Activation likelihood estimation of convergent resting-state brain alterations in diarrhea-predominant IBS: a systematic review and meta-analysis

Introduction

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel habits in the absence of detectable structural abnormalities (1). Among its subtypes, diarrhea-predominant IBS (IBS-D) is particularly burdensome, affecting a large proportion of patients and severely impairing their quality of life. Epidemiological studies estimate that IBS affects approximately 10–15% of the global population, with IBS-D representing 30–40% of these cases (2). Despite its high prevalence, the pathophysiological mechanisms underlying IBS-D remain incompletely understood, posing significant challenges for its effective clinical management. Traditional models have emphasized peripheral gastrointestinal dysfunction, such as altered motility and visceral hypersensitivity (3); however, accumulating evidence suggests that central nervous system dysfunction plays a critical role in symptom generation and disease modulation (4).

IBS is a clinically heterogeneous disorder comprising multiple subtypes, including IBS-D, constipation-predominant IBS, and mixed-type IBS, which differ in symptom profiles, pathophysiological features, and potential neural mechanisms (5). From a neuroimaging perspective, focusing on a single subtype is particularly important, as different IBS subtypes may exhibit distinct patterns of brain functional alterations (6). Among these subtypes, IBS-D has been the most extensively investigated in resting-state functional magnetic resonance imaging (rs-fMRI) studies, especially those employing voxel-wise regional intrinsic activity metrics such as regional homogeneity (ReHo) and amplitude of low-frequency fluctuations (ALFF) (7,8). The present meta-analysis was thus restricted to IBS-D to help reduce clinical and neurobiological heterogeneity, enhance methodological comparability across studies, and enable more reliable identification of spatially convergent brain activity alterations specific to this subtype.

Rs-fMRI has been widely applied to characterize spontaneous brain activity alterations in patients with IBS-D, providing insights into the central mechanisms of visceral hypersensitivity and symptom modulation (9,10). Notably, studies have reported increased ReHo and amplitude of ALFF in regions such as the insula and anterior cingulate cortex, which are crucial for pain perception and emotional processing (7,8). Conversely, decreased activity has been observed in the dorsolateral prefrontal cortex and thalamus, suggesting impaired top-down control over visceral sensations (6). Further, Nisticò et al. (11) highlighted aberrant activation and functional connectivity (FC) in brain regions such as the insula and cingulate cortex in IBS, suggesting shared pathophysiology with functional movement disorders. Nevertheless, the reported patterns of brain activity remain inconsistent across studies, likely due to differences in sample characteristics, imaging protocols, and analytical strategies (12-14). This variability prevents robust conclusions from being drawn about which brain regions are consistently affected in IBS-D, highlighting the need for a systematic meta-analytic approach to identify functionally impaired brain regions.

Although individual rs-fMRI studies have provided valuable insights into brain dysfunction in IBS-D, their findings are often inconsistent and limited by small sample sizes and methodological variability (15). Activation likelihood estimation (ALE) meta-analysis offers a robust, quantitative approach to integrate coordinate-based neuroimaging results across multiple studies (16). By modeling the spatial uncertainty of reported activation foci and combining data, ALE identifies brain regions that consistently exhibit altered activity, highlighting functionally impaired nodes in neural circuits (10,17). By integrating data across studies, ALE provides a reliable framework for identifying brain regions consistently involved in visceral pain processing, interoceptive awareness, and emotional regulation in IBS-D, thereby clarifying the neural circuits that contribute to symptom severity and dysfunction (18,19).

Despite accumulating evidence of altered resting-state brain activity in IBS-D, a comprehensive synthesis of these findings is lacking (7,8,12,20-24). To address this gap in the literature, the present study conducted an ALE meta-analysis to systematically identify functionally impaired brain regions in patients with IBS-D. By quantitatively integrating data from multiple rs-fMRI studies, this study aimed to (I) delineate consistent patterns of altered neural activity, (II) identify the neural circuits consistently altered in IBS-D that contribute to visceral pain processing, interoceptive awareness, and emotional regulation, and (III) establish a rigorous neuroimaging framework to guide future studies and identify potential targets for therapeutic intervention. This appears to be the first ALE meta-analysis to focus specifically on IBS-D, providing a rigorous and objective approach to resolve inconsistencies in the literature and extend understanding of its central pathophysiology. We present this article in accordance with the PRISMA reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2274/rc) (25).

Methods

Literature search

This review was registered with PROSPERO (ID: CRD420251171318) and updated on January 17, 2026, with changes reflected in the registration record. The following five major electronic databases were systematically searched to retrieve relevant studies published up to October 10, 2025: PubMed, Web of Science, Embase, Wanfang Data, and China National Knowledge Infrastructure (CNKI). The search strategy included the following keywords: (“Irritable Bowel Syndrome” OR “IBS”) AND (“resting-state functional magnetic resonance imaging” OR “rs-fMRI” OR “functional MRI” OR “fMRI”) AND (“brain activity” OR “regional homogeneity” OR “ReHo” OR “homogeneity” OR “amplitude of low-frequency fluctuations” OR “ALFF” OR “low-frequency fluctuation” OR “fractional amplitude of low-frequency fluctuations” OR “fALFF” OR “dynamic amplitude of low-frequency fluctuations” OR “dALFF” OR “mean amplitude of low-frequency fluctuations” OR “mALFF”).

Studies were included in the meta-analysis if they met all of the following inclusion criteria: (I) included adult participants (≥18 years) diagnosed with IBS-D according to the Rome criteria; (II) were original research articles; (III) employed a case-control design to compare resting-state neural activity between IBS-D patients and healthy controls (HCs); and (IV) reported whole-brain results in stereotactic space [Montreal Neurological Institute (MNI) or Talairach coordinates] for ReHo, ALFF, fractional ALFF (fALFF), dynamic ALFF (dALFF), or mean ALFF (mALFF) analyses.

Studies were excluded from the meta-analysis if they met any of the following exclusion criteria: (I) focused on the default mode network or FC analyses; (II) employed task-based fMRI or structural MRI; (III) included patients diagnosed with functional constipation or without a specified IBS subtype; (IV) were literature reviews, systematic reviews, or meta-analyses; (V) did not report complete stereotactic coordinates (x, y, z); and/or (VI) involved IBS patients with comorbid medical or psychiatric conditions.

The literature search and study selection were independently conducted by two physicians, and any discrepancies were resolved by consensus.

Data extraction

Two independent reviewers (X.M. and Y.Z.) extracted data from each eligible study using a standardized data extraction form. For each included study, the following information was recorded: first author, publication year, country, sample sizes of IBS-D patients and HCs, diagnostic criteria, imaging parameters, analytic methods (e.g., ReHo, ALFF, fALFF, dALFF, and/or mALFF), reported peak coordinates, and main brain regions with significant between-group differences. Reported coordinates were extracted in Talairach or MNI space; when necessary, Talairach coordinates were converted to MNI space using the icbm2tal transformation implemented in the GingerALE (version 3.0.2) software package.

Quality and risk of bias assessments

To evaluate methodological rigor, the Newcastle-Ottawa Quality Assessment Scale (NOS), a standardized instrument for evaluating non-randomized studies, was used (26). Based on total scores, the risk of bias was categorized as low (7–9), moderate (4–6), or high (<4). Quality assessments were independently performed by two authors (X.M. and Y.Z.), with any discrepancies resolved through discussion with additional team members.

ALE analysis

Resting-state differences in ReHo and ALFF (including dALFF, fALFF, and mALFF) between the IBS-D patients and HCs were analyzed using the ALE method, implemented in GingerALE (version 3.0.2). All Talairach coordinates were transformed into MNI space using the Lancaster transformation implemented in statistical parametric mapping (27). To model reported activation foci, Gaussian smoothing was applied to each study’s coordinates. The full width at half maximum was adjusted according to the sample size, generating modeled activation (MA) maps. ALE scores were computed by combining MA maps across studies to identify brain regions showing statistically convergent patterns of resting-state activity (28). Statistical significance was assessed by voxel-wise comparison, producing three-dimensional (3D) P value maps. Multiple comparisons were corrected using cluster-level family-wise error correction at P<0.05, with 1,000 permutations (29). The threshold for significance was determined based on the 3D distribution of the P values, and the resulting ALE maps highlight regions that survived this corrected threshold (30).

Given the limited number of IBS-D rs-fMRI studies, voxel-wise regional intrinsic activity metrics, including ReHo and ALFF-related measures (ALFF, fALFF, mALFF, and dALFF), were pooled to identify spatially convergent alterations in spontaneous brain activity. As a coordinate-based method, ALE tests the convergence of reported peak coordinates in standard space rather than metric-specific effect sizes, allowing the detection of shared spatial patterns across complementary intrinsic activity indices.

Sensitivity analysis

To evaluate the robustness of the ALE meta-analysis findings, a jackknife sensitivity analysis was performed using GingerALE (version 3.0.2). This procedure involved sequentially removing one study at a time and re-running the ALE analysis on the remaining dataset. By examining how the exclusion of each individual study affected the spatial convergence of activation, regions that consistently appeared across all iterations were identified, providing a measure of the replicability and stability of the results.

Results

Literature search results

A total of 622 articles were retrieved from the database search, of which eight met the predefined inclusion criteria for this meta-analysis (Figure 1). The included studies employed various rs-fMRI analysis methods, including ReHo, ALFF, fALFF, dALFF, and mALFF. Notably, two studies, Chen et al. (7) and Cheng (21), employed distinct combinations of ReHo and ALFF analyses, and were thus treated as separate studies due to the differences in their analytical approaches. Consequently, 10 datasets from eight articles (7,8,12,20-24), comprising 213 IBS-D patients and 172 HCs, were incorporated into the meta-analysis. Among the included datasets, eight showed increased activity in IBS-D patients relative to HCs, whereas seven showed decreased activity. There were no significant differences in age or sex between the IBS-D patients and HCs (P>0.05; Table 1).

Figure 1 The flow diagram of the search strategy and retrieved studies according to the PRISMA guidelines. CNKI, China National Knowledge Infrastructure; IBS, irritable bowel syndrome; rs-fMRI, resting-state functional magnetic resonance imaging.

Risk of bias was assessed using the NOS. All eight included studies achieved NOS scores ≥7, indicating a low risk of bias.

ALE meta-analysis results

The ALE analysis results are summarized in Table 2. The ALE meta-analysis revealed two clusters of hyperactivity in IBS-D patients relative to HCs. The first cluster was located in the right cerebellar culmen (69.4%), extending to the right cerebellar lingula (7.7%) and left fastigial nucleus (22.9%). The second cluster was located in the right parahippocampal gyrus [78.6%, Brodmann area (BA) 36], extending to the right fusiform gyrus (18.6%) and right sub-gyral area of the parahippocampal gyrus (2.8%). In contrast, one cluster of hypoactivity was observed in the right superior frontal gyrus (67.6%, BA 10) and right middle frontal gyrus (32.4%, BAs 9 and 10) (Figure 2).

Figure 2 Brain regions with convergent alterations in IBS-D identified by ALE meta-analysis. (A-C) Compared with HCs, IBS-D patients showed hyperactivity in the right cerebellar culmen, extending to the right cerebellar lingula and left fastigial nucleus (A,B); and in the right parahippocampal gyrus (BA 36), extending to the right fusiform gyrus and right sub-gyral area of the parahippocampal gyrus (C). (D,E) Compared with HCs, IBS-D patients showed hypoactivity in the right superior frontal gyrus (BA 10, D) and in the right middle frontal gyrus (BAs 9 and 10, E). (F) Three-dimensional surface rendering of altered functional activity in IBS-D compared to HCs. Green arrow indicates regions of functional activity reduction, while red arrows represent regions of increased activity (cluster-level family-wise error, P<0.05). A, anterior; ALE, activation likelihood estimation; BA, Brodmann area; HCs, healthy controls; I, inferior; IBS-D, diarrhea-predominant irritable bowel syndrome; L, left; S, superior.

Sensitivity analysis results

The jackknife sensitivity analysis demonstrated high stability of the ALE meta-analysis results. The hyperactive clusters in the right cerebellar culmen and cerebellar lingula regions were consistently replicated in seven of eight iterations, while the left fastigial nucleus cluster was reproduced in six of eight iterations. The cluster located in the right parahippocampal gyrus (extending to the fusiform gyrus and sub-gyral area of the parahippocampal gyrus) was replicated in five of eight iterations.

For the hypoactive regions, the right superior frontal gyrus (BA 10) and middle frontal gyrus (BAs 9 and 10) were consistently identified in six of seven iterations. Wen et al. (24) reported only hyperactive regions and were thus not included in the hypoactivity analysis (Table 3).

Discussion

This coordinate-based meta-analysis revealed convergent alterations in spontaneous neural activity in patients with IBS-D. Two clusters of hyperactivity were observed, involving the cerebellum (including the right cerebellar culmen and cerebellar lingula) and the right parahippocampal gyrus, extending to the right fusiform gyrus and the sub-gyral area of the parahippocampal gyrus. In contrast, one cluster of hypoactivity was observed in the right superior frontal gyrus and right middle frontal gyrus, which are key components of the prefrontal cortex.

Hyperactivity in the cerebellar and parahippocampal regions suggests increased involvement of sensorimotor integration and emotional memory circuits (31,32). Research has shown that IBS patients have abnormal FC in networks involving the limbic system, particularly the insula and cingulate cortex, which are critical for emotional and sensory processing (33). Conversely, reduced activity in the prefrontal cortex may reflect impaired top-down modulation of visceral pain and emotional responses (34). Together, these convergent findings indicate that IBS-D is associated with dysregulated intrinsic activity across neural systems involved in visceral sensation, affective processing, and cognitive regulation (35).

Cerebellar hyperactivity and visceral pain modulation in IBS-D

The most prominent and consistent finding of the present meta-analysis was convergent hyperactivity across multiple cerebellar regions, highlighting the cerebellum as a key node in the altered central processing of IBS-D. Although traditionally associated with motor coordination, the cerebellum is now increasingly recognized as an integral component of pain-related neural circuits, particularly in the modulation of autonomic and visceral sensory processing (36,37). Accordingly, hyperactivity in the cerebellar culmen and cerebellar lingula regions may reflect increased engagement of cerebellar modulatory circuits in response to persistent visceral pain rather than a direct amplification of nociceptive signals (38,39). This interpretation is supported by evidence from neuromodulation research indicating that non-invasive cerebellar stimulation may modulate pain perception and endogenous pain inhibition in humans, suggesting a regulatory role of the cerebellum within central pain modulation systems (40). Similarly, experimental models of visceral hypersensitivity demonstrate that central pain modulation involves coordinated activity across corticolimbic and brainstem pathways rather than isolated sensory amplification (41). In this context, dysfunctional alterations in these cerebellar regions may thus support the presence of abnormal visceral pain modulation in patients with IBS-D.

Importantly, in IBS-D, visceral pain represents a persistent form of internal discomfort rather than a transient nociceptive event. Visceral pain signals are conveyed to cerebellar regions, as evidenced by increased spontaneous activity in the present findings. This altered cerebellar engagement may influence the central processing of visceral pain through cerebello–thalamo–cortical pathways, including projections to prefrontal regions involved in pain appraisal and regulation (7,42). Such dysregulated processing may partly contribute to abnormal pain perception and the clinical manifestation of abdominal pain in IBS-D.

Further, different cerebellar subregions are differentially engaged depending on pain modality and anatomical origin. Anterior cerebellar regions are more frequently involved in somatosensory and visceral afferent integration, while posterior cerebellar regions primarily contribute to cognitive-affective aspects of pain (38,43). Although previous studies have demonstrated predominant involvement of the posterior lobe of the cerebellum in pain processing (44), this ALE meta-analysis showed that anterior lobe regions may also be involved, especially in visceral pain processing. However, further studies are needed to validate the findings of the present study.

Beyond cortico-limbic mechanisms, cerebellar dysfunction may also interact with brainstem pain modulation systems. The periaqueductal gray, a key hub of endogenous pain control, has been implicated in IBS and other chronic pain conditions (45). Although the present ALE analysis focused on resting-state brain activity, established cerebellar-brainstem connectivity suggests that cerebellar dysfunction may indirectly affect periaqueductal gray-mediated descending pain modulation, contributing to the insufficient inhibition of persistent visceral pain signals in IBS-D.

Limbic hyperactivity and affective-memory components of visceral pain

In addition to cerebellar alterations, hyperactivity in the right parahippocampal gyrus, extending to the right fusiform gyrus and right sub-gyral area of the parahippocampal gyrus, suggests abnormal engagement of limbic structures involved in contextual memory and affective processing (46). The parahippocampal gyrus plays a central role in encoding and retrieving contextual representations of bodily states, and its hyperactivity may facilitate heightened recall and anticipation of gastrointestinal discomfort, contributing to hypervigilance and symptom-related anxiety (47).

Although the parahippocampal gyrus is anatomically and functionally related to the amygdala, direct amygdala hyperactivity was not observed in the present ALE analysis. This may reflect methodological constraints inherent to coordinate-based meta-analyses, as well as differences between resting-state regional activity metrics and task-based or connectivity-focused approaches (48). Notably, the involvement of cerebellar-limbic interactions in chronic pain conditions suggests that the dysregulated engagement of these circuits may represent a shared neurofunctional substrate underlying abdominal pain perception and emotional dysregulation in IBS-D (49).

Prefrontal hypoactivity and impaired top-down regulation

In contrast to hyperactive cerebellar-limbic regions, decreased spontaneous activity was observed in the right superior frontal gyrus and right middle frontal gyrus regions, which play critical roles in cognitive control, emotional regulation, and pain modulation (50). Hypoactivity in these prefrontal regions may reflect impaired top-down regulation of limbic and brainstem pain-processing systems, resulting in diminished cognitive control over visceral sensations and emotional responses (7). Previous neuroimaging studies have similarly demonstrated diminished prefrontal engagement in both resting-state and task-based paradigms in IBS, supporting the notion of disrupted executive control over interoceptive and affective processing (6,11). This functional imbalance—characterized by hyperactivity in cerebellar-limbic circuits and hypoactivity in the prefrontal cortex regions involved in pain modulation—may contribute to the maladaptive processing of visceral sensory signals and associated emotional responses, thereby sustaining visceral hypersensitivity and affective symptoms in IBS-D (51).

Network-level mechanisms and the nociplastic pain framework

From a contemporary pain neuroscience perspective, these convergent neurofunctional alterations are highly consistent with the concept of nociplastic pain, which emphasizes altered central pain processing in the absence of ongoing peripheral tissue damage or inflammation (52). Within this framework, pain is driven by dysfunction of central neural circuits involved in sensory integration, affective processing, and cognitive modulation rather than by persistent nociceptive input alone (53).

Specifically, the combination of limbic–cerebellar hyperactivity and prefrontal hypoactivity observed in this ALE analysis suggests central amplification of visceral sensory signals alongside impaired top-down regulatory control, a hallmark feature of nociplastic pain conditions (54). This centrally mediated pain phenotype provides a coherent neurobiological explanation for the persistence of abdominal pain, heightened emotional reactivity, and limited efficacy of purely peripheral treatments in IBS-D (55).

From a network-level perspective, several regions identified in the present meta-analysis overlap with large-scale brain networks implicated in chronic pain, particularly the salience network, which is responsible for detecting behaviorally relevant internal stimuli and prioritizing sensory-affective information (56). The hyperactivity observed in parahippocampal and cerebellar-limbic regions may reflect altered salience attribution to visceral sensory signals, a phenomenon commonly reported in chronic pain conditions and associated with heightened pain attention and emotional reactivity (57,58). Meanwhile, hypoactivity in prefrontal regions suggests impaired top-down regulation of salience-driven limbic responses, leading to reduced cognitive control over pain-related processing (59). This pattern of enhanced salience processing combined with weakened prefrontal modulation represents a core network-level feature shared across chronic pain disorders and provides an important framework for interpreting the present findings in IBS-D (53).

Summary and implications

Taken together, the present ALE meta-analysis provides robust evidence for convergent functional alterations in IBS-D, characterized by hyperactivity in the cerebellar-limbic regions and hypoactivity in the prefrontal cortex. These findings indicate a dysfunctional integration between emotional and sensory systems, together with impaired top-down regulatory mechanisms mediated by prefrontal cortical regions, supporting the concept that IBS-D involves aberrant central processing rather than being purely a peripheral disorder (60).

The identified functionally impaired brain regions may represent potential neural markers for symptom severity and treatment response (61). Clinically, these insights underscore the importance of targeting central mechanisms—such as cognitive-behavioral therapy, neuromodulation (e.g., transcranial direct current stimulation), or mindfulness-based interventions—to restore brain-gut balance and improve patient outcomes (41). Future studies should employ longitudinal designs and multimodal imaging approaches to clarify causal relationships, explore dynamic brain-gut interactions, and assess how therapeutic interventions can modulate these neural circuits.

Limitations

Several limitations should be acknowledged in the present study. First, due to the limited number of eligible studies, the number of experiments included in this ALE meta-analysis fell below thresholds recommended in some methodological guidelines, which may have reduced statistical power and increased the risk of false-negative findings. Second, pooling different regional rs-fMRI metrics (ReHo and ALFF-related indices) may introduce methodological heterogeneity and limit metric-specific physiological interpretations. Accordingly, the present findings should be interpreted as spatially convergent alterations in intrinsic brain activity rather than changes in a single blood oxygen level-dependent component. Third, most of the included studies involved adult populations, limiting the extrapolation of results to pediatric or elderly patients. Finally, ALE meta-analysis is based on reported peak coordinates rather than raw imaging data, which may reduce spatial precision (62). Despite these limitations, the convergent findings provide robust evidence for functionally impaired brain regions in IBS-D and offer valuable insights for future research.

Conclusions

This ALE meta-analysis provides convergent evidence of functional impairment in key brain regions in patients with IBS-D, characterized by cerebellar-limbic hyperactivity and prefrontal hypoactivity. These findings highlight disrupted integration across sensory, affective, and cognitive control networks, providing evidence that IBS-D involves central dysfunction in the brain-gut axis rather than a purely peripheral condition. Identifying these functionally impaired regions may inform neural markers for symptom severity and therapeutic response. Future studies should employ longitudinal and multimodal imaging approaches to clarify causal mechanisms and evaluate interventions targeting these brain regions. Such efforts may help restore brain-gut homeostasis and improve clinical outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2274/rc

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2274/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.

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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