| Part 1.Acute Effect of Chemotherapy on Resting-state Hippocampal Functional Connectivity in Patients with Breast Cancer Objective:To examine the acute effect of chemotherapy on hippocampal subfield functional connectivity in breast cancer patients with resting-state functional MRI,and evaluate its correlation with neuropsychological status and blood indicators.Methods : Twenty-nine breast cancer patients(BC)and 25 age matched healthy controls(HC)were enrolled in this study from April 2017 to Februray 2018,who underwent resting state functional magnetic resonance imaging(rs-fMRI),neuropsychological tests and blood examinations at baseline(t0)and one week after completing chemotherapy(t1)or in the same time interval.Within-group comparisons and group-by-time interactions analysis of hippocampus-and subregionbased functional connectivity were performed between the two groups from t0 to t1.Correlation analyses were used to evaluate the relationships between the significantly functional connectivity changes and blood examination and neuropsychologic test scores changes in the BC group.Results:Within-group comparisons and group-by-time interactions analysis found that BC survivors showed significant hippocampal functional connectivity changes mainly in the left insula,temporal lobe(Gaussian Random Field theory correction,GRF,P < 0.001)and the left inferior frontal gyrus(GRF correction,P < 0.01).The functional connections from the anterior hippocampus to the left temporal lobe were greater than the posterior hippocampus(P< 0.05).The BC group had higher depression and anxiety scores,poorer performance on visual mobility,auditory memory and executive function than HCs(P < 0.05),and significantly abnormal estrodiol,total cholesterol and triglycerides(P < 0.05).The hippocampus functional connectivity alterations were closely related to changes in depression scores,estrodioland triglycerides(all P < 0.05).Conclusions: This study demonstrated chemotherapy induced acute functional connectivity alterations between the hippocampus and the whole brain and which are selectively perturbed in breast cancer survivors.Breast cancer patients had cognitive deficits in auditory,visual and executive functions and persistent anxiety and depression symptoms after chemotherapy.Chemotherapy induced especially anterior hippocampal functional connectivity abnormality,which is related to depression symptom,estrodiol and triglycerides disorders.Abnormal functional connections between the hippocampus and the whole brain may be one of the neuropathologic mechanisms of chemotherapy-induced cognitive impairment.Part 2.Resting-state Hippocampal Functional Connectivity pattern after Chemotherapy in Breast Cancer PatientsObjective: The hippocampus plays a key role in the regulation of cognitive function and emotional.In our previous studies,we found abnormal functional connections between the hippocampus and the whole brain in breast cancer patients after chemotherapy one week.The purpose of the current study is to investigate the evolution and the nature of these previously observed abnormal hippocampal function changes.The correlation with potential risk factors such as anxiety,depression,hemoglobin and blood lipids as well as cognitive assessment scores were analyzed.Methods: Eighteen breast cancer patients scheduled to chemotherapy were evaluated with the f MRI,psychological tests and blood examination before postoperative chemotherapy(t0)and one week after chemotherapy(t1: mean day,six days),and six months after chemotherapy(t2: mean day,171 days).Nineteen age and education matched healthy controls(HC)were assessed at baseline with the same examinations.Functional connectivity pattern based on the regions of interest was calculated by a functional neuroimage software tool-Rest on the MATLAB2012 a platform.One-way repeated measures ANOVA analyzed the with-in subject’s difference.Independent sample t test was used to analyze the differences between the HC groups and BC groups in the baseline.Results:The breast cancer patients had higher total cholesterol,triglyceride,fasting blood glucose and hemoglobin levels compared with HC,and their motor ability,memory and executive function were worse than HC at baseline(P<0.05).These abnormalities remained at abnormal levels or worsened one week after chemotherapy and had a tendency to return to baseline or normal levels six months after chemotherapy.One-way repeated measures ANOVA revealed significant different with-in subject hippocampal functional connectivity which were mainly in left superior temporal gyrus,left superior frontal gyrus,left insula,left angular gyrus and left meddle frontal gyrus(GRF correction,P<0.01).Left middle frontal functional connectivity tended to return to baseline level six months after chemotherapy,additionally,increased Z values from t1-t2 was postitively correlated with the number of days between t1 and t2.Conclusions: The increased functional connectivity between the hippocampus and the middle frontal gyrus provides a neurological basis for the recovery of chemo-induced cognitive impairment after chemotherapy.Longitudinal changes of functional connectivity,basal metabolism and hormone levels may be sensitive biological indicators of chemotherapy-induced neurotoxicity and subsequent recovery.Part 3.Intra-and inter-Resting State Netwrk Changes in Breast Cancer Patients undergoing ChemotherapyObjective: The purpose of this study was to observe the resting state intra-and internetwork FC changes in breast cancer patients before and after chemotherapy.The correlation between these networks changes and potential risk factors such as anxiety,depression,hemoglobin and blood lipids,as well as cognitive assessment scores were analyzed.Methods: Eighteen breast cancer patients scheduled to chemotherapy were evaluated with the f MRI,psychological tests and blood examination before postoperative chemotherapy(t0)and one week after chemotherapy(t1: mean day,six days),and six months after chemotherapy(t2: mean day,171 days).Nineteen age and education matched healthy controls(HC)were assessed at baseline with the same examinations.We performed independent component analysis(ICA)with well-validated software(GIFT).The independent component time series and spatial graph were obtained and then the reconstructed mean spatial map was normalized to the standard functional connection strength.Finally,11 resting state brain networks were selected automatically by template matching.Results:One-way repeated measures ANOVA revealed significant different with-in subject functional connectivity difference which were mainly in the default mode network(DMN),frontoparietal network(FPN),visual network(VN)and self-referential network(SRN).The abnormal nodes in these networks are mainly located in the posterior cingulate gyrus,superior frontal gyrus,superior frontal triangle,supplementary motor area,medial orbital superior frontal gyrus and calcarine sulcus(GRF correction,P<0.001).Post-hoc test showed that within network functional connection decreased one week after chemotherapy and increased six months after chemotherapy.The main differences between networks were the anterior DMN(ADMN)with the central network(CN),the posterior DMN(PDMN)with the sensorimotor network(SMN),and the CN with SMN.The functional connectivity(FC)between PDMN and SMN was decreased one week after chemotherapy and increased six months after chemotherapy.The FC changes between ADMN and CN was negatively correlated with fasting glucose and DST changes from t1 to t2,and SMN and VN FC changes was negatively correlated with E2 and SDS scores changes.Conclusions: Breast cancer survivors showed selective impairment of the resting state network.Partial damaged resting network had a tendency to recover to the baseline 6 months after chemotherapy.Functional networks changes were closely related to the cognitive function and metabolism changes.Thus,this network level FC may serve as a potential biomarker of chemotherapy,and provide valuable targets for further functional recovery treatment. |
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