Jack W. Tsao

Amelioration of Acute Sequelae of Blast Induced Mild Traumatic Brain Injury by N-Acetyl Cysteine: A Double- Blind, Placebo Controlled Study

Background Mild traumatic brain injury (mTBI) secondary to blast exposure is the most common battlefield injury in Southwest Asia. There has been little prospective work in the combat setting to test the efficacy of new countermeasures. The goal of this study was to compare the efficacy of N-acetyl cysteine (NAC) versus placebo on the symptoms associated with blast exposure mTBI in a combat setting. Methods This study was a randomized double blind, placebo-controlled study that was conducted on active duty service members at a forward deployed field hospital in Iraq. All symptomatic U.S. service members who were exposed to significant ordnance blast and who met the criteria for mTBI were offered participation in the study and 81 individuals agreed to participate. Individuals underwent a baseline evaluation and then were randomly assigned to receive either N-acetyl cysteine (NAC) or placebo for seven days. Each subject was re-evaluated at 3 and 7 days. Outcome measures were the presence of the following sequelae of mTBI: dizziness, hearing loss, headache, memory loss, sleep disturbances, and neurocognitive dysfunction. The resolution of these symptoms seven days after the blast exposure was the main outcome measure in this study. Logistic regression on the outcome of ‘no day 7 symptoms’ indicated that NAC treatment was significantly better than placebo (ORu200a=u200a3.6, pu200a=u200a0.006). Secondary analysis revealed subjects receiving NAC within 24 hours of blast had an 86% chance of symptom resolution with no reported side effects versus 42% for those seen early who received placebo. Conclusion This study, conducted in an active theatre of war, demonstrates that NAC, a safe pharmaceutical countermeasure, has beneficial effects on the severity and resolution of sequelae of blast induced mTBI. This is the first demonstration of an effective short term countermeasure for mTBI. Further work on long term outcomes and the potential use of NAC in civilian mTBI is warranted. Trial Registration ClinicalTrials.gov NCT00822263

AltitudeOmics: the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent.

An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1) to describe a phenotype for successful acclimatization and assess its retention and 2) use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS), cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (nu200a=u200a14) or 21 (nu200a=u200a7) days at 1525 m. At 16 days at 5260 m we observed: 1) increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO2 rose 9±4 mmHg to 45±4 while PaCO2 dropped a further 6±3 mmHg to 21±3, and [Hb] rose 1.8±0.7 g/dL to 16±2 g/dL; 2) no AMS; 3) improved cognitive function; and 4) improved exercise performance by 8±8% (all changes p<0.01). Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention.

The Impact of Multiple Concussions on Emotional Distress, Post-Concussive Symptoms, and Neurocognitive Functioning in Active Duty United States Marines Independent of Combat Exposure or Emotional Distress

Controversy exists as to whether the lingering effects of concussion on emotional, physical, and cognitive symptoms is because of the effects of brain trauma or purely to emotional factors such as post-traumatic stress disorder or depression. This study examines the independent effects of concussion on persistent symptoms. The Defense Automated Neurobehavioral Assessment, a clinical decision support tool, was used to assess neurobehavioral functioning in 646 United States Marines, all of whom were fit for duty. Marines were assessed for concussion history, post-concussive symptoms, emotional distress, neurocognitive functioning, and deployment history. Results showed that a recent concussion or ever having experienced a concussion was associated with an increase in emotional distress, but not with persistent post-concussive symptoms (PPCS) or neurocognitive functioning. Having had multiple lifetime concussions, however, was associated with greater emotional distress, PPCS, and reduced neurocognitive functioning that needs attention and rapid discrimination, but not for memory-based tasks. These results are independent of deployment history, combat exposure, and symptoms of post-traumatic stress disorder and depression. Results supported earlier findings that a previous concussion is not generally associated with post-concussive symptoms independent of covariates. In contrast with other studies that failed to find a unique contribution for concussion to PPCS, however, evidence of recent and multiple concussion was seen across a range of emotional distress, post-concussive symptoms, and neurocognitive functioning in this study population. Results are discussed in terms of implications for assessing concussion on return from combat.

Repeated low-level blast exposure: A descriptive human subjects study

The relationship between repeated exposure to blast overpressure and neurological function was examined in the context of breacher training at the U.S. Marine Corps Weapons Training Battalion Dynamic Entry School. During this training, Students are taught to apply explosive charges to achieve rapid ingress into secured buildings. For this study, both Students and Instructors participated in neurobehavioral testing, blood toxin screening, vestibular/auditory testing, and neuroimaging. Volunteers wore instrumentation during training to allow correlation of human response measurements and blast overpressure exposure. The key findings of this study were from high-memory demand tasks and were limited to the Instructors. Specific tests showing blast-related mean differences were California Verbal Learning Test II, Automated Neuropsychological Assessment Metrics subtests (Match-to-Sample, Code Substitution Delayed), and Delayed Matching-to-Sample 10-second delay condition. Importantly, apparent deficits were paralleled with functional magnetic resonance imaging using the n-back task. The findings of this study are suggestive, but not conclusive, owing to small sample size and effect. The observed changes yield descriptive evidence for potential neurological alterations in the subset of individuals with occupational history of repetitive blast exposure. This is the first study to integrate subject instrumentation for measurement of individual blast pressure exposure, neurocognitive testing, and neuroimaging.

Defense Automated Neurobehavioral Assessment (DANA)-psychometric properties of a new field-deployable neurocognitive assessment tool.

The Defense Automated Neurobehavioral Assessment (DANA) is a new neurocognitive assessment tool that includes a library of standardized cognitive and psychological assessments, with three versions that range from a brief 5-minute screen to a 45-minute complete assessment. DANA is written using the Android open-source operating system and is suitable for multiple mobile platforms. This article presents testing of DANA by 224 active duty U.S. service members in five operationally relevant environments (desert, jungle, mountain, arctic, and shipboard). DANA was found to be a reliable instrument and compared favorably to other computer-based neurocognitive assessments. Implications for using DANA in far-forward military settings are discussed.

Reflex-sensitive spinal segmental myoclonus associated with vitamin B12 deficiency

Reflex-sensitive spinal segmental myoclonus is an unusual entity, with myoclonus localized and restricted to an isolated spinal cord level. The myoclonus is enhanced by external stimuli, such as tendon percussion.1-4⇓⇓⇓ We describe two patients with vitamin B12 deficiency who developed reflex-sensitive myoclonus.nnAn 87-year-old man experienced progressively worsening gait. Vitamin B12 deficiency was diagnosed 7 years earlier with a serum B12 level 187) and an abnormal Schilling test. The patient failed to receive prescribed B12 injections, and four additional below-normal serum B12 measurements were documented during the 7 years. The patient also had abdominal jerks persisting during sleep, which had worsened during the preceding 4 years. Mentation was normal. Motor and sensory tests revealed moderate, distal weakness and loss of vibratory and joint position senses in the hands and legs. A thoracic dermatomal sensory gradient was not present. Reflexes were 1+ at the biceps and triceps and absent at the patellar and Achilles tendons. The gait was wide based; Romberg’s sign was strongly positive. Spontaneous myoclonic jerks of abdominal muscles occurred with variable frequency during the examination. In 1 minute, 18 clusters totaling 70 contractions were counted. …

AltitudeOmics: Decreased reaction time after high altitude cognitive testing is a sensitive metric of hypoxic impairment.

Humans experiencing hypoxic conditions exhibit multiple signs of cognitive impairment, and high altitude expeditions may be undermined by abrupt degradation in mental performance. Therefore, the development of psychometric tools to quickly and accurately assess cognitive impairment is of great importance in aiding medical decision-making in the field, particularly in situations where symptoms may not be readily recognized. The present study used the Defense Automated Neurobehavioral Assessment (DANA), a ruggedized and portable neurocognitive assessment tool, to examine cognitive function in healthy human volunteers at sea level, immediately after ascending to an elevation over 5000 m, and following 16 days of acclimatization to this high altitude. The DANA battery begins with a simple reaction time test (SRT1) which is followed by a 20-min series of complex cognitive tests and ends with a second test of simple reaction time (SRT2). Tabulating the performance scores from these two tests allows the calculation of an SRT change score (dSRT=SRT1–SRT2) that reflects the potential effect of mental effort spent during the 20-min testing session. We found that dSRT, but not direct SRT in comparison to sea-level baseline performance, is highly sensitive to acute altitude-related performance deficits and the remission of impairment following successful acclimatization. Our results suggest that dSRT is a potentially useful analytical method to enhance the sensitivity of neurocognitive assessment.

Analysis of Post-Deployment Cognitive Performance and Symptom Recovery in U.S. Marines

Background Computerized neurocognitive testing (NCAT) has been proposed to be useful as a screening tool for post-deployment cognitive deficits in the setting of mild traumatic brain injury (mTBI). We assessed the clinical utility of post-injury/post-deployment Automated Neurocognitive Assessment Metric (ANAM) testing, using a longitudinal design to compare baseline ANAM tests with two post-deployment ANAM tests in a group of Marines who experienced combat during deployment. Methods and Findings Post-deployment cognitive performance and symptom recovery were compared in a subsample of 1324 U.S. Marines with high rates of combat exposure during deployment. Of the sample, 169 Marines had available baseline and twice repeated post-deployment ANAM results. A retrospective analysis of the ANAM data, which consisted of a self-report questionnaire about deployment-related blast exposure, recent history of mTBI, current clinical symptoms, and cognitive performance. Self-reported concussion sustained anytime during deployment was associated with a decrease in cognitive performance measured between 2–8 weeks post-deployment. At the second post-deployment test conducted on average eight months later, performance on the second simple reaction time test, in particular, remained impaired and was the most consistent and sensitive indicator of the cognitive decrements. Additionally, post-concussive symptoms were shown to persist in injured Marines with a self-reported history of concussion for an additional five months after most cognitive deficits resolved. Results of this study showed a measurable deployment effect on cognitive performance, although this effect appears to resolve without lasting clinical sequelae in those without history of deployment-related concussion. Conclusions These results highlight the need for a detailed clinical examination for service members with history of concussion and persistent clinical symptoms. Reliance solely upon computerized neurocognitive testing as a method for identifying service members requiring clinical follow-up post-concussion is not recommended, as cognitive functioning only slowly returned to baseline levels in the setting of persistent clinical symptoms.

Comment on “Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model”

In their recent paper, Goldstein et al. show murine brain tau neuropathology after explosive blast with head rotation but do not present additional evidence that would delineate whether this neuropathology was principally caused by blast exposure alone or by blast exposure plus head rotational injury. None In their recent paper, Goldstein et al. show murine brain tau neuropathology after explosive blast with head rotation but do not present additional evidence that would delineate whether this neuropathology was principally caused by blast exposure alone or by blast exposure plus head rotational injury.

Comparison of baseline-referenced versus norm-referenced analytical approaches for in-theatre assessment of mild traumatic brain injury neurocognitive impairment

Abstract Primary objective: To examine differences between the baseline-referenced and norm-referenced approaches for determining decrements in Automated Neuropsychological Assessment Metrics Version 4 TBI-MIL (ANAM) performance following mild traumatic brain injury (mTBI). Research design: ANAM data were reviewed for 616 US Service members, with 528 of this sample having experienced an mTBI and 88 were controls. Methods and procedures: Post-injury change scores were calculated for each sub-test: (1) normative change score = in-theater score – normative mean and (2) baseline change score = in-theater score – pre-deployment baseline. Reliable change cut-scores were applied to the change and the resulting frequency distributions were compared using McNemar tests. Receiver operator curves (ROC) using both samples (i.e. mTBI and control) were calculated for the change scores for each approach to determine the discriminate ability of the ANAM. Main outcomes and results: There were no statistical differences, p < 0.05 (Bonferonni-Holm corrected), between the approaches. When the area under the curve for the ROCs were averaged across sub-tests, there were no significant differences between either the norm-referenced (0.65) or baseline-referenced (0.66) approaches, p > 0.05. Conclusions: Overall, the findings suggest there is no clear advantage of using the baseline-referenced approach over norm-referenced approach.