Identifying Abnormalities in Regional Brain Activity and Functional Connectivity in Patients With Detrusor Overactivity After Spinal Cord Injury
Article information
Abstract
Purpose
Changes in regional brain activity and functional connectivity (FC) in patients with neurogenic detrusor overactivity (NDO) following spinal cord injury (SCI) remain unclear. This study used resting-state functional magnetic resonance imaging (fMRI) to investigate regional brain activity and FC in NDO patients after SCI.
Methods
Resting-state fMRI scans were obtained from 20 NDO patients after SCI and 20 healthy controls (HCs). Regional brain activity was measured using regional homogeneity (ReHo). Subsequently, a seed-based whole-brain FC analysis was performed using the regions with significantly different ReHo as seeds. Partial correlation analysis was conducted to examine the relationship between FC values and clinical scores in the NDO patients with SCI.
Results
Compared to HC, patients with NDO exhibited significantly decreased ReHo in the right medial frontal gyrus (MFG). Furthermore, compared to HC, NDO patients demonstrated stronger FC between the seed (right MFG) and voxels in the left pyramis, right cerebellum posterior lobe, and left middle temporal gyrus. Weaker FC was observed between the seed (right MFG) and voxels in the right paracentral lobule. Correlation analyses revealed that the Overactive Bladder Symptom Score and urgency urinary incontinence scores were positively correlated with FC values between the right MFG and the left pyramis.
Conclusions
SCI-related NDO patients exhibit abnormalities in both regional brain activity and FC, with supraspinal connectivity deviation extent associated with the severity of lower urinary tract symptom. This study contributes to a better understanding of the potential supraspinal neural mechanisms underlying SCI-related NDO.
INTRODUCTION
Spinal cord injury (SCI) is a devastating incident. Neurogenic lower urinary tract dysfunction (NLUTD) is a common and debilitating consequence of SCI, affecting approximately 70% to 84% of individuals with SCI [1]. This condition significantly disrupts normal bladder storage and voiding functions. Urodynamic investigation is crucial for identifying the functional status of the lower urinary tract (LUT) in these patients. Videourodynamic studies have observed neurogenic detrusor overactivity (NDO) in 67.7% of SCI patients [2], and unfavorable urodynamic findings are common during the acute to subacute stages of SCI [3]. NDO represents a major health challenge for the SCI population, as inappropriate management of NLUTD can lead to severe complications and renal damage [1]. Therefore, reconstructing balanced bladder function and improving urinary control in SCI patients with NLUTD, particularly those with NDO, is a clinical necessity.
The regulation of the human LUT is mediated by complex, multilevel neuronal circuits that are governed not only by peripheral organs and the spinal cord but also by supraspinal brain networks. The brain is involved in both the sensory processing and efferent control of the LUT. Neuroimaging studies can provide valuable information for directly investigating LUT control and its underlying neural mechanisms in humans [4-6]. Regional homogeneity (ReHo) is a metric commonly used to measure regional neural activity in both healthy subjects and patients [7]. Functional connectivity (FC) is widely regarded as an important marker of how large-scale brain systems interact, integrate information, and maintain systemic integrity [8].
Previous neuroimaging studies have suggested abnormal brain activity and FC in patients with bladder dysfunction compared to healthy controls (HCs), with most research primarily focusing on individuals with an overactive bladder (OAB), which is a syndrome characterized by urinary urgency, usually accompanied by daytime frequency and nocturia, with or without urgency urinary incontinence (UUI) [9]. Specifically, idiopathic OAB refers to OAB without an identifiable etiology, whereas SCI-related NDO is an OAB subtype induced by neuropathy and presents with detrusor overactivity (DO). Imaging studies have reported that OAB patients exhibit abnormal FC within regions of the brain-bladder control network [10-13] and show deviations in supraspinal connectivity compared to HC [11]. In contrast, few neuroimaging studies have demonstrated abnormal FC in patients with DO or NDO. In recent years, only 3 studies have focused specifically on DO patients. Yin et al. [14] previously identified brain areas involved in bladder control in patients with DO and those with normal detrusor function. In a secondary analysis of OAB patients, Tadic et al. [15] reported significantly greater activation in regions adjacent to the supplementary motor area and the posterior cortex in the DO subgroup compared to the non-DO subgroup. However, few studies have utilized resting-state functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms of NDO. A study of NDO patients with tethered cord syndrome—who presented with sacrococcygeal neural injuries—identified altered activation in the prefrontal cortex and anterior cingulate cortex compared to HC [16].
Currently, supraspinal alterations of the LUT control network in SCI patients—who presented with suprasacral neural injuries—have not yet been well characterized. In patients with incomplete SCI, a decreased neural response in the right prefrontal area and an increased response in the left prefrontal region have been observed compared to HC [17]. In contrast, patients with complete SCI demonstrated a lack of supraspinal responses at the group level [18]. Whether regional brain activity and FC are altered in patients with NDO after SCI remains unclear. Therefore, this study aimed to identify abnormalities in regional brain activity and FC within the brain-bladder control network in NDO patients after SCI.
MATERIALS AND METHODS
Subjects
This study recruited 20 patients with SCI who were diagnosed with NDO through urodynamic studies. Their mean age was 38.88±11.43 years. A control group of 20 age- and sex-matched HC with a mean age of 39.73±9.37 years was also enrolled. All participants provided written informed consent.
Inclusion criteria for the NDO patients with SCI were: age between 18 and 60 years; a history of traumatic SCI with the spinal shock phase concluded; a urodynamic diagnosis of NDO; and right-handedness. Exclusion criteria included: urinary tract infection, tumor, urinary calculi, or organic obstruction; cognitive impairment or inability to follow commands; concomitant traumatic brain injury; neuropathic pain; severe contractures; skull deformities; psychiatric disorders; contraindications to MRI; and an inability to provide informed consent for the study procedures.
The study was conducted in accordance with the protocols approved by the Medical Ethics Committee of the China Rehabilitation Research Center (approval number: CRRC-IEC-RFSC-005-01). Written informed consent was obtained from all subjects prior to the study.
The Overactive Bladder Symptom Score (OABSS) questionnaire was administered to assess the symptoms of the NDO patients. The questionnaire consists of 4 core items, each rated on a scale from 0 to 4 based on symptom frequency. These items evaluate urinary urgency, UUI, daytime urinary frequency, and nocturia.
MRI Acquisition
All participants emptied their bladders prior to MRI scanning. Imaging was performed on a 3T MRI scanner (Philips Ingenia, The Netherlands) at the China Rehabilitation Research Center. During scanning, subjects were positioned supine. A multichannel head coil was used, and the head was stabilized with clamps to minimize motion-related artifacts. Participants were instructed to keep their eyes closed, remain relaxed and awake, and to refrain from focused thinking during the resting-state acquisition. High-resolution T1-weighted anatomical images were acquired before the functional scan using the following parameters: field of view (FOV)=256 mm×256 mm, matrix size=256 mm×256 mm, slice thickness=0.87 mm, repetition time (TR)=7,600 msec, echo time (TE)=3.7 msec, flip angle (FA)=8°, and voxel size=1 mm×1 mm×1 mm. Resting-state (fMRI) data were obtained using an echo-planar imaging (EPI) sequence with these parameters: slice thickness=3.5 mm, TR=2,000 msec, TE=30 msec, FA=90°, slice gap=0.5 mm, FOV=230 mm×230 mm, matrix size=80×80, and voxel size=3 mm×3 mm×3 mm.
MRI Data Preprocessing
Functional images were preprocessed using the resting-state fMRI Data Analysis Toolkit Plus (RESTplus) toolbox (http://www.restfmri.net). The preprocessing pipeline included the following steps: (1) removal of the first 10-time points to ensure steady-state longitudinal magnetization; (2) slice timing correction; (3) head motion correction, with exclusion criteria set at >2 mm of translation or 2° of rotation in any direction; (4) spatial normalization into the Montreal Neurological Institute template using T1-image unified segmentation, with resampling to 3 mm×3 mm×3 mm voxels; (5) detrending to remove linear drift; (6) regressed out nuisance signals, including Friston-24 head motion parameters, global signal, white matter signal and cerebrospinal fluid signal; and (7) temporal band-pass filtering (0.01–0.08 Hz).
The Calculation of ReHo
ReHo was calculated in the software of RESTplus. The individual ReHo map of each participant was obtained by calculating Kendall’s coefficient of concordance (KCC) of the time series of a given voxel with its 26 neighboring voxels, which was subsequently normalized by dividing by the global mean KCC value. Then KCC was calculated by analyzing the correlation between the time series of a given voxel and those of its nearest neighboring voxels on a voxel-wise basis. Finally, the standardized map was spatially smoothed with a 6- ×6- ×6-mm FWHM Gaussian kernel to decrease spatial noise. For subsequent statistical analysis, voxel-wise z-score normalization was performed across all subjects in the combined cohort (20 SCI-related NDO patients and 20 HCs).
Seed-Based FC Analysis
For the FC analysis, regions of interest (ROIs) were defined based on significant clusters identified in the ReHo maps following 2-sample t-tests. The analysis was performed using RESTplus. The seed reference time course for each ROI was derived by averaging the fMRI time series of all voxels within that region. Voxel-wise FC analysis was then carried out by computing the temporal correlation between the mean time series of the ROI and the time series of every other voxel across the whole brain. Individual correlation coefficients were converted to z-values using Fisher z-transformation, producing a whole-brain z-score map for each ROI in every participant. The whole fMRI analysis pipeline was illustrated in Supplementary Fig. 1.
Statistical Analysis
Statistical analyses were performed using IBM SPSS Statistics ver. 22.0 (IBM Co., USA). Continuous variables were compared using 2-tailed t-tests. Nonnormally distributed data are presented as median (interquartile range). Gender differences were assessed with the chi-square test, with a P-value <0.05 considered statistically significant. Gender and age were included as covariates in the regression model. For the FC analysis, two-sample t-tests (P<0.05) were used to identify regions with significantly increased or decreased FC associated with the predefined ROI between patients with NDO and HC. Multiple comparisons were corrected using family-wise error (FWE) correction at the cluster level (voxel-level P<0.001 uncorrected; cluster-level P<0.05 FWE-corrected. Partial correlation analysis was conducted to examine the relationship between FC values and clinical scores in NDO patients with age and sex as covariates. To correct for multiple comparisons across brain regions and clinical measures, we applied the false discovery rate correction at the cluster level (P<0.05) to avoid potential risk of type I error. A P-value of <0.05 was considered statistically significant for all tests.
RESULTS
Demographic and Clinical Variables
Twenty patients with NDO following SCI (18 males, 2 females; mean age, 38.88±11.43 years) and 20 HCs (18 males, 2 females; mean age, 39.73±9.37 years) were enrolled in the study. All participants were right-handed. No significant differences in age or gender distribution were observed between the 2 groups. Demographic and clinical characteristics are summarized in Table 1.
Clinical characteristics of participants in this study
Altered ReHo in Patients With NDO
ReHo analysis revealed significantly decreased ReHo in the right medial frontal gyrus (MFG) in NDO patients with SCI compared to HC (Fig. 1; Table 2). No brain regions showed increased ReHo in the patient group. The statistical threshold was set at an FWE-corrected P<0.05 at the cluster level, with an initial voxel-level threshold of P<0.001 uncorrected.
Significantly decreased ReHo in right medial frontal gyrus (MFG) in SCI-related NDO patients compared to HC group. The map of the brain regions with statistical differences between NDO patients and HC (A) and 3-dimensional distributions (B). ReHo, regional homogeneity; SCI, spinal cord injury; NDO, neurogenic detrusor overactivity; HC, healthy control; L, left; R, right.
Significant different ReHo between NDO and HC groups
Seed-to-Voxel FC Differences Between Groups
Seed-based FC analysis was performed using the right MFG as the seed region. Compared to HC, patients with NDO showed significantly stronger FC between the right MFG and the left pyramis, right cerebellum posterior lobe (CPL) (Fig. 2; Table 3), and left middle temporal gyrus (MTG) (Fig. 3; Table 3). In contrast, patients with NDO showed weaker FC between the right MFG and the right paracentral lobule (PCL) compared to HC (Fig. 4; Table 3).
Significantly increased FC between MFG_R and pyramis_L, as well as between MFG_R and CPL_R, in NDO patients compared to HC group in seed-to-voxel analysis (MFG_R as a seed, FWE-corrected, P<0.05). FC, functional connectivity; MFG, medial frontal gyrus; CPL, cerebellum posterior lobe; NDO, neurogenic detrusor overactivity; HC, healthy control; L, left; R, right; FWE, family-wise error. *P<0.05. **P<0.001.
Significant seed-to-voxel functional connectivity between NDO and HC groups
Significantly increased FC between MFG_R and MTG_L in NDO patients compared to HC group in seed-to-voxel analysis (MFG_R as a seed, FWE-corrected, P<0.05). FC, functional connectivity; MFG, medial frontal gyrus; MTG, middle temporal gyrus; NDO, neurogenic detrusor overactivity; HC, healthy control; L, left; R, right; FWE, family-wise error. *P<0.05. **P<0.001.
Significantly decreased FC between MFG_R and PCL_R in NDO patients compared to HC group in seed-to-voxel analysis (MFG_R as a seed, FWE-corrected, P<0.05). FC, functional connectivity; MFG, medial frontal gyrus; PCL, paracentral lobule; NDO, neurogenic detrusor overactivity; HC, healthy control; R, right; FWE, family-wise error. *P<0.05. **P<0.001.
Correlation Between Altered FC and Clinical Measurements
Correlation analysis revealed that both the OABSS and UUI scores showed significant positive correlations with FC values between the right MFG and the left pyramis (Fig. 5). Specifically, OABSS scores were positively correlated with FC between the right MFG and the left pyramis (r=0.589, P=0.01; Fig. 5). Similarly, UUI scores were positively correlated with FC between the right MFG and the left pyramis (r=0.662, P=0.003; Fig. 5).
Partial correlation between FC and clinical data. OABSS and UUI scores positively correlate with FC values between MFG_R and pyramis_L. FC, functional connectivity; OABSS, overactive bladder symptom score; UUI, urgency urinary incontinence; MFG, medial frontal gyrus; L, left; R, right.
DISCUSSION
In this study, we investigated abnormalities in regional brain activity and FC in patients with NDO following SCI using ReHo and seed-based FC analyses. Our findings provide new evidence for a potential central mechanism underlying NDO in this population. Compared to HC, patients with NDO exhibited significantly decreased ReHo in the right MFG. Seed-based FC analysis further revealed increased FC between the right MFG and the left pyramis, right CPL, and left MTG, alongside decreased FC between the right MFG and the right PCL in NDO patients relative to HC. Furthermore, both OABSS and UUI scores showed positive correlations with FC between the right MFG and the left pyramis.
We observed that patients with NDO after SCI exhibited significantly reduced ReHo in the right MFG, a region that forms part of the prefrontal cortex (PFC). Previous studies have indicated that the PFC is crucial for bladder control [19], participating in bladder storage and playing a key role in voiding-related decision-making and internal signal transmission [16]. In healthy individuals, greater activation in the orbitofrontal cortex has been associated with improved bladder control, suggesting that impaired bladder function may be specifically linked to insufficient activation of this region [20, 21].
However, abnormal neural activity has also been observed in other conditions involving neurogenic and nonneurogenic DO. While complete SCI patients demonstrated a lack of supraspinal responses at the group level, supraspinal activation in the PFC during bladder filling was detected in 8 of 12 patients at the individual level [18]. In contrast, Gao and Liao [16] reported that NDO patients with tethered cord syndrome exhibited increased ReHo values in the bilateral frontal cortex under strong desire to void compared to HC. Biao et al. [10] found that patients with OAB showed significantly reduced amplitude of low-frequency fluctuations in the left dorsal superior frontal gyrus and medial superior frontal gyrus. Griffiths and Tadic [22] suggested that prefrontal deactivation may represent a neural signature of DO itself. The MFG serves as a key hub of the central executive network and is involved in decision-making processes [8, 23]. Our finding of decreased ReHo in the right MFG in SCI-related NDO patients is consistent with the role of the MFG in suppressing excitatory signals to the pontine micturition center, thereby preventing involuntary voiding and incontinence [24]. The observed reduction in ReHo in the right MFG may therefore reflect impaired control over the risk of urinary leakage in patients with NDO.
At the FC level, we identified altered FC in patients with NDO compared to HC. Specifically, increased FC was observed between the right MFG and the left pyramis, right CPL, and left MTG, while decreased FC was found between the right MFG and right PCL. These findings align with a previous study that reported both increased and decreased FC between the PFC and other brain regions in NDO patients with tethered cord syndrome [16].
The increased FC between the right MFG and left pyramis, as well as between the right MFG and right CPL observed in this study represents a novel finding. In line with previous findings using task-based fMRI, the team reported OAB patients showed significantly stronger cerebellar activity during strong desire to void compared to HC [25]. While weaker seed (ventrolateral PFC) to voxel (cerebellum) connectivity was found in OAB compared to HC in another study [11]. The left pyramis and right CPL are components of the cerebellum. The cerebellum has long been recognized to coordinate voluntary movements, postural balance and cognitive functions [26-28]. There is increasing evidence suggesting it plays a significant role in the brain-bladder network, being frequently activated during both storage and voiding tasks [5]. However, the contribution of the cerebellum to LUT control remains inconsistent across studies and not fully clarified. In healthy individuals, cerebellar activity was observed during bladder filling, shortly before micturition, during actual micturition, and during interruption of micturition [29-31]. Animal study demonstrated the cerebellum plays an inhibitory role in the collecting phase and a facilitatory role in the emptying phase [32]. Cerebellum stroke frequently lead to LUT dysfunction, predominantly DO and detrusor-sphincter-dyssynergia [33]. Therefore, the cerebellum appears to provide both facilitatory and inhibitory inputs to LUT control centers and may be involved in the level setting and fine-tuning of LUT control [19]. In our study, SCI-related NDO patients showed increased FC between the right MFG and the left pyramis, as well as between the right MFG and the right CPL. This increased connection may reflect dysregulation of fronto-cerebellar circuits in NDO patients with SCI. Furthermore, our clinical correlation analysis revealed that both OABSS and UUI scores positively correlated with FC values between the right MFG and the left pyramis. This finding indicates that the severity of clinical symptoms is positively correlated with the strength of brain connectivity in NDO patients. Future longitudinal and interventional studies are needed to clarify whether this fronto-cerebellar FC is compensatory or maladaptive.
In addition, we observed increased FC between the right MFG and left MTG in patients with NDO. The MTG is involved in conflict resolution during decision-making and contributes to emotional processing, selective attention, and working memory [34]. The brain-bladder control network integrates complex sensory, motor, emotional, and cognitive processing of afferent signals from the bladder, enabling appropriate evaluation and response within social contexts [13, 19]. The enhanced FC between the right MFG and left MTG in NDO patients suggests impairments in behavioral and cognitive regulation, potentially associated with anxiety or depressive symptoms [34]. Supporting this, Zuo et al. [12] reported significantly higher self-rating depression scale (SDS) scores in OAB patients compared to controls, with negative correlations between SDS scores and short-range FC strength values in the caudate nucleus. Therefore, emotional disturbances in patients with LUT dysfunction may contribute to abnormal FC patterns in the brain.
Meanwhile, decreased FC between the right MFG and right PCL was observed in NDO patients compared to HC. The PCL represents the medial continuation of the precentral and postcentral gyri. This region is responsible not only for motor and sensory innervation of the lower extremities but also for cortical control of micturition and defecation [35]. As part of the sensorimotor network (SMN), the PCL performs premediated functions that coordinate multiple brain regions to prepare motor responses to sensory input. Consistent with previous findings, Zuo et al. [13] reported significantly decreased FC within the SMN, specifically in the PCL, in patients with OAB. This finding helps explain the abnormal brain connectivity mechanism underlying impaired executive function in patients with NDO and OAB.
Several limitations should be acknowledged in this study. First, the cross-sectional findings are associational and hypothesis-generating, which limits causal inference about the directionality of brain changes, future longitudinal studies would help elucidate causal mechanisms. Second, the relatively modest sample size inherent to this exploratory neuroimaging study may increase the risk of type II error and limit the statistical power to identify subtle but biologically meaningful associations. Third, while 20 participants per group is reasonable for exploratory study of regional brain activity and FC, it may limit generalizability to broader SCI-related NDO populations due to the diverse cohorts (e.g., varying injury durations and injury levels). Fourth, due to not all NDO patients can perceive bladder fullness or maintain a filled bladder, we did not perform resting-state fMRI scanning under different bladder conditions (empty vs. full), future studies should strive to incorporate both bladder emptying and filling states to explore how dynamic bladder volume changes modulate brain connectivity in SCI-related NDO, thereby providing a more comprehensive understanding of neural mechanisms. Fifth, we did not compare brain FC before and after treatment, future interventional studies, such as tibial nerve stimulation, are required to determine whether FC abnormalities are reversible or compensatory.
In conclusion, patients with NDO following SCI demonstrate abnormalities in both regional brain activity and FC. The extent of impairment in supraspinal connectivity correlates with the severity of LUT symptoms. These findings advance our understanding of the potential supraspinal neural mechanisms underlying NDO in SCI patients. Future therapeutic strategies for NDO should consider incorporating supraspinal targets.
SUPPLEMENTARY MATERIAL
Supplementary Fig. 1 is available at https://doi.org/10.5213/inj.2550210.105.
Functional magnetic resonance imaging (fMRI) analysis pipeline. MNI, Montreal Neurological Institute; ReHo, regional homogeneity; KCC, Kendall coefficient of concordance; FC, functional connectivity; ROI, region of interest.
Notes
Grant/Fund Support
This study was supported by National Key Research and Development Program of China (2023YFC3606003).
AUTHOR CONTRIBUTION STATEMENT
· Conceptualization: YG, XL
· Formal analysis: YG, ZW, DS, YP, XL
· Writing - original draft: YG
· Writing - review & editing: ZW