title: Altered resting brain connectivity in persistent cancer related fatigue.
abstract: There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = -0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As the DMN is a network involved in self-referential thinking we speculate that enhanced connectivity between the DMN and the frontal gyrus may be related to mental fatigue and poor sleep quality. In contrast, enhanced connectivity between the DMN and regions in the subgenual cingulate and brainstem may serve a protective function in the non-fatigued group.
authors.affiliation: Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48106, USA.
authors.forename: Johnson P
authors.initials: JP
authors.lastname: Hampson
authors.affiliation: Department of Family Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Suzanna M
authors.initials: SM
authors.lastname: Zick
authors.affiliation: Department of Family Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Tohfa
authors.initials: T
authors.lastname: Khabir
authors.affiliation: Department of Family Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Wright
authors.affiliation: Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48106, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Harris
mesh_terms: D001943:Breast Neoplasms / Q000150:complications*; D063132:Connectome; D005221:Fatigue / Q000209:etiology / Q000503:physiopathology*; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D005222:Mental Fatigue / Q000209:etiology / Q000503:physiopathology; D008875:Middle Aged; D017741:Survivors
keywords: BA, Brodmann area; BCS, breast cancer survivors; BFI, brief fatigue inventory; BOLD, blood-oxygen level dependence; Breast cancer survivors; CFS, chronic fatigue syndrome; DMN, default mode network; Default mode network (DMN); FDR, false discovery rate; FWHM, Full width at half maximum; Functional connectivity magnetic resonance imaging (fcMRI); HADS, hospital anxiety and depression scale; ICA, independent component analysis; IPL, inferior parietal lobule; Independent component analysis (ICA); MFI, multidimensional fatigue Inventory; MNI, Montreal Neurological Institute; PC, posterior cingulate; PCRF, persistent cancer related fatigue; PSQI, Pittsburgh sleep quality index; Persistent cancer related fatigue (PCRF); SFG, superior frontal gyrus; SPM, statistical parametric mapping; STR, spatio-temporal regression; fcMRI, functional connectivity magnetic resonance imaging