Effect of treadmill exercise on serum corticosterone, serum and hippocampal BDNF, hippocampal apoptosis and anxiety behavior in an ovariectomized rat model of post-traumatic stress disorder (PTSD).

There is a sex difference in vulnerability to PTSD and in response to therapeutic interventions. Since relation between gonadal hormones and PTSD has been revealed, this study aimed to understand the severity of PTSD-induced impairments after ovarian hormone deficiency and the influence of exercise on PTSD accompanied by ovarian hormone deficiency. Female adult Wistar rats were subjected to ovariectomy, PTSD, or combination ovariectomy plus PTSD. Twenty days after ovariectomy, PTSD was induced by single prolonged stress (SPS) model. The exercise started 14 days after SPS and continued for 4 weeks. Thirty minutes moderate treadmill exercise was planned for 5 days per week. On day 65, after assessing rats using the elevated plus-maze (EPM) test, corticosterone, BDNF, and apoptotic markers were tested. p < 0.05 was considered as significant level. The results showed that ovariectomy worsened the effect of SPS on hippocampal BDNF and led to greater increase in serum corticosterone and hippocampal caspase 3 and BAX in SPS rats. Also, ovariectomy exacerbated anxiety-like behavior in SPS rats. Exercise improved the alterations of hippocampal BDNF, corticosterone, caspase 3, and BAX in SPS ovariectomized rats. However, exercise had no statistically significant effect on anxiety-like behavior in this group. According to the results, exercise is effective to attenuate SPS-induced impairments in molecular and cellular responses even when the condition becomes more complicated due to ovarian hormone deficiency. However, exercise alone cannot help to improve behavior impairments in PTSD combined with an ovarian hormone deficiency. Therefore, exercise could likely be considered as a complementary intervention to strengthen other treatments.

A cluster analytic approach to examining the role of cortisol in the development of post-traumatic stress and dysphoria in adult traumatic injury survivors.

Identification of specific risk factors for posttraumatic stress disorder (PTSD) versus depression after trauma has been challenging, in part due to the high comorbidity of these disorders. As exposure to trauma triggers activation of the hypothalamic-pituitary-adrenal (HPA)-axis, examining atypical stress responses via HPA-axis hormones, namely cortisol, may help in the delineation of these disorders. Indeed, extant research demonstrates that, following stress, individuals with chronic PTSD exhibit hypocortisolism (e.g., lower cortisol response than controls), while those with chronic depression exhibit hypercortisolism (e.g., higher response than controls). Less is known about the role of cortisol and these seemingly disparate profiles immediately following traumatic injury as well as whether cortisol can be used as a predictor of future development of PTSD versus depression symptoms. In this study cortisol was measured blood from 172 traumatic injury survivors during hospitalization (on average 2.5 days post-injury). PTSD and depression severity were assessed from Clinician Assessed PTSD Scale (CAPS-5) six-eight months later using a two-factor dimensional approach that measures trauma-specific symptoms of PTSD versus dysphoria (akin to depression). Cluster analysis was used to group individuals based on post-injury cortisol, PTSD, and dysphoria. Results demonstrated that trauma survivors who only developed symptoms of dysphoria at six months (with minimal symptoms of PTSD) were differentiated by high post-injury cortisol compared to other groups. By contrast, individuals who developed symptoms of both PTSD and dysphoria were differentiated by low post-injury cortisol and most severe symptoms of PTSD. Findings provide support for the presence of subgroups of trauma survivors defined, in part, by post-trauma cortisol.

Association of Lipid Peroxidation Product 4-Hydroxynonenal with Post-Traumatic Stress Disorder.

Repeated activation of the hypothalamic-pituitary-adrenal axis system, sleep disturbances, and other symptoms related to posttraumatic stress disorder (PTSD) elevate reactive oxygen species, increase inflammation, and accelerate cellular aging, leading to neuroprogression and cognitive decline. However, there is no information about possible involvement of 4-hydroxynonenal (4-HNE), the product of lipid peroxidation associated with stress-associated diseases, in the complex etiology of PTSD. Therefore, the aim of this study was to compare the plasma levels of 4-HNE between war veterans with PTSD (n = 62) and age-, sex- and ethnicity- matched healthy control subjects (n = 58) in order to evaluate the potential of HNE-modified proteins as blood-based biomarker of PTSD. The genuine 4-HNE-Enzyme-Linked Immunosorbent Assay (HNE-ELISA), based on monoclonal antibody specific for HNE-histidine (HNE-His) adducts, was used to determine plasma HNE-protein conjugates. Our results revealed significantly elevated levels of 4-HNE in patients with PTSD. Moreover, the accumulation of plasma 4-HNE seems to increase with aging but in a negative correlation with BMI, showing specific pattern of change for individuals diagnosed with PTSD. These findings suggest that oxidative stress and altered lipid metabolism reflected by increase of 4-HNE might be associated with PTSD. If confirmed with further studies, elevated 4-HNE plasma levels might serve as a potential biomarker of PTSD.

Investigation of C-reactive protein and AIM2 methylation as a marker for PTSD in Australian Vietnam veterans.

Chronic inflammation is a key factor in symptomology and comorbidities of post-traumatic stress disorder (PTSD). Levels of a proinflammatory marker, C-reactive protein (CRP) are increased in individuals with PTSD but it is not clear if this is due to trauma exposure or PTSD. Our study aimed to assess the relationship between serum CRP levels, CRP SNPs, methylation, mRNA expression and PTSD in a homogenous trauma exposed Australian Vietnam veteran cohort. We hypothesized that decreased DNA methylation would be associated with increased gene expression and increased peripheral CRP levels in PTSD patients and that this would be independent of trauma. Participants were 299 Vietnam veterans who had all been exposed to trauma and approximately half were diagnosed with PTSD. We observed higher levels of serum CRP in the PTSD group compared to the non-PTSD group but after controlling for BMI and triglycerides the association did not remain significant. No association was found between CRP SNPs and PTSD or CRP levels. Absent in Melanoma 2 (AIM2) which is a mediator of inflammatory response and a determinant of CRP levels was analysed for DNA methylation and mRNA expression. We observed a trend level association between PTSD and AIM2 methylation after controlling for age, smoking, triglycerides, BMI and cell types. There was no significant interaction between PTSD and CRP levels on AIM2 methylation after controlling for covariates. We observed that as AIM2 methylation levels decreased, AIM2 mRNA expression increased. Elevated CRP levels were associated with AIM2 mRNA in the trauma exposed cohort but there was no significant interaction effect with PTSD. Our results could not confirm that CRP is a marker of PTSD independent of trauma in this group of older veterans. CRP may be a broad marker of disease risk, or a marker of PTSD in younger cohorts than those in this study.

Is PTSD-Phenotype Associated with HPA-Axis Sensitivity? Feedback Inhibition and Other Modulating Factors of Glucocorticoid Signaling Dynamics.

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus-pituitary-adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.

Assessment of trimethylamine N-oxide (TMAO) as a potential biomarker of severe stress in patients vulnerable to posttraumatic stress disorder (PTSD) after acute myocardial infarction.

Background: Posttraumatic stress disorder (PTSD) is a frequently observed stress-related disorder after acute myocardial infarction (AMI) and it is characterized by numerous symptoms, such as flashbacks, intrusions and anxiety, as well as uncontrollable thoughts and feelings related to the trauma. Biological correlates of severe stress might contribute to identifying PTSD-vulnerable patients at an early stage. Objective: Aims of the study were (1) to determine whether blood levels of trimethylamine N-oxide (TMAO) vary immediately after AMI in patients with/without AMI-induced PTSD symptomatology, (2) to investigate whether TMAO is a potential biomarker that might be useful in the prediction of PTSD and the PTSD symptom subclusters re-experiencing, avoidance and hyperarousal, and (3) to investigate whether TMAO varies immediately after AMI in patients with/without depression 6 months after AMI. Method: A total of 114 AMI patients were assessed with the Hamilton-Depression Scale after admission to the hospital and 6 months later. The Clinician Administered PTSD Scale for DSM-5 was used to explore PTSD-symptoms at the time of AMI and 6 months after AMI. To assess patients' TMAO status, serum samples were collected at hospitalization and 6 months after AMI. Results: Participants with PTSD-symptomatology had significantly higher TMAO levels immediately after AMI than patients without PTSD-symptoms (ANCOVA: TMAO(PTSD x time), F = 4.544, df = 1, p = 0.035). With the inclusion of additional clinical predictors in a hierarchical logistic regression model, TMAO became a significant predictor of PTSD-symptomatology. No significant differences in TMAO levels immediately after AMI were detected between individuals with/without depression 6 months after AMI. Conclusions: An elevated TMAO level immediately after AMI might reflect severe stress in PTSD-vulnerable patients, which might also lead to a short-term increase in gut permeability to trimethylamine, the precursor of TMAO. Thus, an elevated TMAO level might be a biological correlate for severe stress that is associated with vulnerability to PTSD.

Antecedentes: El trastorno de estrés postraumático (TEPT) es un trastorno relacionado con el estrés que se observa con frecuencia después de un infarto agudo de miocardio (IAM) y se caracteriza por numerosos síntomas, como flashbacks, intrusiones y ansiedad, así como pensamientos y sentimientos incontrolables relacionados con el trauma. Los correlatos biológicos del estrés severo podrían contribuir a identificar a los pacientes vulnerables al TEPT en una etapa temprana.Objetivo: Los objetivos del estudio fueron (1) determinar si los niveles sanguíneos de N-óxido de trimetilamina (TMAO, por sus siglas en ingles) varían inmediatamente después del IAM en pacientes con o sin sintomatología de TEPT inducida por IAM, (2) investigar si el TMAO es un biomarcador potencial que podría ser útil en la predicción de TEPT y los subgrupos de síntomas de TEPT que experimentan, evitación e hiperactivación, y (3) para investigar si el TMAO varía inmediatamente después del IAM en pacientes con o sin depresión 6 meses después del IAM.Método: Un total de 114 pacientes con IAM fueron evaluados con la Escala de Depresión de Hamilton tras su ingreso al hospital y 6 meses después. La Escala de TEPT para el DSM-5 administrada por el médico se utilizó para explorar los síntomas de TEPT en el momento del IAM y 6 meses después del IAM. Para evaluar el estado de TMAO de los pacientes, se recolectaron muestras de suero en la hospitalización y 6 meses después del IAM.Resultados: Los participantes con sintomatología de TEPT tenían niveles de TMAO significativamente más altos inmediatamente después del IAM que los pacientes sin síntomas de TEPT (ANCOVA: TMAO (TEPT x tiempo), F = 4.544, df = 1, p = 0.035). Con la inclusión de predictores clínicos adicionales en un modelo de regresión logística jerárquica, TMAO se convirtió en un predictor significativo de la sintomatología del TEPT. No se detectaron diferencias significativas en los niveles de TMAO inmediatamente después del IAM entre individuos con o sin depresión 6 meses después del IAM.Conclusiones: Un nivel elevado de TMAO inmediatamente después del IAM podría reflejar un estrés severo en pacientes vulnerables al TEPT, lo que también podría conducir a un aumento a corto plazo de la permeabilidad intestinal a la trimetilamina, el precursor de TMAO. Por lo tanto, un nivel elevado de TMAO podría ser un correlato biológico del estrés severo asociado con la vulnerabilidad al TEPT.

The Development of Posttraumatic Stress Disorder and Depression Symptoms in Iraqi Refugees: Associations with Acculturation and C-reactive Protein.

ABSTRACT: Refugees experience distress from premigration trauma, often exacerbated by postmigration difficulties. To develop effective interventions, risk factors for mental health symptoms need to be determined. Male Iraqi refugees (N = 53) to the United States provided background information and reported predisplacement trauma and psychological health within 1 month of their arrival. An inflammatory biomarker-C-reactive protein (CRP) was assessed approximately 1.5 years after arrival, and a contextual factor-acculturation-and psychological health were assessed 2 years after arrival. We tested whether acculturation and CRP were associated with posttraumatic stress disorder (PTSD) and depression symptoms at the 2-year follow-up, controlling for baseline symptoms, age, body mass index, and predisplacement trauma. Acculturation was inversely related to depression, and CRP was positively related to both PTSD and depression at the 2-year follow-up. Interventions targeting acculturation could help reduce the development of depression symptoms in refugees. The role of CRP in the development of PTSD and depression symptoms warrants further research.

Plasma gamma-aminobutyric acid (GABA) levels and posttraumatic stress disorder symptoms in trauma-exposed women: a preliminary report.

RATIONALE: Aberrations in the stress response are associated with posttraumatic stress disorder (PTSD) symptom development, maintenance, and severity. Gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, may play a key role in stress recovery. OBJECTIVES: In this preliminary study, we examined whether plasma GABA levels differed between women with PTSD and trauma-exposed healthy controls. METHODS: Thirty participants provided plasma samples during two phases of the menstrual cycle: the early follicular phase and the mid-luteal phase. During each phase, blood was drawn after 45 min of rest, and after mild and moderately stressful psychophysiological tasks. Plasma GABA levels were measured using HPLC-mass spectrometry (LC-MS/MS). RESULTS: In analyses using PTSD diagnosis as a categorical group variable, women with and without a diagnosis of PTSD did not differ in plasma GABA levels (ps > .18). However, in analyses examining PTSD symptom severity as a continuous variable, there was a trend-level positive association between more severe PTSD symptoms and higher plasma GABA levels across the four blood draws (p = .06). In analyses examining DSM-IV PTSD symptom clusters separately, dysphoria symptoms were positively and significantly associated with plasma GABA levels (p = .03). Similarly, there was a trend-level positive association between avoidance cluster symptoms and plasma GABA levels (p = .06). Plasma GABA levels were not modulated by experimentally induced stress or menstrual cycle phase. CONCLUSIONS: Dysregulation in GABA may be a neurobiological marker and/or potential treatment target for women with PTSD symptom profiles characterized by prominent dysphoria and avoidance cluster symptoms.

Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD?

Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world, their diagnosis still relies solely on the characterization of subjective symptoms (many of which are shared by multiple disorders) self-reported by patients. Thus, the need for objective measures that aid in the detection of and differentiation between psychiatric disorders becomes urgent. In this paper, we explore the potential of neurosteroids and neurotrophic proteins as biomarkers for MDD and PTSD. Circulating levels of the GABAergic neuroactive steroid, allopregnanolone, are diminished in MDD and PTSD patients, which corroborates the finding of depleted neurosteroid levels observed in animal models of these disorders. The neurotrophic protein, brain-derived neurotropic factor (BDNF), is also reduced in the periphery and in the brain of MDD patients and depressed-like animals that express lower neurosteroid levels. Although the role of BDNF in PTSD psychopathology seems less clear and merits more research, we propose a causal link between allopregnanolone levels and BDNF expression that could function as a biomarker axis for the diagnosis of both MDD and PTSD.

Putative Blood Somatic Mutations in Post-Traumatic Stress Disorder-Symptomatic Soldiers: High Impact of Cytoskeletal and Inflammatory Proteins.

BACKGROUND: We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer's disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targeted repair mechanisms. OBJECTIVE: The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics. METHODS: Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, PTSD) was performed. RESULTS: High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts. CONCLUSION: With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design.

Glucocorticoids and the Brain after Critical Illness.

Treatment for critical illness typically focuses on a patient's short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut-brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.

The effects of laser stimulation at acupoint ST36 on anxiety-like behaviors and anterior cingulate cortex c-Fos expression in a rat post-traumatic stress disorder model.

Post-traumatic stress disorder (PTSD) is a mental disorder that is linked with the onset of multiple anxiety-like behaviors. This study was designed to assess how these behaviors and anterior cingulate cortex (ACC) c-Fos expression were impacted by 10.6-µm laser stimulation at acupoint ST36 a rat model of PTSD. A rat model of PTSD was prepared via prolonged exposure of animals to a stressor, followed by a 7-day period during which animals were allowed to rest undisturbed in their cages. Rats were randomized into four experimental groups (n = 12/group): the control, PTSD, LS, and sham LS groups. Control group animals were not subjected to SPS procedures prior to behavioral testing. LS and sham LS animals were administered LS treatment at bilateral ST36 acupoints or non-acupoints, respectively, for a 7-day period. Animals were then assessed for performance in elevated plus maze (EPM) tests and open-field tests (OFT), and their plasma corticosterone levels were measured. In addition, c-Fos-positive nuclei in the ACC were detected via immunohistochemical staining. Relative to sham LS treatment and PTSD model control rats, LS was associated with increased time spent in both open EPM test arms and in the central area in the OFT (P < 0.05). The PTSD model group exhibited a significant reduction in ACC c-Fox expression, while LS treatment significantly increased this expression (P < 0.001). In addition, a correlation was detected between anxiety-like behaviors and altered ACC neuronal activation. The results of this study indicate that LS at acupoint ST36 can have a previously unreported effect on anxiety-like behaviors in the context of PTSD, with ACC neuronal activation potentially being implicated as a driver of this effect.

Maternal Separation-Induced Histone Acetylation Correlates with BDNF-Programmed Synaptic Changes in an Animal Model of PTSD with Sex Differences.

Maternal separation (MS) causes long-lasting epigenetic changes in the brain and increases vulnerability to traumatic events in adulthood. Of interest, there may be sex-specific differences in these epigenetic changes. In this study, the extent of histone acetylation in the hippocampus (HIP) and the expression of BDNF were measured to determine whether BDNF influences risk of PTSD following MS in early life. Rat offspring were separated from their dams (3 h/day or 6 h/day from PND2~PND14). Then, pups were treated with a single prolonged stress (SPS) procedure when they reached adulthood (PND80). In animals stressed with the SPS procedure in adulthood, those that had increased MS intensity in childhood demonstrated more significant changes in performance on tests of anxiety, depression, and contextual fear memory. Reduced levels of total BDNF mRNA and protein were observed after SPS treatment and further declined in groups with greater MS time in childhood. Interestingly, these changes were correlated with decreased H3K9ac levels and increased HDAC2 levels. Additional MS also led to more severe ultrastructural synaptic damage in rats that experienced the SPS procedure, particularly in the CA1 and CA3 region of the HIP, reflecting impaired synaptic plasticity in these regions. Interestingly, male rats in the MS3h-PTSD group showed decreased anxiety, but no similar changes were found in female rats, suggesting a degree of gender specificity in coping with stress after mild MS. In summary, this study suggests that the epigenetic signatures of the BDNF genes can be linked to HIP responses to stress, providing insights that may be relevant for people at risk of stress-related psychopathologies.

The Two Faces of Janus: Why Thyrotropin as a Cardiovascular Risk Factor May Be an Ambiguous Target.

Elevated concentrations of free thyroid hormones are established cardiovascular risk factors, but the association of thyrotropin (TSH) levels to hard endpoints is less clear. This may, at least in part, ensue from the fact that TSH secretion depends not only on the supply with thyroid hormones but on multiple confounders including genetic traits, medication and allostatic load. Especially psychosocial stress is a still underappreciated factor that is able to adjust the set point of thyroid function. In order to improve our understanding of thyroid allostasis, we undertook a systematic meta-analysis of published studies on thyroid function in post-traumatic stress disorder (PTSD). Studies were identified via MEDLINE/PubMed search and available references, and eligible were reports that included TSH or free thyroid hormone measurements in subjects with and without PTSD. Additionally, we re-analyzed data from the NHANES 2007/2008 cohort for a potential correlation of allostatic load and thyroid homeostasis. The available evidence from 13 included studies and 3386 euthyroid subjects supports a strong association of both PTSD and allostatic load to markers of thyroid function. Therefore, psychosocial stress may contribute to cardiovascular risk via an increased set point of thyroid homeostasis, so that TSH concentrations may be increased for reasons other than subclinical hypothyroidism. This provides a strong perspective for a previously understudied psychoendocrine axis, and future studies should address this connection by incorporating indices of allostatic load, peripheral thyroid hormones and calculated parameters of thyroid homeostasis.

Challenges of post-traumatic stress disorder (PTSD) in Iraq: biochemical network and methodologies. A brief review.

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.

Peripheral blood levels of brain-derived neurotrophic factor in patients with post-traumatic stress disorder (PTSD): A systematic review and meta-analysis.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a crucial role in the survival, differentiation, growth, and plasticity of the central nervous system (CNS). Post-traumatic stress disorder (PTSD) is a complex syndrome that affects CNS function. Evidence indicates that changes in peripheral levels of BDNF may interfere with stress. However, the results are mixed. This study investigates whether blood levels of BDNF in patients with post-traumatic stress disorder (PTSD) are different. METHODS: We conducted a systematic search in the major electronic medical databases from inception through September 2019 and identified Observational studies that measured serum levels of BDNF in patients with PTSD compared to controls without PTSD. RESULTS: 20 studies were eligible to be included in the present meta-analysis. Subjects with PTSD (n = 909) showed lower BDNF levels compared to Non-PTSD controls (n = 1679) (SMD = 0.52; 95% confidence interval: 0.18 to 0.85). Subgroup meta-analyses confirmed higher levels of BDNF in patients with PTSD compared to non-PTSD controls in plasma, not serum, and in studies that used sandwich ELISA, not ELISA, for BDNF measurement. Meta-regressions showed no significant effect of age, gender, NOS, and sample size. CONCLUSIONS: PTSD patients had increased serum BDNF levels compared to healthy controls. Our finding of higher BDNF levels in patients with PTSD supports the notion that PTSD is a neuroplastic disorder.

Acute exposure of rats to a severe stressor alters the circadian pattern of corticosterone and sensitizes to a novel stressor: Relationship to pre-stress individual differences in resting corticosterone levels.

Traumatic events have been proposed to be associated with hypo-activity of the hypothalamic-pituitary-adrenal (HPA) axis, but data in animal models exposed to severe stressors are controversial and have important methodological concerns. Individual differences in resting or stress levels of corticosterone might explain some of the inconsistencies. We then studied this issue in male rats exposed to 2 h immobilization on boards (IMO), a severe stressor. Thirty-six rats were blood sampled under resting conditions four times a day on three non-consecutive days. Then, they were assigned to control (n = 14) or IMO (n = 22) to study the HPA response to IMO, the stressor-induced alterations in the circadian pattern of corticosterone (CPCORT), and the behavioral and HPA responsiveness to an open-field. Individual differences in pre-IMO resting corticosterone were inconsistent, but averaging data markedly improved consistency. The CPCORT was markedly altered on day 1 post-IMO (higher trough and lower peak levels), less altered on day 3 and apparently normal on day 7. Importantly, when rats were classified in low and high resting corticosterone groups (LCORT and HCORT, respectively), on the basis of the area under the curve (AUC) of the averaged pre-IMO data, AUC differences between LCORT and HCORT groups were maintained in controls but disappeared in IMO rats during the post-IMO week. Open-field hypo-activity and corticosterone sensitization were similar in LCORT and HCORT groups nine days after IMO. A single IMO exposure causes long-lasting HPA alterations, some of them dependent on pre-stress resting corticosterone levels, with no evidence for post-IMO resting corticosterone hypo-activity.

A Preliminary Examination of Endogenous Peripheral Oxytocin in a Pilot Randomized Clinical Trial of Oxytocin-Enhanced Psychotherapy for Posttraumatic Stress Disorder.

BACKGROUND: Preclinical and clinical research suggests that the oxytocin system is implicated in the development and maintenance of stress and anxiety-related psychiatric conditions, such as posttraumatic stress disorder (PTSD). Recent research also suggests that intranasal oxytocin holds promise as a treatment for PTSD. However, little is known about the relationship between levels of peripheral oxytocin and PTSD symptom severity, PTSD treatment response, and repeated intranasal oxytocin administration. METHODS: In the current study, we examined associations between PTSD symptom severity and peripheral oxytocin levels measured in plasma before and after a course of prolonged exposure (PE) for PTSD (n = 13); participants were randomized to adjunctive intranasal oxytocin (n = 6) or placebo (n = 7). RESULTS: Baseline peripheral oxytocin levels were not associated with baseline PTSD symptom severity. Change in peripheral oxytocin levels did not differ by treatment condition and did not correspond to change in PTSD symptoms. CONCLUSIONS: This proof-of-concept study illustrates the acceptability and feasibility of measuring peripheral oxytocin among individuals engaged in psychotherapy for PTSD and informs the utilization of these procedures in future adequately powered studies.

Cortisol as a Biomarker of Alcohol Use in Combat Veterans: A Literature Review and Framework for Future Research.

Objective: Alcohol use and alcohol use disorders (AUDs) are an increasing concern among veterans, particularly those from recent conflicts in Iraq and Afghanistan. The study of biomarkers in alcohol use and AUD has moved to enhancing the understanding of the development and maintenance of AUDs, as well as investigating its association with clinical severity and potential predictors of treatment response. Cortisol, a glucocorticoid known as a stress hormone, has been linked with both stress and trauma, as well as increased alcohol suppression effects. Method/Results: The present review summarizes existing literature and presents suggestions for future research to evaluate whether cortisol may be a possible biomarker of alcohol use disorder risk in combat veterans. Specifically, aspects of combat deployments and high levels of PTSD, coupled with the stress of reintegration may dysregulate cortisol and increase risk to AUD. There may also be bidirectional impacts, such that alcohol is used as a coping mechanism and can dysregulate hypothalamic pituitary adrenal (HPA) axis functioning and cortisol. Conclusions: In the context of this framework, cortisol may serve as a biomarker for the development of AUD, as well as a biomarker of risk or relapse. This review ends with both theoretical and clinical implications, as well as directions for future research.