Unsupervised classification of multi-contrast magnetic resonance histology of peripheral arterial disease lesions using a convolutional variational autoencoder with a Gaussian mixture model in latent space: A technical feasibility study.

PURPOSE: To investigate the feasibility of a deep learning algorithm combining variational autoencoder (VAE) and two-dimensional (2D) convolutional neural networks (CNN) for automatically quantifying hard tissue presence and morphology in multi-contrast magnetic resonance (MR) images of peripheral arterial disease (PAD) occlusive lesions. METHODS: Multi-contrast MR images (T2-weighted and ultrashort echo time) were acquired from lesions harvested from six amputated legs with high isotropic spatial resolution (0.078 mm and 0.156 mm, respectively) at 9.4 T. A total of 4014 pseudo-color combined images were generated, with 75% used to train a VAE employing custom 2D CNN layers. A Gaussian mixture model (GMM) was employed to classify the latent space data into four tissue classes: I) concentric calcified (c), II) eccentric calcified (e), III) occluded with hard tissue (h) and IV) occluded with soft tissue (s). Test image probabilities, encoded by the trained VAE were used to evaluate model performance. RESULTS: GMM component classification probabilities ranged from 0.92 to 0.97 for class (c), 1.00 for class (e), 0.82-0.95 for class (h) and 0.56-0.93 for the remaining class (s). Due to the complexity of soft-tissue lesions reflected in the heterogeneity of the pseudo-color images, more GMM components (n=17) were attributed to class (s), compared to the other three (c, e and h) (n=6). CONCLUSION: Combination of 2D CNN VAE and GMM achieves high classification probabilities for hard tissue-containing lesions. Automatic recognition of these classes may aid therapeutic decision-making and identifying uncrossable lesions prior to endovascular intervention.

Conception and implementation of an MRI-compatible device to elicit the bulbocavernosus reflex for an open spinal cord study.

OBJECTIVE: Functional MRI (fMRI) can be employed to assess neuronal activity in the central nervous system. However, investigating the spinal cord using fMRI poses several technical difficulties. Enhancing the fMRI signal intensity in the spinal cord can improve the visualization and analysis of different neural pathways, particularly those involved in bladder function. The bulbocavernosus reflex (BCR) is an excellent method for evaluating the integrity of the sacral spinal cord. Instead of stimulating the glans penis or clitoris, the BCR can be simulated comfortably by tapping the suprapubic region. In this study, we explain the necessity and development of a device to elicit the simulated BCR (sBCR) via suprapubic tapping while conducting an fMRI scan. METHODS: The device was successfully tested on a group of 20 healthy individuals. Two stimulation task block protocols were administered (empty vs. full bladder). Each block consisted of 40 s of suprapubic tapping followed by 40 s of rest, and the entire sequence was repeated four times. RESULTS: Our device can reliably and consistently elicit sBCR noninvasively as demonstrated by electromyographic recording of pelvic muscles and anal winking. Participants did note mild to moderate discomfort and urge to void during the full bladder task. CONCLUSION: Our device demonstrates an efficacious approach to elicit sBCR within an MRI bore to assess sacral spinal cord functional activity without generating any significant motion artifacts. SIGNIFICANCE: This device can explore the mechanisms and processes controlling urinary, digestive, or sexual function within this region in humans.

Evaluating noninvasive brain stimulation to treat overactive bladder in individuals with multiple sclerosis: a randomized controlled trial protocol.

BACKGROUND: Multiple Sclerosis (MS) is an often debilitating disease affecting the myelin sheath that encompasses neurons. It can be accompanied by a myriad of pathologies and adverse effects such as neurogenic lower urinary tract dysfunction (NLUTD). Current treatment modalities for resolving NLUTD focus mainly on alleviating symptoms while the source of the discomfort emanates from a disruption in brain to bladder neural circuitry. Here, we leverage functional magnetic resonance imaging (fMRI), repetitive transcranial magnetic stimulation (rTMS) protocols and the brains innate neural plasticity to aid in resolving overactive bladder (OAB) symptoms associated with NLUTD. METHODS: By employing an advanced neuro-navigation technique along with processed fMRI and diffusion tensor imaging data to help locate specific targets in each participant brain, we are able to deliver tailored neuromodulation protocols and affect either an excitatory (20 min @ 10 Hz, applied to the lateral and medial pre-frontal cortex) or inhibitory (20 min @ 1 Hz, applied to the pelvic supplemental motor area) signal on neural circuitry fundamental to the micturition cycle in humans to restore or reroute autonomic and sensorimotor activity between the brain and bladder. Through a regimen of questionnaires, bladder diaries, stimulation sessions and analysis, we aim to gauge rTMS effectiveness in women with clinically stable MS. DISCUSSION: Some limitations do exist with this study. In targeting the MS population, the stochastic nature of MS in general highlights difficulties in recruiting enough participants with similar symptomology to make meaningful comparisons. As well, for this neuromodulatory approach to achieve some rate of success, there must be enough intact white matter in specific brain regions to receive effective stimulation. While we understand that our results will represent only a subset of the MS community, we are confident that we will accomplish our goal of increasing the quality of life for those burdened with MS and NLUTD. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT06072703), posted on Oct 10, 2023.

Hostile Hemodynamics in Distal Stent Graft-Induced New Entry Prior to Aortic Rupture: A Comparison of Transient versus Steady-State CFD Simulations.

BACKGROUND: Computational fluid dynamics (CFD) simulations model blood flow in aortic pathologies. The aim of our study was to understand the local hemodynamic environment at the site of rupture in distal stent graft-induced new entry (dSINE) after frozen elephant trunk with a clinically time efficient steady-flow simulation versus transient simulations. METHODS: Steady-state simulations were performed for dSINE, prior and after its development and prior to aortic rupture. To account for potential turbulences due geometric changes at the dSINE location, Reynolds-averaged Navier-Stokes equations with the realizable k-ε model for turbulences were applied. Transient simulations were performed for comparison. Hemodynamic parameters were assessed at various locations of the aorta. RESULTS: Post-dSINE, jet-like flow due to luminal narrowing was observed which increased prior to rupture and resulted in focal neighbored regions of high and low wall shear stress (WSS). Prior to rupture, aortic diameter at the rupture site increased lowering WSS at the entire aortic circumference. Concurrently, WSS and turbulence increased locally above the entry tear at the inner aortic curvature. Turbulent kinetic energy and WSS elevation in the downstream aorta demonstrated enhanced stress on the native aorta. Results of steady-state simulations were in good qualitative agreement with transient simulations. CONCLUSION: Steady-flow CFD simulations feasible at clinical time scales prior to aortic rupture reveal a hostile hemodynamic environment at the dSINE rupture site in agreement with lengthy transient simulations. Consequently, our developed approach may be of value in treatment planning where a fast assessment of the local hemodynamic environment is essential.

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.

Assessment of spinal cord injury using ultrasound elastography in a rabbit model in vivo.

The effect of the mechanical micro-environment on spinal cord injury (SCI) and treatment effectiveness remains unclear. Currently, there are limited imaging methods that can directly assess the localized mechanical behavior of spinal cords in vivo. In this study, we apply new ultrasound elastography (USE) techniques to assess SCI in vivo at the site of the injury and at the time of one week post injury, in a rabbit animal model. Eleven rabbits underwent laminectomy procedures. Among them, spinal cords of five rabbits were injured during the procedure. The other six rabbits were used as control. Two neurological statuses were achieved: non-paralysis and paralysis. Ultrasound data were collected one week post-surgery and processed to compute strain ratios. Histologic analysis, mechanical testing, magnetic resonance imaging (MRI), computerized tomography and MRI diffusion tensor imaging (DTI) were performed to validate USE results. Strain ratios computed via USE were found to be significantly different in paralyzed versus non-paralyzed rabbits. The myelomalacia histologic score and spinal cord Young's modulus evaluated in selected animals were in good qualitative agreement with USE assessment. It is feasible to use USE to assess changes in the spinal cord of the presented animal model. In the future, with more experimental data available, USE may provide new quantitative tools for improving SCI diagnosis and prognosis.

Automatic Classification of Magnetic Resonance Histology of Peripheral Arterial Chronic Total Occlusions Using a Variational Autoencoder: A Feasibility Study.

The novel approach of our study consists in adapting and in evaluating a custom-made variational autoencoder (VAE) using two-dimensional (2D) convolutional neural networks (CNNs) on magnetic resonance imaging (MRI) images for differentiate soft vs. hard plaque components in peripheral arterial disease (PAD). Five amputated lower extremities were imaged at a clinical ultra-high field 7 Tesla MRI. Ultrashort echo time (UTE), T1-weighted (T1w) and T2-weighted (T2w) datasets were acquired. Multiplanar reconstruction (MPR) images were obtained from one lesion per limb. Images were aligned to each other and pseudo-color red-green-blue images were created. Four areas in latent space were defined corresponding to the sorted images reconstructed by the VAE. Images were classified from their position in latent space and scored using tissue score (TS) as following: (1) lumen patent, TS:0; (2) partially patent, TS:1; (3) mostly occluded with soft tissue, TS:3; (4) mostly occluded with hard tissue, TS:5. Average and relative percentage of TS was calculated per lesion defined as the sum of the tissue score for each image divided by the total number of images. In total, 2390 MPR reconstructed images were included in the analysis. Relative percentage of average tissue score varied from only patent (lesion #1) to presence of all four classes. Lesions #2, #3 and #5 were classified to contain tissues except mostly occluded with hard tissue while lesion #4 contained all (ranges (I): 0.2-100%, (II): 46.3-75.9%, (III): 18-33.5%, (IV): 20%). Training the VAE was successful as images with soft/hard tissues in PAD lesions were satisfactory separated in latent space. Using VAE may assist in rapid classification of MRI histology images acquired in a clinical setup for facilitating endovascular procedures.

Magnetic Resonance-Guided Stereotaxy for Infusions to the Pig Brain.

The overall goal of this procedure is to perform stereotaxy in the pig brain with real-time magnetic resonance (MR) visualization guidance to provide precise infusions. The subject was positioned prone in the MR bore for optimal access to the top of the skull with the torso raised, the neck flexed, and the head inclined downward. Two anchor pins anchored on the bilateral zygoma held the head steady using the head holder. A magnetic resonance imaging (MRI) flex-coil was placed rostrally across the head holder so that the skull was accessible for the intervention procedure. A planning grid placed on the scalp was used to determine the appropriate entry point of the cannula. The stereotactic frame was secured and aligned iteratively through software projection until the projected radial error was less than 0.5 mm. A hand drill was used to create a burr hole for insertion of the cannula. A gadolinium-enhanced co-infusion was used to visualize the infusion of a cell suspension. Repeated T1-weighted MRI scans were registered in real time during the agent delivery process to visualize the volume of gadolinium distribution. MRI-guided stereotaxy allows for precise and controlled infusion into the pig brain, with concurrent monitoring of cannula insertion accuracy and determination of the agent volume of distribution.

Classification of multiple sclerosis women with voiding dysfunction using machine learning: Is functional connectivity or structural connectivity a better predictor?

Introduction: Machine learning (ML) is an established technique that uses sets of training data to develop algorithms and perform data classification without using human intervention/supervision. This study aims to determine how functional and anatomical brain connectivity (FC and SC) data can be used to classify voiding dysfunction (VD) in female MS patients using ML. Methods: Twenty-seven ambulatory MS individuals with lower urinary tract dysfunction were recruited and divided into two groups (Group 1: voiders [V, n = 14]; Group 2: VD [n = 13]). All patients underwent concurrent functional MRI/urodynamics testing. Results: Best-performing ML algorithms, with highest area under the curve (AUC), were partial least squares (PLS, AUC = 0.86) using FC alone and random forest (RF) when using SC alone (AUC = 0.93) and combined (AUC = 0.96) as inputs. Our results show 10 predictors with the highest AUC values were associated with FC, indicating that although white matter was affected, new connections may have formed to preserve voiding initiation. Conclusions: MS patients with and without VD exhibit distinct brain connectivity patterns when performing a voiding task. Our results demonstrate FC (grey matter) is of higher importance than SC (white matter) for this classification. Knowledge of these centres may help us further phenotype patients to appropriate centrally focused treatments in the future.

First insights into the role of wall shear stress in the development of a distal stent graft induced new entry through computational fluid dynamics simulations.

Background: Distal stent graft induced new entry (dSINE) is an emerging complication after frozen elephant trunk (FET) procedure. The aim of this computational fluid dynamics (CFD) study was to investigate the role of wall shear stress (WSS) after the development of dSINE based on hemodynamic changes. Methods: Aortic diameter and WSS of five patients who developed a dSINE after FET procedure were retrospectively analyzed before and after the occurrence of dSINE. Patient-specific 3-dimentional surface models of the aortic lumen were reconstructed from computed tomography angiographic datasets (pre dSINE: n=5, dSINE: n=5) to perform steady-state CFD simulations with laminar blood flow and zero pressure outlet conditions. WSS was calculated at the level of the stent graft (SG), the landing zone of the SG and at a location further distal to the SG, as well as on the outer and inner curvature of the aorta from SG center to its distal end. Results: Post dSINE occurrence, median WSS increased significantly from 0.87 [interquartile range (IQR): 0.83-1.03] to 1.55 (IQR: 1.09-2.70) Pa, (P=0.043) within the SG and from 1.22 (IQR: 0.81-1.44) to 1.76 (IQR: 1.55-3.60) Pa, (P=0.043) at the landing zone of the SG. A non-significant increase from 1.22 (IQR: 0.59-3.50) to 2.58 (IQR: 1.16-3.78) Pa, (P=0.686) further downstream was observed. WSS at the outer curvature of the SG was significantly higher compared to WSS at the inner curvature for dSINE. Conclusions: Adverse hemodynamic conditions in the form of elevated WSS consist inside and at the distal end of the SG as well as at the outer curvature of the aorta, which may contribute to weakening of the aortic wall. These new findings emphasize the relevance and potential of WSS in dSINE for additional adverse events, such as aortic rupture. Further prospective studies are warranted to explore if the combination of clinical parameters with WSS might be useful to decide which patients require an urgent reintervention in terms of a SG extension.

To Cross or Not to Cross: Using MRI-Histology to Characterize Dense Collagenous Plaque in Critical Limb Ischemia.

Peripheral artery disease (PAD) is caused by atherosclerotic buildup in the lower extremities, leading to obstruction and inadequate perfusion to the peripheral vasculature. Impenetrable plaques initially treated with percutaneous vascular intervention (PVI) have led to worse secondary bypass outcomes and amputation in patients. In this case report, we discuss the importance of using magnetic resonance imaging (MRI) histology in PVI planning in a patient with critical limb ischemia. PVI attempts to recanalize the limb failed because of an impenetrable occlusion in the popliteal artery that was not identified on routine preoperative imaging. Subsequent bypass occluded multiple times eventually requiring an above-knee amputation. An MRI-histology protocol-using ultrashort echo time (UTE) and T2-weighted (T2W) sequences-that was performed prior to the index PVI identified the occlusion as a dense collagen plaque. Histology analysis of the amputated specimen confirmed the MRI finding. This imaging modality offers a novel approach to characterize plaque composition and morphology, thereby identifying lesions at greatest risk of PVI failure and potentially playing an important role in selecting the right candidates for an endovascular-first approach.

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.

The effect of oral medications on fMRI brain activation: A randomized, double blind, controlled pilot trial of older women with overactive bladder.

INTRODUCTION AND AIM: Observational studies have associated oral anticholinergic medications for overactive bladder (OAB) with cognitive impairment. This is the first pilot trial to compare the effects of two classes of OAB medications on brain activity in women. We evaluated the effect of anticholinergic versus non-anticholinergic (Non-Ach) interventions on regional brain activation during a cognitive task. METHODS: Twelve cognitively normal women seeking OAB therapy were recruited to a randomized, double-blind, parallel, controlled pilot trial. Whole-brain regional activity at baseline and 29 ± 1 days postintervention was assessed with functional magnetic resonance imaging during a working memory task. Average activation strength by region was compared after anticholinergic, beta-3 agonist, or placebo. Two-way ANOVA compared effects of group and time on average activation strength in anticholinergic versus Non-Ach (beta-3 agonists or placebo) groups. RESULTS: The mean (SD) age and body mass index of 12 women were 61 (7) years and 36 (7) kg/m2. Baseline depression and learning scores differed in the anticholinergic group (n = 3) versus the Non-Ach group (n = 9). Right mamillary body activation postintervention was higher after Non-Ach exposure (F 4.9, p < 0.04). In the full sample of participants at follow-up, there was less activation of the right middle frontal gyrus (p = 0.02), superior frontal gyrus (p < 0.01), and supramarginal (p < 0.01) gyrus. CONCLUSION: Activation strength in brain regions underlying working memory was lower over time, and recognition scores improved. A powered trial is needed to adequately evaluate for differential effects of OAB oral medications on regional brain activation.

Human Cadaveric Model for Vessel Preparation Device Testing in Calcified Tibial Arteries.

To describe an ex vivo model for vessel preparation device testing in tibial arteries. We performed orbital atherectomy (OA), intravascular lithotripsy (IVL), and plain balloon angioplasty (POBA) on human amputated limbs with evidence of concentric tibial artery calcification. The arterial segments were then harvested for ex vivo processing which included imaging with microCT, decalcification, and histology. The model was tested out in 15 limbs and was successful in 14 but had to be aborted in 1/15 case due to inability to achieve wire access. A total of 22 lesions were treated with OA on 3/22 lesions, IVL on 8/22, and POBA without vessel preparation on the remaining 11/22. Luminal gain was assessed with intravascular ultrasound and histology was able to demonstrate plaque disruption, dissections, and cracks within the calcified lesions. A human cadaveric model using amputated limbs is a feasible, high-fidelity option for evaluating the performance of vessel preparation devices in calcified tibial arteries.

From bench to bedside: A narrative review and institutional experience with experimental models for vascular device design and translation.

The past 2 decades have seen a rise in vascular innovations and a rapid evolution in endovascular device technology, with the emergence of atherectomy, intravascular lithotripsy, drug elution technology, thrombectomy devices, and many more. Like all other medical devices, vascular devices undergo a life cycle composed of a concept phase, a planning and design phase, a regulatory process, a launch phase, and a post-market stage. Experimental and preclinical models are required at various stages of the life cycle to aid in the designing, refining, and feasibility testing of novel devices before they are transferred to clinical practice. The experimental testing of these devices relies heavily on the ability to simulate human anatomy and physiology, and to mimic or induce specific disease processes. Computational and benchtop models play very important roles at the early stages of the manufacturing process, and animal and cadaveric models are indispensable for testing the mechanistic performance, safety, and efficacy of novel devices before they are used in clinical trials and regulatory approval is obtained for public use.

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.

Transcutaneous spinal stimulation alters cortical and subcortical activation patterns during mimicked-standing: A proof-of-concept fMRI study.

Transcutaneous spinal stimulation (TSS) is a non-invasive neuromodulation technique that has been used to facilitate the performance of voluntary motor functions such as trunk control and self-assisted standing in individuals with spinal cord injury. Although it is hypothesized that TSS amplifies signals from supraspinal motor control networks, the effect of TSS on supraspinal activation patterns is presently unknown. The purpose of this study was to investigate TSS-induced activity in supraspinal sensorimotor regions during a lower-limb motor task. Functional magnetic resonance imaging (fMRI) was used to assess changes in neural activation patterns as eleven participants performed mimicked-standing movements in the scanner. Movements were performed without stimulation, as well as in the presence of (1) TSS, (2) stimulation applied to the back muscle, (3) paresthesia stimulation, and (4) neuromuscular electrical stimulation. TSS was associated with greater activation in subcortical and cortical sensorimotor regions involved in relay and processing of movement-related somatosensory information (e.g., thalamus, caudate, pallidum, putamen), as compared to the other stimulation paradigms. TSS also resulted in deactivation in both nucleus accumbens and posterior parietal cortex, suggesting a shift toward somatosensory feedback-based mechanisms and more reflexive motor control. Together, these findings demonstrate that spinal stimulation can alter the activity within supraspinal sensorimotor networks and promote the use of somatosensory feedback, thus providing a plausible neural mechanism for the stimulation-induced improvements of sensorimotor function observed in participants with neurological injuries and disorders.

eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury.

Background: Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Methods/Results: Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. Conclusions: These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.

Supraspinal Neural Changes in Men With Benign Prostatic Hyperplasia Undergoing Bladder Outlet Procedures: A Pilot Functional MRI Study.

OBJECTIVE: To explore brain activation patterns on functional MRI (fMRI) in men with BPH and BOO before and after outlet obstruction procedures. METHODS: Men age ≥45 who failed conservative BPH therapy planning to undergo BOO procedures were recruited. Eligible men underwent a concurrent fMRI/urodynamics testing before and 6 months after BOO procedure. fMRI images were obtained via 3 Tesla MRI. Significant blood-oxygen-level-dependent (BOLD) signal activated voxels (P <.05) were identified at strong desire to void and (attempt at) voiding initiation pre- and post-BOO procedure. RESULTS: Eleven men were enrolled, of which 7 men completed the baseline scan, and 4 men completed the 6-month follow-up scan. Baseline decreased BOLD activity was observed in right inferior frontal gyrus (IFG), bilateral insula, inferior frontal gyrus (IFG) and thalamus. Significant changes in BOLD signal activity following BOO procedures were observed in the insula, IFG, and cingulate cortices. CONCLUSIONS: This represents a pilot study evaluating cortical activity in men with BPH and BOO. Despite limitations we found important changes in supraspinal activity in men with BPH and BOO during filling and emptying phases at baseline and following BOO procedure, with the potential to improve our understanding of neuroplasticity secondary to BPH and BOO. This preliminary data may serve as the foundation for larger future trials.

Altered bladder-related brain network in multiple sclerosis women with voiding dysfunction.

OBJECTIVES: A number of neurourology imaging studies have mainly focused on investigating the brain activations during micturition in healthy and neuropathic patients. It is, however, also necessary to study brain functional connectivity (FC) within bladder-related regions to understand the brain organization during the execution of bladder function. This study aims to identify the altered brain network associated with bladder function in multiple sclerosis (MS) women with voiding dysfunction through comparisons with healthy subjects via concurrent urodynamic study (UDS)/functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: Ten healthy adult women and nine adult ambulatory women with clinically stable MS for ≥6 months and symptomatic voiding phase neurogenic lower urinary tract dysfunction (NLUTD) underwent UDS/fMRI evaluation with a task of bladder filling/emptying that was repeated three to five times. We quantitatively compared their FC within 17 bladder-related brain regions during two UDS phases: "strong desire to void" and "(attempt at) voiding initiation." RESULTS: At "strong desire to void," the healthy group showed significantly stronger FC in regions involved in bladder filling and suppression of voiding compared to the patient group. These regions included the bilateral anterior cingulate cortex, right supplementary motor area, and right middle frontal gyrus. During "(attempt at) voiding initiation," healthy subjects exhibited stronger FC in the right inferior frontal gyrus compared to MS patients. CONCLUSION: Our study offers a new way to identify alterations in the neural mechanisms underlying NLUTD and provides potential targets for clinical interventions (such as cortical neuromodulation) aimed at restoring bladder functions in MS patients.