Brainstem processing of peripheral punctate stimuli in patients with and without chemotherapy-induced peripheral neuropathy: a prospective cohort functional MRI study

Abstract

Background Chemotherapy-induced peripheral neuropathy aff ects 30% of cancer survivors. Findings from animal studies suggest that brainstem descending inhibitory pathways are important in chronic neuropathic pain. An aberrant descending pain modulation system has been implicated in human neuropathic pain. Whether aberrant descending pain modulation before chemotherapy is associated with development of chemotherapy-induced peripheral neuropathy is unclear. We aimed to assess descending pain modulation systems using functional MRI (fMRI) in chemotherapy-naive patients with cancer to determine whether diff erences are associated with subsequent development of the neuropathy. MethodsIn this multicentre prospective cohort study, adult patients with cancer and no chronic pain, neuropathy, or risk factors for neuropathy were recruited from the oncology clinic before onset of chemotherapy. After patients had given written informed consent, descending inhibitory pathways were challenged (jittered punctate stimuli 256 mN Somedic von Frey fi lament) during a 3T fMRI scan, and images analysed with FSL software. Sample size was based on published fMRI estimates. Chemotherapy-induced peripheral neuropathy was diagnosed with the CIPN20 questionnaire.Findings 30 patients were recruited (mean age 60•4 years [SD 7•9]). We report a preliminary analysis of the fi rst 12 patients (60•6 [8•3], six women); six had colorectal cancer, four gynaecological cancer, and two lung cancer. Seven patients (three men, four women) developed chemotherapy-induced peripheral neuropathy. After data brain extraction, registration, B0 unwarping, and motion correction, FEAT was used for fi rst and second level analysis. Mean group level comparisons between patients with and without the neuropathy were conducted with mixed-eff ects analysis (z threshold 2•3, regions considered signifi cant at p<0•05, cluster uncorrected for preliminary analysis) and adjusted for sex, age, and cancer type. Patients with chemotherapy-induced peripheral neuropathy had increased activation in the nucleus cuneiformis and primary somatosensory cortex compared with patients who did not develop the disorder.Interpretation These preliminary results suggest that baseline diff erences exist, before peripheral nerve injury, in the descending pain modulation system of patients who go on to develop chemotherapy-induced peripheral neuropathy. These diff erences might aid development of biomarkers to guide chemotherapy choices. Limitations of the study include the small sample size for the present analysis, the observational nature of the study, and the possibility of unknown confounders. Strengths include the prospective design in a unique patient cohort and the high sensitivity of fMRI.

Neuroimaging reveals a potential brain-based pre-existing mechanism that confers vulnerability to development of chronic painful chemotherapy-induced peripheral neuropathy

“…Consistent with these functional observations, our structural analysis of the NAc, Amygdala, Thalamus and Brainstem similarly found no differences between CIPN+ and CIPN-patients, in contrast to the findings of our preliminary analysis investigating aCIPN, which showed the NAc was significantly smaller in the aCIPN+ group 65 . Further research with more time points for neuroimaging data acquisition is required to better understand the transition from acute to chronic CIPN 66 .…”

Chemotherapy-induced peripheral neuropathy: where are we now?

“…Predictors emerging during early chemotherapy have also been identified, with thermal hyperalgesia predicting development of severe oxaliplatin CIPN [5]. Our preliminary work, using functional neuroimaging, has also found structural and functional changes in the brain in pain processing areas, detected prior to starting chemotherapy, potentially indicating a pre-existing vulnerability to developing CIPN [89]. Treatment strategies-There is a lack of good quality clinical trials focusing on treatment of established painful CIPN, with a pragmatic approach extrapolating from evidence and guidelines for treatment of other types of neuropathic pain.…”