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

Role of Pre-Morbid Factors and Exposure to Blast Mild Traumatic Brain Injury on Post-Traumatic Stress in United States Military Personnel

Mild traumatic brain injury (mTBI), the signature injury of the recent wars in Afghanistan and Iraq, is a prevalent and potentially debilitating condition that is associated with symptoms of post-traumatic stress/post-traumatic stress disorder (PTS/PTSD). Prior mTBI, severity and type of injury (blast vs. non-blast), and baseline psychiatric illness are thought to impact mTBI outcomes. It is unclear if the severity of pre-morbid PTS/PTSD is a risk factor of post-injury levels of PTS and mTBI symptoms. The objective of the study was to examine predictors of post-injury PTS/PTSD, including pre-morbid PTS symptoms, and physical and cognitive symptoms in the sub-acute phase (1 week-3 months) following an acute mTBI. A retrospective review of medical records was performed of 276 servicemen assigned to the United States Army Special Operations Command referred for mTBI evaluation between December 2009 and March 2011. Post-Concussion Symptom Scale and PTSD Checklist scores were captured pre- and post-injury. A total of 276 records were reviewed. Pre-morbid and post-injury data were available for 91% (251/276). Of the 54% (136/251) of personnel with mTBI, 29% (39/136) had positive radiology findings and 11% (15/136) met criteria for clinical PTS symptoms at baseline. Logistic regression analysis found baseline PTS symptoms predicted personnel who met clinical levels of PTSD. Receiver operating characteristic curve analysis revealed that baseline PTS (p = 0.001), baseline mTBI symptoms (p = 0.001), and positive radiology (magnetic resonance imaging or computed tomography) findings for complicated mTBI (p = 0.02) accurately identified personnel with clinical levels of PTSD following mTBI. Years of military service, combat deployment status, age, and injury mechanism (blast vs. non-blast) were not associated with increased risk of PTS following mTBI. Pre-morbid PTS symptoms are associated with an increased risk for clinical levels of PTS following a subsequent mTBI. Symptom severity and positive radiologic findings may amplify this risk. At-risk personnel may benefit from early identification and intervention

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