An insight into the effect of the crosstalk between autonomic function and clinical manifestations of functional constipation

An insight into the effect of the crosstalk between autonomic function and clinical manifestations of functional constipation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article An insight into the effect of the crosstalk between autonomic function and clinical manifestations of functional constipation Ting Yu#, Hongyan Qi#, Xiangyue Gao#, Ya Jiang, Fei Li, Lin Lin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8479442/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Abnormal brain-gut interactions have a role in functional gastrointestinal disorders. The autonomic nervous system (ANS) is influenced by emotions, possibly affecting the disease status of sufferers with functional constipation (FC). However, their correlations are unclear. This research aims to ascertain the association between ANS function and psychological status, constipation severity, and life quality of FC sufferers. Methods According to heart rate variability (HRV) tests, 139 FC sufferers were classified into low frequency (LF)/high frequency (HF) normal, LF/HF sympathetic, and LF/HF parasympathetic groups. The scores of Zung’s Self-Rating Anxiety and Depression Scale (SAS/SDS), Constipation Scoring System (CSS), Patient Assessment of Constipation Symptom (PAC-SYM), and Patient Assessment of Constipation Quality of Life (PAC-QOL) were compared. Anorectal manometry and electrointestinogram parameters were assessed. The associations between the patients’ life quality and ANS function, mental or psychological status, and constipation severity were assessed. Results Anorectal physiology and intestinal electric activity were not different among the groups. Compared with the LF/HF normal group, the sympathetic group had a higher SAS/SDS score, a higher PAC-SYM score and a higher PAC-QOL score. The parasympathetic group manifested the highest CSS score, which might result from a predominance of depression. Regression analysis showed that anxiety/depression and ANS functional state significantly affected the life quality of FC sufferers. Conclusions FC sufferers with autonomic dysfunction apparently coexisted with anxiety/depression. The life quality of FC sufferers was negatively affected by ANS function and anxiety/depression. Autonomic adjustments, psychological interventions, and central nervous system drugs might help to treat FC. autonomic nervous function functional constipation psychological emotion evaluation of patients’ life quality Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Functional constipation (FC) refers to a prevalent non-organic bowel ailment featuring decreased frequency and/or difficult excretion [1,2]. Given the acceleration of societal development and the increase of life pressures, the prevalence of FC has tended to increase [3]. Epidemiological surveys have revealed that FC has a global prevalence of approximately 10.1% to 15% [1]. FC consumes considerable health care resources and direct medical costs, while also undermining the patients’ quality of life [4]. The mechanism of FC is complex, involving intestinal microbiome disorders, visceral paresthesia, slowed gastrointestinal motility, and anorectal dysfunction [5]. In recent years, the role of the brain-gut interaction mechanism in disorders of gut-brain interaction (DGBI) has been widely recognized. Many studies have shown that sufferers with constipation are more prone to anxiety/depression than healthy people [6-8]. However, the mechanism and impact of emotional abnormalities on the symptoms of constipation and life quality are not clear [3,9,10]. The visceral autonomic nervous system (ANS) includes sympathetic nerves and vagal nerves (parasympathetic nerves), which can transmit gastrointestinal signals to the central nervous system (CNS) and then conduct the CNS's innervation of gastrointestinal activity [11]. It has been suggested that patients with chronic constipation might have autonomic dysfunction [12]. Enhanced sympathetic activity or attenuated vagal activity is related to slowed bowel motility [13]. Thus, we ponder whether autonomic function is affected by a patient’s emotional state and whether autonomic function influences anorectal function, symptoms of defecation, and life quality. The non-invasive clinical method to detect visceral autonomic function is called Heart rate variability (HRV) [14-17]. Frequency domain parameters, such as high frequency (HF), low frequency (LF), and the LF/HF ratio can quantitatively evaluate the active states of parasympathetic and sympathetic nerves in the ANS. Based on the results of HRV tests, the present study aimed to analyze the relationships between autonomic function and anorectal manometry, psychological symptoms, symptoms of constipation and life quality in FC sufferers. In addition, we also explored the possible mechanisms of the involvement of the ANS in FC. Methods Participation The data for patients with constipation who attended the Gastrointestinal Motility Center of the First Affiliated Hospital with Nanjing Medical University from August 2021 to December 2022 were analyzed retrospectively. We adopted 139 eligible patients according to the following inclusion criteria: ①met the FC diagnostic criteria of the Rome IV guidelines [2]; ②aged from 18 to 80 years old; ③all the patients accepted tests of heart rate variability (HRV) and high-resolution anorectal manometry (HRAM); and ④being able to effectively communicate with and voluntarily participate in the study. The exclusion criteria comprised: ①constipation caused by organic diseases; ②a history of chronic diseases that might affect gastrointestinal function and autonomic nervous function, such as, diabetes mellitus, hypothyroidism, and mental deseases(not a state of mind); ③experienced previous gastrointestinal surgery or drug-induced constipation: Opioids, NSAIDs, anticholinergics, aluminum and calcium antacids, periwinkle alkaloids, calcium antagonists, diuretics; ④women in pregnancy or lactation; and ⑤people who were treated with pacemaker or implantable cardioverter defibrillator as well as radiofrequency ablation for arrhythmia [18]. This research was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Ethics number :2022-SR-607). Methods Autonomic function test The power spectrum of HRV was used to assess sympathetic and parasympathetic activity in the hospital for 5 minutes [19]. The low frequency band (LF, 0.04–0.15 Hz) in the HRV frequency domain analysis reflects the dual activity of sympathetic and parasympathetic nerves but centers on the former. The high frequency band (HF, 0.15–0.40 Hz) only indicates parasympathetic activity. The ratio of LF/HF implies the balance between sympathetic and parasympathetic nerves [20]. In line with the outcomes of HRV detection, FC sufferers were classified into three groups: The normal group was referred to as the LF/HF normal group, whose balance point of autonomic tension ranged from -1.5σ to 1.5σ; the heavily sympathetic nerve-biased group was referred to as the LF/HF sympathetic group, whose balance point of autonomic tension was ≥1.5σ; and the heavily parasympathetic nerve‑ biased group was referred to as the LF/HF parasympathetic group, whose balance point of autonomic tension was ≤ -1.5σ. The HRV detector (ZSY-1, Shenyang Weijin Gene Technology Co., Ltd., Shenyang, China) detected autonomic function, and the σ represents the statistical data of the instrument after comparing the data of the subject with that of an internal database of healthy peoples' data [21]. Anorectal motility and sensory assessment The HRAM examination was performed using Ningbo Mida Medical Instrument Co., Ltd.'s (Ningbo, Chins) 8-channel water-perfusion anorectal pressure monitor. Before detection, the patients were emptied of rectal stools using a glycerine enema. During the examination, they lay in a left knee-bent position and a manometry catheter with a balloon at the front end was inserted through the anus for at least 6 cm. After a five minutes’ adjustment, they were tested in the following order: resting state, tightening the anus, simulating defecation state, and then recording the resting pressure and length of the anal sphincter, the maximum contraction pressure, the duration of anal contraction and rectal defecation pressure. Rectal sensory function was evaluated simultaneously by injecting air into the rectal balloon continuously and slowly alongside with sequentially recording the patients’ initial sensory threshold, initial bowel movements, first constant sensation volume (FCSV), first desire to defecate volume (FDDV), and maximum tolerated volume [22]. All 139 subjects underwent tests for anorectal motility, whereas one person in the LF/HF parasympathetic group rejected the tests of sensory function because of intolerance. Constipation severity assessment To assess the objective severity, the constipation scoring system (CSS) was employed, with a total score ranging from 0 to 30 points [23]. The higher the score, the more serious the symptoms of constipation. The patient assessment of constipation symptoms (PAC-SYM) reflects the subjective feelings of patients about constipation symptoms, including three subscales of abdominal symptoms, rectal symptoms, and fecal traits. Each of subscales uses a Likert score (0–4 points). The higher the score, the more severe the subjective feelings of constipation symptoms [24]. The patient assessment of constipation quality of life (PAC-QOL) evaluates the life quality of people with constipation, containing 28 items and classified into four dimensions: physical discomfort, psychosocial discomfort, anxiety, and satisfaction. The higher the score, the worse the life quality associated with constipation [25]. Mental state evaluation Zung’ s Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were adopted to assess the anxious and depressive status of patients in the past week before they visited the hospital [26]. The two scales comprise 20 items. When the standard score of SAS is 50 or more and that of SDS is 53 or more, it indicates that patients have obvious anxious and depressive emotions. The severity of anxious and depressive emotions increases with increasing scores [27]. Statistical analysis SPSS25.0 software was utilized for statistical analysis (IBM Corp., Armonk, NY). The normal distributed data are shown as the mean ± standard deviation (± s), and analysis of variance (ANOVA) was employed for comparisons between groups. The median (lower quartile, upper quartile) [M (P25, P75)] was used to describe data with a skewed distribution, and the Kruskal–Wallis H test was applied for comparisons among groups. Categorical data were described as examples (n) and percentages (%), and the chi-squared test or Fisher's exact probability method were utilized for between-group comparisons. To probe the connection between HRV parameters and severity of constipation, anxious and depressive emotions along with life quality, Pearson analysis, and linear regression analysis were carried out after normalization. It was considered statistically significant when the two-tailed test P value was less than 0.05. Moreover, RStudio Team (2020) (RStudio: Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/.) was employed to visualize results, together with GraphPad Prism 9.0 software (GraphPad Inc., La Jolla, CA). Results Baseline data and grouping information. In the present research, 139 patients with FC were adopted and classified into three groups according to the result of LF/HF. There were 69 patients (male/female: 14/55) in the LF/HF normal group, 25 (male/female: 8/17) in the LF/HF sympathetic group, and 45 (male/female: 12/33) in the LF/HF parasympathetic group. We performed principal component analysis on the grouped data (Figure 1). Multivariate analysis of variance (MANOVA) showed that there was a statistically significant difference (P < 0.05), which verified the feasibility of the LF/HF parameters as the grouping criteria. Their age, sex, course of disease, and body mass index (BMI) were compared separately (Table 1), but displayed no significant differences (P > 0.05). Figure 1. Principal component analysis (PCA) of global heart rate variability (HRV)-Profiles of functional constipation patients. Normal group (red circles), sympathetic group (blue circles), and parasympathetic group (green circles), Ellipsoids mark the 95% confidence intervals of the respective groups. ANS, autonomic nervous system. Table 1. Baseline features of functional constipation (FC) sufferers in each HRV group. LF/HF Normal (n = 69) LF/HF Abnormal (n = 70) P Sympathetic (n = 25) Vagal (n = 45) Age [years, M (P25, P75)] 48 (34,54) 37 (29,55) 48 (39.5,55) 0.273 Sex (n, M/F) 14/55 8/17 12/33 0.464 Duration [years, M (P25, P75)] 5 (2,10) 2.5 (2,10) 4 (2,10) 0.868 BMI (kg/m2, mean ± SD) 21.69 ± 2.66 21.35 ± 3.12 21.52 ± 3.30 0.881 BMI: body mass index; M (P25, P75): median (lower quartile, upper quartile); SD: standard deviation. Comparisons of anorectal manometry parameters across different groups No significant differences were found in most anorectal motility and rectal sensory parameters (P > 0.05) (Table 2). Notably, there was a significant difference in anal resting pressure among the groups (P = 0.029). After the post- hoc multiple comparison, it was found that the anal resting pressure of the LF/HF parasympathetic group [53.00 (47.00, 64.50)] was significantly lower than that of the LF/HF normal group [60.20 (52.50, 73.15)] (P = 0.031). In addition, one person in the LF/HF parasympathetic group did not finish the tests of sensory function because of intolerance, which made little difference to the results. Table 2 a. Anorectal motility of patients with functional constipation in each HRV group LF/HF Normal (n = 69) LF/HF Abnormal (n = 70) P Sympathetic (n = 25) Vagal (n = 45) ARP [ mmHg, M (P25, P75)] 60.20 (52.50, 73.15) 62.85 (49.25, 75.00) 53.00 (47.00, 64.50) 0.029* Anal sphincter length [cm, mean ± SD )] 3.36 ± 1.11 3.08 ± 0.94 3.31 ± 1.06 0.525 MSP [ mmHg, M (P25, P75)] 214.60 (189.00, 256.00) 214.30 (189.20, 279.50) 212.50 (177.00, 274.53) 0.950 Squeezing duration [s, M (P25, P75)] 20.00 (16.20, 30.00) 26.80 (15.20, 30.00) 22.50 (10.15, 30.00) 0.613 Intrarectal pressure [ mmHg, M (P25, P75)] 45.00 (34.50, 60.65) 38.00 (34.18, 55.68) 46.50 (33.73, 56.00) 0.599 ARP: Anal resting pressure, MSP: Maximum squeeze pressure, M (P25, P75): median (lower quartile, upper quartile), SD: standard deviation. *, P<0.05; **, P< 0.01 Table 2b. Rectal sensory parameters of patients with functional constipation in each HRV group LF/HF Normal (n = 69) LF/HF Abnormal (n = 69) P Sympathetic (n = 25) Vagal (n = 44) FCSV [ ml, M (P25, P75)] 40.00 (25.00, 59.00) 50.00 (39.50, 60.00) 41.00 (30.00, 50.00) 0.081 FDDV [ ml, M (P25, P75)] 60.00 (47.00, 100.00) 80.00 (62.50, 100.00) 70.00 (50.00, 85.75) 0.176 Sustained urgency volume [ ml, M (P25, P75)] 110.00 (84.00, 145.00) 122.00 (86.25, 150.00) 100.00 (90.00, 120.00) 0.646 Maximum tolerated volume [ ml, M (P25, P75)] 150.00 (100.00, 200.00) 140.00 (112.50, 185.00) 138.00 (110.00, 170.00) 0.757 FCSV: first constant sensation volume; FDDV: first desire to defecate volume, M (P25, P75): median (lower quartile, upper quartile), SD: standard deviation. Comparisons of anxiety/depression across different groups There were statistical differences in SAS and SDS among the groups (SAS, P = 0.005; SDS, P = 0.015). Shown as multiple comparisons, compared with the normal (41.59 ± 7.38) and the parasympathetic group (43.60 ± 5.39), the SAS score of the sympathetic group (49.63 ± 8.76) was the highest. The differences were statistically significant (sympathetic versus normal, P < 0.001; sympathetic versus parasympathetic, P = 0.001). The SDS score of the normal group was lower than that of the sympathetic and parasympathetic group (43.56 ± 6.93 versus 50.19 ± 10.42, P 0.05, Figure 2). Comparisons of constipation severity and life quality across different groups In terms of the objective severity of constipation symptoms (CSS score), there was a significant difference among the three groups (P = 0.01). The score of the LF/HF parasympathetic group [18.00 (16.00, 19.00)] was the highest [sympathetic group, 16.00 (15.00, 18.00); normal group, 16.00 (14.00, 18.00)] and the difference between the parasympathetic and the normal group was statistically significant (P = 0.003). In terms of the subjective feelings of constipation symptoms (PAC-SYM score), there was a significant difference between the sympathetic group [1.67 (1.42, 1.87)] and the normal group [1.50 (1.33, 1.75)] (P = 0.035), among which the dimension of "rectal symptoms " in the LF/HF normal group [0.33 (0.33, 0.67)] was lower than that in the LF/HF sympathetic group [0.67 (0.33, 1.00)], and the difference was statistically significant (P < 0.05). For life quality (PAC-QOL score), compared with the LF/HF normal group, patients in the LF/HF sympathetic group had a poorer life quality, which was mainly reflected in the three dimensions of "physical discomfort", "psychosocial discomfort", and "worry and anxiety" (all P < 0.05) (Table 3, Figure 2C, 2I). To probe the reason why the parasympathetic group manifested the highest CSS score, we made analysis of the CSS scores for different mental state groups. It turned out that the depressive state depicted the highest score.(Figure 3J） Moreover, the present research also revealed a positive correlation between anxiety (r = 0.34, P < 0.0001) or depression (r = 0.46, P < 0.0001) and the CSS score (Figure 3A, 3B). Correlation analysis between HRV parameters and SAS/SDS, severity of constipation and life quality HF correlated negatively with SAS score (r = -0.21, P < 0.05), suggesting that anxiety might be related to decreased parasympathetic activity. Meanwhile, HF also correlated negatively with “physical discomfort” (r = -0.26, P < 0.01), a subscale of PAC-QOL, suggesting that constipation quality of life might be related to decreased parasympathetic activity. The ratio of LF/HF correlated positively with the SAS score (r = 0.18, P < 0.05). The LF/HF ratio also correlated positively with “rectal symptoms” (r = 0.17, P < 0.05), a subscale of the PAC-SYM score, but not with the CSS score, which indicated that FC patients with sympathetic bias/decreased parasympathetic activity had more severe subjective feelings of constipation symptoms, whereas the objective severity of the symptoms of constipation was not strong. The LF/HF ratio also had a positive association with the PAC-QOL score (r = 0.18, P < 0.05) and its subscales of “Physical discomfort” (r = 0.20, P < 0.05) and “Worry/anxiety” (r = 0.21, P < 0.05), demonstrating that the more sympathetic biased the autonomic disorder, the lower the life quality of patients with constipation. In summary, patients with FC with severe autonomic imbalance had obvious anxiety, severe subjective feelings of constipation symptoms, and a low level of life quality. In sympathetic-biased FC sufferers, the lower the parasympathetic activity, the more obvious the anxiety and the stronger the subjective feelings of constipation symptoms, together with worse the physically-related quality of life, without correlation with the objective severity of constipation, as shown in Table 4a and Figure 3C-3I. To further explore the influence of autonomic bias on the symptoms of constipation together with psychological state, regression analysis was performed. The autonomic function bias was set as a dumb variable and used as an independent variable, with SAS, SDS, CSS, PAC-SYM, Rectal symptoms, PAC-QOL, Physical discomfort, Psychosocial discomfort, and Worry/anxiety as dependent variables respectively. As shown in Figure 4A~4B, parasympathetic bias might be related to depression (B = 3.861, 95% confidence interval (CI): 1.093-6.628, P= 0.007) and aggravated objective constipation symptoms (B = 1.515, 95% CI: 0.525-2.505, P = 0.003). Sympathetic bias might affect a patient's psychological state, including anxiety (B = 8.039, 95% CI: 4.770-11.309, P < 0.001) and depression (B = 6.628, 95% CI: 3.256-10.000, P < 0.001), subjective feelings of constipation symptoms (B = 0.206, 95% CI: 0.064-0.347, P = 0.005), and quality of life (B = 0.533, 95% CI: 0.333-0.733, P < 0.001) except objective constipation symptoms. In addition, to ascertain the effect of anxiety/depression on the autonomic function, linear regression analysis was conducted with SAS/SDS scores as independent variables and HRV parameters (the LF/HF ratio and HF) as dependent variables. It turned out that HF correlated negatively with SAS (B = -0.008, 95% CI: -0.013- -0.003, P = 0.003), and the LF/HF ratio correlated positively with SAS (B = 0.021, 95% CI: 0.008- 0.035, P = 0.002). Meanwhile, HF had a positive correlation with SDS (B = 0.005,95% CI: 0.000-0.010, P =0.067), whereas the ratio of LF/HF correlated negatively with SDS (B = -0.016, 95% CI: -0.029- -0.003 P = 0.017), which agreed with the fact that the parasympathetic biased group showed the highest CSS score among the three groups. Thus, the linear regression analysis above suggested that depression might result in parasympathetic bias. Figure 2 . Comparisons of anxiety/depression, severity of constipation and life quality among different heart rate variability (HRV) groups with functional constipation (FC). (A) Self-rating Anxiety Scale (SAS) score for patients with FC in each HRV group. (B) Self-rating Depression Scale (SDS) score for patients with FC in each HRV group. (C) Constipation Scoring System (CSS) scores for patients with FC in each HRV group. (D, E) Patient Assessment of Constipation Symptom (PAC-SYM) and its one dimension of “rectal symptoms” for patients with FC in each HRV group. (F~I) Patient Assessment of Constipation Quality of Life (PAC-QOL) and its three dimensions of “physical discomfort”, “psychosocial discomfort” and “worry/anxiety” for patients with FC in each HRV group.SAS/SDS: Zung’s self-rating anxiety and depression scale. *P < 0.05; **P < 0.01; ***P < 0.001 Figure 3. A-B: Correlation analysis of Self-rating Anxiety Scale (SAS)/Self-rating Depression Scale (SDS) and severity of constipation in patients with functional constipation (FC). C-I: Correlation analysis between heart rate variability (HRV) parameters and severity of constipation and life quality in patients with functional constipation (FC). (A) Between SAS and Constipation Scoring System (CSS) score for patients with FC. (B) Between SDS and CSS score for patients with FC. (C) Between SAS score and high frequency (HF). (D) Between Physical discomfort and HF. (E) Between Self-rating Anxiety Scale (SAS) score and the ratio of low frequency (LF)/HF. (F) Between Rectal symptoms and the ratio of LF/HF. (G-J) Between Patient Assessment of Constipation Quality of Life (PAC-QOL) score and its dimensions of “Physical discomfort” and “Worry/anxiety’. Table 3. Constipation Symptoms and Quality of Life in patients with FC in each HRV group LF/HF Normal (n = 69) LF/HF Abnormal (n = 70) P Sympathetic (n = 25) Vagal (n = 45) CSS [S, M (P25, P75)] 16.00 (14.00,18.00) 16.00 (15.00,18.00) 18.00 (16.00,19.00) 0.013* PAC-SYM [S, M (P25, P75)] 1.50 (1.33,1.75) 1.67 (1.42,1.87) 1.58 (1.33,1.75) 0.035* Abdominal symptoms [S, M (P25, P75)] 1.00 (0.75,1.13) 1.00 (1.00,1.15) 1.00 (0.75,1.25) 0.056 Rectal symptoms [S, M (P25, P75)] 0.33 (0.33,0.67) 0.67 (0.33,1.00) 0.33 (0.33,0.84) 0.017* Defecation symptoms [S, M (P25, P75)] 2.40 (2.20,3.00) 2.60 (2.40,3.00) 2.60 (2.30,2.90) 0.554 PAC-QOL [S, M (P25, P75)] 1.50 (1.14,1.71) 1.89 (1.35,2.77) 1.61 (1.41,1.79) 0.001** Physical discomfort [S, M (P25, P75)] 1.75 (1.25,2.13) 2.25 (1.75,2.75) 1.75 (1.38,2.00) 0.000*** Psychosocial discomfort [S, M (P25, P75)] 0.88 (0.63,1.25) 1.38 (0.75,2.63) 1.12 (0.88,1.38) 0.013* Worry/anxiety [S, M (P25, P75)] 1.17 (0.79,1.50) 1.83 (1.09,2.54) 1.33 (1.17,1.63) 0.000*** Satisfaction [S, M (P25, P75)] 3.00 (2.75,3.50) 3.50 (2.88,4.00) 3.00 (3.00,3.75) 0.169 CSS: constipation scoring system; PAC-SYM: the Patient Assessment of Constipation Symptoms; PAC QOL: Patient Assessment of Constipation Quality of Life. HF: high-frequency; LF/HF: low frequency/high-frequency M (P25, P75): median (lower quartile, upper quartile). *P < 0.05; **P < 0.01; ***P < 0.001. Table 4. Correlation analysis between HRV parameters and anxiety/depression, constipation severity, and quality of life in patients with FC Variable SAS SDS CSS PAC-SYM Rectal symptoms PAC-QOL Physical discomfort Psychosocial discomfort Worry/ anxiety Satisfaction r r r r r r r r r r HF -0.21* -0.07 0.13 -0.10 -0.13 -0.19 -0.26** -0.23 -0.19 -0.02 LF/HF 0.18* 0.01 -0.15 0.11 0.17* 0.18* 0.20* 0.15 0.21* 0.02 SAS/SDS: Zung’s self-rating anxiety and depression scale; CSS: constipation scoring system; PAC SYM: the Patient Assessment of Constipation Symptoms; PAC-QOL: Patient Assessment of Constipation Quality of Life; HF: high-frequency; LF/HF: low-frequency/high-frequency. *P<0.05; **P < 0.01 Predictive value of the normalized HRV parameters on anxiety/ depression The ROC curve indicated that the normalized ratio of LF/HF had a certain predictive value for anxiety/depression in FC sufferers. As shown in Figure 4C~4D, the area under the ROC curve (AUC) for the normalized ratio of LF/HF to predict anxiety in FC patients was 0.70 [AUC=0.70, 95% confidence interval (CI) (0.59–0.82), P = 0.0011]. The optimal cut-off value was 0.2850. The sensitivity was 44.4% and the specificity was 84.8%. It implied that a ratio of LF/HF of 0.2850 was the cut-off value for prognosticating anxiety in patients with FC. The AUC for HF to predict anxiety in patients with FC was 0.74. [AUC = 0.74, 95% CI (0.63–0.86), P = 0.0001]. The cut-off value was 0.2450, with a sensitivity of 51.9% and a specificity of 89.3%. Meanwhile, the AUC for the LF/HF ratio and HF to forecast depression was 0.58 [AUC = 0.58, 95% CI (0.44–0.72), P = 0.23; the optimal cut-off value = 0.2850, sensitivity = 36.4%, specificity = 82.1%] and 0.61 [AUC=0.61, 95% CI (0.47–0.75), P = 0.10; optimal cut-off value = 0.3450, sensitivity = 59.1%, specificity = 65.0%], respectively. Notably, the P value of the ROC to prognosticate depression was larger than 0.05, which might have resulted from the fact that the size of this study’s number of samples was not very large. Figure 4. A-B: Linear regression analysis between autonomic nervous system (ANS) bias and anxiety/depression, constipation severity, and quality of life in patients with functional constipation (FC). C-D: Receiver-operator characteristic (ROC) curve analysis of heart rate variability (HRV) parameters for predicting anxiety/depression in functional constipation patients. (A) Parasympathetic bias as an independent variable. (B) Sympathetic bias as an independent variable. SAS/SDS: Zung’s self-rating anxiety and depression scale; PAC-QOL: Patient Assessment of Constipation Quality of Life; PAC-SYM: Patient Assessment of Constipation Symptom. (C). ROC analysis of HRV parameters for predicting anxiety in functional constipation patients. (D). ROC analysis of HRV parameters for predicting depression in functional constipation patients. AUC: the area under the ROC curve. LF/HF, low frequency/high frequency. Discussion Constipation is a chronic functional disease with recurrent symptoms and involves frequent visits to the doctor, which significantly affects the life quality of patients. We found that some patients with FC did not have prominent symptoms of constipation, but were often accompanied by anxiety and depression. HRV detection found that they had obvious autonomic dysfunction [28]. However, the relationships among the patients' psychological state, autonomic function, symptoms of constipation, and life quality, especially the association between autonomic function and other factors, are not yet evidence-based. In this study, 50.4% of the patients with FC had significant autonomic dysfunction, and 35.7% of them had anxiety and/or depression. Moreover, the autonomic nerve function of patients with FC correlated significantly with SAS and SDS scores. We observed that FC sufferers with sympathetic-biased autonomic function had significantly increased SAS and SDS scores, indicating that patients with FC with sympathetic-biased autonomic function had comorbidities such as anxiety and depression. Other studies have found that decreased HF, referring to parasympathetic activity in HRV detection, was associated with anxiety and depression [29]. However, in this study, it was found that depression aggravated parasympathetic bias. Our results and those of previous studies implied that there was a strong association between autonomic function and anxiety and/or depression. The LF/HF ratio and HF in HRV detection had predictive value for anxiety/depression in patients with FC. Clinically, HRV examination of patients with FC not only showed autonomic function, but also indicated to gastroenterologists that the patient might have anxiety/depression. Previous studies have suggested that anxiety and depression not only interfere with ANS innervation of the colon, but also affect intestinal motility through the central nervous system acting on autonomic nerves [6,30]. Anxiety and depression can affect rectal function in patients with constipation, such as suppressing rectal sensation, increasing rectal compliance, and decreasing rectal sensitivity [31,32]. A previous study also suggested an association between anxiety/depression and symptoms of constipation [33]. However, in this study, we grouped the patients with FC according to the results of HRV detection, and found no significant difference in most anorectal motility and sensation among the three groups, which might have resulted from the fact that this study did not compare the patients with healthy controls and all the included patients with FC had anorectal dysfunction. Thus, the grouping the patients with FC could not reflect significant differences. Notably, we found a significant difference in anal resting pressure between the parasympathetic and the normal groups, which implied that the parasympathetic nerves might inhibit the anal sphincter, as shown in many previous studies [34]. This article showed that the LF/HF ratio had a positive association with the subjective feelings of constipation symptoms instead of the objective severity of constipation symptoms, indicating that sympathetic-bias or decreased parasympathetic activity might be one of the factors affecting more serious feelings of constipation. This might reflect the possibility that most sympathetic patients had comorbidities with anxiety, which could enhance large intestine motility and cancel out the symptoms of constipation to a certain degree [35]. Meanwhile, the present study only involved patients with FC, without healthy controls. Based on the above factors, the difference in CSS score in the sympathetic group in this study was not significant. However, parasympathetic dysfunction might be involved in the occurrence of the symptoms of constipation. The present findings revealed that depression resulted in parasympathetic dysfunction, which then worsened the severity of constipation. As indicated by other studies, pelvic autonomic neuropathy might be present in patients with colonic slow-transit constipation [36,37]. The vagal nerve mainly innervates the left colon and rectum in humans, including two pathways: the vagal sacral reflex and gastrocolic reflex. Vagal dysfunction is associated with slow colonic movement and recto-anal dyssynergia. Increased sympathetic activity releases norepinephrine through cholinergic nerves in the myenteric plexus to inhibit colonic movement, and acts directly on smooth muscle cells to contract the anal sphincter [38]. Clinically, modulating vagal excitability might improve symptoms of constipation. Sacral nerve stimulation (SNS) has been suggested to improve symptoms of constipation by stimulating the presacral vagal plexus, releasing adrenocortical hormones, and thus enhancing colonic or rectal movement through cholinergic nerves [39]. Previous studies have suggested that in patients with FC, symptoms of constipation, anxiety, and depression can affect their quality of life [40]. The present study found that the correlation between anxiety/depression and patients' quality of life cannot be ignored. Moreover, after regression analysis of the patients’ quality of life, we observed that compared with the severity of constipation, the association between autonomic nerve function and the patient's quality of life was more prominent. This could be explained from one aspect: some patients with FC who repeatedly visited the clinic might not have outstanding symptoms of constipation. However, after HRV detection or assessment of anxiety and depression, it was found that the autonomic nerves and psycho-emotion of such patients were abnormal, which affected the quality of life of the patients and led to frequent medical treatment. Under the principle of clinical management to improve the life quality of patients with chronic functional diseases, the close correlation between autonomic function and anxiety/depression and the life quality of FC sufferers provides a basis for clinicians to consider the emotions and autonomic function of patients with FC in clinical diagnosis and treatment. In summary, autonomic function in patients with FC is related to anxiety and depression. Autonomic function tests such as HRV can reflect the anxiety and depression of some patients. Autonomic function and negative emotions correlate significantly with the severity of FC symptoms and disease-related life quality. It makes sense that autonomic nerves, as an important intermediate link in the brain-gut interaction mechanism of functional gastroenteropathy, participate in the mechanism of FC. The results of the present study suggest that more attention should be paid to autonomic function and negative emotions in the clinical diagnosis and treatment of FC, the regulation of which may be a promising treatment option for FC. Declarations Acknowledgements We sincerely thank Elixigen Inc. for polishing up this manuscript. We would like to thank all patients and manufacturers of testing instruments in the study. We declare that the abstract of this paper has been published in NeuroGASTRO 2023, August 31st - September 2nd 2023, Bucharest, Romania. Author Contributions GXY and QHY designed the study, performed the statistical analysis of the data, interpreted the results, and wrote the manuscript; JY, LF, LL, YT and TYR designed the study, interpreted the results, and revised the manuscript. All authors approved the final version of the article. Funding: This work was supported by the National Natural Science foundation of China (grant numbers 82170556, to Yurong Tang). Data availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study conformed to the code of ethics stated in the Declaration of Helsinki. The protocol of this study has received the approval of the clinical research committee of our institution (permission no. 2022-SR-607), and all participants provided written informed consent before enrollment. Consent for publication All authors approved the final manuscript and the submission to the journal. Competing interests The authors declare no competing interests. References Barberio B, Judge C, Savarino EV, et al. Global prevalence of functional constipation according to the Rome criteria: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2021;6:638-648. Aziz I, Whitehead WE, Palsson OS, et al. An approach to the diagnosis and management of Rome IV functional disorders of chronic constipation. Expert Rev Gastroenterol Hepatol 2020;14:39-46. Douglas A Drossman.Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features, and Rome IV. Gastroenterology 2016;S0016-5085(16)00223-7. Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology 2013;144:218-238. Drossman DA. Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features and Rome IV. Gastroenterology 2016; S0016-508500223-7. Chan AO, Cheng C, Hui WM, et al. Differing coping mechanisms, stress level and anorectal physiology in patients with functional constipation. World J Gastroenterol 2005;11:5362-5366. Li GY, Zhang WC, Hu Y, et al. Distinct Basal Brain Functional Activity and Connectivity in the Emotional-Arousal Network and Thalamus in Patients with Functional Constipation Associated with Anxiety and/or Depressive Disorders. Psychosom Med 2021;83:707-714. Mason HJ, Serrano-Ikkos E, Kamm MA. Psychological morbidity in women with idiopathic constipation. Am J Gastroenterol 2000;95:2852-2857. Lorenzo Pasquini, Fatemeh Noohi, Christina R. Veziris,et al.Dynamic autonomic nervous system states arise during emotions and manifest in basal physiology. Psychophysiology 2023;60:e14218. Aysha Karim Kiani,Paolo Enrico Maltese,Astrit Dautaj,et al.Neurobiological basis of chiropractic manipulative treatment of the spine in the care of major depression. Acta Biomed 2020;91:e2020006. Black CJ, Drossman DA, Talley NJ, et al. Functional gastrointestinal disorders: advances in understanding and management. Lancet 2020;396:1664-1674. Liu Q, Wang EM, Yan XJ, et al. Autonomic functioning in irritable bowel syndrome measured by heart rate variability: a meta-analysis. J Dig Dis 2013;14:638-646. Tougas G. The autonomic nervous system in functional bowel disorders. Gut 2000;47 Suppl 4: iv78-80; discussion iv87. M Khawar Ali, Jiande D Z Chen.Roles of Heart Rate Variability in Assessing Autonomic Nervous System in Functional Gastrointestinal Disorders: A Systematic Review. Diagnostics (Basel) 2023;13:293. Rollin McCraty, Fred Shaffer.Heart Rate Variability: New Perspectives on Physiological Mechanisms, Assessment of Self-regulatory Capacity, and Health Risk. Glob Adv Health Med 2015;4:46-61. Aparecida Maria Catai, Carlos Marcelo Pastre, Moacir Fernades de Godoy,et al.Heart rate variability: are you using it properly? Standardisation checklist of procedures. Braz J Phys Ther 2020;24:91-102. Junichiro Hayano, Emi Yuda. Assessment of autonomic function by long-term heart rate variability: beyond the classical framework of LF and HF measurements. J Physiol Anthropol . 2021;40:21. Gong BY, Ma HM, Zang XY, et al. Efficacy of Cranial Electrotherapy Stimulation Combined with Biofeedback Therapy in Patients with Functional Constipation. J Neurogastroenterol Motil 2016;22:497-508. Alberto Hernando, Maria Dolores Pelaez-Coca, Maria Teresa Lozano, et al. IEEE J Biomed Health Inform 2019;23:132-142. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J 1996;17:354-381. Kuo TB, Lin T, Yang CC, et al. Effect of aging on gender differences in neural control of heart rate. Am J Physiol 1999;277:H2233-2239. Scott SM, Carrington EV. The London Classification: Improving Characterization and Classification of Anorectal Function with Anorectal Manometry. Curr Gastroenterol Rep 2020;22:55. Agachan F, Chen T, Pfeifer J, et al. A constipation scoring system to simplify evaluation and management of constipated patients. Dis Colon Rectum 1996;39:681-685. Neri L, Conway PM, Basilisco G, et al. Confirmatory factor analysis of the Patient Assessment of Constipation-Symptoms (PAC-SYM) among patients with chronic constipation. Qual Life Res 2015;24:1597-1605. Marquis P, Loge CDL, Dubois D, et al. Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire. Scand J Gastroenterol 2005;40:540-551. Tanaka-Matsumi J, Kameoka VA. Reliabilities and concurrent validities of popular self-report measures of depression, anxiety, and social desirability. J Consult Clin Psychol 1986;54:328-333. Zung WW. A SELF-RATING DEPRESSION SCALE. Arch Gen Psychiatry 1965;12:63-70. Junichiro Hayano, Emi Yuda. Assessment of autonomic function by long-term heart rate variability: beyond the classical framework of LF and HF measurements. J Physiol Anthropol . 2021;40:21. Shinba T, Kariya N, Matsui Y, et al. Decrease in heart rate variability response to task is related to anxiety and depressiveness in normal subjects. Psychiatry Clin Neurosci 2008;62:603-609. Gue M, Junien J L, Bueno L. Conditioned emotional response in rats enhances colonic motility through the central release of corticotropin-releasing factor. Gastroenterology 1991;100:964-970. Zhou LR, Lin Z, Lin L, et al. Functional constipation: implications for nursing interventions. J Clin Nurs 2010;19:1838-1843. Liu TT, Yi CH, Chen CL, et al. Impact of sleep dysfunction on anorectal motility in healthy humans. J Neurogastroenterol Motil 2011;17:180-184. Jiang Y, Tang YR, Lin L. Clinical Characteristics of Different Primary Constipation Subtypes in a Chinese Population. J Clin Gastroenterol 2020;54:626-632. Mills K, Chess-Williams R. Pharmacology of the internal anal sphincter and its relevance to faecal incontinence. Auton Autacoid Pharmacol 2009;29:85-95. Wilson PB. The Psychobiological Etiology of Gastrointestinal Distress in Sport: A Review. J Clin Gastroenterol 2020;54:297-304. Knowles CH, Scott SM, Lunniss PJ. Slow transit constipation: a disorder of pelvic autonomic nerves? Dig Dis Sci 2001;46:389-401. Raethjen J, Pilot MA, Knowles C. Selective autonomic and sensory deficits in slow transit constipation. J Auton Nerv Syst 1997;66:46-52. Liu LJ, Milkova N, Nirmalathasan J, et al. Diagnosis of colonic dysmotility associated with autonomic dysfunction in patients with chronic refractory constipation. Sci Rep 2022;12:12051. Huang ZH, Li SY, Foreman RD, et al. Sacral nerve stimulation with appropriate parameters improves constipation in rats by enhancing colon motility mediated via the autonomic-cholinergic mechanisms. Am J Physiol Gastrointest Liver Physiol 2019;317:G609-G617. Jiang Y, Tang YR, Xie C, et al. Influence of sleep disorders on somatic symptoms, mental health, and quality of life in patients with chronic constipation. Medicine (Baltimore) 2017;96:e6093. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8479442","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":582778952,"identity":"16230ee3-9865-46ca-a621-2f3ed022bd14","order_by":0,"name":"Ting Yu#","email":"","orcid":"","institution":"The First Affiliated Hospital with Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Yu#","suffix":""},{"id":582778953,"identity":"d766ca30-5efe-4966-bf19-60e03070d565","order_by":1,"name":"Hongyan Qi#","email":"","orcid":"","institution":"The First Affiliated Hospital with Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hongyan","middleName":"","lastName":"Qi#","suffix":""},{"id":582778957,"identity":"2ef27e3b-cbc5-4b5d-864e-62de1d88f5f0","order_by":2,"name":"Xiangyue Gao#","email":"","orcid":"","institution":"The First Affiliated Hospital with Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiangyue","middleName":"","lastName":"Gao#","suffix":""},{"id":582778961,"identity":"dd456c26-0a82-40d9-8183-a266e5c4bd9b","order_by":3,"name":"Ya Jiang","email":"","orcid":"","institution":"The First Affiliated Hospital with Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ya","middleName":"","lastName":"Jiang","suffix":""},{"id":582778964,"identity":"351a8ee2-d4bd-4899-b5bd-3a053e2fd4e1","order_by":4,"name":"Fei Li","email":"","orcid":"","institution":"The First Affiliated Hospital with Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Li","suffix":""},{"id":582778965,"identity":"a377af5c-6f9a-4d04-b5cf-b35f90c9f12f","order_by":5,"name":"Lin Lin","email":"","orcid":"","institution":"The First Affiliated Hospital with Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Lin","suffix":""},{"id":582778966,"identity":"1fb0a131-0223-4a44-acf9-0f044cce6401","order_by":6,"name":"Yurong Tang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYFAD9sbGhx+IUskGJg0YGHgONxtLkKZFIr1NgIcYHfLzm4995mH4k7h95sM2BgkGOzndBgJaDI6xJc/mYTBInHM7se1BAUOysdkBQlrYeIyZQVpmSCe2G0gwHEjcRkiLfBtMi+TBNgkeYrQwHINpkWAkUovBsbRkxjkMxsYzeBKBgWxAhF/kmw8fZnjDICc7g/34w4cfKuzkCGoBASbefwyODRBLiVAOAow/GBjsiVQ7CkbBKBgFIxEAAOuLOiZ/qxcsAAAAAElFTkSuQmCC","orcid":"","institution":"The First Affiliated Hospital with Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yurong","middleName":"","lastName":"Tang","suffix":""}],"badges":[],"createdAt":"2025-12-30 09:08:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8479442/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8479442/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101640587,"identity":"29898690-5aaf-4c02-b5ec-393d64095c38","added_by":"auto","created_at":"2026-02-02 07:28:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56882,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrincipal component analysis (PCA) of global heart rate variability (HRV)-Profiles of functional constipation patients. Normal group (red circles), sympathetic group (blue circles), and parasympathetic group (green circles), Ellipsoids mark the 95% confidence intervals of the respective groups. ANS, autonomic nervous system.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8479442/v1/133b8138b3e1fd6d53cc2f3e.png"},{"id":101640589,"identity":"0904d44a-3877-4eb1-8933-c2f451d82da6","added_by":"auto","created_at":"2026-02-02 07:28:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":109721,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparisons of anxiety/depression, severity of constipation and life quality among different heart rate variability (HRV) groups with functional constipation (FC). \u003c/strong\u003e(A) Self-rating Anxiety Scale (SAS) score for patients with FC in each HRV group. (B) Self-rating Depression Scale (SDS) score for patients with FC in each HRV group. (C) Constipation Scoring System (CSS) scores for patients with FC in each HRV group. (D, E) Patient Assessment of Constipation Symptom (PAC-SYM) and its one dimension of “rectal symptoms” for patients with FC in each HRV group. (F~I) Patient Assessment of Constipation Quality of Life (PAC-QOL) and its three dimensions of “physical discomfort”, “psychosocial discomfort” and “worry/anxiety” for patients with FC in each HRV group.SAS/SDS: Zung’sself-rating anxiety and depression scale. *P \u0026lt; 0.05; **P \u0026lt; 0.01; ***P \u0026lt; 0.001\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8479442/v1/96e5826d38d09b6538fa2129.png"},{"id":101640588,"identity":"9da86ec8-831b-4d05-97dc-f941db7e4bd2","added_by":"auto","created_at":"2026-02-02 07:28:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":212509,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA-B: Correlation analysis of Self-rating Anxiety Scale (SAS)/Self-rating Depression Scale (SDS) and severity of constipation in patients with functional constipation (FC). C-I: Correlation analysis between heart rate variability (HRV) parameters and severity of constipation and life quality in patients with functional constipation (FC). \u003c/strong\u003e(A) Between SAS and Constipation Scoring System (CSS) score for patients with FC. (B) Between SDS and CSS score for patients with FC. (C) Between SAS score and high frequency (HF). (D) Between Physical discomfort and HF. (E) Between Self-rating Anxiety Scale (SAS) score and the ratio of low frequency (LF)/HF. (F) Between Rectal symptoms and the ratio of LF/HF. (G-J) Between Patient Assessment of Constipation Quality of Life (PAC-QOL) score and its dimensions of “Physical discomfort” and “Worry/anxiety’.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8479442/v1/8075baf96ee9e2a5af598195.png"},{"id":101640590,"identity":"6bb68a1e-e9eb-4d71-90b9-1188ba8c6f32","added_by":"auto","created_at":"2026-02-02 07:28:56","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":105060,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA-B: Linear regression analysis between autonomic nervous system (ANS) bias and anxiety/depression, constipation severity, and quality of life in patients with functional constipation (FC). C-D: Receiver-operator characteristic (ROC) curve analysis of heart rate variability (HRV) parameters for predicting anxiety/depression in functional constipation patients.\u003c/strong\u003e (A) Parasympathetic bias as an independent variable. (B) Sympathetic bias as an independent variable. SAS/SDS: Zung’s self-rating anxiety and depression scale; PAC-QOL: Patient Assessment of Constipation Quality of Life; PAC-SYM: Patient Assessment of Constipation Symptom. (C). ROC analysis of HRV parameters for predicting anxiety in functional constipation patients. (D). ROC analysis of HRV parameters for predicting depression in functional constipation patients. AUC: the area under the ROC curve. LF/HF, low frequency/high frequency.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8479442/v1/bc153fe0d0220b424ae92107.png"},{"id":101753264,"identity":"17f413af-8ac8-498e-b5f4-bd85c790a214","added_by":"auto","created_at":"2026-02-03 10:39:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2135880,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8479442/v1/fdcd16bc-7150-4057-ad1c-399057617d89.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"An insight into the effect of the crosstalk between autonomic function and clinical manifestations of functional constipation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFunctional constipation (FC) refers to a prevalent non-organic bowel ailment featuring decreased frequency and/or difficult excretion [1,2]. Given the acceleration of societal development and the increase of life pressures, the prevalence of FC has tended to increase [3]. Epidemiological surveys have revealed that FC has a global prevalence of approximately 10.1% to 15% [1]. FC consumes considerable health care resources and direct medical costs, while also undermining the patients’ quality of life [4].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mechanism of FC is complex, involving intestinal microbiome disorders, visceral paresthesia, slowed gastrointestinal motility, and anorectal dysfunction [5]. In recent years, the role of the brain-gut interaction mechanism in disorders of gut-brain interaction (DGBI) has been widely recognized. Many studies have shown that sufferers with constipation are more prone to anxiety/depression than healthy people [6-8]. However, the mechanism and impact of emotional abnormalities on the symptoms of constipation and life quality are not clear [3,9,10]. The visceral autonomic nervous system (ANS) includes sympathetic nerves and vagal nerves (parasympathetic nerves), which can transmit gastrointestinal signals to the central nervous system (CNS) and then conduct the CNS's innervation of gastrointestinal activity [11]. It has been suggested that patients with chronic constipation might have autonomic dysfunction [12]. Enhanced sympathetic activity or attenuated vagal activity is related to slowed bowel motility [13]. Thus, we ponder whether autonomic function is affected by a patient’s emotional state and whether autonomic function influences anorectal function, symptoms of defecation, and life quality.\u003c/p\u003e\n\u003cp\u003eThe non-invasive clinical method to detect visceral autonomic function is called Heart rate variability (HRV) [14-17]. Frequency domain parameters, such as high frequency (HF), low frequency (LF), and the LF/HF ratio can quantitatively evaluate the active states of parasympathetic and sympathetic nerves in the ANS. Based on the results of HRV tests, the present study aimed to analyze the relationships between autonomic function and anorectal manometry, psychological symptoms, symptoms of constipation and life quality in FC sufferers. In addition, we also explored the possible mechanisms of the involvement of the ANS in FC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eParticipation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data for patients with constipation who attended the Gastrointestinal Motility Center of the First Affiliated Hospital with Nanjing Medical University from August 2021 to December 2022 were analyzed retrospectively. We adopted 139 eligible patients according to the following inclusion criteria:\u0026nbsp;①met the FC diagnostic criteria of the Rome IV guidelines [2];\u0026nbsp;②aged\u0026nbsp;from 18 to 80 years old;\u0026nbsp;③all the patients accepted tests of heart rate variability (HRV) and high-resolution anorectal manometry (HRAM); and\u0026nbsp;④being able to effectively communicate with and voluntarily participate in the study. The exclusion criteria comprised:\u0026nbsp;①constipation caused by organic diseases;\u0026nbsp;②a history of chronic diseases that might affect gastrointestinal function and autonomic nervous function,\u0026nbsp;such as, diabetes mellitus, hypothyroidism, and mental deseases(not a state of mind);\u0026nbsp;③experienced previous gastrointestinal surgery or drug-induced constipation:\u0026nbsp;Opioids, NSAIDs, anticholinergics, aluminum and calcium antacids, periwinkle alkaloids, calcium antagonists, diuretics;\u0026nbsp;④women in pregnancy or lactation; and\u0026nbsp;⑤people who were treated with pacemaker or implantable cardioverter defibrillator as well as radiofrequency ablation for arrhythmia [18]. This research\u0026nbsp;was approved by\u0026nbsp;the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Ethics number :2022-SR-607).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAutonomic function test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe power spectrum of HRV was used to assess sympathetic and parasympathetic activity in the hospital for 5 minutes [19]. The low frequency band (LF, 0.04–0.15 Hz) in the HRV frequency domain analysis reflects the dual activity of sympathetic and parasympathetic nerves but centers on the former. The high frequency band (HF, 0.15–0.40 Hz) only indicates parasympathetic activity. The ratio of LF/HF implies the balance between sympathetic and parasympathetic nerves [20]. In line with the outcomes of HRV detection, FC sufferers were classified into three groups: The normal group\u0026nbsp;was referred to as the LF/HF normal group, whose balance point of autonomic tension\u0026nbsp;ranged from\u0026nbsp; -1.5σ to 1.5σ; the heavily sympathetic nerve-biased group was\u0026nbsp;referred to as the LF/HF sympathetic group, whose balance point of autonomic tension\u0026nbsp;was ≥1.5σ; and the heavily parasympathetic nerve‑ biased group was\u0026nbsp;referred to as the LF/HF parasympathetic group, whose balance point of autonomic tension\u0026nbsp;was ≤\u0026nbsp;-1.5σ. The HRV detector (ZSY-1, Shenyang Weijin Gene Technology Co., Ltd., Shenyang, China) detected autonomic function, and the\u0026nbsp;σ represents the statistical data of the instrument after comparing the data of the subject with that of an internal database of healthy peoples' data [21].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnorectal motility and sensory assessment\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe HRAM examination was performed using Ningbo Mida Medical Instrument Co., Ltd.'s (Ningbo, Chins) 8-channel water-perfusion anorectal pressure monitor. Before detection, the patients were emptied of rectal stools using a glycerine enema. During the examination, they lay in a left knee-bent position and a manometry catheter with a balloon at the front end was inserted through the anus for at least 6 cm. After a five minutes’ adjustment, they were tested in the following order: resting state, tightening the anus, simulating defecation state, and then recording the resting pressure and length of the anal sphincter, the maximum contraction pressure, the duration of anal contraction and rectal defecation pressure. Rectal sensory function was evaluated simultaneously by injecting air into the rectal balloon continuously and slowly alongside with sequentially recording the patients’ initial sensory threshold, initial bowel movements, first constant sensation volume (FCSV), first desire to defecate volume (FDDV), and maximum tolerated volume [22]. All 139 subjects underwent tests for anorectal motility, whereas one person in the LF/HF parasympathetic group rejected the tests of sensory function because of intolerance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConstipation severity assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the objective severity, the constipation scoring system (CSS) was employed, with a total score ranging from 0 to 30 points [23]. The higher the score, the more serious the symptoms of constipation. The patient assessment of constipation symptoms (PAC-SYM) reflects the subjective feelings of patients about constipation symptoms, including three subscales of abdominal symptoms, rectal symptoms, and fecal traits. Each of subscales uses a Likert score (0–4 points). The higher the score, the more severe the subjective feelings of constipation symptoms [24]. The patient assessment of constipation quality of life (PAC-QOL) evaluates the life quality of people with constipation, containing 28 items and classified into four dimensions: physical discomfort, psychosocial discomfort, anxiety, and satisfaction. The higher the score, the worse the life quality associated with constipation [25].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMental state evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZung’ s Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were adopted to assess the anxious and depressive status of patients in the past week before they visited the hospital [26]. The two scales comprise 20 items. When the standard score of SAS is 50 or more and that of SDS is 53 or more, it indicates that patients have obvious anxious and depressive emotions. The severity of anxious and depressive emotions increases with increasing scores [27].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSPSS25.0 software was utilized for statistical analysis (IBM Corp., Armonk, NY). The normal distributed data are shown as the mean ± standard deviation (± s), and analysis of variance (ANOVA) was employed for comparisons between groups. The median (lower quartile, upper quartile) [M (P25, P75)] was used to describe data with a skewed distribution, and the Kruskal–Wallis H test was applied for comparisons among groups. Categorical data were described as examples (n) and percentages (%), and the chi-squared test or Fisher's exact probability method were utilized for between-group comparisons. To probe the connection between HRV parameters and severity of constipation, anxious and depressive emotions along with life quality, Pearson analysis, and linear regression analysis were carried out after normalization. It was considered statistically significant when the two-tailed test P value was less than 0.05. Moreover, RStudio Team (2020) (RStudio: Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/.) was employed to visualize results, together with GraphPad Prism 9.0 software (GraphPad Inc., La Jolla, CA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline data and grouping information.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the present research, 139 patients with FC were adopted and classified into three groups according to the result of LF/HF. There were 69 patients (male/female: 14/55) in the LF/HF normal group, 25 (male/female: 8/17) in the LF/HF sympathetic group, and 45 (male/female: 12/33) in the LF/HF parasympathetic group. We performed principal component analysis on the grouped data (Figure 1). Multivariate analysis of variance (MANOVA) showed that there was a statistically significant difference (P \u0026lt; 0.05), which verified the feasibility of the LF/HF parameters as the grouping criteria. Their age, sex, course of disease, and body mass index (BMI) were compared separately (Table 1), but displayed no significant differences (P \u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003eFigure 1. Principal component analysis (PCA) of global heart rate variability (HRV)-Profiles of functional constipation patients. Normal group (red circles), sympathetic group (blue circles), and parasympathetic group (green circles), Ellipsoids mark the 95% confidence intervals of the respective groups. ANS, autonomic nervous system.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Baseline features of functional constipation (FC) sufferers in each HRV group.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eLF/HF Normal\u003c/p\u003e\n \u003cp\u003e(n = 69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003eLF/HF Abnormal\u003c/p\u003e\n \u003cp\u003e(n = 70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eSympathetic\u003c/p\u003e\n \u003cp\u003e(n = 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eVagal\u003c/p\u003e\n \u003cp\u003e(n = 45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eAge [years, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e48 (34,54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e37 (29,55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e48 (39.5,55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.273\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eSex (n, M/F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e14/55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e8/17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e12/33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.464\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eDuration [years, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e5 (2,10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.5 (2,10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4 (2,10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.868\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eBMI (kg/m2, mean\u0026nbsp;\u0026plusmn;\u0026nbsp;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e21.69 \u0026plusmn; 2.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e21.35 \u0026plusmn; 3.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e21.52 \u0026plusmn; 3.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.881\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBMI: body mass index; M (P25, P75): median (lower quartile, upper quartile); SD: standard deviation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of anorectal manometry parameters across different groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant differences were found in most anorectal motility and rectal sensory parameters (P \u0026gt; 0.05) (Table 2). Notably, there was a significant difference in anal resting pressure among the groups (P = 0.029). After the post- hoc multiple comparison, it was found that the anal resting pressure of the LF/HF parasympathetic group [53.00 (47.00, 64.50)] was significantly lower than that of the LF/HF normal group [60.20 (52.50, 73.15)] (P = 0.031). In addition, one person in the LF/HF parasympathetic group did not finish the tests of sensory function because of intolerance, which made little difference to the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e\u003cstrong\u003ea.\u003c/strong\u003e \u003cstrong\u003eAnorectal motility of patients with functional constipation in each HRV group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"723\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eLF/HF Normal\u003c/p\u003e\n \u003cp\u003e(n = 69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eLF/HF Abnormal\u003c/p\u003e\n \u003cp\u003e(n = 70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003eSympathetic\u003c/p\u003e\n \u003cp\u003e(n = 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eVagal\u003c/p\u003e\n \u003cp\u003e(n = 45)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003eARP [ mmHg, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e60.20 (52.50, 73.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e62.85 (49.25, 75.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e53.00 (47.00, 64.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.029*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eAnal sphincter length [cm, mean \u0026plusmn; SD )]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e3.36 \u0026plusmn; 1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e3.08 \u0026plusmn; 0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e3.31 \u0026plusmn; 1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.525\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eMSP [ mmHg, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e214.60 (189.00, 256.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e214.30 (189.20, 279.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e212.50 (177.00, 274.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.950\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eSqueezing duration [s, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e20.00 (16.20, 30.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e26.80 (15.20, 30.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e22.50 (10.15, 30.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.613\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eIntrarectal pressure [ mmHg, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e45.00 (34.50, 60.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e38.00 (34.18, 55.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e46.50 (33.73, 56.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.599\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eARP: Anal resting pressure, MSP: Maximum squeeze pressure, M (P25, P75): median (lower quartile, upper quartile), SD: standard deviation. *, P\u0026lt;0.05; **, P\u0026lt; 0.01\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2b.\u003c/strong\u003e \u003cstrong\u003eRectal sensory parameters of patients with functional constipation in each HRV group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"723\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eLF/HF Normal\u003c/p\u003e\n \u003cp\u003e(n = 69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eLF/HF Abnormal\u003c/p\u003e\n \u003cp\u003e(n = 69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003eSympathetic\u003c/p\u003e\n \u003cp\u003e(n = 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eVagal\u003c/p\u003e\n \u003cp\u003e(n = 44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eFCSV [ ml, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e40.00 (25.00, 59.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e50.00 (39.50, 60.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e41.00 (30.00, 50.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eFDDV [ ml, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e60.00 (47.00, 100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e80.00 (62.50, 100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e70.00 (50.00, 85.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eSustained urgency volume [ ml, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e110.00 (84.00, 145.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e122.00 (86.25, 150.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e100.00 (90.00, 120.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.646\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 273px;\"\u003e\n \u003cp\u003eMaximum tolerated volume [ ml, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e150.00 (100.00, 200.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e140.00 (112.50, 185.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e138.00 (110.00, 170.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.757\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFCSV: first constant sensation volume; FDDV: first desire to defecate volume, M (P25, P75): median (lower quartile, upper quartile), SD: standard deviation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of anxiety/depression\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eacross different groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were statistical differences in SAS and SDS among the groups (SAS, P = 0.005; SDS, P = 0.015). Shown as multiple comparisons, compared with the normal (41.59 \u0026plusmn; 7.38) and the parasympathetic group (43.60 \u0026plusmn; 5.39), the SAS score of the sympathetic group (49.63 \u0026plusmn; 8.76) was the highest. The differences were statistically significant (sympathetic versus normal, P \u0026lt; 0.001; sympathetic versus parasympathetic, P = 0.001). The SDS score of the normal group was lower than that of the sympathetic and parasympathetic group (43.56 \u0026plusmn; 6.93 versus 50.19 \u0026plusmn; 10.42, P \u0026lt; 0.001; 43.56 \u0026plusmn; 6.93 versus 47.42 \u0026plusmn; 5.61, P = 0.007). No significant difference was discovered between the sympathetic and the parasympathetic groups (P \u0026gt; 0.05, Figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of constipation severity and\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;life quality\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;across different groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn terms of the objective severity of constipation symptoms (CSS score), there was a significant difference among the three groups (P = 0.01). The score of the LF/HF parasympathetic group [18.00 (16.00, 19.00)] was the highest [sympathetic group, 16.00 (15.00, 18.00); normal group, 16.00 (14.00, 18.00)] and the difference between the parasympathetic and the normal group was statistically significant (P = 0.003). In terms of the subjective feelings of constipation symptoms (PAC-SYM score), there was a significant difference between the sympathetic group [1.67 (1.42, 1.87)] and the normal group [1.50 (1.33, 1.75)] (P = 0.035), among which the dimension of \u0026quot;rectal symptoms \u0026quot; in the LF/HF normal group [0.33 (0.33, 0.67)] was lower than that in the LF/HF sympathetic group [0.67 (0.33, 1.00)], and the difference was statistically significant (P \u0026lt; 0.05). For life quality (PAC-QOL score), compared with the LF/HF normal group, patients in the LF/HF sympathetic group had a poorer life quality, which was mainly reflected in the three dimensions of \u0026quot;physical discomfort\u0026quot;, \u0026quot;psychosocial discomfort\u0026quot;, and \u0026quot;worry and anxiety\u0026quot; (all P \u0026lt; 0.05) (Table 3, Figure 2C, 2I).\u003c/p\u003e\n\u003cp\u003eTo probe the reason why the parasympathetic group manifested the highest CSS score, we made analysis of the CSS scores for different mental state groups. It turned out that the depressive state depicted the highest score.(Figure 3J） Moreover, the present research also revealed a positive correlation between anxiety (r = 0.34, P \u0026lt; 0.0001) or depression (r = 0.46, P \u0026lt; 0.0001) and the CSS score (Figure 3A, 3B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation analysis between HRV parameters and SAS/SDS, severity of constipation and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003elife quality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHF correlated negatively with SAS score (r = -0.21, P \u0026lt; 0.05), suggesting that anxiety might be related to decreased parasympathetic activity. Meanwhile, HF also correlated negatively with \u0026ldquo;physical discomfort\u0026rdquo; (r = -0.26, P \u0026lt; 0.01), a subscale of PAC-QOL, suggesting that constipation quality of life might be related to decreased parasympathetic activity. The ratio of LF/HF correlated positively with the SAS score (r = 0.18, P \u0026lt; 0.05). The LF/HF ratio also correlated positively with \u0026ldquo;rectal symptoms\u0026rdquo; (r = 0.17, P \u0026lt; 0.05), a subscale of the PAC-SYM score, but not with the CSS score, which indicated that FC patients with sympathetic bias/decreased parasympathetic activity had more severe subjective feelings of constipation symptoms, whereas the objective severity of the symptoms of constipation was not strong. The LF/HF ratio also had a positive association with the PAC-QOL score (r = 0.18, P \u0026lt; 0.05) and its subscales of \u0026ldquo;Physical discomfort\u0026rdquo; (r = 0.20, P \u0026lt; 0.05) and \u0026ldquo;Worry/anxiety\u0026rdquo; (r = 0.21, P \u0026lt; 0.05), demonstrating that the more sympathetic biased the autonomic disorder, the lower the life quality of patients with constipation. In summary, patients with FC with severe autonomic imbalance had obvious anxiety, severe subjective feelings of constipation symptoms, and a low level of life quality. In sympathetic-biased FC sufferers, the lower the parasympathetic activity, the more obvious the anxiety and the stronger the subjective feelings of constipation symptoms, together with worse the physically-related quality of life, without correlation with the objective severity of constipation, as shown in Table 4a and Figure 3C-3I.\u003c/p\u003e\n\u003cp\u003eTo further explore the influence of autonomic bias on the symptoms of constipation\u003cs\u003e\u0026nbsp;\u003c/s\u003etogether with psychological state, regression analysis was performed. The autonomic function bias was set as a dumb variable and used as an independent variable, with SAS, SDS, CSS, PAC-SYM, Rectal symptoms, PAC-QOL, Physical discomfort, Psychosocial discomfort, and Worry/anxiety as dependent variables respectively. As shown in Figure 4A~4B, parasympathetic bias might be related to depression (B = 3.861, 95% confidence interval (CI): 1.093-6.628, P= 0.007) and aggravated objective constipation symptoms (B = 1.515, 95% CI: 0.525-2.505, P = 0.003). Sympathetic bias might affect a patient\u0026apos;s psychological state, including anxiety (B = 8.039, 95% CI: 4.770-11.309, P \u0026lt; 0.001) and depression (B = 6.628, 95% CI: 3.256-10.000, P \u0026lt; 0.001), subjective feelings of constipation symptoms (B = 0.206, 95% CI: 0.064-0.347, P = 0.005), and quality of life (B = 0.533, 95% CI: 0.333-0.733, P \u0026lt; 0.001) except objective constipation symptoms.\u003c/p\u003e\n\u003cp\u003eIn addition, to ascertain the effect of anxiety/depression on the autonomic function, linear regression analysis was conducted with SAS/SDS scores as independent variables and HRV parameters (the LF/HF ratio and HF) as dependent variables. It turned out that HF correlated negatively with SAS (B = -0.008, 95% CI: -0.013- -0.003, P = 0.003), and the LF/HF ratio correlated positively with SAS (B = 0.021, 95% CI: 0.008- 0.035, P = 0.002). Meanwhile, HF had a positive correlation with SDS (B = 0.005,95% CI: 0.000-0.010, P =0.067), whereas the ratio of LF/HF correlated negatively with SDS (B = -0.016, 95% CI: -0.029- -0.003 P = 0.017), which agreed with the fact that the parasympathetic biased group showed the highest CSS score among the three groups. Thus, the linear regression analysis above suggested that depression might result in parasympathetic bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2\u003c/strong\u003e. \u003cstrong\u003eComparisons of anxiety/depression, severity of constipation and life quality among different heart rate variability (HRV) groups with functional constipation (FC).\u0026nbsp;\u003c/strong\u003e(A) Self-rating Anxiety Scale (SAS) score for patients with FC in each HRV group. (B) Self-rating Depression Scale (SDS) score for patients with FC in each HRV group. (C) Constipation Scoring System (CSS) scores for patients with FC in each HRV group. (D, E) Patient Assessment of Constipation Symptom (PAC-SYM) and its one dimension of \u0026ldquo;rectal symptoms\u0026rdquo; for patients with FC in each HRV group. (F~I) Patient Assessment of Constipation Quality of Life (PAC-QOL) and its three dimensions of \u0026ldquo;physical discomfort\u0026rdquo;, \u0026ldquo;psychosocial discomfort\u0026rdquo; and \u0026ldquo;worry/anxiety\u0026rdquo; for patients with FC in each HRV group.SAS/SDS: Zung\u0026rsquo;s self-rating anxiety and depression scale. *P \u0026lt; 0.05; **P \u0026lt; 0.01; ***P \u0026lt; 0.001\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3.\u003c/strong\u003e \u003cstrong\u003eA-B: Correlation analysis of Self-rating Anxiety Scale (SAS)/Self-rating Depression Scale (SDS) and severity of constipation in patients with functional constipation (FC). C-I: Correlation analysis between heart rate variability (HRV) parameters and severity of constipation and life quality in patients with functional constipation (FC).\u0026nbsp;\u003c/strong\u003e(A) Between SAS and Constipation Scoring System (CSS) score for patients with FC. (B) Between SDS and CSS score for patients with FC. (C) Between SAS score and high frequency (HF). (D) Between Physical discomfort and HF. (E) Between Self-rating Anxiety Scale (SAS) score and the ratio of low frequency (LF)/HF. (F) Between Rectal symptoms and the ratio of LF/HF. (G-J) Between Patient Assessment of Constipation Quality of Life (PAC-QOL) score and its dimensions of \u0026ldquo;Physical discomfort\u0026rdquo; and \u0026ldquo;Worry/anxiety\u0026rsquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eConstipation Symptoms and Quality of Life in patients with FC in each HRV group\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"573\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003eLF/HF Normal\u003c/p\u003e\n \u003cp\u003e(n = 69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 244px;\"\u003e\n \u003cp\u003eLF/HF Abnormal\u003c/p\u003e\n \u003cp\u003e(n = 70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003eSympathetic\u003c/p\u003e\n \u003cp\u003e(n = 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003eVagal\u003c/p\u003e\n \u003cp\u003e(n = 45)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eCSS [S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e16.00 (14.00,18.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e16.00 (15.00,18.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e18.00 (16.00,19.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.013*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePAC-SYM [S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.50 (1.33,1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.67 (1.42,1.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.58 (1.33,1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.035*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAbdominal symptoms\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.00 (0.75,1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.00 (1.00,1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.00 (0.75,1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.056\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eRectal symptoms\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[S, M (P25, P75)]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.33 (0.33,0.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.67 (0.33,1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.33 (0.33,0.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.017*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eDefecation symptoms\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e2.40 (2.20,3.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e2.60 (2.40,3.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e2.60 (2.30,2.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePAC-QOL [S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.50 (1.14,1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.89 (1.35,2.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.61 (1.41,1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;Physical discomfort\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.75 (1.25,2.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e2.25 (1.75,2.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.75 (1.38,2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.000***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePsychosocial discomfort\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.88 (0.63,1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.38 (0.75,2.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.12 (0.88,1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.013*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eWorry/anxiety\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.17 (0.79,1.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.83 (1.09,2.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.33 (1.17,1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.000***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eSatisfaction\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[S, M (P25, P75)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e3.00 (2.75,3.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e3.50 (2.88,4.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e3.00 (3.00,3.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCSS: constipation scoring system; PAC-SYM: the Patient Assessment of Constipation Symptoms; PAC QOL: Patient Assessment of Constipation Quality of Life. HF: high-frequency; LF/HF: low frequency/high-frequency M (P25, P75): median (lower quartile, upper quartile). *P \u0026lt; 0.05; **P \u0026lt; 0.01; ***P \u0026lt; 0.001.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Correlation analysis between HRV parameters and anxiety/depression, constipation severity, and quality of life in patients with FC\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"770\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSAS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCSS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAC-SYM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRectal symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAC-QOL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhysical discomfort\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePsychosocial discomfort\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWorry/\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eanxiety\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSatisfaction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-0.21*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e-0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e-0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e-0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e-0.26**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e-0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e-0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLF/HF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e0.18*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.17*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.18*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.20*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e0.21*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eSAS/SDS: Zung\u0026rsquo;s self-rating anxiety and depression scale; CSS: constipation scoring system; PAC SYM: the Patient Assessment of Constipation Symptoms; PAC-QOL: Patient Assessment of Constipation Quality of Life; HF: high-frequency; LF/HF: low-frequency/high-frequency. *P\u0026lt;0.05; **P \u0026lt; 0.01\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePredictive value of the normalized\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;HRV parameters on anxiety/\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;depression\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ROC curve indicated that the normalized ratio of LF/HF had a certain predictive value for anxiety/depression in FC sufferers. As shown in Figure 4C~4D, the area under the ROC curve (AUC) for the normalized ratio of LF/HF to predict anxiety in FC patients was 0.70 [AUC=0.70, 95% confidence interval (CI) (0.59\u0026ndash;0.82), P = 0.0011]. The optimal cut-off value was 0.2850. The sensitivity was 44.4% and the specificity was 84.8%. It implied that a ratio of LF/HF of 0.2850 was the cut-off value for prognosticating anxiety in patients with FC. The AUC for HF to predict anxiety in patients with FC was 0.74. [AUC = 0.74, 95% CI (0.63\u0026ndash;0.86), P = 0.0001]. The cut-off value was 0.2450, with a sensitivity of 51.9% and a specificity of 89.3%. Meanwhile, the AUC for the LF/HF ratio and HF to forecast depression was 0.58 [AUC = 0.58, 95% CI (0.44\u0026ndash;0.72), P = 0.23; the optimal cut-off value = 0.2850, sensitivity = 36.4%, specificity = 82.1%] and 0.61 [AUC=0.61, 95% CI (0.47\u0026ndash;0.75), P = 0.10; optimal cut-off value = 0.3450, sensitivity = 59.1%, specificity = 65.0%], respectively. Notably, the P value of the ROC to prognosticate depression was larger than 0.05, which might have resulted from the fact that the size of this study\u0026rsquo;s number of samples was not very large.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4.\u003c/strong\u003e \u003cstrong\u003eA-B: Linear regression analysis between autonomic nervous system (ANS) bias and anxiety/depression, constipation severity, and quality of life in patients with functional constipation (FC). C-D: Receiver-operator characteristic (ROC) curve analysis of heart rate variability (HRV) parameters for predicting anxiety/depression in functional constipation patients.\u003c/strong\u003e (A) Parasympathetic bias as an independent variable. (B) Sympathetic bias as an independent variable. SAS/SDS: Zung\u0026rsquo;s self-rating anxiety and depression scale; PAC-QOL: Patient Assessment of Constipation Quality of Life; PAC-SYM: Patient Assessment of Constipation Symptom. (C). ROC analysis of HRV parameters for predicting anxiety in functional constipation patients. (D). ROC analysis of HRV parameters for predicting depression in functional constipation patients. AUC: the area under the ROC curve. LF/HF, low frequency/high frequency.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eConstipation is a chronic functional disease with recurrent symptoms and involves frequent visits to the doctor, which significantly affects the life quality of patients. We found that some patients with FC did not have prominent symptoms of constipation, but were often accompanied by anxiety and depression. HRV detection found that they had obvious autonomic dysfunction [28]. However, the relationships among the patients\u0026apos; psychological state, autonomic function, symptoms of constipation, and life quality, especially the association between autonomic function and other factors, are not yet evidence-based.\u003c/p\u003e\n\u003cp\u003eIn this study, 50.4% of the patients with FC had significant autonomic dysfunction, and 35.7% of them had anxiety and/or depression. Moreover, the autonomic nerve function of patients with FC correlated significantly with SAS and SDS scores. We observed that FC sufferers with sympathetic-biased autonomic function had significantly increased SAS and SDS scores, indicating that patients with FC with sympathetic-biased autonomic function had comorbidities such as anxiety and depression. Other studies have found that decreased HF, referring to parasympathetic activity in HRV detection, was associated with anxiety and depression [29]. However, in this study, it was found that depression aggravated parasympathetic bias. Our results and those of previous studies implied that there was a strong association between autonomic function and anxiety and/or depression. The LF/HF ratio and HF in HRV detection had predictive value for anxiety/depression in patients with FC. Clinically, HRV examination of patients with FC not only showed autonomic function, but also indicated to gastroenterologists that the patient might have anxiety/depression.\u003c/p\u003e\n\u003cp\u003ePrevious studies have suggested that anxiety and depression not only interfere with ANS innervation of the colon, but also affect intestinal motility through the central nervous system acting on autonomic nerves [6,30]. Anxiety and depression can affect rectal function in patients with constipation, such as suppressing rectal sensation, increasing rectal compliance, and decreasing rectal sensitivity [31,32]. A previous study also suggested an association between anxiety/depression and symptoms of constipation [33]. However, in this study, we grouped the patients with FC according to the results of HRV detection, and found no significant difference in most anorectal motility and sensation among the three groups, which might have resulted from the fact that this study did not compare the patients with healthy controls and all the included patients with FC had anorectal dysfunction. Thus, the grouping the patients with FC could not reflect significant differences. Notably, we found a significant difference in anal resting pressure between the parasympathetic and the normal groups, which implied that the parasympathetic nerves might inhibit the anal sphincter, as shown in many previous studies [34]. This article showed that the LF/HF ratio had a positive association with the subjective feelings of constipation symptoms instead of the objective severity of constipation symptoms, indicating that sympathetic-bias or decreased parasympathetic activity might be one of the factors affecting more serious feelings of constipation. This might reflect the possibility that most sympathetic patients had comorbidities with anxiety, which could enhance large intestine motility and cancel out the symptoms of constipation to a certain degree [35]. Meanwhile, the present study only involved patients with FC, without healthy controls. Based on the above factors, the difference in CSS score in the sympathetic group in this study was not significant. However, parasympathetic dysfunction might be involved in the occurrence of the symptoms of constipation. The present findings revealed that depression resulted in parasympathetic dysfunction, which then worsened the severity of constipation. As indicated by other studies, pelvic autonomic neuropathy might be present in patients with colonic slow-transit constipation [36,37]. The vagal nerve mainly innervates the left colon and rectum in humans, including two pathways: the vagal sacral reflex and gastrocolic reflex. Vagal dysfunction is associated with slow colonic movement and recto-anal dyssynergia. Increased sympathetic activity releases norepinephrine through cholinergic nerves in the myenteric plexus to inhibit colonic movement, and acts directly on smooth muscle cells to contract the anal sphincter [38]. Clinically, modulating vagal excitability might improve symptoms of constipation. Sacral nerve stimulation (SNS) has been suggested to improve symptoms of constipation by stimulating the presacral vagal plexus, releasing adrenocortical hormones, and thus enhancing colonic or rectal movement through cholinergic nerves [39].\u003c/p\u003e\n\u003cp\u003ePrevious studies have suggested that in patients with FC, symptoms of constipation, anxiety, and depression can affect their quality of life [40]. The present study found that the correlation between anxiety/depression and patients\u0026apos; quality of life cannot be ignored. Moreover, after regression analysis of the patients\u0026rsquo; quality of life, we observed that compared with the severity of constipation, the association between autonomic nerve function and the patient\u0026apos;s quality of life was more prominent. This could be explained from one aspect: some patients with FC who repeatedly visited the clinic might not have outstanding symptoms of constipation. However, after HRV detection or assessment of anxiety and depression, it was found that the autonomic nerves and psycho-emotion of such patients were abnormal, which affected the quality of life of the patients and led to frequent medical treatment. Under the principle of clinical management to improve the life quality of patients with chronic functional diseases, the close correlation between autonomic function and anxiety/depression and the life quality of FC sufferers provides a basis for clinicians to consider the emotions and autonomic function of patients with FC in clinical diagnosis and treatment.\u003c/p\u003e\n\u003cp\u003eIn summary, autonomic function in patients with FC is related to anxiety and depression. Autonomic function tests such as HRV can reflect the anxiety and depression of some patients. Autonomic function and negative emotions correlate significantly with the severity of FC symptoms and disease-related life quality. It makes sense that autonomic nerves, as an important intermediate link in the brain-gut interaction mechanism of functional gastroenteropathy, participate in the mechanism of FC. The results of the present study suggest that more attention should be paid to autonomic function and negative emotions in the clinical diagnosis and treatment of FC, the regulation of which may be a promising treatment option for FC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank Elixigen Inc. for polishing up this manuscript. We would like to thank all patients and manufacturers of testing instruments in the study. We declare that the abstract of this paper has been published in NeuroGASTRO 2023, August 31st - September 2nd 2023, Bucharest, Romania.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGXY and QHY designed the study, performed the statistical analysis of the data, interpreted the results, and wrote the manuscript; JY, LF, LL, YT and TYR designed the study, interpreted the results, and revised the manuscript. All authors approved the final version of the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science foundation of China (grant numbers 82170556, to Yurong Tang).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study conformed to the code of ethics stated in the Declaration of Helsinki. The protocol of this study has received the approval of the clinical research committee of our institution (permission no. 2022-SR-607), and all participants provided written informed consent before enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript and the submission to the journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBarberio B, Judge C, Savarino EV, et al. Global prevalence of functional constipation according to the Rome criteria: a systematic review and meta-analysis. \u003cem\u003eLancet Gastroenterol Hepatol\u003c/em\u003e 2021;6:638-648.\u003c/li\u003e\n \u003cli\u003eAziz I, Whitehead WE, Palsson OS, et al. 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Slow transit constipation: a disorder of pelvic autonomic nerves? \u003cem\u003eDig Dis Sci\u003c/em\u003e 2001;46:389-401.\u003c/li\u003e\n \u003cli\u003eRaethjen J, Pilot MA, Knowles C. Selective autonomic and sensory deficits in slow transit constipation. \u003cem\u003eJ Auton Nerv Syst\u003c/em\u003e 1997;66:46-52.\u003c/li\u003e\n \u003cli\u003eLiu LJ, Milkova N, Nirmalathasan J, et al. Diagnosis of colonic dysmotility associated with autonomic dysfunction in patients with chronic refractory constipation. \u003cem\u003eSci Rep\u003c/em\u003e 2022;12:12051.\u003c/li\u003e\n \u003cli\u003eHuang ZH, Li SY, Foreman RD, et al. Sacral nerve stimulation with appropriate parameters improves constipation in rats by enhancing colon motility mediated via the autonomic-cholinergic mechanisms. \u003cem\u003eAm J Physiol Gastrointest Liver Physiol\u003c/em\u003e 2019;317:G609-G617.\u003c/li\u003e\n \u003cli\u003eJiang Y, Tang YR, Xie C, et al. Influence of sleep disorders on somatic symptoms, mental health, and quality of life in patients with chronic constipation. \u003cem\u003eMedicine (Baltimore)\u003c/em\u003e 2017;96:e6093.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"autonomic nervous function, functional constipation, psychological emotion, evaluation of patients’ life quality","lastPublishedDoi":"10.21203/rs.3.rs-8479442/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8479442/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAbnormal brain-gut interactions have a role in functional gastrointestinal disorders. The autonomic nervous system (ANS) is influenced by emotions, possibly affecting the disease status of sufferers with functional constipation (FC). However, their correlations are unclear. This research aims to ascertain the association between ANS function and psychological status, constipation severity, and life quality of FC sufferers.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAccording to heart rate variability (HRV) tests, 139 FC sufferers were classified into low frequency (LF)/high frequency (HF) normal, LF/HF sympathetic, and LF/HF parasympathetic groups. The scores of Zung\u0026rsquo;s Self-Rating Anxiety and Depression Scale (SAS/SDS), Constipation Scoring System (CSS), Patient Assessment of Constipation Symptom (PAC-SYM), and Patient Assessment of Constipation Quality of Life (PAC-QOL) were compared. Anorectal manometry and electrointestinogram parameters were assessed. The associations between the patients\u0026rsquo; life quality and ANS function, mental or psychological status, and constipation severity were assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAnorectal physiology and intestinal electric activity were not different among the groups. Compared with the LF/HF normal group, the sympathetic group had a higher SAS/SDS score, a higher PAC-SYM score and a higher PAC-QOL score. The parasympathetic group manifested the highest CSS score, which might result from a predominance of depression. Regression analysis showed that anxiety/depression and ANS functional state significantly affected the life quality of FC sufferers.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eFC sufferers with autonomic dysfunction apparently coexisted with anxiety/depression. The life quality of FC sufferers was negatively affected by ANS function and anxiety/depression. Autonomic adjustments, psychological interventions, and central nervous system drugs might help to treat FC.\u003c/p\u003e","manuscriptTitle":"An insight into the effect of the crosstalk between autonomic function and clinical manifestations of functional constipation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-02 07:28:52","doi":"10.21203/rs.3.rs-8479442/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-24T10:46:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-05T13:30:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160953328206494598108547232672800354400","date":"2026-02-05T07:00:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222128390265330968409751373036353627114","date":"2026-01-29T10:09:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-29T09:46:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-27T08:09:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-06T13:57:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-05T12:28:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2026-01-05T12:19:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4ee39471-6500-495c-b832-b28ff1d6b15d","owner":[],"postedDate":"February 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T07:28:52+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-02 07:28:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8479442","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8479442","identity":"rs-8479442","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}