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.

Functional Organization of Frontoparietal Cortex in the Marmoset Investigated with Awake Resting-State fMRI

Frontoparietal networks contribute to complex cognitive functions in humans and macaques, such as working memory, attention, task-switching, response suppression, grasping, reaching, and eye movement control. However, there has been no comprehensive examination of the functional organization of frontoparietal networks using functional magnetic resonance imaging in the New World common marmoset monkey (Callithrix jacchus), which is now widely recognized as a powerful nonhuman primate experimental animal. In this study, we employed hierarchical clustering of interareal blood oxygen level–dependent signals to investigate the hypothesis that the organization of the frontoparietal cortex in the marmoset follows the organizational principles of the macaque frontoparietal system. We found that the posterior part of the lateral frontal cortex (premotor regions) was functionally connected to the anterior parietal areas, while more anterior frontal regions (frontal eye field [FEF]) were connected to more posterior parietal areas (the region around the lateral intraparietal area [LIP]). These overarching patterns of interareal organization are consistent with a recent macaque study. These findings demonstrate parallel frontoparietal processing streams in marmosets and support the functional similarities of FEF–LIP and premotor–anterior parietal pathways between marmoset and macaque.

Functional organization of frontoparietal cortex in the marmoset investigated with awake resting-state fMRI

Frontoparietal networks contribute to complex cognitive functions in humans and macaques such as working memory, attention, task-switching, response suppression, grasping, reaching, and eye movement control. However, little is known about the organization of frontoparietal networks in the New World common marmoset monkey (Callithrix jacchus) which is now widely recognized as a powerful nonhuman primate experimental animal. In this study, we employed hierarchical clustering of interareal BOLD signals to investigate the hypothesis that the organization of the frontoparietal cortex in the marmoset follows the organizational principles of the macaque frontoparietal system. We found that the posterior part of the lateral frontal cortex (premotor regions) was functionally connected to the anterior parietal areas while more anterior frontal regions (frontal eye field (FEF)) were connected to more posterior parietal areas (the area around lateral intraparietal area (LIP)). These overarching patterns of inter-areal organization are consistent with a recent macaque study. These findings demonstrate parallel frontoparietal processing streams in marmosets and support the functional homologies of FEF-LIP and premotor-anterior parietal pathways between marmoset and macaque.

Concurrent neuroimaging and neurostimulation reveals a causal role for dlPFC in coding of task-relevant information

Dorsolateral prefrontal cortex (dlPFC) is proposed to drive brain-wide focus by biasing processing in favour of task-relevant information. A longstanding debate concerns whether this is achieved through enhancing processing of relevant information and/or by inhibiting irrelevant information. To address this, we applied transcranial magnetic stimulation (TMS) during fMRI, and tested for causal changes in information coding. Participants attended to one feature, whilst ignoring another feature, of a visual object. If dlPFC is necessary for facilitation, disruptive TMS should decrease coding of attended features. Conversely, if dlPFC is crucial for inhibition, TMS should increase coding of ignored features. Here, we show that TMS decreases coding of relevant information across frontoparietal cortex, and the impact is significantly stronger than any effect on irrelevant information, which is not statistically detectable. This provides causal evidence for a specific role of dlPFC in enhancing task-relevant representations and demonstrates the cognitive-neural insights possible with concurrent TMS-fMRI-MVPA.

The Role of Frontoparietal Cortex across the Functional Stages of Visual Search

Areas in frontoparietal cortex have been shown to be active in a range of cognitive tasks and have been proposed to play a key role in goal-driven activities (Dosenbach, N. U. F., Fair, D. A., Miezin, F. M., Cohen, A. L., Wenger, K. K., Dosenbach, R. A. T., et al. Distinct brain networks for adaptive and stable task control in humans. Proceedings of the National Academy of Sciences, U.S.A., 104, 11073–11078, 2007; Duncan, J. The multiple-demand (MD) system of the primate brain: Mental programs for intelligent behavior. Trends in Cognitive Sciences, 14, 172–179, 2010). Here, we examine the role this frontoparietal system plays in visual search. Visual search, like many complex tasks, consists of a sequence of operations: target selection, stimulus–response (SR) mapping, and response execution. We independently manipulated the difficulty of target selection and SR mapping in a novel visual search task that involved identical stimulus displays. Enhanced activity was observed in areas of frontal and parietal cortex during both difficult target selection and SR mapping. In addition, anterior insula and ACC showed preferential representation of SR-stage information, whereas the medial frontal gyrus, precuneus, and inferior parietal sulcus showed preferential representation of target selection-stage information. A connectivity analysis revealed dissociable neural circuits underlying visual search. We hypothesize that these circuits regulate distinct mental operations associated with the allocation of spatial attention, stimulus decisions, shifts of task set from selection to SR mapping, and SR mapping. Taken together, the results show frontoparietal involvement in all stages of visual search and a specialization with respect to cognitive operations.

Deficiency of Mitochondrial Functions and Peroxidation of Frontoparietal Cortex Enhance Isoflurane Sensitivity in Aging Mice

Background: Hypersensitivity to general anesthetics may predict poor postoperative outcomes, especially among the older subjects. Therefore, it is essential to elucidate the mechanism underlying hypersensitivity to volatile anesthetics in the aging population. Given the fact that isoflurane sensitivity increases with aging, we hypothesized that deficiencies of mitochondrial function and elevated oxidative levels in the frontoparietal cortex may contribute to the enhanced sensitivity to isoflurane in aging mice.Methods: Isoflurane sensitivity in aging mice was determined by the concentration of isoflurane that is required for loss of righting reflex (LORR). Mitochondrial bioenergetics of the frontoparietal cortex was measured using a Seahorse XFp analyzer. Protein oxidation and lipid oxidation in the frontoparietal cortex were assessed using the Oxyblot protein oxidation detection kit and thiobarbituric acid reactive substance (TBARS) assay, respectively. Contributions of mitochondrial complex II inhibition by malonate and peroxidation by ozone to isoflurane sensitivity were tested in vivo. Besides, effects of antioxidative therapy on mitochondrial function and isoflurane sensitivity in mice were also measured.Results: The mean concentration of isoflurane that is required for LORR in aging mice (14–16 months old) was 0.83% ± 0.13% (mean ± SD, n = 80). Then, the mice were divided into three groups as sensitive group (S group, mean − SD), medium group (M group), and resistant group (R group, mean + SD) based on individual concentrations of isoflurane required for LORR. Activities of mitochondrial complex II and complex IV in mice of the S group were significantly lower than those of the R group, while frontoparietal cortical malondialdehyde (MDA) levels were higher in the mice of S group. Both inhibition of mitochondrial complexes and peroxidation significantly decreased the concentration of isoflurane that is required for LORR in vivo. After treatment with idebenone, the levels of lipid oxidation were alleviated and mitochondrial function was restored in aging mice. The concentration of isoflurane that required for LORR was also elevated after idebenone treatment.Conclusions: Decreased mitochondrial functions and higher oxidative stress levels in the frontoparietal cortex may contribute to the hypersensitivity to isoflurane in aging mice.