FMRI Study On Brain Dysfunction In Patients With Functional Constipation Associated With Anxiety/depressive Status

Due to changes in people's diet structure and living habits,incidence of pressure and reduced exercise,the incidence of constipation has increased by nearly 16%yearly,seriously affecting the quality of people's lives.Previous studies on functional gastrointestinal disorders have found gut-brain dysfunction involving emotion processing and somatosensory functions,but there have rarely been reports of brain-gut axis interaction mechanisms for functional constipation.Clinical research found that patients with functional constipation(FC)are often accompanied by symptoms such as anxiety/depression resulting in refractory constipation.The ratio of female to male patients is about 2:1,indicating there is an abnormality in gut-brain and brain dysfunction in FC and different anomalous mechanisms between male and female constipation patients,but the central mechanism is not clear.Based on previous reports and the working foundation of our group,functional magnetic resonance imaging(fMRI)was used to explore brain functional differences in FC patients without anxiety/depressive status(FCNAD)and FC patients with anxiety/depression status(FCAD),as well as male and female FC patients during resting state.Hierarchical-clustering algorithm was used to classify 65 FC patients into 37 FCAD and 38 FCNAD subjects based on neuropsychological assessment(anxiety,depression,state/trait anxiety).We also found:First,the research about brain functional differences in FCAD:According to the resting functional imaging data,the results of one-way ANOVA of FCAD,FCNAD and 42 Healthy controls(HC)showed that not only did FCAD have the same abnormal nuclei as FCNAD,but also had decreased activity(fALFF)than HC in regions implicated in emotional-arousal(perigenual anterior cingulate cortex pACC/dorsomedial prefrontal cortex-DMPFC)and self-referential processing(precuneus);FCAD also had reduced brain activity in the precentral gyrus(PreCen)involving motor-control and orbitofrontal cortex(OFC)/thalamus(THA)which participate in emotional-arousal/somatic-sensory control respectively;the research on brain functional connectivity found that enhanced PreCen-THA connectivity and weakened precuneus-THA connectivity in patients with FCAD/FCNAD highlighted THA as the core of the brain network functional connectivity;correlation analysis found that the activity levels of the OFC and pACC/DMPFC,OFC-HIPP and PreCen-THA connectivity strength were not only related to constipation symptoms(abdominal distension),but also related to anxiety and depression scores in the FC AD group;medication analysis showed that the relationship between abdominal-distension and OFC activity was completely mediated by anxiety in FCAD,constipated symptoms might alter OFC activity by influencing patients' anxiety status,reflecting psychological factors that play a critical role in the FCAD group;these findings reveal different neural mechanisms of brain-gut interaction between FCAD and FCNAD patients,and also provide a basis for classification of FC subtypes based on brain functional imaging,providing clues for improving treatment strategies.Second,there are significantly more female patients than males,suggesting that sex differences have important implications for functional constipation.Therefore,the experiment used a 2×2 experimental design of sex(male,female)×group(functional constipation group,healthy control group)(34 female FC patients,34 female healthy controls,17 male FC patients,18 male healthy controls)for the resting state functional imaging,through a two-way analysis of variance to study the sex-related differences in brain activity in patients with functional constipation:analysis of brain activity found that females with functional constipation had lower activity levels in the THA,PreCen,OFC and INS compared with male patients,and OFC and INS activity levels were positively associated with abdominal pain and difficulty of defecation in female patients,respectively;functional connectivity analysis found that the functional connectivity between the INS seed and lateral OFC(1OFC)was lower in female patients than in male patients and was inversely associated with anxiety,and abdominal distension showed a negative correlation with INS-IOFC connectivity in male patients.The above results indicated that female FC patients were more susceptible to constipation symptoms,causing mental symptoms such as anxiety and depression.Finally,for the classification of functional constipation subtypes,it was based on the level of brain activity and functional connectivity in abnormal brain regions of FCAD,using the two-class method of the support vector machine.The results showed that the classification accuracy rate was 89.23%,the sensitivity and specificity were 85.71%and 91.89%respectively,indicating that the abnormal functional images of FCAD patients could be used as effective imaging markers to distinguish FC subtypes.This work provides imaging support for the clinical diagnosis and treatment of functional constipation.In this study,we investigated the abnormalities of brain activity and functional connectivity in patients with functional constipation and found that FCAD patients were responsible for lowering brain activity levels of emotion regulation,somatosensory and motor control,and functional connectivity abnormalities with the thalamus as the core,and abnormality of the INS-1OFC emotional arousal loop regulation ability in female FC patients;it reflects the psychological factors involved in gut-brain interaction and partly clarifies the pathophysiological mechanism of female FC and FCAD,and contributes to the development of personalized treatment combining antipsychotic and constipation drugs.In addition,imaging studies based on FC subtypes provide important clues for improving treatment strategies.