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

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.

Early on a Friday morning in the middle of November, PhD student Anne Hokstad and I, headed towards Trondheim airport, Værnes, to catch the early flight to Copenhagen. We did not spend much time in bed that night as the airport taxi came at 4.20 am. However, there should be good opportunities for sleeping over the next 24 hours, although it had to be in a sitting position, either at Kastrup airport, or during the 13-hour flight to Singapore.

Sleeping in a sitting position on economy class is not easy, and we arrived for a stop-over in Singapore early Saturday morning after only two hours of interrupted sleep. It was tempting to take a short morning nap, but we decided to spend the day on walking along the streets of Singapore, and keep going throughout the day instead. After a good night sleep, in bed, we were ready for some more physical activity the next morning until the departure of our flight to Melbourne, Australia. Again we spent Sunday night in a sitting position on a plane with a few hours of interrupted sleep, again we arrived early in the morning, and again we spent the next day being active, settling in in Melbourne.

The purpose of this exhausting flight was to visit Associate Professor Julie Bernhardt and her colleagues at the Stroke Division at Florey Institutes of Neuroscience and Mental Health in Melbourne, Australia, and to continue our research collaboration on physical activity early after stroke.

So, why all this interest in time spent in bed, in sitting position and on physical activity? It is well known within the stroke society that acute treatment in a comprehensive stroke unit saves lives and reduces disability. Furthermore, from the stroke unit trial in Trondheim we know that early mobilisation and activity is the most significant factor for beneficial outcome, followed by stabilising diastolic blood pressure. It is therefore of great interest and importance to have a closer look at the activity levels offered to stroke patients admitted to stroke units across the world, and furthermore to analyse its association to outcome. 

Physical activity can be measured in different ways, both by observation and by use of body worn sensor systems. Julie Bernhardt has developed the Behavioural Mapping method which is a standard method of observation every 10-minute from 8 am to 5 pm over the course of a single day. At each observation, the patient’s location, who the patient interacts with, and which activity the patient is doing, is registered. Up to 10 patients can be observed at a time. At the Department of Neuroscience at NTNU, we have observed more than 500 patients, including a pilot study of 117 patients from the stroke unit at St. Olavs Hospital and a multisite study of 411 stroke patients admitted to 11 Norwegian stroke units, mainly in Central Norway but also in Bærum, Lillehammer and Tromsø. All behavioural mapping forms completed in these studies have been scanned and sent to Florey for processing and the initial analyses.

The primary aim of our visit this time was to help cleaning up the data and to bring a complete and tidy overview over the activity levels of the patients back home again. In the pilot study we found that an increased proportion of time spent in bed in the early phase after stroke was strongly associated with an increased risk of poor outcome (death or disability) three months later. While, to our surprise time spent on physical activity, like standing, walking and climbing the stairs, did not show the inverse association.

We are now very interested in the results from the 411 patients included in the Life Early After STroke – the LEAST study. Will the results from the pilot study be confirmed? And, will the activity levels provided by the 11 Norwegian hospitals differ significantly? That is what PhD student Anne Hokstad is going to figure out over the next 18 months.

We did not spend very much time in bed during our Melbourne trip. However, a great proportion of the time was spent in a sitting position, either at work at Florey, on the train to Heidelberg, on the plane to Alice springs, or on the 17-hour bus tour from Alice Springs to visit Ayers Rock (or Uluru as the Aboriginals call it) during the weekend in-between.

As we both are aware of the risk of spending too much time in sitting position, we tried to spend a significant proportion of the time also on physical activity like running on the treadmill at the hotel, walking along the Yarra River and also by walking along the streets of Melbourne.

“There is a lot about the brain, and especially brain injury among newborns, that we don’t know about. Over the last 30 years, we have increased our knowledge significantly, but there are still many unanswered questions.”

When injury occurs among newborn children, it happens at a stage when the brain is still not fully developed. This means that hypoxic-ischemic brain injury, in addition to damaging the brain’s structure, also impacts the development of the brain. At the same time, however, it gives rise to the possibility of the brain repairing itself and finding alternative methods for solving various tasks.

Using MRI

In his thesis, “Magnetic Resonance Imaging of Hypoxic-Ischemic Brain Injury Development in the Newborn Rat – Manganese and Diffusion Contrast,” Widerøe finds that the hypoxic-ischemic brain injury process continues for a prolonged period of time after the initial incident, but that anti-inflammatories such as the antibiotic doxycycline can limit the damage.

To map the injury process and treatment effect, Widerøe has developed and adopted new techniques for magnetic resonance imaging (MRI) in newborn animals. The use of MRI means that repeated examinations can be performed without biopsies, and researchers can follow the development in individual animals over a longer period.

The research group he belongs to also uses MRI to assess how too much or too little oxygen affects normal brain development.

It is in connection with this that the researchers have concluded that treatment with an anti-inflammatory gives a more normal brain development after a hypoxic-ischemic brain injury, compared with those who did not receive the same treatment.

The results also confirm previous research which shows that administering pure oxygen can cause further damage and delay maturing-processes in the brain further after an incident of lack of oxygen.

The research using rats will continue, and one of the PhD students in the group will look further into the harmful effects of oxygen in connection with hypoxic-ischemic brain injury. Other PhD students will look at treatments using stem-cells. Using MRI, the researchers can look at the movements of stem-cells in the brain after they have been implanted, and how these can affect inflammation-reactions and the brain’s ability to repair itself. As part of this, the group will continue to study the brain’s development using MRI.

While Widerøe’s part of the group primarily has focused on animal testing, another part of the group, directed by professors Ann-Mari Brubakk and Jon Skranes, has followed children with low birth weight and premature children using MRI and mapped their brain activity into adulthood. Many of these children have had small and/or large brain injury during pregnancy or birth, and the goal has been to follow their brain development and map the long-term effects of impacts around birth.

Viva

Marius Widerøe will defend his thesis on 29 May. A lecture will be given at 09.00 in the Auditorium at Medisinsk teknisk forskningssenter at NTNU. The viva will take place at 11.00.

Hypoxic-ischemic brain injury

Hypoxic-ischemia is a combination of reduced oxygen and limited blood supply to the brain. It is one of the most common causes of brain injury among newborn children and increases mortality, as well as psychological and physiological problems later in life.

Publications:

• Doxycycline treatment in a neonatal rat model of hypoxia-ischemia reduces cerebral tissue and white matter injury: a longitudinal magnetic resonance imaging study. Widerøe M, et.al.
• Longitudinal manganese-enhanced magnetic resonance imaging of delayed brain damage after hypoxic-ischemic injury in the neonatal rat. Widerøe M, et.al.
• Manganese-enhanced magnetic resonance imaging of hypoxic-ischemic brain injury in the neonatal rat. Widerøe M, et.al.