mTBI Subjects Research Articles

Comparative Performance of Three Eye-Tracking Devices in Detection of Mild Traumatic Brain Injury in Acute Versus Chronic Subject Populations.

Presently, traumatic brain injury (TBI) triage in field settings relies on symptom-based screening tools such as the updated Military Acute Concussion Evaluation. Objective eye-tracking may provide an alternative means of neurotrauma screening due to sensitivity to neurotrauma brain-health changes. Previously, the US Army Medical Research and Development Command Non-Invasive NeuroAssessment Devices (NINAD) Integrated Product Team identified 3 commercially available eye-tracking devices (SyncThink EYE-SYNC, Oculogica EyeBOX, NeuroKinetics IPAS) as meeting criteria toward being operationally effective in the detection of TBI in service members. We compared these devices to assess their relative performance in the classification of mild traumatic brain injury (mTBI) subjects versus normal healthy controls. Participants 18 to 45 years of age were assigned to Acute mTBI, Chronic mTBI, or Control group per study criteria. Each completed a TBI assessment protocol with all 3 devices counterbalanced across participants. Acute mTBI participants were tested within 72 hours following injury whereas time since last injury for the Chronic mTBI group ranged from months to years. Discriminant analysis was undertaken to determine device classification performance in separating TBI subjects from controls. Area Under the Curves (AUCs) were calculated and used to compare the accuracy of device performance. Device-related factors including data quality, the need to repeat tests, and technical issues experienced were aggregated for reporting. A total of 63 participants were recruited as Acute mTBI subjects, 34 as Chronic mTBI subjects, and 119 participants without history of TBI as controls. To maximize outcomes, poorer quality data were excluded from analysis using specific criteria where possible. Final analysis utilized 49 (43 male/6 female, mean [x̅] age = 24.3 years, SD [s] = 5.1) Acute mTBI subjects, and 34 (33 male/1 female, x̅ age = 38.8 years, s = 3.9) Chronic mTBI subjects were age- and gender-matched as closely as possible with Control subjects. AUCs obtained with 80% of total dataset ranged from 0.690 to 0.950 for the Acute Group and from 0.753 to 0.811 for the Chronic mTBI group. Validation with the remaining 20% of dataset produced AUCs ranging from 0.600 to 0.750 for Acute mTBI group and 0.490 to 0.571 for the Chronic mTBI group. Potential eye-tracking detection of mTBI, per training model outcomes, ranged from acceptable to excellent for the Acute mTBI group; however, it was less consistent for the Chronic mTBI group. The self-imposed targeted performance (AUC of 0.850) appears achievable, but further device improvements and research are necessary. Discriminant analysis models differed for the Acute versus Chronic mTBI groups, suggesting performance differences in eye-tracking. Although eye-tracking demonstrated sensitivity in the Chronic group, a more rigorous and/or longitudinal study design is required to evaluate this observation. mTBI injuries were not controlled for this study, potentially reducing eye-tracking assessment sensitivity. Overall, these findings indicate that while eye-tracking remains a viable means of mTBI screening, device-specific variability in data quality, length of testing, and ease of use must be addressed to achieve NINAD objectives and DoD implementation.

Lysophospholipids Are Associated With Outcomes in Hospitalized Patients With Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) accounts for 70-90% of all TBI cases. Lipid metabolites have important roles in plasma membrane biogenesis, function, and cell signaling. As TBI can compromise plasma membrane integrity and alter brain cell function, we sought to identify circulating phospholipid alterations after mTBI, and determine if these changes were associated with clinical outcomes. Patients with mTBI (Glasgow Coma Score [GCS] ≥13 and loss of consciousness <30 min) were recruited. A total of 84 mTBI subjects were enrolled after admission to a level I trauma center, with the majority having evidence of traumatic intracranial hemorrhage on brain computed tomography (CT). Plasma samples were collected within 24 h of injury with 32 mTBI subjects returning at 3 months after injury for a second plasma sample to be collected. Thirty-five healthy volunteers were enrolled as controls and had a one-time blood draw. Lipid metabolomics was performed on plasma samples from each subject. Fold change of selected lipid metabolites was determined. Multivariable regression models were created to test associations between lipid metabolites and discharge and 6-month Glasgow Outcomes Scale-Extended (GOSE) outcomes (dichotomized between "good" [GOSE ≥7] and "bad" [GOSE ≤6] functional outcomes). Plasma levels of 31 lipid metabolites were significantly associated with discharge GOSE using univariate models; three of these metabolites were significantly increased, while 14 were significantly decreased in subjects with good outcomes compared with subjects with poor outcomes. In multivariable logistic regression models, higher circulating levels of the lysophospholipids (LPL) 1-linoleoyl-glycerophosphocholine (GPC) (18:2), 1-linoleoyl-GPE (18:2), and 1-linolenoyl-GPC (18:3) were associated with both good discharge GOSE (odds ratio [OR] 12.2 [95% CI 3.35, 58.3], p = 5.23 × 10-4; OR 9.43 [95% CI 2.87, 39.6], p = 7.26 × 10-4; and OR 5.26 [95% CI 1.99, 16.7], p = 2.04 × 10-3, respectively) and 6-month (OR 4.67 [95% CI 1.49, 17.7], p = 0.013; OR 2.93 [95% CI 1.11, 8.87], p = 0.039; and OR 2.57 [95% CI 1.08, 7.11], p = 0.046, respectively). Compared with healthy volunteers, circulating levels of these three LPLs were decreased early after injury and had normalized by 3 months after injury. Logistic regression models to predict functional outcomes were created by adding each of the described three LPLs to a baseline model that included age and sex. Including 1-linoleoyl-GPC (18:2) (8.20% improvement, p = 0.009), 1-linoleoyl-GPE (18:2) (8.85% improvement, p = 0.021), or 1-linolenoyl-GPC (18:3) (7.68% improvement, p = 0.012), significantly improved the area under the curve (AUC) for predicting discharge outcomes compared with the baseline model. Models including 1-linoleoyl-GPC (18:2) significantly improved AUC for predicting 6-month outcomes (9.35% improvement, p = 0.034). Models including principal components derived from 25 LPLs significantly improved AUC for prediction of 6-month outcomes (16.0% improvement, p = 0.020). Our results demonstrate that higher plasma levels of LPLs (1-linoleoyl-GPC, 1-linoleoyl-GPE, and 1-linolenoyl-GPC) after mTBI are associated with better functional outcomes at discharge and 6 months after injury. This class of phospholipids may represent a potential therapeutic target.

Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. Prospective. Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). 3-T, single-shot echo-planar imaging sequence. Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (β = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (β = 5.67, 95% CI 4.56, 6.97), executive function (β = 2.34, 95% CI 1.49, 3.20), and PSMD (β = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. 2 TECHNICAL EFFICACY: Stage 2.

Non-invasive fluid biomarkers in the diagnosis of mild traumatic brain injury (mTBI): a systematic review

BackgroundDespite approximately 55.9 million annual mild traumatic brain injuries (mTBIs) worldwide, the accurate diagnosis of mTBI continues to challenge clinicians due to symptom ambiguity, reliance on subjective report and presentation...

Synthesis of Behavioral Health Outcomes in Mild Traumatic Brain Injury using Principal Component Analysis (PCA) (P8-1.008)

<h3>Objective:</h3> To identify principal components of a battery of cognitive assessments that best capture the clinical state of mTBI patients across multiple time points and can be used to inform selection of outcome measures in future mTBI research studies. <h3>Background:</h3> A current difficulty in the design of mTBI clinical trials is the wide overlap in cognitive domains assessed, use of various assessments to evaluate a single domain, and the large variation in assessments. There is a need for statistically driven data reduction strategies to identify the domains that most accurately capture the clinical state of mTBI patients. <h3>Design/Methods:</h3> 325 patients and 152 controls were enrolled after mTBI. Patients were enrolled at either Encounter 1 (&lt;72 hours post-injury) or Encounter 2 (5–10 days), and returned for Encounter 3 (12–16 days) and Encounter 4 (83–97 days). At each encounter, subjects underwent a neuropsychological assessment battery (RPQ, BSI, TMT, HVLT, WAIS/WISC). A covariance matrix was calculated from clinical assessments. PCA was used as a data reduction strategy to elucidate the core dimensions of the mTBI sequelae. <h3>Results:</h3> In mTBI patients, there was a high degree of covariance among symptoms inventories. Among neurocognitive assessments, TMT correlated significantly with WAIS/WISC and to a lesser degree total recall from HVLT. In the PCA, the primary component correlated mostly with TMT-B (0.6), delayed recall and retention (0.5 each), and BSI (0.4), and explained 89.7% of the variance in the data across visits. The remaining components explained 10.3% of the variance. <h3>Conclusions:</h3> In our population of mTBI patients, 89.7% of the variance was explained by a primary component which remained consistent across all encounters. Clinical and neurocognitive metrics showed a significant degree of correlation suggesting that neurocognitive batteries could be simplified. The results of the study are useful for future clinical trial design of similarly stratified mTBI subjects. <b>Disclosure:</b> Dr. Shetty has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven Pharmaeucticals. Dr. Shetty has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for mTBI, Inc. The institution of Dr. Shetty has received research support from Marker AG. The institution of Dr. Shetty has received research support from Teva Pharmaceuticals Industry. The institution of Dr. Shetty has received research support from GE-NFL. Mr. Westafer has nothing to disclose. Joseph T Nguyen has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for The American Journal of Sports Medicine. Joseph T Nguyen has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for The Women’s Journal of Sports Medicine. Miss Coffey has nothing to disclose.

Central sensorimotor integration assessment reveals deficits in standing balance control in people with chronic mild traumatic brain injury.

Imbalance is common following mild Traumatic Brain Injury (mTBI) and can persist months after the initial injury. To determine if mTBI subjects with chronic imbalance differed from healthy age- and sex-matched controls (HCs) we used both the Central SensoriMotor Integration (CSMI) test, which evaluates sensory integration, time delay, and motor activation properties and the standard Sensory Organization Test (SOT). Four CSMI conditions evoked center-of-mass sway in response to: surface tilts with eyes closed (SS/EC), surface tilts with eyes open viewing a fixed visual surround (SS/EO), visual surround tilts with eyes open standing on a fixed surface (VS/EO), and combined surface and visual tilts with eyes open (SS+VS/EO). The mTBI participants relied significantly more on visual cues during the VS/EO condition compared to HCs but had similar reliance on combinations of vestibular, visual, and proprioceptive cues for balance during SS/EC, SS/EO, and SS+VS/EO conditions. The mTBI participants had significantly longer time delays across all conditions and significantly decreased motor activation relative to HCs across conditions that included surface-tilt stimuli with a sizeable subgroup having a prominent increase in time delay coupled with reduced motor activation while demonstrating no vestibular sensory weighting deficits. Decreased motor activation compensates for increased time delay to maintain stability of the balance system but has the adverse consequence that sensitivity to both internal (e.g., sensory noise) and external disturbances is increased. Consistent with this increased sensitivity, SOT results for mTBI subjects showed increased sway across all SOT conditions relative to HCs with about 45% of mTBI subjects classified as having an "Aphysiologic" pattern based on published criteria. Thus, CSMI results provided a plausible physiological explanation for the aphysiologic SOT pattern. Overall results suggest that rehabilitation that focuses solely on sensory systems may be incomplete and may benefit from therapy aimed at enhancing rapid and vigorous responses to balance perturbations.

Long-term postural control in elite athletes following mild traumatic brain injury.

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

Closed Head Traumatic Brain Injury Drives Protracted Inflammation and Remodeling of Serotonergic Architecture in the Dorsal Raphe Nucleus

Traumatic Brain Injury (TBI) presents a monumental public health burden that affects over 3 million Americans annually, with mild TBI (mTBI)/concussion being the most common form of closed head injury. Chronic neuropsychiatric sequalae are common following TBI, with many individuals spontaneously developing persistent depression, anxiety, social withdrawal and/or PTSD, disorders that have been previously linked to alterations in serotonin (5‐HT) signaling. Currently, the effects of various forms of TBI on the function of the 5‐HT signaling system within the CNS are poorly understood and selective serotonin reuptake inhibitors (SSRIs) fail to mitigate the clinical neuropsychiatric sequalae elicited by TBI. The lack of any FDA‐approved therapies for the treatment of acute or chronic symptoms of TBI necessitates a greater understanding of how TBI alters the environmental milieu of the CNS, including normal, physiologic 5‐HT signaling. We hypothesize that TBI drives the formation of aberrant behavioral states linked to neuropsychiatric disorders through alterations of normal, physiologic 5‐HT signaling stemming from 5‐HT neurons located within the dorsal raphe nucleus (DRN). To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to a single, blast induced mTBI or sham treatment, followed by behavioral and/or molecular analyses 0‐10 days post‐injury (dpi). mTBI subjects exhibited significantly increased righting reflex times (RRT) compared to their sham counterparts immediately post‐injury. Ten dpi, mTBI subjects exhibited significant reductions in sociability and social dominance as compared to their sham counterparts in the Crawley three chamber sociability assay and tube test, respectively. High performance liquid chromatography (HPLC) revealed a time‐dependent increase in total levels of 5‐HT and its metabolite, 5HIAA within the DRN 10 dpi. No effect of mTBI on 5‐HT or 5HIAA levels were found in prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. Ten dpi, DRN punches were subjected to RNA‐sequencing to delineate differential gene‐expression profiles elicited by mTBI. Genes indicative of cellular remodeling, cell‐to‐cell adhesion, monoaminergic processing, and proliferation were identified. Crucially, genes involved in ongoing inflammation including those relevant to peripheral immune recruitment and blood brain barrier permeation were found to be differentially expressed. Quantitative real‐time PCR was subsequently used to confirm differential expression of genes of interest, notably Vegfc, Slc18a1, and Icam1. These studies provide critical insight into ongoing molecular processes following closed head injury that may impact normal, physiologic 5‐HT signaling within the DRN. Further, these studies may provide critical insight into regulation of 5‐HT neuron function within the DRN and yield novel drug candidates for ameliorating the neuropsychiatric complications elicited by TBI.

Association between Altered Cortisol Profiles and Neurobehavioral Impairment after Mild Traumatic Brain Injury in College Students.

Mild traumatic brain injury (mTBI) is the most common form of TBI, with more than 2.5 million TBI cases in the United States annually. Identification of easily obtainable biomarkers that track strongly with mTBI symptoms may improve our understanding of biological factors that contribute to mTBI symptom profiles and long-term outcomes. Notably, some individuals with mTBI exhibit circadian disruptions and elevated stress sensitivity, which in other clinical groups often correlate with disrupted secretion of cortisol, a glucocorticoid hormone that coordinates circadian and stress physiology. Here, we examined whether cortisol profiles could serve as a biomarker to complement the assessment of neurobehavioral sequelae after mTBI. We partnered with our on-campus health clinic to recruit college students seeking medical care after mTBI (n = 46) and compared this population to a well-matched non-injured student control group (n = 44). We collected data at an initial visit (shortly after injury in mTBI subjects) and one week later. At each visit, we evaluated neurobehavioral function using the Automated Neuropsychological Assessment Metric (ANAM). The subjects also provided cortisol samples through at-home saliva collection. We observed strong coherence between ANAM subjective and objective measures, indicating significant multi-dimensional impairment in subjects with mTBI. Further, female mTBI subjects exhibited diminished neurobehavioral function compared with males. Regardless of sex, decreased amplitude of diurnal cortisol and a blunted cortisol awakening response were associated with mTBI symptom severity and neurobehavioral impairment. Taken together, these findings suggest that salivary cortisol profiles may be a sensitive biomarker for studying underlying biological factors that impact mTBI symptoms and outcomes.

Micro-RNA levels and symptom profile after mild traumatic brain injury: A longitudinal cohort study

Micro riboneucleic acids (miRNAs) may be transcribed after brain injury and be detectable in plasma. This study aimed to assess the discriminative ability of seven miRNAs in plasma to differentiate between patients with mild traumatic brain injury (mTBI) and healthy controls. Changes in miRNA levels over 28 days were compared to changes in self-reported symptom profile. This was a prospective cohort study with longitudinal measurements of miRNA levels and symptom self-report. The Rivermead Post-Concussion Symptom Questionnaire (RPQ) was used to determine symptom severity. Mean normalised expression ratios (NER) of miRNAs at day 0 between mTBI and healthy controls were compared. An analysis of response profiles compared the response over time of miRNA species with RPQ symptom severity. miRNA levels of subjects who were defined to have “recovered” on Day 7 and 28 were compared to “non-recovered” subjects. There were 28 mTBI patients and 30 healthy controls included for analysis. Symptom severity was significantly higher on the day of injury among mTBI subjects (p < 0.001), and miRNA 32-5p levels were also higher (p = 0.009). Change of miRNA levels were similar to RPQ change at Day 7, but significantly different at Day 28. Differences were observed among miRNA levels of recovered subjects. This study demonstrated differences in miRNA levels among mTBI subjects compared to healthy controls and different miRNA levels among those who had recovered compared to those reporting symptoms. The change in profiles of miRNAs was different to symptom severity, suggesting that the two measures reflect different aspects of brain injury and recovery.

Spatial patterns of cortical demyelination in geriatric cases of traumatic brain injury and in Alzheimer's disease.

Traumatic brain injury (TBI) causes demyelination and cortical neurodegeneration patterns similar to those of Alzheimer's disease (AD, Irimia et al. 2020). The ratio of T1 - to T2 -weighted magnetic resonance imaging (MRI) intensities is a measure of myelin content (Glasser & Van Essen, 2011). By mapping changes in this ratio, we report on the spatial and extent of demyelination after mild TBI (mTBI) relative to typical aging and AD. At two time points ∼6 months apart, T1 - and T2 -weighted MRIs were acquired from age- and sex-matched healthy control (HC) participants (N = 68; age (years): μ = 76.162, σ = 4.145), mTBI volunteers (N = 19; age: μ = 69.579. σ = 5.143), and AD patients (N = 33; age: μ = 77.420, σ = 5.545). After MRI coregistration, segmentation and bias field correction, the ratio R = T1 /T2 and its time change ΔR were computed at each cortical location. The null hypotheses that the means of ΔR were equal in (a) HCs vs. mTBI, (b) HCs and AD, and (c) mTBI vs. AD were tested (α = 0.05). Age effects were accounted for in statistical analyses. In the mTBI and AD groups, ∼10% and ∼23% of the cortex, respectively, exhibited significant decreases in R compared to HCs (p < 0.05); ∼7% of the cortex exhibited significantly larger myelin decreases in mTBI than in AD. mTBI subjects were found to have significantly less myelin than HCs in anterior limbic areas, the longitudinal frontal gyrus, left supplementary motor areas, and ventrolateral temporal regions. Compared to HCs, AD patients exhibited more demyelination across all lobes. mTBI subjects exhibited more demyelination than AD patients in temporal, supplementary motor, superior frontal, and orbitofrontal areas. Compared to mTBI, AD patients had significantly less myelin in parietal regions. Whereas demyelination occurs in both AD and geriatric mTBI, mTBI effect sizes are comparable to, or even greater than, those observed in AD. Future research should attempt to understand the long-term demyelination trajectories of mTBI relative to AD and leverage this information to forecast AD risk after geriatric TBI.

Comparing the impacts of Alzheimer's disease and geriatric traumatic brain injury on cortical networks.

Alzheimer's disease (AD) causes widespread degeneration and reorganization of white matter connectivity (Ye et al, 2019). Similarly, mild traumatic brain injury (mTBI) results in axonal damage and changes in the connectome (Irimia et al, 2020). Understanding the extent to which the two conditions proceed along similar trajectories can further the use of connectomics as a forecasting tool to identify mTBI victims at high risk for AD. Diffusion weighted images (DWIs) and T1 -weighted magnetic resonance images (MRIs) were acquired from healthy controls (HCs, N = 80, age μ = 76.162; σ = 4.145), AD patients (N = 65, age μ = 77.42; σ = 5.55), and geriatric mTBI patients (N = 32, age μ = 69.58; σ = 5.143). Diffusion tensor imaging (DTI) streamlines were reconstructed in TrackVis; automatic cortical segmentation was performed using FreeSurfer. In each hemisphere, 74 cortical parcels and 7 subcortical structures were identified using the nomenclature of Destrieux et al. (2010). Including the brainstem, this results in 165 brain parcels (Irimia et al. Neuroimage 2012). For all reported results, statistical significance was assessed at p < 0.05 and changes were represented using connectograms (Irimia et al, 2012). In both HCs and mTBI, the mean fractional anisotropy (FA) and connectivity counts of prominent links between the frontal lobe and both the cerebellum and brainstem are significantly higher than in AD patients. Compared to HCs, AD patients have significantly weaker connectivity between frontal and contralateral parietal lobes, and between temporal lobes and insulae. For interhemispheric connections, compared to AD, mTBI subjects exhibit significantly fewer/weaker cortical links but significantly more/stronger subcortical links. AD patients show weaker connectivity than mTBI patients between the subcortex and both temporal and parietal areas. Connections between frontal and occipital areas are significantly weaker in TBI than in AD. Whereas DWI enables measurement of FA, automatic MRI segmentation can complement the examination of connectivity changes between various (sub)cortical regions. By examining how AD and TBI connectomes compare to each other and to HCs, connectome analysis can identify risk indicators for AD in mTBI patients which may not be apparent from volumetric measures.

Investigation of Machine Learning and Deep Learning Approaches for Detection of Mild Traumatic Brain Injury from Human Sleep Electroencephalogram.

Traumatic Brain Injury (TBI) is a highly prevalent and serious public health concern. Most cases of TBI are mild in nature, yet some individuals may develop following-up persistent disability. The pathophysiologic causes for those with persistent postconcussive symptoms are most likely multifactorial and the underlying mechanism is not well understood, although it is clear that sleep disturbances feature prominently in those with persistent disability. The sleep electroencephalogram (EEG) provides a direct window into neuronal activity during an otherwise highly stereotyped behavioral state, and represents a promising quantitative measure for TBI diagnosis and prognosis. With the ever-evolving domain of machine learning, deep convolutional neural networks, and the development of better architectures, these approaches hold promise to solve some of the long entrenched challenges of personalized medicine for uses in recommendation systems and/or in health monitoring systems. In particular, advanced EEG analysis to identify putative EEG biomarkers of neurological disease could be highly relevant in the prognostication of mild TBI, an otherwise heterogeneous disorder with a wide range of affected phenotypes and disability levels. In this work, we investigate the use of various machine learning techniques and deep neural network architectures on a cohort of human subjects with sleep EEG recordings from overnight, in-lab, diagnostic polysomnography (PSG). An optimal scheme is explored for the classification of TBI versus non-TBI control subjects. The results were promising with an accuracy of ∼95% in random sampling arrangement and ∼70% in independent validation arrangement when appropriate parameters were used using a small number of subjects (10 mTBI subjects and 9 age- and sex-matched controls). We are thus confident that, with additional data and further studies, we would be able to build a generalized model to detect TBI accurately, not only via attended, in-lab PSG recordings, but also in practical scenarios such as EEG data obtained from simple wearables in daily life.

Altered Metabolic Interrelationships in the Cortico-Limbic Circuitry in Military Service Members with Persistent Post-Traumatic Stress Disorder Symptoms Following Mild Traumatic Brain Injury.

Introduction: Comorbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common in military service members. The aim of this study is to investigate brain metabolic interrelationships in service members with and without persistent PTSD symptoms after mTBI by using 18F-fluorodeoxyglucose (FDG) positron emission tomography. Methods: Service members (n = 408) diagnosed with mTBI were studied retrospectively. Principal component analysis was applied to identify latent metabolic systems, and the associations between metabolic latent systems and self-report measures of post-concussive and PTSD symptoms were evaluated. Participants were divided into two groups based on DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision) criteria for PTSD, and structural equation modeling was performed to test a priori hypotheses on metabolic interrelationships among the brain regions in the cortico-limbic circuitry responsible for top-down control and bottom-up emotional processing. The differences in metabolic interrelationships between age-matched PTSD-absent (n = 204) and PTSD-present (n = 204) groups were evaluated. Results: FDG uptake in the temporo-limbic system was positively correlated with post-concussive and hyperarousal symptoms. For the bottom-up emotional processing, the insula and amygdala-hippocampal complex in the PTSD-present group had stronger metabolic interrelationships with the bilateral rostral anterior cingulate, left lingual, right lateral occipital, and left superior temporal cortices, but a weaker relationship with the right precuneus cortex, compared with the PTSD-absent group. For the top-down control, the PTSD-present group had decreased metabolic engagements of the dorsolateral prefrontal cortex on the amygdala. Discussion: Our results suggest altered metabolic interrelationships in the cortico-limbic circuitry in mTBI subjects with persistent PTSD symptoms, which may underlie the pathophysiological mechanisms of comorbid mTBI and PTSD. Impact statement This is the first 18F-fluorodeoxyglucose positron emission tomography study to investigate brain metabolic interrelationships in service members with persistent post-traumatic stress disorder (PTSD) symptoms after mild traumatic brain injury (mTBI). We identified that the temporo-limbic metabolic system was associated with post-concussive and hyperarousal symptoms. Further, brain metabolic interrelationships in the cortico-limbic circuitry were altered in mTBI subjects with significant PTSD symptoms compared with those without them.

The detection of mild traumatic brain injury in paediatrics using artificial neural networks

Head computed tomography (CT) is the gold standard in emergency departments (EDs) to evaluate mild traumatic brain injury (mTBI) patients, especially for paediatrics. Data-driven models for successfully classifying head CT scans that have mTBI will be valuable in terms of timeliness and cost-effectiveness for TBI diagnosis. This study applied two different machine learning (ML) models to diagnose mTBI in a paediatric population collected as part of the paediatric emergency care applied research network (PECARN) study between 2004 and 2006. The models were conducted using 15,271 patients under the age of 18 years with mTBI and had a head CT report. In the conventional model, random forest (RF) ranked the features to reduce data dimensionality and the top ranked features were used to train a shallow artificial neural network (ANN) model. In the second model, a deep ANN applied to classify positive and negative mTBI patients using the entirety of the features available. The dataset was divided into two subsets: 80% for training and 20% for testing using five-fold cross-validation. Accuracy, sensitivity, precision, and specificity were calculated by comparing the model's prediction outcome to the actual diagnosis for each patient. RF ranked ten clinical demographic features and twelve CT-findings; the hybrid RF-ANN model achieved an average specificity of 99.96%, sensitivity of 95.98%, precision of 99.25%, and accuracy of 99.74% in identifying positive mTBI from negative mTBI subjects. The deep ANN proved its ability to carry out the task efficiently with an average specificity of 99.9%, sensitivity of 99.2%, precision of 99.9%, and accuracy of 99.9%. The performance of the two proposed models demonstrated the feasibility of using ANN to diagnose mTBI in a paediatric population. This is the first study to investigate deep ANN in a paediatric cohort with mTBI using clinical and non-imaging data and diagnose mTBI with balanced sensitivity and specificity using shallow and deep ML models. This method, if validated, would have the potential to reduce the burden of TBI evaluation in EDs and aide clinicians in the decision-making process.

Introduction of a New Test for Standardizing and Quantifying Monocular Fixation: The Aalen-Pacific Fixation Accuracy &amp; Stability Test (AP-FAST)

Background: This is a two-part paper, in which fixational eye movements are reviewed in part one, and a new clinical test of fixational eye movement accuracy and stability is introduced in part two. Part two also contains a partial validation study and normative results for this new test. The study was designed to explore the following questions: 1. Is there a significant difference in clinically measurable fixation stability and accuracy between symptomatic individuals who have sustained mTBI versus visually normal individuals who have not sustained TBI? 2a. Could the Macular Integrity Tester (MIT) be useful as a diagnostic instrument for differentiating fixation stability and accuracy with mTBI patients versus those without TBI? 2b. If so, could introduction of a standardized test protocol (AP-FAST) allow for more reliable and descriptive quantification of monocular fixation behavior? Methods: To answer the first question posed in our study, data were compared between non-mTBIs and mTBI patients using two different fixation testing methods. One of the methods employed the eyetracker EyeLink II comparing optometry students to mTBI patients. Fixation accuracy and stability were measured with a custom fixation pattern program. Fixation results were compared for both groups. To answer question 2a, we compared fixation behavior for both groups using the MIT diagnostically by having each subject rate accuracy and stability of his/her own fixation posture. To address question 2b, a 15-point rating system protocol was created to help describe and quantify monocular fixation behavior via Haidinger’s brush perception. Two groups of test subjects: mTBI patients versus visually normal subjects were compared using the AP-FAST grid and fixation behavior survey. Results: Regarding question one, there was a significant and clinically relevant difference in monocular fixation stability and accuracy between the visual normal subject group and mTBI patient group, with normals demonstrating better accuracy and stability. Regarding questions 2a and 2b, the mTBI patient group had poorer mean ability (statistically significant) to perceive, localize, and center the Haidinger’s brush than those in the non-TBI group. Based on our results, we propose that the newly developed AP-FAST is useful for helping describe, standardize and quantify how the Haidinger’s brush entoptic phenomenon is perceived monocularly by both mTBI and nonmTBI subjects.

Oculomotor, vestibular, reaction time and cognitive eye-tracking mild traumatic brain injury assessment

Can oculomotor, vestibular, reaction time and cognitive eye-tracking tests (OVRT-C) assess mild traumatic brain injury? OVRT-C tests using eye tracking technology have been employed in our previous studies for assessing mild traumatic brain injury (mTBI). Here we present a composite Concussion Assessment algorithm that incorporates these findings. Concussion Assessment algorithm was based on a data analysis from 406 males and females 18-45 years old. The subjects included 106 patients diagnosed with mTBI and 300 healthy controls. Diagnosis of mTBI was made using accepted medical practice. The participants were tested with a battery of OVRT-C tests delivered on the I-Portal Neuro Otologic Test Center (Dx NOTC) device (Neurolign Technology). A logistic regression model was used to derive the algorithm using a random sample of 70% of the data-set and validated on the remaining 30% of the data-set. Device test-retest reliability and inter-rater variability were assessed in a separate study in healthy control volunteers, ages 19-43 (n = 30). Subjects were tested with OVRT-C tests using the Dx100 which is equivalent to the NOTC. Test-retest reliability was assessed using Intraclass Correlation Coefficient (ICC) and Cronbach's alpha; testers and devices influence were assessed using a random effect regression model. Test-retest reliability of OVRT-C tests using eye tracking technology was acceptable (ICC >0.6 for all variables). The Concussion assessment algorithm was based on six OVRT-C tests. In the validation data Concussion Assessment algorithm was able to separate concussed versus controls with a sensitivity of 78.6% and specificity of 72.3%. OVRT-C tests delivered on I-Portal devices are repeatable and reliable. The assessment can identify mTBI subjects within an acute time post-injury with high sensitivity and specificity. The results support the use of this eye tracking device as well as the assessment to aid in the diagnosis of mTBI for patients 18-45 year old.

S0514 Growth Hormone Normalizes Gastrointestinal Symptoms in mTBI Patients

INTRODUCTION: Chronic inflammatory processes secondary to brain trauma have been hypothesized to significantly alter gastrointestinal metabolism, motility, and microbiome composition in patients with mild traumatic brain injuries (mTBI). This may be exacerbated by pituitary dysfunction and decreased growth hormone (GH) secretion resulting from injury. In this clinical trial, we analyzed the effects of GH treatment on gastrointestinal symptoms experienced by patients with concurrent mTBI and abnormal GH secretion. METHODS: Adult patients with mTBI and peak GH levels of < 10 ng/mL following glucagon stimulation test (n = 10) were given 0.6 mg injections of recombinant human growth hormone (rhGH) daily over a 6 month period. These patients were matched with healthy household controls (HHC) with whom they resided and shared meals with for comparison (Table 1). The Gastrointestinal Symptom Rating Scale (GSRS) measuring constipation, diarrhea, indigestion, abdominal pain, and acid reflux was administered to mTBI subjects (n = 10) and their healthy household controls (HHC; n = 10) every month for 6 months. RESULTS: GSRS scores within the treatment group dropped significantly after only one month of GH treatment (Figure 1, P < 0.01). Although GSRS scores were higher than the HCCs at baseline, the GSRS score of mTBI patients did not differ from the HHCs after receiving GH therapy. GSRS scores of the HHCs did not change significantly throughout the duration of the study (P > 0.05). CONCLUSION: Growth hormone may play a novel role in altering relationships in the gut-brain axis. Our results suggest that GH treatment helps to reduce a myriad of gastrointestinal symptoms in mTBI patients. We speculate this improvement may be attributable to changes in gut flora and overall gut microenvironment in mTBI, resembling that of healthy controls. Future studies can characterize the bacterial composition of gastrointestinal microbiomes of mTBI patients pre- and post-hormone supplementation compared to healthy controls to confirm this hypothesis.Table 1.: Demographics for healthy household controls and mTBI patients enrolled in the study (n = 20) a- Fisher's exact test; b- Parametric unpaired t-testFigure 1.: Gastrointestinal symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS) in mTBI patients receiving 6 months of growth hormone treatment compared to matched healthy household controls.

Sensorimotor conflict tests in an immersive virtual environment reveal subclinical impairments in mild traumatic brain injury

Current clinical tests lack the sensitivity needed for detecting subtle balance impairments associated with mild traumatic brain injury (mTBI). Patient-reported symptoms can be significant and have a huge impact on daily life, but impairments may remain undetected or poorly quantified using clinical measures. Our central hypothesis was that provocative sensorimotor perturbations, delivered in a highly instrumented, immersive virtual environment, would challenge sensory subsystems recruited for balance through conflicting multi-sensory evidence, and therefore reveal that not all subsystems are performing optimally. The results show that, as compared to standard clinical tests, the provocative perturbations illuminate balance impairments in subjects who have had mild traumatic brain injuries. Perturbations delivered while subjects were walking provided greater discriminability (average accuracy ≈ 0.90) than those delivered during standing (average accuracy ≈ 0.65) between mTBI subjects and healthy controls. Of the categories of features extracted to characterize balance, the lower limb accelerometry-based metrics proved to be most informative. Further, in response to perturbations, subjects with an mTBI utilized hip strategies more than ankle strategies to prevent loss of balance and also showed less variability in gait patterns. We have shown that sensorimotor conflicts illuminate otherwise-hidden balance impairments, which can be used to increase the sensitivity of current clinical procedures. This augmentation is vital in order to robustly detect the presence of balance impairments after mTBI and potentially define a phenotype of balance dysfunction that enhances risk of injury.

SUN-311 Adrenal Reserve Testing with the Glucagon Stimulation Test (GST) and Cosyntropin Stimulation Test (CST) in Deployed Veterans with Mild Traumatic Brain Injury

Introduction: Mild Traumatic Brain Injury (mTBI) is associated with anterior pituitary hormone dysfunction. The potential long-term effect of this injury on pituitary function in Veterans is not clear. We reviewed the utility of the fixed dose Glucagon Stimulation Test (GST) compared with the high dose Cosyntropin Stimulation test (CST) for hypothalamic-pituitary-adrenal (HPA) reserve over time in these patients with mTBI. Methods: We present an interim report of our 4-year longitudinal prospective pilot study of pituitary function in Veterans diagnosed with mTBI. Of the 34 mTBI Veterans enrolled, we have tested 28 of them (4 female, 24 male; age and BMI, 31.5±7.0 years and 30.4±6.2, mean±SD, respectively) for baseline pituitary hormone levels and cortisol response to the CST. In 22 subjects growth hormone and cortisol responses to GST were tested at baseline (Year 0). Follow-up testing was done for 18 mTBI subjects in Year 1, 13 subjects in Year 2, 10 subjects in Year 3 and 5 subjects in Year 4. The same baseline data were obtained for 14 age-, sex-, deployment- and BMI-matched control subjects without mTBI (2 female,12 male; age and BMI 34.4±6.8 years and 30.5±4.9, mean±SD, respectively). Cortisol cutoffs of <18 mcg/dL with the CST and <9.0 mcg/dL with the GST were used for the diagnosis of adrenal insufficiency. Results: Secondary adrenal insufficiency (AI), likely partial, was identified during this study on 6 occasions: 3/22 subjects at Year 0, 1/18 at Year 1, 0/13 at Year 2, 1/10 at Year 3 and 1/5 at Year 4. Two baseline subjects with AI reverted to normal in Years 1-3, one relapsed in Year 4 and a third had no further testing. Correlations of the cortisol levels from GST vs the 60-minute cortisol from CST were significant at Year 0 (n=22, r=0.553, p=0.008) and at Year 1 (n=18, r=0.802, p<0.0001). Due to decreased numbers, there were no significant correlations at Years 2 through 4. Similar correlations were obtained using the 30-minute CST values. However, the CST cortisol value predicted the low GST value in only 2/6 subjects. The mean GST cortisol levels and 60-minute CST cortisol levels for subjects at each year were not significantly different over Years 0 through 4 based on ANOVA analyses (CST: F=1.519, p= 0.206; GST: F= 0.796, p=0.532). Conclusions: Secondary adrenal insufficiency, likely partial, related to mTBI was detected by GST on 6 occasions (twice in one patient) over 4 years of observation. GST can provide useful information about HPA axis reserve, and appears to be more reliable than CST. Identification of potential secondary adrenal insufficiency using the GST in Veterans with mTBI can provide a beneficial combined test for these patients when other testing is not feasible.