Targeting brain-peripheral immune responses for secondary brain injury after ischemic and hemorrhagic stroke.

The notion that the central nervous system is an immunologically immune-exempt organ has changed over the past two decades, with increasing evidence of strong links and interactions between the central nervous system and the peripheral immune system, both in the healthy state and after ischemic and hemorrhagic stroke. Although primary injury after stroke is certainly important, the limited therapeutic efficacy, poor neurological prognosis and high mortality have led researchers to realize that secondary injury and damage may also play important roles in influencing long-term neurological prognosis and mortality and that the neuroinflammatory process in secondary injury is one of the most important influences on disease progression. Here, we summarize the interactions of the central nervous system with the peripheral immune system after ischemic and hemorrhagic stroke, in particular, how the central nervous system activates and recruits peripheral immune components, and we review recent advances in corresponding therapeutic approaches and clinical studies, emphasizing the importance of the role of the peripheral immune system in ischemic and hemorrhagic stroke.

Repetitive transcranial magnetic stimulation ameliorates cognitive deficits in mice with radiation-induced brain injury by attenuating microglial pyroptosis and promoting neurogenesis via BDNF pathway.

BACKGROUND: Radiation-induced brain injury (RIBI) is a common and severe complication during radiotherapy for head and neck tumor. Repetitive transcranial magnetic stimulation (rTMS) is a novel and non-invasive method of brain stimulation, which has been applied in various neurological diseases. rTMS has been proved to be effective for treatment of RIBI, while its mechanisms have not been well understood. METHODS: RIBI mouse model was established by cranial irradiation, K252a was daily injected intraperitoneally to block BDNF pathway. Immunofluorescence staining, immunohistochemistry and western blotting were performed to examine the microglial pyroptosis and hippocampal neurogenesis. Behavioral tests were used to assess the cognitive function and emotionality of mice. Golgi staining was applied to observe the structure of dendritic spine in hippocampus. RESULTS: rTMS significantly promoted hippocampal neurogenesis and mitigated neuroinflammation, with ameliorating pyroptosis in microglia, as well as downregulation of the protein expression level of NLRP3 inflammasome and key pyroptosis factor Gasdermin D (GSDMD). BDNF signaling pathway might be involved in it. After blocking BDNF pathway by K252a, a specific BDNF pathway inhibitor, the neuroprotective effect of rTMS was markedly reversed. Evaluated by behavioral tests, the cognitive dysfunction and anxiety-like behavior were found aggravated with the comparison of mice in rTMS intervention group. Moreover, the level of hippocampal neurogenesis was found to be attenuated, the pyroptosis of microglia as well as the levels of GSDMD, NLRP3 inflammasome and IL-1ß were upregulated. CONCLUSION: Our study indicated that rTMS notably ameliorated RIBI-induced cognitive disorders, by mitigating pyroptosis in microglia and promoting hippocampal neurogenesis via mediating BDNF pathway.

A systematic review and meta-analysis on abnormal posturing among brain injury patients.

BACKGROUND: Abnormal motor posturing (AMP), exhibiting as decorticate, decerebrate, or opisthotonos, is regularly noticed among children and adults. OBJECTIVE: This systematic review and meta-analysis examined the risk factors and outcome of posturing among severe head and brain injury subjects. METHODS: Based on the inclusion and exclusion criteria and using MeSH terms: "decerebrate posturing", "opisthotonic posturing", "brain injury", and/or "cerebral injury" articles were searched on Scopus, PubMed, Science Direct, and google scholar databases. Observational studies, case series, and case reports were included. RESULTS: A total of 1953 studies were retrieved initially, and based on the selection criteria, 20 studies were finally selected for review and were analyzed for meta-analysis based on the mortality between the hematomas. The functional outcomes of this study are the risk factors, mortality rate and Glasgow Outcome Scale. Decerebrative patients were higher among the studies related to head injury surgeries. Males were mainly treated for decerebrate postures compared with the female subjects. Extradural hematoma and acute subdural hematoma with cerebral contusion were quite common in the surgical mass lesions. CONCLUSION: The findings reported that the lesion types, the operative procedures, and the age of the decerebrating patients with brain injuries are the significant prognostic factors determining the survival outcomes.

ANTECEDENTES: Postura motora anormal (AMP), exibindo-se como decorticada, descerebrada ou opistótono, é regularmente observada entre crianças e adultos. OBJETIVO: Esta revisão sistemática e metanálise examinou os fatores de risco e os resultados da postura entre indivíduos com lesões graves na cabeça e no cérebro. MéTODOS: Com base nos critérios de inclusão e exclusão e usando termos MeSH: artigos sobre "postura descerebrada", "postura opistótona", "lesão cerebral" e/ou "lesão cerebral" foram pesquisados nas bases de dados Scopus, PubMed, Science Direct e Google Scholar. Foram incluídos estudos observacionais, séries de casos e relatos de casos. RESULTADOS: Um total de 1.953 estudos foram recuperados inicialmente e, com base nos critérios de seleção, 20 estudos foram finalmente selecionados para revisão e analisados para metanálise com base na mortalidade entre os hematomas. Os resultados funcionais deste estudo são os fatores de risco, taxa de mortalidade e Escala de Resultados de Glasgow. Os pacientes descerebrados foram maiores entre os estudos relacionados a cirurgias de traumatismo cranioencefálico. Os homens foram tratados principalmente para posturas descerebradas em comparação com as mulheres. Hematoma extradural e hematoma subdural agudo com contusão cerebral foram bastante comuns nas lesões de massa cirúrgica. CONCLUSãO: Os achados relataram que os tipos de lesões, os procedimentos operatórios e a idade dos pacientes descerebrados com lesões cerebrais são os fatores prognósticos significativos que determinam os resultados de sobrevivência.

"NeuroVanguard": a contemporary strategy in neuromonitoring for severe adult brain injury patients.

Severe acute brain injuries, stemming from trauma, ischemia or hemorrhage, remain a significant global healthcare concern due to their association with high morbidity and mortality rates. Accurate assessment of secondary brain injuries severity is pivotal for tailor adequate therapies in such patients. Together with neurological examination and brain imaging, monitoring of systemic secondary brain injuries is relatively straightforward and should be implemented in all patients, according to local resources. Cerebral secondary injuries involve factors like brain compliance loss, tissue hypoxia, seizures, metabolic disturbances and neuroinflammation. In this viewpoint, we have considered the combination of specific noninvasive and invasive monitoring tools to better understand the mechanisms behind the occurrence of these events and enhance treatment customization, such as intracranial pressure monitoring, brain oxygenation assessment and metabolic monitoring. These tools enable precise intervention, contributing to improved care quality for severe brain injury patients. The future entails more sophisticated technologies, necessitating knowledge, interdisciplinary collaboration and resource allocation, with a focus on patient-centered care and rigorous validation through clinical trials.

ADAMTS13 deficiency exacerbates neuroinflammation by targeting matrix metalloproteinase-9 in ischemic brain injury.

Our design aimed to explore the potential involvement of matrix metalloproteinase-9 (MMP-9) in the inflammatory response associated with acute ischemic stroke (AIS). We also aimed to preliminarily examine the potential impact of a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 (ADAMTS13) on MMP-9 in AIS. We conducted oxygen-glucose deprivation models of microglia cells and mice models of AIS with middle cerebral artery occlusion (MCAO). We assessed the expression pattern of MMP-9 with western blotting (WB) and real-time quantitative PCR both in vivo and in vitro. MMP-9 downregulation was achieved by using ACE inhibitors such as trandolapril. For the MCAO model, we used ADAMTS13-deficient mice. We then evaluated the related neurological function scores, cerebral edema and infarct volume. The levels of inflammation-related proteins, such as COX2 and iNOS, were assessed using WB, and the expression of inflammatory cytokines was measured via enzyme-linked immuno sorbent assay in vivo. Our findings indicated that MMP-9 was up-regulated while ADAMTS13 was down-regulated in the MCAO model. Knockdown of MMP-9 reduced both inflammation and ischemic brain injury. ADAMTS13 prevented brain damage, improved neurological function and decreased the inflammation response in mice AIS models. Additionally, ADAMTS13 alleviated MMP-9-induced neuroinflammation in vivo. It showed that ADAMTS13 deficiency exacerbated ischemic brain injury through an MMP-9-dependent inflammatory mechanism. Therefore, the ADAMTS13-MMP-9 axis could have therapeutic potential for the treatment of AIS.

Acute encephalopathy in the ICU: a practical approach.

PURPOSE OF REVIEW: Acute encephalopathy (AE) - which frequently develops in critically ill patients with and without primary brain injury - is defined as an acute process that evolves rapidly and leads to changes in baseline cognitive status, ranging from delirium to coma. The diagnosis, monitoring, and management of AE is challenging. Here, we discuss advances in definitions, diagnostic approaches, therapeutic options, and implications to outcomes of the clinical spectrum of AE in ICU patients without primary brain injury. RECENT FINDINGS: Understanding and definitions of delirium and coma have evolved. Delirium is a neurocognitive disorder involving impairment of attention and cognition, usually fluctuating, and developing over hours to days. Coma is a state of unresponsiveness, with absence of command following, intelligible speech, or visual pursuit, with no imaging or neurophysiological evidence of cognitive motor dissociation. The CAM-ICU(-7) and the ICDSC are validated, guideline-recommended tools for clinical delirium assessment, with identification of clinical subtypes and stratification of severity. In comatose patients, the roles of continuous EEG monitoring and neuroimaging have grown for the early detection of secondary brain injury and treatment of reversible causes. SUMMARY: Evidence-based pharmacologic treatments for delirium are limited. Dexmedetomidine is effective for mechanically ventilated patients with delirium, while haloperidol has minimal effect of delirium but may have other benefits. Specific treatments for coma in nonprimary brain injury are still lacking.

Acute Respiratory Failure in Severe Acute Brain Injury.

Acute respiratory failure is commonly encountered in severe acute brain injury due to a multitude of factors related to the sequelae of the primary injury. The interaction between pulmonary and neurologic systems in this population is complex, often with competing priorities. Many treatment modalities for acute respiratory failure can result in deleterious effects on cerebral physiology, and secondary brain injury due to elevations in intracranial pressure or impaired cerebral perfusion. High-quality literature is lacking to guide clinical decision-making in this population, and deliberate considerations of individual patient factors must be considered to optimize each patient's care.

Management of Head Trauma.

Traumatic brain injury (TBI) represents a heterogenous spectrum of disease. It is essential to rapidly assess a patient's neurologic status and implement measures to prevent secondary brain injury. Intracranial hypertension, a common sequela of TBI, is managed in a tiered and systematic fashion, starting with the least invasive and moving toward the most invasive. TBI has long-lasting effects on patients and their families and represents a substantial financial and social influence on society. Research regarding the prognosis and treatment of TBI is essential to limit the influence of this widespread disease.

The combination treatment of hypothermia and intranasal insulin ameliorates the structural and functional changes in a rat model of traumatic brain injury.

The present study aimed to investigate the combination effects of hypothermia (HT) and intranasal insulin (INS) on structural changes of the hippocampus and cognitive impairments in the traumatic brain injury (TBI) rat model. The rats were divided randomly into the following five groups (n = 10): Sham, TBI, TBI with HT treatment for 3 h (TBI + HT), TBI with INS (ten microliters of insulin) treatment daily for 7 days (TBI + INS), and TBI with combining HT and INS (TBI + HT + INS). At the end of the 7th day, the open field and the Morris water maze tests were done for evaluation of anxiety-like behavior and memory performance. Then, after sacrificing, the brain was removed for stereological study. TBI led to an increase in the total volume of hippocampal subfields CA1 and DG and a decrease in the total number of neurons and non-neuronal cells in both sub-regions, which was associated with anxiety-like behavior and memory impairment. Although, the combination of HT and INS prevented the increased hippocampal volume and cell loss and improved behavioral performances in the TBI group. Our study suggests that the combined treatment of HT and INS could prevent increased hippocampal volume and cell loss in CA1 and DG sub-regions and consequently improve anxiety-like behaviors and memory impairment following TBI.

Upper limb motor dysfunction is associated with fragmented kinetics after brain injury.

BACKGROUND: Characterization of motor deficits after brain injury is important for rehabilitation personalization. While studies reported abnormalities in the kinematics of paretic and non-paretic elbow extension for patients with brain injuries, kinematic analysis is not sufficient to explore how patients deal with musculoskeletal redundancy and the energetic aspect of movement execution. Conversely, interarticular coordination and movement kinetics can reflect patients' motor strategies. This study investigates motor strategies of paretic and non-paretic upper limb after brain injury to highlight motor deficits or compensation strategies. METHODS: 26 brain-injured hemiplegic patients and 24 healthy controls performed active elbow extensions in the horizontal plane, with both upper limbs for patients and, with the dominant upper limb for controls. Elbow and shoulder kinematics, interarticular coordination, net joint kinetics were quantified. FINDINGS: Results show alterations in kinematics, and a strong correlation between elbow and shoulder angles, as well as time to reach elbow and shoulder peak angular velocity in both upper limbs of patients. Net joint kinetics were lower for paretic limb and highlighted a fragmented motor strategy with increased number of transitions between concentric and eccentric phases. INTERPRETATION: In complement to kinematic results, our kinetic results confirmed patients' difficulties to manage both spatially and temporally the joint degrees of freedom redundancy but revealed a fragmented compensatory motor strategy allowing patients upper limb extension despite quality alteration and decrease in energy efficiency. Motor rehabilitation should improve the management of this fragmentation strategy to improve the performance and the efficiency of active movement after brain injury.

Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment.

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1+ ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants.

Pathophysiology of acute lung injury in patients with acute brain injury: the triple-hit hypothesis.

It has been convincingly demonstrated in recent years that isolated acute brain injury (ABI) may cause severe dysfunction of peripheral extracranial organs and systems. Of all potential target organs and systems, the lung appears to be the most vulnerable to damage after ABI. The pathophysiology of the bidirectional brain-lung interactions is multifactorial and involves inflammatory cascades, immune suppression, and dysfunction of the autonomic system. Indeed, the systemic effects of inflammatory mediators in patients with ABI create a systemic inflammatory environment ("first hit") that makes extracranial organs vulnerable to secondary procedures that enhance inflammation, such as mechanical ventilation (MV), surgery, and infections ("second hit"). Moreover, accumulating evidence supports the knowledge that gut microbiota constitutes a critical superorganism and an organ on its own, potentially modifying various physiological functions of the host. Furthermore, experimental and clinical data suggest the existence of a communication network among the brain, gastrointestinal tract, and its microbiome, which appears to regulate immune responses, gastrointestinal function, brain function, behavior, and stress responses, also named the "gut-microbiome-brain axis." Additionally, recent research evidence has highlighted a crucial interplay between the intestinal microbiota and the lungs, referred to as the "gut-lung axis," in which alterations during critical illness could result in bacterial translocation, sustained inflammation, lung injury, and pulmonary fibrosis. In the present work, we aimed to further elucidate the pathophysiology of acute lung injury (ALI) in patients with ABI by attempting to develop the "double-hit" theory, proposing the "triple-hit" hypothesis, focused on the influence of the gut-lung axis on the lung. Particularly, we propose, in addition to sympathetic hyperactivity, blast theory, and double-hit theory, that dysbiosis and intestinal dysfunction in the context of ABI alter the gut-lung axis, resulting in the development or further aggravation of existing ALI, which constitutes the "third hit."

Lateral fluid percussion injury: A rat model of experimental traumatic brain injury.

Traumatic brain injury (TBI) represents one of the leading causes of disability and death worldwide. The annual economic impact of TBI-including direct and indirect costs-is high, particularly impacting low- and middle-income countries. Despite extensive research, a comprehensive understanding of the primary and secondary TBI pathophysiology, followed by the development of promising therapeutic approaches, remains limited. These fundamental caveats in knowledge have motivated the development of various experimental models to explore the molecular mechanisms underpinning the pathogenesis of TBI. In this context, the Lateral Fluid Percussion Injury (LFPI) model produces a brain injury that mimics most of the neurological and systemic aspects observed in human TBI. Moreover, its high reproducibility makes the LFPI model one of the most widely used rodent-based TBI models. In this chapter, we provide a detailed surgical protocol of the LFPI model used to induce TBI in adult Wistar rats. We further highlight the neuroscore test as a valuable tool for the evaluation of TBI-induced sensorimotor consequences and their severity in rats. Lastly, we briefly summarize the current knowledge on the pathological aspects and functional outcomes observed in the LFPI-induced TBI model in rodents.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

Symptoms and Functional Outcomes Among Traumatic Brain Injury Patients 3- to 12-Months Post-Injury.

BACKGROUND: Patients with traumatic brain injury (TBI) experience a variety of physical, cognitive, and affective symptoms. However, the evolution of symptoms, especially during the 3- to 12-month convalescence period (when recovery of function is still possible), is understudied. OBJECTIVE: This study aims to identify symptoms and the relationships with functional outcomes that occur during the 3- to 12-month period after a TBI. METHODS: Participants who were 3 to 12 months post-TBI were recruited from a South Florida TBI clinic from May 2022 to June 2023. Clinical data were obtained from the electronic health record. Participants completed the Brain Injury Association of Virginia Symptom Checklist, Neuro-Quality of Life Cognitive Function, Anxiety, Depression, and Sleep Disturbance assessments to report symptoms, and the Disability Rating Scale and Satisfaction with Life Scale. Descriptive statistics were used to characterize demographics and symptoms. Linear regression was performed to analyze the relationships between symptoms and outcomes. RESULTS: A total of N = 39 patients participated in the study. Memory problems and difficulty concentrating were the most common symptoms. Hospital length of stay, intensive care unit length of stay, cognitive, and physical symptoms were significantly associated with the Disability Rating Scale score. Physical, cognitive, depressive, and anxiety symptoms had significant associations with the Satisfaction with Life Scale. CONCLUSION: Cognitive symptoms should be integrated into the clinical care of rehabilitating TBI patients. Nurses should monitor for physical, affective, and cognitive symptoms during the recovery phase of TBI.

Clinical characteristics of benign paroxysmal positional vertigo after traumatic brain injury.

INTRODUCTION: The aim of the present study was to evaluate the characteristics of brain injury and to assess the relationship between them and treatment outcomes in patients with traumatic benign paroxysmal positional vertigo (t-BPPV). MATERIALS AND METHODS: Sixty-three consecutive patients who were diagnosed with BPPV within 2 weeks after head trauma were included. RESULTS: Cerebral concussion, intracranial hemorrhages (ICH), skull fracture without ICH, and hemorrhagic contusion were observed in 68%, 24%, 5%, and 3% of t-BPPV patients, respectively. BPPV with single canal involvement was observed in 52 (83%) patients and that with multiple canal involvement was observed in 11 (17%) patients. The number of treatment sessions was not significantly different according to the cause of head trauma (p = 0.252), type of brain injury (p = 0.308) or location of head trauma (p = 0.287). The number of recurrences was not significantly different according to the cause of head trauma (p = 0.308), type of brain injury (p = 0.536) or location of head trauma (p = 0.138). CONCLUSION: The present study demonstrated that there were no significant differences in treatment sessions until resolution and the mean number of recurrences according to the type of brain injury.

Accelerated long-term forgetting in patients with acquired brain injury.

OBJECTIVE: Recent research suggests that patients with neurological disorders without overt seizures may also experience accelerated long-term forgetting (ALF). This term describes unimpaired learning and memory performance after standard retention intervals, but an excessive rate of forgetting over delays of days or weeks. The objective of this retrospective study was to investigate ALF in patients with an acquired brain injury (ABI) and to associate memory performance with executive functions. METHODS: Verbal memory performance (short-term recall, 30-min recall, 1-week recall) was assessed in 34 adult patients with ABI and compared to a healthy control group (n = 54) using an auditory word learning and memory test. RESULTS: Repeated measure analysis showed significant effects of time and group as well as interaction effects between time and group regarding recall and recognition performance. Patients with ABI had a significantly impaired 1-week recall and recognition performance compared to the healthy control group. Correlations between recall performance and executive functions were nonsignificant. DISCUSSION: Our results demonstrate that non-epileptic patients with ABI, especially patients with frontal and fronto-temporal lesions, are prone to ALF. Additionally, our data support the assumption that ALF results from a consolidation impairment since verbal recall and recognition were impaired in patients with ABI.

Feasibility of a novel blended-care intervention for fatigue after acquired brain injury: a pilot study of the Tied by Tiredness intervention.

PURPOSE: Evidence-based treatments for fatigue after brain injury are scarce and often not personalized. An approach to foster personalization is Experience Sampling Methodology (ESM), consisting of repeated daily measurements of fatigue and related factors in daily life. We investigated the feasibility and usability of a novel six-week ESM-based intervention for fatigue after brain injury. MATERIALS AND METHODS: Ten individuals with acquired brain injury (six men; four women) aged between 36-70 years (M = 53.3, SD = 12.9) used a mHealth application for three days each week during six-weeks; seven completed the intervention. Momentary fatigue, activities, mood, worrying, and social context were assessed with ESM and participants received weekly personalized feedback by a therapist.. RESULTS: 56% of ESM-questionnaires (568/1008) were completed, providing detailed insights into individual fatigue patterns. No statistically significant decrease in response rate was found over the course of treatment. Qualitative feedback from participants revealed increased insight into factors underlying fatigue, and no problems with treatment duration or difficulties using the app. Five participants showed a decline in fatigue level during treatment. CONCLUSIONS: This pilot study provides initial support for the feasibility and usability of this novel blended-care intervention, aimed at alleviating fatigue through personalized feedback and treatment strategies.

Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma.

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury.

Acute gastrointestinal permeability after traumatic brain injury in mice precedes a bloom in Akkermansia muciniphila supported by intestinal hypoxia.

Traumatic brain injury (TBI) increases gastrointestinal morbidity and associated mortality. Clinical and preclinical studies implicate gut dysbiosis as a consequence of TBI and an amplifier of brain damage. However, little is known about the association of gut dysbiosis with structural and functional changes of the gastrointestinal tract after an isolated TBI. To assess gastrointestinal dysfunction, mice received a controlled cortical impact or sham brain injury and intestinal permeability was assessed at 4 h, 8 h, 1 d, and 3 d after injury by oral administration of 4 kDa FITC Dextran prior to euthanasia. Quantification of serum fluorescence revealed an acute, short-lived increase in permeability 4 h after TBI. Despite transient intestinal dysfunction, no overt morphological changes were evident in the ileum or colon across timepoints from 4 h to 4 wks post-injury. To elucidate the timeline of microbiome changes after TBI, 16 s gene sequencing was performed on DNA extracted from fecal samples collected prior to and over the first month after TBI. Differential abundance analysis revealed that the phylum Verrucomicrobiota was increased at 1, 2, and 3 d after TBI. The Verrucomicrobiota species was identified by qPCR as Akkermansia muciniphila, an obligate anaerobe that resides in the intestinal mucus bilayer and produces short chain fatty acids (e.g. butyrate) utilized by intestinal epithelial cells. We postulated that TBI promotes intestinal changes favorable for the bloom of A. muciniphila. Consistent with this premise, the relative area of mucus-producing goblet cells in the medial colon was significantly increased at 1 d after injury, while colon hypoxia was significantly increased at 3 d. Our findings reveal acute gastrointestinal functional changes coupled with an increase of beneficial bacteria suggesting a potential compensatory response to systemic stress after TBI.