PROJECT SUMMARY/ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting toxicity that affects over 65% of patients receiving taxane- or platinum-based chemotherapy for breast or gastrointestinal cancers. Not only does CIPN increase mortality by limiting the dose of chemotherapy, CIPN affects walking, writing, eating, and dressing via numbness, tingling, pain, cold sensitivity, and cramping in the hands and feet. There are no FDA-approved treatments for CIPN because we need a greater understanding of the pathophysiology of CIPN in humans. This project is motivated by an innovative perspective that CIPN symptoms are not due simply to peripheral nerve damage, but rather that CIPN symptoms are worsened by changes in the brain, including interoception—the brain’s processing of sensations from the body. This is an observational longitudinal cohort study in 120 patients with breast or gastrointestinal cancer scheduled to receive taxane or platinum chemotherapy along with 60 age-matched healthy controls. The patients will be assessed within 2 weeks before starting chemotherapy, less than one month after completing chemotherapy, and six months after completing chemotherapy. Controls will be assessed at matched time intervals. Each assessment will include (1) measures of neural substrates of interoception (a brain MRI scanning session), (2) patient-reported and clinical features of interoception and peripheral nerve function, and (3) patient-reported CIPN severity. Our aims are to assess changes in interoception along the cancer chemotherapy continuum compared to healthy controls, and to assess the relationships between interoception and CIPN in patients. This is the first study assessing interoception before and after chemotherapy compared to healthy controls, let alone how interoception contributes to CIPN: a common, severe, dose-limiting toxicity with enigmatic mechanisms. By including taxane- and platinum-induced CIPN we can address two common neurotoxic agents that exhibit distinct signs, symptoms, and mechanisms of toxicities, and may respond differently to a given treatment. Our results will inform our novel theoretical framework that CIPN is related to interoception, thereby informing a follow-up clinical trial using interoception-based biomarkers, prophylactics, or treatments for CIPN for example using exercise, meditation, or pharmacological agents. This work will ultimately help alleviate the burden of chemotherapy on patients with cancer.