Deleterious effect of sustained neuroinflammation in pediatric traumatic brain injury.

INTRODUCTION: Despite improved management of traumatic brain injury (TBI), it still leads to lifelong sequelae and disability, particularly in children. Chronic neuroinflammation (the so-called tertiary phase), in particular, microglia/macrophage and astrocyte reactivity, is among the main mechanisms suspected of playing a role in the generation of lesions associated with TBI. The role of acute neuroinflammation is now well understood, but its persistent effect and impact on the brain, particularly during development, are not. Here, we investigated the long-term effects of pediatric TBI on the brain in a mouse model. METHODS: Pediatric TBI was induced in mice on postnatal day (P) 7 by weight-drop trauma. The time course of neuroinflammation and myelination was examined in the TBI mice. They were also assessed by magnetic resonance, functional ultrasound, and behavioral tests at P45. RESULTS: TBI induced robust neuroinflammation, characterized by acute microglia/macrophage and astrocyte reactivity. The long-term consequences of pediatric TBI studied on P45 involved localized scarring astrogliosis, persistent microgliosis associated with a specific transcriptomic signature, and a long-lasting myelination defect consisting of the loss of myelinated axons, a decreased level of myelin binding protein, and severe thinning of the corpus callosum. These results were confirmed by reduced fractional anisotropy, measured by diffusion tensor imaging, and altered inter- and intra-hemispheric connectivity, measured by functional ultrasound imaging. In addition, adolescent mice with pediatric TBI showed persistent social interaction deficits and signs of anxiety and depressive behaviors. CONCLUSIONS: We show that pediatric TBI induces tertiary neuroinflammatory processes associated with white matter lesions and altered behavior. These results support our model as a model for preclinical studies for tertiary lesions following TBI.

Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries.

Approximately 15 million babies are born prematurely every year and many will face lifetime motor and/or cognitive deficits. Children born prematurely are at higher risk of developing perinatal brain lesions, especially white matter injuries (WMI). Evidence in humans and rodents demonstrates that systemic inflammation-induced neuroinflammation, including microglial and astrocyte reactivity, is the prominent processes of WMI associated with preterm birth. Thus, a new challenge in the field of perinatal brain injuries is to develop new neuroprotective strategies to target neuroinflammation to prevent WMI. Serotonin (5-HT) and its receptors play an important role in inflammation, and emerging evidence indicates that 5-HT may regulate brain inflammation by the modulation of microglial reactivity and astrocyte functions. The present study is based on a mouse model of WMI induced by intraperitoneal (i.p.) injections of IL-1ß during the first 5 days of life. In this model, certain key lesions of preterm brain injuries can be summarized by (i) systemic inflammation, (ii) pro-inflammatory microglial and astrocyte activation, and (iii) inhibition of oligodendrocyte maturation, leading to hypomyelination. We demonstrate that Htr7 mRNA (coding for the HTR7/5-HT7 receptor) is significantly overexpressed in the anterior cortex of IL-1ß-exposed animals, suggesting it as a potential therapeutic target. LP-211 is a specific high-affinity HTR7 agonist that crosses the blood-brain barrier (BBB). When co-injected with IL-1ß, LP-211 treatment prevented glial reactivity, the down-regulation of myelin-associated proteins, and the apparition of anxiety-like phenotypes. Thus, HTR7 may represent an innovative therapeutic target to protect the developing brain from preterm brain injuries.

Physician experience improves ability to predict 6-month functional outcome of severe traumatic brain injury.

BACKGROUND: The functional prognosis of severe traumatic brain injury (TBI) during the acute phase is often poor and uncertain. We aimed to quantify the elements that shade the degree of uncertainty in prognostic determination of TBI and to better understand the role of clinical experience in prognostic quality. METHODS: This was an observational, prospective, multicenter study. The medical records of 16 patients with moderate or severe TBI in 2020 were randomly drawn from a previous study and submitted to two groups of physicians: senior and junior. The senior physician group had graduated from a critical care fellowship, and the junior physician group had at least 3 years of anesthesia and critical care residency. They were asked for each patient, based on the reading of clinical data and CT images of the first 24 h, to determine the probability of an unfavorable outcome (Glasgow Outcome Scale < 4) at 6 months between 0 and 100, and their level of confidence. These estimations were compared with the actual evolution. RESULTS: Eighteen senior physicians and 18 junior physicians in 4 neuro-intensive care units were included in 2021. We observed that senior physicians performed better than junior physicians, with 73% (95% confidence interval (CI) 65-79) and 62% (95% CI 56-67) correct predictions, respectively, in the senior and junior groups (p = 0.006). The risk factors for incorrect prediction were junior group (OR 1.71, 95% CI 1.15-2.55), low confidence in the estimation (OR 1.76, 95% CI 1.18-2.63), and low level of agreement on prediction between senior physicians (OR 6.78, 95% CI 3.45-13.35). CONCLUSIONS: Determining functional prognosis in the acute phase of severe TBI involves uncertainty. This uncertainty should be modulated by the experience and confidence of the physician, and especially on the degree of agreement between physicians.

Corticosteroid treatment for refractory intracranial hypertension: a rescue therapy in patients with severe traumatic brain injury with contusional lesions-a feedback.

INTRODUCTION: Refractory intracranial hypertension (rICH) is a severe complication among patients with severe traumatic brain injury (sTBI). Medical treatment may be insufficient, and in some cases, the only viable treatment option is decompressive hemicraniectomy. The assessment of a corticosteroid therapy against vasogenic edema secondary to severe brain injuries seems interesting to prevent this surgery in sTBI patients with rICH caused by contusional areas. METHODS: This is a monocentric retrospective observational study including all consecutive sTBI patients with contusion injuries and a rICH requiring cerebrospinal fluid drainage with external ventricular drainage between November 2013 and January 2018. Patient inclusion criterium was a therapeutic index load (TIL; an indirect measure of TBI severity) > 7. Intracranial pressure (ICP) and TIL were assessed before and 48 h after corticosteroid therapy (CTC). Then, we divided the population into two groups according to the evolution of the TIL: responders and non-responders to corticosteroid therapy. RESULTS: During the study period, 512 patients were hospitalized for sTBI, and among them, 44 (8.6%) with rICH were included. They received 240 mg per day [120 mg, 240 mg] of Solu-Medrol for 2 days [1; 3], 3 days after the sTBI. The average ICP in patients with rICH before the CTC bolus was 21 mmHg [19; 23]. After the CTC bolus, the ICP fell significantly to less than 15 mmHg (p < 0.0001) for at least 7 days. The TIL decreased significantly the day after the CTC bolus and until day 2. Among these 44 patients, 68% were included in the responder group (n = 30). DISCUSSION: Short and systemic corticosteroid therapy in patients with refractory intracranial hypertension secondary to severe traumatic brain injury seems to be a potentially useful and efficient treatment for lowering intracranial pressure and decreasing the need for more invasive surgeries.

PREDICT-TBI: Comparison of Physician Predictions with the IMPACT Model to Predict 6-Month Functional Outcome in Traumatic Brain Injury.

BACKGROUND: Predicting functional outcome in critically ill patients with traumatic brain injury (TBI) strongly influences end-of-life decisions and information for surrogate decision makers. Despite well-validated prognostic models, clinicians most often rely on their subjective perception of prognosis. In this study, we aimed to compare physicians' predictions with the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic model for predicting an unfavorable functional outcome at 6 months after moderate or severe TBI. METHODS: PREDICT-TBI is a prospective study of patients with moderate to severe TBI. Patients were admitted to a neurocritical care unit and were excluded if they died or had withdrawal of life-sustaining treatments within the first 24 h. In a paired study design, we compared the accuracy of physician prediction on day 1 with the prediction of the IMPACT model as two diagnostic tests in predicting unfavorable outcome 6 months after TBI. Unfavorable outcome was assessed by the Glasgow Outcome Scale from 1 to 3 by using a structured telephone interview. The primary end point was the difference between the discrimination ability of the physician and the IMPACT model assessed by the area under the curve. RESULTS: Of the 93 patients with inclusion and exclusion criteria, 80 patients reached the primary end point. At 6 months, 29 patients (36%) had unfavorable outcome. A total of 31 clinicians participated in the study. Physicians' predictions showed an area under the curve of 0.79 (95% confidence interval 0.68-0.89), against 0.80 (95% confidence interval 0.69-0.91) for the laboratory IMPACT model, with no statistical difference (p = 0.88). Both approaches were well calibrated. Agreement between physicians was moderate (κ = 0.56). Lack of experience was not associated with prediction accuracy (p = 0.58). CONCLUSIONS: Predictions made by physicians for functional outcome were overall moderately accurate, and no statistical difference was found with the IMPACT models, possibly due to a lack of power. The significant variability between physician assessments suggests prediction could be improved through peer reviewing, with the support of the IMPACT models, to provide a realistic expectation of outcome to families and guide discussions about end-of-life decisions.

Neuro-Inflammation Modulation and Post-Traumatic Brain Injury Lesions: From Bench to Bed-Side.

Head trauma is the most common cause of disability in young adults. Known as a silent epidemic, it can cause a mosaic of symptoms, whether neurological (sensory-motor deficits), psychiatric (depressive and anxiety symptoms), or somatic (vertigo, tinnitus, phosphenes). Furthermore, cranial trauma (CT) in children presents several particularities in terms of epidemiology, mechanism, and physiopathology-notably linked to the attack of an immature organ. As in adults, head trauma in children can have lifelong repercussions and can cause social and family isolation, difficulties at school, and, later, socio-professional adversity. Improving management of the pre-hospital and rehabilitation course of these patients reduces secondary morbidity and mortality, but often not without long-term disability. One hypothesized contributor to this process is chronic neuroinflammation, which could accompany primary lesions and facilitate their development into tertiary lesions. Neuroinflammation is a complex process involving different actors such as glial cells (astrocytes, microglia, oligodendrocytes), the permeability of the blood-brain barrier, excitotoxicity, production of oxygen derivatives, cytokine release, tissue damage, and neuronal death. Several studies have investigated the effect of various treatments on the neuroinflammatory response in traumatic brain injury in vitro and in animal and human models. The aim of this review is to examine the various anti-inflammatory therapies that have been implemented.

Pathomechanisms behind cognitive disorders following ruptured anterior communicating aneurysms: A diffusion tensor imaging study.

INTRODUCTION: After the rupture of anterior communicating aneurysms, most patients experience debilitating cognitive disorders; and sometimes even without showing morphological anomaly on MRI examinations. Diffusion Tensor Imaging (DTI) may help understanding the pathomechanisms leading to such disorders in this subset of patients. METHODS: After independent assessment, we constituted a population of patients with normal morphological imaging (ACOM group). Then, a case-control study comparing volumetric and voxel-based DTI parameters between the ACOM group and a control population was performed. All patients underwent the full imaging and neuropsychological assessments at 6 months after the aneurysm rupture. Results were considered significant when p<2.02.10-4. RESULTS: Twelve patients were included in the ACOM group: 75% had at least one disabled cognitive domain. Significant differences in DTI parameters of global white matter were noted (average Fractional Anisotropy: 0.915 [±0.05] in ACOM group versus 0.943 (±0.03); p = 1.10-5) and in frontal white matter tracts (superior fronto-occipital fasciculus and anterior parts of the corona radiata) as well as in the fornix. CONCLUSION: Cognitive disorders are under-estimated, and DTI confirmed that, even when conventional MRI examinations were normal, there were still signs of diffuse neuronal injuries that seemed to dominate in frontal areas, close to the site of rupture.

Is Anatomical Variations a Risk Factor for Cerebral Vasospasm in Anterior Communicating Complex Aneurysms Rupture?

Background and Purpose- One-third of ruptured aneurysms are located on the anterior communicating complex with high prevalence of anatomic variations of this arterial segment. In this study, we hypothesized that anatomic variations of the anterior communicating complex increase the risk of angiographic vasospasm. Methods- Retrospective study of prospectively collected data from a monocentric subarachnoid hemorrhage cohort of patients admitted to neurointensive care between 2002 and 2018. Univariate followed by multivariate logistic regression analysis was used to identify factors associated with angiographic vasospasm. Results- One thousand three hundred seventy-four patients with aneurismal subarachnoid hemorrhage were admitted to our institution; 29.8% (n=410) were related to an anterior communicating complex aneurysm rupture; 9.2% (n=38) of them showed an anterior communicating artery variation. Angiographic vasospasm was diagnosed in 55.6% of this subgroup (vs 28.1%, P=0.003). In the multivariate analysis, external ventricular drain (2.2 [1.32-3.65], P=0.003) and anterior communicating artery variation (2.40 [1.2-4.9], P=0.04) were independently and significantly associated with angiographic vasospasm, while age above 60 years (0.3 [0.2-0.7]; P=0.002) was a protective factor. However, anterior communicating artery variation was not statistically associated with ischemic vasospasm or poor neurological outcome after anterior communicating artery aneurysm rupture. Conclusions- Anatomic variation of anterior communicating artery could be a new biomarker to identify patients at risk to develop angiographic vasospasm post-subarachnoid hemorrhage. External validation cohorts are necessary to confirm these results.

Secondary S100B Protein Increase Following Brain Arteriovenous Malformation Rupture is Associated with Cerebral Infarction.

Early S100B protein serum elevation is associated with poor prognosis in patients with ruptured brain arteriovenous malformations (BAVM). The purpose of this study is to determine whether a secondary elevation of S100B is associated with early complications or poor outcome in this population. This is a retrospective study of patients admitted for BAVM rupture. A secondary increase of S100B was defined as an absolute increase by 0.1 µg/L within 30 days of admission. Fisher's and unpaired t tests followed by multivariate analysis were performed to identify markers associated with this increase. Two hundred and twenty-one ruptures met inclusion criteria. Secondary S100B protein serum elevation was found in 17.1% of ruptures and was associated with secondary infarction (p < 0.001), vasospasm-related infarction (p < 0.001), intensive care (p = 0.009), and hospital length of stay (p = 0.005), but not with early rebleeding (p = 0.07) or in-hospital mortality (p = 0.99). Secondary infarction was the only independent predictor of secondary increase of S100B (OR 9.9; 95% CI (3-35); p < 0.001). Secondary elevation of S100B protein serum levels is associated with secondary infarction in ruptured brain arteriovenous malformations.

S100B Serum Elevation Predicts In-Hospital Mortality After Brain Arteriovenous Malformation Rupture.

Background and Purpose- S100B protein serum elevation has been associated with poor prognosis in neurologically ill patients. The purpose of this study is to determine whether elevation of S100B is associated with increased in-hospital mortality after brain arteriovenous malformation rupture. Methods- This is a retrospective study of patients admitted for brain arteriovenous malformation rupture. The study population was divided into derivation and validation cohorts. Univariate followed by multivariate logistic regression was used to determine whether elevation of S100B serum levels above 0.5 µg/L during the first 48 hours after admission (S100Bmax48) was associated with in-hospital mortality. Results- Two hundred and three ruptures met inclusion criteria. Twenty-three led to in-hospital mortality (11%). Mean S100Bmax48 was 0.49±0.62 µg/L. In the derivation cohort (n=101 ruptures), multivariate analysis found Glasgow coma scale score ≤8 (odds ratio, 21; 95% CI, 2-216; 0.001) and an S100Bmax48>0.5 µg/L (odds ratio, 19; 95% CI, 2-188; P=0.001) to be associated with in-hospital mortality. When applied to the validation cohort (n=102 ruptures), the same model found only S100Bmax48>0.5 µg/L (odds ratio, 8; 95% CI, 1.5-44; P=0.01) to be associated with in-hospital mortality. Conclusions- Elevated S100B protein serum level is strongly associated with in-hospital mortality after brain arteriovenous malformation rupture.

Whole-Blood miRNA Sequencing Profiling for Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Arterial vasospasm is a well-known delayed complication of aneurysmal subarachnoid hemorrhage (aSAH). However, no validated biomarker exists to help clinicians discriminating patients with aSAH who will develop vasospasm (VSP+) and identifying those who then deserve aggressive preventive therapy. We hypothesized that whole-blood miRNAs could be a source of candidate biomarkers for vasospasm. Methods- Using a next-generation sequencing approach, we performed whole-blood miRNA profiling between VSP+patients with aSAH and patients who did not develop vasospasm (VSP-) in a prospective cohort of 32 patients. Profiling was performed on the admission day and 3 days before vasospasm. Results- Four hundred forty-two miRNAs were highly expressed in whole blood of patients with aSAH. Among them, hsa-miR-3177-3p demonstrated significant ( P=5.9×10-5; PBonferronicorrected=0.03) lower levels in VSP- compared with VSP+ patients. Looking for whole-blood mRNA correlates of hsa-miR-3177-3p, we observed some evidence that the decrease in hsa-miR-3177-3p levels after aSAH was associated with an increase in LDHA mRNA levels in VSP- ( P<10-3) but not in VSP+ ( P=0.66) patients. Conclusions- Whole-blood miRNA levels of hsa-miR-3177-3p could serve as a biomarker for vasospasm. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01779713.

Early Rebleeding after Brain Arteriovenous Malformation Rupture, Clinical Impact and Predictive Factors: A Monocentric Retrospective Cohort Study.

BACKGROUND: Brain arteriovenous malformations (BAVMs) are a leading cause of intracranial hemorrhage in young adults. This study aimed to identify individual predictive factors of early rebleeding after BAVM rupture and determine its impact on prognosis. METHODS: Early rebleeding was defined as a spontaneous intracranial hemorrhage within 30 days of BAVM rupture in patients with nonobliterated BAVMs. One hundred fifty one patients with 158 BAVM hemorrhagic events admitted to a tertiary care center during 14 years were included. Univariate followed by multivariate logistic regression was performed to assess the impact of early rebleeding on in-hospital mortality and modified Rankin Scale (mRS) score beyond 3 months and to identify independent predictors of early rebleeding. RESULTS: Eight early rebleeding events were observed, 6 of which occurred during the first 7 days. Early rebleeding was independently and significantly associated with poor outcome (mRS ≥3 beyond 3 months, p = 0.004) but not with in-hospital mortality (p = 0.9). Distal flow-related aneurysms (p = 0.009) and altered consciousness with a Glasgow coma scale score of 3 (p = 0.01) were independently associated with early rebleeding. CONCLUSIONS: Early rebleeding is a severe complication that can occur after BAVM-related hemorrhage. Distal flow-related aneurysms and initial altered consciousness are associated with early rebleeding.

Preterm birth: A neuroinflammatory origin for metabolic diseases?

Preterm birth and its related complications have become more and more common as neonatal medicine advances. The concept of "developmental origins of health and disease" has raised awareness of adverse perinatal events in the development of diseases later in life. To explore this concept, we propose that encephalopathy of prematurity (EoP) as a potential pro-inflammatory early life event becomes a novel risk factor for metabolic diseases in children/adolescents and adulthood. Here, we review epidemiological evidence that links preterm birth to metabolic diseases and discuss possible synergic roles of preterm birth and neuroinflammation from EoP in the development of metabolic diseases. In addition, we explore theoretical underlying mechanisms regarding developmental programming of the energy control system and HPA axis.

MRI volumetry and diffusion tensor imaging for diagnosis and follow-up of late post-traumatic injuries.

BACKGROUND: Traumatic Brain Injury (TBI) is a major cause of acquired disability and can cause devastating and progressive post-traumatic encephalopathy. TBI is a dynamic condition that continues to evolve over time. A better understanding of the pathophysiology of these late lesions is important for the development of new therapeutic strategies. OBJECTIVES: The primary objective was to compare the ability of fluid-attenuated reversion recovery (FLAIR) and diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) markers to identify participants with a Glasgow outcome scale extended (GOS-E) score of 7-8, up to 10 years after their original TBI. The secondary objective was to study the brain regionalization of DTI markers. Finally, we analyzed the evolution of late-developing brain lesions using repeated MRI images, also taken up to 10 years after the TBI. METHODS: In this retrospective study, participants were included from a cohort of people hospitalized following a severe TBI. Following their discharge, they were followed-up and clinically assessed, including a DTI-MRI scan, between 2012 and 2016. We performed a cross-sectional analysis on 97 participants at a median (IQR) of 5 years (3-6) post-TBI, and a further post-TBI longitudinal analysis over 10 years on a subpopulation (n = 17) of the cohort. RESULTS: Although the area under the curve (AUC) of FLAIR, fractional anisotropy (FA), and mean diffusivity (MD) were not significantly different, only the AUC of FA was statistically greater than 0.5. In addition, only the FA was correlated with clinical outcomes as assessed by GOS-E score (P<10-4). On the cross-sectional analysis, DTI markers allowed study post-TBI white matter lesions by region. In the longitudinal subpopulation analysis, the observed number of brain lesions increased for the first 5 years post-TBI, before stabilizing over the next 5 years. CONCLUSIONS: This study has shown for the first time that post-TBI lesions can present in a two-phase evolution. These results must be confirmed in larger studies. French Data Protection Agency (Commission nationale de l'informatique et des libertés; CNIL) study registration no: 1934708v0.

Long-Term Cangrelor Administration in Neurology Intensive Care: A Case Series.

Cangrelor is a P2Y12 inhibitor antiplatelet agent, with a rapid onset and offset. The available literature only reviews short-term administration over a few hours. We describe 5 patients who received cangrelor for >1 month in a neurosurgical intensive care unit due to a very high likelihood of requiring emergency revision surgery. Despite multiple therapeutic interruptions for surgical procedures, no hemorrhagic events occurred, and there was only one transient ischemic event, which occurred during transition from cangrelor to ticagrelor. Cangrelor can be a therapeutic option for patients with a high likelihood of requiring revision neurosurgery after intracranial stenting.

[Oxytocin: a new target for neuroprotection?] / Ocytocine : une nouvelle cible de neuroprotection ?

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante-/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders affecting more than 9 million children each year. Most pharmacological candidates to prevent perinatal brain damage have failed to demonstrate substantial benefits. In contrast, environment enrichment based on developmental care, skin-to-skin contact and vocal/music exposure appear to exert positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the neonatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. In particular, excessive cortisol release in response to perinatal stress associated with prematurity or IUGR is recognized to induce brain-programming effects and neuroinflammation, a key predictor of subsequent neurological impairments. These deleterious effects are known to be balanced by oxytocin (OT), a neuropeptide released by the hypothalamus, which plays a role during the perinatal period and in social behavior. In addition, preclinical studies suggest that OT is able to regulate the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with developing white matter damage, we recently reported that carbetocin, a brain permeable OT receptor (OTR) agonist, induced a significant reduction of activated microglia, the primary immune cells of the brain. Moreover, this reduced microglia reactivity was associated with long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the mechanisms linking endogenous OT and central inflammation response to injury have not yet been established. Further studies are needed to assess the protective role of OT in the developing brain through modulation of microglial activation, a key feature of brain injury observed in infants born preterm or growth-restricted. They are expected to have several impacts in the near future not only for improving knowledge of microglial cell physiology and reactivity during brain development, but also to design clinical trials testing interventions associated with endogenous OT release as a relevant strategy to alleviate neuroinflammation in neonates.

Title: Ocytocine  : une nouvelle cible de neuroprotection ? Abstract: Chaque année, dans le monde, 30 millions de nouveau-nés naissent après un retard de croissance intra-utérin (RCIU) et 15 millions naissent prématurément. Ces deux conditions sont les principales causes de stress anté-/périnatal et de lésions cérébrales responsables de troubles neurocognitifs et comportementaux chez plus de 9 millions d'enfants chaque année. La plupart des stratégies pharmacologiques visant à prévenir les lésions cérébrales périnatales n'ont pas réussi à démontrer des bénéfices cliniques substantiels. En revanche, l'enrichissement de l'environnement basé sur les soins de développement, le contact peau à peau et l'exposition vocale/musicale semblent avoir des effets positifs sur la structure et la fonctionnalité du cerveau. Toutefois, les mécanismes qui sous-tendent ces effets restent inconnus. De nombreuses évidences montrent qu'un environnement défavorable pendant la grossesse et la période néonatale peut influencer les réponses hormonales du nouveau-né et avoir des conséquences neurocomportementales durables pendant la petite enfance et à l'âge adulte. L'ocytocine (OT), un neuropeptide libéré par l'hypothalamus, joue un rôle pendant la période périnatale dans l'attachement parents-enfant et dans le comportement social. En outre, des études précliniques suggèrent que l'OT est capable de réguler la réponse inflammatoire centrale aux lésions dans le cerveau adulte. Ces données font de l'OT un candidat prometteur pour la neuroprotection néonatale par la régulation de la neuro-inflammation.

The Role of Oxytocin in Abnormal Brain Development: Effect on Glial Cells and Neuroinflammation.

The neonatal period is critical for brain development and determinant for long-term brain trajectory. Yet, this time concurs with a sensitivity and risk for numerous brain injuries following perinatal complications such as preterm birth. Brain injury in premature infants leads to a complex amalgam of primary destructive diseases and secondary maturational and trophic disturbances and, as a consequence, to long-term neurocognitive and behavioral problems. Neuroinflammation is an important common factor in these complications, which contributes to the adverse effects on brain development. Mediating this inflammatory response forms a key therapeutic target in protecting the vulnerable developing brain when complications arise. The neuropeptide oxytocin (OT) plays an important role in the perinatal period, and its importance for lactation and social bonding in early life are well-recognized. Yet, novel functions of OT for the developing brain are increasingly emerging. In particular, OT seems able to modulate glial activity in neuroinflammatory states, but the exact mechanisms underlying this connection are largely unknown. The current review provides an overview of the oxytocinergic system and its early life development across rodent and human. Moreover, we cover the most up-to-date understanding of the role of OT in neonatal brain development and the potential neuroprotective effects it holds when adverse neural events arise in association with neuroinflammation. A detailed assessment of the underlying mechanisms between OT treatment and astrocyte and microglia reactivity is given, as well as a focus on the amygdala, a brain region of crucial importance for socio-emotional behavior, particularly in infants born preterm.

Magnetic Isolation of Microglial Cells from Neonate Mouse for Primary Cell Cultures.

Microglia, as brain resident macrophages, are fundamental to several functions, including response to environmental stress and brain homeostasis. Microglia can adopt a large spectrum of activation phenotypes. Moreover, microglia that endorse pro-inflammatory phenotype is associated with both neurodevelopmental and neurodegenerative disorders. In vitro studies are widely used in research to evaluate potential therapeutic strategies in specific cell types. In this context studying microglial activation and neuroinflammation in vitro using primary microglial cultures is more relevant than microglial cell lines or stem-cell-derived microglia. However, the use of some primary cultures might suffer from a lack of reproducibility. This protocol proposes a reproducible and relevant method of magnetically isolating microglia from neonate pups. Microglial activation using several stimuli after 4 h and 24 h by mRNA expression quantification and a Cy3-bead phagocytic assay is demonstrated here. The current work is expected to provide an easily reproducible technique for isolating physiologically relevant microglia from juvenile developmental stages.

Incidence and risk factors of epilepsy following brain arteriovenous malformation rupture in adult patients.

BACKGROUND: Little is known about incidence, time of onset, clinical presentation, and risk factors of epileptic seizure following brain arteriovenous malformation (bAVM) rupture. METHODS: We performed a monocentric retrospective cohort study from January 2003 to March 2021. The main objective of this study was to determine the incidence of seizures after spontaneous bAVM rupture in nonepileptic adult patients and describe the corresponding clinical features. The secondary objective was to identify clinical, radiological, or biological predictors for the occurrence of de novo seizures after bAVM rupture. RESULTS: Of the 296 cases of bAVM rupture registered during the study period, 247 nonepileptic patients (male 53%, median age 40) were included in the study. Fifty-nine patients (23.9%) had at least one seizure after bAVM rupture. The use of preventive antiepileptic drugs (10.3 [1.5-74.1]; P = 0.02) and decompressive craniectomy (15.4 [2.0-125]; P < 0.009) were independently associated with the occurrence of epilepsy after the bAVM rupture. The factors independently associated with the absence of any seizure after the rupture were isolated intraventricular hemorrhage (0.3 [0.1-0.99]; P = 0.04) and infratentorial location of the bAVM (0.2 [0.1-0.5]; P = 0.09). The first seizure occurred within the first year or within 5 years in, respectively, 83.1% and 98.3% of the patients. CONCLUSIONS: Epilepsy affects nearly a quarter of patients after bAVM rupture. Decompressive craniectomy represents an independent risk factor significantly associated with the occurrence of epilepsy after bAVM rupture. The introduction of preventive AEDs after rupture could be considered in these most severe patients who have a decompressive craniectomy.