Glymphatic dysfunction in multiple sclerosis and its association with disease pathology and disability.

BACKGROUND: The role of the glymphatic system in multiple sclerosis (MS)-related disability remains underexplored. Diffusion-tensor image analysis along the perivascular space (DTI-ALPS) offers a non-invasive method to assess glymphatic function. OBJECTIVE: To evaluate glymphatic function in MS patients with lower and higher disability. METHODS: This study included 118 MS patients who underwent structural, diffusion-weighted imaging, and clinical assessment. The participants were divided into lower (MS-L, n = 57) and higher disability (MS-H, n = 61) subgroups. Brain parenchymal fraction (BPF), lesion load (LL), and DTI-ALPS index were measured. Subgroup differences and correlations between DTI-ALPS index and other measures were explored. Logistic regression was performed to evaluate BPF, LL, and DTI-ALPS index in classifying lower and higher disability patients. RESULTS: Significant differences in DTI-ALPS index between MS-H and MS-L (d = -0.71, false discovery rate-corrected p-value (p-FDR) = 0.001) were found. The DTI-ALPS index correlated significantly with disease duration (rp = -0.29, p-FDR = 0.002) and EDSS (rsp = -0.35, p-FDR = 0.0002). It also showed significant correlations with BPF and LL. DTI-ALPS index and LL were significant predictors of disability subgroup (DTI-ALPS: odds ratio (OR) = 1.77, p = 0.04, LL: OR = 0.94, p = 0.02). CONCLUSION: Our findings highlight DTI-ALPS index as an imaging biomarker in MS, suggesting the involvement of glymphatic impairment in MS pathology, although further research is needed to elucidate its role in contributing to MS-related disability.

Detection of diffusely abnormal white matter in multiple sclerosis on multiparametric brain MRI using semi-supervised deep learning.

In addition to focal lesions, diffusely abnormal white matter (DAWM) is seen on brain MRI of multiple sclerosis (MS) patients and may represent early or distinct disease processes. The role of MRI-observed DAWM is understudied due to a lack of automated assessment methods. Supervised deep learning (DL) methods are highly capable in this domain, but require large sets of labeled data. To overcome this challenge, a DL-based network (DAWM-Net) was trained using semi-supervised learning on a limited set of labeled data for segmentation of DAWM, focal lesions, and normal-appearing brain tissues on multiparametric MRI. DAWM-Net segmentation performance was compared to a previous intensity thresholding-based method on an independent test set from expert consensus (N = 25). Segmentation overlap by Dice Similarity Coefficient (DSC) and Spearman correlation of DAWM volumes were assessed. DAWM-Net showed DSC > 0.93 for normal-appearing brain tissues and DSC > 0.81 for focal lesions. For DAWM-Net, the DAWM DSC was 0.49 ± 0.12 with a moderate volume correlation (ρ = 0.52, p < 0.01). The previous method showed lower DAWM DSC of 0.26 ± 0.08 and lacked a significant volume correlation (ρ = 0.23, p = 0.27). These results demonstrate the feasibility of DL-based DAWM auto-segmentation with semi-supervised learning. This tool may facilitate future investigation of the role of DAWM in MS.

Serial and parallel organ-at-risk-specific noncoplanar arc optimization for small versus large target volumes in liver SBRT.

Noncoplanar arc optimization has been shown to reduce OAR doses in SRS/SRT and has the potential to reduce doses to OARs in SBRT. Extracranial targets have additional considerations, including large OARs and, in the case of the liver, volume constraints on the healthy liver. Considering pathlengths through OARs that encompass target volumes may lead to specific dose reductions as in the encompassing healthy liver tissue. These optimizations must also leverage delivery efficiency and trajectory sampling to ensure ease of clinical translation. The purpose of this research is to generate optimized static-couch arcs that separately consider serial and parallel OARs and arc delivery efficiency, with a trajectory sampling metric, towards the aim of reducing dose to OARs and the surrounding healthy liver tissue. Separate BEV cost maps were created for parallel, and serial OARs by means of a fast ray-triangle intersection algorithm. An additional BEV cost map was created for the liver which, by definition, encompasses the liver tumors. The individual costs of these maps were summed and combined with the sampling metric for 100 000 random combinations of arc trajectories. A search algorithm was applied to find an arc trajectory solution that satisfied BEV cost and sampling optimization, while also ensuring an efficient delivery was possible with a low number of arcs. This method of arc selection was evaluated for 16 liver SBRT patients characterized by small and large target volumes. Comparisons were made with a clinical arc template of coplanar arcs. Dosimetric plan quality was evaluated using published guidelines and metrics from RTOG1112. Four of five plan quality metrics for the liver were significantly reduced when planned with optimized noncoplanar arcs. Median (range) reductions of the volumes receiving 10, 18, and 21 Gy were found of 140.4 (295.8) cc (p = 0.001), 28.2 (230.6) cc (p = 0.002) and 18.5 (155.5) cc (p = 0.04). A significant increase in median (range) dose to the right kidney of 0.2 ± 0.9 Gy (p = 0.03) was also found using optimized noncoplanar arcs, which was below the tolerance of 10 Gy for all cases. The average number of arcs chosen was 4 ± 1. Optimizing serial and parallel OARs separately during static couch noncoplanar arc selection significantly reduced the dose to the liver during SBRT using a moderate number of arcs.

Voiding Phase Dysfunction in Multiple Sclerosis: Contemporary Review of Terminology, Diagnosis, Management, and Future Directions.

Lower urinary tract symptoms (LUTS) are highly prevalent in individuals with multiple sclerosis (MS). However, assessment of these symptoms is often hindered by vague definitions or absence of screening in asymptomatic patients. It is crucial to exercise caution when applying the non-neurogenic definition of urinary retention in this population. For men with MS experiencing persistent and treatment-resistant LUTS, urodynamic studies should be used to identify the underlying causes of symptoms. Although numerous therapies are presently accessible for managing LUTS in MS, there is a need for further investigation into emerging treatments such as percutaneous tibial nerve, and noninvasive brain stimulation.

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.

Predicting multiple sclerosis severity with multimodal deep neural networks.

Multiple Sclerosis (MS) is a chronic disease developed in the human brain and spinal cord, which can cause permanent damage or deterioration of the nerves. The severity of MS disease is monitored by the Expanded Disability Status Scale, composed of several functional sub-scores. Early and accurate classification of MS disease severity is critical for slowing down or preventing disease progression via applying early therapeutic intervention strategies. Recent advances in deep learning and the wide use of Electronic Health Records (EHR) create opportunities to apply data-driven and predictive modeling tools for this goal. Previous studies focusing on using single-modal machine learning and deep learning algorithms were limited in terms of prediction accuracy due to data insufficiency or model simplicity. In this paper, we proposed the idea of using patients' multimodal longitudinal and longitudinal EHR data to predict multiple sclerosis disease severity in the future. Our contribution has two main facets. First, we describe a pioneering effort to integrate structured EHR data, neuroimaging data and clinical notes to build a multi-modal deep learning framework to predict patient's MS severity. The proposed pipeline demonstrates up to 19% increase in terms of the area under the Area Under the Receiver Operating Characteristic curve (AUROC) compared to models using single-modal data. Second, the study also provides valuable insights regarding the amount useful signal embedded in each data modality with respect to MS disease prediction, which may improve data collection processes.

Identifying the white matter pathways involved in multiple sclerosis-related tremor using diffusion tensor imaging.

Background: Tremor affects up to 45% of patients with Multiple Sclerosis (PwMS). Current understanding is based on insights from other neurological disorders, thus, not fully addressing the distinctive aspects of MS pathology. Objective: To characterize the brain white matter (WM) correlates of MS-related tremor using diffusion tensor imaging (DTI). Methods: In a prospective case-control study, PwMS with tremor were assessed for tremor severity and underwent MRI scans including DTI. PwMS without tremor served as matched controls. After tract selection and segmentation, the resulting diffusivity measures were used to calculate group differences and correlations with tremor severity. Results: This study included 72 PwMS. The tremor group (n = 36) exhibited significant changes in several pathways, notably in the right inferior longitudinal fasciculus (Cohen's d = 1.53, q < 0.001) and left corticospinal tract (d = 1.32, q < 0.001), compared to controls (n = 36). Furthermore, specific tracts showed a significant correlation with tremor severity, notably in the left medial lemniscus (Spearman's coefficient [rsp] = -0.56, p < 0.001), and forceps minor of corpus callosum (rsp = -0.45, p < 0.01). Conclusion: MS-related tremor is associated with widespread diffusivity changes in WM pathways and its severity correlates with commissural and sensory projection pathways, which suggests a role for proprioception or involvement of the dentato-rubro-olivary circuit.

Unfolding the direct connectivity of the occipital cortex with the hypothalamic, septal and BNST nuclei of the human brain.

The hypothalamus plays essential roles in the human brain by regulating feeding, fear, aggression, reproductive behaviors, and autonomic activities. The septal nuclei and the bed nucleus of stria terminalis (BNST) are also known to be involved in control of autonomic, motivational, learning, emotional and associative processes in the human brain. Multiple animal dissection studies have revealed direct connectivity between central limbic gray matter nuclei and occipital cortex, particularly from the hypothalamic, septal and BNST nuclei. However, the detailed anatomy of this connectivity in the human brain has yet to be determined. The primary objective of this study was to explore the utility of high spatial and high angular resolution diffusion weighted tractography techniques for mapping the connectivity pathways between the occipital cortex and central limbic gray matter nuclei in the human brain. We studied 30 healthy adult human brains, delineated, and reconstructed the trajectory of the occipito-hypothalamic/septal/BNST for the first time in the human brain.

Social determinants of health and disparate disability accumulation in a cohort of Black, Hispanic, and White patients with multiple sclerosis.

BACKGROUND: Black and Hispanic patients with multiple sclerosis (MS) have been shown to accumulate greater multiple sclerosis-associated disability (MSAD) than White patients. Disparities in social determinants of health (SDOH) among these groups have also been reported. OBJECTIVE: To determine the extent to which associations of race and ethnicity with MSAD may be attributable to differences in SDOH. METHODS: Retrospective chart analysis of patients at an academic MS center grouped by self-identified Black (n = 95), Hispanic (n = 93), and White (n = 98) race/ethnicity. Individual patient addresses were geocoded and matched with neighborhood-level area deprivation index (ADI) and social vulnerability index (SVI). RESULTS: Average Expanded Disability Status Scale (EDSS) scores at last-recorded evaluations of White patients (1.7 ± 2.0) were significantly lower than Black (2.8 ± 2.4, p = 0.001) and Hispanic (2.6 ± 2.6, p = 0.020) patients. Neither Black race nor Hispanic ethnicity was significantly associated with EDSS in multivariable linear regression models that included individual-level SDOH indicators and either ADI or SVI. CONCLUSION: Black race and Hispanic ethnicity are not significantly associated with EDSS in models that include individual and neighborhood-level SDOH indicators. Further research should elucidate mechanisms by which structural inequities affect MS disease course.

Static couch non-coplanar arc selection optimization for lung SBRT treatment planning.

Objective. Non-coplanar arc geometry optimizations that take advantage of beam's eye view (BEV) geometric overlap information have been proven to reduce dose to healthy organs-at-risk (OARs). Recently, a metric called mean arc distance (MAD) has been developed that quantifies the arc geometry sampling of 4πspace. The purpose of this research is to combine improved BEV overlap information with MAD to generate static couch lung stereotactic body radiotherapy (SBRT) treatment plans deliverable on a C-arm linear accelerator.Approach. An algorithm utilizing the Moller-Trumbore ray-triangle intersection method was employed to compute a cost surrogate for dose to overlapping OARs using distances interpolated onto a PDD. Cost was combined with MAD for 100 000 random combinations of arc trajectories. A pathfinding algorithm for arc selection was created, balancing the contributions of MAD and 4πcost for the final trajectory. This methodology was evaluated for 18 lung SBRT patients. Cases were also planned with arcs from a clinical treatment template protocol for dosimetric and plan quality comparison. Results were evaluated using dose constraints in the context of RTOG0915.Main results. Five of six OARs had maximum dose reductions when planned with the arc trajectory optimization algorithm. Significant maximum dose reductions were found for esophagus (7.41 ± 0.91 Gy,p= 0.00019), trachea (5.56 ± 1.55 Gy,p= 0.0025), spinal cord (2.87 ± 1.13 Gy,p= 0.039), large bronchus (3.47 ± 1.49 Gy,p= 0.0075), and aorta (3.13 ± 0.99 Gy,p= 0.012). Mean dose to contralateral lung was also significantly reduced (0.50 ± 0.06 Gy,p= 0.00019). There were two significant increases in OAR doses: mean dose to ipsilateral lung (0.40 ± 0.09,p= 0.00086) and V5Gyto ipsilateral lung (1.95 ± 0.70%,p= 0.011). Paddick conformity index increased by 0.03 ± 0.02 (p= 0.14), remaining below a limit of 1.2 for both techniques.Significance. Static couch non-coplanar optimization yielded maximum dose reductions to OARs while maintaining target conformity for lung SBRT.

Functional assessment of the dural lymphatic vessels using dynamic contrast MRI in multiple sclerosis.

BACKGROUND AND PURPOSE: The discovery of glymphatic function in the human brain has generated interest in waste clearance mechanisms in neurological disorders such as multiple sclerosis (MS). However, noninvasive in vivo functional assessment is currently lacking. This work studies the feasibility of a novel intravenous dynamic contrast MRI method to assess the dural lymphatics, a purported pathway contributing to glymphatic clearance. METHODS: This prospective study included 20 patients with MS (17 women; age = 46.4 [27, 65] years; disease duration = 13.6 [2.1, 38.0] years, expanded disability status score (EDSS) = 2.0 [0, 6.5]). Patients were scanned on a 3.0T MRI system using intravenous contrast-enhanced fluid-attenuated inversion recovery MRI. Signal in the dural lymphatic vessel along the superior sagittal sinus was measured to calculate peak enhancement, time to maximum enhancement, wash-in and washout slopes, and the area under the time-intensity curve (AUC). Correlation analysis was performed to examine the relationship between the lymphatic dynamic parameters and the demographic and clinical characteristics, including the lesion load and the brain parenchymal fraction (BPF). RESULTS: Contrast enhancement was detected in the dural lymphatics in most patients 2-3 min after contrast administration. BPF had a significant correlation with AUC (p < .03), peak enhancement (p < .01), and wash-in slope (p = .01). Lymphatic dynamic parameters did not correlate with age, BMI, disease duration, EDSS, or lesion load. Moderate trends were observed for correlation between patient age and AUC (p = .062), BMI and peak enhancement (p = .059), and BMI and AUC (p = .093). CONCLUSION: Intravenous dynamic contrast MRI of the dural lymphatics is feasible and may be useful in characterizing its hydrodynamics in neurological diseases.

Trigeminal neuralgia in multiple sclerosis: Association with demyelination and progression.

BACKGROUND: Trigeminal neuralgia (TN) is a well-recognized symptom of multiple sclerosis (MS), yet its clinical characteristics related to MS subtype is poorly studied. Our aim was to evaluate whether development and clinical outcome of TN are influenced by MS phenotype. METHODS: In this retrospective cohort study, our database from 2007 to 2022 was reviewed to identify patients who had both the diagnosis of MS and TN, whether TN was an initial symptom of MS or developed later in diagnosis. A detailed medical history and treatment outcome was obtained. Pain status was assessed retrospectively using the Barrow Neurological Institute Pain Scale (BNI-PS), with BNI-PS I-III considered as good pain control and BNI-PS IV-V as poor pain control. RESULTS: 58 patients had MS-related TN. 44 patients had relapsing remitting multiple sclerosis (RRMS) at the time of TN diagnosis, 11 had secondary progressive multiple sclerosis (SPMS) at the time of TN diagnosis, and type of MS was not clear in 3 patients at the time of TN diagnosis (either RRMS or SPMS). Over a mean follow up of 18.8 (SD=10.9) years, 30 transitioned to SPMS. TN was refractory to medical management in 9 RRMS and 22 SPMS patients (p = 0.001). TN patients with RRMS required lower median number of pain medications compared to SPMS (p = 0.014). Brain MRI was available in 41 of the entire cohort. Of these, 27 patients had demyelinating lesions in the trigeminal sensory pathway and 14 did not. Patients with existing lesions had a higher chance of failure of medical management (74% versus 36%, p = 0.017) and required surgical intervention (55% versus 7%, p = 0.003). DISCUSSION: TN was not seen in primary progressive multiple sclerosis (PPMS). In patients who transitioned to SPMS, TN was more likely to be refractory to medical management. TN was more refractory in the presence of demyelinating plaque involving trigeminal sensory pathway.

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.

Comparison of anatomically informed class solution template trajectories with patient-specific trajectories for stereotactic radiosurgery and radiotherapy.

Class solution template trajectories are used clinically for efficiency, safety, and reproducibility. The aim was to develop class solutions for single cranial metastases radiotherapy/radiosurgery based on intracranial target positioning and compare to patient-specific trajectories in the context of 4π optimization. Template trajectories were constructed based on the open-source Montreal Neurological Institute (MNI) average brain. The MNI brain was populated with evenly spaced spherical target volumes (2 cm diameter, N = 243) and organs-at-risk (OARs) were identified. Template trajectories were generated for six anatomical regions (frontal, medial, and posterior, each with laterality dependence) based on previously published 4π optimization methods. Volumetric modulated arc therapy (VMAT) treatment plans generated using anatomically informed template 4π trajectories and patientspecific 4π trajectories were compared against VMAT plans from a standard four-arc template. Four-arc optimization techniques were compared to the standard VMAT template by placing three spherical targets in each of six anatomical regions of a test patient. This yielded 54 plans to compare various plan quality metrics. Increasing plan technique complexity, the total number of OAR maximum dose reductions compared to the standard arc template for the 6 anatomical classes was 4+/-2 (OFIXEDc) and 7+/-2 (OFIXEDi). In 65.6% of all cases, optimized fixed-couch positions outperformed the standard-arc template. Of the three comparisons, the most complex (OFIXEDi) showed the greatest statistical significance compared to the least complex (VMATi) across 12 plan quality metrics of maximum dose to each OAR, V12Gy, total plan Monitor Units, conformity index, and gradient index (p < 0.00417). In approximately 70% of all cases, 4π optimization methods outperformed the standard-arc template in terms of maximum dose reduction to OAR, by exclusively changing the arc geometry. We conclude that a tradeoff exists between complexity of a class solution methodology compared to patient-specific methods for arc selection, in the context of plan quality improvement.

Return of the math: Markov blankets, dynamical systems theory, and the bounds of mind.

Bruineberg and colleagues highlight work using Markov blankets to demarcate the bounds of the mind. This echoes earlier attempts to demarcate the bounds of the mind from a dynamical systems perspective. Advocates of mechanistic explanation have challenged the dynamical approach to independently motivate the application of the formalism, a challenge that Markov blanket theorists must also meet.

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.

Mean Arc Distance (MAD): a quantity to compare trajectory 4πsampling in single target cranial stereotactic radiotherapy.

Purpose.C-arm linac-based radiotherapy has seen a recent interest in 4πmethods of delivery using simultaneous rotations of couch and gantry to reduce doses to organs-at-risk (OARs) and increase dose compactness. While many methods use heuristics to generate trajectories that avoid OARs, combined with arbitrary trajectory restrictions to prevent oversampling, a quantity has not yet been developed to succinctly compare sampling of the 4πspace for candidate trajectories as a surrogate for dosimetric compactness.Methods.Evenly spaced sampling points were distributed across a 4πsphere centred on isocentre. A metric, mean arc distance (MAD), was defined that quantifies the average arc distance between all sampling points and their nearest field in a radiotherapy trajectory. The relationship between isodose volume and MAD was examined in 2,047 plans: 900 unique trajectories of fixed port DCA plans, 900 unique trajectories of contiguous field DCA plans, 192 VMAT plans (eight volumes in four locations, each with six trajectories) in matRad with 5 VMAT plans repeated for validation in a clinical planning system, and 10 clinical VMAT cases replanned with five trajectories in a clinical treatment planning system.Results.All isodose volumes greater than 10% of the prescription dose decreased with decreasing MAD in all comparisons. In the range of 10% to 100% of the prescription dose, the rate of isodose volume decrease was exponential as a function of MAD in all comparisons. Reduction of absolute isodose volume is seen with increased 4πsampling, with larger target volumes exhibiting larger absolute reductions. Very low isodoses (0% to 10% of prescription) increased with decreasing MAD.Conclusions.MAD is a 4πsampling quantity useful in quantifying the decrease of isodose volume, relevant for sparing normal tissues. By quantifying this feature, candidate dynamic trajectories can be efficiently compared for 4πsampling. This quantity is explored here for single target cranial radiotherapy but may have applications to other radiotherapy treatment sites.

Evaluation of Muscle Synergy During Exoskeleton-Assisted Walking in Persons With Multiple Sclerosis.

OBJECTIVE: Gait deficit after multiple sclerosis (MS) can be characterized by altered muscle activation patterns. There is preliminary evidence of improved walking with a lower limb exoskeleton in persons with MS. However, the effects of exoskeleton-assisted walking on neuromuscular modifications are relatively unclear. The objective of this study was to investigate the muscle synergies, their activation patterns and the differences in neural strategies during walking with (EXO) and without (No-EXO) an exoskeleton. METHODS: Ten subjects with MS performed walking during EXO and No-EXO conditions. Electromyography signals from seven leg muscles were recorded. Muscle synergies and the activation profiles were extracted using non-negative matrix factorization. RESULTS: The stance phase duration was significantly shorter during EXO compared to the No-EXO condition (p<0.05). Moreover, typically 3-5 modules were extracted in each condition. The module-1 (comprising Vastus Medialis and Rectus Femoris muscles), module-2 (comprising Soleus and Medial Gastrocnemius muscles), module-3 (Tibialis Anterior muscle) and module-4 (comprising Biceps Femoris and Semitendinosus muscles) were comparable between conditions. During EXO condition, Semitendinosus and Vastus Medialis emerged in module-5 in 7/10 subjects. Compared to No-EXO, average activation amplitude was significantly reduced corresponding to module-2 during the stance phase and module-3 during the swing phase during EXO. CONCLUSION: Exoskeleton-assistance does not alter the existing synergy modules, but could induce a new module to emerge, and alters the control of these modules, i.e., modifies the neural commands indicated by the reduced amplitude of the activation profiles. SIGNIFICANCE: The work provides insights on the potential underlying mechanism of improving gait functions after exoskeleton-assisted locomotor training.

Characterizing the time course of cerebrovascular reactivity in multiple sclerosis.

BACKGROUND AND PURPOSE: Changes in cerebral perfusion occur early in relapsing and progressive multiple sclerosis (MS) patients, though whether cerebral blood flow (CBF) can be altered by therapy is unknown. We sought to characterize the time course of change in CBF (cerebral vascular reactivity [CVR]), following intravenous (IV) acetazolamide (ACZ) in whole brain and within various gray and white matter brain regions in MS patients. METHODS: We enrolled five relapsing MS patients on injectable therapies. Participants received a 1000 mg IV bolus of ACZ and CBF was measured using pseudocontinuous arterial spin labeling MRI. To quantify differences in time course between patients, we calculated the numerical integration of CVR over time using the trapezoidal rule to estimate area under the curve (AUC(CVR) ). RESULTS: A change in whole brain CBF of 30%-65% was seen in all participants at 15 minutes after ACZ challenge. CBF increases >20% above baseline were sustained for 90 minutes within whole-brain, normal-appearing white matter and total T2-hyperintense lesioned tissue. AUC(CVR) values for both gray (cortical and deep gray matter) and white (normal-appearing and T2-lesioned) matter regions were similar between patients. CONCLUSION: Our findings show a prolonged time course in vascular reactivity after ACZ stimulus in MS patients with a similar time course for both gray and white matter brain regions, including in previously injured tissue. Our preliminary results suggest that blood flow can be augmented in the established MS lesion suggesting that even previously injured tissue might be responsive to treatment.