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1.
Mol Psychiatry ; 27(12): 5062-5069, 2022 12.
Article in English | MEDLINE | ID: mdl-36131047

ABSTRACT

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.


Subject(s)
DNA Copy Number Variations , Stress Disorders, Post-Traumatic , Humans , Stress Disorders, Post-Traumatic/genetics , Genome , Brain , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Genetic Predisposition to Disease
2.
Mol Psychiatry ; 26(8): 4331-4343, 2021 08.
Article in English | MEDLINE | ID: mdl-33288872

ABSTRACT

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.


Subject(s)
Stress Disorders, Post-Traumatic , Cerebral Cortex/diagnostic imaging , Genomics , Humans , Magnetic Resonance Imaging , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/genetics , Temporal Lobe
3.
Soc Psychiatry Psychiatr Epidemiol ; 56(11): 2107-2116, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34480595

ABSTRACT

PURPOSE: Rates of mental disorders in the United States military have increased in recent years. National Guard members may be particularly at risk for mental disorders, given their dual role as citizen-soldiers and their increased involvement in combat deployments during recent conflicts. The Ohio Army National Guard Mental Health Initiative (OHARNG-MHI) was launched to assess the prevalence, incidence, and potential causes and consequences of mental disorders in this unique population. METHODS: OHARNG-MHI is a decade-long dynamic cohort study that followed over 3,000 National Guard members yearly through structured telephone interviews. RESULTS: Findings thus far have applied a pre-, peri-, post-deployment framework, identifying factors throughout the life course associated with mental disorders, including childhood events and more recent events, both during and outside of deployment. An estimated 61% of participants had at least one mental disorder in their lifetime, the majority of which initiated prior to military service. Psychiatric comorbidity was common, as were alcohol use and stressful events. Latent class growth analyses revealed four distinct trajectory paths of both posttraumatic stress and depression symptoms across four years. Only 37% of soldiers with probable past-year mental disorders accessed mental health services in the subsequent year, with substance use disorders least likely to be treated. CONCLUSION: Strengths of this study include a large number of follow-up interviews, detailed data on both military and non-military experiences, and a clinical assessment subsample that assessed the validity of the telephone screening instruments. Findings, methods, and procedures of the study are discussed, and collaborations are welcome.


Subject(s)
Military Personnel , Stress Disorders, Post-Traumatic , Child , Cohort Studies , Humans , Mental Health , Ohio/epidemiology , Prevalence , Stress Disorders, Post-Traumatic/epidemiology , United States/epidemiology
4.
Depress Anxiety ; 37(7): 670-681, 2020 07.
Article in English | MEDLINE | ID: mdl-32306485

ABSTRACT

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with exaggerated threat processing and deficits in emotion modulation circuitry. It remains unknown how neural circuits are associated with response to evidence-based treatments for PTSD. METHOD: We examined associations between PTSD symptoms and indicators of neural response in key emotion processing and modulation regions. Fifty-six military Veterans with PTSD were randomly assigned to one of three evidence-based treatments (prolonged exposure, sertraline, and PE plus sertraline) in a randomized clinical trial ("PROGrESS"; 2018, Contemp Clin Trials, 64, 128-138). Twenty-seven combat-exposed controls (CCs) served as a comparison group at pretreatment. Before and after PTSD treatment, functional magnetic resonance imaging was used to assess brain activation and connectivity during the validated Shifted Attention Emotion Appraisal Task (2003, J Neurosci, 23, 5627-5633; 2013, Biol Psychiatry, 73, 1045-1053). RESULTS: Greater activation in emotion processing (anterior insula) and modulation (prefrontal cortex) regions and increased connectivity between attentional control (dorsolateral prefrontal cortex and superior parietal cortex) and emotion processing (amygdala) regions, at pretreatment, were associated with subsequent PTSD symptom improvement. CONCLUSIONS: This study is one of the first to examine task-based activation and functional connectivity in a PTSD treatment trial, and provides evidence to suggest that activation in and connectivity between emotion processing and modulation regions are important predictors of treatment response.


Subject(s)
Stress Disorders, Post-Traumatic , Amygdala/diagnostic imaging , Brain/diagnostic imaging , Emotions , Humans , Magnetic Resonance Imaging , Stress Disorders, Post-Traumatic/therapy
5.
Depress Anxiety ; 37(10): 1037-1046, 2020 10.
Article in English | MEDLINE | ID: mdl-32668087

ABSTRACT

BACKGROUND: Alterations in resting-state functional connectivity (rsFC) have been reported in posttraumatic stress disorder (PTSD). Here, we examined pre- and post-treatment rsFC during a randomized clinical trial to characterize alterations and examine predictors of treatment response. METHODS: Sixty-four combat veterans with PTSD were randomly assigned to prolonged exposure (PE) plus placebo, sertraline plus enhanced medication management, or PE plus sertraline. Symptom assessment and resting-state functional magnetic resonance imaging (fMRI) scans occurred before and after treatment. Twenty-nine trauma-exposed combat veterans without PTSD served as a control group at intake. Seed-based and region of interest (ROI)-to-ROI connectivities, as well as an exploratory connectome-based approach were used to analyze rsFC patterns. Based on previously reported findings, analyses focused on Salience Network (SN) and Default-Mode Network (DMN). RESULTS: At intake, patients with PTSD showed greater DMN-dorsal attention network (DAN) connectivity (between ventromedial prefrontal cortex and superior parietal lobule; family-wise error corrected p = .011), greater SN-DAN connectivity (between insula and middle frontal gyrus; corrected p = .003), and a negative correlation between re-experiencing symptoms and within-DMN connectivity (between posterior cingulate cortex (PCC) and middle temporal gyrus; corrected p < .001). We also found preliminary evidence for associations between rsFC and treatment response. Specifically, high responders (≥50% PTSD symptom improvement), compared with low responders, had greater SN-DMN segregation (i.e., less pre-treatment amygdala-PCC connectivity; p = .011) and lower pre-treatment global centrality (p = .042). CONCLUSIONS: Our findings suggest neural abnormalities in PTSD and may inform future research examining neural biomarkers of PTSD treatment response.


Subject(s)
Connectome , Stress Disorders, Post-Traumatic , Veterans , Brain/diagnostic imaging , Humans , Magnetic Resonance Imaging , Prefrontal Cortex , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/therapy
6.
Dev Psychopathol ; 30(3): 1009-1021, 2018 08.
Article in English | MEDLINE | ID: mdl-30068406

ABSTRACT

The ability to regulate stress is a critical developmental milestone of early childhood that involves a set of interconnected behavioral and physiological processes and is influenced by genetic and environmental stimuli. Prenatal exposure to traumatic stress and trauma, including intimate partner violence (IPV), increases risk for offspring biobehavioral regulation problems during childhood and adolescence. Although individual differences in susceptibility to prenatal stress have been largely unexplored, a handful of studies suggest children with specific genetic characteristics are most vulnerable to prenatal stress. We evaluated the brain-derived neurotrophic factor Val66Met gene (BDNF) as a moderator of the effect of prenatal IPV exposure on infant temperamental and cortisol regulation in response to a psychosocial challenge. Ninety-nine mother-infant dyads recruited from the community were assessed when infants (51% female) were 11 to 14 months. Maternal reports of IPV during pregnancy and infant temperament were obtained, and infant saliva was collected for genotyping and to assess cortisol reactivity (before and after the Strange Situation Task). Significant genetic moderation effects were found. Among infants with the BDNF Met allele, prenatal IPV predicted worse temperamental regulation and mobilization of the cortisol response, while controlling for infant postnatal exposure to IPV, other maternal traumatic experiences, and infant sex. However, prenatal IPV exposure was not associated with temperamental or cortisol outcomes among infant carriers of the Val/Val genotype. Findings are discussed in relation to prenatal programming and biological susceptibility to stress.


Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Infant Behavior/psychology , Intimate Partner Violence/psychology , Prenatal Exposure Delayed Effects/psychology , Stress, Psychological/psychology , Adult , Child , Female , Gene-Environment Interaction , Humans , Hydrocortisone/analysis , Infant , Male , Mothers/psychology , Pregnancy , Saliva , Stress, Psychological/genetics , Temperament/physiology
7.
Cogn Affect Behav Neurosci ; 17(2): 422-436, 2017 04.
Article in English | MEDLINE | ID: mdl-27966102

ABSTRACT

Prior work has revealed that posttraumatic stress disorder (PTSD) is associated with altered (a) attentional performance and (b) resting-state functional connectivity (rsFC) in brain networks linked to attention. Here, we sought to characterize and link these behavioral and brain-based alterations in the context of Posner and Peterson's tripartite model of attention. Male military veterans with PTSD (N = 49; all deployed to Iraq or Afghanistan) and healthy age-and-gender-matched community controls (N = 26) completed the Attention Network Task. A subset of these individuals (36 PTSD and 21 controls) also underwent functional magnetic resonance imaging (fMRI) to assess rsFC. The behavioral measures revealed that the PTSD group was impaired at disengaging spatial attention, relative to the control group. FMRI measures further revealed that, relative to the control group, the PTSD group exhibited greater rsFC between the salience network and (a) the default mode network, (b) the dorsal attention network, and (c) the ventral attention network. Moreover, problems with disengaging spatial attention increased the rsFC between the networks above in the control group, but not in the PTSD group. The present findings link PTSD to both altered orienting of spatial attention and altered relationships between spatial orienting and functional connectivity involving the salience network. Interventions that target orienting and disengaging spatial attention may be a new avenue for PTSD research.


Subject(s)
Attention/physiology , Brain/physiopathology , Orientation/physiology , Space Perception/physiology , Stress Disorders, Post-Traumatic/physiopathology , Stress Disorders, Post-Traumatic/psychology , Adult , Brain/diagnostic imaging , Brain Mapping , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Male , Neural Pathways/diagnostic imaging , Neural Pathways/physiopathology , Neuropsychological Tests , Psychiatric Status Rating Scales , Rest , Stress Disorders, Post-Traumatic/etiology , Stress Disorders, Post-Traumatic/therapy , Veterans/psychology , War Exposure/adverse effects
8.
J Neurosci Res ; 94(6): 535-43, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26469872

ABSTRACT

Considerable work indicates that early cumulative risk exposure is aversive to human development, but very little research has examined the neurological underpinnings of these robust findings. This study investigates amygdala volume and reactivity to facial stimuli among adults (mean 23.7 years of age, n = 54) as a function of cumulative risk exposure during childhood (9 and 13 years of age). In addition, we test to determine whether expected cumulative risk elevations in amygdala volume would mediate functional reactivity of the amygdala during socioemotional processing. Risks included substandard housing quality, noise, crowding, family turmoil, child separation from family, and violence. Total and left hemisphere adult amygdala volumes were positively related to cumulative risk exposure during childhood. The links between childhood cumulative risk exposure and elevated amygdala responses to emotionally neutral facial stimuli in adulthood were mediated by the corresponding amygdala volumes. Cumulative risk exposure in later adolescence (17 years of age), however, was unrelated to subsequent adult amygdala volume or function. Physical and socioemotional risk exposures early in life appear to alter amygdala development, rendering adults more reactive to ambiguous stimuli such as neutral faces. These stress-related differences in childhood amygdala development might contribute to the well-documented psychological distress as a function of early risk exposure.


Subject(s)
Amygdala/pathology , Risk Factors , Stress, Psychological/pathology , Adult , Amygdala/diagnostic imaging , Cohort Studies , Facial Expression , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Photic Stimulation , Poverty/psychology , Psychosocial Deprivation , Stress, Psychological/diagnostic imaging , Stress, Psychological/psychology , Violence , Young Adult
9.
Depress Anxiety ; 33(4): 289-99, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27038410

ABSTRACT

BACKGROUND: Recent studies suggest that mindfulness may be an effective component for posttraumatic stress disorder (PTSD) treatment. Mindfulness involves practice in volitional shifting of attention from "mind wandering" to present-moment attention to sensations, and cultivating acceptance. We examined potential neural correlates of mindfulness training using a novel group therapy (mindfulness-based exposure therapy (MBET)) in combat veterans with PTSD deployed to Afghanistan (OEF) and/or Iraq (OIF). METHODS: Twenty-three male OEF/OIF combat veterans with PTSD were treated with a mindfulness-based intervention (N = 14) or an active control group therapy (present-centered group therapy (PCGT), N = 9). Pre-post therapy functional magnetic resonance imaging (fMRI, 3 T) examined resting-state functional connectivity (rsFC) in default mode network (DMN) using posterior cingulate cortex (PCC) and ventral medial prefrontal cortex (vmPFC) seeds, and salience network (SN) with anatomical amygdala seeds. PTSD symptoms were assessed at pre- and posttherapy with Clinician Administered PTSD Scale (CAPS). RESULTS: Patients treated with MBET had reduced PTSD symptoms (effect size d = 0.92) but effect was not significantly different from PCGT (d = 0.46). Increased DMN rsFC (PCC seed) with dorsolateral dorsolateral prefrontal cortex (DLPFC) regions and dorsal anterior cingulate cortex (ACC) regions associated with executive control was seen following MBET. A group × time interaction found MBET showed increased connectivity with DLPFC and dorsal ACC following therapy; PCC-DLPFC connectivity was correlated with improvement in PTSD avoidant and hyperarousal symptoms. CONCLUSIONS: Increased connectivity between DMN and executive control regions following mindfulness training could underlie increased capacity for volitional shifting of attention. The increased PCC-DLPFC rsFC following MBET was related to PTSD symptom improvement, pointing to a potential therapeutic mechanism of mindfulness-based therapies.


Subject(s)
Brain/physiopathology , Implosive Therapy/methods , Mindfulness/methods , Stress Disorders, Post-Traumatic/physiopathology , Stress Disorders, Post-Traumatic/therapy , Veterans/psychology , Adult , Afghanistan , Humans , Iraq , Magnetic Resonance Imaging , Male , Psychotherapy, Group/methods , Rest , Veterans/statistics & numerical data
10.
J Neurosci ; 34(40): 13435-43, 2014 Oct 01.
Article in English | MEDLINE | ID: mdl-25274821

ABSTRACT

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression.


Subject(s)
Extinction, Psychological/physiology , Fear , Memory Disorders/etiology , Retention, Psychology/physiology , Stress Disorders, Post-Traumatic , Afghan Campaign 2001- , Brain/blood supply , Conditioning, Classical/physiology , Galvanic Skin Response , Humans , Image Processing, Computer-Assisted , Iraq War, 2003-2011 , Magnetic Resonance Imaging , Male , Mental Recall/physiology , Oxygen/blood , Psychophysiology , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/pathology , Stress Disorders, Post-Traumatic/psychology , United States , United States Department of Veterans Affairs
11.
Psychosom Med ; 77(9): 993-1005, 2015.
Article in English | MEDLINE | ID: mdl-26461854

ABSTRACT

OBJECTIVES: Major life stressors, including major surgeries, are often followed by psychiatric symptoms and disorders. Prior retrospective work found abdominal aortic aneurysm (AAA) repair is followed by increased psychiatric morbidity, which may adversely influence physical and functional recovery. Identifying risk factors before surgery, such as dysregulation in stress response systems, might be useful in improving preventative intervention. METHODS: Two hundred sixteen patients receiving open AAA or aortofemoral bypass surgeries, endovascular AAA repair, or nonsurgical AAA treatment were recruited from two vascular surgery services. Psychiatric symptoms and salivary cortisol measures (waking, 4 PM, and 11 PM, before and after low-dose dexamethasone) were obtained at intake and 3- and 9-month follow-ups. RESULTS: After open surgeries, 18% of patients had new psychiatric disorders, compared with 4% of patients receiving endovascular AAA repair or nonsurgical treatment (odds ratio = 6.0, 95% confidence interval = 1.6-22.1, p = .007). Having a history of major depression predicted the onset of new disorders in surgical patients. Presurgical cortisol levels were associated with both baseline (r = 0.23, p < .05) and 9-month (r = 0.32, p < .01) psychiatric symptoms (cortisol B = 1.0, standard error = 0.48, p < .05, in repeated-measures mixed model). CONCLUSIONS: Open AAA repair surgery is prospectively linked to the development of psychiatric morbidity, and history of depression elevates risk. Cortisol measures before surgery are associated with current and future psychological functioning, suggesting potential neurobiological mechanisms that may contribute to vulnerability. These results can help identify surgical patients at risk and point to potential targets for risk reduction interventions.


Subject(s)
Anxiety Disorders/etiology , Aorta, Abdominal/surgery , Aortic Aneurysm, Abdominal/psychology , Depressive Disorder/complications , Femoral Artery/surgery , Hydrocortisone/analysis , Peripheral Arterial Disease/psychology , Postoperative Complications/epidemiology , Stress Disorders, Post-Traumatic/etiology , Vascular Surgical Procedures/psychology , Aged , Anastomosis, Surgical/psychology , Aortic Aneurysm, Abdominal/complications , Aortic Aneurysm, Abdominal/surgery , Depressive Disorder/blood , Dexamethasone/pharmacology , Disease Progression , Disease Susceptibility , Female , Follow-Up Studies , Humans , Hydrocortisone/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Interview, Psychological , Male , Middle Aged , Peripheral Arterial Disease/complications , Peripheral Arterial Disease/surgery , Pituitary-Adrenal System/physiopathology , Postoperative Complications/psychology , Preoperative Care , Prospective Studies , Risk , Risk Factors , Saliva/chemistry , Self Report , Severity of Illness Index
12.
Depress Anxiety ; 32(3): 204-12, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25639570

ABSTRACT

BACKGROUND: Understanding cognitive and biological mechanisms of PTSD treatment can help refine treatments and increase rates of response. METHODS: Thirty-six veterans with PTSD were randomly assigned to receive Prolonged exposure therapy (PE) or Present-Centered therapy (PCT). We examined symptoms, trauma-related cognitions, and two indices of HPA axis function (cortisol awakening response and cortisol response to a script-driven imagery task). RESULTS: Thirty veterans started treatment and 26 completed. PE resulted in significantly more symptom reduction than PCT (P = .008). High treatment responders collapsed across treatments showed nominally higher cortisol levels measured at pretreatment 30 min after trauma script exposure compared to low responders (P = .08). At midtreatment, high treatment responders showed higher cortisol levels throughout the imagery task (Ps = .03-.04). There were no differences between high and low treatment responders at posttreatment. Thoughts of incompetence (F (1.6, 35.8) = 16.8, P = .000) and a dangerous world (F (1.3, 29.9) = 8.2, P = .004) significantly improved over time in high treatment responders but showed no change in low responders. Script-associated cortisol response prior to treatment and reductions in thoughts of incompetence accounted for 83% of the variance in reductions in PTSD severity with PE. CONCLUSIONS: Both increased cortisol response to personal trauma script prior to PTSD therapy and reductions in cognitive symptoms of PTSD were significantly and uniquely related to reductions in the core symptoms of PTSD in PE. However, contrary to our hypotheses, cortisol measures were not related to cognitive changes.


Subject(s)
Hydrocortisone/blood , Implosive Therapy , Stress Disorders, Post-Traumatic/metabolism , Stress Disorders, Post-Traumatic/psychology , Veterans/psychology , Adult , Biomarkers/blood , Female , Humans , Hypothalamo-Hypophyseal System/metabolism , Implosive Therapy/methods , Male , Middle Aged , Pituitary-Adrenal System/metabolism , Stress Disorders, Post-Traumatic/therapy , Treatment Outcome
14.
medRxiv ; 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39072012

ABSTRACT

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

15.
Depress Anxiety ; 30(7): 638-45, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23596092

ABSTRACT

BACKGROUND: "Mindfulness-based" interventions show promise for stress reduction in general medical conditions, and initial evidence suggests that they are accepted in trauma-exposed individuals. Mindfulness-based cognitive therapy (MBCT) shows substantial efficacy for prevention of depression relapse, but it has been less studied in anxiety disorders. This study investigated the feasibility, acceptability, and clinical outcomes of an MBCT group intervention adapted for combat posttraumatic stress disorder (PTSD). METHODS: Consecutive patients seeking treatment for chronic PTSD at a VA outpatient clinic were enrolled in 8-week MBCT groups, modified for PTSD (four groups, n = 20) or brief treatment-as-usual (TAU) comparison group interventions (three groups, n = 17). Pre and posttherapy psychological assessments with clinician administered PTSD scale (CAPS) were performed with all patients, and self-report measures (PTSD diagnostic scale, PDS, and posttraumatic cognitions inventory, PTCI) were administered in the MBCT group. RESULTS: Intent to treat analyses showed significant improvement in PTSD (CAPS (t(19) = 4.8, P < .001)) in the MBCT condition but not the TAU conditions, and a significant Condition × Time interaction (F[1,35] = 16.4, P < .005). MBCT completers (n = 15, 75%) showed good compliance with assigned homework exercises, and significant and clinically meaningful improvement in PTSD symptom severity on posttreatment assessment in CAPS and PDS (particularly in avoidance/numbing symptoms), and reduced PTSD-relevant cognitions in PTCI (self blame). CONCLUSIONS: These data suggest group MBCT as an acceptable brief intervention/adjunctive therapy for combat PTSD, with potential for reducing avoidance symptom cluster and PTSD cognitions. Further studies are needed to examine efficacy in a randomized controlled design and to identify factors influencing acceptability and efficacy.


Subject(s)
Meditation/methods , Mindfulness/education , Psychotherapy, Brief/methods , Psychotherapy, Group/methods , Stress Disorders, Post-Traumatic/therapy , Veterans/psychology , Analysis of Variance , Humans , Middle Aged , Pilot Projects , Psychiatric Status Rating Scales , Treatment Outcome
16.
Neuropsychopharmacology ; 48(5): 773-780, 2023 04.
Article in English | MEDLINE | ID: mdl-36725867

ABSTRACT

Epigenetic alterations in DNA methylation might mediate gene expression effects of trauma underlying PTSD symptoms, or effects of PTSD on related health problems. PTSD is associated with all-cause morbidity and premature mortality, suggesting accelerated biological aging. We measured genome-wide DNA methylation (Illumina MethylationEPIC BeadChip) in whole blood in a treatment study for combat-related PTSD - "PROGrESS", a multisite RCT comparing sertraline plus enhanced medication management (SERT + EMM), prolonged exposure (PE) therapy plus placebo (PE + PLB), and the combination (SERT + PE). DNA methylation was measured in 140 US military veterans who served in Iraq and/or Afghanistan (112 current PTSD cases enrolled in a PTSD treatment study and 28 veterans without PTSD history controls), and also 59 non-trauma exposed controls at baseline posttreatment (24 weeks after baseline). Increased DNA methylation GrimAge acceleration (p = 8.8e-09) was observed in patients with PTSD compared to a pooled control group (trauma exposed and non-trauma exposed), suggesting a higher risk of premature mortality in those with PTSD. There was no difference in GrimAge acceleration between combat trauma and non-trauma exposed controls. No treatment-related changes in GrimAge acceleration were found in within-subject comparisons of PTSD patients pre- to post-treatment.


Subject(s)
Military Personnel , Stress Disorders, Post-Traumatic , Veterans , Humans , Aging , DNA Methylation , Sertraline/therapeutic use , Stress Disorders, Post-Traumatic/genetics , Stress Disorders, Post-Traumatic/therapy
17.
Psychosom Med ; 74(9): 904-11, 2012.
Article in English | MEDLINE | ID: mdl-23115342

ABSTRACT

OBJECTIVE: Convergent research demonstrates disrupted attention and heightened threat sensitivity in posttraumatic stress disorder (PTSD). This might be linked to aberrations in large-scale networks subserving the detection of salient stimuli (i.e., the salience network [SN]) and stimulus-independent, internally focused thought (i.e., the default mode network [DMN]). METHODS: Resting-state brain activity was measured in returning veterans with and without PTSD (n = 15 in each group) and in healthy community controls (n = 15). Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions and all other voxels of the brain. RESULTS: Compared with control groups, participants with PTSD showed reduced functional connectivity within the DMN (between DMN seeds and other DMN regions) including the rostral anterior cingulate cortex/ventromedial prefrontal cortex (z = 3.31; p = .005, corrected) and increased connectivity within the SN (between insula seeds and other SN regions) including the amygdala (z = 3.03; p = .01, corrected). Participants with PTSD also demonstrated increased cross-network connectivity. DMN seeds exhibited elevated connectivity with SN regions including the insula (z = 3.06; p = .03, corrected), and SN seeds exhibited elevated connectivity with DMN regions including the hippocampus (z = 3.10; p = .048, corrected). CONCLUSIONS: During resting-state scanning, participants with PTSD showed reduced coupling within the DMN, greater coupling within the SN, and increased coupling between the DMN and the SN. Our findings suggest a relative dominance of threat-sensitive circuitry in PTSD, even in task-free conditions. Disequilibrium between large-scale networks subserving salience detection versus internally focused thought may be associated with PTSD pathophysiology.


Subject(s)
Afghan Campaign 2001- , Brain/physiopathology , Combat Disorders/physiopathology , Combat Disorders/psychology , Homeostasis/physiology , Iraq War, 2003-2011 , Nerve Net/physiopathology , Stress Disorders, Post-Traumatic/physiopathology , Stress Disorders, Post-Traumatic/psychology , Veterans/psychology , Adult , Brain Mapping , Cerebral Cortex/physiopathology , Conditioning, Psychological/physiology , Dominance, Cerebral/physiology , Emotions/physiology , Gyrus Cinguli/physiopathology , Humans , Image Interpretation, Computer-Assisted , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Male , Prefrontal Cortex/physiopathology , Reference Values
18.
J Psychiatry Neurosci ; 37(4): 241-9, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22313617

ABSTRACT

BACKGROUND: Converging neuroimaging research suggests altered emotion neurocircuitry in individuals with posttraumatic stress disorder (PTSD). Emotion activation studies in these individuals have shown hyperactivation in emotion-related regions, including the amygdala and insula, and hypoactivation in emotion-regulation regions, including the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). However, few studies have examined patterns of connectivity at rest in individuals with PTSD, a potentially powerful method for illuminating brain network structure. METHODS: Using the amygdala as a seed region, we measured resting-state brain connectivity using 3 T functional magnetic resonance imaging in returning male veterans with PTSD and combat controls without PTSD. RESULTS: Fifteen veterans with PTSD and 14 combat controls enrolled in our study. Compared with controls, veterans with PTSD showed greater positive connectivity between the amygdala and insula, reduced positive connectivity between the amygdala and hippocampus, and reduced anticorrelation between the amygdala and dorsal ACC and rostral ACC. LIMITATIONS: Only male veterans with combat exposure were tested, thus our findings cannot be generalized to women or to individuals with non-combat related PTSD. CONCLUSION: These results demonstrate that studies of functional connectivity during resting state can discern aberrant patterns of coupling within emotion circuits and suggest a possible brain basis for emotion-processing and emotion-regulation deficits in individuals with PTSD.


Subject(s)
Amygdala/physiopathology , Combat Disorders/physiopathology , Emotions/physiology , Stress Disorders, Post-Traumatic/physiopathology , Veterans/psychology , Adult , Brain/physiopathology , Brain Mapping , Humans , Magnetic Resonance Imaging , Male , Neuroimaging
19.
BJPsych Open ; 8(4): e104, 2022 Jun 03.
Article in English | MEDLINE | ID: mdl-35656579

ABSTRACT

The aims of this study were: (a) to examine associations of oxytocin receptor gene (OXTR) single nucleotide polymorphisms (SNPs) with post-traumatic stress disorder (PTSD) and dissociative symptoms and (b) to investigate gene-environment (G × E) interaction with childhood maltreatment. Salivary DNA samples from 228 women of European ancestry were analysed. Two SNPs, rs237895 and rs237897, were associated with dissociative symptoms but not PTSD diagnosis. Another SNP (rs2254298) was associated with dissociation when interacting with history of childhood maltreatment. These results contribute to theorising and evidence suggesting that the oxytocin system and its genetics may be associated with risk for dissociation among European American women, including those with maltreatment history. Replication with larger patient samples, including men and other ancestry groups, is needed.

20.
Sci Rep ; 12(1): 11026, 2022 06 30.
Article in English | MEDLINE | ID: mdl-35773360

ABSTRACT

Depression is a common mental disorder that may comprise distinct, underlying symptom patterns over time. Associations between stressful life events throughout the civilian lifecourse-including during childhood-and adult depression have been documented in many populations, but are less commonly assessed in military samples. We identified different trajectories of depression symptoms across four years in a military cohort using latent class growth analysis, and investigated the relationship between these trajectories and two domains of civilian life experiences: childhood adversity (e.g., being mistreated during childhood) and more proximal stressful experiences (e.g., divorce). A four-group depression model was identified, including a symptom-free group (62%), an increasing symptom group (13%), a decreasing symptom group (16%), and a "chronic" symptom group (9%). Compared to the symptom-free group, soldiers with childhood adversity were more likely to be in the chronic depression, decreasing, and increasing symptom groups. Time-varying adult stressors had the largest effect on depression symptoms for the increasing symptom group compared to other groups, particularly in the last two years of follow-up. This study indicates the importance of considering events from throughout the lifecourse-not only those from deployment-when studying the mental health of servicemembers.


Subject(s)
Military Personnel , Stress Disorders, Post-Traumatic , Adult , Cohort Studies , Depression/epidemiology , Depression/psychology , Humans , Mental Health , Stress Disorders, Post-Traumatic/psychology
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