Trauma-exposed Healthy Controls Research Articles

Application of machine learning techniques in the diagnostic approach of PTSD using MRI neuroimaging data: A systematic review

BackgroundAt present, the diagnosis of post-traumatic stress disorder（PTSD） mainly relies on clinical symptoms and psychological scales, and finding objective indicators that are helpful for diagnosis has always been a challenge in clinical practice and academic research. Neuroimaging is a useful and powerful tool for discovering the biomarkers of PTSD,especially functional MRI (fMRI), structural MRI (sMRI) and Diffusion Weighted Imaging（DTI）are the most commonly used technologies, which can provide multiple perspectives on brain function, structure and its connectivity. Machine learning (ML) is an emerging and potentially powerful method, which has aroused people's interest because it is used together with neuroimaging data to define brain structural and functional abnormalities related to diseases, and identify phenotypes, such as helping physicians make early diagnosis. ObjectivesAccording to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) declaration, a systematic review was conducted to assess its accuracy in distinguishing between PTSD patients, TEHC(Trauma-Exposed Healthy Controls), and HC(healthy controls). MethodsWe searched PubMed, Embase, and Web of Science using common words for ML methods and PTSD until June 2023, with no language or time limits. This review includes 13 studies, with sensitivity, specificity, and accuracy taken from each publication or acquired directly from the authors. ResultsAll ML techniques have an diagnostic accuracy rate above 70%，and support vector machine（SVM） are the most commonly used techniques. This series of studies has revealed significant neurobiological differences in key brain regions among individuals with PTSD, TEHC, and HC. The connectivity patterns of regions such as the Insula and Amygdala hold particular significance in distinguishing these groups. TEHC exhibits more normal connectivity patterns compared to PTSD, providing valuable insights for the application of machine learning in PTSD diagnosis. ConclusionIn contrast to any currently available assessment and clinical diagnosis, ML techniques can be used as an effective and non-invasive support for early identification and detection of patients as well as for early screening of high-risk populations.

Tobacco withdrawal-induced changes in sensorimotor filtering as a predictor of smoking lapse in trauma-exposed individuals

Prepulse inhibition (PPI) is a measure of sensorimotor filtering thought to shield the processing of initial weaker auditory stimuli from interruption by a later startle response. Previous studies have shown smoking withdrawal to have a negative impact on sensorimotor filtering, particularly in individuals with psychopathology. Because tobacco use may alleviate sensory and sensorimotor filtering deficits, we examined whether smoking withdrawal-induced changes in PPI were associated with maintenance of smoking abstinence in trauma-exposed individuals with and without PTSD who were attempting to quit smoking. Thirty-eight individuals (n = 24 with current or past PTSD; 14 trauma-exposed healthy controls) made an acute biochemically-verified smoking cessation attempt supported by 8 days of contingency management (CM) and cognitive behavioral therapy (CBT) for smoking. Participants completed a PPI task at the pre-quit baseline, 2 days post-quit, and 5 days post-quit. Post-quit changes in PPI were compared between those who remained abstinent for the first 8-days of the quit attempt and those who lapsed back to smoking. PPI changes induced by biochemically-verified smoking abstinence were associated with maintenance of abstinence across the 8-day CM/CBT-supported quit attempt. As compared to those who maintained tobacco abstinence, participants who lapsed to smoking had significantly lower PPI at 2 and 5 days post-quit relative to baseline. Thus, among trauma-exposed individuals, decreases in PPI during acute smoking cessation supported by CM/CBT are associated with lapse back to smoking. Interventions that improve PPI during early smoking abstinence may facilitate smoking cessation among such individuals who are at high risk for chronic, refractory tobacco use.

Eye-tracking indices of attention allocation and attention bias variability are differently related to trauma exposure and PTSD

Amplified attention allocation to negative information in one’s environment has been implicated in posttraumatic stress disorder (PTSD). Attention bias variability (ABV), the magnitude of attention fluctuation between negative and neutral cues, has also been found to be elevated in PTSD. While eye-tracking methodology has been used in research on attention allocation in PTSD, ABV was only explored using manual reaction-time-based indices. Thirty-seven participants with PTSD, 34 trauma-exposed healthy controls (TEHC), and 30 non-exposed healthy controls (HC) completed an eye-tracking free-viewing task in which matrices comprised of neutral and negatively-valenced faces were presented. Threat-related attention allocation was calculated as the proportion of dwell time (DT%) on negatively-valenced faces. Eye-tracking-based ABV was calculated as the standard deviation of DT% across matrices. DT% on negatively-valenced faces was greater in participants with PTSD compared to both TEHC (p = .036, d = 0.50) and HC (p < .001, d = 1.03), with TEHCs showing a greater attentional bias compared to HCs (p = .001, d = 0.84). Controlling for average fixation duration, ABV was higher in both the PTSD and TEHC groups relative to the HC group (p = .004, d = 0.40), with no difference between the two trauma-exposed groups. Biased attention allocation toward negative social information is related to PTSD pathology, whereas elevated ABV measured with eye-tracking appear to be related to trauma-exposure per-se.

Attentional bias toward negative stimuli in PTSD: an eye-tracking study.

Research on biased processing of aversive stimuli in posttraumatic stress disorder (PTSD) has produced inconsistent results between response time (RT) and eye-tracking studies. Recent RT-based results of dot-probe studies showed no attentional bias (AB) for threat while eye-tracking research suggested heightened sustained attention for this information. Here, we used both RT-based and eye-tracking measures to explore the dynamics of AB to negative stimuli in PTSD. Twenty-three individuals diagnosed with PTSD, 23 trauma-exposed healthy controls, and 23 healthy controls performed an emotional dot-probe task with pairs of negative and neutral scenes presented for either 1 or 2 s. Analyses included eye movements during the presentation of the scenes and RT associated with target localization. There was no evidence for an AB toward negative stimuli in PTSD from RT measures. However, the main eye-tracking results revealed that all three groups showed longer dwell times on negative pictures than neutral pictures at 1 s and that this AB was stronger for individuals with PTSD. Moreover, although AB disappeared for the two groups of healthy controls with prolonged exposure, it persisted for individuals with PTSD. PTSD is associated with an AB toward negative stimuli, characterized by heightened sustained attention toward negative scenes once detected. This study sheds light on the dynamics of AB to negative stimuli in PTSD and encourages us to consider optimized therapeutic interventions targeting abnormal AB patterns.

Structural brain features signaling trauma, PTSD, or resilience? A systematic exploration.

Studies have searched for neurobiological markers of trauma exposure, posttraumatic stress disorder (PTSD) diagnosis, and resilience to trauma to identify therapeutic targets for PTSD. Despite some promising results, findings are inconsistent. The present study adopted a data-driven approach to systematically explore whether structural brain markers of trauma, PTSD, or resilience emerge when all are explored. Differences between clusters in the proportion of PTSD, healthy controls (HC), and trauma-exposed healthy controls (TEHC) served to indicate the presence of PTSD, trauma, and resilience markers, respectively. A total of 129 individuals, including 46 with PTSD, 49 TEHCs, and 34 HCs not exposed to trauma were scanned. Volumes, cortical thickness, and surface areas of interest were obtained from T1 structural MRI and used to identify data-driven clusters. Two clusters were identified, differing in the proportion of TEHCs but not of PTSDs or HCs. The cluster with the higher proportion of TEHCs, referred to as the resilience cluster, was characterized by higher volume in brain regions implicated in trauma exposure, especially the thalamus and rostral middle frontal gyrus. Cross-validation established the robustness and consistency of the identified clusters. Findings support the existence of structural brain markers of resilience.

Influences of Aging on PTSD Prevalence, Neurobiology, and Clinical Course

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. Recent studies report increasing prevalence rates of PTSD among older adults, and this pattern is anticipated to accelerate as the population skews older and Veterans from recent conflicts age. Most older adults suffer from chronic PTSD, which is associated with at least one disability in nearly 80% of cases. Compared to those without PTSD, individuals with chronic PTSD have exceedingly high rates of Major Depressive Disorder (MDD), triple the rates of drug abuse, and significant functional impairment. Prompt diagnosis and treatment of PTSD in later life is complicated by its differing phenomenology in older compared to younger adults and age-related changes in treatment seeking. Whereas overall symptom severity, intrusive thoughts, and avoidance behaviors are lower among older adults with PTSD, they more frequently report somatic problems (e.g., pain, insomnia, gastrointestinal upset) relative to emotional issues (e.g., specific aspects of the trauma). Older patients may not spontaneously report traumatic experiences or minimize their importance, use generic terms such as “stress”, and generally present to primary medical doctors rather than specialty mental health settings. In terms of treatment, few studies of exposure-based psychotherapies are randomized, older adults are rarely enrolled, and almost none evaluate the most evidence-based psychotherapy for PTSD, Prolonged Exposure therapy. Analyses of prescribing trends using Veterans Affairs (VA) databases suggest that only about half of veterans (all ages) with PTSD receive first-line pharmacotherapy agents such as selective serotonin reuptake inhibitors (SSRIs), with even lower medication prescription in older compared to younger adults.In this symposium the influence of age-related factors will be discussed on the prevalence, development of PTSD given a traumatic stimulus, clinical presentation in terms of symptom profiles, underlying neurobiology, treatment responsivity, and illness course. Speakers will engage the audience in a discussion of what makes PTSD different in older adults compared to younger adults and what are the implications of these differences on clinical evaluation and treatment. Dr. Joan Cook will present data comparing characteristics of younger vs. older sexual assault survivors in order to discuss clinical and research implications. Next, Dr. Vanessa Simiola will present electronic health record and utilization data and discuss age-based differences between diagnoses made in primary care versus specialty mental health, differences in mental health treatment receipt, as well as clinical characteristics of the samples. Then, Dr. Xi Zhu will delve into data suggesting higher rates of MDD in older adults with PTSD and present her analyses of network connectivity differences discriminating PTSD from comorbid PTSD/MDD. Finally, Dr. Bret Rutherford will present data from an ongoing NIMH study in which older adults with PTSD are compared to trauma-exposed healthy controls (TEHCs) on cognitive, physical functioning, and neuroimaging indices. Two-year follow up data will be reviewed to consider the differing cognitive and physical functioning trajectories experienced over time between PTSD and TEHC participants. Finally, an audience discussion synthesizing all three of the talks will be held, with ample opportunity for audience members to ask questions of each speaker.

Blood-Based Biomarkers for Alzheimer's Disease in Older Adults with Posttraumatic Stress Disorder.

Background:Posttraumatic stress disorder (PTSD) is associated with cognitive decline and risk for dementia, but the neuropathology involved is unclear.Objective:The aim of this study was to determine whether PTSD is associated with increased levels of Alzheimer’s disease (AD) blood-based biomarkers.Methods:Individuals aged 50 years and older with PTSD were compared to trauma-exposed healthy controls (TEHCs) at baseline on serum measures of amyloid-β (Aβ) 42 and 40 levels, the Aβ42/Aβ40 ratio, and total tau. Serum was analyzed using ultrasensitive Simoa Human Neurology 3-Plex A assay (N3PA). Linear regressions modeling each AD biomarker as a function of group were used to investigate between-group differences, controlling for age, sex, and educational attainment (years).Results:TEHC participants (N = 26) were 53.8% male with mean age 66.8±10.7, whereas PTSD participants (N = 44) were 47.7% male and aged 62.5±9.1 years. No between-group differences were noted on demographic characteristics or cognitive performance measured with the NIH Toolbox Cognition Battery. There were no significant between-group differences in serum Aβ40 (TEHC 105.8±51.6 versus PTSD 93.2±56.1, p = 0.46), Aβ42 (TEHC 8.1±4.6 versus PTSD 7.8±4.6, p = 0.63), Aβ42/Aβ40 (TEHC 0.08±0.03 versus PTSD 0.09±0.03, p = 0.27), or total tau (TEHC 0.5±0.3 versus PTSD 0.5±0.4, p = 0.77). Likewise, there were no significant interaction effects of amyloid or tau serum concentrations and PTSD group status on cognitive functioning.Conclusion:Findings from cognitive assessments and serum analyses do not support PTSD-induced neurodegeneration of the Alzheimer’s type as a pathway linking PTSD to increased incidence of dementia in older adults.

Right parahippocampal volume deficit in an older population with posttraumatic stress disorder

BackgroundPosttraumatic Stress Disorder (PTSD) is an increasingly prevalent condition among older adults and may escalate further as the general population including veterans from recent conflicts grow older. Despite growing evidence of higher medical comorbidity, cognitive impairment and dementia, and disability in older individuals with PTSD, there are very few studies examining brain cortical structure in this population. Hence, we examined cortical volumes in a cross-sectional study of veterans and civilians aged ≥50 years, of both sexes and exposed to trauma (interpersonal, combat, non-interpersonal). MethodsCortical volumes were obtained from T1-weighted structural MRI and compared between individuals with PTSD and Trauma Exposed Healthy Controls (TEHC) adjusting for age, sex, estimated intracranial volume, depression severity, and time elapsed since trauma exposure. ResultsThe PTSD group (N = 55) had smaller right parahippocampal gyrus compared to TEHC (N = 36), corrected p(pFWER) = 0.034, with an effect size of 0.75 (Cohen's d), with no significant group differences in other cortical areas. ConclusionsThese findings are different from the structural brain findings reported in studies in younger age groups (larger parahippocampal volume in PTSD patients), suggesting a possible significant change in brain structure as PTSD patients age. These results need replication in longitudinal studies across the age-span to test whether they are neuroanatomical markers representing disease vulnerability, trauma resilience or pathological neurodegeneration associated with cognitive impairment and dementia.

Attention allocation in posttraumatic stress disorder: an eye-tracking study.

Eye-tracking-based attentional research implicates sustained attention to threat in posttraumatic stress disorder (PTSD). However, most of this research employed small stimuli set-sizes, small samples that did not include both trauma-exposed healthy participants and non-trauma-exposed participants, and generally failed to report the reliability of used tasks and attention indices. Here, using an established eye-tracking paradigm, we explore attention processes to different negatively-valenced cues in PTSD while addressing these limitations. PTSD patients (n = 37), trauma-exposed healthy controls (TEHC; n = 34), and healthy controls (HC; n = 30) freely viewed three blocks of 30 different matrices of faces, each presented for 6 s. Each block consisted of matrices depicting eight negatively-valenced faces (anger, fear, or sadness) and eight neutral faces. Gaze patterns on negative and neural areas of interest were compared. Internal consistency and test-retest reliability were evaluated for the entire sample and within groups. The two trauma-exposed groups dwelled longer on negatively-valenced faces over neutral faces, while HC participants showed the opposite pattern. This attentional bias was more prominent in the PTSD than the TEHC group. Similar results emerged for first-fixation dwell time, but with no differences between the two trauma-exposed groups. No group differences emerged for first-fixation latency or location. Internal consistency and 1-week test-retest reliability were adequate, across and within groups. Sustained attention on negatively-valenced stimuli emerges as a potential target for therapeutic intervention in PTSD designed to divert attention away from negatively-valenced stimuli and toward neutral ones.

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

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. In this preliminary study, we examined whether plasma GABA levels differed between women with PTSD and trauma-exposed healthy controls. 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). 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. 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.

Connectome-based functional connectivity markers of suicide attempt

BackgroundFunctional brain markers of suicidality can help identify at-risk individuals and uncover underlying neurocognitive mechanism(s). Although some converging evidence has implicated dysfunction in several brain networks, suicide-related neuroimaging markers are inconsistent across studies, due to heterogeneity of neuroimaging approaches, clinical populations, and experimental methods. MethodsThe current study aimed to address these limitations by examining resting-fMRI connectivity in a sample of post-9/11 veterans with a past suicide attempt (SA; n = 16) compared to a psychiatric control group (PC; n = 124) with no SA history but comparable past and present symptomatology, as well as a trauma control group (TC; n = 66) of trauma-exposed healthy controls. We used both a novel graph-analytic and seed-based approach to characterize SA-related connectivity differences across brain networks. ResultsFirst, the graph-analytic approach identified the right amygdala and a region in the cognitive control network (right middle temporal gyrus; MTG) as regional SA-related hubs of dysfunction (HoD), or regions that exhibited a high number of SA-related connections. Aberrant SA-related connectivity between these hubs spanned multiple networks, including the cognitive control, default mode and visual networks. Second, the seed-based connectivity analysis that identifies SA-related differences in the strength of neural connections across the whole brain further implicated the right amygdala. LimitationsSmall sample size and potential underreporting of SA. ConclusionsThese two analytic approaches preliminarily suggest that the right amygdala and right MTG may be specific neural markers of SA that can be differentiated from neural markers of psychopathology more broadly.

Composite contributions of cerebrospinal fluid GABAergic neurosteroids, neuropeptide Y and interleukin-6 to PTSD symptom severity in men with PTSD

Given that multiple neurobiological systems, as well as components within these systems are impacted by stress, and may interact in additive, compensatory and synergistic ways to promote or mitigate PTSD risk, severity, and recovery, we thought that it would be important to consider the collective, as well as separate effects of these neurobiological systems on PTSD risk. With this goal in mind, we conducted a proof-of-concept study utilizing cerebrospinal fluid (CSF) collected from unmedicated, tobacco- and illicit substance-free men with PTSD (n = 13) and trauma-exposed healthy controls (TC) (n = 17). Thirteen neurobiological factors thought to contribute to PTSD risk or severity based on previous studies were assayed. As the small but typical sample size of this lumbar puncture study limited the number of factors that could be considered in a hierarchical regression model, we included only those five factors with at least a moderate correlation (Spearman rho > 0.30) with total Clinician-Administered PTSD Scale (CAPS-IV) scores, and that did not violate multicollinearity criteria. Three of the five factors meeting these criteria—CSF allopregnanolone and pregnanolone (Allo + PA: equipotent GABAergic metabolites of progesterone), neuropeptide Y (NPY), and interleukin-6 (IL-6)—were found to account for over 75% of the variance in the CAPS-IV scores (R2 = 0.766, F = 8.75, p = 0.007). CSF Allo + PA levels were negatively associated with PTSD severity (β = −0.523, p = 0.02) and accounted for 47% of the variance in CAPS-IV scores. CSF NPY was positively associated with PTSD severity (β = 0.410, p = 0.04) and accounted for 14.7% of the CAPS-IV variance. There was a trend for a positive association between PTSD severity and CSF IL-6 levels, which accounted for 15.3% of the variance in PTSD severity (β = 0.423, p = 0.05). Z-scores were then computed for each of the three predictive factors and used to depict the varying relative degrees to which each contributed to PTSD severity at the individual PTSD patient level. This first of its kind, proof-of-concept study bears replication in larger samples. However, it highlights the collective effects of dysregulated neurobiological systems on PTSD symptom severity and the heterogeneity of potential biological treatment targets across individual PTSD patients—thus supporting the need for precision medicine approaches to treatment development and prescribing in PTSD.

Multivariate classification of earthquake survivors with post-traumatic stress disorder based on large-scale brain networks.

The identification of post-traumatic stress disorder (PTSD) among natural disaster survivors is remarkably challenging, and there are no reliable objective signatures that can be used to assist clinical diagnosis and optimize treatment. The current study aimed to establish a neurobiological signature of PTSD from the connectivity of large-scale brain networks and clarify the brain network mechanisms of PTSD. We examined fifty-seven unmedicated survivors with chronic PTSD and 59 matched trauma-exposed healthy controls (TEHCs) using resting-state functional magnetic resonance imaging (rs-fMRI). We extracted the node-to-network connectivity and obtained a feature vector with a dimensionality of 864 (108 nodes×8 networks) to represent each subject's functional connectivity (FC) profile. Multivariate pattern analysis with a relevance vector machine was then used to distinguish PTSD patients from TEHCs. We achieved a promising diagnostic accuracy of 89.2% in distinguishing PTSD patients from TEHCs. The most heavily weighted connections for PTSD classification were among the default mode network (DMN), visual network (VIS), somatomotor network, limbic network, and dorsal attention network (DAN). The strength of the anticorrelation of FC between the ventral medial prefrontal cortex (vMPFC) in DMN and the VIS and DAN was associated with the severity of PTSD. This study achieved relatively high accuracy in classifying PTSD patients vs. TEHCs at the individual level. This performance demonstrates that rs-fMRI-derived multivariate classification based on large-scale brain networks can provide potential signatures both to facilitate clinical diagnosis and to clarify the underlying brain network mechanisms of PTSD caused by natural disasters.

Altered amygdala subregion-related circuits in treatment-naïve post-traumatic stress disorder comorbid with major depressive disorder

Individuals with both post-traumatic stress disorder and major depressive disorder (PTSD+MDD) often show greater social and occupational impairment and poorer treatment response than individuals with PTSD alone. Increasing evidence reveals that the amygdala, a brain region implicated in the pathophysiology of both of these conditions, is a complex of structurally and functionally heterogeneous nuclei. Quantifying the functional connectivity of two key amygdala subregions, the basolateral (BLA) and centromedial (CMA), in PTSD+MDD and PTSD-alone could advance our understanding of the neurocircuitry of these conditions. 18 patients with PTSD+MDD, 28 with PTSD-alone, and 50 trauma exposed healthy controls (TEHC), all from a cohort who survived the same large earthquake in China, underwent resting-state functional magnetic resonance imaging. Bilateral BLA and CMA functional connectivity (FC) maps were created using a seed-based approach for each participant. The analysis of covariance of FC was used to determine between-group differences. A significant interaction between amygdala subregion and diagnostic group suggested that differences in connectivity patterns between the two seeds were mediated by diagnosis. Post-hoc analyses revealed that PTSD+MDD patients showed weaker connectivity between right BLA and (a) left anterior cingulate cortex/supplementary motor area, and (b) bilateral putamen/pallidum, compared with PTSD-alone patients. Higher CMA connectivities left ACC/SMA were also observed in PTSD+MDD compared with PTSD-alone. An inverse relationship between the connectivity of right BLA with right putamen/pallidum and MDD symptoms was found in PTSD+MDD. These findings indicate a relationship between the neural pathophysiology of PTSD+MDD compared with PTSD-alone and TEHC and may inform future clinical interventions.

Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies.

Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers. Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall. Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis. Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of 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

Increased functional segregation of brain network associated with symptomatology and sustained attention in chronic post-traumatic stress disorder

BackgroundTraditional regional or voxel-based analyses only focus on specific brain regions or connectivity rather than the whole brain's functional organization. Using resting state functional magnetic resonance imaging (rs-fMRI), we aimed to explore the altered topological metrics, clinical symptoms and cognitive function in chronic post-traumatic stress disorder (PTSD) in order to identify the brain network mechanisms underlying these clinical and cognitive symptoms. MethodsForty patients with unmedicated chronic PTSD and forty-two matched trauma-exposed healthy controls (TEHCs) underwent rs-fMRI, and the topological organization of the whole-brain network was calculated using graph theory. The Rapid Visual Information Processing (RVP) task and Wechsler Memory Scale-IV (WMS-IV) were used to evaluate the subjects’ sustained attention and memory capacity. All clinical and cognitive measures and topological parameters of the PTSD patients and TEHCs were compared, and the relationships between altered network metrics and symptom severity were explored. ResultsCompared with the TEHCs, the patients showed increases in the normalized clustering coefficient, small-worldness, normalized local efficiency and efficiency-based small-worldness. The left middle occipital gyrus showed increases in nodal global efficiency and nodal degree that were negatively correlated with the severity of PTSD symptoms. The altered connections in PTSD only involved the default mode network (DMN) and the occipital network. LimitationsComorbid conditions were included, and current cross-sectional study cannot conclude on causality. ConclusionsPatients with chronic PTSD showed increased functional brain network segregation, mainly in the occipital cortex, which could be a protective or compensatory mechanism to alleviate clinical symptoms.

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD

Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABAA receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC–MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC–MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ=-0.74, p = 0.006) and CAPS-IV derived Simms dysphoria cluster (ρ=-0.71, p = 0.01) scores. The allo+pregnan to DHEA ratio also was negatively correlated with total CAPS (ρ=-0.74, p = 0.006) and dysphoria cluster (ρ=-0.79, p = 0.002) scores. A PTSD-related decrease in the 5α-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5α-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5α-reductase and 3α-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.

Exposure-based therapy changes amygdala and hippocampus resting-state functional connectivity in patients with posttraumatic stress disorder.

Recent research suggests that posttraumatic stress disorder (PTSD) is associated with altered amygdala and hippocampal resting-state functional connectivity (rsFC). However, less research has examined whether Prolonged Exposure (PE), a first line exposure-based treatment for PTSD, has the potential to alter resting state neural networks. A total of 24 patients with PTSD and 26 matched trauma-exposed healthy controls (TEHCs) underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. PTSD patients were scanned a second time after completing 10-session PE in which patients narrated a detailed trauma account (imaginal exposure) and confronted trauma reminders (in vivo exposure) to extinguish trauma-related fear responses. TEHC were scanned again following a 10-week waiting period. Seed regions of interest (ROIs) included centromedial amygdala (CMA), basolateral amygdala (BLA), and the hippocampus. Post- versus pretreatment comparisons indicated increased rsFC of the BLA and CMA with the orbitofrontal cortex (OFC), and hippocampus-medial prefrontal cortex (mPFC) among patients with PTSD, but not among TEHC participants. Enhanced amygdala and hippocampus rsFC with prefrontal cortical regions following PE could underlie improved capacity for inhibition and re-evaluation of threat, and heightened memory encoding and retrieval ability, respectively. These findings encourage further investigation of this circuitry as a therapeutic target in PTSD.

P.4.e.008 - Sex-dependent differences in oxytocin receptor gene methylation between posttraumatic stress disorder patients and trauma-exposed healthy controls

P.4.e.008 - Sex-dependent differences in oxytocin receptor gene methylation between posttraumatic stress disorder patients and trauma-exposed healthy controls