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Lundengård, Karin
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Publications (6 of 6) Show all publications
Lundengård, K. (2017). Mechanistic modelling - a BOLD response to the fMRI information loss problem. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Mechanistic modelling - a BOLD response to the fMRI information loss problem
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. p. 68
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1591
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:liu:diva-142870 (URN)10.3384/diss.diva-142870 (DOI)9789176854419 (ISBN)
Public defence
2017-11-30, Hugo Theorell, Campus US, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2019-10-28Bibliographically approved
Lundengård, K., Cedersund, G., Sten, S., Leong, F., Smedberg, A., Elinder, F. & Engström, M. (2016). Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI. PloS Computational Biology, 12(6), Article ID e1004971.
Open this publication in new window or tab >>Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI
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2016 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, no 6, article id e1004971Article in journal (Refereed) Published
Abstract [en]

Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:liu:diva-130437 (URN)10.1371/journal.pcbi.1004971 (DOI)000379349700045 ()27310017 (PubMedID)
Note

Funding Agencies|Swedish Research council [2014-6249]; Knut and Alice Wallenbergs foundation, KAW [2013.0076]; Research council of Southeast Sweden [FORSS-481691]; Linkoping University

Available from: 2016-08-06 Created: 2016-08-05 Last updated: 2018-03-19
Walter, S. A., Forsgren, M., Lundengård, K., Simon, R., Torkildsen Nilsson, M., Söderfeldt, B., . . . Engström, M. (2016). Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex. PLoS ONE, 11(3)
Open this publication in new window or tab >>Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3Article in journal (Refereed) Published
Abstract [en]

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.

Place, publisher, year, edition, pages
San Francisco, CA, United States: Public Library of Science, 2016
Keywords
quantitative magnetic resonance imaging; brain tissue modeling; myelin; edema; T-1 relaxation; T-2 relaxation; proton density
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-126192 (URN)10.1371/journal.pone.0148737 (DOI)000371434500011 ()26930498 (PubMedID)
Note

Funding agencies: Linkoping University; County Council of Ostergotland

Available from: 2016-03-18 Created: 2016-03-18 Last updated: 2018-01-10Bibliographically approved
Nyman, E., Lindgren, I., Lövfors, W., Lundengård, K., Cervin, I., Arbring, T., . . . Cedersund, G. (2015). Mathematical modeling improves EC50 estimations from classical dose–response curves. The FEBS Journal, 282(5), 951-962
Open this publication in new window or tab >>Mathematical modeling improves EC50 estimations from classical dose–response curves
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2015 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, no 5, p. 951-962Article in journal (Refereed) Published
Abstract [en]

The beta-adrenergic response is impaired in failing hearts. When studying beta-adrenergic function in vitro, the half-maximal effective concentration (EC50) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC50. Instead, we have applied a mathematical modeling approach to interpret the full dose–response curvein a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose–response characterization. Therefore, an improved estimate of EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180–525 nM) is higher than the classically interpreted EC50 (46–191 nM). Mathematical modeling thus makes it possible to reinterpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible.

Keywords
adrenaline; cardiac b-adrenergic signaling; dynamic mathematical modeling; EC50; ordinary differential equations
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-114788 (URN)10.1111/febs.13194 (DOI)000350650200010 ()25586512 (PubMedID)
Available from: 2015-03-04 Created: 2015-03-04 Last updated: 2019-03-04
Lundengård, K., Cedersund, G., Elinder, F. & Engström, M. (2015). Mechanistic Modelling Investigates the Neural Basis behind the Hemodynamic Response in fMRI. In: 16TH NORDIC-BALTIC CONFERENCE ON BIOMEDICAL ENGINEERING: . Paper presented at 16th Nordic-Baltic Conference on Biomedical Engineering (NBC) / 10th MTD Joint Conference (pp. 86-87). Springer Science Business Media, 48
Open this publication in new window or tab >>Mechanistic Modelling Investigates the Neural Basis behind the Hemodynamic Response in fMRI
2015 (English)In: 16TH NORDIC-BALTIC CONFERENCE ON BIOMEDICAL ENGINEERING, Springer Science Business Media , 2015, Vol. 48, p. 86-87Conference paper, Published paper (Refereed)
Abstract [en]

This work serves as a basis for a new type of fMRI analysis, which is based on a mechanistic interpretation of the hemodynamic response to synaptic activity. Activation was measured in the visual cortex of 12 healthy controls and ordinary differential equation models were fitted to the time series of the hemodynamic response. This allowed us to reject or refine previously proposed mechanistic hypotheses. This is the first attempt to describe the hemodynamic response quantitatively based on recent neurobiological findings. This mechanistic approach stands in contrast to the standard phenomenological description using the gamma variate function.

Place, publisher, year, edition, pages
Springer Science Business Media, 2015
Series
IFMBE Proceedings, ISSN 1680-0737 ; 48
Keywords
functional magnetic resonance imaging (fMRI); blood oxygen level dependent (BOLD) response; mechanistic modeling; ordinary differential equations (ODE); neurovascular coupling
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114431 (URN)10.1007/978-3-319-12967-9_23 (DOI)000347893000023 ()978-3-319-12966-2 (ISBN)
Conference
16th Nordic-Baltic Conference on Biomedical Engineering (NBC) / 10th MTD Joint Conference
Available from: 2015-03-02 Created: 2015-02-20 Last updated: 2018-01-25
Lundengård, K., Elinder, F. & Engström, M. (2013). A mechanistic model for blood flow regulation in response to neuronal activity. In: : . Paper presented at 14th International Conference on Systems Biology (ICSB 2013), 29 August - 3 September 2013, Copenhagen, Denmark.
Open this publication in new window or tab >>A mechanistic model for blood flow regulation in response to neuronal activity
2013 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99388 (URN)
Conference
14th International Conference on Systems Biology (ICSB 2013), 29 August - 3 September 2013, Copenhagen, Denmark
Available from: 2013-10-18 Created: 2013-10-17 Last updated: 2018-01-25
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