The Effects of Adjuvant Chemotherapy on Brain Function in Breast Cancer Patients and a Cancer-Chemotherapy Rodent Model

Treatment with cytotoxic chemotherapy can cause serious side effects in breast cancer patients, which can decrease quality of life. As more patients are surviving breast cancer, issues that affect the quality of life of patients are coming more to the forefront. One such is issue is chemotherapy-induced cognitive impairment (CICI) colloquially known as "chemobrain" or "chemofog". In 1999, the National Coalition for Cancer Survivorship has recognized CICI as a significant problem with a reported incidence ranging between 12-76%. Patients complain of cognitive deficits including but not limited to decreases in memory, attention, processing speed, executive function, fatigue, confusion and the inability to multi-task. These symptoms represent a change in cognitive function, not simply a side effect involving lower order processes.;This dissertation seeks to determine the functional alterations in brain networks involved in attention/distraction, memory and the default mode network that underlie CICI using functional magnetic resonance imaging (fMRI). Patients were able to perform as well as controls on a visual N-Back working memory task. However, regional activation differences presented themselves during the task. Patients had a smaller magnitude of deactivation than controls with areas of the default mode network, even prior to chemotherapy. Without deactivating the areas involved in internal processes the patients were less able to shift attention to the task. CICI, like other cognitive impairments, changes the way the brain shifts to attend to external stimuli. This study also found increased connectivity between the amygdala and the anterior cingulate, prior to treatment. Which is consistent with studies on acute stress and post-traumatic stress. Although CICI is defined as occurring after chemotherapy treatment, this study finds that aspects of neuroactivity change prior to receiving chemotherapy. These changes are hypothesized to be due to heightened feelings of stress and emotion.;Next, a rat cancer-chemotherapy model was used to determine what role the combination of chemotherapy and tumor in modulating behavior, network and brain activation changes. Animals were treated with a carcinogen 7,12-Dimethylbenz[a]anthracene (DMBA) and administered six doses of doxorubicin (DOX), an anthracycline chemotherapy. Treatment with DOX impaired visual-spatial object memory and psychomotor learning. These impairments have been shown in injury to hippocampal-cortical pathways. The impairments in object recognition were attenuated at the 4-week mark. Functional MRI studies in the rat model revealed a main effect of DOX on the response to electrical stimulation. DOX treatment significantly decreased the BOLD response to the forepaw stimulus within the somatosensory cortex. Treatment with DOX decreased the resting-state functional connectivity between the somatosensory cortex and the sensory-motor system compared to controls. Within the visual system, there was a significant effect of DOX on a midrange bilateral visual stimulus and a significant interaction between DOX treatment and treatment with DMBA within the superior colliculus. The deficits found in this dissertation to visual-spatial memory and psychomotor learning have been also been found in clinical studies of chemotherapy-induced cognitive impairment. Visual toxicity due to adjuvant chemotherapy has also been documented in clinical studies. Within brain tissue harvested from the rats, DOX treatment was found to lower reduced glutathione in animals 1-week after their last DOX treatment. Glutathione levels returned to control values in animals 4-weeks after the last DOX treatment. DOX is known to increase reactive oxygen species within the periphery. The changes within the brain suggest a signaling mechanism that is able to cross the blood brain barrier and deplete the antioxidant, reduced glutathione. The use of fMRI on the cancer-chemotherapy model strengthens the underlying information that chemotherapy causes various types of cognitive and hemodynamic changes within cortical and subcortical structures.