Current treatment options for malignant brain tumors not only frequently fail to cure the disease due to local recurrence, but also may severely compromise quality of remaining life even when tumor mass is reduced in large part because they interfere with mechanisms of neuroplasticity and function of bystander tissue. The aims of this dissertation are to: (a) assess neurological impairments associated with rapid focal cortical tissue displacement; (b) evaluate the specific impact of conventional and novel treatments on neurorestoration while controlling tissue compression without the confound of related events linked to tumor physiology; (c) identify the behavioral change pattern during brain tumor progression and investigate the stealth nature of brain tumors; (d) demonstrate how anti-cancer treatments affect brain function especially when administered in the silent stages of brain tumors; and (e) develop treatment strategies that might improve therapeutic effectiveness and brain function. We adopted a new focal mass compression model providing rapid displacement of tissue in the underlying sensorimotor cortex, as well as the traditional rat and mouse glioma xenograft models that exhibit prominent tumor growth and invasion, given the varied aims and contexts of our different studies. Various conventional and novel brain tumor treatments were employed in this dissertation, including local and systemic chemotherapy, antiangiogenic agents, photodynamic therapy, and a glutamate antagonist. A neurorestorative therapy with atorvastatin was evaluated in its effects on functional recovery after photodynamic therapy. Functional outcomes were measured with an array of behavioral tests, which are sensitive to mild focal insults to the sensorimotor cortex and can detect recovery of function. Histopathological assessments consisted of Nissl staining, hematoxylin-andeosin (H&E) staining, and immunohistochemistry, depending on varied purposes, used in conjunction with a computer imaging analysis system. In clinical trials, functional outcome is as critical to gauging the success of a treatment as is patient survival time. Both preclinical screening of anti-cancer interventions for the ability to shrink tumors effectively with minimal disturbance of neuroplasticity and developing combination therapy with neurorestorative regimens following neurotoxic cancer treatments should allow for optimal promotion of plastic mechanisms in the remaining normal brain tissue.

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Glioblastoma (GBM) is the most common and aggressive primary brain tumor and is comprised of transcriptionally heterogeneous cells and a complex microenvironment. Despite decades of research effort, few treatments significantly benefit clinical outcomes. This may be, in part, due to the lack of tools to directly measure functional responses of these heterogeneous cell types under therapy. This thesis aims to advance the understanding of cell type-specific therapeutic response by the development and application of integrated single cell imaging and RNA sequencing technology. Chapter 1 provides an overview of GBM and its heterogeneity, how investigation of cell type-specific phenotypes would benefit the development of GBM treatments, and current sequencing and imaging technologies to examine cell phenotypes with single-cell resolution. Chapter 2 presents a new microfluidic technology for joint single cell imaging and RNA sequencing that can link imaging-based phenotypes and transcriptional identity of the same individual cells with high throughput, molecular capture efficiency, linking accuracy, and user-friendliness. Chapters 3 and 4 present applications of this technology in investigating cell type-specificities of GBM treatments. Chapter 3 focuses on the specificities of 5-aminolevulinic acid (5-ALA), an FDA approved fluorogenic agent, used in fluorescence guided surgery and reveals 5-ALA labeling is not specific to transformed glioma cells, which encourages further studies to systematically compare its performance with potential alternatives. Chapter 4 focuses on the specificities of drug responses by presenting a functional drug screening approach that directly links cell states measured by apoptosis indicators with transcriptional states, which greatly enhances the interpretability of single cell-resolved drug perturbation assays.

Nearly 80% of children treated for cancer are expected to survive, but not without cost. Survivors face unprecedented challenges associated with long-term consequences of treatment, also called late effects. Approximately half of children treated for cancer are at risk for experiencing cognitive late effects, which typically emerge several years post diagnosis. The nature and extent of cognitive late effects appear to be developmental and related to patient, disease, and treatment variables. However, the relationships between these variables is not well understood because there have been few prospective and longitudinal studies that report on the contributions of these variables over time. This dissertation examined the effects of patient, disease, and treatment variables, as well as their interactions over time on neurocognitive functioning in childhood cancer survivors. It comprises part of a large prospective, randomized clinical trial designed to examine changes in cognitive function over three years as a function of different levels of monitoring of school-based intervention based on individual educational plans (IEPs). This dissertation uniquely contributed a new measure (the Treatment Intensity Rating Scale) that was used to systematically classify treatment severity across different types of cancer and cancer treatments. Participants included 61 children ages 7 to 12 years at enrollment who were two to five years from completion of treatment for a brain tumor, leukemia, or lymphoma. Participants received yearly neuropsychological evaluations for a follow-up period of 3 years. Results of these evaluations were used to develop IEPs. Participants were randomized to have their IEPs monitored on a quarterly or annual basis for the duration of the study. Contrary to the progressive decline in neurocognitive functioning that is typically anticipated in pediatric cancer survivors, analyses revealed relative stability of performance on neurocognitive measures over time. Higher neurocognitive performance was noted in children whose IEPs were monitored more frequently versus less frequently. Results also supported gender-specific risk for late effects, with lower performance on select neurocognitive measures in females compared to males. Results of this study provide encouraging evidence of the positive effects of school-based interventions and their close monitoring. This has important implications for quality of life as these children survive well beyond childhood into adulthood.

This study examined the relationship between executive and psychosocial functioning in 45 children and adolescents age 6 to 17 years who had been treated for a brain tumor. Executive functioning deficits can profoundly impact an adult's ability to function successfully in life. The purpose of the study was to evaluate the potential impact of executive functioning deficits on the day-to-day functioning in a pediatric population. The domains of executive functioning assessed included cognitive flexibility, conceptual thinking, sustained attention, and response inhibition. Psychosocial functioning was assessed using both parent and child report. Several significant relationships were found for adolescents ages 15 and older, with effect sizes ranging from medium to large. In particular, cognitive flexibility and conceptual thinking were significantly related to parent report of depression and adaptive functioning. Fewer significant relationships with smaller effect sizes were found for younger children. The results may reflect the developmental emergence of executive functioning abilities and late effects of executive functioning deficits upon psychosocial functioning. The correlational design of this study precludes definitive statements regarding the temporal nature of the relationship. Additional research, including longitudinal research and replicatory studies, will be needed to further investigate the developmental consequences of executive functioning impairment.