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The ISBGroup Blog

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Here you can read about everything that's happening in the ISB Group.

2023 continue to be great – a second publication in PLOS Computational Biology

Uncategorised Posted on Tue, January 10, 2023 08:30:00

Our work “A quantitative model for human neurovascular coupling with translated mechanisms from animals”, previously available at bioRxiv, has now been published in PLOS Computational Biology. In this manuscript we explore if qualitative behaviors of the Neurovascular coupling (NVC), found in different species and data sets, can be applied to the model simulations of other data. Below follows a slightly more detailed summary of the manuscript.

The neurovascular coupling (NVC) is the basis for functional magnetic resonance imaging (fMRI), since the NVC connects neural activity with the observed hemodynamic changes. This connection is highly complex, which warrants a model-based analysis. However, even though NVC-data from several species and many relevant variables are available, a mathematical model for all these data is still missing. Herein, we combine experimental data from mice, monkeys, and humans, to develop a comprehensive model for NVC. Importantly, our new approach to modelling propagates the qualitative insights from each species to the subsequent analysis of data from other species. In mice, we unravel the role of different neuronal sub-populations when producing a biphasic response to prolonged sensory stimulations. The qualitative role of these sub-populations is preserved when analysing primate data. These primate data add knowledge on the interplay between local field potential (LFP) and vascular changes. Similarly, these pre-clinical qualitative insights are propagated to analysis of human data, which contain additional insights regarding blood flow and volume in arterioles and venules, during both positive and negative responses. This work illustrates how data with complementary information from different species can be combined, so that qualitative insights from animals are preserved in the quantitative analysis of human data.

You can read the full article HERE



Celebrating 2023 with new a publication in PLOS Computational Biology

Uncategorised Posted on Tue, January 03, 2023 11:32:57

We are pleased to announce that our manuscript entitled “Mechanistic model for human brain metabolism and its connection to the neurovascular coupling” have recently been accepted for publication in PLoS Computational Biology. In this manuscript we present a mechanistic model for the human cerebral metabolism based on magnetic resonance spectroscopy data. We have also connected this model to our previously published model for the neurovascular coupling. Below follows a slightly more detailed summary of the manuscript. 

The neurovascular and neurometabolic couplings are highly central for several clinical imaging techniques since these frequently use blood oxygenation (the BOLD signal) as a proxy for neuronal activity. This relationship is described by the highly complex neurovascular and neurometabolic couplings, which describe the balancing between increased metabolic demand and blood flow, and which involve several cell types and regulatory systems, which all change dynamically over time. While there are previous works that describe the neurovascular coupling in detail, neither we nor others have developed connections to corresponding mechanistic models for the third aspect, the metabolic aspect. Furthermore, magnetic resonance spectroscopy (MRS) data for such modelling readily is available. In this paper we present a minimal mechanistic model that can describe the metabolic response to visual stimuli. The model is trained to describe experimental data for the relative change in metabolic concentrations of several metabolites in the visual cortex during stimulation. The model is also validated against independent validation data, that was not used for model training. Finally, we also connect this metabolic model to a detailed mechanistic model of the neurovascular coupling. Showing that the model can describe both the metabolic response and a neurovascular response simultaneously. 

You can find the article HERE!

Overview of the modelling work presented A. A table summary of different models and what aspects of the neurovascular coupling they cover. B. A schematic overview of how this work connects pre-existing models for the neurovascular coupling with a description for the cerebral metabolism and how this new interconnected model can be used for informative simulations. C: A detailed illustration of the metabolism model precented in this work. Neuronal activity triggers increased consumption of glucose, which triggers downstream signaling cascades of different metabolites, which can be captured using Magnetic Resonance Spectroscopy (MRS). D. A schematic illustration of the modelling cycle used to develop a minimal model.


VPH News Letter – Dancing digital twins

Uncategorised Posted on Mon, October 17, 2022 09:00:00

The opening ceremony of the Virtual Physiological Human (VPH) conference was something special, it featured a lecture-performance with our physiologically based dancing digital twins. The VPH Institute has now published a news letter were you can read more about the development of the digital twins for the past 20 years, and more about the future visions for using them within biomedical teaching and patient-centric care.

Take your digital twin with you throughout your health journey: from dance performances to patient-centric, preventive healthcare” For link click HERE



ICSB 2022

Uncategorised Posted on Mon, October 10, 2022 09:59:46

The 21st International Conference on Systems Biology (ICSB 2022) was held in Berlin, Germany, these past few days. We had a great time there and had the opportunity to meet great people, take part in interesting discussions, and see some of Berlin. During the conference, we presented several posters and gave some talks (summarized below). We would like to extend our thanks to the ICSB committee for a well-organized conference. Until next time, from the ISB group.

The full program can be found here: https://www.icsb2022.berlin/, and down below is a summary of our contributions.

M4-health: digital twins that follow you throughout your health journey, Gunnar Cedersund

Authors: Gunnar Cedersund

An interconnected multi-level mechanistic model of the human brain, Nicolas Sundqvist

Authors: Nicolas Sundqvist, Henrik Podéus, Malin Ejneby Silverå, Sebastian Sten, Salvador Dura-Bernal, Soroush Safaei, Maria Engström and Gunnar Cedersund

Digital twins and hybrid modelling for simulation of physiological variables and stroke risk, Tilda Herrgårdh

Authors: Tilda Herrgårdh, Elizabeth Hunter, Kajsa Tunedal, John D. Kelleher and Gunnar Cedersund

Insights on hemodynamic changes in hypertension and T2D through non-invasive cardiovascular modeling, Kajsa Tunedal

Authors: Kajsa Tunedal, Carl-Johan Carlhäll, Federica Viola, Tino Ebbers and Gunnar Cedersund

Mathematical modeling of cytokine interplay in human monocytes during LPS stimulation, Niloofar Nikaein

Authors: Niloofar Nikaein, Kedeye Tuerxun, Daniel Eklund, Alexander Persson, Robert Kruse, Eva Särndahl, Eewa Nånberg, Antje Thonig, Gunnar Cedersund, Elin Nyman, Dirk Repsilber and On Behalf Of The X-Hide Consortium

Connecting the Neurovascular coupling and Electrophysiological signaling – a modeling approach, Henrik Podéus

Authors: Henrik Podéus, Gunnar Cedersund and Salvador Dura-Bernal

An in silico resection to estimate global and regional hepatobiliary function in patients undergoing hepatectomy, Christian Simonsson

Authors: Christian Simonsson, Wolf Claus Bartholomä, Anna Lindhoff Larsson, Markus Karlsson, Bengt Norén, Gunnar Cedersund, Nils Dahlström, Per Sandström and Peter Lundberg

A comprehensive mechanistic model of adipocyte signaling with layers of confidence, William Lövfors

Authors: William Lövfors, Cecilia Jönsson, Charlotta S. Olofsson, Gunnar Cedersund and Elin Nyman



VPH 2022 – Less than 2 weeks to the conference! 6-9 September, Porto, Portugal  

Uncategorised Posted on Thu, August 25, 2022 16:41:59

Dont miss the chance to meet us at The Virtual Physiologiacl Human Conference 2022!

We have three presentations and our digital twin will be a part of the welcome reception

Dancing Digital Twins performance

Welcome reception, 7th September, 19:30 Auditorium

Unique collaboration between the Swedish researcher and pianist Gunnar Cedersund and choreographer and dancer Julia Bengtsson fuses digital twin technology and visualization with dance and music

Nicolas Sundqvist

Presentation, 8th September

Session 14: Multiscale modelling. 8.30-10.30, Room 2

An interconnected multi-level mechanistic model of the human brain

Oscar Arrestam

Presentation, 9th September

Session 22: Computational modeling in health and disease 4. 8.45-10.15 Room 2

Digital twin predicting diet response before and after long-term fasting (see poster below)

Gunnar Cedersund

Presentation, 9th September

Session 25: Computational tools and simulation in biomechanics 4

10.30-12.30 Auditorium

M4-health: digital twins that follow you throughout your health journey



New article in PLoS Computational Biology

News, Systems biology and science Posted on Mon, May 02, 2022 07:00:00

Sundqvist N, Grankvist N, Watrous J, Mohit J, Nilsson R, Cedersund G. Validation-based model selection for 13C metabolic flux analysis with uncertain measurement errors. PLoS Comput Biol. 2022 Apr 11;18(4):e1009999. doi: 10.1371/journal.pcbi.1009999

Author summary: Measuring metabolic reaction fluxes in living cells is difficult, yet important. The gold standard is to label extracellular metabolites with 13C, to use mass spectrometry to find out where the 13C-atoms ends up, and finally use mathematical modelling to calculate how quickly each reaction must have flowed, for the 13C-atoms to end up like that. This measurement thus relies on usage of the right mathematical model, which must be selected among various candidate models. In this manuscript, we present a new way to do this model selection step, utilizing validation data. Using an adopted approach to calculate the uncertainty of model predictions, we identify new validation experiments, which are neither too similar, nor too dissimilar, compared to the previous training data. The model candidate that is best at predicting this new validation data is the one chosen. Tests on simulated data where the true model is known, shows that the validation-based method is robust when the magnitude of the error in the measurement uncertainty is unknown, something that conventional methods are not. This improvement is important since true uncertainties can be difficult to estimate for these data. Finally, we demonstrate how the new method can be used on real data, to identify fluxes and important reactions.



Upcoming Ph.D. defense, Sebastian Sten, “Mathematical modelling of neurovascular coupling”

Events, News Posted on Sat, September 05, 2020 01:59:22

On Friday, this coming week, September 11, 2020, at 9AM CET, our Ph.D. student Sebastian Sten will defend his Ph.D. thesis, entitled “Mathematical modelling of neurovascular coupling”.

Sebastian has been co-supervised between Gunnar Cedersund (who leads this group), Fredrik Elinder (BKV and electrophysiological expert), and Maria Engström (who was the main supervisor, and who is an expert on fMRI). In the thesis, Sebastian presents four papers which incrementally unravels more and more mechanistic details of how the main signal in fMRI – the BOLD signal – is generated. In Paper 1, he demonstrates that the main part of the BOLD signal response can not be caused by a negative feedback, as was first believed, but by a combination of a fast positive and a slow negative feedforward arm. In Paper 2, the model from paper 1 is extended with GABA, which makes it able to describe the negative BOLD response. In Paper 3, he unravels more mechanistic details of the two arms, and finds out that there are in fact at least three arms: the fastest positive is the NO-arm from interneurons, the slightly slower positive arm is the PGE2 arm from pyramidal cells, and the slowest negative arm is caused by NPY interneurons. In the final paper 4 (still in ms), these mechanistic details for the signalling and the control of the arteriolar diameter is embedded in a larger model, which also contains the biomechanical flow to capillariies and venules, and the creation of the actual BOLD signal. The final model is – to the best of our knowledge – the most complete and comprehensive model for the BOLD signal, and it simultaneously describes data and extracts information from informative optogenetic stimulation experiments in mice, from unique BOLD and Local Field Potential (LFP) experiments in monkeys, and from advanced MRI measurements of BOLD, volumes and flows, in humans.

Front page of the thesis, illustration done by our other group member Christian Simonsson, who wanted to capture not only the brain, but that experiments, analysis, and mathematical modelling has come together.

Overview of the main processes studied in the thesis.

After the defense, Sebastian will work for two more weeks, wrapping up the final paper. Thereafter, other people in the group will continue to work on these models, e.g. by connecting them to more detailed models for metabolism, electrophysiology, and – eventually – to clinical practice, e.g. by allowing for more measurements to come together into a more comprehensive and complete analysis of fMRI data. However, Sebastian himself will thereafter start a position at AstraZeneca, in the group we have the most contact with there: their metabolic and cardiovascular preclinical modelling group.

A link to the Ph.D. thesis is found here, and a link to the youtube event where the defense is broadcasted is found here.

Sebastian about to do the final formal step before the actual defense: nailing his thesis to the “thesis tree” of the medical faculty.