|Year : 2015 | Volume
| Issue : 2 | Page : 438-442
Abnormal cerebral functional connectivity in esophageal cancer patients with theory of mind deficits in resting state
Yin Cao1, JianBo Xiang2, Nong Qian2, SuPing Sun2, LiJun Hu2, YongGui Yuan3
1 Department of Neurology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou 213003, China
2 Department of Radiology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou 213003, China
3 Department of Psychology, The Affiliated Zhongda Hospital of Southeast University, Nanjing 210000, China
|Date of Web Publication||7-Jul-2015|
Department of Psychology, The Affiliated Zhongda Hospital of Southeast University, No. 87 Hunan Road, Nanjing 210000
Source of Support: None, Conflict of Interest: None
Objective: To explore the function of the default mode network (DMN) in the psychopathological mechanisms of theory of mind deficits in patients with an esophageal cancer concomitant with depression in resting the state.
Subjects and Methods: Twenty-five cases of esophageal cancer with theory of mind deficits (test group) that meet the diagnostic criteria of esophageal cancer and neuropsychological tests, including Beck depression inventory, reading the mind in the eyes, and Faux pas, were included, Another 25 cases of esophageal cancer patients but without theory of mind deficits (control group) were enrolled. Each patient completed a resting-state functional magnetic resonance imaging.
Results: The functional connectivity intensities within the cerebral regions in the DMN of all the enrolled patients were analyzed. The results of each group were compared. The functional connectivity of the bilateral prefrontal central region with the precuneus, bilateral posterior cingulate gyrus and bilateral ventral anterior cingulate gyrus in the patients of the test group were all reduced significantly (P < 0.05). In the resting state, the functional connectivity is abnormal in the cerebral regions in the DMN of esophageal cancer patients with theory of mind deficits.
Conclusions: The theory of mind deficits might have an important function in the pathogenesis of esophageal cancer.
Keywords: Esophageal cancer, esophageal cancer patients with depression, resting-state functional magnetic resonance imaging, theory of mind deficits
|How to cite this article:|
Cao Y, Xiang J, Qian N, Sun S, Hu L, Yuan Y. Abnormal cerebral functional connectivity in esophageal cancer patients with theory of mind deficits in resting state. J Can Res Ther 2015;11:438-42
|How to cite this URL:|
Cao Y, Xiang J, Qian N, Sun S, Hu L, Yuan Y. Abnormal cerebral functional connectivity in esophageal cancer patients with theory of mind deficits in resting state. J Can Res Ther [serial online] 2015 [cited 2020 Jul 16];11:438-42. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/438/144594
| > Introduction|| |
Previous studies only used neuropsychological tests to investigate esophageal cancer complicated with depression. In this study, the cognitive impairment in theory of mind in patients with esophageal cancer complicated with depression was investigated from the perspective of brain functional connectivity. The pathological mechanism of brain functional connectivity was also explored.
Approximately 24% of esophageal cancer patients suffer from depression.  Social cognitive impairment brought by depression and its potential cognitive neuropsychological mechanisms have recently gained increasing attention from researchers.  Previous studies have reported that the cognitive impairment caused by depression principally manifests as episodic memory impairment, executive function decline, psychomotor slowing, and attention deficits.  Moreover, patients with depression also have cognitive impairment in theory of mind. 
Further studies showed that the cognitive impairment caused by depression is associated with specific cerebral regions. For instance, the cognitive dysfunction in patients with depression is correlated with a decline in the local function consistency (regional homogeneity [ReHo]) of the right orbital prefrontal cortex (OFC) in the resting state; the severity of the decline of the local function consistency is positively correlated with the ReHo value of the right OFC.  The prefrontal central region is the important cerebral region for the default mode network (DMN). Thus, the abnormality of the default state in the brain is one of the neurobiological mechanisms of cognitive impairment in patients with depression. Some studies declared that the decline inattention span and word memory in breast cancer patients with depression detected by functional magnetic resonance imaging (fMRI) was related to the decrease of the fractional anisotropy values of the frontal lobe and corpus callosum white matter. The left dorsolateral prefrontal cortex is related to the decreased activation of the premotor cortex and excitatory executive dysfunction. Moreover, whether the effect of cognitive impairment on the related cerebral regions of the patients with the cancer concomitant with depression results from the mechanism of cancer or depression or both remains unknown. Moreover, whether the functional connectivity within the related cerebral regions is abnormal remains unclear.
In our work, there are more esophageal cancer patients than other cancer patients. We conducted this study to investigate the characteristics of the functional connectivity within the related cerebral regions of theory of mind deficits in patients with an esophageal cancer concomitant with depression in resting the state. Thus, this study would provide a basis for clarifying the psychopathological mechanisms of theory of mind deficits in patients with an esophageal cancer concomitant with depression.
| > Subjects and methods|| |
A total of 25 esophageal cancer patients with theory of mind deficits (test group) and 25 esophageal cancer patients without theory of mind deficits (control group) were enrolled in this study. Written, informed content was obtained from each patient (all the enrolled patients knew their disease conditions, and signed an informed consent, which was approved by the Academic Medical Ethics Committee of our hospital).
The patients enrolled in the test group met the following criteria: A score ≥5 in Beck depression inventory; a score <23 in reading the mind in the eyes; , a score <14 in Faux pas awareness and a score <36 in Faux pas control task. , The patients with head trauma history, central nervous system diseases, cancer metastases in the brain, mental illness history and substance dependence history were excluded in this study. A total of 13 males and 12 females, aged 28-60 years old with a mean age of 48.50 ± 4.53 years comprised the test group. Patients obtained education for 9 years to 16 years, with a mean education time of 12.57 ± 1.64 years. The patients in the control group met the following criteria: A score <5 in Beck depression inventory; a score >23 in reading the mind in the eyes; a score >14 in Faux pas awareness and a score >36 in Faux pas control task. All patients in the control group had no histories of neurological and psychiatric disease, substance abuse, or family history of mental illness. A total of 13 males and 12 females, aged 30-64 years old with a mean age of 49.65 ± 3.11 years, were included. These patients obtained 9 years to 16 years of education, with a mean education time of 11.17 ± 1.91 years. No patient in both groups received chemotherapy. All patients had secondary or higher education, were right-handed and with normal vision and hearing. They were all aware of their own conditions.
Achieva 3.0T TX MRI (Philips Company, Amsterdam, Holland) was used in this study. During scanning, the subjects were awake, but with closed eyes, breathing calmly and lying on their backs on the examination bed. Their heads were fixed, and the activities of the head and body were minimized. The patients did not perform any specific cognitive task. The related scan sequence and parameters are outline below.
Anatomical localization imaging
Image acquisition was performed using the fluid-attenuated inversion recovery sequence (T1flaire). Twenty-seven axial layer scans were obtained and paralleled with the line connecting the front with the rear. The scanning parameters were set as: Pulse repetition time/Echo time (TR/TE) =500 ms/14 ms; field of vision (FOV) =240 mm × 240 mm; matrix = 256 × 160; the thickness of each layer was 4 mm. For patients without any abnormal structures in the head (patients with the histories of head trauma, central nervous system diseases and cancer brain metastases before their enrolment were excluded, and pre-enrolment cranial computed tomography (CT) was performed to exclude the intracranial structural abnormalities). Resting-state fMRI (rsfMRI) scans were performed.
Resting-state functional scan
According to the real-time imaging processing of the magnetic resonance imaging (MRI), gradient recalled-echo planar imaging was used to acquire the images. The following parameters were set: TR/TE = 3000 ms/40 ms; FOV = 240 mm × 240 mm; matrix = 64 × 64. Twenty-seven layers were scanned with 4 mm intervals. The total scan duration time was 6 min and 39 s for each subject.
The data on the first 6 time points of fMRI were discarded to avoid the effect of the magnetic field inhomogeneity and the failure of the subjects to adapt to the results. The data on the next 128 time points were included in the subsequent analysis.
Image data format was transformed using MRIcro software (http://www.Mricro.com). The time and space were normalized, and the head movement was calibrated and mapped to a standard brain using SPM5 software (http://www.fil.ion, ucl.ac.uk/spm). The head movement calibration can acquire the images of the horizontal head movement and the images of the rotating head movement. The images of the subjects whose horizontal head movement was <1.5 mm and rotating head movement was <1.5° were included in the subsequent analysis. Image filtering (frequency between 0. 01 Hz and 0.08 Hz) was performed on the images that had been processed using the SPM5 software, and the linear drift was removed.
Selection of the region of interest
Regions of interest were selected from the images that had been preprocessed using the MarsBar (http://www.marsbar.sourceforge.net) toolbox based on the SPM5 software. The major composite cerebral regions of the DMN of the bilateral brain were selected as the regions of interest. According to the admitted results of the previous studies, , the prefrontal central region, the ventral anterior cingulate gyrus, the posterior cingulate gyrus and the precuneus were selected as regions of interest in this study [Figure 1]. The time series of all pixels in the regions of interest at each time point were averaged. Thus, the average time series representing the signal fluctuation of blood flow within the cerebral region can be obtained.
|Figure 1: Selected regions of interest. (a) The prefrontal central region. (b) The ventral anterior cingulate gyrus. (c) The posterior cingulate gyrus. (d) The precuneus, green, the left side; Yellow, the right side|
Click here to view
Based on the previously admitted results, and the advantage theory that the regional brain has consistent function in patients with depression.  Pearson correlation analysis was performed between the average time series of each region of interest and the other three regions of interest at the same side of the brain. The correlation coefficient r was then transformed into z using Fisher's z transformation so that r can be normalized. Moreover, the z value represented the functional connectivity intensity between the cerebral regions. The data were shown as mean ± standard deviation and were analyzed using SPSS software. Comparisons of the functional connectivity between the cerebral regions in the DMN between the test group and the control group were conducted using t-test, and P < 0.05 was regarded as significant.
| > Results|| |
The functional connectivity intensities (z value) between the cerebral regions in the default state network were compared between the two groups. The z values of the bilateral prefrontal central region with the precuneus (z1), the bilateral posterior cingulate gyrus (z2) and the bilateral ventral anterior cingulate gyrus (z3) were all reduced significantly in patients with depression compared with those in patients without depression [P < 0.05, [Table 1]]. However, the z values of the bilateral posterior cingulate gyrus with the precuneus (z4) and that of the bilateral ventral anterior cingulate gyrus (z5) in the test group, as well as the z value of the precuneus with the bilateral ventral anterior cingulate gyrus (z6), were not significantly different from those in the control group [Table 1].
|Table 1: The functional connectivity intensities (Z value) between the cerebral regions in the default state network of the two groups|
Click here to view
| > Discussion|| |
Esophageal cancer concomitant with depression is clinically common. Cognitive impairment induced by depression primarily manifests as episodic memory impairment, executive function decline, psychomotor slowing and attention deficits.  Patients with depression may have the cognitive disorder of theory of mind.  Considering the modular views, cognitive neuropsychiatry divided the theory of mind into two submodules from the perspective of information processing: Social perception processing and social cognitive processing. ,
Over the past decade, researchers have studied the cognitive dysfunction of patients with depression using rsfMRI. Numerous studies found a large number of spontaneous neuronal activities occurring in the brain, even in the awake and resting states with closed eyes , conducted a quantitative research on the brain activity in the resting state and proposed the DMN. The DMN is a network of brain regions that are active when an individual is not focused on the outside world, and the brain is at wakeful rest. In DMN, initiative activities are occurring in the brain, even in the clear and resting state (awake, eye-closed and quiet) without any task. However, the network activity is inhibited while the brain is performing some tasks. Other studies  further confirmed that a functional connectivity is present in the DMN brain regions, either in the task state or in a resting state. Thus, any disorder of the DMN functional connectivity may result in the disturbance of its functions.
In this study, we used rsfMRI to observe the changes in the DMN functional connectivity of esophageal cancer patients with theory of mind deficits. Thus, we explored the effects of DMN on the patho-mechanism of theory of mind deficits in esophageal cancer patients with depression. Our findings showed that the functional connectivity of the bilateral prefrontal central regions with the precuneus, the bilateral posterior cingulate gyrus and the bilateral ventral anterior cingulate gyrus were reduced. Therefore, connection performance degradation and coordination disorders exist in the default state network of esophageal cancer patients with theory of mind deficits. This result is consistent with our original hypothesis.
Studies that used positron emission tomography (PET), single photon emission CT or structural imaging have shown that abnormalities are present in the prefrontal central regions of patients with depression , found the prefrontal oxygenation level changes with the amelioration of depression in breast cancer patients complicated with depression. Our results showed that the functional connectivity of the bilateral prefrontal regions with the precuneus, the posterior cingulate gyrus and the ventral anterior cingulated gyrus were abnormal in the resting state of the esophageal cancer patients with theory of mind deficits. This result may be correlated with the functional abnormality in the prefrontal central regions induced by depression. Dysfunctions in the emotional processing and episodic memory extraction of the prefrontal central regions will result in lower scores in reading the mind in the eyes and Faux pas. Therefore, the theory of mind deficits in patients with an esophageal cancer concomitant with depression may also be associated with the functional abnormality in prefrontal central regions.
The ventral anterior cingulate gyrus is an important area of the default state network, and its function contributes to mood, mental state and self-discipline.  A body of studies has found an abnormal functional activity in the anterior cingulated gyrus of patients with depression.  The complicated depression in pancreatic cancer is related with the glucose metabolism change in anterior cingulate cortex.  We found functional connectivity abnormalities in the bilateral ventral anterior cingulated gyrus with the prefrontal central regions. However, no abnormality was detected in the bilateral ventral anterior cingulated gyrus with the precuneus or the posterior cingulate gyrus. Thus, the functional connectivity abnormalities in the bilateral ventral anterior cingulated gyrus of the prefrontal central regions in esophageal cancer patients with theory of mind deficits is speculated to be elicited by the dysfunction of the prefrontal central regions. The functions of the anterior cingulate gyrus are complex. The dorsal anterior cingulate gyrus is closely correlated with the cognitive task-dependent network, and its ventral part is associated with the DMN. The cognitive disorders induced by depression are also rich and complex, and the theory of mind deficit may be preferably related to the functional connectivity abnormalities in the ventral anterior cingulated gyrus. However, the other cognitive disorders may be associated with functional activity abnormalities in the dorsal anterior cingulate gyrus.
The posterior cingulate gyrus contributes to the episodic memory and the awareness of the human brain of the surrounding environment.  The precuneus contributes to the visual and spatial imagery and the episodic memory extraction.  PET and structural imaging indicated an abnormality in the posterior cingulate gyrus  and the precuneus  of patients with depression. However, no evident abnormality was observed in the functional connectivity between the bilateral posterior cingulate gyrus and the ventral anterior cingulate gyrus or the precuneus in the resting state of esophageal cancer patients with theory of mind deficits. Our results are inconsistent with those of previous studies, which may be attributed to the severity of depression in each study.
In this study, quality controls for the factors that may influence the results were performed as far as possible. For instance, all the patients in the test group underwent an examination and neuropsychological evaluation before receiving antidepressant treatment. Moreover, these patients never received chemotherapy to avoid the influence of chemotherapeutics on cognitive function. However, stratified analysis cannot be implemented on gender, disease severity and other factors because of the small sample size. In addition, whether the difference in functional connectivity in the partial cerebral region between two groups is caused purely by depression or a combination of cancer and depression is unclear. Thus, further in-depth research is needed to support the results obtained in this study.
| > Conclusion|| |
The functional connectivity is abnormal in the cerebral regions in the DMN of esophageal cancer patients with theory of mind deficits in the resting state. The theory of mind deficits may serve an important function in the pathogenesis of esophageal cancer.
| > References|| |
Jia L, Jiang SM, Shang YY, Huang YX, Li YJ, Xie DR, et al.
Investigation of the incidence of pancreatic cancer-related depression and its relationship with the quality of life of patients. Digestion 2010;82:4-9.
Inoue Y, Yamada K, Kanba S. Deficit in theory of mind is a risk for relapse of major depression. J Affect Disord 2006;95:125-7.
Den Hartog HM, Derix MM, Van Bemmel AL, Kremer B, Jolles J. Cognitive functioning in young and middle-aged unmedicated out-patients with major depression: Testing the effort and cognitive speed hypotheses. Psychol Med 2003;33:1443-51.
Yao Z, Wang L, Lu Q, Liu H, Teng G. Regional homogeneity in depression and its relationship with separate depressive symptom clusters: A resting-state fMRI study. J Affect Disord 2009;115:430-8.
Sabbagh MA. Understanding orbitofrontal contributions to theory-of-mind reasoning: Implications for autism. Brain Cogn 2004;55:209-19.
Dempster M, McCorry NK, Brennan E, Donnelly M, Murray LJ, Johnston BT. Illness perceptions among carer-survivor dyads are related to psychological distress among Oesophageal cancer survivors. J Psychosom Res 2011;70:432-9.
Dempster M, McCorry NK, Brennan E, Donnelly M, Murray L, Johnston BT. Psychological distress among survivors of esophageal cancer: The role of illness cognitions and coping. Dis Esophagus 2012;25:222-7.
Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, et al.
Activity and connectivity of brain mood regulating circuit in depression: A functional magnetic resonance study. Biol Psychiatry 2005;57:1079-88.
Yuan Y, Zhang Z, Bai F, Yu H, Shi Y, Qian Y, et al.
Abnormal neural activity in the patients with remitted geriatric depression: A resting-state functional magnetic resonance imaging study. J Affect Disord 2008;111:145-52.
Peng DH, Jiang KD, Fang YR, Xu YF, Shen T, Long XY, et al.
Decreased regional homogeneity in major depression as revealed by resting-state functional magnetic resonance imaging. Chin Med J (Engl) 2011;124:369-73.
Sabbagh MA, Moulson MC, Harkness KL. Neural correlates of mental state decoding in human adults: An event-related potential study. J Cogn Neurosci 2004;16:415-26.
Mazoyer B, Zago L, Mellet E, Bricogne S, Etard O, Houdé O, et al.
Cortical networks for working memory and executive functions sustain the conscious resting state in man. Brain Res Bull 2001;54:287-98.
Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A 2001;98:676-82.
Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A 2003;100:253-8.
Mayberg HS. Positron emission tomography imaging in depression: A neural systems perspective. Neuroimaging Clin N Am 2003;13:805-15.
Gawrysiak MJ, Carvalho JP, Rogers BP, Nicholas CR, Dougherty JH, Hopko DR. Neural changes following behavioral activation for a depressed breast cancer patient: A functional MRI case study. Case Rep Psychiatry 2012;2012:152916.
Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, et al.
The functional neuroanatomy of the placebo effect. Am J Psychiatry 2002;159:728-37.
Davey CG, Harrison BJ, Yücel M, Allen NB. Regionally specific alterations in functional connectivity of the anterior cingulate cortex in major depressive disorder. Psychol Med 2012;42:2071-81.
Inagaki M, Yoshikawa E, Kobayakawa M, Matsuoka Y, Sugawara Y, Nakano T, et al.
Regional cerebral glucose metabolism in patients with secondary depressive episodes after fatal pancreatic cancer diagnosis. J Affect Disord 2007;99:231-6.
Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al.
Molecular, structural, and functional characterization of Alzheimer′s disease: Evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005;25:7709-17.
Cavanna AE, Trimble MR. The precuneus: A review of its functional anatomy and behavioural correlates. Brain 2006;129:564-83.
Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol 2002;12:527-44.
Fitzgerald PB, Sritharan A, Daskalakis ZJ, de Castella AR, Kulkarni J, Egan G. A functional magnetic resonance imaging study of the effects of low frequency right prefrontal transcranial magnetic stimulation in depression. J Clin Psychopharmacol 2007;27:488-92.