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Background: Some clinical trials report improvement in persistent post-concussive symptoms (PCS) with hyperbaric oxygen (HBO2) following mild traumatic brain injury (mTBI), but questions remain regarding the utility of HBO2 for PCS, the effects of HBO2 on post-traumatic stress disorder (PTSD), and the influences of sham control exposures. Methods: A systematic review and pooled analysis was conducted to summarize available evidence for HBO2 in mTBI-associated PCS ± PTSD. Data aggregated from four Department of Defense (DoD) studies with participant-level data (n=254) were grouped into pooled HBO2 and sham intervention groups. Changes from baseline to post-intervention on PCS, PTSD, and neuropsychological measures were assessed using linear mixed models to evaluate main intervention and intervention-by-baseline PTSD effects. Potential dose-response relationships to oxygen partial pressures were investigated. Intervention effects from three other published studies with summary-level participant data (n=135) were also summarized. Results: Pooled DoD data analyses indicated trends toward improvement favoring HBO2 for PCS (Rivermead Total Score: -2.3, 95% CI [-5.6, 1.0], p=0.18); PTSD (PTSD Checklist Total Score: -2.7, 95% CI [-5.8, 0.4], p=0.09); and significant improvement in verbal memory (CVLT-II Trial 1-5 Free Recall: 3.8; 95% CI [1.0, 6.7], p=0.01). A dose-response trend to increasing oxygen partial pressure was also found, with a ..

Introduction: Global outcomes can strengthen inferences from clinical trials. We evaluate global outcomes for persistent post-concussive symptoms (PCS) after mild traumatic brain injury (mTBI) in two clinical trials of hyperbaric oxygen (HBO2) in United States service members. Methods: During study design, outcomes of symptom, cognitive, and functional impairments planned for a trial of HBO2 for PCS (HOPPS) were weighted and grouped into different domains to formulate the composite outcome total score. The composite outcome was compared between the intervention groups in HOPPS and those in a subsequent HBO2 trial (BIMA) for validation. Additionally, two post hoc global outcome measures were explored, including one composed of components that demonstrated favorable characteristics in both studies and another via components used in another TBI randomized trial (COBRIT).  Results: In total, 143 active-duty or veteran military personnel were randomized across the two studies. Composite total scores improved from baseline for HBO2 (mean±SD -2.9±9.0) and sham (-2.9±6.6) groups in HOPPS but did not differ significantly between groups (p=0.33). In BIMA, 13-week changes from baseline favored the HBO2 group (-3.6±6.4) versus sham (-0.3±5.2; p=0.02). No between-group differences were found when COBRIT composite scoring was applied to BIMA. Overall, HBO2 effects were maximized when the post hoc global ..

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow. DOI: 10.22462/13.15.2019.10

To date, several Department of Defense (DoD) and civilian studies have evaluated hyperbaric oxygen for mild forms of traumatic brain injury. Prior to the DoD-sponsored “Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA)” trial, none included post-intervention follow-up beyond three to six months. Post-hoc attempts at long-term follow-up were complicated by low participation and potential self-selection bias. BIMA planned for follow-up through 12 months but was amended to add post-concussive and post-traumatic stress disorder, quality of life, pain, depression, anxiety, and alcohol use assessments at 24 and 36 months. A total of 42 of 71 BIMA participants consented to extended follow-up, and 40 and 14 completed a 24- or 36-month visit, respectively, representing an overall response rate of 59% and 20%. Participants who completed extended follow-up were similar to the study group that did not in terms of demographics, perceived intervention allocation, and initial response to intervention. There were no significant differences at 24 or 36 months between intervention groups, and group mean scores were near pre-intervention values. This return to baseline could be due to waning treatment effect, selection bias, or participant or perception effects. Though ..

Purpose: Eye movements may offer a sensitive method to measure response to intervention in mild traumatic brain injury (mTBI). Methods: The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury Study (BIMA) randomized 71 participants to 40 sessions of hyperbaric oxygen or sham. A companion normative study (Normal) enrolled 75 participants. An eye tracking system measured left and right eye movements for saccadic and smooth pursuit. At baseline two smooth pursuit tasks, circular and horizontal ramp, and four saccadic tasks, horizontal and vertical step, reading, and memory guided-on tasks differentiated BIMA from Normal participants. The change from baseline in these tasks were measured and compared between interventions and against Normal participants at 13 weeks and six-month follow-up using the two-sample t-test. The Holm-Bonferroni procedure was used to adjust for multiple testing. Results: Change from baseline in eyetracker measures for participants assigned to the hyperbaric oxygen arm did not significantly differ from those assigned to the sham arm at post-randomization time points 13 weeks and six months. Consistent shifts of BIMA participant values toward Normal values at 13 weeks and six months were observed for overall fixation duration, forward saccadic duration, and number ..

Introduction: We evaluated magnetic resonance spectroscopy (MRS) in United States military personnel with persistent symptoms after mild traumatic brain injury (mTBI), comparing over time two groups randomized to receive hyperbaric oxygen or sham chamber sessions and a third group of normative controls.  Methods: Active-duty or veteran military personnel and normative controls underwent MRS outcome measures at baseline, 13 weeks (mTBI group only), and six months. Participants received 3.0 Tesla brain MRS for analysis of water-suppressed two-dimensional (2D) multivoxel 1H-MRS of the brain using point resolved spectroscopy (PRESS) with volume selection localized above the lateral ventricles and within the brain parenchyma, of which one voxel was chosen in each hemisphere without artifact. Script-based automatic data processing was used to assess N-acetylaspartate (NAA), creatine (Cr), and choline (Cho). Metabolite ratios for white matter were then calculated for NAA/Cr (Area), Cho/Cr (Area), and Cho/NAA (Area). These ratios were compared using standard analysis methodology. Results: There were no observable differences between participants with mTBI and normative controls nor any observable changes over time in the NAA/Cr (area), Cho/Cr (area), and Cho/NAA (area) ratios. Similarly, the control and injured participants were indistinguishable. Discussion: While participants with mild TBI showed no difference in MRS compared to normative controls, ..

Purpose: Military service members often report both affective and vestibular complaints after mild traumatic brain injury (mTBI), but associations between symptoms and vestibular deficits can be subtle and inconsistent. Methods: From two complementary studies, one of military service members with persistent post-concussive symptoms after mTBI (NCT01611194) and the other of adult volunteers with no history of brain injury (NCT01925963), affective symptoms were compared to postural control, gait, otolith and visuospatial function. Results: The studies enrolled 71 participants with mTBI and 75 normative controls. Participants with mTBI had significantly reduced postural equilibrium on the sensory organization test (SOT), and more so in those with high anxiety or post-traumatic stress. Cervical and ocular vestibular evoked myogenic potentials (cVEMP; oVEMP) showed prolonged latencies in mTBI participants compared to controls; oVEMPs were significantly delayed in mTBI participants with high anxiety, post-traumatic stress or depression. A subset of the mTBI group had abnormal tandem gait and high anxiety. Anxiety, posttraumatic stress, and depression did not correlate with performance on the 6-Minute Walk Test, visuospatial neuropsychological measures, and the Satisfaction with Life Scale in the mTBI group. Conclusions: In this study military service members with mTBI reported affective symptoms, concurrently with vestibular-balance concerns. Worse scores on affective measures ..

Auditory processing disorders are common following mild traumatic brain injury (mTBI), but the neurocircuitry involved is not well understood. The present study used functional MRI to examine auditory cortex activation patterns during a passive listening task in a normative population and mTBI patients with and without clinical central auditory processing deficits (APD) as defined by the SCAN-3:A clinical battery. Patients with mTBI had overall patterns of lower auditory cortex activation during the listening tasks as compared to normative controls. A significant lateralization pattern (pairwise t-test; p<0.05) was observed in normative controls and in those with mTBI and APD during single-side stimulation. Additionally, baseline connectivity between left and right auditory cortices was lower in mTBI patients than in controls (p=0.01) and significantly reduced in the mTBI with APD group (p=0.008). Correlation was also observed between bilateral task-related activation and competing words subscore of the SCAN-3:A. These findings suggest the passive listening task is well suited to probe auditory function in military personnel with an mTBI diagnosis. Further, the study supports the use of multiple approaches for detecting and assessing central auditory deficits to improve monitoring of short- and long-term outcomes. DOI: 10.22462/13.15.2019.5

Introduction: Individuals with persistent symptoms after mild traumatic brain injury (mTBI) often have auditory complaints. In this study, we used the auditory brainstem response (ABR) to determine whether cochlear synaptopathy could explain auditory symptoms.  Methods: 69 adult military service members with mTBI and 25 adults without brain injury (NCT01611194 and NCT01925963) completed pure-tone audiometry, ABR, and central auditory processing tests. All participants were male, ages 21-50. Results: 37/69 mTBI participants had measurable hearing loss, while another 20-30% had hearing complaints or tinnitus. While mTBI participants with measurable hearing loss had reduced wave I and III amplitude and decreased III-V interpeak latency, those with no measurable hearing loss did not significantly differ from controls on any ABR parameter. Those with measurable hearing loss were also more likely to have abnormal central auditory processing. mTBI participants with no measurable hearing loss but who reported hearing concerns had some ABR findings (III-V interpeak latency, I and V amplitudes, V/I amplitude ratio) more like the measurable hearing loss mTBI group than normative controls. Conclusion: Cochlear synaptopathy may have contributed to some of the auditory impairment in service members with mTBI with measurable hearing loss. However, these results are likely confounded by cochlear hair cell damage. DOI: 10.22462/13.15.2019.4

Functional magnetic resonance imaging (fMRI) has been available commercially for clinical diagnostic use for many years. However, both clinical interpretation of fMRI by a neuroradiologist and quantitative analysis of fMRI data can require significant personnel resources that exceed reimbursement. In this report, a fully automated computerbased quantification methodology (Enumerated Auditory Response, EAR) has been developed to provide an auditory fMRI assessment of patients who have suffered a mild traumatic brain injury. Fifty-five study participants with interpretable auditory fMRI sequence data were assessed by EAR analysis, as well as both clinical radiologist fMRI interpretation and voxelwise general linear model (GLM) analysis. Comparison between the clinical interpretation and the two computer analysis methods resulted in 67% concordance (identical), 32% near-concordance (one level difference), and 1% discordant. Comparison between the clinical computer-based quantification (EAR) and GLM analysis yielded significant correlations in right and left ear responses (p<0.05) for the full subject group. Automated fMRI quantification analysis equivalent to EAR might be appropriate for both future research projects with constrained resources, as well as possible routine clinical use. DOI: 10.22462/13.15.2019.3

Background: Audiology clinics have many tools available to evaluate auditory and vestibular complaints. However, many tools lack established normative ranges across the life span. We conducted this study to establish reference ranges across the life span for audiology/ vestibular measures commonly used to evaluate patients with traumatic brain injury. Materials and Methods: In this repeated measures study, 75 adults, ages 18-65 years, without a history of traumatic brain injury, underwent robust auditory/vestibular evaluations three times over six months, including rotational chair, videonystagmography, computerized dynamic posturography, vestibular evoked myogenic potentials, and retinal fundoscopy. Results: Age effect was notable for transient evoked otoacoustic emissions, pure-tone audiometry, auditory brainstem response, auditory middle latency response, and auditory-steady state response at 4000 hertz (Hz). Older participants (50-65 years) were more likely to have delayed latency horizontal saccades, positional nystagmus, slowed lower-extremity motor control responses, and delayed latency ocular vestibular evoked myogenic potentials. Low to mid-frequency horizontal (0.003-4 Hz) and mid-frequency vertical (1-3 Hz) vestibulo-ocular reflex, otolith-mediated reflexes, dynamic visual acuity and balance measures were generally not influenced by age. Females had larger static subjective visual testing offset angles, longer cervical vestibular evoked myogenic potential P1 latency, faster velocity horizontal saccades, and quicker motor control latency for ..

Traumatic brain injury (TBI) is a major cause of death and disability in the United States (U.S.), with the Centers for Disease Control and Prevention reporting approximately 2.8 million TBI-related emergency department visits, hospitalizations, and deaths in 2012 [1]. For those under 45 years of age, TBI is the number one cause of disability and mortality worldwide [2]. Within military populations TBI remains especially problematic. While the incidence of TBI in the U.S. military peaked in 2011, Department of Defense personnel continue to experience approximately 18,000 new cases each year, with 383,473 total cases between 2000 and the first quarter of 2018 [3]. Eighty-two percent of these injuries were classified as mild TBI (mTBI) [3]. DOI: 10.22462/13.15.2019.1