Acute lymphocytic leukemia (ALL) is one of the most common types of pediatric cancers. Improvements in treatment within the last 20 years have resulted in reduced mortality and a greater focus upon quality of life. Several researchers have documented neuropsychological impairments in children following treatment for ALL; however, there have not been any comparative studies documenting differences in neuropsychological functioning based upon treatment modality despite the documented effects of radiation therapy and combined radiation/chemotherapy upon the developing brain. In addition, past studies have focused on unitary measures, ignoring the hierarchical relationship between basic cognitive functions and more abstract skills. This study examined the neuropsychological functioning of 81 children who were treated for ALL at a metropolitan children's hospital. All children were tested a minimum of two years after the final treatment session and were administered the NEPSY. Results do not support any interactions or main effects with the exception of the age of the child at diagnosis. Children diagnosed prior to the age of 5 showed greater impairments on tasks measuring attention, memory, and visuospatial reasoning in comparison to peers diagnosed after age 6.

Executive functions, like the capacity to control and organize thoughts and behavior, develop from childhood to young adulthood. Although task switching and working memory processes are known to undergo strong developmental changes from childhood to adulthood, it is currently unknown how task switching processes are modulated between childhood and adulthood given that working memory processes are central to task switching. The aim of the current study is therefore to examine this question using a combined cue- and memory-based task switching paradigm in children (N = 25) and young adults (N = 25) in combination with neurophysiological (EEG) methods. We obtained an unexpected paradoxical effect suggesting that memory-based task switching is better in late childhood than in young adulthood. No group differences were observed in cue-based task switching. The neurophysiological data suggest that this effect is not due to altered attentional selection (P1, N1) or processes related to the updating, organization, and implementation of the new task-set (P3). Instead, alterations were found in the resolution of task-set conflict and the selection of an appropriate response (N2) when a task has to be switched. Our observation contrasts findings showing that cognitive control mechanisms reach their optimal functioning in early adulthood.

Extensive serotonin (5-HT) fiber innervation throughout the brain corroborates 5-HT’s modulatory role in numerous behaviors including social behavior, emotion regulation, and learning and memory. Abnormal brain 5-HT levels and function are implicated in Autism Spectrum Disorder (ASD) which often co-occurs with other neuropsychiatric conditions. While 5-HT therapeutics are used to treat ASD, variable improvements in symptomatology require further investigation of 5-HT-mediated pathology. Neurexins (Nrxns) are presynaptic cell adhesion molecules that maintain synapse function for proper neural circuit assembly. Given that aberrant Nrxn and 5-HT function independently contribute to signaling pathology and behavioral impairments, it is critical to understand how Nrxn-mediated 5-HT neurotransmission participates in pathological mechanisms underlying ASD. Using fluorescence in situ hybridization, I found that the three Nrxn genes (Nrxn1, Nrxn2, and Nrxn3) are differentially expressed in 5-HT neurons in the dorsal raphe nucleus (DRN) and median raphe nucleus which contain the primary source of 5-HT neurons in the brain. Our lab generated a mouse model with selective deletion of Nrxns in 5-HT neurons to investigate the function of Nrxns in 5-HT signaling. The loss of Nrxns at 5-HT release sites reduced 5-HT release in the DRN and hippocampus and altered 5-HT innervation in specific brain regions. The lack of 5-HTergic Nrxns also reduced sociability and increased depressive-like behavior in males. This mouse model provides mechanisms to shed new light on 5-HT neurotransmission in the generation of complex behaviors.

This dissertation presents a series of neuroimaging investigations and achievements that strive to deepen and broaden our understanding of human problem solving and physics learning. Neuroscience conceives of dynamic relationships between behavior, experience, and brain structure and function, but how neural changes enable human learning across classroom instruction remains an open question. At the same time, physics is a challenging area of study in which introductory students regularly struggle to achieve success across university instruction. Research and initiatives in neuroeducation promise a new understanding into the interactions between biology and education, including the neural mechanisms of learning and development. These insights may be particularly useful in understanding how students learn, which is crucial for helping them succeed. Towards this end, we utilize methods in functional magnetic resonance imaging (fMRI), as informed by education theory, research, and practice, to investigate the neural mechanisms of problem solving and learning in students across semester-long University-level introductory physics learning environments. In the first study, we review and synthesize the neuroimaging problem solving literature and perform quantitative coordinate-based meta-analysis on 280 problem solving experiments to characterize the common and dissociable brain networks that underlie human problem solving across different representational contexts. Then, we describe the Understanding the Neural Mechanisms of Physics Learning project, which was designed to study functional brain changes associated with learning and problem solving in undergraduate physics students before and after a semester of introductory physics instruction. We present the development, facilitation, and data acquisition for this longitudinal data collection project. We then perform a sequence of fMRI analyses of these data and characterize the first-time observations of brain networks underlying physics problem solving in students after university physics instruction. We measure sustained and sequential brain activity and functional connectivity during physics problem solving, test brain-behavior relationships between accuracy, difficulty, strategy, and conceptualization of physics ideas, and describe differences in student physics-related brain function linked with dissociations in conceptual approach. The implications of these results to inform effective instructional practices are discussed. Then, we consider how classroom learning impacts the development of student brain function by examining changes in physics problem solving-related brain activity in students before and after they completed a semester-long Modeling Instruction physics course. Our results provide the first neurobiological evidence that physics learning environments drive
the functional reorganization of large-scale brain networks in physics students. Through this collection of work, we demonstrate how neuroscience studies of learning can be grounded in educational theory and pedagogy, and provide deep insights into the neural mechanisms by which students learn physics.

Indiana University-Purdue University Indianapolis (IUPUI) / The time course and biological mechanisms by which breast cancer (BC) and/or alterations in estrogen status lead to cognitive and brain changes remain unclear. The studies presented here use neuroimaging, cognitive testing, genetics, and biomarkers to investigate how post-chemotherapy interval (PCI), chemotherapy-induced amenorrhea (CIA), and genetic variation in the estrogen pathway affect the brain. Chapter 1 examines the association of post-chemotherapy interval (PCI) with gray matter density (GMD) and working memory-related brain activation in BC survivors (mean PCI 6.4, range 3-10 years). PCI was positively associated with GMD and activation in the right frontal lobe, and GMD in this region was correlated with global neuropsychological function. In regions where BC survivors showed decreased GMD compared to controls, this was inversely related to oxidative DNA damage and learning and memory scores. This is the first study to show neural effects of PCI and relate DNA damage to brain alterations in BC survivors. Chapter 2 demonstrates prospectively, in an independent cohort, decreased combined magnitudes of brain activation and deactivation from pre-to post-chemotherapy in patients undergoing CIA compared to both postmenopausal BC patients undergoing chemotherapy and healthy controls. CIA’s change in activity magnitude was strongly correlated with change in processing speed, suggesting this activity increase reflects effective cognitive compensation. These results demonstrate that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Chapter 3 presents the effects of variation in ESR1, the gene that codes for estrogen receptor-α, on brain structure in healthy older adults. ESR1 variation was associated with hippocampus and amygdala volumes, particularly in females. Single nucleotide polymorphism (SNP) rs9340799 influenced cortical GMD and thickness differentially by gender. Apolipoprotein E (APOE)-ε4 carrier status modulated the effect of SNP rs2234693 on amygdala volumes in women. This study showed that genetic variation in estrogen relates to brain morphology in ways that differ by sex, brain region and APOE-ε4 carrier status. The three studies presented here explore the interplay of BC, estrogen, and cognition, showing that PCI, CIA, and ESR1 genotype influence brain phenotypes. Cognitive correlates of neuroimaging findings indicate potential clinical significance of these results.

Indiana University-Purdue University Indianapolis (IUPUI) / Abuse of alcohol during adolescence continues to be a problem, and it has been shown that earlier onset of drinking predicts increased alcohol abuse problems later in life. High levels of impulsivity have been demonstrated to be characteristic of alcoholics, and impulsivity has also been shown to predict later alcohol use in teenage subjects, showing that impulsivity may be an inherent underlying biological process that precedes the development of alcohol use disorders. These experiments examined adolescent drinking in a high-drinking, relatively impulsive mouse population, and assessed its effects on adult drinking and adult impulsivity. Experiment 1: Selectively bred High-Alcohol Preferring (HAP II) mice, which are shown to be highly impulsive, were given either alcohol (free choice access) or water only for two weeks during middle adolescence or adulthood. All mice were given free choice access to alcohol following 30 days without access, in adulthood. Experiment 2: Adolescent HAP II mice drank alcohol and water, or water alone, for two weeks, and were then trained to perform a delay discounting task as adults to measure impulsivity. In each experiment, effects of volitional ethanol consumption on later behavior were assessed. We expected adolescent alcohol exposure to increase subsequent drinking and impulsivity. Adolescent mice consumed significant quantities of ethanol, reaching average blood ethanol concentrations (BECs) of 142 mg/dl in Experiment 1 and 108 mg/dl in Experiment 2. Adult mice reached average BECs of 154 mg/dl in Experiment 2. Mice pre-exposed to alcohol in either adolescence or adulthood showed a transient increase in ethanol consumption, but we observed no differences in impulsivity in adult mice as a function of whether mice drank alcohol during adolescence. These findings indicate that HAP II mice drink intoxicating levels of alcohol during both adolescence and adulthood, and that this volitional intake has long-term effects on subsequent drinking behavior. Nonetheless, this profound exposure to alcohol during adolescence does not increase impulsivity in adulthood, indicating that long-term changes in drinking are mediated by mechanisms other than impulsivity. Importantly, this research demonstrates that the HAP II mouse is a good candidate for a model of heavy adolescent alcohol consumption.

<p>Tactile speech communication allows individuals to understand speech by sensations transmitted through the sense of touch. Devices that enable tactile speech communication can be an effective means to transmit important messages when the visual and/or auditory systems are overloaded or impaired. This has applications in silent communication and for people with hearing and/or visual impairments. An effective artificial speech communication system must be learned in a reasonable time and be easily remembered. Moreover, it must transmit any word at suitable rates for speech communication. The pursuit of a system that fulfills these requirements is a complex task that requires work in different areas. This thesis presents advancements in four of them. First is the matter of encoding speech information. Here, a phonemic-based approach allowed participants to recognize of tactile phonemes, words, phrases and full sentences. Second is the issue of training users in the use of the system. To this end, this thesis investigated the phenomenon of incidental categorization of vibrotactile stimuli as the foundation of more natural methods to learn a tactile speech communication system. Third is the matter of the neural processing of the tactile speech information. Here, an exploration of the functional characteristics of the phonemic-based approach using EEG was conducted. Finally, there is the matter of implementing the system for consumer use. In this area, this work addresses practical considerations of delivering rich haptic effects with current wearable technologies. These are informative for the design of actuators used in tactile speech communication devices.</p>

<p>Product evaluation throughout the design process is a fundamental task to ensure product success. Virtual prototyping is displacing physical prototyping for product evaluation due to its lower cost and flexibility to easily generate design alternatives (colors, textures, shapes). The thesis provides a deeper understanding of the influence of the presentation medium on product evaluation. The semantic differential technique was applied in to obtain the consumers’ subjective impression when they observed furniture scenes under two different presentation mediums. High-quality realistic renderings were displayed on a computer screen equipped with an eye-tracker. The same scenes were observed by the same users (repeated measures experimental design) with a virtual reality headset equipped with an integrated eye-tracker (HP Reverb G2 Omnicept). Equivalent areas/volumes of interest were defined to calculate the eye- tracking metric dwell time. Statistical analyses then compared dwell times and values of semantic scales in the 2D and VR conditions to determine if the medium of presentation influenced them.</p> <p><br></p> <p>The experimental data obtained in the thesis confirmed that both the consumer’s subjective impression measured through bipolar pairs and the level of confidence in its assessment was influenced by the visual medium. However, the level of confidence in the assessment of a semantic scale of a product presented on VR was not affected by the sense of presence.</p> <p><br></p> <p>The amount of time (dwell time) that subjects spend looking at a specific product on a joint or individual visualization were influenced by the visual medium.</p>

This study provides a precise definition of the term 'Kafkaesque' by enriching literary criticism with scientific theory and practice, including an experiment on readers' responses to Kafka. Dictionary definitions justify taking the term back to its textual origins in Kafka's works, and the works can fruitfully be analysed by investigating how readers engage with them through cognitive processes of imagination. Modern scientific developments posit that vision, imagination, and consciousness should be conceived of not in terms of static pictorialism – reducible to the notion of 'pictures in the head' – but in terms of enaction, i.e. as an ongoing interaction with the external world around us. Most traditional nineteenth-century Realist texts are based on pictorialist assumptions, while Kafka's texts evoke perception non-pictorially and are therefore more cognitively realistic. In his personal writings, Kafka wrestles with problems entailed by pictorialist conceptions of vision, imagination, and the function of language, and comes to enactivist solutions: evocation of perception that does not result in painting static tableaux with words. In his fictional works, Kafka correspondingly evolves a cognitively realistic way of writing to evoke fictional worlds that directly engage the cognitive processes of their readers; Der Proceß is a prime example of the 'Kafkaesque' text and reading experience, defined by being compelling yet simultaneously unsettling. Modulations in narrative perspective and evocation of emotion as enactive also contribute to the experience of the 'Kafkaesque' as compelling; yet Kafka's texts simultaneously unsettle by preventing straightforward emotional identification with the protagonists, and destabilising deep-rooted concepts of selfhood as singular and unified. The theoretical discussion of the 'Kafkaesque' experience as compelling yet unsettling is complemented and refined by an experiment testing readers' responses to a short story by Kafka. The term 'Kafkaesque realism' denotes Kafka's compelling yet unsettling non-pictorial evocation of perception of the fictional world. Kafkaesque realism falls into the broader category of 'cognitive realism', which provides a framework for analysing fictional texts more generally.

A statistical meta-analysis combines the results of several studies that address a set of related research hypotheses, thus increasing the power and reliability of the inference. Meta-analytic methods are over 50 years old and play an important role in science; pooling evidence from many trials to provide answers that any one trial would have insufficient samples to address. On the other hand, the number of neuroimaging studies is growing dramatically, with many of these publications containing conflicting results, or being based on only a small number of subjects. Hence there has been increasing interest in using meta-analysis methods to find consistent results for a specific functional task, or for predicting the results of a study that has not been performed directly. Current state of neuroimaging meta-analysis is limited to coordinate-based meta-analysis (CBMA), i.e., using only the coordinates of activation peaks that are reported by a group of studies, in order to "localize" the brain regions that respond to a certain type of stimulus. This class of meta-analysis suffers from a series of problems and hence cannot result in as accurate results as desired. In this research, we describe the problems that existing CBMA methods are suffering from and introduce a hierarchical mixed-effects image-based metaanalysis (IBMA) solution that incorporates the sufficient statistics (i.e., voxel-wise effect size and its associated uncertainty) from each study. In order to improve the statistical-inference stage of our proposed IBMA method, we introduce a nonparametric technique that is capable of adjusting such an inference for spatial nonstationarity. Given that in common practice, neuroimaging studies rarely provide the full image data, in an attempt to improve the existing CBMA techniques we introduce a fully automatic model-based approach that employs Gaussian-process regression (GPR) for estimating the meta-analytic statistic image from its corresponding sparse and noisy observations (i.e., the collected foci). To conclude, we introduce a new way to approach neuroimaging meta-analysis that enables the analysis to result in information such as “functional connectivity” and networks of the brain regions’ interactions, rather than just localizing the functions.