Changes in memory and cognition during the SARS-CoV-2 human challenge study.

Background: Patient-reported outcomes and cross-sectional evidence show an association between COVID-19 and persistent cognitive problems. The causal basis, longevity and domain specificity of this association is unclear due to population variability in baseline cognitive abilities, vulnerabilities, virus variants, vaccination status and treatment. Methods: Thirty-four young, healthy, seronegative volunteers were inoculated with Wildtype SARS-CoV-2 under prospectively controlled conditions. Volunteers completed daily physiological measurements and computerised cognitive tasks during quarantine and follow-up at 30, 90, 180, 270, and 360 days. Linear modelling examined differences between 'infected' and 'inoculated but uninfected' individuals. The main cognitive endpoint was the baseline corrected global cognitive composite score across the battery of tasks administered to the volunteers. Exploratory cognitive endpoints included baseline corrected scores from individual tasks. The study was registered on ClinicalTrials.gov with the identifier NCT04865237 and took place between March 2021 and July 2022. Findings: Eighteen volunteers developed infection by qPCR criteria of sustained viral load, one without symptoms and the remainder with mild illness. Infected volunteers showed statistically lower baseline-corrected global composite cognitive scores than uninfected volunteers, both acutely and during follow up (mean difference over all time points = -0.8631, 95% CI = -1.3613, -0.3766) with significant main effect of group in repeated measures ANOVA (F (1,34) = 7.58, p = 0.009). Sensitivity analysis replicated this cross-group difference after controlling for community upper respiratory tract infection, task-learning, remdesivir treatment, baseline reference and model structure. Memory and executive function tasks showed the largest between-group differences. No volunteers reported persistent subjective cognitive symptoms. Interpretation: These results support larger cross sectional findings indicating that mild Wildtype SARS-CoV-2 infection can be followed by small changes in cognition and memory that persist for at least a year. The mechanistic basis and clinical implications of these small changes remain unclear. Funding: This study was funded through the UK Vaccine Taskforce of the Department for Business, Energy and Industrial Strategy (BEIS) of Her Majesty's Government. WT was funded by the EPSRC through the CDT for Neurotechnology Imperial College London.

Quantitative susceptibility mapping at 7 T in COVID-19: brainstem effects and outcome associations.

Post-mortem studies have shown that patients dying from severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection frequently have pathological changes in their CNS, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized coronavirus disease 2019 (COVID-19) patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on MRI is inconclusive. We therefore used ultra-high field (7 T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7 T QSM data from 30 patients, scanned 93-548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients' QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-dimer and platelet levels), functional recovery (modified Rankin scale), depression (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7). In COVID-19 survivors, the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. This study contributes to understanding the long-term effects of COVID-19 and recovery. Using non-invasive ultra-high field 7 T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors.

Serum lipidome associates with neuroimaging features in patients with traumatic brain injury.

Acute traumatic brain injury (TBI) is associated with substantial abnormalities in lipid biology, including changes in the structural lipids that are present in the myelin in the brain. We investigated the relationship between traumatic microstructural changes in white matter from magnetic resonance imaging (MRI) and quantitative lipidomic changes from blood serum. The study cohort included 103 patients from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. Diffusion tensor fitting generated fractional anisotropy (FA) and mean diffusivity (MD) maps for the MRI scans while ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry was applied to analyze the lipidome. Increasing severity of TBI was associated with higher MD and lower FA values, which scaled with different lipidomic signatures. There appears to be consistent patterns of lipid changes associating with the specific microstructure changes in the CNS white matter, but also regional specificity, suggesting that blood-based lipidomics may provide an insight into the underlying pathophysiology of TBI.

Exploring Synaptic Pathways in Traumatic Brain Injury: A Cross-Phenotype Genomics Approach.

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from genome-wide association studies with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease, schizophrenia (SCZ), major depressive disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and autism spectrum disorder. Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian randomization to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" (p = 0.0001), "Presynaptic nicotinic acetylcholine receptors" (p = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" (p = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" (p = 0.0001), and "Acetylcholine binding and downstream events" pathways (p = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and SCZ, suggesting possible pathophysiologic commonalities. In this study, we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcomes. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiological overlap with other neuropsychiatric diseases.

Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury.

BACKGROUND: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. METHODS: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. FINDINGS: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. INTERPRETATION: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. FUNDING: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Post-hospitalisation COVID-19 cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers, and reduced anterior cingulate cortex volume one year after COVID-19. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

Covert Consciousness in the ICU.

OBJECTIVES: For critically ill patients with acute severe brain injuries, consciousness may reemerge before behavioral responsiveness. The phenomenon of covert consciousness (i.e., cognitive motor dissociation) may be detected by advanced neurotechnologies such as task-based functional MRI (fMRI) and electroencephalography (EEG) in patients who appear unresponsive on the bedside behavioral examination. In this narrative review, we summarize the state-of-the-science in ICU detection of covert consciousness. Further, we consider the prognostic and therapeutic implications of diagnosing covert consciousness in the ICU, as well as its potential to inform discussions about continuation of life-sustaining therapy for patients with severe brain injuries. DATA SOURCES: We reviewed salient medical literature regarding covert consciousness. STUDY SELECTION: We included clinical studies investigating the diagnostic performance characteristics and prognostic utility of advanced neurotechnologies such as task-based fMRI and EEG. We focus on clinical guidelines, professional society scientific statements, and neuroethical analyses pertaining to the implementation of advanced neurotechnologies in the ICU to detect covert consciousness. DATA EXTRACTION AND DATA SYNTHESIS: We extracted study results, guideline recommendations, and society scientific statement recommendations regarding the diagnostic, prognostic, and therapeutic relevance of covert consciousness to the clinical care of ICU patients with severe brain injuries. CONCLUSIONS: Emerging evidence indicates that covert consciousness is present in approximately 15-20% of ICU patients who appear unresponsive on behavioral examination. Covert consciousness may be detected in patients with traumatic and nontraumatic brain injuries, including patients whose behavioral examination suggests a comatose state. The presence of covert consciousness in the ICU may predict the pace and extent of long-term functional recovery. Professional society guidelines now recommend assessment of covert consciousness using task-based fMRI and EEG. However, the clinical criteria for patient selection for such investigations are uncertain and global access to advanced neurotechnologies is limited.

Association of early blood-based biomarkers and six-month functional outcomes in conventional severity categories of traumatic brain injury: capturing the continuous spectrum of injury.

BACKGROUND: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. METHODS: Exposure-response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. FINDINGS: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13-15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13-15 and positive CT (1.21-2.81), GCS 9-12 (1.16-2.02), GCS 3-8 (1.09-1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51-1.80) percentages of unfavourable outcome were 37-51% in the lowest quintiles of biomarker levels and reached 90-94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83-3.79), the percentages were 2-4% and 19-28% in the lowest and highest biomarker quintiles, respectively. INTERPRETATION: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. FUNDING: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

FlowAtlas: an interactive tool for high-dimensional immunophenotyping analysis bridging FlowJo with computational tools in Julia.

As the dimensionality, throughput and complexity of cytometry data increases, so does the demand for user-friendly, interactive analysis tools that leverage high-performance machine learning frameworks. Here we introduce FlowAtlas: an interactive web application that enables dimensionality reduction of cytometry data without down-sampling and that is compatible with datasets stained with non-identical panels. FlowAtlas bridges the user-friendly environment of FlowJo and computational tools in Julia developed by the scientific machine learning community, eliminating the need for coding and bioinformatics expertise. New population discovery and detection of rare populations in FlowAtlas is intuitive and rapid. We demonstrate the capabilities of FlowAtlas using a human multi-tissue, multi-donor immune cell dataset, highlighting key immunological findings. FlowAtlas is available at https://github.com/gszep/FlowAtlas.jl.git.

Cognitive Motor Dissociation in Disorders of Consciousness.

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

Outcomes and Mechanisms Associated With Selective Thalamic Neuronal Loss in Chronic Traumatic Brain Injury.

Importance: The chronic neuronal burden of traumatic brain injury (TBI) is not fully characterized by routine imaging, limiting understanding of the role of neuronal substrates in adverse outcomes. Objective: To determine whether tissues that appear healthy on routine imaging can be investigated for selective neuronal loss using [11C]flumazenil (FMZ) positron emission tomography (PET) and to examine whether this neuronal loss is associated with long-term outcomes. Design, Setting, and Participants: In this cross-sectional study, data were collected prospectively from 2 centers (University of Cambridge in the UK and Weill Cornell Medicine in the US) between September 1, 2004, and May 31, 2021. Patients with TBI (>6 months postinjury) were compared with healthy control participants (all aged >18 years). Individuals with neurological disease, benzodiazepine use, or contraindication to magnetic resonance imaging were excluded. Data were retrospectively collated with nonconsecutive recruitment, owing to convenience and scanner or PET ligand availability. Data were analyzed between February 1 and September 30, 2023. Exposure: Flumazenil voxelwise binding potential relative to nondisplaceable binding potential (BPND). Main Outcomes and Measures: Selective neuronal loss identified with FMZ PET was compared between groups on voxelwise and regional scales, and its association with functional, cognitive, and psychological outcomes was examined using Glasgow Outcome Scale (GOS) scores, measures of sustained executive attention (animal and sustained fluency), and 36-Item Short Form Health Survey (SF-36) scores. Diffusion tensor imaging was used to assess structural connectivity of regions of cortical damage, and its association with thalamic selective neuronal loss. Results: In this study, 24 patients with chronic TBI (mean [SD] age, 39.2 [12.3] years; 18 men [75.0%]) and 33 healthy control participants (mean [SD] age, 47.6 [20.5] years; 23 men [69.7%]) underwent FMZ PET. Patients with TBI had a median time of 29 (range, 7-95) months from injury to scan. They displayed selective neuronal loss in thalamic nuclei, over and above gross volume loss in the left thalamus, and bilateral central, mediodorsal, ventral-lateral dorsal, anterior, and ventral anterior thalamic nuclei, across a wide range of injury severities. Neuronal loss was associated with worse functional outcome using GOS scores (left thalamus, left ventral anterior, and bilateral central, mediodorsal, and anterior nuclei), worse cognitive outcome on measures of sustained executive attention (left thalamus, bilateral central, and right mediodorsal nuclei), and worse emotional outcome using SF-36 scores (right central thalamic nucleus). Chronic thalamic neuronal loss partially mirrored the location of primary cortical contusions, which may indicate secondary injury mechanisms of transneuronal degeneration. Conclusions and Relevance: The findings of this study suggest that selective thalamic vulnerability may have chronic neuronal consequences with relevance to long-term outcome, suggesting the evolving and potentially lifelong thalamic neuronal consequences of TBI. FMZ PET is a more sensitive marker of the burden of neuronal injury than routine imaging; therefore, it could inform outcome prognostication and may lead to the development of individualized precision medicine approaches.

A synergistic workspace for human consciousness revealed by Integrated Information Decomposition.

How is the information-processing architecture of the human brain organised, and how does its organisation support consciousness? Here, we combine network science and a rigorous information-theoretic notion of synergy to delineate a 'synergistic global workspace', comprising gateway regions that gather synergistic information from specialised modules across the human brain. This information is then integrated within the workspace and widely distributed via broadcaster regions. Through functional MRI analysis, we show that gateway regions of the synergistic workspace correspond to the human brain's default mode network, whereas broadcasters coincide with the executive control network. We find that loss of consciousness due to general anaesthesia or disorders of consciousness corresponds to diminished ability of the synergistic workspace to integrate information, which is restored upon recovery. Thus, loss of consciousness coincides with a breakdown of information integration within the synergistic workspace of the human brain. This work contributes to conceptual and empirical reconciliation between two prominent scientific theories of consciousness, the Global Neuronal Workspace and Integrated Information Theory, while also advancing our understanding of how the human brain supports consciousness through the synergistic integration of information.

The human brain consists of billions of neurons which process sensory inputs, such as sight and sound, and combines them with information already stored in the brain. This integration of information guides our decisions, thoughts, and movements, and is hypothesized to be integral to consciousness. However, it is poorly understood how the brain regions responsible for processing this integration are organized in the brain. To investigate this question, Luppi et al. employed a mathematical framework called Partial Information Decomposition (PID) which can distinguish different types of information: redundancy (available from many regions) and synergy (which reflects genuine integration). The team applied the PID framework to the brain scans of 100 individuals. This allowed them to identify which brain regions combine information from across the brain (known as gateways), and which ones transmit it back to the rest of the brain (known as broadcasters). Next, Luppi et al. set out to find how these regions compared in unconscious and conscious individuals. To do this, they studied 15 healthy volunteers whose brains were scanned (using a technique called functional MRI) before, during, and after anaesthesia. This revealed that the brain integrated less information when unconscious, and that this reduction happens predominantly in gateway rather than broadcaster regions. The same effect was also observed in the brains of individuals who were permanently unconscious due to brain injuries. These findings provide a way of understanding how information is organised in the brain. They also suggest that loss of consciousness due to brain injuries and anaesthesia involve similar brain circuits. This means it may be possible to gain insights about disorders of consciousness from studying how people emerge from anaesthesia.

Repeat traumatic brain injury exacerbates acute thalamic hyperconnectivity in humans.

Repeated mild traumatic brain injury is of growing interest regarding public and sporting safety and is thought to have greater adverse or cumulative neurological effects when compared with single injury. While epidemiological links between repeated traumatic brain injury and outcome have been investigated in humans, exploration of its mechanistic substrates has been largely undertaken in animal models. We compared acute neurological effects of repeat mild traumatic brain injury (n = 21) to that of single injury (n = 21) and healthy controls (n = 76) using resting-state functional MRI and quantified thalamic functional connectivity, given previous identification of its prognostic potential in human mild traumatic brain injury and rodent repeat mild traumatic brain injury. Acute thalamocortical functional connectivity showed a rank-based trend of increasing connectivity with number of injuries, at local and global scales of investigation. Thus, history of as few as two previous injuries can induce a vulnerable neural environment of exacerbated hyperconnectivity, in otherwise healthy individuals from non-specialist populations. These results further establish thalamocortical functional connectivity as a scalable marker of acute injury and long-term neural dysfunction following mild traumatic brain injury.

Unravelling consciousness and brain function through the lens of time, space, and information.

Disentangling how cognitive functions emerge from the interplay of brain dynamics and network architecture is among the major challenges that neuroscientists face. Pharmacological and pathological perturbations of consciousness provide a lens to investigate these complex challenges. Here, we review how recent advances about consciousness and the brain's functional organisation have been driven by a common denominator: decomposing brain function into fundamental constituents of time, space, and information. Whereas unconsciousness increases structure-function coupling across scales, psychedelics may decouple brain function from structure. Convergent effects also emerge: anaesthetics, psychedelics, and disorders of consciousness can exhibit similar reconfigurations of the brain's unimodal-transmodal functional axis. Decomposition approaches reveal the potential to translate discoveries across species, with computational modelling providing a path towards mechanistic integration.

Cost-effectiveness of craniotomy versus decompressive craniectomy for UK patients with traumatic acute subdural haematoma.

OBJECTIVE: To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH). DESIGN: Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial. SETTING: UK secondary care. PARTICIPANTS: 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122). INTERVENTIONS: Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery). MAIN OUTCOME MEASURES: In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists. RESULTS: In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be -£5520 (95% CI -£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be -£4536 (95% CI -£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE. CONCLUSIONS: In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant). ETHICS: Ethical approval for the trial was obtained from the North West-Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076). TRIAL REGISTRATION NUMBER: ISRCTN87370545.

Systematic evaluation of fMRI data-processing pipelines for consistent functional connectomics.

Functional interactions between brain regions can be viewed as a network, enabling neuroscientists to investigate brain function through network science. Here, we systematically evaluate 768 data-processing pipelines for network reconstruction from resting-state functional MRI, evaluating the effect of brain parcellation, connectivity definition, and global signal regression. Our criteria seek pipelines that minimise motion confounds and spurious test-retest discrepancies of network topology, while being sensitive to both inter-subject differences and experimental effects of interest. We reveal vast and systematic variability across pipelines' suitability for functional connectomics. Inappropriate choice of data-processing pipeline can produce results that are not only misleading, but systematically so, with the majority of pipelines failing at least one criterion. However, a set of optimal pipelines consistently satisfy all criteria across different datasets, spanning minutes, weeks, and months. We provide a full breakdown of each pipeline's performance across criteria and datasets, to inform future best practices in functional connectomics.

Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Targeted temperature control following traumatic brain injury: ESICM/NACCS best practice consensus recommendations.

AIMS AND SCOPE: The aim of this panel was to develop consensus recommendations on targeted temperature control (TTC) in patients with severe traumatic brain injury (TBI) and in patients with moderate TBI who deteriorate and require admission to the intensive care unit for intracranial pressure (ICP) management. METHODS: A group of 18 international neuro-intensive care experts in the acute management of TBI participated in a modified Delphi process. An online anonymised survey based on a systematic literature review was completed ahead of the meeting, before the group convened to explore the level of consensus on TTC following TBI. Outputs from the meeting were combined into a further anonymous online survey round to finalise recommendations. Thresholds of ≥ 16 out of 18 panel members in agreement (≥ 88%) for strong consensus and ≥ 14 out of 18 (≥ 78%) for moderate consensus were prospectively set for all statements. RESULTS: Strong consensus was reached on TTC being essential for high-quality TBI care. It was recommended that temperature should be monitored continuously, and that fever should be promptly identified and managed in patients perceived to be at risk of secondary brain injury. Controlled normothermia (36.0-37.5 °C) was strongly recommended as a therapeutic option to be considered in tier 1 and 2 of the Seattle International Severe Traumatic Brain Injury Consensus Conference ICP management protocol. Temperature control targets should be individualised based on the perceived risk of secondary brain injury and fever aetiology. CONCLUSIONS: Based on a modified Delphi expert consensus process, this report aims to inform on best practices for TTC delivery for patients following TBI, and to highlight areas of need for further research to improve clinical guidelines in this setting.

Clinical and Imaging Characteristics, Care Pathways, and Outcomes of Traumatic Epidural Hematomas: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study.

BACKGROUND AND OBJECTIVES: Guideline recommendations for surgical management of traumatic epidural hematomas (EDHs) do not directly address EDHs that co-occur with other intracranial hematomas; the relative rates of isolated vs nonisolated EDHs and guideline adherence are unknown. We describe characteristics of a contemporary cohort of patients with EDHs and identify factors influencing acute surgery. METHODS: This research was conducted within the longitudinal, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury cohort study which prospectively enrolled patients with traumatic brain injury from 65 hospitals in 18 European countries from 2014 to 2017. All patients with EDH on the first scan were included. We describe clinical, imaging, management, and outcome characteristics and assess associations between site and baseline characteristics and acute EDH surgery, using regression modeling. RESULTS: In 461 patients with EDH, median age was 41 years (IQR 24-56), 76% were male, and median EDH volume was 5 cm3 (IQR 2-20). Concomitant acute subdural hematomas (ASDHs) and/or intraparenchymal hemorrhages were present in 328/461 patients (71%). Acute surgery was performed in 99/461 patients (21%), including 70/86 with EDH volume ≥30 cm3 (81%). Larger EDH volumes (odds ratio [OR] 1.19 [95% CI 1.14-1.24] per cm3 below 30 cm3), smaller ASDH volumes (OR 0.93 [95% CI 0.88-0.97] per cm3), and midline shift (OR 6.63 [95% CI 1.99-22.15]) were associated with acute surgery; between-site variation was observed (median OR 2.08 [95% CI 1.01-3.48]). Six-month Glasgow Outcome Scale-Extended scores ≥5 occurred in 289/389 patients (74%); 41/389 (11%) died. CONCLUSION: Isolated EDHs are relatively infrequent, and two-thirds of patients harbor concomitant ASDHs and/or intraparenchymal hemorrhages. EDHs ≥30 cm3 are generally evacuated early, adhering to Brain Trauma Foundation guidelines. For heterogeneous intracranial pathology, surgical decision-making is related to clinical status and overall lesion burden. Further research should examine the optimal surgical management of EDH with concomitant lesions in traumatic brain injury, to inform updated guidelines.