Facilitated Assessment of Tissue Loss Following Traumatic Brain Injury

All experimental models of traumatic brain injury (TBI) result in a progressive loss of brain tissue. The extent of tissue loss reflects the injury severity and can be measured to evaluate the potential neuroprotective effect of experimental treatments. Quantitation of tissue volumes is commonly performed using evenly spaced brain sections stained using routine histochemical methods and digitally captured. The brain tissue areas are then measured and the corresponding volumes are calculated using the distance between the sections. Measurements of areas are usually performed using a general purpose image analysis software and the results are then transferred to another program for volume calculations. To facilitate the measurement of brain tissue loss we developed novel algorithms which automatically separate the areas of brain tissue from the surrounding image background and identify the ventricles. We implemented these new algorithms by creating a new computer program (SectionToVolume) which also has functions for image organization, image adjustments and volume calculations. We analyzed brain sections from mice subjected to severe focal TBI using both SectionToVolume and ImageJ, a commonly used image analysis program. The volume measurements made by the two programs were highly correlated and analysis using SectionToVolume required considerably less time. The inter-rater reliability was high. Given the extensive use of brain tissue loss measurements in TBI research, SectionToVolume will likely be a useful tool for TBI research. We therefore provide both the source code and the program as attachments to this article

Plasticity and Inflammation following Traumatic Brain Injury

Traumatic Brain Injury (TBI) mainly affects young persons in traffic accidents and the elderly in fall accidents. Improvements in the clinical management have significantly improved the outcome following TBI but survivors still suffer from depression, memory problems, personality changes, epilepsy and fatigue. The initial injury starts a series of events that give rise to a secondary injury process and despite several clinical trials there is no drug available for clinical use that targets secondary brain injury mechanisms. Some recovery of function is seen during the first months following injury but is usually limited and there are no drugs that stimulate the recovery of lost function. Some of the recovery is attributed to plasticity, the brains ability to adapt to new circumstances, and enhancing plasticity via increased axonal growth has the potential to partly restore lost function. In this thesis mice were subjected to the controlled cortical impact model of TBI and functional outcome was evaluated using Morris water maze, the cylinder test and the rotarod. Brain tissue loss was measured in all Papers but the additional histological analyses differ among the Papers. Attempts to increase axonal growth were made by interfering with Nogo receptor function in Paper I and by conditional knockout of ephA4 in Paper II. Contrary to the hypothesis cognition was impaired in Paper I but otherwise no effects of treatment were detected in Paper I and II. Much is still unknown about plasticity and despite the discouraging results of Papers I and II this treatment approach is still worth further exploration. It is firmly established that TBI results in an inflammatory response and some aspects of it may damage brain tissue. In Papers III and IV the inflammatory response was attenuated using an IL-1β directed antibody which resulted in reduced tissue loss and edema while improving cognitive function. The results from Papers III and IV are encouraging and the possibility to find a treatment based on IL-1β inhibition appears promising

Structured evaluation of rodent behavioral tests used in drug discovery research

A large variety of rodent behavioral tests are currently being used to evaluate traits such as sensory-motor function, social interactions, anxiety-like and depressive-like behavior, substance dependence and various forms of cognitive function. Most behavioral tests have an inherent complexity, and their use requires consideration of several aspects such as the source of motivation in the test, the interaction between experimenter and animal, sources of variability, the sensory modality required by the animal to solve the task as well as costs and required work effort. Of particular importance is a test's validity because of its influence on the chance of successful translation of preclinical results to clinical settings. High validity may, however, have to be balanced against practical constraints and there are no behavioral tests with optimal characteristics. The design and development of new behavioral tests is therefore an ongoing effort and there are now well over one hundred tests described in the contemporary literature. Some of them are well established following extensive use, while others are novel and still unproven. The task of choosing a behavioral test for a particular project may therefore be daunting and the aim of the present review is to provide a structured way to evaluate rodent behavioral tests aimed at drug discovery research

How Can a Punch Knock You Out?

Several hypotheses have been put forth over time to explain how consciousness can be so rapidly lost, and then spontaneously regained, following mechanical head trauma. The knockout punch in boxing is a relatively homogenous form of traumatic brain injury and can thus be used to test the predictions of these hypotheses. While none of the hypotheses put forth can be considered fully verified, pore formation following stretching of the axonal cell membrane, mechanoporation, is a strong contender. We here argue that the theoretical foundation of mechanoporation can be strengthened by a comparison with the experimental method electroporation

Increased Network Excitability Due to Altered Synaptic Inputs to Neocortical Layer V Intact and Axotomized Pyramidal Neurons after Mild Traumatic Brain Injury

В работе представлены результаты определения состава гидрогенизатов угольных смол методом адсорбционной жидкостной колоночной хроматографии (АЖКХ). Состав хроматографических элюатов подтверждали используя метод ЯМР 1Н. Установлено, что вытеснительный вариант АЖКХ эффективен при разделении поликомпонентных смесей с температурой кипения до 250 0

Prognosis in moderate-severe traumatic brain injury in a Swedish cohort and external validation of the IMPACT models

Background: A major challenge in management of traumatic brain injury (TBI) is to assess the heterogeneity of TBI pathology and outcome prediction. A reliable outcome prediction would have both great value for the healthcare provider, but also for the patients and their relatives. A well-known prediction model is the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) prognostic calculator. The aim of this study was to externally validate all three modules of the IMPACT calculator on TBI patients admitted to Uppsala University hospital (UUH). Method: TBI patients admitted to UUH are continuously enrolled into the Uppsala neurointensive care unit (NICU) TBI Uppsala Clinical Research (UCR) quality register. The register contains both clinical and demographic data, radiological evaluations, and outcome assessments based on the extended Glasgow outcome scale extended (GOSE) performed at 6 months to 1 year. In this study, we included 635 patients with severe TBI admitted during 2008–2020. We used IMPACT core parameters: age, motor score, and pupillary reaction. Results: The patients had a median age of 56 (range 18–93), 142 female and 478 male. Using the IMPACT Core model to predict outcome resulted in an AUC of 0.85 for mortality and 0.79 for unfavorable outcome. The CT module did not increase AUC for mortality and slightly decreased AUC for unfavorable outcome to 0.78. However, the lab module increased AUC for mortality to 0.89 but slightly decreased for unfavorable outcome to 0.76. Comparing the predicted risk to actual outcomes, we found that all three models correctly predicted low risk of mortality in the surviving group of GOSE 2–8. However, it produced a greater variance of predicted risk in the GOSE 1 group, denoting general underprediction of risk. Regarding unfavorable outcome, all models once again underestimated the risk in the GOSE 3–4 groups, but correctly predicts low risk in GOSE 5–8. Conclusions: The results of our study are in line with previous findings from centers with modern TBI care using the IMPACT model, in that the model provides adequate prediction for mortality and unfavorable outcome. However, it should be noted that the prediction is limited to 6 months outcome and not longer time interval

Intracranial pressure- and cerebral perfusion pressure threshold-insults in relation to cerebral energy metabolism in aneurysmal subarachnoid hemorrhage

Background The aim was to investigate the association between intracranial pressure (ICP)- and cerebral perfusion pressure (CPP) threshold-insults in relation to cerebral energy metabolism and clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods In this retrospective study, 75 aSAH patients treated in the neurointensive care unit, Uppsala, Sweden, 2008-2018, with ICP and cerebral microdialysis (MD) monitoring were included. The first 10 days were divided into early (day 1-3), early vasospasm (day 4-6.5), and late vasospasm phase (day 6.5-10). The monitoring time (%) of ICP insults (> 20 mmHg and > 25 mmHg), CPP insults (< 60 mmHg, < 70 mmHg, < 80 mmHg, and < 90 mmHg), and autoregulatory CPP optimum (CPPopt) insults ( increment CPPopt = CPP-CPPopt < - 10 mmHg, increment CPPopt > 10 mmHg, and within the optimal interval increment CPPopt +/- 10 mmHg) were calculated in each phase. Results Higher percent of ICP above the 20 mmHg and 25 mmHg thresholds correlated with lower MD-glucose and increased MD-lactate-pyruvate ratio (LPR), particularly in the vasospasm phases. Higher percentage of CPP below all four thresholds (60/70/80//90 mmHg) also correlated with a MD pattern of poor cerebral substrate supply (MD-LPR > 40 and MD-pyruvate < 120 mu M) in the vasospasm phase and higher burden of CPP below 60 mmHg was independently associated with higher MD-LPR in the late vasospasm phase. Higher percentage of CPP deviation from CPPopt did not correlate with worse cerebral energy metabolism. Higher burden of CPP-insults below all fixed thresholds in both vasospasm phases were associated with worse clinical outcome. The percentage of ICP-insults and CPP close to CPPopt were not associated with clinical outcome. Conclusions Keeping ICP below 20 mmHg and CPP at least above 60 mmHg may improve cerebral energy metabolism and clinical outcome

Low intracranial pressure variability is associated with delayed cerebral ischemia and unfavorable outcome in aneurysmal subarachnoid hemorrhage

Purpose High intracranial pressure variability (ICPV) is associated with favorable outcome in traumatic brain injury, by mechanisms likely involving better cerebral blood flow regulation. However, less is known about ICPV in aneurysmal subarachnoid hemorrhage (aSAH). In this study, we investigated the explanatory variables for ICPV in aSAH and its association with delayed cerebral ischemia (DCI) and clinical outcome. Methods In this retrospective study, 242 aSAH patients, treated at the neurointensive care, Uppsala, Sweden, 2008–2018, with ICP monitoring the first ten days post-ictus were included. ICPV was evaluated on three time scales: (1) ICPV-1 m—ICP slow wave amplitude of wavelengths between 55 and 15 s, (2) ICPV-30 m—the deviation from the mean ICP averaged over 30 min, and (3) ICPV-4 h—the deviation from the mean ICP averaged over 4 h. The ICPV measures were analyzed in the early phase (day 1–3), in the early vasospasm phase (day 4–6.5), and the late vasospasm phase (day 6.5–10). Results High ICPV was associated with younger age, reduced intracranial pressure/volume reserve (high RAP), and high blood pressure variability in multiple linear regression analyses for all ICPV measures. DCI was associated with reduced ICPV in both vasospasm phases. High ICPV-1 m in the post-ictal early phase and the early vasospasm phase predicted favorable outcome in multiple logistic regressions, whereas ICPV-30 m and ICPV-4 h in the late vasospasm phase had a similar association. Conclusions Higher ICPV may reflect more optimal cerebral vessel activity, as reduced values are associated with an increased risk of DCI and unfavorable outcome after aSAH

NT-proBNP and troponin I in high-grade aneurysmal subarachnoid hemorrhage : Relation to clinical course and outcome

Purpose To investigate the association between two cardiac biomarkers, NT-proBNP and TnI, with intracranial pressure (ICP)−/cerebral perfusion pressure (CPP)-insults, cerebral pressure autoregulation, delayed ischemic neurological deficits (DIND), and clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods In this retrospective study, 196 aSAH patients treated at the neurointensive care unit, Uppsala University Hospital, Sweden, 2011–2018, with ICP-monitoring and serial NT-proBNP and TnI measurements were included. The first 10 days were divided into early phase (day 1–3) and vasospasm phase (day 4–10). Results NT-proBNP and TnI were elevated above the reference interval at least once the first 10 days in 175 (89%) and 116 (59%) patients, respectively. In the vasospasm phase, higher NT-proBNP and TnI were associated with increased percentage of CPP below 60 mmHg. Higher TnI also correlated with more ICP-insults above 20 mmHg. NT-proBNP and TnI did not predict worse pressure autoregulation and DIND. Higher NT-proBNP and TnI were associated with mortality and unfavorable outcome in univariate, but not multivariate, analyses. Conclusion Elevated NT-proBNP and TnI correlated with an increased burden of secondary ICP-/CPP-insults, but not with worse pressure autoregulation, DIND, and without independent association with clinical outcome