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Long-term cognitive impairment of breast cancer patients after chemotherapy: A functional MRI study
European Journal of Radiology 85 (2016) 1053–1057
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Long-term cognitive impairment of breast cancer patients after chemotherapy: A functional MRI study Hui Miao a,1 , Jingjing Li b,1 , Sheng Hu a , Xiaoxuan He a , Savannah C. Partridge c , Jian Ren d , Yunpeng Bian a , Yongqiang Yu e,∗ , Bensheng Qiu a,∗ a
Centers for Biomedical Engineering, University of Science and Technology of China, Hefei, Anhui 230027, China Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China c Department of Radiology, University of Washington, 825 Eastlake Ave, Seattle, WA 98109, USA d Electrical and Computer Engineering, Rutgers University, New Brunswick, NJ 08854, USA e Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China b
a r t i c l e
i n f o
Article history: Received 23 December 2015 Received in revised form 8 March 2016 Accepted 13 March 2016 Keywords: Breast cancer Chemotherapy Cognitive impairment Functional connectivity Functional MRI
a b s t r a c t Background: Chemotherapy, a prominent treatment for breast cancer (BC), can have detrimental side effects on the patient’s cognitive functions including the executive function. However, the neurophysiological mechanism of the cognitive impairment remains unclear. Objective: The purpose of this study is to explore long-term chemotherapy-related functional connectivity changes using fMRI and the relationship between the connectivity changes and the executive function impairment in breast cancer patients. Methods: In this study, twenty-three breast cancer patients were treated with chemotherapy and twentysix healthy subjects were recruited as the healthy control (HC) group. The functional connectivity of anterior cingulate cortex (ACC) was calculated from resting-state fMRI of the BC and control groups. The relationship between the functional connectivity of ACC and the executive function was further analyzed based on the patient’ response time of the Stroop Interference Test. Results: The results show that functional connectivity of ACC in the BC group is significantly lower than that in the control group. The correlation analysis within the BC group indicates that the functional connectivity of ACC was significantly correlated with the executive function. Conclusion: These findings provide evidence that the functional connectivity changes might be a pathophysiological basis for long-term chemotherapy-related cognitive dysfunction, along with executive function impairment in breast cancer patients. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Breast cancer is one of the most common diseases that seriously affects the physical and mental health of women. Many patients with breast cancer complain about remarkable impairment in various cognitive domains, such as attention deficit [1], memory loss [2], and executive function impairment [3,4] after chemotherapy. Recently, neuroimaging studies have shown that chemotherapytreated breast cancer patients exhibit structural and functional changes in certain brain areas. Many structural MRI studies have revealed chemotherapy-treated breast cancer patients to have
∗ Corresponding authors. E-mail address: [email protected] (B. Qiu). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.ejrad.2016.03.011 0720-048X/© 2016 Elsevier Ireland Ltd. All rights reserved.
microstructural damage in white matter and decreased density in gray matter, particularly in the frontal lobes [5–7]. A recent functional MRI study of breast cancer patients further showed decreased frontal activation in cognitive tasks after the first month of treatment [8]. Higher survival rate and greater probability of long-term survival in breast cancer patients have been achieved with the development of new strategies for cancer screening and systemic chemotherapy. However, there is limited understanding of the relationship between brain alterations and long-term cognitive impairment of breast cancer patients after chemotherapy, particularly executive function impairment. Executive functions, including working memory, reasoning, task flexibility and problem solving as well as planning and execution, considerably affect the quality of life. The Stroop Interference Test [9], which has been widely used in psychological study, allows us to measure a person’s selective attention capacity and skills, as well
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H. Miao et al. / European Journal of Radiology 85 (2016) 1053–1057
as their ability for information processing [10]. In our study, we employed the Stroop Task to explore the pathophysiological basis of long-term changes in executive function of the population being studied. Several neuroimaging studies also have shown that ACC and dorsolateral prefrontal cortex [11] in the brain are involved in the processing of a Stroop task. Furthermore, we asserted that ACC is primarily involved in response-related processes [12], such as conflict monitoring [13], error detection [14] and response facilitation/inhibition [15]. We therefore hypothesize the connectivity of ACC will be significantly different in BC patients versus controls, and these differences might be associated with Stroop task performance. Resting-state fMRI technology is a non-invasive imaging technique that provides an indirect correlate of neural activity in vivo, which can be used for studying complex cognitive processes or synchronous brain activity during rest. Using this method, researchers have found disrupted functional integration in Alzheimer’s disease, mild cognitive impairment and schizophrenia patients [16,17]. A previous study using advanced resting-state fMRI also indicated the resting state functional brain network to be altered in chemotherapy-treated BC survivors [18]. However, few studies have investigated alterations in resting state functional connectivity within specific brain regions that are related to cognitive function. Therefore, the purpose of the study was to explore long-term functional alterations in the architecture of the brain, and determine the relationship between these changes and executive function impairment using resting-state fMRI. To address these questions, we chose ACC as the seed region and computed its functional connectivity within whole brain at resting-state. We then analyzed the relationship between the functional connectivity strength of ACC and response times in the Stroop Interference Test. 2. Materials and methods 2.1. Participants This study was supported by the Research Ethics Committee of The First Affiliated Hospital of Anhui Medical University. All 23 patients with BC (stages I–III, female) were recruited from the First Affiliated Hospital of Anhui Medical University, where they were treated with the standard-dose chemotherapy regimen (docetaxel/adriamycin/cyclophosphamide (TAC)). These patients were selected 36.6 ± 4.4 months after their chemotherapy treatment. Twenty-six age-matched healthy controls were selected from the patients’ relatives and local universities. The subjects participating in this study had no known neurologic or psychiatric disorders, history of alcohol and drug abuse, metastatic diseases and diseases leading to cognitive dysfunction participated. The detailed information gathered from each participant is described in Table 1. 2.2. Neuropsychological background tests Each participant was required to complete a 30-minute neuropsychological background test, which was administered by skilled psychologists and psychiatrists. The MoCA test was administered to assess general cognitive function. The Chinese version of the Cancer Related Fatigue (CRF) test was performed to evaluate fatigue symptoms [19], and the HAMD and HAMA tests were respectively performed to assess the participants’ potential depression and anxiety symptoms respectively [20]. The Stroop Interference test was considered a measure of executive function in the current study. All participants were required to name the ink color in which a word stimulus was printed, and the level of conflict was manipulated by varying the task-irrelevant property of the stimuli (in this case the word-meaning), from “con-
flicting” or “incongruent” (e.g., the word RED printed in green ink) to “non-conflicting”, or “congruent” properties (e.g., the word RED printed in red ink). When naming the color of the stimulus, people seemed unable to ignore the meaning of the carrier words. Better performance with congruent stimuli than with incongruent ones showed that people were distracted more by the task-irrelevant words rather than their colors. Participants also took much more time to complete the color reading in the conflicting condition than in the non-conflicting condition [9]. The response time for participants in the conflicting condition was used as the response time for assessing executive function in our study. 2.3. Image acquisition All MRI images were collected by using a GE 3T MRI scanner (GE Medical Systems, Milwaukee, Wisconsin) equipped with a standard head coil. The resting-state functional MRI images were recorded with the following parameters: repetition time/echo time ratio = 2000/22.5 ms, flip angle = 30◦ , 33 slices, thickness/gap ratio = 4.0/0.6 mm, voxel size = 3.4 × 3.4 × 4.6 mm3 , matrix size = 64 × 64, and field of view = 220 × 220 mm2 . T1-weighted anatomic images were acquired in sagittal orientation with three-dimensional inversion recovery prepared fast spoiled gradient recalled sequence with the following parameters: repetition time/echo time ratio = 8.676/3.184 ms, inversion time = 800 ms, flip angle = 8◦ , field of view = 256 × 256 mm2 , matrix size = 256 × 256, slice thickness = 1 mm, voxel size = 1 × 1 × 1 mm3 and the number of slices = 188. During the MRI scans, all participants were instructed to close their eyes and keep still. 2.4. Image preprocessing The fMRI data were preprocessed by using the Analysis of Functional NeuroImages (AFNI) software tool (Medical College of Wisconsin, Milwaukee, Wisconsin, USA). First, the anatomical and functional images were reconstructed and realigned using a unified matrix. Then, skull stripping and motion correction were performed, followed by coregistration between functional and anatomical images and normalization to the Montreal Neurological Institute (MNI) 152 standard brain atlas. All the normalized images were resliced by 3.0 × 3.0 × 3.0 mm3 voxels. The motion was also assessed and the data with head motion over 2 mm or 2◦ were excluded. To remove low-frequency drift and highfrequency noises, all fMRI signals were filtered by band-pass filtering (0.01–0.08 Hz) and then spatially smoothed by a 6-mm full width at half maximum Gaussian kernel. After preprocessing, the individual data was used for further connectivity analyses. 2.5. Functional connectivity analysis Functional connectivity in seed regions of ACC was computed. The region of interest (ROI) with 6 mm radius was extracted from the ‘peaks’ of the ACC (MNI coordinate, 6, 14, 46) according to previous study [21]. First, the cerebrospinal fluid, cerebral white matter and the signal of seed point of ACC were extracted. Then, several sources of variance were removed from the data by linear regression as follows: (a) 6 parameters obtained by rigid body correction of head motion, (b) the signal from cerebrospinal fluid, (c) the signal from the region centered in the white matter. 2.6. Group and correlative analysis Intergroup analysis was carried out by using the two sample t-test between BC patients group and HC group. The results were corrected using the Monte Carlo method, in which a whole brain mask of the MNI template was used. The threshold of statistical
H. Miao et al. / European Journal of Radiology 85 (2016) 1053–1057
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Table 1 Demographic and clinical characteristics of the patients receiving chemotherapy treatment and healthy controls. Variable
Age(years) Education(years) Fatigue HAMA HAMD MoCA Stroop Interference test(sec)
BC group(n = 23)
HC group(n = 26)
Mean(SD)
Mean(SD)
41.57(5.67) 11.87(3.00) 22.17 (3.07) 4.96(1.43) 5.04(1.19) 26.00(1.34) 35.04(8.96)
38(7.17) 10.31(2.70) 19.92 (3.73) 4.5(1.22) 4.88(1.23) 26.58(1.74) 30.17(6.49)
T value
P value
1.900 1.867 2.290 1.212 0.457 −1.312 2.138
0.064 0.069 0.027 0.232 0.650 0.196 0.039
Note: Abbreviation: SD, standard deviation; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; MoCA, Montreal Cognitive Assessment Test.
Table 2 Group analysis results of lower functional connectivity areas with ACC. Region (BA)
Superior frontal gyrus(6) Medial frontal gyrus(9) Middle temporal gyrus(21) Cuneus(18) Cuneus Superior frontal gyrus
Side
L L L L R R
MNI coordinates
(Fig. 1 and Table 2). No area showed significant higher functional connectivity.
Peak (Z value)
X(mm)
Y(mm)
Z(mm)
−21 −6 −48 −9 12 15
−3 45 0 −75 −63 15
69 27 −24 18 3 63
3.3. Correlation −3.99 −3.84 −3.46 −3.44 −3.02 −3.92
Note: Abbreviation: BA, Brodmann area; L, left; R, right; MNI, Montreal Neurological Institute. The threshold was set to P ≤ 0.05, ␣ ≤ 0.05 (corrected with the Monte Carlo method).
significance was set to P = 0.05, ␣ = 0.05 and a minimum cluster size of 154 voxels. Pearson’s correlation and linear regression modeling were performed to assess the relationship between the changes in functional connectivity and the Stroop response times. 3. Results 3.1. Neuropsychological evaluation Table 1 shows the clinical characteristics of BC patients receiving chemotherapy treatment and those of HC. The years of education and general cognitive function were not significantly different between BC patients group and HC group (p > 0.05) by two-sample t-test, which indicated that there was no global difference in cognitive impairment between groups. However, the scores of the Stroop test were significantly different (t = 2.138, p < 0.05). The higher score of the Stroop task in the BC patients group than HC group reflects worse performance in their executive functioning (i.e. it took the BC patients longer time to do the same events associated with executive function). In our study, the BC patients exhibited higher scores in fatigue test than controls (t = 2.290, p < 0.05). There is evidence that fatigue might interfere with cognitive function assessment in breast cancer survivors after chemotherapy [22]. However, this was not observed in our study. The fatigue scores of patients were clearly below the cut-off value, and the patients did not have any fatigue symptoms. Moreover, there was no significant correlation between scores of the Stroop test and fatigue, suggesting fatigue was not a significant covariate. 3.2. Functional connectivity By resting-state fMRI, the BC patients group showed significantly lower functional connectivity compared with the HC group in the following areas: the left superior frontal gyrus (LSFG), left medial frontal gyrus (LMedFG), left middle temporal gyrus (LMTG), left cuneus, right cuneus and right superior frontal gyrus (RSFG)
A significant negative correlation was observed between the response times in Stroop Interference Test and the fMRI functional connectivity strength of ACC within low signal areas including LSFG (r = −0.451, p = 0.0309) and left LMedFG (r = −0.419, p = 0.0465) in the BC patients group (Fig. 2). No significant correlation was observed between the Stroop response times and the strength of functional connectivity of ACC within other significantly lower areas. In addition, no significant correlation was observed between fatigue and the strength of functional connectivity of ACC (all p’s >0.10). 4. Discussion In this study, we chose ACC as the seed to analyze alteration of functional connectivity on resting-state fMRI in breast cancer patients compared with healthy controls. The BC patients showed significantly lower functional connectivity of ACC and the most changed areas were found in the frontal lobes, temporal lobes and cuneus. The correlation analysis within the BC patients group also indicated that the functional connectivity of ACC was significantly correlated with the response times of the Stroop Interference Test. Several neuroimaging and lesion studies have identified that executive function is most often associated with particular regions of the prefrontal cortex, including ACC [23,24], which enables us to selectively remain focused on information held in mind, ruling out irrelevant thoughts. Our findings suggest that alterations in functional connectivity of ACC in BC patients receiving chemotherapy may cause deficits in cognitive function. Executive function is thought to originate from the dynamics of the frontal cortical network. The frontal lobes, especially the prefrontal cortex, play a very important role in higher-level cognitive processes, such as executive functioning skills [25]. A Flanker Task Intracerebral Recording study confirmed the involvement of the temporal neocortex in the executive functions and a letter writing task demonstrated that temporal cortex together with frontal areas forms a cognitive network processing executive functions [26]. A study of Alzheimer’s disease also reported that temporal lobe atrophy was associated with lower executive function, general cognitive function, and episodic memory performance [27]. In addition, previous investigations have suggested that the cuneus plays a role not only in DMN, but also more broadly through its engagement under a variety of processing states. It is also associated with many high level cognitive functions, such as episodic memory, self-related information processing and various aspects of consciousness [28]. Functional brain imaging in mild cognitive impairment patients also reveals lower stimulation in the left cuneus and it has been suggested that the cuneus is pivotal for con-
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Fig. 1. Demonstration of the lower connectivity areas with ACC. The ACC used for this analysis was determined by the seed-based method. The threshold was set to P ≤ 0.05, ␣ ≤ 0.05 (corrected with the Monte Carlo method), and cluster size = 154. The colors represent the degree of correlation (Z-value) between functional connectivity strength. The altered connectivity areas included left superior frontal gyrus (LSFG), left medial frontal gyrus (LMedFG), left middle temporal gyrus (LMTG), left cuneus, right cuneus and right superior frontal gyrus (RSFG). L, left hemisphere; R, right hemisphere.
Fig. 2. Scatter plot of ACC functional connectivity and the response times for Stroop Interference Test. A negative correlation between the response times in Stroop Interference Test and the strength of functional connectivity was found. The x-axis represents the response times for Stroop Interference Test (sec) and the y-axis represents the functional connectivity strength. The threshold was set to P ≤ 0.05 (corrected by Pearson correlation analysis). LSFG, left superior frontal gyrus; LMedFG, left medial frontal gyrus.
scious information processing [29,30]. In our study, the correlation analysis results showed that the functional connectivity of ACC with the LSFG and LMedFG are significantly correlated with the response times of the Stroop Interference Test. Taken together, these studies suggest that lower functional connectivity with the frontal cortex in patients treated with chemotherapy might contribute to cognitive dysfunction, especially in executive impairment.
The current study strongly suggested that BC patients receiving chemotherapy treatment have altered functional connectivity of ACC as well as impaired executive function. However, several limitations in our study should be considered. First, the number of BC patients and HC were limited. Future studies with increased sample sizes of BC patients and controls are needed to validate our findings. Second, the study design was cross-sectional. Our study
H. Miao et al. / European Journal of Radiology 85 (2016) 1053–1057
did not assess BC patients early after being diagnosed or prior to beginning chemotherapy treatment. Therefore, we were not able to separate the effects of the cancer diagnosis itself. However, we tried to match the groups of patients and healthy controls on other factors. For the breast cancer survivors, the average time since the last chemotherapy treatment was nearly 3 years, and the mean HAMA and HAMD scores of these patients suggest that they are likely to have cancer-free lifestyles similar to those of the healthy controls. Therefore, we considered them to be comparable in our study. Third, the current study suggested that chemotherapy might alter functional connectivity of ACC, however, it did not determine the mechanism behind this alteration. Therefore, further studies are warranted to explore underlying biologic effects of chemotherapy on brain connectivity. 5. Conclusion In this study, we investigated the long-term effect of chemotherapy on functional connectivity and association with executive function impairment. Our results show significant abnormal functional connectivity of ACC by fMRI, and negative correlation between the strength of functional connectivity of ACC and the response times of the Stroop test in BC patients after chemotherapy. This study provides evidence that chemotherapy-induced functional connectivity changes may impair cognitive function, especially executive function, in breast cancer patients. Conflicts of interest None.
[6]
[7]
[8]
[9] [10] [11]
[12]
[13]
[14] [15] [16]
[17]
[18]
[19]
Acknowledgements [20]
H. Miao and J. Li participated in experimental design, data processing and paper preparation. S. Hu and X. He participated in data processing and paper revision. Y. Bian participated in data processing. S. Partridge and J. Ren participated in paper revision. Y. Yu and B. Qiu participated in the experimental design and paper revision. This work was supported by National Science Foundation of China (Grant number: 81371537, 91432301), Major State Basic Research Development Program of China (973 Program) (Grant number: 2013CB733803) and Fundamental Research Funds for the Central Universities of China (WK2070000033).
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[23] [24]
[25]
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Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Long-term cognitive impairment of breast cancer patients after chemotherapy: A functional MRI study Hui Miao a,1 , Jingjing Li b,1 , Sheng Hu a , Xiaoxuan He a , Savannah C. Partridge c , Jian Ren d , Yunpeng Bian a , Yongqiang Yu e,∗ , Bensheng Qiu a,∗ a
Centers for Biomedical Engineering, University of Science and Technology of China, Hefei, Anhui 230027, China Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China c Department of Radiology, University of Washington, 825 Eastlake Ave, Seattle, WA 98109, USA d Electrical and Computer Engineering, Rutgers University, New Brunswick, NJ 08854, USA e Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China b
a r t i c l e
i n f o
Article history: Received 23 December 2015 Received in revised form 8 March 2016 Accepted 13 March 2016 Keywords: Breast cancer Chemotherapy Cognitive impairment Functional connectivity Functional MRI
a b s t r a c t Background: Chemotherapy, a prominent treatment for breast cancer (BC), can have detrimental side effects on the patient’s cognitive functions including the executive function. However, the neurophysiological mechanism of the cognitive impairment remains unclear. Objective: The purpose of this study is to explore long-term chemotherapy-related functional connectivity changes using fMRI and the relationship between the connectivity changes and the executive function impairment in breast cancer patients. Methods: In this study, twenty-three breast cancer patients were treated with chemotherapy and twentysix healthy subjects were recruited as the healthy control (HC) group. The functional connectivity of anterior cingulate cortex (ACC) was calculated from resting-state fMRI of the BC and control groups. The relationship between the functional connectivity of ACC and the executive function was further analyzed based on the patient’ response time of the Stroop Interference Test. Results: The results show that functional connectivity of ACC in the BC group is significantly lower than that in the control group. The correlation analysis within the BC group indicates that the functional connectivity of ACC was significantly correlated with the executive function. Conclusion: These findings provide evidence that the functional connectivity changes might be a pathophysiological basis for long-term chemotherapy-related cognitive dysfunction, along with executive function impairment in breast cancer patients. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Breast cancer is one of the most common diseases that seriously affects the physical and mental health of women. Many patients with breast cancer complain about remarkable impairment in various cognitive domains, such as attention deficit [1], memory loss [2], and executive function impairment [3,4] after chemotherapy. Recently, neuroimaging studies have shown that chemotherapytreated breast cancer patients exhibit structural and functional changes in certain brain areas. Many structural MRI studies have revealed chemotherapy-treated breast cancer patients to have
∗ Corresponding authors. E-mail address: [email protected] (B. Qiu). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.ejrad.2016.03.011 0720-048X/© 2016 Elsevier Ireland Ltd. All rights reserved.
microstructural damage in white matter and decreased density in gray matter, particularly in the frontal lobes [5–7]. A recent functional MRI study of breast cancer patients further showed decreased frontal activation in cognitive tasks after the first month of treatment [8]. Higher survival rate and greater probability of long-term survival in breast cancer patients have been achieved with the development of new strategies for cancer screening and systemic chemotherapy. However, there is limited understanding of the relationship between brain alterations and long-term cognitive impairment of breast cancer patients after chemotherapy, particularly executive function impairment. Executive functions, including working memory, reasoning, task flexibility and problem solving as well as planning and execution, considerably affect the quality of life. The Stroop Interference Test [9], which has been widely used in psychological study, allows us to measure a person’s selective attention capacity and skills, as well
1054
H. Miao et al. / European Journal of Radiology 85 (2016) 1053–1057
as their ability for information processing [10]. In our study, we employed the Stroop Task to explore the pathophysiological basis of long-term changes in executive function of the population being studied. Several neuroimaging studies also have shown that ACC and dorsolateral prefrontal cortex [11] in the brain are involved in the processing of a Stroop task. Furthermore, we asserted that ACC is primarily involved in response-related processes [12], such as conflict monitoring [13], error detection [14] and response facilitation/inhibition [15]. We therefore hypothesize the connectivity of ACC will be significantly different in BC patients versus controls, and these differences might be associated with Stroop task performance. Resting-state fMRI technology is a non-invasive imaging technique that provides an indirect correlate of neural activity in vivo, which can be used for studying complex cognitive processes or synchronous brain activity during rest. Using this method, researchers have found disrupted functional integration in Alzheimer’s disease, mild cognitive impairment and schizophrenia patients [16,17]. A previous study using advanced resting-state fMRI also indicated the resting state functional brain network to be altered in chemotherapy-treated BC survivors [18]. However, few studies have investigated alterations in resting state functional connectivity within specific brain regions that are related to cognitive function. Therefore, the purpose of the study was to explore long-term functional alterations in the architecture of the brain, and determine the relationship between these changes and executive function impairment using resting-state fMRI. To address these questions, we chose ACC as the seed region and computed its functional connectivity within whole brain at resting-state. We then analyzed the relationship between the functional connectivity strength of ACC and response times in the Stroop Interference Test. 2. Materials and methods 2.1. Participants This study was supported by the Research Ethics Committee of The First Affiliated Hospital of Anhui Medical University. All 23 patients with BC (stages I–III, female) were recruited from the First Affiliated Hospital of Anhui Medical University, where they were treated with the standard-dose chemotherapy regimen (docetaxel/adriamycin/cyclophosphamide (TAC)). These patients were selected 36.6 ± 4.4 months after their chemotherapy treatment. Twenty-six age-matched healthy controls were selected from the patients’ relatives and local universities. The subjects participating in this study had no known neurologic or psychiatric disorders, history of alcohol and drug abuse, metastatic diseases and diseases leading to cognitive dysfunction participated. The detailed information gathered from each participant is described in Table 1. 2.2. Neuropsychological background tests Each participant was required to complete a 30-minute neuropsychological background test, which was administered by skilled psychologists and psychiatrists. The MoCA test was administered to assess general cognitive function. The Chinese version of the Cancer Related Fatigue (CRF) test was performed to evaluate fatigue symptoms [19], and the HAMD and HAMA tests were respectively performed to assess the participants’ potential depression and anxiety symptoms respectively [20]. The Stroop Interference test was considered a measure of executive function in the current study. All participants were required to name the ink color in which a word stimulus was printed, and the level of conflict was manipulated by varying the task-irrelevant property of the stimuli (in this case the word-meaning), from “con-
flicting” or “incongruent” (e.g., the word RED printed in green ink) to “non-conflicting”, or “congruent” properties (e.g., the word RED printed in red ink). When naming the color of the stimulus, people seemed unable to ignore the meaning of the carrier words. Better performance with congruent stimuli than with incongruent ones showed that people were distracted more by the task-irrelevant words rather than their colors. Participants also took much more time to complete the color reading in the conflicting condition than in the non-conflicting condition [9]. The response time for participants in the conflicting condition was used as the response time for assessing executive function in our study. 2.3. Image acquisition All MRI images were collected by using a GE 3T MRI scanner (GE Medical Systems, Milwaukee, Wisconsin) equipped with a standard head coil. The resting-state functional MRI images were recorded with the following parameters: repetition time/echo time ratio = 2000/22.5 ms, flip angle = 30◦ , 33 slices, thickness/gap ratio = 4.0/0.6 mm, voxel size = 3.4 × 3.4 × 4.6 mm3 , matrix size = 64 × 64, and field of view = 220 × 220 mm2 . T1-weighted anatomic images were acquired in sagittal orientation with three-dimensional inversion recovery prepared fast spoiled gradient recalled sequence with the following parameters: repetition time/echo time ratio = 8.676/3.184 ms, inversion time = 800 ms, flip angle = 8◦ , field of view = 256 × 256 mm2 , matrix size = 256 × 256, slice thickness = 1 mm, voxel size = 1 × 1 × 1 mm3 and the number of slices = 188. During the MRI scans, all participants were instructed to close their eyes and keep still. 2.4. Image preprocessing The fMRI data were preprocessed by using the Analysis of Functional NeuroImages (AFNI) software tool (Medical College of Wisconsin, Milwaukee, Wisconsin, USA). First, the anatomical and functional images were reconstructed and realigned using a unified matrix. Then, skull stripping and motion correction were performed, followed by coregistration between functional and anatomical images and normalization to the Montreal Neurological Institute (MNI) 152 standard brain atlas. All the normalized images were resliced by 3.0 × 3.0 × 3.0 mm3 voxels. The motion was also assessed and the data with head motion over 2 mm or 2◦ were excluded. To remove low-frequency drift and highfrequency noises, all fMRI signals were filtered by band-pass filtering (0.01–0.08 Hz) and then spatially smoothed by a 6-mm full width at half maximum Gaussian kernel. After preprocessing, the individual data was used for further connectivity analyses. 2.5. Functional connectivity analysis Functional connectivity in seed regions of ACC was computed. The region of interest (ROI) with 6 mm radius was extracted from the ‘peaks’ of the ACC (MNI coordinate, 6, 14, 46) according to previous study [21]. First, the cerebrospinal fluid, cerebral white matter and the signal of seed point of ACC were extracted. Then, several sources of variance were removed from the data by linear regression as follows: (a) 6 parameters obtained by rigid body correction of head motion, (b) the signal from cerebrospinal fluid, (c) the signal from the region centered in the white matter. 2.6. Group and correlative analysis Intergroup analysis was carried out by using the two sample t-test between BC patients group and HC group. The results were corrected using the Monte Carlo method, in which a whole brain mask of the MNI template was used. The threshold of statistical
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Table 1 Demographic and clinical characteristics of the patients receiving chemotherapy treatment and healthy controls. Variable
Age(years) Education(years) Fatigue HAMA HAMD MoCA Stroop Interference test(sec)
BC group(n = 23)
HC group(n = 26)
Mean(SD)
Mean(SD)
41.57(5.67) 11.87(3.00) 22.17 (3.07) 4.96(1.43) 5.04(1.19) 26.00(1.34) 35.04(8.96)
38(7.17) 10.31(2.70) 19.92 (3.73) 4.5(1.22) 4.88(1.23) 26.58(1.74) 30.17(6.49)
T value
P value
1.900 1.867 2.290 1.212 0.457 −1.312 2.138
0.064 0.069 0.027 0.232 0.650 0.196 0.039
Note: Abbreviation: SD, standard deviation; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; MoCA, Montreal Cognitive Assessment Test.
Table 2 Group analysis results of lower functional connectivity areas with ACC. Region (BA)
Superior frontal gyrus(6) Medial frontal gyrus(9) Middle temporal gyrus(21) Cuneus(18) Cuneus Superior frontal gyrus
Side
L L L L R R
MNI coordinates
(Fig. 1 and Table 2). No area showed significant higher functional connectivity.
Peak (Z value)
X(mm)
Y(mm)
Z(mm)
−21 −6 −48 −9 12 15
−3 45 0 −75 −63 15
69 27 −24 18 3 63
3.3. Correlation −3.99 −3.84 −3.46 −3.44 −3.02 −3.92
Note: Abbreviation: BA, Brodmann area; L, left; R, right; MNI, Montreal Neurological Institute. The threshold was set to P ≤ 0.05, ␣ ≤ 0.05 (corrected with the Monte Carlo method).
significance was set to P = 0.05, ␣ = 0.05 and a minimum cluster size of 154 voxels. Pearson’s correlation and linear regression modeling were performed to assess the relationship between the changes in functional connectivity and the Stroop response times. 3. Results 3.1. Neuropsychological evaluation Table 1 shows the clinical characteristics of BC patients receiving chemotherapy treatment and those of HC. The years of education and general cognitive function were not significantly different between BC patients group and HC group (p > 0.05) by two-sample t-test, which indicated that there was no global difference in cognitive impairment between groups. However, the scores of the Stroop test were significantly different (t = 2.138, p < 0.05). The higher score of the Stroop task in the BC patients group than HC group reflects worse performance in their executive functioning (i.e. it took the BC patients longer time to do the same events associated with executive function). In our study, the BC patients exhibited higher scores in fatigue test than controls (t = 2.290, p < 0.05). There is evidence that fatigue might interfere with cognitive function assessment in breast cancer survivors after chemotherapy [22]. However, this was not observed in our study. The fatigue scores of patients were clearly below the cut-off value, and the patients did not have any fatigue symptoms. Moreover, there was no significant correlation between scores of the Stroop test and fatigue, suggesting fatigue was not a significant covariate. 3.2. Functional connectivity By resting-state fMRI, the BC patients group showed significantly lower functional connectivity compared with the HC group in the following areas: the left superior frontal gyrus (LSFG), left medial frontal gyrus (LMedFG), left middle temporal gyrus (LMTG), left cuneus, right cuneus and right superior frontal gyrus (RSFG)
A significant negative correlation was observed between the response times in Stroop Interference Test and the fMRI functional connectivity strength of ACC within low signal areas including LSFG (r = −0.451, p = 0.0309) and left LMedFG (r = −0.419, p = 0.0465) in the BC patients group (Fig. 2). No significant correlation was observed between the Stroop response times and the strength of functional connectivity of ACC within other significantly lower areas. In addition, no significant correlation was observed between fatigue and the strength of functional connectivity of ACC (all p’s >0.10). 4. Discussion In this study, we chose ACC as the seed to analyze alteration of functional connectivity on resting-state fMRI in breast cancer patients compared with healthy controls. The BC patients showed significantly lower functional connectivity of ACC and the most changed areas were found in the frontal lobes, temporal lobes and cuneus. The correlation analysis within the BC patients group also indicated that the functional connectivity of ACC was significantly correlated with the response times of the Stroop Interference Test. Several neuroimaging and lesion studies have identified that executive function is most often associated with particular regions of the prefrontal cortex, including ACC [23,24], which enables us to selectively remain focused on information held in mind, ruling out irrelevant thoughts. Our findings suggest that alterations in functional connectivity of ACC in BC patients receiving chemotherapy may cause deficits in cognitive function. Executive function is thought to originate from the dynamics of the frontal cortical network. The frontal lobes, especially the prefrontal cortex, play a very important role in higher-level cognitive processes, such as executive functioning skills [25]. A Flanker Task Intracerebral Recording study confirmed the involvement of the temporal neocortex in the executive functions and a letter writing task demonstrated that temporal cortex together with frontal areas forms a cognitive network processing executive functions [26]. A study of Alzheimer’s disease also reported that temporal lobe atrophy was associated with lower executive function, general cognitive function, and episodic memory performance [27]. In addition, previous investigations have suggested that the cuneus plays a role not only in DMN, but also more broadly through its engagement under a variety of processing states. It is also associated with many high level cognitive functions, such as episodic memory, self-related information processing and various aspects of consciousness [28]. Functional brain imaging in mild cognitive impairment patients also reveals lower stimulation in the left cuneus and it has been suggested that the cuneus is pivotal for con-
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Fig. 1. Demonstration of the lower connectivity areas with ACC. The ACC used for this analysis was determined by the seed-based method. The threshold was set to P ≤ 0.05, ␣ ≤ 0.05 (corrected with the Monte Carlo method), and cluster size = 154. The colors represent the degree of correlation (Z-value) between functional connectivity strength. The altered connectivity areas included left superior frontal gyrus (LSFG), left medial frontal gyrus (LMedFG), left middle temporal gyrus (LMTG), left cuneus, right cuneus and right superior frontal gyrus (RSFG). L, left hemisphere; R, right hemisphere.
Fig. 2. Scatter plot of ACC functional connectivity and the response times for Stroop Interference Test. A negative correlation between the response times in Stroop Interference Test and the strength of functional connectivity was found. The x-axis represents the response times for Stroop Interference Test (sec) and the y-axis represents the functional connectivity strength. The threshold was set to P ≤ 0.05 (corrected by Pearson correlation analysis). LSFG, left superior frontal gyrus; LMedFG, left medial frontal gyrus.
scious information processing [29,30]. In our study, the correlation analysis results showed that the functional connectivity of ACC with the LSFG and LMedFG are significantly correlated with the response times of the Stroop Interference Test. Taken together, these studies suggest that lower functional connectivity with the frontal cortex in patients treated with chemotherapy might contribute to cognitive dysfunction, especially in executive impairment.
The current study strongly suggested that BC patients receiving chemotherapy treatment have altered functional connectivity of ACC as well as impaired executive function. However, several limitations in our study should be considered. First, the number of BC patients and HC were limited. Future studies with increased sample sizes of BC patients and controls are needed to validate our findings. Second, the study design was cross-sectional. Our study
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did not assess BC patients early after being diagnosed or prior to beginning chemotherapy treatment. Therefore, we were not able to separate the effects of the cancer diagnosis itself. However, we tried to match the groups of patients and healthy controls on other factors. For the breast cancer survivors, the average time since the last chemotherapy treatment was nearly 3 years, and the mean HAMA and HAMD scores of these patients suggest that they are likely to have cancer-free lifestyles similar to those of the healthy controls. Therefore, we considered them to be comparable in our study. Third, the current study suggested that chemotherapy might alter functional connectivity of ACC, however, it did not determine the mechanism behind this alteration. Therefore, further studies are warranted to explore underlying biologic effects of chemotherapy on brain connectivity. 5. Conclusion In this study, we investigated the long-term effect of chemotherapy on functional connectivity and association with executive function impairment. Our results show significant abnormal functional connectivity of ACC by fMRI, and negative correlation between the strength of functional connectivity of ACC and the response times of the Stroop test in BC patients after chemotherapy. This study provides evidence that chemotherapy-induced functional connectivity changes may impair cognitive function, especially executive function, in breast cancer patients. Conflicts of interest None.
[6]
[7]
[8]
[9] [10] [11]
[12]
[13]
[14] [15] [16]
[17]
[18]
[19]
Acknowledgements [20]
H. Miao and J. Li participated in experimental design, data processing and paper preparation. S. Hu and X. He participated in data processing and paper revision. Y. Bian participated in data processing. S. Partridge and J. Ren participated in paper revision. Y. Yu and B. Qiu participated in the experimental design and paper revision. This work was supported by National Science Foundation of China (Grant number: 81371537, 91432301), Major State Basic Research Development Program of China (973 Program) (Grant number: 2013CB733803) and Fundamental Research Funds for the Central Universities of China (WK2070000033).
[21] [22]
[23] [24]
[25]
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