Function In Posttraumatic Stress Disorder Research Articles

Reward functioning in posttraumatic stress disorder, metabolic syndrome, and psychological resilience

BackgroundReward system dysfunction may play a role in the comorbidity of metabolic syndrome (MetS) in posttraumatic stress disorder (PTSD). Psychological resilience, through its effects on the reward system, may modulate outcomes in PTSD. Utilising a monetary incentive delay task during functional magnetic resonance imaging in a case-control study (PTSD, n = 88, trauma-exposed controls [TEC], n = 85), we aimed to investigate reward system function in relation to PTSD, MetS, and psychological resilience. MethodsUsing repeated measures analysis of variance, we assessed change in activation in the ventral striatum (VS) during reward anticipation and in the orbitofrontal cortex (OFC) during reward outcome, in relation to PTSD, MetS, and psychological resilience, controlling for possible confounders including depression severity, childhood trauma and trauma load. ResultsActivation in the VS and OFC didn't differ in relation to PTSD and MetS. When we controlled for depression severity, PTSD cases had significantly lower activation in the VS and a greater increase in activation in the OFC compared to TEC. Psychological resilience was significantly associated with decreased change in activation in the VS and increased change in activation in the OFC. We also observed a greater increase in activation during reward outcome in the OFC in those with greater childhood trauma exposure and those with exposure to fewer lifetime traumatic events. ConclusionsThe effects of depression and psychological resilience on reward system function in PTSD can be utilised towards developing interventions targeted at altering positive valence systems in PTSD.

Unveiling the link between glymphatic function and cortical microstructures in post-traumatic stress disorder

PurposeThe discovery of the glymphatic system, crucial for cerebrospinal and interstitial fluid exchange, has enhanced our grasp of brain protein balance and its potential role in neurodegenerative disease prevention and therapy. Detecting early neurodegenerative shifts via noninvasive biomarkers could be key in identifying at-risk individuals for Alzheimer's disease (AD). Our research explores a diffusion tensor imaging (DTI) method that measures cortical mean diffusivity (cMD), potentially a more sensitive indicator of neurodegeneration than traditional macrostructural methods. Materials and methodsWe analyzed 67 post-traumatic stress disorder (PTSD)-diagnosed veterans from the Alzheimer's Disease Neuroimaging Initiative database. Participants underwent structural MRI, DTI, Aβ PET imaging, and cognitive testing. We focused on the DTI-ALPS technique to assess glymphatic function and its relation to cMD, cortical Aβ accumulation, and thickness, accounting for age and APOE ε4 allele variations. ResultsThe cohort, all male with an average age of 68.1 (SD 3.4), showed a strong inverse correlation between DTI-ALPS and cMD in AD-affected regions, especially in the entorhinal, parahippocampal, and fusiform areas. Higher DTI-ALPS readings were consistently linked with greater cortical thickness, independent of Aβ deposits and genetic risk factors. Age and cMD emerged as inversely proportional predictors of DTI-ALPS, indicating a complex interaction with age. ConclusionThe study confirms a meaningful association between glymphatic efficiency and cMD in AD-sensitive zones, accentuating cortical microstructural alterations in PTSD. It positions DTI-ALPS as a viable biomarker for assessing glymphatic function in PTSD, implicating changes in DTI-ALPS as indicative of glymphatic impairment.

Executive functioning in posttraumatic stress disorder: Understanding how inhibition, switching, and test modality affect reaction times.

Posttraumatic stress disorder (PTSD) has been linked to deficits in executive functioning, but the literature suggests these associations are inconsistent. Results vary depending on the task used, test modality, and the specific subdomain being measured, such as inhibitory control (interference resolution, response inhibition) or set shifting (task switching, rule switching). Notably, deficits are more consistently observed in computerized tasks that measure precise reaction times (RTs) than in classic paper-and-pencil measures, but few studies have parsed specific executive functioning deficits in PTSD using detailed analyses of RT data. The present study used a cued-switching Stroop Task to examine both interference resolution and task switching in 28 veterans with PTSD and 28 age-matched controls. Each trial required attending to a randomly presented cue and responding to the specified target while ignoring irrelevant or opposing information. Analyses of RT distributions estimated both Gaussian (normal) and ex-Gaussian (exponential) parameters. Veterans with PTSD had slower and more variable RTs than the controls on trials that required ignoring conflicting information (interference resolution, d' = .68). These effects were confined to the normal distribution, not to excessively slow responses (as estimated by ex-Gaussian parameters). Veterans with PTSD also showed modestly slower RTs on trials that required switching between cues, but Bayesian evidence for this was weak, and measures by ex-Gaussian parameters were not significant. These results highlight the importance of examining executive functioning in PTSD with a more nuanced approach, as clarity around these deficits may have important implications for future intervention and rehabilitation strategies. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Evidence for Locus Coeruleus–Norepinephrine System Abnormality in Military Posttraumatic Stress Disorder Revealed by Neuromelanin-Sensitive Magnetic Resonance Imaging

BackgroundThe complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment. One such alteration could be an overactive locus coeruleus (LC)–norepinephrine system, which may be linked to hyperarousal symptoms, a characteristic and burdensome aspect of the disorder. MethodsStudy participants were Canadian Armed Forces veterans with PTSD related to deployment to combat zones (n = 34) and age- and sex-matched healthy control participants (n = 32). Clinical measures included the Clinician-Administered PTSD Scale for DSM-5, and neuroimaging measures included a neuromelanin-sensitive magnetic resonance imaging scan to measure the LC signal. Robust linear regression analyses related the LC signal to clinical measures. ResultsCompared with control participants, the LC signal was significantly elevated in the PTSD group (t62 = 2.64, p = .010), and this group difference was most pronounced in the caudal LC (t56 = 2.70, Cohen’s d = 0.72). The caudal LC signal was also positively correlated with the severity of Clinician-Administered PTSD Scale for DSM-5 hyperarousal symptoms in the PTSD group (t26 = 2.16, p = .040). ConclusionsThese findings are consistent with a growing body of evidence indicative of elevated LC-norepinephrine system function in PTSD. Furthermore, they indicate the promise of neuromelanin-sensitive magnetic resonance imaging as a noninvasive method to probe the LC-norepinephrine system that has the potential to support subtyping and treatment of PTSD or other neuropsychiatric conditions.

0228 Using Blue Light Therapy to Facilitate Recovery of Sleep and Psychological Functioning in PTSD

Abstract Introduction Sleep problems are often described as the “hallmark symptoms” of post-traumatic stress disorder (PTSD). Patients with PTSD show numerous disruptions of emotional functioning. Experimental evidence has shown that the ability to retain extinction memories following fear conditioning is impaired in people with PTSD. Because of the key role of sleep in memory consolidation and emotional regulation, we hypothesized that regulating sleep and circadian rhythms with morning blue-wavelength light therapy would facilitate emotional recovery and the ability to retain extinction memories. Methods Eighty-four individuals with PTSD (56 female; Age=31.38, SD=8.9) underwent a well-validated fear conditioning and extinction protocol and were then randomly assigned to receive either 6-weeks of BLUE (469 nm; n=44) or placebo AMBER (578 nm; n=40) morning light therapy for 30-minutes daily. Participants returned to undergo post-treatment extinction recall when exposed to the same previously conditioned stimuli, and a functional magnetic resonance imaging (fMRI) while the same images were presented. Participants also completed a variety of emotional and mental health outcome measures and wore an actigraph to measure sleep over the 6-weeks. Results There was a significant interaction between light condition and time in bed and total sleep time (p<.05) indicating significant increases in sleep with blue versus amber light over treatment. Additionally, declines in symptoms of PTSD on the Clinician Administered PTSD Scale (CAPS-5) correlated with improvements in sleep for the blue, but not the amber light, group (all p-values <.05). During the fear conditioning and extinction paradigm, blue light was associated with significantly greater extinction recall compared to the amber light condition (p=.05). Finally, blue light resulted in decreased fMRI activation within the right amygdala and increased activation within the ventromedial prefrontal cortex to the previously feared and extinguished stimuli. Conclusion Blue light treatment was more effective than amber placebo at increasing sleep quantity, shifting circadian bedtime, reducing PTSD symptom severity, facilitating the retention of extinction memories, and reducing neural fear responses to previously feared stimuli. We suggest that improvements in sleep led to greater consolidation of extinction memories. These findings suggest that blue light treatment may facilitate treatment gains by improving sleep. Support (If Any)

The Difference of Cognitive Function in Posttraumatic Stress Disorder and Major Depressive Disorder According to Severity of Symptom

The Difference of Cognitive Function in Posttraumatic Stress Disorder and Major Depressive Disorder According to Severity of Symptom

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.

The DRD2 Taq1A polymorphism moderates the effect of PTSD symptom severity on the left hippocampal CA3 volume: a pilot study

Rationale and objectivesThe hippocampus, especially the CA1, CA3, and dentate gyrus (DG) subfields, is reported to be associated with post-traumatic stress disorder (PTSD) after trauma. However, neuroimaging studies of the associations between PTSD and hippocampal subfield volumes have failed to yield consistent findings. The aim of this study is to examine whether the dopamine D2 receptor (DRD2) Taq1A polymorphism, which is associated with both hippocampal function and PTSD, moderated the association between PTSD severity and hippocampal CA1, CA3 and DG volumes.MethodsT1-weighted images were acquired from 142 trauma survivors from the 2008 Wenchuan earthquake using a 3.0-T magnetic resonance imaging system. Hippocampal subfield segmentations were performed with FreeSurfer v6.0. We used the simple moderation model from the PROCESS v3.4 tool for SPSS 23.0 to examine the association between the rs1800497 polymorphism, PTSD severity, and hippocampal CA3 and DG volumes.ResultsA significant genotype × PTSD symptom severity interaction was found for the left CA3 volume (ΔF = 5.01, p = 0.008, ΔR2 = 0.05). Post hoc, exploratory analyses deconstructing the interaction revealed that severe PTSD symptomatology were associated with reduced left CA3 volume among TC heterozygotes (t = − 2.86, p = 0.005).ConclusionsThis study suggests that DRD2 Taq1A polymorphism moderates the association between PTSD symptomatology and left CA3 volume, which promotes an etiological understanding of the hippocampal atrophy at the subfield level. This highlights the complex effect of environmental stress, and provides possible mechanism for the relationship between the dopaminergic system and hippocampal function in PTSD.

Restoring large scale brain networks in the aftermath of trauma: implications for neuroscientifically-informed treatments

Background: Several intrinsic networks in the brain, including the default mode network, the salience network, and the central executive network, have shown to be critical to higher cognitive functioning. Importantly, these networks have been demonstrated to be compromised in psychopathology, including posttraumatic stress disorder (PTSD) (Akiki, Averill, & Abdallah, 2017; Lanius, Frewen, Tursich, Jetly, & McKinnon, 2015; Lanius, Terpou, & McKinnon, 2020; Szeszko & Yehuda, 2020). Objective: 1) To outline the major large-scale networks of the human brain and their impaired functioning in PTSD; 2) to describe neuroscientifically-informed interventions targeting directly the abnormalities observed in these brain networks in PTSD. Methods: Literature relevant to this topic will be reviewed. Results: Increasing evidence for impaired functioning of the default mode network, the salience network, the central executive network, and the dorsal/ventral attention networks in PTSD has been described. Each network has been proposed to be associated with specific clinical symptoms observed in PTSD, including an altered sense of self (default mode network), increased or decreased or arousal/interoception (salience network), cognitive dysfunction (central executive network; attentional networks). Specific neuroscientifically-informed treatments designed to restore each of these brain networks and the related clinical symptomatology will be discussed. Conclusions: Neuroscientifically-informed treatments will be critical to future research and personalized medicine agendas aimed at targeting specific PTSD symptomatology and restoring functioning in the aftermath of this often devastating disorder.

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.

Cognitive functioning in posttraumatic stress disorder before and after cognitive-behavioral therapy

Although substantial evidence suggests altered executive functioning and autobiographical memory in posttraumatic stress disorder (PTSD), the clinical significance of these findings remains unclear. Here, we investigated the effects of cognitive-behavioral therapy (CBT) on different aspects of cognitive functioning (working memory, interference susceptibility, conflict adaptation, autobiographical memory) in PTSD patients in a pre-post control group design with a nested cross-sectional element. Cross-sectional analyses at baseline were conducted on 58 PTSD patients, 39 traumatized (TC), and 45 non-traumatized controls (NTC). Intervention effects were investigated before and after 25 CBT sessions in 25 PTSD and 34 untreated NTC individuals assessed in parallel. At baseline, PTSD patients showed higher conflict adaptation than the NTC group and less autobiographical memory specificity than both control groups, suggesting particularly the latter to be a correlate of PTSD. No consistent evidence for treatment-induced improvements in cognitive functioning emerged on the group level or from associations between intra-individual clinical and cognitive changes. Analyses on the role of cognitive functioning on subsequent treatment effects revealed a predictive effect of backward digit span on CBT-induced reductions of depressiveness, but no other significant effects. Our findings highlight the need for further research to identify more relevant predictors of differential treatment response.

Autonomic Reactivity to Acute Mental Stress Differs Between Women and Men with Post Traumatic Stress Disorder (PTSD)

Over 7 million Americans are affected by post‐traumatic stress disorder (PTSD), a debilitating mental illness that is associated with significant cardiovascular disease risk. Women are twice as likely as men to develop PTSD after a traumatic event. A prior study from our laboratory showed that sympathetic nervous system reactivity during combat related and non‐combat related stress is heightened in PTSD; however, this study was conducted in a predominantly male cohort and did not consider the potential influence of sex on neural cardiovascular function in PTSD. The aim of the current study was to determine if women with PTSD have heightened blood pressure (BP), heart rate (HR), and sympathetic reactivity to acute mental stress than men with PTSD. We recruited 15 women and 18 men clinically diagnosed with PTSD and confirmed using the Clinician Administered PTSD Scale (CAPS) and PTSD Checklist‐Military (PCL‐M) surveys. We measured muscle sympathetic nerve activity (MSNA), continuous BP, HR and heart rate variability (HRV) at baseline and during 3 minutes of mental arithmetic. Women and men were matched for race, age (41±2 vs 38±2 years, p=0.191), body mass index (31±2 vs 29±2 kg/m2, p=0.368), CAPS (71 ±9 vs 74 ±4, p=0.732) and PCLM (57 ±5 vs 68 ±4, p=0.129) scores. Likewise, baseline systolic BP (131±5 vs 128±4 mmHg), diastolic BP (76±4 vs 74±2 mmHg) and HR (70±3 vs 64±2 beats/min) were comparable (P>0.05) between women and men. Although resting HRV measures were not different between groups (p>0.05), resting MSNA was higher (p=0.008) in women compared to men (27±3 vs 16±3 bursts/min). In response to mental arithmetic, systolic BP reactivity was higher in women compared to men (Δ+5.1±1 versus Δ+2.2±1 mm Hg, p<0.001). Diastolic BP (p=0.366) and HR (p=0.170) responses were not different. However, MSNA reactivity was higher (p=0.04) in women compared to men (Δ15.2±5 versus Δ6.4±3 bursts/min), suggesting an exaggerated sympathetic response to acute stress. Although RMSSD reactivity was similar between both groups (p=0.347), HF response to mental stress was blunted (p=0.05) in women compared to men, suggesting a greater withdrawal of parasympathetic control of the heart during acute stress. In summary, women with PTSD show an exaggerated blood pressure and sympathetic response to acute mental stress coupled with a blunted parasympathetic control of the heart. These results provide important insight into the physiological mechanisms linking the high risk of PTSD in women and the associated cardiovascular disease and hypertension risk.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) Grant R01 HL135183; NIH R61 AT010457, VA Merit I01CX001065, the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Decatur, Georgia, and the APS STRIDE Undergraduate Summer Research Fellowship, grant program number NHLBI; 1 R25 HL115473‐01.

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.

Novel Pharmacological Targets for Combat PTSD-Metabolism, Inflammation, The Gut Microbiome, and Mitochondrial Dysfunction.

Current pharmacological treatments of post-traumatic stress disorder (PTSD) have limited efficacy. Although the diagnosis is based on psychopathological criteria, it is frequently accompanied by somatic comorbidities and perhaps "accelerated biological aging," suggesting widespread physical concomitants. Such physiological comorbidities may affect core PTSD symptoms but are rarely the focus of therapeutic trials. To elucidate the potential involvement of metabolism, inflammation, and mitochondrial function in PTSD, we integrate findings and mechanistic models from the DOD-sponsored "Systems Biology of PTSD Study" with previous data on these topics. Data implicate inter-linked dysregulations in metabolism, inflammation, mitochondrial function, and perhaps the gut microbiome in PTSD. Several inadequately tested targets of pharmacological intervention are proposed, including insulin sensitizers, lipid regulators, anti-inflammatories, and mitochondrial biogenesis modulators. Systemic pathologies that are intricately involved in brain functioning and behavior may not only contribute to somatic comorbidities in PTSD, but may represent novel targets for treating core psychiatric symptoms.

The relationship between negative trauma-related cognitions and psychosocial functioning in veterans with posttraumatic stress disorder and alcohol use disorder

Background: The comorbidity of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is highly prevalent and associated with especially poor psychosocial functioning. Negative trauma-related cognitions are theoretically proposed to be associated with poor psychosocial functioning in PTSD, but few studies have examined the association between negative trauma-related cognitions and psychosocial functioning in PTSD/AUD. Evaluating this association may provide evidence of a potential treatment target for improving psychosocial functioning in PTSD/AUD. We hypothesized that negative trauma-related cognitions, including cognitions about the self, world, and self-blame, would be independently associated with poor psychosocial functioning in the following domains: vitality, psychosocial well-being, role limitations due to emotional distress, and social functioning. Methods: We examined the relationship between negative trauma-related cognitions and psychosocial functioning in 145 treatment-seeking veterans with PTSD/AUD using multiple linear regression analyses while controlling for PTSD and alcohol abuse and dependence severity. Results: Our hypotheses were partially supported. We found that negative trauma-related cognitions were uniquely associated with greater psychosocial functional impairment, independent of PTSD and alcohol abuse and dependence severity. Specifically, negative trauma-related cognitions about the self were associated with greater psychosocial functional impairment across all domains, cognitions about the world were associated with worse social functioning and psychological well-being, and self-blame was associated with impaired psychological well-being. Conclusions: Given that improvements in negative trauma-related cognitions are a mechanism of trauma-focused treatment, future studies should examine whether changes in negative trauma-related cognitions through trauma-focused treatment are associated with improved psychosocial functioning.

A common neural substrate for elevated PTSD symptoms and reduced pulse rate variability in combat-exposed veterans.

Previous studies have identified reduced heart rate variability (HRV) in post-traumatic stress disorder (PTSD), which may temporally precede the onset of the disorder. A separate line of functional neuroimaging research in PTSD has consistently demonstrated hypoactivation of the ventromedial prefrontal cortex (vmPFC), a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate. No research to date, however, has simultaneously investigated whether altered vmPFC activation is associated with reduced HRV and elevated PTSD symptoms in the same individuals. Here, we collected fMRI data during alternating conditions of threat of shock and safety from shock in 51 male combat-exposed veterans with either high or low levels of PTSD symptoms. Pulse rate variability (PRV)-a HRV surrogate calculated from pulse oximetry-was assessed during a subsequent resting scan. Correlational analyses tested for hypothesized relationships between reduced vmPFC activation, lower PRV, and elevated PTSD symptomatology. We found that PTSD re-experiencing symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Reduced vmPFC activation for the contrast of safety-threat was associated both with lower HF-PRV and elevated PTSD re-experiencing symptoms. These results tie together previous observations of reduced HRV/PRV and impaired vmPFC function in PTSD and call for further research on reciprocal brain-body relationships in understanding PTSD pathophysiology.

Glucocorticoids and Hippocampal Structure and Function in PTSD.

This review examines the putative link between glucocorticoid and hippocampal abnormalities in posttraumatic stress disorder (PTSD). Increased glucocorticoid receptor (GR) sensitivity in PTSD may permit enhanced negative feedback inhibition of cortisol at the pituitary, hypothalamus, or other brain regions comprising the hypothalamic-pituitary-adrenal (HPA) axis and would be expected to affect other physiological systems that are regulated by glucocorticoids. Molecular and transcriptional studies of cortisol are consistent with the hypothesis that cortisol actions may be amplified in PTSD as a result of enhanced GR sensitivity in monocytes and some brain regions, although cortisol levels themselves are unchanged and oftentimes lower than normal. Concurrently, magnetic resonance imaging studies have demonstrated that individuals with PTSD have smaller hippocampal volume than individuals without PTSD. Initial hypotheses regarding the mechanism underlying hippocampal alterations in PTSD focused on elevated glucocorticoid levels in combination with extreme stress as the primary cause, but this explanation has not been well supported in human studies. Lack of data from neuroimaging studies preclude a firm link between PTSD onset and hippocampal volume changes. Rather, the available evidence is consistent with the possibility that smaller hippocampal volume (like reduced cortisol levels and enhanced GR sensitivity) may be a vulnerability factor for developing the disorder; limitations of hippocampal-based models of PTSD are described. We further review neuroimaging studies examining hippocampal structure and function following manipulation of glucocorticoid levels and also examining changes in the hippocampus in relationship to other brain regions. Evidence that the GR may be an important therapeutic target for the treatment of PTSD, especially for functions subserved by the hippocampus, is discussed. Implications of the current review for future research are described, with an emphasis on the need to integrate findings of glucocorticoid abnormalities with functional-imaging paradigms to formulate a comprehensive model of HPA-axis functioning in PTSD.

Inflammatory markers and their possible effects on cognitive function in women with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) has been associated with increased inflammation, albeit with some controversy. Another key feature of PTSD is compromised function in wide-ranging cognitive domains. Increased peripheral inflammation can contribute to cognitive dysfunction, although this relationship has not been studied in patients with PTSD. Here, we examined blood inflammatory markers in adult patients with PTSD compared to healthy controls taking account of potentially confounding effects of childhood maltreatment and comorbid major depressive disorder (MDD), and explored the association between inflammation and cognition. We enrolled 40 women with PTSD, most of whom developed the disorder after interpersonal violence during adulthood, and 65 healthy control women. Diagnoses were made based on DSM-IV. History of childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ). Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Blood samples were collected for the measurement of 5 inflammatory markers including interleukin-6 (IL-6), soluble IL-6 receptor, interleukin-1β, high-sensitivity tumor necrosis factor-α, and high-sensitivity C-reactive protein. Compared to controls, patients with PTSD showed significantly higher IL-6 levels (p = 0.009) and lower scores on all RBANS domains (all p < 0.01). IL-6 levels in patients were not significantly associated with the presence/absence of comorbid MDD or CTQ scores. IL-6 levels in patients were significantly negatively correlated with RBANS visuospatial construction (p = 0.046), language (p = 0.008), attention (p = 0.036) and total score (p = 0.008). These results suggest that elevated IL-6 is associated with PTSD and that the lower cognitive function in PTSD may be due at least partly to increased inflammation.

P.2.040 - Cognitive functioning in post-traumatic stress disorder: a meta-analysis of evidence from animal models and clinical studies

In the aftermath of a traumatic experience, some people develop post-traumatic stress disorder (PTSD). Cognitive processes play a crucial role in current clinical diagnosis and treatment of PTSD. Three core symptom clusters of PTSD are cognitive in nature (i.e. re-experiencing, avoidance and negative alterations in cognitions) [1] and cognitive processes form a major component in evidence-based therapies for PTSD (e.g. EMDR, cognitive behavioural therapy) [2]. To improve the prevention and treatment of PTSD in the future, (fundamental) research needs to elaborate on underlying mechanisms and identify opportunities for (new) treatment strategies. However, research efforts need to align with clinical reality since only translational findings will foster clinical progress. In the case of PTSD, this implies research attention for the cognitive domain (including learning & memory). The aim of the current meta-analysis was firstly to review and integrate the existing knowledge on learning, memory and fear conditioning in PTSD patients compared to healthy controls. Subsequently, data from animal models of PTSD was analysed and compared to patient-data, to investigate if preclinical data follows the same patterns as clinical data, and identify possible explanations for potential discrepancies. The database search was conducted in PubMed and only original research articles were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and guidelines were used to conduct the searches, to guide data extraction, to summarize evidence and to report the results [3]. 184 articles were included in this study (60,9% preclinical data). In 53,8% of the studies fear-conditioning experiments were performed, the other studies assessed learning and memory of more neutral information. The results indicate that PTSD patients are better in learning and memory of emotional or fearful information, but perform worse than healthy controls in learning and memory of neutral information. Importantly, preclinical data showed comparable results, with even stronger associations between PTSD and parameters of learning and memory. The stronger effect found in animal models, could be due to the more controlled nature of preclinical research, which is for example reflected in subject background (e.g. laboratory animals vs. patients with variations in comorbidity and medication use) and experimental environment. Differences in learning and memory of trauma-related, visual, verbal and spatial memory are discussed. Analysis revealed that included papers varied in timing between encoding and retrieval, as well as between trauma and cognitive testing. In addition, preclinical studies predominantly used fear conditioning approaches, whereas learning and memory of emotional or neutral information was mainly assessed in clinical studies. Insight in the discrepancies mentioned above could inspire future experimental designs of (pre)clinical studies to adopt a more translational, thereby more valuable, set-up. Overall, the results underline the importance of the learning and memory deficits in PTSD and suggest that animal models can be used to model the cognitive domain of PTSD.

Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD.

Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms. Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively. Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum. Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics.