Dysfunction In Posttraumatic Stress Disorder Research Articles

Prefrontal metabolite alterations in individuals with posttraumatic stress disorder: a 7T magnetic resonance spectroscopy study.

Evidence from animal and human studies suggests glutamatergic dysfunction in posttraumatic stress disorder (PTSD). The purpose of this study was to investigate glutamate abnormalities in the dorsolateral prefrontal cortex (DLFPC) of individuals with PTSD using 7T MRS, which has better spectral resolution and signal-to-noise ratio than lower field strengths, thus allowing for better spectral quality and higher sensitivity. We hypothesized that individuals with PTSD would have lower glutamate levels compared to trauma-exposed individuals without PTSD and individuals without trauma exposure. Additionally, we explored potential alterations in other neurometabolites and the relationship between glutamate and psychiatric symptoms. Individuals with PTSD (n=27), trauma-exposed individuals without PTSD (n=27), and individuals without trauma exposure (n=26) underwent 7T MRS to measure glutamate and other neurometabolites in the left DLPFC. The severities of PTSD, depression, anxiety, and dissociation symptoms were assessed. We found that glutamate was lower in the PTSD and trauma-exposed groups compared to the group without trauma exposure. Furthermore, N-acetylaspartate (NAA) was lower and lactate was higher in the PTSD group compared to the group without trauma exposure. Glutamate was negatively correlated with depression symptom severity in the PTSD group. Glutamate was not correlated with PTSD symptom severity. In this first 7T MRS study of PTSD, we observed altered concentrations of glutamate, NAA, and lactate. Our findings provide evidence for multiple possible pathological processes in individuals with PTSD. High-field MRS offers insight into the neurometabolic alterations associated with PTSD and is a powerful tool to probe trauma- and stress-related neurotransmission and metabolism in vivo.

Prefrontal Metabolite Alterations in Individuals with Posttraumatic Stress Disorder: A 7T Magnetic Resonance Spectroscopy Study

Background Evidence from animal and human studies suggests glutamatergic dysfunction in posttraumatic stress disorder (PTSD). The purpose of this study was to investigate glutamate abnormalities in the dorsolateral prefrontal cortex (DLFPC) of individuals with PTSD using 7T MRS, which has better spectral resolution and signal-to-noise ratio than lower field strengths, thus allowing for better spectral quality and higher sensitivity. We hypothesized that individuals with PTSD would have lower glutamate levels compared to trauma-exposed individuals without PTSD and individuals without trauma exposure. Additionally, we explored potential alterations in other neurometabolites and the relationship between glutamate and psychiatric symptoms. Methods Individuals with PTSD (n = 27), trauma-exposed individuals without PTSD (n = 27), and individuals without trauma exposure (n = 26) underwent 7T MRS to measure glutamate and other neurometabolites in the left DLPFC. The severities of PTSD, depression, anxiety, and dissociation symptoms were assessed. Results We found that glutamate was lower in the PTSD and trauma-exposed groups compared to the group without trauma exposure. Furthermore, N-acetylaspartate (NAA) was lower and lactate was higher in the PTSD group compared to the group without trauma exposure. Glutamate was negatively correlated with depression symptom severity in the PTSD group. Glutamate was not correlated with PTSD symptom severity. Conclusion In this first 7T MRS study of PTSD, we observed altered concentrations of glutamate, NAA, and lactate. Our findings provide evidence for multiple possible pathological processes in individuals with PTSD. High-field MRS offers insight into the neurometabolic alterations associated with PTSD and is a powerful tool to probe trauma- and stress-related neurotransmission and metabolism in vivo.

Circulating PACAP levels are associated with increased amygdala-default mode network resting-state connectivity in posttraumatic stress disorder

The pituitary adenylate cyclase-activating polypeptide (PACAP) system is implicated in posttraumatic stress disorder (PTSD) and related amygdala-mediated arousal and threat reactivity. PTSD is characterized by increased amygdala reactivity to threat and, more recently, aberrant intrinsic connectivity of the amygdala with large-scale resting state networks, specifically the default mode network (DMN). While the influence of PACAP on amygdala reactivity has been described, its association with intrinsic amygdala connectivity remains unknown. To fill this gap, we examined functional connectivity of resting-state functional magnetic resonance imaging (fMRI) in eighty-nine trauma-exposed adults (69 female) screened for PTSD symptoms to examine the association between blood-borne (circulating) PACAP levels and amygdala-DMN connectivity. Higher circulating PACAP levels were associated with increased amygdala connectivity with posterior DMN regions, including the posterior cingulate cortex/precuneus (PCC/Precun) and left angular gyrus (lANG). Consistent with prior work, this effect was seen in female, but not male, participants and the centromedial, but not basolateral, subregions of the amygdala. Clinical association analyses linked amygdala-PCC/Precun connectivity to anxious arousal symptoms, specifically exaggerated startle response. Taken together, our findings converge with previously demonstrated effects of PACAP on amygdala activity in PTSD-related processes and offer novel evidence for an association between PACAP and intrinsic amygdala connectivity patterns in PTSD. Moreover, these data provide preliminary evidence to motivate future work ascertaining the sex- and subregion-specificity of these effects. Such findings may enable novel mechanistic insights into neural circuit dysfunction in PTSD and how the PACAP system confers risk through a disruption of intrinsic resting-state network dynamics.

Autonomic dysfunction and cardiovascular risk in post-traumatic stress disorder.

Patients with post-traumatic stress disorder (PTSD) have an increased risk for cardiovascular disease. The underlying mechanisms are unclear but impaired autonomic function may contribute. However, research in this field has shown contradictory results and the causal links between PTSD, autonomic dysfunction, and cardiovascular risk remain unknown. This brief review summarizes the current knowledge on alterations in autonomic function and cardiovascular risk in patients with PTSD. A PubMed search of the literature was performed using the following keywords: autonomic function, heart rate variability, blood pressure variability, sympathetic activity, baroreflex function, and cardiovascular risk in combination with PTSD. Evidence-based studies conducted between 2000 and 2021 were selected. In total 1221 articles were identified and of these, 61 (48 original research papers, 13 review articles) were included in this review. Many, though not all, studies have reported increased activity of the sympathetic nervous system and decreased activity of the parasympathetic nervous system (namely, autonomic imbalance) in PTSD patients. There seems to be enough evidence to suggest impairments in baroreflex function in PTSD, leading to blood pressure dysregulation. It appears that the chronicity of PTSD diagnosis and symptom severity are independent risk factors for cardiovascular disease, which may be linked with impaired autonomic function. Increased cardiovascular risk may be associated with autonomic dysfunction in PTSD. Whether autonomic dysfunction can serve as a biomarker for the onset and progression of PTSD remains to be determined. It also needs to determine if autonomic imbalance increases the risk of developing PTSD.

Dysconnectivity of the amygdala and dorsal anterior cingulate cortex in drug-naive post-traumatic stress disorder

Convergent studies have highlighted the amygdala-based and dorsal anterior cingulate cortex (dACC)-based circuit or network dysfunction in post-traumatic stress disorder (PTSD). However, previous studies are often complicated by various traumatic types, psychiatric comorbidities, chronic illness duration, and medication effect on brain function. Besides, little is known whether the functional integration with amygdala–dACC interaction disrupted or not in PTSD. Here, we investigated effective connectivity (EC) between the amygdala-dACC and rest of the cortex by applying psycho-physiological interaction (PPI) approach to resting-state functional magnetic resonance imaging data of 63 drug-naive PTSD patients and 74 matched trauma-exposed non-PTSD controls. Pearson correlation analysis was performed between EC values extracted from regions with between-group difference and clinical profiles in PTSD patients. We observed distinct amygdala-dACC interaction pattern between PTSD group and the control group, which is composed primarily by positive EC in the former and negative in the latter. In addition, compared with non-PTSD controls, PTSD patients showed increased EC between amygdala-dACC and the prefrontal cortex, left inferior parietal lobule, and bilateral ventral occipital cortex, and decreased EC between amygdala-dACC and the left fusiform gyrus. The EC increase between amygdala-dACC and the right middle frontal gyrus was negatively correlated with the clinician-administered PTSD scale scores in PTSD patients. Aberrent communication between amgydala-dACC and brain regions involved in central executive network and visual systems might be associated with the pathophysiology of PTSD. Further, these findings suggested that dysconnectivity of the amygdala and dACC could be adapted as a relatively early course diagnostic biomarker of PTSD.

Unique neurocircuitry activation profiles during fear conditioning and extinction among women with posttraumatic stress disorder

BackgroundNeurocircuitry models of posttraumatic stress disorder (PTSD) suggest specific alterations in brain structures linked with fear conditioning and extinction. Most models assume a unitary pattern of neurocircuitry dysfunction in PTSD and little attention has focused on defining unique profiles of neurocircuitry engagement (i.e., biotypes), despite known clinical heterogeneity in PTSD. Here, we aim to address this gap using a data-driven approach to characterize unique neurocircuitry profiles among women with PTSD. MethodsSeventy-six women with PTSD related to assaultive violence exposure competed a task during fMRI that alternated between fear conditioning, where a geometric shape predicted the occurrence of an electric shock, and fear extinction, where the geometric shape no longer predicted electric shock. A multivariate clustering analysis was applied to neurocircuitry patterns constrained within an a priori mask of structures linked with emotion processing. Resulting biotypes were compared on clinical measures of neurocognition, trauma exposure, general mental health symptoms, and PTSD symptoms and on psychophysiological responding during the task. ResultsThe clustering analysis identified three biotypes (BT), differentiated by patterns of engagement within salience, default mode, and visual processing networks. BT1 was characterized by higher working memory, fewer general mental health symptoms, and low childhood sexual abuse, and lower PTSD symptom severity. BT2 was characterized by lower verbal IQ but better extinction learning as defined by psychophysiology and threat expectancy. BT3 was characterized by low childhood sexual abuse, anxious arousal, and re-experiencing symptoms. Conclusion: This data demonstrates unique profiles of neurocircuitry engagement in PTSD, each associated with different clinical characteristics, and suggests further research defining distinct biotypes of PTSD. Clinicaltrials.gov, https://clinicaltrials.gov/ct2/home, NCT02560389.

Autonomic dysfunction in posttraumatic stress disorder indexed by heart rate variability: a meta-analysis.

Changes in autonomic nervous system (ANS) function have been observed in a variety of psychological disorders, including posttraumatic stress disorder (PTSD). Analysis of heart rate variability (HRV) provides insight into the functioning of the ANS. Previous research on PTSD found lower HRV in PTSD patients compared to controls, indicating altered sympathetic and parasympathetic activity, but findings are inconsistent. The purpose of this meta-analysis was to examine differences in HRV indices between individuals with PTSD and healthy controls at baseline and during stress. The included primary studies present an aggregate of studies analyzing different HRV indices. Examined HRV indices were standard deviation of the normalized NN-intervals (SDNN), root mean square of successive differences (RMSSD), low-frequency (LF) and high-frequency (HF) spectral components, LF/HF ratio, and heart rate (HR). Moderating effects of study design, HRV and PTSD assessment, and sample characteristics were examined via subgroup-analyses and meta-regressions. Random-effects meta-analyses for HRV parameters at rest revealed significant group differences for RMSSD and HF-HRV, suggesting lower parasympathetic activity in PTSD. The aggregated effect size for SDNN was medium, suggesting diminished total variability in PTSD. A small effect was found for LF-HRV. A higher LF/HF ratio was found in the PTSD sample as compared to controls. Individuals with PTSD showed significantly higher HR. During stress, individuals with PTSD showed higher HR and lower HF-HRV, both indicated by small effect sizes. Findings suggest that PTSD is associated with ANS dysfunction.

Neurostimulation for treatment-resistant posttraumatic stress disorder: an update on neurocircuitry and therapeutic targets.

Posttraumatic stress disorder (PTSD) is a widespread and often devastating psychiatric condition. Core symptoms include intrusive and distressing thoughts, heightened reactivity, mood changes, cognitive impairments, and consequent avoidance of trauma-related stimuli. Symptoms of PTSD are often refractory to standard treatments, and neuromodulatory techniques have therefore drawn significant interest among the most treatment-resistant patients. Transcranial magnetic stimulation has demonstrated minimal efficacy, and deep brain stimulation trials are currently ongoing. PTSD is a disorder of neural circuitry; the current understanding includes involvement of the amygdala (basolateral and central nuclei), the prefrontal cortex (ventral medial and dorsolateral regions), and the hippocampus. Neuroimaging and optogenetic studies have improved the understanding of large-scale neural networks and the effects of microcircuitry manipulation, respectively. This review discusses the current PTSD literature and ongoing neurostimulation trials, and it highlights the current understanding of neuronal circuit dysfunction in PTSD. The authors emphasize the anatomical correlations of PTSD's hallmark symptoms, offer another potential deep brain stimulation target for PTSD, and note the need for continued research to identify useful biomarkers for the development of closed-loop therapies. Although there is hope that neuromodulation will become a viable treatment modality for PTSD, this concept remains theoretical, and further research should involve institutional review board-approved controlled prospective clinical studies.

Correlating Kynurenine Pathway and Heart Rate Variability: A Novel Method to Assess Blood-Brain Barrier Dysfunction in Post-Traumatic Stress Disorder With and Without Alcohol Use Disorder

Increased binge alcohol intake is reported among United States veterans suffering with Post-traumatic stress disorder (PTSD). PTSD is a psychiatric disorder that can occur following exposure to a traumatic incident in which grave physical harm occurred or was perceived. PTSD is marked by clear biological changes as well as psychological symptoms. In addition to debilitating physical and psychological health declines, PTSD is associated with increased rates of Alcohol Use Disorder (AUD). It is important to understand the molecular mechanism behind this pathology to target novel treatment. Severe psychological trauma can activate corticotrophin releasing factor (CRF) in the brain. We hypothesize PTSD and AUD is associated with low High Frequency-Heart Rate Variability (HF-HRV) and upregulation of AQP4 in astrocytes, subsequently leads to BBB dysfunction (BBBD).

Dysregulation of inflammation, neurobiology, and cognitive function in PTSD: an integrative review.

Compelling evidence from animal and human research suggest a strong link between inflammation and posttraumatic stress disorder (PTSD). Furthermore, recent findings support compromised neurocognitive function as a key feature of PTSD, particularly with deficits in attention and processing speed, executive function, and memory. These cognitive domains are supported by brain structures and neural pathways that are disrupted in PTSD and which are implicated in fear learning and extinction processes. The disruption of these supporting structures potentially results from their interaction with inflammation. Thus, the converging evidence supports a model of inflammatory dysregulation and cognitive dysfunction as combined mechanisms underpinning PTSD symptomatology. In this review, we summarize evidence of dysregulated inflammation in PTSD and further explore how the neurobiological underpinnings of PTSD, in the context of fear learning and extinction acquisition and recall, may interact with inflammation. We then present evidence for cognitive dysfunction in PTSD, highlighting findings from human work. Potential therapeutic approaches utilizing novel pharmacological and behavioral interventions that target inflammation and cognition also are discussed.

The BDNF Val66Met polymorphism affects negative memory bias in civilian women with PTSD

Memory abnormalities are considered a core feature of posttraumatic stress disorder (PTSD). Studies attempting to quantify such memory dysfunction in PTSD have reported that individuals with this disorder exhibit selective memory bias toward negative material. The low expression Met allele of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with the aetiology of PTSD and with memory abnormalities. It is therefore possible that the BDNF Val66Met polymorphism can moderate the relationship between PTSD and memory bias. Here we examined this association in 50 civilian women with PTSD and 70 non-trauma-exposed healthy control women. All subjects were genotyped for the BDNF Val66Met (rs6265) polymorphism. Negative memory bias was assessed using a recognition memory task. Patients showed significantly greater negative memory bias compared to controls. In patients, negative memory bias significantly increased with increasing numbers of Met alleles; while no significant relationship was seen in controls. Further pairwise analyses revealed that patients with the Met allele had significantly greater negative memory bias than controls. These results suggest that the relationship between PTSD and negative memory bias can be moderated by the BDNF Val66Met polymorphism. More studies are needed to further clarify the relationship between this polymorphism and memory abnormalities in PTSD.

Clinical Implication of Altered Inhibitory Response in Patients with Post-traumatic Stress Disorder: Electrophysiological Evidence from a Go/Nogo Task.

Inhibitory dysfunction is closely associated to post-traumatic stress disorder (PTSD). The present study investigated the neurophysiological evidence for and the brain regions related to inhibitory dysfunction in PTSD. Fifty patients with PTSD and 63 healthy controls (HCs) participated in a Go/Nogo task combined with electroencephalographic recordings. The N2-P3 complexes of event-related potentials (ERPs) elicited during the Nogo condition were compared between groups. Participants underwent structural magnetic resonance imaging to examine cortical volumes and completed questionnaires. Correlations between altered ERPs and cortical volumes of regions of interest as well as psychological symptoms were analysed. Nogo-N2 latencies at five electrode sites (Fz, FCz, Cz, CPz, and Pz) were significantly delayed in patients with PTSD compared to HCs. Nogo-N2 latency had a significant negative correlation with the volume of gyrus in the inferior frontal cortex, orbitofrontal cortex, amygdala, and medial prefrontal cortex. Nogo-N2 latency was significantly and positively correlated with catastrophizing, anxiety, and perceived threat. These findings show inhibitory dysfunction in patients with PTSD, reflected by the delay in Nogo-N2 latencies. They also indicate that Nogo-N2 latencies are associated with smaller cortical volumes responsible for inhibition as well as with major symptoms of PTSD.

TLR4/MyD88/NF-κB-Mediated Inflammation Contributes to Cardiac Dysfunction in Rats of PTSD.

Post-traumatic stress disorder (PTSD) is related with myocardial injury and cardiac dysfunction, while the molecular mechanism has not been clear. This study investigated whether TLR4/MyD88/NF-κB-mediated inflammation involved in myocardial injury of PTSD. Adult male Wistar rats were exposed to single-prolonged stress (SPS), which was used broadly as a animal model of PTSD. Morris Water Maze (MWM) test and forced swimming test (FST) was carried out for behavioral testing. The protein expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the left ventricular of heart and TLR4/MyD88/NF-κB-mediated inflammation were examined. Our results showed that there were obvious increased in the protein expression of ANP and BNP in heart after exposure to SPS, SPS also significantly enhanced the serum level of IL-1β and TNF-α, and meanwhile, the TLR4/MyD88/NF-κB pathway were activated. These results demonstrated that the TLR4/MyD88/NF-κB pathway were involved in the myocardial injury of PTSD, which might be one of possible molecular mechanism contributed to the pathogenesis ofcardiac dysfunction in PTSD.

The bed nucleus of the stria terminalis and functionally linked neurocircuitry modulate emotion processing and HPA axis dysfunction in posttraumatic stress disorder

BackgroundThe bed nucleus of the stria terminalis (BNST) plays an important role in rodent posttraumatic stress disorder (PTSD), but evidence to support its relevance to human PTSD is limited. We sought to understand the role of the BNST in human PTSD via fMRI, behavioral, and physiological measurements. Methods29 patients with PTSD (childhood sexual abuse) and 23 healthy controls (HC) underwent BOLD imaging with an emotional word paradigm. Symptom severity was assessed using the Clinician-Administered PTSD Scale and HPA-axis dysfunction was assessed by measuring the diurnal cortisol amplitude index (DCAI). A data-driven multivariate analysis was used to determine BNST task-based functional co-occurrence (tbFC) across individuals. ResultsIn the trauma-versus-neutral word contrast, patients showed increased activation compared to HC in the BNST, medial prefrontal cortex (mPFC), posterior cingulate gyrus (PCG), caudate heads, and midbrain, and decreased activation in dorsolateral prefrontal cortex (DLPFC). Symptom severity positively correlated with activity in the BNST, caudate head, amygdala, hippocampus, dorsal anterior cingulate gyrus (dACG), and PCG, and negatively with activity in the medial orbiotofrontal cortex (mOFC) and DLPFC. Patients and HC showed marked differences in the relationship between the DCAI and BOLD activity in the BNST, septal nuclei, dACG, and PCG. Patients showed stronger tbFC between the BNST and closely linked limbic and subcortical regions, and a loss of negative tbFC between the BNST and DLPFC. ConclusionsBased upon novel data, we present a new model of dysexecutive emotion processing and HPA-axis dysfunction in human PTSD that incorporates the role of the BNST and functionally linked neurocircuitry.

Neurophysiology of threat processing bias in combat-related post-traumatic stress disorder.

Post‐traumatic stress disorder (PTSD) is a debilitating condition that may develop after experiencing a traumatic event. Combat exposure increases an individual's chance of developing PTSD, making veterans especially susceptible to the disorder. PTSD is characterized by dysregulated emotional networks, memory deficits, and a hyperattentive response to perceived threatening stimuli. Recently, there have been a number of imaging studies that show structural and functional abnormalities associated with PTSD; however, there have been few studies utilizing electroencephalography (EEG). The goal of this study was to characterize **EEG brain dynamics in individuals with PTSD, in order to better understand the neurophysiological underpinnings of some of the salient features of PTSD, such as threat‐processing bias. Veterans of Operation Enduring Freedom/Iraqi Freedom completed an implicit visual threat semantic memory recognition task with stimuli that varied on both category (animals, items, nature, and people) and feature (threatening and nonthreatening) membership, including trauma‐related stimuli. Combat veterans with PTSD had slower reaction times for the threatening stimuli relative to the combat veterans without PTSD (VETC). There were trauma‐specific effects in frontal regions, with theta band EEG power reductions for the threatening combat scenes in the PTSD patients compared to the VETC group. Additionally, a moderate negative correlation was observed between trauma‐specific frontal theta power and hyperarousal symptoms as measured by clinically administered PTSD scale. These findings complement and extend current models of cortico‐limbic dysfunction in PTSD. The moderate negative correlation between frontal theta power and hyperarousal endorsements suggests the utility of these measures as therapeutic markers of symptomatology in PTSD patients.

The Predictive Processing Model of EMDR.

Eye Movement Desensitization and Reprocessing Therapy (EMDR) is an effective treatment for Post-traumatic Stress Disorder (PTSD). The Adaptive Information Processing Model (AIP) guides the development and practice of EMDR. The AIP postulates inadequately processed memory as the foundation of PTSD pathology. Predictive Processing postulates that the primary function of the brain is prediction that serves to anticipate the next moment of experience in order to resist the dissipative force of entropy thus facilitating continued survival. Memory is the primary substrate of prediction, and is optimized by an ongoing process of precision weighted prediction error minimization that refines prediction by updating the memories on which it is based. The Predictive Processing model of EMDR postulates that EMDR facilitates the predictive processing of traumatic memory by overcoming the bias against exploration and evidence accumulation. The EMDR protocol brings the traumatic memory into an active state of re-experiencing. Defensive responding and/or low sensory precision preclude evidence accumulation to test the predictions of the traumatic memory in the present. Sets of therapist guided eye movements repeatedly challenge the bias against evidence accumulation and compel sensory sampling of the benign present. Eye movements reset the theta rhythm organizing the flow of information through the brain, facilitating the deployment of both overt and covert attention, and the mnemonic search for associations. Sampling of sensation does not support the predictions of the traumatic memory resulting in prediction error that the brain then attempts to minimize. The net result is a restoration of the integrity of the rhythmic deployment of attention, a recalibration of sensory precision, and the updating (reconsolidation) of the traumatic memory. Thus one prediction of the model is a decrease in Attention Bias Variability, a core dysfunction in PTSD, following successful treatment with EMDR.

Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: role of glucocorticoid receptor sensitivity.

Posttraumatic stress disorder (PTSD) is associated with neuroendocrine alterations and metabolic abnormalities; however, how metabolism is affected by neuroendocrine disturbances is unclear. The data from combat-exposed veterans with PTSD show increased glycolysis to lactate flux, reduced TCA cycle flux, impaired amino acid and lipid metabolism, insulin resistance, inflammation, and hypersensitive hypothalamic-pituitary-adrenal (HPA) axis. To analyze whether the co-occurrence of multiple metabolic abnormalities is independent or arises from an underlying regulatory defect, we employed a systems biological approach using an integrated mathematical model and multiomic analysis. The models for hepatic metabolism, HPA axis, inflammation, and regulatory signaling were integrated to perform metabolic control analysis (MCA) with respect to the observations from our clinical data. We combined the metabolomics, neuroendocrine, clinical laboratory, and cytokine data from combat-exposed veterans with and without PTSD to characterize the differences in regulatory effects. MCA revealed mechanistic association of the HPA axis and inflammation with metabolic dysfunction consistent with PTSD. This was supported by the data using correlational and causal analysis that revealed significant associations between cortisol suppression, high-sensitivity C-reactive protein, homeostatic model assessment of insulin resistance, γ-glutamyltransferase, hypoxanthine, and several metabolites. Causal mediation analysis indicates that the effects of enhanced glucocorticoid receptor sensitivity (GRS) on glycolytic pathway, gluconeogenic and branched-chain amino acids, triglycerides, and hepatic function are jointly mediated by inflammation, insulin resistance, oxidative stress, and energy deficit. Our analysis suggests that the interventions to normalize GRS and inflammation may help to manage features of metabolic dysfunction in PTSD.

COGNITIVE AND NEURAL MECHANISMS OF THE ACCELERATED AGING PHENOTYPE IN PTSD

Introduction Posttraumatic Stress Disorder (PTSD) affects 6.8% of adults in the United States and is associated with high rates of disability, comorbid medical and psychiatric disorders, and suicide. Older adults make up an increasingly large proportion of PTSD patients as the population skews older and Veterans from recent conflicts age. PTSD in older adults is often chronic, leads to increased mortality from cardiovascular disease and other medical conditions, and promotes adverse aging associated syndromes such as frailty. Moreover, older PTSD patients exhibit faster cognitive decline and have twice the risk of dementia compared to individuals without PTSD. Accelerated biological aging may explain these findings, as PTSD is associated with similar brain changes to those occurring with cognitive aging, including bilateral hippocampal volume reductions specifically in the cornu ammonis 3 (CA3) and dentate gyrus (DG) sub-regions and increased microvascular lesions (white matter hyperintensities). The goal of this presentation is to describe ongoing work from our laboratories characterizing the mechanisms by which PTSD accelerates aging cognitively and physically. We will present data linking cognitive dysfunction in PTSD with indicators of brain health such as DG CBV and increased white matter hyperintensities and physical decline with increased levels of inflammation and oxidative stress. Methods To date. N=17 adults 50 years and older with PTSD and N=9 trauma exposed healthy controls (TEHCs) have undergone testing to assess cognitive function and physical performance. Neuropsychological testing and magnetic resonance imaging (MRI) including cerebral blood volume (CBV)-fMRI were used to assess cognitive function and brain health. Neuropsychology testing included a modified form of the Benton Visual Retention Task (ModBent), a task that has been validated as a measure of DG function relative to age. Tasks such as gait speed and tests of strength, including grip strength and the short physical performance battery, were used to assess physical decline. Inflammatory markers IL-6, CRP, and telomere length, and urinary isoprostanes, a measure of oxidative stress, were also used to examine physical decline. Measures were compared between the PTSD patients and trauma exposed healthy controls. We expect to substantially increase the sample size available for presentation by the time of the Annual Meeting. Results Enrolled PTSD subjects to date show deficits in every cognitive domain when compared to the TEHC, particularly on measures of processing speed and executive function, where their performance is > 1 SD below that of age-matched TEHCs. CBV fMRI (N=15) analyzed to date shows PTSD patients to have diminished DG CBV compared to TEHC, and lower DG CBV is associated with increasing symptom severity as measured by the Clinician Administered PTSD Scale (r=-0.49). Reaction time on ModBent increased (worsened) with increasing symptom severity (r=0.50). Overall hippocampus volume is smaller in PTSD patients than TEHC (d=-.23), although PTSD patients have on average greater ICV (d=0.30). PTSD patients also display deficits in every physical performance task compared to the TEHC patients and report reduced physical activity and worse physical conditions. PTSD patients have higher levels of inflammatory markers IL-6 (d=0.18) and CRP (d=0.25) as well as urinary isoprostanes (d=0.05), a marker of oxidative stress. Conclusions These data indicate that PTSD, particularly chronic PTSD, is associated with unhealthy aging trajectories. These findings are consistent with the hypothesis that older adults with PTSD have marked neurocognitive and physiologic performance decrements compared to age-matched TEHC. This research was funded by NIMH. PDF: http://submissions.mirasmart.com/Verify/AAGP2019/Original/AAGP2019-000325/AAGP2019-000325_Fig1.pdf

Functional rs6265 polymorphism in the brain‐derived neurotrophic factor gene confers protection against neurocognitive dysfunction in posttraumatic stress disorder among Chinese patients with hepatocellular carcinoma

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that plagues trauma survivors. Evidence shows that brain-derived neurotrophic factor (BDNF) may be involved in the occurrence and development of PTSD. Here we tried to demonstrate whether BDNF gene polymorphisms are correlated with neurocognitive function following PTSD in patients with hepatocellular carcinoma (HCC). This study included 102 patients withHCC complicated with PTSD, 146 HCC patients, and 152 healthy volunteers. Initially, we evaluated the neurocognitive function of the study subjects. Next, we measured BDNF G11757C and rs6265 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. The correlation of BDNF polymorphisms and BDNF level with HCC complicated with PTSD was evaluated. The results revealed that HCC complicated with PTSD showed decreased serum BDNF level and Mini-mental state examination (MMSE) score. Serum BDNF level of HCC and HCC complicated with PTSD was positively correlated with MMSE score. GA + AA allele and A allele of rs6265 increased the risk of PTSD among patients with HCC. GA and AA genotypes of rs6265 were correlated with the decreased MMSE score of HCC complicated with PTSD. Haplotype GA of rs6265 and G11757C increased the risk of PTSD for HCC, while haplotype CG decreased this risk. Lastly, the logistic regression analysis suggested that low BDNF level was a contributor to HCC complicated with PTSD, while GG genotype of rs6265 served as a protective factor. Collectively, this study defines the GG genotype of BDNF rs6265 polymorphism as a protector to HCC complicated with PTSD. In addition, these results provided a promising target for PTSD prevention in patients with HCC.

Trauma exposure acutely alters neural function during Pavlovian fear conditioning

Posttraumatic stress disorder (PTSD) is associated with dysfunction of the neural circuitry that supports fear learning and memory processes. However, much of what is known about neural dysfunction in PTSD is based on research in chronic PTSD populations. Less is known about neural function that supports fear learning acutely following trauma exposure. Determining the acute effects of trauma exposure on brain function would provide new insight into the neural processes that mediate the cognitive-affective dysfunction associated with PTSD. Therefore, the present study investigated neural activity that supports fear learning and memory processes in recently Trauma-Exposed (TE) and Non-Trauma-Exposed (NTE) participants. Participants completed a Pavlovian fear conditioning procedure during functional magnetic resonance imaging (fMRI). During fMRI, participants’ threat expectancy was continuously monitored. NTE participants showed greater threat expectancy during warning than safety cues, while no difference was observed in the TE group. This finding suggests TE participants overgeneralized the fear association to the safety cue. Further, only the TE group showed a negative relationship between fMRI signal responses within dorsomedial prefrontal cortex (PFC) and threat expectancy during safety cues. These results suggest the dorsomedial PFC mediates overgeneralization of learned fear as an acute result of trauma exposure. Finally, neural activity within the PFC and inferior parietal lobule showed a negative relationship with PTSD symptom severity assessed three months posttrauma. Thus, neural activity measured acutely following trauma exposure predicted future PTSD symptom severity. The present findings elucidate the acute effects of trauma exposure on cognitive-affective function and provide new insight into the neural mechanisms of PTSD.