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Puberty is a sensitive developmental period during which stressors can cause lasting brain and behavioural deficits. While the acute effects of pubertal lipopolysaccharide (LPS) and antimicrobial (AMNS) treatments are known, their enduring impacts on neurodegeneration-related mechanisms and behaviours remain unclear. This study examined these effects in male and female mice. At five weeks old, mice received 200ul of either broad-spectrum antimicrobials or water through oral gavage twice daily for seven days. At six weeks of age, they received an intraperitoneal injection of either saline or LPS. Four weeks later, adult mice underwent neurodegeneration-related behavioural tests, including the rotarod, forepaw stride length, reversed grid hang, open field, and buried pellet tests. Two days after the final test, brain and ileal samples were collected. Results showed that female mice treated with both AMNS and LPS exhibited deficits in neuromuscular strength, while males treated with LPS alone showed increased anxiety-like behaviours. Males treated with AMNS alone had decreased sigma-1 receptor (S1R) expression in the cornu ammonis 1 (CA1) and dentate gyrus (DG), while females treated with both AMNS and LPS had decreased S1R expression. Additionally, males treated with either LPS or AMNS had lower glial-derived neurotrophic factor receptor alpha-1 (GFRA1) expression in the primary motor cortex (M1) than females. Mice treated with LPS alone had decreased GFRA1 expression in the DG and decreased S1R expression in the secondary motor cortex (M2). These findings suggest that pubertal AMNS and LPS treatments may lead to enduring changes in biomarkers and behaviours related to neurodegeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Identifying patients with acute brain injury among patients who present to the Emergency Department (ED) with severe hypertension can be challenging. We explored rates of brain injury in a cohort of ED patients with severe hypertension in whom acute target-organ damage was or was not initially suspected., Methods: We conducted a retrospective chart-review study at two different hospitals within the same urban health system. Consecutive adult patients seen from 10/1/2020 to 5/1/2022 with a systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥120 mmHg were included., Results: A total of 972 patients met our eligibility criteria. The average age was 59 years (SD: 16.5), 454 (46.7%) were women, and 582 (59.9%) were non-White. A total of 186/972 (19.1%) patients were initially thought to have acute target-organ damage in the ED with 97/186 (52.2%) diagnosed with stroke or TIA. The remaining 786/972 (80.9%) patients were not initially diagnosed with target-organ damage (hypertensive urgency [HU]). Of the 786 patients with HU, a head CT was obtained in 216/786 (27.7%) and brain MRI in 74/786 (9.4%). Of the HU patients with a brain MRI, 23/74 (31.1%) had acute abnormalities; most abnormalities on brain MRI (17/23 [73.9%]) were not seen on preceding head CT., Conclusions: In a multicenter study of ED patients, nearly 1 in 5 patients though to have HU who eventually underwent brain MRI had unexpected acute neurological findings, though brain MR was obtained in only 9%., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Purpose: Our study aimed to investigate the factors associated with the acceptance of virtual reality (VR) games among older adults living in LTC, with a particular emphasis on identifying social and individual factors that have been overlooked in existing technology acceptance models., Materials and Methods: We conducted VR gaming sessions, followed by a composite questionnaire to explore the factors associated with the acceptance of VR games among residents of LTC with a focus on technology acceptance models (TAM) and social factors derived from Selective Optimization with Compensation (SOC) theory and Socioemotional Selectivity Theory (SST)., Results: We studied 20 older adults aged 65 and older. Participants were moderately sedentary, with the majority of them having prior gaming experience. Participants with prior gaming experience had higher mean scores in most SOC theory and SST subscales, except for elective selection. Participants perceived the technology as useful and easy to use, with no heightened gaming-related anxiety. Significant correlations were found between perceived ease of use and selection strategies, and between attitudes towards gaming and elective selection strategies. No significant score differences were observed between male and female participants., Conclusions: The positive correlation between VR acceptance and using SOC strategies suggests a positive response to straightforward experiences. Our study highlights VR exergaming's potential benefits for encouraging LTC residents' engagement in valued activities and pursuing goals. Moreover, social theories of aging can inform technology acceptance and guide the design and marketing of VR exergames to better suit older adults' needs and preferences in LTC.IMPLICATIONS FOR REHABILITATIONThe findings of this study have important implications for rehabilitation programs aimed at enhancing physical activity (PA) and engagement among older adults living in long-term care (LTC) facilities. The use of virtual reality (VR) games can be an important tool to promote PA and improve the overall well-being of LTC residents. Based on the results, the following implications can be drawn:Integrating VR exergaming in rehabilitation:The positive perception of VR technology's usefulness and ease of use among older adults in LTC suggests that VR exergaming can be effectively integrated into rehabilitation programs. Healthcare professionals and rehabilitation specialists in LTC facilities can consider incorporating VR-based exercise routines and gaming sessions to motivate and engage residents in physical activities. By doing so, they can create enjoyable and interactive rehabilitation experiences that may lead to improved adherence to exercise regimens.Addressing social factors for VR acceptance:Our study highlights the significance of social factors derived from theories of aging, such as Selective Optimization with Compensation (SOC) and Socioemotional Selectivity Theory (SST), in influencing VR acceptance among LTC residents. Rehabilitation programs should take into account these social aspects and create a supportive and encouraging environment for older adults to engage with VR exergames. Encouraging social interactions and providing opportunities for residents to share their experiences with VR gaming may enhance acceptance and overall engagement.Tailoring VR exergames for older adults:The correlation between VR acceptance and the use of SOC strategies indicates that customized experiences may be well-received by LTC residents. Game developers and rehabilitation specialists should consider designing VR exergames that align with the specific preferences and needs of older adults. This could involve providing choices and options for users to optimize their gaming experiences based on their individual abilities and interests.Recognizing gaming experience:Our study highlights that prior gaming experience positively influenced participants' attitudes towards VR gaming. Rehabilitation professionals should acknowledge and leverage this prior experience when introducing VR exergaming to older adults in LTC. By incorporating elements familiar to older adults or providing guidance for those new to gaming, rehabilitation programs can foster a more seamless and enjoyable transition to VR exergames.Promoting goal pursuit and valued activities:Our study suggests that VR exergaming has the potential to encourage LTC residents' engagement in valued activities and goal pursuit. Rehabilitation programs can utilize VR exergaming as a means to help residents achieve specific rehabilitation goals and engage in activities that are meaningful to them. This approach can contribute to a sense of purpose and satisfaction in the rehabilitation process.Overall, the integration of VR exergaming in rehabilitation for older adults in LTC facilities has promising implications for improving physical activity levels, enhancing engagement, and addressing the holistic well-being of residents. By considering the social factors influencing VR acceptance and tailoring experiences to individual preferences, rehabilitation professionals can optimize the potential benefits of VR technology in LTC settings.

Naked mole-rats, Heterocephalus glaber, are champion hypoxia-tolerant rodents that live under low oxygen conditions in their subterranean burrows. Detrimental effects of low oxygen can be mitigated through metabolic rate depression (MRD), metabolic reorganization, and global downregulation of nonessential cellular processes. Recent research has progressively implicated epigenetic modifications - rapid, reversible changes to gene expression that do not alter the DNA sequence itself - as major players in implementing and maintaining MRD. N 6 -adenosine (m 6 A) methylation is the most prevalent mammalian RNA modification and is responsible for pre-mRNA processing and mRNA export from the nucleus. Hence, m 6 A -mediated conformational changes alter the cellular fate of transcripts. The present study investigated the role of m 6 A RNA methylation responses to 24 h of hypoxia exposure in H. glaber cardiac tissue. Total protein levels of m 6 A writers/readers/erasers, m 6 A demethylase activity, and total m 6 A quantification were measured under normoxic vs. hypoxic conditions in H. glaber heart. While there was no change in either demethylase activity or total m 6 A content, many proteins of the m 6 A pathway were downregulated during hypoxia. Overall, m 6 A may not be a signature hypoxia-responsive characteristic in H. glaber heart, but downregulation of the protein machinery involved in m 6 A cycling points to an alternate biological involvement. Further research will explore other forms of RNA modifications and other epigenetic mechanisms to determine the controls on hypoxia endurance in this subterranean mammal., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cardiac point-of-care ultrasound (cPOCUS) can aid in the diagnosis and treatment of cardiac disorders. Such disorders can arise as complications of acute brain injury, but most neurologic intensive care unit (NICU) providers do not receive formal training in cPOCUS. Caption artificial intelligence (AI) uses a novel deep learning (DL) algorithm to guide novice cPOCUS users in obtaining diagnostic-quality cardiac images. The primary objective of this study was to determine how often NICU providers with minimal cPOCUS experience capture quality images using DL-guided cPOCUS as well as the association between DL-guided cPOCUS and change in management and time to formal echocardiograms in the NICU., Methods: From September 2020 to November 2021, neurology-trained physician assistants, residents, and fellows used DL software to perform clinically indicated cPOCUS scans in an academic tertiary NICU. Certified echocardiographers evaluated each scan independently to assess the quality of images and global interpretability of left ventricular function, right ventricular function, inferior vena cava size, and presence of pericardial effusion. Descriptive statistics with exact confidence intervals were used to calculate proportions of obtained images that were of adequate quality and that changed management. Time to first adequate cardiac images (either cPOCUS or formal echocardiography) was compared using a similar population from 2018., Results: In 153 patients, 184 scans were performed for a total of 943 image views. Three certified echocardiographers deemed 63.4% of scans as interpretable for a qualitative assessment of left ventricular size and function, 52.6% of scans as interpretable for right ventricular size and function, 34.8% of scans as interpretable for inferior vena cava size and variability, and 47.2% of scans as interpretable for the presence of pericardial effusion. Thirty-seven percent of screening scans changed management, most commonly adjusting fluid goals (81.2%). Time to first adequate cardiac images decreased significantly from 3.1 to 1.7 days (p < 0.001)., Conclusions: With DL guidance, neurology providers with minimal to no cPOCUS training were often able to obtain diagnostic-quality cardiac images, which informed management changes and significantly decreased time to cardiac imaging., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Purpose: This scoping review aims to identify evidence on older adults' acceptance of PA VR games in LTC facilities, describe research designs used, define key acceptance concepts, and identify knowledge gaps for future research., Materials and Methods: Following Arksey and O'Malley's framework, data from published and unpublished articles (Jan 2000-May 2023) were collected. Twelve databases and additional sources were searched for studies on LTC residents (≥65 years), PA video games (including VR and console games), acceptance, and attitudes. Data extraction included article details, design, population, intervention, outcomes, and limitations., Results: Five studies met inclusion criteria from 1628 initial titles. They assessed acceptance of PA VR games among older adults in LTC facilities, showing varying levels of acceptance. Most studies used analytical designs, including RCTs. Key concepts of VR acceptance were poorly defined, with only one study using a validated TAM questionnaire. Knowledge gaps highlight the need for further research to understand PA VR acceptance among older adults in LTC facilities., Conclusion: Validated acceptance questionnaires are needed in study of VR acceptance by older adults. Use of qualitative and quantitative methods can enhance understanding of technology acceptance, alongside exploration of individual, environmental, and age-related factors. Detailed reporting of VR interventions is recommended to comprehend acceptance factors.

The prevalence of depression significantly increases during puberty and adolescence. Puberty is the period during which sexual maturity is attained, while adolescence persists beyond puberty and includes physiological, social, emotional, and cognitive maturation. A stressor that has been shown previously to induce depression is chronic sleep disruption. Probiotics can prevent stress-induced depression. However, it was unclear whether probiotics could prevent depression following chronic sleep disruption and what mechanism may be involved. Therefore, we investigated whether pubertal probiotic treatment could prevent depression-like behavior in mice following chronic sleep disruption. We also examined whether probiotic treatment could improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in chronically sleep-disrupted mice. We hypothesized that probiotic treatment would prevent depression-like behavior, improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in sleep-disrupted mice. Male and female mice (N=120) received cannula and electroencephalogram (EEG) electrode implants at postnatal day (PND) 26. Mice received Lacidofil® or Cerebiome® probiotics (PND 33-51) and were sleep-disrupted for the first 4 hours of the light phase (sleep period) (PND 40-51). Hippocampal L-lactate and glucose concentrations and sleep were measured over a 24-h period (PND 48-49). Depression-like behaviour was evaluated using tail suspension (PND 49) and forced swim tests (PND 50). Chronic sleep disruption increased depression-like behaviour and NREM duration in the dark phase, and reduced all metabolites and neuromodulating biomolecules measured within the brain. However, mice treated with probiotics did not display depression-like behaviour or decreased hippocampal L-lactate following chronic sleep disruption. Cerebiome prevented decreases to prefrontal serotonin and hippocampal glucose concentrations, while Lacidofil increased NREM duration in the latter half of the light phase. The current study not only replicates previous findings linking chronic sleep disruption to depression, but also demonstrates that pubertal probiotic treatment can mitigate the effects of chronic sleep disruption on depression-like behaviour and on the neural mechanisms underlying depression in a strain-dependent manner., Competing Interests: Declaration of Competing Interest We have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Early diagnosis of previously unknown cancer (i.e., occult cancer) after an acute ischemic stroke (AIS) could result in faster initiation of cancer therapy and potentially improve clinical outcomes. Our study aimed to compare mortality rates between AIS patients with occult cancer diagnosed during the index stroke hospitalization versus those diagnosed after hospital discharge., Methods: Among consecutive AIS patients treated at our stroke center from 2015 through 2020, we identified new cancer diagnoses made within the year after the AIS. We used multivariable Cox regression analyses to evaluate the association between the timing of occult cancer diagnosis (during the AIS hospitalization versus after discharge) and long-term survival., Results: Of 3894 AIS patients with available long-term follow-up data, 59 (1.5 %) were diagnosed with a new cancer within one year after index stroke. Of these, 27 (46 %) were diagnosed during the index hospitalization and 32 (54 %) were diagnosed after discharge. During a median follow-up of 406 days (interquartile range, 89-1073), 70 % (n = 19) of patients whose cancer was diagnosed during hospitalization had died, compared to 63 % (n = 20) of patients whose cancer was diagnosed after discharge (p= 0.58). In our main multivariable model, there was no difference in long-term mortality between patient groups (adjusted hazard ratio, 1.16; 95 % confidence interval, 0.53-2.52; p= 0.71)., Conclusions: In this analysis, timing of a new cancer diagnosis after AIS did not seem to influence patients' long-term survival. Given the fairly small number of included patients with previously occult cancer, larger multicenter studies are needed to confirm our results., Competing Interests: Declaration of competing interest Morin Beyeler reports research support from the “Kurt und Senta Hermann-Stiftung”, the Department of Neurology, Inselspital, Bern University Hospital and the University of Bern, Switzerland. None of the other authors report any conflicts of interest in relation with this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

There is evidence that tumor necrosis factor alpha (TNFα) influences autonomic processes coordinated within the hypothalamic paraventricular nucleus (PVN), however, the signaling mechanisms subserving TNFα's actions in this brain area are unclear. In non-neuronal cell types, TNFα has been shown to play an important role in canonical NADPH oxidase (NOX2)-mediated production of reactive oxygen species (ROS), molecules also known to be critically involved in hypertension. However, little is known about the role of TNFα in NOX2-dependent ROS production in the PVN within the context of hypertension. Using dual labeling immunoelectron microscopy and dihydroethidium (DHE) microfluorography, we provide structural and functional evidence for interactions between TNFα and NOX2 in the PVN. The TNFα type 1 receptor (TNFR1), the major mediator of TNFα signaling in the PVN, was commonly co-localized with the catalytic gp91 phox subunit of NOX2 in postsynaptic sites of PVN neurons. Additionally, there was an increase in dual labeled dendritic profiles following fourteen-day slow-pressor angiotensin II (AngII) infusion. Using DHE microfluorography, it was also shown that TNFα application resulted in a NOX2-dependent increase in ROS in isolated PVN neurons projecting to the spinal cord. Further, TNFα-mediated ROS production was heightened after AngII infusion. The finding that TNFR1 and gp91 phox are positioned for rapid interactions, particularly in PVN-spinal cord projection neurons, provides a molecular substrate by which inflammatory signaling and oxidative stress may jointly contribute to AngII hypertension., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Objectives: Cardiovascular magnetic resonance imaging (CMRI) is the noninvasive technique of choice for early detection of cardiac involvement in Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), but is seldom used in routine clinical practice in the Indian context. We sought to determine the prevalence of CMRI abnormalities in patients with DMD and BMD and to compare the CMRI parameters with the phenotypic and genotypic characteristics., Methods: A prospective, observational study was conducted on patients genetically diagnosed with DMD and BMD who could complete CMRI between March 2020 and March 2022. Abnormal CMRI was the presence of any late gadolinium enhancement (LGE) that signifies myocardial fibrosis (LGE positivity), regional wall motion abnormality, or reduced left ventricular ejection fraction (LVEF <55%)., Results: A total of 46 patients were included: 38 patients with DMD and eight with BMD. Cardiac abnormality was seen in 23 (50%) patients. LGE was more common than impaired LVEF in DMD (16, 42.1%), while impaired LVEF was more common in BMD (5, 62.5%). LGE was most frequently found in lateral wall (18/19) followed by inferior (6/19), septal (5/19), anterior (2/19), and apex (1/19). Among the various clinicodemographic parameters, only age (r = 0.495, P = 0.002) and disease duration (r = 0.407, P = 0.011) were found to significantly correlate with LGE in patients with DMD. No association was found between the various CMRI parameters and the genotype., Conclusions: The current study highlights the differences in myocardial fibrosis and LV dysfunction between DMD and BMD, along with other CMRI parameters. Notably, a genotype-CMRI correlation was not found in the current cohort, which needs to be further explored., (Copyright © 2024 Copyright: © 2024 Annals of Indian Academy of Neurology.)

Background: Cancer is associated with an increased risk of atrial fibrillation. Whether cancer is also associated with atrial cardiopathy, another atrial pathology associated with heightened ischemic stroke risk, is uncertain., Methods: We conducted a retrospective cross-sectional study among consecutive patients hospitalized with acute ischemic stroke at a quaternary care center in New York, United States from 2011 through 2016. The study exposure was active cancer. The study outcome was atrial cardiopathy, defined as a left atrial volume index ≥35 mL/m 2 on echocardiography. We used multivariable logistic regression, adjusting for baseline characteristics, to evaluate the relationship between cancer (active or historical) and atrial cardiopathy. We performed a subgroup analysis among patients with embolic stroke of undetermined source (ESUS)., Results: The final cohort included 1104 patients with acute ischemic stroke, of whom 10% had active cancer and 47% had atrial cardiopathy. Patients with atrial cardiopathy, compared to those without, were older (median age, 77 versus 68 years), and more frequently had hypertension, coronary disease, and atrial fibrillation. Active cancer was present in 9.6% of patients with atrial cardiopathy (n=50/520) and 10.4% of patients without (n=61/584). There was no association between active cancer and atrial cardiopathy among the overall ischemic stroke cohort (adjusted odds ratio [OR], 0.91; 95% confidence interval [CI], 0.60-1.37) nor in patients with ESUS (aOR, 0.64; 95% CI, 0.30-1.36). When the cancer exposure was broadened to include any history of cancer (n=236, 21.4%), there still was no significant association with atrial cardiopathy (aOR, 0.93; 95% CI, 0.68-1.25)., Conclusions: When defining atrial cardiopathy by left atrial volume, we did not find an association between cancer and atrial cardiopathy in patients with ischemic stroke, including among those with ESUS. Future studies, evaluating other atrial cardiopathy biomarkers and settings, are needed to further investigate any potential link between cancer and atrial cardiopathy., Competing Interests: Declaration of competing interest Dr. Beyeler has received research support from the University of Bern, Switzerland. Dr. Navi has received personal fees for serving on an adjudication committee for MindRhythm Inc. Dr. Kamel reports serving as a PI for the ARCADIA trial (NIH/NINDS U01NS095869), which received in-kind study drug from the BMS-Pfizer Alliance for Eliquis® and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, U01NS106513); serving as Deputy Editor for JAMA Neurology; serving on clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; serving on endpoint adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: Duchenne muscular dystrophy (DMD) is a rare disease that causes progressive muscle degeneration resulting in life-threatening cardiac complications. The objective of this systematic literature review was to describe and grade the published evidence of predictors of cardiac disease in DMD., Methods: The review encompassed searches of Embase, MEDLINE ALL, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of cardiac disease in DMD. The certainty of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework., Results: We included 33 publications encompassing 9,232 patients with DMD. We found moderate- to high-quality evidence that cardiac medication (i.e., ACE inhibitors [enalapril and perindopril], β-blockers [carvedilol], and mineralocorticoid receptor antagonists [eplerenone]) are significantly associated with preserved left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular circumferential strain (LVCS). DMD mutations in exons 51 and 52 were found to be significantly associated with lower risk of cardiomyopathy; deletions treatable by exon 53 skipping and mutations in the Dp116 coding region with improved LVEF and prolonged cardiac dysfunction-free survival; and exons 45-50 and 52 with early left ventricular systolic dysfunction (low/very low-quality evidence). We found high-quality evidence that glucocorticoids (deflazacort) are significantly associated with preserved LVEF and improved fractional shortening (FS), and low-quality evidence that glucocorticoids (deflazacort, prednisone, and/or prednisolone) are associated with improved ejection fraction (EF) and lower risk of cardiomyopathy, ventricular dysfunction, and heart failure-related mortality. Full-time mechanical ventilation was found to be significantly correlated with LVEF (low-quality evidence), muscle strength with FS (low-quality evidence), and genetic modifiers (i.e., LTBP4 rs10880 and ACTN3) with LVEF, lower risk of cardiomyopathy and left ventricular dilation (low-quality evidence)., Conclusion: Several sources of cardiac disease heterogeneity are well-studied in patients with DMD. Yet, the certainty of evidence is generally low, and little is known of the contribution of non-pharmacological interventions, as well as the impact of different criteria for initiation of specific treatments. Our findings help raise awareness of prevailing unmet needs, shape expectations of treatment outcomes, and inform the design of future research., (© 2024. The Author(s).)

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in sepsis-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammation. In the acute phase, we identified novel molecular (e.g., upregulation of plasmalemma vesicle-associated protein, PLVAP, a driver of endothelial permeability, and the procoagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small-molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small-molecule BBB permeability, elevated levels of PAI-1, intra-/perivascular fibrin/fibrinogen deposition, and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor, suggesting diffuse axonal injury, synapse degeneration, and impaired neurotrophism. Our study serves as a standardized mouse model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Ávila-Gómez et al.)

Excitatory glutamatergic NMDA receptors (NMDARs) are key regulators of spinal pain processing, and yet the biophysical properties of NMDARs in dorsal horn nociceptive neurons remain poorly understood. Despite the clinical implications, it is unknown whether the molecular and functional properties of synaptic NMDAR responses are conserved between males and females or translate from rodents to humans. To address these translational gaps, we systematically compared individual and averaged excitatory synaptic responses from lamina I pain-processing neurons of adult Sprague-Dawley rats and human organ donors, including both sexes. By combining patch-clamp recordings of outward miniature excitatory postsynaptic currents with non-biased data analyses, we uncovered a wide range of decay constants of excitatory synaptic events within individual lamina I neurons. Decay constants of synaptic responses were distributed in a continuum from 1-20 ms to greater than 1000 ms, suggesting that individual lamina I neurons contain AMPA receptor (AMPAR)-only as well as GluN2A-, GluN2B- and GluN2D-NMDAR-dominated synaptic events. This intraneuronal heterogeneity in AMPAR- and NMDAR-mediated decay kinetics was observed across sex and species. However, we discovered an increased relative contribution of GluN2A-dominated NMDAR responses at human lamina I synapses compared with rodent synapses, suggesting a species difference relevant to NMDAR subunit-targeting therapeutic approaches. The conserved heterogeneity in decay rates of excitatory synaptic events within individual lamina I pain-processing neurons may enable synapse-specific forms of plasticity and sensory integration within dorsal horn nociceptive networks. KEY POINTS: Synaptic NMDA receptors (NMDARs) in spinal dorsal horn nociceptive neurons are key regulators of pain processing, but it is unknown whether their functional properties are conserved between males and females or translate from rodents to humans. In this study, we compared individual excitatory synaptic responses from lamina I pain-processing neurons of male and female adult Sprague-Dawley rats and human organ donors. Individual lamina I neurons from male and female rats and humans contain AMPA receptor-only as well as GluN2A, GluN2B- and GluN2D-NMDAR-dominated synaptic events. This may enable synapse-specific forms of plasticity and sensory integration within dorsal horn nociceptive networks. Human lamina I synapses have an increased relative contribution of GluN2A-dominated NMDAR responses compared with rodent synapses. These results uncover a species difference relevant to NMDAR subunit-targeting therapeutic approaches., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Case reports describe arterial thrombosis including ischemic stroke associated with severe ovarian hyperstimulation syndrome (OHSS), but the prevalence of major ischemic events during or shortly after OHSS is unknown., Methods: Using publicly available administrative datasets in the United States between 2015 and 2020, we conducted two separate cross-sectional studies of patients with OHSS. We included all patients with OHSS. Our study outcome was any hospitalization for acute ischemic stroke, acute myocardial infarction, cerebral venous sinus thrombosis, pulmonary embolism, or acute deep venous thrombosis during the index hospitalization or within 90 days of OHSS diagnosis., Results and Conclusions: We found very few major ischemic events in patients with OHSS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Miller and Dr. Navi have received personal fees for serving as neurology expert witnesses. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Enhancing the interactions between study participants, clinicians, and investigators is imperative for advancing Parkinson's disease (PD) research. The Canadian Open Parkinson Network (C-OPN) stands as a nationwide endeavor, connecting the PD community with ten accredited universities and movement disorders research centers spanning, at the time of this analysis, British Columbia, Alberta, Ontario, and Quebec., Objective: Our aim is to showcase C-OPN as a paradigm for bolstering national collaboration to accelerate PD research and to provide an initial overview of already collected data sets., Methods: The C-OPN database comprises de-identified data concerning demographics, symptoms and signs, treatment approaches, and standardized assessments. Additionally, it collects venous blood-derived biomaterials, such as for analyses of DNA, peripheral blood mononuclear cells (PBMC), and serum. Accessible to researchers, C-OPN resources are available through web-based data management systems for multi-center studies, including REDCap., Results: As of November 2023, the C-OPN had enrolled 1,505 PD participants. The male-to-female ratio was 1.77:1, with 83% (n = 1098) residing in urban areas and 82% (n = 1084) having pursued post-secondary education. The average age at diagnosis was 60.2±10.3 years. Herein, our analysis of the C-OPN PD cohort encompasses environmental factors, motor and non-motor symptoms, disease management, and regional differences among provinces. As of April 2024, 32 research projects have utilized C-OPN resources., Conclusions: C-OPN represents a national platform promoting multidisciplinary and multisite research that focuses on PD to promote innovation, exploration of care models, and collaboration among Canadian scientists.

Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Recent studies have reported significant advances in modeling the biological basis of heterogeneity in major depressive disorder, but investigators have also identified important technical challenges, including scanner-related artifacts, a propensity for multivariate models to overfit, and a need for larger samples with more extensive clinical phenotyping. The goals of the current study were to evaluate dimensional and categorical solutions to parsing heterogeneity in depression that are stable and generalizable in a large, single-site sample., Methods: We used regularized canonical correlation analysis to identify data-driven brain-behavior dimensions that explain individual differences in depression symptom domains in a large, single-site dataset comprising clinical assessments and resting-state functional magnetic resonance imaging data for 328 patients with major depressive disorder and 461 healthy control participants. We examined the stability of clinical loadings and model performance in held-out data. Finally, hierarchical clustering on these dimensions was used to identify categorical depression subtypes., Results: The optimal regularized canonical correlation analysis model yielded 3 robust and generalizable brain-behavior dimensions that explained individual differences in depressed mood and anxiety, anhedonia, and insomnia. Hierarchical clustering identified 4 depression subtypes, each with distinct clinical symptom profiles, abnormal resting-state functional connectivity patterns, and antidepressant responsiveness to repetitive transcranial magnetic stimulation., Conclusions: Our results define dimensional and categorical solutions to parsing neurobiological heterogeneity in major depressive disorder that are stable, generalizable, and capable of predicting treatment outcomes, each with distinct advantages in different contexts. They also provide additional evidence that regularized canonical correlation analysis and hierarchical clustering are effective tools for investigating associations between functional connectivity and clinical symptoms., (Copyright © 2024. Published by Elsevier Inc.)

Exercise training represents a health behavior for the treatment and management of the multi-faceted manifestations of multiple sclerosis (MS). This paper provides a comprehensive overview of evidence from randomized controlled trials (RCTs) regarding benefits, safety, participation, and guidelines for exercise training in MS, based on systematic reviews and meta-analyses. The paper then provides our opinions based on extensive experience regarding challenges for improving and expanding future RCTs that will advance our understanding of exercise training in MS. The comprehensive review of evidence from RCTs indicates that exercise training yields substantial improvements in aerobic and muscle fitness, mobility, fatigue and depression, quality of life, and participation outcomes. There is a non-significant increase in the risk of adverse events or serious adverse events with exercise training compared with control conditions or healthy populations. Rates of adherence and compliance with exercise training (i.e., participation) approximate 80% and 70%, respectively. The current prescriptive guidelines suggest 2-3 days per week of aerobic and resistance exercise training as the minimal dose for safely benefiting from exercise training in MS. We propose 10 important topics as avenues for expanding the body of research and improving its scope for evidence-based practice in MS. Overall, the research on exercise training in MS is strong, but it can get stronger. The expansion and advancement of evidence are critical for moving exercise training into the clinical armamentarium of MS disease treatment and management., (© 2024. The Author(s).)

Ameliorating the deleterious impact of systemic or tissue-level hypoxia or ischemia is key to preventing or treating many human diseases and pathologies. Usefully, environmental hypoxia is also a common challenge in many natural habitats; animals that are native to such hypoxic niches often exhibit strategies that enable them to thrive with limited O 2 availability. Studying how such species have evolved to tolerate systemic hypoxia offers a promising avenue of discovery for novel strategies to mitigate the deleterious effects of hypoxia in human diseases and pathologies. Of particular interest are naked mole-rats, which are among the most hypoxia-tolerant mammals. Naked mole-rats that tolerate severe hypoxia in a laboratory setting are also protected against clinically relevant mimics of heart attack and stroke. The mechanisms that support this tolerance are currently being elucidated but results to date suggest that metabolic rate suppression, reprogramming of metabolic pathways, and mechanisms that defend against deleterious perturbations of cellular signaling pathways all provide layers of protection. Herein, we synthesize and discuss what is known regarding adaptations to hypoxia in the naked mole-rat cardiopulmonary system and brain, as these systems comprise both the primary means of delivering O 2 to tissues and the most hypoxia-sensitive organs in mammals., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Heart failure (HF) is an important comorbidity for patients with ischemic stroke, present in 11 %-18 % of patients, and may also independently increase the risk of first-ever and recurrent ischemic stroke. HF is categorized based on ejection fraction (EF) into HF with reduced (HFrEF), mildly-reduced (HFmrEG) and preserved ejection fraction (HFpEF), with the efficacy of HF therapies differing between the three subcategories. Despite this classification, the incidence, recurrence rates and outcomes of ischemic stroke do not appear to differ significantly between the three subtypes, even when considering the concurrent presence of atrial fibrillation. However, several randomized-controlled clinical trials of anticoagulation defined HF based on reduced EF, inevitably excluding a large proportion of patients with HFpEF. This exclusion is significant considering marked differences between heart failure phenotypes. Such discrepancies raise concerns about the broad applicability of the results of these studies, including those of primary or secondary stroke prevention in HF. Future trials should include both patients with HFrEF and HFpEF to evaluate the safety and efficacy of antiocoagulation therapies in primary and secondary stroke prevention across the spectrum of the EF., (Copyright © 2024 Elsevier B.V. All rights reserved.)

SUMMARYThe human microbiota encompasses the diverse communities of microorganisms that reside in, on, and around various parts of the human body, such as the skin, nasal passages, and gastrointestinal tract. Although research is ongoing, it is well established that the microbiota exert a substantial influence on the body through the production and modification of metabolites and small molecules. Disruptions in the composition of the microbiota-dysbiosis-have also been linked to various negative health outcomes. As humans embark upon longer-duration space missions, it is important to understand how the conditions of space travel impact the microbiota and, consequently, astronaut health. This article will first characterize the main taxa of the human gut microbiota and their associated metabolites, before discussing potential dysbiosis and negative health consequences. It will also detail the microbial changes observed in astronauts during spaceflight, focusing on gut microbiota composition and pathogenic virulence and survival. Analysis will then turn to how astronaut health may be protected from adverse microbial changes via diet, exercise, and antibiotics before concluding with a discussion of the microbiota of spacecraft and microbial culturing methods in space. The implications of this review are critical, particularly with NASA's ongoing implementation of the Moon to Mars Architecture, which will include weeks or months of living in space and new habitats., Competing Interests: The authors declare no conflict of interest.

Theta burst stimulation (TBS) is a promising therapy for treatment-resistant major depressive disorder (MDD), but a significant proportion of individuals do not respond adequately, necessitating alternative approaches. This study explores whether individuals meeting minimum recommended physical activity levels demonstrate better responses to TBS compared to physically inactive individuals. Using data from a randomized controlled trial (n = 43), participants were categorized as physically active or inactive based on baseline International Physical Activity Questionnaire (IPAQ) scores. Depression scores (Hamilton Rating Scale for Depression, 17-item; HRSD-17) were assessed at baseline, 4, and 6 weeks of TBS treatment. A significant Time X Group effect adjusted for age and baseline depression was observed. Physically active individuals consistently exhibited lower depression scores across time points. At 4 and 6 weeks, there was a significant increase in between-group differences, indicating that the physically active group derived greater benefits from treatment. At 6 weeks, a significantly higher proportion of responders (≥50 % HRSD-17 reduction) were observed in the physically active compared to inactive group. Physical activity significantly contributed to regression and logistic models predicting treatment response. These findings support the potential role of baseline physical activity in enhancing TBS therapy for MDD., Competing Interests: Declaration of competing interest The authors declare that there are no financial or personal interests that could have affected the findings of this work. There are no potential competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aim: While it is currently assumed that liver assessment is only possible during normothermic machine perfusion (NMP), there is uncertainty regarding a reliable and quick prediction of graft injury during ex situ hypothermic oxygenated perfusion (HOPE). We therefore intended to test, in an international liver transplant cohort, recently described mitochondrial injury biomarkers measured during HOPE before liver transplantation., Study Design: Perfusate samples of human livers from 10 centers in 7 countries with HOPE-experience were analyzed for released mitochondrial compounds, i.e. flavin mononucleotide (FMN), NADH, purine derivates and inflammatory markers. Perfusate FMN was correlated with graft loss due to primary non-function or symptomatic non-anastomotic biliary strictures (NAS), and kidney failure, as well as liver injury after transplantation. Livers deemed unsuitable for transplantation served as negative control., Results: We collected 473 perfusate samples of human DCD (n=315) and DBD livers (n=158). Fluorometric assessment of FMN in perfusate was validated by mass spectrometry (R=0.7011,p<0.0001). Graft loss due to primary non-function or cholangiopathy was predicted by perfusate FMN values (c-statistic mass spectrometry 0.8418 (95%CI 0.7466-0.9370,p<0.0001), c-statistic fluorometry 0.7733 (95%CI 0.7006-0.8461,p<0.0001). Perfusate FMN values were also significantly correlated with symptomatic NAS and kidney failure, and superior in prediction of graft loss when compared to conventional scores derived from donor and recipient parameters, such as the donor risk index and the balance of risk score. Mitochondrial FMN values in liver tissues of non-utilized livers were low, and inversely correlated to high perfusate FMN values and purine metabolite release., Conclusions: This first international study validates the predictive value of the mitochondrial co-factor FMN, released from complex I during HOPE, and may therefore contribute to a better risk stratification of injured livers before implantation., Impact and Implications: Analysis of 473 perfusates, collected from 10 international centers during hypothermic oxygenated perfusion (HOPE), revealed that mitochondria derived flavin mononucleotide (FMN) values in perfusate is predictive for graft loss, cholangiopathy, and kidney failure after liver transplantation. This result is of high clinical relevance, as recognition of graft quality is urgently needed to improve the safe utilization of marginal livers. Ex-situ machine perfusion approaches, such as HOPE, are therefore likely to increase the number of useable liver grafts., (Copyright © 2024. Published by Elsevier B.V.)

Background: The National Institutes of Health Stroke Scale (NIHSS) is a pivotal clinical tool used to assess patients with acute stroke. However, substantial heterogeneity in the application and interpretation of stroke scale items can occur. This systematic review aimed to elucidate heterogeneity in measuring the NIHSS., Material and Methods: A literature search was performed on PubMed/OVID/Cochran's CENTRAL from inception to 2023. The references of the included papers were reviewed for further eligible articles. Clinical characteristic, NIHSS values, and sources of heterogeneity were recorded. Non-human and non-English language articles were excluded. The study quality was assessed using MINORS and GRADE. Meta-analysis and meta-regression were performed using a random-effects model to explore the sources of heterogeneity., Results: Twenty-one papers for a total of 818 patients (mean per study: 39 ± 37) and 9696 NIHSS examinations (median per study: 8 [CI95% 2 to 42]) were included. Motor function had a higher ICC agreement (ranging from 0.85 ["Right Leg"] to 0.90 ["Right Arm"]) compared to the remaining items (ranging from 0.58 ["Facial Palsy"] to 0.85 ["Level of consciousness commands"]. The meta-regression showed a low effect size of covariates such as language version, remote evaluation, and retrospective analysis on NIHSS items (e.g., for "Level of consciousness commands," language effect was 0.30 [CI95% 0.20 to 0.48] and for "Visual", the retrospective assessment effect was -0.27 [CI95% -0.51 to -0.03])., Conclusion: The NIHSS scores showed moderate to excellent inter-rater agreement, with the highest heterogeneity in non-motor function evaluation. Using a non-English version, remote evaluation and retrospective analysis had small effects in terms of heterogeneity in the NIHSS scores., (© 2024. Fondazione Società Italiana di Neurologia.)

The global public health emergency of COVID-19 in January 2020 prompted a surge in research focusing on the pathogenesis and clinical manifestations of the virus. While numerous reports have been published on the acute effects of COVID-19 infection, the review explores the multifaceted long-term implications of COVID-19, with a particular focus on severe maternal COVID-19 infection, gut microbiome dysbiosis, and neurodevelopmental disorders in offspring. Severe COVID-19 infection has been associated with heightened immune system activation and gastrointestinal symptoms. Severe COVID-19 may also result in gut microbiome dysbiosis and a compromised intestinal mucosal barrier, often referred to as 'leaky gut'. Increased gut permeability facilitates the passage of inflammatory cytokines, originating from the inflamed intestinal mucosa and gut, into the bloodstream, thereby influencing fetal development during pregnancy and potentially elevating the risk of neurodevelopmental disorders such as autism and schizophrenia. The current review discusses the role of cytokine signaling molecules, microglia, and synaptic pruning, highlighting their potential involvement in the pathogenesis of neurodevelopmental disorders following maternal COVID-19 infection. Additionally, this review addresses the potential of probiotic interventions to mitigate gut dysbiosis and inflammatory responses associated with COVID-19, offering avenues for future research in optimizing maternal and fetal health outcomes., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Different kinds of traumatic experiences like natural catastrophes vs. relational traumatic experiences (e.g., sex/physical abuse, interpersonal partner violence) are involved in the development of the self and PTSD psychopathological manifestations. Looking at a neuroscience approach, it has been proposed a nested hierarchical model of self, which identifies three neural-mental networks: (i) interoceptive; (ii) exteroceptive; (iii) mental. However, it is still unclear how the self and its related brain networks might be affected by non-relational vs relational traumatic experiences. Departing from this background, the current study aims at conducting a meta-analytic review of task-dependent fMRI studies (i.e., emotional processing task) among patients with PTSD due to non-relational (PTSD-NR) and relational (PTSD-R) traumatic experiences using two approaches: (i) a Bayesian network meta-analysis for a region-of-interest-based approach; (ii) a coordinated-based meta-analysis. Our findings suggested that the PTSD-NR mainly recruited areas ascribed to the mental self to process emotional stimuli. Whereas, the PTSD-R mainly activated regions associated with the intero-exteroceptive self. Accordingly, the PTSD-R compared to the PTSD-NR might not reach a higher symbolic capacity to process stimuli with an emotional valence. These results are also clinically relevant in support of the development of differential treatment approaches for non-relational vs. relational PTSD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Previous cohort studies of hospitalized patients with a delayed diagnosis of ischemic stroke found that these patients often had an initial emergency department (ED) diagnosis of a fall. We sought to evaluate whether ED visits for a fall resulting in discharge to home (ie, treat-and-release visits) were associated with increased short-term ischemic stroke risk., Methods: A case-crossover design was used to compare ED visits for falls during case periods (0-15, 16-30, 31-90, and 91-180 days before stroke) and control periods (equivalent time periods exactly 1 year before stroke) using administrative data from the Healthcare Cost and Utilization Project on all hospital admissions and ED visits across 10 states from 2016 to 2020. To identify ED treat-and-release visits for a fall and patients hospitalized for acute ischemic stroke, we used previously validated International Classification of Diseases, Tenth Revision, Clinical Modification codes. Odds ratios and 95% CIs were calculated using conditional logistic regression., Results: Among 90 592 hospitalized patients with ischemic stroke, 5230 (5.8%) had an ED treat-and-release visit for a fall within 180 days before their stroke. Patients with an ED treat-and-release visit for a fall were older (mean age, 74.7 [SD, 14.6] versus 70.8 [SD, 15.1] years), more often female (61.9% versus 53.4%), and had higher rates of vascular comorbidities than other patients with stroke. ED treat-and-release visits for a fall were significantly more common in the 15 days before stroke compared with the 15-day control period 1 year earlier (odds ratio, 2.7 [95% CI, 2.4-3.1]). The association between stroke and a preceding ED treat-and-release visit for a fall decreased in magnitude with increasing temporal distance from stroke., Conclusions: ED treat-and-release visits for a fall are associated with significantly increased short-term ischemic stroke risk. These visits may be opportunities to improve stroke diagnostic accuracy and treatment in the ED., Competing Interests: Dr Navi has received personal fees for medicolegal consulting and for serving on an adjudication committee for MindRhythm Inc. Dr Kamel reports: PI for the ARCADIA trial ([Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy]; National Institutes of Health [NIH]/National Institute of Neurological Disorders and Stroke U01NS095869), which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, and U01NS106513); Deputy Editor for JAMA Neurology; clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; end point adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. The other authors report no conflicts.

Exposure to stressors during puberty can disrupt normal development and possibly increase susceptibility to neurodegenerative disorders later in life. However, the mechanisms underlying the relationship between pubertal stress exposure and neurodegeneration remain unclear. As such, the current study was designed to examine the effects of pubertal antimicrobial (AMNS) and lipopolysaccharide (LPS) treatments on intestinal and blood-brain-barrier (BBB) permeability in male and female mice. Moreover, we also examined the sex-specific effects of pubertal AMNS and LPS treatments on gross motor activity, heart rate, and core body temperature. At four weeks of age, male and female CD1 mice were implanted with the G2 HR E-Mitter telemetry system. At five weeks of age, mice received 200 μL of broad-spectrum antimicrobial or water, through oral gavage, twice daily for seven days. Mice received an intraperitoneal injection of either saline or LPS at six weeks of age. BBB and intestinal permeability were examined 24 h, 72 h, and one week post-LPS/saline treatment. Telemetric data was collected for 48 h post-LPS/saline treatment. The results showed that pubertal AMNS and LPS treatments increased sickness behaviours and decreased body temperature and heart rate, in a sex-dependent manner. Furthermore, pubertal AMNS and LPS treatments resulted in sex-dependent regional increases in BBB permeability 24 h and 72 h post-LPS/saline treatment, while global increases in BBB permeability were only observed one week post-LPS/saline treatment. These results further our understanding of the combined effects of AMNS and LPS treatments on physiology and on the enduring negative changes observed following pubertal exposure to stressors., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tau post-translational modifications (PTMs) result in the gradual build-up of abnormal tau and neuronal degeneration in tauopathies, encompassing variants of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Tau proteolytically cleaved by active caspases, including caspase-6, may be neurotoxic and prone to self-aggregation. Also, our recent findings show that caspase-6 truncated tau represents a frequent and understudied aspect of tau pathology in AD in addition to phospho-tau pathology. In AD and Pick's disease, a large percentage of caspase-6 associated cleaved-tau positive neurons lack phospho-tau, suggesting that many vulnerable neurons to tau pathology go undetected when using conventional phospho-tau antibodies and possibly will not respond to phospho-tau based therapies. Therefore, therapeutic strategies against caspase cleaved-tau pathology could be necessary to modulate the extent of tau abnormalities in AD and other tauopathies., Methods: To understand the timing and progression of caspase activation, tau cleavage, and neuronal death, we created two mAbs targeting caspase-6 tau cleavage sites and probed postmortem brain tissue from an individual with FTLD due to the V337M MAPT mutation. We then assessed tau cleavage and apoptotic stress response in cortical neurons derived from induced pluripotent stem cells (iPSCs) carrying the FTD-related V337M MAPT mutation. Finally, we evaluated the neuroprotective effects of caspase inhibitors in these iPSC-derived neurons., Results: FTLD V337M MAPT postmortem brain showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months post-differentiation showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau, phospho-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by the inhibition of effector caspases., Conclusions: Our results suggest an upstream, time-dependent accumulation of caspase-6 cleaved tau in V337M MAPT neurons promoting neurotoxicity. These processes can be reversed by caspase inhibition. These results underscore the potential of developing caspase-6 inhibitors as therapeutic agents for FTLD and other tauopathies. Additionally, they highlight the promise of using caspase-cleaved tau as biomarkers for these conditions., Competing Interests: Declaration of competing interest Michelle R. Arkin is cofounder of Elgia Therapeutics, which is developing caspase-6 inhibitors for inflammatory diseases. The other authors have declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Approximately half of ischemic strokes (IS) in cancer patients are cryptogenic, with many presumed cardioembolic. We evaluated whether there were specific miRNA and mRNA transcriptome architectures in peripheral blood of IS patients with and without comorbid cancer, and between cardioembolic versus noncardioembolic IS etiologies in comorbid cancer., Methods: We studied patients with cancer and IS (CS; n = 42), stroke only (SO; n = 41), and cancer only (n = 28), and vascular risk factor-matched controls (n = 30). mRNA-Seq and miRNA-Seq data, analyzed with linear regression models, identified differentially expressed genes in CS versus SO and in cardioembolic versus noncardioembolic CS, and miRNA-mRNA regulatory pairs. Network-level analyses identified stroke etiology-specific responses in CS., Results: A total of 2,085 mRNAs and 31 miRNAs were differentially expressed between CS and SO. In CS, 122 and 35 miRNA-mRNA regulatory pairs, and 5 and 3 coexpressed gene modules, were associated with cardioembolic and noncardioembolic CS, respectively. Complement, growth factor, and immune/inflammatory pathways showed differences between IS etiologies in CS. A 15-gene biomarker panel assembled from a derivation cohort (n = 50) correctly classified 81% of CS and 71% of SO participants in a validation cohort (n = 33). Another 15-gene panel correctly identified etiologies for 13 of 13 CS-cardioembolic and 11 of 11 CS-noncardioembolic participants upon cross-validation; 11 of 16 CS-cryptogenic participants were predicted cardioembolic., Interpretation: We discovered unique mRNA and miRNA transcriptome architecture in CS and SO, and in CS with different IS etiologies. Cardioembolic and noncardioembolic etiologies in CS showed unique coexpression networks and potential master regulators. These may help distinguish CS from SO and identify IS etiology in cryptogenic CS patients. ANN NEUROL 2024;96:565-581., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Importance: Approximately 10% to 15% of ischemic strokes are associated with cancer; cancer-associated stroke, particularly when cryptogenic, is associated with high rates of recurrent stroke and major bleeding. Limited data exist on the safety and efficacy of different antithrombotic strategies in patients with cancer and cryptogenic stroke., Objective: To compare apixaban vs aspirin for the prevention of adverse clinical outcomes in patients with history of cancer and cryptogenic stroke., Design, Setting, and Participants: Post hoc analysis of data from 1015 patients with a recent cryptogenic stroke and biomarker evidence of atrial cardiopathy in the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial, a multicenter, randomized, double-blind clinical trial conducted from 2018 to 2023 at 185 stroke centers in North America. Data analysis was performed from October 15, 2023, to May 23, 2024., Exposures: Oral apixaban, 5 mg (or 2.5 mg if criteria met), twice daily vs oral aspirin, 81 mg, once daily. Subgroups of patients with and without cancer at baseline were examined., Main Outcomes and Measures: The primary outcome for this post hoc analysis was a composite of major ischemic or major hemorrhagic events. Major ischemic events were recurrent ischemic stroke, myocardial infarction, systemic embolism, and symptomatic deep vein thrombosis or pulmonary embolism. Major hemorrhagic events included symptomatic intracranial hemorrhage and any major extracranial hemorrhage., Results: Among 1015 participants (median [IQR] age, 68 [60-76] years; 551 [54.3%] female), 137 (13.5%) had a history of cancer. The median (IQR) follow-up was 1.5 (0.6-2.5) years for patients with history of cancer and 1.5 (0.6-3.0) years for those without history of cancer. Participants with history of cancer, compared with those without history of cancer, had a higher risk of major ischemic or major hemorrhagic events (hazard ratio [HR], 1.73; 95% CI, 1.10-2.71). Among those with history of cancer, 8 of 61 participants (13.1%) randomized to apixaban and 16 of 76 participants (21.1%) randomized to aspirin had a major ischemic or major hemorrhagic event; however, the risk was not significantly different between groups (HR, 0.61; 95% CI, 0.26-1.43). Comparing participants randomized to apixaban vs aspirin among those with cancer, events included recurrent stroke (5 [8.2%] vs 9 [11.8%]), major ischemic events (7 [11.5%] vs 14 [18.4%]), and major hemorrhagic events (1 [1.6%] vs 2 [2.6%])., Conclusions and Relevance: Among participants in the ARCADIA trial with history of cancer, the risk of major ischemic and hemorrhagic events did not differ significantly with apixaban compared with aspirin., Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson's disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration. Nonetheless, CHCHD2 T61I mice exhibited robust molecular changes in the brain including increased CHCHD2 insolubility, accumulation of CHCHD2 protein preferentially in the substantia nigra (SN), and elevated levels of α-synuclein. Metabolic analyses revealed an increase in glucose metabolism through glycolysis relative to the TCA cycle with increased respiratory exchange ratio, and immune-electron microscopy revelated disrupted mitochondria in DA neurons. Moreover, spatial genomics revealed decreased expression of mitochondrial complex I and III respiratory chain proteins, while proteomics revealed increased respiratory chain and other mitochondrial protein-protein interactions. As such, the CHCHD2 T61I point-mutation mice exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis. These findings thus establish CHCHD2 T61I mice as a new model for mitochondrial-based PD, and implicate disrupted respiratory chain function as a likely causative driver.

Background: ARCADIA compared apixaban to aspirin for secondary stroke prevention in patients with cryptogenic stroke and atrial cardiopathy. One possible explanation for the neutral result is that biomarkers used did not optimally identify atrial cardiopathy. We examined the relationship between biomarker levels and subsequent detection of AF, the hallmark of atrial cardiopathy., Methods: Patients were randomized if they met criteria for atrial cardiopathy, defined as P-wave terminal force >5000 μV*ms in ECG lead V 1 (PTFV 1 ), NT-proBNP >250 pg/mL, or left atrial diameter index (LADI) ⩾3 cm/m 2 . For this analysis, the outcome was AF detected per routine care., Results: Of 3745 patients who consented to screening for atrial cardiopathy, 254 were subsequently diagnosed with AF; 96 before they could be randomized and 158 after randomization. In unadjusted analyses, ln(NT-proBNP) (RR per SD, 1.99; 95% CI, 1.85-2.13), PTFV 1 (RR per SD, 1.15; 95% CI, 1.03-1.28) and LADI (RR per SD, 1.34; 95% CI, 1.20-1.50) were associated with AF. In a model containing all 3 biomarkers, demographics, and AF risk factors, age (RR per 10 years, 1.24; 95% CI, 1.09-1.41), ln(NT-proBNP) (RR per SD, 1.88; 95% CI, 1.67-2.11) and LADI (RR per SD, 1.25; 95% CI, 1.14-1.37) were associated with AF. These three variables together had a c-statistic of 0.82 (95% CI, 0.79-0.85) but only modest calibration. Discrimination was attenuated in sensitivity analyses of patients eligible for randomization who may have been more closely followed for AF., Conclusions: Biomarkers used to identify atrial cardiopathy in ARCADIA were moderately predictive of subsequent AF., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Kamel reports serving as Deputy Editor for JAMA Neurology; serving on clinical trial steering/executive committees for the STROKE-AF (Medtronic), LIBREXIA-AF (Janssen), and LAAOS-4 (Boston Scientific) trials; serving as a consultant or endpoint adjudication committee member for AbbVie, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and household ownership interests in TETMedical, Spectrum Plastics Group, and Ascential Technologies. Dr. Healey reports research grants and speaking fees from BMS/Pfizer, Servier, Boston Scientific, and Medtronic. Dr. Kasner reports grant funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, and Diamedica, consulting fees from AstraZeneca, Abbie, and Novo Nordisk, and royalties from UpToDate. Dr. Elkind reports employment by the American Heart Association, royalties from UpToDate for chapters on stroke, and honoraria for lectures from the Atria Academy for Science and Medicine. The other authors report no conflicts of interest.

Introduction: Physiological fitness, encompassing cardiorespiratory fitness (CRF) and body composition, are important markers of overall health, functional capacity, and quality of life in general and clinical populations. Characterizing fitness is important for the development of tailored interventions and strategies to optimize well-being across the spectrum of disability in multiple sclerosis (MS). While existing research has explored fitness in people with mild-to-moderate disability, there is a scarcity of data in people with advanced MS (Expanded Disability Severity Scale, EDSS≥7.0)., Objective: To characterize CRF and body composition and their associations with fatigue, quality of life, and function in individuals with advanced MS., Methods: Participants (n=18, mean age=60.7 years-old, median EDSS=7.5) underwent a cardiopulmonary exercise test and dual-energy X-ray absorptiometry scanning. Main outcomes included peak volume of oxygen uptake (V̇O 2peak ) and whole and regional body fat, lean mass, bone mineral content, and bone density. Symptoms of fatigue (Modified Fatigue Impact Scale, MFIS), quality of life (29-item MS Impact Scale, MSIS-29), and daily function (Late-Life Function and Disability Instrument, LLFDI) were collected., Results: Participants exhibited notably low CRF levels (V̇O 2peak =9.8 mL/min/kg) and poor body composition (lower lean mass, bone mineral content and density) compared to previous studies in the general population and in individuals with MS with lower disability. V̇O 2peak was most consistently associated with function in daily life (LLFDI scores, r s ≥0.637, p≤0.004)., Conclusion: These findings reinforce the potential importance of physiological fitness to preserve function in people with advanced MS., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest related to this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Radiation therapy and stereotactic radiosurgery are common treatments for brain malignancies. However, the impact of radiation on underlying neuronal circuits is poorly understood. In the prefrontal cortex (PFC), neurons communicate via action potentials that control cognitive processes, thus it is important to understand the impact of radiation on these circuits. Here we present a novel protocol to investigate the effect of radiation on the activity and survival of PFC networks in vitro. Escalating doses of radiation were applied to PFC slices using a robotic radiosurgery platform at a standard dose rate of 10 Gy/min. High-density multielectrode array recordings of radiated slices were collected to capture extracellular activity across 4,096 channels. Radiated slices showed an increase in firing rate, functional connectivity, and complexity. Graph-theoretic measures of functional connectivity were altered following radiation. These results were compared to pharmacologically induced epileptic slices where neural complexity was markedly elevated, and functional connections were strong but remained spatially focused. Finally, propidium iodide staining revealed a dose-dependent effect of radiation on apoptosis. These findings provide a novel assay to investigate the impacts of clinically relevant doses of radiation on brain circuits and highlight the acute effects of escalating radiation doses on PFC neurons., (© 2024. The Author(s).)

The blood-brain barrier (BBB) protects the brain and maintains neuronal homeostasis. BBB properties can vary between brain regions to support regional functions, yet how BBB heterogeneity occurs is poorly understood. Here, we used single-cell and spatial transcriptomics to compare the mouse median eminence, one of the circumventricular organs that has naturally leaky blood vessels, with the cortex. We identified hundreds of molecular differences in endothelial cells (ECs) and perivascular cells, including astrocytes, pericytes and fibroblasts. Using electron microscopy and an aqueous-based tissue-clearing method, we revealed distinct anatomical specializations and interaction patterns of ECs and perivascular cells in these regions. Finally, we identified candidate regionally enriched EC-perivascular cell ligand-receptor pairs. Our results indicate that both molecular specializations in ECs and unique EC-perivascular cell interactions contribute to BBB functional heterogeneity. This platform can be used to investigate BBB heterogeneity in other regions and may facilitate the development of central nervous system region-specific therapeutics., (© 2024. The Author(s).)

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) like fluoxetine remain a first-line treatment for major depression, but are effective in less than half of patients and can take 4-8 weeks to show results. In this study, we examined cF1ko mice with genetically induced upregulation of 5-HT1A autoreceptors that reduces 5-HT neuronal activity. These mice display anxiety- and depression-related behaviors that did not respond to chronic fluoxetine treatment. We examined treatment with NLX-101, a biased agonist that preferentially targets 5-HT1A heteroreceptors. By testing different doses of NLX-101, we found that a dose of 0.2 mg/kg was effective in reducing depression-related behavior in cF1ko mice without causing hypothermia, a 5-HT1A autoreceptor-mediated response. After 1 h, this dose activated dorsal raphe 5-HT neurons and cells in the medial prefrontal cortex (mPFC), increasing nuclear c-fos labelling in cF1ko mice. In cF1ko mice but not wild-type littermates, 0.2 mg/kg NLX-101 administered 1 h prior to each behavioral test for two weeks reduced depressive behavior in the forced swim test, but increased anxiety-related behaviors in the open field, elevated plus maze, and novelty suppressed feeding tests. During this treatment, NLX-101 induced widespread increases in the density of 5-HT axons, varicosities, and especially synaptic and triadic structures, particularly in depression-related brain regions including mPFC, hippocampal CA1 and CA2/3, amygdala and nucleus accumbens of cF1ko mice. Overall, NLX-101 was rapid and effective in reducing depressive behavior in SSRI-resistant mice, but also induced anxiety-related behaviors. The increase in serotonin innervation induced by intermittent NLX-101 may contribute to its behavioral actions., Competing Interests: Declaration of competing interest The authors FV-A, AFF-A, MD and PRA declare no conflict of interest. The author A.N.-T. is an employee and stockholder of Neurolixis, M.P., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Spontaneous and sensory-evoked activity sculpts developing circuits. Yet, how these activity patterns intersect with cellular programs regulating the differentiation of neuronal subtypes is not well understood. Through electrophysiological and in vivo longitudinal analyses, we show that C-X-C motif chemokine ligand 14 (Cxcl14), a gene previously characterized for its association with tumor invasion, is expressed by single-bouquet cells (SBCs) in layer I (LI) of the somatosensory cortex during development. Sensory deprivation at neonatal stages markedly decreases Cxcl14 expression. Additionally, we report that loss of function of this gene leads to increased intrinsic excitability of SBCs-but not LI neurogliaform cells-and augments neuronal complexity. Furthermore, Cxcl14 loss impairs sensory map formation and compromises the in vivo recruitment of superficial interneurons by sensory inputs. These results indicate that Cxcl14 is required for LI differentiation and demonstrate the emergent role of chemokines as key players in cortical network development., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Vannucci procedure is widely used to model cerebral hypoxic-ischemic (HI) injury in neonatal rodents. Identifying minimally invasive biomarkers linked to brain injury would improve stratification of pups to experimental treatments. We hypothesized that extreme blood glucose (BG) and β-hydroxybutyrate (bHB) levels immediately after HI will correlate with severity of brain injury in this model., Methods: C57BL6 mice of both sexes underwent the Vannucci procedure with BG and bHB measured immediately after hypoxia. GFAP and α-fodrin were measured to assess injury severity at 4h, P11, P18 and P40. Open field (OF), Y-maze (YM), and Object-location task (OLT) were tested at P40., Results: Clinical seizures-like stereotypies during hypoxia were associated with lower post-hypoxia BG in HI-injured mice. Low BG after HI was related to higher GFAP expression, higher α-fodrin breakdown, lower residual regional volume, and worse working memory. BG was superior to bHB in ROC analysis with BG threshold of <111 mg/dL providing 100% specificity with 72% sensitivity for hippocampal HI-injury., Conclusions: Post-hypoxic BG is a minimally invasive screening tool to identify pups with significant HI brain injury in the Vannucci model modified for mice improving our ability to stratify pups to experimental treatments to assess effectiveness., Impact: End hypoxic-ischemic blood glucose levels are a reliable and inexpensive biomarker to detect hypoxic-ischemic brain injury in mice. Screening with blood glucose levels post-hypoxia allows appropriate stratification of those mouse pups most likely to be injured to experimental treatments improving validity and translatability of the results. These findings provide biological plausibility to the clinical observation that extreme blood glucose levels relate to worse outcomes after hypoxia-ischemia., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The astrocyte-to-neuron lactate shuttle model entails that, upon glutamatergic neurotransmission, glycolytically derived pyruvate in astrocytes is mainly converted to lactate instead of being entirely catabolized in mitochondria. The mechanism of this metabolic rewiring and its occurrence in human brain are unclear. Here by using immunohistochemistry (4 brains) and imaging mass cytometry (8 brains) we show that astrocytes of the adult human neocortex and hippocampal formation express barely detectable amounts of mitochondrial proteins critical for performing oxidative phosphorylation (OXPHOS). These data are corroborated by queries of transcriptomes (107 brains) of neuronal versus non-neuronal cells fetched from the Allen Institute for Brain Science for genes coding for a much larger repertoire of entities contributing to OXPHOS, showing that human non-neuronal elements barely expressed mRNAs coding for such proteins. With less OXPHOS, human brain astrocytes are thus bound to produce more lactate to avoid interruption of glycolysis., (© 2024. The Author(s).)

Post-translational modifications (PTMs) of α-synuclein (α-syn) such as acetylation and phosphorylation play important yet distinct roles in regulating α-syn conformation, membrane binding, and amyloid aggregation. However, how PTMs regulate α-syn function in presynaptic terminals remains unclear. Previously, we reported that α-syn clusters synaptic vesicles (SV) 1 , and neutral phospholipid lysophosphatidylcholine (LPC) can mediate this clustering 2 . Here, based on our previous findings, we further demonstrate that N-terminal acetylation, which occurs under physiological conditions and is irreversible in mammalian cells, significantly enhances the functional activity of α-syn in clustering SVs. Mechanistic studies reveal that this enhancement is caused by the N-acetylation-promoted insertion of α-syn's N-terminus and increased intermolecular interactions on the LPC-containing membrane. Our work demonstrates that N-acetylation fine-tunes α-syn-LPC interaction for mediating α-syn's function in SV clustering.

Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors and genetic manipulations together with mitochondrial ROS imaging and multiomic profiling, we found that CIII is the dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS production was dependent on nuclear factor-κB (NF-κB) and the mitochondrial sodium-calcium exchanger (NCLX) and caused oxidation of select cysteines within immune and metabolism-associated proteins linked to neurological disease. CIII-ROS amplified metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitated neuronal toxicity in a non-cell-autonomous manner. As proof-of-concept, suppression of CIII-ROS in mice decreased dementia-linked tauopathy and neuroimmune cascades and extended lifespan. Our findings establish CIII-ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease., Competing Interests: Competing Interests A.L.O. and A.G.O. have a patent application WO20221333237A2 for the use of SELs in treating neurodegenerative disorders and STAT3-linked cancers. E.T.C is co-founder of Matchpoint Therapeutics and co-founder of Aevum Therapeutics.

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties., Competing Interests: Competing interests statement:The authors declare no competing interest.

Next-generation sequencing (NGS) has revolutionized genomic research by enabling high-throughput, cost-effective genome and transcriptome sequencing accelerating personalized medicine for complex diseases, including cancer. Whole genome/transcriptome sequencing (WGS/WTS) provides comprehensive insights, while targeted sequencing is more cost-effective and sensitive. In comparison to short-read sequencing, which still dominates the field due to high speed and cost-effectiveness, long-read sequencing can overcome alignment limitations and better discriminate similar sequences from alternative transcripts or repetitive regions. Hybrid sequencing combines the best strengths of different technologies for a more comprehensive view of genomic/transcriptomic variations. Understanding each technology's strengths and limitations is critical for translating cutting-edge technologies into clinical applications. In this study, we sequenced DNA and RNA libraries of reference samples using various targeted DNA and RNA panels and the whole transcriptome on both short-read and long-read platforms. This study design enables a comprehensive analysis of sequencing technologies, targeting protocols, and library preparation methods. Our expanded profiling landscape establishes a reference point for assessing current sequencing technologies, facilitating informed decision-making in genomic research and precision medicine., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Patients with brain injury who are unresponsive to commands may perform cognitive tasks that are detected on functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). This phenomenon, known as cognitive motor dissociation, has not been systematically studied in a large cohort of persons with disorders of consciousness., Methods: In this prospective cohort study conducted at six international centers, we collected clinical, behavioral, and task-based fMRI and EEG data from a convenience sample of 353 adults with disorders of consciousness. We assessed the response to commands on task-based fMRI or EEG in participants without an observable response to verbal commands (i.e., those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus) and in participants with an observable response to verbal commands. The presence or absence of an observable response to commands was assessed with the use of the Coma Recovery Scale-Revised (CRS-R)., Results: Data from fMRI only or EEG only were available for 65% of the participants, and data from both fMRI and EEG were available for 35%. The median age of the participants was 37.9 years, the median time between brain injury and assessment with the CRS-R was 7.9 months (25% of the participants were assessed with the CRS-R within 28 days after injury), and brain trauma was an etiologic factor in 50%. We detected cognitive motor dissociation in 60 of the 241 participants (25%) without an observable response to commands, of whom 11 had been assessed with the use of fMRI only, 13 with the use of EEG only, and 36 with the use of both techniques. Cognitive motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In contrast, responses on task-based fMRI or EEG occurred in 43 of 112 participants (38%) with an observable response to verbal commands., Conclusions: Approximately one in four participants without an observable response to commands performed a cognitive task on fMRI or EEG as compared with one in three participants with an observable response to commands. (Funded by the James S. McDonnell Foundation and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Changes in EEG have been reported in both major depressive disorder (MDD) and bipolar disorder (BD). Specifically, power changes in EEG alpha and theta frequency bands during rest and task are known in both disorders. This leaves open whether there are changes in yet another component of the electrophysiological EEG signal, namely phase-related processes that may allow for distinguishing MDD and BD. For that purpose, we investigate EEG-based spontaneous phase in the resting state of MDD, BD and healthy controls. Our main findings show: (i) decreased spontaneous phase variability in frontal theta of both MDD and BD compared to HC; (ii) decreased spontaneous phase variability in central-parietal alpha in MDD compared to both BD and HC; (iii) increased delays or lags of alpha phase cycles in MDD (but not in BD), which (iv) correlate with the decreased phase variability in MDD. Together, we show similar (decreased frontal theta variability) and distinct (decreased central-parietal alpha variability with increased lags or delays) findings in the spontaneous phase dynamics of MDD and BD. This suggests potential relevance of theta and alpha phase dynamics in distinguishing MDD and BD in clinical differential-diagnosis., Competing Interests: Declaration of competing interest None of the authors declare any conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Meditation encompasses a range of practices employing diverse induction techniques, each characterized by a distinct attentional focus. In Mantra meditation, for instance, practitioners direct their attention narrowly to a given sentence that is recursively repeated, while other forms of meditation such as Shoonya meditation are induced by a wider attentional focus. Here we aimed to identify the neural underpinnings and correlates associated with this spectrum of distinct attentional foci. To accomplish this, we used EEG data to estimate the brain's intrinsic neural timescales (INTs), that is, its temporal windows of activity, by calculating the Autocorrelation Window (ACW) of the EEG signal. The autocorrelation function measures the similarity of a timeseries with a time-lagged version of itself by correlating the signal with itself on different time lags, consequently providing an estimation of INTs length. Therefore, through using the ACW metric, our objective was to explore whether there is a correspondence between the length of the brain's temporal windows of activity and the width of the attentional scope during various meditation techniques. This was performed on three groups of highly proficient practitioners belonging to different meditation traditions, as well as a meditation-naïve control group. Our results indicated that practices with a wider attentional focus, like Shoonya meditation, exhibit longer ACW durations compared to practices requiring a narrower attentional focus, such as Mantra meditation or body-scanning Vipassana meditation. Together, we demonstrated that distinct meditation techniques with varying widths of attentional foci exhibit unique durations in their brain's INTs. This may suggest that the width of the attentional scope during meditation relates and corresponds to the width of the brain's temporal windows in its neural activity. SIGNIFICANCE STATEMENT: Our research uncovered the neural mechanisms that underpin the attentional foci in various meditation techniques. We revealed that distinct meditation induction techniques, featured by their range of attentional widths, are characterized by varying lengths of intrinsic neural timescales (INTs) within the brain, as measured by the Autocorrelation Window function. This finding may bridge the gap between the width of attentional windows (subjective) and the width of the temporal windows in the brain's neural activity (objective) during different meditation techniques, offering a new understanding of how cognitive and neural processes are related to each other. This work holds significant implications, especially in the context of the increasing use of meditation in mental health and well-being interventions. By elucidating the distinct neural foundations of different meditation techniques, our research aims to pave the way for developing more tailored and effective meditation-based treatments., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)