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Gerber L, Müller MM, Oender A, Urbanczyk S, Radermacher P, Brucker C, Stein B, Waller C, Rohleder N. Psychological, neuroendocrine and inflammatory stress responses in women after miscarriage or stillbirth: investigating early psychobiological adaptations to potential traumatic events. J Neural Transm (Vienna) 2025:10.1007/s00702-025-02927-x. [PMID: 40299067 DOI: 10.1007/s00702-025-02927-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 04/05/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Miscarriage (MC) and stillbirth (SB) can be considered as potentially traumatic events (PTE) and affect approximately 10-20% of all pregnancies. PTEs can lead to the development of post-traumatic stress disorder (PTSD). While the psychobiology of PTSD is well-understood, our knowledge on psychobiological adaptations shortly after a PTE is limited. This study aimed to shed light on early psychobiological changes associated with MC and SB. METHODS We included 25 women who had experienced a MC/SB within the previous three months and compared them with 28 healthy control women. All participants were asked to attend a study appointment, during which they participated in a socially evaluated cold-pressor test (SECPT) to induce psychosocial stress. Saliva and blood samples were collected at rest, immediately and at 20, 45 and 90 min after the SECPT. We determined salivary cortisol levels and α-amylase (sAA) activity, and plasma interleukin-6 (IL-6) concentrations. We assessed symptoms of PTSD, anxiety and depression using self-report questionnaires. RESULTS Women who had experienced MC or SB reported significantly more symptoms of PTSD (p < 0.001) and anxiety (p < 0.001), when compared to the control group. Despite elevated psychological distress in the MC/SB group, there were no significant differences of salivary cortisol, sAA and IL-6 levels between the two groups at rest or after SECPT induced stress. CONCLUSIONS Despite the high psychological strain on women after MC/SB, the stress is not yet reflected at a biological level. These results highlight the complex relationship between early trauma, PTSD symptoms, and biological responses. Further research is needed to understand the long-term effects of trauma related to MC/SB, and the development of PTSD, as well as the underlying mechanisms contributing to the observed psychological and biological changes.
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Affiliation(s)
- Luis Gerber
- General Hospital Nuremberg, Department of Psychosomatic Medicine and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany
| | - Markus M Müller
- General Hospital Nuremberg, Department of Psychosomatic Medicine and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany
| | - Alexandra Oender
- General Hospital Nuremberg, Department of Psychosomatic Medicine and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany
| | - Sophia Urbanczyk
- General Hospital Nuremberg, Department of Psychosomatic Medicine and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany
| | - Peter Radermacher
- Anesthesiological Pathophysiology and Process Engineering, Ulm University Hospital, Ulm, Germany
| | - Cosima Brucker
- University Women's Hospital, Paracelsus Medical University, Nuremberg, Germany
| | - Barbara Stein
- General Hospital Nuremberg, Department of Psychosomatic Medicine and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany
| | - Christiane Waller
- General Hospital Nuremberg, Department of Psychosomatic Medicine and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany
| | - Nicolas Rohleder
- Chair of Health Psychology, Institute of Psychology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 49a, 91052, Erlangen, Germany.
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Schmitt A, Andrews N, Yasuda K, Hodge M, Ryznar R. Acute Stress and Autoimmune Markers: Evaluating the Psychoneuroimmunology Axis in Firefighter Recruits. Int J Mol Sci 2025; 26:3945. [PMID: 40362185 PMCID: PMC12071583 DOI: 10.3390/ijms26093945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/12/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Chronic psychological stress is known to influence immune function and contribute to development of autoimmune disorders through dysregulated inflammatory responses. This study investigates relationships between acute stress, life trauma, and autoimmune salivary biomarkers in firefighter recruits during psychophysical stress training. Salivary samples were collected from firefighter recruits during two stress tests to evaluate responses to acute stress. Samples were obtained at three time points-pre-stress, post-stress, and recovery-across both tests. Cortisol was measured to characterize acute stress response (ASR) profiles, while immune function was assessed through the analyzing C-reactive Protein (CRP), Complement C4 (C4), Pigment Epithelium Derived Factor (PEDF), and Serum Amyloid P (SAP). Results showed significant changes in CRP, C4, and PEDF after stress inoculation. Higher previous life trauma was associated with lower baseline cortisol (r = -0.489) and delay in cortisol recovery (r = 0.514), suggesting a learned biological response, potentially protective against stress-induced dysregulation. Cluster analysis revealed four distinct cortisol ASR profiles which were found to have significantly different past life trauma (p = 0.031). These findings suggest that trauma history influences stress biomarker dynamics, potentially reflecting individualized adaptive or maladaptive responses. The insights gained may inform strategies to enhance stress resilience and mitigate autoimmune risk among high-stress populations.
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Affiliation(s)
- Andrea Schmitt
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (A.S.); (N.A.); (K.Y.); (M.H.)
| | - Nathan Andrews
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (A.S.); (N.A.); (K.Y.); (M.H.)
| | - Krista Yasuda
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (A.S.); (N.A.); (K.Y.); (M.H.)
| | - Mitchell Hodge
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (A.S.); (N.A.); (K.Y.); (M.H.)
| | - Rebecca Ryznar
- Department of Biomedical Sciences, College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA
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Kale MB, Rahangdale SR, Banarase TA, Siddiqui MS, Taksande BG, Aglawe MM, Upaganlawar AB, Kopalli SR, Koppula S, Umekar MJ, Wankhede NL. Agmatine diminishes behavioral and endocrine alterations in a rat model of post-traumatic stress disorder. Neurosci Lett 2025; 845:138074. [PMID: 39645070 DOI: 10.1016/j.neulet.2024.138074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/25/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024]
Abstract
Post-traumatic stress disorder (PTSD), is a severe anxiety disorder characterized by associative fear conditioning. Single prolonged stress (SPS) is a widely accepted reliable animal model to stimulate PTSD. Agmatine is an endogenous neuromodulator of stress; however, its effect on PTSD remains to be investigated. This study explored the role of agmatine in conditioned fear response (CFR) in PTSD and highlighted the role of imidazoline receptors in the effect of agmatine. Intra-cerebroventricular (icv) surgery was done in order to facilitate drug administration. Animals were subjected to SPS. Agmatine and the involvement of imidazoline receptors (I1 and I2) were assessed for their effect in fear conditioning apparatus. During weeks 1, 2, and 3, in CFR, agmatine (40 µg/rat, icv) showed significantly decreased freezing time whereas other doses of agmatine (10 and 20 µg/rat, icv). Imidazoline (I1 and I2) receptor agonists Moxonidine (25 µg/rat, icv) and 2-BFI, (10 µg/rat, icv) respectively, at their sub-effective doses, with a submaximal dose of agmatine (20 µg/rat, icv) significantly decreased the altered freezing time during weeks 1, 2 and 3 compared to SPS animals. Moreover, the effective dose of agmatine (40 µg/rat, icv) with imidazoline (I1 and I2) receptor antagonists Efaroxan (10 µg/rat, icv) and Idazoxan (4 µg/rat, icv) respectively does not reversed the effect of agmatine on freezing. Agmatine and its combination with I1 and I2 agonists, normalized the altered freezing behavior, corticosterone level, organ coefficient of adrenal gland, neuroinflammatory and neurotrophic factor due to SPS during CFR projecting its strong therapeutic effect in SPS induced PTSD.
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Affiliation(s)
- Mayur B Kale
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Sandip R Rahangdale
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Trupti A Banarase
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Mohd Shahnavaj Siddiqui
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Brijesh G Taksande
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Manish M Aglawe
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Aman B Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India
| | - Spandana Rajendra Kopalli
- Department of Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul 05006, Republic of Korea
| | - Sushruta Koppula
- College of Biomedical and Health Sciences, Konkuk University, Chungju-Si, Chungcheongbuk Do 27478, Republic of Korea.
| | - Milind J Umekar
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Nitu L Wankhede
- Division of Neuroscience, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India.
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Timmer-Murillo SC, Mowrer A, Wang AZ, Jazinski-Chambers K, Piña I, Rundell MR, Bennett JM, Wagner AJ, deRoon-Cassini TA. Examining emotion regulation and inflammation as predictors of maternal mental health after fetal anomaly diagnosis. Brain Behav Immun 2024; 122:1-8. [PMID: 39106938 DOI: 10.1016/j.bbi.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 07/09/2024] [Accepted: 08/01/2024] [Indexed: 08/09/2024] Open
Abstract
OBJECTIVE Fetal anomalies occur in approximately 3% of pregnancies and receiving the diagnosis may be a potentially traumatic experience for families. The mental health of mothers receiving diagnoses and what predicts resilience or poor mental health is understudied. Emotion regulation is an important, modifiable, transdiagnostic factor of mental health, and may be protective post-diagnosis. Evaluating biomarkers of stress, including IL-6 and Allostatic Load (AL), can also serve as early indicators of risk, indicative of early intervention. This study assessed whether reappraisal, suppression, IL-6, and AL was associated with mental health outcomes and resilience in women after receiving a fetal anomaly diagnosis. METHODS Pregnant women (N=108) presenting to a fetal concerns clinic for initial consultation completed measures of emotion regulation (i.e., reappraisal and suppression), depression, anxiety, posttraumatic stress symptoms, and resilience between 2019-2022. A blood draw was used to assess IL-6 and create composite allostatic load measure including: IL-6, blood pressure, heart rate, glucose, cortisol, and body mass index. RESULTS Linear regressions controlling for age, gestational age, and perceived fetal diagnosis severity, demonstrated that IL-6 was negatively associated with resilience and positively associated with depression. Reappraisal was positively associated to resilience and negatively associated with depression, anxiety, and PTSD, whereas state insurance status was positively associated to anxiety and PTS symptoms. Suppression and allostatic load were not significant. CONCLUSIONS Women experiencing fetal anomaly diagnosis represent an understudied population with unaddressed mental health needs. Reappraisal serves as not only a protective factor, but one that can be enhanced to promote maternal resilience and mental health. Furthermore, elevated IL-6 may be a critical early indicator of potential intervention needs among women who are pregnant, to mitigate negative psychological states and enhance resilience.
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Affiliation(s)
- Sydney C Timmer-Murillo
- Medical College of Wisconsin, Division of Trauma and Acute Care Surgery, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA.
| | - Alyssa Mowrer
- Medical College of Wisconsin, Division of Pediatric Surgery, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA.
| | - Amy Z Wang
- University of Wisconsin, Milwaukee, Department of Psychology, 2441 E. Hartford Ave. Milwaukee, WI 53211, USA.
| | - Kelley Jazinski-Chambers
- Medical College of Wisconsin, Division of Trauma and Acute Care Surgery, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA.
| | - Isela Piña
- Medical College of Wisconsin, Division of Trauma and Acute Care Surgery, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA.
| | - Maddie R Rundell
- Medical College of Wisconsin, Division of Pediatric Surgery, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA.
| | - Jeanette M Bennett
- UNC Charlotte, Department of Psychological Science, 9201 University City Blvd Charlotte, NC 28223, USA.
| | - Amy J Wagner
- Medical College of Wisconsin, Division of Pediatric Surgery, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA.
| | - Terri A deRoon-Cassini
- Medical College of Wisconsin, Division of Trauma and Acute Care Surgery, 8701 W Watertown Plank Rd., Milwaukee, WI 53226, USA; Comprehensive Injury Center, Division of Data Surveillance & Informatics, 10000 Innovation Dr. Milwaukee, WI 53226, USA.
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Schuchman M, Brady TM, Glenn DA, Tuttle KR, Cara-Fuentes G, Levy RV, Gonzalez-Vicente A, Alakwaa FM, Srivastava T, Sethna CB. Association of mental health-related patient reported outcomes with blood pressure in adults and children with primary proteinuric glomerulopathies. J Nephrol 2024; 37:647-660. [PMID: 38512380 PMCID: PMC11729569 DOI: 10.1007/s40620-024-01919-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 02/01/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION The prevalence of mental health disorders including anxiety and depression is increasing and is linked to hypertension in healthy individuals. However, the relationship of psychosocial patient-reported outcomes on blood pressure (BP) in primary proteinuric glomerulopathies is not well characterized. This study explored longitudinal relationships between psychosocial patient-reported outcomes and BP status among individuals with proteinuric glomerulopathies. METHODS An observational cohort study was performed using data from 745 adults and children enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). General Estimating Equations for linear regression and binary logistic analysis for odds ratios were performed to analyze relationships between the exposures, longitudinal Patient-Reported Outcome Measurement Information System (PROMIS) measures and BP and hypertension status as outcomes. RESULTS In adults, more anxiety was longitudinally associated with higher systolic and hypertensive BP. In children, fatigue was longitudinally associated with increased odds of hypertensive BP regardless of the PROMIS report method. More stress, anxiety, and depression were longitudinally associated with higher systolic BP index, higher diastolic BP index, and increased odds of hypertensive BP index in children with parent-proxy patient-reported outcomes. DISCUSSION/CONCLUSION Chronically poor psychosocial patient-reported outcomes may be significantly associated with higher BP and hypertension in adults and children with primary proteinuric glomerulopathies. This interaction appears strong in children but should be interpreted with caution, as multiple confounders related to glomerular disease may influence both mental health and BP independently. That said, access to mental health resources may help control BP, and proper disease and BP management may improve overall mental health.
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Affiliation(s)
- Matthew Schuchman
- Northwell, Cohen Children's Medical Center, Division of Pediatric Nephrology, New Hyde Park, NY, USA
| | - Tammy M Brady
- Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dorey A Glenn
- Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Katherine R Tuttle
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA
- Division of Nephrology, University of Washington School of Medicine, Spokane, WA, USA
| | - Gabriel Cara-Fuentes
- Section of Pediatric Nephrology, Children's Hospital Colorado, University of Colorado, Aurora, CO, USA
| | - Rebecca V Levy
- Division of Nephrology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
- Division of Pediatric Nephrology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA
| | - Agustin Gonzalez-Vicente
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Fadhl M Alakwaa
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, MI, USA
| | - Tarak Srivastava
- Pediatric Nephrology, Children's Mercy Hospital, Kansas City, MO, USA
| | - Christine B Sethna
- Northwell, Cohen Children's Medical Center, Division of Pediatric Nephrology, New Hyde Park, NY, USA.
- Feinstein Institutes for Medical Research, Manhasset, NY, USA.
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Maihofer AX, Ratanatharathorn A, Hemmings SMJ, Costenbader KH, Michopoulos V, Polimanti R, Rothbaum AO, Seedat S, Mikita EA, Smith AK, Salem RM, Shaffer RA, Wu T, Sebat J, Ressler KJ, Stein MB, Koenen KC, Wolf EJ, Sumner JA, Nievergelt CM. Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes. Transl Psychiatry 2024; 14:172. [PMID: 38561342 PMCID: PMC10984931 DOI: 10.1038/s41398-024-02869-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 02/21/2024] [Accepted: 03/11/2024] [Indexed: 04/04/2024] Open
Abstract
Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.
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Affiliation(s)
- Adam X Maihofer
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
- Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
- Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
| | - Andrew Ratanatharathorn
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA
| | - Sian M J Hemmings
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, Western Cape, South Africa
- South African Medical Research Council/Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Karen H Costenbader
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Vasiliki Michopoulos
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | - Renato Polimanti
- VA Connecticut Healthcare Center, West Haven, CT, USA
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Alex O Rothbaum
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
- Department of Research and Outcomes, Skyland Trail, Atlanta, GA, USA
| | - Soraya Seedat
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, Western Cape, South Africa
- South African Medical Research Council/Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Elizabeth A Mikita
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
- Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - Alicia K Smith
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
- Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA
| | - Rany M Salem
- Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA
| | - Richard A Shaffer
- Department of Epidemiology and Health Sciences, Naval Health Research Center, San Diego, CA, USA
| | - Tianying Wu
- Division of Epidemiology and Biostatistics, School of Public Health, San Diego State University, San Diego, CA, USA
- Moores Cancer Center, University of California, San Diego, San Diego, CA, USA
| | - Jonathan Sebat
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
| | - Kerry J Ressler
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
- McLean Hospital, Belmont, MA, USA
| | - Murray B Stein
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
- Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA
| | - Karestan C Koenen
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Erika J Wolf
- VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA
- Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Jennifer A Sumner
- Department of Psychology, University of California Los Angeles, Los Angeles, CA, USA
| | - Caroline M Nievergelt
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
- Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
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Hsu TW, Bai YM, Tsai SJ, Chen TJ, Chen MH, Liang CS. Risk of autoimmune diseases after post-traumatic stress disorder: a nationwide cohort study. Eur Arch Psychiatry Clin Neurosci 2024; 274:487-495. [PMID: 37322294 DOI: 10.1007/s00406-023-01639-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 06/03/2023] [Indexed: 06/17/2023]
Abstract
This longitudinal study aimed to investigate the risk of subsequent autoimmune disease in patients with post-traumatic stress disorder (PTSD) in Asian population. Between 2002 and 2009, we enrolled 5273 patients with PTSD and 1:4 matched controls from the National Health Insurance Database of Taiwan, and followed up the patients until December 31, 2011, or death. The investigated autoimmune diseases included thyroiditis, lupus, rheumatic arthritis, inflammatory bowel disease, Sjogren's syndrome, dermatomyositis, and polymyositis. The Cox regression model was used to estimate the risk of developing autoimmune diseases, with adjustment for demographics and psychiatric and medical comorbidities. Furthermore, we examined the psychiatric clinics utility of patients with PTSD indicating the severity of PTSD in association with autoimmune diseases. After adjusting for confounders, patients with PTSD had a 2.26-fold higher risk of developing any autoimmune diseases (reported as hazard ratios with 95% confidence intervals: 1.82-2.80) than the controls. For specific autoimmune diseases, patients with PTSD had a 2.70-fold higher risk (1.98-3.68) of thyroiditis, a 2.95-fold higher risk (1.20-7.30) of lupus, and a 6.32-fold higher risk (3.44-11.60) of Sjogren's syndrome. Moreover, the PTSD severity was associated with the risk of autoimmune diseases in a dose-dependent manner. The patient with the highest psychiatric clinics utility was associated with an 8.23-fold higher risk (6.21-10.90) of any autoimmune diseases than the controls. Patients with PTSD had an increased risk of autoimmune diseases, and such risk was associated with the severity of PTSD in a dose-dependent manner. However, the present study did not provide a direct effect between PTSD and autoimmune diseases, but rather an association. Further studies are warranted to examine the underlying pathophysiological mechanisms.
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Affiliation(s)
- Tien-Wei Hsu
- Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Ya-Mei Bai
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec. 2, Shihpai Road, Beitou District, Taipei, 11217, Taiwan
- Department of Psychiatry, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec. 2, Shihpai Road, Beitou District, Taipei, 11217, Taiwan
- Department of Psychiatry, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Tzeng-Ji Chen
- Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec. 2, Shihpai Road, Beitou District, Taipei, 11217, Taiwan.
- Department of Psychiatry, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
| | - Chih-Sung Liang
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, No. 60, Xinmin Road, Beitou District, Taipei, 11243, Taiwan.
- Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan.
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Nameni G, Jazayeri S, Salehi M, Esrafili A, Hajebi A, Motevalian SA. Association between visceral adiposity and generalized anxiety disorder (GAD). BMC Psychol 2024; 12:49. [PMID: 38273394 PMCID: PMC10811950 DOI: 10.1186/s40359-024-01542-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 01/15/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Due to an increased rate of inflammation in generalized anxiety disorder (GAD), insight into the mediating factors in the onset and recurrence of the inflammatory response can help to achieve novel treatments for alleviating the risk of GAD. In the current study, we aimed to evaluate the possible relationship between visceral adipose tissue (VAT) as an important intermediary in inflammation pathways and GAD in participants of the Employees' Health Cohort Study of Iran (EHCSIR). METHOD We analyzed the data from 3889 included participants aged > 18 years in the EHCSIR study, which were collected from 2017 to 2020. Lifetime and 12-month GAD were assessed using the Composite International Diagnostic Interview (CIDI-2.1) questionnaire. The adjusted prevalence ratio was computed to evaluate the association between GAD and visceral adiposity index (VAI), GAD and visceral fat area (VFA), GAD and body mass index (BMI) and ultimately GAD and waist circumference (WC) in males and females using STATA software. RESULTS Log-binomial analysis showed a higher prevalence ratio of 12-month GAD associated with VFA in women [PR: 1.42, CI: 1.07-1.87, P: 0.015]. The prevalence of lifetime GAD was higher in obese women (BM1 > 30) [PR: 2.35, CI: 1.07-5.13, P:0.03] than in women with normal BMI. Women with higher VAI were also significantly more likely to suffer lifetime GAD [PR: 1.25, CI: 1.05]. 1.48, P:0.01]. In males, the prevalence of lifetime diagnosed GAD per 1 standard deviation increase in VFA was 0.65 [CI: 0.46-0.91, P: 0.01]. CONCLUSION Visceral adiposity as a positive agent was associated with GAD prevalence in women. The presence of GAD symptoms showed no relationship to VFA in men.
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Affiliation(s)
- Ghazaleh Nameni
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences , Tehran, Iran
| | - Shima Jazayeri
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences , Tehran, Iran.
| | - Masoud Salehi
- Department of Biostatistics, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Esrafili
- Department of Environmental Health Engineering, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Ahmad Hajebi
- Research Center for Addiction & Risky Behaviors (ReCARB), Psychosocial Health Research Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
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9
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Kinsman LM, Norrie HJ, Rachor GS, Asmundson GJG. Exercise and PTSD. Curr Top Behav Neurosci 2024; 67:241-262. [PMID: 39112812 DOI: 10.1007/7854_2024_500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2024]
Abstract
Evidence indicating that exercise benefits mental health symptoms across a range of mental health diagnoses spans decades of scientific literature; however, fewer studies have examined the impact of exercise on posttraumatic stress disorder (PTSD). Exercise is an accessible, cost-effective, and scalable treatment option that has the potential to improve both physiological and psychological symptoms among individuals with PTSD. The purpose of this chapter is to review empirical literature on the role of exercise in the treatment of PTSD. Researchers have demonstrated that exercise improves PTSD symptoms as both a stand-alone treatment and as an adjunct to cognitive behavioral and trauma-focused therapies. Additional research is needed to clarify mechanisms that account for the impacts of exercise on PTSD and to identify which components of exercise (e.g., type of exercise, dose, intensity, frequency) are the most beneficial.
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Affiliation(s)
- Laura M Kinsman
- Department of Psychology, University of Regina, Regina, SK, Canada
| | - Holden J Norrie
- Department of Psychology, University of Regina, Regina, SK, Canada
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10
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Raza Z, Hussain SF, Foster VS, Wall J, Coffey PJ, Martin JF, Gomes RSM. Exposure to war and conflict: The individual and inherited epigenetic effects on health, with a focus on post-traumatic stress disorder. FRONTIERS IN EPIDEMIOLOGY 2023; 3:1066158. [PMID: 38455905 PMCID: PMC10910933 DOI: 10.3389/fepid.2023.1066158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/03/2023] [Indexed: 03/09/2024]
Abstract
War and conflict are global phenomena, identified as stress-inducing triggers for epigenetic modifications. In this state-of-the-science narrative review based on systematic principles, we summarise existing data to explore the outcomes of these exposures especially in veterans and show that they may result in an increased likelihood of developing gastrointestinal, auditory, metabolic and circadian issues, as well as post-traumatic stress disorder (PTSD). We also note that, despite a potential "healthy soldier effect", both veterans and civilians with PTSD exhibit the altered DNA methylation status in hypothalamic-pituitary-adrenal (HPA) axis regulatory genes such as NR3C1. Genes associated with sleep (PAX8; LHX1) are seen to be differentially methylated in veterans. A limited number of studies also revealed hereditary effects of war exposure across groups: decreased cortisol levels and a heightened (sex-linked) mortality risk in offspring. Future large-scale studies further identifying the heritable risks of war, as well as any potential differences between military and civilian populations, would be valuable to inform future healthcare directives.
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Affiliation(s)
- Zara Raza
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
- Hull York Medical School, University of York, York, United Kingdom
| | - Syeda F Hussain
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
| | - Victoria S Foster
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
- St George's Hospital Medical School, London, United Kingdom
| | - Joseph Wall
- Hull York Medical School, University of York, York, United Kingdom
- Haxby Group Hull, General Practice Surgery, Hull, United Kingdom
| | - Peter J Coffey
- Development, Ageing and Disease, UCL Institute of Ophthalmology, University College London, London, United Kingdom
| | - John F Martin
- Centre for Cardiovascular Biology and Medicine, University College London, London, United Kingdom
| | - Renata S M Gomes
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
- Northern Hub for Veterans and Military Families Research, Department of Nursing, Midwifery and Health, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
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11
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Lushchak O, Strilbytska O, Koliada A, Storey KB. An orchestrating role of mitochondria in the origin and development of post-traumatic stress disorder. Front Physiol 2023; 13:1094076. [PMID: 36703926 PMCID: PMC9871262 DOI: 10.3389/fphys.2022.1094076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/22/2022] [Indexed: 01/11/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) is one of the most discussed and actively researched areas in medicine, psychiatry, neurophysiology, biochemistry and rehabilitation over the last decades. Multiple causes can trigger post-traumatic stress disorder. Humans subjected to violence, participants in hostilities, victims of terrorist attacks, physical or psychological persecution, witnessing scenes of cruelty, survival of natural disasters, and more, can strongly affect both children and adults. Pathological features of post-traumatic stress disorder that are manifested at molecular, cellular and whole-organism levels must be clearly understood for successful diagnosis, management, and minimizing of long-term outcomes associated with post-traumatic stress disorder. This article summarizes existing data on different post-traumatic stress disorder causes and symptoms, as well as effects on homeostasis, genetic instability, behavior, neurohumoral balance, and personal psychic stability. In particular, we highlight a key role of mitochondria and oxidative stress development in the severity and treatment of post-traumatic stress disorder. Excessive or prolonged exposure to traumatic factors can cause irreversible mitochondrial damage, leading to cell death. This review underlines the exceptional importance of data integration about the mechanisms and functions of the mitochondrial stress response to develop a three-dimensional picture of post-traumatic stress disorder pathophysiology and develop a comprehensive, universal, multifaceted, and effective strategy of managing or treatment post-traumatic stress disorder.
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Affiliation(s)
- Oleh Lushchak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine,Research and Development University, Ivano-Frankivsk, Ukraine,*Correspondence: Oleh Lushchak,
| | - Olha Strilbytska
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Alexander Koliada
- Institute of Food Biotechnology and Genomics, NAS of Ukraine, Kyiv, Ukraine
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12
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Johnston KJ, Huckins LM. Chronic Pain and Psychiatric Conditions. Complex Psychiatry 2023; 9:24-43. [PMID: 37034825 PMCID: PMC10080192 DOI: 10.1159/000527041] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 09/01/2022] [Indexed: 11/19/2022] Open
Abstract
Introduction Chronic pain is a common condition with high socioeconomic and public health burden. A wide range of psychiatric conditions are often comorbid with chronic pain and chronic pain conditions, negatively impacting successful treatment of either condition. The psychiatric condition receiving most attention in the past with regard to chronic pain comorbidity has been major depressive disorder, despite the fact that many other psychiatric conditions also demonstrate epidemiological and genetic overlap with chronic pain. Further understanding potential mechanisms involved in psychiatric and chronic pain comorbidity could lead to new treatment strategies both for each type of disorder in isolation and in scenarios of comorbidity. Methods This article provides an overview of relationships between DSM-5 psychiatric diagnoses and chronic pain, with particular focus on PTSD, ADHD, and BPD, disorders which are less commonly studied in conjunction with chronic pain. We also discuss potential mechanisms that may drive comorbidity, and present new findings on the genetic overlap of chronic pain and ADHD, and chronic pain and BPD using linkage disequilibrium score regression analyses. Results Almost all psychiatric conditions listed in the DSM-5 are associated with increased rates of chronic pain. ADHD and BPD are significantly genetically correlated with chronic pain. Psychiatric conditions aside from major depression are often under-researched with respect to their relationship with chronic pain. Conclusion Further understanding relationships between psychiatric conditions other than major depression (such as ADHD, BPD, and PTSD as exemplified here) and chronic pain can positively impact understanding of these disorders, and treatment of both psychiatric conditions and chronic pain.
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Affiliation(s)
- Keira J.A. Johnston
- Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Psychiatry, Yale University, New Haven, Connecticut, USA
| | - Laura M. Huckins
- Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Psychiatry, Yale University, New Haven, Connecticut, USA
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13
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Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev 2023; 75:62-158. [PMID: 36757901 PMCID: PMC9832385 DOI: 10.1124/pharmrev.122.000618] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.
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Affiliation(s)
- Breana Channer
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Vasiliki Pappa
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Yash Agarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Jason Wickman
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
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14
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Choi JJ, Martins JS, Hwang S, Sinha R, Seo D. Neural correlates linking trauma and physical symptoms. Psychiatry Res Neuroimaging 2022; 327:111560. [PMID: 36327865 PMCID: PMC9757618 DOI: 10.1016/j.pscychresns.2022.111560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/13/2022] [Accepted: 10/23/2022] [Indexed: 11/06/2022]
Abstract
Trauma and chronic pain frequently co-occur, but the underlying neurological mechanisms are poorly understood. The current study investigated the neural correlates of stress and physical symptoms in trauma patients using functional magnetic resonance imaging (fMRI) and follow-up smartphone surveys. Participants were 10 patients diagnosed with Trauma- and Stressor-Related Disorders and 18 demographically-matched healthy controls who completed a fMRI stress provocation task in which they viewed stressful and neutral-relaxing images. Subsequently, participants completed daily smartphone surveys which prospectively monitored their stress and physical symptoms for 30 days. The trauma group experienced a significantly higher frequency of physical symptoms than controls during the follow-up period. During stress, trauma patients exhibited increased activity in the hippocampus, insula, and sensorimotor areas, but decreased activity in the ventromedial prefrontal cortex (vmPFC), lateral prefrontal cortex (LPFC), and dorsal striatum relative to controls. In all participants, higher physical symptom frequency was significantly associated with a hyperactive left hippocampal response to stress. The current study reports that trauma is characterized by greater physical symptoms and decreased prefrontal but increased limbic responses to stress. Our findings suggest that trauma may increase physical health symptoms by compromising hippocampal function, which could also increase vulnerability to stress- and pain-related disorders.
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Affiliation(s)
- Justin J Choi
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States of America.
| | - Jorge S Martins
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States of America; William James Center for Research, ISPA-Instituto Universitário, Lisbon, Portugal
| | - Seungju Hwang
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States of America
| | - Rajita Sinha
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States of America; Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States of America
| | - Dongju Seo
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States of America.
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15
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Anwar F, Sparrow NA, Rashid MH, Guidry G, Gezalian MM, Ley EJ, Koronyo-Hamaoui M, Danovitch I, Ely EW, Karumanchi SA, Lahiri S. Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury. Crit Care 2022; 26:274. [PMID: 36100846 PMCID: PMC9469063 DOI: 10.1186/s13054-022-04159-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 09/04/2022] [Indexed: 11/10/2022] Open
Abstract
Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.
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16
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Taft TH, McGarva J, Omprakash TA, Tomasino K, Pandit A, Mutlu EA, Hanauer SB. Hospitalization Experiences and Post-traumatic Stress in Inflammatory Bowel Disease: Opportunities for Change. Inflamm Bowel Dis 2022; 29:675-683. [PMID: 35894686 DOI: 10.1093/ibd/izac148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Indexed: 12/09/2022]
Abstract
INTRODUCTION Medical trauma related to IBD (IBD-PTS) affects approximately 25% of patients and is associated with poor outcomes. Prior studies identify common hospitalization experiences as potentially traumatic but have not measured risk relationships for the development of IBD-PTS. We aim to investigate what aspects of hospitalizations may increase the chance of medical trauma and IBD-PTS development. METHODS Adult patients with IBD enrolled in the IBD Partners database were recruited. Study specific questionnaires included PTSD checklist, 5th edition (PCL-5), patient experience questionnaire, and items about the patient's most stressful hospitalization and nonhospital sources of medical trauma. Established criteria for the PCL-5 identified significant IBD-PTS symptoms (re-experiencing, avoidance, mood change, hyperarousal, global diagnosis). Select disease and treatment information was obtained from the main IBD Partners dataset. Univariate and multivariate statistics evaluated the relationships between hospitalization data and IBD-PTS. RESULTS There were 639 participants with at least 1 hospitalization for IBD included. Approximately two-thirds had Crohn's disease; most were White, non-Hispanic, female, middle-aged, and reported their IBD as being in remission. Forty percent of patients stated a hospitalization was a source of IBD-PTS. Frequent anxiety while hospitalized increased the odds of IBD-PTS 2 to 4 times; similar relationships existed for pain/pain control. Higher quality communication, information, and listening skills reduced the odds of IBD-PTS, albeit marginally. CONCLUSIONS Patients with IBD consistently cite hospitalizations as potential sources of medical trauma. Poorly managed anxiety and pain demonstrate the greatest chance for IBD-PTS development. Gender and racial/ethnic differences emerged for these risks. Positive interactions with the medical team may help mitigate in-hospital IBD-PTS development.
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Affiliation(s)
- Tiffany H Taft
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology & Hepatology, Chicago, Illinois, USA
| | - Josie McGarva
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology & Hepatology, Chicago, Illinois, USA
| | | | - Kathryn Tomasino
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology & Hepatology, Chicago, Illinois, USA
| | - Anjali Pandit
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology & Hepatology, Chicago, Illinois, USA
| | - Ece A Mutlu
- University of Illinois, Division of Gastroenterology, Chicago, Illinois, USA
| | - Stephen B Hanauer
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology & Hepatology, Chicago, Illinois, USA
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Zhang Y, Rosen R, Reibman J, Shao Y. Posttraumatic Stress Disorder Mediates the Association between Traumatic World Trade Center Dust Cloud Exposure and Ongoing Systemic Inflammation in Community Members. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19148622. [PMID: 35886474 PMCID: PMC9322679 DOI: 10.3390/ijerph19148622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022]
Abstract
Exposure to World Trade Center (WTC) dust/fumes and traumas on 11 September 2001 has been reported as a risk factor for post-traumatic stress disorder (PTSD) and other mental/physical health symptoms in WTC-affected populations. Increased systemic inflammation and oxidative stress from the exposure and subsequent illnesses have been proposed as contributors to the underlying biological processes. Many blood-based biomarkers of systemic inflammation, including C-reactive protein (CRP), are useful for non-invasive diagnostic and monitoring of disease process, and also potential targets for therapeutic interventions. Twenty years after 9/11, however, the relationships between WTC exposure, chronic PTSD, and systemic inflammation are only beginning to be systematically investigated in the WTC-affected civilian population despite the fact that symptoms of PTSD and systemic inflammation are still common and persistent. This paper aims to address this knowledge gap, using enrollees of the WTC Environmental Health Center (EHC), a federally designated treatment and surveillance program for community members (WTC Survivors) exposed to the 9/11 terrorist attack. We conducted a mediation analysis to investigate the association between acute WTC dust cloud traumatic exposure (WDCTE) on 9/11, chronic PTSD symptoms, and levels of systemic inflammation. The data indicate that the chronic PTSD symptoms and some specific symptom clusters of PTSD significantly mediate the WDCTE on systemic inflammation, as reflected by the CRP levels. As both chronic PTSD and systemic inflammation are long-term risk factors for neurodegeneration and cognitive decline, further research on the implications of this finding is warranted.
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Affiliation(s)
- Yian Zhang
- Department of Population Health, NYU Grossman School of Medicine, 180 Madison Avenue, New York, NY 10016, USA;
- HHC World Trade Center Environmental Health Center, 462 First Avenue, New York, NY 10016, USA;
- NYU Alzheimer Disease Research Center, 145 E 32 Street, New York, NY 10016, USA
| | - Rebecca Rosen
- HHC World Trade Center Environmental Health Center, 462 First Avenue, New York, NY 10016, USA;
- Department of Psychiatry, NYU Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Joan Reibman
- HHC World Trade Center Environmental Health Center, 462 First Avenue, New York, NY 10016, USA;
- Department of Medicine, NYU Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
- Correspondence: (J.R.); (Y.S.)
| | - Yongzhao Shao
- Department of Population Health, NYU Grossman School of Medicine, 180 Madison Avenue, New York, NY 10016, USA;
- HHC World Trade Center Environmental Health Center, 462 First Avenue, New York, NY 10016, USA;
- NYU Alzheimer Disease Research Center, 145 E 32 Street, New York, NY 10016, USA
- Correspondence: (J.R.); (Y.S.)
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Núñez-Rios DL, Martínez-Magaña JJ, Nagamatsu ST, Andrade-Brito DE, Forero DA, Orozco-Castaño CA, Montalvo-Ortiz JL. Central and Peripheral Immune Dysregulation in Posttraumatic Stress Disorder: Convergent Multi-Omics Evidence. Biomedicines 2022; 10:1107. [PMID: 35625844 PMCID: PMC9138536 DOI: 10.3390/biomedicines10051107] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/29/2022] [Accepted: 05/04/2022] [Indexed: 11/16/2022] Open
Abstract
Posttraumatic stress disorder (PTSD) is a chronic and multifactorial disorder with a prevalence ranging between 6-10% in the general population and ~35% in individuals with high lifetime trauma exposure. Growing evidence indicates that the immune system may contribute to the etiology of PTSD, suggesting the inflammatory dysregulation as a hallmark feature of PTSD. However, the potential interplay between the central and peripheral immune system, as well as the biological mechanisms underlying this dysregulation remain poorly understood. The activation of the HPA axis after trauma exposure and the subsequent activation of the inflammatory system mediated by glucocorticoids is the most common mechanism that orchestrates an exacerbated immunological response in PTSD. Recent high-throughput analyses in peripheral and brain tissue from both humans with and animal models of PTSD have found that changes in gene regulation via epigenetic alterations may participate in the impaired inflammatory signaling in PTSD. The goal of this review is to assess the role of the inflammatory system in PTSD across tissue and species, with a particular focus on the genomics, transcriptomics, epigenomics, and proteomics domains. We conducted an integrative multi-omics approach identifying TNF (Tumor Necrosis Factor) signaling, interleukins, chemokines, Toll-like receptors and glucocorticoids among the common dysregulated pathways in both central and peripheral immune systems in PTSD and propose potential novel drug targets for PTSD treatment.
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Affiliation(s)
- Diana L. Núñez-Rios
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; (D.L.N.-R.); (J.J.M.-M.); (S.T.N.); (D.E.A.-B.)
- VA CT Healthcare Center, West Haven, CT 06516, USA
| | - José J. Martínez-Magaña
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; (D.L.N.-R.); (J.J.M.-M.); (S.T.N.); (D.E.A.-B.)
- VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Sheila T. Nagamatsu
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; (D.L.N.-R.); (J.J.M.-M.); (S.T.N.); (D.E.A.-B.)
- VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Diego E. Andrade-Brito
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; (D.L.N.-R.); (J.J.M.-M.); (S.T.N.); (D.E.A.-B.)
- VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Diego A. Forero
- Health and Sport Sciences Research Group, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 110231, Colombia; (D.A.F.); (C.A.O.-C.)
| | - Carlos A. Orozco-Castaño
- Health and Sport Sciences Research Group, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 110231, Colombia; (D.A.F.); (C.A.O.-C.)
| | - Janitza L. Montalvo-Ortiz
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; (D.L.N.-R.); (J.J.M.-M.); (S.T.N.); (D.E.A.-B.)
- VA CT Healthcare Center, West Haven, CT 06516, USA
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19
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Doney E, Cadoret A, Dion‐Albert L, Lebel M, Menard C. Inflammation-driven brain and gut barrier dysfunction in stress and mood disorders. Eur J Neurosci 2022; 55:2851-2894. [PMID: 33876886 PMCID: PMC9290537 DOI: 10.1111/ejn.15239] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 03/18/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023]
Abstract
Regulation of emotions is generally associated exclusively with the brain. However, there is evidence that peripheral systems are also involved in mood, stress vulnerability vs. resilience, and emotion-related memory encoding. Prevalence of stress and mood disorders such as major depression, bipolar disorder, and post-traumatic stress disorder is increasing in our modern societies. Unfortunately, 30%-50% of individuals respond poorly to currently available treatments highlighting the need to further investigate emotion-related biology to gain mechanistic insights that could lead to innovative therapies. Here, we provide an overview of inflammation-related mechanisms involved in mood regulation and stress responses discovered using animal models. If clinical studies are available, we discuss translational value of these findings including limitations. Neuroimmune mechanisms of depression and maladaptive stress responses have been receiving increasing attention, and thus, the first part is centered on inflammation and dysregulation of brain and circulating cytokines in stress and mood disorders. Next, recent studies supporting a role for inflammation-driven leakiness of the blood-brain and gut barriers in emotion regulation and mood are highlighted. Stress-induced exacerbated inflammation fragilizes these barriers which become hyperpermeable through loss of integrity and altered biology. At the gut level, this could be associated with dysbiosis, an imbalance in microbial communities, and alteration of the gut-brain axis which is central to production of mood-related neurotransmitter serotonin. Novel therapeutic approaches such as anti-inflammatory drugs, the fast-acting antidepressant ketamine, and probiotics could directly act on the mechanisms described here improving mood disorder-associated symptomatology. Discovery of biomarkers has been a challenging quest in psychiatry, and we end by listing promising targets worth further investigation.
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Affiliation(s)
- Ellen Doney
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQCCanada
| | - Alice Cadoret
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQCCanada
| | - Laurence Dion‐Albert
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQCCanada
| | - Manon Lebel
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQCCanada
| | - Caroline Menard
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQCCanada
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20
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Occean JR, Wani AH, Donglasan J, Aiello AE, Galea S, Koenen KC, Qu A, Wildman DE, Uddin M. DNA methylation of Nuclear Factor of Activated T Cells 1 mediates the prospective relation between exposure to different traumatic event types and post-traumatic stress disorder. Psychiatry Res 2022; 311:114510. [PMID: 35349860 PMCID: PMC9018623 DOI: 10.1016/j.psychres.2022.114510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 02/26/2022] [Accepted: 03/12/2022] [Indexed: 11/25/2022]
Abstract
The mechanisms through which exposure to differing trauma types become biologically embedded to shape the risk for post-traumatic stress disorder (PTSD) is unclear. DNA methylation (5-mC), particularly in stress-relevant genes, may play a role in this relationship. Here, we conducted path analysis using generalized structural equation modeling to investigate whether blood-derived 5-mC in Nuclear Factor of Activated T Cells 1 (NFATC1) mediates the prospective association between each of five different trauma types ("assaultive violence", "other injury or shocking experience", "learning of trauma to loved one", "sudden, unexpected death of a close friend or relative", and "other") and lifetime PTSD. All five trauma types were significantly associated with reduced methylation at NFATC1 CpG site, cg17057218. Two of the five trauma types were significantly associated with increased methylation at NFATC1 CpG site, cg22324981. Moreover, methylation at cg17057218 significantly mediated 21-32% of the total effect for four of the five trauma types, while methylation at cg22324981 mediated 27-40% of the total effect for two of the five trauma types. These CpG sites were differentially associated with transcription factor binding sites and chromatin state signatures. NFATC1 5-mC may be a potential mechanism in the relationship between some trauma types and prospective risk for PTSD.
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Affiliation(s)
- James R Occean
- Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA; Present address: Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Agaz H Wani
- Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA
| | - Janelle Donglasan
- Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA
| | - Allison E Aiello
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sandro Galea
- Boston University School of Public Health, Boston University, Boston, MA, USA
| | - Karestan C Koenen
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Psychiatric and Neurodevelopmental Genetics Unit & Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Annie Qu
- Department of Statistics, University of California Irvine, Irvine, CA, USA
| | - Derek E Wildman
- Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA
| | - Monica Uddin
- Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA.
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21
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Busbee PB, Bam M, Yang X, Abdulla OA, Zhou J, Ginsberg JPJ, Aiello AE, Uddin M, Nagarkatti M, Nagarkatti PS. Dysregulated TP53 Among PTSD Patients Leads to Downregulation of miRNA let-7a and Promotes an Inflammatory Th17 Phenotype. Front Immunol 2022; 12:815840. [PMID: 35058939 PMCID: PMC8763839 DOI: 10.3389/fimmu.2021.815840] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/15/2021] [Indexed: 12/31/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is a psychiatric disorder and patients diagnosed with PTSD often express other comorbid health issues, particularly autoimmune and inflammatory disorders. Our previous reports investigating peripheral blood mononuclear cells (PBMCs) from PTSD patients showed that these patients exhibit an increased inflammatory T helper (Th) cell phenotype and widespread downregulation of microRNAs (miRNAs), key molecules involved in post-transcriptional gene regulation. A combination of analyzing prior datasets on gene and miRNA expression of PBMCs from PTSD and Control samples, as well as experiments using primary PBMCs collected from human PTSD and Controls blood, was used to evaluate TP53 expression, DNA methylation, and miRNA modulation on Th17 development. In the current report, we note several downregulated miRNAs were linked to tumor protein 53 (TP53), also known as p53. Expression data from PBMCs revealed that compared to Controls, PTSD patients exhibited decreased TP53 which correlated with an increased inflammatory Th17 phenotype. Decreased expression of TP53 in the PTSD population was shown to be associated with an increase in DNA methylation in the TP53 promotor region. Lastly, the most significantly downregulated TP53-associated miRNA, let-7a, was shown to negatively regulate Th17 T cells. Let-7a modulation in activated CD4+ T cells was shown to influence Th17 development and function, via alterations in IL-6 and IL-17 production, respectively. Collectively, these studies reveal that PTSD patients could be susceptible to inflammation by epigenetic dysregulation of TP53, which alters the miRNA profile to favor a proinflammatory Th17 phenotype.
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Affiliation(s)
- Philip B Busbee
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Marpe Bam
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Xiaoming Yang
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Osama A Abdulla
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Juhua Zhou
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Jay Paul Jack Ginsberg
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States.,Departments of Psychophysiology, Clinical Psychology, and Research Office, Saybrook University, Pasadena, CA, United States
| | - Allison E Aiello
- Department of Epidemiology, University of North Carolina (UNC) Gillings School of Global Public Health, University of North Carolina, Mcgavran-Greenberg Hall, Chapel Hill, NC, United States
| | - Monica Uddin
- Genomics Program, University of South Florida College of Public Health, Tampa, FL, United States
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Prakash S Nagarkatti
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
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22
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Exploring the relationship between the gut microbiome and mental health outcomes in a posttraumatic stress disorder cohort relative to trauma-exposed controls. Eur Neuropsychopharmacol 2022; 56:24-38. [PMID: 34923209 DOI: 10.1016/j.euroneuro.2021.11.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 11/15/2021] [Accepted: 11/22/2021] [Indexed: 12/17/2022]
Abstract
Posttraumatic stress disorder (PTSD) imposes a significant burden on patients and communities. Although the microbiome-gut-brain axis has been proposed as a mediator or moderator of PTSD risk and persistence of symptoms, clinical data directly delineating the gut microbiome's relationship to PTSD are sparse. This study investigated associations between the gut microbiome and mental health outcomes in participants with PTSD (n = 79) and trauma-exposed controls (TECs) (n = 58). Diagnoses of PTSD, major depressive disorder (MDD), and childhood trauma were made using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), MINI International Neuropsychiatric Interview (MINI), and Childhood Trauma Questionnaire (CTQ), respectively. Microbial communities from stool samples were profiled using 16S ribosomal RNA gene V4 amplicon sequencing and tested for associations with PTSD-related variables of interest. Random forest models identified a consortium of four genera, i.e., a combination of Mitsuokella, Odoribacter, Catenibacterium, and Olsenella, previously associated with periodontal disease, that could distinguish PTSD status with 66.4% accuracy. The relative abundance of this consortium was higher in the PTSD group and correlated positively with CAPS-5 and CTQ scores. MDD diagnosis was also associated with increased relative abundance of the Bacteroidetes phylum. Current use of psychotropics significantly impacted community composition and the relative abundances of several taxa. Early life trauma may prime the microbiome for changes in composition that facilitate a pro-inflammatory cascade and increase the risk of development of PTSD. Future studies should rigorously stratify participants into healthy controls, TECs, and PTSD (stratified by psychotropic drug use) to explore the role of the oral-gut-microbiome-brain axis in trauma-related disorders.
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23
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Lee B. Neuroprotective Effect of Acupuncture against Single Prolonged Stress-Induced Memory Impairments and Inflammation in Rat Brain via Modulation of Brain-Derived Neurotrophic Factor Expression. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:4430484. [PMID: 35251208 PMCID: PMC8890831 DOI: 10.1155/2022/4430484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/25/2022] [Indexed: 01/04/2023]
Abstract
Posttraumatic stress disorder (PTSD) is a serious mental disorder that can appear after exposure to extreme stress. Acupuncture is an alternative therapy that is widely used to treat various neurodegenerative diseases, as well as cognitive and memory impairments. The aim of this study was to examine whether acupuncture stimulation at a specific acupoint (Shenmen or heart meridian, HT7) could improve memory defects caused by single prolonged stress (SPS) in rats. After exposure to SPS, acupuncture on the HT7 acupoint in male rats was performed, once daily for 21 days. We confirmed that this treatment improved fear memory, cognitive function, and spatial memory by modulating the neuroinflammation and expression of brain-derived neurotrophic factor (BDNF) mRNA in the brain. It also significantly inhibited the activation of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β and the enzyme cyclooxygenase-2 in the brain; it increased the expression of BDNF mRNA in the hippocampus. Our findings provide valuable information concerning the clinical usefulness of acupuncture in the treatment of PTSD.
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Affiliation(s)
- Bombi Lee
- Acupuncture and Meridian Science Research Center, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
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24
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Clouston SAP, Hall CB, Kritikos M, Bennett DA, DeKosky S, Edwards J, Finch C, Kreisl WC, Mielke M, Peskind ER, Raskind M, Richards M, Sloan RP, Spiro A, Vasdev N, Brackbill R, Farfel M, Horton M, Lowe S, Lucchini RG, Prezant D, Reibman J, Rosen R, Seil K, Zeig-Owens R, Deri Y, Diminich ED, Fausto BA, Gandy S, Sano M, Bromet EJ, Luft BJ. Cognitive impairment and World Trade Centre-related exposures. Nat Rev Neurol 2022; 18:103-116. [PMID: 34795448 PMCID: PMC8938977 DOI: 10.1038/s41582-021-00576-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2021] [Indexed: 02/03/2023]
Abstract
On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story 'Twin Towers'. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these 'WTC-affected' individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals.
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Affiliation(s)
- Sean A P Clouston
- Program in Public Health, Department of Family, Population, and Preventive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA.
| | - Charles B Hall
- Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Minos Kritikos
- Program in Public Health, Department of Family, Population, and Preventive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush Medical College, Rush University, Chicago, IL, USA
| | - Steven DeKosky
- Evelyn F. and William L. McKnight Brain Institute and Florida Alzheimer's Disease Research Center, Department of Neurology and Neuroscience, University of Florida, Gainesville, FL, USA
| | - Jerri Edwards
- Department of Psychiatry and Behavioral Neuroscience, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Caleb Finch
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - William C Kreisl
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA
| | - Michelle Mielke
- Specialized Center of Research Excellence on Sex Differences, Department of Neurology, Department of Epidemiology, Mayo Clinic, Rochester, MN, USA
| | - Elaine R Peskind
- Veteran's Association VISN 20 Northwest Mental Illness Research, Education, and Clinical Center, Veteran's Affairs Puget Sound Health Care System, Seattle, WA, USA
- Alzheimer's Disease Research Center, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Murray Raskind
- Veteran's Association VISN 20 Northwest Mental Illness Research, Education, and Clinical Center, Veteran's Affairs Puget Sound Health Care System, Seattle, WA, USA
- Alzheimer's Disease Research Center, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Marcus Richards
- Medical Research Council Unit for Lifelong Health and Ageing, Population Health Sciences, University College London, London, UK
| | - Richard P Sloan
- Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Avron Spiro
- Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Department of Veterans Affairs Boston Healthcare System, Boston, MA, USA
| | - Neil Vasdev
- Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Center, Center for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Robert Brackbill
- World Trade Center Health Registry, New York Department of Health and Mental Hygiene, New York, NY, USA
| | - Mark Farfel
- World Trade Center Health Registry, New York Department of Health and Mental Hygiene, New York, NY, USA
| | - Megan Horton
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sandra Lowe
- The World Trade Center Mental Health Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Roberto G Lucchini
- Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA
| | - David Prezant
- World Trade Center Health Program, Fire Department of the City of New York, Brooklyn, NY, USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Joan Reibman
- Department of Environmental Medicine, New York University Langone Health, New York, NY, USA
| | - Rebecca Rosen
- World Trade Center Environmental Health Center, Department of Psychiatry, New York University, New York, NY, USA
| | - Kacie Seil
- World Trade Center Health Registry, New York Department of Health and Mental Hygiene, New York, NY, USA
| | - Rachel Zeig-Owens
- World Trade Center Health Program, Fire Department of the City of New York, Brooklyn, NY, USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yael Deri
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
- Department of Psychiatry, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Erica D Diminich
- Program in Public Health, Department of Family, Population, and Preventive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Bernadette A Fausto
- Center for Molecular & Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Sam Gandy
- Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, USA
- Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Department of Psychiatry, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Mary Sano
- Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, USA
- Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Department of Psychiatry, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Evelyn J Bromet
- Department of Psychiatry, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Benjamin J Luft
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
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25
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Watanabe N, Takeda M. Neurophysiological dynamics for psychological resilience: A view from the temporal axis. Neurosci Res 2021; 175:53-61. [PMID: 34801599 DOI: 10.1016/j.neures.2021.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 10/19/2022]
Abstract
When an individual is faced with adversity, the brain and body work cooperatively to adapt to it. This adaptive process is termed psychological resilience, and recent studies have identified several neurophysiological factors ("neurophysiological resilience"), such as monoamines, oscillatory brain activity, hemodynamics, autonomic activity, stress hormones, and immune systems. Each factor is activated in an interactive manner during specific time windows after exposure to stress. Thus, the differences in psychological resilience levels among individuals can be characterized by differences in the temporal dynamics of neurophysiological resilience. In this review, after briefly introducing the frequently used approaches in this research field and the well-known factors of neurophysiological resilience, we summarize the temporal dynamics of neurophysiological resilience. This viewpoint clarifies an important time window, the more-than-one-hour scale, but the neurophysiological dynamics during this window remain elusive. To address this issue, we propose exploring brain-wide oscillatory activities using concurrent functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) techniques.
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Affiliation(s)
- Noriya Watanabe
- Research Center for Brain Communication, Research Institute, Kochi University of Technology, Kochi, Japan; Center for Information and Neural Networks, National Institute of Information and Communications Technology, Osaka, Japan.
| | - Masaki Takeda
- Research Center for Brain Communication, Research Institute, Kochi University of Technology, Kochi, Japan
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26
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Gupta S, Guleria RS, Szabo YZ. MicroRNAs as biomarker and novel therapeutic target for posttraumatic stress disorder in Veterans. Psychiatry Res 2021; 305:114252. [PMID: 34739954 PMCID: PMC8857765 DOI: 10.1016/j.psychres.2021.114252] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/04/2021] [Accepted: 10/23/2021] [Indexed: 12/16/2022]
Abstract
Posttraumatic stress disorder (PTSD) is a common psychiatric disorder for military Veterans, characterized by hyperarousal, intrusive thoughts, flashbacks, hypervigilance, and distress after experiencing traumatic events. Some of the known physiological effects of PTSD include hypothalamic-pituitary-adrenal (HPA)-axis imbalance, a cortical function resulting in neuronal deficit and changes in behavior. Moreover, excessive discharge of inflammatory molecules and a dysregulated immune system are implicated in the pathophysiology of PTSD. Due to complex nature of this disorder, the biological underpinnings of PTSD remain inexplicable. Investigating novel biomarkers to understanding the pathogenesis of PTSD may reflect the underlying molecular network for therapeutic use and treatment. Circulatory microRNAs (miRNAs) and exosomes are evolving biomarkers that have shown a key role in psychiatric and neurological disorders including PTSD. Given the unique nature of combat trauma, as well as evidence that a large portion of Veterans do not benefit from frontline treatments, focus on veterans specifically is warranted. In the present review, we delineate the identification and role of several miRNAs in PTSD among veterans. An association of miRNA with HPA-axis regulation through FKBP5, a key modulator in PTSD is discussed as an emerging molecule in psychiatric diseases. We conclude that miRNAs may be used as circulatory biomarker detection in Veterans with PTSD.
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Affiliation(s)
- Sudhiranjan Gupta
- VISN 17 Center of Excellence for Research on Returning War Veterans, Biomarkers & Genetics Core, Central Texas Veterans Health Care System, 4800 Memorial Drive (151C), Waco, TX, 76711, USA.
| | - Rakeshwar S. Guleria
- VISN 17 Center of Excellence for Research on Returning War Veterans, Biomarkers & Genetics Core, Central Texas Veterans Health Care System, 4800 Memorial Drive (151C), Waco, Texas, 76711
| | - Yvette Z. Szabo
- VISN 17 Center of Excellence for Research on Returning War Veterans, Biomarkers & Genetics Core, Central Texas Veterans Health Care System, 4800 Memorial Drive (151C), Waco, Texas, 76711
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27
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Persistent level of mental distress in PTSD patients is not reflected in cytokine levels 1 year after the treatment. Acta Neuropsychiatr 2021; 33:254-260. [PMID: 33902770 DOI: 10.1017/neu.2021.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Cross-sectional data show that post-traumatic stress disorder (PTSD) patients often have increased levels of circulating inflammatory markers. There is, however, still a paucity of longitudinal studies with long follow-up times on levels of cytokines in such patients. The current study assesses patients with and without PTSD diagnosis 1 year after discharge from inpatient treatment. METHODS Patients in treatment for serious non-psychotic mental disorders were recruited at the beginning of their treatment stay at a psychiatric centre in Norway. Ninety patients submitted serum samples and filled out the Hopkins Symptom Checklist-90 Revised Global Severity Index (HSCL-90R GSI) questionnaire during their mainstay and at a follow-up stay 1 year after discharge. Of these patients, 33 were diagnosed with PTSD, 48 with anxiety, depression, or eating disorder, while 9 patients had missing data. The patients were diagnosed using the Mini-International Neuropsychiatric Interview (MINI). RESULTS At the follow-up stay (T3), PTSD patients had higher levels of GSI scores than non-PTSD patients (p = 0.048). These levels were unchanged from the year before (T2) in both groups. The levels of circulating cytokines/chemokine did not differ between the PTSD and non-PTSD patients at T3. At T2, however, the PTSD and non-PTSD groups exhibited different levels of interleukin 1β (IL-1β) (p = 0.053), IL-1RA (p = 0.042), and TNF-α (p = 0.037), with the PTSD patients having the higher levels. CONCLUSION Despite exhibiting different mental distress scores, the PTSD and non-PTSD patients did not differ regarding levels of circulating inflammatory markers at 1-year follow-up.
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Psychological Traumas and Cardiovascular Disease: A Case-Control Study. Healthcare (Basel) 2021; 9:healthcare9070875. [PMID: 34356253 PMCID: PMC8304858 DOI: 10.3390/healthcare9070875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/24/2021] [Accepted: 06/29/2021] [Indexed: 11/16/2022] Open
Abstract
Adverse childhood experiences could be important determinants of adult disease. The present study analyzed the association between early traumatic experiences and the onset of cardiovascular disease (CVDs). It was hypothesized that patients with CVD would report a higher number of traumatic experiences during childhood and that this association would be stronger in women. The Traumatic Experiences Checklist (TEC) was fulfilled by 75 patients with a first-time diagnosis of CVD and 84 healthy controls randomly selected from the general population. The two groups were not balanced for age and sex. Multivariate analyses of covariance (MANCOVAs) and analyses of covariance (ANCOVAs), with group (clinical vs. control) and gender (male vs. female) as between-subjects factors, and age of participants as covariate, were performed on the number and the impact of the traumatic experiences (emotional neglect, emotional abuse, physical abuse, sexual harassment, and sexual abuse) for the three age group in which the trauma was experienced (from 0 to 10, from 11 to 18, from 19 years onwards). The main results showed that participants with CVDs have experienced a higher number of early traumatic experiences compared to the control group, such as emotional neglect (p = 0.023), emotional abuse (0.008 ≤ p ≤ 0.033), and physical abuse (0.001 < p ≤ 0.038). The results also revealed that women with CVDs have experienced more traumatic events compared to the women of the control group (0.001 < p ≤ 0.020). These results seem to highlight an association between traumatic experiences in childhood and CVD in adulthood, particularly in women. Such findings could have relevant implications for clinical practice, suggesting the importance of adopting an integrated approach in the care of the patient with cardiovascular diseases paying attention also to the clinical psychological risk factors.
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Bowers SJ, Lambert S, He S, Lowry CA, Fleshner M, Wright KP, Turek FW, Vitaterna MH. Immunization with a heat-killed bacterium, Mycobacterium vaccae NCTC 11659, prevents the development of cortical hyperarousal and a PTSD-like sleep phenotype after sleep disruption and acute stress in mice. Sleep 2021; 44:6025170. [PMID: 33283862 DOI: 10.1093/sleep/zsaa271] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 11/20/2020] [Indexed: 12/27/2022] Open
Abstract
STUDY OBJECTIVES Sleep deprivation induces systemic inflammation that may contribute to stress vulnerability and other pathologies. We tested the hypothesis that immunization with heat-killed Mycobacterium vaccae NCTC 11659 (MV), an environmental bacterium with immunoregulatory and anti-inflammatory properties, prevents the negative impacts of 5 days of sleep disruption on stress-induced changes in sleep, behavior, and physiology in mice. METHODS In a 2 × 2 × 2 experimental design, male C57BL/6N mice were given injections of either MV or vehicle on days -17, -10, and -3. On days 1-5, mice were exposed to intermittent sleep disruption, whereby sleep was disrupted for 20 h per day. Immediately following sleep disruption, mice were exposed to 1-h social defeat stress or novel cage (control) conditions. Object location memory (OLM) testing was conducted 24 h after social defeat, and tissues were collected 6 days later to measure inflammatory markers. Sleep was recorded using electroencephalography (EEG) and electromyography (EMG) throughout the experiment. RESULTS In vehicle-treated mice, only the combination of sleep disruption followed by social defeat (double hit): (1) increased brief arousals and NREM beta (15-30 Hz) EEG power in sleep immediately post-social defeat compared to baseline; (2) induced an increase in the proportion of rapid-eye-movement (REM) sleep and number of state shifts for at least 5 days post-social defeat; and (3) induced hyperlocomotion and lack of habituation in the OLM task. Immunization with MV prevented most of these sleep and behavioral changes. CONCLUSIONS Immunization with MV ameliorates a stress-induced sleep and behavioral phenotype that shares features with human posttraumatic stress disorder.
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Affiliation(s)
- Samuel J Bowers
- Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL.,Department of Neurobiology, Northwestern University, Evanston, IL
| | - Sophie Lambert
- Department of Neurobiology, Northwestern University, Evanston, IL
| | - Shannon He
- Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL.,Department of Neurobiology, Northwestern University, Evanston, IL
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.,Center for Neuroscience, University of Colorado Boulder, Boulder, CO
| | - Monika Fleshner
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.,Center for Neuroscience, University of Colorado Boulder, Boulder, CO
| | - Kenneth P Wright
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.,Center for Neuroscience, University of Colorado Boulder, Boulder, CO.,Sleep and Chronobiology Laboratory, University of Colorado Boulder, Boulder, CO
| | - Fred W Turek
- Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL.,Department of Neurobiology, Northwestern University, Evanston, IL.,The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Martha H Vitaterna
- Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL.,Department of Neurobiology, Northwestern University, Evanston, IL
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Taft TH, Quinton S, Jedel S, Simons M, Mutlu EA, Hanauer SB. Posttraumatic Stress in Patients With Inflammatory Bowel Disease: Prevalence and Relationships to Patient-Reported Outcomes. Inflamm Bowel Dis 2021; 28:710-719. [PMID: 34137449 PMCID: PMC8344426 DOI: 10.1093/ibd/izab152] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with chronic illness are at increased risk for traumatic stress because of medical trauma. Initial studies of posttraumatic stress (PTS) in patients with inflammatory bowel disease (IBD) have found that approximately one-third of patients may experience significant PTS symptoms including flashbacks, nightmares, hypervigilance, disrupted sleep, and low mood. We aim to better characterize PTS in IBD and its relationship with patient outcomes in a large cohort of patients with IBD. METHODS Adult patients registered with the Crohn's & Colitis Foundation/University of North Carolina IBD Partners database were invited to complete a supplementary survey between February and July 2020. The Post Traumatic Stress Disorder Checklist-5th edition was administered as a supplemental survey. Additional data from IBD Partners included disease severity, surgery and hospital history, demographics, and health care utilization. RESULTS A total of 797 patients participated (452 with Crohn disease, 345 with ulcerative colitis). No impacts on response patterns because of the COVID-19 pandemic were found. Although 5.6% of the sample reported an existing PTS diagnosis because of IBD experiences, 9.6% of participants met the full IBD-related PTS diagnostic criteria per the Post Traumatic Stress Disorder Checklist-5th edition. Female patients, younger patients, those with less educational attainment, non-White patients, and Hispanic patients reported higher levels of PTS symptoms. Patients with higher PTS symptoms were more likely to have been hospitalized, have had surgery, have more severe symptoms, and not be in remission. Increased PTS was also associated with increased anxiety, depression, pain interference, fatigue, and health care utilization. CONCLUSIONS The present findings support prior research that approximately one-quarter to one-third of patients with IBD report significant symptoms of PTS directly from their disease experiences, and certain demographic groups are at higher risk. In addition, PTS is associated with several IBD outcomes. Patients with higher PTS symptoms are less likely to be in remission and may utilize more outpatient gastrointestinal services. Intervention trials to mitigate PTS symptoms in patients with IBD are warranted.
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Affiliation(s)
- Tiffany H Taft
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology and Hepatology, Chicago, Illinois, USA,Address correspondence to: Tiffany Taft, PsyD, MIS, 676 North Saint Clair Street, Suite 1400, Chicago, IL 60611 ()
| | - Sarah Quinton
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology and Hepatology, Chicago, Illinois, USA
| | - Sharon Jedel
- Rush University, Department of Digestive Disease and Nutrition, Chicago, Illinois, USA
| | - Madison Simons
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology and Hepatology, Chicago, Illinois, USA
| | - Ece A Mutlu
- Rush University, Department of Digestive Disease and Nutrition, Chicago, Illinois, USA
| | - Stephen B Hanauer
- Northwestern University Feinberg School of Medicine, Division of Gastroenterology and Hepatology, Chicago, Illinois, USA
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31
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TMGH-Global COVID-19 Collaborative. Psychological Impacts and Post-Traumatic Stress Disorder among People under COVID-19 Quarantine and Isolation: A Global Survey. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:5719. [PMID: 34073524 PMCID: PMC8199241 DOI: 10.3390/ijerph18115719] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 01/02/2023]
Abstract
Understanding the presence of post-traumatic stress disorder (PTSD) symptoms in quarantined/isolated individuals is essential for decreasing morbidity and mortality caused by the COVID-19 pandemic. However, there is a paucity of evidence quantifying PTSD status globally during confinement in quarantine/isolation facilities during COVID-19. Therefore, we aimed to assess the PTSD status and factors contributing to PTSD development in quarantined/isolated people during pandemic. Using the Impact of Event Scale-Revised (IES-R) scale, our multicentre, multinational, and cross-sectional online survey assessed the psychological impacts on the quarantine/isolation experience of participants suspected or confirmed to have COVID-19, their PTSD status, and various correlates with developing PTSD. We had 944 (35.33%) valid responses (51.1% from females), mostly from Asian countries (635, 71.4%), and 33.9% were healthcare workers. The number of quarantine days in the PTSD symptoms group (using the IES-R cutoff of 24 for symptomatic or full PTSD) was significantly shorter compared to the non-PTSD group (14 (range 14-40) vs. 14 (14-23.75), p = 0.031). Lower rates of PTSD symptoms were observed in participants practicing Buddhist religion than in participants having no religion (OR: 0.30; 95% CI: 0.13-0.68; p = 0.005); individuals with vocational training had a higher risk of developing PTSD symptoms (OR: 2.28 (1.04-5.15); p = 0.043) compared to university graduates. Individuals forced to be quarantined/isolated had higher odds of developing PTSD symptoms than those voluntarily quarantined/isolated (OR: 2.92 (1.84-4.74); p < 0.001). We identified several PTSD correlations among individuals quarantined/isolated during the COVID-19 pandemic, including religious practice, reason for quarantine/isolation, education level, and being a case of the infection. These findings can inform worldwide policies to minimize the adverse effects of such social control measures.
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Jung YJ, Tweedie D, Scerba MT, Kim DS, Palmas MF, Pisanu A, Carta AR, Greig NH. Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders. Front Neurosci 2021; 15:656921. [PMID: 33854417 PMCID: PMC8039148 DOI: 10.3389/fnins.2021.656921] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.
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Affiliation(s)
- Yoo Jin Jung
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
- Stanford Neurosciences Interdepartmental Program, Stanford University School of Medicine, Stanford, CA, United States
| | - David Tweedie
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Michael T Scerba
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Dong Seok Kim
- AevisBio, Inc., Gaithersburg, MD, United States
- Aevis Bio, Inc., Daejeon, South Korea
| | | | - Augusta Pisanu
- National Research Council, Institute of Neuroscience, Cagliari, Italy
| | - Anna R Carta
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Nigel H Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
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33
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Cotrone TS, Hocog CB, Ramsey JT, Sanchez MA, Sullivan HM, Scrimgeour AG. Phenotypic characterization of frontal cortex microglia in a rat model of post-traumatic stress disorder. Brain Behav 2021; 11:e02011. [PMID: 33434400 PMCID: PMC7994680 DOI: 10.1002/brb3.2011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 01/11/2023] Open
Abstract
INTRODUCTION Post-traumatic stress disorder (PTSD) is an anxiety disorder induced by psychologically traumatic events. Using a rat model, this study aimed to determine whether psychological trauma alters relative expression between pro-inflammatory and anti-inflammatory markers in microglia. To meet this goal, expression of genes encoding i-NOS, arginase, TNF-α, interleukin-10, CD74, and Mannose Receptor C was analyzed on multiple days following trauma exposure. METHODS Single-prolonged stress (SPS) was used to model PTSD in male Sprague-Dawley rats. Twenty-four rats (12 Controls and 12 SPS-exposed) were sacrificed on Days 1, 3, and 7 post-SPS. Twenty-four (12 Controls and 12 SPS-exposed) additional rats were exposed to classical fear conditioning on Day 7, and fear extinction on Days 8, 9, 10, 15, 16, and 17. Freezing behavior was measured to assess fear resolution. Microglial isolates were collected from the frontal cortex, and RNA was extracted. Changes in relative expression of target genes were quantified via RT-PCR. RESULTS SPS rats showed significant decreases in IL-10 and TNF-α expression and increases in the i-NOS:Arginase and TNF-α:IL-10 ratios compared to Controls on Day 1, but not on Day 3 or Day 7 for any of the dependent variables. Day 17 SPS rats showed a significant decrease in IL-10 expression and an increase in the TNF-α:IL-10 ratio, further characterized by a significant inverse relationship between IL-10 expression and fear persistence. CONCLUSION Psychological trauma impacts the immunological phenotype of microglia of the frontal cortex. Consequently, future studies should further evaluate the mechanistic role of microglia in PTSD pathology.
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Affiliation(s)
- Thomas S Cotrone
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Charina B Hocog
- Veterinary Support and Oversight Branch, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Joseph T Ramsey
- Veterinary Support and Oversight Branch, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Marcus A Sanchez
- Veterinary Support and Oversight Branch, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Heather M Sullivan
- Veterinary Support and Oversight Branch, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Angus G Scrimgeour
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
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Sommer JL, Reynolds K, El-Gabalawy R, Pietrzak RH, Mackenzie CS, Ceccarelli L, Mota N, Sareen J. Associations between physical health conditions and posttraumatic stress disorder according to age. Aging Ment Health 2021; 25:234-242. [PMID: 31769298 DOI: 10.1080/13607863.2019.1693969] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
OBJECTIVES Posttraumatic stress disorder (PTSD) is associated with various physical health conditions. However, it is unclear whether the relationship between PTSD and physical health conditions differs according to age. This study aims to examine the associations between PTSD and physical health conditions across four adult age categories. METHODS We analyzed data from the 2012 to 2013 National Epidemiologic Survey on Alcohol and Related Conditions (N = 36,309). The Alcohol Use Disorder and Associated Disabilities Interview Schedule-5 assessed past-year DSM-5 PTSD. Multiple regression analyses examined associations between PTSD (reference = no PTSD) with number and type of physical health conditions in each age category (18-34: "younger adults," 35-49: "middle-aged adults," 50-64: "young-old adults," 65+: "older adults"). RESULTS The prevalence of nearly all physical health conditions increased according to age, whereas the prevalence of PTSD tended to decrease with age. After adjustment, PTSD was associated with a greater number of physical health conditions among all age categories (b range: 0.62-1.29). Regardless of age category, PTSD was associated with increased odds of cardiovascular and musculoskeletal conditions (AOR range: 1.54-2.34). PTSD was also associated with increased odds of gastrointestinal, hepatobiliary, endocrine/metabolic, respiratory, neurologic conditions, cancer, sleep disorders, and anemia among select age categories (AOR range: 1.70-3.31). For most physical health conditions, the largest effect sizes emerged for younger and middle-aged adults. CONCLUSIONS PTSD is associated with many physical health conditions across the age spectrum, particularly among younger and middle-aged adults. Results may inform targeted screening and intervention strategies to mitigate risk of physical health conditions among adults with PTSD.
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Affiliation(s)
- Jordana L Sommer
- Department of Psychology, University of Manitoba, Winnipeg, Canada.,Department of Anesthesiology, Perioperative and Pain Medicine, University of Manitoba, Winnipeg, Canada
| | - Kristin Reynolds
- Department of Psychology, University of Manitoba, Winnipeg, Canada
| | - Renée El-Gabalawy
- Department of Anesthesiology, Perioperative and Pain Medicine, University of Manitoba, Winnipeg, Canada.,Department of Clinical Health Psychology, University of Manitoba, Winnipeg, Canada
| | - Robert H Pietrzak
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.,U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, USA
| | | | - Laura Ceccarelli
- Department of Psychology, University of Manitoba, Winnipeg, Canada
| | - Natalie Mota
- Department of Clinical Health Psychology, University of Manitoba, Winnipeg, Canada
| | - Jitender Sareen
- Department of Psychiatry, University of Manitoba, Winnipeg, Canada
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Vasudev K, Ionson E, Inam S, Speechley M, Chaudhari S, Ghodasara S, Newman RI, Vasudev A. Sudarshan Kriya Yoga Program in Posttraumatic Stress Disorder: A Feasibility Study. Int J Yoga 2020; 13:239-246. [PMID: 33343155 PMCID: PMC7735495 DOI: 10.4103/ijoy.ijoy_16_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/29/2020] [Accepted: 06/08/2020] [Indexed: 11/25/2022] Open
Abstract
Background: Sudarshan Kriya Yoga (SKY), a breath-based yoga intervention, has demonstrated safety and efficacy in posttraumatic stress disorder (PTSD) patients subsequent to natural disaster or war, but has not been explored in civilians with PTSD from a wider range of trauma. We hypothesized that it would be feasible to conduct a clinical trial of SKY in PTSD resulting from a wide range of trauma. Methods: Outcomes were feasibility measures including rates of enrollment and retention, adherence to study protocol; as well as changes in PTSD symptoms, other mood symptoms, and physiological measures. Male and female participants aged 18–75 years were enrolled in a feasibility trial. They attended a 6-day learning phase of SKY followed by 7 sessions over 11 weeks as an adjunct to their usual treatment. Results: Forty-seven participants were screened and 32 were enrolled over 9 months. Consistent with retention rates of other PTSD trials, 13 withdrew from the study prior to week 12. Twenty-one participants met intervention attendance requirements, completed 95% of planned study assessments and were included in final analyses. Participants experienced clinically significant decrease in PTSD symptoms on the posttraumatic stress disorder checklist (PCL-5) scores at week 12 mean difference, Mdiff (standard deviation [SD]) = −10.68 (14.03), P = 0.004; Cohen's d = 0.58, which was sustained at week 24 Mdiff (SD) = −16.11 (15.20), P < 0.001; Cohen's d = 0.91. Conclusions: It is possible to conduct a clinical trial of SKY in a routine psychiatry clinic serving patients with PTSD due to a wide range of trauma. Future studies should include an RCT design.
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Affiliation(s)
- Kamini Vasudev
- Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Department of Psychiatry, London Health Sciences Centre, London, ON, Canada.,Department of Psychiatry, Mental Health Care, Parkwood Institute, St. Joseph's Health Care London, London, ON, Canada.,Lawson Health Research Institute, London, ON, Canada
| | - Emily Ionson
- Department of Psychiatry, London Health Sciences Centre, London, ON, Canada.,Department of Psychiatry, Mental Health Care, Parkwood Institute, St. Joseph's Health Care London, London, ON, Canada.,Lawson Health Research Institute, London, ON, Canada
| | - Samin Inam
- Department of Psychiatry, London Health Sciences Centre, London, ON, Canada
| | - Mark Speechley
- Department of Epidemiology and Biostatistics, Schulich Interfaculty Program in Public Health, Western University, London, ON, Canada
| | - Sumit Chaudhari
- Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Department of Psychiatry, London Health Sciences Centre, London, ON, Canada
| | - Sheena Ghodasara
- Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Department of Psychiatry, London Health Sciences Centre, London, ON, Canada
| | - Ronnie I Newman
- Department of Research and Health Promotion, International Association of Human Values, Washington, DC, USA.,Health Professions Division, Lifelong Learning Institute, Nova Southeastern University, Davie, Florida, USA
| | - Akshya Vasudev
- Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Department of Psychiatry, London Health Sciences Centre, London, ON, Canada.,Department of Psychiatry, Mental Health Care, Parkwood Institute, St. Joseph's Health Care London, London, ON, Canada.,Lawson Health Research Institute, London, ON, Canada
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Bremner JD, Gurel NZ, Jiao Y, Wittbrodt MT, Levantsevych OM, Huang M, Jung H, Shandhi MH, Beckwith J, Herring I, Rapaport MH, Murrah N, Driggers E, Ko YA, Alkhalaf ML, Soudan M, Song J, Ku BS, Shallenberger L, Hankus AN, Nye JA, Park J, Vaccarino V, Shah AJ, Inan OT, Pearce BD. Transcutaneous vagal nerve stimulation blocks stress-induced activation of Interleukin-6 and interferon-γ in posttraumatic stress disorder: A double-blind, randomized, sham-controlled trial. Brain Behav Immun Health 2020; 9:100138. [PMID: 34589887 PMCID: PMC8474180 DOI: 10.1016/j.bbih.2020.100138] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/24/2020] [Accepted: 08/26/2020] [Indexed: 01/02/2023] Open
Abstract
Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory function. Vagus nerve stimulation (VNS) decreases inflammation, however few studies have examined the effects of non-invasive VNS on physiology in human subjects, and no studies in patients with PTSD. The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on inflammatory responses to stress. Thirty subjects with a history of exposure to traumatic stress with (N = 10) and without (N = 20) PTSD underwent exposure to stressful tasks immediately followed by active or sham tcVNS and measurement of multiple biomarkers of inflammation (interleukin-(IL)-6, IL-2, IL-1β, Tumor Necrosis Factor alpha (TNFα) and Interferon gamma (IFNγ) over multiple time points. Stressful tasks included exposure to personalized scripts of traumatic events on day 1, and public speech and mental arithmetic (Mental Stress) tasks on days 2 and 3. Traumatic scripts were associated with a pattern of subjective anger measured with Visual Analogue Scales and increased IL-6 and IFNγ in PTSD patients that was blocked by tcVNS (p < .05). Traumatic stress had minimal effects on these biomarkers in non-PTSD subjects and there was no difference between tcVNS or sham. No significant differences were seen between groups in IL-2, IL-1β, or TNFα. These results demonstrate that tcVNS blocks behavioral and inflammatory responses to stress reminders in PTSD.
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Affiliation(s)
- J. Douglas Bremner
- Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
- Departments of Radiology, and Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
| | - Nil Z. Gurel
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Yunshen Jiao
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Matthew T. Wittbrodt
- Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | | | - Minxuan Huang
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Hewon Jung
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - MdMobashir H. Shandhi
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Joy Beckwith
- Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Isaias Herring
- Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Mark H. Rapaport
- Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Nancy Murrah
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Emily Driggers
- Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Yi-An Ko
- Departments of Biostatistics and Bioinformatics, Rollins School of Public Health, Atlanta, GA, USA
| | | | - Majd Soudan
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Jiawei Song
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Benson S. Ku
- Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Lucy Shallenberger
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Allison N. Hankus
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Jonathon A. Nye
- Departments of Radiology, and Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jeanie Park
- Departments of Renal Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
| | - Viola Vaccarino
- Departments of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Amit J. Shah
- Departments of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
| | - Omer T. Inan
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
- Coulter Department of Bioengineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Bradley D. Pearce
- Departments of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA
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Parekh SV, Paniccia JE, Lebonville CL, Lysle DT. Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning. Psychopharmacology (Berl) 2020; 237:3653-3664. [PMID: 32860071 PMCID: PMC7686097 DOI: 10.1007/s00213-020-05645-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022]
Abstract
Converging evidence suggests opioid abuse can increase the incidence and severity of post-traumatic stress disorder (PTSD) in clinical populations. Interestingly, opioid withdrawal alone can produce symptoms similar to those of PTSD. Despite this association, the neural mechanisms underlying the relationship of opioid abuse, withdrawal, and PTSD is poorly understood. Our laboratory has investigated the neurobiological underpinnings of stress-enhanced fear learning (SEFL), an animal model of PTSD-like symptoms. We have previously shown that, in SEFL, a severe footshock induces an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and subsequent fear learning is blocked by DH IL-1 receptor antagonism (IL-1RA). Given that opioids and stress engage similar neuroimmune mechanisms, the present experiments investigate whether the same mechanisms drive heroin withdrawal to induce a PTSD-like phenotype. First, we tested the effect of a chronic escalating heroin dose and withdrawal regimen on fear learning and found it produces enhanced future fear learning. Heroin withdrawal also induces a time-dependent, region-specific increase in IL-1β and glial fibrillary acidic protein (GFAP) immunoreactivity within the dentate gyrus of the DH. IL-1β was significantly colocalized with GFAP, indicating astrocytes may be involved in increased IL-1β. Moreover, intra-DH infusions of IL-1RA 0, 24, and 48 h into heroin withdrawal prevents the development of enhanced fear learning but does not alter withdrawal-induced weight loss. Collectively, our data suggests heroin withdrawal is sufficient to produce enhanced fear learning, astrocytes may play a role in heroin withdrawal-induced IL-1β, and DH IL-1 signaling during withdrawal mediates the development of heroin withdrawal-enhanced fear learning.
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Affiliation(s)
- Shveta V. Parekh
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, CB#3270, Chapel Hill, NC 27599-3270 USA
| | - Jacqueline E. Paniccia
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, CB#3270, Chapel Hill, NC 27599-3270 USA
| | - Christina L. Lebonville
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, CB#3270, Chapel Hill, NC 27599-3270 USA
| | - Donald T. Lysle
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, CB#3270, Chapel Hill, NC 27599-3270 USA,Corresponding Author: , Telephone: +1-919-962-3088, Fax: +1-919-962-2537
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Linher-Melville K, Shah A, Singh G. Sex differences in neuro(auto)immunity and chronic sciatic nerve pain. Biol Sex Differ 2020; 11:62. [PMID: 33183347 PMCID: PMC7661171 DOI: 10.1186/s13293-020-00339-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/20/2020] [Indexed: 01/13/2023] Open
Abstract
Chronic pain occurs with greater frequency in women, with a parallel sexually dimorphic trend reported in sufferers of many autoimmune diseases. There is a need to continue examining neuro-immune-endocrine crosstalk in the context of sexual dimorphisms in chronic pain. Several phenomena in particular need to be further explored. In patients, autoantibodies to neural antigens have been associated with sensory pathway hyper-excitability, and the role of self-antigens released by damaged nerves remains to be defined. In addition, specific immune cells release pro-nociceptive cytokines that directly influence neural firing, while T lymphocytes activated by specific antigens secrete factors that either support nerve repair or exacerbate the damage. Modulating specific immune cell populations could therefore be a means to promote nerve recovery, with sex-specific outcomes. Understanding biological sex differences that maintain, or fail to maintain, neuroimmune homeostasis may inform the selection of sex-specific treatment regimens, improving chronic pain management by rebalancing neuroimmune feedback. Given the significance of interactions between nerves and immune cells in the generation and maintenance of neuropathic pain, this review focuses on sex differences and possible links with persistent autoimmune activity using sciatica as an example.
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Affiliation(s)
- Katja Linher-Melville
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
| | - Anita Shah
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Gurmit Singh
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada.
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Persike DS, Al-Kass SY. Challenges of post-traumatic stress disorder (PTSD) in Iraq: biochemical network and methodologies. A brief review. Horm Mol Biol Clin Investig 2020; 41:/j/hmbci.ahead-of-print/hmbci-2020-0037/hmbci-2020-0037.xml. [PMID: 33155990 DOI: 10.1515/hmbci-2020-0037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 09/10/2020] [Indexed: 11/15/2022]
Abstract
Post-traumatic stress disorder (PTSD) is a multifaceted syndrome due to its complex pathophysiology. Signals of illness include alterations in genes, proteins, cells, tissues, and organism-level physiological modifications. Specificity of sensitivity to PTSD suggests that response to trauma depend on gender and type of adverse event being experienced. Individuals diagnosed with PTSD represent a heterogeneous group, as evidenced by differences in symptoms, course, and response to treatment. It is clear that the biochemical mechanisms involved in PTSD need to be elucidated to identify specific biomarkers. A brief review of the recent literature in Pubmed was made to explore the major biochemical mechanisms involved in PTSD and the methodologies applied in the assessment of the disease. PTSD shows pre-exposure vulnerability factors in addition to trauma-induced alterations. The disease was found to be associated with dysfunctions of the hypothalamic-pituitary-adrenal axis (HPA) and hypothalamus-pituitary-thyroid axis. Sympathetic nervous system (SNS) activity play a role in PTSD by releasing norepinephrine and epinephrine. Cortisol release from the adrenal cortex amplifies the SNS response. Cortisol levels in PTSD patients, especially women, are later reduced by a negative feedback mechanism which contributes to neuroendocrine alterations and promotes structural changes in the brain leading to PTSD. Gender differences in normal HPA responsiveness may be due to an increased vulnerability in women to PTSD. Serotonin and dopamine levels were found to be abnormal in the presence of PTSD. Mechanisms such as the induction of neuroinflammation and alterations of mitochondrial energy processing were also associated with PTSD.
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Affiliation(s)
- Daniele Suzete Persike
- Department of Medicinal Chemistry, College of Pharmacy, University of Dohuk, Kurdistan Region, Iraq
| | - Suad Yousif Al-Kass
- Department of Medicinal Chemistry, College of Pharmacy, University of Dohuk, Kurdistan Region, Iraq
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Gurel NZ, Wittbrodt MT, Jung H, Shandhi MMH, Driggers EG, Ladd SL, Huang M, Ko YA, Shallenberger L, Beckwith J, Nye JA, Pearce BD, Vaccarino V, Shah AJ, Inan OT, Bremner JD. Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial. Neurobiol Stress 2020; 13:100264. [PMID: 33344717 PMCID: PMC7739181 DOI: 10.1016/j.ynstr.2020.100264] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/08/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Exacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device. METHODS Using a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n = 25) using noninvasive sensing modalities. Participants received either sham (n = 12) or active tcVNS (n = 13) after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated. RESULTS Relative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted β = -5.7%; 95% CI: ±3.6%, effect size d = 0.43, p < 0.01), increased photoplethysmogram amplitude (peripheral vasodilation) (30.8%; ±28%, 0.29, p < 0.05), and increased pulse arrival time (vascular function) (6.3%; ±1.9%, 0.57, p < 0.0001). Similar (p < 0.05) autonomic, cardiovascular, and vascular effects were observed when tcVNS was applied after mental stress or without acute stress. CONCLUSION tcVNS attenuates sympathetic arousal associated with stress related to traumatic memories as well as mental stress in patients with PTSD, with effects persisting throughout multiple traumatic stress and stimulation testing days. These findings show that tcVNS has beneficial effects on the underlying neurophysiology of PTSD. Such autonomic metrics may also be evaluated in daily life settings in tandem with tcVNS therapy to provide closed-loop delivery and measure efficacy.ClinicalTrials.gov Registration # NCT02992899.
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Affiliation(s)
- Nil Z. Gurel
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Matthew T. Wittbrodt
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Hewon Jung
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Md. Mobashir H. Shandhi
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Emily G. Driggers
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Stacy L. Ladd
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
- Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Minxuan Huang
- Department of Epidemiology, Rollins School of Pu;blic Health, Atlanta, GA, USA
| | - Yi-An Ko
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Atlanta, GA, USA
| | - Lucy Shallenberger
- Department of Epidemiology, Rollins School of Pu;blic Health, Atlanta, GA, USA
| | - Joy Beckwith
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Jonathon A. Nye
- Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Bradley D. Pearce
- Department of Epidemiology, Rollins School of Pu;blic Health, Atlanta, GA, USA
| | - Viola Vaccarino
- Department of Epidemiology, Rollins School of Pu;blic Health, Atlanta, GA, USA
- Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Amit J. Shah
- Department of Epidemiology, Rollins School of Pu;blic Health, Atlanta, GA, USA
- Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
| | - Omer T. Inan
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
- Coulter Department of Bioengineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - J. Douglas Bremner
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
- Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
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Sarapultsev A, Sarapultsev P, Dremencov E, Komelkova M, Tseilikman O, Tseilikman V. Low glucocorticoids in stress-related disorders: the role of inflammation. Stress 2020; 23:651-661. [PMID: 32401103 DOI: 10.1080/10253890.2020.1766020] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
There is evidence that plasma cortisol concentration can be either increased or decreased in patients with depression and related anxiety and stress-related disorders; the exact pathophysiological mechanisms of this state are not almost clear. Several distinct theories were proposed and mechanisms, which could lead to decreased glucocorticoid signaling and/or levels, were described. However, there is a possible drawback in almost all the theories proposed: insufficient attention to the inflammatory process, which is undoubtedly present in several stress-related disorders, including post-traumatic stress disorder (PTSD). Previous studies only briefly mentioned the presence of an inflammatory reaction's signs in PTSD, without giving it due importance, although recognizing that it can affect the course of the disease. With that, the state of biochemical changes, characterized by the low glucocorticoids, glucocorticoid receptor's resistance and the signs of the persistent inflammation (with the high levels of circulating cytokines) might be observed not only in PTSD but in coronary heart diseases and systemic chronic inflammatory diseases (rheumatoid arthritis) as well. That is why the present review aims to depict the pathophysiological mechanisms, which lead to a decrease in glucocorticoids in PTSD due to the action of inflammatory stimuli. We described changes in the glucocorticoid system and inflammatory reaction as parts of an integral system, where glucocorticoids and the glucocorticoid receptor reside at the apex of a regulatory network that blocks several inflammatory pathways, while decreased glucocorticoid signaling and/or level leads to unchecked inflammatory reactions to promote pathologies such as PTSD. LAY SUMMARY This review emphasizes the importance of inflammatory reaction in the development of puzzling conditions sometimes observed in severe diseases including post-traumatic stress disorder - the decreased levels of glucocorticoids in the blood. Following the classical concepts, one would expect an increase in glucocorticoid hormones, since they are part of the feedback mechanism in the immune system, which reduces stress and inflammation. However, low levels of glucocorticoid hormones are also observed. Thus, this review describes potential mechanisms, which can lead to the development of such a state.
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Affiliation(s)
- Alexey Sarapultsev
- Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia
| | - Petr Sarapultsev
- Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia
| | - Eliyahu Dremencov
- Institute of Molecular Physiology and Genetics, Centre for Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maria Komelkova
- Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia
- School of Medical Biology, South Ural State University, Chelyabinsk, Russia
| | - Olga Tseilikman
- School of Medical Biology, South Ural State University, Chelyabinsk, Russia
| | - Vadim Tseilikman
- School of Medical Biology, South Ural State University, Chelyabinsk, Russia
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42
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Sukiasyan SG, Tadevosyan MY. [Combat stress and organic brain injury: type of the dynamics of posttraumatic stress disorder]. Zh Nevrol Psikhiatr Im S S Korsakova 2020; 120:19-27. [PMID: 33081443 DOI: 10.17116/jnevro202012009119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To study a role of traumatic brain injury (TBI) in the development of posttraumatic stress disorder (PTSD) in ex combatants. MATERIAL AND METHODS Eighty-seven ex combatants were studied. The duration of follow-up was 15-18 years. The diagnosis was established in accordance with ICD-10 criteria. Patients were stratified by diagnosis into main group (PTSD) and comparison group (organic brain injury with reduced symptoms of PTSD ). A psychopathological method and a battery of questionnaires and scales, including those adapted for assessment of consequences of combat trauma, were administered. RESULTS AND CONCLUSION Clinical presentations of both groups in posttraumatic period show the similarity and homogeneity of posttraumatic disorders in these groups. In the future, the pathogenetic role of TBI severity appears more clearly, which, depending on the severity, leads to the formation of an organic lesion of the brain or performs only a pathoplastic role, giving some features to the clinical picture of PTSD. It was found that the more severe the injury, the greater the likelihood of PTSD transition to organic brain damage. It is emphasized that PTSD treatment is a continuous, long-term, complex and graded process that includes pharmacotherapy, psychotherapy, psychosocial interventions.
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Affiliation(s)
- S G Sukiasyan
- Medical Rehabilitation Center «Artmed», Yerevan, Armenia.,Armenian Medical Institute, Yerevan, Armenia.,Yerevan State Medical University, Yerevan, Armenia
| | - M Ya Tadevosyan
- Medical Rehabilitation Center «Artmed», Yerevan, Armenia.,Armenian Medical Institute, Yerevan, Armenia.,Yerevan State Medical University, Yerevan, Armenia
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Reddaway J, Brydges NM. Enduring neuroimmunological consequences of developmental experiences: From vulnerability to resilience. Mol Cell Neurosci 2020; 109:103567. [PMID: 33068720 PMCID: PMC7556274 DOI: 10.1016/j.mcn.2020.103567] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 09/14/2020] [Accepted: 10/12/2020] [Indexed: 12/14/2022] Open
Abstract
The immune system is crucial for normal neuronal development and function (neuroimmune system). Both immune and neuronal systems undergo significant postnatal development and are sensitive to developmental programming by environmental experiences. Negative experiences from infection to psychological stress at a range of different time points (in utero to adolescence) can permanently alter the function of the neuroimmune system: given its prominent role in normal brain development and function this dysregulation may increase vulnerability to psychiatric illness. In contrast, positive experiences such as exercise and environmental enrichment are protective and can promote resilience, even restoring the detrimental effects of negative experiences on the neuroimmune system. This suggests the neuroimmune system is a viable therapeutic target for treatment and prevention of psychiatric illnesses, especially those related to stress. In this review we will summarise the main cells, molecules and functions of the immune system in general and with specific reference to central nervous system development and function. We will then discuss the effects of negative and positive environmental experiences, especially during development, in programming the long-term functioning of the neuroimmune system. Finally, we will review the sparse but growing literature on sex differences in neuroimmune development and response to environmental experiences.
The immune system is essential for development and function of the central nervous system (neuroimmune system) Environmental experiences can permanently alter neuroimmune function and associated brain development Altered neuroimmune function following negative developmental experiences may play a role in psychiatric illnesses Positive experiences can promote resilience and rescue the effects of negative experiences on the neuroimmune system The neuroimmune system is therefore a viable therapeutic target for preventing and treating psychiatric illnesses
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Affiliation(s)
- Jack Reddaway
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Nichola M Brydges
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
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Increased persistence of avoidance behaviour and social deficits with L.rhamnosus JB-1 or selective serotonin reuptake inhibitor treatment following social defeat. Sci Rep 2020; 10:13485. [PMID: 32778662 PMCID: PMC7417579 DOI: 10.1038/s41598-020-69968-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 07/22/2020] [Indexed: 11/25/2022] Open
Abstract
Chronic social defeat (CSD) in mice has been suggested as a model for studying post-traumatic stress disorder (PTSD). Our previous work indicated that exposure to Lactobacillus rhamnosus JB-1 (JB-1) during CSD can attenuate subsequent behavioural and immune disruption, suggesting a potential for microbe based therapeutic approaches in PTSD. In the current study, we assessed the ability of JB-1 to mitigate the behavioral consequences of CSD when treatment is instigated in the early post-stress period and compared the probiotic effects with those of the selective serotonin reuptake inhibitor (SSRI), sertraline. JB-1 or sertraline were administered orally 48 h following 10-days of CSD in male C57BL/6 mice. Contrary to our hypothesis of a beneficial effect, 30 days of treatment with either JB-1 or sertraline increased the persistence of both aggressor avoidance and reduced sociability in defeated mice. This was accompanied by lower hippocampal mRNA expression for genes related to fear memory. Defeated mice treated with either JB-1 or sertraline also exhibited systemic immune changes, with a decrease in Th1 cells, activated monocytes, and the monocyte chemoattractant CCL2. This study identifies potentially detrimental effects of both JB-1 and sertraline if administered in the early post-trauma period and suggests caution should be applied when considering psychobiotic or SSRI based approaches for early intervention in trauma related psychiatric disorders.
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Speer KE, Semple S, McKune AJ. Acute Physiological Responses Following a Bout of Vigorous Exercise in Military Soldiers and First Responders with PTSD: An Exploratory Pilot Study. Behav Sci (Basel) 2020; 10:bs10020059. [PMID: 32069784 PMCID: PMC7071390 DOI: 10.3390/bs10020059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/03/2020] [Accepted: 02/11/2020] [Indexed: 12/16/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is a prevalent and debilitating condition associated with psychological conditions and chronic diseases that may be underpinned by dysfunction in the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis and chronic systemic low-grade inflammation. The objective of this pilot study was to determine psychological, ANS [heart rate variability (HRV)], HPA (salivary cortisol) and inflammatory (salivary C-Reactive Protein) responses to a bout of vigorous exercise in male first responders, military veterans and active duty personnel with (n = 4) and without (n = 4) PTSD. Participants (50.1 ± 14.8 years) performed a thirteen-minute, vigorous intensity (70%–80% of heart rate max), one-on-one boxing session with a certified coach. Physiological and psychological parameters were measured before, during, immediately after to 30 min post-exercise, and then at 24 h and 48 h post. The effect sizes demonstrated large to very large reductions in HRV that lasted up to 48 h post-exercise in the PTSD group compared with unclear effects in the trauma-exposed control (TEC) group. There were unclear effects for depression, anxiety and stress as well as salivary biomarkers for both groups at all time-points. Findings may reflect stress-induced changes to the ANS for PTSD sufferers.
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Affiliation(s)
- Kathryn E Speer
- Faculty of Health, Discipline of Sport and Exercise Science, University of Canberra, Canberra 2617 (ACT), Australia; (S.S.); or (A.J.M.)
- Research Institute for Sport and Exercise Science, University of Canberra, Canberra 2617 (ACT), Australia
- Correspondence:
| | - Stuart Semple
- Faculty of Health, Discipline of Sport and Exercise Science, University of Canberra, Canberra 2617 (ACT), Australia; (S.S.); or (A.J.M.)
- Research Institute for Sport and Exercise Science, University of Canberra, Canberra 2617 (ACT), Australia
| | - Andrew J McKune
- Faculty of Health, Discipline of Sport and Exercise Science, University of Canberra, Canberra 2617 (ACT), Australia; (S.S.); or (A.J.M.)
- Research Institute for Sport and Exercise Science, University of Canberra, Canberra 2617 (ACT), Australia
- Discipline of Biokinetics, Exercise and Leisure Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban (KwaZulu-Natal) 4041, South Africa
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Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases. Int J Mol Sci 2020; 21:ijms21031115. [PMID: 32046139 PMCID: PMC7036760 DOI: 10.3390/ijms21031115] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/05/2020] [Accepted: 02/05/2020] [Indexed: 02/06/2023] Open
Abstract
The intricate relationships between innate immunity and brain diseases raise increased interest across the wide spectrum of neurodegenerative and neuropsychiatric disorders. Barriers, such as the blood–brain barrier, and innate immunity cells such as microglia, astrocytes, macrophages, and mast cells are involved in triggering disease events in these groups, through the action of many different cytokines. Chronic inflammation can lead to dysfunctions in large-scale brain networks. Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are associated with a substrate of dysregulated immune responses that impair the central nervous system balance. Recent evidence suggests that similar phenomena are involved in psychiatric diseases, such as depression, schizophrenia, autism spectrum disorders, and post-traumatic stress disorder. The present review summarizes and discusses the main evidence linking the innate immunological response in neurodegenerative and psychiatric diseases, thus providing insights into how the responses of innate immunity represent a common denominator between diseases belonging to the neurological and psychiatric sphere. Improved knowledge of such immunological aspects could provide the framework for the future development of new diagnostic and therapeutic approaches.
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Panisch LS. Conceptualizations of dissociation and somatization in literature on chronic pelvic pain in women: A scoping review. EUROPEAN JOURNAL OF TRAUMA & DISSOCIATION 2020. [DOI: 10.1016/j.ejtd.2019.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Lee Y, Chang HY, Kim SH, Yang MS, Koh YI, Kang HR, Choi JH, Kim CW, Park HK, Kim JH, Nam YH, Kim TB, Hur GY, Jung JW, Park KH, Kim MA, Kim J, Yoon J, Ye YM. A Prospective Observation of Psychological Distress in Patients With Anaphylaxis. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2020; 12:496-506. [PMID: 32141262 PMCID: PMC7061156 DOI: 10.4168/aair.2020.12.3.496] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/29/2019] [Accepted: 01/07/2020] [Indexed: 02/01/2023]
Abstract
Purpose Anaphylaxis is an immediate allergic reaction characterized by potentially life-threatening, severe, systemic manifestations. While studies have evaluated links between serious illness and posttraumatic stress disorder (PTSD), few have investigated PTSD after anaphylaxis in adults. We sought to investigate the psychosocial burden of recent anaphylaxis in Korean adults. Methods A total of 203 (mean age of 44 years, 120 females) patients with anaphylaxis were recruited from 15 university hospitals in Korea. Questionnaires, including the Impact of Event Scale-Revised-Korean version (IES-R-K), the Korean version of the Beck Anxiety Inventory (K-BAI), and the Korean version of the Beck Depression Inventory (K-BDI), were administered. Demographic characteristics, causes and clinical features of anaphylaxis, and serum inflammatory markers, including tryptase, platelet-activating factor, interleukin-6, tumor necrosis factor-α, and C-reactive protein, were evaluated. Results PTSD (IES-R-K ≥ 25) was noted in 84 (41.4%) patients with anaphylaxis. Of them, 56.0% had severe PTSD (IES-R-K ≥ 40). Additionally, 23.2% and 28.1% of the patients had anxiety (K-BAI ≥ 22) and depression (K-BDI ≥ 17), respectively. IES-R-K was significantly correlated with both K-BAI (r = 0.609, P < 0.0001) and K-BDI (r = 0.550, P < 0.0001). Among the inflammatory mediators, tryptase levels were lower in patients exhibiting PTSD; meanwhile, platelet-activating factor levels were lower in patients exhibiting anxiety and depression while recovering from anaphylaxis. In multivariate analysis, K-BAI and K-BDI were identified as major predictive variables of PTSD in patients with anaphylaxis. Conclusions In patients with anaphylaxis, we found a remarkably high prevalence of PTSD and associated psychological distresses, including anxiety and depression. Physicians ought to be aware of the potential for psychological distress in anaphylactic patients and to consider psychological evaluation.
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Affiliation(s)
- Youngsoo Lee
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - Hyoung Yoon Chang
- Department of Psychiatry and Behavioral Sciences, Ajou University School of Medicine, Suwon, Korea
| | - Sang Ha Kim
- Department of Internal Medicine, Wonju Severance Christian Hospital, Wonju, Korea
| | - Min Suk Yang
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Young Il Koh
- Division of Allergy, Asthma, and Clinical Immunology, Chonnam National University Medical School, Gwangju, Korea
| | - Hye Ryun Kang
- Division of Allergy and Clinical Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Hee Choi
- Division of Pulmonary, Allergy, and Critical Care Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Cheol Woo Kim
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Hye Kyung Park
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Joo Hee Kim
- Division of Pulmonary, Allergy, and Critical Care Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea
| | - Young Hee Nam
- Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea
| | - Tae Bum Kim
- Department of Allergy and Clinical Immunology, Asan Medical Center, Seoul, Korea
| | - Gyu Young Hur
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea
| | - Jae Woo Jung
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Kyung Hee Park
- Division of Allergy and Immunology, Yonsei University College of Medicine, Seoul, Korea
| | - Mi Ae Kim
- Division of Pulmonary, Allergy and Critical Care Medicine, CHA University, Seongnam, Korea
| | - Jiwoong Kim
- Clinical Trial Center, Ajou University Hospital, Suwon, Korea
| | - Jiwon Yoon
- Clinical Trial Center, Ajou University Hospital, Suwon, Korea
| | - Young Min Ye
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
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49
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Conrad D, Wilker S, Schneider A, Karabatsiakis A, Pfeiffer A, Kolassa S, Freytag V, Vukojevic V, Vogler C, Milnik A, Papassotiropoulos A, J.‐F. de Quervain D, Elbert T, Kolassa I. Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts. Psychophysiology 2020; 57:e13288. [PMID: 30328613 PMCID: PMC7379258 DOI: 10.1111/psyp.13288] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 12/17/2022]
Abstract
The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.
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Affiliation(s)
- Daniela Conrad
- Clinical Psychology and NeuropsychologyUniversity of KonstanzKonstanzGermany
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Sarah Wilker
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Anna Schneider
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Alexander Karabatsiakis
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
| | - Anett Pfeiffer
- Clinical Psychology and NeuropsychologyUniversity of KonstanzKonstanzGermany
| | | | - Virginie Freytag
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
| | - Vanja Vukojevic
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Department Biozentrum, Life Sciences Training FacilityUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Christian Vogler
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Annette Milnik
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Andreas Papassotiropoulos
- Division of Molecular NeuroscienceUniversity of BaselBaselSwitzerland
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Department Biozentrum, Life Sciences Training FacilityUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
| | - Dominique J.‐F. de Quervain
- Transfaculty Research Platform Molecular and Cognitive NeurosciencesUniversity of BaselBaselSwitzerland
- Psychiatric University ClinicsUniversity of BaselBaselSwitzerland
- Division of Cognitive NeuroscienceUniversity of BaselBaselSwitzerland
| | - Thomas Elbert
- Clinical Psychology and NeuropsychologyUniversity of KonstanzKonstanzGermany
| | - Iris‐Tatjana Kolassa
- Clinical & Biological Psychology, Institute of Psychology and EducationUlm UniversityUlmGermany
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50
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Fonkoue IT, Marvar PJ, Norrholm S, Li Y, Kankam ML, Jones TN, Vemulapalli M, Rothbaum B, Bremner JD, Le NA, Park J. Symptom severity impacts sympathetic dysregulation and inflammation in post-traumatic stress disorder (PTSD). Brain Behav Immun 2020; 83:260-269. [PMID: 31682970 PMCID: PMC6906238 DOI: 10.1016/j.bbi.2019.10.021] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 10/30/2019] [Accepted: 10/31/2019] [Indexed: 12/11/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is associated with a greater risk of incident hypertension and cardiovascular disease. Inflammation, impaired baroreflex sensitivity (BRS) decreased parasympathetic nervous system (PNS) and overactive sympathetic nervous system (SNS) activity are suggested as contributing mechanisms. Increasing severity of PTSD symptoms has been linked to greater cardiovascular risk; however, the impact of PTSD symptom severity on inflammation and autonomic control of blood pressure has not yet been explored. We hypothesized that increasing PTSD symptom severity is linked to higher inflammation, greater SNS activity, lower PNS reactivity and impaired BRS. Seventy Veterans participated in this study: 28 with severe PTSD ((Clinical Administered PTSD Scale (CAPS) > 60; S-PTSD), 16 with moderate PTSD (CAPS ≥ 45 ≤ 60; M-PTSD) and 26 Controls (CAPS < 45; NO-PTSD). We recorded continuous blood pressure (BP), heart rate (HR) via EKG, heart rate variability (HRV) markers reflecting PNS and muscle sympathetic nerve activity (MSNA) at rest, during arterial baroreflex sensitivity (BRS) testing via the modified Oxford technique, and during 3 min of mental stress via mental arithmetic. Blood samples were analyzed for 12 biomarkers of systemic and vascular inflammation. While BP was comparable between severity groups, HR tended to be higher (p = 0.055) in S-PTSD (76 ± 2 beats/min) than in Controls (67 ± 2 beats/min) but comparable to M-PTSD (70 ± 3 beats/min). There were no differences in resting HRV and MSNA between groups; however, cardiovagal BRS was blunted (p = 0.021) in S-PTSD (10 ± 1 ms/mmHg) compared to controls (16 ± 3 ms/mmHg) but comparable to M-PTSD (12 ± 2 ms/mmHg). Veterans in the S-PTSD group had a higher (p < 0.001) combined inflammatory score compared to both M-PTSD and NO-PTSD. Likewise, while mental stress induced similar SNS and cardiovascular responses between the groups, there was a greater reduction in HRV in S-PTSD compared to both M-PTSD and NO-PTSD. In summary, individuals with severe PTSD symptoms have higher inflammation, greater impairment of BRS, a trend towards higher resting HR and exaggerated PNS withdrawal at the onset of mental stress that may contribute to cardiovascular risk in severe PTSD.
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Affiliation(s)
- Ida T. Fonkoue
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA,Research Service Line, Atlanta Veterans Affairs Health Care System (VAHCS), Decatur, GA
| | - Paul J. Marvar
- Department of Pharmacology and Physiology, Institute for Neuroscience, George Washington University, Washington, DC
| | - Seth Norrholm
- Research Service Line, Atlanta Veterans Affairs Health Care System (VAHCS), Decatur, GA,Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Yunxiao Li
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA
| | - Melanie L. Kankam
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA,Research Service Line, Atlanta Veterans Affairs Health Care System (VAHCS), Decatur, GA
| | - Toure N. Jones
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA,Research Service Line, Atlanta Veterans Affairs Health Care System (VAHCS), Decatur, GA
| | - Monica Vemulapalli
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA,Research Service Line, Atlanta Veterans Affairs Health Care System (VAHCS), Decatur, GA
| | - Barbara Rothbaum
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - J. Douglas Bremner
- Research Service Line, Atlanta Veterans Affairs Health Care System (VAHCS), Decatur, GA,Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA,Department of Radiology, Emory University School of Medicine, Atlanta, GA
| | - Ngoc-Anh Le
- Biomarker Core Laboratory, Atlanta VAHCS, Decatur, GA, USA
| | - Jeanie Park
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Research Service Line, Atlanta Veterans Affairs Health Care System (VAHCS), Decatur, GA, USA.
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