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A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis
Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
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2011 (English)In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 49, no 12, 1459-1469 p.Article in journal (Refereed) Published
Abstract [en]

Microdialysis can be used in parallel to deep brain stimulation (DBS) to relate biochemical changes to the clinical outcome. The aim of the study was to use the finite element method to predict the tissue volume of influence (TVI(max)) and its cross-sectional radius (r (TVImax)) when using brain microdialysis, and visualize the TVI(max) in relation to patient anatomy. An equation based on Fick's law was used to simulate the TVI(max). Factorial design and regression analysis were used to investigate the impact of the diffusion coefficient, tortuosity and loss rate on the r (TVImax). A calf brain tissue experiment was performed to further evaluate these parameters. The model was implemented with pre-(MRI) and post-(CT) operative patient images for simulation of the TVI(max) for four patients undergoing microdialysis in parallel to DBS. Using physiologically relevant parameter values, the r (TVImax) for analytes with a diffusion coefficient D = 7.5 × 10(-6) cm(2)/s was estimated to 0.85 ± 0.25 mm. The simulations showed agreement with experimental data. Due to an implanted gold thread, the catheter positions were visible in the post-operative images. The TVI(max) was visualized for each catheter. The biochemical changes could thereby be related to their anatomical origin, facilitating interpretation of results.

Place, publisher, year, edition, pages
Springer Publishing Company, 2011. Vol. 49, no 12, 1459-1469 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-72911DOI: 10.1007/s11517-011-0841-0ISI: 000297550600012PubMedID: 22081236OAI: oai:DiVA.org:liu-72911DiVA: diva2:463578
Available from: 2011-12-09 Created: 2011-12-09 Last updated: 2017-06-19Bibliographically approved
In thesis
1. Modeling and Simulation of Microdialysis in the Deep Brain Structures
Open this publication in new window or tab >>Modeling and Simulation of Microdialysis in the Deep Brain Structures
2012 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Microdialysis is a method for monitoring of the local biochemical environment in a region of interest. The method uses a catheter, mimicking the function of a blood capillary, to sample substances from the surrounding medium through diffusion. A recent application for microdialysis is the sampling of neuroactive substances in the deep brain, or basal ganglia, during deep brain stimulation (DBS) for patients with Parkinson’s disease. The basal ganglia consist of nuclei interconnected by chemical synapses, and it is hypothesized that the levels of neurotransmitter substances around the synapses are affected by DBS treatment. In order to relate the microdialysis data to their anatomical origin and to the effects of DBS, it is suitable to estimate the tissue volume which is sampled during a microdialysis experiment. In this thesis, the maximum tissue volume of influence (TVImax) for a microdialysis catheter was simulated and evaluated using the finite element method (FEM), to allow interpretation of biochemical data in relation to anatomical structures.

A FEM model for simulation of the TVImax for a microdialysis catheter placed in grey brain matter was set up, using Fick’s law of diffusion. The model was used to investigate the impact of the analyte diffusion coefficient (D), the tissue tortuosity (λ) and the loss rate constant (k) on the size of the TVImax by regression analysis. Using relevant parameter intervals, the radius of the TVImax of a neurotransmitter was estimated to 0.85 ± 0.25 mm. A microdialysis experiment on calf brain tissue showed agreement with the regression model. A heterogeneous anisotropic FEM model based on diffusion tensor imaging (DTI) showed that the radius of the TVImax may vary by up to 0.5 mm as a consequence of local tissue properties, which was reasonable in relation to the 95% confidence interval from the regression estimation. The TVImax was simulated and patient-specifically visualized in relation to MRI images for four patients undergoing microdialysis in parallel to DBS. The size of the TVImax showed to be relevant in relation to the basal ganglia nuclei, and the obtained microdialysis data indicated that the biochemical response to DBS depends on the catheter position. The simulations of the TVImax were combined with patient-specific DBS electric field simulations, for further interpretation of the results in relation to the effects of DBS.

In conclusion, simulations and visualizations of the TVImax allowed relating microdialysis data to its anatomical origin. Detailed knowledge about the parameters affecting the microdialysis sampling volume is valuable for the current application as well as other applications related to the migration of analytes in tissue.

Abstract [sv]

Mikrodialys är en metod som används för studera lokala nivåer av biokemiska substanser i ett specifict organ eller struktur. Metoden använder sig av en kateter med ett semipermeabelt membran, över vilket utbyte av substanser sker genom diffusion. Mikrodialys har nyligen använts för att studera nivåer av neurotransmittorer i de djupa hjärnstrukturerna, ävan kallade basala ganglierna, under djup hjärnstimulering (DBS) för patienter med Parkinsons sjukdom. De basala ganglierna består av ett antal millimeterstora hjärnstrukturer, sammankopplade via biokemiska synapser, och nivåerna av signalsubstanser runt dessa synapser tros påverkas av DBS. För att relatera mikrodialysmätningarna till dess anatomiska ursprung, och till effekterna av DBS, är det önskvärt att få en uppskattning av den vävnadsvolym som påverkar mätningen från en mikrodialyskateter. Målet med denna licentiatavhandling har varit att simulera och utvärdera den maximala påverkansvolymen (TVImax) för en mikrodialyskateter med hjälp av finita element-metoden (FEM), för att underlätta tolkningen av de biokemiska data som samlats in.

En FEM-modell sattes upp för att simulera TVImax för en kateter placerad i grå hjärnvävnad, baserat på Ficks diffusionslag och lämpliga rand- och initialvillkor. Modellen användes för att göra en regressionsanalys av hur TVImax påverkades av analytens diffusionskoefficient (D), hjärnvävnadens tortuositet (λ) och analytens nedbrytningshastighet (k), och radien för TVImax för en neurotransmitter uppskattades till 0.85 ± 0.25 mm då fysiologiskt relevanta parameterintervall användes. En experimentell studie av mikrodialys på hjärnvävnad från kalv gav god överensstämmelse med simuleringsresultaten. En heterogen och anisotrop FEM-modell sattes upp med hjälp av diffusionstensordata (DTI), vilket visade att lokala vävnadsegenskaper påverkar diffusionen av analyter i de basala ganglierna med upp till 0.5 mm i enighet med den regressionsmodell som tagits fram. TVImax simulerades och visualiserades sedan i relation till MRI-bilder för fyra patienter som genomgått mikrodialys parallellt med DBS. Målområdena för mikrodialysmätningarna visade sig skilja mellan patienterna, och den insamlade mikrodialysdatan indikerade att den biokemiska responsen på DBS berodde på kateterns position. För att ytterligare underlätta tolkningen av resultatet i relation till effekterna av DBS, kombinerades TVImax-simuleringarna med simuleringar av det elektriska fältet runt DBS-elektroderna.

Sammanfattningsvis kan simuleringar av TVImax vara en hjälp vid den fysiologiska tolkningen av insamlad mikrodialysdata, vilket underlättar jämförelser mellan patienter. Detaljerad kunskap om de parametrar som påverkar samplingsvolymen för en mikrodialyskateter är värdefulla både för den aktuella applikationen, och övriga applikationer relaterade till diffusion av substanser i vävnad.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 52 p.
Series
Linköping Studies in Science and Technology. Thesis, ISSN 0280-7971 ; 1549
National Category
Engineering and Technology Natural Sciences Medical Engineering
Identifiers
urn:nbn:se:liu:diva-84277 (URN)978-91-7519-805-7 (ISBN)
Presentation
2012-10-19, IMT1, plan 13, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2016-05-04Bibliographically approved
2. Biochemical and pharmacokinetic studies in vivo in Parkinson’s disease
Open this publication in new window or tab >>Biochemical and pharmacokinetic studies in vivo in Parkinson’s disease
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease (PD) is a neurodegenerative disease affecting approximately 25000 people in Sweden. The main cause of the disease is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) projecting to the striatum. The motor symptoms of PD, due to decreased levels of dopamine, includes bradykinesia, rigidity and tremor.

During the 1960ies oral L-dopa treatment was introduced increasing quality of life for PD patients. In recent decades, enzyme inhibitors have been introduced, increasing bioavailability of L-dopa in plasma. After 5-10 years of L-dopa treatment, 50% of PD patients develop disabling dyskinesias. This can be due to rapid changes in L-dopa conentrations with non physiological stimulation of the dopamine receptor.

For over 20 years deep brain stimulation (DBS) has grown to be a good neurosurgical procedure for improving quality of life in advanced PD with disabling dyskinesias. With stereotactic technique, electrodes are implanted in the brain and connected to a pacemaker sending electrical impulses. The most common target in PD is the subthalamic nucleus (STN). The knowledge about DBS mechanism(s) and its interaction with L-dopa is unsatisfactory.

The aims of this thesis were; to study the effect of the enzyme inhibitor entacapone on the L-dopa concentration over the blood brain barrier (BBB); to study possible interactions between L-dopa and DBS; to study alterations in neurotransmitters during DBS; to visualize microdialysis catheters in anatomical targets and to estimate sampling area of the catheters.

In all four papers the microdialysis technique was used. It is a well-established technique for continuous sampling of small water-soluble molecules within the extracellular fluid space in vivo, allowing studies of pharmaceutical drugs and neurotransmitters.

We showed that entacapone increases the bioavailability of L-dopa in blood with a subsequent increase of L-dopa peak levels in the cerebrospinal fluid. This in turn may cause a larger burden on the dopaminergic neurons causing an increased degeneration rate and worsening of the dyskinesias; we showed that 18% of L-dopa crosses the BBB and that there is a possible interaction between L-dopa and DBS, L-dopa concentrations increase during concomitant STN DBS, which can clarify why its possible to decrease L-dopa medication after DBS surgery. The research has also shown that STN DBS has an effect on various neurotransmitter systems, mainly L-dopa, dopamine and GABA. We showed that STN DBS may have an effect on the SNc, resulting in putaminal dopamine release.

We have shown that with stereotactic technique, it is safe to do microdialysis sampling in specific areas in the human brain. Simulations with the finite element method combined with patient specific preoperative MRI and postoperative CT images gave us exact knowledge about the positions of the catheters and that the studied structures were the intended. The research has given an assumption of the maximum tissue volume that can be sampled around the microdialysis catheters.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 78 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1345
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-91294 (URN)978-91-7519-737-1 (ISBN)
Public defence
2013-05-17, Berzeliussalen, Hälsouniversitetet, Campusu US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-19 Created: 2013-04-19 Last updated: 2017-04-15Bibliographically approved

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Diczfalusy, ElinZsigmond, PeterDizdar, NilKullman, AnitaLoyd, DanWårdell, Karin

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