| 1. |
- Haj-Hosseini, Neda, 1980-
(författare)
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Fluorescence Spectroscopy for Quantitative Demarcation of Glioblastoma Using 5-Aminolevulinic Acid
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Total resection of glioblastoma, the highly malignant brain tumor, is difficult to accomplish due to its diffuse growth and similarity to the surrounding brain tissue. A total resection is proven to increase patient survival. The aim of this thesis was to evaluate fiber-optical based fluorescence spectroscopy for quantitative demarcation of malignant brain tumors during the surgery. Five-aminolevulinic acid (5-ALA) was used as a fluorescence contrast agent that accumulated as protoporphyrin IX (PpIX) in the tumor.The method was evaluated at the Department of Neurosurgery, Linköping University Hospital. The patients (n = 22) received an oral dose of 5 mg/kg body weight 5-ALA two hours prior to craniotomy. Measurements with a developed fluorescence spectroscopy system were performed under the general procedure of surgery. The collected fluorescence spectra were quantified by defining a fluorescence ratio and the main challenges of measuring and quantifying spectra were investigated. The fluorescence ratio was compared to visual diagnosis of the surgeon, histopathological examination and ultrasound-based neuronavigation. The main challenges of using a fluorescence spectroscopy system in the operating room were the disturbing ambient light, photobleaching and blood interference which affect the signal quantification. The superimposition of ambient light was removed by modulating the system.Using principal component analysis (PCA) the photobleaching sequences could be described by three spectral components of autofluorescence, PpIX fluorescence and blue-shift. To investigate the photobleaching induced prior to the measurements, a dynamic model was developed based on the PCA derived spectral components. Modulation and increased power of the excitation light resulted in a faster photobleaching; however, photobleaching was saturated at higher excitation powers. The system was adjusted to induce minimal photobleaching. In addition, effect of blood absorption on the fluorescence spectrum was investigated experimentally by placing blood drops on skin and theoretically by using Beer-Lambert law. The theoretical model was used to compensate for the distorted fluorescence ratio. According to the theoretical model of blood interference, a total 300 µm blood layer blocked the brain fluorescence signal totally and when the fluorescence signal was partially blocked, the fluorescence ratio was overestimated. The fluorescence ratio was corrected for blood layers thinner than 50 µm.The tissue in and around the tumor was categorized into necrosis, low and high grade tumor and gliosis. The median fluorescence ratio confirmed with histopathological examination (n = 45) had a lower fluorescence ratio for low grade malignancies (0.3) than high grade malignancies (2.4) (p < 0.05). Gliosis (1.6) and necrosis (1.0) showed a moderate fluorescence ratio. Ultrasound-based navigation in combination with fluorescence spectroscopy showed improvement in the results; however, a more extensive study is needed to confirm benefits of the method combination. In conclusion, fluorescence spectroscopy of 5-ALA induced PpIX provided an objective method for differentiating tumor from the healthy tissue intra-operatively. Fluorescence ratios were indicative of tissue type and tumor malignancy degree.
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| 2. |
- Latorre, Malcolm, 1967-
(författare)
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The Physical Axon : Modeling, Simulation and Electrode Evaluation
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Electrodes are used in medicine for detection of biological signals and for stimulating tissue, e.g. in deep brain stimulation (DBS). For both applications, an understanding of the functioning of the electrode, and its interface and interaction with the target tissue involved is necessary. To date, there is no standardized method for medical electrode evaluation that allows transferability of acquired data. In this thesis, a physical axon (Paxon) potential generator was developed as a device to facilitate standardized comparisons of different electrodes. The Paxon generates repeatable, tuneable and physiological-like action potentials from a peripheral nerve. It consists of a testbed comprising 40 software controlled 20 μm gold wires embedded in resin, each wire mimicking a node of Ranvier. ECG surface Ag-AgCl electrodes were systematically tested with the Paxon. The results showed small variations in orientation (rotation) and position (relative to axon position) which directly impact the acquired signal. Other electrode types including DBS electrodes can also be evaluated with the Paxon.A theoretical comparison of a single cable neuronal model with an alternative established double cable neuron model was completed. The output with regards to DBS was implemented to comparing the models. These models were configured to investigate electrode stimulation activity, and in turn to assess the activation distance by DBS for changes in axon diameter (1.5-10 μm), pulse shape (rectangular biphasic and rectangular, triangular and sinus monophasic) and drive strength (1-5 V or mA). As both models present similar activation distances, sensitivity to input shape and computational time, the neuron model selection for DBS could be based on model complexity and axon diameter flexibility. An application of the in-house neuron model for multiple DBS lead designs, in a patient-specific simulation study, was completed. Assessments based on the electric field along multiple sample planes of axons support previous findings that a fixed electric field isolevel is sufficient for assessments of tissue activation distances for a predefined axon diameter and pulse width in DBS.
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| 3. |
- Rejmstad, Peter, 1986-
(författare)
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Optical Monitoring of Cerebral Microcirculation
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The cerebral microcirculation consists of a complex network of small blood vessels that support nerve cells with oxygen and nutrition. The blood flow and oxygen delivery in the microcirculatory blood vessels are regulated through mechanisms which may be influenced or impaired by disease or brain damage resulting from conditions such as brain tumors, traumatic brain injury or subarachnoid hemorrhage (SAH). Monitoring of parameters relating to the microvascular circulation is therefore needed in the clinical setting. Optical techniques such as diffuse reflectance spectroscopy (DRS) and laser Doppler flowmetry (LDF) are capable of estimating the oxygen saturation (SO2) and tracking the microvascular blood flow (perfusion) using a fiber optic probe. This thesis presents the work carried out to adapt DRS and LDF for monitoring cerebral microcirculation in the human brain.A method for real-time estimation of SO2 in brain tissue was developed based on the P3 approximation of diffuse light transport and quadratic polynomial fit to the measured DRS signal. A custom-made fiberoptic probe was constructed for measurements during tumor surgery and in neurointensive care. Software modules with specific user interface for LDF and DRS were programmed to process, record and present parameters such as perfusion, total backscattered light, heart rate, pulsatility index, blood fraction and SO2 from acquired signals.The systems were evaluated on skin, and experimentally by using optical phantoms with properties mimicking brain tissue. The oxygen pressure (pO2) in the phantoms was regulated to track spectroscopic changes coupled with the level of SO2. Clinical evaluation was performed during intraoperative measurements during tumor surgery (n = 10) and stereotactic deep brain stimulation implantations (n = 20). The LDF and DRS systems were also successfully assessed in the neurointensive care unit for a patient treated for SAH. The cerebral autoregulation was studied by relating the parameters from the optical systems to signals from the standard monitoring equipment in neurointensive care.In summary, the presented work takes DRS and LDF one step further toward clinical use for optical monitoring of cerebral microcirculation.
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| 4. |
- Häggblad, Erik, 1972-
(författare)
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In Vivo Diffuse Reflectance Spectroscopy of Human Tissue : From Point Measurements to Imaging
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis presents the non-invasive use of diffuse reflectance spectroscopy (DRS) to provide information about the biochemical composition of living tissue. During DRS measurements, the incident, visible light is partially absorbed by chromophores but also scattered in the tissue before being remitted.Human skin and heart, the main tissue objects in this thesis, are dependent on a sufficient inflow of oxygenized blood, and outflow of metabolic byproducts. This process could be monitored by DRS using the spectral fingerprints of the most important tissue chromophores, oxyhemoglobin and deoxyhemoglobin.The Beer-Lambert law was used to produce models for the DRS and has thus been a foundation for the analyses throughout this work. Decomposition into the different chromophores was performed using least square fitting and tabulated data for chromophore absorptivity.These techniques were used to study skin tissue erythema induced by a provocation of an applied heat load on EMLA-treated skin. The absorbance differences, attributed to changes in the hemoglobin concentrations, were examined and found to be related to, foremost, an increase in oxyhemoglobin.To estimate UV-induced border zones between provoked and nonprovoked tissue a modified Beer-Lambert model, approximating the scattering effects, was used. An increase of chromophore content of more than two standard deviations above mean indicated responsive tissue. The analysis revealed an edge with a rather diffuse border, contradictory to the irradiation pattern.Measuring in the operating theater, on the heart, it was necessary to calculate absolute chromophore values in order to assess the state of the myocardium. Therefore, a light transport model accounting for the optical properties, and a calibrated probe, was adopted and used. The absolute values and fractions of the chromophores could then be compared between sites and individuals, despite any difference of the optical properties in the tissue.A hyperspectral imaging system was developed to visualize the spatial distribution of chromophores related to UV-provocations. A modified Beer-Lambert approximation was used including the chromophores and a baseline as an approximate scattering effect. The increase in chromophore content was estimated and evaluated over 336 hours.In conclusion, advancing from a restricted Beer-Lambert model, into a model estimating the tissue optical properties, chromophore estimation algorithms have been refined progressively. This has allowed advancement from relative chromophore analysis to absolute values, enabling precise comparisons and good prediction of physiological conditions.
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| 5. |
- Latorre, Malcolm
(författare)
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Action Potential Generator and Electrode Testing
- 2015
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Design, validation and application of a test platform for electrode characterization and comparison is a problem today. Development of target specific electrodes is increasing, for example surface cloth electrodes, non-contact electrodes, and deep brain stimulation electrodes. Whenever these new designs are implemented, there is always a need for testing. How these tests should be performed to verify the function of the electrode in an environment like the one they are designed for is still not solved.In this thesis, a physical axon, the Paxon, is suggested as a possibility to overcome this issue. The intent of the Paxon was to generate an electric field that is similar to the external field created by a live axonal process when an action potential is propagating along its length, and to do this in a stable, repeatable manner. In order to meet these specifications, the Paxon was designed with a microcontroller to drive the sequence of events and control the output parameters. A chamber with gold wire nodes entering through the bottom was manufactured as a dimensional mimic to a myelinated 20 μm diameter nerve axon segment. The chamber was flooded with normal saline solution mimicking the intervening tissues and to allow ionic coupling of electrodes to the electrical field produced in the chamber.The initial validation tests demonstrated that the timing is stable (196.4 ± 0.06 ms between trigger to action potential), as is the output “detected” amplitude (1.5 ± 0.05 mV with a gain of 40).Once the Paxon test platform was verified as functional for its intended application of testing electrodes for comparison, it was then used to compare a set of six electrodes (used as a set of three differential pairs) from a single manufacturer lot and batch number.With this approach, better assessment of the stability of the manufactured electrode, as well as longer term stability, can be attained. As more electrodes of similar and differing types are tested, the data can be used for inter-electrode comparisons and eventually verification of newelectrode designed.
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| 6. |
- Åstrand, Anders P, 1961-
(författare)
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A Tactile Resonance Sensor System for Detection of Prostate Cancer ex vivo : Design and Evaluation on Tissue Models and Human Prostate
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background The most common form of cancer among males in Europe and the USA is prostate cancer, PCa. Surgical removal of the prostate is the most common form of curative treatment. PCa can be suspected by a blood test for a specific prostate antigen, a PSA-test, and a digital rectal examination, DRE where the physician palpates the prostate through the rectum. Stiff nodules that can be detected during the DRE, and elevated levels of PSA are indications for PCa, and a reason for further examination. Biopsies are taken from the prostate by guidance of a transrectal ultrasound. Superficial cancer tumours can indicate that the cancer has spread to other parts of the body. Tactile resonance sensors can be used to detect areas of different stiffness in soft tissue. Healthy prostate tissue is usually of different stiffness compared to tissue with PCa.AimThe general aim of this doctoral thesis was to design and evaluate a flexible tactile resonance sensor system (TRSS) for detection of cancer in soft human tissue, specifically prostate cancer. The ability to detect cancer tumours located under the surface was evaluated through measurements on tissue phantoms such as silicone and biological tissues. Finally measurements on resected whole prostate glands were made for the detection of cancer tumours.Methods The sensor principle was based on an oscillating piezoelectric element that was indented into the soft tissue. The measured parameters were the change in resonance frequency, Δf, and the contact force F during indentation. From these, a specific stiffness parameter was obtained. The overall accuracy of the TRSS was obtained and the performance of the TRSS was also evaluated on tissue models made of silicone, biological tissue and resected whole human prostates in order to detect presence of PCa. Prostate glands are generally spherical and a special rotatable sample holder was included in the TRSS. Spherically shaped objects and uneven surfaces call for special attention to the contact angle between the sensor-tip and the measured surface, which has been evaluated. The indentation velocity and the depth sensitivity of the sensor were evaluated as well as the effect on the measurements caused by the force with which spherical samples were held in place in the sample holder. Measurements were made on silicone models and biological tissue of chicken and pork muscles, with embedded stiff silicone nodules, both on flat and spherical shaped samples. Finally, measurements were made on two excised whole human prostates.ResultsA contact angle deviating ≤ 10° from the perpendicular of the surface of the measured object was acceptable for reliable measurements of the stiffness parameter. The sensor could detect stiff nodules ≤ 4 mm under the surface with a small indentation depth of 0.4 to 0.8 mm.Measurements on the surface of resected human prostate glands showed that the TRSS could detect stiff areas (p < 0.05), which were confirmed by histopathological evaluation to be cancer tumours on, and under the surface.Conclusions A flexible resonance sensor system was designed and evaluated on soft tissue models as well as resected whole prostate glands. Evaluations on the tissue models showed that the TRSS can detect stiffer volumes hidden below the surface on both flat and spherical samples. The measurements on resected human prostate glands showed that PCa could be detected both on and under the surface of the gland. Thus the TRSS provides a promising instrument aimed for stiffness measurements of soft human tissue that could contribute to a future quantitative palpation method with the purpose of diagnosing cancer.
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| 7. |
- Åström, Mattias
(författare)
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Modelling, Simulaltion, and Visualization of Deep Brain Stimulation
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Deep brain stimulation (DBS) is an effective surgical treatment for neurological diseases such as essential tremor, Parkinsonʹs disease (PD) and dystonia. DBS has so far been used in more than 70 000 patients with movement disorders, and is currently in trial for intractable Gilles de la Tourette’s syndrome, obsessive compulsive disorders, depression, and epilepsy. DBS electrodes are implanted with stereotactic neurosurgical techniques in the deep regions of the brain. Chronic electrical stimulation is delivered to the electrodes from battery-operated pulse generators that are implanted below the clavicle.The clinical benefit of DBS is largely dependent on the spatial distribution of the electric field in relation to brain anatomy. To maximize therapeutic benefits while avoiding unwanted side-effects, knowledge of the distribution of the electric field in relation anatomy is essential. Due to difficulties in measuring electric fields in vivo, computerized analysis with finite element models have emerged as an alternative.The aim of the thesis was to investigate technical and clinical aspects of DBS by means of finite element models, simulations, and visualizations of the electric field and tissue anatomy. More specifically the effects of dilated perivascular spaces filled with cerebrospinal fluid on the electrical field generated by DBS was evaluated. A method for patient-specific finite element modelling and simulation of DBS was developed and used to investigate the anatomical distribution of the electric field in relation to clinical effects and side effects. Patient-specific models were later used to investigate the electric field in relation to effects on speech and movement during DBS in patients with PD (n=10). Patient-specific models and simulations were also used to evaluate the influence of heterogeneous isotropic and heterogeneous anisotropic tissue on the electric field during DBS. In addition, methods were developed for visualization of atlas-based and patient-specific anatomy in 3D for interpretation of anatomy, visualization of neural activation with the activating function, and visualization of tissue micro structure. 3D visualization of anatomy was used to assess electrode contact locations in relation to stimulation-induced side-effects (n=331) during DBS for patients with essential tremor (n=28). The modelling, simulation, and visualization of DBS provided detailed information about the distribution of the electric field and its connection to clinical effects and side-effects of stimulation. In conclusion, the results of this thesis provided insights that may help to improve DBS as a treatment for movement disorders as well as for other neurological diseases in the future.
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| 8. |
- Ewerlöf, Maria, 1987-
(författare)
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Multispectral imaging of hemoglobin oxygen saturation in skin microcirculation
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The ability to measure microcirculatory parameters such as hemoglobin oxygen saturation is important since it mirrors the microcirculatory state of the body. The microcirculation delivers oxygen and nutrients to the cells of the body and, if impaired, may be a sign of circulatory failure. Human skin microcirculation can be accessed non-invasively with bio-optical technologies, where skin acts as a diagnostic window. Diffuse reflectance spectroscopy (DRS) is a technique that access skin microcirculatory parameters, especially hemoglobin oxygen saturation. Basic systems are fiber optic probebased and measure in one point, often in firm contact with the skin. Multispectral diffuse reflectance imaging (MSI) enables spatially resolved DRS, imaging skin optical parameters from spectrally resolved backscattered intensities. Spectral information detected by MSI systems contain information on, e.g., hemoglobin oxygen saturation and optical properties of the tissue. Both spatial and temporal resolved information of hemoglobin oxygen saturation is beneficial for better diagnostics in most clinical applications, e.g., to monitor progression of wound healing processes, or other microcirculatory diseases reflected in hemoglobin spectral changes. Analysis of acquired MSI multispectral data cubes to access information on tissue parameters with high contrast to these variations can be performed in several ways using models and simulations. Time resolved continuous measurements that are spectrally and spatially resolved generate large amounts of data, requiring both storage space and fast analysis. Reducing the number of wavelengths is one way to limit the amount of data, if it does not reduce the quality of interpreted results. Therefore, in my work, I investigated theoretically how to reduce the number of wavelengths, and later implemented my findings using a snapshot MSI camera. Monte Carlo (MC) simulations were used to estimate hemoglobin oxygen saturation from captured MSI data. I also performed temporally resolved in vivo measurements on healthy test subjects during vascular occlusion provocations with a 16-channel snapshot MSI system. The acquired data were analyzed using two different methods: inverse MC and trained artificial neural networks (ANNs). For inverse MC, the acquired spectrum was iteratively compared to simulated spectra, where different optical properties were used for the simulation, trying to find the best fit. ANNs were trained to intensity data measured with the MSI system, using concurrently measured hemoglobin oxygen saturation values from a validated probe-based system as target data. The results and outcome of this thesis indicate good possibility to accurately estimate hemoglobin oxygen saturation with as few as four wavelengths. Estimated hemoglobin oxygen saturation values from analysis of in vivo measurements from the 16-channel snapshot MSI camera show high conformance to values measured by the validated probe-based system. Using the ANN-approach reduces time for analysis of a 512 × 270-pixel image to 0.056 s, compared to 1 h 58 min required by the inverse MC algorithm to analyze the same data. The method enables real-time analysis, and is, consequently, preferable in many clinical situations.
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| 9. |
- Pham, Tuan, Professor, 1962-, et al.
(författare)
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Classification of Short Time Series in Early Parkinson’s Disease With Deep Learning of Fuzzy Recurrence Plots
- 2019
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Ingår i: IEEE/CAA Journal of Automatica Sinica. - 2329-9266 .- 2329-9274. ; 6:6, s. 1306-1317
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Tidskriftsartikel (refereegranskat)abstract
- There are many techniques using sensors and wearable devices for detecting and monitoring patients with Parkinson's disease (PD). A recent development is the utilization of human interaction with computer keyboards for analyzing and identifying motor signs in the early stages of the disease. Current designs for classification of time series of computer-key hold durations recorded from healthy control and PD subjects require the time series of length to be considerably long. With an attempt to avoid discomfort to participants in performing long physical tasks for data recording, this paper introduces the use of fuzzy recurrence plots of very short time series as input data for the machine training and classification with long short-term memory (LSTM) neural networks. Being an original approach that is able to both significantly increase the feature dimensions and provides the property of deterministic dynamical systems of very short time series for information processing carried out by an LSTM layer architecture, fuzzy recurrence plots provide promising results and outperform the direct input of the time series for the classification of healthy control and early PD subjects.
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