 feet. At this altitude the barometric pressure is only 1/5 of sea level pressure.

Inside the aircraft the pressurisation system ensures that the cabin altitude according to international regulations will never exceed 8000 feet = ¾ of sea level pressure. So while you are travelling, you are actually performing a little mountain-excursion to the same altitude as Norway’s highest mountain, Galdhøpiggen.

Now imagine that you are flying twice as high as your airliner. At an altitude of 70,000+ feet the barometric pressure is 1/25th of an atmosphere. You can see the curvature of the earth and the blackness of space above. This is where the U-2 pilots are working. If you lose the cabin pressure in this environment, an oxygen mask will be of no help. You need to wear a space suit that will instantly inflate to a pressure of 0.3 bar (corresponding to 30,000 feet) and supply you with a breathing gas of 100% oxygen.

The U-2 planes have been operating since the 50s and are still in active duty. In fact, U-2 pilots have actually been flying more the last 10 years as other high-altitude reconnaissance airplanes have retired. This has resulted in an increased number of neurologic decompression sickness episodes.

A US Air Force research team has published findings of what are called white matter hyperintensities in the brain on magnetic resonance imaging (MRI) of U-2 pilots (McGuire et al., 2013) . Recently they have discovered similar findings in U.S. Air Force altitude chamber instructors (McGuire et al., 2014). This group works inside hypobaric chambers, training aircrew including U-2 pilots, in the effect of loss of cabin pressure and lack of oxygen. The altitude exposure in hypobaric chamber training is usually much shorter and less severe than in U-2 operations. None of the other U.S. Air Force control groups they have tested so far, including Air Force doctors, have had similar changes.

The U.S. Air Force research team visited the Institute for Aviation Medicine, Oslo, Norway, and wanted to meet Norwegian research groups that might contribute to understanding the pathophysiology behind the findings. Members of the NTNU Barophysiology group were invited based on their merits for a long time commitment to research on man in extreme environments.

Most of the work of the NTNU Barophysiology group has been related to the activity of diving and the adverse effects of working under water. Presently, the research is funded by the Norwegian Research Council through the Petromaks programme.

From left: Berit Holte Munkeby, MD, PhD, Norwegian Armed Forces, Dr Paul Sherman, USAF, Andreas Møllerløkken, PhD NTNU, Marianne Bjordal Havnes, PhD, NTNU, Dr Stephen McGuire USAF.

One of the technologies we are using in assessing possible stress after a dive is ultrasound detection of gas bubbles found in blood veins. These bubbles will form in nearly all diving activity, and it is recognised that the risk of decompression sickness increases with increasing amounts of bubbles.

Our way of observing vascular gas bubbles after diving has become a recognised method for evaluating procedures.  It has also been shown both in animals and humans that the bubbles themselves influence the endothelium lining all blood vessels. When going to high altitudes, the pressure changes are opposite of diving. But there are many similarities as well, and the formation of bubbles is thought to be involved in the formation of the white matter hyperintensities.

After the meeting in Oslo, the researchers from NTNU did some preliminary investigations, and were invited to Lackland Air Force Base in Texas where the main investigation is taking place. The results from the tests at NTNU have already been presented at a NATO high altitude exposure meeting this summer in Paris, and has gained a lot of attention within NATO. Together with the Institute of Aviation Medicine in Oslo, the researchers from the Department of circulation and medical imaging are eager to continue the investigations.

Menno Witter and Clifford Kentros.

The Olav Thon foundation announced today that Menno Witter will receive 10 million NOK for a collaborative project with Cliff Kentros, also at the Kavli Institue at NTNU, and Gunnar Gouras at Lund University and Heikki Tanila at the University of Eastern Finland.

The project ‘Interactions between reelin and amyloid in the entorhinal cortex – A possible initiator of Alzheimer’s disease’, is based on a new concept on one of the possible early stages of the disease, suggesting that the interactions between reelin and amyloid will eventually lead to neuron loss.

According to the Olav Thon Foundation’s evaluation, the hypothesis is original and innovative.

Blogger: Torstein Vik
Professor in the CEBRA Group at the Department of Laboratory Medicine, Children’s and Women’s Health (LBK)

Many children with cerebral palsy have feeding difficulties and a significant proportion is malnourished. This may lead to impaired growth, but also to overweight and obesity, since many of the children are unable to walk. Moreover, some of the children are at risk for bone fractures following small traumas.

To further understand the etiology and consequences of these problems were the main topic of MD Ane-Kristine Finbråten’s PhD-thesis, Nutritional status, growth and bone health of children with cerebral palsy, that she defended on November 18th. Among a number of important findings were that nutritional status is not assessed appropriately in this population.

Body mass index (BMI), the most commonly used assessment of nutritional status in children without disabilities, is more or less useless in children with cerebral palsy. In fact, the use of BMI will underestimate nutritional status in many children, and this may increase the risk that the children are overfed, and become obese. Instead, Ane argues that one should measure skinfold thickness with a calliper to assess nutritional status, and that linear growth should be assessed by taking segmental measures, such as knee-height. These measures can be applied to estimate body fat and standing height.

Three out of four children with cerebral palsy are vitamin D deficient.

Another important finding was that three out of four children were vitamin D deficient, in particular those children who were able to walk. This finding suggests that children with cerebral palsy need extra vitamin D supplements.

Finally, Ane found that children, even those who were able to walk, had low bone density in the distal part of the femur (the part of the thigh bone, closest to the knee), meaning that they have increased risk for fractures in this area, following minor traumas.

Ane’s opponents were Professor Richard Henderson, University of North Carolina in the US, and Associate Professor Lena Westbom from Lund’s University (Picture).

From left Rich Henderson (1. opponent), Ane-Kristine Finbråten (PhD-Candidate), Marite Rygg (acting dean), Lena Westbom (2. oponent) and Ingrid Løvold Mostad (3rd opononent).

This was the fourth PhD dissertation on cerebral palsy in 2015 from our research group at NTNU. The first was MD Magnus Dahlseng, who defended his thesis in January, entitled “Growth, nutritional status, and feeding difficulties in children with cerebral palsy”, which underscores our interest in this important topic!

Another main topic of our group’s research is etiology, and in June MD Kristin Melheim Strand defended her thesis, where she studied the role of placental dysfunction in the etiology of cerebral palsy (see video in this previous blog post).

Finally, in September, MD Espen Lien defended his thesis on how genetics may affect the clinical manifestations of cerebral palsy.

Altogether, 2015 has been an “all-time high” for our research group including a number of seminars, guest lectures and presentations on these and other aspects of cerebral palsy and early brain injury.

We congratulate the four PhDs and are proud of them, and we hope that in the long term these small pieces of research may contribute to prevention and to better care of children with cerebral palsy in the future!

The Cerebral Palsy Group.

Over the last couple of years Edvard Moser and scientists of the MPI of Neurobiology are closely collaborating. As part of this scientific exchange, Edvard Moser has spent many days and weeks at the Institute in Martinsried. Currently, he and Tobias Bonhoeffer, director at the MPI of Neurobiology, work on imaging the activity of grid cells with the help of 2-Photon-Microscopy. Based on the existing intense collaboration the directors of the Institute proposed to appoint Edvard Moser as External Scientific Member of the MPI of Neurobiology. Edvard Moser has accepted this offer and has thereby also become a Scientific Member of the Max Planck Society. The MPI of Neurobiology has now three External Scientific Members:

• Prof. Dr. Yves-Alain Barde, Cardiff School of Biosciences (UK)
• Prof. Dr. Reinhard Hohlfeld, Institute for Clinical Neuroimmunology of the Ludwig-Maximilians-University of Munich
• Prof. Dr. Edvard Moser, Kavli Institute for Systems Neuroscience and Centre for Neural Computation (Trondheim/Norway)

Emilio Kropff, lead author of the speed cell paper.

Speed cells, a missing element in the brain’s dynamic map of space, have been discovered in rat brains by Emilio Kropff and his coworkers in the Moser group, at the Kavli Institute for Systems Neuroscience and Centre for Neural Computation. The discovery is reported in an article in Nature.

Speed cells are cells whose firing rates increase linearly with the speed of the animal. The faster the animal is running, the faster the cells are spiking. These neurons provide information that is essential for the grid map to be updated, with no delay, in accordance with our changing position in the environment.

Speed cells have been predicted for years and the present work confirms current models of how grid cells operate to map our changing position in the environment.

The article in Nature: Speed cells in the medial entorhinal cortex

Researcher Hiroshi Ito

Ito and his colleagues, including his supervisors, 2014 Nobel Laureates May-Britt and Edvard Moser, sampled a specific neural pathway to figure out if it is the location of the mechanism that enables animals to code their plan to get from one place to another. Their study confirms that this pathway, the medial prefrontal cortex via a thalamic nucleus to the hippocampus, does.

The code that predicts behaviour

The researchers designed a study that would help them better understand how this signalling pathway works. They trained rats to run in an alternating fashion in a continuous T-maze that actually looks more like the infinity sign with a wide waist, or stem.

“We learned that the differential strength of firing of specific neurons accurately predicts the trajectory the animal will chose,” Ito said.

Rat in alternating continuous T-maze

While the rats ran the maze, electrophysiological recordings were made from prefrontal cortex, thalamus and hippocampus. The researchers analysed the activity of neurons while the rat was on the stem of the maze, where it had to decide whether to go left or right at the upcoming junction.

See video of rat in T-maze
Hear May-Britt Moser explain this during her Nobel Lecture – on Soundcloud 
May-Britt Moser’s Nobel Lecture

The decision pathway

Researchers know there are pathways from the prefrontal cortex via the thalamus to the CA1 area of the hippocampus. However, there is no link to the CA3 area immediately adjacent to CA1 (which is also in the hippocampus). Given this, the researchers first checked to see if they could detect a difference in the coding between the two areas that would reflect the trajectory the rat would subsequently choose. There was a clear difference. The CA1 showed far more coding for any upcoming choice than the CA3.

The code was visible in the intensity of firing, although not in which cell fired, or where. To understand how this works, think of a choir all singing the same song, but where different voices are louder at the same point in the song during different performances. The words, melody, and singers are the same, but the change in the volume of each voice changes the performance. Since they are familiar with “the choir”, the researchers looked for the conductor, which they found in the frontal cortex.

Researchers have known that the code for trajectory choice could be found in CA1. The researchers at the Kavli Institute showed that a similar code is present in nucleus reuniens (NR) in the thalamus as well as anterior cingulate (AC) and prelimbic cortex (PC), both in the medial prefrontal cortex (mPFC). The researchers continued to find out where the signals arise, and tested the contribution of the mPFC-NR pathway.  The researchers were able to establish that without the input from mPFC through NR, the CA1 also loses its code for upcoming choice of trajectory. They were able to confirm this by blocking signalling in the NR, using two different approaches. This shows that the code needs mPFC and NR, much like a choir needs its conductor.

Professor May-Britt Moser

“Planning our movement to a desired location requires more than a map of where we are,” Professor May-Britt Moser says. “We must have a sense of both where we are at the moment, and where we want to go at the same time. It seems that the cells involved in navigation use both internal and external clues to pinpoint exact locations, and on top of the firing pattern there is a code of differential firing intensity that contains information on the next move.”

Moser explains that this intensity pattern appears to be under the guidance of the prefrontal cortex, a brain area known in primates for decision making and executive function.

“We believe these findings collectively suggest that the new pathway in charge of intended movement is crucial for animals to choose their actions to a desired place in a map,” Moser said.  “The data also provide evidence for a role of the thalamus in long-range communication between cortical regions.”

The article in Nature: A prefrontal-thalamo-hippocampal circuit for goal-directed spatial coding