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Neurobiology and Treatment of Posttraumatic Stress Disorder
Shalev, Arieh; Cho, Dayeon; Marmar, Charles R
The recent worldwide surge of warfare and hostilities exposes increasingly large numbers of individuals to traumatic events, placing them at risk of developing posttraumatic stress disorder (PTSD) and challenging both clinicians and service delivery systems. This overview summarizes and updates the core knowledge of the genetic, molecular, and neural circuit features of the neurobiology of PTSD and advances in evidence-based psychotherapy, pharmacotherapy, neuromodulation, and digital treatments. While the complexity of the neurobiology and the biological and clinical heterogeneity of PTSD have challenged clinicians and researchers, there is an emerging consensus concerning the underlying mechanisms and approaches to diagnosis, treatment, and prevention of PTSD. This update addresses PTSD diagnosis, prevalence, course, risk factors, neurobiological mechanisms, current standard of care, and innovations in next-generation treatment and prevention strategies. It provides a comprehensive summary and concludes with areas of research for integrating advances in the neurobiology of the disorder with novel treatment and prevention targets.
PMID: 39086292
ISSN: 1535-7228
CID: 5696462
Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder
Nievergelt, Caroline M; Maihofer, Adam X; Atkinson, Elizabeth G; Chen, Chia-Yen; Choi, Karmel W; Coleman, Jonathan R I; Daskalakis, Nikolaos P; Duncan, Laramie E; Polimanti, Renato; Aaronson, Cindy; Amstadter, Ananda B; Andersen, Soren B; Andreassen, Ole A; Arbisi, Paul A; Ashley-Koch, Allison E; Austin, S Bryn; Avdibegoviç, Esmina; Babić, Dragan; Bacanu, Silviu-Alin; Baker, Dewleen G; Batzler, Anthony; Beckham, Jean C; Belangero, Sintia; Benjet, Corina; Bergner, Carisa; Bierer, Linda M; Biernacka, Joanna M; Bierut, Laura J; Bisson, Jonathan I; Boks, Marco P; Bolger, Elizabeth A; Brandolino, Amber; Breen, Gerome; Bressan, Rodrigo Affonseca; Bryant, Richard A; Bustamante, Angela C; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Børglum, Anders D; Børte, Sigrid; Cahn, Leah; Calabrese, Joseph R; Caldas-de-Almeida, Jose Miguel; Chatzinakos, Chris; Cheema, Sheraz; Clouston, Sean A P; Colodro-Conde, LucÃa; Coombes, Brandon J; Cruz-Fuentes, Carlos S; Dale, Anders M; Dalvie, Shareefa; Davis, Lea K; Deckert, Jürgen; Delahanty, Douglas L; Dennis, Michelle F; Desarnaud, Frank; DiPietro, Christopher P; Disner, Seth G; Docherty, Anna R; Domschke, Katharina; Dyb, Grete; Kulenović, Alma Džubur; Edenberg, Howard J; Evans, Alexandra; Fabbri, Chiara; Fani, Negar; Farrer, Lindsay A; Feder, Adriana; Feeny, Norah C; Flory, Janine D; Forbes, David; Franz, Carol E; Galea, Sandro; Garrett, Melanie E; Gelaye, Bizu; Gelernter, Joel; Geuze, Elbert; Gillespie, Charles F; Goleva, Slavina B; Gordon, Scott D; Goçi, Aferdita; Grasser, Lana Ruvolo; Guindalini, Camila; Haas, Magali; Hagenaars, Saskia; Hauser, Michael A; Heath, Andrew C; Hemmings, Sian M J; Hesselbrock, Victor; Hickie, Ian B; Hogan, Kelleigh; Hougaard, David Michael; Huang, Hailiang; Huckins, Laura M; Hveem, Kristian; Jakovljević, Miro; Javanbakht, Arash; Jenkins, Gregory D; Johnson, Jessica; Jones, Ian; Jovanovic, Tanja; Karstoft, Karen-Inge; Kaufman, Milissa L; Kennedy, James L; Kessler, Ronald C; Khan, Alaptagin; Kimbrel, Nathan A; King, Anthony P; Koen, Nastassja; Kotov, Roman; Kranzler, Henry R; Krebs, Kristi; Kremen, William S; Kuan, Pei-Fen; Lawford, Bruce R; Lebois, Lauren A M; Lehto, Kelli; Levey, Daniel F; Lewis, Catrin; Liberzon, Israel; Linnstaedt, Sarah D; Logue, Mark W; Lori, Adriana; Lu, Yi; Luft, Benjamin J; Lupton, Michelle K; Luykx, Jurjen J; Makotkine, Iouri; Maples-Keller, Jessica L; Marchese, Shelby; Marmar, Charles; Martin, Nicholas G; MartÃnez-Levy, Gabriela A; McAloney, Kerrie; McFarlane, Alexander; McLaughlin, Katie A; McLean, Samuel A; Medland, Sarah E; Mehta, Divya; Meyers, Jacquelyn; Michopoulos, Vasiliki; Mikita, Elizabeth A; Milani, Lili; Milberg, William; Miller, Mark W; Morey, Rajendra A; Morris, Charles Phillip; Mors, Ole; Mortensen, Preben Bo; Mufford, Mary S; Nelson, Elliot C; Nordentoft, Merete; Norman, Sonya B; Nugent, Nicole R; O'Donnell, Meaghan; Orcutt, Holly K; Pan, Pedro M; Panizzon, Matthew S; Pathak, Gita A; Peters, Edward S; Peterson, Alan L; Peverill, Matthew; Pietrzak, Robert H; Polusny, Melissa A; Porjesz, Bernice; Powers, Abigail; Qin, Xue-Jun; Ratanatharathorn, Andrew; Risbrough, Victoria B; Roberts, Andrea L; Rothbaum, Alex O; Rothbaum, Barbara O; Roy-Byrne, Peter; Ruggiero, Kenneth J; Rung, Ariane; Runz, Heiko; Rutten, Bart P F; de Viteri, Stacey Saenz; Salum, Giovanni Abrahão; Sampson, Laura; Sanchez, Sixto E; Santoro, Marcos; Seah, Carina; Seedat, Soraya; Seng, Julia S; Shabalin, Andrey; Sheerin, Christina M; Silove, Derrick; Smith, Alicia K; Smoller, Jordan W; Sponheim, Scott R; Stein, Dan J; Stensland, Synne; Stevens, Jennifer S; Sumner, Jennifer A; Teicher, Martin H; Thompson, Wesley K; Tiwari, Arun K; Trapido, Edward; Uddin, Monica; Ursano, Robert J; Valdimarsdóttir, Unnur; Van Hooff, Miranda; Vermetten, Eric; Vinkers, Christiaan H; Voisey, Joanne; Wang, Yunpeng; Wang, Zhewu; Waszczuk, Monika; Weber, Heike; Wendt, Frank R; Werge, Thomas; Williams, Michelle A; Williamson, Douglas E; Winsvold, Bendik S; Winternitz, Sherry; Wolf, Christiane; Wolf, Erika J; Xia, Yan; Xiong, Ying; Yehuda, Rachel; Young, Keith A; Young, Ross McD; Zai, Clement C; Zai, Gwyneth C; Zervas, Mark; Zhao, Hongyu; Zoellner, Lori A; Zwart, John-Anker; deRoon-Cassini, Terri; van Rooij, Sanne J H; van den Heuvel, Leigh L; ,; ,; ,; ,; Stein, Murray B; Ressler, Kerry J; Koenen, Karestan C
Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
PMID: 38637617
ISSN: 1546-1718
CID: 5655872
Circulating cell-free mitochondrial DNA levels and glucocorticoid sensitivity in a cohort of male veterans with and without combat-related PTSD
Blalock, Zachary N; Wu, Gwyneth W Y; Lindqvist, Daniel; Trumpff, Caroline; Flory, Janine D; Lin, Jue; Reus, Victor I; Rampersaud, Ryan; Hammamieh, Rasha; Gautam, Aarti; ,; Doyle, Francis J; Marmar, Charles R; Jett, Marti; Yehuda, Rachel; Wolkowitz, Owen M; Mellon, Synthia H
Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a biomarker of cellular injury or cellular stress and is a potential novel biomarker of psychological stress and of various brain, somatic, and psychiatric disorders. No studies have yet analyzed ccf-mtDNA levels in post-traumatic stress disorder (PTSD), despite evidence of mitochondrial dysfunction in this condition. In the current study, we compared plasma ccf-mtDNA levels in combat trauma-exposed male veterans with PTSD (n = 111) with those who did not develop PTSD (n = 121) and also investigated the relationship between ccf mt-DNA levels and glucocorticoid sensitivity. In unadjusted analyses, ccf-mtDNA levels did not differ significantly between the PTSD and non-PTSD groups (t = 1.312, p = 0.191, Cohen's d = 0.172). In a sensitivity analysis excluding participants with diabetes and those using antidepressant medication and controlling for age, the PTSD group had lower ccf-mtDNA levels than did the non-PTSD group (F(1, 179) = 5.971, p = 0.016, partial η2 = 0.033). Across the entire sample, ccf-mtDNA levels were negatively correlated with post-dexamethasone adrenocorticotropic hormone (ACTH) decline (r = -0.171, p = 0.020) and cortisol decline (r = -0.149, p = 0.034) (viz., greater ACTH and cortisol suppression was associated with lower ccf-mtDNA levels) both with and without controlling for age, antidepressant status and diabetes status. Ccf-mtDNA levels were also significantly positively associated with IC50-DEX (the concentration of dexamethasone at which 50% of lysozyme activity is inhibited), a measure of lymphocyte glucocorticoid sensitivity, after controlling for age, antidepressant status, and diabetes status (β = 0.142, p = 0.038), suggesting that increased lymphocyte glucocorticoid sensitivity is associated with lower ccf-mtDNA levels. Although no overall group differences were found in unadjusted analyses, excluding subjects with diabetes and those taking antidepressants, which may affect ccf-mtDNA levels, as well as controlling for age, revealed decreased ccf-mtDNA levels in PTSD. In both adjusted and unadjusted analyses, low ccf-mtDNA levels were associated with relatively increased glucocorticoid sensitivity, often reported in PTSD, suggesting a link between mitochondrial and glucocorticoid-related abnormalities in PTSD.
PMCID:10781666
PMID: 38200001
ISSN: 2158-3188
CID: 5626542
Amygdala-derived-EEG-fMRI-pattern neurofeedback for the treatment of chronic post-traumatic stress disorder. A prospective, multicenter, multinational study evaluating clinical efficacy
Fruchter, Eyal; Goldenthal, Nadav; Adler, Lenard A; Gross, Raz; Harel, Eiran V; Deutsch, Lisa; Nacasch, Nitsa; Grinapol, Shulamit; Amital, Daniela; Voigt, Jeffrey D; Marmar, Charles R
We conducted a prospective, single arm, multisite, multinational, open label trial assessing the safety and efficacy of a novel amygdala derived neurofeedback treatment, designated Amygdala-Derived-EFP, for chronic PTSD. Participants, including veterans and civilians, underwent screening, training, 15 neurofeedback sessions over 8 weeks and; baseline, termination (8 weeks) and 3 month post treatment assessments with validated measures. The primary endpoint was more than 50 % of the participants demonstrating a Minimally Clinically Important Difference (MCID) defined as a 6-point reduction, on the Clinician Administered PTSD Scale (CAPS-5) total score at 3 months. Secondary measures included the PCL-5, ERQ, PHQ-9, and CGI. Statistical analyses were performed using SAS®V9.4. The primary endpoint was met, with a CAPS-5 MCID response rate of 66.7 %. The average reduction in CAPS-5 total scores at 3 month follow up was 13.5 points, more than twice the MCID. Changes from baseline in CAPS-5, PCL-5, PHQ-9 scores at 8 weeks and the 3 month follow-up demonstrated statistically significant improvements in response and; demonstrated effect sizes ranging from 0.46 to 1.07. Adverse events were mild and resolved after treatment. This study builds on prior research demonstrating similar outcomes using amygdala-derived neurofeedback. Positive attributes of this therapy include monitoring by non-physician personnel, affordability, accessibility, and tolerability.
PMID: 38325159
ISSN: 1872-7123
CID: 5632712
Pilot Study of Prism EFP NeuroFeedback in Adult ADHD
Adler, Lenard A; Anbarasan, Deepti; Leon, Terry; Sardoff, Taylor; Descorbeth, Olivia; Cho, Dayeon; Stern, Yaki; Kraft, Oded; Hendler, Talma; Marmar, Charles R
OBJECTIVE/UNASSIGNED:A pilot study to preliminarily examine the effects of Prism EFP NeuroFeedback (NF) in adult ADHD. METHOD/UNASSIGNED:Prism EFP NF is a form of NF specifically designed to target emotional dysregulation (ED) through down regulation of amygdala activity. Prism EFP NF has been shown to improve other disorders with significant ED. Nine participants with adult ADHD received an open trial of Prism EFP NF consisting of fifteen sessions over 8 weeks; all completed at least 5 weeks of treatment with seven completing all 8 weeks. Outcomes were assessed by change in ADHD symptoms from baseline to End of Treatment. RESULTS/UNASSIGNED:About two-third reduction was seen in total DSM ADHD symptom scores (primary outcome measure) with improvement observed in all other clinical measures. No significant adverse events were seen. CONCLUSION/UNASSIGNED:This preliminary trial found substantial effects of Prism EFP NF on ADHD/ED symptoms and global impairment.
PMID: 38152997
ISSN: 1557-1246
CID: 5623272
Integrated analysis of proteomics, epigenomics and metabolomics data revealed divergent pathway activation patterns in the recent versus chronic post-traumatic stress disorder
Muhie, Seid; Gautam, Aarti; Misganaw, Burook; Yang, Ruoting; Mellon, Synthia H; Hoke, Allison; Flory, Janine; Daigle, Bernie; Swift, Kevin; ,; Hood, Leroy; Doyle, Francis J; Wolkowitz, Owen M; Marmar, Charles R; Ressler, Kerry; Yehuda, Rachel; Hammamieh, Rasha; Jett, Marti
Metabolomics, proteomics and DNA methylome assays, when done in tandem from the same blood sample and analyzed together, offer an opportunity to evaluate the molecular basis of post-traumatic stress disorder (PTSD) course and pathogenesis. We performed separate metabolomics, proteomics, and DNA methylome assays on blood samples from two well-characterized cohorts of 159 active duty male participants with relatively recent onset PTSD (<1.5 years) and 300 male veterans with chronic PTSD (>7 years). Analyses of the multi-omics datasets from these two independent cohorts were used to identify convergent and distinct molecular profiles that might constitute potential signatures of severity and progression of PTSD and its comorbid conditions. Molecular signatures indicative of homeostatic processes such as signaling and metabolic pathways involved in cellular remodeling, neurogenesis, molecular safeguards against oxidative stress, metabolism of polyunsaturated fatty acids, regulation of normal immune response, post-transcriptional regulation, cellular maintenance and markers of longevity were significantly activated in the active duty participants with recent PTSD. In contrast, we observed significantly altered multimodal molecular signatures associated with chronic inflammation, neurodegeneration, cardiovascular and metabolic disorders, and cellular attritions in the veterans with chronic PTSD. Activation status of signaling and metabolic pathways at the early and late timepoints of PTSD demonstrated the differential molecular changes related to homeostatic processes at its recent and multi-system syndromes at its chronic phase. Molecular alterations in the recent PTSD seem to indicate some sort of recalibration or compensatory response, possibly directed in mitigating the pathological trajectory of the disorder.
PMID: 37516387
ISSN: 1090-2139
CID: 5618912
Molecular signatures of post-traumatic stress disorder in war-zone-exposed veteran and active-duty soldiers
Muhie, Seid; Gautam, Aarti; Yang, Ruoting; Misganaw, Burook; Daigle, Bernie J; Mellon, Synthia H; Flory, Janine D; Abu-Amara, Duna; Lee, Inyoul; Wang, Kai; Rampersaud, Ryan; Hood, Leroy; Yehuda, Rachel; Marmar, Charles R; Wolkowitz, Owen M; Ressler, Kerry J; Doyle, Francis J; Hammamieh, Rasha; Jett, Marti
Post-traumatic stress disorder (PTSD) is a multisystem syndrome. Integration of systems-level multi-modal datasets can provide a molecular understanding of PTSD. Proteomic, metabolomic, and epigenomic assays are conducted on blood samples of two cohorts of well-characterized PTSD cases and controls: 340 veterans and 180 active-duty soldiers. All participants had been deployed to Iraq and/or Afghanistan and exposed to military-service-related criterion A trauma. Molecular signatures are identified from a discovery cohort of 218 veterans (109/109 PTSD+/-). Identified molecular signatures are tested in 122 separate veterans (62/60 PTSD+/-) and in 180 active-duty soldiers (PTSD+/-). Molecular profiles are computationally integrated with upstream regulators (genetic/methylation/microRNAs) and functional units (mRNAs/proteins/metabolites). Reproducible molecular features of PTSD are identified, including activated inflammation, oxidative stress, metabolic dysregulation, and impaired angiogenesis. These processes may play a role in psychiatric and physical comorbidities, including impaired repair/wound healing mechanisms and cardiovascular, metabolic, and psychiatric diseases.
PMCID:10213980
PMID: 37196634
ISSN: 2666-3791
CID: 5503572
Screening for PTSD and TBI in Veterans using Routine Clinical Laboratory Blood Tests
Xu, Mu; Lin, Ziqiang; Siegel, Carole E; Laska, Eugene M; Abu-Amara, Duna; Genfi, Afia; Newman, Jennifer; Jeffers, Michelle K; Blessing, Esther M; Flanagan, Steven R; Fossati, Silvia; Etkin, Amit; Marmar, Charles R
Post-traumatic stress disorder (PTSD) is a mental disorder diagnosed by clinical interviews, self-report measures and neuropsychological testing. Traumatic brain injury (TBI) can have neuropsychiatric symptoms similar to PTSD. Diagnosing PTSD and TBI is challenging and more so for providers lacking specialized training facing time pressures in primary care and other general medical settings. Diagnosis relies heavily on patient self-report and patients frequently under-report or over-report their symptoms due to stigma or seeking compensation. We aimed to create objective diagnostic screening tests utilizing Clinical Laboratory Improvement Amendments (CLIA) blood tests available in most clinical settings. CLIA blood test results were ascertained in 475 male veterans with and without PTSD and TBI following warzone exposure in Iraq or Afghanistan. Using random forest (RF) methods, four classification models were derived to predict PTSD and TBI status. CLIA features were selected utilizing a stepwise forward variable selection RF procedure. The AUC, accuracy, sensitivity, and specificity were 0.730, 0.706, 0.659, and 0.715, respectively for differentiating PTSD and healthy controls (HC), 0.704, 0.677, 0.671, and 0.681 for TBI vs. HC, 0.739, 0.742, 0.635, and 0.766 for PTSD comorbid with TBI vs HC, and 0.726, 0.723, 0.636, and 0.747 for PTSD vs. TBI. Comorbid alcohol abuse, major depressive disorder, and BMI are not confounders in these RF models. Markers of glucose metabolism and inflammation are among the most significant CLIA features in our models. Routine CLIA blood tests have the potential for discriminating PTSD and TBI cases from healthy controls and from each other. These findings hold promise for the development of accessible and low-cost biomarker tests as screening measures for PTSD and TBI in primary care and specialty settings.
PMCID:9944218
PMID: 36810280
ISSN: 2158-3188
CID: 5448152
Pilot Study of Prism EFP NeuroFeedback in Adult ADHD
Adler, Lenard A.; Anbarasan, Deepti; Leon, Terry; Sardoff, Taylor; Descorbeth, Olivia; Cho, Dayeon; Stern, Yaki; Kraft, Oded; Hendler, Talma; Marmar, Charles R.
Objective: A pilot study to preliminarily examine the effects of Prism EFP NeuroFeedback (NF) in adult ADHD. Method: Prism EFP NF is a form of NF specifically designed to target emotional dysregulation (ED) through down regulation of amygdala activity. Prism EFP NF has been shown to improve other disorders with significant ED. Nine participants with adult ADHD received an open trial of Prism EFP NF consisting of fifteen sessions over 8 weeks; all completed at least 5 weeks of treatment with seven completing all 8 weeks. Outcomes were assessed by change in ADHD symptoms from baseline to End of Treatment. Results: About two-third reduction was seen in total DSM ADHD symptom scores (primary outcome measure) with improvement observed in all other clinical measures. No significant adverse events were seen. Conclusion: This preliminary trial found substantial effects of Prism EFP NF on ADHD/ED symptoms and global impairment.
SCOPUS:85181227103
ISSN: 1087-0547
CID: 5630972
Traumatic stress symptoms in family caregivers of patients with acute leukaemia: protocol for a multisite mixed methods, longitudinal, observational study
Jibb, Lindsay A; Nanos, Stephanie M; Alexander, Sarah; Malfitano, Carmine; Rydall, Anne; Gupta, Sumit; Schimmer, Aaron D; Zimmermann, Camilla; Hales, Sarah; Nissim, Rinat; Marmar, Charles; Schultebraucks, Katharina; Mah, Kenneth; Rodin, Gary
INTRODUCTION:The diagnosis, progression or recurrence of cancer is often highly traumatic for family caregivers (FCs), but systematic assessments of distress and approaches for its prevention and treatment are lacking. Acute leukaemia (AL) is a life-threatening cancer of the blood, which most often presents acutely, requires intensive treatment and is associated with severe physical symptoms. Consequently, traumatic stress may be common in the FCs of patients with AL. We aim to determine the prevalence, severity, longitudinal course and predictors of traumatic stress symptoms in FCs of patients with AL in the first year after diagnosis, and to understand their lived experience of traumatic stress and perceived support needs. METHODS AND ANALYSIS:This two-site longitudinal, observational, mixed methods study will recruit 223 adult FCs of paediatric or adult patients newly diagnosed with AL from two tertiary care centres. Quantitative data will be collected from self-report questionnaires at enrolment, and 1, 3, 6, 9 and 12 months after admission to hospital for initial treatment. Quantitative data will be analysed using descriptive and machine learning approaches and a multilevel modelling (MLM) approach will be used to confirm machine learning findings. Semi-structured qualitative interviews will be conducted at 3, 6 and 12 months and analysed using a grounded theory approach. ETHICS AND DISSEMINATION:This study is funded by the Canadian Institutes of Health Research (CIHR number PJT 173255) and has received ethical approval from the Ontario Cancer Research Ethics Board (CTO Project ID: 2104). The data generated have the potential to inform the development of targeted psychosocial interventions for traumatic stress, which is a public health priority for high-risk populations such as FCs of patients with haematological malignancies. An integrated and end-of-study knowledge translation strategy that involves FCs and other stakeholders will be used to interpret and disseminate study results.
PMCID:9639100
PMID: 36332954
ISSN: 2044-6055
CID: 5365212