Review of recent non-hyperbaric oxygen interventions for mild traumatic brain injury.

Traumatic brain injury (TBI) affects 3.2 to 5.3 million persons in the United States (U.S.), and the impact in the U.S. military is proportionally higher. Consensus is lacking regarding an accepted outcome to measure the effectiveness of interventions to improve the symptoms associated with TBI, and no standard-of-care treatment exists for mild TBI (mTBI). A recent literature review evaluated hyperbaric oxygen therapy (HBO₂) interventions, and findings were mixed. We conducted a systematic review of non-HBO₂ mTBI interventional trials published in 2005-2015 in military and civilian populations. A total of 154 abstracts, seven randomized controlled trials (RCTs) and five pilot studies were reviewed. RCTs were evaluated using Consolidated Standards of Reporting Trials criteria. Results indicated that studies published within the period of review were small pilot studies for rehabilitation therapy and motion capture or virtual reality gaming interventions. Neuropsychological assessments were commonly specified outcomes, and most studies included a combination of symptom and neuropsychological assessments. Findings indicated a lack of large-scale, well-controlled trials to address the symptoms and sequelae of this condition, but results of small exploratory studies show evidence of potentially promising interventions.

Neuropsychological assessments in a hyperbaric trial of post-concussive symptoms.

Results of studies addressing the effect of mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) on symptoms and neuropsychological assessments are mixed regarding cognitive deficits in these populations. Neuropsychological assessments were compared between U.S. military service members with mTBI only (n=36) vs. those with mTBI÷ PTSD (n=35) from a randomized interventional study of mTBI participants with persistent post-concussive symptoms (PCS). The mTBI group endorsed worse symptoms than published norms on PCS, PTSD and pain scales (⟩50% abnormal on Neurobehavioral Symptom Inventory (NSI), PTSD Checklist-Civilian, McGill Pain Questionnaire-Short Form) and some quality of life domains. Worse symptom reporting was found in the mTBI÷ PTSD group compared to mTBI (e.g., mean NSI total score in mTBI 27.5 (SD=12.7), mTBI÷ PTSD 39.9 (SD=13.6), p⟨0.001). The mTBI÷PTSD group performed worse than mTBI on the Weschler Adult Intelligence Scale digit span (mean difference -1.5, 95% CI[-2.9,-0.1], p=0.04) and symbol search (mean difference -1.5, 95% CI[-2.7,-0.2], p=0.03) and Grooved Pegboard (dominant hand mean difference -7.0, 95% CI[-11.5,-2.4], p=0.003; non-dominant mean difference -9.8, 95% CI[-14.9,-4.7], p⟨0.001). Differences were detected in ANAM simple reaction time (p=0.04) and mathematical processing (p=0.03) but not verbal fluency or visuospatial memory assessments. Results indicate increased symptom severity and some cognitive deficits in mTBI÷ PTSD compared to mTBI alone.

Baseline EEG abnormalities in mild traumatic brain injury from the BIMA study.

The Brain Injury and Mechanisms of Action of HBO₂ for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (BIMA), sponsored by the Department of Defense, is a randomized, double-blind, sham-controlled trial of hyperbaric oxygen (HBO₂) in service members with persistent post-concussive symptoms following mild TBI, undergoing comprehensive assessments. The clinical EEG was assessed by neurologists for slow wave activity, ictal/interictal epileptiform abnormalities, and background periodic discharges. There is scant literature about EEG findings in this population, so we report baseline clinical EEG results and explore associations with other evaluations, including demographics, medication, neurological assessments, and clinical MRI outcomes. Seventy-one participants were enrolled: median age 32 years, 99% male, 49% comorbid PTSD, 28% with mTBI in the previous year, 32% blast injuries only, and 73% multiple injuries. All participants reported medication use (mean medications = 8, SD = 5). Slowing was present in 39%: generalized 37%, localized 8%, both 6%. No other abnormalities were identified. Slowing was not significantly associated with demographics, medication or neurological evaluation. Participants without EEG abnormalities paradoxically had significantly higher number of white matter hyperintensities as identified on MRI (p = 0.003). EEG slowing is present in more than one-third of participants in this study without evidence of associations with demographics, medications or neurological findings.

Linear analysis of heart rate variability in post-concussive syndrome.

Heart rate variability (HRV) represents measurable output of coordinated structural and functional systems within the body and brain. Both mild traumatic brain injury (mTBI) and HRV are modulated by changes in autonomic nervous system function. We present baseline HRV results from an ongoing mTBI clinical trial. HRV was assessed via 24-hour ambulatory electrocardiography; recordings were segmented by physiological state (sleep, wakefulness, exercise, standing still). Time, frequency, and spatial domain measures were summarized and compared with symptoms, sleep quality, and neurological examination. Median low frequency/high frequency (LF/HF) ratio exceeded 1.0 across segments, indicating prevalence of sympathetic modulation. Abnormal Sharpened Romberg Test was associated with 29% LF/HF decrease (95% CI [2.1, 47.7], p=0.04); pathological nystagmus associated with decreased standard deviation of electrocardiogram R-R interval (SDNN) index (25% decrease, 95% CI [0.8, 43.4], p=0.04). Increased sympathetic modulation was associated with increased anger scores (19% LF/HF increase with 5-point State Trait Anger Expression Inventory-2 trait anger increase (95% CI [1.2, 39.1], p=0.04)). A 13% HF increase (95% CI [2.1, 25.7], p=0.02) was observed with increased Pittsburgh Sleep Quality Index scores. These results support autonomic nervous system dysfunction in service members after mTBI.

Sleep assessments for a mild traumatic brain injury trial in a military population.

Baseline sleep characteristics were explored for 71 U.S. military service members with mild traumatic brain injury (mTBI) enrolled in a post-concussive syndrome clinical trial. The Pittsburgh Sleep Quality Index (PSQI), sleep diary, several disorder-specific questionnaires, actigraphy and polysomnographic nap were collected. Almost all (97%) reported ongoing sleep problems. The mean global PSQI score was 13.5 (SD=3.8) and 87% met insomnia criteria. Sleep maintenance efficiency was 79.1% for PSQI, 82.7% for sleep diary and 90.5% for actigraphy; total sleep time was 288, 302 and 400 minutes, respectively. There was no correlation between actigraphy and subjective questionnaires. Overall, 70% met hypersomnia conditions, 70% were at high risk for obstructive sleep apnea (OSA), 32% were symptomatic for restless legs syndrome, and 6% reported cataplexy. Nearly half (44%) reported coexisting insomnia, hypersomnia and high OSA risk. Participants with post-traumatic stress disorder (PTSD) had higher PSQI scores and increased OSA risk. Older participants and those with higher aggression, anxiety or depression also had increased OSA risk. The results confirm poor sleep quality in mTBI with insomnia, hypersomnia, and OSA risk higher than previously reported, and imply sleep disorders in mTBI may be underdiagnosed or exacerbated by comorbid PTSD.

Executive summary: The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) Study.

The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) study, sponsored by the Department of Defense and held under an investigational new drug application by the Office of the Army Surgeon General, is one of the largest and most complex clinical trials of hyperbaric oxygen (HBO₂) for post-concussive symptoms (PCS) in U.S. military service members.

Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients.

Background: Recent clinical studies in stroke and traumatic brain injury (TBI) victims suffering chronic neurological injury present evidence that hyperbaric oxygen therapy (HBOT) can induce neuroplasticity. Objective: To assess the neurotherapeutic effect of HBOT on prolonged post-concussion syndrome (PPCS) due to TBI, using brain microstructure imaging. Methods: Fifteen patients afflicted with PPCS were treated with 60 daily HBOT sessions. Imaging evaluation was performed using Dynamic Susceptibility Contrast-Enhanced (DSC) and Diffusion Tensor Imaging (DTI) MR sequences. Cognitive evaluation was performed by an objective computerized battery (NeuroTrax). Results: HBOT was initiated 6 months to 27 years (10.3 ± 3.2 years) from injury. After HBOT, DTI analysis showed significantly increased fractional anisotropy values and decreased mean diffusivity in both white and gray matter structures. In addition, the cerebral blood flow and volume were increased significantly. Clinically, HBOT induced significant improvement in the memory, executive functions, information processing speed and global cognitive scores. Conclusions: The mechanisms by which HBOT induces brain neuroplasticity can be demonstrated by highly sensitive MRI techniques of DSC and DTI. HBOT can induce cerebral angiogenesis and improve both white and gray microstructures indicating regeneration of nerve fibers. The micro structural changes correlate with the neurocognitive improvements.

Neuroprotective effect of hyperbaric oxygen therapy in a juvenile rat model of repetitive mild traumatic brain injury.

Repetitive mild traumatic brain injury (rmTBI) is an important medical concern for adolescent athletes that can lead to long-term disabilities. Multiple mild injuries may exacerbate tissue damage resulting in cumulative brain injury and poor functional recovery. In the present study, we investigated the increased brain vulnerability to rmTBI and the effect of hyperbaric oxygen treatment using a juvenile rat model of rmTBI. Two episodes of mild cortical controlled impact (3 days apart) were induced in juvenile rats. Hyperbaric oxygen (HBO) was applied 1 hour/day × 3 days at 2 atmosphere absolute consecutively, starting at 1 day after initial mild traumatic brain injury (mTBI). Neuropathology was assessed by multi-modal magnetic resonance imaging (MRI) and tissue immunohistochemistry. After repetitive mTBI, there were increases in T2-weighted imaging-defined cortical lesions and susceptibility weighted imaging-defined cortical microhemorrhages, correlated with brain tissue gliosis at the site of impact. HBO treatment significantly decreased the MRI-identified abnormalities and tissue histopathology. Our findings suggest that HBO treatment improves the cumulative tissue damage in juvenile brain following rmTBI. Such therapy regimens could be considered in adolescent athletes at the risk of repeated concussions exposures.