Abstract
Purpose
We compared brain activation patterns between female multiple sclerosis (MS) patients with voiding dysfunction (VD) and those without. We aim to expand current knowledge on supraspinal correlates of voiding initiation within a cohort of female MS patients with and without VD.
Materials and Methods
Twenty-eight ambulatory female MS patients with stable disease and lower urinary tract dysfunction were recruited for this study. Subjects were divided into group 1; without VD (n=14) and group 2; with VD (n=14), defined as post-void residual urine of ≥ 40% of maximum cystometric capacity or need for self-catheterization. We recorded brain activity via functional magnetic imaging (fMRI) with simultaneous urodynamic testing. Average fMRI activation maps (student t-test) were created for both groups, and areas of significant activation were identified (p<0.05). A priori regions of interest (ROIs), identified by prior meta-analysis to be involved in voiding, were selected.
Results
Group-averaged blood oxygen level dependent (BOLD) activation maps demonstrated significant differences between groups 1 and 2 during initiation of voiding with group 2 showing significantly lower levels of activation in all ROIs except for the left cerebellum and right cingulate gyrus. Interestingly, Group 2 displayed negative BOLD signals, while group 1 displayed positive signals in the right and left pontine micturition center (PMC), right periaqueductal gray (PAG), left thalamus, and left cingulate gyrus. The activation map of group 1 was similar to healthy controls.
Conclusions
Our results support the hypothesis that distinct supraspinal activation patterns exist between female MS patients with VD and those without.
Introduction
Multiple sclerosis (MS) is an immune-mediated chronic inflammatory disease of the central nervous system (CNS)1 affecting up to 1 in 800 people in North America and Europe with women two to three times more likely than men to have the disease. With an average age of onset between 20 and 40 years old, it is one of the most common causes of neurologic disability in the US1,2. The disease is characterized by demyelinating lesions (known as plaques) in the white matter, which disrupt saltatory conduction of neuronal action potentials in the brain and spinal cord. This leads to sensory, visual, and motor disturbances including neurogenic bowel and bladder where symptoms that can significantly decrease quality of life3.
Over 80% of patients with MS have lower urinary tract symptoms (LUTS), with bladder overactivity and urinary incontinence being most common4. However, 19% to 40% of MS patients experience difficulty voiding5. The control center that switches storage of urine to initiation of voiding is located in the supraspinal centers, and its role in initiating or modulating voiding in patients with neurogenic or non-neurogenic voiding dysfunction has not been well-studied6.
A previous study examined brain activation using functional magnetic resonance imaging (fMRI) during the entire micturition cycle (storage and voiding phases) in a cohort of MS patients with neurogenic lower urinary tract dysfunction (NLUTD) and found predominantly decreased levels of activation in regions of interest (during full urge and initiation of voiding) compared to healthy controls7. We seek to enhance current understanding of the neurological correlates of initiation of voiding in MS patients with NLUTD by comparing regional blood oxygen level dependent (BOLD) signals in MS women who are able to void and those with voiding dysfunction. We hypothesized that MS patients with neurogenic bladder and voiding dysfunction would have BOLD patterns on fMRI that are distinct from MS patients who are able to void. To our knowledge this is the first study to investigate the differences and similarities of brain regions involved in initiation of voiding in MS patients.
Methods
We recruited twenty eight adult female MS patients with NLUTD for this study, which was approved by our Institutional Board Review. All subjects were ambulatory with clinically stable MS for ≥6 months before the study and an Expanded Disability Status Score (EDSS) ≤6.5. All subjects had neurogenic lower urinary tract dysfunction and had already undergone clinic urodynamic studies (UDS). Men were excluded to avoid possible confounding from prostate pathology. In our study, patients were determined to have VD if they performed self-catheterization regularly or if they had a post-void residual urine volume of ≥40% of their maximum cystometric capacity. Subjects were divided into two groups. Group 1 was made up of 14 subjects without voiding dysfunction (voiders), and group 2 was made up of 14 subjects with voiding dysfunction (VD). All patients underwent a detailed history and physical examination, baseline UDS, urinalysis, and post-void residual urine measurement. In addition, all subjects underwent evaluation with the EDSS, Urogenital Distress Inventory (UDI)-6, Incontinence Impact Questionnaire (IIQ)-7, and MRI Safety Screening Questionnaire, and the Hamilton Anxiety Rating Scale. Pregnant patients and those with active urinary tract infections were excluded. Eleven healthy females (not age-matched) without any urinary complaints completed a clinic UDS and were recruited as health controls (HCs). Scanning instructions were the same for all MS patients and HCs.
Concurrent Urodynamic Study and functional Magnetic Resonance Imaging (fMRI) Procedure
Patients were asked to empty their bladders spontaneously or with catheterization. Double lumen 7Fr MRI compatible bladder and rectal UDS catheters were placed prior to fMRI. Tubing was brought out of the scanner room and connected to a UDS system in an adjacent room. All unnecessary stimuli including visual and auditory disturbances were removed as much as possible to limit confounding brain activations. Structural scans were performed with the bladder in the empty state. Resting state functional scanning was performed and combined with practice hand signal algorithms as previously detailed 7, 8. Then the concurrent fMRI/UDS portion of the study was started by filling the bladder with room temperature sterile saline at 75 ml per minute. Patients used right hand signals to indicate a strong desire to urinate. Bladder infusion was then stopped at this point, and patients were asked to hold for 30 seconds. After 30 seconds, patients were given permission to void onto absorbent pads on the scanner table while lying supine. They used a hand signal to indicate initiation of voiding (or attempt at voiding), and completion of voiding (or completion of attempt at voiding). This cycle was repeated up to 4 times for each subject. Complete UDS data and post-void residuals were recorded. Bladder was aspirated manually if voiding was not completed. Functional MRI times were limited to 30 minutes. All MRI was performed at our institutional imaging MRI Core using an Ingenia 3.0 Tesla full body scanner (Philips, Eindhoven, The Netherlands) with a standard 12-channel Laborie urodynamic testing. Clinic UDS data and UDS data from fMRI scanning sessions are included in Table 1 and Table 2 in the appendix. An example of an fMRI UDS tracing can also be found in Figure 1 in the appendix.
After motion correction, the Generalized Linear Model created individual fMRI activation maps at initiation of voiding. A high-resolution structural scan of the brain transformed the individual fMRI activation maps into Talairach space. From these transformed datasets, an average fMRI activation map (student t-test) was created, from which areas of significant activation were identified (p<0.05). Earlier neuroimaging studies have identified brain regions directly involved in initiating or continuing voiding in healthy individuals. These regions include: Precentral Gyrus, Supplementary Motor Area, Dorsolateral Prefrontal Lobe, Inferior Frontal Gyrus (IFG), Cingulate Gyrus, Insula, Hypothalamus, PAG, and Pons (PMC) 6,9,10,11. a priori regions of interest (ROIs) were identified based on the literature and our prior investigation in MS patients as: pontine micturition center, periaqueductal grey, prefrontal cortex, cerebellum, thalamus, and cingulate.
Results
Patient demographics, including the clinic UDS, are summarized in Table 1. Mean fMRI time was 17.8 minutes. Group averaged ROI analysis yielded consistent areas of increased BOLD signal activation in all ROIs in group 1 compared to group 2 except in the left cerebellum (all p-values < 1.5e-4). (Figure 1). There was significantly lower levels of activation in all ROIs in the VD group with the exception of the left cerebellum and the right cingulate gyrus. Interestingly, several ROIs displayed negative BOLD signals among the VD patients and positive BOLD signals among the voiders (complete reverse activation patterns). These areas include the right reticular formation, right and left PMC, right PAG, left thalamus, and left cingulate gyrus. The only ROI that had a negative BOLD signal in the voiding group was the right cingulate gyrus. Figure 1 also demonstrates the BOLD activation patterns in HCs at initiation of voiding. MS voiders displayed activation patterns that were very similar to HCs, although lower in amplitude. Overall, at initiation of micturition, the patients with voiding dysfunction displayed a BOLD activation pattern that was significantly distinct from the BOLD activation pattern of the MS patients who did not have voiding dysfunction.
Table 1.
Patient demographics.
| Overall | Patients without VD | Patients with VD | |
|---|---|---|---|
| Number of patients | 28 | 14 | 14 |
| Mean age (min-max) | 51.3 (33–85) | 49.6 (37–66) | 52.9 (33–85) |
| BMI (min-max) | 28.2 (20–40.4) | 29.9 (21.3–40.4) | 26.5 (20–37.4) |
| Duration of Multiple Sclerosis (min-max) | 15.8 (2–38) | 15.1 (2–38) | 16.5 (3–47) |
| Voiding patterns | |||
| Strictly voiding spontaneously (%) | 18 (64.3) | 14 (100) | 4 (28.6) |
| Strictly on self-catheterization (%) | 10 (35.7) | 0 (0) | 10 (71.4) |
| Voiding spontaneously and on self-catheterization (%) | 2 (7.1) | 0 (0) | 2 (14.3)* |
| Mean UDI-6 (min-max) | 11.3 (2–21) | 10.9 (2–24) | 11.6 (6–21) |
| UDI-6, Q5 (voiding) | 2.8 (0–4) | 2.3 (0–4) | 3.4 (0–4) |
| Mean IIQ-7 (min-max) | 8.6 (0–21) | 7.9 (0–21) | 9.2 (0–18) |
| Previous Hysterectomy (%) | 5 (27.8) | 3 (21.4) | 2 (14.3) |
| Overactive bladder medication use at baseline (%) | 24 (85.7) | 12 (85.7) | 12 (85.7) |
| Urodynamic data | |||
| Mean maximum cystometric capacity, ml (min-max) | 388.1 (191–680) | 412.6 (194–680) | 363.6 (191–645) |
| Detrusor Sphincter dyssenergia (%) | 4 (14.3) | 1(7.1) | 3 (21.4) |
| Mean post void residual, ml (min-max) | 128.04 (0–370) | 49.5 (0–150) | 206.57 (60–370) |
| % Post void residual/Maximum cystometric capacity (min-max) | 35 (0–100) | 13.1 (0–33.5) | 57 (30.6–100) |
| Baseline MRI findings | |||
| Presence of general cortical atrophy (%) | 6 (21.4) | 3 (21.4) | 3 (21.4) |
| Presence of enhancing lesions (%) | 4 (14.3) | 1 (7.1) | 3 (21.4) |
| Location of lesions | |||
| Cerebrum (%) | 28 (100) | 14 (100) | 14 (100) |
| Cerebellum (%) | 8 (28.6) | 2 (14.2) | 6 (42.9) |
| Brainstem (%) | 11 (39.2) | 7 (50) | 4 (28.6) |
| Spinal cord (%) | 15 (53.6) | 8 (57.1) | 7 (50) |
Figure 1.
A: Group-averaged fMRI BOLD activation patterns for MS patients with and without voiding dysfunction. Distinct differences in both patterns can be appreciated. B: Average BOLD activity in selected regions of interest (ROI) derived from the BOLD maps in A as well as from healthy controls. A predominantly higher BOLD effect is observed for patients who are able to void compared to those with voiding dysfunction (p<1.5e-4). Negative BOLD effect is noted in selected ROIs (Cereb: cerebellum, Cing: cingulate, Front: prefrontal cortex, Midb: midbrain, PMC: pontine micturition center, Thalam: thalamus, PAG: periaqueductal gray, RetForm: reticular formation).
Discussion
Lower urinary tract symptoms are common amongst patients with MS, with voiding dysfunction present in a substantial subset5. It is not clear why some MS patients develop voiding difficulty while others experience predominantly storage phase dysfunction. Our study seeks to shed light on differences in supraspinal activation between voiders and VD patients in MS by examining differences in BOLD patterns on fMRI during initiation of voiding.
While our knowledge of the intricacies of the brain circuitry controlling micturition is far from complete, it is generally established that the pontine micturition center (PMC) is part of a brainstem switch that controls efferent output from the brain to the spinal cord. Previous studies of brainstem tumors and lesions have shown that damage to the dorsolateral pons and the reticular formation are associated with difficulty voiding13. A basic model postulates that during bladder filling, afferent signals are sent to the periaqueductal gray (PAG) via the thalamus and then to the insula and the cingulate cortex, regions involved in sensation and urgency. These signals are also transmitted to regions in the forebrain (including the medial and orbital prefrontal cortex) and limbic system, which process decision making, emotion, and social context. These areas, in turn, project back on the PAG and then the PMC to initiate micturition in a socially acceptable situation14, 15. Our study showed significant and distinct differences in BOLD signals in several of these regions between MS patients who have voiding dysfunction and those who do not.
BOLD signal intensity is inversely related to the blood deoxyhemoglobin level. Greater signal intensity represents increased cerebral blood flow and, therefore, a relative increase in neuronal activity in the region of interest16. It is particularly interesting that a negative BOLD response (NBR) was seen in the PMC, PAG, left cingulate, left thalamus and the reticular formation on group averaged BOLD activation maps of the voiding dysfunction group. In contrast, these regions were strongly positive for the voiding group and healthy controls. The origin of the sustained NBR is still under investigation. The dominant hypothesis is that the NBR reflects decreased neuronal activity17. The decrease in activation below baseline is then reflected in a decrease in the supply of oxygenated blood, and, therefore, a negative BOLD signal. Our results showed significant NBR in the PAG and PMC in the non-voiding group during initiation of micturition, while the voiding group showed a strong positive BOLD response at the same time point. Whether this is a cause or effect of voiding dysfunction in female MS patients is unclear. However, both patients with VD and voiders showed similarly positive BOLD responses in the pre-frontal cortex during initiation of micturition. It is possible that damage to the white matter connections or even functional connectivity18 between the prefrontal cortex and the PAG and PMC leads to decreased PAG and PMC activation despite the subjects making an executive decision to initiate voiding (reflected in the positive prefrontal BOLD response).
Another hypothesis for the origin of the sustained NBR is that it is a hemodynamic response to increased activation away from the ROI. The areas with increased activation divert oxygenated blood from neighboring areas leading to an NBR in these neighboring regions19, 20. Interestingly, other investigators have found that patients with MS show activation in regions not typically activated in healthy controls during a motor task, which they attributed to brain plasticity in response to pathologic changes21. Our current study utilized a region of interest analysis, thus, we are unable to determine if the NBR in the PMC, PAG, left cingulate, left thalamus and the reticular formation is associated with positive BOLD responses and increased activity in adjacent areas.
While MS is generally thought to be a demyelinating disease, it is now known that gray matter is also significantly affected22. Differential patterns in gray matter damage may contribute to the differences in the BOLD responses between voiders and dysfunctional voiders. Our group has previously found that MS patients with voiding dysfunction had significantly less similar functional connectivity patterns compared to MS patients who were able to void suggesting a possible failure in the cortical compensation mechanism for voiding18. The results of this study also complement this hypothesis. However the phenomenon of compensation in the micturition has not been thoroughly studied. Previous studies have found increased activity in contralateral sensorimotor and non-motor regions to be adaptive for motor tasks in MS patients23. In contrast, MS patients overall (with and without voiding dysfunction) tend to have decreased activation during initiation of voiding in regions involved in micturition compared to healthy controls7. Future studies are necessary to clarify these findings.
Limitations
Most MS patients originally present with storage symptoms such as frequency, urgency and urge urinary incontinence. As their disease progresses patients will start experiencing voiding phase symptoms. Female voiding dysfunction lacks a consensus definition, and there is no agreed upon classification, creating a controversial and challenging issue to manage and study 24, 25. The International Continence Society and International Urogynecological Association define voiding dysfunction as an abnormally slow and/or incomplete micturition26. Voiding Dysfunction in MS patients is a spectrum with urinary retention and needing to catheterize (indwelling catheter or self-catheterization) at one end and having some hesitancy and some incomplete bladder emptying at the other end. Abnormally slow urine and abnormally high post void residuals are the basis for the diagnosis of voiding dysfunction, although, the normal ranges for these parameters vary in the literature. Our study focuses on the voiding phase and did not account for abnormalities during the filling phase.
The inherently unnatural environment of the fMRI and UDS set up is a confounding factor that may increase voiding difficulty especially in those who already may strain to void. Supine positioning, the presence of a UDS catheter in the urethra, and supraphysiologic bladder filling are factors that may alter brain activation compared to physiologic voiding while sitting. Simultaneous UDS while undergoing fMRI also requires much longer lengths of tubing that pass through a port in a wall separating the MRI machine and the UDS tower. Therefore, the tracings are not directly comparable to clinic UDS tracings. Also, because the patients voided onto an absorbent pad in the MRI machine, flow rates could not be measured. The fMRI UDS tracings were used to look for characteristic patterns to indicate voiding, and we utilized baseline clinic UDS to characterize detailed filling and voiding patterns for individual patients.
Furthermore, MS is a heterogeneous and dynamic disease in terms of lesion location, disease course, and level of disability, making it difficult to generalize observations. Our study evaluated differences in supraspinal activation during micturition. Spinal cord lesions are also common in MS and have major effects on sensory and motor function. We controlled for ambulatory status, disease stability, and disability status but did not control for total lesion burden or location.
Conclusions
We are just beginning to understand how the pathophysiology of MS correlates with different lower urinary tract symptoms. Our current study uses fMRI to demonstrate significant differences in supraspinal activation in a cohort of female patients with MS. Women with MS with voiding dysfunction were found to have very different BOLD patterns in the ROIs studied compared to subjects with MS without voiding as well as healthy controls. While we are still in the early stages of understanding the role of cortical changes in voiding dysfunction, it is our hope that a deeper comprehension of these processes will lead to novel therapies to aid in bladder emptying.
Acknowledgments
Extra-institutional funding
K23DK118209, by National Institute of Heath, NIDDK
Key
- MS
Multiple sclerosis
- CNS
Central nervous system
- LUTS
Lower urinary tract symptoms
- fMRI
functional magnetic resonance imaging
- NLUTD
Neurogenic lower urinary tract dysfunction
- BOLD
Blood oxygen level dependent
- VD
Voiding dysfunction
- ROI
Region of interest
- EDSS
Expanded Disability Status Score
- UDS
Urodynamic studies
- UDI
Urogenital Distress Inventory
- IIQ
Incontinence Impact Questionnaire
- HC
Healthy control
- PMC
Pontine micturition center
- PAG
Periaqueductal gray
Appendix
Figure 1.
Example of a UDS tracing during fMRI scanning. Patients underwent 4 cycles of filling and voiding while being scanned. Intravesical and intraabdominal pressures were recorded. Flow and volume voided were not recorded because patients voided into a pad while in the scanner.
Table 1.
Clinic UDS and fMRI UDS data for patients without voiding dysfunction.
| Clinic UDS | fMRI UDS | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Subject ID | Presence or absence of IDC | MDP during 1st IDC (cmH2O) | Volume at 1st IDC (cc) | Qmax (cc/s) | Pdet at Qmax (cmH2O) | Valsalva during voiding or attempt of voiding | Volume voided (cc) | Post void residual (cc) | Detrusor sphincter dyssynergia present | Presence or absence of IDC | Detrusor contraction present during voiding | Valsalva during voiding or attempt of voiding | Post void residual (cc) | Able to void (or partially void) in scanner |
| No VD1 | No | N/A | N/A | 38 | ** | Yes | 430 | 56 | No | No | No | No | 420 | No |
| No VD2 | Yes | 3 | 550 | 25 | ** | Yes | 535 | 15 | No | No | No | No | 600 | Yes |
| No VD3 | No | N/A | N/A | 8 | ** | No | 398 | 89 | Yes | No | Yes | No | 125 | Yes |
| No VD4 | No | N/A | N/A | 11 | 10 | Yes | 425 | 150 | No | No | Yes | Yes | 425 | Yes |
| No VD5 | No | N/A | N/A | 8 | ** | Yes | 500 | 50 | No | No | No | No | 820 | No |
| No VD6 | Yes | 10 | 313 | 9 | 16 | Yes | 368 | 254 | No | Yes | Yes | Yes | 190 | Yes |
| No VD7 | No | N/A | N/A | 41 | ** | Yes | 682 | 0 | No | No | No | No | 628 | No |
| No VD8 | No | N/A | N/A | 21 | 8 | Yes | 747 | 0 | No | No | No | Yes | 650 | No |
| No VD9 | Yes | 38 | 188 | 12 | 37 | Yes | 281 | 0 | No | Yes | Yes | Yes | 550 | No |
| No VD10 | Yes | 12 | 90 | 16 | 37 | No | 359 | 139 | No | No | No | Yes | 532 | No |
| No VD11 | Yes | 22 | 250 | 50 | ** | Yes | 159 | 50 | No | No | Yes | Yes | 380 | Yes |
| No VD12 | No | N/A | N/A | 11 | 26 | Yes | 271 | 56 | No | No | Yes | No | 92 | Yes |
| No VD13 | No | N/A | N/A | 23 | 28 | No | 287 | 0 | No | No | No | No | *** | Yes |
| No VD14 | Yes | 2 | 322 | 12 | 10 | Yes | 141 | 37 | No | Yes | Yes | No | 300 | Yes |
| Mean | 14.5 | 285.5 | 20.36 | 21.5 | 398.79 | 64 | 439.38 | |||||||
IDC: Idiopathic detrusor contraction. MDP: Maximum detrusor pressure. Qmax: Maximum flow rate. Pdet: Detrusor pressure.
Unmeasurable as patient’s Qmax was recorded in a Uroflow after catheter removal.
Post void residual was not recorded.
Table 2.
Clinic UDS and fMRI UDS data for patients with voiding dysfunction.
| Clinic UDS | fMRI UDS | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Subject ID | Presence or absence of IDC | MDP during 1st IDC (cmH2O) | Volume at 1st IDC (cc) | Qmax (cc/s) | Pdet at Qmax (cmH2O) | Valsalva during voiding or attempt of voiding | Volume voided (cc) | Post void residual (cc) | Detrusor sphincter dyssynergia present | Presence or absence of IDC | Detrusor contraction present during voiding | Valsalva during voiding or attempt of voiding | Post void residual (cc) | Able to void (or partially void) in scanner |
| No VD1 | No | N/A | N/A | 38 | ** | Yes | 430 | 56 | No | No | No | No | 420 | No |
| No VD2 | Yes | 3 | 550 | 25 | ** | Yes | 535 | 15 | No | No | No | No | 600 | Yes |
| No VD3 | No | N/A | N/A | 8 | ** | No | 398 | 89 | Yes | No | Yes | No | 125 | Yes |
| No VD4 | No | N/A | N/A | 11 | 10 | Yes | 425 | 150 | No | No | Yes | Yes | 425 | Yes |
| No VD5 | No | N/A | N/A | 8 | ** | Yes | 500 | 50 | No | No | No | No | 820 | No |
| No VD6 | Yes | 10 | 313 | 9 | 16 | Yes | 368 | 254 | No | Yes | Yes | Yes | 190 | Yes |
| No VD7 | No | N/A | N/A | 41 | ** | Yes | 682 | 0 | No | No | No | No | 628 | No |
| No VD8 | No | N/A | N/A | 21 | 8 | Yes | 747 | 0 | No | No | No | Yes | 650 | No |
| No VD9 | Yes | 38 | 188 | 12 | 37 | Yes | 281 | 0 | No | Yes | Yes | Yes | 550 | No |
| No VD10 | Yes | 12 | 90 | 16 | 37 | No | 359 | 139 | No | No | No | Yes | 532 | No |
| No VD11 | Yes | 22 | 250 | 50 | ** | Yes | 159 | 50 | No | No | Yes | Yes | 380 | Yes |
| No VD12 | No | N/A | N/A | 11 | 26 | Yes | 271 | 56 | No | No | Yes | No | 92 | Yes |
| No VD13 | No | N/A | N/A | 23 | 28 | No | 287 | 0 | No | No | No | No | *** | Yes |
| No VD14 | Yes | 2 | 322 | 12 | 10 | Yes | 141 | 37 | No | Yes | Yes | No | 300 | Yes |
| Mean | 14.5 | 285.5 | 20.36 | 21.5 | 398.79 | 64 | 439.38 | |||||||
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