Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury.

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability.

Efficacy of a Disease Management Program of a Tertiary Center and Ophthalmologic Practitioners for the Treatment of Neovascular Age-Related Macular Degeneration.

PURPOSE: The aim of the study was to examine real-world data of patients with neovascular age-related macular degeneration (nAMD) within a disease management program (DMP) treated with anti-VEGF. METHODS: A monocentric, retrospective chart review of 379 eyes of a local DMP was conducted at the Department of Ophthalmology, Kepler University Clinic Linz. Eyes were treated either with bevacizumab or aflibercept using a pro re nata scheme, consisting of 3 injections every 4 weeks in case of presence of disease activity. The observational period was up to 24 months. Disease activity was monitored by visual acuity (VA), clinical examination, and optical coherence tomography (OCT). For (re-)treatments, ophthalmologic practitioners referred patients directly to the intravitreal injection, avoiding redundant examinations. RESULTS: VA improved significantly for all patients after 2 months (logMAR 0.47 ± 0.36; p = 0.000) compared to baseline (0.55 ± 0.37), and for the aflibercept group for up to 6 months (0.36 ± 0.27; p = 0.018). After 12 months, VA remained stable without further significant improvement and decreased by 24 months compared to baseline. The median number of injections was 6 over the first 12 months and 4 in the second year. CONCLUSION: Data revealed the efficacy of a DMP for nAMD involving both ophthalmologic practitioners and a tertiary center. Avoiding redundant examinations increased the efficacy of a clinical setting.

Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke.

Stroke is a major cause of serious disability due to the brain's limited capacity to regenerate damaged tissue and neuronal circuits. After ischemic injury, a multiphasic degenerative and inflammatory response is coupled with severely restricted vascular and neuronal repair, resulting in permanent functional deficits. Although clinical evidence indicates that revascularization of the ischemic brain regions is crucial for functional recovery, no therapeutics that promote angiogenesis after cerebral stroke are currently available. Besides vascular growth factors, guidance molecules have been identified to regulate aspects of angiogenesis in the central nervous system (CNS) and may provide targets for therapeutic angiogenesis. In this study, we demonstrate that genetic deletion of the neurite outgrowth inhibitor Nogo-A or one of its corresponding receptors, S1PR2, improves vascular sprouting and repair and reduces neurological deficits after cerebral ischemia in mice. These findings were reproduced in a therapeutic approach using intrathecal anti-Nogo-A antibodies; such a therapy is currently in clinical testing for spinal cord injury. These results provide a basis for a therapeutic blockage of inhibitory guidance molecules to improve vascular and neural repair after ischemic CNS injuries.

The Gigantocellular Reticular Nucleus Plays a Significant Role in Locomotor Recovery after Incomplete Spinal Cord Injury.

Traditionally, the brainstem has been seen as hardwired and poorly capable of plastic adaptations following spinal cord injury (SCI). Data acquired over the past decades, however, suggest differently: following SCI in various animal models (lamprey, chick, rodents, nonhuman primates), different forms of spontaneous anatomic plasticity of reticulospinal projections, many of them originating from the gigantocellular reticular nucleus (NRG), have been observed. In line with these anatomic observations, animals and humans with incomplete SCI often show various degrees of spontaneous motor recovery of hindlimb/leg function. Here, we investigated the functional relevance of two different modes of reticulospinal fiber growth after cervical hemisection, local rewiring of axotomized projections at the lesion site versus compensatory outgrowth of spared axons, using projection-specific, adeno-associated virus-mediated chemogenetic neuronal silencing. Detailed assessment of joint movements and limb kinetics during overground locomotion in female adult rats showed that locally rewired as well as compensatory NRG fibers were responsible for different aspects of recovered forelimb and hindlimb functions (i.e., stability, strength, coordination, speed, or timing). During walking and swimming, both locally rewired as well as compensatory NRG plasticity were crucial for recovered function, while the contribution of locally rewired NRG plasticity to wading performance was limited. Our data demonstrate comprehensively that locally rewired as well as compensatory plasticity of reticulospinal axons functionally contribute to the observed spontaneous improvement of stepping performance after incomplete SCI and are at least partially causative to the observed recovery of function, which can also be observed in human patients with spinal hemisection lesions.SIGNIFICANCE STATEMENT Following unilateral hemisection of the spinal cord, reticulospinal projections are destroyed on the injured side, resulting in impaired locomotion. Over time, a high degree of recovery can be observed in lesioned animals, like in human hemicord patients. In the rat, recovery is accompanied by pronounced spontaneous plasticity of axotomized and spared reticulospinal axons. We demonstrate the causative relevance of locally rewired as well as compensatory reticulospinal plasticity for the recovery of locomotor functions following spinal hemisection, using chemogenetic tools to selectively silence newly formed connections in behaviorally recovered animals. Moving from a correlative to a causative understanding of the role of neuroanatomical plasticity for functional recovery is fundamental for successful translation of treatment approaches from experimental studies to the clinics.

Safety and Feasibility of Lumbar Cerebrospinal Fluid Pressure and Intraspinal Pressure Studies in Cervical Stenosis: A Case Series.

INTRODUCTION: Degenerative cervical myelopathy (DCM) leads to functional impairment by compression of the spinal cord and nerve roots. In DCM, the dynamics of cerebrospinal fluid pressure (CSFP) and intraspinal pressure (ISP), as well as spinal cord perfusion pressure (SCPP) remain not investigated yet. Recent technical advances have enabled investigation of these parameters in acute spinal cord injury (SCI). We aim to investigate the properties of CSFP/ISP and spinal cord hemodynamics during and after decompressive surgery in DCM. MATERIALS AND METHODS: Four patients with DCM were enrolled; during surgery and 24 h postoperative, ISP at level was measured in one patient, and CSFP was measured in two patients. In one patient, CSFP was recorded at bedside before surgery. RESULTS: All measurements were conducted without adverse events and were well tolerated. With CSFP analysis, post-decompression Queckenstedt's test was responsive in two patients (i.e., jugular vein compression resulted in an elevation of CSFP pressure). In the patient whose CSFP was tested at bedside, Queckenstedt's test was not responsive before decompression. Individual optimum SCPPs were calculated to be between 70 and 75 mmHg. CONCLUSION: ISP and CSFP can reflect spinal compression and sufficient decompression. A better understanding and systematic monitoring possibly lead to improved hemodynamic management and may allow early recognition of postoperative complications such as swelling and bleeding.

Anti-Nogo-A Antibodies As a Potential Causal Therapy for Lower Urinary Tract Dysfunction after Spinal Cord Injury.

Loss of bladder control is common after spinal cord injury (SCI) and no causal therapies are available. Here we investigated whether function-blocking antibodies against the nerve-fiber growth inhibitory protein Nogo-A applied to rats with severe SCI could prevent development of neurogenic lower urinary tract dysfunction. Bladder function of rats with SCI was repeatedly assessed by urodynamic examination in fully awake animals. Four weeks after SCI, detrusor sphincter dyssynergia had developed in all untreated or control antibody-infused animals. In contrast, 2 weeks of intrathecal anti-Nogo-A antibody treatment led to significantly reduced aberrant maximum detrusor pressure during voiding and a reduction of the abnormal EMG high-frequency activity in the external urethral sphincter. Anatomically, we found higher densities of fibers originating from the pontine micturition center in the lumbosacral gray matter in the anti-Nogo-A antibody-treated animals, as well as a reduced number of inhibitory interneurons in lamina X. These results suggest that anti-Nogo-A therapy could also have positive effects on bladder function clinically.SIGNIFICANCE STATEMENT After spinal cord injury, loss of bladder control is common. Detrusor sphincter dyssynergia is a potentially life-threatening consequence. Currently, only symptomatic treatment options are available. First causal treatment options are urgently needed in humans. In this work, we show that function-blocking antibodies against the nerve-fiber growth inhibitory protein Nogo-A applied to rats with severe spinal cord injury could prevent development of neurogenic lower urinary tract dysfunction, in particular detrusor sphincter dyssynergia. Anti-Nogo-A therapy has entered phase II clinical trial in humans and might therefore soon be the first causal treatment option for neurogenic lower urinary tract dysfunction.

Enhancing rehabilitation and functional recovery after brain and spinal cord trauma with electrical neuromodulation.

PURPOSE OF REVIEW: This review discusses recent advances in the rehabilitation of motor deficits after traumatic brain injury (TBI) and spinal cord injury (SCI) using neuromodulatory techniques. RECENT FINDINGS: Neurorehabilitation is currently the only treatment option for long-term improvement of motor functions that can be offered to patients with TBI or SCI. Major advances have been made in recent years in both preclinical and clinical rehabilitation. Activity-dependent plasticity of neuronal connections and circuits is considered key for successful recovery of motor functions, and great therapeutic potential is attributed to the combination of high-intensity training with electrical neuromodulation. First clinical case reports have demonstrated that repetitive training enabled or enhanced by electrical spinal cord stimulation can yield substantial improvements in motor function. Described achievements include regaining of overground walking capacity, independent standing and stepping, and improved pinch strength that recovered even years after injury. SUMMARY: Promising treatment options have emerged from research in recent years using neurostimulation to enable or enhance intense training. However, characterizing long-term benefits and side-effects in clinical trials and identifying patient subsets who can benefit are crucial. Regaining lost motor function remains challenging.

Urodynamic measurements reflect physiological bladder function in rats.

AIMS: Our objective was to investigate and compare bladder function in rats assessed by metabolic cage and by urodynamic measurements in fully awake animals. METHODS: Bladder function of female Lewis rats was investigated in naïve animals by metabolic cage at baseline, 14-16 days after bladder catheter and external urethral sphincter electromyography electrode implantation in fully awake animals by urodynamics, and again by metabolic cage. RESULTS: Investigating the same animals (n = 8), voided volume, average flow, and duration of voiding were similar (P > 0.05) in naïve animals measured by metabolic cage and after catheter implantation by urodynamic measurements and by metabolic cage. In naïve animals measured by metabolic cage, voided volumes were significantly different in the light (resting phase) versus the dark (active phase) part of the 24 h cycle (mean difference 0.14 mL, 21%, P = 0.004, n = 27). CONCLUSIONS: Lower urinary tract function assessed by metabolic cage or by urodynamic meaurements in fully awake rats was indistinguishable. Thus, catheter implantation did not significantly change physiological bladder function. This shows that urodynamic measurements in awake animals are an appropriate approach to study lower urinary tract function in health and disease in animal models, directly paralleling the human diagnostic procedures.

Electrical stimulation of the cuneiform nucleus enhances the effects of rehabilitative training on locomotor recovery after incomplete spinal cord injury.

Most human spinal cord injuries are anatomically incomplete, leaving some fibers still connecting the brain with the sublesional spinal cord. Spared descending fibers of the brainstem motor control system can be activated by deep brain stimulation (DBS) of the cuneiform nucleus (CnF), a subnucleus of the mesencephalic locomotor region (MLR). The MLR is an evolutionarily highly conserved structure which initiates and controls locomotion in all vertebrates. Acute electrical stimulation experiments in female adult rats with incomplete spinal cord injury conducted in our lab showed that CnF-DBS was able to re-establish a high degree of locomotion five weeks after injury, even in animals with initially very severe functional deficits and white matter lesions up to 80-95%. Here, we analyzed whether CnF-DBS can be used to support medium-intensity locomotor training and long-term recovery in rats with large but incomplete spinal cord injuries. Rats underwent rehabilitative training sessions three times per week in an enriched environment, either with or without CnF-DBS supported hindlimb stepping. After 4 weeks, animals that trained under CnF-DBS showed a higher level of locomotor performance than rats that trained comparable distances under non-stimulated conditions. The MLR does not project to the spinal cord directly; one of its main output targets is the gigantocellular reticular nucleus in the medulla oblongata. Long-term electrical stimulation of spared reticulospinal fibers after incomplete spinal cord injury via the CnF could enhance reticulospinal anatomical rearrangement and in this way lead to persistent improvement of motor function. By analyzing the spared, BDA-labeled giganto-spinal fibers we found that their gray matter arborization density after discontinuation of CnF-DBS enhanced training was lower in the lumbar L2 and L5 spinal cord in stimulated as compared to unstimulated animals, suggesting improved pruning with stimulation-enhanced training. An on-going clinical study in chronic paraplegic patients investigates the effects of CnF-DBS on locomotor capacity.

Cranio-cervical and traumatic brain injury patterns-do they differ between electric bicycle, bicycle, and motorcycle-induced accidents?

PURPOSE: With the growing technical options of power transmission and energy-saving options in electric drives, the number of E-bike-related accidents especially in an elderly population has increased. The aim of the current study was to compare if the increased velocity in comparison to conventional bikes translates into different injury patterns in the cranio-cervical and head region. METHODS: A retrospective cohort study was performed in patients admitted to our level one trauma center between 2009 and 2019 after being involved in an accident with either an E-bike, bicycle, or motorcycle and suffered cranio-cervical or traumatic brain injury. OUTCOMES: cranio-cervical/intracranial injury pattern. Data interpretation was conducted in an interdisciplinary approach. RESULTS: From 3292 patients treated in this period, we included 1068 patients. E-bikers were significantly older than bicyclists (or motorcyclists) and lay between the other two groups in terms of helmet use. Overall injury patterns of E-bikers resembled those found in motorcyclists rather than in bicyclists. E-bikers had a higher incidence of different cerebral bleedings, especially if no helmet was worn. Helmet protection of E-bikers resulted in a comparable frequency of intracranial bleeding to the helmeted bicyclists. CONCLUSION: The overall pattern of head and cervical injuries in E-bikers resembles more to that of motorcyclists than that of bicyclists. As they are used by a more senior population, multiple risk factors apply in terms of complications and secondary intracranial bleeding. Our study suggests that preventive measures should be reinforced, i.e., use of helmets to prevent from intracranial injury.

Early Transcutaneous Tibial Nerve Stimulation Acutely Improves Lower Urinary Tract Function in Spinal Cord Injured Rats.

Despite the fact that a majority of patients with an injury to the spinal cord develop lower urinary tract dysfunction, only few treatment options are available currently once the dysfunction arises. Tibial nerve stimulation has been used in pilot clinical trials, with some promising results. Hence, we investigated whether the early application of transcutaneous tibial nerve stimulation in the animal model of spinal cord injured rats can prevent the development of detrusor overactivity and/or detrusor-sphincter-dyssynergia. Rats were implanted with a bladder catheter and external urethral sphincter electromyography electrodes. A dorsal over-hemisection, resulting in an incomplete spinal cord injury at the T8/9 spinal level, induced immediate bladder paralysis. One week later, the animals received daily tibial nerve or sham stimulation for 15 days. Effects of stimulation on the lower urinary tract function were assessed by urodynamic investigation. Measurements showed improvements of several key parameters of lower urinary tract function-in particular, non-voiding bladder contractions and intravesical pressure-immediately after the completion of the stimulation period in the stimulated animals. These differences extinguished one week later, however. In the dorsal horn of the lumbosacral spinal cord, a small significant increase of the density of C-fiber afferents layers I-II was found in the stimulated animals at four weeks after spinal cord injury. Tibial nerve stimulation applied acutely after spinal cord injury in rats had an immediate beneficial effect on lower urinary tract dysfunction; however, the effect was transitory and did not last over time. To achieve more sustainable, longer lasting effects, further studies are needed looking into different stimulation protocols using optimized stimulation parameters, timing, and treatment schedules.

Spinous-Process-Splitting Versus Conventional Decompression for Lumbar Spinal Stenosis: Comparative Study with Respect to Short-Term Postoperative Pain and Analgesics Use.

OBJECTIVE: Several microsurgical techniques are available for the decompression of lumbar spinal stenosis (LSS). More recently, a spinous process-splitting laminectomy (SPSL) technique was introduced, with the premise of diminishing paraspinal muscle damage. This study aims to compare the neurologic and functional outcomes, as well as the differences in early postoperative pain and analgesic use during hospitalization after conventional decompression (CD) versus SPSL surgery for LSS. METHODS: Single-center retrospective analysis of all spinal decompression procedures (CD or SPSL) that were performed or supervised by one consulting spine surgeon, performed for LSS between 2015 and 2020. Preoperative neurologic symptoms, functional outcomes, as well as perioperative analgesic use and reported pain scales during hospitalization were analyzed. RESULTS: From a total of 106 patients, 58 were treated using CD and 48 using SPSL. In both groups, around one-third of the patients were taking opiates preoperatively (38% for CD, 31% for SPSL). Patients submitted to SPSL reported more pain on first postoperative day but significantly less pain in the further postoperative course (day 3 numeric rating scale [NRS] 2.4 vs. 3.4, P = 0.03 and on day 5 NRS 2.5 vs. 3.7, P = 0.009). Equal or less cumulative doses of analgesics were administered postoperatively (significantly less paracetamol on day 5 compared with CD; P = 0.013). Both groups showed a similarly favorable outcome in terms of improved mobility and there were no significant differences between complications and re-stenosis rates between both techniques. CONCLUSIONS: Patients treated with SPSL technique for LSS showed an equivalent favorable functional outcome compared to CD. However, SPSL patients showed significantly less subacute postoperative pain while using equal amounts or fewer analgesics postoperatively.

Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection.

Neurogenic lower urinary tract dysfunction typically develops after spinal cord injury. We investigated the time course and the anatomical changes in the spinal cord that may be causing lower urinary tract symptoms following injury. Rats were implanted with a bladder catheter and external urethral sphincter electromyography electrodes. Animals underwent a large, incomplete spinal transection at the T8/9 spinal level. At 1, 2-3, and 4 weeks after injury, the animals underwent urodynamic investigations. Urodynamic investigations showed detrusor overactivity and detrusor-sphincter-dyssynergia appearing over time at 3-4 weeks after injury. Lower urinary tract dysfunction was accompanied by an increase in density of C-fiber afferents in the lumbosacral dorsal horn. CRF-positive Barrington's and 5-HT-positive bulbospinal projections drastically decreased after injury, with partial compensation for the CRF fibers at 3-4 weeks. Interestingly, a decrease over time was observed in the number of GABAergic neurons in the lumbosacral dorsal horn and lamina X, and a decrease of glutamatergic cells in the dorsal horn. Detrusor overactivity and detrusor-sphincter-dyssynergia might therefore arise from a discrepancy in inhibitory/excitatory interneuron activity in the lumbosacral cord as well as input changes which develop over time after injury. The processes point to spinal plastic changes leading to malfunction of the important physiological pathway of lower urinary tract control.

Evaluation of patient STress level caused by radiological Investigations in early Postoperative phase After CRANIOtomy (IPAST-CRANIO): protocol of a Swiss prospective cohort study.

INTRODUCTION: Postoperative imaging after neurosurgical interventions is usually performed in the first 72 hours after surgery to provide an accurate assessment of postoperative resection status. Patient frequently report that early postoperative examination after craniotomy for tumour and vascular procedures is associated with distress, exertion, nausea and pain. Delayed postoperative imaging (between 36 and 72 hours postoperatively) may have an advantage regarding psychological and physical stress compared with early imaging. The goal of this study is to evaluate and determine the optimal time frame for postoperative imaging with MRI and CT in terms of medical and neuroradiological implications and patient's subjective stress level. METHODS AND ANALYSIS: Data will be prospectively collected from all patients aged 18-80 years who receive postoperative MRI or CT imaging following a craniotomy for resection of a cerebral tumour (benign and malignant) or vascular surgery. Participants have to complete questionnaires containing visual analogue scores (VAS) for headache and nausea, Body Part Discomfort score and a single question addressing subjective preference of timing of postoperative imaging after craniotomy. The primary endpoint of the study is the difference in subjective stress due to imaging studies after craniotomy, measured just before and after postoperative MRI or CT with the above-mentioned instruments. Subjective stress is defined as a combination of the scores VAS pain, VAS nausea and 0.5* Body Part Discomfort core.This study determines whether proper timing of postoperative imaging can improve patient satisfaction and reduce pain, stress and discomfort caused by postoperative imaging. Factors causing additional postoperative stress are likely responsible for delayed recovery of neurosurgical patients. ETHICS AND DISSEMINATION: The institutional review board (Kantonale Ethikkommission Zürich) approved this study on 4 August 2020 under case number BASEC 2020-01590. The authors are planning to publish the data of this study in a peer-reviewed paper. After database closure, the data will be exported to the local data repository (Zurich Open Repository and Archive) of the University of Zurich. The sponsor (LR) and the project leader (MR.G) will make the final decision on the publication of the results. The data that support the findings of this study are available on request from the corresponding author LT. The data are not publicly available due to privacy/ethical restrictions. TRIAL REGISTRATION NUMBER: NCT05112575; ClinicalTrials.gov.

Failure of diffusion-weighted imaging in intraoperative 3 Tesla MRI to identify hyperacute strokes during glioma surgery.

Intraoperatively acquired diffusion-weighted imaging (DWI) sequences in cranial tumor surgery are used for early detection of ischemic brain injuries, which could result in impaired neurological outcome and their presence might thus influence the neurosurgeon's decision on further resection. The phenomenon of false-negative DWI findings in intraoperative magnetic resonance imaging (ioMRI) has only been reported in single cases and therefore yet needs to be further analyzed. This retrospective single-center study's objective was the identification and characterization of false-negative DWI findings in ioMRI with new or enlarged ischemic areas on postoperative MRI (poMRI). Out of 225 cranial tumor surgeries with intraoperative DWI sequences, 16 cases with no additional resection after ioMRI and available in-time poMRI (< 14 days) were identified. Of these, a total of 12 cases showed false-negative DWI in ioMRI (75%). The most frequent tumor types were oligodendrogliomas and glioblastomas (4 each). In 5/12 cases (41.7%), an ischemic area was already present in ioMRI, however, volumetrically increased in poMRI (mean infarct growth + 2.1 cm3; 0.48-3.6), whereas 7 cases (58.3%) harbored totally new infarcts on poMRI (mean infarct volume 0.77 cm3; 0.05-1.93). With this study we provide the most comprehensive series of false-negative DWI findings in ioMRI that were not followed by additional resection. Our study underlines the limitations of intraoperative DWI sequences for the detection and size-estimation of hyperacute infarction. The awareness of this phenomenon is crucial for any neurosurgeon utilizing ioMRI.

Deep brain stimulation for locomotion in incomplete human spinal cord injury (DBS-SCI): protocol of a prospective one-armed multi-centre study.

INTRODUCTION: Spinal cord injury (SCI) is a devastating condition with immediate impact on the individual's health and quality of life. Major functional recovery reaches a plateau 3-4 months after injury despite intensive rehabilitative training. To enhance training efficacy and improve long-term outcomes, the combination of rehabilitation with electrical modulation of the spinal cord and brain has recently aroused scientific interest with encouraging results. The mesencephalic locomotor region (MLR), an evolutionarily conserved brainstem locomotor command and control centre, is considered a promising target for deep brain stimulation (DBS) in patients with SCI. Experiments showed that MLR-DBS can induce locomotion in rats with spinal white matter destructions of >85%. METHODS AND ANALYSIS: In this prospective one-armed multi-centre study, we investigate the safety, feasibility, and therapeutic efficacy of MLR-DBS to enable and enhance locomotor training in severely affected, subchronic and chronic American Spinal Injury Association Impairment Scale C patients in order to improve functional recovery. Patients undergo an intensive training programme with MLR-DBS while being regularly followed up until 6 months post-implantation. The acquired data of each timepoint are compared with baseline while the primary endpoint is performance in the 6-minute walking test. The clinical trial protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials checklist. ETHICS AND DISSEMINATION: This first in-man study investigates the therapeutic potential of MLR-DBS in SCI patients. One patient has already been implanted with electrodes and underwent MLR stimulation during locomotion. Based on the preliminary results which promise safety and feasibility, recruitment of further patients is currently ongoing. Ethical approval has been obtained from the Ethical Committee of the Canton of Zurich (case number BASEC 2016-01104) and Swissmedic (10000316). Results will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03053791.

Deep brain stimulation effects on lower urinary tract function: Systematic review and meta-analysis.

INTRODUCTION: While efficacy of deep brain stimulation for motor symptoms of neurological disorders is well accepted, its effects on the autonomic system remain controversial. We aimed to systematically assess all available evidence of deep brain stimulation effects on lower urinary tract function. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were identified by electronic search of Cochrane Central Register of Controlled Trials, Embase, Medline, Scopus, and Web of Science (last search July 12, 2019) and by screening of reference lists and reviews. RESULTS: After screening 577 articles, we included 29 studies enrolling a total of 1293 patients. Deep brain stimulation of the globus pallidus internus (GPi), pedunculopontine nucleus (PPN), and subthalamic nucleus (STN) had an inhibitory effect on detrusor function, while deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM) showed an excitatory effect. In the meta-analysis, deep brain stimulation of the STN led to a significant increase in maximum bladder capacity (mean difference 124 mL, 95% confidence interval 60-187 mL, p = 0.0001) but had no clinically relevant effects on other urodynamic parameters. Adverse events (reported in thirteen studies) were most commonly respiratory issues, postural instability, and dysphagia. Risk of bias and confounding was relatively low. CONCLUSIONS: Deep brain stimulation does not impair lower urinary tract function and might even have beneficial effects. This needs to be considered in the deep brain stimulation decision-making process helping to encourage and to reassure prospective patients.

Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke.

Angiogenesis is a key restorative process following stroke but has also been linked to increased vascular permeability and blood brain barrier (BBB) disruption. Previous pre-clinical approaches primarily focused on the administration of vascular endothelial growth factor (VEGF) to promote vascular repair after stroke. Although shown to improve angiogenesis and functional recovery from stroke, VEGF increased the risk of blood brain barrier disruption and bleedings to such an extent that its clinical use is contraindicated. As an alternative strategy, antibodies against the neurite growth inhibitory factor Nogo-A have recently been shown to enhance vascular regeneration in the ischemic central nervous system (CNS); however, their effect on vascular permeability is unknown. Here, we demonstrate that antibody-mediated Nogo-A neutralization following stroke has strong pro-angiogenic effects but does not increase vascular permeability as opposed to VEGF. Moreover, VEGF-induced vascular permeability was partially prevented when VEGF was co-administered with anti-Nogo-A antibodies. This study may provide a novel therapeutic strategy for vascular repair and maturation in the ischemic brain.

Stroke Promotes Systemic Endothelial Inflammation and Atherosclerosis.

Patients who survive a stroke have an increased risk for recurrent vascular events. The mechanisms underlying the events are barely understood. A recent study suggests that stroke-enhanced atherosclerosis is induced through brain-released alarmins, which lead to systemic vascular inflammation and plaque formation. Interfering with these processes may lead to novel therapeutic approaches.