Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Aberrant reward learning, but not negative reinforcement learning, is related to depressive symptoms: an attentional perspective.

BACKGROUND: Aberrant reward functioning is implicated in depression. While attention precedes behavior and guides higher-order cognitive processes, reward learning from an attentional perspective - the effects of prior reward-learning on subsequent attention allocation - has been mainly overlooked. METHODS: The present study explored the effects of reward-based attentional learning in depression using two separate, yet complimentary, studies. In study 1, participants with high (HD) and low (LD) levels of depression symptoms were trained to divert their gaze toward one type of stimuli over another using a novel gaze-contingent music reward paradigm - music played when fixating the desired stimulus type and stopped when gazing the alternate one. Attention allocation was assessed before, during, and following training. In study 2, using negative reinforcement, the same attention allocation pattern was trained while substituting the appetitive music reward for gazing the desired stimulus type with the removal of an aversive sound (i.e. white noise). RESULTS: In study 1 both groups showed the intended shift in attention allocation during training (online reward learning), while generalization of learning at post-training was only evident among LD participants. Conversely, in study 2 both groups showed post-training generalization. Results were maintained when introducing anxiety as a covariate, and when using a more powerful sensitivity analysis. Finally, HD participants showed higher learning speed than LD participants during initial online learning, but only when using negative, not positive, reinforcement. CONCLUSIONS: Deficient generalization of learning characterizes the attentional system of HD individuals, but only when using reward-based positive reinforcement, not negative reinforcement.

Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Resting state connectivity predictors of symptom change during gaze-contingent music reward therapy of social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is common, first-line treatments are often only partially effective, and reliable predictors of treatment response are lacking. Here, we assessed resting state functional connectivity (rsFC) at pre-treatment and during early treatment as a potential predictor of response to a novel attention bias modification procedure, gaze-contingent music reward therapy (GC-MRT). METHODS: Thirty-two adults with SAD were treated with GC-MRT. rsFC was assessed with multi-voxel pattern analysis of fMRI at pre-treatment and after 2-3 weeks. For comparison, 20 healthy control (HC) participants without treatment were assessed twice for rsFC over the same time period. All SAD participants underwent clinical evaluation at pre-treatment, early-treatment (week 2-3), and post-treatment. RESULTS: SAD and depressive symptoms improved significantly from pre-treatment to post-treatment. After 2-3 weeks of treatment, decreased connectivity between the executive control network (ECN) and salience network (SN), and increased connectivity within the ECN predicted improvement in SAD and depressive symptoms at week 8. Increased connectivity between the ECN and default mode network (DMN) predicted greater improvement in SAD but not depressive symptoms at week 8. Connectivity within the DMN decreased significantly after 2-3 weeks of treatment in the SAD group, while no changes were found in HC over the same time interval. CONCLUSION: We identified early changes in rsFC during a course of GC-MRT for SAD that predicted symptom change. Connectivity changes within the ECN, ECN-DMN, and ECN-SN may be related to mechanisms underlying the clinical effects of GC-MRT and warrant further study in controlled trials.

Attention allocation to negatively-valenced stimuli in PTSD is associated with reward-related neural pathways.

BACKGROUND: In a recent eye-tracking study we found a differential dwell time pattern for negatively-valenced and neutral faces among patients with posttraumatic stress disorder (PTSD), trauma-exposed healthy control (TEHCs), and healthy control (HC) participants. Here, we explored whether these group differences relate to resting-state functional connectivity (rsFC) patterns of brain areas previously linked to both attention processes and PTSD. These encompass the amygdala, dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and nucleus accumbens (NAcc). METHODS: Ten minutes magnetic resonance imaging rsFC scans were recorded in 17 PTSD patients, 21 TEHCs, and 16 HCs. Participants then completed a free-viewing eye-tracking task assessing attention allocation outside the scanner. Dwell time on negatively-valenced stimuli (DT%) were assessed relative to functional connectivity in the aforementioned seed regions of interest (amygdala, dACC, dlPFC, vlPFC, and NAcc) to whole-brain voxel-wise rsFC. RESULTS: As previously reported, group differences occurred in attention allocation to negative-valence stimuli, with longer dwell time on negatively valence stimuli in the PTSD and TEHC groups than the HC group. Higher DT% correlated with weaker NAcc-orbitofrontal cortex (OFC) connectivity in patients with PTSD. Conversely, a positive association emerged in the HC group between DT% and NAcc-OFC connectivity. CONCLUSIONS: While exploratory in nature, present findings may suggest that reward-related brain areas are involved in disengaging attention from negative-valenced stimuli, and possibly in regulating ensuing negative emotions.

Reward functioning from an attentional perspective and obsessive-compulsive symptoms-an eye-tracking study.

BACKGROUND: Recently, a novel approach to obsessive-compulsive disorder has emerged, implicating altered reward functioning in the disorder. Yet, no study to date has directly examined the attentional aspect of reward functioning in participants with obsessive-compulsive (OC) symptoms, with past research mostly relying on reaction-time-based tasks. METHODS: A reward-based value-modulated attentional capture task was completed by a sample of nonclinical student participants-44 with high (HOC) and 48 with low (LOC) levels of OC symptoms. We measured the extent to which high and low reward-signaling distractors captured attention and impaired performance on the task, resulting in a lower possibility of obtaining a monetary reward. Attentional capture was indexed via fixation data, and further explored using saccade data. RESULTS: Both groups performed more poorly when a high-reward signaling distractor was present, compared to when a low-reward signaling distractor was present. Importantly, this difference was significantly greater in the HOC group, and was found to be driven by the specific effects of reward-signaling distractors. Similar results emerged when exploring saccade data, and remained significant after controlling for both addiction-related compulsivity and depressive symptoms. CONCLUSIONS: Current findings suggest that attentional reward-related functioning may be associated with OC symptoms. Different aspects of reward functioning, including attention, should be further explored and incorporated into future research and clinical endeavors.

Attention bias modification add-on to inpatient treatment for young women with anorexia nervosa-A randomized controlled trial.

Patients with anorexia nervosa (AN) display elevated anxiety and attention biases (ABs) in threat processing. Attention bias modification treatment (ABMT) is considered promising for anxiety disorders, but its potential for AN is limited. In this study, 154 young women hospitalised because of AN were assigned to ED-related and anxiety-related threat stimuli, or to a non-ABMT intervention control condition in a randomized control trial. Hundred-and-ten patients completed the study. ABMT was an add-on to the regular inpatient treatment. Research participants completed two pretreatment training sessions and eight biweekly sessions of ABMT. AB, ED-related symptoms, depression, anxiety and stress were assessed before and after ABMT in the research groups, and, similarly, 5 weeks apart, in the controls. We found that despite the different patterns of change in AB between the three groups following ABMT, the reduction in AB, or the between-group differences in AB-reduction, were not significant. While the severity of ED-symptoms, depression, anxiety and stress was reduced following ABMT, or control condition, in all groups, there were no between-group differences in these changes. Changes in AB were not correlated with baseline and pre-post-treatment changes in ED-related and comorbid symptomatology. Methodological and inpatient treatment-related considerations may explain our negative ABMT-related results.

Video intervention to increase treatment-seeking by healthcare workers during the COVID-19 pandemic: randomised controlled trial.

BACKGROUND: Many healthcare workers do not seek help, despite their enormous stress and greater risk for anxiety, depression and post-traumatic stress disorder (PTSD). AIMS: This study screened for psychopathology and evaluated the efficacy of a brief, social contact-based video intervention in increasing treatment-seeking intentions among healthcare workers (trial registration: NCT04497415). We anticipated finding high rates of psychopathology and greater treatment-seeking intentions post-intervention. METHOD: Healthcare workers (n = 350) were randomised to (a) a brief video-based intervention at day 1, coupled with a booster video at day 14; (b) the video at day 1 only; or (c) a non-intervention control. In the 3 min video, a female nurse described difficulty coping with stress, her anxieties and depression, barriers to care and how therapy helped her. Assessments were conducted pre- and post-intervention and at 14- and 30-day follow-ups. RESULTS: Of the 350 healthcare workers, 281 (80%) reported probable anxiety, depression and/or PTSD. Participants were principally nurses (n = 237; 68%), physicians (n = 52; 15%) and emergency medical technicians (n = 30; 9%). The brief video-based intervention yielded greater increases in treatment-seeking intentions than the control condition, particularly among participants in the repeat-video group. Exploratory analysis revealed that in both video groups, we found greater effect among nurses than non-nurses. CONCLUSIONS: A brief video-based intervention increased treatment-seeking intention, possibly through identification and emotional engagement with the video protagonist. A booster video magnified that effect. This easily disseminated intervention could increase the likelihood of seeking care and offer employers a proactive approach to encourage employees to search for help if needed.

Are people with obsessive-compulsive disorder under-confident in their memory and perception? A review and meta-analysis.

People with obsessive-compulsive disorder (OCD) tend to distrust their memory, perception, and other cognitive functions, and many OCD symptoms can be traced to diminished confidence in one's cognitive processes. For example, poor confidence in recall accuracy can cause doubt about one's memory and motivate repeated checking. At the same time, people with OCD also display performance deficits in a variety of cognitive tasks, so their reduced confidence must be evaluated in relation to their actual performance. To that end, we conducted an exhaustive review and meta-analysis of studies in which OCD participants and non-clinical control participants performed cognitive tasks and reported their confidence in their performance. Our search resulted in 19 studies that met criteria for inclusion in the quantitative analysis, with all studies addressing either memory or perception. We found that both performance and reported confidence were lower in OCD than in control participants. Importantly, however, confidence was more impaired than performance in participants with OCD. These findings suggest that people with OCD are less confident in their memory and perception than they should be, indicating a genuine under-confidence in this population. We discuss potential mechanisms that might account for this finding and suggest avenues for further research into under-confidence and related meta-cognitive characteristics of OCD.

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

BACKGROUND: 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. AIMS: 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. MATERIALS & METHODS: 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. RESULTS: 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. DISCUSSION & CONCLUSION: Findings support the existence of structural brain markers of resilience.

Elucidating behavioral and functional connectivity markers of aberrant threat discrimination in PTSD.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) tend to overgeneralize threat to safe stimuli, potentially reflecting aberrant stimuli discrimination. Yet, it is not clear whether threat overgeneralization reflects general discrimination deficits, or rather a specific bias related to aversive stimuli. Here we tested this question and characterized the neural correlates of threat discrimination. METHODS: One-hundred and eight participants (33 PTSD; 43 trauma-exposed controls; 32 healthy controls) completed an emotionally neutral complex shape discrimination task involving identifying in 42 similar pairs the previously observed shape; and an emotionally aversive discrimination task, involving providing risk ratings for an aversive conditioned stimulus (CS+), and for several stimuli gradually differing in size from the original CS+. Resting state functional connectivity (rsFC) was collected before completing the tasks. RESULTS: No group differences emerged on the emotionally neutral task. Conversely, on the emotionally aversive task, individuals with PTSD had steeper linear risk rating slopes as the stimuli more resembled the conditioned stimulus. Finally, lower rsFC of amygdala-default mode network (DMN) and DMN-salience network (SN) were associated with steeper risk slopes, while for hippocampus-SN, lower rsFC was found only among participants with PTSD. CONCLUSIONS: Individuals with PTSD show deficits in discrimination only when presented with aversive stimuli. Dysregulated discrimination pattern may relate to a lack of input from regulatory brain areas (e.g., DMN/hippocampus) to threat-related brain areas (e.g., SN/amygdala).

Neural changes following equine-assisted therapy for posttraumatic stress disorder: A longitudinal multimodal imaging study.

BACKGROUND: While effective treatments for posttraumatic stress disorder (PTSD) exist, many individuals, including military personnel and veterans fail to respond to them. Equine-assisted therapy (EAT), a novel PTSD treatment, may complement existing PTSD interventions. This study employs longitudinal neuro-imaging, including structural magnetic resonance imaging (sMRI), resting state-fMRI (rs-fMRI), and diffusion tensor imaging (DTI), to determine mechanisms and predictors of EAT outcomes for PTSD. METHOD: Nineteen veterans with PTSD completed eight weekly group sessions of EAT undergoing multimodal MRI assessments before and after treatment. Clinical assessments were conducted at baseline, post-treatment and at 3-month follow-up. RESULTS: At post-treatment patients showed a significant increase in caudate functional connectivity (FC) and reduction in the gray matter density of the thalamus and the caudate. The increase of caudate FC was positively associated with clinical improvement seen immediately at post-treatment and at 3-month follow-up. In addition, higher baseline caudate FC was associated with greater PTSD symptom reduction post-treatment. CONCLUSIONS: This exploratory study is the first to demonstrate that EAT can affect functional and structural changes in the brains of patients with PTSD. The findings suggest that EAT may target reward circuitry responsiveness and produce a caudate pruning effect from pre- to post-treatment.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A randomized controlled trial of gaze-contingent music reward therapy for major depressive disorder.

BACKGROUND: Heightened attention allocation toward negative-valanced information and reduced attention allocation toward positive-valanced information represent viable targets for attention bias modification in major depressive disorder. Accordingly, we conducted a randomized controlled trial testing the efficacy of a novel gaze-contingent attention bias modification procedure for major depressive disorder. METHOD: Sixty patients with major depressive disorder were randomly assigned to either eight training sessions of feedback-based gaze-contingent music reward therapy designed to divert patients' gaze toward positive over sad stimuli, or to a control condition which entailed eight sessions of gaze-noncontingent music. Clinician-rated and self-reported measures of depression, and proportion of dwell-time on sad faces, were assessed pretreatment, posttreatment, and at a 3-month follow-up. RESULTS: Gaze-contingent music reward therapy produced a greater reduction in dwell-time on sad faces compared with the control condition, but it failed to generalize to novel faces. Both groups manifested similarly significant reductions in depression symptoms from pre- to posttreatment that were maintained at follow-up. Exploratory analyses suggest that first-episode patients may benefit more from this therapy than patients with a history of multiple episodes. CONCLUSIONS: Gaze-contingent music reward therapy can modify attention biases in depression, but clear differential clinical effects did not emerge. Theoretical and practical implications are discussed.

Increasing treatment-seeking intentions of US veterans in the Covid-19 era: A randomized controlled trial.

BACKGROUND: Veterans have higher rates of anxiety, depression, and posttraumatic stress disorder (PTSD), and may be vulnerable to mental health consequences of the Covid-19 pandemic. More than half of veterans who meet mental illness criteria do not seek help. This study screened for clinical symptoms and evaluated the efficacy of a brief, online social-contact-based video intervention in increasing treatment-seeking intentions among veterans. We hypothesized that the video-based intervention would increase treatment-seeking intentions more than written vignette and control conditions. METHODS: One hundred seventy-two veterans were randomized to either a (a) brief video-based intervention; (b) written vignette intervention, or (c) nonintervention control group. In the 3-min video, a veteran previously diagnosed with PTSD described his symptom reactivation by Covid-19, his barriers to care, and how therapy helped him to cope. Assessments were conducted at baseline, postintervention, and at 14- and 30-day follow-ups. RESULTS: A total of 91 (53%) veterans reported high levels of clinical symptoms, especially those self-reporting Covid-19 exposure. The brief video-based intervention yielded greater increase in treatment-seeking intentions among veterans. Within the video group, women showed an increase in treatment-seeking intentions from baseline to postintervention only, whereas men showed a more sustained effect, from baseline to Day 14. CONCLUSIONS: Surveyed veterans reported high symptoms levels. A brief video intervention increased treatment-seeking intention, likely through identification and emotional engagement with the video protagonist. This easily disseminable video-based intervention has the potential to increase likelihood of seeking care. Future research should examine longer term sustainability and changes in help-seeking behavior.

Psychiatric symptoms and moral injury among US healthcare workers in the COVID-19 era.

BACKGROUND: Emerging cross-sectional data indicate that healthcare workers (HCWs) in the COVID-19 era face particular mental health risks. Moral injury - a betrayal of one's values and beliefs, is a potential concern for HCWs who witness the devastating impact of acute COVID-19 illness while too often feeling helpless to respond. This study longitudinally examined rates of depression, generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and moral injury among United States HCWs in the COVID-19 era. We anticipated finding high levels of clinical symptoms and moral injury that would remain stable over time. We also expected to find positive correlations between clinical symptoms and moral injury. METHODS: This three-wave study assessed clinical symptoms and moral injury among 350 HCWs at baseline, 30, and 90 days between September and December 2020. Anxiety, depression, PTSD, and moral injury were measured using the Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Primary Care PTSD Screen (PC-PTSD), and Moral Injury Events Scale (MIES). RESULTS: Of the 350 HCWs, 72% reported probable anxiety, depression, and/or PTSD disorders at baseline, 62% at day 30, and 64% at day 90. High level of moral injury was associated with a range of psychopathology including suicidal ideation, especially among healthcare workers self-reporting COVID-19 exposure. CONCLUSIONS: Findings demonstrate broad, persisting, and diverse mental health consequences of the COVID-19 pandemic among United States HCWs. This study is the first to longitudinally examine the relationships between moral injury and psychopathology among HCWs, emphasizing the need to increase HCWs' access to mental healthcare.

On the validity of the centrality hypothesis in cross-sectional between-subject networks of psychopathology.

BACKGROUND: In the network approach to psychopathology, psychiatric disorders are considered networks of causally active symptoms (nodes), with node centrality hypothesized to reflect symptoms' causal influence within a network. Accordingly, centrality measures have been used in numerous network-based cross-sectional studies to identify specific treatment targets, based on the assumption that deactivating highly central nodes would proliferate to other nodes in the network, thereby collapsing the network structure and alleviating the overall psychopathology (i.e., the centrality hypothesis). METHODS: Here, we summarize three types of evidence pertaining to the centrality hypothesis in psychopathology. First, we discuss the validity of the theoretical assumptions underlying the centrality hypothesis in psychopathology. We then summarize the methodological aspects of extant studies using centrality measures as predictors of symptom change following treatment, while delineating their main findings and several of their limitations. Finally, using a specific dataset of 710 treatment-seeking patients with posttraumatic stress disorder (PTSD) as an example, we empirically examine node centrality as a predictor of therapeutic change, replicating the approach taken by previous studies, while addressing some of their limitations. Specifically, we investigated whether three pre-treatment centrality indices (strength, predictability, and expected influence) were significantly correlated with the strength of the association between a symptom's change and the change in the severity of all other symptoms in the network from pre- to post-treatment (Δnode-Δnetwork association). Using similar analyses, we also examine the predictive validity of two simple non-causal node properties (mean symptom severity and infrequency of symptom endorsement). RESULTS: Of the three centrality measures, only expected influence successfully predicted how strongly changes in nodes/symptoms were associated with change in the remainder of the nodes/symptoms. Importantly, when excluding the amnesia node, a well-documented outlier in the phenomenology of PTSD, none of the tested centrality measures predicted symptom change. Conversely, both mean symptom severity and infrequency of symptom endorsement, two standard non-network-derived indices, were found to be more predictive than expected influence and remained significantly predictive also after excluding amnesia from the network analyses. CONCLUSIONS: The centrality hypothesis in its current form is ill-defined, showing no consistent supporting evidence in the context of cross-sectional, between-subject networks.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Anterior hippocampal volume predicts affect-focused psychotherapy outcome.

BACKGROUND: The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)]. METHODS: Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes. RESULTS: Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome. CONCLUSIONS: This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the 'limbic' AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.

Symptom structure of PTSD and co-morbid depressive symptoms - a network analysis of combat veteran patients.

BACKGROUND: Despite extensive research, symptom structure of posttraumatic stress disorder (PTSD) is highly debated. The network approach to psychopathology offers a novel method for understanding and conceptualizing PTSD. However, extant studies have mainly used small samples and self-report measures among sub-clinical populations, while also overlooking co-morbid depressive symptoms. METHODS: PTSD symptom network topology was estimated in a sample of 1489 treatment-seeking veteran patients based on a clinician-rated PTSD measure. Next, clinician-rated depressive symptoms were incorporated into the network to assess their influence on PTSD network structure. The PTSD-symptom network was then contrasted with the network of 306 trauma-exposed (TE) treatment-seeking patients not meeting full criteria for PTSD to assess corresponding network differences. Finally, a directed acyclic graph (DAG) was computed to estimate potential directionality among symptoms, including depressive symptoms and daily functioning. RESULTS: The PTSD symptom network evidenced robust reliability. Flashbacks and getting emotionally upset by trauma reminders emerged as the most central nodes in the PTSD network, regardless of the inclusion of depressive symptoms. Distinct clustering emerged for PTSD and depressive symptoms within the comorbidity network. DAG analysis suggested a key triggering role for re-experiencing symptoms. Network topology in the PTSD sample was significantly distinct from that of the TE sample. CONCLUSIONS: Flashbacks and psychological reactions to trauma reminders, along with their strong connections to other re-experiencing symptoms, have a pivotal role in the clinical presentation of combat-related PTSD among veterans. Depressive and posttraumatic symptoms constitute two separate diagnostic entities, but with meaningful between-disorder connections, suggesting two mutually-influential systems.