Neural Mechanisms Underlying Breast Cancer Related Fatigue: A Systematic Review of Neuroimaging Studies

Introduction: Fatigue and cognitive dysfunction commonly co-occur in breast cancer patients and survivors. However, the underlying neural mechanism is not clear. We performed a systematic review of studies that used neuroimaging methods to investigate structural and functional changes in the brain associated with fatigue in breast cancer patients and survivors. Methods: We searched PubMed, Scopus, EmBase, and Cochrane CENTRAL from January 2009 to May 2021 for studies that reported brain neuroimaging findings in relationship to fatigue in breast cancer patients or survivors. Neuroimaging methods included magnetic resonance imaging (MRI), positron emission tomography (PET), and electroencephalogram (EEG). We summarized structural and functional neuroimaging changes associated with fatigue. Results: Of the 176 articles retrieved, ten MRI studies reported neuroimaging findings in relationship to fatigue. Together these studies compared 385 breast cancer patients or survivors to 205 controls. Fatigue was associated with reduced white matter integrity and increased glutamate in the insula but changes in gray matter volume were not associated with fatigue score. Nine of the ten studies found significant associations between fatigue and functional changes in the frontoparietal cortex. In response to memory and planning tasks, fatigue was associated with increased activations in several regions of the frontoparietal cortex, however, overall performance on tasks was not reduced. Fatigue was also associated with extensive changes in the connectivity of brain networks that filter endogenous signals (salience network), internal attention (default mode network), and external attention (dorsal attention network). Subcortical regions associated with fatigue included insula (interoception), superior colliculus (sleep regulation), and thalamus (alertness). Functional brain changes before initiation of chemotherapy were a better predictor of post-treatment fatigue than chemotherapy itself. Conclusions: Fatigue in breast cancer is associated with widespread functional changes of brain regions and networks that affect executive function including memory, planning, internal and external attention. Observed changes likely represent a compensatory mechanism through which breast cancer patients and survivors try to maintain adequate executive function. Breast cancer patients scheduled to undergo chemotherapy are at high risk for developing fatigue even before the start of treatment.