AxoDetect: an automated nerve image segmentation and quantification workflow for computational nerve modeling.

Objective.Bioelectronic treatments targeting near-organ innervation have unprecedented clinical applications. Particularly in the spleen, the inhibition of the cholinergic inflammatory response by near-organ nerve stimulation has potential to replace pharmacological treatments in chronic and autoimmune diseases. A caveat is that the optimization of therapeutic stimulation parameters relies onin vivoexperimentation, which becomes challenging due to the small nerve diameters (2 µm), complex anatomy, and mixed axon type composition of the autonomic nerves. Effective development ofin silicomodels requires tools which allow for fast and efficient quantification of axonal composition of specific nerves. Current approaches to generate such information rely on manual image segmentation and quantification.Approach.We developed a combined image-segmentation and model-generation software called AxoDetect: a target- and format-agnostic computer vision algorithm which can segment myelin, endo/epineurium, and both myelinated and unmyelinated fibers from a nerve image without training.Main results.AxoDetect is over 10 times faster on average when compared with current automatic methods while maintaining flexibility through the use of tunable pixel threshold filters to detect different types of tissue. When compared to a distribution-based and a manually segmented model of the splenic nerve terminal branch 1, the model generated with AxoDetect had comparable threshold prediction and was able to accurately detect an increase in activation threshold caused by the addition of surrounding fat tissue to the modeled nerve.Significance.AxoDetect contributes to the acceleration of neuromodulation treatment development through faster model design and iteration without requiring training. Furthermore, the computer vision approach and tunable nature of the filters in our method allow for its use in a variety of histological applications. Our approach will impact not only the study of nerves but also the design of implantable neural interfaces to enhance bioelectronic therapeutic options.

Real-world Impact of Fremanezumab on Migraine-Related Health Care Resource Utilization in Patients with Comorbidities, Acute Medication Overuse, and/or Unsatisfactory Prior Migraine Preventive Response.

INTRODUCTION: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, is indicated for preventive treatment of migraine in adults. Real-world evidence assessing the effect of fremanezumab on migraine-related medication use, health care resource utilization (HCRU), and costs in patient populations with comorbidities, acute medication overuse (AMO), and/or unsatisfactory prior migraine preventive response (UPMPR) is needed. METHODS: Data for this US, retrospective claims analysis were obtained from the Merative® MarketScan® Commercial and supplemental databases. Eligible adults with migraine initiated fremanezumab between 1 September 2018 and 30 June 2019 (date of earliest fremanezumab claim is the index date), had ≥ 12 months of continuous enrollment prior to initiation (preindex period) and ≥ 6 months of data following initiation (postindex period; variable follow-up after 6 months), and had certain preindex migraine comorbidities (depression, anxiety, and cardiovascular disease), potential AMO, or UPMPR. Changes in migraine-related concomitant acute and preventive medication use, HCRU, and costs were assessed pre- versus postindex. RESULTS: In total, 3193 patients met the eligibility criteria. From pre- to postindex, mean (SD) per patient per month (PPPM) number of migraine-related acute medication and preventive medication claims (excluding fremanezumab), respectively, decreased from 0.97 (0.90) to 0.86 (0.87) (P < 0.001) and 0.94 (0.74) to 0.81 (0.75) (P < 0.001). Migraine-related outpatient and neurologist office visits, emergency department visits, and other outpatient services PPPM decreased pre- versus postindex (P < 0.001 for all), resulting in a reduction in mean (SD) total health care costs PPPM from US$541 (US$858) to US$490 (US$974) (P = 0.003). Patients showed high adherence and persistence rates, with mean (SD) proportion of days covered of 0.71 (0.29), medication possession ratio of 0.74 (0.31), and persistence duration of 160.3 (33.2) days 6 months postindex. CONCLUSIONS: Patients with certain migraine comorbidities, potential AMO, and/or UPMPR in a real-world setting had reduced migraine-related medication use, HCRU, and costs following initiation of fremanezumab. Graphical abstract available for this article.

Active monitoring of long-eared owl (Asio otus) nestlings reveals widespread exposure to anticoagulant rodenticides across different agricultural landscapes.

The widespread use of anticoagulant rodenticides (ARs) poses a worldwide threat to farmland wildlife. These compounds accumulate in tissues of both target and non-target species, potentially endangering both direct consumers and their predators. However, investigations on ARs in blood of free-ranging predatory birds are rare. Here, the long-eared owl (Asio otus) has been used as a model predator to assess AR exposure in different agricultural landscapes from a Mediterranean semiarid region. A total of 69 owlets from 38 nests were blood-sampled over 2021 and 2022, aiming to detect AR residues and explore factors that determine their exposure, such as land uses. In addition, prothrombin time (PT) test was conducted to assess potential effects of AR contamination. Overall, nearly all the samples (98.6 %) tested positive for at least one compound and multiple ARs were found in most of the individuals (82.6 %). Among the ARs detected, flocoumafen was the most common compound (88.4 % of the samples). AR total concentration (ΣARs) in blood ranged from 0.06 to 34.18 ng mL-1, detecting the highest levels in the most intensively cultivated area. The analysis of owl pellets from 19 breeding territories showed relevant among-site differences in the contribution of rodents and birds into the diet of long-eared owls, supporting its high dietary plasticity and indicating AR presence at multiple trophic levels. Moreover, a positive and significant correlation was found between ΣARs and PT (Rho = 0.547, p < 0.001), which demonstrates the direct effect of ARs on free-living nestlings. Our results provide a preliminary overview of AR exposure in a little-studied owl species inhabiting agricultural and rural landscapes. Despite the low detected levels, these findings indicate widespread exposure -often to multiple compounds- from early life stages, which raises concern and draws attention to an ongoing and unresolved contamination issue.

Pleiotrophin-Neuregulin1 promote axon regeneration and sorting in conduit repair of critical nerve gap injuries.

Significant challenges remain in the treatment of critical nerve gap injuries using artificial nerve conduits. We previously reported successful axon regeneration across a 40 mm nerve gap using a biosynthetic nerve implant (BNI) with multi-luminal synergistic growth factor release. However, axon sorting, remyelination, and functional recovery were limited. Neuregulin1 (NRG1) plays a significant role in regulating the proliferation and differentiation of Schwann cells (SCs) during development and after injury. We hypothesize that the release of NRG1 type III combined with pleiotrophin (PTN) in the BNI will enhance axon growth, remyelination, and function of regenerated nerves across a critical gap. A rabbit 40 mm peroneal gap injury model was used to investigate the therapeutic efficacy of BNIs containing either NRG1, PTN, or PTN+NRG1 growth factor release. We found that NRG1 treatment doubled the number of regenerated axons (1276±895) compared to empty controls (633±666) and PTN tripled this number (2270±989). NRG1 also significantly increased the number of SOX10+ Schwann cells in mid-conduit (20.42%±11.78%) and reduced the number of abnormal Remak axon bundles. The combination of PTN+NRG1 increased axon diameter (1.70±1.06) vs control (1.21±0.77) (p<0.01), with 15.35% of axons above 3 µm, comparable to autograft. However, the total number of remyelinated axons was not increased by the added NRG1 release, which correlated with absence of axonal NRG1 type III expression in the regenerated axons. Electrophysiological evaluation showed higher muscle force recruitment (23.8±16.0 mN vs 17.4±1.4 mN) and maximum evoked compound motor action potential (353 µV vs 37 µV) in PTN-NRG1 group versus control, which correlated with the improvement in the toe spread recovery observed in PTN-NRG1 treated animals (0.64±0.02) vs control (0.50±0.01). These results revealed the need of a combination of pro-regenerative and remyelinating growth factor combination therapy for the repair of critical nerve gaps.

Biomechanics Characterization of Autonomic and Somatic Nerves by High Dynamic Closed-Loop MEMS force sensing.

The biomechanics of peripheral nerves are determined by the blood-nerve barrier (BNB), together with the epineural barrier, extracellular matrix, and axonal composition, which maintain structural and functional stability. These elements are often ignored in the fabrication of penetrating devices, and the implant process is traumatic due to the mechanical distress, compromising the function of neuroprosthesis for sensory-motor restoration in amputees. Miniaturization of penetrating interfaces offers the unique opportunity of decoding individual nerve fibers associated to specific functions, however, a main issue for their implant is the lack of high-precision standardization of insertion forces. Current automatized electromechanical force sensors are available; however, their sensitivity and range amplitude are limited (i.e. mN), and have been tested only in-vitro. We previously developed a high-precision bi-directional micro-electromechanical force sensor, with a closed-loop mechanism (MEMS-CLFS), that while measuring with high-precision (-211.7µN to 211.5µN with a resolution of 4.74nN), can be used in alive animal. Our technology has an on-chip electrothermal displacement sensor with a shuttle beam displacement amplification mechanism, for large range and high-frequency resolution (dynamic range of 92.9 dB), which eliminates the adverse effect of flexural nonlinearity measurements, observed with other systems, and reduces the mechanical impact on delicate biological tissue. In this work, we use the MEMS-CLFS for in-vivo bidirectional measurement of biomechanics in somatic and autonomic nerves. Furthermore we define the mechanical implications of irrigation and collagen VI in the BNB, which is different for both autonomic and somatic nerves (~ 8.5-8.6 fold density of collagen VI and vasculature CD31+ in the VN vs ScN). This study allowed us to create a mathematical approach to predict insertion forces. Our data highlights the necessity of nerve-customization forces to prevent injury when implanting interfaces, and describes a high precision MEMS technology and mathematical model for their measurements.

Secondary urethral sphincter function of the rabbit pelvic and perineal muscles.

Perineal and pelvic floor muscles play an important role in continence by providing mechanical support to pelvic organs. It is also known that the pubococcygeus muscle (PcM) contracts in the storage phase and is inactive during voiding, while the bulbospongiosus muscle (BsM) is active during the voiding phase. Recent evidence suggested an additional role of these muscles in supporting urethral closure in rabbits. However, the individual role of perineal and pelvic muscles as urethral sphincters is not well-defined. Here we evaluated the individual, sequential and synergistic roles of the PcM and BsM in assisting urethral closure and defined the optimal electrical stimulation parameters that can effectively contract these muscles and increase the urethral pressure (P ura ) in young nulliparous animals (n = 11). Unilateral stimulation of either the BsM or PcM at 40 Hz induced modest increases in average P ura (0.23 ± 0.10 and 0.07 ± 0.04 mmHg, respectively). Investigation on the changes in P ura evoked by stimulation frequencies between 5 and 60 Hz show that sequential contralateral PcM-BsM activation at 40 Hz induced a 2-fold average P ura increase (0.23 ± 0.07 mmHg) compared to that evoked by PcM stimulation. Simultaneous activation of PcM and BsM at 40 Hz also showed an increased average P ura (0.26 ± 0.04 mmHg), with a 2-fold increase in average P ura observed during the unilateral sequential PcM-BsM stimulation at 40 Hz (0.69 ± 0.2 mmHg). Finally, stimulation at 40 Hz of the bulbospongiosus nerve (BsN) induced an approximate 4-fold increase in average P ura (0.87 ± 0.44 mmHg; p < 0.04) compared to that elicited by BsM stimulation, confirming that direct nerve stimulation is more effective. Together, this study shows that in the female rabbit, both perineal and pelvic muscles support of the urethral function during continence, and that unilateral stimulation of the BsN at 40-60 Hz is sufficient to achieve maximal secondary sphincter activity. The results also support the potential clinical value of neuromodulation of pelvic and perineal nerves as bioelectronic therapy for stress urinary incontinence.

Liquid crystal elastomer based dynamic device for urethral support: Potential treatment for stress urinary incontinence.

Stress urinary incontinence (SUI) is characterized by the involuntary loss of urine due to increased intra-abdominal pressure during coughing, sneezing, or exercising. SUI affects 20-40% of the female population and is exacerbated by aging. Severe SUI is commonly treated with surgical implantation of an autologous or a synthetic sling underneath the urethra for support. These slings, however, are static, and their tension cannot be non-invasively adjusted, if needed, after implantation. This study reports the fabrication of a novel device based on liquid crystal elastomers (LCEs) capable of changing shape in response to temperature increase induced by transcutaneous IR light. The shape change of the LCE-based device was characterized in a scar tissue phantom model. An in vitro urinary tract model was designed to study the efficacy of the LCE-based device to support continence and adjust sling tension with IR illumination. Finally, the device was acutely implanted and tested for induced tension changes in female multiparous New Zealand white rabbits. The LCE device achieved 5.6% ± 1.1% actuation when embedded in an agar gel with an elastic modulus of 100 kPa. The corresponding device temperature was 44.9 °C ± 0.4 °C, and the surrounding agar temperature stayed at 42.1 °C ± 0.4 °C. Leaking time in the in vitro urinary tract model significantly decreased (p < 0.0001) when an LCE-based cuff was sutured around the model urethra from 5.2min ± 1min to 2min ±0.5min when the cuff was illuminated with IR light. Normalized leak point force (LPF) increased significantly (p = 0.01) with the implantation of an LCE-CB cuff around the bladder neck of multiparous rabbits. It decreased significantly (p = 0.023) when the device was actuated via IR light illumination. These results demonstrate that LCE material could be used to fabricate a dynamic device for treating SUI in women.

Commentary: Constipation caused by anti-calcitonin gene-related peptide migraine therapeutics explained by antagonism of calcitonin gene-related peptide's motor-stimulating and prosecretory function in the intestine.

Calcitonin gene-related peptide (CGRP) pathway-targeted treatments have been shown to be efficacious in the prevention of episodic and chronic migraine. Currently approved therapies include monoclonal antibodies (mAbs) that target CGRP (eptinezumab, fremanezumab, and galcanezumab) and the CGRP receptor (erenumab), and small molecule CGRP receptor antagonists (atogepant and rimegepant). While CGRP pathway-targeted treatments are generally well-tolerated, in a review article by Holzer and Holzer-Petsche published in the January 2022 issue of Frontiers in Physiology the authors discussed the role of the CGRP pathway in gastrointestinal physiology, with a specific focus on constipation associated with the use of CGRP pathway-targeted treatments. The authors state that real-world surveys have shown constipation to be a "major adverse event" reported in "more than 50% of patients treated with erenumab, fremanezumab or galcanezumab." As described in the current commentary, the limited data from the cited references in the review article by Holzer and Holzer-Petsche do not support that statement.

Predation impact on threatened spur-thighed tortoises by golden eagles when main prey is scarce.

A reduction in adult survival in long-living species may compromise population growth rates. The spur-thighed tortoise (Testudo graeca) is a long-lived reptile that is threatened by habitat loss and fragmentation. Golden eagles (Aquila chrysaetos), whose breeding habitats overlap that of tortoises, may predate them by dropping them onto rocks and breaking their carapaces. In SE Spain, the number of golden eagles has increased in the last decades and the abundance of their main prey (i.e., rabbits Oryctolagus cuniculus) has decreased. Our aims were to 1) describe the role of tortoises in golden eagles' diet, and 2) estimate the predation impact of golden eagles on tortoises in eagles' territories and in the regional tortoise population. We collected regurgitated pellets and prey remains under eagle nests and roosts, and obtained information on tortoise abundance and population structure and rabbit abundance. We found that tortoises were an alternative prey to rabbits, so that eagles shifted to the former where the latter were scarce. The average predation rate on tortoises was very low at the two studied scales. However, eagles showed a marked selection for adult female tortoises, which led the tortoise sex ratio to be biased towards males in those eagle territories with higher tortoise predation. Whether this may compromise the spur-thighed tortoise long-term population viability locally deserves further attention.

Renal Nerve Activity and Arterial Depressor Responses Induced by Neuromodulation of the Deep Peroneal Nerve in Spontaneously Hypertensive Rats.

Hypertension is a main cause of death in the United States with more than 103 million adults affected. While pharmacological treatments are effective, blood pressure (BP) remains uncontrolled in 50-60% of resistant hypertensive subjects. Using a custom-wired miniature electrode, we previously reported that deep peroneal nerve stimulation (DPNS) elicited acute cardiovascular depressor responses in anesthetized spontaneously hypertensive rats (SHRs). Here, we further study this effect by implementing a wireless system and exploring different stimulation parameters to achieve a maximum depressor response. Our results indicate that DPNS consistently induces a reduction in BP and suggests that renal sympathetic nerve activity (RSNA) is altered by this bioelectronic treatment. To test the acute effect of DPNS in awake animals, we developed a novel miniaturized wireless microchannel electrode (w-µCE), with a Z-shaped microchannel through which the target nerves slide and lock into the recording/stimulation chamber. Animals implanted with w-µCE and BP telemetry systems for 3 weeks showed an average BP of 150 ± 14 mmHg, which was reduced significantly by an active DPNS session to 135 ± 8 mmHg (p < 0.04), but not in sham-treated animals. The depressor response in animals with an active w-µCE was progressively returned to baseline levels 14 min later (164 ± 26 mmHg). This depressor response was confirmed in restrained fully awake animals that received DPNS for 10 days, where tail-cuff BP measurements showed that systolic BP in SHR lowered 10% at 1 h and 16% 2 h after the DPNS when compared to the post-implantation baseline. Together, these results support the use of DPN neuromodulation as a possible strategy to lower BP in drug-resistant hypertension.

Biomaterials and Regenerative Medicine in Pain Management.

PURPOSE OF REVIEW: Pain presents a unique challenge due to the complexity of the biological pathways involved in the pain perception, the growing concern regarding the use of opioid analgesics, and the limited availability of optimal treatment options. The use of biomaterials and regenerative medicine in pain management is being actively explored and showing exciting progress in improving the efficacy of conventional pharmacotherapy and as novel non-pharmacological therapy for chronic pain caused by degenerative diseases. In this paper we review current clinical applications, and promising research in the use of biomaterials and regenerative medicine in pain management. RECENT FINDINGS: Regenerative therapies have been developed to repair damaged tissues in back, joint, and shoulder that lead to chronic and inflammatory pain. Novel regenerative biomaterials have been designed to incorporate biochemical and physical pro-regenerative cues that augment the efficacy of regenerative therapies. New biomaterials improve target localization with improved tunability for controlled drug delivery, and injectable scaffolds enhance the efficacy of regenerative therapies through improving cellular migration. Advanced biomaterial carrier systems have been developed for sustained and targeted delivery of analgesic agents to specific tissues and organs, showing improved treatment efficacy, extended duration of action, and reduced dosage. Targeting endosomal receptors by nanoparticles has shown promising anti-nociception effects. Biomaterial scavengers are designed to remove proinflammatory reactive oxygen species that trigger nociceptors and cause pain hypersensitivity, providing a proactive approach for pain management. Pharmacotherapy remains the method of choice for pain management; however, conventional analgesic agents are associated with adverse effects. The relatively short duration of action when applied as free drug limited their efficacy in postoperative and chronic pain treatment. The application of biomaterials in pain management is a promising strategy to improve the efficacy of current pharmacotherapy through sustained and targeted delivery of analgesic agents. Regenerative medicine strategies target the damaged tissue and provide non-pharmacological alternatives to manage chronic and inflammatory pain. In the future, the successful development of regenerative therapies that completely repair damaged tissues will provide a more optimal alternative for the treatment of chronic pain caused. Future studies will leverage on the increasing understanding of the molecular mechanisms governing pain perception and transmission, injury response and tissue regeneration, and the development of new biomaterials and tissue regenerative methods.

Towards the Automation of Infrared Thermography Inspections for Industrial Maintenance Applications.

The maintenance of industrial equipment extends its useful life, improves its efficiency, reduces the number of failures, and increases the safety of its use. This study proposes a methodology to develop a predictive maintenance tool based on infrared thermographic measures capable of anticipating failures in industrial equipment. The thermal response of selected equipment in normal operation and in controlled induced anomalous operation was analyzed. The characterization of these situations enabled the development of a machine learning system capable of predicting malfunctions. Different options within the available conventional machine learning techniques were analyzed, assessed, and finally selected for electronic equipment maintenance activities. This study provides advances towards the robust application of machine learning combined with infrared thermography and augmented reality for maintenance applications of industrial equipment. The predictive maintenance system finally selected enables automatic quick hand-held thermal inspections using 3D object detection and a pose estimation algorithm, making predictions with an accuracy of 94% at an inference time of 0.006 s.

Blood Toxic Elements and Effects on Plasma Vitamins and Carotenoids in Two Wild Bird Species: Turdus merula and Columba livia.

Birds have historically suffered adverse effects by toxic elements, such as As, Pb, Hg, and Cd. However, reports on exposure to a wide range of elements, including rare earth elements and other minor elements of emerging concern, and the potential consequences for wildlife are still scarce. This study evaluates blood concentrations of 50 elements and their related effects on lutein and vitamin levels in the Eurasian blackbird (Turdus merula) and wild rock pigeon (Columba livia), inhabiting different scenarios of contaminant exposure. Blood concentrations of As, Cd, and Pb (and Mn in T. merula) were increased in both species captured in the mining area, compared to the control site. T. merula also showed increased As, Cd, and Pb concentrations in blood in the agricultural-urban area, as compared to the control area, together with the highest Hg levels, which could be related to agricultural practices and industrial activities. Decreases of 33 and 38% in the plasma retinol levels in T. merula inhabiting the mining and the agricultural-urban areas, respectively, as compared to the control site, were associated with increased Pb, As, and Cd exposure. This could be due to a metal-driven suppressive effect in retinol metabolism and/or its over-use for coping with metal-related oxidative stress.

Platinized graphene fiber electrodes uncover direct spleen-vagus communication.

Neural interfacing nerve fascicles along the splenic neurovascular plexus (SNVP) is needed to better understand the spleen physiology, and for selective neuromodulation of this major organ. However, their small size and anatomical location have proven to be a significant challenge. Here, we use a reduced liquid crystalline graphene oxide (rGO) fiber coated with platinum (Pt) as a super-flexible suture-like electrode to interface multiple SNVP. The Pt-rGO fibers work as a handover knot electrodes over the small SNVP, allowing sensitive recording from four splenic nerve terminal branches (SN 1-4), to uncover differential activity and axon composition among them. Here, the asymmetric defasciculation of the SN branches is revealed by electron microscopy, and the functional compartmentalization in spleen innervation is evidenced in response to hypoxia and pharmacological modulation of mean arterial pressure. We demonstrate that electrical stimulation of cervical and sub-diaphragmatic vagus nerve (VN), evokes activity in a subset of SN terminal branches, providing evidence for a direct VN control over the spleen. This notion is supported by adenoviral tract-tracing of SN branches, revealing an unconventional direct brain-spleen projection. High-performance Pt-rGO fiber electrodes, may be used for the fine neural modulation of other small neurovascular plexus at the point of entry of major organs as a bioelectronic medical alternative.

Toward a More Comprehensive Assessment of School Age Children with Hemiplegic Cerebral Palsy.

BACKGROUND: Cerebral palsy (CP) is the leading cause of disability in children. While motor deficits define CP, many patients experience behavioral and cognitive deficits which limit participation. The purpose of this study was to contribute to our understanding of developmental delay and how to measure these deficits among children with CP. METHODS: Children 5 to 15 years with hemiplegic CP were recruited. Cognition and motor ability were assessed. The brain injury associated with observed motor deficits was identified. Accelerometers measured real-world bilateral upper extremity movement and caregivers completed behavioral assessments. RESULTS: Eleven children participated, 6 with presumed perinatal stroke. Four children scored below average intelligence quotient while other measures of cognition were within normal limits (except processing speed). Motor scores confirmed asymmetrical deficits. Approximately one third of scores indicated deficits in attention, behavior, or depression. CONCLUSIONS: Our findings corroborate that children with CP experience challenges that are broader than motor impairment alone. Despite the variation in brain injury, all participants completed study procedures. IMPLICATIONS: Our findings suggest that measuring behavior in children with CP may require a more comprehensive approach and that caregivers are amenable to using online collection tools which may assist in addressing the therapeutic needs of children with CP.

Targeted neuromodulation of pelvic floor nerves in aging and multiparous rabbits improves continence.

Pelvic floor muscle stretch injury during pregnancy and birth is associated with the incidence of stress urinary incontinence (SUI), a condition that affects 30-60% of the female population and is characterized by involuntary urine leakage during physical activity, further exacerbated by aging. Aging and multiparous rabbits suffer pelvic nerve and muscle damage, resulting in alterations in pelvic floor muscular contraction and low urethral pressure, resembling SUI. However, the extent of nerve injury is not fully understood. Here, we used electron microscopy analysis of pelvic and perineal nerves in multiparous rabbits to describe the extent of stretch nerve injury based on axon count, axon size, myelin-to-axon ratio, and elliptical ratio. Compared to young nulliparous controls, mid-age multiparous animals showed an increase in the density of unmyelinated axons and in myelin thickness in both nerves, albeit more significant in the bulbospongiosus nerve. This revealed a partial but sustained damage to these nerves, and the presence of some regenerated axons. Additionally, we tested whether electrical stimulation of the bulbospongiosus nerve would induce muscle contraction and urethral closure. Using a miniature wireless stimulator implanted on this perineal nerve in young nulliparous and middle age multiparous female rabbits, we confirmed that these partially damaged nerves can be acutely depolarized, either at low (2-5 Hz) or medium (10-20 Hz) frequencies, to induce a proportional increase in urethral pressure. Evaluation of micturition volume in the mid-age multiparous animals after perineal nerve stimulation, effectively reversed a baseline deficit, increasing it 2-fold (p = 0.02). These results support the notion that selective neuromodulation of pelvic floor muscles might serve as a potential treatment for SUI.

Both high fat and high carbohydrate diets impair vagus nerve signaling of satiety.

Obesity remains prevalent in the US. One potential treatment is vagus nerve stimulation (VNS), which activates the sensory afferents innervating the stomach that convey stomach volume and establish satiety. However, current VNS approaches and stimulus optimization could benefit from additional understanding of the underlying neural response to stomach distension. In this study, obesity-prone Sprague Dawley rats consumed a standard, high-carbohydrate, or high-fat diet for several months, leading to diet-induced obesity in the latter two groups. Under anesthesia, the neural activity in the vagus nerve was recorded with a penetrating microelectrode array while the stomach was distended with an implanted balloon. Vagal tone during distension was compared to baseline tone prior to distension. Responses were strongly correlated with stomach distension, but the sensitivity to distension was significantly lower in animals that had been fed the nonstandard diets. The results indicate that both high fat and high carbohydrate diets impair vagus activity.

Cingulo-opercular control network and disused motor circuits joined in standby mode.

Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.