Serum biomarkers and disease progression in CT-negative mild traumatic brain injury.

Blood proteins are emerging as potential biomarkers for mild traumatic brain injury (mTBI). Molecular pathology of mTBI underscores the critical roles of neuronal injury, neuroinflammation, and vascular health in disease progression. However, the temporal profile of blood biomarkers associated with the aforementioned molecular pathology after CT-negative mTBI, their diagnostic and prognostic potential, and their utility in monitoring white matter integrity and progressive brain atrophy remain unclear. Thus, we investigated serum biomarkers and neuroimaging in a longitudinal cohort, including 103 CT-negative mTBI patients and 66 matched healthy controls (HCs). Angiogenic biomarker vascular endothelial growth factor (VEGF) exhibited the highest area under the curve of 0.88 in identifying patients from HCs. Inflammatory biomarker interleukin-1ß and neuronal cell body injury biomarker ubiquitin carboxyl-terminal hydrolase L1 were elevated in acute-stage patients and associated with deterioration of cognitive function from acute-stage to 6-12 mo post-injury period. Notably, axonal injury biomarker neurofilament light (NfL) was elevated in acute-stage patients, with higher levels associated with impaired white matter integrity in acute-stage and progressive gray and white matter atrophy from 3- to 6-12 mo post-injury period. Collectively, our findings emphasized the potential clinical value of serum biomarkers, particularly NfL and VEGF, in diagnosing mTBI and monitoring disease progression.

Brain age prediction using interpretable multi-feature-based convolutional neural network in mild traumatic brain injury.

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.

Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

Changes in decision-making function in patients with subacute mild traumatic brain injury.

Although awareness regarding patients with mild traumatic brain injury has increased, they have not received sufficient attention in clinics; hence, many patients still experience only partial recovery. Deficits in decision-making function are frequently experienced by these patients. Accurate identification of impairment in the early stages after brain injury is particularly crucial for timely intervention and the prevention of long-term cognitive consequences. Therefore, we investigated the changes in decision-making ability under tasks of ambiguity and risk in patients with mild traumatic brain injury with a rule-based neuropsychological paradigm. In this study, patients (n = 39) and matched healthy controls (n = 38) completed general neuropsychological background tests and decision-making tasks (Iowa Gambling Task and Game of Dice Task). We found that patients had extensive cognitive impairment in general attention, memory and information processing speed in the subacute phase, and confirmed that patients had different degrees of impairment in decision-making abilities under ambiguity and risk. Furthermore, the decline of memory and executive function may be related to decision-making dysfunction.

Associations of prior concussion severity with brain microstructure using mean apparent propagator magnetic resonance imaging.

Magnetic resonance imaging (MRI) diffusion studies have shown chronic microstructural tissue abnormalities in athletes with history of concussion, but with inconsistent findings. Concussions with post-traumatic amnesia (PTA) and/or loss of consciousness (LOC) have been connected to greater physiological injury. The novel mean apparent propagator (MAP) MRI is expected to be more sensitive to such tissue injury than the conventional diffusion tensor imaging. This study examined effects of prior concussion severity on microstructure with MAP-MRI. Collegiate-aged athletes (N = 111, 38 females; ≥6 months since most recent concussion, if present) completed semistructured interviews to determine the presence of prior concussion and associated injury characteristics, including PTA and LOC. MAP-MRI metrics (mean non-Gaussian diffusion [NG Mean], return-to-origin probability [RTOP], and mean square displacement [MSD]) were calculated from multi-shell diffusion data, then evaluated for associations with concussion severity through group comparisons in a primary model (athletes with/without prior concussion) and two secondary models (athletes with/without prior concussion with PTA and/or LOC, and athletes with/without prior concussion with LOC only). Bayesian multilevel modeling estimated models in regions of interest (ROI) in white matter and subcortical gray matter, separately. In gray matter, the primary model showed decreased NG Mean and RTOP in the bilateral pallidum and decreased NG Mean in the left putamen with prior concussion. In white matter, lower NG Mean with prior concussion was present in all ROI across all models and was further decreased with LOC. However, only prior concussion with LOC was associated with decreased RTOP and increased MSD across ROI. Exploratory analyses conducted separately in male and female athletes indicate associations in the primary model may differ by sex. Results suggest microstructural measures in gray matter are associated with a general history of concussion, while a severity-dependent association of prior concussion may exist in white matter.

Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries.

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aß) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aß pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2-4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aß pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1ß, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.

Enhancing T1 signal of normal-appearing white matter with divided subtracted inversion recovery: A pilot study in mild traumatic brain injury.

Magnetic resonance imaging (MRI) and cognitive profiles in patients with mild traumatic brain injury (mTBI) are often discordant. Conventional MRI seldom captures the full extent of pathological changes in the normal-appearing white matter (NAWM). The divided subtracted inversion recovery (dSIR) technique may enhance T1 differences in NAWM, making them easily visible. We aimed to implement dSIR on a clinical scanner and tested results in mTBI patients. To produce dSIR images, Inversion Recovery-Turbo Spin Echo sequences were modified using six different inversion times (TI) on a 3-T scanner in healthy participants and patients with mTBI. The multiple TIs determined normal white (TIshort) and gray matter (TIlong) nulling points in healthy subjects, which were used to create dSIR images. In one patient, the protocol was repeated at 3 months to identify changes after rehabilitation. Diffusion tensor imaging (DTI)-derived mean diffusivity (MD) and fractional anisotropy (FA) maps were aligned to dSIR images to ensure that signal was not artefactual. Ten healthy participants (five females; age 24 ± 3 [95% CI: 21, 26] years) were included. TIshort and TIlong were set at 450 and 750 ms, respectively. In both patients (one male, age 17 years; one female, age 14 years), dSIR images revealed areas with increased T1 in the NAWM not visible on conventional MRI. dSIR-based hyperintensities corresponded to elevated MD and reduced FA. Substantial changes were found at follow-up with improvement in DTI-based parameters. dSIR images enhance subtle changes in the NAWM of patients with mTBI by amplifying their intrinsic T1 signal.

Executive functioning, behavior, and white matter microstructure in the chronic phase after pediatric mild traumatic brain injury: results from the adolescent brain cognitive development study.

BACKGROUND: Mild traumatic brain injury (mTBI) is common in children. Long-term cognitive and behavioral outcomes as well as underlying structural brain alterations following pediatric mTBI have yet to be determined. In addition, the effect of age-at-injury on long-term outcomes is largely unknown. METHODS: Children with a history of mTBI (n = 406; Mage = 10 years, SDage = 0.63 years) who participated in the Adolescent Brain Cognitive Development (ABCD) study were matched (1:2 ratio) with typically developing children (TDC; n = 812) and orthopedic injury (OI) controls (n = 812). Task-based executive functioning, parent-rated executive functioning and emotion-regulation, and self-reported impulsivity were assessed cross-sectionally. Regression models were used to examine the effect of mTBI on these domains. The effect of age-at-injury was assessed by comparing children with their first mTBI at either 0-3, 4-7, or 8-10 years to the respective matched TDC controls. Fractional anisotropy (FA) and mean diffusivity (MD), both MRI-based measures of white matter microstructure, were compared between children with mTBI and controls. RESULTS: Children with a history of mTBI displayed higher parent-rated executive dysfunction, higher impulsivity, and poorer self-regulation compared to both control groups. At closer investigation, these differences to TDC were only present in one respective age-at-injury group. No alterations were found in task-based executive functioning or white matter microstructure. CONCLUSIONS: Findings suggest that everyday executive function, impulsivity, and emotion-regulation are affected years after pediatric mTBI. Outcomes were specific to the age at which the injury occurred, suggesting that functioning is differently affected by pediatric mTBI during vulnerable periods. Groups did not differ in white matter microstructure.

Pathophysiology, blood biomarkers, and functional deficits after intimate partner violence-related brain injury: Insights from emergency department patients and a new rat model.

Intimate partner violence is a serious, but underappreciated, issue that predominantly affects women and often results in concussion (i.e., mild traumatic brain injury). However, concussion in intimate partner violence is unique because it often involves a concomitant strangulation which may exacerbate or alter the physiology and clinical presentation of the brain injury. Therefore, here we conducted human and rodent studies to provide insight into knowledge gaps related to the detection, pathophysiology, and functional consequences of intimate partner violence-related brain injury. We conducted the first study to analyze blood biomarkers and symptoms of brain injury in intimate partner violence patients presenting to an emergency department within 72 h of concussion. Intimate partner violence concussion patients, some of whom had also experienced a concomitant strangulation, had elevated serum neurofilament light and worse brain injury symptoms compared to healthy control, orthopedic trauma, and non-intimate partner violence concussion groups. We also developed the first rat model of non-fatal strangulation and examined the consequences of strangulation and concussion in isolation and in combination on pathophysiology, blood biomarkers, and behavior at 2 h and 1wk post-injury. Rats exposed to combined strangulation and concussion had exacerbated motor and cognitive deficits, neuroinflammation, and serum glial fibrillary acidic protein levels compared with either injury in isolation. Taken together, these rodent findings demonstrate that a concomitant strangulation modifies and exacerbates concussion pathophysiology, biomarkers, and functional consequences. Overall, these findings provide novel insights into intimate partner violence-related brain injury and provides a foundation for future translational studies.

Feasibility of superimposed supine cycling and lower body negative pressure as an effective means of prolonging exercise tolerance in individuals experiencing persisting post-concussive symptoms: Preliminary results.

To examine the feasibility, utility and safety of superimposed lower body negative pressure (LBNP) and tilt during supine cycling in individuals suffering from persisting post-concussive symptoms (PPCS). Eleven individuals aged 17-31 (6 females/5 males) participated in two randomized separate visits, 1 week apart. A ramp-incremental test was performed during both visits until volitional failure. Visits included no pressure (control) or LBNP at -40 Torr (experimental) with head-up tilt at 15 degrees (females) or 30 degrees (males). Transcranial Doppler ultrasound was utilized to quantify middle cerebral artery velocity (MCAv), while symptom reports were filled out before and 0, 10, and 60 min post-exertion. Ratings of exertion and overall condition followed similar trends for participants across both tests. The relative increase in MCAv was blunted during the experimental condition (8%) compared to control (24%), while a greater heart rate (17 beats/min) was achieved during the LBNP condition (P = 0.047). Symptom severity at the 0 and 10 min post-exertion time points displayed negligible-to-small effect sizes between conditions (Wilcoxon's r < 0.11). Symptom reporting was lower at the 60 min post-exertion time point with these displaying a moderate effect size (Wilcoxon's r = 0.31). The combination of LBNP and tilt during supine cycling did not change the participants' subjective interpretation of the exertional test but attenuated the hyperpnia-induced vasodilatory MCAv response, while also enabling participants to achieve a higher heart rate during exercise and reduced symptoms 1 h later. As this protocol is safe and feasible, further research is warranted in this area for developing PPCS treatment options. HIGHLIGHTS: What is the central question of this study? What are the feasibility, safety and utility of combining head-up tilt with lower body negative pressure during supine cycling for blunting the increase in cerebral blood velocity seen during moderate-intensity exercise in individuals experiencing persisting post-concussion symptoms? What is the main finding and its importance? Although no differences were found in symptoms between conditions within the first 10 min following exertion, symptom severity scores showed a clinically meaningful reduction 60 min following the experimental condition compared to the non-experimental control condition.

Acute limbic system connectivity predicts chronic cognitive function in mild traumatic brain injury: An individualized differential structural covariance network study.

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.

Role of Occupational Therapy Cognitive Assessment in Mild Traumatic Brain Injury: Is Universal Consultation Required?

INTRODUCTION: Mild traumatic brain injury (mTBI) or concussion is prevalent among trauma patients, but symptoms vary. Assessing discharge safety is not standardized. At our institution, occupational therapy (OT) performs cognitive assessments for mTBI to determine discharge readiness, potentially increasing resource utilization. We aimed to describe characteristics and outcomes in mTBI trauma patients and hypothesized that OT consultation was associated with increased length of stay (LOS). METHODS: This is a retrospective study at a level 1 trauma center over 17 mo. All patients with mTBI, without significant concomitant injuries, were included. We collected data regarding OT assessment, LOS, mechanism of injury, Glasgow coma score, injury severity score (ISS), concussion symptoms, and patient disposition. Statistical analysis was performed, and significance was determined when P < 0.05. RESULTS: Two hundred thirty three patients were included. Median LOS was 1 d and ISS 5. Ninety percent were discharged home. The most common presenting symptom was loss of consciousness (85%). No symptoms were associated with differences in LOS or discharge disposition (P > 0.05). OT consult (n = 114, 49%) was associated with longer LOS and higher ISS (P < 0.01). Representation with concussive symptoms, discharge disposition, mechanism of injury, and patient demographics were no different regardless of OT consultation (P > 0.05). CONCLUSIONS: mTBI is common and assessment for discharge safety is not standardized. OT cognitive assessment was associated with longer LOS and higher injury severity. Despite institutional culture, OT consultation was variable and not associated with improved concussion-related outcomes. Our data suggest that OT is not required for mTBI discharge readiness assessment. To improve resource utilization, more selective OT consultation should be considered. Further prospective data are needed to identify which patients would most benefit.

Traumatic brain injury and long-term associations with work, divorce and academic achievement.

OBJECTIVE: Traumatic brain injuries (TBI), irrespective of severity, may have long-term social implications. This study explores the relationships between TBI severity and outcomes related to work stability, divorce, and academic achievement. METHODS: Using a Danish nationwide sample of persons with and without TBI, we employed case-control and longitudinal cohort designs. The case-control design utilized individuals aged 18 to 60 years and examined work stability. Each case, employed at time of TBI, was compared with 10 matched controls. The cohort design utilized individuals alive from 1980 to 2016 with and without TBI and assessed the likelihood of 1) divorce and 2) higher-level education. TBI exposures included concussion, skull fractures, or confirmed TBI. RESULTS: TBI cases exhibited higher odds ratios (OR) for work instability at all follow-ups compared to controls. Increased TBI severity was associated with a higher risk of work instability at 2-year follow-up (concussion: OR = 1.83; skull fracture: OR = 2.22; confirmed TBI: OR = 4.55), and with a higher risk of not working at 10-year follow-up (confirmed TBI: OR = 2.82; concussion: OR = 1.63). The divorce incidence rate ratio (IRR) was elevated in individuals with TBI (males: IRR = 1.52; females: IRR = 1.48) compared to those without TBI. Individuals with childhood TBI had reduced chances of attaining high school degree or higher (males: IRR = 0.79; females: IRR = 0.85) compared to those without TBI. CONCLUSION: TBI is associated with an increased long-term risk of social consequences, including work instability, divorce, and diminished chances of higher education, even in cases with concussion.

The association between symptom burden and processing speed and executive functioning at 4 and 12 weeks following pediatric concussion.

OBJECTIVES: Symptoms and cognition are both utilized as indicators of recovery following pediatric concussion, yet their interrelationship is not well understood. This study aimed to investigate: 1) the association of post-concussion symptom burden and cognitive outcomes (processing speed and executive functioning [EF]) at 4 and 12 weeks after pediatric concussion, and 2) the moderating effect of sex on this association. METHODS: This prospective, multicenter cohort study included participants aged 5.00-17.99 years with acute concussion presenting to four Emergency Departments of the Pediatric Emergency Research Canada network. Five processing speed and EF tasks and the Post-Concussion Symptom Inventory (PCSI; symptom burden, defined as the difference between post-injury and retrospective [pre-injury] scores) were administered at 4 and 12 weeks post-concussion. Generalized least squares models were conducted with task performances as dependent variables and PCSI and PCSI*sex interaction as the main predictors, with important pre-injury demographic and injury characteristics as covariates. RESULTS: 311 children (65.0% males; median age = 11.92 [IQR = 9.14-14.21 years]) were included in the analysis. After adjusting for covariates, higher symptom burden was associated with lower Backward Digit Span (χ2 = 9.85, p = .043) and Verbal Fluency scores (χ2 = 10.48, p = .033) across time points; these associations were not moderated by sex, ps ≥ .20. Symptom burden was not associated with performance on the Coding, Continuous Performance Test, and Color-Word Interference scores, ps ≥ .17. CONCLUSIONS: Higher symptom burden is associated with lower working memory and cognitive flexibility following pediatric concussion, yet these associations were not moderated by sex. Findings may inform concussion management by emphasizing the importance of multifaceted assessments of EF.

Confounding factors of the expression of mTBI biomarkers, S100B, GFAP and UCH-L1 in an aging population.

OBJECTIVES: To evaluate some confounding factors that influence the concentrations of S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L-1 (UCH-L1) in older individuals. Indeed, recent guidelines have proposed the combined use of S100B and the "GFAP-UCH-L1" mTBI test to rule out mild traumatic brain injuries (mTBI). As older adults are the most at risk of mTBI, it is particularly important to understand the confounding factors of those mTBI rule-out biomarkers in aging population. METHODS: The protein S100B and the "GFAP and UCH-L1" mTBI test were measured using Liaison XL (Diasorin) and Alinity I (Abbott), respectively, in 330 and 341 individuals with non-suspected mTBI from the SarcoPhAge cohort. RESULTS: S100B, GFAP and UCH-L1 were all significantly correlated with renal function whereas alcohol consumption, Geriatric Depression Score (GDS), smoking habits and anticoagulant intake were not associated with any of these three biomarkers. Body mass index (BMI) and age were associated with GFAP and UCH-L1 expression while sex and mini-mental state examination (MMSE) were only associated with GFAP. According to the manufacturer's cut-offs for mTBI rule-out, only 5.5 % of participants were positive for S100B whereas 66.9 % were positive for the "GFAP-UCH-L1" mTBI test. All positive "GFAP-UCH-L1" mTBI tests were GFAP+/UCH-L1-. Among individuals with cystatin C>1.55 mg/L, 25 % were positive for S100B while 90 % were positive for the mTBI test. CONCLUSIONS: Our data show that confounding factors have different impacts on the positivity rate of the "GFAP-UCH-L1" mTBI test compared to S100B.

Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury.

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

The effect of a minor health shock on labor market outcomes: The case of concussions.

The literature on health shocks finds that minor injuries have only short-term labor market impacts. However, mild traumatic brain injuries (mTBIs, commonly referred to as concussions) may be different as the medical literature highlights that they can have longer-term health and cognitive effects. Moreover, TBIs are one of the most common causes of disability globally, with the vast majority being mild. Thus, it is important to understand the impact of mTBIs on labor market outcomes. We use administrative data on all medically-diagnosed mild traumatic brain injuries (mTBIs) in New Zealand linked to monthly tax records to examine the labor market effects of a mTBI. We use a comparison group of those who suffer a mTBI at a later date to overcome potential endogeneity issues, and employ a doubly-robust difference-in-differences method. We find that suffering a mTBI has negative labor market effects. Rather than dissipating over time, these negative effects grow, representing a decrease in employment of 20 percentage points and earning losses of about a third after 48 months. Our results highlight the need for timely diagnosis and treatment to mitigate the effect of mTBIs to reduce economic and social costs.

Brain dynamics in triple-network interactions and its relation to multiple cognitive impairments in mild traumatic brain injury.

Traumatic brain injury (TBI) disrupt the coordinated activity of triple-network and produce impairments across several cognitive domains. The triple-network model posits a key role of the salience network (SN) that regulates interactions with the central executive network (CEN) and default mode network (DMN). However, the aberrant dynamic interactions among triple-network and associations with neurobehavioral symptoms in mild TBI was still unclear. In present study, we used brain network interaction index (NII) and dynamic functional connectivity to examine the time-varying cross-network interactions among the triple-network in 109 acute patients, 41 chronic patients, and 65 healthy controls. Dynamic cross-network interactions were significantly increased and more variable in mild TBI compared to controls. Crucially, mild TBI exhibited an increased NII as enhanced integrations between the SN and CEN while reduced coupling of the SN with DMN. The increased NII also implied much severer and multiple domains of cognitive impairments at both acute and chronic mild TBI. Abnormities in time-varying engagement of triple-network is a clinically relevant neurobiological signature of psychopathology in mild TBI. The findings provided align with and advance an emerging perspective on the importance of aberrant brain dynamics associated with highly disparate cognitive and behavioral outcomes in trauma.

Monitoring the acute and subacute recovery of cognitive ocular motor changes after a sports-related concussion.

Identifying when recovery from a sports-related concussion (SRC) has occurred remains a challenge in clinical practice. This study investigated the utility of ocular motor (OM) assessment to monitor recovery post-SRC between sexes and compared to common clinical measures. From 139 preseason baseline assessments (i.e. before they sustained an SRC), 18 (12 males, 6 females) consequent SRCs were sustained and the longitudinal follow-ups were collected at 2, 6, and 13 days post-SRC. Participants completed visually guided, antisaccade (AS), and memory-guided saccade tasks requiring a saccade toward, away from, and to a remembered target, respectively. Changes in latency (processing speed), visual-spatial accuracy, and errors were measured. Clinical measures included The Sports Concussion Assessment Tool, King-Devick test, Stroop task, and Digit span. AS latency was significantly longer at 2 days and returned to baseline by 13-days post-SRC in females only (P < 0.001). Symptom numbers recovered from 2 to 6 days and 13 days (P < 0.05). Persistently poorer AS visual-spatial accuracy was identified at 2, 6 and 13 days post-SRC (P < 0.05) in both males and females but with differing trajectories. Clinical measures demonstrated consistent improvement reminiscent of practice effects. OM saccade assessment may have improved utility in tracking recovery compared to conventional measures and between sexes.

Hierarchical brain structural-functional coupling associated with cognitive impairments in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) disrupts the integrity of white matter microstructure, which affects brain functional connectivity supporting cognitive function. Although the relationship between structural and functional connectivity (SC and FC), here called SC-FC coupling, has been studied on global level in brain disorders, the long-term disruption of SC-FC coupling in mTBI at regional scale was still unclear. The current study investigated the alteration pattern of regional SC-FC coupling in 104 acute mTBI patients (41 with 6-12 months of follow-up) and 56 healthy controls (HCs). SC and FC networks were constructed to measure regional, intra-network, and inter-network SC-FC coupling. Compared with HCs, acute mTBI exhibited altered SC-FC coupling of the sensorimotor network (SMN). The coupling laterality indicators of the SMN can identify mTBI from controls. The persistent SC-FC decoupling of the SMN and the additional decoupling of the default mode network (DMN) were observed in chronic mTBI. Crucially, decoupling of the SMN and DMN predicted better cognitive outcomes. The findings revealed the SC-FC coupling alternations exhibited hierarchical trend originating from the sensorimotor cortex to high-order cognitive regions with the progression of mTBI. The regional and hierarchical SC-FC coupling may be a prognostic biomarker to provide insights into the pathophysiology mechanism of mTBI.