Ph.D. Theses
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Item Human muscle structure-function relation in-vivo using magnetic resonance imaging modalities(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022) Karakuzu, Agah.; Yücesoy, Can A.Non-uniform muscle deformation has become a frequent finding in biomechanics research, using imaging modalities operating at different resolution levels from sarcom eres to fascicles. Mainly due to technical limitations, interpretations of these findings are detached from a theoretical foundation that considers the muscle with mechanical links to its surrounding. To enable this vital consideration, this thesis aims at devel oping and testing the validity of a multimodal MRI method that bridges the under standing between non-uniform mechanical deformations and their myofascial origins, in-vivo. 1) Supplemented with DTI tractography, registration-based fiber direction deformations and principal strains on NVTs characterized the myofascial loads in re lation to the strain heterogeneity pattern in active muscle (proximally shortened (up to 22%), distally lengthened (up to 108%) fascicles). Inter-subject deviations from the general pattern were in agreement with subject specific anatomy. 2) A multiverse analysis was performed on the tuning parameters of the demons registration algorithm to assess the validity of strain distribution pattern against algorithmic choices. Results showed that the overall deformation pattern was immune to such perturbations, yet the strains amplitudes underwent significant changes. 3) To add orthogonal information to the myofascial origin assessment and validation of strain distributions, quantitative and velocimetry MRI were used. T1 mapping showed promising results in associating microstructural content with the strain distribution pattern. SR patterns from 2D VE PC showed weak similarities with registration-based principal strains, whereas those from compressed sensing 4D-PC showed much better agreement. Collectively, these studies show a way forward for the understanding of in-vivo muscle structure function relationship with implications for muscle physiology in health and disease. NOTE Keywords : Magnetic Resonance Imaging (MRI); Diffusion Tensor Imaging (DTI); Myofascial loads; quantitative MRI; Velocimetry; Validation.Item Multimodal investigation of fMRI and fNIRS derived breath hold BOLD signals with an expanded balloon model(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2008., 2008.) Emir, Uzay Emrah.; Akın, Ata.; Öztürk, Cengizhan.Multimodal investigation of blood oxygenation level-dependent (BOLD) signal, using both functional near infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI), may give further insight to the underlying physiological principles and the detailed transient dynamics of the vascular response. Utilizing a breath hold task (BHT), we measured deoxy-hemoglobin (HbR) and oxy-hemoglobin (HbO) changes via fNIRS and blood oxygen level dependent (BOLD) changes by fMRI. Measurements were taken in four volunteers asynchronously and carefully aligned for comparative analysis. In order to describe the main stimulus in BHT, partial pressure of carbon dioxide (PaCO2) parameter was integrated into the balloon model as the driving function of cerebral blood ow (CBF) which led to the development of an expanded balloon model (EBM). During BHT, the increase in HbR was observed later than the BOLD peak and coincided temporally with its post stimulus undershoot. Further investigation of these transients with PaCO2 integrated balloon model suggests that post stimulus undershoot measured by fMRI is dominated by slow return of cerebral blood volume (CBV). This was con rmed by fNIRS measurements. In addition, BOLD signal decreased with the increase of the initial level of PaCO2 derived from EBM, indicating an e ect of basal CBF level on the BOLD signal. In conclusion, a multimodal approach with an appropriate biophysical model gave a comprehensive description of the hemodynamic response during BHT.|Keywords: Functional near-infrared spectroscopy, Functional magnetic resonance imaging, BOLD signal, Partial pressure of CO2, Balloon model, Post stimulus undershoot.Item Development of software tools for improved 1H magnetic resonance spectroscopic imaging(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022.) Cengiz, Sevim.; Öztürk Işık, Esin.Proton magnetic resonance spectroscopic imaging (1H-MRSI) provides a non invasive, spatially resolved evaluation of brain metabolism. In the first part of this study, an open-source data analysis software, which includes modules for visualization of raw 1H-MRSI data and LCModel outputs, chemical shift correction, tissue fraction calculation, metabolite map production, and registration onto standard MNI152 brain atlas while providing automatic spectral quality control, is presented. In the second part of this study, we investigated metabolic changes of mild cognitive impairment in Parkinson’s disease (PD-MCI) using 1H-MRSI data. This could be summarized mainly as ’posterior cortical metabolic changes’ related with cognitive dysfunction. In the last part of this thesis, the spatial resolution of 1H-MRSI images were increased using super resolution convolutional neural networks (SRCNN) and enhanced deep residual networks for single image super-resolution (EDSR) models trained with the anatomical MR images. Our results indicated that deep learning based super resolution models would contribute to reconstructing higher resolution 1H-MRSI. This thesis contributed to the literature in terms of developing Oryx-MRSI, which provides an unprecedented detailed data analysis pipeline for 1H-MRSI, identifying metabolic correlates of PD MCI, which might aid the clinicians for the diagnosis of MCI, and implementing deep learning based super resolution approaches that might increase the spatial resolution of 1H-MRSI.|Keywords : Parkinson’s disease, mild cognitive impairment, proton magnetic reso nance spectroscopic imaging, super resolution, deep learning, convolutional neural networks, open-source software.Item Assessment of active state titin's effects on muscle mechanics using finite element modeling(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022.) Çankaya, Alican Onur.; Yücesoy, Can A.Calcium dependent mechanical behaviors characterize titin's contribution to force production in three-myo lament paradigm: (1) Sti ening of PEVK (Proline, Glutamate, Valine, Lysine) segment, and (2) reduction of free-spring length via N2A titin binding. This thesis is focused on the introduction of an alternative perspective to the analysis of titin with incorporating epimuscular myofascial loads. Isolated and integrated rat muscle nite element model variations were used with three titin models: passive state titin, active state titin-I and active state titin-II. Results of isolated model showed that active state titin-I and II limits sarcomere shortening (lm = 32.7mm: up to 10% and 20%, respectively). Such shorter sarcomere e ect characterizes active state titin's mechanism of e ects. Integrated models showed that the shorter sarcomere e ect becomes an inconsistent and variable mechanism: Shorter sarcomere e ect is further enhanced for proximal fascicle interfaces (by 30.2% and 31.0%, respectively) whereas it is also diminished for remaining fascicles (by 10.3% and 14.0%, respectively), but even a longer sarcomere e ect is shown. Overall, titin's mechanism of e ect and functionality are manipulated by epimuscular myofascial force transmission. This implies a new approach for the 3-miyo lament model: For the analysis of the components of the contractile machinery, contribution to force production and contribution to muscle mechanics should be assessed with alternative perspectives. Titin's calcium dependent mechanical behaviors belong to former as these increases its sti ness, whereas shorter sarcomere e ect belongs to latter as this mechanism further translates its e ect to other components as well as to length-force characteristics. These together comprehensively de ne titin's contribution as a third myo lament.|Keywords : Force Enhancement, Titin, Shorter Sarcomere Effect, Epimuscular My ofascial Force Transmission, Epimuscular Myofascial Loads, Finite Element Modeling .Item Indocyanine green loaded poly(lactic acid) nanoparticles mediated phototherapy of cancer(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022.) Güney, Melike.; Gülsoy, Murat,Phototherapy is a promising approach for cancer treatment which can be uti lized alone or in combination with other treatment modalities. Among the available photosensitizers for phototherapy, indocyanine green (ICG) merits special attention, owing to its near infrared absorption characteristics and low dark toxicity. However, a strong tendency for protein-binding and aggregate-forming limits its use as a pho totherapeutic agent. Such a drawback can be eliminated with the utilization of nano sized drug delivery systems to encapsulate and protect ICG molecules. Numerous drug delivery systems incorporating ICG for phototherapeutic or imaging purposes are reported in the literature. However; these systems mostly contain other therapeutic agents as well, making it difficult to assess the effects of ICG alone. Hence, this study was aimed to explore the impact of only-ICG encapsulating polymeric nanoparticles as a phototherapeutic agent. Poly(lactic acid) nanoparticles produced via a single-step nanoprecipitation method for encapsulation and delivery of ICG molecules were used to this end and their phototherapeutic effects on prostate cancer cells were examined. This study demonstrated that ICG-encapsulating poly(lactic acid) nanoparticles could be utilized as a phototherapeutic agent in order to inhibit cellular viability on prostate cancer cells and that the decrease in cell viability was primarily due to photothermal effect.|Keywords: Anticancer Phototherapy, Photodynamic Therapy, Photothermal Therapy, Indocyanine Green, Polymeric Nanoparticles, Nanoprecipitation.Item Biomedical applications of sharkskin mimicked polymeric membranes(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022.) Rostami, Sabra.; Garipcan, Bora.Infection is one of the biggest challenges of implantable biomaterials. The diffi culty of eliminating implant-associated infection imposes a huge burden on the patient's life quality aside from the considerable financial cost of the treatment. Thus, effective approaches must be explored to design biomaterials with enhanced antibacterial ac tivity. Sharks have been investigated via biomimetic and bioinspiration approaches and discoveries have shown that sharkskin possesses antibacterial effects due to the reduced drag force on the skin whilst swimming which is because of their skin’s surface microstructure. In this thesis the antibacterial properties of sharkskin mimicked poly meric membranes in static conditions, with and without the aid of antibacterial and bactericidal chemicals was studied. The aim was to understand the adhesion behav ior of both bacteria and mammalian cells onto the biomimicked polymeric membranes and how the surface topography affected these properties. Moreover, the impact of surface topography on drug release and bactericidal activity of these membranes was investigated by examining the physicochemical, antibacterial, and cytocompatibility properties of fabricated membranes. In vitro experiments were conducted to evaluate cellular responses of mammalian cells along with bactericidal properties using human keratinocyte (HaCaT), mouse fibroblast (L929), and human dermal primary fibroblast (HDFa) cell lines as model cells and Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus bacterial strains as model bacteria species. The results presented in this thesis show that sharkskin polymeric membranes have great potential for reduc ing bacterial biofilm formation most probably via preventing bacterial adhesion. Also, the cell adhesion on these membranes can be enhanced via chemical modifications.|Keywords: Sharkskin, Biomimetic, Antibacterial, Cytocompatibility, Chitosan, Graph ene Oxide, Ampicillin Sodium Salt, Caffeic Acid Phenethyl Ester.Item Investigation of kinesio taping effects on muscular mechanics with novel imaging analyses(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022.) Yıldız, Seda.; Yücesoy, Can A.Kinesio Taping (KT) is an elastic therapeutic tape that is utilized for the pre vention and treatment of various neuromusculoskeletal disorders and sports injuries. Despite its widespread use especially improving muscular function, there is a lack of understanding of its effects on muscular mechanics. In vivo analyzes of muscle mechan ical response to external loads caused by KT is crucial to define its unknown action mechanism and to improve this kind of therapeutic approaches. Due to continuity of fascial system by muscular connective structures (epimysium, perimysium, and en domysium) and the interaction between muscle fibers and extra cellular matrix, loading effects imposed by KT are likely to be distributed to deep muscular fascia via force transmission. This thesis aims to address these effects by tensiomyography (TMG) and combination of Magnetic Resonance Imaging (MRI) based deformation and Diffusion Tensor Imaging (DTI) based fiber tracking analyzes. TMG analysis revealed that KT caused an increase in muscle tissue stiffness and a decrease in muscle rate of force de velopment. Results of MRI-based deformation and DTI-based fiber tracking indicated that KT-imposed external loads lead to along-fascicle shear strains and along-fascicle length changes in terms of lengthening and shortening and strain distribution were heterogeneous for all subjects. In summary, non-invasive in vivo analyzes were used to evaluate the effects of KT on muscular mechanics. Among these analyzes, the TMG method was used to measure the effects of KT on the mechanical properties of the muscle, while the MRI and DTI methods were used to measure the effects of KT on along-muscle fascicle shear strains and length changes.|Keywords : Kinesio Taping, Tensiomyography, Diffusion Tensor Imaging, Magnetic Resonance Imaging, Myofascial Loads.Item Photodynamic therapy with upconversion nanoparticles(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022.) Güleryüz, Burcu.; Gülsoy, Murat,; Ünal, Uğur.Photodynamic therapy (PDT) is an alternative approach to conventional meth ods (i e. chemotherapy and radiotherapy) that can be utilized to treat various cancers with less side effects. However, PDT has some restrictions such as photosensitizers delivery and light penetration depth. It was realized that these problems can be over come with the improvements in nanotechnology; and today, many researchers have been initiated to study on PDT with various combinations of photosensitizers-nanoparticles. Recently, upconversion nanoparticles (UCNP) have revealed promising results with different surface designs. UCNP’s unique anti-Stokes conversion capabilities en able the transmission of near-infrared (NIR) to visible light, providing a solution to the light penetration depth problem of traditional PDT. Since they have organic struc ture, UCNP do not show high biotoxicity and additional surface modifications allow photosensitizers delivery to the desired region of a body. In this study, Yb/Er doped UCNP was synthesized and coated with porous sil ica to merge MC540 and ZnPc photosensitizers. In order to prevent photosensitizers leakage over time and optically strengthen the nanoparticles for PDT activity, silica surface was conjugated with APTES-gold nanoparticles. Experiments on prostate can cer cells with this novel design revealed two notable results: (I) nanoplatforms exerted high biocompatibility that even 2 mg/ml concentration could be employed, and (II) the viability of cells was successfully reduced up to 35%. Furthermore, PDT effect of 3-4 nm sized gold nanoparticles on cells was detected for the first time.|Keywords : Photodynamic Therapy, Upconversion Nanoparticles, Mesoporous Silica, Gold Nanoparticles, MC540 and ZnPc Photosensitizers, Prostate Cancer.Item Skeletal muscle mechanics and spasticity management :|human and animal experiments(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2022., 2022.) Kaya Keleş, Cemre Su.; Yücesoy, Can A.Being the most common motor disability in childhood, cerebral palsy (CP) describes a movement disorder for which the exact underlying mechanism is unclear, and no cure is available. Yet, local injection of botulinum toxin type-A (BTX-A) is used for spasticity management. In this thesis, the relationship between the mechanics of spastic muscles and the impaired joint motion was investigated in patients, and the long-term effects of BTX-A on muscular mechanics were assessed in animals. Exper iments on spastic knee flexors showed that passive muscle forces are much less than active forces (e.g., 26%), and epimuscular myofascial force transmission (EMFT) arising from intermuscular mechanical interactions significantly increases active forces (up to 132%). Combined with musculoskeletal models developed based on gait analysis data, EMFT effects were shown to be compatible with metrics characterizing patients’ patho logical gait, indicating that intermuscular mechanical interactions may be a source of high flexor forces in flexed joint positions. Experiments in the rat anterior crural com partment showed that long-term after injection, BTX-A yields in addition to decreased active forces, both unintended (a narrower range of force exertion by 23% and increased passive forces by 12%, for the injected muscle) and uncontrolled effects (similar effects on compartmental muscles due to the spread of the toxin). BTX-A also leads to col lagen content increase (by several folds) for muscles exposed, which explains elevated passive forces and impacts also active forces. These effects are of high potential clinical importance as they conflict with therapeutic goals. Particularly, controlling the effects of BTX-A on connective tissue adaptation is critical for better spasticity management.|Keywords : Epimuscular myofascial force transmission, Cerebral palsy, Spastic muscle, Muscle force-joint angle/length characteristics, Gait analysis, OpenSim, Botulinum toxin type-A, Rat anterior crural compartment, Collagen.Item Three dimensional modeling of the knee joint: prediction of ligament related gait abnormalities(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2007., 2007.) Akalan, N. Ekin.; Özkan, Mehmed.The purpose of this study is to investigate the affect of anterior bundle of ACL (aACL), anterior portion of posterior cruciate ligament PCL (aPCL), anterior and deep portions of MCL (aMCL, dMCL) and the tibiofemoral articular contacts on to passive knee motion. A well accepted reference model for a normal tibio-femoral joint was reconstructed from the literature in which attachments of the bundles of the ligaments and the articular surfaces in medial and the lateral components were carefully defined. Another three dimensional dynamic tibiofemoral model which includes the isometric fascicles, aACL, aPCL, aMCL, dMCL, and the medial-lateral articular surfaces were represented as the constraints to predict the trajectory of the tibia on the femur during flexion. The tibiofemoral model was also integrated in to the dynamic patella-tibio-femoral model. The behavior of the knee model was also tested by simulating dynamic and static clinical tests such as knee extension exercise and drawing test. The patello- tibio-femoral model was integrated into full-body model to simulate people walk with normal and ACL deficient patterns. The predictions were closely agreed with the literatures and correspond well to measurements of the model which represents natural patello-tibio-femoral joint. The aACL, aPCL, aMCL, dMCL bundles and the medial-lateral articular surfaces might play a primary role to give the nature of distal femoral sphere like shape. The clinical significance of the work is that anything which changes the lengths and locations of the related ligaments may demolish natural constraints and force the articular structures in to unnatural shape which may make the knee to change contact behavior on the articular surface and may cause pain. The surgical treatments must be accurate enough to provide both ligament bundle geometries and articular geometry to achieve a problem free knee kinematics after the surgery.|Keywords: Knee, Kinematics, Geometry, Three-dimensional model, Ligament surgery.Item Prediction of psychophysical responses from spike recordings in rat sensorimotor cortex by using Bayesian models(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Öztürk, Sevgi.; Güçlü, Burak.In this thesis, we studied the fundamental question in neuroscience: how per ception is built based on the sensory stimuli from the physical world and turned into motor actions in the face of uncertain neural representations. The vast body of lit erature contains models using neural activity to decode stimulus parameters, motor responses, and behavioral patterns. In particular, this line of research became more important as sensorimotor neuroprostheses and brain-computer interfaces (BCI) were made possible by recent technology. The main goal of the thesis is to use Bayesian models to understand sensorimotor processing and develop a novel approach for future BCIs. Speci cally, spike data were collected from behaving rats during a yes/no de tection task. Within a Bayesian framework, priors and posterior beliefs are calculated to match the observed choice of the animal. The random variables for stimulus pre sentation, neural activity, and motor responses were combined in a probabilistic graph network. First, a somatosensory neuroprosthesis application is demonstrated. Next, the Bayesian model was used to predict trial-by-trial responses o ine. It was found that psychophysically low-performing rats could be modelled better with the Bayesian approach. These results were compared to predictions of other supervised learning algorithms. The Bayesian prediction was among the best performing algorithms for low-performing rats. Finally, to reveal the e ect of choice history on the current trial's response prediction, previous responses were also included into various Bayesian models incrementally. The results showed that the mean ring rates in a population of neurons are mostly adequate to predict lever presses with high sensitivity and low bias. This thesis provides new insights into computational modeling to understand sensorimotor processing and development of future BCIs. Bayesian modeling can be particularly useful in rehabilitation and during the training period of neuroprostheses.Item Bioimpedance spectroscopy in prediction of type I osteoporosis in menopaused women(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Matur, Fırat.; Kocatürk, Özgür.; Ülgen, Yekta.Bone mineral density (BMD) is a measure of survival for men and women, and it is used to diagnose Osteoporosis that can be diagnosed and treated with an e ective screening. We measured bioimpedance spectroscopy (BIS) parameters of 129 menopaused women and compared them with their DEXA reference measurements. We observed a region speci city for the central BMD assessment using BIS. When sensing electrodes are on the dominant hand and infraclavicular fossa, dominant arm fc correlates with the hip BMD (r = −0.412, P < 0.05), and fcut for Osteoporosis is 49.565 kHz. When sensing electrodes are over the hands, fc correlates with lumbar BMD (r = 0.580, P < 0.05), and fcut is 32.4 kHz. BMI also a ects BIS measure ments, and if BMI < 30 kg/m2 , the correlation of fc with the hip BMD is improved (r = −0.456, P < 0.05). fc may be alternatively calculated using the proposed origi nal 3P-Nyquist method. Both fc and the phase angle of the impedance measured at a single frequency are a function of the same impedance model parameters, and measure ment at a single frequency is less complicated than BIS. Phase angle of the measured impedance at 5 kHz has correlations with both lumbar (r = 0.403, P < 0.05) and hip (r = 0.559, P < 0.05) BMDs. When DEXA devices are not available or inaccessible, with its high mobility, non-invasive and cost-e ective nature, BIS can be a good substi tute in screening for BMD; however, clinical studies should be continued over a larger population to obtain the normative BIS cuto frequency or phase angle values. A prac tical 2D-ROC method for combining two discrete markers in a 2-way classi er is also proposed: both for simulated and clinical data, the AV ERAGE function combining markers has higher correct classi cation rates than the individual markers.|Keywords : Osteoporosis, Bone Mineral Density, Bioimpedance Spectroscopy, 3-Point Nyquist, Single Frequency Phase Angle, Characteristic Frequency, 2D-ROC.Item Investigating the brain energy dynamics during language activity(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Mutlu, Murat Can.; Saybaşılı, Hale.; Canbeyli, Reşit.The present dissertation aimed to measure the overall cognitive cost of language and visual processing to the brain with ear temperature measurement. Three verbal auditory experiments revealed that processing words caused a greater temperature in crease in the left ear than the right ear, indicating an expected left-hemispheric activity for language processing. Furthermore, processing words from a non-native language (English) caused greater cognitive cost (greater temperature increase) compared to words from the native language (Turkish). Lastly, it was found that the greatest tem perature increase was caused by the most difficult task. The last auditory experiment assessed the frontal cortex hemodynamics with functional near-infrared spectroscopy (fNIRS) and showed that the left hemisphere was active throughout the experiment, while the most difficult task caused the most widespread neuronal activity. A visual discrimination task revealed a greater temperature increase in the right ear compared to the left ear. These findings suggested that ear temperature can capture the overall cognitive cost of lateralized brain functions and can dissociate the task difficulty. A novel mental rotation (MR) and Turkish relative clause (RC) processing experiments were carried out with fNIRS to further investigate the cognitive cost of visual and lan guage processing as well as to assess the hemisphere’s contributions to processing. The MR experiment revealed a core neuronal activity in the right hemisphere regardless of the task difficulty and increased left-hemispheric activity with increased task difficulty. RC processing in Turkish was investigated with a neuroimaging method for the first time and it was shown that processing object RCs causes greater cognitive load than subject RCs, reflected by more widespread neuronal activity in the prefrontal cortex and greater non-significant hemodynamic activity in Broca’s Area.|Keywords: Tympanic Membrane Temperature, fNIRS, Language Processing, Visual Processing, Cognitive Cost.Item Novel biopsy needle and assisted robotic system design for prostate biopsy procedure under MRI(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Mahçiçek, Davut İbrahim.; Kocatürk, Özgür.Prostate cancer (PCa) is one of the most common cancer type among men. The mortality rate for prostate cancer is signi cantly high compared to other common cancer types which makes it even more concerning for elderly males. For this reason the early and accurate diagnosis of PCa is vital to avoid deaths caused by PCa. In clinical practice, PCa is diagnosed with ultrasound guided biopsy procedure (TRUS-guided biopsy) after observing signs of PCa with di erent pre-screening methods. However, diagnosing PCa with the TRUS-guided prostate biopsy is controversial mainly because US imaging is not able to provide contrast di erence between healthy tissue and le sion. For this reason, biopsy samples are taken statistically from di erent regions of the prostate. On the other hand, magnetic resonance imaging (MRI) can help to dis tinguish lesions from healthy tissues. Therefore, the optimal way to perform prostate biopsy is to perform it under MRI guidance in order to eliminate accuracy concerns. In this thesis, a novel hydraulic needle delivery system that is designed for perform ing MRI-guided prostate biopsy procedure is proposed. The needle delivery system is composed of the main robotic unit, control unit, hydraulic actuator, biopsy gun and biopsy needle. All of these components were designed, manufactured and assembled in the scope of this thesis. The feasibility of the overall system was evaluated through in-vitro phantom experiments under an MRI guidance. The in vitro experiments per formed using a certi ed prostate phantom (incorporating MRI visible lesions). MRI experiments showed that overall hydraulic biopsy needle delivery system has excellent MRI compatibility (SNR Loss < 3%), provides acceptable targeting accuracy (average 2.05 ± 0.46 mm) and procedure time (average 40 minutes).|Keywords : Image Guided Intervention, Minimally Invasive Devices, MRI compatible robotics, Prostate Biopsy, Hydraulic Actuation, Biopsy Needle.Item Investigation of functional brain connectivity patterns in temporal lobe epilepsy(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Dumlu, Seda Nilgün.; Ademoğlu, Ahmet.In this study, functional connectivity using both Pearson and partial correla tion coe cients and inter-subject variability were investigated in resting state func tional resonance imaging (rs-fMRI) scans that belong to healthy and temporal lobe epileptic (TLE) patient populations. The main purpose of this thesis is to reveal the discrepancies between the healthy population and the patients with TLE in terms of functional connectivity revealing the temporal dependency among di erent brain re gions. According to inter-subject variability results, TLE population exhibited higher inter-subject variability in frontoparietal control, default mode, dorsal/ventral atten tion, visual, limbic and somatomotor networks in line with the broad seizure onset and propagation pathway. We mostly found a signi cantly reduced functional connectivity in bilateral frontoparietal control, somatomotor, default mode and ventral attention networks with an implication of dysfunctioning in attention, long/short term memory, cognitive functioning and consciousness in patients with TLE as a result of 17-network parcellation. We also found a decreased functional connectivity between/within the networks of the frontoparietal control, the default mode and the ventral attention im plying that these three networks as well show a variability, although to a lesser extent. This result signi es these networks are severely deteriorated in patients with TLE. On the other hand, to compute the direct functional connectivity among di erent brain regions, partial correlation coe cients estimation is used. In doing so, we took advan tage of Random Matrix Theory to well approximate the partial correlations, by virtue of, the inverse covariance matrices. As a result, the bilateral homologous structures in dorsal/ventral attention, frontoparietal control and default mode networks were also decreased in patient population con rming our results using Pearson's corelation coef- cients.|Keywords : Resting State fMRI, Functional Connectivity, Temporal Lobe Epilepsy.Item Deep learning approaches for the localization of capsule endoscope(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Altuğ, Kutsev Bengisu.; Garipcan, Bora.; Turan, Mehmet.Deep learning techniques hold promise to develop dense topography reconstruc tion and pose estimation methods for endoscopic videos. However, currently available datasets do not support effective quantitative benchmarking. In this thesis, we in troduce a comprehensive endoscopic simultaneous localization and mapping (SLAM) dataset consisting of 3D point cloud data for six porcine organs, capsule and stan dard endoscopy recordings, synthetically generated data as well as clinically in use conventional endoscope recording of the phantom colon with computed tomography scan ground truth. To verify the applicability of this data for use with real clinical systems, we recorded a video sequence with a state-of-the-art colonoscope from a full representation silicon colon phantom. Additionally, we propound Endo-SfMLearner, an unsupervised monocular depth and pose estimation method that combines residual networks with a spatial attention module in order to dictate the network to focus on dis tinguishable and highly textured tissue regions. The proposed approach makes use of a brightness-aware photometric loss to improve the robustness under fast frame-to-frame illumination changes that are commonly seen in endoscopic videos. To exemplify the use-case of the EndoSLAM dataset, the performance of Endo-SfMLearner is extensively compared with the state-of-the-art: SC-SfMLearner, Monodepth2, and SfMLearner.|Keywords : SLAM Dataset, Capsule Endoscopy, Spatial Attention Module, Monocu lar Depth Estimation, Visual Odometry.Item A study in cultured neuronal networks(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Bayat, Fazıl Kemal.; Güveniş, Albert.; Gülçür, Halil Özcan.In this study, two platforms, combining multi-electrode arrays and optogenetic methods, were developed to study living neural networks in vitro. Both platforms, which included stimulation of neural networks developed in culture and monitoring of their activities, were tested using primary neuronal cultures obtained from mice and their operability and usability were demonstrated. In the rst platform, dorsal root ganglion cells were made to emit uorescent light when calcium in ux occurs by optoge netic technique. In this platform stimulation was provided electrically through multiple electrode arrays and experiments were performed under uorescent microscopy. The evoked activity was monitored through calcium transitions and the analyzed results re vealed the network connections. Next, the network connections determined by analysis were con rmed by immunostaining that showed connections physically. The results obtained illustrated that the dorsal root ganglion nerve cells could establish connec tions with each other to form networks. In the second platform, hippocampal cells were used and neurons were made excitable with light using the optogenetic approach. After that, the optical stimulation using a digital micro mirror device for excitation was performed locally and focused. Spontaneous and stimulated extracellular elec trical activity was monitored and recorded with multiple electrode arrays. On this platform, bilateral and closed-loop electrophysiology applications were performed and multi-channel and experiment examples were presented. The results show that the new platform designed for extracellular electrophysiology applications, with the option of multi-channel, artifact-free and closed-loop experimentation, eliminates the de ciencies and problems of those proposed in the previous studies. In conclusion, in the presented study, it has been shown that multi-electrode arrays can be successfully integrated with optogenetic methods that have both activity monitoring and stimulation purposes.Item Clinical grade medical device technologies for interventional cardivascular magnetic resonance imaging procedures(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Yıldırım, Dursun Korel.; Kocatürk, Özgür.Magnetic Resonance Imaging (MRI) is a promising candidate against X-ray fluoroscopy for the image-guidance of minimally invasive procedures thanks to its ion izing radiation-free, exquisite soft tissue contrast and ability of 3D real-time imaging in arbitrary planes. However, interventional MRI (iMRI) is hampered by the lack of clinical grade MRI-compatible interventional devices. In this thesis study, first, a low profile iMRI device fabrication method was introduced by modifying the conductive ink printing method which was previously introduced by our group. Next, three most fundamental iMRI device designs including a 20 G active iMRI needle, a 0.035” outer di ameter metallic active iMRI guidewire and a 6 FR, MRI-safe, metallic braided catheter were successfully introduced to expand interventional cardiovascular MRI applications. Electromagnetic simulation tools were employed to optimize the device radio frequency (RF) antenna geometry for optimal device visibility, and to assess RF-safety of iMRI devices. Proposed iMRI device designs were prototyped using biocompatible materials. In-vitro mechanical, RF-induced heating and MRI visibility performance of the proto types were tested per international medical device test standards. In-vivo mechanical and MRI visibility tests were performed in swine per local animal study regulations. Test results were compared to commercially available equivalents. RF-induced temper ature rise of all three prototypes remained within clinically acceptable limits. Active iMRI needle and active iMRI guidewire prototypes were clearly visible during in-vitro and in-vivo tests. All prototypes demonstrated comparable mechanical performance with commercially available equivalents. Proposed iMRI device designs will meet the most urgent need in the iMRI field enabling a broad range of iMRI applications.|Keywords : interventional MRI, active device design, active iMRI needle, active iMRI guidewire, CMR-safe metal braided catheter.Item Improved multi inversion time arterial spin labeling MRI of the brain(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Arslan, Dilek Betül.; Öztürk Işık, Esin.Arterial spin labeling magnetic resonance imaging (ASL MRI) measures cere bral blood flow (CBF) quantitively without using any contrast agent or radiation.The calculation of labelled blood arrival time to tissue and arterial vessels provides hemody namic information, which may be useful in understanding neurodegenerative disorders. Separate pseudo-continuous ASL (pCASL) MR can be done at multiple inversion times (TI) to avoid inaccurate CBF estimation due to uncertainties in arrival times, which is time consuming and limits the number of averages. ASL MRI using Look-Locker (LL) readout and the time-encoded pCASL MRI (te-pCASL) using Hadamard matrix are two approaches for acquiring ASL data at multiple TIs. ASL-MRI with LL readout requires a complex model to accurately estimate CBF. On the other hand, te-pCASL MRI has a shine-through effect, which might cause errors in CBF estimation. In the first part of this thesis, the brain perfusion deficits in Parkinson’s disease with mild cognitive impairment (PD-MCI) were investigated using ASL MRI with LL readout. PD-MCI patients displayed a posterior hypoperfusion pattern, which classified these patients with over 90% accuracy in comparison to healthy controls. Moreover, geneti cally risky PD with microtubule-associated protein tau gene (MAPT) H1/H1 haplotype had visual hypoperfusion as compared with non-risky PD. In the second part of the thesis, the possible reasons of shine-through effect in te-pCASL MRI were assessed using simulations and in-vivo data. Based on the theoretical model, pCASL and te pCASL MRI resulted in the same ASL signals. On the other hand, our experimental results showed that the use of selective background suppression inversion pulses could lead to the appearance of the shine-through effect.|Keywords : Arterial spin labeling, Parkinson’s disease, mild cognitive impairment, te-pCASL, Look-Locker readout, Parkinson’s disease, shine-through effect.Item Biophysical approaches for modulating neural differentiation(Thesis (Ph.D.)-Bogazici University. Institute of Biomedical Engineering, 2021., 2021.) Özgün, Alp.; Garipcan, Bora.Neural differentiation of stem cells is central to regenerative strategies towards neurodegenerative diseases. The vast majority of literature shows chemical, biochem ical and genetic approaches to control and utilize intrinsic or extrinsic stem cells for neural regeneration. However, biophysical factors are also able to regulate stem cell fate with some added advantages. They can be administered to organisms completely non-invasively or used as an integral part of in vitro models. Effects of substrate stiff ness and electromagnetic fields on neural differentiation are reported in the literature but common for both is a lack of understanding how these biophysical factors interact with cells. The overarching goal of this thesis is to reveal new clues about the effect mechanism of these factors on neural differentiation. Towards this end, three differ ent in vitro neural differentiation models were used in a mechanistic investigation. In the first segment, the results highlight a novel, integrin-independent and biomimetic mechanosensitivity of human neuroblastoma differentiation, along with new caveats attached to using this in vitro biological model. The following segments on electro magnetic fields reveal an unprecedented finding where zinc ions rush into the cells during chronic exposure to 50 Hz electromagnetic field and facilitate other, previously known effects of electromagnetic fields. Moreover, two different ion channels were asso ciated with these effects, for the first time in the literature. Overall, the output of this thesis identifies three new key players for sensing biophysical factors during neural dif ferentiation that will substantially contribute to future efforts towards their utilization in neural regeneration research.|Keywords : Mechanotransduction, extremely low frequency electromagnetic fields, neural differentiation, calcium influx, NMDA receptor, zinc, TRP channels.