Intrusive Traumatic Re-Experiencing Domain (ITRED) – Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium

Background Intrusive Traumatic Re-Experiencing Domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods Data was collected from nine sites taking part in the ENIGMA-PTSD Consortium (n=584) and included itemized PTSD symptoms scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and Trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. Random forest classification model was built on a training set using cross-validation (CV), and the averaged CV model performance for classification was evaluated using area-under-the-curve (AUC). The model was tested using a fully independent portion of the data (test dataset), and the test AUC was evaluated. Results RsFC signatures differentiated TE-only participants from PTSD and from ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and from ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontal-parietal network, differentiated TE-only participants from one group (PTSD or ITRED-only), but to a lesser extent from the other. Conclusion Neural network connectivity supports ITRED as a novel neurobiologically-based approach to classifying post-trauma psychopathology

The relation between anxious personality traits and fear generalization in healthy subjects : A systematic review and meta-analysis

Background: Anxious personality characteristics form a risk factor for anxiety disorders. A proposed mechanistic pathway is that anxious personality could lead to greater vulnerability by increasing fear generalization. Here, we investigate if there is evidence for this relationship before the onset of pathological anxiety, with a meta-analysis in healthy subjects. Methods: Our search (anxious personality & fear generalization) was performed in PubMed, PsychInfo, and Embase and via snowballing. Results: In total, 4892 studies were screened and 19 studies (1348 participants) were included in the current review (meta-analysis: 18 studies, 1310 participants). The meta-analysis showed a significant, small, positive relationship between anxious personality and fear generalization (r =.19, 95%CI [.126,.260], p <.001). No moderators of the relationship were identified. Conclusions: The identified robust relation suggests that people who score high on anxious personality have a somewhat stronger tendency to generalize fear to safe or novel situations. This might explain their vulnerability to anxiety disorders mechanistically, yet future (prospective) studies are warranted to confirm the hypothesized directionality of this effect

The predictive value of dorsal cingulate activity and fractional anisotropy on long-term PTSD symptom severity

BACKGROUND: Posttraumatic stress disorder (PTSD) can be treated with trauma-focused therapy, although only about 50% of the patients recover on the short-term. In order to improve response rates it is important to identify who will and will not recover from trauma-focused therapy. Although previous studies reported dorsal anterior cingulate cortex (ACC) activity, as well as dorsal cingulum bundle white matter microstructure integrity as markers for the persistence of PTSD symptoms on the short-term, it remains unclear whether these markers also predict long-term PTSD symptom severity. METHODS: PTSD patients (n = 57) were investigated with clinical interviews and an MRI protocol before the start of treatment. Clinical interviews were repeated after 6-8 months of treatment (short-term follow-up), and on average 4 years later (long-term follow-up). Twenty-eight PTSD patients returned for the long-term follow-up. Dorsal ACC activity in response to negative images, and fractional anisotropy (FA) of the dorsal cingulum were the neural markers investigated. RESULTS: In this long-term follow-up sample (n = 28), dorsal ACC activity and dorsal cingulum FA values significantly predicted CAPS scores on short- and long-term follow-up. The results remained significant after controlling for baseline CAPS score, early trauma, and comorbidity. CONCLUSION: This study confirms the importance of the cingulate cortex activation and white matter integrity not only for short-term treatment outcome, but also for PTSD long-term symptom severity. Future treatments should target ACC function in particular during treatment in order to improve response rates

The predictive value of dorsal cingulate activity and fractional anisotropy on long-term PTSD symptom severity

Background: Posttraumatic stress disorder (PTSD) can be treated with trauma-focused therapy, although only about 50% of the patients recover on the short-term. In order to improve response rates it is important to identify who will and will not recover from trauma-focused therapy. Although previous studies reported dorsal anterior cingulate cortex (ACC) activity, as well as dorsal cingulum bundle white matter microstructure integrity as markers for the persistence of PTSD symptoms on the short-term, it remains unclear whether these markers also predict long-term PTSD symptom severity. Methods: PTSD patients (n = 57) were investigated with clinical interviews and an MRI protocol before the start of treatment. Clinical interviews were repeated after 6-8 months of treatment (short-term follow-up), and on average 4 years later (long-term follow-up). Twenty-eight PTSD patients returned for the long-term follow-up. Dorsal ACC activity in response to negative images, and fractional anisotropy (FA) of the dorsal cingulum were the neural markers investigated. Results: In this long-term follow-up sample (n = 28), dorsal ACC activity and dorsal cingulum FA values significantly predicted CAPS scores on short- and long-term follow-up. The results remained significant after controlling for baseline CAPS score, early trauma, and comorbidity. Conclusion: This study confirms the importance of the cingulate cortex activation and white matter integrity not only for short-term treatment outcome, but also for PTSD long-term symptom severity. Future treatments should target ACC function in particular during treatment in order to improve response rates

Predicting Treatment Outcome in PTSD : A Longitudinal Functional MRI Study on Trauma-Unrelated Emotional Processing

In about 30-50% of patients with posttraumatic stress disorder (PTSD), symptoms persist after treatment. Although neurobiological research has advanced our understanding of PTSD, little is known about the neurobiology underlying persistence of PTSD. Two functional MRI scans were collected from 72 war veterans with and without PTSD over a 6-To 8-month interval, during which PTSD patients received trauma-focused therapy. All participants performed a trauma-unrelated emotional processing task in the scanner. Based on post-Treatment symptom severity, a distinction was made between remitted and persistent patients. Behavioral and imaging measures of trauma-unrelated emotional processing were compared between the three groups (remitted patients, N=21; persistent patients, N=22; and combat controls, N=25) with repeated-measures (pre-and post-Treatment) analyses. Second, logistic regression was used to predict treatment outcome. Before and after treatment, persistent patients showed a higher dorsal anterior cingulate cortex (dACC) and insula response to negative pictures compared with remitted patients and combat controls. Before treatment, persistent patients showed increased amygdala activation in response to negative pictures compared with remitted patients. The remitted patients and combat controls did not differ on the behavioral or imaging measures. Finally, higher dACC, insula, and amygdala activation before treatment were significant predictors of symptom persistence. Our results highlight a pattern of brain activation that may predict poor response to PTSD treatment. These findings can contribute to the development of alternative or additional therapies. Further research is needed to elucidate the heterogeneity within PTSD and describe how differences in neural function are related to treatment outcome. Such approaches are critical for defining parameters to customize PTSD treatment and improve treatment response rates

Pre-treatment cortisol awakening response predicts symptom reduction in posttraumatic stress disorder after treatment

Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or without PTSD. Decreasing HPA-axis reactivity to different stress cues has been reported during PTSD treatment. The cortisol awakening response (CARi) is a well-validated, standardized measure of HPA-axis reactivity which can be easily acquired in the clinical setting. Whether CARi changes over time in traumatized individuals are specific to PTSD treatment is unknown. Furthermore, a possible role for the baseline CARi in predicting symptom reduction after treatment in PTSD has not been examined before. To answer these questions, a cohort study was conducted in which the awakening cortisol was measured in both PTSD (N=41) and non-PTSD (N=25) combat-exposed male subjects. Measurements took place at inclusion and 6-8 months after inclusion for both the PTSD and the non-PTSD group. During the 6-8 months interval, PTSD patients received trauma-focused focused psychotherapy, whereas non-PTSD patients received no treatment. We found a decrease in the CARi over time in both groups, suggesting it was not specific to PTSD or the effect of treatment. Therefore, caution is warranted when attributing diminished HPA-axis reactivity over time to effects of PTSD treatment. Second, CARi prior to treatment predicted PTSD symptom reduction (CAPS score change) after treatment, and accounted for 10% of the variance, even when adjusted for changes in depressive symptoms and medication use during the study period. A putative role emerges for CARi as a predictive biomarker of symptom reduction in male individuals with combat-related PTSD

Psychological factors for the onset of depression: A meta-analysis of prospective studies

Objectives A comprehensive overview of the evidence for factors derived from leading psychological theories of the onset of major depressive disorder (MDD) that underpin psychological interventions is scarce. We aimed to systematically investigate the prospective evidence for factors derived from the behavioural, cognitive, diathesis-stress, psychodynamic and personality-based theories for the first onset of MDD. Design Systematic review and meta-analysis. Methods Databases PubMed, PsycINFO, Cochrane and Embase and published articles were systematically searched from inception up to August 2019. Prospective, longitudinal studies that investigated theory-derived factors before the first onset of MDD, established by a clinical interview, were included. Screening, selection and data extraction of articles were conducted by two screeners. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to estimate level of confidence and risk of bias. Meta-analysis was conducted using random-effects models and mixed-method subgroup analyses. Primary and secondary outcome measures Effect size of a factor predicting the onset of MDD (OR, risk ratio or HR). Results From 42 133 original records published to August 2019, 26 studies met the inclusion criteria. Data were only available for the cognitive (n=6585) and personality-based (n=14 394) theories. Factors derived from cognitive theories and personality-based theories were related to increased odds of MDD onset (pooled OR=2.12, 95% CI: 1.12 to 4.00; pooled OR=2.43, 95% CI: 1.41 to 4.19). Publication bias and considerable heterogeneity were observed. Conclusion There is some evidence that factors derived from cognitive and personality-based theories indeed predict the onset of MDD (ie, dysfunctional attitudes and negative emotionality). There were no studies that prospectively studied factors derived from psychodynamic theories and not enough studies to examine the robust evidence for behavioural and diathesis-stress theories. Overall, the prospective evidence for psychological factors of MDD is limited, and more research on the leading psychological theories is needed. PROSPERO registration number CRD42017073975

Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis

Leading biological hypotheses propose that biological changes may underlie major depressive disorder onset and relapse/recurrence. Here, we investigate if there is prospective evidence for biomarkers derived from leading theories. We focus on neuroimaging, gastrointestinal factors, immunology, neurotrophic factors, neurotransmitters, hormones, and oxidative stress. Searches were performed in Pubmed, Embase and PsychInfo for articles published up to 06/2019. References and citations of included articles were screened to identify additional articles. Inclusion criteria were having an MDD diagnosis as outcome, a biomarker as predictor, and prospective design search terms were formulated accordingly. PRISMA guidelines were applied. Meta-analyses were performed using a random effect model when three or more comparable studies were identified, using a random effect model. Our search resulted in 67,464 articles, of which 75 prospective articles were identified on: Neuroimaging (N = 24), Gastrointestinal factors (N = 1), Immunology (N = 8), Neurotrophic (N = 2), Neurotransmitters (N = 1), Hormones (N = 39), Oxidative stress (N = 1). Meta-analyses on brain volumes and immunology markers were not significant. Only cortisol (N = 19, OR = 1.294, p = 0.024) showed a predictive effect on onset/relapse/recurrence of MDD, but not on time until MDD onset/relapse/recurrence. However, this effect disappeared when studies including participants with a baseline clinical diagnosis were removed from the analyses. Other studies were too heterogeneous to compare. Thus, there is a lack of evidence for leading biological theories for onset and maintenance of depression. Only cortisol was identified as potential predictor for MDD, but results are influenced by the disease state. High-quality (prospective) studies on MDD are needed to disentangle the etiology and maintenance of MDD

Resting state functional connectivity of the anterior cingulate cortex in veterans with and without post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is an anxiety disorder that is associated with structural and functional alterations in several brain areas, including the anterior cingulate cortex (ACC). Here, we examine resting state functional connectivity of ACC subdivisions in PTSD, using a seed-based approach. Resting state magnetic resonance images were obtained from male veterans with (n = 31) and without (n = 25) PTSD, and healthy male civilian controls (n = 25). Veterans with and without PTSD (combat controls) had reduced functional connectivity compared to healthy controls between the caudal ACC and the precentral gyrus, and between the perigenual ACC and the superior medial gyrus and middle temporal gyrus. Combat controls had increased connectivity between the rostral ACC and precentral/middle frontal gyrus compared to PTSD patients and healthy civilian controls. The resting state functional connectivity differences in the perigenual ACC network reported here indicate that veterans differ from healthy controls, potentially due to military training, deployment, and/or trauma exposure. In addition, specific alterations in the combat controls may potentially be related to resilience. These results underline the importance of distinguishing trauma-exposed (combat) controls from healthy civilian controls when studying PTSD