Abnormal structural changes and disturbed functional connectivity in patients with Crohn’s disease and abdominal pain: a voxel-based morphometry and functional magnetic resonance imaging study

Introduction

Crohn’s disease (CD) is a chronic inflammatory bowel disease of uncertain etiology that impacts the entire gastrointestinal tract, but especially the terminal ileum or adjacent colon (1). The incidence and prevalence of CD are higher in developed countries than in developing countries (2). The incidence of CD is 20.2 per 100,000 person-years in Canada, 10.6 per 100,000 person-years in Northern Europe, 16.5 per 100,000 person-years in New Zealand, and 29.3 per 100,000 person-years in Australia (3). Despite its prevalence, CD has no cure, and thus patients must endure lifelong medical treatment and care, significantly diminishing their quality of life. Chronic abdominal pain is the most prevalent and incapacitating sign of CD and can aggravate patient’s psychological distress (4,5). Statistically, 20–70% of patients with CD experience abdominal pain (4). Therefore, understanding the underlying mechanisms of pain is crucial for revealing its neuroimaging characteristics and establishing a theoretical foundation for future research on pain management.

Neuroimaging techniques can effectively assess cerebral structure or function (6). Voxel-based morphometry (VBM) employs a distinct algorithm to quantify an individual’s gray-matter volume (GMV) (7). Resting-state functional connectivity (rs-FC) quantifies the coordinated activity of several brain regions during rest, indicating their functional collaboration (8). Recent applications of structural and functional magnetic resonance imaging (fMRI) have identified changes in the brain’s structure and function in patients with CD. Structural investigations indicate that patients with CD have abnormalities in GMV, notably in the insula (9), precentral gyrus, frontal lobe (10), and cerebellum (11), as well as irregularities in cortical thickness, particularly in the middle temporal gyrus, lingual gyrus, and hippocampus (10). fMRI studies have demonstrated that patients with CD exhibit aberrant FC between the frontoparietal network (FPN) and the salience network (SN), between the FPN and the default mode network (DMN) (12), within the insula (9), and within the cerebellum (11).

Recent research on the pathophysiology of patients with CD and abdominal pain indicates that pain is influenced by the gut microbiota via a signaling route within the microbiota-gut-brain axis, which affects central nervous system function (13,14). Further investigations into the structural and functional variations in the brains of patients with CD with and without abdominal pain have been conducted as research has advanced. Central nervous system sensitivity or reconfiguration may contribute to chronic abdominal pain in patients CD (15). A VBM-based study examined the alterations in gray-matter structure in patients with CD and abdominal pain, revealing modifications in GMV in the anterior cingulate cortex (ACC) and insula (16). A resting-state fMRI study indicated that regional homogeneity was diminished in the middle cingulate cortex (MCC), insula, and supplementary motor area in patients with CD and abdominal pain (17). In another neuroimaging study conducted on patients with CD and abdominal pain, the occurrence of abdominal pain seemed to be mostly associated with abnormalities in the brain regions belonging to the DMN. Another recent resting-state FC (rs-FC) study also demonstrated that patients with CD and abdominal pain had altered FC between the periaqueductal gray matter (GM) and the DMN (18). Alteration in brain areas within this network may contribute to chronic pain (19,20). However, few studies have examined both GMV and rs-FC to characterize the pain-related alterations in structure and FC in patients with CD, and little is known regarding the impact of pain on the brain of patients with CD.

Therefore, in this study, we used VBM to examine the structural changes in GMV in patients with CD and abdominal pain and extracted the data from brain regions with pain-related changes as seed spots to characterize the modifications in FC throughout the brain. Subsequently, we assessed potential correlations between clinical data and neuroimaging results. We hypothesized that chronic abdominal pain in patients with CD is associated with alterations in key pain-processing regions (such as the ACC) and the DMN, reflecting abnormal emotional and sensory processing. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2572/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Ethics Committee of Chongqing General Hospital in China approved all of the procedures in this study (approval No. KY S2023-019-01). All participants were informed of all experimental procedures related to the experiment and signed informed consent prior to its implementation.

Participants

This study prospectively recruited 50 patients with CD, with illness durations ranging from 1 to 18 years, with a consecutive enrollment strategy being applied to ensure patient selection reflected real clinical distributions. Additionally, 25 healthy control (HC) volunteers, matched for age, sex, and education with the CD cohort, were included in the study. All participants were of Han ethnicity. Fifty patients with CD were recruited from Chongqing General Hospital between October 2023 and March 2024. Additionally, 50 patients with CD were divided into two groups by professional gastroenterologists who were blinded to the neuroimaging data based strictly on whether or not they had abdominal pain: 24 patients were placed in the CD and abdominal pain (pain CD) group and 26 patients in the CD without abdominal pain (nonpain CD) group. All patients received a comprehensive systemic and gastrointestinal evaluation, which included a colonoscopy and a pathological tissue biopsy. Measures of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were obtained from all patients. The 25 HCs were recruited through advertisements in the local community at random. All healthy participants are matched for right-handedness, age, sex, and education with the groups of patients with CD. The healthy individuals received no drugs and reported no gastrointestinal complaints or pain-related conditions.

The inclusion criteria for patients with CD were as follows: (I) CD diagnosed at least 12 months previous to study inclusion via gastrointestinal endoscopy and pathological tissue biopsy, (II) aged above 18 and under 55 years, (III) Han ethnicity, and (IV) right-handedness.

Among patients with CD experiencing abdominal pain, the pain was consistently characterized as cramping in nature (21). The criteria for persistent abdominal pain in all patients with CD were determined by scores on a visual analog scale (VAS). Chronic abdominal pain was diagnosed if the patient reported a pain level of ≥3/10 on the VAS for 3 out of 6 months (22).

The following exclusion criteria were applicable to all participants: (I) a history of abdominal surgery related to CD; (II) the use corticosteroids, anti-tumor necrosis factor alpha (anti-TNF-α) agents, or psychotropic medications within the 3 months prior to study inclusion; (III) psychiatric or neurological disorders—either personally or in first-degree relatives—history of head trauma, or consciousness disorders; (IV) contraindications to MRI; (V) suboptimal image quality; (VI) substance abuse; (VII) a Crohn’s Disease Activity Index (CDAI) greater than 450 and a Simple Endoscopic Score for CD (SES-CD) exceeding 15; and (VIII) gastrointestinal diseases other than CD. Furthermore, a review of medical records confirmed that none of the participants had been administered nonsteroidal anti-inflammatory drugs (NSAIDs), such as analgesics, during the actual imaging was required for participant inclusion.

Three patients (one from the pain CD group and two from the nonpain CD group) were excluded due to poor image quality, as determined by two independent neuroimaging specialists who were blinded to clinical group assignments.

Clinical assessment

Blood test results for patients with CD were collected, with the primary focus being CRP and ESR. Abdominal pain was assessed via the VAS in all individuals with CD. The VAS is an uncomplicated, accessible, and patient-centric technique that can quantify the intensity of abdominal pain and uses a 100-mm horizontal line ranging from 0 mm, signifying “no pain at all”, to 100 mm, denoting “worst pain tolerable” (23). The CDAI was applied to assess the disease status of individuals with CD (24), while the Gastrointestinal Quality of Life Index (GIQLI) (25) was used to assess the quality of life related to gastrointestinal disorders in all participants.

The Beck Depression Inventory (BDI) (26) scale was used to evaluate the psychological depression status of all participants, while the Trait Anxiety Inventory (T-AI) (27) was used to evaluate the more general and long-standing quality of “trait anxiety”in patients. The Pain Sensitivity Questionnaire (PSQ) (28) scale was also employed and serves as a straightforward alternative to clinical and experimental studies on pain intensity, aimed at assessing pain sensitivity in individuals with chronic disease. The Pain Catastrophizing Scale (PCS) (29) was used to assess the degree of catastrophizing thoughts and behaviors in patients with CD. The PCS consists of three subscales—helplessness, magnification, and rumination—totaling 13 items, each rated on a 5-point scale, with higher scores indicating increased catastrophizing (29,30).

Image acquisition

MRI data were obtained with a 3T clinical scanner (MAGNETOM Skyra, Siemens Healthineers, Erlangen, Germany) equipped with a 20-channel phased array head coil via syngo MR E11 software (Siemens Healthineers) in the Department of Radiology at Chongqing General Hospital. During the MRI examination, all participants were instructed to relax with their eyes closed in a dimly lit room to minimize external stimuli while avoiding sleep and specific thoughts. All participants were positioned supine, with their heads stabilized via foam pads and earplugs installed to reduce motion and scanner noise, respectively. T1-weighted (T1W) axial anatomical scans were obtained with T1W three-dimensional magnetization-prepared rapid acquisition gradient echo sequences under the accompanying parameters: repetition time (TR) =2,200 ms, echo time (TE) =2.44 ms, flip angle (FA) =8°, data matrix =224×224, field of view (FOV) =230 mm × 230 mm, and voxel size =1.0 mm × 1.0 mm × 1.0 mm. Ultimately, a total of 144 continuous axial slices were obtained. The resting-state functional images, dependent on blood oxygenation levels, were obtained with an echo-planar imaging (EPI) sequence under the following parameters: TR =2,000 ms, TE =30 ms, FA =68°, data matrix =70×70, FOV =210 mm × 210 mm, and voxel size =3.0 mm × 3.0 mm × 3.0 mm. Ultimately, a total of 33 interleaved slices were obtained, comprising 220 measurements.

Image preprocessing

Structural MRI

Structural images were processed via Computational Anatomy Toolbox 12 (CAT12) (https://www.fil.ion.ucl.ac.uk/spm), an extension of Statistical Parametric Mapping version 12 (SPM12; Wellcome Department of Cognitive Neurology, London, UK; https://www.fil.ion.ucl.ac.uk/spm) designed for computational anatomy. The processing pipeline started with a detailed segmentation of T1W structural MR images. This step involved advanced algorithms and tissue probability maps (TPMs) to precisely divide the images into three main components: GM, white matter (WM), and cerebrospinal fluid (CSF). This segmentation formed the basis for subsequent calculations of GMV and total intracranial volume (TIV), ensuring the accuracy of morphological analyses. Next, the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) method was employed to spatially normalize the segmented GM to the Montreal Neurological Institute (MNI) template. During this process, each individual’s GM image underwent nonlinear transformations to match the standard template, with a voxel size of 1.5 mm × 1.5 mm × 1.5 mm set to balance spatial resolution and computational efficiency. To ensure that the normalized images retained the original tissue volume information, modulation with performed with only the nonlinear components, which adjusted the voxel values to reflect local volume changes induced by the nonlinear transformations. Furthermore, a crucial bias-field correction step was completed via the N4ITK (Nonparametric Nonuniform intensity Normalization) method before segmentation to eliminate intensity nonuniformities in the images caused by magnetic field inhomogeneities or other artifacts, thereby improving segmentation accuracy. Finally, to reduce noise and enhance the signal-to-noise ratio, the GM probability values were smoothed with a 3D isotropic Gaussian kernel with a full-width at half-maximum (FWHM) of 8 mm. This step facilitated the detection of subtle differences in GMV across participants in subsequent analyses. All settings were configured in accordance with normal options. Structural images were with a quality rating of “C” or lower were rejected.

Functional MRI

Resting-state fMRI data underwent preprocessing via Resting-State fMRI Data Analysis Toolkit Plus (RESTplus) version 1.2 (http://restfmri.net/forum/RESTplus). The data were first converted to Neuroimaging Informatics Technology Initiative (NIfTI) format for standardization. To ensure stability, the initial 10 time points were removed. Slice-timing correction was applied to align temporal information across slices. Head motion correction was performed to eliminate artifacts from movements exceeding 2 mm or a 2° rotation. The T1W images were normalized to a standard template using DARTEL registration to enable group comparisons. To enhance the signal-to-noise ratio and to account for spatial variations in brain anatomy, the normalized fMRI data were smoothed via a Gaussian kernel with a three-dimensional FWHM of 6 mm. Linear trends were removed to focus on neural fluctuations. Nuisance covariates, including CSF and WM, were regressed out to reduce noise. Finally, bandpass temporal filtering (0.01–0.08 Hz) was applied to minimize physiological noise and drift, with the relevant neural activity frequency band being isolated.

Data processing

VBM data analysis

VBM analysis was performed with SPM12, a toolkit compatible with MATLAB R2022a (MathWorks, Inc., Natick, MA, USA). An ABSOLUTE mask was applied during modulation, using a threshold of 0.2, which required all included voxels to have a GM probability greater than 0.2 across all participants.

Seed-to-voxel rs-FC analysis

The rs-FC study was conducted through use of a seed-based methodology via the RESTplus toolbox (http://restfmri.net/forum/RESTplus). Any GMV exhibiting differences post-VBM analysis was designated as a seed, and a voxel-wise correlation analysis was then conducted. The seed region was defined as a 6-mm sphere centered at the location of maximum statistical variance. The individual seed connectivity map was generated through a computation of the temporal correlation (with Fisher r-to-z transformation being used for normalization) between the time series of the seed area and the time series of all other brain voxels. Specifically, for each voxel, we calculated the correlation coefficient between its time series and that of the predefined seed area.

Statistical analysis

The demographic and clinical data, along with correlation analysis, were analyzed with SPSS 27.0 software (IBM Corp., Armonk, NY, USA). One-way analysis of variance (ANOVA) was conducted to examine the differences in age and education among the pain CD group, nonpain CD group, and HC group. The Chi-squared test was employed to compare the sex differences between the three groups. Clinical characteristics (i.e., disease duration, CRP, ESR, and scale scores) were examined with a two-sample t-test or a nonparametric Mann-Whitney test (when results did not conform to a normal distribution) and one-way ANOVA.

Analysis of covariance (ANCOVA) was employed to ascertain the differences in GMV and FC between the pain CD, nonpain CD, and HC groups, with sex, age, years of education, TIV, CDAI, BDI, T-AI, PCS-Magnification, and PSQ total score being controlled for as covariates. The threshold for group differences was established at P<0.05 with Gaussian random field (GRF) correction (voxel-wise: P<0.001; cluster level: P<0.05). Subsequently, post hoc two-by-two comparisons were conducted to identify significant differences between the groups.

Partial correlation analyses were employed to determine the association of differential GMV and FC results with clinical features, including CRP, ESR, and scale scores, with age, sex, years of education, CDAI scores, and duration of disease being controlled for as covariates. The significance level was established at P<0.05.

Results

Clinical characteristics

The process of participant inclusion is shown in Figure 1. The final cohort comprised 23 patients with CD (age 27.17±6.43 years; 15 males and 8 females), 24 patients with CD and no pain (age 27.75±6.13 years; 19 males and 5 females), and 25 HCs (age 27±4.5 years; 21 males and 4 females). Age, sex, and years of education were not significantly different between the pain CD, nonpain CD, and HC groups (P>0.05), as indicated by Table 1. The pain CD group and nonpain group had no statistically significant differences in terms of illness duration, CRP, or ESR (P>0.05). The medication usage of the pain CD and nonpain CD groups is shown in Table 1.

Figure 1 Flowchart of the inclusion process. CD, Crohn’s disease; HCs, healthy controls; VAS, visual analog scale.

The scores of the VAS and CDAI scales of the pain CD group were significantly higher than were those of the nonpain group (P<0.001). Among the pain CD, nonpain CD, and HC groups, the pain CD group had the highest PCS scale scores while the HC group had the lowest (P<0.05); meanwhile, the nonpain CD group had the highest PSQ scale score and the HC group had the lowest (P<0.05). The BDI scale score of the pain CD group was higher than that of the nonpain CD and HC groups (P<0.001), as shown in Table 2.

VBM and FC results

VBM results

Compared with the HC group, the pain CD group and nonpain CD group had a greater GMV in the right ACC (P<0.05, corrected for GRF). In addition, the nonpain CD group also had a higher GMV in the bilateral hippocampus (HIP) than did the HC group. The GMV of the right inferior frontal gyrus-orbital part (ORBinf), left middle frontal gyrus-orbital part (ORBmid), left superior frontal gyrus-orbital part (ORBsup), and right superior frontal gyrus-medial part (SFGmed) in the pain CD and nonpain CD groups were smaller than those of the HC group (P<0.05, corrected for GRF). Compared with the nonpain CD group, the pain CD group had a smaller GMV in the bilateral HIP, right ACC, left ORBmid, and left ORBsup and a greater GMV in the right ORBinf (Table 3, Figure 2A,2B).

Figure 2 The distribution of brain regions with significant differences in gray-matter volume among the groups (P<0.05, corrected). The color bar represents the F-statistic values, with only positive values shown, reflecting the overall variance between groups. (A) Brain regions showing significant intergroup differences in gray-matter volume based on ANCOVA. (B) Post hoc tests showed that the pain CD and nonpain CD groups had significant alterations in gray-matter volume in most of these regions as compared with controls. *, P<0.05; **, P<0.01; ***, P<0.001. ACC, anterior cingulate cortex; HC, healthy control; HIP, hippocampus; L, left; nonpain CD, patients with Crohn’s disease and without abdominal pain; ORBinf, inferior frontal gyrus-orbital part; ORBmid, middle frontal gyrus-orbital part; ORBsup, superior frontal gyrus-orbital part; pain CD, patients with Crohn’s disease and abdominal pain; R, right; SFGmed, superior frontal gyrus-medial part.

FC results

ANCOVA indicated significant intergroup differences between the three groups in terms of FC when differential GMV was used generating seed points. Specifically, the right ACC showed altered FC with the left parahippocampal gyrus (PHG), left superior parietal gyrus (SPG), right postcentral gyrus (PoCG), and left Rolandic operculum (ROL) (all P values <0.05, corrected for GRF), as shown in Figure 3A. Post hoc comparisons showed that the pain CD group exhibited stronger FC between the right ACC and the left PHG and the left ROL, as compared to both the nonpain CD and HC groups (P<0.05). Additionally, the pain CD group had stronger FC between the right ACC and the left SPG compared with the nonpain CD group. The nonpain CD group, in contrast, showed increased FC between the right ACC and the left PHG but decreased FC between the right ACC and the right PoCG as compared to the HC group, as shown in Figure 3B and Table 4.

Figure 3 Brain regions showing significant differences in rs-FC based on the ACC seed and left ORBmid among the pain CD, nonpain CD, and HC groups (P<0.05, corrected). The color bar represents the F-statistic values, with only positive values shown, reflecting the overall variance between groups. (A,C) FC with significant group differences identified by ANCOVA. (B,D) Post hoc tests revealed significant FC alterations in most of these regions in both the pain and nonpain CD groups as compared to the HC group. *, P<0.05; **, P<0.01; ***, P<0.001. ACC, anterior cingulate cortex; ANCOVA, analysis of covariance; FC, functional connectivity; HC, healthy control; L, left; MFG, middle frontal gyrus; nonpain CD, patients with Crohn’s disease and without abdominal pain; ORBmid, orbital parts of the middle frontal gyri; pain CD, patients with Crohn’s disease and abdominal pain; PHG, parahippocampal gyrus; PoCG, postcentral gyrus; R, right; ROI, region of interest; ROL, Rolandic operculum; rs-FC, resting-state functional connectivity; SPG, superior parietal gyrus; THA, thalamus.

Furthermore, when the left ORBmid, a region with altered GMV, was used as the seed point, significant differences were also observed in its FC with the left thalamus (THA), left ACC, and right middle frontal gyrus (MFG) between the three groups (all P values <0.05, GRF corrected), as shown Figure 3C. Post hoc comparisons indicated that the FC between the left ORBmid and key pain-processing regions, including the left THA and left ACC, was significantly increased in the pain CD group as compared to both the nonpain CD and HC groups (P<0.05). Moreover, the FC between the left ORBmid and the right MFG was significantly higher in the pain CD group than the nonpain CD group. Notably, the nonpain CD group showed reduced FC between the left ORBmid and the left THA as compared to the HC group (Figure 3D and Table 4).

Correlation of differential GMV and FC with clinical characteristics

After gender, age, education level, disease duration, and CDAI score were controlled for, partial correlation analysis indicated that the BDI score in the pain CD group was negatively correlated with the FC between the right ACC and the left PHG (r=–0.548; P=0.019), as shown in Figure 4A. Additionally, the PSQ score was negatively correlated with the FC between the left ORBmid and the right MFG in the pain CD group (r=–0.495; P=0.037), as shown in Figure 4B.

Figure 4 Association between clinical scales and altered FC in pain CD group. (A) The FC between the ACC and the left PHG was negatively correlated with BDI score. (B) The FC between the left ORBmid and the right MFG showed a negative correlation. ACC, anterior cingulate cortex; BDI, Beck Depression Inventory; FC, functional connectivity; L, left; MFG, middle frontal gyrus; ORBmid, orbital parts of the middle frontal gyri; pain CD, patients with Crohn’s disease and abdominal pain; PHG, parahippocampal gyrus; PSQ-total, Pain Sensitivity Questionnaire total score; R, right.

Discussion

In this study, we integrated VBM and resting-state fMRI to investigate structural and functional brain alterations in patients with CD and abdominal pain. We found that the pain CD group had altered GMV in the right ACC, SFGmed, and orbitofrontal cortex (OFC) (ORBsup, ORBmid, and ORBinf) as compared to the nonpain CD and HC groups. Functionally, the pain CD group demonstrated heightened ACC connectivity with DMN nodes (PHG, ROL, PoCG, and SPG) and augmented ORBmid-thalamocortical connection involving key pain hubs (THA, left ACC, and MFG). Notably, the FC between the ACC and PHG was inversely correlated with depressive symptoms, whereas the FC between ORBmid and MFG synchronization was negatively correlated with pain sensitivity. These findings suggest that orbitofrontal-ACC reorganization may be linked to visceral nociception processing, while ACC-DMN overconnectivity may be associated with abnormal emotional processing in chronic pain. These findings represent novel insights into the neurological pathways driving abdominal pain in CD.

GMV changes associated with pain and inflammation

Compared with the nonpain CD group, the pain CD group had abnormally decreased GMV in the right ACC cortex, bilateral HIP, and OFC. The ACC, a portion of the ventromedial frontal cortex, is recognized as being significantly linked to pain perception (31). Multiple neuroimaging studies on pain, including those related to migraine (32), chronic low back pain (33), and irritable bowel syndrome (34), have demonstrated that those with chronic pain exhibit anatomical alterations in the ACC. The HIP is intricately linked to pain perception (35), while the OFC is a component of the prefrontal cortex (PFC) and is believed to play a role in pain modulation (36). Both animal model studies and neuroimaging studies in humans have suggested that the ACC, HIP, and the PFC may play an important regulatory role in the pain circuit. For example, rats with increased visceral pain stimulation showed activated cholinergic neurons in the ACC (37), inhibited pyramidal neurons in the HIP (37), and increased cellular activation in the PFC (38). Abnormal alterations in GMV at the ACC, HIP, and PFC have been reported in patients with irritable bowel syndrome (39), chronic pelvic pain (40), and multisite chronic pain (41). Additionally, abnormally altered GMV in the ACC, HIP, and insula has been found in patients with CD and pain (16). Our findings are in agreement with these previous studies and suggest that the intrinsic causes of GMV alterations may be related to chronic nociceptive input or inflammation, as well as subsequent brain repair and functional reorganization (16).

We further found that compared with the HC group, the nonpain CD and pain CD groups had decreased GMV in the OFC and SFGmed. The OFC and SFGmed are components of the medial prefrontal cortex (mPFC), which is integral to the contextual assessment of the regulation of mood and affective states (42). In animal experiments, mice with inflammatory bowel disease exhibited reduced microglia activity in the mPFC, which may be one of the risk factors for psychiatric disorders (43). In neuroimaging studies in humans, patients with functional diarrhea (FD) exhibited reduced cortical thickness in brain regions involved in emotional regulation, including the mPFC and ACC. This structural alteration is associated with impaired emotional regulation, as indicated by an increased dyspepsia (44). A study on ulcerative colitis (UC) indicated that higher cortical stability of the mPFC in patients with UC is significantly associated with increased state-trait anxiety and depression (45). The structural anomalies of the mPFC observed in our study on CD are consistent with those previously reported in other gastrointestinal disorders, such as UC and FD, which similarly involve abdominal pain and disruptions in the gut-brain axis. This may suggest that chronic and recurring gut inflammation affects brain structures related to emotions.

Another key finding of our study was that compared with the HC group, the nonpain CD group showed increased GMV in the HIP. The HIP may modulate vagus nerve activity indirectly via relay regions, which can influence the release of acetylcholine to regulate the activity of immune cells in the intestinal wall (16). In animal experiments, mice with colitis exhibited impaired blood-brain barrier permeability regulators in the HIP, suggesting that inflammation induces a neuroimmune response in this region (46). Another study identified aberrant functional magnetic resonance signals in the HIP of patients with inflammatory bowel disease (47), which aligns with our findings. This suggests that the increased GMV in the HIP may be a compensatory result of inflammation. In summary, for patients with CD, intestinal inflammatory signals may be relayed to the brain through the brain-gut axis, potentially resulting in structural or functional alterations in the brain regions associated with this pathway.

Differences in FC associated with pain and inflammation

The pain CD group exhibited decreased GMV in the right ACC and left ORBmid as compared to the nonpain CD group. The ACC is a crucial center in pain processing, and further investigation into its function in modulating visceral sensitization is warranted (31,48). Numerous studies have identified distinctive changes in GMV in the ACC among patients with pain (49-51). In addition, as a key region involved in emotional regulation, the ORBmid has recently been implicated in pain regulation across multiple studies (52,53). Therefore, both the ACC and ORBmid were selected as seed regions in this study so that their FC with the whole brain in patients with chronic abdominal pain could be determined.

Gut inflammation and pain signaling are conveyed to the brain through the brain-gut axis, potentially resulting in modifications to several functional brain networks (54). We found that compared with the nonpain CD group, the pain CD group had stronger FC between the right ACC and each of the following regions: the left PHG the left ROL and the left SPG. The PHG, SPG, and ROL are all part of the DMN, which embodies the “default state” of the brain and is associated with complex psychological processes such as memory integration and spontaneous thought generation (55,56). Comparable alterations in FC, particularly involving emotional and reward-related networks, have also been reported in chronic pain conditions such as chronic low back pain and failed back surgery syndrome (57,58). Chronic pain’s impact on the DMN has been documented in previous research (59); however, our study uniquely examined the specific enhancement of FC within the DMN in patients with CD and chronic pain. This suggests that chronic pain in patients with CD might be particularly linked to alterations in the connectivity patterns of brain regions involved in memory, self-referential thinking, and emotional processing. A previous study by Chen et al. found that patients with CD and abdominal pain had altered FC between the central aqueduct and the DMN (18). Similarly, abnormalities in the DMN and emotional arousal network have been reported in patients with irritable bowel syndrome and pain (18). Moreover, in the Acceptance and Commitment Therapy (ACT) trial for chronic pain, DMN activation function improved in pain patients after they received an ACT intervention (60). In contrast, our findings extend previous research by demonstrating that chronic exposure to nociceptive stimuli in patients with CD and pain may be associated with enhanced FC specifically within the DMN, suggesting a potential mechanism through which chronic pain can modulate brain connectivity. These novel findings offer insights into how an altered brain network can contribute to chronic pain sensitivity and pain memory, although further studies are required to fully clarify the long-term effects of these neural changes.

The OFC, particularly the ORBmid, is a crucial node within the prefrontal-limbic circuitry, playing a key role in modulating both the affective and sensory aspects of pain (61). In our study, the pain CD group exhibited increased FC between the left ORBmid and several pain-relevant regions, including the left THA, left ACC, and right MFG, as compared to both the nonpain CD and HC groups. In mice with colitis-induced visceral pain, the THA plays a key role in transmitting chronic pain signals (62). Neuroimaging studies on CD have also shown that the FC between the THA in the FPN and the OFC in the visual network is increased in patients with CD; this indicates that the FC changes between the networks may be related to the severity of inflammation and abdominal pain (63), which aligns with our findings. Enhanced FC between the ORBmid and THA may reflect heightened thalamo-cortical interaction under chronic pain conditions, potentially reflecting abnormal sensory integration or persistent attention toward visceral pain signals. Increased FC between the ORBmid and ACC, as observed in our study, might suggest a maladaptive engagement of affective circuits involved in pain appraisal and emotion regulation. The ACC and OFC are frequently coactivated in response to unpleasant stimuli and have been shown to form a network implicated in the cognitive and affective dimensions of pain processing (64). Similarly, the increased ORBmid-MFG FC suggests a demand for executive regulation of pain and emotional stress in patients with CD and pain, as the MFG, part of the dorsolateral prefrontal cortex, modulates pain through the top-down regulation of sensory and limbic regions (65).

Compared with the HC group, both the pain-CD and nonpain CD groups exhibited altered FC between the ACC and regions of the DMN, including the PHG and the ROL. This pattern aligns with previous findings that suggest the presence of altered FC within the DMN in patients with CD (66), indicating a potential baseline alteration in intrinsic brain connectivity associated with chronic inflammation, even in the absence of pain. The ACC plays a critical role in integrating emotional, cognitive, and visceral information, while the DMN is central to self-referential processing and internal mentation. The altered ACC–DMN FC in both the CD subgroups may reflect an adaptive or compensatory mechanism in response to persistent gut inflammation, potentially related to heightened interoceptive awareness or altered affective processing. In addition, patients with CD showed significant differences in FC between the ORBmid and THA. Regardless of whether abdominal pain was present, patients with CD exhibited altered connectivity between these regions, with a distinct pattern of connectivity observed as compared to HCs. Even in the absence of abdominal pain, changes in ORBmid-THA FC suggest that CD may affect the functional integration between these critical brain regions early in the disease. Overall, these results support the notion that CD is linked to a broad spectrum of brain functional reorganization, in which inflammation alone induces detectable neural changes, with the presence of chronic pain further modulating this network activity.

Correlation of pain-related differential FC with abnormal emotional and sensory processing

Upon examining the correlation with clinical scores, we found that the increased FC between the ACC and PHG was associated with lower BDI scores in the pain CD group; similarly, the increased FC between the left ORBmid and right MFG was associated with lower PSQ scores. Intriguingly, these specific FCs were also the highest in pain CD group, as compared to the nonpain CD and HC groups. The ACC is a key node in the SN, integrating emotional and sensory inputs, while the PHG is critically involved in contextual memory and emotional modulation (67,68). The enhanced FC between ACC and PHG in the patients with CD and pain may reflect a compensatory mechanism for counteracting depressive symptoms by upregulating top-down emotional regulation. In addition, the ORBmid-MFG pathway is involved in reward processing and emotional regulation (69).

Finally, FC strength was negatively correlated with PSQ scores, suggesting that stronger connectivity may reduce pain sensitization by enhancing the prefrontal inhibition of nociceptive signals in patients with CD and abdominal pain (64).

Limitations

There are several limitations to this study which should be addressed. First, we employed a cross-sectional design, which restricts our ability to determine whether brain abnormalities in patients with CD and abdominal were are due to pain alone or a combined effect of inflammation and pain. Interoception, the perception of internal sensations such as abdominal pain, is closely linked to brain structure and function, with females typically showing greater sensitivity (70,71). Although we controlled for age and sex as covariates, future studies should incorporate sex-stratified analyses to better clarify their roles in pain perception and brain changes. Second, although we controlled for demographic variables and included the CDAI as a covariate to account for disease activity, the use of individual inflammatory markers such as CRP and ESR was not directly included in our analysis. Although the CDAI is a widely used index for reflecting overall disease activity, it does not fully capture the impact of specific inflammatory markers on brain function. Inflammation itself can influence central nervous system activity, and thus future studies should incorporate CRP and ESR directly as covariates or consider subgroup analyses with matched inflammatory levels to better isolate the neural correlates of visceral pain. Third, due to the complexity and individual variability of medication regimens in patients with CD, it is challenging to achieve complete control over all types of medications in practical research settings. Nevertheless, we strictly adhered to the inclusion and exclusion criteria and specifically excluded individuals using medications known to exert significant effects on the central nervous system, such as corticosteroids and anti-TNF-α therapies. In subsequent work, we aim to expand the sample size and incorporate more systematic documentation and appropriate standardization of medication use to minimize potential confounding effects.

Conclusions

We demonstrated that abdominal pain in patients with CD is associated with both structural and functional brain alterations, particularly involving the ACC and orbitofrontal regions. These changes may underlie the neural mechanisms of visceral pain processing and emotional dysregulation. Furthermore, enhanced ACC-DMN FC and ORB-thalamic circuitry suggests that chronic inflammatory and pain may lead to widespread reorganization of brain networks. These findings point to the neural mechanisms involved in pain regulation, providing novel imaging evidence to enhance the understanding of visceral pain in patients with CD.

Acknowledgments

We thank all the participants for their cooperation in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2572/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2572/dss

Funding: This study was supported by Sichuan Science and Technology Program (No. 2024ZYD0272).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2572/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Ethics Committee of Chongqing General Hospital in China approved all of the procedures of this study (approval No. KY S2023-019-01). Participants were informed of all experimental procedures related to the experiment and signed informed consent prior to the experiment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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