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Sara Montemerani,1 Cosimo Fabrizi,1 Cecilia Sacchi,2 Antoine Belperio,3 Lorenzo Moriani,3 Samuele Pacchi,3 Cinzia Garofalo,4 Giovanni Sbrana,5 Duccio Venezia,6 Maurizio Zanobetti,1 Simone Nocentini3 1UOC Medicina d’Emergenza Urgenza e Pronto Soccorso Ospedale San Donato, Dipartimento Emergenza Urgenza, Azienda USL Toscana Sud Est, Arezzo, Italia; 2Scuola di specializzazione in Medicina d’Emergenza Urgenza, Università degli Studi di Siena, Siena, Italia; 3COES Arezzo, Dipartimento Emergenza Territoriale, Azienda USL Toscana Sud Est, Arezzo, Italia; 4UOC Direzione Infermieristica Emergenza e Urgenza Area provinciale Arezzo, Siena e Grosseto, Azienda USL Toscana Sud Est, Arezzo, Italia; 5UOC Elisoccorso ed Emergenza Territoriale 118 area provinciale grossetana, Dipartimento Emergenza Territoriale, Azienda USL Toscana Sud Est Grosseto, Arezzo, Italia; 6UOC Radiologia Ospedale San Donato, Azienda USL Toscana Sud Est, Arezzo, ItaliaCorrespondence: Sara Montemerani, UOC Medicina d’Emergenza Urgenza e Pronto Soccorso Ospedale San Donato, Dipartimento Emergenza Urgenza, Azienda USL Toscana Sud Est, Via Curtatone, Arezzo, 52100, Italia, Email sara.montemerani@uslsudest.toscana.itPurpose: Mild Traumatic brain injury is classified based on Glasgow Coma Scale (GCS 13– 15), it also involves transient alteration of brain function, which may lead to severe short- and long-term sequelae. When treating a patient with a mild head injury outside the hospital, it is of crucial importance to decide whether to transport him to a center without neurosurgery or to a center equipped with neurosurgery (primary centralization). Recent decades have seen exploration of portable, non-invasive devices for intracranial injury and stroke detection, with microwave frequency electromagnetic field technology showing promising clinical outcomes. This clinical investigation aims to assess the diagnostic accuracy of the TES HT100 medical device, utilizing electromagnetic fields for endocranial lesion screening.Patients and Methods: Patients with mild traumatic brain injury were randomly enrolled according to inclusion criteria. Twenty-three patients recruited from the Intensive Short-Term Observation (ISTO) unit at San Donato Hospital in Arezzo. The sensitivity and specificity of the TES HT were evaluated statistically against cranial computed tomography (CT), the gold standard.Results: A preliminary analysis shows a sensitivity of 100% and a specificity of 100%. Based on these results, there is maximum concordance between the two examinations, and the AUC is 1. No adverse events related to the use of TES HT100 or the examination.Conclusion: The device’s ability to differentiate patients with intracranial lesions from those without can streamline the diagnostic and therapeutic process, potentially leading to improved patient outcomes. If Temnography will maintain high standards of sensitivity and specificity with the expansion of the enrolled population, it could be considered as a stable screening tool in the Emergency Room (ER). We could think to apply this technology to reduce the length of stay that patients with mTBI have to spend in ER for observation. Temnography could also be useful in special categories of patients such as pregnant women or the pediatric population. Moreover, another front of future development of this technology could be extending the study to include Territorial Emergency. In this context, Temnography could aid centralized decision-making in patient care.Keywords: temnography, mild traumatic brain injury, mTBI, traumatic brain injury, TBI, emergency medicine, pre-hospital

Aims. Mild Traumatic Brain Injury (mTBI) is the most common type of craniocerebral injury. Proper management appears to be a key factor in preventing post-concussion syndrome. The aim of this prospective study was to evaluate the effect and safety of selected training protocol in patients after mTBI. Methods. This was a prospective study that included 25 patients with mTBI and 25 matched healthy controls. Assessments were performed in two sessions and included a post-concussion symptoms questionnaire, battery of neurocognitive tests, and magnetic resonance with tractography. Participants were divided into two groups: a passive subgroup with no specific recommendations and an active subgroup with simple physical and cognitive training. Results. The training program with slightly higher initial physical and cognitive loads was well tolerated and was harmless according to the noninferiority test. The tractography showed overall temporal posttraumatic changes in the brain. The predictive model was able to distinguish between patients and controls in the first (AUC=0.807) and second (AUC=0.652) sessions. In general, tractography had an overall predictive dominance of measures. Conclusion. The results from our study objectively point to the safety of our chosen training protocol, simultaneously with the signs of slight benefits in specific cognitive domains. The study also showed the capability of machine learning and predictive models in mTBI patient recognition.

Purpose: To determine the psychological and neuropsychological status of patients with both blast-related ocular injury and mild traumatic brain injury (TBI) late after the traumatic event. Material and Methods: Thirty patients with blast-related ocular injury, reduced visual function and comorbid mild TBI were included in the study. The following methods of psychological and neuropsychological assessment were used: formalized interview; Suicidality, Post-traumatic Stress Disorder (PTSD), Alcohol Dependence, and Drug Dependence scales of the Mini-International Neuropsychiatric Interview (MINI); Raven’s Progressive Matrix scale; Personal and Social Performance (PSP) scale; PROMIS® Pain-Interference scale; Hospital Anxiety and Depression Scale (HADS); Mazes subtest of the Neuropsychological Assessment Battery (NAB); and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results: The following significant correlations were found: PSP functioning and support from the family (r = 0.533, p = 0.002); total RBANS score and Mazes subtest score (r = 0.466, p = 0.009); total RBANS score and self-reported stress score (negative correlation, r = -0.492, p = 0.006); HADS depression and self-reported stress score (r = 0.646, p = 0.000114); PROMIS pain scale and PTSD scale (r = 0.482, p = 0.007). No association was found between the number of mild TBI events experienced and neuropsychological and psychological measurements. Conclusion: Blast-related mild TBI concomitant with ocular injury has a substantial and long-term impact on casualty’s cognitive and psychological functions. In such patients, the most prominent cognitive deficits occur in the domain of executive function (including cognitive control and planning and problem-solving skills). In the presence of reduced visual function, these deficits have a substantial impact on total cognitive scores, scores of other psychic functions (namely, attention and memory) and significantly affect the patient’s capacity for independent functioning.

Abstract Introduction Mild traumatic brain injury (mTBI) represents a major public health concern and affects millions of people worldwide every year. Diagnosis mainly relies on clinical criteria and computed tomography (CT) scans. GFAP (glial fibrillary acidic protein) and UCH-L1 (ubiquitin carboxyl-terminal hydrolase-L1) have been recently studied as potential biomarkers of mTBI. This study retrospectively evaluated the possible use of these combined biomarkers as negative predictors for excluding brain injuries in patients with suspected mTBI in the emergency department. Methods Adult patients (n = 130) enrolled at Tor Vergata University Hospital (Rome, Italy), consecutively registered at the triage of the emergency department between October 2022 and January 2023, with non-penetrating TBI and Glasgow Coma Scale (GCS) score of 13–15, were considered. All eligible patients underwent intracranial CT scans and blood tests, within 12 h after trauma, for GFAP and UCH-L1 serum concentrations. Results Intracranial CT detected injuries in only seven patients (5%); GFAP and UCH-L1 tested positive in 96 patients and negative in 34 patients (74% vs. 26%). Combined biomarkers had a sensitivity equal to 1.00 (95% CI 0.64-1.00) and a negative predictive value (NPV) of 1.00 (0.99-1.00) in mTBI diagnosis with a negative CT. Conclusions Combined laboratory tests for GFAP and UCH-L1 biomarkers might play a potential clinical role in avoiding unnecessary head CT scans after mTBI in emergency departments.

Abstract Background Mild traumatic brain injury (mTBI), i.e. a TBI with an admission Glasgow Coma Scale (GCS) of 13–15, is a common cause of emergency department visits. Only a small fraction of these patients will develop a traumatic intracranial hemorrhage (tICH) with an even smaller subgroup suffering from severe outcomes. Limitations in existing management guidelines lead to overuse of computed tomography (CT) for emergency department (ED) diagnosis of tICH which may result in patient harm and higher healthcare costs. Objective To perform a systematic review and meta-analysis to characterize known and potential novel risk factors that impact the risk of tICH in patients with mTBI to provide a foundation for improving existing ED guidelines. Methods The literature was searched using MEDLINE, EMBASE and Web of Science databases. Reference lists of major literature was cross-checked. The outcome variable was tICH on CT. Odds ratios (OR) were pooled for independent risk factors. Results After completion of screening, 17 papers were selected for inclusion, with a pooled patient population of 26,040 where 2,054 cases of tICH were verified through CT (7.9%). Signs of a skull base fracture (OR 11.71, 95% CI 5.51–24.86), GCS

Summary: Background: Following mild traumatic brain injury (mTBI), elevated concentrations of brain-specific blood proteins glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) may be indicative of intracranial lesions normally detected by head CT scans. We sought to validate the performance of this combination of biomarkers at predetermined cutoff values with an automated immunoassay to predict which patients did not have intracranial lesions. Methods: This prospective, observational study was conducted in France and Spain at 16 emergency departments. Adult patients with mTBI were eligible if they had a head CT scan and gave a 10-ml blood sample within 12 h of injury. GFAP and UCH-L1 serum concentrations were measured and analysed, in less than an hour time, according to predefined cutoff values of 22 pg/ml and 327 pg/ml, respectively. Serum concentrations of S100B protein were concomitantly determined in a subset of patients. The primary outcome measures were the sensitivity and negative predictive value (NPV) of the combined GFAP–UCH-L1 test to rule out intracranial lesions on head CT scans. ClinicalTrials.gov (NCT04032509). Findings: Between August 2019 and June 2021, 1508 patients were recruited, and 1438 were included in the main analysis. Median age was 69 years (IQR 44–83). Most patients (74%) presented 3 h after trauma. 179 (12.4%) patients were positive for intracranial lesions by CT. The sensitivity of the combined test was 98.3% (95% CI 95.0–99.7) and the specificity 24.9 (95% CI 22.6–27.4), with a NPV of 99.1% (95% CI 97.1–99.8). Three patients with a positive CT scan had negative biomarker test results. S100B had a sensitivity of 83.0% (95% CI 76.2–88.2) and a NPV of 94.2% (95% CI 91.6–96.0). Patients with higher biomarker values more frequently had poorer recovery at 3 months after injury. Interpretation: Testing for GFAP and UCH-L1, using validated cutoffs obtained with a new, fast automated immunoassay platform, accurately predicted the absence of intracranial lesions on head CT following mTBI. Funding: This study is co-funded by the European Institute of Innovation and Technology (EIT) Health, a body of the European Union (Grant nº19474). Biomarkers tests were funded by bioMérieux.

Abstract Objective The insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed of functionally different subdivisions and each of which plays different role in PTH neuropathology. Methods Ninety-four mTBI patients were included in this study. Based on perfusion imaging data obtained from arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI), this study evaluated the insular subregion perfusion-based functional connectivity (FC) and its correlation with clinical characteristic parameters in patients with PTH after mTBI and non-headache mTBI patients. Results The insular subregions of mTBI + PTH (mTBI patients with PTH) and mTBI-PTH (mTBI patients without PTH) group had positive perfusion-based functional connections with other insular nuclei and adjacent discrete cortical regions. Compared with mTBI-PTH group, significantly increased resting-state perfusion-based FC between the anterior insula (AI) and middle cingulate cortex (MCC)/Rolandic operculum (ROL), between posterior insula (PI) and supplementary motor area (SMA), and decreased perfusion-based FC between PI and thalamus were found in mTBI + PTH group. Changes in the perfusion-based FC of the left posterior insula/dorsal anterior insula with the thalamus/MCC were significant correlated with headache characteristics. Conclusions Our findings provide new ASL-based evidence for changes in the perfusion-based FC of the insular subregion in PTH patients attributed to mTBI and the association with headache features, revealing the possibility of potential neuroplasticity after PTH. These findings may contribute to early diagnosis of the disease and follow-up of disease progression.

Aims. Mild Traumatic Brain Injury (mTBI) is the most common type of craniocerebral injury. Proper management appears to be a key factor in preventing post-concussion syndrome. The aim of this prospective study was to evaluate the effect and safety of selected training protocol in patients after mTBI. Methods. This was a prospective study that included 25 patients with mTBI and 25 matched healthy controls. Assessments were performed in two sessions and included a post-concussion symptoms questionnaire, battery of neurocognitive tests, and magnetic resonance with tractography. Participants were divided into two groups: a passive subgroup with no specific recommendations and an active subgroup with simple physical and cognitive training. Results. The training program with slightly higher initial physical and cognitive loads was well tolerated and was harmless according to the noninferiority test. The tractography showed overall temporal posttraumatic changes in the brain. The predictive model was able to distinguish between patients and controls in the first (AUC=0.807) and second (AUC=0.652) sessions. In general, tractography had an overall predictive dominance of measures. Conclusion. The results from our study objectively point to the safety of our chosen training protocol, simultaneously with the signs of slight benefits in specific cognitive domains. The study also showed the capability of machine learning and predictive models in mTBI patient recognition. [ABSTRACT FROM AUTHOR]

IntroductionEducation is strongly advocated as a key component of treatment for mild traumatic brain injury (mTBI) in clinical guidelines. However, there is mixed evidence on the benefit of education. This study aimed to evaluate a new education resource for mTBI. CLARITY is a freely available animated video based on a biopsychosocial conceptualization of mTBI, explaining the complex psychological, environmental and biological mechanisms behind symptoms and recovery.1Methods24 adults with a history of mTBI participated in this mixed method study to examine prior experience of mTBI education and to evaluate CLARITY. Following viewing of the education video participants’ were invited to engage in a semi-structured interview and to share their perceptions of it via an online anonymous questionnaire.ResultsThematic analysis of semi-structured interviews revealed one overarching theme: education is the foundation of recovery. Participants emphasised the critical role of coherent education in facilitating understanding, engagement in rehabilitation, and positive expectations during recovery. However, the first subtheme was that existing foundations are weak. Participants’ previous education was often limited in scope, inconsistent, and delivered in inaccessible ways. The second subtheme was that new foundations are stronger. Participants responded positively to CLARITY, highlighting its explanatory biopsychosocial approach, focus on mental health factors and accessible delivery methods as key strengths. Questionnaire responses revealed favourable endorsement of CLARITY’s utility, comprehensibility and accessibility.DiscussionRecommendations for minor refinements to CLARITY were provided and made, as well as for its use in health care services.

Background: Convolutional neural network (CNN) can capture the structural features changes of brain aging based on MRI, thus predict brain age in healthy individuals accurately. However, most studies use single feature to predict brain age in healthy individuals, ignoring adding information from multiple sources and the changes in brain aging patterns after mild traumatic brain injury (mTBI) were still unclear. Methods: Here, we leveraged the structural data from a large, heterogeneous dataset (N = 1464) to implement an interpretable 3D combined CNN model for brain-age prediction. In addition, we also built an atlas-based occlusion analysis scheme with a fine-grained human Brainnetome Atlas to reveal the age-sstratified contributed brain regions for brain-age prediction in healthy controls (HCs) and mTBI patients. The correlations between brain predicted age gaps (brain-PAG) following mTBI and individual's cognitive impairment, as well as the level of plasma neurofilament light were also examined. Results: Our model utilized multiple 3D features derived from T1w data as inputs, and reduced the mean absolute error (MAE) of age prediction to 3.08 years and improved Pearson's r to 0.97 on 154 HCs. The strong generalizability of our model was also validated across different centers. Regions contributing the most significantly to brain age prediction were the caudate and thalamus for HCs and patients with mTBI, and the contributive regions were mostly located in the subcortical areas throughout the adult lifespan. The left hemisphere was confirmed to contribute more in brain age prediction throughout the adult lifespan. Our research showed that brain-PAG in mTBI patients was significantly higher than that in HCs in both acute and chronic phases. The increased brain-PAG in mTBI patients was also highly correlated with cognitive impairment and a higher level of plasma neurofilament light, a marker of neurodegeneration. The higher brain-PAG and its correlation with severe cognitive impairment showed a longitudinal and persistent nature in patients with follow-up examinations. Conclusion: We proposed an interpretable deep learning framework on a relatively large dataset to accurately predict brain age in both healthy individuals and mTBI patients. The interpretable analysis revealed that the caudate and thalamus became the most contributive role across the adult lifespan in both HCs and patients with mTBI. The left hemisphere contributed significantly to brain age prediction may enlighten us to be concerned about the lateralization of brain abnormality in neurological diseases in the future. The proposed interpretable deep learning framework might also provide hope for testing the performance of related drugs and treatments in the future.

Mild traumatic brain injury (mTBI) is a known risk factor for neurodegenerative diseases, yet the precise pathophysiological mechanisms remain poorly understand, often obscured by group-level analysis in non-invasive neuroimaging studies. Individual-based method is critical to exploring heterogeneity in mTBI. We recruited 80 mTBI patients and 40 matched healthy controls, obtaining high-resolution structural MRI for constructing Individual Differential Structural Covariance Networks (IDSCN). Comparisons were conducted at both the individual and group levels. Connectome-based Predictive Modeling (CPM) was applied to predict cognitive performance based on whole-brain connectivity. During the acute stage of mTBI, patients exhibited significant heterogeneity in the count and direction of altered edges, obscured by group-level analysis. In the chronic stage, the number of altered edges decreased and became more consistent, aligning with clinical observations of acute cognitive impairment and gradual improvement. Subgroup analysis based on loss of consciousness/post-traumatic amnesia revealed distinct patterns of alterations. The temporal lobe, particularly regions related to the limbic system, significantly predicted cognitive function from acute to chronic stage. The use of IDSCN and CPM has provided valuable individual-level insights, reconciling discrepancies from previous studies. Additionally, the limbic system may be an appropriate target for future intervention efforts.

Patients with mild traumatic brain injury have a diverse clinical presentation, and the underlying pathophysiology remains poorly understood. Magnetic resonance imaging is a non-invasive technique that has been widely utilized to investigate neurobiological markers after mild traumatic brain injury. This approach has emerged as a promising tool for investigating the pathogenesis of mild traumatic brain injury. Graph theory is a quantitative method of analyzing complex networks that has been widely used to study changes in brain structure and function. However, most previous mild traumatic brain injury studies using graph theory have focused on specific populations, with limited exploration of simultaneous abnormalities in structural and functional connectivity. Given that mild traumatic brain injury is the most common type of traumatic brain injury encountered in clinical practice, further investigation of the patient characteristics and evolution of structural and functional connectivity is critical. In the present study, we explored whether abnormal structural and functional connectivity in the acute phase could serve as indicators of longitudinal changes in imaging data and cognitive function in patients with mild traumatic brain injury. In this longitudinal study, we enrolled 46 patients with mild traumatic brain injury who were assessed within 2 weeks of injury, as well as 36 healthy controls. Resting-state functional magnetic resonance imaging and diffusion-weighted imaging data were acquired for graph theoretical network analysis. In the acute phase, patients with mild traumatic brain injury demonstrated reduced structural connectivity in the dorsal attention network. More than 3 months of follow-up data revealed signs of recovery in structural and functional connectivity, as well as cognitive function, in 22 out of the 46 patients. Furthermore, better cognitive function was associated with more efficient networks. Finally, our data indicated that small-worldness in the acute stage could serve as a predictor of longitudinal changes in connectivity in patients with mild traumatic brain injury. These findings highlight the importance of integrating structural and functional connectivity in understanding the occurrence and evolution of mild traumatic brain injury. Additionally, exploratory analysis based on subnetworks could serve a predictive function in the prognosis of patients with mild traumatic brain injury.

Large animal models of mild traumatic brain injury (mTBI) are needed to elucidate the pathophysiology of mechanical insult to a gyrencephalic brain. Sheep (ovis aries) are an attractive model for mTBI because of their neuroanatomical similarity to humans; however, few histological studies of sheep mTBI models have been conducted. We previously developed a sheep mTBI model to pilot methods for investigating the mechanical properties of brain tissue after injury. Here, we sought to histologically characterize the cortex under the impact site in this model. Three animals received a closed skull mTBI with unconstrained head motion, delivered with an impact stunner, and 3 sham animals were anesthetized but did not receive an impact. Magnetic resonance imaging (MRI) of the brain was performed before and after the impact and revealed variable degrees of damage to the skull and brain. Fluorescent immunohistochemistry revealed regions of hemorrhage in the cortex underlying the impact site in 2 of 3 mTBI sheep, the amount of which correlated with the degree of damage observed on the post-impact MRI scans. Labeling for microtubule-associated protein 2 and neuronal nuclear protein revealed changes in cellular anatomy, but, unexpectedly, glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 labeling were relatively unchanged compared to sham animals. Our findings provide preliminary evidence of vascular and neuronal damage with limited glial reactivity and highlight the need for further in-depth histological assessment of large animal mTBI models.

Abstract Background Mild traumatic brain injury (TBI) occupies majority of head traumas in most emergency units. Although patients with mild TBI can be reviewed and discharged on head injury advice, a sizeable number require admission for observation or intervention due to operable intracranial lesions. The aim of the study was to establish the prevalence of operable lesions in patients with mild TBI. Materials and methods This was a prospective study of consecutive adult patients with mild TBI who had cranial computerized tomography (CT) done at the National Trauma Centre, Abuja. All participants gave informed consent and the study had ethical clearance in the Hospital. Results One hundred and three mild TBI patients with cranial CTs were recruited aged 16–76 years with mean age of 32.25 $$\pm$$ ± 12.35 years. With intention to treat, twenty (20.4%) of them were diagnosed with operable intracranial lesions on CT scans, 19 males and 2 females. Majority of them (14; 66.7%) were young adults within 20–40 years of age. The lesions were 16 extradural haematomas (76.2%), 3 subdural haematomas (14.3%) and 2 depressed skull fractures (9.5%) of the operable cohort. Conclusions Significant number of patients with mild TBI had operable intracranial lesions. Therefore, there is need to screen patients with mild TBI appropriately in order to avoid missed operable lesions.

Mild traumatic brain injury (mTBI) is a prevalent health concern with variable recovery trajectories, necessitating reliable prognostic markers. Insulin-like growth factor 1 (IGF-1) emerges as a potential candidate because of its role in cellular growth, repair, and neuroprotection. However, limited studies investigate IGF-1 as a prognostic marker in mTBI patients. This study aimed to explore the correlation of IGF-1 with cognitive functions assessed using the Wisconsin Card Sorting Test (WCST) in mTBI patients. We analyzed data from 295 mTBI and 200 healthy control participants, assessing demographic characteristics, injury causes, and IGF-1 levels. Cognitive functions were evaluated using the WCST. Correlation analyses and regression models were used to investigate the associations between IGF-1 levels, demographic factors, and WCST scores. Significant differences were observed between mTBI and control groups in the proportion of females and average education years. Falls and traffic accidents were identified as the primary causes of mTBI. The mTBI group demonstrated worse cognitive outcomes on the WCST, except for the ?Learning to Learn? index. Correlation analyses revealed significant relationships between IGF-1 levels, demographic factors, and specific WCST scores. Regression models demonstrated that IGF-1, age, and education years significantly influenced various WCST scores, suggesting their roles as potential prognostic markers for cognitive outcomes in mTBI patients. We provide valuable insights into the potential correlation of IGF-1 with cognitive functions in mTBI patients, particularly in tasks requiring cognitive flexibility and problem solving.

Background: Although patients with mild traumatic brain injury (mTBI) rarely exhibit an identifiable lesion on neuroimaging, they frequently experience neurocognitive problems. Objectives: The present study aimed to determine the cut-off point, sensitivity, and specificity of the Montreal Cognitive Assessment (MoCA) test in mTBI patients. Methods: In this cross-sectional-analytical study, the case group included 79 patients with mTBI were enrolled in the trauma, neurosurgery, and ICU ward of PourSina hospital (northern Iran), and there were 79 healthy individuals in the control group. Both groups were participating in this study were cognitively evaluated by the MoCA and MMSE test. Moreover, as retesting reliability and determining the concurrent and convergent validity of the MoCA, and Pearson correlation coefficient between two groups, MMSE test was performed on 20 mTBI patients with an average time interval of 3 days. The independent t-test, Cronbach’s alpha and discriminant analysis used for determining the distribution, internal consistency reliability and sensitivity, specificity, and diagnostic value of the MoCA test between groups respectively. Results: The results showed a cut-off point of 26/27 as the probable point of cognitive impairment in mTBI. Also, in order to identify cognitive impairment in mTBI patients, this test reported sensitivity of 0.62 and specificity of 0.81 with Youden's index of 0.43. Conclusion: In screening for possible mild cognitive impairment in mTBI patients, the MoCA is relatively useful and should not be used only as a substitute for a complete neuropsychological assessment with diagnostic purposes.

ObjectiveThere is preliminary evidence that children after traumatic brain injury (TBI) have accelerated long-term forgetting (ALF), i.e., an adequate learning and memory performance in standardized memory tests, but an excessive rate of forgetting over delays of days or weeks. The main aim of this study was to investigate episodic memory performance, including delayed retrieval 1 week after learning, in children after mild TBI (mTBI).MethodsThis prospective study with two time-points (T1: 1 week after injury and T2: 3–6 months after injury), included data of 64 children after mTBI and 57 healthy control children aged between 8 and 16 years. We assessed episodic learning and memory using an auditory word learning test and compared executive functions (interference control, working memory, semantic fluency and flexibility) and divided attention between groups. We explored correlations between memory performance and executive functions. Furthermore, we examined predictive factors for delayed memory retrieval 1 week after learning as well as for forgetting over time.ResultsCompared to healthy controls, patients showed an impaired delayed recall and recognition performance 3–6 months after injury. Executive functions, but not divided attention, were reduced in children after mTBI. Furthermore, parents rated episodic memory as impaired 3–6 months after injury. Additionally, verbal learning and group, but not executive functions, were predictive for delayed recall performance at both time-points, whereas forgetting was predicted by group.DiscussionDelayed recall and forgetting over time were significantly different between groups, both post-acutely and in the chronic phase after pediatric mTBI, even in a very mildly injured patient sample. Delayed memory performance should be included in clinical evaluations of episodic memory and further research is needed to understand the mechanisms of ALF.

Traumatic brain injury (TBI) is a global public health problem with 50–60 million incidents per year, most of which are considered mild (mTBI) and many of these repetitive (rmTBI). Despite their massive implications, the pathologies of mTBI and rmTBI are not fully understood, with a paucity of information on brain lipid dysregulation following mild injury event(s). To gain more insight on mTBI and rmTBI pathology, a non-targeted spatial lipidomics workflow utilizing high resolution mass spectrometry imaging was developed to map brain region-specific lipid alterations in rats following injury. Discriminant multivariate models were created for regions of interest including the hippocampus, cortex, and corpus callosum to pinpoint lipid species that differentiated between injured and sham animals. A multivariate model focused on the hippocampus region differentiated injured brain tissues with an area under the curve of 0.99 using only four lipid species. Lipid classes that were consistently discriminant included polyunsaturated fatty acid-containing phosphatidylcholines (PC), lysophosphatidylcholines (LPC), LPC-plasmalogens (LPC-P) and PC potassium adducts. Many of the polyunsaturated fatty acid-containing PC and LPC-P selected have never been previously reported as altered in mTBI. The observed lipid alterations indicate that neuroinflammation and oxidative stress are important pathologies that could serve to explain cognitive deficits associated with rmTBI. Therapeutics which target or attenuate these pathologies may be beneficial to limit persistent damage following a mild brain injury event.

Objectives: People may experience a myriad of symptoms after mild traumatic brain injury (mTBI), but the relationship between symptoms and objective assessments is poorly characterized. This study sought to investigate the association between symptoms, resting heart rate (HR), and exercise tolerance in individuals following mTBI, with a secondary aim to examine the relationship between symptom-based clinical profiles and recovery. Methods: Prospective observational study of adults aged 18 to 65 years who had sustained mTBI within the previous 7 days. Symptoms were assessed using the Post-Concussion Symptom Scale, HR was measured at rest, and exercise tolerance was assessed using the Buffalo Concussion Bike Test. Symptom burden and symptom-based clinical profiles were examined with respect to exercise tolerance and resting HR. Results: Data from 32 participants were assessed (mean age 36.5 ± 12.6 years, 41% female, 5.7 ± 1.1 days since injury). Symptom burden (number of symptoms and symptom severity) was significantly associated with exercise intolerance (P = .002 and P = .025, respectively). Physiological and vestibular-ocular clinical profile composite groups were associated with exercise tolerance (P = .001 and P = .014, respectively), with individuals who were exercise intolerant having a higher mean number of symptoms in each profile than those who were exercise tolerant. Mood-related and autonomic clinical profiles were associated with a higher resting HR (>80 bpm) (P = .048 and P = .028, respectively), suggesting altered autonomic response for participants with symptoms relating to this profile. After adjusting for age and mechanism of injury (sports- or non–sports-related), having a higher mood-related clinical profile was associated with persisting symptoms at 3 months postinjury (adjusted odds ratio = 2.08; 95% CI, 1.11-3.90; P = .013). Conclusion: Symptom-based clinical profiles, in conjunction with objective measures such as resting HR and exercise tolerance, are important components of clinical care for those having sustained mTBI. These results provide preliminary support for the concept that specific symptoms are indicative of autonomic dysfunction following mTBI. [ABSTRACT FROM AUTHOR]

Abstract Objective: To examine the associations between recent stressful life events and self-reported fatigue and depressive symptoms in patients with mild traumatic brain injury. Design: Observational cohort study. Participants: Patients (aged 18–68 years) with mild traumatic brain injury (n = 99) or lower extremity orthopaedic injury (n = 34). Methods: Data on stressful life events and self-reported symptoms were collected 3 months post-injury. Stressful life events in the last 12 months were assessed as part of a structured interview using a checklist of 11 common life events, self-reported fatigue with Barrow Neurological Institute Fatigue Scale, and depressive symptoms with Beck Depression Inventory – Fast Screen. Results: Median number of stressful life events was 1 (range 0–7) in the mild traumatic brain injury group and 1.5 (range 0–6) in the orthopaedic injury group. The groups did not differ significantly in terms of fatigue or depressive symptoms. In the mild traumatic brain injury group, the total number of recent stressful life events correlated significantly with self-reported fatigue (rs = 0.270, p = 0.007) and depressive symptoms (rs = 0.271, p = 0.007). Conclusion: Stressful life events are associated with self-reported fatigue and depressive symptoms in patients with mild traumatic brain injury. Clinicians should consider stressful life events when managing patients who experience these symptoms, as this may help identifying potential targets for intervention.

Abstract INTRODUCTION We evaluated how the apolipoprotein E (APOE) ε4 allele modulated the spatial patterns of longitudinal atrophy in the Alzheimer's disease–vulnerable brain areas of patients with mild traumatic brain injury (mTBI) from the acute to chronic phase post injury. METHODS Fifty‐nine adult patients with acute mTBI and 48 healthy controls with APOE ε4 allele testing underwent T1‐weighted magnetic resonance imaging and neuropsychological assessments with 6 to 12 months of follow‐up. Progressive brain volume loss was compared voxel‐wise in the temporal lobes. RESULTS Patients with the APOE ε4 allele presented significant longitudinal atrophy in the left superior and middle temporal gyri, where the progressive gray matter volume loss predicted longitudinal impairment in language fluency, whereas mTBI APOE ε4 allele noncarriers showed mainly significant longitudinal atrophy in the medial temporal lobes, without significant neuropsychological relevance. DISCUSSION The atrophy progression observed in mTBI patients with the APOE ε4 allele may increase the possibility of developing a specific phenotype of Alzheimer's disease with language dysfunction. Highlights The apolipoprotein E (APOE) ε4 allele and mild traumatic brain injury (mTBI) are risk factors for Alzheimer's disease (AD) progression. It is unclear how the interaction of mTBI with the APOE ε4 allele impacts the progressive atrophy topography in AD‐vulnerable brain regions. In this study, patients with the APOE ε4 allele showed progressive atrophy patterns similar to the early stage of logopenic variant of primary progressive aphasia (lvPPA) phenotype of AD. APOE ε4 allele carriers with mTBI history may be at the risk of developing a given AD phenotype with language dysfunction.

Background: The purpose of the study was to identify whether the presence of a pre-injury psychiatric history, subacute post-concussive symptoms (PCS) and personality traits were predictive of less favorable social reintegration for 3 months following a mild traumatic brain injury (mTBI). Method: A total of 76 patients with mTBI were included, and the presence of a pre-injury psychiatric history was identified from the medical chart. One-month post-accident, these patients completed the Millon Multiaxial Clinical Inventory, 3rd Edition assessing personality traits and the Rivermead Post-Concussion Symptoms Questionnaire to measure subacute PCS. Social reintegration was measured using the Mayo-Portland Adaptability Inventory, 4th Edition at 3-month post-accident. Results: The presence of pre-injury psychiatric history, high levels of subacute PCS and Cluster B personality traits such as histrionic and borderline features were significant predictors of social reintegration quality at 3-month post injury. Conclusion: This study provides new insights on cluster B personality traits and its influence on recovery and social reintegration at 3-month post mTBI. [ABSTRACT FROM AUTHOR]

The high incidence of mild traumatic brain injury (mTBI) and the associated post-concussion symptoms, such as headache and cognitive deficits, have captured the significant attention from researchers globally. Magnetic resonance spectroscopy (MRS), a non-invasively technique derived from Magnetic Resonance Imaging (MRI), provides a complement approach to investigating brain metabolites as biomarkers for in vivo pathophysiological changes following mTBI, which are not evident in traditional MRI or CT scans. However, the separate review of MRS in mTBI patients has been limited, given the myriad factors involved and wide spectrum of TBI severity. In this review, we first delve into metabolite changes after mTBI, highlighting a reduction in N-acetyl-aspartate (NAA) as a relatively stable marker associated with neuronal loss or disfunction following mTBI. We then discuss the varying results observed for different metabolites and enumerate possible factors contributing to these inconsistent findings. These factors include variations in experimental methods, such as scanner types, acquisition methods, and region of interest. Additionally, we address subjects-specific factors, such as occupation, cause of injury, control group selection, injury stage, severity, the number of traumatic events, and the assessment of clinical features. Finally, we discuss the trend for future research in this field.

Mild traumatic brain injury (mTBI) is a public health concern. The present study aimed to develop an automatic classifier to distinguish between patients with chronic mTBI (n = 83) and healthy controls (HCs) (n = 40). Resting-state functional MRI (rs-fMRI) and positron emission tomography (PET) imaging were acquired from the subjects. We proposed a novel deep-learning-based framework, including an autoencoder (AE), to extract high-level latent and rectified linear unit (ReLU) and sigmoid activation functions. Single and multimodality algorithms integrating multiple rs-fMRI metrics and PET data were developed. We hypothesized that combining different imaging modalities provides complementary information and improves classification performance. Additionally, a novel data interpretation approach was utilized to identify top-performing features learned by the AEs. Our method delivered a classification accuracy within the range of 79–91.67% for single neuroimaging modalities. However, the performance of classification improved to 95.83%, thereby employing the multimodality model. The models have identified several brain regions located in the default mode network, sensorimotor network, visual cortex, cerebellum, and limbic system as the most discriminative features. We suggest that this approach could be extended to the objective biomarkers predicting mTBI in clinical settings.

Mild traumatic brain injury (mTBI) is a significant public health concern, specially characterized by a complex pattern of abnormal neural activity and functional connectivity. It is often associated with a broad spectrum of short-term and long-term cognitive and behavioral symptoms including memory dysfunction, headache, and balance difficulties. Furthermore, there is evidence that oxidative stress significantly contributes to these symptoms and neurophysiological changes. The purpose of this study was to assess the effect of N-acetylcysteine (NAC) on brain function and chronic symptoms in mTBI patients. Fifty patients diagnosed with chronic mTBI participated in this study. They were categorized into two groups including controls (CN, n = 25), and patients receiving treatment with N-acetyl cysteine (NAC, n = 25). NAC group received 50 mg/kg intravenous (IV) medication once a day per week. In the rest of the week, they took one 500 mg NAC tablet twice per day. Each patient underwent rs-fMRI scanning at two timepoints including the baseline and 3 months later at follow-up, while the NAC group received a combination of oral and IV NAC over that time. Three rs-fMRI metrics were measured including fractional amplitude of low frequency fluctuations (fALFF), degree centrality (DC), and functional connectivity strength (FCS). Neuropsychological tests were also assessed at the same day of scanning for each patient. The alteration of rs-fMRI metrics and cognitive scores were measured over 3 months treatment with NAC. Then, the correlation analysis was executed to estimate the association of rs-fMRI measurements and cognitive performance over 3 months (p

The US population suffers 1.5 million head injuries annually, of which mild traumatic brain injuries (mTBI) comprise 75%. Many individuals subsequently experience long-lasting negative symptoms, including anxiety. Previous rat-based work in our laboratory has shown that mTBI changes neuronal counts in the hippocampus and amygdala, regions associated with anxiety. Specifically, mTBI increased neuronal death in the dorsal CA1 sub-region of the hippocampus, but attenuated it in the medial (MeA) and the basolateral nuclei of the amygdala nine days following injury, which was associated with greater anxiety. We have also shown that glucocorticoid receptor (GR) antagonism prior to concomitant stress and mTBI extinguishes anxiety-like behaviors. Using immunohistochemistry, this study examines the expression of brain-derived neurotrophic factor (BDNF) following social defeat and mTBI, and whether this is affected by prior glucocorticoid receptor antagonism as a potential mechanism behind these anxiety and neuronal differences. Here, stress and mTBI upregulate BDNF in the MeA, and both GR and mineralocorticoid receptor antagonism downregulate BDNF in the dorsal hippocampal CA1 and dentate gyrus, as well as the central nucleus of the amygdala. These findings suggest BDNF plays a role in the mechanism underlying neuronal changes following mTBI in amygdalar and hippocampal subregions, and may participate in stress elicited changes to neural plasticity in these regions. Taken together, these results suggest an essential role for BDNF in the development of anxiety behaviors following concurrent stress and mTBI.

• Individuals with mild traumatic brain injury (mTBI) performed worse on both cognitive and physical assessments compared with healthy participants. • Combining complex gait tasks with cognitive demands offers insights into functional performance after mTBI. • Complex tasks showed stronger correlations between cognitive and physical performance than simple walking tasks. To investigate the relation between cognitive and motor performance in individuals with mild traumatic brain injury (mTBI) and examine differences in both cognitive and motor performance between adults after mTBI and healthy controls. Multi-center, cross-sectional study. Three institutional sites (Courage Kenny Research Center, Minneapolis, MN, Oregon Health & Science University, Portland, OR, and University of Utah, Salt Lake City, UT). Data were collected from 110 participants (N=110), including those with mTBI and healthy controls, who completed cognitive and physical performance assessments. Not applicable. Cognitive assessments involved the Automated Neuropsychological Assessment Metrics to evaluate domains of attention, memory, reaction time, processing speed, and executive function. Physical performance was evaluated through clinical performance assessments, such as the 1-min walk test, the modified Illinois Agility Test, the Functional Gait Assessment Tool, the High-Level Mobility Assessment Tool, a complex turning course, and a 4-Item Hybrid Assessment of Mobility for mTBI. Participants also completed additional trials of the 1-min walk test, modified Illinois Agility Test, and complex turning course with a simultaneous cognitive task. Individuals with mTBI performed worse on cognitive assessments, as well as several of the physical performance assessments compared with healthy controls. Complex tasks were more strongly related to cognitive assessments compared with simple walking tasks. Combining complex motor tasks with cognitive demands may better demonstrate functional performance in individuals recovering from mTBI. By understanding the relation between cognitive and physical performance in individuals recovering from mTBI, clinicians may be able to improve clinical care and assist in return to activity decision-making. [ABSTRACT FROM AUTHOR]

Sleep disturbances occur in up to 70% of patients with mild traumatic brain injury (mTBI). Modern mTBI management recommends targeted treatment for the patient's unique clinical manifestations (i.e., obstructive sleep apnea, insomnia). The purpose of this study was to evaluate the association of plasma biomarkers with symptom reports, overnight sleep evaluations, and response to treatment for sleep disturbances secondary to mTBI. This study is a secondary analysis of a prospective multiple interventional trial of patients with chronic issues related to mTBI. Pre- and post-intervention assessments were conducted, including overnight sleep apnea evaluation, the Pittsburgh Sleep Quality Index (PSQI), and blinded analysis of blood biomarkers. Bivariate Spearman correlations were conducted for pre-intervention plasma biomarker concentrations and 1) PSQI change scores and 2) pre-intervention sleep apnea outcomes (i.e., oxygen saturation measures). A backward logistic regression model was built to evaluate the association of pre-intervention plasma biomarkers with improvement in PSQI over the treatment period (p?0.05). Participants were 36.3???8.6 years old and 6.1???3.8 years from their index mTBI. Participants reported subjective improvements (PSQI?=??3.7???3.8), whereas 39.3% (n?=?11) had improved PSQI scores beyond the minimum clinically important difference (MCID). PSQI change scores correlated with von Willebrand factor (vWF; ??=??0.50; p?=?0.02) and tau (??=??0.53; p?=?0.01). Hyperphosphorylated tau correlated with average saturation (??=??0.29; p?=?0.03), lowest desaturation (??=??0.27; p?=?0.048), and baseline saturation (??=??0.31; p?=?0.02). The multi-variate model (R2?=?0.33; p?=?0.001) retained only pre-intervention vWF as a predictor (odds ratio?=?3.41; 95% confidence interval, 1.44?8.08; p?=?0.005) of improving PSQI scores beyond the MCID. vWF had good discrimination (area under the curve?=?0.83; p?=?0.01), with an overall accuracy of 77%, sensitivity of 46.2%, and specificity of 90.0%. Validation of vWF as a potential predictive biomarker of sleep improvement post-mTBI could optimize personalized management and healthcare utilization.

Abstract Background Neuroanatomical alterations have been associated with cognitive deficits in mild traumatic brain injury (MTBI). However, most studies have focused on the abnormal gray matter volume in widespread brain regions using a cross-sectional design in MTBI. This study investigated the neuroanatomical restoration of key regions in salience network and the outcomes in MTBI. Methods Thirty-six MTBI patients with posttraumatic headache (PTH) and 34 matched healthy controls were enrolled in this study. All participants underwent magnetic resonance imaging scans and were assessed with clinical measures during the acute and subacute phases. Surface-based morphometry was conducted to get cortical thickness (CT) and cortical surface area (CSA) of neuroanatomical regions which were defined by the Desikan atlas. Then mixed analysis of variance models were performed to examine CT and CSA restoration in patients from acute to subacute phase related to controls. Finally, mediation effects models were built to explore the relationships between neuroanatomical restoration and symptomatic improvement in patients. Results MTBI patients with PTH showed reduced headache impact and improved cognitive function from the acute to subacute phase. Moreover, patients experienced restoration of CT of the left caudal anterior cingulate cortex (ACC) and left insula and cortical surface area of the right superior frontal gyrus from acute to subacute phase. Further mediation analysis found that CT restoration of the ACC and insula mediated the relationship between reduced headache impact and improved cognitive function in patients. Conclusions These results showed that neuroanatomical restoration of key regions in salience network correlated reduced headache impact with cognitive function improvement in MTBI with PTH, which further substantiated the vital role of salience network and provided an alternative clinical target for cognitive improvement in MTBI patients with PTH. Graphical Abstract

Objective Background Methods Results Conclusions The objective of this study was to examine the association between white matter hyperintensities and migraine‐like headache in United States military veterans with a history of mild traumatic brain injury.White matter hyperintensities on magnetic resonance imaging (MRI) may be associated with migraine; however, little is currently known about the relationship between white matter hyperintensities and headache following mild traumatic brain injury in military veterans.This cross‐sectional study consisted of a retrospective chart review of veterans from a Southeastern Department of Veterans Affairs polytrauma clinic who had a verified history of mild traumatic brain injury. Participants were included if they had undergone an MRI of the brain. Images were reviewed for the presence and severity of periventricular and deep white matter hyperintensities. Headache and migraine‐like headache were defined based on responses from the Neurobehavioral Symptom Inventory.This cohort included 83 veterans, mostly consisting of males (78/83 [94%]) with a median (interquartile range [IQR]) age of 36 (13) years, who were a median (IQR) of 9 (8) years since their most recent mild traumatic brain injury. Most of the veterans reported experiencing migraine‐like headache (67/83 [81%]). Periventricular white matter hyperintensities were identified on MRI among 35% (29/83) of the cohort, and deep white matter hyperintensities were identified on MRI of 25% (21/83) of the cohort. There was no association between the odds of displaying white matter hyperintensities and the presence of migraine‐like headache (periventricular: unadjusted odds ratio [OR] 2.75, 95% confidence interval [CI] 0.71–10.6; deep white matter: OR 0.69, 95% CI 0.208–2.29; all p > 0.05), nor headache severity (periventricular: moderate headache OR 2.92, 95% CI 0.67–12.8; severe headache OR 3.11, 95% CI 0.77–12.6; deep white matter: moderate headache OR 1.44, 95% CI 0.358–5.8; severe headache OR 0.94, 95% CI 0.246–3.62; all p > 0.05).Our findings suggest that neither migraine‐like headache nor severity of headache is associated with increased prevalence of white matter hyperintensities in veterans with a history of mild traumatic brain injury. [ABSTRACT FROM AUTHOR]