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Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus coeruleus-norepinephrine (LC-NE) system is a critical regulator of arousal levels and higher executive processes affected by TBI including attention, working memory, and decision making. LC-NE axon injury and impaired signaling within the prefrontal cortex (PFC) is a potential contributor to the neuropsychiatric symptoms after single, moderate to severe TBI. The majority of TBIs are mild, yet long-term cognitive deficits and increased susceptibility for further injury can accumulate after each repetitive mild TBI. As a potential treatment for restoring cognitive function and daytime sleepiness after injury psychostimulants, including methylphenidate (MPH) that increase levels of NE within the PFC, are being prescribed "off-label". The impact of mild and repetitive mild TBI on the LC-NE system remains limited. Therefore, we determined the extent of LC-NE and arousal dysfunction and response to therapeutic doses of MPH in rats following experimentally induced single and repetitive mild TBI. Microdialysis measures of basal NE efflux from the medial PFC and arousal measures were significantly lower after repetitive mild TBI. Females showed higher baseline PFC-NE efflux than males following single and repetitive mild TBI. In response to MPH challenge, males exhibited a blunted PFC-NE response and persistent arousal levels following repetitive mild TBI. These results provide critical insight into the role of catecholamine system dysfunction associated with cognitive deficits following repeated injury, outcome differences between sex/gender, and lack of success of MPH as an adjunctive therapy to improve cognitive function following injury., 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. Published by Elsevier B.V.)

Intracranial pressure monitoring enables the detection and treatment of intracranial hypertension, a potentially lethal insult after traumatic brain injury. Despite its widespread use, robust evidence supporting intracranial pressure monitoring and treatment remains sparse. International studies have shown large variations between centres regarding the indications for intracranial pressure monitoring and treatment of intracranial hypertension. Experts have reviewed these two aspects and, by consensus, provided practical approaches for monitoring and treatment. Advances have occurred in methods for non-invasive estimation of intracranial pressure although, for now, a reliable way to non-invasively and continuously measure intracranial pressure remains aspirational. Analysis of the intracranial pressure signal can provide information on brain compliance (ie, the ability of the cranium to tolerate volume changes) and on cerebral autoregulation (ie, the ability of cerebral blood vessels to react to changes in blood pressure). The information derived from the intracranial pressure signal might allow for more individualised patient management. Machine learning and artificial intelligence approaches are being increasingly applied to intracranial pressure monitoring, but many obstacles need to be overcome before their use in clinical practice could be attempted. Robust clinical trials are needed to support indications for intracranial pressure monitoring and treatment. Progress in non-invasive assessment of intracranial pressure and in signal analysis (for targeted treatment) will also be crucial., Competing Interests: Declaration of interests EB reports scholarships from the Gates Cambridge Trust and the Medical Research Council (UK). GWJH reports grants from the Department of Defense (USA); is a board member of Global Neuro (Switzerland), a not-for profit provider of educational material on the topic of neurotrauma; and is medical director of the Brain Trauma Foundation (USA). TH reports patents (US patent number 8,366,627; PCT application number PCT/US2019/029776; and PCT/US2023/076170) that all resulted from academic work, are owned by the Massachusetts Institute of Technology, have not been licensed to any commercial entity, and no royalty or license fees have been obtained by MIT or the co-inventors. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Traumatic brain injury (TBI) represents a major cause of death and disability, significantly impacting the lives of 2.5 million people annually in the United States. Long-term natural history studies have clarified that functional recovery continues for up to a decade, even among those who sustain severe TBI. Despite these findings, nihilistic attitudes regarding prognosis persist among clinicians, highlighting the need for improved understanding of the natural history of recovery from TBI and the factors that influence outcome. Recent advances in neuroimaging technologies and blood-based biomarkers are shedding new light on injury detection, severity classification and the physiologic mechanisms underlying recovery and decline postinjury. Rehabilitation is an essential component of clinical management after moderate to severe TBI and can favorably influence mortality and functional outcome. However, systemic barriers, including healthcare policy, insurance coverage and social determinants of health often limit access to inpatient rehabilitation services. Posttraumatic amnesia and confusion contribute to morbidity after TBI; however, early initiation and sustained provision of rehabilitation interventions optimize long-term outcome. Evidence-based reviews have clearly shown that cognitive rehabilitation strategies can effectively restore or compensate for the cognitive sequelae of TBI when used according to existing practice guidelines. Neurostimulant agents are commonly employed off-label to enhance functional recovery, however, only amantadine hydrochloride has convincingly demonstrated effectiveness when used under tested parameters. Noninvasive brain stimulation procedures, including transcranial direct current stimulation and transcranial magnetic stimulation, have emerged as promising treatments in view of their ability to modulate aberrant neuronal activity and augment adaptive neuroplasticity, but assessment of safety and effectiveness during the acute period has been limited. Understanding the natural history of recovery from TBI and the effectiveness of available therapeutic interventions is essential to ensuring appropriate clinical management of this complex population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Impact kinematics are widely employed to investigate mechanisms of traumatic brain injury (TBI). However, they are susceptible to noise and artefacts; thus, require data filtering. Few studies have focused on how data filtering affects brain strain most relevant to TBI. Here, we report that impact-induced brain strains are much less sensitive to data filtering than kinematics based on three filtering methods: CFC180, lowpass 200 Hz, and a new method called Head Exposure to Acceleration Database in Sport (HEADSport)., Methods: Using mouthguard-measured head impacts in elite rugby (N = 5694), average Euclidean distances between the three filtered angular velocity profiles and their unfiltered counterparts are used to identify three groups of impacts with large variations: 90-95th, 95-99th, and >99th percentile. From each group, 20 impacts are randomly selected for simulation using the anisotropic Worcester Head Injury Model (WHIM) V1.0., Results and Conclusion: HEADSport and CFC180 are the most and least effective, respectively, in suppressing "unphysical artefacts" shown as sharp spikes with a rather short impulse duration (e.g., <3 ms) in angular velocity. However, maximum principal strain (MPS), especially that in the corpus callosum, is much less sensitive to data filtering compared to kinematic peaks (e.g., reduction of 3% vs. 47% and 90% for peak angular velocity and acceleration with HEADSport for impacts of >99th percentile)., Significance: These findings confirm that the brain acts as a low-pass filter, itself, to suppress high frequency noise in impact kinematics. Therefore, brain strain can serve as a common metric for TBI biomechanical studies to maximize relevance to the injury, as it is not sensitive to kinematic filters.

Objective: Wearable devices are developed to measure head impact kinematics but are intrinsically noisy because of the imperfect interface with human bodies. This study aimed to improve the head impact kinematics measurements obtained from instrumented mouthguards using deep learning to enhance traumatic brain injury (TBI) risk monitoring., Methods: We developed one-dimensional convolutional neural network (1D-CNN) models to denoise mouthguard kinematics measurements for tri-axial linear acceleration and tri-axial angular velocity from 163 laboratory dummy head impacts. The performance of the denoising models was evaluated on three levels: kinematics, brain injury criteria, and tissue-level strain and strain rate. Additionally, we performed a blind test on an on-field dataset of 118 college football impacts and a test on 413 post-mortem human subject (PMHS) impacts., Results: On the dummy head impacts, the denoised kinematics showed better correlation with reference kinematics, with relative reductions of 36% for pointwise root mean squared error and 56% for peak absolute error. Absolute errors in six brain injury criteria were reduced by a mean of 82%. For maximum principal strain and maximum principal strain rate, the mean error reduction was 35% and 69%, respectively. On the PMHS impacts, similar denoising effects were observed and the peak kinematics after denoising were more accurate (relative error reduction for 10% noisiest impacts was 75.6%)., Conclusion: The 1D-CNN denoising models effectively reduced errors in mouthguard-derived kinematics measurements on dummy and PMHS impacts., Significance: This study provides a novel approach for denoising head kinematics measurements in dummy and PMHS impacts, which can be further validated on more real-human kinematics data before real-world applications.

Background: Noradrenaline is a standard treatment for hypotension in acute care. The precise effects of noradrenaline on cerebral blood flow in health and disease remain unclear., Methods: We systematically reviewed and synthesised data from studies examining changes in cerebral blood flow in healthy participants and patients with traumatic brain injury and critical illness., Results: Twenty-eight eligible studies were included. In healthy subjects and patients without critical illness or traumatic brain injury, noradrenaline did not significantly change cerebral blood flow velocity (-1.7%, 95%CI -4.7-1.3%) despite a 24.1% (95%CI 19.4-28.7%) increase in mean arterial pressure. In patients with traumatic brain injury, noradrenaline significantly increased cerebral blood flow velocity (21.5%, 95%CI 11.0-32.0%), along with a 33.8% (95%CI 14.7-52.9%) increase in mean arterial pressure. In patients who were critically ill, noradrenaline significantly increased cerebral blood flow velocity (20.0%, 95%CI 9.7-30.3%), along with a 32.4% (95%CI 25.0-39.9%) increase in mean arterial pressure. Our analyses suggest intact cerebral autoregulation in healthy subjects and patients without critical illness or traumatic brain injury., and impaired cerebral autoregulation in patients with traumatic brain injury and who were critically ill. The extent of mean arterial pressure changes and the pre-treatment blood pressure levels may affect the magnitude of cerebral blood flow changes. Studies assessing cerebral blood flow using non-transcranial Doppler methods were inadequate and heterogeneous in enabling meaningful meta-analysis., Conclusions: Noradrenaline significantly increases cerebral blood flow in humans with impaired, not intact, cerebral autoregulation, with the extent of changes related to the severity of functional impairment, the extent of mean arterial pressure changes and pre-treatment blood pressure levels., (© 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Although several studies have documented the chronic phase of traumatic brain injury (TBI), few verified the nature and severity of cognitive impairments during the acute phase. Among the studies carried out during the acute phase, instrumental functions were rarely examined compared to attention, memory, and executive functions. This study aimed to compare the nature and intensity of cognitive problems in the acute phase according to TBI severity and age. It was hypothesized that cognitive impairments would increase in line with TBI severity and age, and that instrumental functions would be less affected in victims of mild or moderate TBI than in those with severe TBI. The Brief Cognitive Exam in Traumatology (EXACT), a new and reliable test specifically designed and validated to briefly assess global cognitive functioning during the acute phase, was administered to 319 mild to severe TBI victims (aged 16 to 96 years), within three months post-accident. The EXACT evaluates five domains: Language, Instrumental functions (other than language), Attention and working memory, Episodic memory, and Executive functions and behavioral regulation. Results confirmed the negative influence of TBI severity and age on global cognitive functioning. Also, compared to victims with a mild or moderate TBI, a higher proportion of those with a severe TBI presented impaired instrumental functions (calculation, praxis, and gnosis). Thus, during the acute phase, the nature and severity of cognitive impairments vary according to TBI severity.

Background: Preliminary evidence demonstrates that visit-to-visit systolic blood pressure (SBP) variability is a prognostic factor of TBI. However, literature regarding the impact of initial blood pressure management on the outcomes of TBI patients is limited. We aimed to further validate the clinical significance of BPV on the prognostic outcomes of patients with TBI., Methods: We performed the analysis by using individual patient-level data acquired from the eICU-CRD, which collected 200,859 ICU admissions of 139,367 patients in 2014 and 2015 from 208 US hospitals. Adult patients with traumatic intraparenchymal hemorrhage or contusion were included. The primary outcome was in-hospital mortality and the secondary outcome was discharge-home rate. Blood pressure variability (BPV) was calculated according to standard criteria: at least six measurements were taken in the first 24 h (hyperacute group) and 36 over days 2-7 (acute group). We estimated the associations between BPV and outcomes with logistic and proportional odds regression models. The key parameter for BPV was standard deviation (SD) of SBP, categorized into quintiles. We also calculated the average real variability (ARV), as well as maximum, minimum, and mean SBP for comparison in our analysis., Results: We studied 1486 patients in the hyperacute group and 857 in the acute group. SD of SBP had a significant association with the in-hospital mortality for both the hyperacute group (highest quintile adjusted OR 2.28 95% CI 1.18-4.42; p trend <0.001) and the acute group (highest quintile adjusted OR 2.17, 95% CI 1.08-4.36; p trend <0.001). The strongest predictors of primary outcome were SD of SBP in the hyperacute phase and minimum SBP in the acute phase. Associations were similar for the discharge-home rate (for the hyperacute group, highest quintile adjusted OR 0.58, 95% CI 0.37-0.89; p trend <0.001; for the acute group OR 0.55, 95% CI 0.32-0.95; p trend <0.001)., Conclusion: Systolic BPV seems to predict a poor outcome in patients with TBI. The benefits of early treatment to maintain appropriate SBP level might be enhanced by smooth and sustained control., (© 2024. The Author(s).)

Traumatic brain injury (TBI) survivors face debilitating long-term psychosocial consequences, including social isolation and depression. TBI modifies neurovascular physiology and behavior but the chronic physiological implications of altered brain perfusion on social interactions are unknown. Adult C57/BL6 male mice received a moderate cortical TBI, and social behaviors were assessed at baseline, 3-, 7-, 14-, 30-, and 60-days post injury (dpi). Magnetic resonance imaging (MRI, 9.4T) using dynamic susceptibility contrast perfusion weighted MRI were acquired. At 60dpi mice underwent histological angioarchitectural mapping. Analysis utilized standardized protocols followed by cross-correlation metrics. Social behavior deficits at 60dpi emerged as reduced interactions with a familiar cage-mate (partner) that mirrored significant reductions in cerebral blood flow (CBF) at 60dpi. CBF perturbations were dynamic temporally and across brain regions including regions known to regulate social behavior such as hippocampus, hypothalamus, and rhinal cortex. Social isolation in TBI-mice emerged with a significant decline in preference to spend time with a cage mate. Cortical vascular density was also reduced corroborating the decline in brain perfusion and social interactions. Thus, the late emergence of social interaction deficits mirrored the reduced vascular density and CBF in regions known to be involved in social behaviors. Vascular morphology and function improved prior to the late decrements in social function and our correlations strongly implicate a linkage between vascular density, cerebral perfusion, and social interactions. Our study provides a clinically relevant timeline of alterations in social deficits alongside functional vascular recovery that can guide future therapeutics., (© 2024. The Author(s).)

Sleep slow waves are the hallmark of deeper non-rapid eye movement sleep. It is generally assumed that gray matter properties predict slow-wave density, morphology, and spectral power in healthy adults. Here, we tested the association between gray matter volume (GMV) and slow-wave characteristics in 27 patients with moderate-to-severe traumatic brain injury (TBI, 32.0 ± 12.2 years old, eight women) and compared that with 32 healthy controls (29.2 ± 11.5 years old, nine women). Participants underwent overnight polysomnography and cerebral MRI with a 3 Tesla scanner. A whole-brain voxel-wise analysis was performed to compare GMV between groups. Slow-wave density, morphology, and spectral power (0.4-6 Hz) were computed, and GMV was extracted from the thalamus, cingulate, insula, precuneus, and orbitofrontal cortex to test the relationship between slow waves and gray matter in regions implicated in the generation and/or propagation of slow waves. Compared with controls, TBI patients had significantly lower frontal and temporal GMV and exhibited a subtle decrease in slow-wave frequency. Moreover, higher GMV in the orbitofrontal cortex, insula, cingulate cortex, and precuneus was associated with higher slow-wave frequency and slope, but only in healthy controls. Higher orbitofrontal GMV was also associated with higher slow-wave density in healthy participants. While we observed the expected associations between GMV and slow-wave characteristics in healthy controls, no such associations were observed in the TBI group despite lower GMV. This finding challenges the presumed role of GMV in slow-wave generation and morphology., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Purpose: After a traumatic brain injury (TBI), monitoring of both macrovascular and microvascular blood circulation can potentially yield a better understanding of pathophysiology of potential secondary brain lesions. We investigated the changes in phase shift (PS) between cardiac-induced oscillations of cerebral blood flow (CBF) measured at macro (ultrasound Doppler) and microvascular (laser Doppler) level. Further we assessed the impact of intracranial pressure (ICP) on PS in TBI patients. A secondary aim was to compare PS to TCD-derived cerebral arterial time constant (τ), a parameter that reflects the circulatory transit time., Methods: TCD blood flow velocities (FV) in the middle cerebral artery, laser Doppler blood microcirculation flux (LDF), arterial blood pressure (ABP), and ICP were monitored in 29 consecutive patients with TBI. Eight patients were excluded because of poor-quality signals. For the remaining 21 patients (median age = 23 (Q1: 20-Q3: 33); men:16,) data were retrospectively analysed. PS between the fundamental harmonics of FV and LDF signals was determined using spectral analysis. τ was estimated as a product of cerebrovascular resistance and compliance, based on the mathematical transformation of FV and ABP, ICP pulse waveforms., Results: PS was negative (median: -26 (Q1: -38-Q3: -15) degrees) indicating that pulse LDF at a heart rate frequency lagged behind TCD pulse. With rising mean ICP, PS became more negative (R = -0.51, p < 0.019) indicating that delay of LDF pulse increases. There was a significant correlation between PS and cerebrovascular time constant (R = -0.47, p = 0.03)., Conclusions: Pulse divergence between FV and LDF became greater with elevated ICP, likely reflecting prolonged circulatory travel time., (© 2024. The Author(s).)

Background: Traumatic brain injury (TBI), which is the brain impairment and lesion caused by the external force injuring the head and the underlying brain, can cause pediatric death, disability, neurological disorders, and even lifelong disability. This study was to explore the effect of riboflavin (RF) on neurological rehabilitation and functional recovery after TBI., Methods: The rat models of TBI were constructed by treating rats with controlled cortical impact (CCI). By treating TBI rats with RF, we investigated whether the administration of RF would affect the sensorimotor function and cognitive ability recovery through adhesive removal test, modified neurological severity score (mNSS), corner test, wire-grip test and the Morris water maze. The effects of RF on lesion volume and water content were investigated using hematoxylin and eosin (H&E) staining and wet-dry method. The Nissl staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were used to demonstrate the effect of RF on neural apoptosis. Inflammation-related cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were measured by enzyme-linked immunosorbent assay (ELISA) to evaluate the effect of RF on neuroinflammation. The impact of RF on oxidative stress was assessed by measuring malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, and the platelet endothelial cell adhesion molecule-1 (CD31) staining for observing vessel density, the reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for measuring vascular endothelial growth factor ( VEGF ) mRNA expression and western blot for VEGF protein expression were used for evaluated angiogenesis., Results: The administration of RF could facilitate the recovery of neurological function by promoting the recovery of sensorimotor function and cognitive ability ( p < 0.05). Furthermore, RF could reduce the lesion volume and water content after TBI and ameliorate neural apoptosis, neuroinflammation, and oxidative stress ( p < 0.05). Finally, RF increased vessel density ( p < 0.01) and VEGF levels ( p < 0.01) in brain tissues after TBI, promoting angiogenesis., Conclusion: RF benefits neurological rehabilitation after TBI by promoting neurological function recovery, ameliorating the pathogenesis after TBI, and facilitating brain vascular remodeling. These findings provide a novel mechanism for RF treating pediatric TBI.

Competing Interests: Dr. Stevens received funding from Ceribell and B-Secur. Dr. Azad disclosed that he does not have any potential conflicts of interest.

Brain injuries resulting from mechanical trauma represent an ongoing global public health issue. Several in vitro and in vivo models for traumatic brain injury (TBI) continue to be developed for delineating the various complex pathophysiological processes involved in its onset and progression. Developing an in vitro TBI model that is based on cortical spheroids is especially of great interest currently because they can replicate key aspects of in vivo brain tissue, including its electrophysiology, physicochemical microenvironment, and extracellular matrix composition. Being able to mechanically deform the spheroids are a key requirement in any effective in vitro TBI model. The spheroids' shape and size, however, make mechanically loading them, especially in a high-throughput, sterile, and reproducible manner, quite challenging. To address this challenge, we present an idea for a spheroid-based, in vitro TBI model in which the spheroids are mechanically loaded by being spun by a centrifuge. (An experimental demonstration of this new idea will be published shortly elsewhere.) An issue that can limit its utility and scope is that imaging techniques used in 2D and 3D in vitro TBI models cannot be readily applied in it to determine spheroid strains. In order to address this issue, we developed a continuum mechanics-based theory to estimate the spheroids' strains when they are being spun at a constant angular velocity. The mechanics theory, while applicable here to a special case of the centrifuge-based TBI model, is also of general value since it can help with the further exploration and development of TBI models., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aimed to explore the effects of the cluster nursing strategy applied to traumatic brain injury (TBI) patients. Ninety-eight TBI patients admitted to the hospital were selected as the study subjects. They were randomized into two groups, the control group and the cluster group, with 49 cases in each group. The control group received routine nursing methods, while the cluster group received cluster nursing strategy. The intervention effects were compared between the two groups. After 3 months, the total occurrence of complications in the cluster group was significantly lower than that in the control group. Postintervention, the cluster group had a significantly lower National Institutes of Health Stroke Scale score and significantly higher Fugl-Meyer score and Loewenstein Occupational Therapy Cognitive Assessment score compared with the control group. The serum level of glial fibrillary acidic protein in the control group was significantly higher than that in the cluster group, while the serum level of brain-derived neurotrophic factor was significantly lower. The application of the cluster nursing strategy in the care of patients with TBI could effectively reduce the risk of complications and improve neurological, motor, and cognitive functions.

Traumatic brain injury (TBI) poses a significant global public health challenge necessitating a profound understanding of cerebral physiology. The dynamic nature of TBI demands sophisticated methodologies for modeling and predicting cerebral signals to unravel intricate pathophysiology and predict secondary injury mechanisms prior to their occurrence. In this comprehensive scoping review, we focus specifically on multivariate cerebral physiologic signal analysis in the context of multi-modal monitoring (MMM) in TBI, exploring a range of techniques including multivariate statistical time-series models and machine learning algorithms. Conducting a comprehensive search across databases yielded 7 studies for evaluation, encompassing diverse cerebral physiologic signals and parameters from TBI patients. Among these, five studies concentrated on modeling cerebral physiologic signals using statistical time-series models, while the remaining two studies primarily delved into intracranial pressure (ICP) prediction through machine learning models. Autoregressive models were predominantly utilized in the modeling studies. In the context of prediction studies, logistic regression and Gaussian processes (GP) emerged as the predominant choice in both research endeavors, with their performance being evaluated against each other in one study and other models such as random forest, and decision tree in the other study. Notably among these models, random forest model, an ensemble learning approach, demonstrated superior performance across various metrics. Additionally, a notable gap was identified concerning the absence of studies focusing on prediction for multivariate outcomes. This review addresses existing knowledge gaps and sets the stage for future research in advancing cerebral physiologic signal analysis for neurocritical care improvement., Competing Interests: Declaration of competing interest The authors assert that they have no conflicts of interest to disclose regarding this work, confirming the absence of any financial interests, affiliations, or personal relationships that may have influenced or biased this research., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The neurological examination has remained key for the detection of worsening in neurocritical care patients, particularly after traumatic brain injury (TBI). New-onset, unreactive anisocoria frequently occurs in such situations, triggering aggressive diagnostic and therapeutic measures to address life-threatening elevations in intracranial pressure (ICP). As such, the field needs objective, unbiased, portable, and reliable methods for quickly assessing such pupillary changes. In this area, quantitative pupillometry (QP) proves promising, leveraging the analysis of different pupillary variables to indirectly estimate ICP. Thus, this scoping review seeks to describe the existing evidence for the use of QP in estimating ICP in adult patients with TBI as compared with invasive methods, which are considered the standard practice. This review was conducted in accordance with the Joanna Briggs Institute methodology for scoping reviews, with a main search of PubMed and EMBASE. The search was limited to studies of adult patients with TBI published in any language between 2012 and 2022. Eight studies were included for analysis, with the vast majority being prospective studies conducted in high-income countries. Among QP variables, serial rather than isolated measurements of neurologic pupillary index, constriction velocity, and maximal constriction velocity demonstrated the best correlation with invasive ICP measurement values, particularly in predicting refractory intracranial hypertension. Neurologic pupillary index and ICP also showed an inverse relationship when trends were simultaneously compared. As such, QP, when used repetitively, seems to be a promising tool for noninvasive ICP monitoring in patients with TBI, especially when used in conjunction with other clinical and neuromonitoring data., (© 2024. The Author(s).)

Objectives: The first aim was to investigate the combined effect of insult intensity and duration of the pressure reactivity index (PRx) and deviation from the autoregulatory cerebral perfusion pressure target (∆CPPopt = actual CPP - optimal CPP [CPPopt]) on outcome in traumatic brain injury. The second aim was to determine if PRx influenced the association between intracranial pressure (ICP), CPP, and ∆CPPopt with outcome., Design: Observational cohort study., Setting: Neurocritical care unit, Cambridge, United Kingdom., Patients: Five hundred fifty-three traumatic brain injury patients with ICP and arterial blood pressure monitoring and 6-month outcome data (Glasgow Outcome Scale [GOS])., Intervention: None., Measurements and Main Results: The insult intensity (mm Hg or PRx coefficient) and duration (minutes) of ICP, PRx, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In these plots, there was a transition from favorable to unfavorable outcome when PRx remained positive for 30 minutes and this was also the case for shorter durations when the intensity was higher. In a similar plot of ∆CPPopt, there was a gradual transition from favorable to unfavorable outcome when ∆CPPopt went below -5 mm Hg for 30-minute episodes of time and for shorter durations for more negative ∆CPPopt. Furthermore, the percentage of monitoring time with certain combinations of PRx with ICP, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In the combined PRx/ICP heatmap, ICP above 20 mm Hg together with PRx above 0 correlated with unfavorable outcome. In a PRx/CPP heatmap, CPP below 70 mm Hg together with PRx above 0.2-0.4 correlated with unfavorable outcome. In the PRx-/∆CPPopt heatmap, ∆CPPopt below 0 together with PRx above 0.2-0.4 correlated with unfavorable outcome., Conclusions: Higher intensities for longer durations of positive PRx and negative ∆CPPopt correlated with worse outcome. Elevated ICP, low CPP, and negative ∆CPPopt were particularly associated with worse outcomes when the cerebral pressure autoregulation was concurrently impaired., Competing Interests: Dr. Begiri received funding from the Medical Research Council (grant MR N013433-1) and the Gates Cambridge Scholarship. Dr. Bögli received funding from the Swiss National Science Foundation (grant 210839). Dr. Helmy’s institution received funding from the Medical Research Council; they received support for article research from the Research Councils UK. Dr. Smielewski receives part of the licensing fees for ICM+ software, licensed by Cambridge Enterprise Ltd, University of Cambridge, Cambridge. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background and Objectives: Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) with both often preceded by traumatic brain injury (TBI). FS and ES emergence and occurrence after TBI may be linked to aberrant neurobehavioral stress responses. We hypothesized that neural activity signatures in response to a psychosocial stress task would differ between TBI + FS and TBI + ES after controlling for TBI status (TBI-only)., Methods: In the current multicenter study, participants were recruited prospectively from Rhode Island Hospital, Providence Rhode Island Veterans Administration Medical Center, and the University of Alabama at Birmingham Medical Center. Previous diagnoses of TBI, ES, and FS were verified based on data collected from participants, medical chart and record review, and, where indicated, results of EEG and/or video-EEG confirmatory diagnosis. TBI + ES (N = 21) and TBI + FS (N = 21) were matched for age and sex and combined into an initial group (TBI + SZ; N = 42). A TBI-only group (N = 42) was age and sex matched to the TBI with seizures (TBI + SZ) group. All participants completed an fMRI control math task (CMT) and stress math task (SMT) based on the Montreal Imaging Stress Task (MIST)., Results: The TBI + SZ group (n = 24 female) did not differ in mood or anxiety severity compared to TBI-only group (n = 24 female). However, TBI + FS group (n = 11 female) reported greater severity of these symptoms compared to TBI + ES (n = 13 female). The linear mixed effects analysis identified neural responses that differed between TBI-only and TBI + SZ during math performance within the left premotor cortex and during auditory feedback within bilateral prefrontal cortex and hippocampus/amygdala regions. Additionally, neural responses differed between TBI + ES and TBI + FS during math performance within the right dorsolateral prefrontal cortex and bilateral amygdala during auditory feedback within the supplementary motor area. All tests comparing neural stress responses to psychiatric symptom severity failed to reach significance., Discussion: Controlling for TBI and seizure status, these findings implicate specific nodes within frontal, limbic, and sensorimotor networks that may maintain functional neurological symptoms and possibly distinguish FS from ES. This study provides class II evidence of differences in neural responses to psychosocial stress between ES and FS after TBI., 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 Elsevier Inc. All rights reserved.)

Intracranial hypertension (IH) is a key driver of secondary brain injury in patients with traumatic brain injury. Lowering intracranial pressure (ICP) as soon as IH occurs is important, but a preemptive approach would be more beneficial. We systematically reviewed the artificial intelligence (AI) models, variables, performances, risks of bias, and clinical machine learning (ML) readiness levels of IH prediction models using AI. We conducted a systematic search until 12-03-2023 in three databases. Only studies predicting IH or ICP in patients with traumatic brain injury with a validation of the AI model were included. We extracted type of AI model, prediction variables, model performance, validation type, and prediction window length. Risk of bias was assessed with the Prediction Model Risk of Bias Assessment Tool, and we determined the clinical ML readiness level. Eleven out of 399 nonduplicate publications were included. A gaussian processes model using ICP and mean arterial pressure was most common. The maximum reported area under the receiver operating characteristic curve was 0.94. Four studies conducted external validation, and one study a prospective clinical validation. The prediction window length preceding IH varied between 30 and 60 min. Most studies (73%) had high risk of bias. The highest clinical ML readiness level was 6 of 9, indicating "real-time model testing" stage in one study. Several IH prediction models using AI performed well, were externally validated, and appeared ready to be tested in the clinical workflow (clinical ML readiness level 5 of 9). A Gaussian processes model was most used, and ICP and mean arterial pressure were frequently used variables. However, most studies showed a high risk of bias. Our findings may help position AI for IH prediction on the path to ultimate clinical integration and thereby guide researchers plan and design future studies., (© 2024. The Author(s).)

Background and Objectives: Severe traumatic brain injury (sTBI) represents a diffuse, heterogeneous disease where therapeutic targets for optimizing clinical outcome remain unclear. Mean pressure reactivity index (PRx) values have demonstrated associations with clinical outcome in sTBI. However, the retrospective derivation of a mean value diminishes its bedside significance. We evaluated PRx temporal profiles for patients with sTBI and identified time thresholds suggesting optimal neuroprognostication., Methods: Patients with sTBI and continuous bolt intracranial pressure monitoring were identified. Outcomes were dichotomized by disposition status ("good outcome" was denoted by home and acute rehabilitation). PRx values were obtained every minute by taking moving correlation coefficients of intracranial pressures and mean arterial pressures. Average PRx trajectories for good and poor outcome groups were calculated by extending the last daily averaged PRx value to day 18. Each patient also had smoothed PRx trajectories that were used to generate "candidate features." These "candidate features" included daily average PRx's, cumulative first-order changes in PRx and cumulative second-order changes in PRx. Changes in sensitivity over time for predicting poor outcome was then evaluated by generating penalized logistic regression models that were derived from the "candidate features" and maximized specificity., Results: Among 33 patients with sTBI, 18 patients achieved good outcome and 15 patients had poor outcome. Average PRx trajectories for the good and poor outcome groups started on day 6 and consistently diverged at day 9. When targeting a specificity >83.3%, an 85% maximum sensitivity for determining poor outcome was achieved at hospital day 6. Subsequent days of PRx monitoring showed diminishing sensitivities., Conclusion: Our findings suggest that in a population of sTBI, PRx sensitivities for predicting poor outcome was maximized at hospital day 6. Additional study is warranted to validate this model in larger populations., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Mild-moderate traumatic brain injuries (TBIs) are prevalent, and while many individuals recover, there is evidence that a significant number experience long-term health impacts, including increased vulnerability to neurodegenerative diseases. These effects are influenced by other risk factors, such as cardiovascular disease. Our study tested the hypothesis that a pre-injury reduction in cerebral blood flow (CBF), mimicking cardiovascular disease, worsens TBI recovery. We induced bilateral carotid artery stenosis (BCAS) and a mild-moderate closed-head TBI in male and female mice, either alone or in combination, and analyzed CBF, spatial learning, memory, axonal damage, and gene expression. Findings showed that BCAS and TBI independently caused a ~10% decrease in CBF. Mice subjected to both BCAS and TBI experienced more significant CBF reductions, notably affecting spatial learning and memory, particularly in males. Additionally, male mice showed increased axonal damage with both BCAS and TBI compared to either condition alone. Females exhibited spatial memory deficits due to BCAS, but these were not worsened by subsequent TBI. Gene expression analysis in male mice highlighted that TBI and BCAS individually altered neuronal and glial profiles. However, the combination of BCAS and TBI resulted in markedly different transcriptional patterns. Our results suggest that mild cerebrovascular impairments, serving as a stand-in for preexisting cardiovascular conditions, can significantly worsen TBI outcomes in males. This highlights the potential for mild comorbidities to modify TBI outcomes and increase the risk of secondary diseases., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Sleep - wake disturbances (SWDs) are one of the most common complaints following traumatic brain injury (TBI). The high prevalence and socioeconomic burden of SWDs post-TBI have only been recognized in the past decade. Common SWDs induced by TBI include excessive daytime sleepiness (EDS), hypersomnia, insomnia, obstructive sleep apnea (OSA), and circadian rhythm sleep disorders. Sleep disturbances can significantly compromise quality of life, strain interpersonal relationships, diminish work productivity, exacerbate other clinical conditions, and impede the rehabilitation process of TBI patients. Consequently, the prompt regulation and enhancement of sleep homeostasis in TBI patients is of paramount importance. Although studies have shown that abnormal neural network function, neuroendocrine changes, disturbance of sleep - wake regulators, and immune inflammatory responses related to brain structural damage induced by TBI are involved in the development of SWDs, the exact neuropathological mechanisms are still poorly understood. Therefore, we systematically review the current clinical and experimental studies on the characteristics and possible neural mechanisms of post-TBI SWDs. Elucidating the neural underpinnings of post-TBI SWDs holds the potential to diversify and enhance therapeutic approaches for these conditions. Such advancements could hasten the recuperation of TBI patients and ameliorate their overall quality of life. It is our aspiration that departments specializing in neurosurgery, rehabilitation, and neuropsychiatry will be able to recognize and address these conditions promptly, thereby facilitating the healing journey of affected individuals.

Background: The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO 2 ) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation., Methods: Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO 2 . Autoregulatory function was measured by interrogating changes in ICP and PbtO 2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP., Results: Individualized limits of autoregulation were computed in 55 patients (mean age 38 years, mean monitoring time 92 h). We identified 35 episodes of brain tissue hypoxia (PbtO 2  < 20 mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14 mm Hg to 79 ± 17 mm Hg (p = 0.15), and mean PbtO 2 improved from 18.4 ± 5.6 mm Hg to 21.9 ± 5.6 mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60 min after compared with before an intervention (11% vs. 23%, p = 0.05)., Conclusions: Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Key Points: Patients with traumatic brain injury (TBI) had worse olfactory quality of life (QoL) and Sino-Nasal Outcome Test-22 scores compared to a normal cohort. A worse olfactory QoL correlated with concussion symptom burden. Olfactory dysfunction among TBI patients should be addressed to improve overall outcomes., (© 2024 ARS‐AAOA, LLC.)

Background: Moderate-to-severe traumatic brain injury (TBI) has a global mortality rate of about 30%, resulting in acquired life-long disabilities in many survivors. To potentially improve outcomes in this TBI population, the management of secondary injuries, particularly the failure of cerebrovascular reactivity (assessed via the pressure reactivity index; PRx, a correlation between intracranial pressure (ICP) and mean arterial blood pressure (MAP)), has gained interest in the field. However, derivation of PRx requires high-resolution data and expensive technological solutions, as calculations use a short time-window, which has resulted in it being used in only a handful of centers worldwide. As a solution to this, low resolution (longer time-windows) PRx has been suggested, known as Long-PRx or LPRx. Though LPRx has been proposed little is known about the best methodology to derive this measure, with different thresholds and time-windows proposed. Furthermore, the impact of ICP monitoring on cerebrovascular reactivity measures is poorly understood. Hence, this observational study establishes critical thresholds of LPRx associated with long-term functional outcome, comparing different time-windows for calculating LPRx as well as evaluating LPRx determined through external ventricular drains (EVD) vs intraparenchymal pressure device (IPD) ICP monitoring., Methods: The study included a total of n = 435 TBI patients from the Karolinska University Hospital. Patients were dichotomized into alive vs. dead and favorable vs. unfavorable outcomes based on 1-year Glasgow Outcome Scale (GOS). Pearson's chi-square values were computed for incrementally increasing LPRx or ICP thresholds against outcome. The thresholds that generated the greatest chi-squared value for each LPRx or ICP parameter had the highest outcome discriminatory capacity. This methodology was also completed for the segmentation of the population based on EVD, IPD, and time of data recorded in hospital stay., Results: LPRx calculated with 10-120-min windows behaved similarly, with maximal chi-square values ranging at around a LPRx of 0.25-0.35, for both survival and favorable outcome. When investigating the temporal relations of LPRx derived thresholds, the first 4 days appeared to be the most associated with outcomes. The segmentation of the data based on intracranial monitoring found limited differences between EVD and IPD, with similar LPRx values around 0.3., Conclusion: Our work suggests that the underlying prognostic factors causing impairment in cerebrovascular reactivity can, to some degree, be detected using lower resolution PRx metrics (similar found thresholding values) with LPRx found clinically using as low as 10 min-by-minute samples of MAP and ICP. Furthermore, EVD derived LPRx with intermittent cerebrospinal fluid draining, seems to present similar outcome capacity as IPD. This low-resolution low sample LPRx method appears to be an adequate substitute for the clinical prognostic value of PRx and may be implemented independent of ICP monitoring method when PRx is not feasible, though further research is warranted., (© 2024. The Author(s).)

Coagulopathy and traumatic brain injury (TBI) are complexly intertwined. In isolated TBI, coagulopathy may contribute to hemorrhagic lesion development, progression, or recurrence, as it may lead to a particular pattern of coagulopathy called TBI-induced coagulopathy (TBI-IC). We performed a retrospective and descriptive evaluation of 63 patients admitted to the Emergency Clinical Hospital Bucharest with the diagnosis of moderate/severe brain injury. In addition to demographic data, all included patients had a complete paraclinical evaluation that included rotational thromboelastometric (ROTEM) blood-clot analysis. The platelet component (PLTEM) and the endotheliopathy activation and stress index score (EASIX) were calculated. These parameters were presented comparatively according to survival at 30 days and helped define the two study groups: survivors and non-survivors at 30 days. The contribution of platelets to clot strength is derived from maximum clot elasticity (MCE) and maximum clot firmness (MCF). MCE is defined as (MCF × 100)/(100 - MCF), and PLTEM is defined as EXTEM MCE-FIBTEM MCE. EASIX is a novel biomarker recently studied in TBI patients, calculated according to the following formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (10 9 cells/L). Regarding the demographic data, there were no significant differences between the survivors and non-survivors. All ROTEM parameters related to clot amplitude (A5, A10, A20, MCF in EXTEM and FIBTEM channels) were higher in the group of patients who survived. Also, PLTEM was decreased in the group of deceased patients (89.71 ± 22.86 vs. 132.3 ± 16.56 p < 0.0001). The cut-off point determined with the ROC curve is 114.10, with a sensitivity of 94.74% and a specificity of 93.18%, for the detection of the negative prognosis (death at 30 days). The EASIX score was significantly higher in the patients who survived the traumatic event, with a median difference value of 1.15 ( p < 0.0001). The ROC analysis of this biomarker highlights a cut-off point of 2.12, with a sensitivity of 88.64% and a specificity of 94.74% (AUC = 0.95, p < 0.0001), for the prediction of mortality. The comparative analysis of the two studied markers was performed using the Cox proportional hazard ratio and highlighted the greater influence that PLTEM has on survival time (b value = -0.05, p < 0.0001) compared to EASIX (b value = 0.49, p = 0.0026). The present retrospective study indicates the potential of the TBI-IC reflecting parameters PLTEM and EASIX as markers of mortality prognosis. Larger prospective studies are needed to confirm their combined prognostic value and use in decision-making and reduction in the burden of disease by adequate allocation of resources in a personalized and timely manner.

Importance: Treatment for intracranial pressure (ICP) has been increasingly informed by machine learning (ML)-derived ICP waveform characteristics. There are gaps, however, in understanding how ICP monitor type may bias waveform characteristics used for these predictive tools since differences between external ventricular drain (EVD) and intraparenchymal monitor (IPM)-derived waveforms have not been well accounted for., Objectives: We sought to develop a proof-of-concept ML model differentiating ICP waveforms originating from an EVD or IPM., Design, Setting, and Participants: We examined raw ICP waveform data from the ICU physiology cohort within the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury multicenter study., Main Outcomes and Measures: Nested patient-wise five-fold cross-validation and group analysis with bagged decision trees (BDT) and linear discriminant analysis were used for feature selection and fair evaluation. Nine patients were kept as unseen hold-outs for further evaluation., Results: ICP waveform data totaling 14,110 hours were included from 82 patients (EVD, 47; IPM, 26; both, 9). Mean age, Glasgow Coma Scale (GCS) total, and GCS motor score upon admission, as well as the presence and amount of midline shift, were similar between groups. The model mean area under the receiver operating characteristic curve (AU-ROC) exceeded 0.874 across all folds. In additional rigorous cluster-based subgroup analysis, targeted at testing the resilience of models to cross-validation with smaller subsets constructed to develop models in one confounder set and test them in another subset, AU-ROC exceeded 0.811. In a similar analysis using propensity score-based rather than cluster-based subgroup analysis, the mean AU-ROC exceeded 0.827. Of 842 extracted ICP features, 62 were invariant within every analysis, representing the most accurate and robust differences between ICP monitor types. For the nine patient hold-outs, an AU-ROC of 0.826 was obtained using BDT., Conclusions and Relevance: The developed proof-of-concept ML model identified differences in EVD- and IPM-derived ICP signals, which can provide missing contextual data for large-scale retrospective datasets, prevent bias in computational models that ingest ICP data indiscriminately, and control for confounding using our model's output as a propensity score by to adjust for the monitoring method that was clinically indicated. Furthermore, the invariant features may be leveraged as ICP features for anomaly detection., Competing Interests: Dr. Foreman received honoraria from UCB Pharma, grant funding from the National Institute of Neurological Disorders And Stroke (NINDS) of the National Institutes of Health (NIH; K23NS101123), and he is a member of the Curing Coma Campaign Scientific Advisory Committee. Dr. Rosenthal receives grant funding (R01NS117904 from the NIH/NINDS, K23NS105950 from the NIH/NINDS, OT2OD032701 from the NIH/Office of the Director, W81XWH-18-DMRDP-PTCRA from the U.S. Army (subcontract from Moberg Analytics), and R01NS113541 from the NIH/NINDS, and he is a member of the Curing Coma Campaign Scientific Advisory Committee and Technical Working Group. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

In this article, we develop an analytical approach for estimating brain connectivity networks that accounts for subject heterogeneity. More specifically, we consider a novel extension of a multi-subject Bayesian vector autoregressive model that estimates group-specific directed brain connectivity networks and accounts for the effects of covariates on the network edges. We adopt a flexible approach, allowing for (possibly) nonlinear effects of the covariates on edge strength via a novel Bayesian nonparametric prior that employs a weighted mixture of Gaussian processes. For posterior inference, we achieve computational scalability by implementing a variational Bayes scheme. Our approach enables simultaneous estimation of group-specific networks and selection of relevant covariate effects. We show improved performance over competing two-stage approaches on simulated data. We apply our method on resting-state functional magnetic resonance imaging data from children with a history of traumatic brain injury (TBI) and healthy controls to estimate the effects of age and sex on the group-level connectivities. Our results highlight differences in the distribution of parent nodes. They also suggest alteration in the relation of age, with peak edge strength in children with TBI, and differences in effective connectivity strength between males and females., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Therapeutic interventions for disorders of consciousness lack consistency; evidence supports non-invasive brain stimulation, but few studies assess neuromodulation in acute-to-subacute brain-injured patients. This study aims to validate the feasibility and assess the effect of a multi-session transcranial alternating current stimulation (tACS) intervention in subacute brain-injured patients on recovery of consciousness, related brain oscillations and brain network dynamics., Methods and Analyses: The study is comprised of two phases: a validation phase (n=12) and a randomised controlled trial (n=138). Both phases will be conducted in medically stable brain-injured adult patients (traumatic brain injury and hypoxic-ischaemic encephalopathy), with a Glasgow Coma Scale score ≤12 after continuous sedation withdrawal. Recruitment will occur at the intensive care unit of a Level 1 Trauma Centre in Montreal, Quebec, Canada. The intervention includes a 20 min 10 Hz tACS at 1 mA intensity or a sham session over parieto-occipital cortical sites, repeated over five consecutive days. The current's frequency targets alpha brain oscillations (8-13 Hz), known to be associated with consciousness. Resting-state electroencephalogram (EEG) will be recorded four times daily for five consecutive days: pre and post-intervention, at 60 and 120 min post-tACS. Two additional recordings will be included: 24 hours and 1-week post-protocol. Multimodal measures (blood samples, pupillometry, behavioural consciousness assessments (Coma Recovery Scale-revised), actigraphy measures) will be acquired from baseline up to 1 week after the stimulation. EEG signal analysis will focus on the alpha bandwidth (8-13 Hz) using spectral and functional network analyses. Phone assessments at 3, 6 and 12 months post-tACS, will measure long-term functional recovery, quality of life and caregivers' burden., Ethics and Dissemination: Ethical approval for this study has been granted by the Research Ethics Board of the CIUSSS du Nord-de-l'Île-de-Montréal (Project ID 2021-2279). The findings of this two-phase study will be submitted for publication in a peer-reviewed academic journal and submitted for presentation at conferences. The trial's results will be published on a public trial registry database (ClinicalTrials.gov)., Trial Registration Number: NCT05833568., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuroimaging studies have suggested an important role for the default mode network (DMN) in disorders of consciousness (DoC). However, the extent to which DMN connectivity can discriminate DoC states-unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS)-is less evident. Particularly, it is unclear whether effective DMN connectivity, as measured indirectly with dynamic causal modelling (DCM) of resting EEG can disentangle UWS from healthy controls and from patients considered conscious (MCS+). Crucially, this extends to UWS patients with potentially "covert" awareness (minimally conscious star, MCS*) indexed by voluntary brain activity in conjunction with partially preserved frontoparietal metabolism as measured with positron emission tomography (PET+ diagnosis; in contrast to PET- diagnosis with complete frontoparietal hypometabolism). Here, we address this gap by using DCM of EEG data acquired from patients with traumatic brain injury in 11 UWS (6 PET- and 5 PET+) and in 12 MCS+ (11 PET+ and 1 PET-), alongside with 11 healthy controls. We provide evidence for a key difference in left frontoparietal connectivity when contrasting UWS PET- with MCS+ patients and healthy controls. Next, in a leave-one-subject-out cross-validation, we tested the classification performance of the DCM models demonstrating that connectivity between medial prefrontal and left parietal sources reliably discriminates UWS PET- from MCS+ patients and controls. Finally, we illustrate that these models generalize to an unseen dataset: models trained to discriminate UWS PET- from MCS+ and controls, classify MCS* patients as conscious subjects with high posterior probability (pp > .92). These results identify specific alterations in the DMN after severe brain injury and highlight the clinical utility of EEG-based effective connectivity for identifying patients with potential covert awareness., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ihalainen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Heart rate variability (HRV), defined as the variability between successive heart beats, is a noninvasive measure of autonomic nervous system (ANS) function, which may be altered following traumatic brain injury (TBI). This scoping review summarizes the existing literature regarding changes in HRV after TBI as well as the association between measures of HRV and outcomes following TBI., Methods: A literature search for articles assessing 'heart rate variability' and 'brain injury' or 'concussion' was completed. Articles were included if HRV was measured in human subjects with TBI or concussion. Review articles, protocol papers, and studies including non-traumatic injuries were excluded., Results: Sixty-three articles were included in this review. Varied methods were used to measure HRV in the different studies. Forty articles included information about differences in HRV measures after TBI and/or longitudinal changes after TBI. Fifteen studies assessed HRV and symptoms following TBI, and 15 studies assessed HRV and either functional or cognitive outcomes after TBI., Conclusions: HRV has been studied in the context of mortality, clinical symptoms, and medical, functional, or cognitive outcomes following TBI. Methods used to measure HRV have varied amongst the different studies, which may impact findings, standardized protocols are needed for future research.

Aims: To assess the predictive value of early-stage physiological time-series (PTS) data and non-interrogative electronic health record (EHR) signals, collected within 24 h of ICU admission, for traumatic brain injury (TBI) patient outcomes., Methods: Using data from TBI patients in the multi-center eICU database, we focused on in-hospital mortality, neurological status based on the Glasgow Coma Score (mGCS) motor subscore at discharge, and prolonged ICU stay (PLOS). Three machine learning (ML) models were developed, utilizing EHR features, PTS signals collected 24 h after ICU admission, and their combination. External validation was performed using the MIMIC III dataset, and interpretability was enhanced using the Shapley Additive Explanations (SHAP) algorithm., Results: The analysis included 1085 TBI patients. Compared to individual models and existing scoring systems, the combination of EHR and PTS features demonstrated comparable or even superior performance in predicting in-hospital mortality (AUROC = 0.878), neurological outcomes (AUROC = 0.877), and PLOS (AUROC = 0.835). The model's performance was validated in the MIMIC III dataset, and SHAP algorithms identified six key intervention points for EHR features related to prognostic outcomes. Moreover, the EHR results (All AUROC >0.8) were translated into online tools for clinical use., Conclusion: Our study highlights the importance of early-stage PTS signals in predicting TBI patient outcomes. The integration of interpretable algorithms and simplified prediction tools can support treatment decision-making, contributing to the development of accurate prediction models and timely clinical intervention., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point., Methods: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores., Results: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play., Conclusions: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.

Unexplained neurological deterioration is occasionally observed in patients with traumatic brain injuries (TBIs). We aimed to describe the clinical features of post-traumatic transient neurological dysfunction and provide new insight into its pathophysiology. We retrospectively collected data from patients with focal neurological deterioration of unknown origin during hospitalization for acute TBI for 48 consecutive months. Brain imaging, including computed tomography, diffusion-weighted imaging and perfusion-weighted imaging, and electroencephalography were conducted during the episodes. Fourteen (2.0%) patients experienced unexplained focal neurological deterioration among 713 patients who were admitted for traumatic intracranial hemorrhage during the study period. Aphasia was the predominant symptom in all patients, and hemiparesis or hemianopia was accompanied in three patients. These symptoms developed within 14 days after trauma. Structural imaging did not show any significant interval change, and electroencephalography showed persistent arrhythmic slowing in the corresponding hemisphere in most patients. Perfusion imaging revealed increased cerebral blood flow in the symptomatic hemisphere. Surgical intervention and anti-seizure medications were ineffective in abolishing the symptoms. The symptoms disappeared spontaneously after 4 h to 1 month. Transient neurological dysfunction (TND) can occur during the acute phase of TBI. Although TND may last longer than a typical transient ischemic attack or seizure, it eventually resolves regardless of treatment. Based on our observation, we postulate that this is a manifestation of spreading depolarization occurring in the injured brain, which is analogous to migraine aura.

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Monitoring intracranial pressure (ICP) is pivotal in the management of severe traumatic brain injury (TBI), but secondary brain injuries can arise despite normal ICP levels. Cerebral tissue oxygenation monitoring (PbtO2) may detect neuronal tissue infarction thresholds, enhancing neuroprotection. We performed a systematic review and meta-analysis to evaluate the effects of combined cerebral tissue oxygenation (PbtO2) and ICP compared to isolated ICP monitoring in patients with TBI. PubMed, Embase, Cochrane, and Web of Sciences databases were searched for trials published up to June 2023. A total of 16 studies comprising 37,820 patients were included. ICP monitoring was universal, with additional placement of PbtO2 in 2222 individuals (5.8%). The meta-analysis revealed a reduction in mortality (OR 0.57, 95% CI 0.37-0.89, p = 0.01), a greater likelihood of favorable outcomes (OR 2.28, 95% CI 1.66-3.14, p < 0.01), and a lower chance of poor outcomes (OR 0.51, 95% CI 0.34-0.79, p < 0.01) at 6 months for the PbtO2 plus ICP group. However, these patients experienced a longer length of hospital stay (MD 2.35, 95% CI 0.50-4.20, p = 0.01). No significant difference was found in hospital mortality rates (OR 0.81, 95% CI 0.61-1.08, p = 0.16) or intensive care unit length of stay (MD 2.46, 95% CI - 0.11-5.04, p = 0.06). The integration of PbtO2 to ICP monitoring improved mortality outcomes and functional recovery at 6 months in patients with TBI. PROSPERO (International Prospective Register of Systematic Reviews) CRD42022383937; https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=383937., (© 2024. Fondazione Società Italiana di Neurologia.)

Purpose of Review: Headache is one of the most common symptoms of traumatic brain injury, and it is more common in patients with mild, rather than moderate or severe, traumatic brain injury. Posttraumatic headache can be the most persistent symptom of traumatic brain injury. In this article, we review the current understanding of posttraumatic headache, summarize the current knowledge of its pathophysiology and treatment, and review the research regarding predictors of long-term outcomes., Recent Findings: To date, posttraumatic headache has been treated based on the semiology of the primary headache disorder that it most resembles, but the pathophysiology is likely to be different, and the long-term prognosis differs as well. No models exist to predict long-term outcomes, and few studies have highlighted risk factors for the development of acute and persistent posttraumatic headaches. Further research is needed to elucidate the pathophysiology and identify specific treatments for posttraumatic headache to be able to predict long-term outcomes. In addition, the effect of managing comorbid traumatic brain injury symptoms on posttraumatic headache management should be further studied. Posttraumatic headache can be a persistent symptom of traumatic brain injury, especially mild traumatic brain injury. It has traditionally been treated based on the semiology of the primary headache disorder it most closely resembles, but further research is needed to elucidate the pathophysiology of posttraumatic headache and determine risk factors to better predict long-term outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study aims to describe resting state networks (RSN) in patients with disorders of consciousness (DOC)s after acute severe traumatic brain injury (TBI)., Methods: Adult patients with TBI with a GCS score <8 who remained in a coma, minimally conscious state (MCS), or unresponsive wakefulness syndrome (UWS), between 2017 and 2020 were included. Blood-oxygen-level dependent imaging was performed to compare their RSN with 10 healthy volunteers., Results: Of a total of 293 patients evaluated, only 13 patients were included according to inclusion criteria: 7 in coma (54%), 2 in MCS (15%), and 4 (31%) had an UWS. RSN analysis showed that the default mode network (DMN) was present and symmetric in 6 patients (46%), absent in 1 (8%), and asymmetric in 6 (46%). The executive control network (ECN) was present in all patients but was asymmetric in 3 (23%). The right ECN was absent in 2 patients (15%) and the left ECN in 1 (7%). The medial visual network was present in 11 (85%) patients. Finally, the cerebellar network was symmetric in 8 patients (62%), asymmetric in 1 (8%), and absent in 4 (30%)., Conclusions: A substantial impairment in activation of RSN is demonstrated in patients with DOC after severe TBI in comparison with healthy subjects. Three patterns of activation were found: normal/complete activation, 2) asymmetric activation or partially absent, and 3) absent activation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Severe traumatic brain injuries typically result in loss of consciousness or coma. In deeply comatose patients with traumatic brain injury, cortical dynamics become simple, repetitive, and predictable. We review evidence that this low-complexity, high-predictability state results from a passive cortical state, represented by a stable repetitive attractor, that hinders the flexible formation of neuronal ensembles necessary for conscious experience. Our data and those from other groups support the hypothesis that this cortical passive state is because of the loss of thalamocortical input. We identify the unpredictability and complexity of cortical dynamics captured by local field potential as a sign of recovery from this passive coma attractor. In this Perspective article, we discuss how these electrophysiological biomarkers of the recovery of consciousness could inform the design of closed-loop stimulation paradigms to treat disorders of consciousness., (© 2024 Massachusetts Institute of Technology.)

Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. Impact variability influences the origin, spread, and classification of molecular dysfunction which limits strategies for comprehensive clinical intervention. Indeed, there are currently no clinically approved therapeutics for treating the secondary consequences associated with TBI. Thus, examining pathophysiological changes from heterogeneous impacts is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Here we utilized TBI models that varied in both injury mechanism and severity including severe traditional controlled cortical impact (CCI), modified mild CCI (MTBI), and multiple severities of closed-head diffuse TBI (DTBI), and assessed pathophysiological changes. Severe CCI induced cortical lesions and necrosis, while both MTBI and DTBI lacked lesions or significant necrotic damage. Autophagy was activated in the ipsilateral cortex following CCI, but acutely impaired in the ipsilateral hippocampus. Additionally, autophagy was activated in the cortex following DTBI, and autophagic impairment was observed in either the cortex or hippocampus following impact from each DTBI severity. Thus, we provide evidence that autophagy is a therapeutic target for both mild and severe TBI. However, dramatic increases in necrosis following CCI may negatively impact the clinical translatability of therapeutics designed to treat acute dysfunction in TBI. Overall, these results provide evidence that injury sequalae affiliated with TBI heterogeneity is linked through autophagy activation and/or impaired autophagic flux. Thus, therapeutic strategies designed to intervene in autophagy may alleviate pathophysiological consequences, in addition to the cognitive and behavioral deficits observed in TBI., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Traumatic brain injury (TBI) affects a large population, resulting in severe cognitive impairments. Although cognitive rehabilitation is an accepted treatment for some deficits, studies in patients are limited in ability to probe physiological and behavioral mechanisms. Therefore, animal models are needed to optimize strategies. Frontal TBI in a rat model results in robust and replicable cognitive deficits, making this an ideal candidate for investigating various behavioral interventions. In this study, we report three distinct frontal TBI experiments assessing behavior well into the chronic post-injury period using male Long-Evans rats. First, we evaluated the impact of frontal injury on local field potentials recorded simultaneously from 12 brain regions during a probabilistic reversal learning (PbR) task. Next, a set of rats were tested on a similar PbR task or an impulsivity task (differential reinforcement of low-rate behavior [DRL]) and half received salient cues associated with reinforcement contingencies to encourage engagement in the target behavior. After intervention on the PbR task, brains were stained for markers of activity. On the DRL task, cue relevance was decoupled from outcomes to determine if beneficial effects persisted on impulsive behavior. TBI decreased the ability to detect reinforced outcomes; this was evident in task performance and reward-feedback signals occurring at beta frequencies in lateral orbitofrontal cortex (OFC) and associated frontostriatal regions. The behavioral intervention improved flexibility and increased OFC activity. Intervention also reduced impulsivity, even after cues were decoupled, which was partially mediated by improvements in timing behavior. The current study established a platform to begin investigating cognitive rehabilitation in rats and identified a strong role for dysfunctional OFC signaling in probabilistic learning after frontal TBI.

Despite different etiologies, people with schizophrenia (SCZ) or with traumatic brain injury (TBI) both show aberrant neuroplasticity. One neuroplastic mechanism that may be affected is prediction error coding. We used a roving mismatch negativity (rMMN) paradigm which uses different lengths of standard tone trains and is optimized to assess predictive coding. Twenty-five SCZ, 22 TBI (mild to moderate), and 25 healthy controls were assessed. We used a frequency-deviant rMMN in which the number of standards preceding the deviant was either 2, 6, or 36. We evaluated repetition positivity to the standard tone immediately preceding a deviant tone (repetition positivity [RP], to assess formation of the memory trace), deviant negativity to the deviant stimulus (deviant negativity [DN], which reflects signaling of a prediction error), and the difference wave between the 2 (the MMN). We found that SCZ showed reduced DN and MMN compared with healthy controls and with people with mild to moderate TBI. We did not detect impairments in any index (RP, DN, or MMN) in people with TBI compared to controls. Our findings suggest that prediction error coding assessed with rMMN is aberrant in SCZ but intact in TBI, though there is a suggestion that severity of head injury results in poorer prediction error coding., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This single-center, retrospective study investigated the outcome effect of the combined intensity and duration of differences between actual cerebral perfusion pressure (CPP) and optimal cerebral perfusion pressure (CPPopt), and also for absolute CPP, in patients with traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (aSAH)., Methods: A total of 378 TBI and 432 aSAH patients treated in a neurointensive care unit between 2008 and 2018 with at least 24 hours of CPPopt data during the first 10 days following injury, and with 6-month (TBI) or 12-month (aSAH) extended Glasgow Outcome Scale (GOS-E) scores, were included in the study. ∆CPPopt-insults (∆CPPopt=actual CPP-CPPopt) and CPP-insults were visualized as 2-dimensional plots to highlight the combined effect of insult intensity (mm Hg) and duration (min) on patient outcome., Results: In TBI patients, a zone of ∆CPPopt ± 10 mm Hg was associated with more favorable outcome, with transitions towards unfavorable outcome above and below this zone. CPP in the range of 60 to 80 mm Hg was associated with higher GOS-E, whereas CPP outside this range was associated with lower GOS-E. In aSAH patients, there was no clear transition from higher to lower GOS-E for ∆CPPopt-insults; however, there was a transition from favorable to unfavorable outcome when CPP was <80 mm Hg., Conclusions: TBI patients with CPP close to CPPopt exhibited better clinical outcomes, and absolute CPP within the 60 to 80 mm Hg range was also associated with favorable outcome. In aSAH patients, there was no clear transition for ∆CPPopt-insults in relation to outcome, whereas generally high absolute CPP values were associated overall with favorable recovery., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Schroeder, LH, McDaniel, AT, Wang, Y, Dickens, GM, Pantani, V, and Kubinak, H. Evaluating neck-strengthening protocols to reduce the incidence of traumatic brain injury: traditional vs. nontraditional neck-strengthening techniques. J Strength Cond Res 38(7): 1266-1274, 2024-A common cause of traumatic brain injuries (TBIs) is the head's kinematic response to rapid movement, which can be reduced with dynamic neck strengthening. This study aimed to determine the most effective neck-strengthening program by comparing a traditional and nontraditional program. Isometric neck strength was assessed in 32 subjects randomly assigned to one of the traditional and nontraditional neck-strengthening programs. The nontraditional program used a novel neck-strengthening device. After weeks 6 and 10 of training, isometric neck strength was reassessed. With the collected data, linear mixed models were established to compare the changes in neck strength between the 2 groups during the 10-week training period. Statistical analysis results suggest that, for both cervical extension (CE) and cervical flexion (CF), subjects in the novel neck-strengthening device group had a significantly higher gain of strength during the 10 weeks than the traditional group. With test statistics of -2.691 and -3.203 and corresponding 2-sided p -value of 0.01289 and 0.003889, respectively, we conclude that there is a statistically significant difference in the linear slopes of increase for both CE and CF between the 2 groups. As to left cervical lateral flexion and right cervical lateral flexion, the novel neck strength group had increased strength gains compared with the traditional group. However, the increase was not enough to demonstrate significant findings. Results were considered significant at p < 0.05. The results of this study show that the novel neck-strengthening device may be an effective mechanism for preventing mild TBIs., (Copyright © 2023 National Strength and Conditioning Association.)

Objectives: To examine if increasing blood pressure improves brain tissue oxygenation (PbtO 2 ) in adults with severe traumatic brain injury (TBI)., Design: Retrospective review of prospectively collected data., Setting: Level-I trauma center teaching hospital., Patients: Included patients greater than or equal to 18 years of age and with severe (admission Glasgow Coma Scale [GCS] score < 9) TBI who had advanced neuromonitoring (intracranial blood pressure [ICP], PbtO 2 , and cerebral autoregulation testing)., Interventions: The exposure was mean arterial pressure (MAP) augmentation with a vasopressor, and the primary outcome was a PbtO 2 response. Cerebral hypoxia was defined as PbtO 2 less than 20 mm Hg (low)., Main Results: MAP challenge test results conducted between ICU admission days 1-3 from 93 patients (median age 31; interquartile range [IQR], 24-44 yr), 69.9% male, White ( n = 69, 74.2%), median head abbreviated injury score 5 (IQR 4-5), and median admission GCS 3 (IQR 3-5) were examined. Across all 93 tests, a MAP increase of 25.7% resulted in a 34.2% cerebral perfusion pressure (CPP) increase and 16.3% PbtO 2 increase (no MAP or CPP correlation with PbtO 2 [both R2 = 0.00]). MAP augmentation increased ICP when cerebral autoregulation was impaired (8.9% vs. 3.8%, p = 0.06). MAP augmentation resulted in four PbtO 2 responses (normal and maintained [group 1: 58.5%], normal and deteriorated [group 2: 2.2%; average 45.2% PbtO 2 decrease], low and improved [group 3: 12.8%; average 44% PbtO 2 increase], and low and not improved [group 4: 25.8%]). The average end-tidal carbon dioxide (ETCO 2 ) increase of 5.9% was associated with group 2 when cerebral autoregulation was impaired ( p = 0.02)., Conclusions: MAP augmentation after severe TBI resulted in four distinct PbtO 2 response patterns, including PbtO 2 improvement and cerebral hypoxia. Traditionally considered clinical factors were not significant, but cerebral autoregulation status and ICP responses may have moderated MAP and ETCO 2 effects on PbtO 2 response. Further study is needed to examine the role of MAP augmentation as a strategy to improve PbtO 2 in some patients., Competing Interests: Dr. Lele received funding from LifeCenter Northwest. Dr. Vavilala received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Traumatic brain injury (TBI) is often followed by post-traumatic epilepsy (PTE), a condition often difficult to treat and leading to a substantial decline in quality of life as well as increased long-term mortality. The latent period between TBI and the emergence of spontaneous recurrent seizures provides an opportunity for pharmacological intervention to prevent epileptogenesis. Biomarkers capable of predicting PTE development are urgently needed to facilitate clinical trials of putative anti-epileptogenic drugs. EEG is a widely available and flexible diagnostic modality that plays a fundamental role in epileptology. We systematically review the advances in the field of the discovery of EEG biomarkers for the prediction of PTE in humans. Despite recent progress, the field faces several challenges including short observation periods, a focus on early post-injury monitoring, difficulties in translating findings from animal models to scalp EEG, and emerging evidence indicating the importance of assessing altered background scalp EEG activity alongside epileptiform activity using quantitative EEG methods while also considering sleep abnormalities in future studies., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Considerable strides in medical interventions during the acute phase of traumatic brain injury (TBI) have brought improved overall survival rates. However, following TBI, people often face ongoing, persistent and debilitating long-term complications. Here, we review the recent literature to propose possible mechanisms that lead from TBI to long-term complications, focusing particularly on the involvement of a compromised blood-brain barrier (BBB). We discuss evidence for the role of spreading depolarization as a key pathological mechanism associated with microvascular dysfunction and the transformation of astrocytes to an inflammatory phenotype. Finally, we summarize new predictive and diagnostic biomarkers and explore potential therapeutic targets for treating long-term complications of TBI., (© 2024. Springer Nature Limited.)

To validate the intracranial pressure (ICP) dose-response visualization plot for the first time in a novel prospectively collected pediatric traumatic brain injury (pTBI) data set from the multi-center, multi-national KidsBrainIT consortium. Prospectively collected minute-by-minute ICP and mean arterial blood pressure time series of 104 pTBI patients were categorized in ICP intensity-duration episodes. These episodes were correlated with the 6-month Glasgow Outcome Score (GOS) and displayed in a color-coded ICP dose-response plot. The influence of cerebrovascular reactivity and cerebral perfusion pressure (CPP) were investigated. The generated ICP dose-response plot on the novel data set was similar to the previously published pediatric plot. This study confirmed that higher ICP episodes were tolerated for a shorter duration of time, with an approximately exponential decay curve delineating the positive and negative association zones. ICP above 20 mm Hg for any duration in time was associated with poor outcome in our patients. Cerebrovascular reactivity state did not influence their respective transition curves above 10 mm Hg ICP. CPP below 50 mm Hg was not tolerated, regardless of ICP and duration, and was associated with worse outcome. The ICP dose-response plot was reproduced in a novel and independent pTBI data set. ICP above 20 mm Hg and CPP below 50 mm Hg for any duration in time were associated with worse outcome. This highlighted a pressing need to reduce pediatric ICP therapeutic thresholds used at the bedside.