White matter and hypoxic hypobaria in humans.

Occupational exposure to hypobaria (low atmospheric pressure) is a risk factor for reduced white matter integrity, increased white matter hyperintensive burden, and decline in cognitive function. We tested the hypothesis that a discrete hypobaric exposure will have a transient impact on cerebral physiology. Cerebral blood flow, fractional anisotropy of water diffusion in cerebral white matter, white matter hyperintensity volume, and concentrations of neurochemicals were measured at baseline and 24 hr and 72 hr postexposure in N = 64 healthy aircrew undergoing standard US Air Force altitude chamber training and compared to N = 60 controls not exposed to hypobaria. We observed that hypobaric exposure led to a significant rise in white matter cerebral blood flow (CBF) 24 hr postexposure that remained elevated, albeit not significantly, at 72 hr. No significant changes were observed in structural measurements or gray matter CBF. Subjects with higher baseline concentrations of neurochemicals associated with neuroprotection and maintenance of normal white matter physiology (glutathione, N-acetylaspartate, glutamate/glutamine) showed proportionally less white matter CBF changes. Our findings suggest that discrete hypobaric exposure may provide a model to study white matter injury associated with occupational hypobaric exposure.

White matter hyperintensities and hypobaric exposure.

OBJECTIVE: Demonstrate that occupational exposure to nonhypoxic hypobaria is associated with subcortical white matter hyperintensities (WMHs) on fluid-attenuated inversion recovery magnetic resonance imaging (MRI). METHODS: Eighty-three altitude chamber personnel (PHY), 105 U-2 pilots (U2P), and 148 age- controlled and health-matched doctorate degree controls (DOC) underwent high-resolution MRI. Subcortical WMH burden was quantified as count and volume of subcortical WMH lesions after transformation of images to the Talairach atlas-based stereotactic frame. RESULTS: Subcortical WMHs were more prevalent in PHY (volume p = 0.011/count p = 0.019) and U2P (volume p < 0.001/count p < 0.001) when compared to DOC, whereas PHY were not significantly different than U2P. INTERPRETATION: This study provides strong evidence that nonhypoxic hypobaric exposure may induce subcortical WMHs in a young, healthy population lacking other risk factors for WMHs and adds this occupational exposure to other environmentally related potential causes of WMHs. Ann Neurol 2014;76:719-726.

Aeromedical decision making and seizure risk after traumatic brain injury: longitudinal outcome.

INTRODUCTION: Traumatic brain injury (TBI) is common in young adults and therefore of significant concern to an aircrew population. This paper reports the occurrences of seizures in U.S. Air Force (USAF) aircrew following receipt of an aeromedical waiver for TBI. METHODS: Using both an aeromedical waiver tracking system database and medical records, we identified surrogate seizure markers such as all episodes of subsequent TBI, seizure, loss of consciousness, or prescription of anticonvulsant medications from the time of initial TBI until the last medical visit or entry recorded in either the database or medical records for our study population. RESULTS: The seizure rate for aircrew who met USAF waiver criteria was 24.53/100,000 person-years. One pilot experienced a major motor seizure 14.9 yr following a severe TBI for an incidence of 308.64/100,000 person-years. DISCUSSION: The USAF waiver process following TBI was sufficiently effective in removing aircrew with elevated risk for seizure following TBI. While our rates of post-traumatic seizure appear to be lower than previously published civilian population rates, direct comparison cannot be made secondary to differences in study design and selection criteria. Further areas of study could involve a more detailed analysis of aircrew neurocognitive status following TBI for subtle changes, crosschecking USAF Safety Center data for changes in accident rates among post-TBI aircrew, and analysis of lost aircrew flying time as a result of TBI and the degree of burden that loss places on the flying mission. CONCLUSION: Application of these stringent criteria is sufficient to fulfill aeromedical safety standards, but costs remain undetermined.

Hyperintense white matter lesions in 50 high-altitude pilots with neurologic decompression sickness.

INTRODUCTION: Neurologic decompression sickness (NDCS) can affect high-altitude pilots, causing variable central nervous system symptoms. Five recent severe episodes prompted further investigation. METHODS: We report the hyperintense white matter (HWM) lesion imaging findings in 50 U-2 pilot volunteers, and compare 12 U-2 pilots who experienced clinical NDCS to 38 U-2 pilots who did not. The imaging data were collected using a 3T magnetic resonance imaging scanner and high-resolution (1-mm isotropic) three-dimensional fluid-attenuated inversion recovery sequence. Whole-brain and regional lesion volume and number were compared between groups. RESULTS: The NDCS group had significantly increased whole brain and insular volumes of HWM lesions. The intergroup difference in lesion numbers was not significant. CONCLUSION: A clinical episode of NDCS was associated with a significant increase in HWM lesion volume, especially in the insula. We postulate this to be due to hypobaric exposure rather than hypoxia since all pilots were maintained on 100% oxygen throughout the flight. Further studies will be necessary to better understand the pathophysiology underlying these lesions.

Miniature pig model of human adolescent brain white matter development.

BACKGROUND: Neuroscience research in brain development and disorders can benefit from an in vivo animal model that portrays normal white matter (WM) development trajectories and has a sufficiently large cerebrum for imaging with human MRI scanners and protocols. NEW METHOD: Twelve three-month-old Sinclair™ miniature pigs (Sus scrofa domestica) were longitudinally evaluated during adolescent development using advanced diffusion weighted imaging (DWI) focused on cerebral WM. Animals had three MRI scans every 23.95 ±â€¯3.73 days using a 3-T scanner. The DWI imaging protocol closely modeled advanced human structural protocols and consisted of fifteen b-shells (b = 0-3500 s/mm2) with 32-directions/shell. DWI data were analyzed using diffusion kurtosis and bi-exponential modeling that provided measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axial kurtosis, tortuosity, and permeability-diffusivity index (PDI). RESULTS: Significant longitudinal effects of brain development were observed for whole-brain average FA, KA, and PDI (all p < 0.001). There were expected regional differences in trends, with corpus callosum fibers showing the highest rate of change. COMPARISON WITH EXISTING METHOD(S): Pigs have a large, gyrencephalic brain that can be studied using clinical MRI scanners/protocols. Pigs are less complex than non-human primates thus satisfying the "replacement" principle of animal research. CONCLUSIONS: Longitudinal effects were observed for whole-brain and regional diffusion measurements. The changes in diffusion measurements were interepreted as evidence for ongoing myelination and maturation of cerebral WM. Corpus callosum and superficial cortical WM showed the expected higher rates of change, mirroring results in humans.

Reproducibility of quantitative structural and physiological MRI measurements.

INTRODUCTION: Quantitative longitudinal magnetic resonance imaging and spectroscopy (MRI/S) is used to assess progress of brain disorders and treatment effects. Understanding the significance of MRI/S changes requires knowledge of the inherent technical and physiological consistency of these measurements. This longitudinal study examined the variance and reproducibility of commonly used quantitative MRI/S measurements in healthy subjects while controlling physiological and technical parameters. METHODS: Twenty-five subjects were imaged three times over 5 days on a Siemens 3T Verio scanner equipped with a 32-channel phase array coil. Structural (T1, T2-weighted, and diffusion-weighted imaging) and physiological (pseudocontinuous arterial spin labeling, proton magnetic resonance spectroscopy) data were collected. Consistency of repeated images was evaluated with mean relative difference, mean coefficient of variation, and intraclass correlation (ICC). Finally, a "reproducibility rating" was calculated based on the number of subjects needed for a 3% and 10% difference. RESULTS: Structural measurements generally demonstrated excellent reproducibility (ICCs 0.872-0.998) with a few exceptions. Moderate-to-low reproducibility was observed for fractional anisotropy measurements in fornix and corticospinal tracts, for cortical gray matter thickness in the entorhinal, insula, and medial orbitofrontal regions, and for the count of the periependymal hyperintensive white matter regions. The reproducibility of physiological measurements ranged from excellent for most of the magnetic resonance spectroscopy measurements to moderate for permeability-diffusivity coefficients in cingulate gray matter to low for regional blood flow in gray and white matter. DISCUSSION: This study demonstrates a high degree of longitudinal consistency across structural and physiological measurements in healthy subjects, defining the inherent variability in these commonly used sequences. Additionally, this study identifies those areas where caution should be exercised in interpretation. Understanding this variability can serve as the basis for interpretation of MRI/S data in the assessment of neurological disorders and treatment effects.

Utilization of MRI for Cerebral White Matter Injury in a Hypobaric Swine Model-Validation of Technique.

BACKGROUND: Repetitive hypobaric exposure in humans induces subcortical white matter change, observable on magnetic resonance imaging (MRI) and associated with cognitive impairment. Similar findings occur in traumatic brain injury (TBI). We are developing a swine MRI-driven model to understand the pathophysiology and to develop treatment interventions. METHODS: Five miniature pigs (Sus scrofa domestica) were repetitively exposed to nonhypoxic hypobaria (30,000 feet/FIO2 100%/transcutaneous PO2 >90%) while under general anesthesia. Three pigs served as controls. Pre-exposure and postexposure MRIs were obtained that included structural sequences, dynamic contrast perfusion, and diffusion tensor quantification. Statistical comparison of individual subject and group change was performed utilizing a two-tailed t test. FINDINGS: No structural imaging change was noted on T2-weighted or three-dimensional fluid-attenuated inversion recovery imaging between MRI 1 and MRI 2. No absolute difference in dynamic contrast perfusion was observed. A trend (p = 0.084) toward increase in interstitial extra-axonal fluid was noted. When individual subjects were examined, this trend toward increased extra-axonal fluid paralleled a decrease in contrast perfusion rate. DISCUSSION/IMPACT/RECOMMENDATIONS: This study demonstrates high reproducibility of quantitative noninvasive MRI, suggesting MRI is an appropriate assessment tool for TBI and hypobaric-induced injury research in swine. The lack of fluid-attenuated inversion recovery change may be multifactorial and requires further investigation. A trend toward increased extra-axonal water content that negatively correlates with dynamic contrast perfusion implies generalized axonal injury was induced. This study suggests this is a potential model for hypobaric-induced injury as well as potentially other axonal injuries such as TBI in which similar subcortical white matter change occurs. Further development of this model is necessary.

Reproducibility of tract-based white matter microstructural measures using the ENIGMA-DTI protocol.

BACKGROUND: In preparation for longitudinal analyses of white matter development in youths with family histories of substance use disorders (FH+) or without such histories (FH-), we examined the reproducibility and reliability of global and regional measures of fractional anisotropy (FA) values, measured using the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA)-diffusion tensor imaging (DTI) protocol. Highly reliable measures are necessary to detect any subtle differences in brain development. METHODS: First, we analyzed reproducibility data in a sample of 12 healthy young adults (ages 20-28) imaged three times within a week. Next, we calculated the same metrics in data collected 1-year apart in the sample of 68 FH+ and 21 FH- adolescents. This is a timeframe where within subject changes in white matter microstructure are small compared to between subject variance. Reproducibility was estimated by examining mean coefficients of variation (MCV), mean absolute differences (MAD), and intraclass correlations (ICC) for global and tract-specific FA values. RESULTS: We found excellent reproducibility for whole-brain DTI-FA values and most of the white matter tracts, except for the corticospinal tract and the fornix in both adults and youths. There was no significant effect of FH-group on reproducibility (p = .4). Reproducibility metrics were not significantly different between adolescents and adults (all p > .2). In post hoc analyses, the reproducibility metrics for regional FA values showed a strong positive correlation (r = .6) with the regional FA heritability measures previously reported by ENIGMA-DTI. CONCLUSION: Overall, this study demonstrated an excellent reproducibility of ENIGMA-DTI FA, positing it as viable analysis tools for longitudinal studies and other protocols that repeatedly assess white matter microstructure.

White Matter Integrity in High-Altitude Pilots Exposed to Hypobaria.

INTRODUCTION: Nonhypoxic hypobaric (low atmospheric pressure) occupational exposure, such as experienced by U.S. Air Force U-2 pilots and safety personnel operating inside altitude chambers, is associated with increased subcortical white matter hyperintensity (WMH) burden. The pathophysiological mechanisms underlying this discrete WMH change remain unknown. The objectives of this study were to demonstrate that occupational exposure to nonhypoxic hypobaria is associated with altered white matter integrity as quantified by fractional anisotropy (FA) measured using diffusion tensor imaging and relate these findings to WMH burden and neurocognitive ability. METHODS: There were 102 U-2 pilots and 114 age- and gender-controlled, health-matched controls who underwent magnetic resonance imaging. All pilots performed neurocognitive assessment. Whole-brain and tract-wise average FA values were compared between pilots and controls, followed by comparison within pilots separated into high and low WMH burden groups. Neurocognitive measurements were used to help interpret group difference in FA values. RESULTS: Pilots had significantly lower average FA values than controls (0.489/0.500, respectively). Regionally, pilots had higher FA values in the fronto-occipital tract where FA values positively correlated with visual-spatial performance scores (0.603/0.586, respectively). There was a trend for high burden pilots to have lower FA values than low burden pilots. DISCUSSION: Nonhypoxic hypobaric exposure is associated with significantly lower average FA in young, healthy U-2 pilots. This suggests that recurrent hypobaric exposure causes diffuse axonal injury in addition to focal white matter changes.McGuire SA, Boone GRE, Sherman PM, Tate DF, Wood JD, Patel B, Eskandar G, Wijtenburg SA, Rowland LM, Clarke GD, Grogan PM, Sladky JH, Kochunov PV. White matter integrity in high-altitude pilots exposed to hypobaria. Aerosp Med Hum Perform. 2016; 87(12):983-988.

Lower neurocognitive function in U-2 pilots: Relationship to white matter hyperintensities.

OBJECTIVE: Determine whether United States Air Force (USAF) U-2 pilots (U2Ps) with occupational exposure to repeated hypobaria had lower neurocognitive performance compared to pilots without repeated hypobaric exposure and whether U2P neurocognitive performance correlated with white matter hyperintensity (WMH) burden. METHODS: We collected Multidimensional Aptitude Battery-II (MAB-II) and MicroCog: Assessment of Cognitive Functioning (MicroCog) neurocognitive data on USAF U2Ps with a history of repeated occupational exposure to hypobaria and compared these with control data collected from USAF pilots (AFPs) without repeated hypobaric exposure (U2Ps/AFPs MAB-II 87/83; MicroCog 93/80). Additional comparisons were performed between U2Ps with high vs low WMH burden. RESULTS: U2Ps with repeated hypobaric exposure had significantly lower scores than control pilots on reasoning/calculation (U2Ps/AFPs 99.4/106.5), memory (105.5/110.9), information processing accuracy (102.1/105.8), and general cognitive functioning (103.5/108.5). In addition, U2Ps with high whole-brain WMH count showed significantly lower scores on reasoning/calculation (high/low 96.8/104.1), memory (102.9/110.2), general cognitive functioning (101.5/107.2), and general cognitive proficiency (103.6/108.8) than U2Ps with low WMH burden (high/low WMH mean volume 0.213/0.003 cm(3) and mean count 14.2/0.4). CONCLUSION: In these otherwise healthy, highly functioning individuals, pilots with occupational exposure to repeated hypobaria demonstrated lower neurocognitive performance, albeit demonstrable on only some tests, than pilots without repeated exposure. Furthermore, within the U2P population, higher WMH burden was associated with lower neurocognitive test performance. Hypobaric exposure may be a risk factor for subtle changes in neurocognition.