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CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans

Ramos-Cejudo, J; Genfi, A; Abu-Amara, D; Debure, L; Qian, M; Laska, E; Siegel, C; Milton, N; Newman, J; Blessing, E; Li, M; Etkin, A; Marmar, C R; Fossati, S
Background and Objective: Posttraumatic stress disorder (PTSD) is a serious and frequently debilitating psychiatric condition that can occur in people who have experienced traumatic stressors, such as war, violence, sexual assault and other life-threatening events. Treatment of PTSD and traumatic brain injury (TBI) in veterans is challenged by diagnostic complexity, partially due to PTSD and TBI symptoms overlap and to the fact that subjective self-report assessments may be influenced by a patient's willingness to share their traumatic experiences and resulting symptoms. Corticotropin-releasing factor (CRF) is one of the main mediators of hypothalamic pituitary adrenal (HPA)-axis responses in stress and anxiety.
Methods and Results: We analyzed serum CRF levels in 230 participants including heathy controls (64), and individuals with PTSD (53), TBI (70) or PTSD + TBI (43) by enzyme immunoassay (EIA). Significantly lower CRF levels were found in both the PTSD and PTSD + TBI groups compared to healthy control (PTSD vs. Controls: P = 0.0014, PTSD + TBI vs. Controls: P = 0.0011) and chronic TBI participants (PTSD vs. TBI: P < 0.0001, PTSD + TBI vs. TBI: P < 0.0001), suggesting a PTSD-related mechanism independent from TBI and associated with CRF reduction. CRF levels negatively correlated with PTSD severity on the Clinically Administered PTSD Scale (CAPS-5) scale in the whole study group.
Conclusion(s): Hyperactivation of the HPA axis has been classically identified in acute stress. However, the recognized enhanced feedback inhibition of the HPA axis in chronic stress supports our findings of lower CRF in PTSD patients. This study suggests that reduced serum CRF in PTSD should be further investigated. Future validation studies will establish if CRF is a possible blood biomarker for PTSD and/or for differentiating PTSD and chronic TBI symptomatology.
ISSN: 2575-5609
CID: 4935152

Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder

Dean, Kelsey R; Hammamieh, Rasha; Mellon, Synthia H; Abu-Amara, Duna; Flory, Janine D; Guffanti, Guia; Wang, Kai; Daigle, Bernie J; Gautam, Aarti; Lee, Inyoul; Yang, Ruoting; Almli, Lynn M; Bersani, F Saverio; Chakraborty, Nabarun; Donohue, Duncan; Kerley, Kimberly; Kim, Taek-Kyun; Laska, Eugene; Young Lee, Min; Lindqvist, Daniel; Lori, Adriana; Lu, Liangqun; Misganaw, Burook; Muhie, Seid; Newman, Jennifer; Price, Nathan D; Qin, Shizhen; Reus, Victor I; Siegel, Carole; Somvanshi, Pramod R; Thakur, Gunjan S; Zhou, Yong; Hood, Leroy; Ressler, Kerry J; Wolkowitz, Owen M; Yehuda, Rachel; Jett, Marti; Doyle, Francis J; Marmar, Charles
Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.
PMID: 31501510
ISSN: 1476-5578
CID: 4071472

Predeployment neurocognitive functioning predicts postdeployment posttraumatic stress in Army personnel

Samuelson, Kristin W; Newman, Jennifer; Abu Amara, Duna; Qian, Meng; Li, Meng; Schultebraucks, Katharina; Purchia, Emily; Genfi, Afia; Laska, Eugene; Siegel, Carole; Hammamieh, Rasha; Gautam, Aarti; Jett, Marti; Marmar, Charles R
OBJECTIVE:The Fort Campbell Cohort study was designed to assess predeployment biological and behavioral markers and build predictive models to identify risk and resilience for posttraumatic stress disorder (PTSD) following deployment. This article addresses neurocognitive functioning variables as potential prospective predictors. METHOD/METHODS:In a sample of 403 soldiers, we examined whether PTSD symptom severity (using the PTSD Checklist) as well as posttraumatic stress trajectories could be prospectively predicted by measures of executive functioning (using two web-based tasks from WebNeuro) assessed predeployment. RESULTS:Controlling for age, gender, education, prior number of deployments, childhood trauma exposure, and PTSD symptom severity at Phase 1, linear regression models revealed that predeployment sustained attention and inhibitory control performance were significantly associated with postdeployment PTSD symptom severity. We also identified two posttraumatic stress trajectories utilizing latent growth mixture models. The "resilient" group consisted of 90.9% of the soldiers who exhibited stable low levels of PTSD symptoms from pre- to postdeployment. The "increasing" group consisted of 9.1% of the soldiers, who exhibited an increase in PTSD symptoms following deployment, crossing a threshold for diagnosis based on PTSD Checklist scores. Logistic regression models predicting trajectory revealed a similar pattern of findings as the linear regression models, in which predeployment sustained attention (95% CI of odds ratio: 1.0109, 1.0558) and inhibitory control (95% CI: 1.0011, 1.0074) performance were significantly associated with postdeployment PTSD trajectory. CONCLUSIONS:These findings have clinical implications for understanding the pathogenesis of PTSD and building preventative programs for military personnel. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
PMID: 31789568
ISSN: 1931-1559
CID: 4217962

An Electroencephalography Connectomic Profile of Posttraumatic Stress Disorder

Toll, Russell T; Wu, Wei; Naparstek, Sharon; Zhang, Yu; Narayan, Manjari; Patenaude, Brian; De Los Angeles, Carlo; Sarhadi, Kasra; Anicetti, Nicole; Longwell, Parker; Shpigel, Emmanuel; Wright, Rachael; Newman, Jennifer; Gonzalez, Bryan; Hart, Roland; Mann, Silas; Abu-Amara, Duna; Sarhadi, Kamron; Cornelssen, Carena; Marmar, Charles; Etkin, Amit
OBJECTIVE/UNASSIGNED:The authors sought to identify brain regions whose frequency-specific, orthogonalized resting-state EEG power envelope connectivity differs between combat veterans with posttraumatic stress disorder (PTSD) and healthy combat-exposed veterans, and to determine the behavioral correlates of connectomic differences. METHODS/UNASSIGNED:The authors first conducted a connectivity method validation study in healthy control subjects (N=36). They then conducted a two-site case-control study of veterans with and without PTSD who were deployed to Iraq and/or Afghanistan. Healthy individuals (N=95) and those meeting full or subthreshold criteria for PTSD (N=106) underwent 64-channel resting EEG (eyes open and closed), which was then source-localized and orthogonalized to mitigate effects of volume conduction. Correlation coefficients between band-limited source-space power envelopes of different regions of interest were then calculated and corrected for multiple comparisons. Post hoc correlations of connectomic abnormalities with clinical features and performance on cognitive tasks were conducted to investigate the relevance of the dysconnectivity findings. RESULTS/UNASSIGNED:Seventy-four brain region connections were significantly reduced in PTSD (all in the eyes-open condition and predominantly using the theta carrier frequency). Underconnectivity of the orbital and anterior middle frontal gyri were most prominent. Performance differences in the digit span task mapped onto connectivity between 25 of the 74 brain region pairs, including within-network connections in the dorsal attention, frontoparietal control, and ventral attention networks. CONCLUSIONS/UNASSIGNED:Robust PTSD-related abnormalities were evident in theta-band source-space orthogonalized power envelope connectivity, which furthermore related to cognitive deficits in these patients. These findings establish a clinically relevant connectomic profile of PTSD using a tool that facilitates the lower-cost clinical translation of network connectivity research.
PMID: 31964161
ISSN: 1535-7228
CID: 4273872

Individual Patterns of Abnormality in Resting-State Functional Connectivity Reveal Two Data-Driven PTSD Subgroups

Maron-Katz, Adi; Zhang, Yu; Narayan, Manjari; Wu, Wei; Toll, Russell T; Naparstek, Sharon; De Los Angeles, Carlo; Longwell, Parker; Shpigel, Emmanuel; Newman, Jennifer; Abu-Amara, Duna; Marmar, Charles; Etkin, Amit
OBJECTIVE/UNASSIGNED:A major challenge in understanding and treating posttraumatic stress disorder (PTSD) is its clinical heterogeneity, which is likely determined by various neurobiological perturbations. This heterogeneity likely also reduces the effectiveness of standard group comparison approaches. The authors tested whether a statistical approach aimed at identifying individual-level neuroimaging abnormalities that are more prevalent in case subjects than in control subjects could reveal new clinically meaningful insights into the heterogeneity of PTSD. METHODS/UNASSIGNED:Resting-state functional MRI data were recorded from 87 unmedicated PTSD case subjects and 105 war zone-exposed healthy control subjects. Abnormalities were modeled using tolerance intervals, which referenced the distribution of healthy control subjects as the "normative population." Out-of-norm functional connectivity values were examined for enrichment in cases and then used in a clustering analysis to identify biologically defined PTSD subgroups based on their abnormality profiles. RESULTS/UNASSIGNED:The authors identified two subgroups among PTSD cases, each with a distinct pattern of functional connectivity abnormalities with respect to healthy control subjects. Subgroups differed clinically on levels of reexperiencing symptoms and improved case-control discriminability and were detectable using independently recorded resting-state EEG data. CONCLUSIONS/UNASSIGNED:The results provide proof of concept for the utility of abnormality-based approaches for studying heterogeneity within clinical populations. Such approaches, applied not only to neuroimaging data, may allow detection of subpopulations with distinct biological signatures so that further clinical and mechanistic investigations can be focused on more biologically homogeneous subgroups.
PMID: 31838870
ISSN: 1535-7228
CID: 4243432

Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder

Etkin, Amit; Maron-Katz, Adi; Wu, Wei; Fonzo, Gregory A; Huemer, Julia; Vértes, Petra E; Patenaude, Brian; Richiardi, Jonas; Goodkind, Madeleine S; Keller, Corey J; Ramos-Cejudo, Jaime; Zaiko, Yevgeniya V; Peng, Kathy K; Shpigel, Emmanuel; Longwell, Parker; Toll, Russ T; Thompson, Allison; Zack, Sanno; Gonzalez, Bryan; Edelstein, Raleigh; Chen, Jingyun; Akingbade, Irene; Weiss, Elizabeth; Hart, Roland; Mann, Silas; Durkin, Kathleen; Baete, Steven H; Boada, Fernando E; Genfi, Afia; Autea, Jillian; Newman, Jennifer; Oathes, Desmond J; Lindley, Steven E; Abu-Amara, Duna; Arnow, Bruce A; Crossley, Nicolas; Hallmayer, Joachim; Fossati, Silvia; Rothbaum, Barbara O; Marmar, Charles R; Bullmore, Edward T; O'Hara, Ruth
A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.
PMID: 30944165
ISSN: 1946-6242
CID: 3799822

Prevalence of Cerebral Microhemorrhage following Chronic Blast-Related Mild Traumatic Brain Injury in Military Service Members Using Susceptibility-Weighted MRI

Lotan, E; Morley, C; Newman, J; Qian, M; Abu-Amara, D; Marmar, C; Lui, Y W
BACKGROUND AND PURPOSE/OBJECTIVE:Cerebral microhemorrhages are a known marker of mild traumatic brain injury. Blast-related mild traumatic brain injury relates to a propagating pressure wave, and there is evidence that the mechanism of injury in blast-related mild traumatic brain injury may be different from that in blunt head trauma. Two recent reports in mixed cohorts of blunt and blast-related traumatic brain injury in military personnel suggest that the prevalence of cerebral microhemorrhages is lower than in civilian head injury. In this study, we aimed to characterize the prevalence of cerebral microhemorrhages in military service members specifically with chronic blast-related mild traumatic brain injury. MATERIALS AND METHODS/METHODS:Participants were prospectively recruited and underwent 3T MR imaging. Susceptibility-weighted images were assessed by 2 neuroradiologists independently for the presence of cerebral microhemorrhages. RESULTS:Our cohort included 146 veterans (132 men) who experienced remote blast-related mild traumatic brain injury (mean, 9.4 years; median, 9 years after injury). Twenty-one (14.4%) reported loss of consciousness for <30 minutes. Seventy-seven subjects (52.7%) had 1 episode of blast-related mild traumatic brain injury; 41 (28.1%) had 2 episodes; and 28 (19.2%) had >2 episodes. No cerebral microhemorrhages were identified in any subject, as opposed to the frequency of SWI-detectable cerebral microhemorrhages following blunt-related mild traumatic brain injury in the civilian population, which has been reported to be as high as 28% in the acute and subacute stages. CONCLUSIONS:Our results may reflect differences in pathophysiology and the mechanism of injury between blast- and blunt-related mild traumatic brain injury. Additionally, the chronicity of injury may play a role in the detection of cerebral microhemorrhages.
PMID: 29794235
ISSN: 1936-959x
CID: 3192142

Executive function in post-traumatic stress disorder

Chapter by: Newman, Jennifer; Marmar, Charles R
in: Post-traumatic stress disorder by Nemeroff, Charles B [Ed]; Marmar, Charles R [Ed]
New York, NY, US: Oxford University Press, 2018
pp. 245-278
ISBN: 9780190259440
CID: 4374282

Executive function in posttraumatic stress disorder

Chapter by: Newman, Jennifer; Marmar, Charles
in: Executive functions in health and disease by Goldberg, Elkhonon [Ed]
San Diego, CA, US: Elsevier Academic Press, 2017
pp. 487-524
ISBN: 978-0-12-803676-1
CID: 2901082

Impact of traumatic and violent victimization experiences in individuals with schizophrenia and schizoaffective disorder

Newman, Jennifer M; Turnbull, Ayme; Berman, Brady A; Rodrigues, Stephanie; Serper, Mark R
Individuals with schizophrenia or schizoaffective disorder (SZ) experience more violent victimization and noninterpersonal traumatic experiences than the general population. Earlier studies, however, have generally excluded one or grouped together victimization and trauma experiences into single outcome variables, which may obscure their contributory role to SZ symptoms. This issue is important because there is some evidence that intentionally induced violence produces higher rates of psychopathology than nonintentional traumatic experiences. We examined the independent contribution of both types of victimization experiences on SZ patients' symptomatology. We were also interested in determining whether SZ patients' pattern of acute symptom presentation could discriminate between SZ patients with and without posttraumatic stress disorder (PTSD) comorbidity. SZ inpatients (n = 70) were assessed for the presence of comorbid PTSD diagnosis, violent victimization, and noninterpersonal traumatic experiences. Patients were also rated on SZ symptom severity and general psychopathology measures. Past violent victimization experiences predicted severity of dysphoria and anxiety in SZ. Past traumatic experiences, however, predicted severity of psychosis. Victimization predicted severity of patients' autistic/cognitive symptoms. SZ patients with comorbid PTSD presented with significantly more anxiety and dysphoria symptoms and SZ illness chronicity than their non-PTSD counterparts. Discriminant function analysis revealed that the severity of positive, dysphoric, autistic/cognitive, and anxiety symptoms differentiated comorbid PTSD patients from their non-PTSD counterparts, with an overall 72.9% classification rate. Past traumatic and victimization experiences are significantly associated with SZ patients' symptom severity and illness course in partially overlapping domains. Use of common assessment strategies may be employed to increase detection of PTSD in SZ patients presenting for acute treatment.
PMID: 20921860
ISSN: 0022-3018
CID: 948042