The Working Memory and Dorsolateral Prefrontal-Hippocampal Functional Connectivity Changes in Long-Term Survival Breast Cancer Patients Treated with Tamoxifen

Abstract

Background:Tamoxifen is the most widely used drug for treating patients with estrogen receptor-sensitive breast cancer. There is evidence that breast cancer patients treated with tamoxifen exhibit cognitive dysfunction. However, the underlying neural mechanism remains unclear. The present study aimed to investigate the neural mechanisms underlying working memory deficits in combination with functional connectivity changes in premenopausal women with breast cancer who received long-term tamoxifen treatment.Methods:A total of 31 premenopausal women with breast cancer who received tamoxifen and 32 matched healthy control participants were included. The participants completed n-back tasks and underwent resting-state functional magnetic resonance imaging, which measure working memory performance and brain functional connectivity, respectively. A seed-based functional connectivity analysis within the whole brain was conducted, for which the dorsolateral prefrontal cortex was chosen as the seed region.Results:Our results indicated that the tamoxifen group had significant deficits in working memory and general executive function performance and significantly lower functional connectivity of the right dorsolateral prefrontal cortex with the right hippocampus compared with the healthy controls. There were no significant changes in functional connectivity in the left dorsolateral prefrontal cortex within the whole brain between the tamoxifen group and healthy controls. Moreover, significant correlations were found in the tamoxifen group between the functional connectivity strength of the dorsolateral prefrontal cortex with the right hippocampus and decreased working memory performance.Conclusion:This study demonstrates that the prefrontal cortex and hippocampus may be affected by tamoxifen treatment, supporting an antagonistic role of tamoxifen in the long-term treatment of breast cancer patients.

Hippocampus—Related Cognitive and Affective Impairments in Patients With Breast Cancer—A Systematic Review

“…Structure-and Connectivity-Related Hippocampal Changes or Differences in BCP Compared to HC All seven studies illustrated structure-and connectivityrelated hippocampal changes or differences compared to HC, including hippocampal volume loss (52-54, 56, 58), hippocampal deformation (58) as well as changes in bilateral hippocampal (57) and whole-brain functional connectivity (55). Reduced hippocampal volume was reported in most of the studies, referring mainly to the left hippocampus (53,54) and posterior regions (52,54).…”

“…In contrast to hippocampal volume reduction, hippocampal deformation (meaning specific morphological abnormalities and differences in shape compared to healthy controls) in BCP who underwent chemotherapy and endocrine therapy were mainly observed in the right hippocampus after controlling for age compared to HC (58). In addition to structural differences, two studies measured differences in functional connectivity, including whole brain functional connectivity (55) and bilateral hippocampal network connectivity (57). Thereby, Chen et al (55) found decreased functional connectivity of the Dorsolateral prefrontal cortex (DLPFC) with the right hippocampus in BCP treated with tamoxifen compared to HC.…”

“…In addition to structural differences, two studies measured differences in functional connectivity, including whole brain functional connectivity (55) and bilateral hippocampal network connectivity (57). Thereby, Chen et al (55) found decreased functional connectivity of the Dorsolateral prefrontal cortex (DLPFC) with the right hippocampus in BCP treated with tamoxifen compared to HC. Additionally, Cheng et al (57) found right hippocampus in BCP treated with tamoxifen compared to HC.…”

“…Two studies (55,57) indicate that the functional connectivity between the right hippocampus and other brain regions is associated with working memory performance. In this context, correlations between the functional connectivity strength of the right dorsal lateral prefrontal lobe (DLPFC) with the right hippocampus and accuracy in the 1-back and 2-back task of the DS test and the reaction time in the 2-back task were measured (55). Moreover, connectivity between the right hippocampus and bilateral precuneus was negatively correlated with DS performance (57).…”

Trajectories of Cognitive Function and Associated Phenotypic and Genotypic Factors in Breast Cancer

“…Deterioration in multiple cognitive domains has been observed in women receiving selective estrogen receptor modulators (SERMs), such as tamoxifen (Castellon et al, 2004; Chen et al, 2017; Ganz, Petersen, Bower, & Crespi, 2016; Palmer, Trotter, Joy, & Carlson, 2008; Schilder et al, 2009, 2010). Less is known about the changes in cognitive function associated with AI therapy because few studies have focused on cognitive function with these agents.…”