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Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging to exclude more severe forms of injury. However, identifying patients at risk for a poor outcome or protracted recovery is challenging, in part due to the lack of early objective tests that reflect the relevant underlying pathology. While the pathophysiology of mTBI is poorly understood, axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. Understanding the pathological processes that determine serum NfL dynamics over time, and the ability of NfL to reflect underlying pathology will be critical for future clinical research aimed at reducing the burden of disability after mild TBI. Using a gyrencephalic model of head rotational acceleration scaled to human concussion, we demonstrate significant elevations in serum NfL, with a peak at 3 days post-injury. Moreover, increased serum NfL was detectable out to 2 weeks post-injury, with some evidence it follows a biphasic course. Subsequent quantitative histological examinations demonstrate that axonal pathology, including in the absence of neuronal somatic degeneration, was the likely source of elevated serum NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum NfL. Interestingly, the extent of blood–brain barrier (BBB) permeability offered more robust correlations with serum NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI. [ABSTRACT FROM AUTHOR]

Diffuse axonal injury (DAI) results in aberrant functional connectivity and is significantly linked to cognitive impairment. Nevertheless, the network mechanisms influencing neurocognitive function following DAI remain unclear. This study aimed to examine the characteristics of static and dynamic functional network connectivity (FNC) in patients with DAI. Resting-state functional magnetic resonance imaging data were collected from 26 patients with DAI and 27 healthy controls. Resting-state networks were extracted using independent component analysis. We evaluated the connectivity strength through spatial maps and static FNC, and then further dynamic properties were identified using a sliding time-window approach and k-means clustering, and investigated their associations with clinical variables. Patients with DAI showed stronger intra-network spatial maps in the default mode network and subcortical network than healthy controls, but static inter-network functional connectivity remained stable. Furthermore, three recurring states for dynamic connectivity were identified in all participants, and state 1 occurred most frequently in patients with DAI and exhibited higher fractional time, and as well as longer mean dwell time, which was positively associated with MMSE scores. Meanwhile, patients with DAI exhibited mostly increased functional connectivity strength of dynamic FNC in all states, particularly within the default mode network and visual network. These findings suggest that patients with DAI are characterized by altered dynamic FNC and temporal properties, which provide distinct complementary information different from static functional connectivity, and new insights into the neural pathophysiology of DAI associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is associated with diffuse axonal injury (DAI), a primary pathology linked to progressive neurodegeneration and neuroinflammation, including chronic astrogliosis, which influences long-term post-TBI recovery and morbidity. Sex-based differences in blood-brain barrier (BBB) permeability increases the risk of accelerated brain aging and early-onset neurodegeneration. However, few studies have evaluated chronic time course of astrocytic responses around cerebrovascular in the context of aging after TBI and sex dependence. We observed increased glial fibrillary acidic protein (GFAP)-labeled accessory processes branching near and connecting with GFAP-ensheathed cortical vessels, suggesting a critical nuance in astrocyte-vessel interactions after TBI. To quantify this observation, male and female Sprague Dawley rats (∼3 months old, n = 5–6/group) underwent either sham surgery or midline fluid percussion injury. Using immunohistochemical analysis, we quantified GFAP-labeled astrocyte primary and accessory processes that contacted GFAP-ensheathed vessels in the somatosensory barrel cortex at 7, 56, and 168 days post-injury (DPI). TBI significantly increased GFAP-positive primary processes at 7 DPI (P < 0.01) in both sexes. At 56 DPI, these vessel-process interactions remained significantly increased exclusively in males (P < 0.05). At 168 DPI, both sexes showed a significant reduction in vessel-process interactions compared to 7 DPI (P < 0.05); however, a modest but significant injury effect reemerged in females (P < 0.05). A similar sex-dependent pattern in the number of accessory processes provides novel evidence of long-term temporal changes in astrocyte-vessel interactions. TBI-induced changes in astrocyte-vessel interactions may indicate chronic BBB vulnerability and processes responsible for early onset vascular and neurodegenerative pathology. [ABSTRACT FROM AUTHOR]

Abstract Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging to exclude more severe forms of injury. However, identifying patients at risk for a poor outcome or protracted recovery is challenging, in part due to the lack of early objective tests that reflect the relevant underlying pathology. While the pathophysiology of mTBI is poorly understood, axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. Understanding the pathological processes that determine serum NfL dynamics over time, and the ability of NfL to reflect underlying pathology will be critical for future clinical research aimed at reducing the burden of disability after mild TBI. Using a gyrencephalic model of head rotational acceleration scaled to human concussion, we demonstrate significant elevations in serum NfL, with a peak at 3 days post-injury. Moreover, increased serum NfL was detectable out to 2 weeks post-injury, with some evidence it follows a biphasic course. Subsequent quantitative histological examinations demonstrate that axonal pathology, including in the absence of neuronal somatic degeneration, was the likely source of elevated serum NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum NfL. Interestingly, the extent of blood–brain barrier (BBB) permeability offered more robust correlations with serum NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI.

Abstract Diffuse axonal injury (DAI) results in aberrant functional connectivity and is significantly linked to cognitive impairment. Nevertheless, the network mechanisms influencing neurocognitive function following DAI remain unclear. This study aimed to examine the characteristics of static and dynamic functional network connectivity (FNC) in patients with DAI. Resting-state functional magnetic resonance imaging data were collected from 26 patients with DAI and 27 healthy controls. Resting-state networks were extracted using independent component analysis. We evaluated the connectivity strength through spatial maps and static FNC, and then further dynamic properties were identified using a sliding time-window approach and k-means clustering, and investigated their associations with clinical variables. Patients with DAI showed stronger intra-network spatial maps in the default mode network and subcortical network than healthy controls, but static inter-network functional connectivity remained stable. Furthermore, three recurring states for dynamic connectivity were identified in all participants, and state 1 occurred most frequently in patients with DAI and exhibited higher fractional time, and as well as longer mean dwell time, which was positively associated with MMSE scores. Meanwhile, patients with DAI exhibited mostly increased functional connectivity strength of dynamic FNC in all states, particularly within the default mode network and visual network. These findings suggest that patients with DAI are characterized by altered dynamic FNC and temporal properties, which provide distinct complementary information different from static functional connectivity, and new insights into the neural pathophysiology of DAI associated with cognitive impairment.

BACKGROUND: Behavioral and neuropsychological functions are frequent longterm sequelae of severe traumatic brain injury (TBI). Neuropeptides, such as nerve growth factor (NGF), can enhance neurogenesis and improve cognitive functions after TBI, playing a pivotal role in neuroplasticity. A limited number of studies documented the safety and efficacy of intranasal NGF administration in children with severe TBI. CASE REPORT: A fourteen-year-old boy with a diffuse axonal injury secondary to severe TBI was treated with human-recombinant NGF administration. This patient underwent treatment with intranasal hr-NGF administration at a total dose of 50 gamma/kg, three times a day for seven consecutive days. The treatment schedule was performed for 4 cycles, at one month distance each. NGF administration improved radiologic functional assessment evaluated with positron emission tomography scan (PET) and single photon emission computed tomography (SPECT), with an important improvement in clinical conditions. Significant improvements were also observed, mainly in cognitive processes, memory, the planning of a communication strategy, execution skills, attention, and verbal expression. No side effects were reported. CONCLUSIONS: Additional studies are required to gain a deeper insight into this neurotrophin's neuroprotective function, but our findings reveal a potential efficacy of intranasal hr-NGF administration in enhancing cognitive and clinical outcomes among children with diffuse axonal injury after severe TBI. [ABSTRACT FROM AUTHOR]

Background Between 3 and 15% of winter sports–related injuries are related to head injuries, which are the primary cause of mortality and disability among skiers. Despite the widespread adoption of helmets in winter sports, which has reduced the incidence of direct head injury, there is a paradoxical trend of an increasing number of individuals wearing helmets sustaining diffuse axonal injuries (DAI), which can result in severe neurologic sequelae. Methods We retrospectively reviewed 100 cases collected by the senior author of this work from 13 full winter seasons during the period from 1981 to 1993 and compared them with 17 patients admitted during the more shortened 2019 to 2020 ski season due to COVID-19. All data analyzed come from a single institution. Population characteristics, mechanism of injury, helmet use, need for surgical treatment, diagnosis, and outcome were collected. Descriptive statistics were used to compare the two databases. Results From February 1981 to January 2020, most skiers with head injuries were men (76% for the 1981–1993 and 85% for 2020). The proportion of patients aged over 50 increased from <20% in 1981 to 65% in 2020 (p < 0.01), with a median age of 60 years (range: 22–83 years). Low- to medium-velocity injuries were identified in 76% (13) of cases during the 2019 to 2020 season against 38% (28/74) during the 1981 to 1993 seasons (p < 0.01). All injured patients during the 2020 season wore a helmet, whereas none of the patients between 1981 and 1993 wore one (p < 0.01). DAI was observed in six cases (35%) for the 2019 to 2020 season against nine cases (9%) for the 1981 to 1993 season (p < 0.01). Thirty-four percent (34) of patients during the 1981 to 1993 seasons and 18% (3) of patients during the 2019 to 2020 season suffered skeletal fractures (p = 0.02). Among the 100 patients of the 1981 to 1993 seasons, 13 (13%) died against 1 (6%) from the recent season during care at the hospital (p = 0.15). Neurosurgical intervention was performed in 30 (30%) and 2 (12%) patients for the 1981 to 1993 and 2019 to 2020 seasons, respectively (p = 0.003). Neuropsychological sequelae were reported in 17% (7/42) of patients from the 1981 to 1993 seasons and cognitive evaluation before discharge detected significant impairments in 24% (4/17) of the patients from the 2019 to 2020 season (p = 0.29). Conclusion Helmet use among skiers sustaining head trauma has increased from none in the period from 1981 to 1993 to 100% during the 2019 to 2020 season, resulting in a reduction in the number of skull fractures and deaths. However, our observations suggest a marked shift in the type of intracranial injuries sustained, including a rise in the number of skiers experiencing DAI, sometimes with severe neurologic outcomes. The reasons for this paradoxical trend can only be speculated upon, leading to the question of whether the perceived benefits of helmet use in winter sports are actually misinterpreted. [ABSTRACT FROM AUTHOR]

This study aimed to clarify the differences between the previously reported mechanisms of sports-related concussion (SRC) injuries without a loss of consciousness in contact and collision sports and the mechanisms of SRC injuries in our cases. Based on two videos of SRC injuries occurring during a men's rhythmic gymnastics competition (three people were injured), the risk of SRC occurrence was estimated from various parameters using a multibody analysis and eight brain injury evaluation criteria. In the present study, the three SRC impacts that occurred in men's rhythmic gymnastics showed significant characteristics in duration compared to previously reported cases in the contact sports. This suggests that the occurrence of SRC may have been caused by a different type of impact from that which causes SRC in contact sports (e.g., tackling). In addition, calculation of the strain indicating the rate of brain deformation suggested a risk of nerve swelling in all cases involving type 2 axonal injuries. Therefore, when reexamining sports-related head injuries, it is important to recognize the characteristics and mechanisms of SRC that occur in each different sport, as well as the symptoms and course of SRC after injury. [ABSTRACT FROM AUTHOR]

Traumatic axonal injury (TAI) is a common finding on magnetic resonance imaging (MRI) in patients with moderate–severe traumatic brain injury (TBI), and the burden of TAI is associated with outcome in this patient group. Lesion mapping offers a way to combine imaging findings from numerous individual patients into common lesion maps where the findings from a whole patient cohort can be assessed. The aim of this study was to evaluate the spatial distribution of TAI lesions on different MRI sequences and its associations to outcome with use of lesion mapping. Included prospectively were 269 patients (8–70 years) with moderate or severe TBI and MRI within six weeks after injury. The TAI lesions were evaluated and manually segmented on fluid-attenuated inversed recovery (FLAIR), diffusion weighted imaging (DWI), and either T2* gradient echo (T2*GRE) or susceptibility weighted imaging (SWI). The segmentations were registered to the Montreal Neurological Institute space and combined to lesion frequency distribution maps. Outcome was assessed with Glasgow Outcome Scale Extended (GOSE) score at 12 months. The frequency and distribution of TAI was assessed qualitatively by visual reading. Univariable associations to outcome were assessed qualitatively by visual reading and also quantitatively with use of voxel-based lesion-symptom mapping (VLSM). The highest frequency of TAI was found in the posterior half of corpus callosum. The frequency of TAI was higher in the frontal and temporal lobes than in the parietal and occipital lobes, and in the upper parts of the brainstem than in the lower. At the group level, all voxels in mesencephalon had TAI on FLAIR. The patients with poorest outcome (GOSE scores ≤4) had higher frequencies of TAI. On VLSM, poor outcome was associated with TAI lesions bilaterally in the splenium, the right side of tectum, tegmental mesencephalon, and pons. In conclusion, we found higher frequency of TAI in posterior corpus callosum, and TAI in splenium, mesencephalon, and pons were associated with poor outcome. If lesion frequency distribution maps containing outcome information based on imaging findings from numerous patients in the future can be compared with the imaging findings from individual patients, it would offer a new tool in the clinical workup and outcome prediction of the patient with TBI. [ABSTRACT FROM AUTHOR]

Diffuse axonal injury (DAI) following sudden acceleration and deceleration can lead to cognitive function decline. Various treatments have been proposed. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive stimulation technique, is a potential treatment for enhancing neuroplasticity in cases of brain injury. The therapeutic efficacy of rTMS on cognitive function remains unconfirmed. This study investigated the effects of rTMS and the underlying molecular biomechanisms using a rat model of DAI. Sprague–Dawley rats (n = 18) were randomly divided into two groups: one receiving rTMS after DAI and the other without brain stimulation. All rats were subjected to sudden acceleration and deceleration using a DAI modeling machine to induce damage. MRI was performed to confirm the DAI lesion. The experimental group received rTMS at a frequency of 1 Hz over the frontal cortex for 10 min daily for five days. To assess spatial memory, we conducted the Morris water maze (MWM) test one day post-brain damage and one day after the five-day intervention. A video tracking system recorded the escape latency. After post-MWM tests, all rats were euthanized, and their brain tissues, particularly from the hippocampus, were collected for immunohistochemistry and western blot analyses. The escape latency showed no difference on the MWM test after DAI, but a significant difference was observed after rTMS between the two groups. Immunohistochemistry and western blot analyses indicated increased expression of BDNF, VEGF, and MAP2 in the hippocampal brain tissue of the DAI-T group. In conclusion, rTMS improved cognitive function in the DAI rat model. The increased expression of BDNF, VEGF, and MAP2 in the DAI-T group supports the potential use of rTMS in treating cognitive impairments associated with DAI. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function. [ABSTRACT FROM AUTHOR]

Diffuse axonal injury (DAI) following sudden acceleration and deceleration can lead to cognitive function decline. Various treatments have been proposed. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive stimulation technique, is a potential treatment for enhancing neuroplasticity in cases of brain injury. The therapeutic efficacy of rTMS on cognitive function remains unconfirmed. This study investigated the effects of rTMS and the underlying molecular biomechanisms using a rat model of DAI. Sprague–Dawley rats (n = 18) were randomly divided into two groups: one receiving rTMS after DAI and the other without brain stimulation. All rats were subjected to sudden acceleration and deceleration using a DAI modeling machine to induce damage. MRI was performed to confirm the DAI lesion. The experimental group received rTMS at a frequency of 1 Hz over the frontal cortex for 10 min daily for five days. To assess spatial memory, we conducted the Morris water maze (MWM) test one day post-brain damage and one day after the five-day intervention. A video tracking system recorded the escape latency. After post-MWM tests, all rats were euthanized, and their brain tissues, particularly from the hippocampus, were collected for immunohistochemistry and western blot analyses. The escape latency showed no difference on the MWM test after DAI, but a significant difference was observed after rTMS between the two groups. Immunohistochemistry and western blot analyses indicated increased expression of BDNF, VEGF, and MAP2 in the hippocampal brain tissue of the DAI-T group. In conclusion, rTMS improved cognitive function in the DAI rat model. The increased expression of BDNF, VEGF, and MAP2 in the DAI-T group supports the potential use of rTMS in treating cognitive impairments associated with DAI.

Cristina-Mihaela Popescu,1 Virginia Marina,2 Georgiana Avram,3 Carmen Laura Cristescu Budala3 1Dental-Medicine Department, Faculty of Medicine and Pharmacy, “dun&abreve;rea de Jos” University, Galați, 800201, Romania; 2Medical Department of Occupational Health, Faculty of Medicine and Pharmacy, “Dun&abreve;rea de Jos” University, Galați, 800201, Romania; 3“sf. Ioan” Clinical Emergency Children’s Hospital, Galați, 800487, RomaniaCorrespondence: Virginia Marina, Tel +40-770-89-82-74, Email virginia.marina@ugal.roAbstract: Head trauma (HT) in pediatric patients is the number one cause of mortality and morbidity in children. Although computer tomography (CT) imaging provides ample information in assessing acute traumatic brain injuries (TBIs), there are instances when magnetic resonance imaging (MRI) is needed. Due to its high sensitivity in diagnosing small bleeds, MRI offers a well-documented evaluation of primary acute TBIs. Our pictorial essay aims to present some of the latest imaging protocols employed in head trauma and review some practical considerations. Injury mechanisms in accidental HT, lesions’ topography, and hematoma signal variability over time are also discussed. Acute primary intra- and extra-axial lesions and their MRI aspect are showcased using images from patients in our hospital. This pictorial essay has an educational purpose. It is intended to guide young emergency and intensive care unit doctors, neurologists, and neurosurgeons in diagnosing acute primary TBIs on MRI while waiting for the official radiologist’s report. The presentation focuses on the most frequent traumatic lesions encountered in acute pediatric head trauma.Keywords: paediatric head trauma, traumatic brain injury, diffuse axonal injury, haemorrhagic cortical contusions, epidural haematoma

We performed a clinical-radiographic association study investigating the hypothesis that paroxysmal sympathetic hyperactivity (PSH) occurs in traumatic brain injury (TBI) patients with structural damage to the central autonomic network (CAN). To this end, we identified critically ill acute TBI patients who underwent magnetic resonance imaging (MRI) of the brain between January 2016 and July 2018. All patients were scored retrospectively according to the PSH-Assessment Measure (PSH-AM), which provides a clinical feature score, a diagnosis likelihood score, and a total score. All MRIs were reviewed for lesions within a priori CAN regions of interest, including the brainstem, ventral diencephalon, thalamus, medial temporal lobes, insula, anterior cingulate/medial prefrontal cortex, corpus callosum, and bilateral hemispheric white matter, on diffusion-weighted imaging (DWI), fluid attenuated inversion recovery (FLAIR), and susceptibility-weighted imaging (SWI) sequences. PSH-AM scores were compared using non-parametric tests according to lesion presence in each region and sequence. Imaging features independently associated with PSH-AM scores were ascertained from multivariable linear regression models using backwards elimination feature selection. The strongest predictive models were adjusted for known PSH risk factors including age, sex, and Glasgow Coma Scale (GCS), to determine the independent contribution of imaging features to PSH-AM scores. We found that of 128 patients meeting inclusion criteria, 60 (47%) were clinically diagnosed with PSH. PSH-AM diagnosis likelihood and total scores and clinical diagnosis were strongly associated with CAN lesions. The strongest multivariable model, adjusted for age, sex, and GCS, identified SWI lesions in the corpus callosum and medial temporal lobes as independent imaging predictors of PSH diagnosis likelihood. This exploratory study supports the hypothesis that structural damage to CAN regions is associated with the clinical syndrome of PSH after TBI, and provides foundational evidence for future data-driven studies.

Traumatic brain injury (TBI) is associated with diffuse axonal injury (DAI), a primary pathology linked to progressive neurodegeneration and neuroinflammation, including chronic astrogliosis, which influences long-term post-TBI recovery and morbidity. Sex-based differences in blood-brain barrier (BBB) permeability increases the risk of accelerated brain aging and early-onset neurodegeneration. However, few studies have evaluated chronic time course of astrocytic responses around cerebrovascular in the context of aging after TBI and sex dependence. We observed increased glial fibrillary acidic protein (GFAP)-labeled accessory processes branching near and connecting with GFAP-ensheathed cortical vessels, suggesting a critical nuance in astrocyte-vessel interactions after TBI. To quantify this observation, male and female Sprague Dawley rats (∼3 months old, n = 5–6/group) underwent either sham surgery or midline fluid percussion injury. Using immunohistochemical analysis, we quantified GFAP-labeled astrocyte primary and accessory processes that contacted GFAP-ensheathed vessels in the somatosensory barrel cortex at 7, 56, and 168 days post-injury (DPI). TBI significantly increased GFAP-positive primary processes at 7 DPI (P < 0.01) in both sexes. At 56 DPI, these vessel-process interactions remained significantly increased exclusively in males (P < 0.05). At 168 DPI, both sexes showed a significant reduction in vessel-process interactions compared to 7 DPI (P < 0.05); however, a modest but significant injury effect reemerged in females (P < 0.05). A similar sex-dependent pattern in the number of accessory processes provides novel evidence of long-term temporal changes in astrocyte-vessel interactions. TBI-induced changes in astrocyte-vessel interactions may indicate chronic BBB vulnerability and processes responsible for early onset vascular and neurodegenerative pathology.

(1) Background: Traumatic brain injury (TBI) often results in cognitive impairments, including in visuospatial planning and executive function. Methylphenidate (MPh) demonstrates potential improvements in several cognitive domains in patients with TBI. The Tower of London (TOL) is a visuospatial planning task used to assess executive function. (2) Methods: Volunteers with a history of TBI (n = 16) participated in a randomised, double-blinded, placebo-controlled, fMRI study to investigate the neurobiological correlates of visuospatial planning and executive function, on and off MPh. (3) Results: Healthy controls (HCs) (n = 18) and patients on placebo (TBI-placebo) differed significantly in reaction time (p < 0.0005) and accuracy (p < 0.0001) when considering all task loads, but especially for high cognitive loads for reaction time (p < 0.001) and accuracy (p < 0.005). Across all task loads, TBI-MPh were more accurate than TBI-placebo (p < 0.05) but remained less accurate than HCs (p < 0.005). TBI-placebo substantially improved in accuracy with MPh administration (TBI-MPh) to a level statistically comparable to HCs at low (p = 0.443) and high (p = 0.175) cognitive loads. Further, individual patients that performed slower on placebo at low cognitive loads were faster with MPh (p < 0.05), while individual patients that performed less accurately on placebo were more accurate with MPh at both high and low cognitive loads (p < 0.005). TBI-placebo showed reduced activity in the bilateral inferior frontal gyri (IFG) and insulae versus HCs. MPh normalised these regional differences. MPh enhanced within-network connectivity (between parietal, striatal, insula, and cerebellar regions) and enhanced beyond-network connectivity (between parietal, thalamic, and cerebellar regions). Finally, individual changes in cerebellar-thalamic (p < 0.005) and cerebellar-parietal (p < 0.05) connectivity with MPh related to individual changes in accuracy with MPh. (4) Conclusions: This work highlights behavioural and neurofunctional differences between HCs and patients with chronic TBI, and that adverse differences may benefit from MPh treatment. [ABSTRACT FROM AUTHOR]

Background: The diagnosis and prognosis of diffuse axonal injury (DAI) remain challenging. This research aimed to analyze the impact on activities of daily living (ADL), functional outcomes, quality of life (QoL), and the association between lesion severity and DAI location identified through imaging exams. Methods: This prospective cohort study included 95 patients diagnosed with DAI. Data were collected at admission, three, six, and twelve months post-injury. The associations between variables were evaluated using a mixed-effects model. Results: Functional recovery and QoL improved between three and twelve months after DAI. An interaction was observed between independence in performing ADL and subarachnoid hemorrhage (p = 0.043) and intraventricular hemorrhage (p = 0.012). Additionally, an interaction over time was observed between the Glasgow Outcome Scale (GOS) and DAI severity (p < 0.001), brain lesions (p = 0.014), and the Disability Rating Scale (DRS) with injury in brain hemispheres (p = 0.026) and Adams classification (p = 0.013). Interaction effects over time were observed with the general health perceptions and energy/vitality domains with intraventricular hemorrhage, and the social functioning domain with the obliteration of basal cisterns and Gentry's classification. Conclusion: The use of CT in the acute phase of DAI is important for predicting outcomes. The severity and location of DAI are associated with functional outcomes, ADL, and QoL. [ABSTRACT FROM AUTHOR]

Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes. [ABSTRACT FROM AUTHOR]

Diffuse axonal injury (DAI), with high mortality and morbidity both in children and adults, is one of the most severe pathological consequences of traumatic brain injury. Currently, clinical diagnosis, disease assessment, disability identification, and postmortem diagnosis of DAI is mainly limited by the absent of specific molecular biomarkers. In this review, we first introduce the pathophysiology of DAI, summarized the reported biomarkers in previous animal and human studies, and then the molecular biomarkers such as β-Amyloid precursor protein, neurofilaments, S-100β, myelin basic protein, tau protein, neuron-specific enolase, Peripherin and Hemopexin for DAI diagnosis is summarized. Finally, we put forward valuable views on the future research direction of diagnostic biomarkers of DAI. In recent years, the advanced technology has ultimately changed the research of DAI, and the numbers of potential molecular biomarkers was introduced in related studies. We summarized the latest updated information in such studies to provide references for future research and explore the potential pathophysiological mechanism on diffuse axonal injury. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a global concern, and many people suffer from TBI annually. Determining the outcome of patients with brain injury has a valuable clinical impact and results in better management of patients. In this study, we aimed to investigate the predictive value of magnetic resonance spectrometry (MRS) in patients with diffuse axonal injury (DAI). Method: This is a prospective cohort study on patients with DAI in 6 months at a tertiary medical center. According to the eligibility criteria, the patients were enrolled in the study. The MRS scan was conducted on days 3 and 30, and the correlation of metabolites of MRS according to the GCS score of patients on days 3 and 30 was investigated to determine the prognostic impact of MRS in patients with DAI. Results: A total of 50 patients with DAI, including 39 males and 11 females, were recruited. MRS of patients on day 3 and 30 was conducted and showed that the level phosphocreatine (r = -0.56, P

Traumatic brain injury (TBI) results from mechanical force to the brain and leads to a series of biochemical responses that further damage neurons and supporting cells. Clinically, most TBIs result from an impact to the intact skull, making closed head TBI pre-clinical models highly relevant. However, most of these closed head TBI models use lissencephalic rodents, which may not transduce biomechanical load in the same manner as gyrencephalic humans. To address this translational gap, this study aimed to characterize acute axonal injury and microglial responses in ferrets?the smallest gyrencephalic mammal. Injury was induced in male ferrets (Mustela furo; 1.20?1.51?kg; 6?9 months old) with the novel Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) model. Animals were randomly allocated to either sham (n?=?4), a 22J (joules) impact (n?=?4), or a 27J impact (n?=?4). Axonal injury was examined histologically with amyloid precursor protein (APP), neurofilament M (RMO 14.9) (RMO-14), and phosphorylated tau (AT180) and the microglial response with ionized calcium-binding adaptor molecule 1 at 24?h post-injury in gray and white matter regions. Graded axonal injury was observed with modest increases in APP and RMO-14 immunoreactivity in the 22J TBI group, mostly within the corpus callosum and fornix and more extensive diffuse axonal injury encompassing gray matter structures like the thalamus and hypothalamus in the 27J group. Accompanying microglial activation was only observed in the 27J group, most prominently within the white matter tracts in response to the larger amounts of axonal injury. The 27J, but not the 22J, group showed an increase in AT180 within the base of the sulci post-injury. This could suggest that the strain may be highest in this region, demonstrating the different responses in gyrencephalic compared to lissencephalic brains. The CHIMERA model in ferrets mimic many of the histopathological features of human closed head TBI acutely and provides a promising model to investigate the pathophysiology of TBI.

This study aimed to clarify the differences between the previously reported mechanisms of sports-related concussion (SRC) injuries without a loss of consciousness in contact and collision sports and the mechanisms of SRC injuries in our cases. Based on two videos of SRC injuries occurring during a men’s rhythmic gymnastics competition (three people were injured), the risk of SRC occurrence was estimated from various parameters using a multibody analysis and eight brain injury evaluation criteria. In the present study, the three SRC impacts that occurred in men’s rhythmic gymnastics showed significant characteristics in duration compared to previously reported cases in the contact sports. This suggests that the occurrence of SRC may have been caused by a different type of impact from that which causes SRC in contact sports (e.g., tackling). In addition, calculation of the strain indicating the rate of brain deformation suggested a risk of nerve swelling in all cases involving type 2 axonal injuries. Therefore, when reexamining sports-related head injuries, it is important to recognize the characteristics and mechanisms of SRC that occur in each different sport, as well as the symptoms and course of SRC after injury.

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.

Aim Different deposition patterns and grading systems used to define and identify DAI remain discordant and to date these are a challenge in clinical practice. Our main objective was to study the post-mortem axonal changes and develop a grading system to identify DAI on the basis of histopathological and immunoreactive β-amyloid precursor protein (β-APP) observations in severe TBI cases.

Introduction/background Non convulsive seizures (NCS) following traumatic brain injury (TBI) may remain undiagnosed due to lack of overt clinical manifestation and can have long-term sequelae due to delay in timely treatment. Occurrence of early NCS is known to have subsequent neurologic sequelae due to excitotoxic neuronal injury. Case report This is a case report of a young girl who sustained a TBI due to a motor vehicle accident (MVA) and was admitted with a fluctuating level of consciousness. Her clinical presentation was attributed to TBI; however as her conscious level did not recover, an electroencephalogram (EEG) was requested, which detected non convulsive status epilepticus (NCSE). Anti-seizure medication (ASM) was started. Her follow-up EEG and magnetic resonance imaging (MRI) were suggestive of the potential adverse effects of prolonged NCSE. Conclusion NCS may remain undiagnosed in TBI due to a paucity of overt clinical manifestations. Every patient with TBI and altered consciousness at presentation should be evaluated by continuous EEG monitoring immediately, if possible, in the emergency department to avoid long-term sequelae of NCS in such cases.

Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner violence (IPV) in their lifetime, often with TBI, yet remarkably little is known about the range of autopsy neuropathologies encountered in IPV. We report a prospectively accrued case series from a single institution, the New York City Office of Chief Medical Examiner, evaluated in partnership with the Brain Injury Research Center of Mount Sinai, using a multimodal protocol comprising clinical history review, ex vivo imaging in a small subset, and comprehensive neuropathological assessment by established consensus protocols. Fourteen brains were obtained over 2 years from women with documented IPV (aged 3rd–8th decade; median, 4th) and complex histories including prior TBI in 6, nonfatal strangulation in 4, cerebrovascular, neurological, and/or psychiatric conditions in 13, and epilepsy in 7. At autopsy, all had TBI stigmata (old and/or recent). In addition, white matter regions vulnerable to diffuse axonal injury showed perivascular and parenchymal iron deposition and microgliosis in some subjects. Six cases had evidence of cerebrovascular disease (lacunes and/or chronic infarcts). Regarding neurodegenerative disease pathologies, Alzheimer disease neuropathologic change was present in a single case (8th decade), with no chronic traumatic encephalopathy neuropathologic change (CTE-NC) identified in any. Findings from this initial series then prompted similar exploration in an expanded case series of 70 archival IPV cases (aged 2nd–9th decade; median, 4th) accrued from multiple international institutions. In this secondary case series, we again found evidence of vascular and white matter pathologies. However, only limited neurodegenerative proteinopathies were encountered in the oldest subjects, none meeting consensus criteria for CTE-NC. These observations from this descriptive exploratory study reinforce a need to consider broad co-morbid and neuropathological substrates contributing to brain health outcomes in the context of IPV, some of which may be potentially modifiable. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the role of soluble epoxide hydrolase for hyperglycemia induced‐disruption of blood‐brain barrier (BBB) integrity after diffuse axonal injury (DAI). Methods: Rat DAI hyperglycemia model was established by a lateral head rotation device and intraperitoneal injection of 50% glucose. Glial fibrillary acidic protein, ionized calcium‐binding adapter molecule‐1, β‐amyloid precursor protein, neurofilament light chain, and neurofilament heavy chain was detected by immunohistochemistry. Cell apoptosis was examined by terminal deoxynucleotidyl transferase nick‐end labeling (TUNEL) assay. The permeability of blood‐brain barrier (BBB) was assessed by expression of tight junction proteins, leakage of Evans blue and brain water content. The soluble epoxide hydrolase (sEH) pathway was inhibited by 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU) and the nuclear transcription factor kappa B (NF‐κB) pathway was inhibited by pyrrolidine dithiocarbamate and activated by phorbol‐12‐myristate‐13‐acetate in vivo and/or vitro, respectively. The inflammatory factors were detected by enzyme‐linked immunosorbent assay. Results: Hyperglycemia could exacerbate axonal injury, aggravate cell apoptosis and glial activation, worsen the loss of BBB integrity, increase the release of inflammatory factors, and upregulate the expression of sEH and NF‐κB. Inhibition of sEH could reverse all these damages and protect BBB integrity by upregulating the expression of tight junction proteins and downregulating the levels of inflammatory factors in vivo and vitro, while the agonist of NF‐κB pathway abrogated the protective effects of TPPU on BBB integrity in vitro. Conclusions: sEH was involved in mediating axonal injury induced by hyperglycemia after DAI by disrupting BBB integrity through inducing inflammation via the NF‐κB pathway. [ABSTRACT FROM AUTHOR]

Introduction:Traumatic Brain Injuries (TBI) are a leading cause of morbidity and mortality. Considering the vast number of individuals in the economically productive age group who are afflicted by this entity, it is important to realise the epidemiology, risk factors and other essential data to effectively prognosticate the outcome in these patients so that the limited resources are put to optimal use. We have endeavoured to study the efficacy of the admission neurological status (Glasgow Coma Score - GCS) and the radiological findings (Marshall, Rotterdam and MRI scoring systems) in prognostication of Diffuse Axonal Injury (DAI) using the Glasgow Outcome Score (GOS) to quantify the clinical outcome. Material & Methods: This is a prospective observational study of 158 consecutive Diffuse Axonal Injury (DAI) patients conducted at Madras Medical College. GCS at admission was taken as the clinical data. Marshall's, Rotterdam and MRI scores were taken as radiological data. The patients' GOS at 1 month was taken as clinical outcome. Statistical analyses were then made to correlate the clinical and radiological data with the one-month outcome of the patients. Statistical analysis was done using the SPSS software - version 16, using statistical tests like Pearson's coefficient and ANOVA. A p-value of less than 0.05 was considered statistically significant. Results:The admission GCS and MRI grade of DAI showed a statistically significant correlation with the clinical outcome, but the Marshall and Rotterdam scores did not. Conclusion: Proper neurological evaluation of the patient with GCS score on admission and MRI brain when feasible, with both having a statistically significant correlation with clinical outcome, provide reliable prediction models for prognosticating outcome in DAI patients. [ABSTRACT FROM AUTHOR]

Introduction: It is yet unclear what kind of long-term effects such widespread brain damage would have. Apart from the etiology of subdural hematomas and coup injuries, which are characteristic of outer focal head trauma, widespread degeneration of cerebral white matter is linked to sagittal and lateral acceleration with centroaxial trauma. Diffuse axonal injury has a higher mortality rate than outer cerebral injury, with over 50% of sufferers passing away within two weeks. Methods: Between February 2022 to January 2023, at Department of Neurosurgery, Gandhi Medical College, Secunderabad, Hyderabad, Telangana, India, conducted a prospective cross-sectional research of 30 patients. Results: Pathognomonic lesions were found at autopsy in this investigation, even though CT brain scans were normal in most patients. Hypoxic changes including cellular swelling, Microhemorrages, white matter degeneration, and axonal swelling were observed on microscopic examination. The most frequent of these was hypoxic changes accompanied by cell enlargement. Conclusion: Our research shows that the results of a CT of the brain do not reliably predict how severe a patient's head injury would be. Studies performed after death have determined that hypoxia and free radicals were major contributors to death, specifically edema in the brain stem and corpus callosum. The researcher plans to tackle these issues in future studies by doing biochemical analytical studies and studies with larger samples. [ABSTRACT FROM AUTHOR]

To evaluate the altered network topological properties and their clinical relevance in patients with posttraumatic diffuse axonal injury (DAI). Forty-seven participants were recruited in this study, underwent 3D T1-weighted and resting-state functional MRI, and had single-subject morphological brain networks (MBNs) constructed by Kullback–Leibler divergence and functional brain networks (FBNs) constructed by Pearson correlation measurement interregional similarity. The global and regional properties were analyzed and compared using graph theory and network-based statistics (NBS), and the relationship with clinical manifestations was assessed. Compared with those of the healthy subjects, MBNs of patients with DAI showed a higher path length ( Lp : P = 0.021, λ : P = 0.011), lower clustering (γ : P = 0.002) and less small-worldness (σ : P = 0.002), but there was no significant difference in the global properties of FBNs (P: 0.161–0.216). For nodal properties of MBNs and FBNs, several regions showed significant differences between patients with DAI and healthy controls (HCs) (P < 0.05, FDR corrected). NBS analysis revealed that MBNs have more altered morphological connections in the frontal parietal control network and interhemispheric connections (P < 0.05). DAI-related global or nodal properties of MBNs were correlated with physical disability or dyscognition (P < 0.05/7, with Bonferroni correction), and the alteration of functional topology properties mediates this relationship. Our results suggested that disrupted morphological topology properties, which are mediated by FBNs and correlated with clinical manifestations of DAI, play a critical role in the short-term and medium-term phases after trauma. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) are each leading causes of mortality and morbidity worldwide, and present additional treatment considerations when they are comorbid (TBI+HS) as a result of competing pathophysiological responses. The current study rigorously quantified injury biomechanics with high precision sensors and examined whether blood-based surrogate markers were altered in general trauma as well as post-neurotrauma. Eighty-nine sexually mature male and female Yucatan swine were subjected to a closed-head TBI+HS (40% of circulating blood volume; n = 68), HS only (n = 9), or sham trauma (n = 12). Markers of systemic (e.g., glucose, lactate) and neural functioning were obtained at baseline, and at 35 and 295 min post-trauma. Opposite and approximately twofold differences existed for both magnitude (device > head) and duration (head > device) of quantified injury biomechanics. Circulating levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase L1 (UCH-L1) demonstrated differential sensitivity for both general trauma (HS) and neurotrauma (TBI+HS) relative to shams in a temporally dynamic fashion. GFAP and NfL were both strongly associated with changes in systemic markers during general trauma and exhibited consistent time-dependent changes in individual sham animals. Finally, circulating GFAP was associated with histopathological markers of diffuse axonal injury and blood–brain barrier breach, as well as variations in device kinematics following TBI+HS. Current findings therefore highlight the need to directly quantify injury biomechanics with head mounted sensors and suggest that GFAP, NfL, and UCH-L1 are sensitive to multiple forms of trauma rather than having a single pathological indication (e.g., GFAP = astrogliosis). [ABSTRACT FROM AUTHOR]

Drug development in traumatic brain injury (TBI) has been impeded by the complexity and heterogeneity of the disease pathology, as well as limited understanding of the secondary injury cascade that follows the initial trauma. As a result, patients with TBI have an unmet need for effective pharmacological therapies. One promising drug candidate is cyclosporine, a polypeptide traditionally used to achieve immunosuppression in transplant recipients. Cyclosporine inhibits mitochondrial permeability transition, thereby reducing secondary brain injury, and has shown neuroprotective effects in multiple preclinical models of TBI. Moreover, the cyclosporine formulation NeuroSTAT® displayed positive effects on injury biomarker levels in patients with severe TBI enrolled in the Phase Ib/IIa Copenhagen Head Injury Ciclosporin trial (NCT01825044). Future research on neuroprotective compounds such as cyclosporine should take advantage of recent advances in fluid-based biomarkers and neuroimaging to select patients with similar disease pathologies for clinical trials. This would increase statistical power and allow for more accurate assessment of long-term outcomes. [ABSTRACT FROM AUTHOR]

Abstract Objectives We aimed to investigate the role of soluble epoxide hydrolase for hyperglycemia induced‐disruption of blood‐brain barrier (BBB) integrity after diffuse axonal injury (DAI). Methods Rat DAI hyperglycemia model was established by a lateral head rotation device and intraperitoneal injection of 50% glucose. Glial fibrillary acidic protein, ionized calcium‐binding adapter molecule‐1, β‐amyloid precursor protein, neurofilament light chain, and neurofilament heavy chain was detected by immunohistochemistry. Cell apoptosis was examined by terminal deoxynucleotidyl transferase nick‐end labeling (TUNEL) assay. The permeability of blood‐brain barrier (BBB) was assessed by expression of tight junction proteins, leakage of Evans blue and brain water content. The soluble epoxide hydrolase (sEH) pathway was inhibited by 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU) and the nuclear transcription factor kappa B (NF‐κB) pathway was inhibited by pyrrolidine dithiocarbamate and activated by phorbol‐12‐myristate‐13‐acetate in vivo and/or vitro, respectively. The inflammatory factors were detected by enzyme‐linked immunosorbent assay. Results Hyperglycemia could exacerbate axonal injury, aggravate cell apoptosis and glial activation, worsen the loss of BBB integrity, increase the release of inflammatory factors, and upregulate the expression of sEH and NF‐κB. Inhibition of sEH could reverse all these damages and protect BBB integrity by upregulating the expression of tight junction proteins and downregulating the levels of inflammatory factors in vivo and vitro, while the agonist of NF‐κB pathway abrogated the protective effects of TPPU on BBB integrity in vitro. Conclusions sEH was involved in mediating axonal injury induced by hyperglycemia after DAI by disrupting BBB integrity through inducing inflammation via the NF‐κB pathway.

The article presents a case study of a 36-year-old male with a traumatic brain injury, specifically diffuse axonal injury (DAI), and a history of bipolar 1 disorder. It discusses the challenges in managing his altered mental status, which was initially attributed to his brain injury but later diagnosed as an atypical presentation of neuroleptic malignant syndrome (NMS).

Diffuse axonal injury (DAI) is a devastating traumatic neurologic injury with variable prognosis. Although outcomes such as mortality have been described, the time course of neurologic progression is poorly understood. We investigated the association between DAI neuroanatomic injury pattern and neurologic recovery timing. A retrospective review of our institution's trauma registry identified patients diagnosed with DAI from 2017–2021. The neuroradiologist's review of a head computed tomography scan was used to score DAI severity. In-hospital neurologic examinations were reviewed, and the Glasgow Coma Scale (GCS) was calculated for all patients throughout the hospital stay. Categorical variables were analyzed using the Fisher exact test, and continuous variables were analyzed using the Kruskal-Wallis test. Nineteen DAI patients (grade 1 = 8; grade 2 = 1; grade 3 = 10) were included (mean age 31 years, 79% male). Mean Rotterdam computed tomography score, Injury Severity Scale, and admission GCS were comparable across DAI grades. Mean time in days to follow commands was shorter for those with grade 1 DAI (9.3) compared with grade 2 (17 days) or grade 3 (19 days) DAI (P = 0.02). Throughout hospitalization, patients with grade 1 DAI had higher motor (P = 0.006), eye (P = 0.001), and total GCS (P = 0.011) scores compared with those with grade 2 or 3 DAI. At the time of discharge, total GCS and the frequency of command following was similar across DAI grades. Patients with grade 1 DAI demonstrated the fastest short-term neurologic recovery, although final discharge neurologic examination was comparable across DAI grades. DAI classification can provide useful short-term prognostic information regarding in-hospital neurologic improvement. [ABSTRACT FROM AUTHOR]

Aim Different deposition patterns and grading systems used to define and identify DAI remain discordant and to date these are a challenge in clinical practice. Our main objective was to study the post-mortem axonal changes and develop a grading system to identify DAI on the basis of histopathological and immunoreactive β-amyloid precursor protein (β-APP) observations in severe TBI cases. Methods Prospective study with 35 decedents with sTBI (GCS score ≤ 8) was conducted and samples were collected from three different sites–corpus callosum, thalamus and brain stem. Serial sections from each site were stained with hematoxylin and eosin (H&E), and immunohistochemistry (IHC) of β-APP. Results We developed a grading system based on histopathological characteristics to assess the overall damage of axonal injury. We found maximum histopathological changes in cases with prolonged stay. Corpus callosum showed maximum changes in both gradings. Curiously, we also detected axonal swellings with H&E staining. Usually neglected, the thalamus also showed significant histopathological and immunoreactive changes for sTBI. Conclusion Our study based on histopathological and β-APP scoring system to define and identify DAI thus facilitates accurate diagnosis of DAI post mortem, which has forensic implications, and may further contribute toward survival and improvement of quality of life of sTBI patients. [ABSTRACT FROM AUTHOR]

More than two decades ago, Marmarou published a valid model for producing diffuse axonal injury (DAI) in rats. Since then, both mild and severe injuries have been obtained by researchers using the original method and a weight of 450 g. However, the diffuse brain injuries produced in rats were only similar to those seen in humans when the rats sustained severe brain injuries. In these cases, rat mortality in the original article was around 50%, and the cause of death was prolonged apnea post‐impact. Rat survival after impact is critical for studying the progression of DAI. In order to explain the cause of death in human victims with cranial trauma who do not show gross brain injury, testing for the presence of DAI is essential. Thus, in order to minimize local and cervical injuries to increase rat survival, attention should be paid to the following aspects: a wider head protector disc should be used, the head of the rat should be elevated at the time of impact, and the foam bed should be soft enough to allow the movement caused by acceleration. With our modified method, rat survival increased by 30% compared to the original model (80% versus 50%). Moreover, 85.7% of rats demonstrated DAI after 24 h of survival. With these modifications, injuries appear in the same locations as in humans; thus, the method is suitable for the study of traumatic DAI in humans. [ABSTRACT FROM AUTHOR]

The aim of our study was to investigate the potential of advanced radiomics in analyzing diffusion kurtosis MRI (DKI) to increase the informativeness of DKI in diffuse axonal injury (DAI). We hypothesized that DKI radiomic features could be used to detect microstructural brain injury and predict outcomes in DAI. The study enrolled 31 patients with DAI (mean age 31.48 ± 11.10 years, 8 (25.8%) female) and 12 healthy volunteers (mean age 33.67 ± 11.06 years, 4 (33.3%) female). A total of 342,300 radiomic features were calculated (2282 features per each combination of 10 parametric DKI maps with 15 ROIs). Our results showed that several radiomic features were capable of distinguishing between healthy and injured brain tissue and accurately predicting outcomes with an accuracy of over 0.9. Advanced DKI radiomic features show high diagnostic and prognostic potential in DAI and may outperform average ROI values in DKI maps. [ABSTRACT FROM AUTHOR]

Abstract Background Magnetic resonance imaging (MRI) carries prognostic importance after traumatic brain injury (TBI), especially when computed tomography (CT) fails to fully explain the level of unconsciousness. However, in critically ill patients, the risk of deterioration during transfer needs to be balanced against the benefit of detecting prognostically relevant information on MRI. We therefore aimed to assess if day of injury serum protein biomarkers could identify critically ill TBI patients in whom the risks of transfer are compensated by the likelihood of detecting management-altering neuroimaging findings. Methods Data were obtained from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Eligibility criteria included: TBI patients aged ≥ 16 years, Glasgow Coma Score (GCS)

Purpose: Mild traumatic brain injuries (mTBI) sustained during contact sports like amateur boxing are found to have long-term sequelae, being linked to an increased risk of developing neurological conditions like Parkinson's disease. The aim of this study was to assess differences in volume of anatomical brain structures between amateur boxers and control subjects with a special interest in the affection of deep grey matter structures. Methods: A total of 19 amateur boxers and 19 healthy controls (HC), matched for age and intelligence quotient (IQ), underwent 3T magnetic resonance imaging (MRI) as well as neuropsychological testing. Body mass index (BMI) was evaluated for every subject and data about years of boxing training and number of fights were collected for each boxer. The acquired 3D high resolution T1 weighted MR images were analyzed to measure the volumes of cortical grey matter (GM), white matter (WM), cerebrospinal fluid (CSF) and deep grey matter structures. Multivariate analysis was applied to reveal differences between groups referencing deep grey matter structures to normalized brain volume (NBV) to adjust for differences in head size and brain volume as well as adding BMI as cofactor. Results: Total intracranial volume (TIV), comprising GM, WM and CSF, was lower in boxers compared to controls (by 7.1%, P = 0.009). Accordingly, GM (by 5.5%, P = 0.038) and WM (by 8.4%, P = 0.009) were reduced in boxers. Deep grey matter showed statistically lower volumes of the thalamus (by 8.1%, P = 0.006), caudate nucleus (by 11.1%, P = 0.004), putamen (by 8.1%, P = 0.011), globus pallidus (by 9.6%, P = 0.017) and nucleus accumbens (by 13.9%, P = 0.007) but not the amygdala (by 5.5%, P = 0.221), in boxers compared to HC. Conclusion: Several deep grey matter structures were reduced in volume in the amateur boxer group. Furthermore, longitudinal studies are needed to determine the damage pattern affecting deep grey matter structures and its neuropsychological relevance. [ABSTRACT FROM AUTHOR]

Background: The diagnosis and prognosis of diffuse axonal injury (DAI) remain challenging. This research aimed to analyze the impact on activities of daily living (ADL), functional outcomes, quality of life (QoL), and the association between lesion severity and DAI location identified through imaging exams. Methods: This prospective cohort study included 95 patients diagnosed with DAI. Data were collected at admission, three, six, and twelve months post-injury. The associations between variables were evaluated using a mixed-effects model. Results: Functional recovery and QoL improved between three and twelve months after DAI. An interaction was observed between independence in performing ADL and subarachnoid hemorrhage (p = 0.043) and intraventricular hemorrhage (p = 0.012). Additionally, an interaction over time was observed between the Glasgow Outcome Scale (GOS) and DAI severity (p < 0.001), brain lesions (p = 0.014), and the Disability Rating Scale (DRS) with injury in brain hemispheres (p = 0.026) and Adams classification (p = 0.013). Interaction effects over time were observed with the general health perceptions and energy/vitality domains with intraventricular hemorrhage, and the social functioning domain with the obliteration of basal cisterns and Gentry’s classification. Conclusion: The use of CT in the acute phase of DAI is important for predicting outcomes. The severity and location of DAI are associated with functional outcomes, ADL, and QoL.

Hiba Abuelgasim Fadlelmoula Abdelrahman,1 Shiho Ubukata,2 Keita Ueda,1 Gaku Fujimoto,1 Naoya Oishi,2 Toshihiko Aso,3 Toshiya Murai1 1Kyoto University Graduate School of Medicine-Department of Psychiatry, Kyoto, 606-8507, Japan; 2Kyoto University Graduate School of Medicine-Medical Innovation Center, Kyoto, 606-8507, Japan; 3Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, JapanCorrespondence: Hiba Abuelgasim Fadlelmoula Abdelrahman, Email hiba.abulgasim@gmail.comAim: Diffuse axonal injury (DAI) is one of the most common pathological features of traumatic brain injury (TBI). Diffusion tensor imaging (DTI) indices can be used to identify and quantify white matter microstructural changes following DAI. Recently, many studies have used DTI with various machine learning approaches to predict white matter microstructural changes following TBI. The current study sought to examine whether our classification approach using multiple DTI indices in conjunction with machine learning is a useful tool for diagnosing/classifying TBI patients and healthy controls.Methods: Participants were adult patients with chronic TBI (n = 26) with DAI pathology, and age- and sex-matched healthy controls (n = 26). DTI images were obtained from all participants. Tract-based spatial statistics analyses were applied to DTI images. Classification models were built using principal component analysis and support vector machines. Receiver operator characteristic curve analysis and area under the curve were used to assess the classification performance of the different classifiers.Results: Tract-based spatial statistics revealed significantly decreased fractional anisotropy, as well as increased mean diffusivity, axial diffusivity, and radial diffusivity in patients with TBI compared with healthy controls (all p-values < 0.01). The principal component analysis and support vector machine-based machine learning classification using combined DTI indices classified patients with TBI and healthy controls with an accuracy of 90.5% with an area under the curve of 93 ± 0.09.Conclusion: These results highlight the potential of our approach combining multiple DTI measures to identify patients with TBI.Keywords: diffuse axonal injury, diffusion tensor imaging, machine learning, screening, traumatic brain injury

Background: Appropriate clinical measures to prevent secondary brain damage in traumatic brain injury are of critical importance. Objectives: This study aims to investigate the relationships between serum electrolyte disturbances and Glasgow Coma Scale (GCS) score in patients with Diffuse Axonal Injury (DAI) at the time of admission and discharge. Materials & Methods: In this retrospective cross-sectional study, we evaluated 101 patients with DAI having GCS score

Traumatic brain injury (TBI) is among the most common injuries in forensic medicine, the identification of which is of particular importance in forensic practice. To reveal the circumstances and trends of TBI in the forensic field, we used the Web of Science (WoS) database for comprehensive retrieval. We made a metrological analysis of 1,089 papers in the past 50 years (1972-2021). The United States and Germany have the most forensic research on TBI. Diffuse axonal injury (DAI) has been the focus of attention for many years, and much effort has been devoted to its diagnosis in forensic pathology. Infants and children are the subgroups of most concern, especially in infant and child abuse cases. Research on identifying shaken baby syndrome has received increasing attention in recent years. Overall, our study provides a comprehensive list and analysis of the articles regarding TBI in legal medicine, which may shed light on recognizing the trends and research hotspots in this field. [ABSTRACT FROM AUTHOR]

Background and purpose: Traumatic brain injury (TBI), especially the severe TBI are often followed by persistent cognitive sequalae, including decision-making difficulties, reduced neural processing speed and memory deficits. Diffuse axonal injury (DAI) is classified as one of the severe types of TBI. Part of DAI patients are marginalized from social life due to cognitive impairment, even if they are rated as favorable outcome. The purpose of this study was to elucidate the specific type and severity of cognitive impairment in DAI patients with favorable outcome. Methods: The neurocognition of 46 DAI patients with favorable outcome was evaluated by the Chinese version of the Montreal Cognitive Assessment Basic (MoCA-BC), and the differences in the domains of cognitive impairment caused by different grades of DAI were analyzed after data conversion of scores of nine cognitive domains of MoCA-BC by Pearson correlation analysis. Results: Among the 46 DAI patients with favorable outcome, eight had normal cognitive function (MoCA-BC ≥ 26), and 38 had cognitive impairment (MoCA-BC < 26). The MoCA-BC scores were positively correlated with pupillary light reflex (r = 0.361, p = 0.014), admission Glasgow Coma Scale (GCS) (r = 0.402, p = 0.006), and years of education (r = 0.581, p < 0.001). Return of consciousness (r = -0.753, p < 0.001), Marshall CT (r = -0.328, p = 0.026), age (r = -0.654, p < 0.001), and DAI grade (r = -0.403, p = 0.006) were found to be negatively correlated with the MoCA-BC scores. In patients with DAI grade 1, the actually deducted scores (Ads) of memory (r = 0.838, p < 0.001), abstraction (r = 0.843, p < 0.001), and calculation (r = 0.782, p < 0.001) were most related to the Ads of MoCA-BC. The Ads of nine cognitive domains and MoCA-BC were all proved to be correlated, among patients with DAI grade 2. However, In the DAI grade 3 patients, the highest correlation with the Ads of MoCA-BC were the Ads of memory (r = 0.904, p < 0.001), calculation (r = 0.799, p = 0.006), orientation (r = 0.801, p = 0.005), and executive function (r = 0.869, p = 0.001). Conclusion: DAI patients with favorable outcome may still be plagued by cognitive impairment, and different grades of DAI cause different domains of cognitive impairment. [ABSTRACT FROM AUTHOR]

Abstract Cognitive-linguistic functions are an essential part of adequate communication competence. Cognitive-linguistic deficits are common after traumatic diffuse axonal injury (DAI). We aimed to examine the integrity of perisylvian white matter tracts known to be associated with linguistic functions in individuals with DAI and their eventual association with poor cognitive-linguistic outcomes. Diffusion tensor imaging (DTI) results of 44 adults with moderate-to-severe DAI were compared with those of 67 controls. Fractional anisotropy (FA) values of the superior longitudinal fasciculus (SLF), arcuate fasciculus (AF), SLF with frontal connections to the lower parietal cortex, and AF with temporal connections to the lower parietal cortex were measured using tractography. The associations between white matter integrity FA values and cognitive-linguistic deficits were studied in the DAI group. Cognitive-linguistic deficits were determined based on our earlier study using the novel KAT test. No previous studies have examined the associations between white matter integrity and cognitive-linguistic deficits determined using the KAT test. Patients with DAI showed lower FA values in all left-side tracts than the controls. Unexpectedly, the poor cognitive-linguistic outcome in the language comprehension and production domains was associated with high FA values of several tracts. After excluding five cases with the poorest cognitive-linguistic performance, but with the highest values in the DTI variables, no significant associations with DTI metrics were found. The association between white matter integrity and cognitive-linguistic functioning is complex in patients with DAI of traumatic origin, probably reflecting the heterogeneity of TBI. [ABSTRACT FROM AUTHOR]