Early neural signatures of cancer‐related fatigue: A longitudinal magnetic resonance imaging study of cortical micro‐ and macrostructural changes during breast cancer chemotherapy

BACKGROUND: Cancer-related fatigue is a prevalent and debilitating symptom in patients with breast cancer (BC) undergoing chemotherapy (CTx), yet its early neural correlates remain incompletely understood. METHODS: This longitudinal study included 61 female patients with BC and 41 healthy female controls assessed before CTx and after two cycles of CTx, or at matched intervals. Assessments included 3T brain magnetic resonance imaging, patient-reported fatigue and quality-of-life measures, clinician-rated affective symptom scales, and an objective cognitive screening measure. Surface-based analyses were used to extract cortical microstructural measures, including cortical mean diffusivity (cMD), and macrostructural measures. Linear mixed-effects models were used to examine longitudinal changes and group-by-time interaction effects in clinical, patient-reported, cognitive, and cortical structural outcomes, as well as their associations during early CTx. RESULTS: During early CTx, patients with BC showed worsening fatigue and worsened emotional well-being, and changes in these outcomes were positively associated. cMD decreased over time in the left isthmus cingulate cortex, and the magnitude of this decrease was associated with worsening fatigue and worsened emotional well-being. Mediation analysis suggested an indirect association between cMD changes in this region and fatigue through worsened emotional well-being. CONCLUSION: These findings suggest that early increases in fatigue during CTx are linked to worsening emotional well-being and region-specific cortical microstructural changes. The results highlight a potentially informative neural-affective pathway in the early emergence of fatigue, while requiring replication and further validation before clinical translation.