Case report: Cerebral sinus vein thrombosis in VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome is a newly described hemato-inflammatory acquired monogenic entity that presents in adulthood. One of the main features of VEXAS syndrome is a high venous thromboembolism (VTE) burden, with approximately 30-40% experiencing lower extremity deep vein thrombosis and a lower incidence of pulmonary embolism at approximately 10%. To date, VEXAS syndrome has not been associated with rarer forms of VTE such as cerebral sinus vein thrombosis (CSVT) and Budd-Chiari syndrome, which are well-recognized vascular manifestations in Behcet's disease, another autoinflammatory vasculitic disease. Herein, we describe a case of acute severe extensive and fatal CSVT in a patient with VEXAS syndrome. The event occurred during a period of apparently quiescent inflammatory status, while the patient was receiving tocilizumab and a low dose of glucocorticoids. Despite treatment with anticoagulation, high-dose glucocorticoids, endovascular thrombectomy, and intracranial pressure-lowering agents, the patient suffered severe neurologic damage and ultimately succumbed to the condition 3 weeks after the onset of CSVT. To the best of our knowledge, this is the first reported case of CVST in a patient with VEXAS syndrome.

The pivotal role of timing of intravenous thrombolysis bridging treatment prior to endovascular thrombectomy.

Background: The role of intravenous thrombolysis (IVT) as bridging treatment prior to endovascular thrombectomy (EVT) is under debate and better patient selection is needed. Objectives: As the efficacy and safety of IVT diminish with time, we aimed to examine the impact of bridging treatment within different time frames from symptom onset. Design: A retrospective registry study. Methods: Data were extracted from ongoing prospective EVT registries in two large tertiary centers. The current study included IVT-eligible patients with onset to door (OTD) < 4 h. We examined the efficacy and safety of bridging treatment through a comparison of the IVT + EVT group with the direct-EVT group by different time frames. Results: In all, 408 patients (age 71.1 ± 14.6, 50.6% males) were included, among them 195 received IVT + EVT and 213 underwent direct EVT. Both groups had similar characteristics. In the IVT + EVT group only, longer OTD was associated with lower rates of favorable outcome (p = 0.021) and higher rates of hemorrhagic transformation (HT; p = 0.001). In patients with OTD ⩽ 2 h, IVT + EVT compared to direct EVT had higher rates of TICI 2b-3 (86.2% versus 80.7%, p = 0.038). In patients with OTD > 2 h, IVT + EVT had lower rates of favorable outcome (33.3% versus 56.9%, p = 0.021), worse discharge National Institutes of Health Stroke Scale [7 (2-13) versus 3 (1-8), p = 0.024], and higher rates of HT (34.0% versus 8.5%, p < 0.001). Discussion: In this study, we found OTD times to have a significant effect on the impact of IVT bridging treatment. Our study shows that among patients with OTD < 2 h bridging treatment may be associated with higher rates of successful recanalization. By contrast, in patients with OTD > 2 h, bridging treatment was associated with worse outcomes. Further time-sensitive randomized trials are needed.

Sexual behavior and drive: Is it all in your brain?

Male mating behavior involves a series of behaviors aimed to recognize, approach and mate with a female. A new study in mice reveals an elaborated neural circuit that drives both sexual recognition, sexual reward, and copulatory behavior.

Circle of Willis integrity in acute middle cerebral artery occlusion: does the posterior communicating artery matter?

BACKGROUND: Collateral circulation is an important determinant of outcome in people with acute ischemic stroke due to large vessel occlusion (LVO). OBJECTIVE: To explore the impact of the circle of Willis (CW) anatomical characteristics ipsilateral to the occlusion site, particularly the posterior communicating artery (PComA) and the A1-portion of the anterior cerebral artery (A1-ACA), on stroke outcomes in a cohort of patients with LVO and middle cerebral artery (MCA) occlusion, undergoing endovascular thrombectomy (EVT). METHODS: This is a retrospective cohort study performed in a comprehensive tertiary stroke center. The study population consisted of consecutive patients with LVO with proximal MCA occlusion (M1) between June 2016 and April 2021, undergoing EVT. Demographic, clinical, and imaging information was extracted from patient files. Patency and diameters of ipsilateral A1-ACA and PComA were manually measured on admission CT angiography images in the core laboratory. RESULTS: One hundred and five patients with LVO comprised the study cohort, mean age 72.3 years, 43.8% were male, mean National Institutes of Health Stroke Scale score at admission 15.2. The cohort was grouped according to CW vessel characteristics. On univariate analysis, a well-developed PComA was associated with lower rates of hemorrhagic transformation (1.8% vs 14.3%, P=0.01) and a trend towards lower mortality rates (8.9% vs 20.4%, P=0.08).On multivariable regression analysis a well-developed PComA emerged as an independent predictor for survival (aOR=0.09, 95% CI 0.01 to 0.4 for survival at discharge, P=0.009, aOR=0.22, 95% CI 0.05 to 0.8 for survival at 90 days, P=0.02). CONCLUSIONS: In a cohort of patients with LVO due to M1 occlusion undergoing EVT, a well-developed PComA was associated with significantly lower hemorrhagic transformation rates, a trend towards better functional outcomes, and independently predicted survival. Larger studies are needed to understand the differential effect of CW collateral conduits on stroke outcome and evaluate the practicality of incorporating such factors in the clinical decision-making process prior to EVT.

Functional MRI of murine olfactory bulbs at 15.2T reveals characteristic activation patters when stimulated by different odors.

Thanks to its increased sensitivity, single-shot ultrahigh field functional MRI (UHF fMRI) could lead to valuable insight about subtle brain functions such as olfaction. However, UHF fMRI experiments targeting small organs next to air voids, such as the olfactory bulb, are severely affected by field inhomogeneity problems. Spatiotemporal Encoding (SPEN) is an emerging single-shot MRI technique that could provide a route for bypassing these complications. This is here explored with single-shot fMRI studies on the olfactory bulbs of male and female mice performed at 15.2T. SPEN images collected on these organs at a 108 µm in-plane resolution yielded remarkably large and well-defined responses to olfactory cues. Under suitable T2* weightings these activation-driven changes exceeded 5% of the overall signal intensity, becoming clearly visible in the images without statistical treatment. The nature of the SPEN signal intensity changes in such experiments was unambiguously linked to olfaction, via single-nostril experiments. These experiments highlighted specific activation regions in the external plexiform region and in glomeruli in the lateral part of the bulb, when stimulated by aversive or appetitive odors, respectively. These strong signal activations were non-linear with concentration, and shed light on how chemosensory signals reaching the olfactory epithelium react in response to different cues. Second-level analyses highlighted clear differences among the appetitive, aversive and neutral odor maps; no such differences were evident upon comparing male against female olfactory activation regions.

Sex-dependent control of pheromones on social organization within groups of wild house mice.

Dominance hierarchy is a fundamental social phenomenon in a wide range of mammalian species, critically affecting fitness and health. Here, we investigate the role of pheromone signals in the control of social hierarchies and individual personalities within groups of wild mice. For this purpose, we combine high-throughput behavioral phenotyping with computational tools in freely interacting groups of wild house mice, males and females, in an automated, semi-natural system. We show that wild mice form dominance hierarchies in both sexes but use sex-specific strategies, displaying distinct male-typical and female-typical behavioral personalities that were also associated with social ranking. Genetic disabling of VNO-mediated pheromone detection generated opposite behavioral effects within groups, enhancing social interactions in males and reducing them in females. Behavioral personalities in the mutated mice displayed mixtures of male-typical and female-typical behaviors, thus blurring sex differences. In addition, rank-associated personalities were abolished despite the fact that both sexes of mutant mice formed stable hierarchies. These findings suggest that group organization is governed by pheromone-mediated sex-specific neural circuits and pave the way to investigate the mechanisms underlying sexual dimorphism in dominance hierarchies under naturalistic settings.

Endovascular thrombectomy is beneficial for functional nonagenarians - a multicenter cohort analysis.

INTRODUCTION: The use of endovascular thrombectomy (EVT) has dramatically increased in recent years. However, most existing studies used an upper age limit of 80 and data regarding the safety and efficacy of EVT among nonagenarians is still lacking. METHODS: 767 consecutive patients undergoing EVT for large vessel occlusion (LVO) in three participating centers were recruited into a prospective ongoing database. Demographic, clinical and imaging characteristics were documented. Statistical analysis was done to evaluate EVT outcome among nonagenarians compared to younger patients. RESULTS: The current analysis included 41 (5.4%) patients older than 90 years. Compared to younger patients, nonagenarians were more often female (78% versus 50.3%, p ≤ 0.001), had worse baseline mRS scores (2 [0-3] versus 0 [0-2], p < 0.001), higher rates of hypertension and hyperlipidemia and a higher admission NIHSS (20 [14-23] versus 16 [11-20], p < 0.001). No differences were found between groups regarding the involved vessel, stroke etiology, time from symptoms to door or symptoms to EVT, successful recanalization rates and hemorrhagic transformation rates. Nonagenarians had worse mRS at 90 days (5 [3-6] versus 3 [2-5], p = 0.001), similar discharge NIHSS (5 [1-11] versus 4 [1-11], p = 0.78) and higher mortality rates (36.6% versus 15.8%, p < 0.001). All nonagenarians with baseline mRS 4 have died within 90 days. 36.4% of nonagenarian patients with baseline MRS of 3 or less had favorable outcome. DISCUSSION: This study demonstrates that nonagenarian stroke patients with baseline mRS of 3 or less benefit from EVT with no significant difference in the rate of favorable outcome compared to octogenarians.

Safety and Efficacy of Intravenous Alteplase before Endovascular Thrombectomy: A Pooled Analysis with Focus on the Elderly.

Current guidelines advocate intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) for all patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). We evaluated outcomes with and without IVT pretreatment. Our institutional protocols allow AIS patients presenting early (<4 h from onset or last seen normal) who have an Alberta Stroke Program Early CT Score (ASPECTS) ≥6 to undergo EVT without IVT pretreatment if the endovascular team is in the hospital (direct EVT). Rates of recanalization and hemorrhagic transformation (HT) and neurological outcomes were retrospectively compared in consecutive patients undergoing IVT+EVT vs. direct EVT with subanalyses in those ≥80 years and ≥85 years. In the overall cohort (IVT+EVT = 147, direct EVT = 162), and in subsets of patients ≥80 years (IVT+EVT = 51, direct EVT = 50) and ≥85 years (IVT+EVT = 19, direct EVT = 32), the IVT+EVT cohort and the direct EVT group had similar baseline characteristics, underwent EVT after a comparable interval from symptom onset, and reached similar rates of target vessel recanalization. No differences were observed in the HT frequency, or in disability at discharge or after 90 days. Patients receiving direct EVT underwent more stenting of the carotid artery due to stenosis during the EVT procedure (22% vs. 6%, p = 0.001). Direct EVT and IVT+EVT had comparable neurological outcomes in the overall cohort and in the subgroups of patients ≥80 and ≥85 years, suggesting that direct EVT should be considered in patients with an elevated risk for HT.

Use of Intraoperative Neuronavigation to Identify Transdural Collaterals in Moyamoya Vasculopathy: A Simple Way to Make It Safer.

INTRODUCTION: Transdural collaterals (TC) from the external carotid artery must be preserved when operating on patients with moyamoya vasculopathy. Several techniques have been used to identify the superficial temporal artery (STA) and middle meningeal artery (MMA) during surgery and prevent their damage. However, the use of neuronavigation for this specific purpose has never been described in the literature. We describe an operative case in which neuronavigation was used to preserve the TC (originating from the MMA), detailing our technique step by step and reviewing alternative methods previously reported. CASE PRESENTATION: A 6-year-old girl with moyamoya disease, who had developed marked bilateral TC from the MMA sparing the middle cerebral artery territory, underwent staged bilateral indirect revascularization surgery. Intraoperative neuronavigation was used to identify the STA and MMA with their main branches during skin incision, craniotomy, and dural opening. The neuronavigation matched the intraoperative findings exactly, and the target structures remained undamaged. The patient was discharged home after both surgeries with no neurological deficits. One year following surgery, the patient has excellent collateralization from both STAs and is asymptomatic and neurologically intact. CONCLUSION: With the use of intraoperative neuronavigation, the STA, MMA, and their main branches, as well as their relationship to the bone, can be identified and preserved. This approach can help in preventing undesirable injury to TC during surgery and may potentially prevent perioperative stroke in patients with moyamoya vasculopathy undergoing revascularization surgery.

Alone, in the dark: The extraordinary neuroethology of the solitary blind mole rat.

On the social scale, the blind mole rat (BMR; Spalax ehrenbergi) is an extreme. It is exceedingly solitary, territorial, and aggressive. BMRs reside underground, in self-excavated tunnels that they rarely leave. They possess specialized sensory systems for social communication and navigation, which allow them to cope with the harsh environmental conditions underground. This review aims to present the blind mole rat as an ideal, novel neuroethological model for studying aggressive and solitary behaviors. We discuss the BMR's unique behavioral phenotype, particularly in the context of 'anti-social' behaviors, and review the available literature regarding its specialized sensory adaptations to the social and physical habitat. To date, the neurobiology of the blind mole rat remains mostly unknown and holds a promising avenue for scientific discovery. Unraveling the neural basis of the BMR's behavior, in comparison to that of social rodents, can shed important light on the underlying mechanisms of psychiatric disorders in humans, in which similar behaviors are displayed.

Skin exposure to UVB light induces a skin-brain-gonad axis and sexual behavior.

Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions.

Do all mice smell the same? Chemosensory cues from inbred and wild mouse strains elicit stereotypic sensory representations in the accessory olfactory bulb.

BACKGROUND: For many animals, chemosensory cues are vital for social and defensive interactions and are primarily detected and processed by the vomeronasal system (VNS). These cues are often inherently associated with ethological meaning, leading to stereotyped behaviors. Thus, one would expect consistent representation of these stimuli across different individuals. However, individuals may express different arrays of vomeronasal sensory receptors and may vary in the pattern of connections between those receptors and projection neurons in the accessory olfactory bulb (AOB). In the first part of this study, we address the ability of individuals to form consistent representations despite these potential sources of variability. The second part of our study is motivated by the fact that the majority of research on VNS physiology involves the use of stimuli derived from inbred animals. Yet, it is unclear whether neuronal representations of inbred-derived stimuli are similar to those of more ethologically relevant wild-derived stimuli. RESULTS: First, we compared sensory representations to inbred, wild-derived, and wild urine stimuli in the AOBs of males from two distinct inbred strains, using them as proxies for individuals. We found a remarkable similarity in stimulus representations across the two strains. Next, we compared AOB neuronal responses to inbred, wild-derived, and wild stimuli, again using male inbred mice as subjects. Employing various measures of neuronal activity, we show that wild-derived and wild stimuli elicit responses that are broadly similar to those from inbred stimuli: they are not considerably stronger or weaker, they show similar levels of sexual dimorphism, and when examining population-level activity, cluster with inbred mouse stimuli. CONCLUSIONS: Despite strain-specific differences and apparently random connectivity, the AOB can maintain stereotypic sensory representations for broad stimulus categories, providing a substrate for common stereotypical behaviors. In addition, despite many generations of inbreeding, AOB representations capture the key ethological features (i.e., species and sex) of wild-derived and wild counterparts. Beyond these broad similarities, representations of stimuli from wild mice are nevertheless distinct from those elicited by inbred mouse stimuli, suggesting that laboratory inbreeding has indeed resulted in marked modifications of urinary secretions.

The social network: Neural control of sex differences in reproductive behaviors, motivation, and response to social isolation.

Social animal species present a vast repertoire of social interactions when encountering conspecifics. Reproduction-related behaviors, such as mating, parental care, and aggression, are some of the most rewarding types of social interactions and are also the most sexually dimorphic ones. This review focuses on rodent species and summarizes recent advances in neuroscience research that link sexually dimorphic reproductive behaviors to sexual dimorphism in their underlying neuronal circuits. Specifically, we present a few possible mechanisms governing sexually-dimorphic behaviors, by hypothalamic and reward-related brain regions. Sex differences in the neural response to social isolation in adulthood are also discussed, as well as future directions for comparative studies with naturally solitary species.

The Role of 3D Reconstruction of the Skull in Patients with Suspected Shunt Malfunction.

BACKGROUND: Mechanical shunt malfunction may lead to significant morbidity and mortality. Shunt series assessments help evaluate shunt integrity; however, they are of limited value in the area of the skull due to skull curvature, thickness, and air sinuses. We describe the role of 3D bone reconstruction CT (3DCT) in demonstrating the shunt integrity over the skull, comparing this technique to skull X-rays (SXR). METHODS: Data were collected retrospectively for shunted patients with concurrent SXR and 3DCT and for patients presenting with shunt failures at the region of the skull, including clinical course and radiological findings. We compared the SXR and 3DCT findings. The 3DCT was reconstructed from standard diagnostic CT protocols performed during evaluation of suspected shunt malfunction and not thin-slice CT protocols. RESULTS: Forty-eight patients with 57 shunts underwent SXR and 3DCT. Interobserver agreement was high for most variables. Both SXR and 3DCT had a high sensitivity, specificity, and accuracy identifying tubing disconnections (between 0.83 and 1). Full valve type and setting were significantly more accurate based on SXR versus 3DCT (>90 vs. <20%), and valve integrity was significantly more readily verified on 3DCT versus SXR (100 vs. 52%). CONCLUSIONS: 3DCT and SXR complement each other in diagnosing mechanical shunt malfunctions over the skull. The main limitation of 3DCT is identification of valve type and settings, which are clearer on SXR, while the main limitation of SXR is a less ability to evaluate valve integrity. 3DCT also enables an intuitive 3D understanding of the shunt tubing over the skull.

The Nasopalatine Ducts Are Required for Proper Pheromone Signaling in Mice.

The vomeronasal organ (VNO) specializes in detection of chemosignals, mainly pheromones, which control social communication and reproduction in many mammals. These pheromones must solubilize with nasal fluids before entering the VNO, and it was suggested that they are delivered to and cleared from the VNO by active pumping. Yet, the details of this pheromone delivery process are unclear. In this study, we first constructed a high-resolution 3D morphological image of the whole adult mouse snout, by using ultra-high-resolution micro-CT. We identified a net of micro tunnels starting from the nostrils and extending around and through the VNO. These micro tunnels connect the nasal cavity with the VNO and the oral cavity via the nasopalatine ducts (NPD). Other micro tunnels connect the nasal cavity to the main olfactory epithelium. We next demonstrated that physical obstruction of the NPD severely impairs the clearance of dissolved compounds from the VNO lumen. Moreover, we found that mice with blocked NPD display alterations in chemosignaling-evoked neuronal activation in brain regions associated with the vomeronasal system. Finally, NPD-blocked male mice exhibit reduced preference for female chemosignals, and impaired social interaction behavior. Taken together, our findings indicate that the NPD in mice are connected to both the nasal and oral cavity, serving an essential role in regulating the flow of soluble chemosignals through the VNO, and are required for proper pheromone-mediated social communication.

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program.

Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer's and Parkinson's disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.

Social Minds Sync Alike.

In this issue of Cell, Zhang and Yatsev, 2019 and Kingsbury et al. (2019) provide insight into the emergence of synchronized neuronal activity between prefrontal cortices of two brains that share the same social context via electrophysiology recordings in bats and calcium-imaging in mice.