Multimodal neuroimaging insights into central mechanisms of overactive bladder with an empty bladder: a cross-sectional study

Abstract

Background and objective

Overactive bladder (OAB) is a complex condition involving central nervous system (CNS) processes that are not fully understood. We conducted a detailed neuroimaging study to investigate the CNS role in OAB, focusing on the bladder emptying state.

Methods

This cross-sectional study included 168 OAB patients and 133 matched controls. Participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) during the bladder emptying state. Data were analyzed using tract-based spatial statistics (TBSS), graph theory, functional connectivity, and structure–function coupling. The Overactive Bladder Symptom Score (OABSS) and the Overactive Bladder Questionnaire Short Form (OAB-q SF) were also utilized.

Key findings and limitations

TBSS revealed three white matter tracts with higher fractional anisotropy in OAB patients; the largest of these, including the body of the corpus callosum (bCC) and bilateral anterior corona radiata (ACR), correlated positively with OAB-q scores. Functional connectivity analysis indicated increased connectivity between the left dorsolateral superior frontal gyrus (SFGdor.L) and bilateral supplementary motor areas, and reduced connectivity between the left middle temporal gyrus (MTG.L) and the right inferior temporal gyrus (ITG.R). The left amygdala (AMYG.L) exhibited enhanced structure–function coupling, which was positively associated with OABSS and OAB-q scores. However, the study's cross-sectional design precludes determining causal relationships due to the lack of longitudinal data.

Conclusions and clinical implications

This study identified distinct functional and structural brain alterations in OAB patients during the bladder emptying state. These findings offer new perspectives for investigating innovative treatment strategies.

Trial registration This study was registered on the UK's Clinical Study Registry (ISRCTN11583354).

Supplementary Information

The online version contains supplementary material available at 10.1186/s40001-025-03542-y.

Introduction

Overactive bladder (OAB) is a complex clinical syndrome characterized by urgency, frequent urination, and nocturia, with or without urgency incontinence [1]. The condition often recurs even after treatment, causing significant physical and emotional distress and placing a substantial burden on society.

The central nervous system (CNS) plays a vital role in managing bladder function through a complex network of nerves, involving regions like the medial prefrontal cortex, hypothalamus, and pontine micturition center, as well as key neurotransmitters such as dopamine, 5-hydroxytryptamine, and acetylcholine [2]. Dysfunctions in the CNS can disrupt this balance, leading to urinary issues like incontinence, retention, frequency, and urgency, often seen in conditions such as multiple sclerosis, spinal cord injuries, and cerebral palsy [3]. In OAB, symptoms are similarly tied to CNS abnormalities, including altered brain activity, neurotransmitter imbalances, and impaired neural pathways, underscoring the need for comprehensive research and treatment strategies [4].

Advanced brain imaging techniques, such as resting-state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI), and blood oxygenation level-dependent fMRI (BOLD-fMRI), have enhanced our understanding of OAB's neural mechanisms. Studies have explored prefrontal cortical activity, white matter microstructure changes, and OAB subtypes during bladder filling [5–7]. However, these studies often focus on the filling phase, which emphasizes sensation and inhibitory control, while bladder emptying involves distinct processes like cortical deactivation and brainstem activation for detrusor contraction and sphincter relaxation [5, 8]. Additionally, urgency in OAB may arise from central sensitization, heightening bladder sensations even at low volumes, a phenomenon potentially masked during filling-focused neuroimaging [7]. This highlights the need to examine CNS function in the empty-bladder state, a gap yet to be addressed by multimodal neuroimaging.

This study employs a multimodal approach, integrating rs-fMRI and DTI, to investigate brain functional and structural connectivity in OAB patients during the empty-bladder state. With a substantial sample size, we assessed global functional connectivity, white matter integrity, brain network topology, and structure–function coupling. We hypothesized that OAB patients would exhibit distinct CNS alterations even without bladder distention, potentially reflecting persistent central sensitization. These insights could identify novel targets for neuromodulation or behavioral therapies.

Patients and methods

Study design

This study was approved by the Institutional Ethics Board of Jiangnan University Medical Center (2024-Y-26) and registered with the Chinese Clinical Trial Registry (ChiCTR2400092006). All participants provided written informed consent. Eligible participants included Han Chinese, right-handed individuals aged > 18 years, with OAB patients diagnosed by two urologists per ICS guidelines and no recent (72 h) use of anticholinergic drugs. The diagnosis of OAB was based on symptomatic criteria per ICS guidelines, which do not routinely recommend urodynamic testing for uncomplicated cases. Healthy controls were age-, sex-, and education level-matched volunteers from the hospital’s physical examination center. These controls were selected using a groupwise matching approach to ensure overall demographic comparability between the OAB patient group and the control group. The final sample size of 243 participants (119 OAB patients and 124 controls) was determined by convenience sampling over a fixed recruitment period. Exclusion criteria comprised pregnancy/lactation; prior genitourinary/reproductive tract surgery; severe systemic diseases or recent (3 months) anti-anxiety/antidepressant use; neurodegenerative disorders (e.g., Alzheimer’s or Parkinson’s disease); conditions potentially confounding urinary symptoms (e.g., vaginitis); MRI contraindications (e.g., metal implants); or T1-weighted imaging-evident brain abnormalities (e.g., infarction/vascular lesions). All participants fasted from fluids for 4 h prior to MRI and demonstrated pre-/post-scan residual urine volumes < 20 mL (via bladder scan), ensuring standardized bladder emptiness during acquisition.

Clinical assessment

OAB patients completed the Overactive Bladder Symptom Score (OABSS) and the Overactive Bladder Questionnaire Short Form (OAB-q SF). The OAB-q SF contains two validated subscales: the Symptom Bother scale (OAB-q SB; assessing symptom severity) and the Health-Related Quality of Life scale (OAB-q HRQL; evaluating life impact). Higher OAB-q SB scores indicate greater symptom severity, while lower OAB-q HRQL scores reflect poorer quality of life.

MRI examination

MRI data were acquired using a Siemens Magnetom Vida 3.0 T scanner with a 32-channel head coil. Key preprocessing steps for the rs-fMRI data included slice timing correction, realignment, normalization to MNI space, and spatial smoothing. For DTI data, preprocessing included eddy current correction and head motion correction, followed by tensor fitting to derive fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) maps. FA reflects the degree of directional water diffusion, indicating white matter microstructural integrity and fiber coherence. MD represents the overall magnitude of water diffusion. AD measures the rate of water diffusion parallel to the axonal fibers, often interpreted as an indicator of axonal integrity, while RD measures the rate of diffusion perpendicular to the fibers, which is more closely related to the status of myelin sheaths. Before scanning, all subjects emptied their bladder and were instructed to remain awake and still. Head stabilization and noise reduction were achieved using sponge pads and earplugs. The specific MRI Imaging protocols and Data preprocessing are detailed in the Supplementary Data (Supplementary Methods Section).

Statistical analysis

Statistical analyses were performed using SPSS (v25.0.1.0). The Kolmogorov–Smirnov test assessed the distribution of variables. Normally distributed variables were presented as mean ± SD and compared using two-tailed t-tests. Non-normally distributed variables were presented as median with interquartile range and analyzed using Mann–Whitney U tests. Chi-square tests compared categorical variables (e.g., gender) between the OAB and HC groups. Statistical analysis methods for TBSS and Network comparisons can be seen in the Supplementary Data (Supplementary Methods Section).

Results

Basic information of participants

The flow chart of this study is shown in Fig. 1. A total of 243 participants finally completed the study, comprising 119 patients with OAB (39 men, 80 women) and 124 healthy controls (37 men, 87 women). Both groups were well-matched on key demographic variables. Statistical analysis revealed no significant differences between groups in gender ratio, age, height, weight, or years of education (Supplementary Table 1). This demographic comparability strengthens the validity of our between-group comparisons.

Fig. 1.

The flowchart of the present study

Clinical assessments demonstrated clear differences between groups. OAB patients scored significantly higher on all symptom measures compared to healthy controls, including OABSS, OAB-q SB, and OAB-q HRQL (Supplementary Table 1). These elevated scores confirm the presence of substantial urinary symptoms in the patient group.

Altered white matter fractional anisotropy in OAB patients

TBSS analysis revealed three distinct white matter clusters in OAB patients characterized by significantly higher FA values compared to controls (Fig. 2A). Cluster 1, spanning 121 voxels (peak MNI coordinates: -40, -37, -3), involved the left retroinsular cortex (RIC.L), left posterior thalamic radiation (PTR.L), and left suprasylvian area (SS.L). Cluster 2, containing 927 voxels (peak coordinates: -31, -68, 2), was localized to the left posterior thalamic radiation (PTR.L). Cluster 3, the most extensive distribution (33,937 voxels; peak coordinates: 23, -17, 36), encompassed multiple regions including the body of corpus callosum (bCC), bilateral anterior corona radiata (ACR.L/R), splenium of corpus callosum (sCC), right posterior thalamic radiation (PTR.R), and middle cerebellar peduncle (MCP), suggesting widespread structural involvement (Supplementary Table 2).

Fig. 2.

Significant differences in white matter structure between OAB patients and controls. A Distribution of three clusters with significantly higher fractional anisotropy (FA, a measure of white matter integrity) in OAB patients, revealed by TBSS analysis. B–D Group comparisons of mean diffusivity (MD, reflects overall water diffusion), axial diffusivity (AD, reflects axonal integrity), and radial diffusivity (RD, reflects myelin integrity) values within the identified clusters. E Brain region showing a significantly higher normalized clustering coefficient (NCp, a graph theory metric indicating local network efficiency) in the right superior temporal gyrus (STG.R) of OAB patients

Further analysis of diffusion tensor metrics within these clusters identified additional differences between the groups. While MD values did not significantly differ between groups (Fig. 2B), OAB patients showed significantly higher AD values in all three clusters (Cluster 1: P = 0.040, 95% CI [0.01, 0.50]; Cluster 2: P < 0.001, 95% CI [0.24, 0.73]; Cluster 3: P = 0.031, 95% CI [0.03, 0.51]) (Fig. 2C). Additionally, RD values were significantly lower in clusters 2 and 3 in the OAB group (Cluster 2: P = 0.039, 95% CI [− 0.45, − 0.01]; Cluster 3: P = 0.041, 95% CI [− 0.48, − 0.01]) (Fig. 2D). These combined findings suggest enhanced white matter fiber integrity or organization within these specific brain regions during the bladder emptying state in OAB patients.

Graph theory analysis of DTI data revealed a significantly increased normalized clustering coefficient (NCp) in the right superior temporal gyrus (STG.R) of OAB patients compared to healthy controls (FDR-corrected, P = 0.049) (Fig. 2E), suggesting enhanced functional integration in this region. This localized alteration occurred despite no significant between-group differences in global network metrics (Sigma, Cp, Lp, Eg, Eloc, detailed in the Supplementary Data). Furthermore, no other local network measures, aside from the NCp in the STG.R, showed significant differences between the groups.

Altered whole-brain functional connectivity in OAB patients

Whole-brain FC analysis identified three significantly altered functional connections in OAB patients (Fig. 3A–C). Two connections showed enhanced connectivity in the OAB group: the functional connectivity between the left dorsal superior frontal gyrus (SFGdor.L) and the left supplementary motor area (SMA.L) was significantly strengthened (FDR correction, P = 0.016, 95% CI [0.31, 0.79]), as was connectivity between the SFGdor.L and the right supplementary motor area (SMA.R) (FDR correction, P = 0.010, 95% CI [0.34, 0.82]). The functional connection between the left middle frontal gyrus (MFG.L) and right inferior temporal gyrus (ITG.R) was markedly reduced in OAB patients (FDR correction, P = 0.012, 95% CI [-0.80, -0.32]) (Fig. 3D).

Fig. 3.

Significant differences in functional brain connectivity between OAB patients and controls. A, B Whole brain functional connectivity analysis matrix. C Schematic diagram of the 3 functional connections altered in OAB patients. D Schematic diagram of OAB patient-specific brain functional connections

Altered structural–functional coupling in the amygdala of OAB patients

Structure–function coupling analysis revealed no significant differences in global metrics between OAB patients and healthy controls (Fig. 4A, B). However, an examination of local indices revealed that the left amygdala (AMYG.L) exhibited significantly higher structure–function coupling in OAB patients (FDR correction, P = 0.008, 95% CI [0.25, 0.74]) (Fig. 4C).

Fig. 4.

Significant enhancement of structural–functional coupling in the left amygdala (AMYG.L) of OAB patients. A, B Group-level structure–function coupling matrices. Structure–function coupling reflects the correspondence between white matter structural connectivity and functional connectivity. C The AMYG.L brain region, where coupling was significantly stronger in the OAB group

Correlation between brain alterations and clinical symptoms in OAB patients

Partial correlation analysis, controlling for age and gender, revealed significant associations between brain alterations and clinical symptoms (Fig. 5). The average FA value in Cluster 3 positively correlated with OAB-q HRQL scores (R = 0.253, P = 0.026, FDR-corrected), with a trend-level association observed for OAB-q SB scores (R = 0.225, P = 0.015, FDR-P = 0.054). Notably, structure–function coupling in the AMYG.L demonstrated the most robust and consistent associations, showing significant positive correlations with OABSS scores (R = 0.347, P = 0.002, FDR-P < 0.001), OAB-q SB scores (R = 0.286, P = 0.010, FDR-P = 0.010), and OAB-q HRQL scores (R = 0.241, P = 0.032, FDR-P = 0.032). Clinical measures did not significantly associate with the NCp in STG.R, SFGdor.L-SMA.L connectivity, SFGdor.L-SMA.R connectivity, or MFG.L-ITG.R connectivity.

Fig. 5.

Correlation between brain alterations and clinical symptoms in OAB patients. The heat map showed results of the partial correlation analysis, controlling for age and gender. It revealed significant associations between brain alterations and clinical symptoms. *P < 0.05, **P < 0.01, ***P < 0.001

Discussion

This study leveraged multimodal neuroimaging to investigate CNS alterations in OAB during the rarely studied empty-bladder state. By integrating DTI and rs-fMRI, we identified region-specific white matter microstructural changes, altered FC, and enhanced structure–function coupling, particularly involving the amygdala. These findings offer novel evidence of persistent central sensitization and dysfunctional emotional-autonomic regulation in OAB.

White matter microstructure alterations

Our results revealed significantly elevated FA in major white matter pathways, including the corpus callosum, corona radiata, and prethalamic radiation, contrasting with prior reports of decreased FA during bladder-filling states [6, 9]. These discrepancies may reflect bladder-state-dependent neuroplasticity, emphasizing the importance of imaging across different voiding phases. Elevated FA in our study may suggest altered axonal packing or myelin organization, although alternative interpretations, such as glial remodeling or reduced crossing fibers, must be considered [10]. Importantly, FA in the corpus callosum and corona radiata showed a positive correlation with symptom severity, suggesting trait-like structural adaptations rather than transient urgency effects. Similar FA elevations have been reported in osteoarthritis [11], supporting the hypothesis of shared central sensitization mechanisms across chronic conditions.

Regional network topology disruption

Graph theory analysis showed increased clustering in the STG.R, indicating enhanced local network efficiency in this region. Although not classically part of the bladder-control network [12, 13], the STG has been implicated in spatial awareness and interoceptive processing. Prior studies have also shown STG activation during bladder control and gray matter reductions in OAB [14, 15], reinforcing its potential role in urgency perception and sensorimotor integration.Our DTI analysis revealed a significantly higher clustering coefficient in the STG.R of OAB patients compared to controls, while global network measures remained unchanged. This finding points to specific regional alterations rather than overall network disruption in OAB pathophysiology. The increased clustering in STG.R indicates enhanced local efficiency, suggesting either compensatory hyperconnectivity or altered information processing.

Functional connectivity reorganization

OAB patients exhibited increased FC between the SFGdor.L and SMA, areas involved in voluntary motor control and urgency suppression. This may reflect compensatory top-down regulation. In contrast, decreased connectivity between the middle frontal and inferior temporal gyri may represent maladaptive sensory integration. These patterns align with previous findings of disrupted prefrontal-limbic circuits in OAB and highlight the complexity of emotional-autonomic interplay [13].

Structure–function coupling in the amygdala

A key finding was enhanced SC-FC coupling in the AMYG.L, which positively correlated with clinical symptom burden [16–21]. The amygdala is central to emotional regulation and autonomic arousal and may contribute to urgency through emotional amplification pathways [22–24]. The increased coupling may reflect a "hypersensitized" paralimbic-prefrontal network that sustains urgency perception even in the absence of bladder distension. These findings position amygdala coupling as a promising biomarker for central sensitization and therapeutic targeting.

Clinical implications

The distinct CNS alterations identified in this study suggest several avenues for personalized interventions. Neuromodulatory techniques such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) targeting the SMA or prefrontal cortex may help restore motor-autonomic balance. Cognitive-behavioral therapies and mindfulness-based interventions could modulate limbic hyperactivity and emotional amplification of urgency. Additionally, pharmacological strategies aimed at reducing limbic system excitability (e.g., selective serotonin reuptake inhibitors) may benefit patients with pronounced amygdala-prefrontal coupling abnormalities. Overall, incorporating neuroimaging-derived CNS phenotyping into clinical decision-making may enhance treatment stratification and outcomes in OAB.

Limitations and future directions

This study has several limitations. First, its cross-sectional design limits causal inference. Second, the absence of a bladder-filling condition prevents state-trait comparisons. Third, while omitting urodynamic data allowed focus on central mechanisms, it limits understanding of peripheral contributions. Fourth, the sample was ethnically homogeneous (Han Chinese), which may restrict generalizability. Fifth, although harmonized acquisition protocols were used, scanner-specific biases cannot be fully excluded. Finally, modest effect sizes (R = 0.25–0.34) reflect typical findings in neuroimaging of complex disorders and suggest that CNS alterations are one component of a broader pathophysiology. Future studies should include multi-state designs (filling vs. voiding), longitudinal follow-up, urodynamic correlation, and multi-ethnic cohorts to refine mechanistic understanding and inform biomarker-guided interventions in OAB.

Conclusions

In conclusion, our multimodal neuroimaging findings suggest that OAB patients may exhibit sustained functional and structural reorganization within the central nervous system, even in the absence of bladder filling. These observed central alterations could potentially contribute to the persistence of OAB symptoms and might be a factor in the limited efficacy of conventional therapies that focus primarily on peripheral mechanisms.

Author contributions

Ye Hua, Jianfeng Shao and Yi Fan designed this study and provided guidance. Yifan Sun, Deshui Yu, Huihui Song, Kaixin Zhang, Feng Lu, Xi Liu, Xiuhong Hua, Siyi Fu, Jia Xu conducted data collection, data analysis, data interpretation for this study. Yangkun Feng, Yuwei Zhang and Ju Zhang drafted the initial manuscript. All authors reviewed the manuscript, provided comments and approved the final version.

Funding

This study was supported by grants from Postgraduate Research & Practice Innovation Program of Jiangsu Province (no: SJCX25_1351 to YK.F.), the Wuxi City Science and Technology Innovation and Entrepreneurship Fund "Taihu Light" Science and Technology Research Program (no. Y20242111 to Y.H.), and the Top Talent Support Program for young and middleaged people of Wuxi Health Committee (no. HB2023035 to Y.H.).

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Ethics Board of Jiangnan University Medical Center (2024-Y-26).

Patient consent statement

All participants provided written informed consent.

Competing interests

The authors declare no competing interests.