Chronic Mild Traumatic Brain Injury Research Articles

Functional connectivity-hemodynamic (un)coupling changes in chronic mild brain injury are associated with mental health and neurocognitive indices: a resting state fMRI study.

To examine hemodynamic and functional connectivity alterations and their association with neurocognitive and mental health indices in patients with chronic mild traumatic brain injury (mTBI). Resting-state functional MRI (rs-fMRI) and neuropsychological assessment of 37 patients with chronic mTBI were performed. Intrinsic connectivity contrast (ICC) and time-shift analysis (TSA) of the rs-fMRI data allowed the assessment of regional hemodynamic and functional connectivity disturbances and their coupling (or uncoupling). Thirty-nine healthy age- and gender-matched participants were also examined. Patients with chronic mTBI displayed hypoconnectivity in bilateral hippocampi and parahippocampal gyri and increased connectivity in parietal areas (right angular gyrus and left superior parietal lobule (SPL)). Slower perfusion (hemodynamic lag) in the left anterior hippocampus was associated with higher self-reported symptoms of depression (r = - 0.53, p = .0006) and anxiety (r = - 0.484, p = .002), while faster perfusion (hemodynamic lead) in the left SPL was associated with lower semantic fluency (r = - 0.474, p = .002). Finally, functional coupling (high connectivity and hemodynamic lead) in the right anterior cingulate cortex (ACC)) was associated with lower performance on attention and visuomotor coordination (r = - 0.50, p = .001), while dysfunctional coupling (low connectivity and hemodynamic lag) in the left ventral posterior cingulate cortex (PCC) and right SPL was associated with lower scores on immediate passage memory (r = - 0.52, p = .001; r = - 0.53, p = .0006, respectively). Uncoupling in the right extrastriate visual cortex and posterior middle temporal gyrus was negatively associated with cognitive flexibility (r = - 0.50, p = .001). Hemodynamic and functional connectivity differences, indicating neurovascular (un)coupling, may be linked to mental health and neurocognitive indices in patients with chronic mTBI.

Long Noncoding RNA VLDLR-AS1 Levels in Serum Correlate with Combat-Related Chronic Mild Traumatic Brain Injury and Depression Symptoms in US Veterans.

More than 75% of traumatic brain injuries (TBIs) are mild (mTBI) and military service members often experience repeated combat-related mTBI. The chronic comorbidities concomitant with repetitive mTBI (rmTBI) include depression, post-traumatic stress disorder or neurological dysfunction. This study sought to determine a long noncoding RNA (lncRNA) expression signature in serum samples that correlated with rmTBI years after the incidences. Serum samples were obtained from Long-Term Impact of Military-Relevant Brain-Injury Consortium Chronic Effects of Neurotrauma Consortium (LIMBIC CENC) repository, from participants unexposed to TBI or who had rmTBI. Four lncRNAs were identified as consistently present in all samples, as detected via droplet digital PCR and packaged in exosomes enriched for CNS origin. The results, using qPCR, demonstrated that the lncRNA VLDLR-AS1 levels were significantly lower among individuals with rmTBI compared to those with no lifetime TBI. ROC analysis determined an AUC of 0.74 (95% CI: 0.6124 to 0.8741; p = 0.0012). The optimal cutoff for VLDLR-AS1 was ≤153.8 ng. A secondary analysis of clinical data from LIMBIC CENC was conducted to evaluate the psychological symptom burden, and the results show that lncRNAs VLDLR-AS1 and MALAT1 are correlated with symptoms of depression. In conclusion, lncRNA VLDLR-AS1 may serve as a blood biomarker for identifying chronic rmTBI and depression in patients.

Deep learning-based multimodality classification of chronic mild traumatic brain injury using resting-state functional MRI and PET imaging.

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.

Treatment effects of N-acetyl cysteine on resting-state functional MRI and cognitive performance in patients with chronic mild traumatic brain injury: a longitudinal study.

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 < 0.05). Two significant group-by-time effects demonstrated the changes of rs-fMRI metrics particularly in the regions located in the default mode network (DMN), sensorimotor network, and emotional circuits that were significantly correlated with cognitive function recovery over 3 months treatment with NAC (p < 0.05). NAC appears to modulate neural activity and functional connectivity in specific brain networks, and these changes could account for clinical improvement. This study confirmed the short-term therapeutic efficacy of NAC in chronic mTBI patients that may contribute to understanding of neurophysiological effects of NAC in mTBI. These findings encourage further research on long-term neurobehavioral assessment of NAC assisting development of therapeutic plans in mTBI.

White Matter Organization and Cortical Thickness Differ Among Active Duty Service Members With Chronic Mild, Moderate, and Severe Traumatic Brain Injury.

Abstract This study compared findings from whole-brain diffusion tensor imaging (DTI) and volumetric magnetic resonance imaging (MRI) among 90 Active Duty Service Members with chronic mild traumatic brain injury (TBI; n = 52), chronic moderate-to-severe TBI (n = 17), and TBI-negative controls (n = 21). Data were collected on a Philips Ingenia 3T MRI with DTI in 32 directions. Results demonstrated that history of TBI was associated with differences in white matter microstructure, white matter volume, and cortical thickness in both mild TBI and moderate-to-severe TBI groups relative to controls. However, the presence, pattern, and distribution of these findings varied substantially depending on the injury severity. Spatially-defined forms of DTI fractional anisotropy (FA) analyses identified altered white matter organization within the chronic moderate-to-severe TBI group, but they did not provide clear evidence of abnormalities within the chronic mild TBI group. In contrast, DTI FA "pothole" analyses identified widely distributed areas of decreased FA throughout the white matter in both the chronic mild TBI and chronic moderate-to-severe TBI groups. Additionally, decreased white matter volume was found in several brain regions for the chronic moderate-to-severe TBI group compared with the other groups. Greater number of DTI FA potholes and reduced cortical thickness were also related to greater severity of self-reported symptoms. In sum, this study expands upon a growing body of literature using advanced imaging techniques to identify potential effects of brain injury in military Service Members. These findings may differ from work in other TBI populations due to varying mechanisms and frequency of injury, as well as a potentially higher level of functioning in the current sample related to the ability to maintain continued Active Duty status after injury. In conclusion, this study provides DTI and volumetric MRI findings across the spectrum of TBI severity. These results provide support for the use of DTI and volumetric MRI to identify differences in white matter microstructure and volume related to TBI. In particular, DTI FA pothole analysis may provide greater sensitivity for detecting subtle forms of white matter injury than conventional DTI FA analyses.

Evaluating Targeted Therapeutic Response With Predictive Blood-Based Biomarkers in Patients With Chronic Mild Traumatic Brain Injury.

Chronic consequences of mild traumatic brain injury (mTBI) are heterogeneous, but may be treatable with targeted medical and rehabilitation interventions. A biological signature for the likelihood of response to therapy (i.e., "predictive" biomarkers) would empower personalized medicine post-mTBI. The purpose of this study was to correlate pre-intervention blood biomarker levels and the likelihood of response to targeted interventions for patients with chronic issues attributable to mTBI. Patients with chronic symptoms and/or disorders secondary to mTBI >3 months previous (104 days to 15 years; n = 74) were enrolled. Participants completed pre-intervention assessments of symptom burden, comprehensive clinical evaluation, and blood-based biomarker measurements. Multi-domain targeted interventions for specific symptoms and impairments across a 6-month treatment period were prescribed. Participants completed a follow-up testing after the treatment period. An all-possible model's backward logistic regression was built to identify predictors of improvement in relation to blood biomarker levels before intervention. The minimum clinically important difference (MCID) of the change score (post-intervention subtracted from pre-intervention) for the Post-Concussion Symptom Scale (PCSS) to identify treatment responders from non-responders was the primary outcome. The MCID for total PCSS score was 10. The model to predict change in PCSS score over the 6-month intervention was significant (R2 = 0.09; p = 0.01) and identified ubiquitin C-terminal hydrolase L1 (odds ratio [OR] = 2.53; 95% confidence interval [CI], 1.18-5.46; p = 0.02) and hyperphosphorylated tau (p-tau; OR = 0.70; 95% CI, 0.51-0.96; p = 0.03) as significant predictors of symptom improvement beyond the PCSS MCID. In this cohort of chronic TBI subjects, blood biomarkers before rehabilitation intervention predicted the likelihood of response to targeted therapy for chronic disorders post-TBI.

Associations of mTBI and post-traumatic stress to amygdala structure and functional connectivity in military Service Members.

Traumatic brain injury (TBI) is one of the highest public health priorities, especially among military personnel where comorbidity with post-traumatic stress symptoms and resulting consequences is high. Brain injury and post-traumatic stress symptoms are both characterized by dysfunctional brain networks, with the amygdala specifically implicated as a region with both structural and functional abnormalities. This study examined the structural volumetrics and resting state functional connectivity of 68 Active Duty Service Members with or without chronic mild TBI (mTBI) and comorbid symptoms of Post-Traumatic Stress (PTS). Structural analysis of the amygdala revealed no significant differences in volume between mTBI and healthy comparison participants with and without post-traumatic stress symptoms. Resting state functional connectivity with bilateral amygdala revealed decreased anterior network connectivity and increased posterior network connectivity in the mTBI group compared to the healthy comparison group. Within the mTBI group, there were significant regions of correlation with amygdala that were modulated by PTS severity, including networks implicated in emotional processing and executive functioning. An examination of a priori regions of amygdala connectivity in the default mode network, task positive network, and subcortical structures showed interacting influences of TBI and PTS, only between right amygdala and right putamen. These results suggest that mTBI and PTS are associated with hypo-frontal and hyper-posterior amygdala connectivity. Additionally, comorbidity of these conditions appears to compound these neural activity patterns. PTS in mTBI may change neural resource recruitment for information processing between the amygdala and other brain regions and networks, not only during emotional processing, but also at rest.

Journey to the other side of the brain: asymmetry in patients with chronic mild or moderate traumatic brain injury.

Patients with chronic mild or moderate traumatic brain injury have some regions of brain atrophy (including cerebral white matter) but even more regions of abnormal brain enlargement (including other cerebral regions). Ipsilateral injury and atrophy cause the eventual development of contralateral compensatory hypertrophy. 50 patients with mild or moderate traumatic brain injury were compared to 80 normal controls (n=80) with respect to MRI brain volume asymmetry. Asymmetry-based correlations were used to test the primary hypothesis. The group of patients had multiple regions of abnormal asymmetry. The correlational analyses supported the conclusion that acute injury to ipsilateral cerebral white matter regions caused atrophy, leading eventually to abnormal enlargement of contralateral regions due to compensatory hypertrophy.

Executive function and relation to static balance metrics in chronic mild TBI: A LIMBIC-CENC secondary analysis.

Among patients with traumatic brain injury (TBI), postural instability often persists chronically with negative consequences such as higher fall risk. One explanation may be reduced executive function (EF) required to effectively process, interpret and combine, sensory information. In other populations, a decline in higher cognitive functions are associated with a decline in walking and balance skills. Considering the link between EF decline and reduction in functional capacity, we investigated whether specific tests of executive function could predict balance function in a cohort of individuals with a history of chronic mild TBI (mTBI) and compared to individuals with a negative history of mTBI. Secondary analysis was performed on the local LIMBIC-CENC cohort (N = 338, 259 mTBI, mean 45 ± STD 10 age). Static balance was assessed with the sensory organization test (SOT). Hierarchical regression was used for each EF test outcome using the following blocks: (1) the number of TBIs sustained, age, and sex; (2) the separate Trail making test (TMT); (3) anti-saccade eye tracking items (error, latency, and accuracy); (4) Oddball distractor stimulus P300 and N200 at PZ and FZ response; and (5) Oddball target stimulus P300 and N200 at PZ and FZ response. The full model with all predictors accounted for between 15.2% and 21.5% of the variability in the balance measures. The number of TBI's) showed a negative association with the SOT2 score (p = 0.002). Additionally, longer times to complete TMT part B were shown to be related to a worse SOT1 score (p = 0.038). EEG distractors had the most influence on the SOT3 score (p = 0.019). Lastly, the SOT-composite and SOT5 scores were shown to be associated with longer inhibition latencies and errors (anti-saccade latency and error, p = 0.026 and p = 0.043 respectively). These findings show that integration and re-weighting of sensory input when vision is occluded or corrupted is most related to EF. This indicates that combat-exposed Veterans and Service Members have greater problems when they need to differentiate between cues when vision is not a reliable input. In sum, these findings suggest that EF could be important for interpreting sensory information to identify balance challenges in chronic mTBI.

Identification of chronic mild traumatic brain injury using resting state functional MRI and machine learning techniques.

[clinicaltrials.gov], identifier [NCT03241732].

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.

The Efficacy of Hyperbaric Oxygen Therapy in Traumatic Brain Injury Patients: Literature Review and Clinical Guidelines

Introduction: The application of hyperbaric oxygen therapy for patients with both acute and chronic traumatic brain injury has been suggested for over five decades. In the past decade, the design and quality of studies were more detailed and thorough leading to an improved unerstanding of the uses of HBOT and the profiles of the patients who can benefit the most. Objectives: Perform a comprehensive literature review of hyperbaric oxygen therapy application for the treatment of patients with both acute, subacute and chronic traumatic brain injury. Methods: Extensive literature search from 1969 to April 2023 was performed on April 1st 2023 within the following databases: Cochrane Library, PubMed, Google Scholar, and Web of Science, including humans clinical data, in articles providing information on the type of treatment and clinical outcomes. Articles were first categorized into acute-subacute traumatic brain inury and chronic traumatic brain injury and further classified into low, medium or high level quality. Results: There was high level evidence including nine randomized controlled trials, one meta-analysis and two prospective study evaluating the clinical effects of hyperbaric oxygen therapy in patients suffering from traumatic brain injuries in the acute and subacute settings. Mortality was significantly reduced in all studies that used it as an endpoint, while favorable functional outcomes in survivors showed mixed results. In chronic severe traumatic brain injury, there is low to moderate evidence including two uncontrolled prospective studies, two cohort studies and eight case reports suggesting improved outcomes. In chronic mild traumatic brain injury, there is high level evidence including seven randomized controlled trials, and six prospective studies suggesting significant improvement in cognitive function, symptoms and quality of life. Conclusions: Hyperbaric oxygen therapy may be recommended in acute moderate-severe traumatic brain injury patients (Type 2a recommendation, level A evidence). However, further studies are needed to both evaluate outcomes and to determine the optimal treatment protocols for the different types of injuries (Type 1 recommendation, level A evidence). Hyperbaric oxygen threrapy should be recommended in chronic traumatic brain injury for a selected group of patients suffering from prolonged post-concussion syndrome who have clear evidence of metabolic dysfunctional brain regions as determined by neuroimaging (Type 2a recommendation, level B-R evidence). Patients should be properly evaluated by standardized cognitive tests and functional brain imaging (Type 1 recommendation, level B-R evidence).

Executive function improvement in response to meta-cognitive training in chronic mTBI / PTSD.

We tested Goal Management Training (GMT), which has been recommended as an executive training protocol that may improve the deficits in the complex tasks inherent in life role participation experienced by those with chronic mild traumatic brain injury and post-traumatic stress disease (mTBI/PTSD). We assessed, not only cognitive function, but also life role participation (quality of life). We enrolled and treated 14 individuals and administered 10 GMT sessions in-person and provided the use of the Veterans Task Manager (VTM), a Smartphone App, which was designed to serve as a "practice-buddy" device to ensure translation of in-person learning to independent home and community practice of complex tasks. Pre-/post-treatment primary measure was the NIH Examiner, Unstructured Task. Secondary measures were as follows: Tower of London time to complete (cTOL), Community Reintegration of Service Members (CRIS) three subdomains [Extent of Participation; Limitations; Satisfaction of Life Role Participation (Satisfaction)]. We analyzed pre-post-treatment, t-test models to explore change, and generated descriptive statistics to inspect given individual patterns of change across measures. There was statistically significant improvement for the NIH EXAMINER Unstructured Task (p < .02; effect size = .67) and cTOL (p < .01; effect size = .52. There was a statistically significant improvement for two CRIS subdomains: Extent of Participation (p < .01; effect size = .75; Limitations (p < .05; effect size = .59). Individuals varied in their treatment response, across measures. In Veterans with mTBI/PTSD in response to GMT and the VTM learning support buddy, there was significant improvement in executive cognition processes, sufficiently robust to produce significant improvement in community life role participation. The individual variations support need for precision neurorehabilitation. The positive results occurred in response to treatment advantages afforded by the content of the combined GMT and the employment of the VTM learning support buddy, with advantages including the following: manualized content of the GMT; incremental complex task difficulty; GMT structure and flexibility to incorporate individualized functional goals; and the VTM capability of ensuring translation of in-person instruction to home and community practice, solidifying newly learned executive cognitive processes. Study results support future study, including a potential randomized controlled trial, the manualized GMT and availability of the VTM to ensure future clinical deployment of treatment, as warranted.

Chronic Mild Traumatic Brain Injury: Aberrant Static and Dynamic Connectomic Features Identified Through Machine Learning Model Fusion

Traumatic Brain Injury (TBI) is a frequently occurring condition and approximately 90% of TBI cases are classified as mild (mTBI). However, conventional MRI has limited diagnostic and prognostic value, thus warranting the utilization of additional imaging modalities and analysis procedures. The functional connectomic approach using resting-state functional MRI (rs-fMRI) has shown great potential and promising diagnostic capabilities across multiple clinical scenarios, including mTBI. Additionally, there is increasing recognition of a fundamental role of brain dynamics in healthy and pathological cognition. Here, we undertake an in-depth investigation of mTBI-related connectomic disturbances and their emotional and cognitive correlates. We leveraged machine learning and graph theory to combine static and dynamic functional connectivity (FC) with regional entropy values, achieving classification accuracy up to 75% (77, 74 and 76% precision, sensitivity and specificity, respectively). As compared to healthy controls, the mTBI group displayed hypoconnectivity in the temporal poles, which correlated positively with semantic (r = 0.43, p < 0.008) and phonemic verbal fluency (r = 0.46, p < 0.004), while hypoconnectivity in the right dorsal posterior cingulate correlated positively with depression symptom severity (r = 0.54, p < 0.0006). These results highlight the importance of residual FC in these regions for preserved cognitive and emotional function in mTBI. Conversely, hyperconnectivity was observed in the right precentral and supramarginal gyri, which correlated negatively with semantic verbal fluency (r=-0.47, p < 0.003), indicating a potential ineffective compensatory mechanism. These novel results are promising toward understanding the pathophysiology of mTBI and explaining some of its most lingering emotional and cognitive symptoms.

Use of person-centered goals to direct interdisciplinary care for military service members and Veterans with chronic mTBI and co-occurring psychological conditions.

To explore the use of person-centered goals (PCGs) to direct interdisciplinary care to support PCG attainment in military service members and Veterans (SM/Vs) with chronic mild traumatic brain injury (mTBI) and co-occurring psychological conditions. A retrospective chart review was completed for 146 United States military SM/Vs reporting chronic symptoms following mTBI and co-occurring psychological conditions who received care in the SHARE Military Initiative intensive outpatient program, a donor-funded program administered by a not-for-profit hospital, between April 1, 2015 and March 31, 2019. PCGs were used to direct care consisting of individual and group-based interventions and therapies delivered by an interdisciplinary, co-located team including behavioral health, case management, neurology or physiatry, nursing, occupational therapy, physical therapy, recreation therapy, speech-language pathology, and transition support. The primary outcome measure was PCG attainment measured via goal attainment scaling. Increased PCG attainment was demonstrated at program discharge and throughout the first year following program discharge. Predictors of goal attainment at discharge included longer participation in treatment, greater reduction in depressive symptoms and greater improvement in adjustment at discharge, male gender, and higher cognitive and physical abilities on admission. This sample of military SM/Vs with mTBI and co-occurring psychological conditions who received intensive, interdisciplinary, PCG directed care demonstrated increased PCG attainment at program discharge which further increased with transition support over the year post-discharge. Results suggest PGC goal directed care is a feasible, promising methodology of individualizing treatment in this population. This exploratory study lays a foundation for future prospective, controlled, comparative effectiveness research that will further understanding of the effectiveness of intensive, interdisciplinary, PCG directed care.

Deficits in visuospatial attentional cueing following mild traumatic brain injury

Visual attentional deficits are frequently reported in patients with mild traumatic brain injury (TBI). In the present study, the ability to orient visual attention (i.e., the use of endogenous and exogenous visual cues) was investigated using a modified Posner visual search task, in which the participant was required to search for a target shape (radial frequency patterns) amongst distractor shapes. Participants were required to determine whether a target radial frequency pattern was present or absent from an array of distractors. Attention to the target location was cued using central or peripheral cueing procedures to investigate endogenous or exogenous attention allocation. Predictability was not manipulated between central and peripheral cues. Search difficulty was varied by systematically changing the radial frequency difference between target and distractors (and thereby shape difference), and cues could be valid or invalid in that they correctly or incorrectly indicated the position of the target shape. Both target discriminability (i.e., identifying the presence or absence of the target) and reaction times were measured. Thirteen patients with chronic mild TBI and 21 age-, sex-, and IQ -matched healthy controls participated in the study. For control participants, both discrimination accuracy and reaction times improved with visual search efficiency, and they were sensitive to the type of cue, with performance worst for cue invalid conditions than valid conditions. However, the results for TBI patients were strikingly different; we find that discrimination accuracy slightly improved with visual search difficulty (compared to controls), but not reaction times, and TBI patients were largely insensitive to the type of visual cue, and did not show a selective deficit for central or peripheral cues, suggesting an impairment in both endogenous and exogenous visual attention. In conclusion, patients with mild TBI exhibit a poor ability to orient visual attention.

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.

The effects of augmenting traditional rehabilitation with audio biofeedback in people with persistent imbalance following mild traumatic brain injury.

Complaints of non-resolving imbalance are common in individuals with chronic mild traumatic brain injury (mTBI). Vestibular rehabilitation therapy may be beneficial for this population. Additionally, wearable sensors can enable biofeedback, specifically audio biofeedback (ABF), and aid in retraining balance control mechanisms in people with balance impairments. In this study, we described the effectiveness of vestibular rehabilitation therapy with and without ABF to improve balance in people with chronic mTBI. Participants (n = 31; females = 22; mean age = 40.9 ± 11 y) with chronic (>3 months) mTBI symptoms of self-reported imbalance were randomized into vestibular rehabilitation with ABF (n = 16) or without ABF (n = 15). The intervention was a standard vestibular rehabilitation, with or without ABF, for 45 min biweekly for 6 weeks. The ABF intervention involved a smartphone that provided auditory feedback when postural sway was outside of predetermined equilibrium parameters. Participant's completed the Post-Concussion Symptom Scale (PCSS). Balance was assessed with the sensory organization test (SOT) and the Central Sensorimotor Integration test which measured sensory weighting, motor activation, and time delay with sway evoked by surface and/or visual surround tilts. Effect sizes (Hedge's G) were calculated on the change between pre-and post-rehabilitation scores. Both groups demonstrated similar medium effect-sized decreases in PCSS and large increases in SOT composite scores after rehabilitation. Effect sizes were minimal for increasing sensory weighting for both groups. The with ABF group showed a trend of larger effect sizes in increasing motor activation (with ABF = 0.75, without ABF = 0.22) and in decreasing time delay (with ABF = −0.77, without ABF = −0.52) relative to the without ABF group. Current clinical practice focuses primarily on sensory weighting. However, the evaluation and utilization of motor activation factors in vestibular rehabilitation, potentially with ABF, may provide a more complete assessment of recovery and improve outcomes.

Challenging the Vestibular System Affects Gait Speed and Cognitive Workload in Chronic Mild Traumatic Brain Injury and Healthy Adults.

People with persistent symptoms after mild traumatic brain injury (mTBI) report imbalance during walking with head movements. The purpose of this study was (1) to compare usual walk gait speed to walking with head turns (HT) between people with mTBI and controls, (2) to compare the cognitive workload from usual walk to HT walk between groups, and (3) to examine if gaze stability deficits and mTBI symptoms influence gait speed. Twenty-three individuals (mean age 55.7 ± 9.3 years) with persistent symptoms after mTBI (between 3 months to 2 years post-injury) were compared with 23 age and sex-matched controls. Participants walked a 12-inch wide, 60-foot walkway when looking ahead and when walking with HT to identify letters and their colors. Gait speed during usual walk and HT walk were calculated. Pupillary responses during both walks were converted to the Index of Cognitive Activity (ICA) as a measure of cognitive workload. Gaze stability was examined by the dynamic visual acuity (DVA) test in the yaw plane. The post-concussion symptom scale (PCSS) was used to collect symptom severity. Within group analysis showed that gait speed was lower during HT walk compared to usual walk in the people with mTBI (p < 0.001) as well as in controls (p < 0.001). ICA was higher with HT compared to usual walk in the mTBI group in the right eye (p = 0.01) and left eye (p = 0.001), and in controls in the right eye (p = 0.01) and left eye (p = 0.01). Participants in the mTBI group had slower usual (p < 0.001), and HT gait speed (p < 0.001) compared to controls. No differences were noted in ICA in the right or left eye during usual walk and HT walk between groups (p > 0.05). DVA loss in the yaw plane to the right and left was not different between groups (p > 0.05) and were not correlated with gait speed. PCSS scores were correlated with usual walk (r = −0.50, p < 0.001) and HT gait speed (r = −0.44, p = 0.002). Slower gait speed, poorer stability, and higher cognitive workload during walking with head turns may reduce community participation in people with mTBI and persistent symptoms.

0320 Sex Differences in Sleep Quality and Biomarker Levels in Service Members and Veterans with Chronic Mild Traumatic Brain Injury

Abstract Introduction Sleep disorders are highly prevalent in military populations and are frequently associated with a history of traumatic brain injury (TBI). Despite the recent increase in female representation in the military, few studies have focused on sex differences in sleep quality in military populations. In this study, we examined biological sex differences in self-reported sleep quality and blood levels of protein biomarkers of TBI in a cohort of service members and veterans with chronic mild TBI (mTBI). Methods Participants (n=1,121) were enrolled in the Chronic Effects of Neurotrauma Consortium (CENC)/Long Term Impact of Military Brain Injury Consortium (LIMBIC) study. Females (n=147) and males (n=974) were classified into control (n=192, no TBI history) or mTBI (n=929, positive history of mTBI) groups. Self-reported sleep quality was assessed using PSQI (Pittsburgh Sleep Quality Index). Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), Tau, interleukin (IL)-10, IL-6, and tumor necrosis factor-alpha (TNFα) were analyzed using a Simoa HD-X analyzer. Results Regression models revealed higher PSQI scores in females than males (ß(SE)=1.36(0.40), p =0.001) and in the TBI group (ß(SE)=1.97(0.36), p&amp;lt;0.001) in comparison to controls. TBI x sex interaction was not statistically significant. Within the mTBI group, females had higher PSQI scores (p=0.031) and GFAP levels (p&amp;lt;0.001) than males, which remained significant when controlling for demographics, number of mTBIs, and time since last mTBI. No other significant differences in biomarker levels were observed. In men, but not women, higher levels of GFAP were associated with lower PSQI scores (ß(SE)=-1.38(0.43), p=0.001). Conclusion Our findings suggest sex differences in sleep quality after mTBI, providing insights into possible mechanisms underlying the development of chronic symptoms in military populations. Our results support the need for considering biological sex in the development of personalized therapeutic strategies for chronic TBI-related sleep disorders. Support (If Any) This work was supported by grant funding from: The U.S. Army Medical Research and Material Command, from the U.S. Department of Veterans Affairs Long-term Impact of Military-related Brain Injury Consortium/Chronic Effects of Neurotrauma Consortium under Award No.1I01CX002097-01 and the U.S Department of Defense under Award No.W81XWH-18-PH/TBIRP-LIMBIC.