What clinical parameter strongly associates white matter tract alterations in a Multiple Sclerosis population with voiding dysfunction? A prospective exploratory study.

Purpose: To correlate clinical and urodynamics parameters in Multiple Sclerosis patients (MS) presenting Lower Urinary Tract Symptoms (LUTS) with both Expanded Disability Status Scale (EDSS) and changes in white matter integrity as seen on Diffusion Tensor Images (DTI). LUTS worsen throughout MS, as does lesion burden. We investigated which symptoms correlated best with structural changes in white matter structure. Materials and Methods: Ten adult women >18 years were recruited with stable MS for ≥3 months and voiding dysfunction defined as %PVR/BV > 20%. Patients participated in a clinical Urodynamic Study (UDS) and completed several questionnaires (i.e., HAM, AUASS, NBS-QoL). DTI images were acquired using a 7-Tesla Siemens MAGNETOM Terra MRI scanner. DTI maps were constructed, and individual patients were co-registered with the ICBM-DTI-81 white matter atlas to extract fractional anisotropy (FA) and mean diffusivity (MD). Pearson's correlation test was performed between each WMT and clinical parameters and between clinical parameters and the EDSS score as well. P-values < 0.05 were considered significant. Results: Of the clinical parameters, %PVR/BV obtained from the average of multiple un-instrumented uroflow assessments had significant correlations to the greatest number of WMTs. Furthermore, we observed that in all recorded clinical parameters, %PVR/BV was the only significant parameter correlated to the EDSS score. Conclusion: This study demonstrates that %PVR/BV can be used as an objective parameter to gauge WMT changes and disease progression in MS patients. Future studies are needed to refine this model.

Is the Brainstem Activation Different Between Healthy Young Male and Female Volunteers at Initiation of Voiding? A High Definition 7-Tesla Magnetic Resonance Imaging Study.

PURPOSE: Assessing brainstem function in humans through typical neuroimaging modalities has been challenging. Our objective was to evaluate brain and brainstem activation patterns during initiation of voiding in healthy males and females utilizing a 7 Tesla magnetic resonance imaging (MRI) scanner and a noninvasive brain-bladder functional MRI (fMRI) protocol. METHODS: Twenty healthy adult volunteers (10 males and 10 females) with no history of urinary symptoms were recruited. Each volunteer underwent a clinic uroflow and postvoid residual assessment and was asked to consume water prior to entering the scanner. Anatomical and diffusion tensor images were obtained first, followed by a blood oxygenation level dependent (BOLD) resting-state fMRI (rs-fMRI) during the empty bladder. Subjects indicated when they felt the urge to void, and a full bladder rs-fMRI was obtained. Once completed, the subjects began 5 voiding cycles, where the first 7.5 seconds of each voiding cycle was identified as "initiation of voiding." BOLD activation maps were generated, and regions of interests with a t-value greater than 2.1 were deemed statistically significant. RESULTS: We present 5 distinct regions within the periaqueductal gray (PAG) and pontine micturition center (PMC) with statistically significant activation associated with an initiation of voiding in both men and women, 3 within the PAG and 2 within the PMC. Several additional areas in the brain also demonstrated activation as well. When comparing males to females, there was an overall lower BOLD activation seen in females throughout all regions, with the exception of the caudate lobe. CONCLUSION: Our study effectively defines regions within the PAG and PMC involved in initiation of voiding in healthy volunteers. To our knowledge, this is the first study investigating differences between male and female brainstem activation utilizing an ultra-high definition 7T MRI.

Disruption of specific white matter tracts is associated with neurogenic lower urinary tract dysfunction in women with multiple sclerosis.

OBJECTIVE: To identify specific white matter tracts (WMTs) whose disruption is associated with the severity of neurogenic lower urinary tract dysfunction (NLUTD) in two independent cohorts of women with multiple sclerosis (MS) and NLUTD. METHODS: Cohort 1 consisted of twenty-eight women with MS and NLUTD. The validation cohort consisted of 10 women with MS and NLUTD. Eleven healthy women served as controls. Participants of both MS cohorts had the same inclusion and exclusion criteria. Both MS cohorts and the healthy controls underwent the same clinical assessment and functional MRI (fMRI) protocol, except that the validation MS cohort underwent 7-Tesla fMRI scan. Fifteen WMTs (six coursing to relevant brainstem areas) involved in bladder control were a priori regions of interest (ROI). Spearman's correlation test was performed between each the Fractional Anisotropy (FA) and mean diffusivity (MD) of each WMT and the clinical parameters. RESULTS: Overall, we found a very high degree of overlap (100% of a priori ROI) in the tracts identified by our correlation analysis as having the greatest contribution to NLUTD symptoms in MS women. The right inferior cerebellar peduncle, left posterior limb of internal capsule, and left superior cerebellar peduncle displayed significant associations to the greatest number of clinical parameters. CONCLUSIONS: Our correlation analysis supports the role of specific WMT disruptions in the contribution of symptoms in women with MS and NLUTD, as confirmed in two independent MS cohorts.

Predictors for outcomes of noninvasive, individualized transcranial magnetic neuromodulation in multiple sclerosis women with neurogenic voiding dysfunction.

Purpose: Multiple sclerosis (MS) is a multifocal demyelinating disease that affects the central nervous system (CNS) and commonly leads to neurogenic lower urinary tract dysfunction (NLUTD). Proper storage and release of urine relies on synchronized activity of the LUT, which is meticulously regulated by supraspinal circuits, making it vulnerable to diseases such as MS. NLUTD, characterized by voiding dysfunction (VD), storage issues, or a combination of both is a common occurrence in MS. Unfortunately, there are limited treatment options for NLUTD, making the search for alternative treatments such as transcranial rotating permanent magnet stimulation (TRPMS) of utmost importance. To assess effectiveness of treatment we also need to understand underlying factors that may affect outcomes, which we addressed here. Methods: Ten MS subjects with VD and median age of 54.5 years received daily TRPMS sessions for two weeks. Five pre-determined regions of interest (ROIs) known to be involved in the micturition cycle were modulated (stimulated or inhibited) using TRPMS. Clinical data (non-instrumented uroflow and urodynamics parameters, PVR, bladder symptom questionnaires) and neuro-imaging data were collected at baseline and following TRPMS via 7-Tesla Siemens MAGNETOM Terra magnetic resonance imaging (MRI) scanner. Each participant underwent functional MRI (fMRI) concurrently with a repeated urodynamic study (UDS). Baseline data of each arm was evaluated to determine any indicators of successful response to treatment.

White Matter Integrity in Men With Benign Prostatic Hyperplasia and Bladder Outlet Obstruction and Its Contribution to Lower Urinary Tract Symptoms.

PURPOSE: Lower urinary tract symptoms (LUTS) associated with bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH) can negatively impact quality of life. We evaluated the structural connectivity of the brain in men with BPH with chronic BOO using diffusion tensor imaging (DTI). METHODS: Ambulatory male patients aged ≥45 years with BPH and BOO were recruited. LUTS was defined as an International Prostate Symptom Score (IPSS) ≥12 and a maximum urinary flow rate ≤15 mL/sec. Upon recruitment, uroflowmetry and validated questionnaires regarding bladder status were collected. DTI images from each subject were aligned with the ICBM-DTI-81 atlas, defining 50 white matter tracts (WMTs). The mean values of DTI parameters-fractional anisotropy and mean diffusivity-for each WMT were extracted. These measures were then utilized to compute Pearson correlation coefficients with clinical parameters. Objective clinical parameters included uroflowmetry parameters, postvoid residual (PVR) volume, and bladder capacity. Subjective clinical parameters were assessed using validated questionnaires: the IPSS, Incontinence Symptom Index, and Sexual Health Inventory for Men. RESULTS: The correlation analysis revealed 15 WMTs that showed statistically significant associations (P<0.05) with objective and subjective clinical parameters. Eight tracts were associated with uroflowmetry parameters: maximum flow rate (Qmax), mean flow rate (Qmean), and PVR. Among these tracts, the middle cerebellar peduncles and left medial lemniscus were associated with Qmax; the genu of the corpus callosum, left superior corona radiata, corticospinal tract, right medial lemniscus, posterior corona radiata with Qmean; and the left posterior corona radiata with PVR. Seven tracts also demonstrated significant associations with the IPSS. CONCLUSION: Our results suggest correlations between the preserved white matter integrity of specific WMTs and the severity of LUTS based on objective and subjective clinical parameters, leading us to believe that a distinct pathology of the central nervous system might exist.

Biomechanical regulation of breast cancer metastasis and progression.

Physical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.