The ISBGroup Blog

A couple of weeks before defending a thesis, it is common that the PhD student nails their thesis to a log in some of the common areas of the university. This is done to annouce that the student intends to defend their thesis and that anyone who wishes may read it and attend the defense to ask questions. The nailing is then celebrated with delicious cake.

I, Karin Lundengård, have now nailed my thesis ”Mechanistic Modelling – a BOLD Response to the fMRI Information Loss Problem” and I will defend it on the 30:th of November, 13.15 in Hugo Theorells sal (Northern Entrance, Floor 9). My opponent will be Kamil Uludag, Associate Professor at the Faculty of Psychology and Neuroscience at Maastricht University in the Netherlands.

Anyone who wants to attend the defense is welcome.

The full thesis is available at the following link: https://doi.org/10.3384/diss.diva-142870

English abstract:
Functional Magnetic Resonance Imaging (fMRI) is a common technique for imaging brain activity in humans. However, the fMRI signal stems from local changes in oxygen level rather than from neuronal excitation. The change in oxygen level is referred to as the Blood Oxygen Level Dependent (BOLD) response, and is connected to neuronal excitation and the BOLD response are connected by the neurovascular coupling. The neurons affect the oxygen metabolism, blood volume and blood flow, and this in turn controls the shape of the BOLD response. This interplay is complex, and therefore fMRI analysis often relies on models. However, none of the previously existing models are based on the intracellular mechanisms of the neurovascular coupling. Systems biology is a relatively new field where mechanistic models are used to integrate data from many different parts of a system in order to holistically analyze and predict system properties. This thesis presents a new framework for analysis of fMRI data, based on mechanistic modelling of the neurovascular coupling, using systems biology methods.
Paper I presents the development of the first intracellular signaling model of the neurovascular coupling. Using models, a feed-forward and a feedback hypothesis are tested against each other. The resulting model can mechanistically explain both the initial dip, the main response and the post-peak undershoot of the BOLD response. It is also fitted to estimation data from the visual cortex and validated against variations in frequency and intensity of the stimulus. In Paper II, I present a framework for separating activity from noise by investigating the influence of the astrocytes on the blood vessels via release of vasoactive sub- stances, using observability analysis. This new method can recognize activity in both measured and simulated data, and separate differences in stimulus strength in simulated data. Paper III investigates the effects of the positive allosteric GABA modulator diazepam on working memory in healthy adults. Both positive and negative BOLD was measured during a working memory task, and activation in the cingulate cortex was negatively correlated to the plasma concentration of diazepam. In this area, the BOLD response had decreased below baseline in test subjects with >0.01 mg/L diazepam in the blood. Paper IV expands the model presented in Paper I with a GABA mechanism so that it can describe neuronal inhibition and the negative BOLD response. Sensitization of the GABA receptors by diazepam was added, which enabled the model to explain how changes to the BOLD response described in Paper III could occur without a change in the balance between the GABA and glutamate concentrations.
The framework presented herein may serve as the basis for a new method for identification of both brain activity and useful potential biomarkers for brain diseases and disorders, which will bring us a deeper understanding of the functioning of the human brain.

As part of the collaboration with ”Forska Utan Djurförsök” (The Swedish Fund for Research without Animal Experiments), ISB group is going to Almedalen in July. Almedalen is the biggest political event of the year in Sweden, and Gunnar Cedersund has been invited to participate in two events:

* Monday July 3, 13-14.30 in Maltfabriken. Then Gunnar and a few others will give short initial presentations, followed by a panel debate with politicians, and ended with some hands-on tutorials, by some of the students from ISBgroup. If you want to try to simulate our own models for diabetes, you should come then. (link to more info)

* Thursday July 6, 10-11.30 in Maltfabriken. Then a short introduction will be followed by a longer session with hands-on testing, not only regarding mathematical models but also regarding other experimental alternatives to animal experiments. The focus then is on chemicals and cosmetics testing (involving e.g. the qsar model). (more info)

Apart from these two events, Forska utan djurförsök will also have a final opportunity to come and talk with them on Friday July 7, at 10-11.30 in Maltfabriken. This will be a more informal event, with the opportunity to come and talk and have coffee with people who know a lot about these issues (link).

Welcome!
Karin for ISBgroup

Functional Magnetic Resonance Imaging (fMRI) is a popular way of measuring brain activity in humans. However, this technique does not measure true neuronal activity but instead it measures changes in oxygen level in the blood, which are connected to the neuronal activity through the neurovascular coupling. In order to investigate the mechanisms of the neurovascular coupling, we have constructed and analysed a new mechanistic model. This model is based on current hypotheses of the mechanisms of the neurovascular coupling, and the model can both describe the estimation data and predict validation data. Unlike previous models of the fMRI signal, our model describes the biological system without predetermening the shape of the signal, and therefore opens up to a new way of analysing fMRI data.

Read the full article at PLOS computational biology

Reference:
Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI
Karin Lundengård, Gunnar Cedersund, Sebastian Sten, Felix Leong, Alexander Smedberg, Fredrik Elinder, Maria Engström
PLoS Comput Biol 12(6): e1004971. doi:10.1371/journal.pcbi.1004971

It is my pleasure to announce that two projects which has modellers from the systems biology core facility involved has been chosen as this years flagship projects for CMIV (Center for Medical Image science and Visualisation). One is the SAND:MAN project, in which we are modelling the neurovascular coupling that is the link between the neuronal activity of the brain and the signal measured in an MRI scanner when we study the activity of the brain. This will give us a deeper understanding of how the brain works and how the neuronal signalling changes in different diseases and disorders of the brain.

The other project is the non-invasive liver biopsy (NILB) project in which we models how contrast fluid travels through the liver and how that differs between healthy persons and patients who have liver disease. This model is being developed into a tool that will help medical doctors make better diagnosis for their patients.

The flagship projects were presented at a seminar on the 29th of February at CMIV. The third flagship project is the Seeing Organ Function project, which is also connected to the SAND:MAN project.

All the new flagship projects will soon be featured with a more in depth presentation on the front page of the CMIV webpage.

Karin Lundengård just did her half-time, and it’s on youtube!

“My research project is on the activity of the human brain. The activity can be measured by functional Magnetic Resonance Imaging, which measures the Blood Oxygen Level Dependent (BOLD) response. As the name states, it is the oxygen levels being measured, but they are connected to the electrical signaling of the neurons via the neurovascular coupling. There are several hypothesis about the underlying mechanisms of the neurovascular coupling and here we have used mechanistic dynamic models to investigate two of them. So go have a look at the video to see how it went!”

Hopefully the article will be submitted for press before Christmas.

Karin Lundengård
PhD student at IMH and CMIV

Recently,
I made a short visit (only the first day) to the joined conferences
16th Nordic-Baltic Conference on Biomedical Engineering and Medical
Physics and 10th Medicinteknikdagarna in Gothenburg to present our fMRI
model in the neuroengineering session.
It was a small but rather well attended conference with a leisurely
tempo that gave ample time for discussions. There were several
researchers form Linköping present, although not from our group.
Unfortunately most of us were placed in the same session and
although I found Haj-Hosseinis talk about ”Photodiagnostics in Brain
Tumor Surgery”, Dunås talk about ”Towards automatic identification of
cerebral arteries in 4D flow MRI” and Latorres talk about ”Paxon: The
Physical Axon Model” interesting, I had heard them
before.

Most inspiring during the day were two different presentations: the
first was the plenary session where Dremstrup spoke about ”Technology in
the rehabilitation after stroke” and showed how they had identified the
right point in time and space to deliver a small
electric chock to nerves in the foot or hip in order to help stroke
patients walk again, and the second was ”Human stem cell neuronal
cultures and activity – from 2D to 3D” with the finnish researcher
Hyttinen who experimented on neuronal stem cells growing
in a 3D matrix. The latter is something that is highly interesting for
our research as it investigates the actions of the astrocytes in the
brain.

My presentation was well received and led to interesting discussions
afterwards, most notably with Hyttinen and later with a medical doctor
who proposed TENS for stimulation of brain areas.

Karin Lundengård
PhD student at IMH and CMIV