1 4632 121 NEUROIMAGING GENETIC APPROACHES TO POSTTRAUMATIC STRESS DISORDER. NEUROIMAGING GENETIC STUDIES THAT ASSOCIATE GENETIC AND EPIGENETIC VARIATION WITH NEURAL ACTIVITY OR STRUCTURE PROVIDE AN OPPORTUNITY TO LINK GENES TO PSYCHIATRIC DISORDERS, OFTEN BEFORE PSYCHOPATHOLOGY IS DISCERNABLE IN BEHAVIOR. HERE WE REVIEW NEUROIMAGING GENETICS STUDIES WITH PARTICIPANTS WHO HAVE POSTTRAUMATIC STRESS DISORDER (PTSD). RESULTS SHOW THAT GENES RELATED TO THE PHYSIOLOGICAL STRESS RESPONSE (E.G., GLUCOCORTICOID RECEPTOR AND ACTIVITY, NEUROENDOCRINE RELEASE), LEARNING AND MEMORY (E.G., PLASTICITY), MOOD, AND PAIN PERCEPTION ARE TIED TO NEURAL INTERMEDIATE PHENOTYPES ASSOCIATED WITH PTSD. THESE GENES ARE ASSOCIATED WITH AND SOMETIMES PREDICT NEURAL STRUCTURE AND FUNCTION IN AREAS INVOLVED IN ATTENTION, EXECUTIVE FUNCTION, MEMORY, DECISION-MAKING, EMOTION REGULATION, SALIENCE OF POTENTIAL THREATS, AND PAIN PERCEPTION. EVIDENCE SUGGESTS THESE RISK POLYMORPHISMS AND NEURAL INTERMEDIATE PHENOTYPES ARE VULNERABILITIES TOWARD DEVELOPING PTSD IN THE AFTERMATH OF TRAUMA, OR VULNERABILITIES TOWARD PARTICULAR SYMPTOMS ONCE PTSD HAS DEVELOPED. WORK DISTINGUISHING BETWEEN THE RE-EXPERIENCING AND DISSOCIATIVE SUB-TYPES OF PTSD, AND EXAMINING OTHER PTSD SYMPTOM CLUSTERS IN ADDITION TO THE RE-EXPERIENCING AND HYPERAROUSAL SYMPTOMS, WILL FURTHER CLARIFY NEUROBIOLOGICAL MECHANISMS AND INCONSISTENT FINDINGS. FURTHERMORE, AN EXCITING POSSIBILITY IS THAT GENETIC ASSOCIATIONS WITH PTSD MAY EVENTUALLY BE UNDERSTOOD THROUGH DIFFERENTIAL INTERMEDIATE PHENOTYPES OF NEURAL CIRCUIT STRUCTURE AND FUNCTION, POSSIBLY UNDERLYING THE DIFFERENT SYMPTOM CLUSTERS SEEN WITHIN PTSD. 2016 2 2630 33 EPIGENOME-WIDE ASSOCIATION STUDY OF POSTTRAUMATIC STRESS DISORDER IDENTIFIES NOVEL LOCI IN U.S. MILITARY VETERANS. POSTTRAUMATIC STRESS DISORDER (PTSD) IS A CHRONIC AND DISABLING PSYCHIATRIC DISORDER PREVALENT IN MILITARY VETERANS. EPIGENETIC MECHANISMS HAVE BEEN IMPLICATED IN THE ETIOLOGY OF PTSD, WITH DNA METHYLATION BEING THE MOST STUDIED TO IDENTIFY NOVEL MOLECULAR BIOMARKERS ASSOCIATED WITH THIS DISORDER. WE PERFORMED ONE OF THE LARGEST SINGLE-SAMPLE EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) OF PTSD TO DATE. OUR SAMPLE INCLUDED 1135 MALE EUROPEAN-AMERICAN U.S. VETERANS WHO PARTICIPATED IN THE NATIONAL HEALTH AND RESILIENCE IN VETERANS STUDY (NHRVS). DNA WAS COLLECTED FROM SALIVA SAMPLES AND THE ILLUMINA HUMANMETHYLATION EPIC BEADCHIP WAS USED FOR THE METHYLATION ANALYSIS. PTSD WAS ASSESSED USING THE PTSD CHECKLIST. AN EWAS WAS CONDUCTED USING LINEAR REGRESSION ADJUSTED FOR AGE, CELL-TYPE PROPORTIONS, FIRST 10 PRINCIPAL COMPONENTS, AND SMOKING STATUS. AFTER BONFERRONI CORRECTION, WE IDENTIFIED SIX GENOME-WIDE SIGNIFICANT (GWS) CPG SITES ASSOCIATED WITH PAST-MONTH PTSD AND THREE CPGS WITH LIFETIME PTSD (P(RANGE) = 10(-10)-10(-8)). THESE CPG SITES MAP TO GENES INVOLVED IN IMMUNE FUNCTION, TRANSCRIPTION REGULATION, AXONAL GUIDANCE, CELL SIGNALING, AND PROTEIN BINDING. AMONG THESE, SENP7, WHICH IS INVOLVED IN TRANSCRIPTION REGULATION AND HAS BEEN LINKED TO RISK-TAKING BEHAVIOR AND ALCOHOL CONSUMPTION IN GENOME-WIDE ASSOCIATION STUDIES, REPLICATED IN AN INDEPENDENT VETERAN COHORT AND WAS DOWNREGULATED IN MEDIAL ORBITOFRONTAL CORTEX OF PTSD POSTMORTEM BRAIN TISSUE. THESE FINDINGS SUGGEST POTENTIAL EPIGENETIC BIOMARKERS OF PTSD THAT MAY HELP INFORM THE PATHOPHYSIOLOGY OF THIS DISORDER IN VETERANS AND OTHER TRAUMA-AFFECTED POPULATIONS. 2022 3 1750 29 EARLY LIFE STRESS AND PEDIATRIC POSTTRAUMATIC STRESS DISORDER. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS. TWO THIRDS OF YOUTH ARE EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17, AND APPROXIMATELY 5% OF ADOLESCENTS MEET LIFETIME CRITERIA FOR POSTTRAUMATIC STRESS DISORDER (PTSD). THE ROLE OF THE STRESS SYSTEM IS THE MAINTENANCE OF HOMEOSTASIS IN THE PRESENCE OF REAL/PERCEIVED AND ACUTE/CHRONIC STRESSORS. EARLY-LIFE STRESS (ELS) HAS AN IMPACT ON NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING. STUDIES ON PEDIATRIC PTSD REVEAL DIVERSE NEUROENDOCRINE RESPONSES TO ADVERSE EVENTS AND RELATED LONG-TERM NEUROENDOCRINE AND EPIGENETIC ALTERATIONS. NEUROENDOCRINE, NEUROIMAGING, AND GENETIC STUDIES IN CHILDREN WITH PTSD AND ELS EXPERIENCES ARE CRUCIAL IN UNDERSTANDING RISK AND RESILIENCE FACTORS, AND ALSO THE NATURAL HISTORY OF PTSD. 2020 4 325 36 ALLELE-SPECIFIC DNA METHYLATION LEVEL OF FKBP5 IS ASSOCIATED WITH POST-TRAUMATIC STRESS DISORDER. BACKGROUND: FK506-BINDING PROTEIN 5 (FKBP5) BINDS TO GLUCOCORTICOID RECEPTORS AND MODULATES GLUCOCORTICOID SENSITIVITY. THE FKBP5 GENE HAS BEEN IMPLICATED IN THE DYSREGULATION OF HUMAN STRESS RESPONSES, CONTRIBUTING TO THE RISK AND TREATMENT RESPONSE OF STRESS-RELATED DISORDERS. THE PRESENT STUDY EXAMINED WHETHER EPIGENETIC CHANGES IN FKBP5 ARE ASSOCIATED WITH CHRONIC POST-TRAUMATIC STRESS DISORDER (PTSD) STATUS IN THE CONTEXT OF FKBP5 GENETIC VARIATION (RS1360780 POLYMORPHISM) AMONG MALE VETERANS EXPOSED TO COMBAT TRAUMA. METHODS: KOREAN MALE VETERANS WHO SERVED ON ACTIVE DUTY DURING THE VIETNAM WAR WERE CATEGORIZED INTO 2 GROUPS: WITH PTSD (N = 123) AND WITHOUT PTSD (N = 116). THE GENOTYPE OF FKBP5 RS1360780 AND DNA METHYLATION LEVELS OF TWO CPG SITES AT THE FKBP5 INTRON 7 REGION WERE ASSESSED IN PERIPHERAL BLOOD. ANALYSIS OF COVARIANCE WAS PERFORMED TO EXAMINE MAIN AND INTERACTION EFFECTS OF PTSD STATUS AND FKBP5 GENOTYPE ON FKBP5 DNA METHYLATION LEVEL, WITH AGE, TRAUMA LEVELS, AND ALCOHOL USE AS COVARIATES. RESULTS: A SIGNIFICANT MAIN EFFECT OF FKBP5 RS1360780 AND PTSD AND AN INTERACTION EFFECT BETWEEN GENOTYPE AND PTSD STATUS WERE FOUND ON MEAN FKBP5 DNA METHYLATION LEVEL. THE T ALLELE OF RS1360780 WAS ASSOCIATED WITH LOWER FKBP5 METHYLATION LEVEL. IN ADDITION, THE PTSD GROUP SHOWED SIGNIFICANTLY HIGHER METHYLATION THAN DID THE NON-PTSD GROUP AMONG VETERANS CARRYING THE RISK T ALLELE (N = 96), WHILE NO GROUP DIFFERENCE WAS OBSERVED ON METHYLATION LEVELS AMONG VETERANS WITH THE CC GENOTYPE (N = 143). AMONG VETERANS CARRYING THE T ALLELE, FKBP5 METHYLATION LEVELS WERE POSITIVELY CORRELATED WITH THE SEVERITY OF PTSD SYMPTOMS. CONCLUSIONS: THE PRESENT STUDY DEMONSTRATED DIFFERENT FKBP5 METHYLATION LEVELS IN PTSD DEPENDING ON FKBP5 GENETIC VARIATION AMONG VETERANS EXPOSED TO COMBAT TRAUMA. THE PRESENT FINDING SUGGESTS THAT THE GENETIC AND EPIGENETIC MODULATION OF FKBP5 IS INVOLVED IN THE PATHOPHYSIOLOGY OF PTSD. FURTHER LONGITUDINAL RESEARCH INVOLVING PEOPLE EXPOSED TO TRAUMA IS REQUIRED TO UNDERSTAND CAUSAL RELATIONSHIPS OF FKBP5 IN THE DEVELOPMENT AND RECOVERY OF PTSD. 2019 5 5171 28 PREDATOR-BASED PSYCHOSOCIAL STRESS ANIMAL MODEL OF PTSD: PRECLINICAL ASSESSMENT OF TRAUMATIC STRESS AT COGNITIVE, HORMONAL, PHARMACOLOGICAL, CARDIOVASCULAR AND EPIGENETIC LEVELS OF ANALYSIS. RESEARCH ON POST-TRAUMATIC STRESS DISORDER (PTSD) IS FACED WITH THE CHALLENGE OF UNDERSTANDING HOW A TRAUMATIC EXPERIENCE PRODUCES LONG-LASTING DETRIMENTAL EFFECTS ON BEHAVIOR AND BRAIN FUNCTIONING, AND MORE GLOBALLY, HOW STRESS EXACERBATES SOMATIC DISORDERS, INCLUDING CARDIOVASCULAR DISEASE. MOREOVER, THE DESIGN OF TRANSLATIONAL RESEARCH NEEDS TO LINK ANIMAL MODELS OF PTSD TO CLINICALLY RELEVANT RISK FACTORS WHICH ADDRESS WHY ONLY A SUBSET OF TRAUMATIZED INDIVIDUALS DEVELOP PERSISTENT PSYCHOPATHOLOGY. IN THIS REVIEW, WE HAVE SUMMARIZED OUR PSYCHOSOCIAL STRESS RODENT MODEL OF PTSD WHICH IS BASED ON WELL-DESCRIBED PTSD-INDUCING RISK FACTORS, INCLUDING A LIFE-THREATENING EXPERIENCE, A SENSE OF HORROR AND UNCONTROLLABILITY, AND INSUFFICIENT SOCIAL SUPPORT. SPECIFICALLY, OUR ANIMAL MODEL OF PTSD INTEGRATES ACUTE EPISODES OF INESCAPABLE EXPOSURE OF IMMOBILIZED RATS TO A PREDATOR WITH CHRONIC DAILY SOCIAL INSTABILITY. THIS STRESS REGIMEN PRODUCES PTSD-LIKE EFFECTS IN RATS AT BEHAVIORAL, COGNITIVE, PHYSIOLOGICAL, PHARMACOLOGICAL AND EPIGENETIC LEVELS OF ANALYSIS. WE HAVE DISCUSSED A RECENT EXTENSION OF OUR ANIMAL MODEL OF PTSD IN WHICH STRESS EXACERBATED CORONARY PATHOLOGY FOLLOWING AN ISCHEMIC EVENT, ASSESSED IN VITRO. IN ADDITION, WE HAVE REVIEWED OUR RESEARCH INVESTIGATING PHARMACOLOGICAL AND NON-PHARMACOLOGICAL THERAPEUTIC STRATEGIES WHICH MAY HAVE VALUE IN CLINICAL APPROACHES TOWARD THE TREATMENT OF TRAUMATIZED PEOPLE. OVERALL, OUR TRANSLATIONAL APPROACH BRIDGES THE GAP BETWEEN HUMAN AND ANIMAL PTSD RESEARCH TO CREATE A FRAMEWORK WITH WHICH TO ENHANCE OUR UNDERSTANDING OF THE BIOLOGICAL BASIS OF TRAUMA-INDUCED PATHOLOGY AND TO ASSESS THERAPEUTIC APPROACHES IN THE TREATMENT OF PSYCHOPATHOLOGY. 2016 6 6278 28 THE PATHWAYS BETWEEN CORTISOL-RELATED REGULATION GENES AND PTSD PSYCHOTHERAPY. POST-TRAUMATIC STRESS DISORDER (PTSD) ONLY DEVELOPS AFTER EXPOSURE TO A TRAUMATIC EVENT IN SOME INDIVIDUALS. PTSD CAN BE CHRONIC AND DEBILITATING, AND IS ASSOCIATED WITH CO-MORBIDITIES SUCH AS DEPRESSION, SUBSTANCE USE, AND CARDIOMETABOLIC DISORDERS. ONE OF THE MOST IMPORTANT PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING THE DEVELOPMENT OF PTSD AND ITS SUBSEQUENT MAINTENANCE IS A DYSFUNCTIONAL HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. THE CORTICOTROPHIN-RELEASING HORMONE, CORTISOL, GLUCOCORTICOID RECEPTOR (GR), AND THEIR RESPECTIVE GENES ARE SOME OF THE MEDIATORS OF PTSD'S PATHOPHYSIOLOGY. SEVERAL TREATMENTS ARE AVAILABLE, INCLUDING MEDICATION AND PSYCHOTHERAPIES, ALTHOUGH THEIR SUCCESS RATE IS LIMITED. SOME PHARMACOLOGICAL THERAPIES BASED ON THE HPA AXIS ARE CURRENTLY BEING TESTED IN CLINICAL TRIALS AND CHANGES IN HPA AXIS BIOMARKERS HAVE BEEN FOUND TO OCCUR IN RESPONSE NOT ONLY TO PHARMACOLOGICAL TREATMENTS, BUT ALSO TO PSYCHOTHERAPY-INCLUDING THE EPIGENETIC MODIFICATION OF THE GR GENE. PSYCHOTHERAPIES ARE CONSIDERED TO BE THE FIRST LINE TREATMENTS FOR PTSD IN SOME GUIDELINES, EVEN THOUGH THEY ARE EFFECTIVE FOR SOME, BUT NOT FOR ALL PATIENTS WITH PTSD. THIS REVIEW AIMS TO ADDRESS HOW KNOWLEDGE OF THE HPA AXIS-RELATED GENETIC MAKEUP CAN INFORM AND PREDICT THE OUTCOMES OF PSYCHOTHERAPEUTIC TREATMENTS. 2020 7 6478 26 TOPICAL REVIEW: THE EMERGING FIELD OF EPIGENETICS: INFORMING MODELS OF PEDIATRIC TRAUMA AND PHYSICAL HEALTH. OBJECTIVE: TRAUMA EXPERIENCED DURING CHILDHOOD AND ADOLESCENCE HAS BEEN LINKED TO A NUMBER OF CHRONIC MEDICAL CONCERNS. WE HIGHLIGHT MAJOR FINDINGS FROM THE PEDIATRIC TRAUMA LITERATURE TO PROVIDE A MODEL FOR UNDERSTANDING THIS ASSOCIATION. METHODS: STUDIES EXAMINING THE EFFECTS OF TRAUMA WERE SYSTEMATICALLY REVIEWED AND SYNTHESIZED INTO A MODEL PROPOSING A CENTRAL ROLE FOR EPIGENETICS IN THE WAYS THAT CHILDHOOD EXPERIENCES CAN AFFECT HEALTH. RESULTS: EARLY HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS RESPONSE MAY IMPACT INITIAL TRAUMA EXPERIENCE, WITH DOWNSTREAM EFFECTS ON POSTTRAUMA ADJUSTMENT REFLECTED IN POSTTRAUMA NEUROBIOLOGY, PSYCHOLOGICAL HEALTH, AND PHYSICAL HEALTH. CONCLUSIONS: PROSPECTIVE RESEARCH WITH CHILDREN AND ADOLESCENTS EXPOSED TO TRAUMA IS NEEDED TO BETTER CHARACTERIZE THE GENETIC AND EPIGENETIC INFLUENCES ON THE COURSE OF HPA AND IMMUNE PROCESSES AS RELATED TO POSTTRAUMA PSYCHOLOGICAL AND PHYSICAL HEALTH OUTCOMES. 2016 8 6315 30 THE RELATIONSHIP OF MATERNAL AND CHILD METHYLATION OF THE GLUCOCORTICOID RECEPTOR NR3C1 DURING EARLY CHILDHOOD AND SUBSEQUENT CHILD PSYCHOPATHOLOGY AT SCHOOL-AGE IN THE CONTEXT OF MATERNAL INTERPERSONAL VIOLENCE-RELATED POST-TRAUMATIC STRESS DISORDER. INTRODUCTION: INTERPERSONAL VIOLENT (IPV) EXPERIENCES WHEN THEY BEGIN IN CHILDHOOD AND CONTINUE IN VARIOUS FORMS DURING ADULTHOOD OFTEN LEAD TO CHRONIC POST-TRAUMATIC STRESS DISORDER (PTSD) THAT IS ASSOCIATED IN MULTIPLE STUDIES WITH HYPOCORTISOLISM AND LOWER PERCENTAGE OF METHYLATION OF THE PROMOTER REGION OF THE GENE CODING FOR THE GLUCOCORTICOID RECEPTOR (NR3C1). THIS PROSPECTIVE, LONGITUDINAL STUDY EXAMINED THE RELATIONSHIP OF NR3C1 METHYLATION AMONG MOTHERS WITH IPV-RELATED PTSD AND THEIR TODDLERS AND THEN LOOKED AT THE RELATIONSHIP OF MATERNAL NR3C1 METHYLATION AND CHILD PSYCHOPATHOLOGY AT SCHOOL AGE. METHODS: FORTY-EIGHT MOTHERS WERE EVALUATED FOR LIFE-EVENTS HISTORY AND POST-TRAUMATIC STRESS DISORDER VIA STRUCTURED CLINICAL INTERVIEW WHEN THEIR CHILDREN WERE AGES 12-42 MONTHS (MEAN AGE 26.7 MONTHS, SD 8.8). THEIR CHILDREN'S PSYCHOPATHOLOGY IN TERMS OF INTERNALIZING SYMPTOMS AND EXTERNALIZING BEHAVIORS WAS EVALUATED USING THE CHILD BEHAVIOR CHECKLIST AT AGES 5-9 YEARS (MEAN AGE 7 YEARS, SD 1.1). PERCENTAGE OF METHYLATION FOR THE NR3C1 GENE PROMOTER REGION WAS ASSESSED FROM DNA EXTRACTED FROM MATERNAL AND CHILD SALIVA USING BISULFITE PYROSEQUENCING. DATA ANALYSIS INVOLVED PARAMETRIC AND NON-PARAMETRIC CORRELATIONS AND MULTIPLE LINEAR AND LOGISTIC REGRESSION MODELING. RESULTS: LOGISTIC REGRESSION MODELS USING CHILD NR3C1 METHYLATION AS THE DEPENDENT VARIABLE AND MATERNAL NR3C1 METHYLATION AND PTSD GROUP STATUS AS PREDICTORS, AS WELL AS THE INTERACTION INDICATED THAT ALL THREE OF THESE SIGNIFICANTLY PREDICTED CHILD NR3C1 METHYLATION. THESE FINDINGS REMAINED SIGNIFICANT WHEN CONTROLLING FOR CHILD AGE, SEX AND MATERNAL CHILD ABUSE HISTORY. OVERALL, MATERNAL NR3C1 METHYLATION WHEN CHILDREN WERE TODDLERS WAS NEGATIVELY AND SIGNIFICANTLY ASSOCIATED WITH CHILD EXTERNALIZING BEHAVIOR SEVERITY AT SCHOOL AGE. DISCUSSION: WE FOUND THAT CORRELATIONS BETWEEN MOTHERS AND THEIR CHILDREN OF NR3C1 METHYLATION LEVELS OVERALL AND AT ALL INDIVIDUAL CPG SITES OF INTEREST WERE SIGNIFICANT ONLY IN THE IPV-PTSD GROUP. THE LATTER FINDINGS SUPPORT THAT NR3C1 METHYLATION IN MOTHERS POSITIVELY AND STATISTICALLY SIGNIFICANTLY CORRELATES WITH NR3C1 METHYLATION IN THEIR CHILDREN ONLY IN PRESENCE OF IPV-PTSD IN THE MOTHERS. THIS MATERNAL EPIGENETIC SIGNATURE WITH RESPECT TO THIS GLUCOCORTICOID RECEPTOR IS SIGNIFICANTLY ASSOCIATED WITH CHILD BEHAVIOR THAT MAY WELL POSE A RISK FOR INTERGENERATIONAL TRANSMISSION OF VIOLENCE AND RELATED PSYCHOPATHOLOGY. 2022 9 92 30 A PILOT STUDY INVESTIGATING THE ROLE OF GENDER IN THE INTERGENERATIONAL RELATIONSHIPS BETWEEN GENE EXPRESSION, CHRONIC PAIN, AND ADVERSE CHILDHOOD EXPERIENCES IN A CLINICAL SAMPLE OF YOUTH WITH CHRONIC PAIN. CHRONIC PAIN IS A HIGHLY PREVALENT AND COSTLY ISSUE THAT OFTEN EMERGES DURING CHILDHOOD OR ADOLESCENCE AND PERSISTS INTO ADULTHOOD. ADVERSE CHILDHOOD EXPERIENCES (ACES) INCREASE RISK FOR SEVERAL ADVERSE HEALTH CONDITIONS, INCLUDING CHRONIC PAIN. RECENT EVIDENCE SUGGESTS THAT PARENTAL TRAUMA (ACES, POST-TRAUMATIC STRESS DISORDER (PTSD) SYMPTOMS) CONFERS RISK OF POOR HEALTH OUTCOMES IN THEIR CHILDREN. INTERGENERATIONAL RELATIONSHIPS BETWEEN PARENTAL TRAUMA AND CHILD CHRONIC PAIN MAY BE MEDIATED BY EPIGENETIC MECHANISMS. A CLINICAL SAMPLE OF YOUTH WITH CHRONIC PAIN AND THEIR PARENTS COMPLETED PSYCHOMETRICALLY SOUND QUESTIONNAIRES ASSESSING ACES, PTSD SYMPTOMS, AND CHRONIC PAIN, AND PROVIDED A SALIVA SAMPLE. THESE WERE USED TO INVESTIGATE THE INTERGENERATIONAL RELATIONSHIPS BETWEEN FOUR EPIGENETIC BIOMARKERS (COMT, DRD2, GR, AND SERT), TRAUMA, AND CHRONIC PAIN. THE RESULTS INDICATED THAT THE SIGNIFICANT BIOMARKERS WERE DEPENDENT UPON THE GENDER OF THE CHILD, WHEREIN PARENTAL ACES SIGNIFICANTLY CORRELATED WITH CHANGES IN DRD2 EXPRESSION IN FEMALE CHILDREN AND ALTERED COMT EXPRESSION IN THE PARENTS OF MALE CHILDREN. ADDITIONALLY, THE NATURE OF THE ACE (MALTREATMENT VS. HOUSEHOLD DYSFUNCTION) WAS ASSOCIATED WITH THE SPECIFIC EPIGENETIC CHANGES. THERE MAY BE DIFFERENT PATHWAYS THROUGH WHICH PARENTAL ACES CONFER RISK FOR POOR OUTCOMES FOR MALES AND FEMALES, HIGHLIGHTING THE IMPORTANCE OF CHILD GENDER IN FUTURE INVESTIGATIONS. 2021 10 1513 29 DNA METHYLATION AND PSYCHOTHERAPY RESPONSE IN TRAUMA-EXPOSED MEN WITH APPETITIVE AGGRESSION. EXPOSURE TO VIOLENCE CAN LEAD TO APPETITIVE AGGRESSION (AA), THE POSITIVE FEELING AND FASCINATION ASSOCIATED WITH VIOLENCE, AND POSTTRAUMATIC STRESS DISORDER (PTSD), CHARACTERISED BY HYPERAROUSAL, REEXPERIENCE AND FEELINGS OF ONGOING THREAT. PSYCHOTHERAPEUTIC INTERVENTIONS MAY ACT VIA DNA METHYLATION, AN ENVIRONMENTALLY SENSITIVE EPIGENETIC MECHANISM THAT CAN INFLUENCE GENE EXPRESSION. WE INVESTIGATED EPIGENETIC SIGNATURES OF PSYCHOTHERAPY FOR PTSD AND AA SYMPTOMS IN SOUTH AFRICAN MEN WITH CHRONIC TRAUMA EXPOSURE. PARTICIPANTS WERE ASSIGNED TO ONE OF THREE GROUPS: NARRATIVE EXPOSURE THERAPY FOR FORENSIC OFFENDER REHABILITATION (FORNET), COGNITIVE BEHAVIOURAL THERAPY OR WAITING LIST CONTROL (N = 9-10/GROUP). PARTICIPANTS PROVIDED SALIVA AND COMPLETED THE APPETITIVE AGGRESSION SCALE AND PTSD SYMPTOM SEVERITY INDEX AT BASELINE, 8-MONTH AND 16-MONTH FOLLOW-UP. THE RELATIONSHIP, OVER TIME, BETWEEN METHYLATION IN 22 GENE PROMOTER REGION SITES, SYMPTOM SCORES, AND TREATMENT WAS ASSESSED USING LINEAR MIXED MODELS. COMPARED TO BASELINE, PTSD AND AA SYMPTOM SEVERITY WERE SIGNIFICANTLY REDUCED AT 8 AND 16 MONTHS, RESPECTIVELY, IN THE FORNET GROUP. INCREASED METHYLATION OF GENES IMPLICATED IN DOPAMINERGIC NEUROTRANSMISSION (NR4A2) AND SYNAPTIC PLASTICITY (AUTS2) WAS ASSOCIATED WITH REDUCED PTSD SYMPTOM SEVERITY IN PARTICIPANTS RECEIVING FORNET. ANALYSES ACROSS PARTICIPANTS REVEALED A PROPORTIONAL RELATIONSHIP BETWEEN AA AND METHYLATION OF TFAM, A GENE INVOLVED IN MITOCHONDRIAL BIOSYNTHESIS. 2021 11 4622 31 NEUROBIOLOGICAL DEVELOPMENT IN THE CONTEXT OF CHILDHOOD TRAUMA. NEUROBIOLOGICAL SYSTEMS MAY BE PARTICULARLY SUSCEPTIBLE TO DELETERIOUS IMPACT OF CHILDHOOD TRAUMA, AND THE IMPACT OF CHILDHOOD TRAUMA ON DEVELOPMENT AND SUBSEQUENT FUNCTIONAL OUTCOMES ACROSS THE LIFESPAN HAS BEEN WELL-DOCUMENTED. THE CURRENT REVIEW ADDRESSES THE NEUROBIOLOGICAL IMPACT OF EXPOSURE TO INTERPERSONAL TRAUMA IN CHILDHOOD IN THE CONTEXT OF EXECUTIVE FUNCTION, EMOTION REGULATION, AND DISSOCIATION/INTEROCEPTIVE AWARENESS. SUBSEQUENT RISK FOR PTSD AND DEPRESSION IS ALSO DISCUSSED. THE PATHWAY OF RISK FROM CHILDHOOD TRAUMA TO THESE COGNITIVE, EMOTIONAL, AND PSYCHIATRIC OUTCOMES IS ADDRESSED IN TERMS OF POTENTIAL STRUCTURAL AND FUNCTIONAL ALTERATIONS WITHIN THE HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA RESULTING FROM CHRONIC OR REPEATED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ITS INTERACTION WITH AND INFLUENCE ON GENETIC AND EPIGENETIC PROCESSES DURING SENSITIVE PERIODS OF DEVELOPMENT. IMPLICATIONS FOR PRACTICE ARE DISCUSSED. 2017 12 6627 36 UNDERSTANDING RESILIENCE: NEW APPROACHES FOR PREVENTING AND TREATING PTSD. ALL INDIVIDUALS EXPERIENCE STRESSFUL LIFE EVENTS, AND UP TO 84% OF THE GENERAL POPULATION WILL EXPERIENCE AT LEAST ONE POTENTIALLY TRAUMATIC EVENT. IN SOME CASES, ACUTE OR CHRONIC STRESSORS LEAD TO THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD) OR OTHER PSYCHOPATHOLOGY; HOWEVER, THE MAJORITY OF PEOPLE ARE RESILIENT TO SUCH EFFECTS. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. A WEALTH OF RESEARCH HAS BEGUN TO IDENTIFY THE GENETIC, EPIGENETIC, NEURAL, AND ENVIRONMENTAL UNDERPINNINGS OF RESILIENCE, AND HAS INDICATED THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES ENCOMPASSING SEVERAL ENVIRONMENTAL FACTORS, NEURAL CIRCUITS, NUMEROUS NEUROTRANSMITTERS, AND MOLECULAR PATHWAYS. THE FIRST PART OF THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING THE GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS AS WELL AS NEURAL CIRCUITS AND MOLECULAR PATHWAYS THAT UNDERLIE THE DEVELOPMENT OF RESILIENCE. EMERGING AND EXCITING AREAS OF RESEARCH AND NOVEL METHODOLOGICAL APPROACHES, INCLUDING GENOME-WIDE GENE EXPRESSION STUDIES, IMMUNE, ENDOCANNABINOID, OXYTOCIN, AND GLUTAMATERGIC SYSTEMS, ARE EXPLORED TO HELP DELINEATE INNOVATIVE MECHANISMS THAT MAY CONTRIBUTE TO RESILIENCE. THE SECOND PART REVIEWS SEVERAL INTERVENTIONS AND PREVENTATIVE APPROACHES DESIGNED TO ENHANCE RESILIENCE IN BOTH DEVELOPMENTAL AND ADULT POPULATIONS. SPECIFICALLY, THE REVIEW WILL DELINEATE APPROACHES AIMED TO BOLSTER RESILIENCE IN INDIVIDUALS WITH PTSD. FURTHERMORE, WE DISCUSS NOVEL PHARMACOLOGIC APPROACHES, INCLUDING THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR KETAMINE AND NEUROPEPTIDE Y (NPY), AS EXCITING NEW PROSPECTS FOR NOT ONLY THE TREATMENT OF PTSD BUT AS NEW TARGETS TO ENHANCE RESILIENCE. OUR GROWING UNDERSTANDING OF RESILIENCE AND INTERVENTIONS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW STRATEGIES FOR NOT JUST TREATING PTSD BUT ALSO SCREENING AND EARLY IDENTIFICATION OF AT-RISK YOUTH AND ADULTS. TAKEN TOGETHER, EFFORTS AIMED AT DISSEMINATION AND IMPLEMENTATION OF NOVEL INTERVENTIONS TO ENHANCE RESILIENCE WILL HAVE TO KEEP PACE WITH THE GROWTH OF NEW PREVENTIVE AND TREATMENT STRATEGIES. 2016 13 575 40 BDNF METHYLATION AND MATERNAL BRAIN ACTIVITY IN A VIOLENCE-RELATED SAMPLE. IT IS KNOWN THAT INCREASED CIRCULATING GLUCOCORTICOIDS IN THE WAKE OF EXCESSIVE, CHRONIC, REPETITIVE STRESS INCREASES ANXIETY AND IMPAIRS BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) SIGNALING. RECENT STUDIES OF BDNF GENE METHYLATION IN RELATION TO MATERNAL CARE HAVE LINKED HIGH BDNF METHYLATION LEVELS IN THE BLOOD OF ADULTS TO LOWER QUALITY OF RECEIVED MATERNAL CARE MEASURED VIA SELF-REPORT. YET THE SPECIFIC MECHANISMS BY WHICH THESE PHENOMENA OCCUR REMAIN TO BE ESTABLISHED. THE PRESENT STUDY EXAMINES THE LINK BETWEEN METHYLATION OF THE BDNF GENE PROMOTER REGION AND PATTERNS OF NEURAL ACTIVITY THAT ARE ASSOCIATED WITH MATERNAL RESPONSE TO STRESSFUL VERSUS NON-STRESSFUL CHILD STIMULI WITHIN A SAMPLE THAT INCLUDES MOTHERS WITH INTERPERSONAL VIOLENCE-RELATED PTSD (IPV-PTSD). 46 MOTHERS UNDERWENT FMRI. THE CONTRAST OF NEURAL ACTIVITY WHEN WATCHING CHILDREN-INCLUDING THEIR OWN-WAS THEN CORRELATED TO BDNF METHYLATION. CONSISTENT WITH THE EXISTING LITERATURE, THE PRESENT STUDY FOUND THAT MATERNAL BDNF METHYLATION WAS ASSOCIATED WITH HIGHER LEVELS OF MATERNAL ANXIETY AND GREATER CHILDHOOD EXPOSURE TO DOMESTIC VIOLENCE. FMRI RESULTS SHOWED A POSITIVE CORRELATION OF BDNF METHYLATION WITH MATERNAL BRAIN ACTIVITY IN THE ANTERIOR CINGULATE (ACC), AND VENTROMEDIAL PREFRONTAL CORTEX (VMPFC), REGIONS GENERALLY CREDITED WITH A REGULATORY FUNCTION TOWARD BRAIN AREAS THAT ARE GENERATING EMOTIONS. FURTHERMORE WE FOUND A NEGATIVE CORRELATION OF BDNF METHYLATION WITH THE ACTIVITY OF THE RIGHT HIPPOCAMPUS. SINCE OUR STIMULI FOCUS ON STRESSFUL PARENTING CONDITIONS, THESE DATA SUGGEST THAT THE CORRELATION BETWEEN VMPFC/ACC ACTIVITY AND BDNF METHYLATION MAY BE LINKED TO MOTHERS WHO ARE AT A DISADVANTAGE WITH RESPECT TO EMOTION REGULATION WHEN FACING STRESSFUL PARENTING SITUATIONS. OVERALL, THIS STUDY PROVIDES EVIDENCE THAT EPIGENETIC SIGNATURES OF STRESS-RELATED GENES CAN BE LINKED TO FUNCTIONAL BRAIN REGIONS REGULATING PARENTING STRESS, THUS ADVANCING OUR UNDERSTANDING OF MOTHERS AT RISK FOR STRESS-RELATED PSYCHOPATHOLOGY. 2015 14 6626 30 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013 15 801 32 CENTRAL AND PERIPHERAL IMMUNE DYSREGULATION IN POSTTRAUMATIC STRESS DISORDER: CONVERGENT MULTI-OMICS EVIDENCE. 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. 2022 16 3977 26 LONG-TERM EFFECT OF POST-TRAUMATIC STRESS IN ADOLESCENCE ON DENDRITE DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN MALE RAT HIPPOCAMPUS AND PREFRONTAL CORTEX. EXPOSURE TO A HARSH ENVIRONMENT IN EARLY LIFE INCREASES IN THE RISK OF POST-TRAUMATIC STRESS DISORDER (PTSD) OF AN INDIVIDUAL. BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) PLAYS AN IMPORTANT ROLE IN NEURODEVELOPMENT IN DEVELOPMENTAL STAGES. BOTH CHRONIC AND TRAUMATIC STRESSES INDUCE A DECREASE IN THE LEVEL OF BDNF AND REDUCE NEURAL PLASTICITY, WHICH IS LINKED TO THE PATHOGENESIS OF PTSD. ALSO, STUDIES HAVE SHOWN THAT STRESS ALTERS THE EPIGENETIC MARKER H3K9ME2, WHICH CAN BIND TO THE PROMOTER REGION OF THE BDNF GENE AND REDUCE BDNF PROTEIN LEVEL. HOWEVER, THE LONG-TERM EFFECTS OF TRAUMATIC STRESS DURING ADOLESCENCE ON H3K9ME2, BDNF EXPRESSION AND DENDRITE DEVELOPMENT ARE NOT WELL-KNOWN. THE PRESENT STUDY ESTABLISHED A MODEL OF PTSD IN ADOLESCENT RATS USING AN INESCAPABLE FOOT SHOCK (IFS) PROCEDURE. ANXIETY-LIKE BEHAVIORS, SOCIAL INTERACTION BEHAVIOR AND MEMORY FUNCTION WERE ASSESSED BY THE OPEN FIELD TEST, ELEVATED PLUS MAZE TEST, THREE-CHAMBER SOCIABILITY TEST AND MORRIS WATER MAZE TEST. IN ADDITION, NEURONAL DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN HIPPOCAMPUS (HIP) AND PREFRONTAL CORTEX (PFC) WERE EVALUATED BY GOLGI STAINING, WESTERN BLOTTING, QRT-PCR ANALYSIS AND CHIP-QPCR ANALYSIS. ADDITIONALLY, THE UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (EHMT2) WAS USED FOR INTERVENTION. THE RESULTS SHOWED THAT THE IFS PROCEDURE INDUCED THE PTSD-LIKE BEHAVIORS IN RATS, RESULTED IN FEWER DENDRITE BRANCHES AND SHORTER DENDRITE LENGTH IN CA1 OF HIP AND PFC, INCREASED H3K9ME2 LEVEL AND DECREASED BDNF EXPRESSION IN HIP AND PFC. ALSO, ALTHOUGH ALL THE CHANGES CAN PERSIST TO ADULTHOOD, UNC0642 ADMINISTRATION RELIEVED MOST OF ALTERATIONS. OUR STUDY SUGGESTS THAT TRAUMATIC STRESS IN ADOLESCENCE LEADS TO IMMEDIATE AND LONG-TERM MENTAL DISORDERS, NEURONAL MORPHOLOGICAL CHANGES, LOWER BDNF LEVEL AND INCREASED H3K9ME2 LEVEL IN THE HIP AND PFC, INDICATING THAT H3K9ME2/BDNF DYSFUNCTION PLAYS A KEY ROLE IN PATHOGENESIS OF PTSD. 2020 17 6240 30 THE MANUAL STIMULATION OF ACUPUNCTURE POINTS IN THE TREATMENT OF POST-TRAUMATIC STRESS DISORDER: A REVIEW OF CLINICAL EMOTIONAL FREEDOM TECHNIQUES. BACKGROUND: THE MANUAL STIMULATION OF ACUPUNCTURE POINTS HAS BEEN COMBINED WITH COMPONENTS OF COGNITIVE AND EXPOSURE THERAPIES INTO A CLINICAL AND SELF-HELP APPROACH KNOWN AS EMOTIONAL FREEDOM TECHNIQUES (EFT). MORE THAN 40 CLINICAL TRIALS AND FOUR META-ANALYTIC REVIEWS OF EFT TREATMENTS HAVE DEMONSTRATED LARGE EFFECT SIZES WITH A RANGE OF CONDITIONS, INCLUDING PAIN, PTSD (IN BOTH CIVILIAN AND MILITARY VETERAN POPULATIONS), PHOBIAS, ANXIETY, AND DEPRESSION. OBJECTIVE: THIS REVIEW DESCRIBES THE APPROACH, WITH A FOCUS ON PTSD IN VETERANS AND SERVICE MEMBERS, PROVIDES AN OVERVIEW OF HOW EFT IS MOST COMMONLY APPLIED, AND OUTLINES OBSTACLES AND CAUTIONS RELATED TO ITS IMPLEMENTATION. METHODS: PEER-REVIEWED CLINICAL TRIALS AND META-ANALYSES OF EFT IN THE TREATMENT OF PTSD ARE ASSESSED TO IDENTIFY THE CHARACTERISTICS OF THE APPROACH THAT RENDER IT SUITABLE FOR THE TREATMENT OF PTSD. RESULTS: THE LITERATURE DEMONSTRATES THAT REMEDIATION OF PTSD AND COMORBID CONDITIONS IS TYPICALLY ACCOMPLISHED WITHIN BRIEF TIME FRAMES, RANGING FROM ONE SESSION FOR PHOBIAS TO BETWEEN FOUR AND TEN SESSIONS FOR PTSD. CLINICAL EFT HAS BEEN SHOWN TO REGULATE STRESS HORMONES AND LIMBIC FUNCTION AND TO IMPROVE VARIOUS NEUROLOGIC MARKERS OF GENERAL HEALTH. THE EPIGENETIC EFFECTS OF EFT INCLUDE UPREGULATION OF IMMUNITY GENES AND DOWNREGULATION OF INFLAMMATION GENES. SIX DISMANTLING STUDIES HAVE INDICATED THAT THE ACUPRESSURE COMPONENT OF EFT IS AN ACTIVE INGREDIENT AND NOT PLACEBO. CONCLUSIONS: SEVEN EMPIRICALLY SUPPORTED STRENGTHS OF THE APPROACH WERE IDENTIFIED THAT MAKE IT ESPECIALLY SUITABLE FOR USE WITH VETERANS AND ACTIVE MILITARY: (1) THE DEPTH AND BREADTH OF TREATMENT EFFECTS; (2) THE RELATIVELY BRIEF TIMEFRAMES REQUIRED FOR SUCCESSFUL TREATMENT; (3) THE LOW RISK OF ADVERSE EVENTS; (4) THE MINIMAL TRAINING TIME REQUIRED FOR THE APPROACH TO BE APPLIED EFFECTIVELY; (5) THE SIMULTANEOUS REDUCTION OF PHYSICAL AND PSYCHOLOGIC SYMPTOMS; (6) THE UTILITY AND COST-EFFECTIVENESS OF CLINICAL EFT IN A LARGE GROUP FORMAT; AND (7) THE METHOD'S ADAPTABILITY TO ONLINE AND TELEMEDICINE APPLICATIONS. 2017 18 5200 26 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES. 2016 19 2646 35 EPIGENOMIC LINKS BETWEEN SOCIAL DETERMINANTS OF HEALTH AND SYMPTOMS: A SCOPING REVIEW. SOCIAL DETERMINANTS OF HEALTH (SDOH) IMPACT HEALTH AND WELLNESS. THE LINK BETWEEN SDOH AND ADVERSE HEALTH OUTCOMES, INCLUDING SYMPTOM OCCURRENCE AND SEVERITY, MAY BE EXPLAINED BY AN INDIVIDUAL'S PHYSIOLOGIC RESPONSE TO ONE OR MORE SDOH. ONE POTENTIAL MECHANISM UNDERLYING THIS PHYSIOLOGIC RESPONSE LINKING SDOH AND SYMPTOMS IS THE DYNAMIC EPIGENOME. THE PURPOSE OF THIS SCOPING REVIEW OF THE LITERATURE WAS TO EXAMINE DIFFERENTIAL SUSCEPTIBILITY FOR SYMPTOMS BY IDENTIFYING AND SUMMARIZING RESEARCH LINKING SDOH AND SYMPTOMS THROUGH EPIGENOMIC MECHANISMS. PUBMED WAS SEARCHED TO IDENTIFY EMPIRICAL RESEARCH WHERE AT LEAST ONE SDOH WAS AN INDEPENDENT OR DEPENDENT VARIABLE, AT LEAST ONE SYMPTOM WAS INVESTIGATED, AND THE INVESTIGATION INCLUDED AN EPIGENOMIC MEASURE. OF THE 484 ARTICLES INITIALLY RETRIEVED, AFTER THOROUGH VETTING, 41 ARTICLES MET ELIGIBILITY. THE MOST STUDIED SYMPTOM WAS DEPRESSIVE SYMPTOMS FOLLOWED BY ANXIETY, COGNITIVE FUNCTION, SLEEP DYSFUNCTION, AND PAIN. THE MOST FREQUENTLY STUDIED SDOH WERE: 1) STRESS, PARTICULARLY EARLY LIFE STRESS AND ACCULTURATIVE STRESS; AND 2) TRAUMA, PREDOMINANTLY CHILDHOOD TRAUMA. DNA METHYLATION AND TELOMERE LENGTH WERE THE MOST STUDIED EPIGENOMIC MEASURES. FOUR GENES (SLC6A4, BDNF, NR3C1, OXTR) HAD EVIDENCE FROM MULTIPLE STUDIES AND ACROSS METHODOLOGICAL APPROACHES LINKING SDOH TO SYMPTOMS. THIS REVIEW SUPPORTS THE INCLUSION OF EPIGENOMIC APPROACHES TO BETTER UNDERSTAND THE LINK BETWEEN SDOH AND SYMPTOMS AND PROVIDES EVIDENCE THAT SDOH IMPACT TELOMERE LENGTH AND THE METHYLATION OF GENES INVOLVED IN NEUROTRANSMITTER SIGNALING, NEURONAL SURVIVAL, BEHAVIOR, INFLAMMATION AND STRESS RESPONSE. 2023 20 3854 35 IS PTSD AN EVOLUTIONARY SURVIVAL ADAPTATION INITIATED BY UNRESTRAINED CYTOKINE SIGNALING AND MAINTAINED BY EPIGENETIC CHANGE? INTRODUCTION: TREATMENT OUTCOMES FOR PTSD WITH CURRENT PSYCHOLOGICAL THERAPIES ARE POOR, WITH VERY FEW PATIENTS ACHIEVING SUSTAINED SYMPTOM REMISSION. A NUMBER OF AUTHORS HAVE IDENTIFIED PHYSIOLOGICAL AND IMMUNE DISTURBANCES IN POST TRAUMATIC STRESS DISORDER (PTSD) PATIENTS, BUT THERE IS NO UNIFYING HYPOTHESIS THAT EXPLAINS THE MYRIAD FEATURES OF THE DISORDER. MATERIALS AND METHODS: THE MEDICAL LITERATURE WAS REVIEWED OVER A 6-YEAR PERIOD PRIMARILY USING THE MEDICAL DATABASE PUBMED. RESULTS: THE LITERATURE CONTAINS NUMEROUS PAPERS THAT HAVE IDENTIFIED A RANGE OF PHYSIOLOGICAL AND IMMUNE DYSFUNCTION IN ASSOCIATION WITH PTSD. THIS PAPER PROPOSES THAT UNRESTRAINED CYTOKINE SIGNALING INDUCES EPIGENETIC CHANGES THAT PROMOTE AN EVOLUTIONARY SURVIVAL ADAPTATION, WHICH MAINTAINS A DEFENSIVE PTSD PHENOTYPE. THE BRAIN CAN ASSOCIATE IMMUNE SIGNALING WITH PAST THREAT AND INITIATE A DEFENSIVE BEHAVIORAL RESPONSE. THE SYMPATHETIC NERVOUS SYSTEM IS PRO-INFLAMMATORY, WHILE THE PARASYMPATHETIC NERVOUS SYSTEM IS ANTI-INFLAMMATORY. PROLONGED CHOLINERGIC WITHDRAWAL WILL PROMOTE A CHRONIC INFLAMMATORY STATE. THE INNATE IMMUNE CYTOKINE IL-1BETA HAS PLEIOTROPIC PROPERTIES AND CAN REGULATE AUTONOMIC, GLUCOCORTICOID, AND GLUTAMATE RECEPTOR FUNCTIONS, SLEEP, MEMORY, AND EPIGENETIC ENZYMES. CHANGES IN EPIGENETIC ENZYME ACTIVITY CAN POTENTIALLY ALTER PHENOTYPE AND INDUCE AN ADAPTATION. LEVELS OF IL-1BETA CORRELATE WITH SEVERITY AND DURATION OF PTSD AND PTSD CAN BE PREVENTED BY BOLUS ADMINISTRATION OF HYDROCORTISONE IN ACUTE SEPSIS, CONSISTENT WITH UNRESTRAINED INFLAMMATION BEING A RISK FACTOR FOR PTSD. THE NERVOUS AND IMMUNE SYSTEMS ENGAGE IN CROSSTALK, GOVERNED BY COMMON RECEPTORS. THE BENEFITS OF CURRENTLY USED PSYCHIATRIC MEDICATION MAY ARISE FROM IMMUNE, AS WELL AS SYNAPTIC, MODULATION. THE PSYCHEDELIC DRUGS (3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA), PSILOCYBIN, AND KETAMINE) HAVE POTENT IMMUNOSUPPRESSIVE AND ANTI-INFLAMMATORY EFFECTS ON THE ADAPTIVE IMMUNE SYSTEM, WHICH MAY CONTRIBUTE TO THEIR REPORTED BENEFIT IN PTSD. THERE MAY BE DISTINCT PTSD PHENOTYPES INDUCED BY INNATE AND ADAPTIVE CYTOKINE SIGNALING. CONCLUSION: IN ORDER FOR AN ORGANISM TO SURVIVE, IT MUST ADAPT TO ITS ENVIRONMENT. CYTOKINES SIGNAL DANGER TO THE BRAIN AND CAN INDUCE EPIGENETIC CHANGES THAT RESULT IN A PERSISTENT DEFENSIVE PHENOTYPE. PTSD MAY BE THE PRICE INDIVIDUALS PAY FOR THE GENOMIC FLEXIBILITY THAT PROMOTES ADAPTATION AND SURVIVAL. 2022