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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., (© 2024. The Author(s).)

Identification of Traumatic axonal injury (TAI) is critical in clinical practice, particularly in terms of long-term prognosis, but also for medico-legal issues, to verify whether the death or the after-effects were attributable to trauma. Multidisciplinary approaches are an undeniable asset when it comes to solving these problems. The aim of this work is therefore to list the different techniques needed to identify axonal lesions and to understand the lesion mechanisms involved in their formation. Imaging can be used to assess the consequences of trauma, to identify indirect signs of TAI, to explain the patient's initial symptoms and even to assess the patient's prognosis. Three-dimensional reconstructions of the skull can highlight fractures suggestive of trauma. Microscopic and immunohistochemical techniques are currently considered as the most reliable tools for the early identification of TAI following trauma. Finite element models use mechanical equations to predict biomechanical parameters, such as tissue stresses and strains in the brain, when subjected to external forces, such as violent impacts to the head. These parameters, which are difficult to measure experimentally, are then used to predict the risk of injury. The integration of imaging data with finite element models allows researchers to create realistic and personalized computational models by incorporating actual geometry and properties obtained from imaging techniques. The personalization of these models makes their forensic approach particularly interesting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Traumatic brain injury (TBI) is associated with sleep deficits, but it is not clear why some report sleep disturbances and others do not. The objective of this study was to assess the associations between axonal injury, sleep, and memory in chronic and acute TBI., Methods: Data were acquired from two independent datasets which included 156 older adult veterans (69.8 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with prior moderate-to-severe TBIs and 90 (69.2 years) controls and 374 (39.6 years) from Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) with a recent mild TBI (mTBI) and 87 controls (39.6 years), all who completed an MRI, memory assessment, and sleep questionnaire., Results: Older adults with a prior TBI had a significant association between axonal injury and sleep disturbances [β = 9.52, 95% CI (4.1, 14.9), p = 0.01]. Axonal injury predicted changes in memory over 1-year in TBI [β = -8.72, 95% CI (-18, -2.7), p = 0.03]. We externally validated those findings in TRACK-TBI where axonal injury within 2 weeks after mTBI was significantly associated with higher sleep disturbances in the TBI group at 2 weeks[β = -7.2, 95% CI (-14, -0.50), p = 0.04], 6 months [β = -16, 95% CI (-24, -7.6), p ≤ 0.01], and 12 months post-injury [β = -11, 95% CI (-19, -0.85), p = 0.03]. These associations were not significant in controls., Interpretations: Axonal injury, specifically to the left anterior internal capsule is robustly associated with sleep disturbances in multiple TBI populations. Early assessment of axonal injury following mTBI could identify those at risk for persistent sleep disturbances following injury., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: We analysed magnetic resonance imaging (MRI) findings after traumatic brain injury (TBI) aiming to improve the grading of traumatic axonal injury (TAI) to better reflect the outcome., Methods: Four-hundred sixty-three patients (8-70 years) with mild (n = 158), moderate (n = 129), or severe (n = 176) TBI and early MRI were prospectively included. TAI presence, numbers, and volumes at predefined locations were registered on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging, and presence and numbers on T2*GRE/SWI. Presence and volumes of contusions were registered on FLAIR. We assessed the outcome with the Glasgow Outcome Scale Extended. Multivariable logistic and elastic-net regression analyses were performed., Results: The presence of TAI differed between mild (6%), moderate (70%), and severe TBI (95%). In severe TBI, bilateral TAI in mesencephalon or thalami and bilateral TAI in pons predicted worse outcomes and were defined as the worst grades (4 and 5, respectively) in the Trondheim TAI-MRI grading. The Trondheim TAI-MRI grading performed better than the standard TAI grading in severe TBI (pseudo-R 2 0.19 vs. 0.16). In moderate-severe TBI, quantitative models including both FLAIR volume of TAI and contusions performed best (pseudo-R 2 0.19-0.21). In patients with mild TBI or Glasgow Coma Scale (GCS) score 13, models with the volume of contusions performed best (pseudo-R 2 0.25-0.26)., Conclusions: We propose the Trondheim TAI-MRI grading (grades 1-5) with bilateral TAI in mesencephalon or thalami, and bilateral TAI in pons as the worst grades. The predictive value was highest for the quantitative models including FLAIR volume of TAI and contusions (GCS score <13) or FLAIR volume of contusions (GCS score ≥ 13), which emphasise artificial intelligence as a potentially important future tool., Clinical Relevance Statement: The Trondheim TAI-MRI grading reflects patient outcomes better in severe TBI than today's standard TAI grading and can be implemented after external validation. The prognostic importance of volumetric models is promising for future use of artificial intelligence technologies., Key Points: Traumatic axonal injury (TAI) is an important injury type in all TBI severities. Studies demonstrating which MRI findings that can serve as future biomarkers are highly warranted. This study proposes the most optimal MRI models for predicting patient outcome at 6 months after TBI; one updated pragmatic model and a volumetric model. The Trondheim TAI-MRI grading, in severe TBI, reflects patient outcome better than today's standard grading of TAI and the prognostic importance of volumetric models in all severities of TBI is promising for future use of AI., Competing Interests: Compliance with ethical standards Guarantor Associate professor Kent Gøran Moen, NTNU and first author of the present study, is the scientific guarantor of this publication. Conflict of interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry One of the authors has significant statistical expertise (Turid Follestad is a statistician at NTNU). Informed consent Written informed consent was obtained from all subjects or for children < 16 years and incapacitated individuals by their next of kind. Ethical approval Institutional Review Board approval was obtained. The study was approved by the Regional Committee for Medical Research Ethics (2017/1214). Study subjects or cohorts overlap Some study subjects or cohorts have been previously reported in ref. no. 13: Moe HK, Follestad T, Andelic N et al (2020) Traumatic axonal injury on clinical MRI: association with the Glasgow Coma Scale score at the scene of the injury or at admission and prolonged posttraumatic amnesia. Journal of Neurosurgery. 10.3171/2020.6.Jns20112:1-12. This is also indicated in detail in the manuscript and the supplemental materials. Methodology ProspectiveDiagnostic or prognostic studyMulticenter study, (© 2024. The Author(s).)

Background: Many children with severe traumatic brain injury (TBI) receive magnetic resonance imaging (MRI) during hospitalization. There are insufficient data on how different patterns of injury on early MRI inform outcomes., Methods: Children (3-17 years) admitted in 2010-2021 for severe TBI (Glasgow Coma Scale [GCS] score < 9) were identified using our site's trauma registry. We used multivariable modeling to determine whether the hemorrhagic diffuse axonal injury (DAI) grade and the number of regions with restricted diffusion (subcortical white matter, corpus callosum, deep gray matter, and brainstem) on MRI obtained within 7 days of injury were independently associated with time to follow commands and with Functional Independence Measure for Children (WeeFIM) scores at the time of discharge from inpatient rehabilitation. We controlled for the clinical variables age, preadmission cardiopulmonary resuscitation, pupil reactivity, motor GCS score, and fever (> 38 °C) in the first 12 h., Results: Of 260 patients, 136 (52%) underwent MRI within 7 days of injury at a median of 3 days (interquartile range [IQR] 2-4). Patients with early MRI were a median age of 11 years (IQR 7-14), 8 (6%) patients received cardiopulmonary resuscitation, 19 (14%) patients had bilateral unreactive pupils, the median motor GCS score was 1 (IQR 1-4), and 82 (60%) patients had fever. Grade 3 DAI was present in 46 (34%) patients, and restricted diffusion was noted in the corpus callosum in 75 (55%) patients, deep gray matter in 29 (21%) patients, subcortical white matter in 23 (17%) patients, and the brainstem in 20 (15%) patients. After controlling for clinical variables, an increased number of regions with restricted diffusion, but not hemorrhagic DAI grade, was independently associated with longer time to follow commands (hazard ratio 0.68, 95% confidence interval 0.53-0.89) and worse WeeFIM scores (estimate β - 4.67, 95% confidence interval - 8.33 to - 1.01)., Conclusions: Regional restricted diffusion on early MRI is independently associated with short-term outcomes in children with severe TBI. Multicenter cohort studies are needed to validate these findings and elucidate the association of early MRI features with long-term outcomes in children with severe TBI., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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.

Objective: Previous studies have reported various predictive indicators of diffuse axonal injury (DAI), but no consensus has not been reached. Although the efficiency of automated pupillometry in patients with consciousness disorder has been widely reported, there are few reports of its use in patients with DAI. This study aimed to investigate the significance of pupillary findings in predicting the prognosis of DAI., Patients and Methods: We included patients admitted to our center with a diagnosis of DAI from June 1, 2021 to June 30, 2022. Pupillary findings in both eyes were quantitatively measured by automated pupillometry every 2 hours after admission. We statistically examined the correlations between automated pupillometry parameters, the patients' characteristics, and outcomes such as the Glasgow Outcome Scale Extended (GOSE) after 6 months from injury, the time to follow command, and so on., Results: Among 22 patients included in this study, five had oculomotor nerve palsy. Oculomotor nerve palsy was correlated with all outcomes, whereas Marshall computed tomography (CT) classification, Injury severity score (ISS) and DAI grade were correlated with few outcomes. Some of the automated pupillometry parameters were significantly correlated with GOSE at 6 months after injury, and many during the first 24 hours of measurement were correlated with the time to follow command. Most of these results were not affected by adjustment using sedation period, ISS or Marshall CT classification. A subgroup analysis of patients without oculomotor nerve palsy revealed that many of the automated pupillometry parameters during the first 24 hours of measurement were significantly correlated with most of the outcomes. The cutoff values that differentiated a good prognosis (GOSE 5-8) from a poor prognosis (GOSE 1-4) were constriction velocity (CV) 1.43 (AUC = 0.81(0.62-1), p = 0.037) and maximum constriction velocity (MCV) 2.345 (AUC = 0.78 (0.58-0.98), p = 0.04). The cutoff values that differentiated the time to follow command into within 7 days and over 8 days were percentage of constriction 8 (AUC = 0.89 (0.68-1), p = 0.011), CV 0.63 (AUC = 0.92 (0.78-1), p = 0.013), MCV 0.855 (AUC = 0.9 (0.74-1), p = 0.017) and average dilation velocity 0.175 (AUC = 0.95 (0.86-1), p = 0.018)., Conclusions: The present results indicate that pupillary findings in DAI are a strong predictive indicator of the prognosis, and that quantitative measurement of them using automated pupillometry could facilitate enhanced prediction for the prognosis of DAI., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) significantly contributes to death and disability worldwide. However, treatment options remain limited. Here, we focus on a specific pathology of TBI, diffuse axonal brain injury (DABI), which describes the process of the tearing of nerve fibers in the brain after blunt injury. Most protocols to study DABI do not incorporate a specific model for that type of pathology, limiting their ability to identify mechanisms and comorbidities of DABI. In this study, we developed a magnetic resonance imaging (MRI) protocol for DABI in a rat model using a 3-T clinical scanner. We compared the neuroimaging outcomes with histologic and neurologic assessments. In a sample size of 10 rats in the sham group and 10 rats in the DABI group, we established neurological severity scores before the intervention and at 48 h following DABI induction. After the neurological evaluation after DABI, all rats underwent MRI scans and were subsequently euthanized for histological evaluation. As expected, the neurological assessment showed a high sensitivity for DABI lesions indicated using the β-APP marker. Surprisingly, however, we found that the MRI method had greater sensitivity in assessing DABI lesions compared to histological methods. Out of the five MRI parameters with pathological changes in the DABI model, we found significant changes compared to sham rats in three parameters, and, as shown using comparative tests with other models, MRI was the most sensitive parameter, being even more sensitive than histology. We anticipate that this DABI protocol will have a significant impact on future TBI and DABI studies, advancing research on treatments specifically targeted towards improving patient quality of life and long-term outcomes.

Traumatic axonal injury (TAI) may result in the disruption of brain functional networks and is strongly associated with cognitive impairment. However, the neural mechanisms affecting the neurocognitive function after TAI remain to be elucidated. We collected the resting-state functional magnetic resonance imaging data from 28 patients with TAI and 28 matched healthy controls. An automated anatomical labeling atlas was used to construct a functional brain connectome. We utilized a graph theoretical approach to investigate the alterations in global and regional network topologies, and network-based statistics analysis was utilized to localize the connected networks more precisely. The current study revealed that patients with TAI and healthy controls both showed a typical small-world topology of the functional brain networks. However, patients with TAI exhibited a significantly lower local efficiency compared to healthy controls, whereas no significant difference emerged in other small-world properties (Cp, Lp, γ, λ, and σ) and global efficiency. Moreover, patients with TAI exhibited aberrant nodal centralities in some regions, including the frontal lobes, parietal lobes, caudate nucleus, and cerebellum bilaterally, and right olfactory cortex. The network-based statistics results showed alterations in the long-distance functional connections in the subnetwork in patients with TAI, involving these brain regions with significantly altered nodal centralities. These alterations suggest that brain networks of individuals with TAI present aberrant topological attributes that are associated with cognitive impairment, which could be potential biomarkers for predicting cognitive dysfunction and help understanding the neuropathological mechanisms in patients with TAI., (© 2023. The Author(s).)

Objective: Diffuse axonal injury (DAI), a frequent consequence of pediatric traumatic brain injury (TBI), presents challenges in predicting long-term recovery. This study investigates the relationship between the severity of DAI and neurological outcomes in children., Methods: We conducted a retrospective analysis of 51 pediatric TBI patients diagnosed with DAI using Adam's classification. Neurological function was assessed at 2, 3, and 6 weeks, and 12 months post-injury using the Pediatric Glasgow Outcome Scale-Extended (PGOSE)., Results: PGOSE scores significantly improved over time across all DAI grades, suggesting substantial recovery potential even in initially severe cases. Despite indicating extensive injury, patients with DAI grades II and III demonstrated significant improvement, achieving a good recovery by 12 months. Although the initial Glasgow Coma Scale (GCS) score did not show a statistically significant association with long-term outcomes in our limited sample, these findings suggest that the severity of DAI alone may not fully predict eventual recovery., Conclusions: Our study highlights the potential for significant neurological recovery in pediatric patients with DAI, emphasizing the importance of long-term follow-up and individualized rehabilitation programs. Further research with larger cohorts and extended follow-up periods is crucial to refine our understanding of the complex relationships between DAI severity, injury mechanisms, and long-term neurological outcomes in children., Competing Interests: Declaration of Competing Interest The authors declare no potential conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diffuse axonal injury (DAI) disrupts the integrity of white matter microstructure and affects brain functional connectivity, resulting in persistent cognitive, behavioral and affective deficits. Mounting evidence suggests that altered cortical-subcortical connectivity is a major contributor to cognitive dysfunction. The functional integrity of the striatum is particularly vulnerable to DAI, but has received less attention. This study aimed to investigate the alteration patterns of striatal subdivision functional connectivity. Twenty-six patients with DAI and 27 healthy controls underwent resting-state fMRI scans on a 3.0 T scanner. We assessed striatal subdivision functional connectivity using a seed-based analysis in DAI. Furthermore, a partial correlation was used to measure its clinical association. Compared to controls, patients with DAI showed decreased functional connectivity between the right inferior ventral striatum and right inferior frontal gyrus, as well as the right inferior parietal lobule, between the left inferior ventral striatum and right inferior frontal gyrus, between the right superior ventral striatum and bilateral cerebellar posterior lobe, between the bilateral dorsal caudal putamen and right anterior cingulate gyrus, and between the right dorsal caudal putamen and right inferior parietal lobule. Moreover, decreased functional connectivity was observed between the left dorsal caudate and the right cerebellar posterior lobe, while increased functional connectivity was found between the left dorsal caudate and right inferior parietal lobule. Correlation analyses showed that regions with functional connectivity differences in the DAI group correlated with multiple clinical scoring scales, including cognition, motor function, agitated behavior, and anxiety disorders. These findings suggest that abnormalities in cortico-striatal and cerebellar-striatal functional connectivity are observed in patients with DAI, enriching our understanding of the neuropathological mechanisms of post-injury cognitive disorders and providing potential neuroimaging markers for the diagnosis and treatment of DAI., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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 ([Formula: see text]: P = 0.021, [Formula: see text]: P = 0.011), lower clustering ([Formula: see text]: P = 0.002) and less small-worldness ([Formula: see text]: 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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.

Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.

Diffuse axonal injury (DAI) is a subtype of traumatic brain injury that causes acute-phase consciousness disorders and widespread chronic-phase brain atrophy. Considering the importance of brainstem damage in DAI, a valid method for evaluating brainstem volume is required. We obtained volume measurements from 182 healthy adults by analyzing T1-weighted magnetic resonance images, and created an age-/sex-/intracranial volume-based quantitative model to estimate the normal healthy volume of the brainstem and cerebrum. We then applied this model to the volume measurements of 22 DAI patients, most of whom were in the long-term chronic phase and had no gross focal injury, to estimate the percentage difference in volume from the expected normal healthy volume in different brain regions, and investigated its association with the duration of posttraumatic amnesia (which is an early marker of injury severity). The average loss of the whole brainstem was 13.9%. Moreover, the percentage loss of the whole brainstem, and particularly of the pons and midbrain, was significantly negatively correlated with the duration of posttraumatic amnesia. Our findings suggest that injury severity, as denoted by the duration of posttraumatic amnesia, is among the factors affecting the chronic-phase brainstem volume in patients with DAI., (© 2023. The Author(s).)

Objective: The paper aimed at exploring the correlation between CT findings of diffuse axonal injury and the expression of neuronal aquaporin in patients with craniocerebral injury., Patients and Methods: 150 patients with diffuse axonal injury diagnosed by CT and 50 healthy physical examinators were selected as the study objects. According to the craniocerebral CT and GCS scale scores, the patients were divided into DAI light group, medium group, and heavy group. The general conditions of patients were observed and recorded, and the brain pathological morphology, craniocerebral edema and CT imaging results of the patients in each group were compared. Changes in serum and brain AQP-4 levels were detected by RT-PCR and Western blot, and the correlation between CT manifestations of DAI and the expression of neuronal aquaporin was investigated., Results: The results of DAI's pathological morphology, cerebral edema and CT imaging showed that the brain tissue of each group of DAI had a certain degree of injury. With the increase of the injury degree, the degree of edema and the number of axonal injuries sharply increased, and the difference was significant (p-value < 0.05). Therefore, CT could be used as an effective basis for the rapid and efficient diagnosis of DAI. RT-PCR, Western blot and Spearman correlation analysis showed that the levels of AQP-4 in the serum and brain tissue of DAI patients were significantly increased. With the increase of the degree of diffuse axonal injury, the expression level of AQP-4 was further increased, and the difference was significant (p-value < 0. 05). The CT manifestations of patients in each group were positively correlated with the expression level of AQP-4 protein., Conclusions: AQP-4 can be used as an important molecular index to judge the condition and prognosis of DAI, providing a new non-invasive detection method for the clinical diagnosis and treatment of DAI, which has high clinical application value.

Background: Traumatic brain injury (TBI) is the leading cause of death and disability in children, but effective tools for predicting outcome remain elusive. Although many pediatric patients receive early magnetic resonance imaging (MRI), data on its utility in prognostication are lacking. Diffuse axonal injury (DAI) is a hallmark of TBI detected on early MRI and was shown previously to improve prognostication in adult patients with TBI. In this exploratory study, we investigated whether DAI grade correlates with functional outcome and improves prognostic accuracy when combined with core clinical variables and computed tomography (CT) biomarkers in pediatric patients with moderate-severe TBI (msTBI)., Methods: Pediatric patients (≤ 19 years) who were admitted to two regional level one trauma centers with a diagnosis of msTBI (Glasgow Coma Scale [GCS] score < 13) between 2011 and 2019 were identified through retrospective chart review. Patients who underwent brain MRI within 30 days of injury and had documented clinical follow-up after discharge were included. Age, pupil reactivity, and initial motor GCS score were collected as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Imaging was reviewed to calculate the Rotterdam score (CT) and DAI grade (MRI) and to evaluate for presence of hypoxic-ischemic injury (MRI). The primary outcome measure was the Pediatric Cerebral Performance Category Scale (PCPCS) score at 6 months after TBI, with favorable outcome defined as PCPCS scores 1-3 and unfavorable outcome defined as PCPCS scores 4-6. The secondary outcome measure was discharge disposition to home versus to an inpatient rehabilitation facility., Result: Of 55 patients included in the study, 45 (82%) had severe TBI. The most common mechanism of injury was motor vehicle collision (71%). Initial head CT scans showed acute hemorrhage in 84% of patients. MRI was acquired a median of 5 days after injury, and hemorrhagic DAI lesions were detected in 87% of patients. Each 1-point increase in DAI grade increased the odds of unfavorable functional outcome by 2.4-fold. When controlling for core IMPACT clinical variables, neither the DAI grade nor the Rotterdam score was independently correlated with outcome and neither significantly improved outcome prediction over the IMPACT model alone., Conclusions: A higher DAI grade on early MRI is associated with worse 6-month functional outcome and with discharge to inpatient rehabilitation in children with acute msTBI in a univariate analysis but does not independently correlate with outcome when controlling for the GCS score. Addition of the DAI grade to the core IMPACT model does not significantly improve prediction of poor neurological outcome. Further study is needed to elucidate the utility of early MRI in children with msTBI., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Diffuse axonal injury occurs with high acceleration and deceleration forces in traumatic brain injury (TBI). This lesion leads to disarrangement of the neuronal network, which can result in some degree of deficiency. The Extended Glasgow Outcome Scale (GOS-E) is the primary outcome instrument for the evaluation of TBI victims. Diffusion tensor imaging (DTI) assesses white matter (WM) microstructure based on the displacement distribution of water molecules., Objective: To investigate WM microstructure within the first year after TBI using DTI, the patient's clinical outcomes, and associations., Methods: We scanned 20 moderate and severe TBI victims at 2 months and 1 year after the event. Imaging processing was done with the FMRIB software library; we used the tract-based spatial statistics software yielding fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for statistical analyses. We computed the average difference between the two measures across subjects and performed a one-sample t-test and threshold-free cluster enhancement, using a corrected p-value < 0.05. Clinical outcomes were evaluated with the GOS-E. We tested for associations between outcome measures and significant mean FA clusters., Results: Significant clusters of altered FA were identified anatomically using the JHU WM atlas. We found increasing spotted areas of FA with time in the right brain hemisphere and left cerebellum. Extensive regions of increased MD, RD, and AD were observed. Patients presented an excellent overall recovery., Conclusions: There were no associations between FA and outcome scores, but we cannot exclude the existence of a small to moderate association.

Background: Diffuse axonal injury (DAI) is a frequent mechanism of traumatic brain injury (TBI) that triggers a sequence of parenchymal changes that progresses from focal axonal shear injuries up to inflammatory response and delayed axonal disconnection., Objective: The main purpose of this study is to evaluate changes in the axonal/myelinic content and the brain volume up to 12 months after TBI and to correlate these changes with neuropsychological results., Methods: Patients with DAI (n = 25) were scanned at three time points after trauma (2, 6, and 12 months), and the total brain volume (TBV), gray matter volume, and white matter volume (WMV) were calculated in each time point. The magnetization transfer ratio (MTR) for the total brain (TB MTR), gray matter (GM MTR), and white matter (WM MTR) was also quantified. In addition, Hopkins verbal learning test (HVLT), Trail Making Test (TMT), and Rey-Osterrieth Complex Figure test were performed at 6 and 12 months after the trauma., Results: There was a significant reduction in the mean TBV, WMV, TB MTR, GM MTR, and WM MTR between time points 1 and 3 (p < .05). There was also a significant difference in HVLT-immediate, TMT-A, and TMT-B scores between time points 2 and 3. The MTR decline correlated more with the cognitive dysfunction than the volume reduction., Conclusion: A progressive axonal/myelinic rarefaction and volume loss were characterized, especially in the white matter (WM) up to 1 year after the trauma. Despite that, specific neuropsychological tests revealed that patients' episodic verbal memory, attention, and executive function improved during the study. The current findings may be valuable in developing long-term TBI rehabilitation management programs., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Aim: To evaluate diffuse axonal injury (DAI) patients according to DAI stage to identify risk factors that may affect clinical outcome., Material and Methods: A total of 992 traumatic brain injury (TBI) patients visited our hospital between 2011 and 2016. Thirtyseven patients diagnosed with DAI were enrolled in this study and stratified by DAI stage: Stage I, 20 patients (54.1%); Stage II, 4 patients (10.8%); and Stage III, 13 patients (35.1%)., Results: The mean age and the median follow-up period were 45.43 years and 13 months, respectively. Patient demographic data and clinical findings on admission showed no differences according to DAI stage, except for the revised trauma score (RTS) (p=0.026). In univariate analysis, stages I and II vs. III (p=0.001) and stages I vs. II and III (p=0.019), transfusion within 24 hours of visit (p=0.033), shock or cardiac arrest (p=0.006), traumatic subarachnoid hemorrhage (T-SAH) (p=0.011), and subdural hematoma (SDH) (p=0.009) were significantly correlated with Glasgow outcome score (GOS). In multivariate analysis, DAI stage I and II vs. III (p=0.005) and SDH (p=0.040) were significant., Conclusion: Clinically, Stage II was more correlated with Stage I, rather than stage III. Stage III showed a much poorer outcome compared to stages I and II. Magnetic resonance imaging (MRI) should be promptly performed in all TBI patients when a patient?s level of consciousness and cranialcomputed tomography (CT) does not match, as there is a possibility of stage III DAI.

The objective of the study was to investigate and characterize the clinical presentation, and establish macroscopic diagnostic signs of diffuse axonal injury (DAI) in the early (up to 3 days) post-injury period. In DAI, coma develops immediately after head injury and persists for 3 days post-injury until death. The coma is accompanied by dominant primary stem neurological symptoms, hemodynamic and respiratory disturbances and does not progress to a vegetative state. Lifetime computed tomography reveals cerebral hemorrhage in 40.5% of cases. We established the macroscopic signs of head injury in DAI. For the postmortem diagnosis of DAI, a detailed macroscopic appearance of pathognomonic cerebral hemorrhages is given, which are most frequently (67.5%) localized in the corpus callosum (CC), namely in the area from its genu to the middle of the trunk (97%). A rational, improved scheme of excision of CC trunk areas for the histological study is proposed.

Studies show conflicting results regarding the prognostic significance of traumatic axonal injuries (TAI) in patients with traumatic brain injury (TBI). Therefore, we documented the presence of TAI in several brain regions, using different magnetic resonance imaging (MRI) sequences, and assessed their association to patient outcomes using machine learning. Further, we created a novel MRI-based TAI grading system with the goal of improving outcome prediction in TBI. We subsequently evaluated the performance of several TAI grading systems. We used a genetic algorithm to identify TAI that distinguish favorable from unfavorable outcomes. We assessed the discriminatory performance (area under the curve [AUC]) and goodness-of-fit (Nagelkerke pseudo-R 2 ) of the novel Stockholm MRI grading system and the TAI grading systems of Adams and associates, Firsching and coworkers. and Abu Hamdeh and colleagues, using both univariate and multi-variate logistic regression. The dichotomized Glasgow Outcome Scale was considered the primary outcome. We examined the MRI scans of 351 critically ill patients with TBI. The TAI in several brain regions, such as the midbrain tegmentum, were strongly associated with unfavorable outcomes. The Stockholm MRI grading system exhibited the highest AUC (0.72 vs. 0.68-0.69) and Nagelkerke pseudo-R 2 (0.21 vs. 0.14-0.15) values of all TAI grading systems. These differences in model performance, however, were not statistically significant (DeLong test, p  > 0.05). Further, all included TAI grading systems improved outcome prediction relative to established outcome predictors of TBI, such as the Glasgow Coma Scale (likelihood-ratio test, p  < 0.001). Our findings suggest that the detection of TAI using MRI is a valuable addition to prognostication in TBI.

The National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH-NINDS) Traumatic Brain Injury (TBI) Imaging Common Data Elements (CDEs) are standardized definitions for pathological intracranial lesions based on their appearance on neuroimaging studies. The NIH-NINDS TBI Imaging CDEs were designed to be as consistent as possible with the U.S. Food and Drug Administration (FDA) definition of biomarkers as "an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention." However, the FDA qualification process for biomarkers requires proof of reliable biomarker test measurements. We determined the interrater reliability of TBI Imaging CDEs on subacute brain magnetic resonance imaging (MRI) performed on 517 mild TBI patients presenting to 11 U.S. level 1 trauma centers. Three U.S. board-certified neuroradiologists independently evaluated brain MRI performed 2 weeks post-injury for the following CDEs: traumatic axonal injury (TAI), diffuse axonal injury (DAI), and brain contusion. We found very high interrater agreement for brain contusion, with prevalence- and bias-adjusted kappa (PABAK) values for pairs of readers from 0.92 [95% confidence interval, 0.88-0.95] to 0.94 [0.90-0.96]. We found intermediate agreement for TAI and DAI, with PABAK values of 0.74-0.78 [0.70-0.82]. The near-perfect agreement for subacute brain contusion is likely attributable to the high conspicuity and distinctive appearance of these lesions on T1-weighted images. Interrater agreement for TAI and DAI was lower, because signal void in small vascular structures, and artifactual foci of signal void, can be difficult to distinguish from the punctate round or linear areas of slight hemorrhage that are a common hallmark of TAI/DAI on MRI.

The identification of children with traumatic brain injury (TBI) who are at risk of death or poor global neurological functional outcome remains a challenge. Magnetic resonance imaging (MRI) can detect several brain pathologies that are a result of TBI; however, the types and locations of pathology that are the most predictive remain to be determined. Forty-two critically ill children with TBI were recruited prospectively from pediatric intensive care units at five Canadian children's hospitals. Pathologies detected on subacute phase MRIs included cerebral hematoma, herniation, cerebral laceration, cerebral edema, midline shift, and the presence and location of cerebral contusion or diffuse axonal injury (DAI) in 28 regions of interest were assessed. Global functional outcome or death more than 12 months post-injury was assessed using the Pediatric Cerebral Performance Category score. Linear modeling was employed to evaluate the utility of an MRI composite score for predicting long-term global neurological function or death after injury, and nonlinear Random Forest modeling was used to identify which MRI features have the most predictive utility. A linear predictive model of favorable versus unfavorable long-term outcomes was significantly improved when an MRI composite score was added to clinical variables. Nonlinear Random Forest modeling identified five MRI variables as stable predictors of poor outcomes: presence of herniation, DAI in the parietal lobe, DAI in the subcortical white matter, DAI in the posterior corpus callosum, and cerebral contusion in the anterior temporal lobe. Clinical MRI has prognostic value to identify children with TBI at risk of long-term unfavorable outcomes.

A better understanding of white matter tract damage in patients with diffuse axonal injury (DAI) and mild traumatic brain injury (MTBI) is important to obtain an objective basis for sequelae. The purpose of this study was to clarify the characteristics of white matter tract degeneration in DAI and MTBI using automated tractography. T1-weighted and diffusion tensor imaging (DTI) was performed on seven DAI and seven MTBI patients as well as on nine healthy subjects. Automated probabilistic tractography analysis was performed using FreeSurfer and TRACULA (tracts constrained by underlying anatomy) for the reconstruction of major nerve fibers. We investigated the difference between DTI quantitative values in each white matter nerve fiber between groups and attempted to evaluate the classification accuracy of DAI and MTBI using receiver operator curve analysis. Both DAI and MTBI appeared to exhibit axonal degeneration along the nerve fiber tract in a scattered manner. The mean diffusivity of the ampulla of the corpus callosum was significantly higher in DAI than that in MTBI patients, suggesting axonal degeneration of the corpus callosum in DAI patients. Using mean diffusivity of the right cingulum-angular bundle, DAI and MTBI could be discriminated with an area under the curve of 94%. Both DAI and MTBI exhibited scattered axonal degeneration; however, DAI appeared to exhibit more pronounced axonal degeneration in the ampulla of the corpus callosum than MTBI. Our results suggest that DAI and MTBI can be accurately distinguished using DTI., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We investigate the characteristics of injury of four portions of the Papez circuit in patients with diffuse axonal injury (DAI), using diffusion tensor tractography (DTT). Thirty-four consecutive patients with DAI and 30 normal control subjects were recruited. Four portions of the Papez circuit were reconstructed: the fornix, cingulum, thalamocingulate tract, and mammillothalamic tract. Analysis of DTT parameters [fractional anisotropy (FA) and tract volume (TV)] and configuration (narrowing, discontinuation, or non-reconstruction) was performed for each portion of the Papez circuit. The Memory Assessment Scale (MAS) was used for the estimation of cognitive function. In the group analysis, decreased fractional anisotropy and tract volume of the entire Papez circuit were observed in the patient group compared with the control group (p < 0.05). In the individual analysis, all four portions of the Papez circuit were injured in terms of DTT parameters or configuration. Positive correlation was observed between TV of the fornix and short-term memory on MAS r = 0.618, p < 0.05), and between FA of the fornix and total memory on MAS (r = 0.613, p < 0.05). We found that all four portions of the Papez circuit in the patient group were vulnerable to DAI, and among four portions of the Papez circuit, the fornix was the most vulnerable portion in terms of injury incidence and severity., (© 2020. Belgian Neurological Society.)

Objective: A traumatic axonal injury (TAI) diagnosis has traditionally been based on conventional MRI, especially on those sequences with a higher sensitivity to edema and blood degradation products. A more recent technique, diffusion tensor imaging (DTI), can infer the microstructure of white matter (WM) due to the restricted diffusion of water in organized tissues. However, there is little information regarding the correlation of the findings obtained by both methods and their use for outcome prognosis. The main objectives of this study were threefold: 1) study the correlation between DTI metrics and conventional MRI findings; 2) evaluate whether the prognostic information provided by the two techniques is supplementary or complementary; and 3) determine the incremental value of the addition of these variables compared to a traditional prognostic model., Methods: The authors studied 185 patients with moderate to severe traumatic brain injury (TBI) who underwent MRI with DTI study during the subacute stage. The number and volume of lesions in hemispheric subcortical WM, corpus callosum (CC), basal ganglia, thalamus, and brainstem in at least four conventional MRI sequences (T1-weighted, T2-weighted, FLAIR, T2* gradient recalled echo, susceptibility-weighted imaging, and diffusion-weighted imaging) were determined. Fractional anisotropy (FA) was measured in 28 WM bundles using the region of interest method. Nonparametric tests were used to evaluate the colocalization of macroscopic lesions and FA. A multivariate logistic regression analysis was performed to assess the independent prognostic value of each neuroimaging modality after adjustment for relevant clinical covariates, and the internal validation of the model was evaluated in a contemporary cohort of 92 patients., Results: Differences in the lesion load between patients according to their severity and outcome were found. Colocalization of macroscopic nonhemorrhagic TAI lesions (not microbleeds) and lower FA was limited to the internal and external capsule, corona radiata, inferior frontooccipital fasciculus, CC, and brainstem. However, a significant association between the FA value and the identification of macroscopic lesions in distant brain regions was also detected. Specifically, lower values of FA of some hemispheric WM bundles and the splenium of the CC were related to a higher number and volume of hyperintensities in the brainstem. The regression analysis revealed that age, motor score, hypoxia, FA of the genu of the CC, characterization of TAI lesions in the CC, and the presence of thalamic/basal ganglia lesions were independent prognostic factors. The performance of the proposed model was higher than that of the IMPACT (International Mission on Prognosis and Analysis of Clinical Trials in TBI) model in the validation cohort., Conclusions: Very limited colocalization of hyperintensities (none for microbleeds) with FA values was discovered. DTI and conventional MRI provide complementary prognostic information, and their combination can improve the performance of traditional prognostic models.

Objective: Diffuse axonal injury (DAI) is a common pathological process after traumatic brain injury, which may cause survivors severe functional disorders, including cognitive impairment and physical disability. Recent literature indicated lateral hypothalamus and medial hypothalamus damage during DAI. Thus, we aim to investigate whether there is imaging evidence of hypothalamic injury in patients with DAI and its clinical association., Methods: Twenty-four patients with diagnosed DAI and 26 age and sex-matched healthy controls underwent resting-state functional MRI. We assessed the lateral hypothalamus and medial hypothalamus functional connectivity with seed-based analysis in DAI. Furthermore, a partial correlation was used to measure its clinical association. The prediction of the severity of DAI from the altered lateral hypothalamus and medial hypothalamus connectivity was conducted using a general linear model., Results: Compared with healthy control, the DAI group showed significantly decreased lateral hypothalamus functional connectivity with the basal ganglia and cingulate gyrus, which was positively correlated with mini-mental state examination scores (Bonferroni correction at P < 0.0125). Importantly, this disrupted functional connectivity can be used to predict the patients' cognitive state reliably (P = 0.006; P = 0.009, respectively) in DAI. Moreover, we also observed increased connectivity of medial hypothalamus with the superior temporal gyrus and the regions around the operculum. Furthermore, there was a trend of negative correlation between the medial hypothalamus functional connectivity changes to the right superior temporal gyrus and the disability rating scale scores in the DAI group., Conclusion: Our results suggest that there are alterations of medial hypothalamus and lateral hypothalamus connectivity in DAI and further understand its clinical symptoms, including related cognitive impairment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Diffuse axonal injury (DAI) is present in approximately 50% of the cases with severe traumatic brain injury. It is one of the leading causes of morbidity and mortality among children and young individuals worldwide. Generally, DAI occurs as a result of high-velocity accidents. Typically, it presents with loss of consciousness for at least 6 hours and neurological deficit dependent on the brain area that is affected by the injury. The final diagnosis is confirmed by neuroimaging studies such as computed tomography and magnetic resonance imaging. According to the injured brain site, DAI is classified into three grades: Grade I-DAI with axonal lesions in the cerebral hemispheres; Grade II-DAI with focal axonal lesions in the corpus callosum; Grade III-DAI with focal or multiple axonal lesions in the brainstem. Each of the three grades is associated with different outcome.Due to the high disability and mortality rate, DAI represents an important medical, personal and social problem. The aim of the current review is to address the unsolved issues connected with the pathogenesis, diagnostics, treatment and outcome of the diffuse axonal injury., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Axonal injury is a major contributor to the clinical symptomatology in patients with traumatic brain injury. Conventional neuroradiological tools, such as CT and MRI, are insensitive to diffuse axonal injury (DAI) caused by trauma. Diffusion tensor MRI parameters may change in DAI lesions; however, the nature of these changes is inconsistent. Multidimensional MRI is an emerging approach that combines T1, T2, and diffusion, and replaces voxel-averaged values with distributions, which allows selective isolation of specific potential abnormal components. By performing a combined post-mortem multidimensional MRI and histopathology study, we aimed to investigate T1-T2-diffusion changes linked to DAI and to define their histopathological correlates. Corpora callosa derived from eight subjects who had sustained traumatic brain injury, and three control brain donors underwent post-mortem ex vivo MRI at 7 T. Multidimensional, diffusion tensor, and quantitative T1 and T2 MRI data were acquired and processed. Following MRI acquisition, slices from the same tissue were tested for amyloid precursor protein (APP) immunoreactivity to define DAI severity. A robust image co-registration method was applied to accurately match MRI-derived parameters and histopathology, after which 12 regions of interest per tissue block were selected based on APP density, but blind to MRI. We identified abnormal multidimensional T1-T2, diffusion-T2, and diffusion-T1 components that are strongly associated with DAI and used them to generate axonal injury images. We found that compared to control white matter, mild and severe DAI lesions contained significantly larger abnormal T1-T2 component (P = 0.005 and P < 0.001, respectively), and significantly larger abnormal diffusion-T2 component (P = 0.005 and P < 0.001, respectively). Furthermore, within patients with traumatic brain injury the multidimensional MRI biomarkers differentiated normal-appearing white matter from mild and severe DAI lesions, with significantly larger abnormal T1-T2 and diffusion-T2 components (P = 0.003 and P < 0.001, respectively, for T1-T2; P = 0.022 and P < 0.001, respectively, for diffusion-T2). Conversely, none of the conventional quantitative MRI parameters were able to differentiate lesions and normal-appearing white matter. Lastly, we found that the abnormal T1-T2, diffusion-T1, and diffusion-T2 components and their axonal damage images were strongly correlated with quantitative APP staining (r = 0.876, P < 0.001; r = 0.727, P < 0.001; and r = 0.743, P < 0.001, respectively), while producing negligible intensities in grey matter and in normal-appearing white matter. These results suggest that multidimensional MRI may provide non-invasive biomarkers for detection of DAI, which is the pathological substrate for neurological disorders ranging from concussion to severe traumatic brain injury., (Published by Oxford University Press on behalf of the Guarantors of Brain 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: It is well known that lipids are vital for axonal myelin repair. Diffuse axonal injury (DAI) is characterized by widespread axonal injury. The association between serum lipids and DAI is not well known. The purpose of this study was to investigate the associations of serum lipid profile variables (triglycerides, high- and low-density lipoproteins, and total cholesterol) with DAI detected by magnetic resonance imaging (MRI) and with clinical outcome for patients suffering from traumatic brain injury (TBI)., Methods: This study included 176 patients with a history of TBI who had undergone initial serum lipid measurements within 1 week and brain MRIs within 30 days. Based on MRI findings, patients were divided into negative and positive DAI groups., Results: Of the 176 patients, 70 (39.8%) were assigned to DAI group and 106 (60.2%) patients to non-DAI group. Compared with the non-DAI group, patients with DAI had significantly lower levels of high-density lipoprotein cholesterol (HDL-C) in serum during the first week following TBI. Multivariate analysis identified HDL-C as an independent predictor of DAI. Patients with lower serum HDL-C levels were less likely to regain consciousness within 6 months in TBI patients with DAI lesions identified by MRI., Conclusions: Plasma levels of HDL-C may be a viable addition to biomarker panels for predicting the presence and prognosis of DAI on subsequent MRI following TBI.

Rationale and Objectives: Recently, advanced magnetic resonance imaging has been widely adopted to investigate altered structure and functional activities in patients with diffuse axonal injury (DAI), this patient presumed to be caused by shearing forces and results in significant neurological effects. However, little is known regarding cerebral temporal dynamics and its predictive ability in the clinical dysfunction of DAI., Materials and Methods: In this study, static and dynamic fractional amplitude of low-frequency fluctuation (fALFF), an improved approach to detect the intensity of intrinsic neural activities, and their temporal variability were applied to examine the alteration between DAI patients (n = 24) and healthy controls (n = 26) at the voxel level. Then, the altered functional index was used to explore the clinical relationship and predict dysfunction in DAI patients., Results: We discovered that, compared to healthy controls, DAI patients showed commonly altered regions of static fALFF, and its variability was mainly located in the left cerebellum posterior lobe. Furthermore, decreased static fALFF values over the left cerebellum posterior lobe and bilateral medial frontal gyrus showed significant correlations with disease duration and Mini-Mental State Examination scores. More important, the increased temporal variability of dynamic fALFF in the left caudate could predict the severity of the Glasgow Coma Scale score in DAI patients., Conclusion: Overall, these results suggested selective abnormalities in intrinsic neural activities with reduced intensity and increased variability, and this novel predictive marker may be developed as a useful indicator for future connectomics or artificial intelligence analyses., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Aim: To identify the relationship between subcallosal haemorrhage and diffuse axonal injury (DAI) grading., Materials and Methods: Computed tomography (CT) and magnetic resonance imaging (MRI) images of all patients with traumatic brain injury over the past 5 years were reviewed. Subcallosal haemorrhage was defined as the presence of haemorrhage on admission CT underneath the corpus callosum. Grading of DAI was performed using MRI or CT exclusive of subcallosal haemorrhage status. The association of demographic factors, mechanism of injury, Glasgow Coma Scale (GCS) on admission, and positive subcallosal haemorrhage status with the presence of moderate-severe DAI was assessed. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of subcallosal haemorrhage status in predicting DAI severity. Median modified Rankin Scale (mRS) scores were compared between subcallosal haemorrhage positive and negative cases., Results: The images of 1,150 patients were reviewed with 301 patients showing DAI. Of those, 64 patients (21.2%) and 237 patients (78.7%) were positive and negative for subcallosal haemorrhage, respectively. Isolated subcallosal haemorrhage was noted in 15 patients (23.4%). A subcallosal haemorrhage positive status (OR=5.16, p < 0.001) was statistically significantly associated with moderate-severe DAI. The ROC curve for predicting moderate-severe DAI with subcallosal haemorrhage status showed an area under the curve of 0.625 (95% confidence interval [CI]: 0.561-0.688, p < 0.001). The median mRS score was significantly higher (p < 0.001) in the subcallosal haemorrhage positive group (median 4.5, interquartile range [IQR] 2-6) versus the negative group (median 2, IQR 2-3). Isolated subcallosal haemorrhage group showed moderate-severe DAI in 80% (12/15) of cases., Conclusion: Subcallosal haemorrhage is a highly specific radiographic predictor of moderate-severe DAI (grade 2-3)., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Diffuse axonal injury (DAI) is a microscopic damage of axons in the brain. Its occurrence results from head trauma with acceleration or deceleration. This article presents current knowledge about DAI and two cases of patients who experienced DAI as a consequence of a traffic accident. A26 years old man was brought to hospital after traffic accident during which his vehicle had overturned. Computed tomography (CT) showed features of brain edema and disseminated small petechiae. Psychiatric consultation on ninth day of hospitalization showed memory deficits presenting as retrograde and anterograde amnesia, attention deficits and lack of criticism in regard to his condition. A 38 years old woman who was hit by a car while cycling was admitted to hospital. CT scan showed features of brain edema, subarachnoid hemorrhage and multiple fractures. On the tenth day of hospitalization the patient was confused, did not remember new information, her psychomotor drive was increased and she presented lack of criticism in regard to her condition. While suspecting DAI we should be vigilant, particularly in cases of patients hospitalized due to traffic accidents with behavioral problems, features of amnestic syndrome and without significant focal neurological symptoms.

Objective : The goal is to evaluate longitudinally with diffusion tensor imaging (DTI) the integrity of cerebral white matter in patients with moderate and severe DAI and to correlate the DTI findings with cognitive deficits. Methods : Patients with DAI (n = 20) were scanned at three timepoints (2, 6 and 12 months) after trauma. A healthy control group (n = 20) was evaluated once with the same high-field MRI scanner. The corpus callosum (CC) and the bilateral superior longitudinal fascicles (SLFs) were assessed by deterministic tractography with ExploreDTI. A neuropschychological evaluation was also performed. Results : The CC and both SLFs demonstrated various microstructural abnormalities in between-groups comparisons. All DTI parameters demonstrated changes across time in the body of the CC, while FA (fractional anisotropy) increases were seen on both SLFs. In the splenium of the CC, progressive changes in the mean diffusivity (MD) and axial diffusivity (AD) were also observed. There was an improvement in attention and memory along time. Remarkably, DTI parameters demonstrated several correlations with the cognitive domains. Conclusions : Our findings suggest that microstructural changes in the white matter are dynamic and may be detectable by DTI throughout the first year after trauma. Likewise, patients also demonstrated improvement in some cognitive skills.

Introduction: Traumatic axonal injury (TAI) is a condition defined as multiple, scattered, small hemorrhagic, and/or non-hemorrhagic lesions, alongside brain swelling, in a more confined white matter distribution on imaging studies, together with impaired axoplasmic transport, axonal swelling, and disconnection after traumatic brain injury (TBI). Ever since its description in the 1980s and the grading system by Adams et al., our understanding of the processes behind this entity has increased., Methods: We performed a scoping systematic, narrative review by interrogating Ovid MEDLINE, Embase, and Google Scholar on the pathophysiology, biomarkers, and diagnostic tools of TAI patients until July 2020., Results: We underline the misuse of the Adams classification on MRI without proper validation studies, and highlight the hiatus in the scientific literature and areas needing more research. In the past, the theory behind the pathophysiology relied on the inertial force exerted on the brain matter after severe TBI inducing a primary axotomy. This theory has now been partially abandoned in favor of a more refined theory involving biochemical processes such as protein cleavage and DNA breakdown, ultimately leading to an inflammation cascade and cell apoptosis, a process now described as secondary axotomy., Conclusion: The difference in TAI definitions makes the comparison of studies that report outcomes, treatments, and prognostic factors a daunting task. An even more difficult task is isolating the outcomes of isolated TAI from the outcomes of severe TBI in general. Targeted bench-to-bedside studies are required in order to uncover further pathways involved in the pathophysiology of TAI and, ideally, new treatments.

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine whether neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured in serum relate to traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) measures of traumatic axonal injury (TAI) in patients with TBI., Methods: Patients with TBI (n = 162) and controls (n = 68) were prospectively enrolled between 2011 and 2019. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days, and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury., Results: At enrollment, patients with TBI had increased serum NfL compared to controls ( p < 0.0001). Serum NfL decreased over the course of 5 years but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with an area under the receiver-operating characteristic curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrollment, serum GFAP was elevated in patients with TBI compared to controls ( p < 0.001). GFAP showed a biphasic release in serum, with levels decreasing during the first 6 months of injury but increasing over the subsequent study visits. The highest AUROC for GFAP was measured at 30 days, distinguishing patients with moderate and severe TBI from controls (both 0.89). Serum tau and UCH-L1 showed weak associations with TBI severity and neuroimaging measures. Longitudinally, serum NfL was the only biomarker that was associated with the likely rate of MRI brain atrophy and DTI measures of progression of TAI., Conclusions: Serum NfL shows greater diagnostic and prognostic utility than GFAP, tau, and UCH-L1 for subacute and chronic TBI., Classification of Evidence: This study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls., (© 2020 American Academy of Neurology.)

Objective: To determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI)., Methods: Participants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury., Results: In athletes with paired specimens, CSF NfL and serum NfL were correlated ( r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve [AUROC] 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI ( p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = -0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI., Conclusions: Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI., Classification of Evidence: This study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls., (© 2020 American Academy of Neurology.)

Background: Mild traumatic brain injury (mTBI) is a public health problem that is recognized as a 'silent epidemic' in its late stages due to undiagnosed axonal damage rated 13 and above on the Glasgow Coma Scale (GCS). Injury-related microhemorrhages often cannot be detected on computed tomography (CT) scans and conventional magnetic resonance imaging (MRI). This study aims to investigate whether susceptibility-weighted imaging is feasible in mTBI patients., Methods: Fifty-eight patients with GCS scores of 14 and 15 and with symptoms of brief mental fogs, impairment of concentration, memory loss, headache, dizziness, or imbalance after brain injury were examined at the emergency service. A brain CT scan and MRI containing diffusion-weighted and susceptibility-weighted imaging (SWI) sequences were performed on the patients whose symptoms did not seem to alleviate after the sixth hour. Thirteen patients were excluded from this study because of advanced age, diabetes, a history of hypertension or its chronic sequelae, or acute cerebrovascular disease; 45 patients were included in this study., Results: The patients' CT results were normal, and no diffusion restrictions were observed. The SWI revealed microhemorrhages in seven patients (15.6%). Five of these patients had hyperintense areas in conventional sequences corresponding to the hemorrhages spotted in the SWI. In three of the five patients, these pockets of hemorrhages were higher in number and size in comparison with conventional in the SWI sequence., Conclusion: Susceptibility-weighted imaging, which can be used to assess the presence and severity of microhemorrhages due to diffuse axonal injury, is recommended for determining the cause of symptoms in patients with mTBI, to continue targeted treatment and prevent complications that may develop.

Purpose: Diffuse axonal injury (DAI) is the rupture of multiple axons due to acceleration and deceleration forces during a closed head injury. Most traumatic brain injuries (TBI) have some degree of DAI, especially severe TBI. Computed tomography (CT) remains the first imaging test performed in the acute phase of TBI, but has low sensitivity for detecting DAI, since DAI is a cellular lesion. The aim of this study is to search in the literature for CT signs, in the first 24 h after TBI, that may help to differentiate patients in groups with a better versus worst prognosis., Methods: We searched for primary scientific articles in the PubMed database, in English, indexed since January 1st, 2000., Results: Five articles were selected for review. In the DAI group, traffic accidents accounted 70% of the cases, 79% were male, and the mean age was 41 years. There was an association between DAI and intraventricular hemorrhage (IVH) and traumatic subarachnoid hemorrhage (tSAH); an association between the IVH grade and number of corpus callosum lesions; and an association between blood in the interpeduncular cisterns (IPC) and brainstem lesions., Conclusion: In closed TBI with no tSAH, severe DAI is unlikely. Similarly, in the absence of IVH, any DAI is unlikely. If there is IVH, patients generally are clinically worse; and the more ventricles affected, the worse the prognosis.

A high-resolution, three-dimensional, optical imaging technique for the murine brain was developed to identify the effects of different therapeutic windows for preclinical brain research. This technique tracks the same cells over several weeks. We conducted a pilot study of a promising drug to treat diffuse axonal injury (DAI) caused by traumatic brain injury, using two different therapeutic windows, as a means to demonstrate the utility of this novel longitudinal imaging technique. DAI causes immediate, sporadic axon damage followed by progressive secondary axon damage. We administered minocycline for three days commencing one hour after injury in one treatment group and beginning 72 hours after injury in another group to demonstrate the method's ability to show how and when the therapeutic drug exerts protective and/or healing effects. Fewer varicosities developed in acutely treated mice while more varicosities resolved in mice with delayed treatment. For both treatments, the drug arrested development of new axonal damage by 30 days. In addition to evaluation of therapeutics for traumatic brain injury, this hybrid microlens imaging method should be useful to study other types of brain injury and neurodegeneration and cellular responses to treatment.

Purpose : Functional outcome prediction for patients with traumatic axonal injury (TAI) is not highly related to the MRI classifications. The aim of this study was to assess the accuracy in predicting functional outcome in patients with TAI with several MRI scoring methods and to define the most accurate method. Methods : Patients with TAI (2008-2014) confirmed on MRI <6 months after injury were included in this retrospective study. Long-term functional outcome was prospectively assessed using the Glasgow Outcome Score Extended. The Gentry classification is most used in clinical practice. This method was compared to methods that score lesion load, lesion locations, and to modified Gentry classifications. The area under the curve (AUC) was calculated for the scoring methods. Results : A total of 124 patients with TAI were included, medium follow-up 52 months. The AUC for the Gentry classification was 0.64. All tested methods were poor predictors for functional outcome, except for the 6-location score (area under the curve: 0.71). No method was significantly better than the Gentry classification. Conclusion : The Gentry classification for TAI correlates with functional outcome, but is a poor predictor for the long-term functional outcome. None of the other tested methods was significantly better.

Objectives: No studies have investigated differences in injury of the corticospinal tract (CST) and corticoreticulospinal tract (CRT) following diffuse axonal injury (DAI) to date. Therefore, we investigated differences in injury of the CST and CRT in patients with DAI using diffusion tensor tractography (DTT). Methods: Twenty consecutive patients with DAI and 20 control subjects were recruited. CST and CRT were reconstructed. Each part of the CST and CRT was analyzed in terms of DTT parameters and configuration. Results: Upon group analysis, decreased FA and TV values were observed in both the CST and CRT in the patient group compared with the control group (%) ( p < .05). In the individual analysis in terms of the TV, significantly higher injury incidence was observed for the CRT (47.5%) than the CST (25.0%) ( p < .05). Evaluation of the DTT configuration revealed significantly higher injury incidence for the CRT (50.0%) than the CST (17.5%) ( p < .05). Specifically, the incidence of discontinuation was significantly higher for the CRT (40.0%) than the CST (10.0%) ( p < .05). Conclusions: Injury of the CST and CRT was detected in patients with DAI using DTT. In terms of the incidence and severity of neural injury, the CRT appeared to be more vulnerable to DAI than the CST.

Diffuse axonal injury (DAI) grade III forms a distinct subset of traumatic brain injury wherein it is difficult to predict the outcome and the time taken for early recovery in terms of sustained eye opening and standing with minimal assistance. This study seeks to determine differences in the fractional anisotropy (FI) and diffusion-weighted image (DWI) values obtained from the seeds placed at an appropriate region of interest (ROI) within the magnetic resonance (MR) tractography of the brainstem of brain-injured patients. We found that differences in the DWI values along the corticospinal tract were associated with the days required for early recovery. Moreover, dysautonomia was an independent variable governing a delayed recovery in these patients. The lesions posterior to the corticospinal tract in the brainstem conferred increased odds for the subsequent development of dysautonomia. We conclude that MR tractography, in addition to depicting the anatomical integrity of the concerned tracts, has the potential of becoming a surrogate clinical imaging marker for effectively predicting days for early recovery among patients with DAI grade III.