Hippocampal and Cognitive Function, Exercise, and Ovarian Cancer: A Pilot Study

Many patients receiving chemotherapy for cancer report difficulties with concentration, memory, multi-tasking, and planning ability, a phenomenon popularly referred to as 'chemobrain.' Originally identified in breast cancer patients, research now suggests that the same constellation of symptoms also affects survivors of other cancers, including ovarian cancer, with chemotherapy-associated cognitive changes affecting 17% to 75% of patients. While patients have complained about this for many years, oncologists have been slow to recognize the reality of 'chemobrain' for a variety of reasons. Patients receive many different kinds of treatments, e.g., surgery, radiation, chemotherapy, in varying combinations, each of which may affect cognitive function differently. In addition, the wide variety of chemotherapeutic agents used to treat cancers may affect different brain pathways, leading to diverse types of cognitive symptoms. The result is such a wide variety of complaints by patients about the impact of treatment on their cognitive functioning that clinicians and researchers initially concluded that there was no sound basis for claims of cognitive disruption following chemotherapy.

In this application, we propose to address this problem by focusing primarily on a single post-chemotherapy complaint in a single cancer: problems with memory in patients with ovarian cancer. We focus on this problem for three reasons: (1) according to the Ovarian Cancer National Alliance, memory problems are among the most frequently cited by patients; (2) by narrowly targeting our inquiry, we will avoid the 'noise' in the data associated with different treatment regimens and correspondingly different cognitive complaints; and, (3) there are decades of neuroscience research, some of it from our group, indicating that memory impairment, such as the kind reported in the context of chemotherapy, is mediated primarily by a region of the brain called the hippocampus. In this application, we propose to investigate the possibility that standard chemotherapy regimen used to treat ovarian cancer leads to memory impairment because it arrests the normal processes of neurogenesis, the growth of new nerve cells, in this brain region. In addition, because a growing body of research studies shows that physical exercise leads to improvement in memory and learning and that exercise targets the same brain regions responsible for chemotherapy-induced memory problems, we propose to conduct a pilot study of an intervention to increase patients' physical activity to test whether this will slow this effect of chemotherapy on nerve cell growth in the hippocampus and subsequently offset memory decline.

The proposed pilot study will lead to important information for ovarian cancer patients specifically and, potentially, for all cancer patients receiving chemotherapy. If in this small pilot study, we are able to collect data suggesting that the standard chemotherapy regimen for ovarian cancer leads to cognitive impairment, that this impairment is associated with a deficit in neurogenesis in the hippocampus, and that increased physical activity attenuates this effect, then we can propose to conduct a larger, more definitive study that would lead to the development of interventions that specifically target hippocampal neurogenesis and block these chemotherapy-related deficits. Pilot data demonstrating that chemotherapy for ovarian cancer leads to problems with memory and learning based on deficits in hippocampal neurogenesis will encourage similar studies in other cancers that use different chemotherapeutic agents. Pilot data suggesting an effect of exercise will lead to the search for other interventions that have the same, or better, effects. Even more broadly, learning how chemotherapy interferes with hippocampal neurogenesis may inform the development of treatments for other conditions that affect human memory, including the ordinary decline in memory we all experience with increasing age.