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Introduction: Traumatic brain injury to thalamo-cortical pathways is associated with posttraumatic morbidity. Diffuse mechanical forces to white matter tracts and deep grey matter regions induce an inflammatory response and vascular damage resulting in progressive neurodegeneration. Pro-inflammatory cytokines, including interleukin-1β (IL-1β), may contribute to the link between inflammation and the injured capillary network after TBI. This study investigates whether IL-1β is a key contributor to capillary alterations and changes in pericyte coverage in the thalamus and cortex after TBI., Methods: Animals were subjected to central fluid percussion injury (cFPI), a model of TBI causing widespread axonal and vascular pathology, or sham injury and randomized to receive a neutralizing anti-IL-1β or a control, anti-cyclosporin A antibody, at 30 min post-injury. Capillary length and pericyte coverage of cortex and thalamus were analyzed by immunohistochemistry at 2- and 7-days post-injury., Results and Conclusion: Our results show that early post-injury attenuation of IL-1β dependent inflammatory signaling prevents capillary damage by increasing pericyte coverage in the thalamus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Özen, Clausen, Flygt, Marklund and Paul.)

Background: Traumas to the head and neck are common in sports and often affects otherwise healthy young individuals. Sports-related concussions (SRC), defined as a mild traumatic brain injury (mTBI), may inflict persistent neck and shoulder pain, and headache, but also more complex symptoms, such as imbalance, dizziness, and visual disturbances. These more complex symptoms are difficult to identify with standard health care diagnostic procedures., Objective: To investigate postural control in a group of former elite athletes with persistent post-concussive symptoms (PPCS) at least 6 months after the incident., Method: Postural control was examined using posturography during quiet stance and randomized balance perturbations with eyes open and eyes closed. Randomized balance perturbations were used to examine motor learning through sensorimotor adaptation. Force platform recordings were converted to reflect the energy used to maintain balance and spectrally categorized into total energy used, energy used for smooth corrective changes of posture (i.e., <0.1 Hz), and energy used for fast corrective movements to maintain balance (i.e., >0.1 Hz)., Results: The mTBI group included 20 (13 males, mean age 26.6 years) elite athletes with PPCS and the control group included 12 athletes (9 males, mean age 26.4 years) with no history of SRC. The mTBI group used significantly more energy during balance perturbations than controls: +143% total energy, p = 0.004; +122% low frequency energy, p = 0.007; and +162% high frequency energy, p = 0.004. The mTBI subjects also adapted less to the balance perturbations than controls in total (18% mTBI vs. 37% controls, p = 0.042), low frequency (24% mTBI vs. 42% controls, p = 0.046), and high frequency (6% mTBI vs. 28% controls, p = 0.040). The mTBI subjects used significantly more energy during quiet stance than controls: +128% total energy, p = 0.034; +136% low-frequency energy, p = 0.048; and +109% high-frequency energy, p = 0.015., Conclusion: Athletes with previous mTBI and PPCS used more energy to stand compared to controls during balance perturbations and quiet stance and had diminished sensorimotor adaptation. Sports-related concussions are able to affect postural control and motor learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Al-Husseini, Gard, Fransson, Tegner, Magnusson, Marklund and Tjernström.)

Objective: There are growing concerns about the short- and long-term consequences of sports-related concussion, which account for about 5-9% of all sports injuries. We hypothesized there may be sex differences in concussion history and concussion-related symptoms, evaluated among elite soccer players in Sweden. Design: Retrospective survey study. Participants and Setting: Soccer players ( n = 1,030) from 55 Swedish elite soccer teams. Questionnaires were completed prior to the start of the 2017 season. Assessment of Risk Factors: Player history of soccer-related concussion (SoRC), symptoms and management following a SoRC were evaluated. Main Outcome Measures: Before the start of the season the players completed a baseline questionnaire assessing previous concussions. The Sports Concussion Assessment Tool 3 was included with regard to symptom evaluation. Results: Out of 993 responding players 334 (34.6%) reported a previous SoRC and 103 players (10.4%) reported a SoRC during the past year. After sustaining a SoRC, 114 players (34.2%) reported that they continued their ongoing activity without a period of rest, more commonly female (44.9%) than male players (27.7%; P = 0.002). Symptom resolution time was 1 week or less for 61.3% of the players that reported having persisting symptoms. A positive correlation was observed between number of previous concussions and prevalence of three persisting symptoms: fatigue ( P < 0.001), concentration/memory issues ( P = 0.002) and headache ( P = 0.047). Conclusion: About 35% of male and female elite soccer players in Sweden have experienced a previous SoRC, and about 10% experienced a SoRC during the last year. Female players continued to play after a SoRC, without a period of rest, more often than males. A higher risk of persisting symptoms was observed in players with a history of multiple concussions., (Copyright © 2020 Hänni, Vedung, Tegner, Marklund and Johansson.)

Traumatic brain injury (TBI) is a multidimensional and highly complex disease commonly resulting in widespread injury to axons, due to rapid inertial acceleration/deceleration forces transmitted to the brain during impact. Axonal injury leads to brain network dysfunction, significantly contributing to cognitive and functional impairments frequently observed in TBI survivors. Diffuse axonal injury (DAI) is a clinical entity suggested by impaired level of consciousness and coma on clinical examination and characterized by widespread injury to the hemispheric white matter tracts, the corpus callosum and the brain stem. The clinical course of DAI is commonly unpredictable and it remains a challenging entity with limited therapeutic options, to date. Although axonal integrity may be disrupted at impact, the majority of axonal pathology evolves over time, resulting from delayed activation of complex intracellular biochemical cascades. Activation of these secondary biochemical pathways may lead to axonal transection, named secondary axotomy, and be responsible for the clinical decline of DAI patients. Advances in the neurocritical care of TBI patients have been achieved by refinements in multimodality monitoring for prevention and early detection of secondary injury factors, which can be applied also to DAI. There is an emerging role for biomarkers in blood, cerebrospinal fluid, and interstitial fluid using microdialysis in the evaluation of axonal injury in TBI. These biomarker studies have assessed various axonal and neuroglial markers as well as inflammatory mediators, such as cytokines and chemokines. Moreover, modern neuroimaging can detect subtle or overt DAI/white matter changes in diffuse TBI patients across all injury severities using magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography. Importantly, serial neuroimaging studies provide evidence for evolving axonal injury. Since axonal injury may be a key risk factor for neurodegeneration and dementias at long-term following TBI, the secondary injury processes may require prolonged monitoring. The aim of the present review is to summarize the clinical short- and long-term monitoring possibilities of axonal injury in TBI. Increased knowledge of the underlying pathophysiology achieved by advanced clinical monitoring raises hope for the development of novel treatment strategies for axonal injury in TBI.

The most fundamental clinical monitoring tool in traumatic brain injury (TBI) patients is the repeated clinical examination. In the severe TBI patient treated by continuous sedation in a neurocritical care (NCC) unit, sedation interruption is required to enable a clinical evaluation (named the neurological wake-up test; NWT) assessing the level of consciousness, pupillary diameter and reactivity to light, and presence of focal neurological deficits. There is a basic conflict regarding the NWT in the NCC setting; can the clinical information obtained by the NWT justify the risk of inducing a stress response in a severe TBI patient? Furthermore, in the presence of advanced multimodal monitoring and neuroimaging, is the NWT necessary to identify important clinical alterations? In studies of severe TBI patients, the NWT was consistently shown to induce a stress reaction including brief increases in intracranial pressure (ICP) and changes in cerebral perfusion pressure (CPP). However, it has not been established whether these short-lived ICP and CPP changes are detrimental to the injured brain. Daily interruption of sedation is associated with a reduced ventilator time, shorter hospital stay and reduced mortality in many studies of general intensive care unit patients, although such clinical benefits have not been firmly established in TBI. To date, there is no consensus on the use of the NWT among NCC units and systematic studies are scarce. Thus, additional studies evaluating the role of the NWT in clinical decision-making are needed. Multimodal NCC monitoring may be an adjunct in assessing in which TBI patients the NWT can be safely performed. At present, the NWT remains the golden standard for clinical monitoring and detection of neurological changes in NCC and could be considered in TBI patients with stable baseline ICP and CPP readings. The focus of the present review is an overview of the existing literature on the role of the NWT as a clinical monitoring tool for severe TBI patients.

A synthetic peptide with antisecretory activity, antisecretory factor (AF)-16, improves injury-related deficits in water and ion transport and decreases intracranial pressure after experimental cold lesion injury and encephalitis although its role in traumatic brain injury (TBI) is unknown. AF-16 or an inactive reference peptide was administrated intranasally 30 min following midline fluid percussion injury (mFPI; n  = 52), a model of diffuse mild-moderate TBI in rats. Sham-injured ( n  = 14) or naïve ( n  = 24) animals were used as controls. The rats survived for either 48 h or 15 days post-injury. At 48 h, the animals were tested in the Morris water maze (MWM) for memory function and their brains analyzed for cerebral edema. Here, mFPI-induced brain edema compared to sham or naïve controls that was significantly reduced by AF-16 treatment ( p  < 0.05) although MWM performance was not altered. In the 15-day survival groups, the MWM learning and memory abilities as well as histological changes were analyzed. AF-16-treated brain-injured animals shortened both MWM latency and swim path in the learning trials ( p  < 0.05) and improved probe trial performance compared to brain-injured controls treated with the inactive reference peptide. A modest decrease by AF-16 on TBI-induced changes in hippocampal glial acidic fibrillary protein (GFAP) staining ( p  = 0.11) was observed. AF-16 treatment did not alter any other immunohistochemical analyses (degenerating neurons, beta-amyloid precursor protein (β-APP), and Olig2). In conclusion, intranasal AF-16-attenuated brain edema and enhanced visuospatial learning and memory following diffuse TBI in the rat. Intranasal administration early post-injury of a promising neuroprotective substance offers a novel treatment approach for TBI.

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.

Traumatic brain injury (TBI) survivors frequently suffer from life-long deficits in cognitive functions and a reduced quality of life. Axonal injury, observed in many severe TBI patients, results in accumulation of amyloid precursor protein (APP). Post-injury enzymatic cleavage of APP can generate amyloid-β (Aβ) peptides, a hallmark finding in Alzheimer's disease (AD). At autopsy, brains of AD and a subset of TBI victims display some similarities including accumulation of Aβ peptides and neurofibrillary tangles of hyperphosphorylated tau proteins. Most epidemiological evidence suggests a link between TBI and AD, implying that TBI has neurodegenerative sequelae. Aβ peptides and tau may be used as biomarkers in interstitial fluid (ISF) using cerebral microdialysis and/or cerebrospinal fluid (CSF) following clinical TBI. In the present review, the available clinical and experimental literature on Aβ peptides and tau as potential biomarkers following TBI is comprehensively analyzed. Elevated CSF and ISF tau protein levels have been observed following severe TBI and suggested to correlate with clinical outcome. Although Aβ peptides are produced by normal neuronal metabolism, high levels of long and/or fibrillary Aβ peptides may be neurotoxic. Increased CSF and/or ISF Aβ levels post-injury may be related to neuronal activity and/or the presence of axonal injury. The heterogeneity of animal models, clinical cohorts, analytical techniques, and the complexity of TBI in the available studies make the clinical value of tau and Aβ as biomarkers uncertain at present. Additionally, the link between early post-injury changes in tau and Aβ peptides and the future risk of developing AD remains unclear. Future studies using methods such as rapid biomarker sampling combined with enhanced analytical techniques and/or novel pharmacological tools could provide additional information on the importance of Aβ peptides and tau protein in both the acute pathophysiology and long-term consequences of TBI.

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.