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Diczfalusy, Elin
Publications (10 of 21) Show all publications
Diczfalusy, E., Andersson, M. & Wårdell, K. (2015). A diffusion tensor-based finite element model of microdialysis in the deep brain. Computer Methods in Biomechanics and Biomedical Engineering, 18(2), 201-212
Open this publication in new window or tab >>A diffusion tensor-based finite element model of microdialysis in the deep brain
2015 (English)In: Computer Methods in Biomechanics and Biomedical Engineering, ISSN 1025-5842, E-ISSN 1476-8259, Vol. 18, no 2, p. 201-212Article in journal (Refereed) Published
Abstract [en]

Microdialysis of the basal ganglia was recently used to study neurotransmitter levels in relation to deep brain stimulation. In order to estimate the anatomical origin of the obtained data, the maximum tissue volume of influence (TVImax) for a microdialysis catheter was simulated using the finite element method. This study investigates the impact of brain heterogeneity and anisotropy on the TVImax using diffusion tensor imaging (DTI) to create a second-order tensor model of the basal ganglia. Descriptive statistics showed that the maximum migration distance for neurotransmitters varied by up to 55% (n = 98,444) for DTI-based simulations compared with an isotropic reference model, and the anisotropy differed between different targets in accordance with theory. The size of the TVImax was relevant in relation to the size of the anatomical structures of interest, and local tissue properties should be accounted for when relating microdialysis data to their anatomical targets.

Place, publisher, year, edition, pages
Taylor & Francis, 2015
National Category
Other Medical Engineering
Identifiers
urn:nbn:se:liu:diva-91886 (URN)10.1080/10255842.2013.789103 (DOI)000343606800011 ()23627319 (PubMedID)
Available from: 2013-05-03 Created: 2013-05-03 Last updated: 2017-12-06Bibliographically approved
Wårdell, K., Kefalopoulou, Z., Diczfalusy, E., Andersson, M., Åström, M., Limousin, P., . . . Hariz, M. (2015). Deep Brain Stimulation of the Pallidum Internum for Gilles de la Tourette Syndrome: A Patient-Specific Model-Based Simulation Study of the Electric Field. Neuromodulation (Malden, Mass.) (2), 90-96
Open this publication in new window or tab >>Deep Brain Stimulation of the Pallidum Internum for Gilles de la Tourette Syndrome: A Patient-Specific Model-Based Simulation Study of the Electric Field
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2015 (English)In: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403, no 2, p. 90-96Article in journal (Refereed) Published
Abstract [en]

Objectives

The aim of this study was to investigate the deep brain stimulation (DBS) electric field distribution in proton-density MRI scans visualizing the globus pallidus internus (GPi) of patients with Gilles de la Tourette syndrome (GTS), along with its relation to the anatomy.

Methods

Patient-specific brain tissue models (n = 7) with bilateral DBS electrodes in the GPi were set up using the finite element method in five patients who had undergone stereotactic proton-density MRI-guided surgery and showed variable improvement with DBS. Simulations (n = 27) of the electric field were performed and the results visualized on the respective preoperative stereotactic MRI scans. The mean electric field volumes (n = 81) within the 0.1, 0.15, and 0.2 V/mm isosurfaces were calculated and compared with the anatomy.

Results

Visualization of the simulated electric field confirmed that the anteromedial limbic GPi was the main stimulated target for four of the patients and the posteromedial sensorimotor GPi for one. Larger volumes extended asymmetrically, with parts of fields stretching into the lamina between GPi and globus pallidus externus and into the internal capsule. There was a high correlation (r = 0.994, n = 54) between volumes and brain sides, but with a systematic shift toward the right side, especially for the larger volumes. Simulations with homogeneous tissue models showed no differences.

Conclusions

Patient-specific DBS electric field simulations in the GPi as visualized on proton-density MR scans can be implemented in patients with GTS. Visualization of electric fields together with stereotactic thin-slice MRI can provide further support when predicting anatomical structures possibly influenced by DBS in this complex disorder.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
Keywords
Deep brain stimulation, electric field simulation, globus pallidus internus, modeling and simulation, Tourette syndrome
National Category
Medical Biotechnology Medical Bioscience
Identifiers
urn:nbn:se:liu:diva-113589 (URN)10.1111/ner.12248 (DOI)000350461600004 ()25284508 (PubMedID)
Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2017-12-05Bibliographically approved
Åström, M., Diczfalusy, E., Martens, H. & Wårdell, K. (2015). Relationship between Neural Activation and Electric Field Distribution during Deep Brain Stimulation. IEEE Transactions on Biomedical Engineering, 62(2), 664-72
Open this publication in new window or tab >>Relationship between Neural Activation and Electric Field Distribution during Deep Brain Stimulation
2015 (English)In: IEEE Transactions on Biomedical Engineering, ISSN 0018-9294, E-ISSN 1558-2531, Vol. 62, no 2, p. 664-72Article in journal (Refereed) Published
Abstract [en]

Models and simulations are commonly used to study deep brain stimulation (DBS). Simulated stimulation fields are often defined and visualized by electric field isolevels or volumes of tissue activated (VTA). The aim of the present study was to evaluate the relationship between stimulation field strength as defined by the electric potential V, the electric field E, and the divergence of the electric field ∇(2) V, and neural activation. Axon cable models were developed and coupled to finite-element DBS models in three-dimensional (3-D). Field thresholds ( VT , ET, and ∇(2) VT ) were derived at the location of activation for various stimulation amplitudes (1 to 5 V), pulse widths (30 to 120 μs), and axon diameters (2.0 to 7.5 μm). Results showed that thresholds for VT and ∇(2) VT were highly dependent on the stimulation amplitude while ET were approximately independent of the amplitude for large axons. The activation field strength thresholds presented in this study may be used in future studies to approximate the VTA during model-based investigations of DBS without the need of computational axon models.

Place, publisher, year, edition, pages
IEEE, 2015
National Category
Medical Bioscience Medical Biotechnology
Identifiers
urn:nbn:se:liu:diva-113588 (URN)10.1109/TBME.2014.2363494 (DOI)000348297000029 ()25350910 (PubMedID)
Note

This work was supported by the European Union's Seventh Framework Programme IMPACT (Grant 305814) and by the Swedish Research Council (Grant 621-2013-6078). Asterisk indicates corresponding author.

Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2017-12-05Bibliographically approved
Zsigmond, P., Nord, M., Kullman, A., Diczfalusy, E., Wårdell, K. & Dizdar (Dizdar Segrell), N. (2014). Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease. Neurology and Clinical Neuroscience, 2(5), 149-155
Open this publication in new window or tab >>Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease
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2014 (English)In: Neurology and Clinical Neuroscience, ISSN 2049-4173, Vol. 2, no 5, p. 149-155Article in journal (Refereed) Published
Abstract [en]

Background The mechanism by which deep brain stimulation of the nucleus subthalamicus improves Parkinson’s disease symptoms remains unclear. In a previous perioperative study, we showed that there might be alterations of neurotransmitter levels in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus. Aim In this study, we examined whether deep brain stimulation of the nucleus subthalamicus and levodopa infusion interact and affect the levels of neurotransmitters. Methods Five patients with advanced Parkinson’s disease took part in the study. During subthalamic nucleus surgery, microdialysis catheters were inserted bilaterally in the globus pallidum interna and unilaterally in the right putamen. A study protocol was set up and was followed for 3 days. Levodopa infusion with and without concomitant bilateral deep brain stimulation of the nucleus subthalamicus was also carried out. Results The putaminal dopamine levels increased during deep brain stimulation of the nucleus subthalamicus. In addition, an increase of gamma amino buturic acid concentrations in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus and during levodopa infusion was found. Conclusions These findings provide evidence that the subthalamic nucleus has a direct action on the substantia nigra pars compacta, and that deep brain stimulation of the nucleus subthalamicus might indirectly release putaminal dopamine. There is also evidence that deep brain stimulation of the nucleus subthalamicus interferes with levodopa therapy resulting in higher levels of levodopa in the brain, explaining why it is possible to decrease levodopa medication after deep brain stimulation surgery.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
Keywords
deep brain stimulation, levodopa, microdialysis, neurotransmitters, Parkinson
National Category
Medical Bioscience Medical Biotechnology Basic Medicine
Identifiers
urn:nbn:se:liu:diva-113590 (URN)10.1111/ncn3.109 (DOI)
Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2019-02-11Bibliographically approved
Wårdell, K., Åström, M., Diczfalusy, E. & Martens, H. (2014). Surgical Therapy: Parkinson's disease. In: Movement DisordersSupplement: Abstracts of the Eighteenth International Congress of Parkinson's Disease and Movement Disorders. Paper presented at The MDS 18th International Congress of Parkinson's Disease and Movement Disorders, June 8-12, 2014, Stockholm, Sweden (pp. 1170-1170). John Wiley & Sons, 29, Article ID Suppl 1:1170.
Open this publication in new window or tab >>Surgical Therapy: Parkinson's disease
2014 (English)In: Movement DisordersSupplement: Abstracts of the Eighteenth International Congress of Parkinson's Disease and Movement Disorders, John Wiley & Sons, 2014, Vol. 29, p. 1170-1170, article id Suppl 1:1170Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Objective: To analyze the relationship between the electric field and the volume of tissue activated (VTA) during model-based investigations of deep brain stimulation (DBS).

Background: An important factor for the therapeutic outcome of DBS is the spatial distribution of the stimulation field in the target area. Finite element models and simulations of DBS are increasingly being used to study the distribution of the stimulation field in relation to patient specific anatomy. The stimulation field is often defined as a VTA derived from computational axon models that are coupled to the finite element simulations. This approach however, is not feasible in many research centers due to the complexity of developing a computational axon model, as well as the extensive execution time when solving such models.

Methods: A detailed computer axon cable model was developed to study axonal activation in response to various DBS stimulation configurations. A range of axon models were set up and coupled to finite element models of DBS. DBS simulations were performed for Medtronic lead model 3389 during monopolar configurations for a range of amplitudes and pulse widths. Activation thresholds for the electric fields were derived by measuring the field strength at the maximum radius of activation for each configuration.

Results: Simulations showed that the electric field thresholds were related to stimulation amplitude, pulse width, and axon diameter. For large axons, the electric field threshold was not dependent on the amplitude, thus implying a low sensitivity of the electric field curvature.

Conclusions: Electric field thresholds can be used to predict the VTA during model-based investigations of DBS without the necessity of computer axon models. The use of electric field thresholds may substantially simplify the process of performing model-based investigations of DBS in the future.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
National Category
Other Medical Engineering
Identifiers
urn:nbn:se:liu:diva-107597 (URN)10.1002/mds.25914 (DOI)
Conference
The MDS 18th International Congress of Parkinson's Disease and Movement Disorders, June 8-12, 2014, Stockholm, Sweden
Available from: 2014-06-17 Created: 2014-06-17 Last updated: 2017-02-13Bibliographically approved
Zsigmond, P., Nord, M., Kullman, A., Diczfalusy, E., Wårdell, K. & Dizdar (Segrell), N. (2013). Neurotransmitter levels in basal ganglia during L-dopa and Deep Brain Stimulation treatment in Parkinson’s Disease.
Open this publication in new window or tab >>Neurotransmitter levels in basal ganglia during L-dopa and Deep Brain Stimulation treatment in Parkinson’s Disease
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Bilateral deep brain stimulation of the nucleus subthalamicus (STN DBS) is a wellestablishedtreatment in patients with advanced Parkinson’s disease (PD). The mechanism bywhich STN DBS improves the PD symptoms remains unclear. In a previous perioperativestudy we have shown that there might be alterations of neurotransmitter levels in the Globuspallidum interna (GPi) during STN DBS. In this study we wanted to examine if STN DBSand L-dopa infusion interact and affect the levels of neurotransmitters.

Methods: Five patients with advanced PD took part in the study. During STN surgery microdialysis catheters were inserted bilaterally in the GPi and unilaterally in the right putamen. A study protocol was set up and was followed for three days including STN DBS left side, right side and bilateral. L-dopa infusion with and without concomitant bilateral STN DBS was also performed.

Results: The putaminal dopamine levels increase during STN DBS. In addition an increase of GABA concentrations in the GPi during STN DBS and during L-dopa infusion was found.

Conclusions: These findings can provide evidence that the STN has a direct action on the substantia nigra pars compacta (SNc) and that STN DBS may indirectly release putaminal dopamine. There is also evidence that STN DBS interferes with L-dopa therapy resulting in higher levels of Ldopa in the brain explaining why its possible to decrease L-dopa medication after DBS surgery.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-91293 (URN)
Available from: 2013-04-19 Created: 2013-04-19 Last updated: 2017-06-19Bibliographically approved
Diczfalusy, E. (2012). Modeling and Simulation of Microdialysis in the Deep Brain Structures. (Licentiate dissertation). Linköping: Linköping University Electronic Press
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. p. 52
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
Wårdell, K., Diczfalusy, E., Andersson, M., Åström, M., Foltynie, T., Limousine, P., . . . Hariz, M. (2012). Patient-specific visualization of the DBS-electric field in Tourette syndrome. In: : . Paper presented at 20th Congress of the European Society for Stereotactic and Functional Neurosurgery (ESSFN), September 26 – 29, 2012, Cascais, Lisboa, Portugal. Lisbon
Open this publication in new window or tab >>Patient-specific visualization of the DBS-electric field in Tourette syndrome
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2012 (English)Conference paper, Oral presentation with published abstract (Other academic)
Place, publisher, year, edition, pages
Lisbon: , 2012
National Category
Medical Engineering
Identifiers
urn:nbn:se:liu:diva-81374 (URN)
Conference
20th Congress of the European Society for Stereotactic and Functional Neurosurgery (ESSFN), September 26 – 29, 2012, Cascais, Lisboa, Portugal
Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-02-03Bibliographically approved
Diczfalusy, E., Dizdar (Dizdar Segrell), N., Zsigmond, P., Kullman, A., Loyd, D. & Wårdell, K. (2012). Simulations and visualizations for interpretation of brain microdialysis data during deep brain stimulation. In: IEEE Engineering in Medicine and Biology Society (EMBC), 2012: . Paper presented at 34th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC 2012), 28 August - 1 September 2012, San Diego, CA, USA (pp. 6438-6441). IEEE
Open this publication in new window or tab >>Simulations and visualizations for interpretation of brain microdialysis data during deep brain stimulation
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2012 (English)In: IEEE Engineering in Medicine and Biology Society (EMBC), 2012, IEEE , 2012, p. 6438-6441Conference paper, Published paper (Refereed)
Abstract [en]

Microdialysis of the basal ganglia was used in parallel to deep brain stimulation (DBS) for patients with Parkinson’s disease. The aim of this study was to patientspecifically simulate and visualize the maximum tissue volume of influence (TVImax) for each microdialysis catheter and the electric field generated around each DBS electrode. The finite element method (FEM) was used for the simulations. The method allowed mapping of the anatomical origin of the microdialysis data and the electric stimulation for each patient. It  was seen that the sampling and stimulation targets differed among the patients, and the results will therefore be used in the future interpretation of the biochemical data.

Place, publisher, year, edition, pages
IEEE, 2012
Series
IEEE Engineering in Medicine and Biology Society Conference Proceedings, ISSN 1557-170X
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84275 (URN)10.1109/EMBC.2012.6347468 (DOI)000313296506155 ()23367403 (PubMedID)9781424441198 (ISBN)9781424441204 (ISBN)9781457717871 (ISBN)
Conference
34th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC 2012), 28 August - 1 September 2012, San Diego, CA, USA
Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2018-01-12Bibliographically approved
Diczfalusy, E., Zsigmond, P., Dizdar (Dizdar Segrell), N., Kullman, A., Loyd, D. & Wårdell, K. (2011). A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis. Medical and Biological Engineering and Computing, 49(12), 1459-1469
Open this publication in new window or tab >>A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis
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2011 (English)In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 49, no 12, p. 1459-1469Article 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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72911 (URN)10.1007/s11517-011-0841-0 (DOI)000297550600012 ()22081236 (PubMedID)
Available from: 2011-12-09 Created: 2011-12-09 Last updated: 2018-01-12Bibliographically approved
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