Deep learning-based improvement for the outcomes of glaucoma clinical trials

Glaucoma is the leading cause of irreversible blindness worldwide. It is a progressive optic neuropathy in which retinal ganglion cell (RGC) axon loss, probably as a consequence of damage at the optic disc, causes a loss of vision, predominantly affecting the mid-peripheral visual field (VF). Glaucoma results in a decrease in vision-related quality of life and, therefore, early detection and evaluation of disease progression rates is crucial in order to assess the risk of functional impairment and to establish sound treatment strategies. The aim of my research is to improve glaucoma diagnosis by enhancing state of the art analyses of glaucoma clinical trial outcomes using advanced analytical methods. This knowledge would also help better design and analyse clinical trials, providing evidence for re-evaluating existing medications, facilitating diagnosis and suggesting novel disease management. To facilitate my objective methodology, this thesis provides the following contributions: (i) I developed deep learning-based super-resolution (SR) techniques for optical coherence tomography (OCT) image enhancement and demonstrated that using super-resolved images improves the statistical power of clinical trials, (ii) I developed a deep learning algorithm for segmentation of retinal OCT images, showing that the methodology consistently produces more accurate segmentations than state-of-the-art networks, (iii) I developed a deep learning framework for refining the relationship between structural and functional measurements and demonstrated that the mapping is significantly improved over previous techniques, iv) I developed a probabilistic method and demonstrated that glaucomatous disc haemorrhages are influenced by a possible systemic factor that makes both eyes bleed simultaneously. v) I recalculated VF slopes, using the retinal never fiber layer thickness (RNFLT) from the super-resolved OCT as a Bayesian prior and demonstrated that use of VF rates with the Bayesian prior as the outcome measure leads to a reduction in the sample size required to distinguish treatment arms in a clinical trial

Three-Dimensional Morphometric Analysis of the Craniofacial Complex in the Unaffected Relatives of Individuals with Nonsyndromic Orofacial Clefts

Numerous studies have described altered patterns of craniofacial form in the unaffected relatives of individuals with nonsyndromic oral clefts. Unfortunately, results from these studies have been highly variable and have failed to provide a reliable method for discriminating at-risk relatives from controls. In the present study, we compared craniofacial shape between a sample of unaffected relatives (33 females; 14 males) from CL/P multiplex families and an equal number of age/sex/ethnicity-matched controls. A total of 16 x,y,z facial landmark coordinates derived from 3D photogrammetry were analyzed via Euclidean Distance Matrix Analysis (EDMA), while 14 additional linear distances from direct anthropometry were analyzed via t-tests. Variables identified as significantly different (p ≤ 0.10 from EDMA; 0.05 from t-tests) were then entered into a two-group discriminant function analysis. All analyses were carried out for each sex separately. Compared to controls, female unaffected relatives demonstrated increased upper facial width, midface reduction and lateral displacement of the alar cartilage. A single discriminant function was derived (canonical correlation = 0.43; p = 0.01) which correctly classified 70% of female unaffected relatives and 73% of female controls. Male unaffected relatives demonstrated increased upper facial and cranial base width, increased lower facial height and decreased upper facial height. Again, a single discriminant function was derived (canonical correlation = 0.79; p < 0.001) which correctly classified 86% of male unaffected relatives and 93% of male controls. In both males and females, upper facial width contributed most to group discrimination. Based on the discriminant function results, unaffected relatives were classified into risk/liability classes (high risk or low risk) based on the degree of phenotypic divergence from controls. Results suggest that the craniofacial shape differences characterizing unaffected relatives are partly sex-specific and perhaps more pronounced in males. The pattern of relative-control differences observed in both sexes is in broad agreement with previous findings from both humans and animal models. Although preliminary, these results suggest that a quantitative assessment of the craniofacial phenotype may allow for the identification of at-risk individuals within CL/P multiplex families. Importantly, the identification of such individuals could lead to improvements in recurrence risk estimation and gene mapping

Modulation of the central vestibular networks through aging and high-strength magnetic fields

The importance of the vestibular system usually goes unnoticed in our daily lives and its significance is only experienced by patients suffering from vestibular diseases. The vestibular system is essential for orientation in space, and perception of motion, as well as keeping balance, and maintaining stable visual perception while moving in a three-dimensional world. Functional imaging has long been used to study the multisensory vestibular network in healthy subjects, as well as in patients with diseases of the vestibular system. The majority of these previous studies sought to associate brain areas with vestibular processing, by evaluating increases or decreases in blood-oxygen-level dependent signal (BOLD-signal) during application of artificial vestibular stimulations. However, many basic network properties of the multisensory vestibular cortical network still remain unknown. Since it is now possible to infer networks from functional connectivity analysis, that associates areas into networks based on their spatiotemporal signal behavior, a few of the remaining questions can be addressed. The dynamics of the vestibular networks and other co-activated networks in regard to the processing of a multisensory stimulation remain largely unknown. Do subjects of different ages respond differently to a vestibular challenge? Furthermore, a new form of vestibular stimulation, termed magnetic vestibular stimulation (MVS), has recently been discovered. It occurs in strong magnetic fields (≥1.5 tesla), that are commonly used in functional magnetic resonance imaging (fMRI), and raises questions about a possible modulation of vestibular networks during fMRI, potentially biasing functional neuroimaging results. The purpose of this thesis is to develop suggestions for studying the multisensory vestibular network and the influence of vestibular modulations on resting-state networks with fMRI. The focus lies on basic scientific investigations of (1) the influence of aging on the ability of subjects to respond to a challenge of the multisensory vestibular network and (2) the modulatory influence of magnetic fields (the MR environment) on functional imaging and resting-state networks in general. To this end, we carried out two studies. The first study was a cross-sectional aging study investigating the modulation of vestibular, somatosensory and motor networks in healthy adults (N=39 of 45 in total, age 20 to 70 years, 17 males). We used galvanic vestibular stimulation (GVS) to stimulate all afferences of the peripheral vestibular end organs or vestibular nerve in order to activate the entire multisensory vestibular network, as age-associated changes might be specific to sensory processing. We also controlled for changes of the motor network, structural fiber integrity (fractional anisotropy – FA), and volume changes to simultaneously compare the effects of aging across structure and function. The second study investigated the influence of the static magnetic field of the MR environment in a group of healthy subjects (N=27 of 30 in total, age 21 to 38 years, 19 females), as it was recently shown that a strong magnetic field produces a vestibular imbalance in healthy subjects. We examined MVS at field strengths of 1.5 tesla and 3 tesla. The associated spontaneous nystagmus, the scaling of the nystagmus’ slow phase velocity (SPV) across field strengths, the between subject variance of the SPV were analysed, and the analogous scaling relationship was identified in the modulation of resting-state network amplitudes, like the default mode network (DMN), between 1.5 tesla and 3 tesla to reveal its effect on fMRI results. Aging and MVS modulated networks associated with vestibular function and resting-state networks known for vestibular interactions. The results from our aging study imply that the dynamics of vestibular networks is limited by the influence of aging even in healthy adults without any noticeable vestibular deficit. Vestibular networks show a decline of functional connectivity with age and an increase of temporal variability (in excess of stimulation induced changes) with age. In contrast somatosensory and motor networks did not show any significant linear relationship with age or any significant changes between the youngest and oldest participants. Age-associated structural changes (gray matter volume changes or structural connectivity changes) did not explain the decline in functional connectivity or increase in temporal variability. Furthermore, stimulation thresholds did not change with age (nor did they correlate with the functional connectivity amplitudes or temporal variability), indicating that the age-associated changes that were found for the vestibular network, were not dependent on peripheral decline, as GVS is thought to directly stimulate the vestibular nerve. The results from our study of the influence of the static magnetic field of the MR environment showed that MVS was already present at a field strength of 1.5 tesla, as evident from the induced nystagmus, indicating a state of vestibular imbalance. Furthermore, MVS scaled linearly with field strength between 1.5 tesla and 3 tesla, and identified the effects of MVS in the scaling of functional resting-state network fluctuations, showing that MVS does indeed influence resting-state networks due to vestibular imbalance. Specifically, MVS does influence DMN resting-state network dynamics in accordance with the predicted scaling of MVS based on the Lorentz-force model for MVS. These results taken together not only imply that subjects were in a vestibular state of imbalance, but also that the extent and direction of the state of imbalance showed more variance between subjects with increasing field strength. In summary, the following suggestions for vestibular research can be delineated to extend the kind of questions that can be answered by functional MRI experiments and to improve these investigations for the benefit of clinically relevant research of healthy controls and patients. Regarding the influence of age, we suggest that researchers comparing patients with vestibular deficits and healthy controls should separate the age-matched group into age-strata (non-overlapping subgroups with different age spans, e.g. 20-40 years, 40-60 years and above 60 years of age). Each stratum should be compared and interpreted separately given that different age-groups have different levels of vestibular network dynamics available for compensation (or responding to a challenge). This is particularly relevant when patients show a wide age-distribution, e.g. in the case of vestibular neuritis patients. With respect to the influence of magnetic fields, we suggest that MVS should be seen as a new way of manipulating networks that either process vestibular information or show vestibular interactions, by using strong magnetic fields (≥1.5 tesla), as commonly used in MRI. The potential of modulating vestibular influences on networks via MVS lies in being able to induce or manipulate vestibular imbalances. In the healthy this can be used to create states that are similar to the diseased state, but without peripheral or central lesions. In patients this will allow to extend or reduce vestibular imbalances. In both cases this can be done while performing functional MRI simply by using the magnetic field of the MRI scanner and adjusting the head position of the subject in question. In studies that need to avoid vestibular perturbations MVS should be controlled by adjusting the head position of the subject and measuring the resulting eye movements. This should then be seen as an effort to remove unwanted variance, i.e., as an effort to homogenize the group, and achieve better statistical results due to less (uncontrolled) MVS interference that increases bias and variance with increasing field strength. In summary, these suggestions result in three short questions that researchers could ask themselves when thinking about vestibular research projects in the future. Age-grouping: “Is the response to a challenge different for younger adults than older adults, i.e., does each age-group compensate differently?” MVS modulation: “Can a manipulation of the imbalance state of our subjects with MVS help us to reveal more about the vestibular network’s response to a challenge or should we avoid interference by MVS in the imbalance state of our subjects?” Sensitivity: “Is the measure that I want to use sensitive enough to show the differences that I am looking for?” Connectivity and temporal variability might be sensitive enough, but many clinical tests might not be sufficient

Degenerative Joint Disease in Captive Large Cats: the radiographic characteristics and clinical presentation of DJD in captive cheetahs (Acinonyx jubatus), lions (Panthera leo) and tigers (Panthera tigris)

Lions, tigers and cheetahs are commonly held in zoos, experiencing greater longevity in captivity than the wild. As a result, they are more likely to develop age-related diseases, including degenerative joint disease (DJD). However, the prevalence, distribution, severity and clinical presentation of DJD in these species is currently unclear. To address these knowledge gaps, 14 institutions provided radiographic studies and matched clinical records for all cheetahs, lions and tigers that underwent imaging between 1979-2019. Radiographic arthropathies were identified and the correlation between arthropathy status and a range of predictors was examined. Radiographic DJD status was then matched with clinical entries to investigate the presenting signs of DJD in these three species. Arthropathies were found to be common and almost exclusively degenerative in nature. Increasing age was the strongest predictor for joint disease, and a significantly lower prevalence of disease was recorded for the cheetah. Whilst all species showed unique patterns of disease, similarities existed between the lion and tiger, with severe axial DJD a feature. There was a conspicuous absence of appendicular DJD detected in older cheetahs, however axial DJD is reported in this species for the first time, with both increased prevalence and severity found in cheetahs from urban compared with open-range zoos. The meniscal ossicle and supinator sesamoid bone were identified as normal structures that become radiographically evident with skeletal maturation, with the supinator sesamoid bone reported in the tiger, and the meniscal ossicle in the Sumatran tiger, for the first time. A spectrum of DJD-associated presenting clinical signs was established for the three species. Combined, these findings will facilitate radiographic diagnosis of DJD and enhance understanding of the clinical impact of this disease in captive nondomestic felids, whilst also providing impetus for further research in this area

Trauma, Tumors, Spine, Functional Neurosurgery

This book is written for graduate students, researchers, and practitioners who are interested in learning how the knowledge from research can be implemented in clinical competences. The first section is dedicated to deep brain stimulation, a surgical procedure which is the paramount example of how clinical practice can take advantage from fundamental research. The second section gathers four chapters on four different topics and illustrates how significant is the challenge to translate scientific advances into clinical practice because the route from evidence to action is not always obvious. It is hoped that this book will stimulate the interest in the process of translating research into practice for a broader range of neurosurgical topics than the one covered by this book, which could result in a forthcoming more comprehensive publication

Epilepsy

With the vision of including authors from different parts of the world, different educational backgrounds, and offering open-access to their published work, InTech proudly presents the latest edited book in epilepsy research, Epilepsy: Histological, electroencephalographic, and psychological aspects. Here are twelve interesting and inspiring chapters dealing with basic molecular and cellular mechanisms underlying epileptic seizures, electroencephalographic findings, and neuropsychological, psychological, and psychiatric aspects of epileptic seizures, but non-epileptic as well