Open-source virtual bronchoscopy for image guided navigation

This thesis describes the development of an open-source system for virtual bronchoscopy used in combination with electromagnetic instrument tracking. The end application is virtual navigation of the lung for biopsy of early stage cancer nodules. The open-source platform 3D Slicer was used for creating freely available algorithms for virtual bronchscopy. Firstly, the development of an open-source semi-automatic algorithm for prediction of solitary pulmonary nodule malignancy is presented. This approach may help the physician decide whether to proceed with biopsy of the nodule. The user-selected nodule is segmented in order to extract radiological characteristics (i.e., size, location, edge smoothness, calcification presence, cavity wall thickness) which are combined with patient information to calculate likelihood of malignancy. The overall accuracy of the algorithm is shown to be high compared to independent experts' assessment of malignancy. The algorithm is also compared with two different predictors, and our approach is shown to provide the best overall prediction accuracy. The development of an airway segmentation algorithm which extracts the airway tree from surrounding structures on chest Computed Tomography (CT) images is then described. This represents the first fundamental step toward the creation of a virtual bronchoscopy system. Clinical and ex-vivo images are used to evaluate performance of the algorithm. Different CT scan parameters are investigated and parameters for successful airway segmentation are optimized. Slice thickness is the most affecting parameter, while variation of reconstruction kernel and radiation dose is shown to be less critical. Airway segmentation is used to create a 3D rendered model of the airway tree for virtual navigation. Finally, the first open-source virtual bronchoscopy system was combined with electromagnetic tracking of the bronchoscope for the development of a GPS-like system for navigating within the lungs. Tools for pre-procedural planning and for helping with navigation are provided. Registration between the lungs of the patient and the virtually reconstructed airway tree is achieved using a landmark-based approach. In an attempt to reduce difficulties with registration errors, we also implemented a landmark-free registration method based on a balanced airway survey. In-vitro and in-vivo testing showed good accuracy for this registration approach. The centreline of the 3D airway model is extracted and used to compensate for possible registration errors. Tools are provided to select a target for biopsy on the patient CT image, and pathways from the trachea towards the selected targets are automatically created. The pathways guide the physician during navigation, while distance to target information is updated in real-time and presented to the user. During navigation, video from the bronchoscope is streamed and presented to the physician next to the 3D rendered image. The electromagnetic tracking is implemented with 5 DOF sensing that does not provide roll rotation information. An intensity-based image registration approach is implemented to rotate the virtual image according to the bronchoscope's rotations. The virtual bronchoscopy system is shown to be easy to use and accurate in replicating the clinical setting, as demonstrated in the pre-clinical environment of a breathing lung method. Animal studies were performed to evaluate the overall system performance.

Human-Computer interaction methodologies applied in the evaluation of haptic digital musical instruments

Recent developments in interactive technologies have seen major changes in the manner in which artists, performers, and creative individuals interact with digital music technology; this is due to the increasing variety of interactive technologies that are readily available today. Digital Musical Instruments (DMIs) present musicians with performance challenges that are unique to this form of computer music. One of the most significant deviations from conventional acoustic musical instruments is the level of physical feedback conveyed by the instrument to the user. Currently, new interfaces for musical expression are not designed to be as physically communicative as acoustic instruments. Specifically, DMIs are often void of haptic feedback and therefore lack the ability to impart important performance information to the user. Moreover, there currently is no standardised way to measure the effect of this lack of physical feedback. Best practice would expect that there should be a set of methods to effectively, repeatedly, and quantifiably evaluate the functionality, usability, and user experience of DMIs. Earlier theoretical and technological applications of haptics have tried to address device performance issues associated with the lack of feedback in DMI designs and it has been argued that the level of haptic feedback presented to a user can significantly affect the user’s overall emotive feeling towards a musical device. The outcome of the investigations contained within this thesis are intended to inform new haptic interface.

Interaction of additive and quantization noises in digital PLLs

Phase-locked loops (PLLs) are a crucial component in modern communications systems. Comprising of a phase-detector, linear filter, and controllable oscillator, they are widely used in radio receivers to retrieve the information content from remote signals. As such, they are capable of signal demodulation, phase and carrier recovery, frequency synthesis, and clock synchronization. Continuous-time PLLs are a mature area of study, and have been covered in the literature since the early classical work by Viterbi [1] in the 1950s. With the rise of computing in recent decades, discrete-time digital PLLs (DPLLs) are a more recent discipline; most of the literature published dates from the 1990s onwards. Gardner [2] is a pioneer in this area. It is our aim in this work to address the difficulties encountered by Gardner [3] in his investigation of the DPLL output phase-jitter where additive noise to the input signal is combined with frequency quantization in the local oscillator. The model we use in our novel analysis of the system is also applicable to another of the cases looked at by Gardner, that is the DPLL with a delay element integrated in the loop. This gives us the opportunity to look at this system in more detail, our analysis providing some unique insights into the variance `dip' seen by Gardner in [3]. We initially provide background on the probability theory and stochastic processes. These branches of mathematics are the basis for the study of noisy analogue and digital PLLs. We give an overview of the classical analogue PLL theory as well as the background on both the digital PLL and circle map, referencing the model proposed by Teplinsky et al. [4, 5]. For our novel work, the case of the combined frequency quantization and noisy input from [3] is investigated first numerically, and then analytically as a Markov chain via its Chapman-Kolmogorov equation. The resulting delay equation for the steady-state jitter distribution is treated using two separate asymptotic analyses to obtain approximate solutions. It is shown how the variance obtained in each case matches well to the numerical results. Other properties of the output jitter, such as the mean, are also investigated. In this way, we arrive at a more complete understanding of the interaction between quantization and input noise in the first order DPLL than is possible using simulation alone. We also do an asymptotic analysis of a particular case of the noisy first-order DPLL with delay, previously investigated by Gardner [3]. We show a unique feature of the simulation results, namely the variance `dip' seen for certain levels of input noise, is explained by this analysis. Finally, we look at the second-order DPLL with additive noise, using numerical simulations to see the effects of low levels of noise on the limit cycles. We show how these effects are similar to those seen in the noise-free loop with non-zero initial conditions.

Identifying novel molecular mechanisms of ghrelin receptor signalling underlying neural control of food intake: interaction with stress and impulsivity

The gut-hormone, ghrelin, activates the centrally expressed growth hormone secretagogue 1a (GHS-R1a) receptor, or ghrelin receptor. The ghrelin receptor is a G-protein coupled receptor (GPCR) expressed in several brain regions, including the arcuate nucleus (Arc), lateral hypothalamus (LH), ventral tegmental area (VTA), nucleus accumbens (NAcc) and amygdala. Activation of the GHS-R1a mediates a multitude of biological activities, including release of growth hormone and food intake. The ghrelin signalling system also plays a key role in the hedonic aspects of food intake and activates the dopaminergic mesolimbic circuit involved in reward signalling. Recently, ghrelin has been shown to be involved in mediating a stress response and to mediate stress-induced food reward behaviour via its interaction with the HPA-axis at the level of the anterior pituitary. Here, we focus on the role of the GHS-R1a receptor in reward behaviour, including the motivation to eat, its anxiogenic effects, and its role in impulsive behaviour. We investigate the functional selectivity and pharmacology of GHS-R1a receptor ligands as well as crosstalk of the GHS-R1a receptor with the serotonin 2C (5-HT2C) receptor, which represent another major target in the regulation of eating behaviour, stress-sensitivity and impulse control disorders. We demonstrate, to our knowledge for the first time, the direct impact of GHS-R1a signalling on impulsive responding in a 2-choice serial reaction time task (2CSRTT) and show a role for the 5-HT2C receptor in modulating amphetamine-associated impulsive action. Finally, we investigate differential gene expression patterns in the mesocorticolimbic pathway, specifically in the NAcc and PFC, between innate low- and high-impulsive rats. Together, these findings are poised to have important implications in the development of novel treatment strategies to combat eating disorders, including obesity and binge eating disorders as well as impulse control disorders, including, substance abuse and addiction, attention deficit hyperactivity disorder (ADHD) and mood disorders.