Temporal Dynamics of Decision-Making during Motion Perception in the Visual Cortex

How does the brain make decisions? Speed and accuracy of perceptual decisions covary with certainty in the input, and correlate with the rate of evidence accumulation in parietal and frontal cortical "decision neurons." A biophysically realistic model of interactions within and between Retina/LGN and cortical areas V1, MT, MST, and LIP, gated by basal ganglia, simulates dynamic properties of decision-making in response to ambiguous visual motion stimuli used by Newsome, Shadlen, and colleagues in their neurophysiological experiments. The model clarifies how brain circuits that solve the aperture problem interact with a recurrent competitive network with self-normalizing choice properties to carry out probablistic decisions in real time. Some scientists claim that perception and decision-making can be described using Bayesian inference or related general statistical ideas, that estimate the optimal interpretation of the stimulus given priors and likelihoods. However, such concepts do not propose the neocortical mechanisms that enable perception, and make decisions. The present model explains behavioral and neurophysiological decision-making data without an appeal to Bayesian concepts and, unlike other existing models of these data, generates perceptual representations and choice dynamics in response to the experimental visual stimuli. Quantitative model simulations include the time course of LIP neuronal dynamics, as well as behavioral accuracy and reaction time properties, during both correct and error trials at different levels of input ambiguity in both fixed duration and reaction time tasks. Model MT/MST interactions compute the global direction of random dot motion stimuli, while model LIP computes the stochastic perceptual decision that leads to a saccadic eye movement.

Spiking Dynamics during Perceptual Grouping in the Laminar Circuits of Visual Cortex

Grouping of collinear boundary contours is a fundamental process during visual perception. Illusory contour completion vividly illustrates how stable perceptual boundaries interpolate between pairs of contour inducers, but do not extrapolate from a single inducer. Neural models have simulated how perceptual grouping occurs in laminar visual cortical circuits. These models predicted the existence of grouping cells that obey a bipole property whereby grouping can occur inwardly between pairs or greater numbers of similarly oriented and co-axial inducers, but not outwardly from individual inducers. These models have not, however, incorporated spiking dynamics. Perceptual grouping is a challenge for spiking cells because its properties of collinear facilitation and analog sensitivity to inducer configurations occur despite irregularities in spike timing across all the interacting cells. Other models have demonstrated spiking dynamics in laminar neocortical circuits, but not how perceptual grouping occurs. The current model begins to unify these two modeling streams by implementing a laminar cortical network of spiking cells whose intracellular temporal dynamics interact with recurrent intercellular spiking interactions to quantitatively simulate data from neurophysiological experiments about perceptual grouping, the structure of non-classical visual receptive fields, and gamma oscillations.

Working Memory Networks for Learning Temporal Order, with Application to 3-D Visual Object Recognition

Working memory neural networks are characterized which encode the invariant temporal order of sequential events. Inputs to the networks, called Sustained Temporal Order REcurrent (STORE) models, may be presented at widely differing speeds, durations, and interstimulus intervals. The STORE temporal order code is designed to enable all emergent groupings of sequential events to be stably learned and remembered in real time, even as new events perturb the system. Such a competence is needed in neural architectures which self-organize learned codes for variable-rate speech perception, sensory-motor planning, or 3-D visual object recognition. Using such a working memory, a self-organizing architecture for invariant 3-D visual object recognition is described. The new model is based on the model of Seibert and Waxman (1990a), which builds a 3-D representation of an object from a temporally ordered sequence of its 2-D aspect graphs. The new model, called an ARTSTORE model, consists of the following cascade of processing modules: Invariant Preprocessor --> ART 2 --> STORE Model --> ART 2 --> Outstar Network.

Genetically Generated Neural Networks I: Representational Effects

This paper studies several applications of genetic algorithms (GAs) within the neural networks field. After generating a robust GA engine, the system was used to generate neural network circuit architectures. This was accomplished by using the GA to determine the weights in a fully interconnected network. The importance of the internal genetic representation was shown by testing different approaches. The effects in speed of optimization of varying the constraints imposed upon the desired network were also studied. It was observed that relatively loose constraints provided results comparable to a fully constrained system. The type of neural network circuits generated were recurrent competitive fields as described by Grossberg (1982).

Store Working Memory Networks for Storage and Recall of Arbitrary Temporal Sequences

Neural network models of working memory, called Sustained Temporal Order REcurrent (STORE) models, are described. They encode the invariant temporal order of sequential events in short term memory (STM) in a way that mimics cognitive data about working memory, including primacy, recency, and bowed order and error gradients. As new items are presented, the pattern of previously stored items is invariant in the sense that, relative activations remain constant through time. This invariant temporal order code enables all possible groupings of sequential events to be stably learned and remembered in real time, even as new events perturb the system. Such a competence is needed to design self-organizing temporal recognition and planning systems in which any subsequence of events may need to be categorized in order to to control and predict future behavior or external events. STORE models show how arbitrary event sequences may be invariantly stored, including repeated events. A preprocessor interacts with the working memory to represent event repeats in spatially separate locations. It is shown why at least two processing levels are needed to invariantly store events presented with variable durations and interstimulus intervals. It is also shown how network parameters control the type and shape of primacy, recency, or bowed temporal order gradients that will be stored.

Towards a regional understanding of Irish traditional music

The geography of Irish traditional music is a complex, popular and largely unexplored element of the narrative of the tradition. Geographical concepts such as the region are recurrent in the discourse of Irish traditional music but regions and their processes are, for the most part, blurred or misunderstood. This thesis explores the geographical approach to the study of Irish traditional music focusing on the concept of the region and, in particular, the role of memory in the construction and diffusion of regional identities. This is a tripartite study considering people, place and music. Each of these elements impacts on our experience of the other. All societies have created music. Music is often associated with or derived from places. Some places construct or reinforce their identity through the music and musicians through which they are associated. The thesis challenges conventional discourse on regional styles that construct an imagined pattern of regions based on subtle musical differences that may, though are not always, shared by people in that region and focuses on the social networks through which the music is disseminated. The thesis also challenges the abandonment of regional styles and the concept of regions in understanding the complex geographies of Irish traditional music (Morton, 2001). It seeks to find a middle ground between discourse analysis, musical analysis, the experience of music and place, and the representation of music and place. The dissertation is divided into three parts. Part one considers the development of music geography, noting and critiquing the abandonment of useful paradigms in both geography and ethnomusicology in search of new ways of understanding. Of particular interest is the concept of the region but it also considers the study of landscape and the humanist approach in cultural geography. The second part focuses on the discourse and study of regions in Irish traditional music and the various agents and processes that shape the concept of the region in Irish traditional music. The final part presents a case study of the Sliabh Luachra region combining and applying the various perspectives and paradigms drawn from geographical, ethnomusicological and anthropological sources. It attempts to generate an understanding of Sliabh Luachra as a region in the Irish traditional music narrative that is based on a combination of musical, socio-cultural and locational/environmental factors.

Representations of Catholicism in selected works by Colm Tóibín

The aim of this thesis is to provide an original and extensive study of Colm Tóibín as the “secular revisionist who acknowledges Catholicism as an enduring element of Irish society” (Ryan, Ireland and Scotland 251). Tóibín is uniquely placed to interpret many aspects of Ireland in the latter half of the twentieth century and I will argue that intertwined with his revisionism of Irish history is a reimagining of Ireland and Catholicism in fictive terms. An extensive amount of material from Tóibín’s time as a journalist and travel writer will feature in my research because it validates my argument concerning his prolonged engagement with Catholicism. Similarly, a broad range of Tóibín’s prose will be studied because it affords opportunities for an exploration of a literary Catholic oeuvre in his fiction. Therefore, I am emphasizing that a crucial linkage of Catholicism is identifiable throughout Tóibín’s diverse canon of work. However, I will argue that divergences of attitude and mode can be found in how Tóibín depicts Catholicism in his journalism and fiction. My argument identifies Tóibín’s recurrent journalistic questioning of the Church’s teaching and leadership but I classify a benignity towards Catholicism in his travel writing and fiction. Overall, Tóibín’s fiction merits significant status in this thesis because of the representations of Catholicism in the work of a writer who has been short-listed three times for The Booker Prize.

Between respectability and disgrace: schismogenesis and the regeneration of inequality, stigma and social exclusion in Limerick

The thesis examines cultural processes underpinning the emergence, institutionalisation and reproduction of class boundaries in Limerick city. The research aims to bring a new understanding to the contemporary context of the city’s urban regeneration programme. Acknowledging and recognising other contemporary studies of division and exclusion, the thesis creates a distinctive approach which focuses on uncovering the cultural roots of inequality, educational disadvantage, stigma and social exclusion and the dynamics of their social reproduction. Using Bateson’s concept of schismogenesis (1953), the thesis looks to the persistent, but fragmented culture of community and develops a heuristic ‘symbolic order of the city’. This is defined as “…a cultural structure, the meaning making aspect of hierarchy, the categorical structures of world understanding, the way Limerick people understand themselves, their local and larger world” (p. 37). This provides a very different departure point for exploring the basis for urban regeneration in Limerick (and everywhere). The central argument is that if we want to understand the present (multiple) crises in Limerick we need to understand the historical, anthropological and recursive processes underpinning ‘generalised patterns of rivalry and conflict’. In addition to exploring the historical roots of status and stigma in Limerick, the thesis explores the mythopoesis of persistent, recurrent narratives and labels that mark the boundaries of the city’s identities. The thesis examines the cultural and social function of ‘slagging’ as a vernacular and highly particularised form of ironic, ritualised and, often, ‘cruel’ medium of communication (often exclusion). This is combined with an etymology of the vocabulary of Limerick slang and its mythological base. By tracing the origins of many normalised patterns of Limerick speech ‘sayings’, which have long since forgotten their roots, the thesis demonstrates how they perform a significant contemporary function in maintaining and reinforcing symbolic mechanisms of inclusion/exclusion. The thesis combines historical and archival data with biographical interviews, ethnographic data married to a deep historical hermeneutic analysis of this political community.

Composition portfolio and commentaries

In an attempt to provide an analytical entry point into my compositional practice, I have identified eight themes which are significantly recurrent: reduction – the selection of a small number of elements; imperfection – a damaged or warped characteristic of sound; hierarchy – a concern with the roles of instruments with regard to their relative prominence; motion – apparently static sound masses consist of fine internal movement; listener perception – expectations for change influence the experience of affect; translation – the transitioning of electronic sounds to the acoustic realm, and vice versa; immersion – the creation of an accommodating soundscape; blurring – smearing and overlapping sounds or genres. Each of these eight factors is associated with relevant precedents in the history and theory of music that have been influential on my work. These include the minimalist compositions of Steve Reich and Arvo Pärt; the lo-fi aesthetic of Boards of Canada and My Bloody Valentine; concerns with political hierarchy in the work of Louis Andriessen; the variations of dynamics and microtonal shifts of Giacinto Scelsi; Leonard B. Meyer's account of expectation in music; cross-fertilisation of the acoustic and electronic in pieces by Gérard Grisey and Gyorgy Ligeti; the immersive technique of Brian Eno's ambient music; and the overlapping sounds of Aphex Twin. These eight factors are variously applicable to the eleven submitted pieces, which are individually analysed with reference to the most significant of the categories. Together they form a musical language that sustains the interaction of a variety of techniques, concepts and genres.

The early years in Irish multigrade classes: trajectories of practice and identity

This study investigates how the experiences of Junior Infants are shaped in multigrade classes. Multigrade classes are composed of two or more grades within the same classroom with one teacher having responsibility for the instruction of all grades in this classroom within a time-tabled period (Little, 2001, Mason and Doepner, 1998). The overall aim of the research is to problematize the issues of early childhood pedagogy in multigrade classes in the context of children negotiating identities, positioning and power relations. A Case Study approach was employed to explore the perspectives of the teachers, children and their parents in eight multigrade schools. Concurrent with this, a nation-wide Questionnaire Survey was also conducted which gave a broader context to the case study findings. Findings from the research study suggest that institutional context is vitally important and finding the space to implement pedagogic practices is a highly complex matter for teachers. While a majority of teachers reported the benefits for younger children being in mixed-age settings alongside older children, only a minority of case study school teachers demonstrated how it is possible to promote classroom climates which were provided multiple opportunities for younger children to engage fully in classrooms. The findings reveal constraints on pedagogical practice which included: time pressures within the job, an increase in diversity in pupil population, meeting special needs, large class sizes, high pupil/teacher ratios, and planning/organisation of tasks which intensified the complexities of addressing the needs of children who differ significantly in age, cognitive, social and emotional levels. An emergent and recurrent theme of this study is the representation of Junior Infants as apprentices in their ‘communities of practice’ who contributed in peripheral ways to the practices of their groups (Lave and Wenger, 1991, Wenger, 1998). Through a continuous process of negotiation of meaning, these pupils learned the knowledge and skills within their communities of practice that empowered some to participate more fully than others. The children in their ‘figured worlds’ (Holland, Lachiotte, Skinner and Caine 1998) occupy identities which are influenced by established arrangements of resources and practices within that community as well as by their own agentive actions. Finally, the findings of the study also demonstrate how the dimension of power is central to the exercise of social relations and pedagogical practices in multigrade classes.

Outcomes of metallic stents for malignant ureteral obstruction.

PURPOSE: Malignant ureteral obstruction often necessitates chronic urinary diversion and is associated with high rates of failure with traditional ureteral stents. We evaluated the outcomes of a metallic stent placed for malignant ureteral obstruction and determined the impact of risk factors previously associated with increased failure rates of traditional stents. MATERIALS AND METHODS: Patients undergoing placement of the metallic Resonance® stent for malignant ureteral obstruction at an academic referral center were identified retrospectively. Stent failure was defined as unplanned stent exchange or nephrostomy tube placement for signs or symptoms of recurrent ureteral obstruction (recurrent hydroureteronephrosis or increasing creatinine). Predictors of time to stent failure were assessed using Cox regression. RESULTS: A total of 37 stents were placed in 25 patients with malignant ureteral obstruction. Of these stents 12 (35%) were identified to fail. Progressive hydroureteronephrosis and increasing creatinine were the most common signs of stent failure. Three failed stents had migrated distally and no stents required removal for recurrent infection. Patients with evidence of prostate cancer invading the bladder at stent placement were found to have a significantly increased risk of failure (HR 6.50, 95% CI 1.45-29.20, p = 0.015). Notably symptomatic subcapsular hematomas were identified in 3 patients after metallic stent placement. CONCLUSIONS: Failure rates with a metallic stent are similar to those historically observed with traditional polyurethane based stents in malignant ureteral obstruction. The invasion of prostate cancer in the bladder significantly increases the risk of failure. Patients should be counseled and observed for subcapsular hematoma formation with this device.

Plantar Loading During Cutting While Wearing a Rigid Carbon Fiber Insert.

Context : Stress fractures are one of the most common injuries in sports, accounting for approximately 10% of all overuse injuries. Treatment of fifth metatarsal stress fractures involves both surgical and nonsurgical interventions. Fifth metatarsal stress fractures are difficult to treat because of the risks of delayed union, nonunion, and recurrent injuries. Most of these injuries occur during agility tasks, such as those performed in soccer, basketball, and lacrosse. Objective : To examine the effect of a rigid carbon graphite footplate on plantar loading during 2 agility tasks. Design :  Crossover study. Setting : Laboratory. Patients or Other Participants : A total of 19 recreational male athletes with no history of lower extremity injury in the past 6 months and no previous metatarsal stress fractures were tested. Main Outcome Measure(s) :  Seven 45° side-cut and crossover-cut tasks were completed in a shoe with or without a full-length rigid carbon plate. Testing order between the shoe conditions and the 2 cutting tasks was randomized. Plantar-loading data were recorded using instrumented insoles. Peak pressure, maximum force, force-time integral, and contact area beneath the total foot, the medial and lateral midfoot, and the medial, middle, and lateral forefoot were analyzed. A series of paired t tests was used to examine differences between the footwear conditions (carbon graphite footplate, shod) for both cutting tasks independently (α = .05). Results : During the side-cut task, the footplate increased total foot and lateral midfoot peak pressures while decreasing contact area and lateral midfoot force-time integral. During the crossover-cut task, the footplate increased total foot and lateral midfoot peak pressure and lateral forefoot force-time integral while decreasing total and lateral forefoot contact area. Conclusions : Although a rigid carbon graphite footplate altered some aspects of the plantar- pressure profile during cutting in uninjured participants, it was ineffective in reducing plantar loading beneath the fifth metatarsal.

Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas

Gliomagenesis is driven by a complex network of genetic alterations and while the glioma genome has been a focus of investigation for many years; critical gaps in our knowledge of this disease remain. The identification of novel molecular biomarkers remains a focus of the greater cancer community as a method to improve the consistency and accuracy of pathological diagnosis. In addition, novel molecular biomarkers are drastically needed for the identification of targets that may ultimately result in novel therapeutics aimed at improving glioma treatment. Through the identification of new biomarkers, laboratories will focus future studies on the molecular mechanisms that underlie glioma development. Here, we report a series of genomic analyses identifying novel molecular biomarkers in multiple histopathological subtypes of glioma and refine the classification of malignant gliomas. We have completed a large scale analysis of the WHO grade II-III astrocytoma exome and report frequent mutations in the chromatin modifier, alpha thalassemia mental retardation x-linked (ATRX), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), and mutations in tumor protein 53 (TP53) as the most frequent genetic mutations in low grade astrocytomas. Furthermore, by analyzing the status of recurrently mutated genes in 363 brain tumors, we establish that highly recurrent gene mutational signatures are an effective tool in stratifying homogeneous patient populations into distinct groups with varying outcomes, thereby capable of predicting prognosis. Next, we have established mutations in the promoter of telomerase reverse transcriptase (TERT) as a frequent genetic event in gliomas and in tissues with low rates of self renewal. We identify TERT promoter mutations as the most frequently mutated gene in primary glioblastoma. Additionally, we show that TERT promoter mutations in combination with IDH1 and IDH2 mutations are able to delineate distinct clinical tumor cohorts and are capable of predicting median overall survival more effectively than standard histopathological diagnosis alone. Taken together, these data advance our understanding of the genetic alterations that underlie the transformation of glial cells into neoplasms and we provide novel genetic biomarkers and multi – gene mutational signatures that can be utilized to refine the classification of malignant gliomas and provide opportunity for improved diagnosis.

Integrative Genomics Reveals a Role for GNA13 in Lymphomagenesis

Lymphomas comprise a diverse group of malignancies derived from immune cells. High throughput sequencing has recently emerged as a powerful and versatile method for analysis of the cancer genome and transcriptome. As these data continue to emerge, the crucial work lies in sorting through the wealth of information to hone in on the critical aspects that will give us a better understanding of biology and new insight for how to treat disease. Finding the important signals within these large data sets is one of the major challenges of next generation sequencing.

In this dissertation, I have developed several complementary strategies to describe the genetic underpinnings of lymphomas. I begin with developing a better method for RNA sequencing that enables strand-specific total RNA sequencing and alternative splicing profiling in the same analysis. I then combine this RNA sequencing technique with whole exome sequencing to better understand the global landscape of aberrations in these diseases. Finally, I use traditional cell and molecular biology techniques to define the consequences of major genetic alterations in lymphoma.

Through this analysis, I find recurrent silencing mutations in the G alpha binding protein GNA13 and associated focal adhesion proteins. I aim to describe how loss-of-function mutations in GNA13 can be oncogenic in the context of germinal center B cell biology. Using in vitro techniques including liquid chromatography-mass spectrometry and knockdown and overexpression of genes in B cell lymphoma cell lines, I determine protein binding partners and downstream effectors of GNA13. I also develop a transgenic mouse model to study the role of GNA13 in the germinal center in vivo to determine effects of GNA13 deletion on germinal center structure and cell migration.

Thus, I have developed complementary approaches that span the spectrum from discovery to context-dependent gene models that afford a better understanding of the biological function of aberrant events and ultimately result in a better understanding of disease.

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.