Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study.

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. We studied the chronic effect of COVID-19 on cerebrovascular health, in relation to acute severity, adverse clinical outcomes and in contrast to control group data. Here we assess cerebrovascular health in 45 patients six months after hospitalisation for acute COVID-19 using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Acute COVID-19 severity was indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. Chronic widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. The level of cerebrovascular dysfunction was associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

Validation of cross-sectional and longitudinal ComBat harmonization methods for magnetic resonance imaging data on a travelling subject cohort.

Background: The growth in multi-center neuroimaging studies generated a need for methods that mitigate the differences in hardware and acquisition protocols across sites i.e., scanner effects. ComBat harmonization methods have shown promise but have not yet been tested on all the data types commonly studied with magnetic resonance imaging (MRI). This study aimed to validate neuroCombat, longCombat and gamCombat on both structural and diffusion metrics in both cross-sectional and longitudinal data. Methods: We used a travelling subject design whereby 73 healthy volunteers contributed 161 scans across two sites and four machines using one T1 and five diffusion MRI protocols. Scanner was defined as a composite of site, machine and protocol. A common pipeline extracted two structural metrics (volumes and cortical thickness) and two diffusion tensor imaging metrics (mean diffusivity and fractional anisotropy) for seven regions of interest including gray and (except for cortical thickness) white matter regions. Results: Structural data exhibited no significant scanner effect and therefore did not benefit from harmonization in our particular cohort. Indeed, attempting harmonization obscured the true biological effect for some regions of interest. Diffusion data contained marked scanner effects and was successfully harmonized by all methods, resulting in smaller scanner effects and better detection of true biological effects. LongCombat less effectively reduced the scanner effect for cross-sectional white matter data but had a slightly lower probability of incorrectly finding group differences in simulations, compared to neuroCombat and gamCombat. False positive rates for all methods and all metrics did not significantly exceed 5%. Conclusions: Statistical harmonization of structural data is not always necessary and harmonization in the absence of a scanner effect may be harmful. Harmonization of diffusion MRI data is highly recommended with neuroCombat, longCombat and gamCombat performing well in cross-sectional and longitudinal settings.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort.

Background: Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods: 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings: COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=​​0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation: Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed. Funding: This work was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC), NIHR Cambridge Clinical Research Facility (BRC-1215-20014), the Addenbrooke's Charities Trust and NIHR COVID-19 BioResource RG9402. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. JBR is supported by the Wellcome Trust (220258) and Medical Research Council (SUAG/051 G101400). VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Post-acute blood biomarkers and disease progression in traumatic brain injury.

There is substantial interest in the potential for traumatic brain injury to result in progressive neurological deterioration. While blood biomarkers such as glial fibrillary acid protein (GFAP) and neurofilament light have been widely explored in characterizing acute traumatic brain injury (TBI), their use in the chronic phase is limited. Given increasing evidence that these proteins may be markers of ongoing neurodegeneration in a range of diseases, we examined their relationship to imaging changes and functional outcome in the months to years following TBI. Two-hundred and three patients were recruited in two separate cohorts; 6 months post-injury (n = 165); and >5 years post-injury (n = 38; 12 of whom also provided data ∼8 months post-TBI). Subjects underwent blood biomarker sampling (n = 199) and MRI (n = 172; including diffusion tensor imaging). Data from patient cohorts were compared to 59 healthy volunteers and 21 non-brain injury trauma controls. Mean diffusivity and fractional anisotropy were calculated in cortical grey matter, deep grey matter and whole brain white matter. Accelerated brain ageing was calculated at a whole brain level as the predicted age difference defined using T1-weighted images, and at a voxel-based level as the annualized Jacobian determinants in white matter and grey matter, referenced to a population of 652 healthy control subjects. Serum neurofilament light concentrations were elevated in the early chronic phase. While GFAP values were within the normal range at ∼8 months, many patients showed a secondary and temporally distinct elevations up to >5 years after injury. Biomarker elevation at 6 months was significantly related to metrics of microstructural injury on diffusion tensor imaging. Biomarker levels at ∼8 months predicted white matter volume loss at >5 years, and annualized brain volume loss between ∼8 months and 5 years. Patients who worsened functionally between ∼8 months and >5 years showed higher than predicted brain age and elevated neurofilament light levels. GFAP and neurofilament light levels can remain elevated months to years after TBI, and show distinct temporal profiles. These elevations correlate closely with microstructural injury in both grey and white matter on contemporaneous quantitative diffusion tensor imaging. Neurofilament light elevations at ∼8 months may predict ongoing white matter and brain volume loss over >5 years of follow-up. If confirmed, these findings suggest that blood biomarker levels at late time points could be used to identify TBI survivors who are at high risk of progressive neurological damage.

Influence of Concomitant Extracranial Injury on Functional and Cognitive Recovery From Mild Versus Moderateto Severe Traumatic Brain Injury.

OBJECTIVE: To determine the effect of extracranial injury (ECI) on 6-month outcome in patients with mild traumatic brain injury (TBI) versus moderate-to-severe TBI. PARTICIPANTS/SETTING: Patients with TBI (n = 135) or isolated orthopedic injury (n = 25) admitted to a UK major trauma center and healthy volunteers (n = 99). DESIGN: Case-control observational study. MAIN MEASURES: Primary outcomes: (a) Glasgow Outcome Scale Extended (GOSE), (b) depression, (c) quality of life (QOL), and (d) cognitive impairment including verbal fluency, episodic memory, short-term recognition memory, working memory, sustained attention, and attentional flexibility. RESULTS: Outcome was influenced by both TBI severity and concomitant ECI. The influence of ECI was restricted to mild TBI; GOSE, QOL, and depression outcomes were significantly poorer following moderate-to-severe TBI than after isolated mild TBI (but not relative to mild TBI plus ECI). Cognitive impairment was driven solely by TBI severity. General health, bodily pain, semantic verbal fluency, spatial recognition memory, working memory span, and attentional flexibility were unaffected by TBI severity and additional ECI. CONCLUSION: The presence of concomitant ECI ought to be considered alongside brain injury severity when characterizing the functional and neurocognitive effects of TBI, with each presenting challenges to recovery.

Is there a broader role for independent mental capacity advocates in critical care? An exploratory study.

BACKGROUND: This research explores the current and potential future role of independent mental capacity advocates (IMCAs) in critical care. The Mental Capacity Act (MCA) of 2005 introduced IMCAs as advocates for patients without anyone to represent their best interests, but research suggests that this role is not well understood or implemented. No existing research explores the role of IMCAs in critical care or their potential use when families are judged 'appropriate to act' on the patient's behalf. It is suggested that families may not be best placed to advocate for their sick family member when they themselves are in a state of shock. AIM: To investigate existing levels of knowledge and awareness of the MCA and understanding of the role of IMCAs in critical care as a prelude to considering whether the role of IMCAs might usefully be extended. The concept of 'IMCA clinics' is introduced and explored. DESIGN AND METHODS: A small-scale qualitative study using thematic analysis of 15 interviews across two NHS sites and a survey of IMCA services were undertaken. RESULTS: Some knowledge of the MCA was evident across both study sites, but training on MCA remains unsatisfactory, with confusion about the role of IMCAs and when they should become involved. Overall, participants felt that the broader involvement of IMCAs on a regular basis within critical care could be useful. CONCLUSIONS: There was evidence of good practice when instructing IMCAs, but further work needs to be conducted to ensure that critical care staff are informed about the referral process. It was clear that expanding the role of an advocate warrants further investigation. RELEVANCE TO CLINICAL PRACTICE: Further training on the role of IMCAs within critical care is required, and good practice examples should be shared with other units to improve referral rates to the IMCA service and ensure that vulnerable patients are properly represented.

Dynamic Changes in White Matter Abnormalities Correlate With Late Improvement and Deterioration Following TBI: A Diffusion Tensor Imaging Study.

OBJECTIVE: Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome. METHODS: Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. RESULTS: Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. CONCLUSIONS: These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point.

Microstructural basis of contusion expansion in traumatic brain injury: insights from diffusion tensor imaging.

Traumatic brain injury (TBI) is often exacerbated by events that lead to secondary brain injury, and represent potentially modifiable causes of mortality and morbidity. Diffusion tensor imaging was used to characterize tissue at-risk in a group of 35 patients scanned at a median of 50 hours after injury. Injury progression was assessed in a subset of 16 patients with two scans. All contusions within the first few days of injury showed a core of restricted diffusion, surrounded by an area of raised apparent diffusion coefficient (ADC). In addition to these two well-defined regions, a thinner rim of reduced ADC was observed surrounding the region of increased ADC in 91% of patients scanned within the first 3 days after injury. In patients who underwent serial imaging, the rim of ADC hypointensity was subsumed into the high ADC region as the contusion enlarged. Overall contusion enlargement tended to be more frequent with early lesions, but its extent was unrelated to the time of initial imaging, initial contusion size, or the presence of hemostatic abnormalities. This rim of hypointensity may characterize a region of microvascular failure resulting in cytotoxic edema, and may represent a 'traumatic penumbra' which may be rescued by effective therapy.

Mapping traumatic axonal injury using diffusion tensor imaging: correlations with functional outcome.

BACKGROUND: Traumatic brain injury is a major cause of morbidity and mortality worldwide. Ameliorating the neurocognitive and physical deficits that accompany traumatic brain injury would be of substantial benefit, but the mechanisms that underlie them are poorly characterized. This study aimed to use diffusion tensor imaging to relate clinical outcome to the burden of white matter injury. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-eight patients, categorized by the Glasgow Outcome Score, underwent magnetic resonance imaging at a median of 11.8 months (range 6.6 months to 3.7 years) years post injury. Control data were obtained from 36 age-matched healthy volunteers. Mean fractional anisotropy, apparent diffusion coefficient (ADC), and eigenvalues were obtained for regions of interest commonly affected in traumatic brain injury. In a subset of patients where conventional magnetic resonance imaging was completely normal, diffusion tensor imaging was able to detect clear abnormalities. Significant trends of increasing ADC with worse outcome were noted in all regions of interest. In the white matter regions of interest worse clinical outcome corresponded with significant trends of decreasing fractional anisotropy. CONCLUSIONS/SIGNIFICANCE: This study found that clinical outcome was related to the burden of white matter injury, quantified by diffusivity parameters late after traumatic brain injury. These differences were seen even in patients with the best outcomes and patients in whom conventional magnetic resonance imaging was normal, suggesting that diffusion tensor imaging can detect subtle injury missed by other techniques. An improved in vivo understanding of the pathology of traumatic brain injury, including its distribution and extent, may enhance outcome evaluation and help to provide a mechanistic basis for deficits that remain unexplained by other approaches.

Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury.

Cognitive dysfunction is a devastating consequence of traumatic brain injury that affects the majority of those who survive with moderate-to-severe injury, and many patients with mild head injury. Disruption of key monoaminergic neurotransmitter systems, such as the dopaminergic system, may play a key role in the widespread cognitive dysfunction seen after traumatic axonal injury. Manifestations of injury to this system may include impaired decision-making and impulsivity. We used the Cambridge Gambling Task to characterize decision-making and risk-taking behaviour, outside of a learning context, in a cohort of 44 patients at least six months post-traumatic brain injury. These patients were found to have broadly intact processing of risk adjustment and probability judgement, and to bet similar amounts to controls. However, a patient preference for consistently early bets indicated a higher level of impulsiveness. These behavioural measures were compared with imaging findings on diffusion tensor magnetic resonance imaging. Performance in specific domains of the Cambridge Gambling Task correlated inversely and specifically with the severity of diffusion tensor imaging abnormalities in regions that have been implicated in these cognitive processes. Thus, impulsivity was associated with increased apparent diffusion coefficient bilaterally in the orbitofrontal gyrus, insula and caudate; abnormal risk adjustment with increased apparent diffusion coefficient in the right thalamus and dorsal striatum and left caudate; and impaired performance on rational choice with increased apparent diffusion coefficient in the bilateral dorsolateral prefrontal cortices, and the superior frontal gyri, right ventrolateral prefrontal cortex, the dorsal and ventral striatum, and left hippocampus. Importantly, performance in specific cognitive domains of the task did not correlate with diffusion tensor imaging abnormalities in areas not implicated in their performance. The ability to dissociate the location and extent of damage with performance on the various task components using diffusion tensor imaging allows important insights into the neuroanatomical basis of impulsivity following traumatic brain injury. The ability to detect such damage in vivo may have important implications for patient management, patient selection for trials, and to help understand complex neurocognitive pathways.

Juguloarterial endothelin-1 gradients after severe traumatic brain injury.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor and is thought to be responsible for secondary ischemia and vasogenic edema after traumatic brain injury (TBI). Both CSF and plasma concentrations have been shown to be increased after TBI, but there is little evidence to confirm an intracranial site of production. METHODS: Using paired arterial and jugular venous bulb sampling, we measured arterial and jugular levels of ET-1 and its precursor, big endothelin (Big ET), and calculated juguloarterial (JA) gradients for the first 5 days post-TBI. RESULTS: Arterial levels of both Big ET and ET-1 were maximal on day 1 post-TBI, and decreased thereafter (P < 0.05). Arterial levels of Big ET and ET-1 showed correlation across all 5 days of the study (r(2) = 0.25, P < 0.001). While there was no significant JA gradient for Big ET, significant gradients were observed for ET-1 on days 1-4 post-TBI (P < 0.05). There was no correlation between JA gradients for Big ET and ET-1 (r(2) < 0.1, P > 0.9). These data suggest parenchymal production of ET-1 by brain tissue with spill over into the blood, rather than local intraluminal cleavage of Big ET in the cerebral vasculature. Systemic ET-1 levels and JA gradients of ET-1 were unrelated to the injury severity, APACHE II score, Marshall Grade, the presence of subarachnoid or subdural hemorrhage, or eventual outcome. CONCLUSIONS: These findings confirm the synthesis of Big ET and its cleavage to ET-1 within the brain after TBI. More work is needed to elucidate the pathophysiological role and the outcome impact of ET-1 generation after TBI.

Early metabolic characteristics of lesion and nonlesion tissue after head injury.

We defined lesion and structurally normal regions using magnetic resonance imaging at follow-up in patients recovering from head injury. Early metabolic characteristics in these regions of interest (ROIs) were compared with physiology in healthy volunteers. Fourteen patients with severe head injury had positron emission tomography within 72 h, and magnetic resonance imaging at 3 to 18 months after injury. Cerebral blood flow (CBF), oxygen utilization (CMRO(2)), and oxygen extraction fraction (OEF) were all lower in lesion ROIs, compared with nonlesion and control ROIs (P<0.001); however, there was substantial overlap in physiology. Control ROIs showed close coupling among CBF, blood volume (CBV), and CMRO(2), whereas relationships within lesion and nonlesion ROIs were abnormal. The relationship between CBF and CMRO(2) generally remained coupled but the slope was reduced; that for CBF and OEF was variable; whereas that between CBF and CBV was highly variable. There was considerable heterogeneity between and within patients. Although irreversibly damaged tissue is characterized by marked derangements in physiology, a more detailed analysis shows acute changes in physiology and physiologic relationships within regions of the brain that appear structurally normal at follow-up. Such pathophysiological derangements may result in selective neuronal loss and impact on functional outcome.

Early derangements in oxygen and glucose metabolism following head injury: the ischemic penumbra and pathophysiological heterogeneity.

INTRODUCTION: Conclusive evidence of cerebral ischemia following head injury has been elusive. We aimed to use (15)O and (18)Fluorodeoxyglucose positron emission tomography (PET) to investigate pathophysiological derangements following head injury. RESULTS: Eight patients underwent PET within 24 h of injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), oxygen extraction fraction (OEF), and cerebral glucose metabolism (CMRglc). Physiological regions of interest (ROI) were generated for each subject using a range of OEF values from very low (<10), low (10-30), normal range (30-50), high (50-70), and critically high (> or =70%). We applied these ROIs to each subject to generate data that would examine the balance between blood flow and metabolism across the injured brain independent of structural injury. DISCUSSION: Compared to the normal range, brain regions with higher OEF demonstrate a progressive CBF reduction (P < 0.01), CMRO2 increase (P < 0.05), and no change in CMRglc, while regions with lower OEF are associated with reductions in CBF, CMRO2, and CMRglc (P < 0.01). Although all subjects demonstrate a decrease in CBF with increases in OEF > 70%, CMRO2 and CMRglc were generally unchanged. One subject demonstrated a reduction in CBF and small fall in CMRO2 within the high OEF region (>70%), combined with a progressive increase in CMRglc. CONCLUSIONS: The low CBF and maintained CMRO2 in the high OEF ROIs is consistent with classical cerebral ischemia and the presence of an 'ischemic penumbra' following early head injury, while the metabolic heterogeneity that we observed suggests significant pathophysiological complexity. Other mechanisms of energy failure are clearly important and further study is required to delineate the processes involved.

Serum albumin level as a predictor of outcome in traumatic brain injury: potential for treatment.

BACKGROUND: Serum albumin level is correlated with outcome in various clinical situations. Albumin has multiple physiologic properties that could be beneficial in brain injury. The Lund therapy for elevated intracranial pressure uses albumin as part of its protocol and demonstrates favorable outcome. We sought to find out if albumin is associated with outcome after traumatic brain injury to justify conducting a randomized trial. METHODS: A retrospective study of traumatic brain injury patients was conducted. Characteristics known to influence outcome were included in a multiple logistic regression model to analyze predictors of poor outcome at 6 months. RESULTS: Data were available for 138 patients. The majority of patients (65%) had a severe injury (Glasgow Coma Scale score <9). Seventy percent of patients had a favorable outcome. Albumin levels decrease considerably from normal values in the first few days after injury irrespective of outcome. Albumin remained <25 g/L for a longer period of time in patient with an unfavorable outcome (6 days vs. 3 days, p = 0.012). Multiple logistic regression analysis identified albumin levels, age, Glasgow Coma Scale score at admission, and Injury Severity Score as predictors of poor outcome. CONCLUSION: Serum albumin level seems to be an independent predictor of poor outcome. The model also identified classic predictors of poor outcome that tends to strengthen its adequacy. Because albumin level is the only modifiable factor influencing outcome, it seems justified to carry out a randomized trial of the use of albumin in the treatment of brain injury.

Effect of hyperoxia on regional oxygenation and metabolism after severe traumatic brain injury: preliminary findings.

OBJECTIVE: To determine the effect of normobaric hyperoxia on cerebral metabolism in patients with severe traumatic brain injury. DESIGN: Prospective clinical investigation. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Eleven patients with severe traumatic brain injury. INTERVENTIONS: Cerebral microdialysis, brain tissue oximetry (PbO2), and oxygen-15 positron emission tomography (15O-PET) were undertaken at normoxia and repeated at hyperoxia (FiO2 increase of between 0.35 and 0.50). MEASUREMENTS AND MAIN RESULTS: Established models were used to image cerebral blood flow, blood volume, oxygen metabolism, and oxygen extraction fraction. Physiology was characterized in a focal region of interest (surrounding the microdialysis catheter) and correlated with microdialysis and oximetry. Physiology was also characterized in a global region of interest (including the whole brain), and a physiologic region of interest (defined using a critical cerebral metabolic rate of oxygen threshold). Hyperoxia increased mean +/- sd PbO2 from 28 +/- 21 mm Hg to 57 +/- 47 mm Hg (p = .015). Microdialysate lactate and pyruvate were unchanged, but the lactate/pyruvate ratio showed a statistically significant reduction across the study population (34.1 +/- 9.5 vs. 32.5 +/- 9.0, p = .018). However, the magnitude of reduction was small, and its clinical significance doubtful. The focal region of interest and global 15O-PET variables were unchanged. "At-risk" tissue defined by the physiologic region of interest, however, showed a universal increase in cerebral metabolic rate of oxygen from a median (interquartile range) of 23 (22-25) micromol x 100 mL(-1) x min(-1) to 30 (28-36) micromol x 100 mL(-1) x min(-1) (p < .01). CONCLUSIONS: In severe traumatic brain injury, hyperoxia increases PbO2 with a variable effect on lactate and lactate/pyruvate ratio. Microdialysis does not, however, predict the universal increases in cerebral metabolic rate of oxygen in at-risk tissue, which imply preferential metabolic benefit with hyperoxia.

Concordant biology underlies discordant imaging findings: diffusivity behaves differently in grey and white matter post acute neurotrauma.

BACKGROUND: Cerebral edema is a common sequelum post traumatic brain injury (TBI). Quantification of the apparent diffusion coefficient (ADC) using diffusion tensor imaging (DTI) may help to characterize the pathophysiology of brain swelling. METHODS: Twenty-two patients with moderate-to-severe TBI underwent magnetic resonance (MR) imaging, including DTI, within five days of injury. The mean ADCs in whole brain white matter, whole brain grey matter and entire brain were calculated and compared to twenty-five controls. FINDINGS: A significant decrease in the grey matter ADC (p < 0.001), significant increase in the white matter ADC (p < 0.001) and no significant change in the whole brain ADC (p = 0.771) was observed. No significant correlation was found between DTI parameters in any of the three regions of interest (ROI) and GCS, time to scan, intracranial pressure (ICP) before and during the time of the scan, cerebral perfusion pressure at time of scan, or Glasgow Outcome Score (GCS). CONCLUSIONS: The decrease in ADC seen in the grey matter is consistent with cytotoxic edema. The increase in ADC in the white matter indicates damage that has led to an overall less restricted diffusion. This study assists in the interpretation of the ADC by showing that the acute changes are different in the whole brain white and grey matter ROIs post TBI.

Variability and fractal analysis of middle cerebral artery blood flow velocity and arterial blood pressure in subarachnoid hemorrhage.

Higher biologic systems operate far from equilibrium resulting in order, complexity, fluctuation of inherent parameters, and dissipation of energy. According to the decomplexification theory, disease is characterized by a loss of system complexity. We analyzed such complexity in patients after subarachnoid hemorrhage (SAH), by applying the standard technique of variability analysis and the novel method of fractal analysis to middle cerebral artery blood flow velocity (FV) and arterial blood pressure (ABP). In 31 SAH -patients, FV (using transcranial Doppler sonography) and direct ABP were measured. The standard deviations (s.d.) and coefficients of variation (CV=relative s.d.) for FV and ABP time series of length 2(10) secs were calculated as measures of variability. The spectral index beta(low) and the Hurst coefficient H(bdSWV) were analyzed as fractal measures. Outcome was assessed 1 year after SAH according to the Glasgow Outcome Scale (GOS). Both FV (beta(low)=2.2+/-0.4, mean+/-s.d.) and ABP (beta(low)=2.3+/-0.4) were classified as nonstationary (fractal Brownian motion) signals. FV showed significantly (P<0.05) higher variability (CV=7.2+/-2.5%) and Hurst coefficient (H(bdSWV)=0.26+/-0.13) as compared with ABP (CV=5.5+/-2.7%, H(bdSWV)=0.19+/-0.11). Better outcome (GOS) correlated significantly (P<0.05) with higher s.d. of FV (Spearman's r(s)=0.51, r(s)(2)=0.26) and ABP (r(s)=0.57, r(s)(2)=0.32), as well as with a higher Hurst coefficient of ABP (r(s)=0.46, r(s)(2)=0.21). Cerebral vasospasm reduced CV of FV, but left H(bdSWV) unchanged. FV and ABP fluctuated markedly despite homeostatic control. A reduced variability of FV and ABP might indicate a loss of complexity and was associated with a less favorable outcome. Therefore, the decomplexification theory of illness may apply to SAH.

Mechanism-based MRI classification of traumatic brainstem injury and its relationship to outcome.

While computed tomography (CT) is the appropriate technique for the urgent detection of hematomas and contusions in the cerebral hemispheres, it is much less effective at documenting diffuse injury and posterior fossa lesions, and is therefore only partially predictive of outcome. More recently, magnetic resonance imaging (MRI) has been used, particularly to examine posterior fossa structures, but the relationship between brainstem injury and outcome is unclear and the types of brainstem injury are poorly understood. The aim of this study was to use acute MRI to examine the types of brainstem injury following severe traumatic brain injury (TBI) and their relationship to supratentorial injury. We also aimed to correlate these findings with outcome at 6 months (Glasgow Outcome Scale [GOS] score). Forty-six patients (mean age, 34 years, range, 16-70 years; 76% male) admitted to a regional neurocritical care unit with TBI requiring ventilation underwent CT and MRI (T2, FLAIR, gradient echo) scanning within 3 days (median, 1 day) of injury. GOS was ascertained by outpatient interview. Brainstem lesions were detected in 13 patients by MRI, only two of which were detected by CT. Eleven out of 13 patients with brainstem injury had an unfavorable outcome (death, vegetative state, or severe disability), of whom five died. Of the 33 patients without brainstem lesions, 18 had an unfavorable outcome, of whom four died. The direct relationship between brainstem lesions and unfavorable outcome was statistically significant (p < 0.05, chi-squared test). With regard to supratentorial injury, all but two brainstem lesions were seen either in the context of severe diffuse axonal injury or a significant mass lesion, and all of these patients had a poor outcome. However, the two patients with brainstem injury and good outcome had relatively few supratentorial abnormalities. From these observations, we have devised a simple classification system that is useful clinically and has potential associations with outcome. Poor prognosis is common following major TBI but is more common in those with brainstem injury. However, brainstem injury is not an absolute indicator of poor outcome. Understanding the anatomy and extent of brainstem injury, as well as its relationship to supratentorial abnormalities, will facilitate a more accurate use of early MRI as a prognostic tool and assist in the counseling of families.

Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism.

OBJECTIVE: To determine whether hyperventilation exacerbates cerebral ischemia and compromises oxygen metabolism (CMRO2) following closed head injury. DESIGN: A prospective interventional study. SETTING: A specialist neurocritical care unit. PATIENTS: Ten healthy volunteers and 30 patients within 10 days of closed head injury. INTERVENTIONS: Subjects underwent oxygen-15 positron emission tomography imaging of cerebral blood flow, cerebral blood volume, CMRO2, and oxygen extraction fraction. In patients, positron emission tomography studies, somatosensory evoked potentials, and jugular venous saturation (SjO2) measurements were obtained at Paco2 levels of 36+/-3 and 29+/-2 torr. MEASUREMENTS AND MAIN RESULTS: We estimated the volume of ischemic brain and examined the efficiency of coupling between oxygen delivery and utilization using the sd of the oxygen extraction fraction distribution. We correlated CMRO2 to cerebral electrophysiology and examined the effects of hyperventilation on the amplitude of the cortical somatosensory evoked potential response. Patients showed higher ischemic brain volume than controls (17+/-22 vs. 2+/-3 mL; p