Effects of stress on neural processing of combat-related stimuli in deployed soldiers: an fMRI study.

Severe trauma exposure may lead to symptoms of both posttraumatic stress disorder and depression. Neuroanatomical theories suggest that both disorders may share imbalances in fronto-limbic circuits. Longitudinal studies are necessary to better understand the impact of a stressful life situation on potential long-term fronto-limbic imbalances. Here we investigated soldiers neural processing of combat-related stimuli versus negative affective stimuli before and after the deployment in different war zones. In the final analysis we included 104 deployed soldiers (combat group) and 36 soldiers that were not deployed (control group). Behaviorally, we found a significant group by time interaction regarding depression symptom scores with an increase in the combat group. Depressive symptoms were subclinical. On the neural level, neither the whole brain analysis nor the region of interest (ROI) analyses including frontal and limbic ROIs revealed any significant results in the group by time interaction. However, extracted ROI values of the group by time interaction of amygdala and hippocampus were positively associated with the change in depression symptom scores in the combat group, but not in the control group. These results highlight the role of depression in individuals that experience stressful life situations. Future studies may need to investigate the role of depressive symptoms after trauma exposure with different tasks that may be particularly sensitive to changes due to depressive symptoms.

Assessment for residual disease after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

Objectives: Pulmonary endarterectomy (PEA) is recommended for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH) and is potentially curative. However, persistent/recurrent CTEPH post-PEA can occur. Here we describe symptom and diagnostic assessment rates for residual disease post-PEA and longitudinal diagnostic patterns before and after riociguat approval for persistent/recurrent CTEPH after PEA. Methods: This US retrospective cohort study analysed MarketScan data (1 January 2002-30 September 2018) from patients who underwent PEA following a CTEPH/pulmonary hypertension (PH) claim with at least 730 days of continuous enrolment post-PEA. Data on pre-specified PH symptoms and the types and timings of diagnostic assessments were collected. Results: Of 103 patients (pre-riociguat approval, n=55; post-riociguat approval, n=48), residual PH symptoms >3 months after PEA were reported in 89% of patients. Overall, 89% of patients underwent one or more diagnostic tests (mean 4.6 tests/patient), most commonly echocardiography (84%), with only 5% of patients undergoing right heart catheterisation (RHC). In the post- versus pre-riociguat approval subgroup, assessments were more specific for CTEPH with an approximately two-fold increase in 6-min walk distance and N-terminal prohormone of brain natriuretic protein measurements and ventilation/perfusion scans, and a four-fold increase in RHCs. Conclusions: Low RHC rates suggest that many patients with PH symptoms post-PEA are not being referred for full diagnostic workup. Changes to longitudinal diagnostic patterns may indicate increased recognition of persistent/recurrent CTEPH post-PEA; however, there remains a need for greater awareness around the importance of continued follow-up for patients with residual PH symptoms post-PEA.

Extrastriatal Dopamine D2/3 Receptor Availability in Alcohol Use Disorder and Individuals at High Risk.

INTRODUCTION: Reduced striatal dopamine D2/3 receptor availability in alcohol use disorder (AUD) has been demonstrated in recent clinical studies and meta-analyses. However, only a limited number of studies investigated extrastriatal D2/3 availability in AUD or in at-risk populations. In line with a dimensional understanding of addiction, extrastriatal dopaminergic neuroadaptations have been suggested to be relevant from a pathobiological perspective. METHODS: We investigated D2/3 receptor availability via 18F-fallypride positron emission tomography applying a region of interest (ROI) approach. We selected ROIs for the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC). Our sample included 19 healthy controls (low risk [LR]), 19 individuals at high risk (HR) to develop addiction, and 20 recently detoxified AUD patients. RESULTS: We found significantly higher D2/3 receptor availability of HR compared to AUD in the left and right rostral ACC (rACC), as well as in the left ventrolateral PFC (vlPFC). We did not observe a significant difference between AUD and LR. After corrections for multiple comparisons none of the ROIs reached significance throughout the group comparison. The D2/3 receptor availability in the left rACC was inversely correlated with symptom severity assessed with the Alcohol Dependency Scale. DISCUSSION: To our knowledge, the present work is the first study investigating extrastriatal D2/3 receptor availabilities in individuals at HR and patients with AUD. The observation that D2/3 receptor availabilities are highest in HR might suggest that their pathobiology differs from subjects with AUD. Future studies are necessary to clarify the intraindividual course of this biomarker over different disease stages and its possible role as a risk or protective factor.

Spend time outdoors for your brain - an in-depth longitudinal MRI study.

OBJECTIVES: The effects of nature on physical and mental health are an emerging topic in empirical research with increasing influence on practical health recommendations. Here we set out to investigate the association between spending time outdoors and brain structural plasticity in conjunctions with self-reported affect. METHODS: We established the Day2day study, which includes an unprecedented in-depth assessment of variability of brain structure in a serial sequence of 40-50 structural magnetic resonance imaging (MRI) acquisitions of each of six young healthy participants for 6-8 months (n = 281 MRI scans in total). RESULTS: A whole-brain analysis revealed that time spent outdoors was positively associated with grey matter volume in the right dorsolateral prefrontal cortex and positive affect, also after controlling for physical activity, fluid intake, free time, and hours of sunshine. CONCLUSIONS: Results indicate remarkable and potentially behaviorally relevant plasticity of cerebral structure within a short time frame driven by the daily time spent outdoors. This is compatible with anecdotal evidence of the health and mood-promoting effects of going for a walk. The study may provide the first evidence for underlying cerebral mechanisms of so-called green prescriptions with possible consequences for future interventions in mental disorders.

Real-World Assessment of Interferon-ß-1b and Interferon-ß-1a Adherence Before and After the Introduction of the BETACONNECT® Autoinjector: A Retrospective Cohort Study.

BACKGROUND: Both interferon beta-1b (IFN-ß-1b) and interferon beta-1a (IFN-ß-1a) are immunomodulators that require regular subcutaneous self-administration by patients with multiple sclerosis (MS). However, no electronic autoinjector is available for IFN-ß-1a in the US. OBJECTIVE: This retrospective cohort study investigated adherence to two subcutaneous disease-modifying therapies, IFN-ß-1b and IFN-ß-1a, during two periods (before and after the introduction of the BETACONNECT® autoinjector for IFN-ß-1b). PATIENTS AND METHODS: Data were evaluated from the MarketScan database for adults in the US with an MS diagnosis and a medical claim for subcutaneous IFN-ß-1b or IFN-ß-1a, either before (October 2013-September 2015) or after the introduction of BETACONNECT (October 2016-September 2018). Patient populations were propensity-score matched by demographic and clinical characteristics. Persistence was recorded, and adherence was evaluated by medication possession ratio (MPR). RESULTS: The study included 196 IFN-ß-1b and 365 IFN-ß-1a people with MS (PwMS) (pre-BETACONNECT period), and 126 IFN-ß-1b and 223 IFN-ß-1a PwMS (post-BETACONNECT period). In the pre-BETACONNECT period, the proportion with at least 80% MPR was higher for IFN-ß-1a (90%) than for IFN-ß-1b (83%), but in the post-BETACONNECT period the proportion with ≥ 80% MPR was higher for IFN-ß-1b (92%) than for IFN-ß-1a (86%). In the pre-BETACONNECT period, median persistence (in days) was higher for IFN-ß-1a (199) than for IFN-ß-1b (152), while in post-BETACONNECT period persistence was higher for IFN-ß-1b (327) than for IFN-ß-1a (229). CONCLUSIONS: Following the introduction of BETACONNECT, this exploratory study suggested that PwMS taking IFN-ß-1b were more adherent compared with those taking IFN-ß-1a, with higher persistence, and more than 90% reached 80% MPR, a threshold commonly used to define good adherence.

The brain at war: effects of stress on brain structure in soldiers deployed to a war zone.

In search of the neural basis of severe trauma exposure and post-traumatic stress disorder (PTSD), a multitude of cross-sectional studies have been conducted, most of them pointing at structural deficits in the hippocampus and medial prefrontal cortex including the anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (vmPFC). Since cross-sectional studies are silent to causality, the core question remains: which brain structural alterations constitute a risk factor for disease and therewith precede the stressor, and which brain regions may undergo alterations as a consequence of exposure to the stressor. We assessed 121 soldiers before and after deployment to regions of war and 40 soldiers as controls, who were not deployed. Analysis using voxel-based morphometry revealed volumetric reductions in the ACC, vmPFC (region of interest analysis, effect does not survive conservative multiple test correction) and in bilateral thalamus (whole-brain analysis) in the deployment group. Remarkably, the ACC and vmPFC volume decrease was not limited to the period of deployment, but continued over the following 6 months after deployment. Volumetric reductions did not correlate with increases in PTSD symptoms. The volume decreases in medial prefrontal cortex and thalamus seem to be driven by trauma exposure rather than a vulnerability factor for PTSD. However, data indicate that the volume decrease in medial prefrontal cortex surpasses the time period of deployment. This may hint at an initiated pathobiological process below a symptom threshold, potentially paving the way to future mental health problems.

Dopamine D2/3 receptor availability in alcohol use disorder and individuals at high risk: Towards a dimensional approach.

Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine-related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying 18 F-fallypride positron emission tomography (18 F-PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low-risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.

Longitudinal changes in risk status in pulmonary arterial hypertension.

AIMS: Low-risk status in pulmonary arterial hypertension (PAH) predicts better survival. The present study aimed to describe changes in risk status and treatment approaches over multiple clinical assessments in PAH, taking age and comorbidity burden into consideration. METHODS AND RESULTS: The study included incident patients from the Swedish PAH registry, diagnosed with PAH in 2008-2019. Group A (n = 340) were ≤75 years old with <3 comorbidities. Group B (n = 163) were >75 years old with ≥3 comorbidities. Assessments occurred at baseline, first-year (Y1) and third-year (Y3) follow-ups. The study used an explorative and descriptive approach. Group A: median age was 65 years, 70% were female, and 46% had no comorbidities at baseline. Baseline risk assessment yielded low (23%), intermediate (66%), and high risk (11%). Among patients at low, intermediate, or high risk at baseline, 51%, 18%, and 13%, respectively, were at low risk at Y3. At baseline, monotherapy was the most common therapy among low (68%) and intermediate groups (60%), while dual therapy was the most common among high risk (69%). In patients assessed as low, intermediate, or high risk at Y1, 66%, 12%, and 0% were at low risk at Y3, respectively. Of patients at intermediate or high risk at Y1, 35% received monotherapy and 13% received triple therapy. In low-risk patients at Y1, monotherapy (40%) and dual therapy (43%) were evenly distributed. Group B: median age was 77 years, 50% were female, and 44% had ≥3 comorbidities at baseline. At baseline, 8% were at low, 80% at intermediate, and 12% at high risk. Monotherapy was the most common therapy (62%) in Group B at baseline. Few patients maintained or reached low risk at follow-ups. CONCLUSIONS: Most patients with PAH did not meet low-risk criteria during the 3 year follow-up. The first year from diagnosis seems important in defining the longitudinal risk status.

Poor outcome of patients with pulmonary arterial hypertension with insufficient response to phosphodiesterase-5 inhibitors alone or in combination with other specific therapy: a registry-based study.

Phosphodiesterase-5 inhibitors are commonly used in pulmonary arterial hypertension but, as suggested by the RESPITE study, phosphodiesterase-5 inhibitor therapy (mono-/combination) does not always have a satisfactory treatment effect. This study aimed to investigate the clinical course of pulmonary arterial hypertension patients not at treatment goal after at least 90 days of treatment with phosphodiesterase-5 inhibitors, alone or in combination with other pulmonary arterial hypertension therapies. The study included 106 incident patients from the Swedish Pulmonary Arterial Hypertension Registry, treated with phosphodiesterase-5 inhibitors for ≥90 days, who were not at a pre-specified treatment goal, i.e. in World Health Organisation functional class III, with 6-min walking distance 165-440 m, and N-terminal prohormone of brain natriuretic peptide >300 ng/L. Changes in World Health Organisation functional class, 6-min walking distance, N-terminal prohormone of brain natriuretic peptide, and risk group between index and follow-up were assessed. Of patients with complete follow-up data, (n = 53) 77% were on combination therapy and risk assessment yielded 98% at intermediate risk at index. At follow-up, 11 patients transitioned from World Health Organisation functional class III to World Health Organisation functional class II, the median (Q1; Q3) change in 6-min walking distance was 6 (-30; 42) meters and in N-terminal prohormone of brain natriuretic peptide 47 (-410; 603) ng/L, while 89% remained at an intermediate risk. Of those without complete follow-up data, 11 patients died and 2 underwent lung transplantation. In conclusion, pulmonary arterial hypertension patients treated with phosphodiesterase-5 inhibitors, as single or combination therapy and not achieving the pre-specified treatment goals after ≥90 days have an unfavourable clinical course.

Trauma, treatment and Tetris: video gaming increases hippocampal volume in male patients with combat-related posttraumatic stress disorder.

Background: Tetris has been proposed as a preventative intervention to reduce intrusive memories of a traumatic event. However, no neuroimaging study has assessed Tetris in patients with existing posttraumatic stress disorder (PTSD) or explored how playing Tetris may affect brain structure. Methods: We recruited patients with combat-related PTSD before psychotherapy and randomly assigned them to an experimental Tetris and therapy group (n = 20) or to a therapy-only control group (n = 20). In the control group, participants completed therapy as usual: eye movement desensitization and reprocessing (EMDR) psychotherapy. In the Tetris group, in addition to EMDR, participants also played 60 minutes of Tetris every day from onset to completion of therapy, approximately 6 weeks later. Participants completed structural MRI and psychological questionnaires before and after therapy, and we collected psychological questionnaire data at follow-up, approximately 6 months later. We hypothesized that the Tetris group would show increases in hippocampal volume and reductions in symptoms, both directly after completion of therapy and at follow-up. Results: Following therapy, hippocampal volume increased in the Tetris group, but not the control group. As well, hippocampal increases were correlated with reductions in symptoms of PTSD, depression and anxiety between completion of therapy and follow-up in the Tetris group, but not the control group. Limitations: Playing Tetris may act as a cognitive interference task and as a brain-training intervention, but it was not possible to distinguish between these 2 potential mechanisms. Conclusion: Tetris may be useful as an adjunct therapeutic intervention for PTSD. Tetris-related increases in hippocampal volume may ensure that therapeutic gains are maintained after completion of therapy.

Identifying predictors of within-person variance in MRI-based brain volume estimates.

Adequate reliability of measurement is a precondition for investigating individual differences and age-related changes in brain structure. One approach to improve reliability is to identify and control for variables that are predictive of within-person variance. To this end, we applied both classical statistical methods and machine-learning-inspired approaches to structural magnetic resonance imaging (sMRI) data of six participants aged 24-31 years gathered at 40-50 occasions distributed over 6-8 months from the Day2day study. We explored the within-person associations between 21 variables covering physiological, affective, social, and environmental factors and global measures of brain volume estimated by VBM8 and FreeSurfer. Time since the first scan was reliably associated with Freesurfer estimates of grey matter volume and total cortex volume, in line with a rate of annual brain volume shrinkage of about 1 percent. For the same two structural measures, time of day also emerged as a reliable predictor with an estimated diurnal volume decrease of, again, about 1 percent. Furthermore, we found weak predictive evidence for the number of steps taken on the previous day and testosterone levels. The results suggest a need to control for time-of-day effects in sMRI research. In particular, we recommend that researchers interested in assessing longitudinal change in the context of intervention studies or longitudinal panels make sure that, at each measurement occasion, (a) a given participant is measured at the same time of day; (b) all participants are measured at about the same time of day. Furthermore, the potential effects of physical activity, including moderate amounts of aerobic exercise, and testosterone levels on MRI-based measures of brain structure deserve further investigation.

Neural correlates of response bias: Larger hippocampal volume correlates with symptom aggravation in combat-related posttraumatic stress disorder.

The diagnosis of posttraumatic stress disorder (PTSD) is vulnerable to the simulation or exaggeration of symptoms as it depends on the individual's self-report of symptoms. The use of symptom validity tests is recommended to detect malingering in PTSD. However, in neuroimaging research, PTSD diagnosis is often taken at face validity. To date, no neuroimaging study has compared credible PTSD patients with those identified as malingering, and the potential impacts of including malingerers along with credible patients on results is unclear. We classified male patients with combat-related PTSD as either credible (n = 37) or malingerers (n = 9) based on the Morel Emotional Numbing Test and compared structural neuroimaging and psychological questionnaire data. Patients identified as malingerers had larger gray matter volumes in the hippocampus, right inferior frontal gyrus and thalamus, and reported higher PTSD symptoms than credible PTSD patients. This is the first structural neuroimaging study to compare credible PTSD patients and malingerers. We find evidence of structural differences between these groups, in regions implicated in PTSD, inhibition and deception. These results emphasize the need for the inclusion of SVTs in neuroimaging studies of PTSD to ensure future findings are not confounded by an unknown mix of valid PTSD patients and malingerers.

Hippocampal gray matter increases following multimodal psychological treatment for combat-related post-traumatic stress disorder.

Introduction: Smaller hippocampal volumes are one of the most consistent findings in neuroimaging studies of post-traumatic stress disorder (PTSD). However, very few prospective studies have assessed changes in hippocampal gray matter prior to and following therapy for PTSD, and no neuroimaging studies to date have longitudinally assessed military populations. Methods: A pilot study was conducted, assessing patients with combat-related PTSD with structural MRI. Participants were then assigned either to a treatment group or waiting-list control group. After the treatment group received multimodal psychological therapy for approximately 6 weeks, both groups completed a second neuroimaging assessment. Results: Region-of-interest analysis was used to measure gray matter volume in the hippocampus and amygdala. There was a group by time interaction; the therapy group (n = 6) showed a significant increase in hippocampal volume and a nonsignificant trend toward an increase in amygdala volume following therapy, while no change was observed in the waiting-list group (n = 9). Conclusions: This study provides initial evidence for increases in gray matter volume in the hippocampus in response to therapy for combat-related PTSD.

Community violence exposure correlates with smaller gray matter volume and lower IQ in urban adolescents.

Adolescents' exposure to community violence is a significant public health issue in urban settings and has been associated with poorer cognitive performance and increased risk for psychiatric illnesses, including PTSD. However, no study to date has investigated the neural correlates of community violence exposure in adolescents. Sixty-five healthy adolescents (age = 14-18 years; 36 females, 29 males) from moderate- to high-crime neighborhoods in Los Angeles reported their violence exposure, parents' education level, and free/reduced school lunch status (socio-economic status, SES), and underwent structural neuroimaging and intelligence testing. Violence exposure negatively correlated with measures of SES, IQ, and gray matter volume. Above and beyond the effect of SES, violence exposure negatively correlated with IQ and with gray matter volume in the left inferior frontal gyrus and anterior cingulate cortex, regions involved in high-level cognitive functions and autonomic modulation, and previously shown to be reduced in PTSD and combat-exposed military populations. The current results provide first evidence that frontal brain regions involved in cognition and affect appear to be selectively affected by exposure to community violence, even in healthy nondelinquent adolescents who are not the direct victims or perpetrators of violence.

Day2day: investigating daily variability of magnetic resonance imaging measures over half a year.

BACKGROUND: Most studies of brain structure and function, and their relationships to cognitive ability, have relied on inter-individual variability in magnetic resonance (MR) images. Intra-individual variability is often ignored or implicitly assumed to be equivalent to the former. Testing this assumption empirically by collecting enough data on single individuals is cumbersome and costly. We collected a dataset of multiple MR sequences and behavioural covariates to quantify and characterize intra-individual variability in MR images for multiple individuals. METHODS AND DESIGN: Eight participants volunteered to undergo brain scanning 40-50 times over the course of 6 months. Six participants completed the full set of sessions. T1-weighted, T2*-weighted during rest, T2-weighted high-resolution hippocampus, diffusion-tensor imaging (DTI), and proton magnetic resonance spectroscopy sequences were collected, along with a rich set of stable and time-varying physical, behavioural and physiological variables. Participants did not change their lifestyle or participated in any training programs during the period of data collection. CONCLUSION: This imaging dataset provides a large number of MRI scans in different modalities for six participants. It enables the analysis of the time course and correlates of intra-individual variability in structural, chemical, and functional aspects of the human brain.

Resting-state fMRI correlations: From link-wise unreliability to whole brain stability.

The functional architecture of spontaneous BOLD fluctuations has been characterized in detail by numerous studies, demonstrating its potential relevance as a biomarker. However, the systematic investigation of its consistency is still in its infancy. Here, we analyze within- and between-subject variability and test-retest reliability of resting-state functional connectivity (FC) in a unique data set comprising multiple fMRI scans (42) from 5 subjects, and 50 single scans from 50 subjects. We adopt a statistical framework that enables us to identify different sources of variability in FC. We show that the low reliability of single links can be significantly improved by using multiple scans per subject. Moreover, in contrast to earlier studies, we show that spatial heterogeneity in FC reliability is not significant. Finally, we demonstrate that despite the low reliability of individual links, the information carried by the whole-brain FC matrix is robust and can be used as a functional fingerprint to identify individual subjects from the population.