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A Decade of mTBI Experience: What Have We Learned? A Summary of Proceedings From a NATO Lecture Series on Military mTBI

Robinson-Freeman, Katherine E; Collins, Kassondra L; Garber, Bryan; Terblanche, Ronel; Risling, Marten; Vermetten, Eric; Besemann, Markus; Mistlin, Alan; Tsao, Jack W
Mild traumatic brain injury (mTBI, also known as a concussion) as a consequence of battlefield blast exposure or blunt force trauma has been of increasing concern to militaries during recent conflicts. This concern is due to the frequency of exposure to improvised explosive devices for forces engaged in operations both in Iraq and Afghanistan coupled with the recognition that mTBI may go unreported or undetected. Blasts can lead to mTBI through a variety of mechanisms. Debate continues as to whether exposure to a primary blast wave alone is sufficient to create brain injury in humans, and if so, exactly how this occurs with an intact skull. Resources dedicated to research in this area have also varied substantially among contributing NATO countries. Most of the research has been conducted in the US, focused on addressing uncertainties in management practices. Development of objective diagnostic tests should be a top priority to facilitate both diagnosis and prognosis, thereby improving management. It is expected that blast exposure and blunt force trauma to the head will continue to be a potential source of injury during future conflicts. An improved understanding of the effects of blast exposure will better enable military medical providers to manage mTBI cases and develop optimal protective measures. Without the immediate pressures that come with a high operational tempo, the time is right to look back at lessons learned, make full use of available data, and modify mitigation strategies with both available evidence and new evidence as it comes to light. Toward that end, leveraging our cooperation with the civilian medical community is critical because the military experience over the past 10 years has led to a renewed interest in many similar issues pertaining to mTBI in the civilian world. Such cross-fertilization of knowledge will undoubtedly benefit all. This paper highlights similarities and differences in approach to mTBI patient care in NATO and partner countries and provides a summary of and lessons learned from a NATO lecture series on the topic of mTBI, demonstrating utility of having patients present their experiences to a medical audience, linking practical clinical care to policy approaches.
PMID: 32982907
ISSN: 1664-2295
CID: 4956462

Performance on the DANA Brief Cognitive Test Correlates With MACE Cognitive Score and May Be a New Tool to Diagnose Concussion

Pryweller, Jennifer R; Baughman, Brandon C; Frasier, Samuel D; O'Conor, Ellen C; Pandhi, Abhi; Wang, Jiajing; Morrison, Aimee A; Tsao, Jack W
Nearly 380,000 U.S. service members between 2000 and 2017 were, and at least 300,000 athletes annually are, diagnosed with concussion. It is imperative to establish a gold-standard diagnostic test to quickly and accurately diagnose concussion. In this non-randomized, prospective study, we examined the reliability and validity of a novel neurocognitive assessment tool, the Defense Automated Neurobehavioral Assessment (DANA), designed to be a more sensitive, yet efficient, measure of concussion symptomatology. In this study, the DANA Brief version was compared to an established measure of concussion screening, the Military Acute Concussion Evaluation (MACE), in a group of non-concussed service members. DANA Brief subtests demonstrated low to moderate reliability, as measured by intra-class correlation coefficient (ICC; values range: 0.28-0.58), which is comparable to other computerized neurocognitive tests that are widely-implemented to diagnose concussion. Statistically significant associations were found between learning and memory components of the DANA Brief and the diagnostic MACE cognitive test score (DANA Brief subtests: CDD: R 2 = 0.05, p = 0.023; CDS: R 2 = 0.10, p = 0.010). However, a more robust relationship was found between DANA Brief components involving attention and working memory, including immediate memory, and the MACE cognitive test score (DANA Brief subtests: GNG: R 2 = 0.08, p = 0.003; PRO: R 2 = 0.08, p = 0.002). These results provide evidence that the DANA Rapid version, a 5-min assessment self-administered on a hand-held portable device, based on the DANA Brief version, may serve as a clinically useful and improved neurocognitive concussion screen to minimize the time between injury and diagnosis in settings where professional medical evaluation may be unavailable or delayed. The DANA's portability, durability, shorter test time and lack of need for a medical professional to diagnose concussion overcome these critical limitations of the MACE.
PMID: 32982908
ISSN: 1664-2295
CID: 4956472

Practice Current: How do you diagnose and treat post-concussive headache?

Dave, Ajal; Ganesh, Aravind; Adil, Malik Muhammad; Tsao, Jack W
A common complaint after concussion is the development of new or worsening headaches which can make it difficult or even impossible for patients to work or function in their day-to-day lives. Uncertainties associated with the complaints and a wide variety of approaches exist regarding the appropriate work-up and management of these patients. Areas of ongoing debate include the need for neuroimaging; optimal, acute, and preventative treatment; and proper counseling and expectation management. Given the wide variety of potential approaches and the lack of consensus, we sought expert opinion from around the globe on how to evaluate and manage patients with headache following concussion. Similar questions were posed to the rest of our readership in an online survey (, the results of which are also presented.
PMID: 31341715
ISSN: 2163-0402
CID: 4956432

Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity

Sapio, Matthew R; Iadarola, Michael J; LaPaglia, Danielle M; Lehky, Tanya; Thurm, Audrey E; Danley, Kristen M; Fuhr, Shannon R; Lee, Mark D; Huey, Amanda E; Sharp, Stephen J; Tsao, Jack W; Yanovski, Jack A; Mannes, Andrew J; Han, Joan C
Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.
PMID: 30855519
ISSN: 1872-6623
CID: 4956362

Eye Movement Dynamics Differ between Encoding and Recognition of Faces

Arizpe, Joseph M; Noles, Danielle L; Tsao, Jack W; Chan, Annie W-Y
Facial recognition is widely thought to involve a holistic perceptual process, and optimal recognition performance can be rapidly achieved within two fixations. However, is facial identity encoding likewise holistic and rapid, and how do gaze dynamics during encoding relate to recognition? While having eye movements tracked, participants completed an encoding ("study") phase and subsequent recognition ("test") phase, each divided into blocks of one- or five-second stimulus presentation time conditions to distinguish the influences of experimental phase (encoding/recognition) and stimulus presentation time (short/long). Within the first two fixations, several differences between encoding and recognition were evident in the temporal and spatial dynamics of the eye-movements. Most importantly, in behavior, the long study phase presentation time alone caused improved recognition performance (i.e., longer time at recognition did not improve performance), revealing that encoding is not as rapid as recognition, since longer sequences of eye-movements are functionally required to achieve optimal encoding than to achieve optimal recognition. Together, these results are inconsistent with a scan path replay hypothesis. Rather, feature information seems to have been gradually integrated over many fixations during encoding, enabling recognition that could subsequently occur rapidly and holistically within a small number of fixations.
PMID: 31735810
ISSN: 2411-5150
CID: 4956442

Wartime neurology: Serving the neediest in an austere environment [Editorial]

Etienne, Mill; Tsao, Jack W
PMID: 30859000
ISSN: 2163-0402
CID: 4956372

Lowering systolic blood pressure does not increase stroke risk: an analysis of the SPRINT and ACCORD trial data

O'Conor, Ellen C; Wang, Jiajing; Gibney, Kyla D; Yu, Xinhua; Young, Garrett R; Jones, Tamekia; Alexandrov, Anne W; Johnson, Karen C; Cushman, William C; Tsao, Jack W
Objective:Traditional neurology teaching states that when mean arterial pressure dips below a 60 mm Hg threshold, there is an increase in stroke risk due to cerebral hypoperfusion. The aim of this study was to determine whether intensive lowering of systolic blood pressure increases adverse cardiovascular outcomes by examining the association between achieved blood pressure values, specifically mean arterial pressure and pulse pressure, and risk of stroke. Methods:Data from participants in the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure (BP) trial were examined, using survival analysis to model minimal arterial pressure and average pulse pressure during the study period against risk of stroke, hypotension, and syncope, with death as a competing risk. Results:In both SPRINT and ACCORD participants, there was no increase in stroke risk with achieved mean arterial pressure values below 60 mm Hg. In SPRINT participants, achieved mean arterial pressure values greater than 90 mm Hg were associated with a 247% (HR: 3.47, 95% CI: 2.06-5.85) higher risk of stroke compared with participants in the 80-89 mmHg reference group. No association was found between low achieved pulse pressure values and greater stroke risk in either the SPRINT or ACCORD participants, as well as no association between mean arterial pressure and pulse pressure values and risk of syncope. Interpretation:Intensive lowering of systolic blood pressure does not increase risk of stroke in hypertensive patients, despite extremely low mean arterial pressure or pulse pressure values.
PMID: 30656192
ISSN: 2328-9503
CID: 4956352

Neuroimaging and Neuropsychological Studies in Sports-Related Concussions in Adolescents: Current State and Future Directions

Narayana, Shalini; Charles, Christopher; Collins, Kassondra; Tsao, Jack W; Stanfill, Ansley Grimes; Baughman, Brandon
Sports-related concussion, is a serious neurological concern that many adolescent athletes will face during their athletic careers. In some instances, the effects of sports-related head injury are long-lasting. Due to their still-developing brains, adolescents appear to be more vulnerable to long-term repercussions of these injuries. As all sports-related concussions are mild traumatic brain injuries (mTBI), this review we will examine the pathophysiology of mTBI, its acute effects and long-term risks from sustaining injury, and current and needed advancements in the areas of neuropsychological testing, accelerometer telemetry, and neuroimaging. Current methods do not adequately measure the extent of an injury that an athlete may sustain, potentially putting these athletes at a much greater risk for long-term effects. To better understand mTBI, neuropsychological testing best practices need to be developed, standardized, and implemented based on sound scientific evidence in order to be propagated as clinical guidelines. Wearable accelerometers can be used to assess thresholds for mTBI and cumulative effects of concussive and subconcussive injuries. Novel neuroimaging methods that can detect anatomical abnormalities and functional deficits with more specificity and sensitivity should be developed. Young athletes are particularly a vulnerable population warranting immediate and significant research aimed at protecting them against sports related injury and mitigating their long-term deficits.
PMID: 31178818
ISSN: 1664-2295
CID: 4956382

Visual responsiveness in sensorimotor cortex is increased following amputation and reduced after mirror therapy

Chan, Annie W-Y; Bilger, Emily; Griffin, Sarah; Elkis, Viktoria; Weeks, Sharon; Hussey-Anderson, Lindsay; Pasquina, Paul F; Tsao, Jack W; Baker, Chris I
Phantom limb pain (PLP) following amputation, which is experienced by the vast majority of amputees, has been reported to be relieved with daily sessions of mirror therapy. During each session, a mirror is used to view the reflected image of the intact limb moving, providing visual feedback consistent with the movement of the missing/phantom limb. To investigate potential neural correlates of the treatment effect, we measured brain responses in volunteers with unilateral leg amputation using functional magnetic resonance imaging (fMRI) during a four-week course of mirror therapy. Mirror therapy commenced immediately following baseline scans, which were repeated after approximately two and four week intervals. We focused on responses in the region of sensorimotor cortex corresponding to primary somatosensory and motor representations of the missing leg. At baseline, prior to starting therapy, we found a strong and unexpected response in sensorimotor cortex of amputees to visually presented images of limbs. This response was stronger for images of feet compared to hands and there was no such response in matched controls. Further, this response to visually presented limbs was no longer present at the end of the four week mirror therapy treatment, when perceived phantom limb pain was also reduced. A similar pattern of results was also observed in extrastriate and parietal regions typically responsive to viewing hand actions, but not in regions corresponding to secondary somatosensory cortex. Finally, there was a significant correlation between initial visual responsiveness in sensorimotor cortex and reduction in PLP suggesting a potential marker for predicting efficacy of mirror therapy. Thus, enhanced visual responsiveness in sensorimotor cortex is associated with PLP and modulated over the course of mirror therapy.
PMID: 31226622
ISSN: 2213-1582
CID: 4956392

Relationships Between Sleepiness, Mood, and Neurocognitive Performance in Military Personnel

Haran, F J; Schumacher, Patrick; Markwald, Rachel; Handy, Justin D; Tsao, Jack W
Neurocognitive computerized assessment tools (NCATs) were developed to assist military clinicians with the tracking of recovery from injury and return to full duty decisions with a recent focus on the setting of post-concussion evaluations. However, there is limited data on the impact of deployment on neurocognitive functioning, sleepiness, and mood in healthy, non-concussed Service members. Automated Neuropsychological Assessment Metrics version 4 TBI Military (ANAM) data was obtained for a sample of active duty deployed personnel (n = 72) without recent history of mild traumatic brain injury (mTBI). A linear regression was conducted to examine the effects of sleepiness and mood state on neurocognitive performance. The overall multivariate regression was statistically significant. Negative mood states were the most salient predictors of neurocognitive performance with higher levels of endorsement associated with lower scores. The findings support measures of negative mood state, but not sleepiness, as relevant predictors of neurocognitive performance as measured by the ANAM. These results indicate that mood needs to be considered when reviewing neurocognitive data to ensure that appropriate clinical decisions are made; in particular for return-to-duty decisions in deployed settings after concussion recovery.
PMID: 31316453
ISSN: 1664-2295
CID: 4956412