A regulatory pathway model of neuropsychological disruption in Havana syndrome

IntroductionIn 2016 diplomatic personnel serving in Havana, Cuba, began reporting audible sensory phenomena paired with onset of complex and persistent neurological symptoms consistent with brain injury. The etiology of these Anomalous Health Incidents (AHI) and subsequent symptoms remains unknown. This report investigates putative exposure-symptom pathology by assembling a network model of published bio-behavioral pathways and assessing how dysregulation of such pathways might explain loss of function in these subjects using data available in the published literature. Given similarities in presentation with mild traumatic brain injury (mTBI), we used the latter as a clinically relevant means of evaluating if the neuropsychological profiles observed in Havana Syndrome Havana Syndrome might be explained at least in part by a dysregulation of neurotransmission, neuro-inflammation, or both.MethodAutomated text-mining of >9,000 publications produced a network consisting of 273 documented regulatory interactions linking 29 neuro-chemical markers with 9 neuropsychological constructs from the Brief Mood Survey, PTSD Checklist, and the Frontal Systems Behavior Scale. Analysis of information flow through this network produced a set of regulatory rules reconciling to within a 6% departure known mechanistic pathways with neuropsychological profiles in N = 6 subjects.ResultsPredicted expression of neuro-chemical markers that jointly satisfy documented pathways and observed symptom profiles display characteristically elevated IL-1B, IL-10, NGF, and norepinephrine levels in the context of depressed BDNF, GDNF, IGF1, and glutamate expression (FDR < 5%). Elevations in CRH and IL-6 were also predicted unanimously across all subjects. Furthermore, simulations of neurological regulatory dynamics reveal subjects do not appear to be “locked in” persistent illness but rather appear to be engaged in a slow recovery trajectory.DiscussionThis computational analysis of measured neuropsychological symptoms in Havana-based diplomats proposes that these AHI symptoms may be supported in part by disruption of known neuroimmune and neurotransmission regulatory mechanisms also associated with mTBI

Residual Effects of Combat-Related Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) has gained considerable notoriety during the past decade of conflict in Afghanistan and Iraq. However, the relationship between combat-related mTBI and residual mTBI symptoms, post-traumatic stress disorder (PTSD) symptoms, and neurocognitive deficits remains unclear. The purpose of the study was to compare residual mTBI and PTSD symptoms, and neurocognitive deficits among U.S. Army Special Operations Command (USASOC) personnel with diagnosed blunt, blast, and blast-blunt combination mTBIs. This study involved a retrospective medical records review of 27,169 USASOC personnel who completed a military version of the Immediate Post-Concussion Assessment Cognitive Test (ImPACT), Post-Concussion Symptom Scale (PCSS), and PTSD Checklist (PCL) between November 2009 and December 2011. Of the 22,203 personnel who met criteria for the study, 2,813 (12.7%) had a diagnosis of at least one mTBI. A total of 28% (n=410) of USASOC personnel with a history of diagnosed mTBI reported clinical levels of PTSD symptoms. Personnel with a history of diagnosed blunt (OR=3.58), blast (OR=4.23) or combination (OR=5.73) mTBI were at significantly (p=0.001) greater risk of reporting clinical levels of PTSD symptoms than those with no history of mTBI. A dose-response gradient for exposure to blast/combination mTBI on clinical levels of PTSD symptoms was also significant (p=0.001). Individuals with blast/combination mTBIs scored higher in residual mTBI (p=0.001) and PTSD symptoms (p=0.001), and performed worse on tests of visual memory (p=0.001), and reaction time (p=0.001) than those with blunt or no mTBI history. Individuals with combination mTBIs scored lower in verbal memory (p=0.02) than those with blunt mTBIs. Residual PTSD and mTBI symptoms appear to be more prevalent in personnel with blast mTBI. A dose-response gradient for blast mTBI and symptoms suggests that repeated exposures to these injuries may have lingering effects

Dysregulated mitochondria-focused genes in US military service members with PTSD

Background: Posttraumatic Stress Disorder (PTSD) is a complex mental disorder with functional and structural changes in the brain that may result from mitochondria-centered responses to harmful stresses. PTSD is an ongoing issue in the military. However, at present, there is no biological tool for PTSD diagnosis. Diagnosis for PTSD is established on the basis of clinical history and mental status examination, using a clinically structured interview based on a symptom checklist or patient self-report. It is often under-diagnosis. The clinical assessment would benefit substantially from a more objective means to identify PTSD patients. Here, we present evidence that there are significant differences of expression profiles of mitochondria-focused gene in the blood between PTSD and non-PTSD control US military service members. Methods: Using a mitochondria-focused gene cDNA array, we examined the expression profiles of 1170 mitochondria-focused genes across samples from subjects with (n=28) or without (n=31) probable PTSD who were active duty US Army Special Operations soldiers deployed to the Iraq and/or Afghanistan war and who were evaluated for probable current PTSD using the PTSD Checklist (PCL). Using the analytical approach of unsupervised pattern recognition with algorithmic basis of clustering, 10 clusters or pathways were revealed from the mitochondria-focused gene microarray data. Results: Significance tests demonstrated different expression levels in 26 genes between PTSD and non-PTSD controls. A relationship analysis found that among the 26 genes, the expression levels of five genes were significantly correlated with the total PCL score in the PTSD subjects. Conclusion: The expression of mitochondria-focused gene fingerprints and dysregulated genes in the blood of PTSD patients warrants a large size study to determine their clinical utility in military population

PTSD symptom severity and sensitivity to blood, injury, and mutilation in U.S. army special operations soldiers

Sensitivity to blood, injury, and mutilation (SBIM) may increase risk for posttraumatic stress disorder (PTSD), given that traumatic events often involve actual or perceived threat of bodily harm to oneself and/or others, including exposure to blood and other mutilation-related stimuli. A self-report questionnaire was administered to male, active duty, U.S. Army Special Operations Command soldiers who had deployed to Iraq and Afghanistan (n =694 males). We first used exploratory factor analysis to examine whether the 30-item Mutilation Questionnaire (Klorman et al., 1974) comprised a unitary measure of SBIM, finding that 10 of the items form a cohesive SBIM factor. Summed, those 10 SBIM items had a significant bivariate correlation with PTSD symptom severity. In a multiple regression analysis that included demographic characteristics and lifetime trauma exposure, SBIM was positively associated with PTSD symptom severity. Other significant multivariate predictors were high lifetime trauma exposure and junior enlisted rank. When trait neuroticism was added to the model to test the robustness of these findings, the association of SBIM with PTSD symptom severity remained significant. The results suggest that SBIM may be a risk factor for PTSD in male soldiers. Further research is warranted to improve measurement and understanding of SBIM

A regulatory pathway model of neuropsychological disruption in Havana syndrome

Introduction: In 2016 diplomatic personnel serving in Havana, Cuba, began reporting audible sensory phenomena paired with onset of complex and persistent neurological symptoms consistent with brain injury. The etiology of these Anomalous Health Incidents (AHI) and subsequent symptoms remains unknown. This report investigates putative exposure-symptom pathology by assembling a network model of published bio-behavioral pathways and assessing how dysregulation of such pathways might explain loss of function in these subjects using data available in the published literature. Given similarities in presentation with mild traumatic brain injury (mTBI), we used the latter as a clinically relevant means of evaluating if the neuropsychological profiles observed in Havana Syndrome Havana Syndrome might be explained at least in part by a dysregulation of neurotransmission, neuro-inflammation, or both. Method: Automated text-mining of \u3e 9,000 publications produced a network consisting of 273 documented regulatory interactions linking 29 neuro-chemical markers with 9 neuropsychological constructs from the Brief Mood Survey, PTSD Checklist, and the Frontal Systems Behavior Scale. Analysis of information flow through this network produced a set of regulatory rules reconciling to within a 6% departure known mechanistic pathways with neuropsychological profiles in N = 6 subjects. Results: Predicted expression of neuro-chemical markers that jointly satisfy documented pathways and observed symptom profiles display characteristically elevated IL-1B, IL-10, NGF, and norepinephrine levels in the context of depressed BDNF, GDNF, IGF1, and glutamate expression (FDR \u3c 5%). Elevations in CRH and IL-6 were also predicted unanimously across all subjects. Furthermore, simulations of neurological regulatory dynamics reveal subjects do not appear to be locked in persistent illness but rather appear to be engaged in a slow recovery trajectory. Discussion: This computational analysis of measured neuropsychological symptoms in Havana-based diplomats proposes that these AHI symptoms may be supported in part by disruption of known neuroimmune and neurotransmission regulatory mechanisms also associated with mTBI

Tajik Basin and Southwestern Tian Shan, Northwestern India-Asia Collision Zone: 1. Structure, Kinematics, and Salt Tectonics in the Tajik Fold-and-Thrust Belt of the Western Foreland of the Pamir

International audienceSurface, seismic, and borehole data characterize the Neogene-Recent Tajik fold-and-thrust belt of the Tajik basin. The basin experienced little sub-detachment basement deformation, acting as a rigid foreland plate during the Pamir orogeny. The Tajik fold-and-thrust belt contains variable thinskinned structural styles, changing along and across strike as a function of the thickness and facies of Upper Jurassic evaporites, which constitute the basal detachment, and the influence of the surrounding thickskinned belts. The southern Tajik fold-and-thrust belt shows regularly spaced, salt-cored, thrusted detachment anticlines that transition northward into imbricated thrust sheets grouped in oppositely verging stacks facing each other across a common footwall syncline. The width of the fold-and-thrust belt decreases northeastward accommodated by the Ilyak fault, a lateral ramp developed over a seismically active dextral basement fault. The southeastern Tajik fold-and-thrust belt contains massive subaerial salt sheets, formed by squeezing of preexisting salt diapirs. The salt-tectonic domain originates from a local depocenter within the Late Jurassic Amu Darya-Tajik evaporitic basin. Serial cross sections, integrating the structural geometries, yielded minimum thinskinned shortening oriented at~90°to the India-Asia convergence direction, increasing from~93 km in the south to~148 km in the center, and dropping tõ 22 km in the northeast; total shortening-including the foreland buttress-is ≥170 km. Most of the shortening in the central-southern Tajik fold-and-thrust belt occurred by hinterland-vergent, high-displacement back thrusts. The Pamir played a dominant role in the transfer of shortening to the sedimentary infill of the Tajik basin with the Tian Shan acting as a semi-passive buttress