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The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Background. Oculomotor studies have found saccadic abnormalities in obsessive-compulsive disorder (OCD), lending support for models postulating a central role for inhibition in OCD. Saccadic abnormalities in OCD may also be potential candidates for a biological marker, important for more endophenotype-oriented research. Saccadic abnormalities have not been examined in psychotropic-naive patients with OCD without co-morbidity. Method. We compared the error rates and latencies of 14 carefully selected adult psychotropic-naive patients with OCD with no co-morbid diagnosis and 14 pairwise matched healthy controls on a fixation task, on a prosaccade task and on an antisaccade task. Results. Patients with OCD showed normal error rates on all tasks, but latencies on the antisaccade task were significantly increased. Conclusions. Our results indicate that patients with OCD have no gross impairment of oculomotor inhibitory capacities, but may have a disturbed capacity to deliberately initiate a saccade to an imagined target. [ABSTRACT FROM AUTHOR]

Introduction: Ketamine demonstrates robust and rapidly occurring antidepressant effects in patients with difficult-to-treat major depressive disorder. Ketamine's antidepressant effects and its impact on functional networks in non-resistant forms of major depressive disorder are expected to provide valuable insight into ketamine's mechanism of action related to depression., Methods: This study employs an existing network model of major depressive disorder to investigate the effects of ketamine on resting state connectivity in a therapy-non-resistant major depressive disorder population. In a randomized, double-blind, placebo-controlled, cross-over study, 0.5 mg/kg racemic ketamine or 0.9%NaCl was administered intravenously in 16 MDD patients. We applied resting-state functional magnetic resonance imaging (rs-fMRI) to explore changes in functional brain connectivity directly at 50, 80 and 165 min (acute) and 24 h (delayed) following ketamine administration. A clinician-rated 10-item scale (MADRS) was administered at 165 min and 24 h after ketamine administration. Connections-of-interest (COIs) were based on the previously published corticolimbic-insular-striatalpallidal-thalamic (CLIPST) circuitry model of major depressive disorder., Results: Compared with placebo, ketamine significantly ( p < 0.0014) reduced the mean (SD) MADRS total score from 21.2 (5.9) pre-dose to 10.3 (4.6) 24 h post-dose. At both acute ( p < 0.0172) and delayed ( p < 0.0488) time points, significant rs-fMRI connectivity changes occurred only in MDD-related COIs as proposed by the CLIPST model. No changes in functional connectivity were found in non-CLIPST connections., Discussion: This study demonstrates that ketamine specifically affects depression-related circuitry. Analyzing functional connectivity based on a neurocircuitry model of a specific CNS disease and drug action may be an effective approach that could result in a more targeted analysis in future pharmaco-fMRI studies in CNS drug development., Competing Interests: Author KN was employed by the company Sumitomo Pharma Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Sumitomo Pharma Co., Ltd. The funder had the following involvement in the study: conceptualization of the study design and publication., (Copyright © 2025 Recourt, Van Gerven, Drenth, van der Grond, Nishigori, Van Der Wee and Jacobs.)

Adverse childhood experiences (ACEs) may result in long-term mental health complications, including post-traumatic stress disorder (PTSD). ACEs are known to be more frequent among military personnel, despite their need to maintain their mental health to accomplish their missions. Self-compassion, or treating oneself with kindness and understanding, can mitigate the psychological effects of adversity but is also affected by adversity. This cross-sectional study aimed to identify the complex relationships between ACEs, self-compassion, and PTSD symptoms among 752 new recruits of the Japan Air Self-Defense Force, of whom 537 with ACEs completed the PTSD Checklist for DSM-5. Hierarchical multiple regression analysis was used to examine the independent effect of self-compassion, measured using the Self-Compassion Scale, on PTSD symptoms. Mediation effect analysis with self-compassion as a mediator was conducted on the relationship between ACEs and PTSD symptoms. We confirmed high levels of ACEs among our participants compared to a healthy population of a previous study, and approximately 6% presented PTSD symptoms above a threshold. Self-compassion was significantly negatively associated with PTSD symptoms (β = -.22, 95% confidence interval [CI], -.34 to -.11). Mediation effect analysis revealed that self-compassion partially mediated the relationship between ACEs and PTSD symptoms, explaining 6.9% of this effect, and ACEs were negatively associated with self-compassion (β = -.13, 95% CI, -.22 to -.04). These findings suggested that self-compassion is a protective factor against PTSD symptoms, whereas ACEs can decrease self-compassion. Further research should explore educational interventions to enhance self-compassion among individuals with ACEs to mitigate PTSD symptoms., Competing Interests: Declaration of competing interest The author declares no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., Competing Interests: IA received speaker’s honorarium Lundbeck; OAA is a consultant to Cortechs.ai and Precision Health, speaker’s honorarium from Lundbeck, Janssen, Otsuka, Sunovion; HB is an Advisory Board Member or Consultant to Biogen, Eisai, Eli Lilly, Roche, Skin2Neuron, Cranbrook Care and Montefiore Homes; CRKC has received past partial research support from Biogen, Inc. (Boston, USA) for work unrelated to the topic of this manuscript; AMD is the Principal Investigator of a research agreement between General Electric Healthcare and the University of California, San Diego (UCSD); he is a Founder of and hold equity in CorTechs Labs, Inc. I am a member of the Scientific Advisory Board of Human Longevity, Inc., and the Mohn Medical Imaging and Visualization Center in Bergen, Norway. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies; BF has received educational speaking fees from Medice; HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care; DPH is a full time employee of Genentech, Inc; NH is a shareholder various manufacturers of medical technology; AM-L has received consultant fees from Daimler und Benz Stiftung, EPFL Brain Mind Institute, Fondation FondaMental, Hector Stiftung II, Invisio, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, Neurotorium, MedinCell, The LOOP Zürich, University Medical Center Utrecht, University of Washington, Verein für Mentales Wohlbefinden, von Behring-Röntgen-Stiftung; speaker fees from Ärztekammer Nordrhein, Caritas, Clarivate, Dt. Gesellschaft für Neurowissenschaftliche Begutachtung, Gentner Verlag, Landesärztekammer Baden-Württemberg, LWL Bochum, Northwell Health, Ruhr University Bochum, Penn State University, Society of Biological Psychiatry, University Prague, Vitos Klinik Rheingau and editorial and/or author fees fromAmerican Association for the Advancement of Science, ECNP, Servier Int., Thieme Verlag; WN is founder of Quantib BV and was scientific lead of Quantib BV until Jan 31, 2023; MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH (Fürth, Germany), for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, and for serving as a consultant for EVERIS Belgique SPRL in a project of the European Commission (REFORM/SC2020/029). MMN receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work; BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); NIH NHLBI (MESA Observational Study Monitoring Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior); MSreceived funding from Pfizer Inc. for a project not related to this research; ES received speaker fees from bfd buchholz fachinformationsdienst gmbh; PMT receives partial research support from Biogen, Inc., for research unrelated to this manuscript; MWW serves on Editorial Boards for Alzheimer’s & Dementia, and the Journal for Prevention of Alzheimer’s disease. He has served on Advisory Boards for Acumen Pharmaceutical, Alzheon, Inc., Cerecin, Merck Sharp & Dohme Corp., and NC Registry for Brain Health. He also serves on the USC ACTC grant which receives funding from Eisai for the AHEAD study. MWW has provided consulting to Boxer Capital, LLC, Cerecin, Inc., Clario, Dementia Society of Japan, Eisai, Guidepoint, Health and Wellness Partners, Indiana University, LCN Consulting, Merck Sharp & Dohme Corp., NC Registry for Brain Health, Prova Education, T3D Therapeutics, University of Southern California (USC), and WebMD. MWW has acted as a speaker/lecturer for China Association for Alzheimer’s Disease (CAAD) and Taipei Medical University, as well as a speaker/lecturer with academic travel funding provided by: AD/PD Congress, Cleveland Clinic, CTAD Congress, Foundation of Learning; Health Society (Japan), INSPIRE Project; U. Toulouse, Japan Society for Dementia Research, and Korean Dementia Society, Merck Sharp & Dohme Corp., National Center for Geriatrics and Gerontology (NCGG; Japan), University of Southern California (USC). MWW holds stock options with Alzeca, Alzheon, Inc., ALZPath, Inc., and Anven. MWW received support for his research from the following funding sources: National Institutes of Health (NIH)/NINDS/National Institute on Aging (NIA), Department of Defense (DOD), California Department of Public Health (CDPH), University of Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer’s Association, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI-BHR), The Stroke Foundation, and the Veterans Administration; AIC is currently employed by the Regeneron Genetics Center, a wholly-owned subsidiary of Regeneron Pharmaceuticals, Inc., and may hold Regeneron stock or stock options. All other authors declare no competing interests.

Importance: Peacekeepers in United Nations missions experience potentially traumatic events, resulting in increased risk for posttraumatic stress disorder (PTSD). Understanding the course and risk factors of PTSD symptom severity is crucial to ensure personnel safety., Objective: To investigate the incidence of PTSD, symptom severity trajectories, and potential risk factors associated with adverse trajectories among Japanese peacekeepers deployed in South Sudan., Design, Setting, and Participants: Data for this 6-year prospective cohort study were collected from December 2011 to December 2018 from Japan Ground Self-Defense Force personnel deployed at the United Nations Mission in South Sudan, corresponding to before and up to 78 months after deployment. Of 3799 potential participants, 80 were excluded because of multiple deployments and 757 because of missing data, incomplete responses, or not providing informed consent. Therefore, 2962 participants were included in the analysis. Data analysis was performed from February 2022 to February 2024., Exposure: The participants were deployed to United Nations Mission in South Sudan for 6 months., Main Outcomes and Measures: The 22-item Impact of Event Scale-Revised was used to assess PTSD symptoms, with 25 or more points indicating probable PTSD (p-PTSD). Sociodemographic data were collected, and the 30-item General Health Questionnaire was administered before deployment to identify risk factors for PTSD symptom severity., Results: In the 2962 participants studied (2901 [97.9%] male; mean [SD] age, 33.9 [7.2] years), the incidence of p-PTSD was 3.95%. Latent growth mixture models identified 4 symptom severity trajectories: resilient (2143 [72.3%]), recovery (479 [16.2%]), protracted (182 [6.1%]), and delayed (158 [5.3%]). Multinomial logistic regression showed that sleep disturbance was a common risk factor for the 2 most severe trajectories (protracted: odds ratio [OR], 1.29; 95% CI, 1.08-1.54; delayed: OR, 1.26; 95% CI, 1.03-1.53), whereas older age (OR, 1.25; 95% CI, 1.06-1.48), anxiety and dysphoria (OR, 1.45; 95% CI, 1.20-1.75), and general illness (OR, 1.30; 95% CI, 1.06-1.59) were associated with the protracted trajectory., Conclusions and Relevance: This cohort study found that approximately 4% of the participants developed p-PTSD and identified 4 distinct PTSD symptom trajectories. The findings suggest that addressing sleep disturbance and general health issues could effectively prevent PTSD symptoms among peacekeepers.

Objective: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia., Method: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior., Results: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments., Conclusions: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Acute withdrawal of headache medication in chronic migraine patients with medication overuse may lead to a dramatic reduction in headache frequency and severity. However, the brain networks underlying chronic migraine and a favorable response to acute withdrawal are still poorly understood. The goal of the present study was to characterize the pattern of intrinsic magnetic resonance imaging (MRI) functional connectivity (FC) specific to chronic migraine and to identify changes in FC that characterize subjects with CM reverting to less frequent headaches. Subjects with chronic migraine (N = 99) underwent a resting-state functional MRI scan before and after three months of medication withdrawal therapy. In addition, we included four control groups who were scanned once: healthy participants (N = 27), patients with episodic migraine (N = 25), patients with chronic back pain (N = 22), and patients with clinical depression (N = 17). Using dual regression analysis, we compared whole-brain voxel-level functional connectivity with ten well-known resting-state networks between chronic migraine and control groups, and between responders to treatment (≥50 % reduction in monthly headache days) and non-responders (<50 % reduction), before and after treatment. Subjects with chronic migraine showed differences in FC with a number of RS-networks, most of which involved the visual cortex, compared with healthy controls. A comparison with patients with episodic migraine, chronic pain and depression showed differences in the same direction, suggesting that altered patterns of functional connectivity in chronic migraine patients could to some extent be explained by shared symptomatology with other pain, depression, or migraine conditions. A comparison between responders and non-responders indicated that effective withdrawal reduced FC with the visual cortex for responders. Interestingly, responders already differed in functional connectivity of the visual cortex at baseline compared with non-responders. Altogether, we show that chronic migraine and successful medication withdrawal therapy are linked to changes in the functional connectivity of the visual cortex. These neuroimaging findings provide new insights into the pathways underlying migraine chronification and its reversibility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: First responders to disasters are at risk of developing post-traumatic stress disorder (PTSD). The trajectories of post-traumatic stress symptom severity differ among individuals, even if they are exposed to similar events. These trajectories have not yet been reported in non-Western first responders., Aims: We aimed to explore post-traumatic stress symptom severity trajectories and their risk factors in first responders to the 2011 Great East Japan Earthquake (GEJE) - a historically large earthquake that resulted in a tsunami and a nuclear disaster., Method: A total of 55 632 Japan Ground Self-Defense Force (JGSDF) personnel dispatched to the GEJE were enrolled in this 7-year longitudinal cohort study. PTSD symptom severity was measured using the Impact of Event Scale-Revised. Trajectories were identified using latent growth mixture models (LGMM). Nine potential risk factors for the symptom severity trajectories were analysed using multinomial logistic regression., Results: Five symptom severity trajectories were identified: 'resilient' (54.8%), 'recovery' (24.6%), 'incomplete recovery' (10.7%), 'late-onset' (5.7%), and 'chronic' (4.3%). The main risk factors for the four non-resilient trajectories were older age, personal disaster experiences and working conditions. These working conditions included duties involving body recovery or radiation exposure risk, longer deployment length, later or no post-deployment leave and longer post-deployment overtime., Conclusions: The majority of first responders to GEJE were resilient and developed few or no PTSD symptoms. A substantial minority experienced late-onset and chronic symptom severity trajectories. The identified risk factors can inform policies for prevention, early detection and intervention in individuals at risk of developing symptomatic trajectories.

The global public health crisis caused by COVID-19 has lasted longer than many of us would have hoped and expected. With its high uncertainty and limited control, the COVID-19 pandemic has undoubtedly asked a lot from all of us. One important central question is: how resilient have we proved in face of the unprecedented and prolonged coronavirus pandemic? There is a vast and rapidly growing literature that has examined the impact of the pandemic on mental health both on the shorter (2020) and longer (2021) term. This not only concerns pandemic-related effects on resilience in the general population, but also how the pandemic has challenged stress resilience and mental health outcomes across more specific vulnerable population groups: patients with a psychiatric disorder, COVID-19 diagnosed patients, health care workers, children and adolescents, pregnant women, and elderly people. It is challenging to keep up to date with, and interpret, this rapidly increasing scientific literature. In this review, we provide a critical overview on how the COVID-19 pandemic has impacted mental health and how human stress resilience has been shaped by the pandemic on the shorter and longer term. The vast literature is dominated by a wealth of data which are, however, not always of the highest quality and heavily depend on online and self-report surveys. Nevertheless, it appears that we have proven surprisingly resilient over time, with fast recovery from COVID-19 measures. Still, vulnerable groups such as adolescents and health care personnel that have been severely impacted by the COVID-19 pandemic do exist. Large interindividual differences exist, and for future pandemics there is a clear need to comprehensively and integratively assess resilience from the start to provide personalized help and interventions tailored to the specific needs for vulnerable groups., Competing Interests: Conflicts of Interest There are no conflicts of interest, (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Lupus fog is ill-defined. We aimed to study whether lupus fog is the result of dissociation by studying the prevalence of dissociation and dissociative fog in patients with SLE and neuropsychiatric manifestations of inflammatory and non-inflammatory origin., Methods: Patients visiting the tertiary referral center for neuropsychiatric systemic lupus erythematosus (NPSLE) of the LUMC between 2007-2019 were included. Patients were classified as having neuropsychiatric symptoms of inflammatory or non-inflammatory origin. Dissociation was studied using the Dissociative Experience Scale-II (DES), in which the presence of 28 dissociative symptoms is rated (0-100% of the time), of which one question assesses the presence of a dissociative fog directly. Average scores are calculated and scores ≥ 25 are considered indicative of a dissociative disorder. A score of ≥ 30 on question 28 (dissociative fog) was considered indicative for the presence of a fog. Summary scores in the general adult population range from 4.4 to 14. Multiple regression analysis (MRA) was performed to study the association between inflammatory neuropsychiatric symptoms and dissociation. DES results are presented as median (range) and MRA as B and 95% confidence interval (CI)., Results: DES questionnaires were available for 337 patients, of which 69 had an inflammatory NPSLE phenotype (20%). Mean age in the total study population was 43 ± 14 years and the majority was female (87%). The median dissociation score was 7.1 (0-75) and did not differ between patients with neuropsychiatric symptoms of inflammatory or non-inflammatory origin (B: -0.04 (95% CI: -0.17; 0.09)). 35 patients (10%) had a score indicative of a dissociative disorder. The most common type of dissociation was absorption/imagination. 43 patients (13%) reported a dissociative fog., Discussion: In most patients with SLE and neuropsychiatric symptoms, dissociative symptoms are within normal range, regardless of underlying etiology. Dissociative fog is present, but uncommon. Lupus fog is most likely not associated with dissociation.

Introduction: We aimed to investigate risk factors for fatigue in patients with systemic lupus erythematosus (SLE) and neuropsychiatric symptoms in order to identify potential interventional strategies., Methods: Patients visiting the neuropsychiatric SLE (NPSLE) clinic of the Leiden University Medical Center between 2007-2019 were included. In a multidisciplinary consensus meeting, SLE patients were classified as having neuropsychiatric symptoms of inflammatory origin (inflammatory phenotype) or other origin (non-inflammatory phenotype). Fatigue was assessed with the SF-36 vitality domain (VT) since 2007 and the multidimensional fatigue inventory (MFI) and visual analogue scale (VAS) since 2011. Patients with a score on the SF-36 VT ≥1 standard deviation (SD) away from the mean of age-related controls of the general population were classified as fatigued; patients ≥2 SD away were classified as extremely fatigued. Disease activity was measured using the SLE disease activity index-2000. The influence of the presence of an inflammatory phenotype, disease activity and symptoms of depression and anxiety as measured by the hospital anxiety and depression scale (HADS) was analyzed using multiple regression analyses corrected for age, sex and education., Results: 348 out of 371 eligible patients filled in questionnaires and were included in this study . The majority was female (87%) and the mean age was 43 ± 14 years. 72 patients (21%) had neuropsychiatric symptoms of an inflammatory origin. Fatigue was present in 78% of all patients and extreme fatigue was present in 50% of patients with an inflammatory phenotype vs 46% in the non-inflammatory phenotype. Fatigue was similar in patients with an inflammatory phenotype compared to patients with a non-inflammatory phenotype on the SF-36 VT (β: 0.8 (95% CI -4.8; 6.1) and there was less fatigue in patients with an inflammatory phenotype on the MFI and VAS (β: -3.7 (95% CI: -6.9; -0.5) and β: -1.0 (95% CI -1.6; -0.3)). There was no association between disease activity and fatigue, but symptoms of anxiety and depression (HADS) associated strongly with all fatigue measurements., Conclusion: This study suggests that intervention strategies to target fatigue in (NP)SLE patients may need to focus on symptoms of anxiety and depression rather than immunosuppressive treatment.

Importance: First responders are at risk for developing symptoms of posttraumatic stress disorder (PTSD). Little is known about the risk factors for developing PTSD during a years-long period after complex mass disasters., Objective: To explore the long-term course of PTSD symptoms and to identify risk factors and their relative association with PTSD among first responders dispatched to the 2011 Japanese earthquake, tsunami, and nuclear disaster., Design, Setting, and Participants: This 6-year, large, prospective cohort study was part of a continuous longitudinal study of Japan Ground Self-Defense Force first responders. The data were collected at 1, 6, 12, 24, 36, 48, 60, and 72 months after mission completion from 2011 to 2017. Of approximately 70 000 eligible participants, 56 388 were enrolled in this study. Data were analyzed from 2017 to 2020., Exposures: Stress exposures owing to personal or professional disaster experience (eg, duties with body recovery or radiation exposure risk) and working conditions (eg, deployment length, postdeployment overtime work)., Main Outcomes and Measures: The Impact of Event Scale-Revised score assessed PTSD symptoms; scores of at least 25 were defined as probable PTSD. Cox proportional hazards regression models assessed the risk factors for incidence of probable PTSD., Results: Among the 56 388 participants, 97.1% were men, and the median age at enrollment was 34 (range, 18-63) years. A probable PTSD rate was 2.7% at 1 month and showed a downward trend in the first year and a subsequent plateau. The cumulative incidence of probable PTSD was 6.75%. The severity of PTSD symptoms demonstrated a high degree of rank-order stability over time. Rather than professional disaster experience, sociodemographic factors and working conditions were independently associated with the incidence of probable PTSD: personal experience of the disaster (hazard ratio [HR], 1.96; 95% CI, 1.72-2.24), deployment length of at least 3 months (HR vs <1 month, 1.75; 95% CI, 1.52-2.02), increased age (HR for ≥46 vs ≤25 years, 2.28; 95% CI, 1.79-2.92), and postdeployment overtime work of at least 3 months (HR vs little to none, 1.61; 95% CI, 1.39-1.87)., Conclusions and Relevance: Given these findings, in the future, first responders' PTSD symptoms might be mitigated by shortening deployment length, avoiding postdeployment overtime work, and paying special attention to the needs of personnel with personal experience of the disaster or older age. Efforts to alleviate responders' initial symptoms will be required.

Exposure to childhood adverse events is associated with severe consequences for general health and structural and functional changes in the brain of its survivors. In order to unravel and in the end influence the pathway linking adversity and pathology, neuroimaging research is crucial. Up till now studies in minors are scarce and differ in type of adversity or methodology. Almost all studies report lower cortical thickness, but in a broad variety of regions. In this study we investigated cortical thickness measures and clinical data in a well circumscribed group of adolescents with PTSD related to childhood sexual abuse (CSA) (N = 21) and a healthy non-traumatised control group (N = 21). The ventromedial PFC (vmPFC), ACC, insula, and middle/superior temporal gyrus were chosen as ROI's due to their respective roles in emotion and information processing. No significant effect of group was found for cortical thickness, surface area or volume in any of the ROIs. This is in line with the results of research in adult women with sexual abuse related PTSD, suggesting that this may be specific to this group, independent of age. Recent research points to differential biological and pathological consequences of different types of childhood adversity.

Adverse childhood experiences (ACE) substantially increase the risk of later psychiatric and somatic pathology. While neurobiological factors are likely to play a mediating role, specific insights are lacking. The scarce neuroimaging studies in traumatised pediatric populations have provided inconsistent results, potentially due to the inclusion of different types of trauma. To further improve our understanding of the neurobiology of pediatric psychotrauma, this study seeks to investigate abnormalities in grey matter volume (GMV) in a homogeneous group of adolescents with posttraumatic stress disorder (PTSD) due to childhood sexual abuse (CSA) and the relationship between GMV and symptom severity. We performed a voxel based morphometry (VBM) analysis in 21 adolescents with CSA-related PTSD and 25 matched non-traumatised, non-clinical adolescents. Hippocampus, amygdala, anterior cingulate cortex (ACC), medial PFC (mPFC) and superior temporal gyrus (STG) were chosen as regions of interest (ROIs). Trauma symptomatology was measured with the Trauma Symptom Checklist for Children (TSCC) and dissociation symptoms with the Adolescent Dissociative Experiences Scale (A-DES). The ROI analysis showed that the CSA-related PTSD group had significant smaller volumes of the dorsal ACC as compared to healthy controls. However, no correlations were found between GMV and scores on the TSCC and A-DES. The smaller ACC volume is partly in line with previous studies in traumatised youth and is a consistent finding in traumatised adults. Taken together our results suggest that the dorsal ACC is implicated in the neurobiological sequelae of CSA, potentially associated with an altered evaluative processing of emotion, but not directly with PTSD severity., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Objective: To determine the contribution of reassessment in the attribution process of neuropsychiatric (NP) events to SLE or other aetiologies in a large, prospective and multidisciplinary assessed NPSLE cohort and to compare these results with other available attribution models for NP events occurring in SLE., Methods: Three hundred and four consecutive SLE patients presenting NP events were evaluated. All subjects underwent standardized multidisciplinary medical, neuropsychological, laboratory and radiological examination on the inclusion and reassessment dates. Diagnosis was always established by multidisciplinary consensus. The final diagnosis after reassessment also took into account disease course and response to treatment. These data were compared with currently available attribution models for NP events in SLE., Results: A total of 463 NP events were established. After reassessment, attribution to SLE was discordant in 64 (13.8%) NP events when compared with the first visit. We show that 14.5% of NP events previously attributed to SLE reclassified as non-NPSLE. In 86.4% of these patients immunosuppressive therapy was started after the first visit. When reassessment and available attribution models were compared, NPSLE cases overlapped considerably. Although specificity was high for all comparisons (0.81-0.95), an important variation in sensitivity (0.39-0.83) and agreement estimates (κ = 0.29-0.68) was observed. The Italian algorithm showed the highest sensitivity and specificity (>0.80) and moderate agreement (0.59-0.64)., Conclusion: In clinical practice NP events presenting in SLE are too often attributed to an immune-mediated origin. Multidisciplinary reassessment avoids misclassification in NPSLE. Multidisciplinary reassessment is the reference standard in NP events presenting in SLE and cannot be replaced by available attribution models., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: The developmental trajectory of psychopathy seemingly begins early in life and includes the presence of callous-unemotional (CU) traits (e.g., deficient emotional reactivity, callousness) in conduct-disordered (CD) youth. Though subregion-specific anomalies in amygdala function have been suggested in CU pathophysiology among antisocial populations, system-level studies of CU traits have typically examined the amygdala as a unitary structure. Hence, nothing is yet known of how amygdala subregional network function may contribute to callous-unemotionality in severely antisocial people., Methods: We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral amygdala (BLA) and centromedial amygdala (CMA) networks across three matched groups of juveniles: CD offenders with CU traits (CD/CU+; n = 25), CD offenders without CU traits (CD/CU-; n = 25), and healthy control subjects (n = 24). We additionally examined whether perturbed amygdala subregional connectivity coincides with altered volume and shape of the amygdaloid complex., Results: Relative to CD/CU- and healthy control youths, CD/CU+ youths showed abnormally increased BLA connectivity with a cluster that included both dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices, along with posterior cingulate, sensory associative, and striatal regions. In contrast, compared with CD/CU- and healthy control youths, CD/CU+ youths showed diminished CMA connectivity with ventromedial/orbitofrontal regions. Critically, these connectivity changes coincided with local hypotrophy of BLA and CMA subregions (without being statistically correlated) and were associated to more severe CU symptoms., Conclusions: These findings provide unique insights into a putative mechanism for perturbed attention-emotion interactions, which could bias salience processing and associative learning in youth with CD/CU+., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity.

Objective The objective of this study was to assess whether clinical and patient's reported outcomes are associated with a different pathophysiological origin of neuropsychiatric events presenting in systemic lupus erythematosus. Methods A total of 232 neuropsychiatric events presenting in 131 systemic lupus erythematosus patients were included. Neuropsychiatric systemic lupus erythematosus diagnosis was established per event by multidisciplinary evaluation. All neuropsychiatric events were divided according to a suspected underlying pathophysiological process into one of the following: non-neuropsychiatric systemic lupus erythematosus related, inflammatory and ischaemic neuropsychiatric systemic lupus erythematosus. The clinical outcome of all neuropsychiatric events was determined by a physician-completed four-point Likert scale. Health-related quality of life was measured with the subscales of the patient-generated Short Form 36 (SF-36) health survey questionnaire. The change between scores at paired visits of all domain scores, mental component summary (SF-36 MCS) and physical component summary (SF-36 PCS) scores were retrospectively calculated and used as patient-reported outcome. The association among these outcomes and the different origin of neuropsychiatric events was obtained using multiple logistic regression analysis. Results The clinical status of 26.8% non-neuropsychiatric systemic lupus erythematosus events, 15.8% ischaemic neuropsychiatric systemic lupus erythematosus and 51.6% inflammatory neuropsychiatric systemic lupus erythematosus improved after re-assessment. Almost all SF-36 domains had a positive change at re-assessment in all groups independently of the origin of neuropsychiatric events. Neuropsychiatric systemic lupus erythematosus ( B = 0.502; p < 0.001) and especially inflammatory neuropsychiatric systemic lupus erythematosus ( B = 0.827; p < 0.001) had better clinical outcome, with change in disease activity being the only important predictor. The change in SF-36 MCS was also independently associated with neuropsychiatric systemic lupus erythematosus ( B = 5.783; p < 0.05) and inflammatory neuropsychiatric systemic lupus erythematosus ( B = 11.133; p < 0.001). Disease duration and change in disease activity were the only predictors in both cases. The change in SF-36 PCS was only negatively associated with age. Conclusion Inflammatory neuropsychiatric systemic lupus erythematosus events have better clinical outcome and meaningful improvement in SF-36 MCS than ischaemic neuropsychiatric systemic lupus erythematosus or non-neuropsychiatric systemic lupus erythematosus.

Early onset is regarded as an important characteristic of anxiety disorders, associated with higher severity. However, previous findings diverge, as definitions of early onset vary and are often unsubstantiated. We objectively defined early onset in social phobia, panic disorder, agoraphobia, and generalised anxiety disorder, using cluster analysis with data gathered in the general population. Resulting cut-off ages for early onset were ≤22 (social phobia), ≤31 (panic disorder), ≤21 (agoraphobia), and ≤27 (generalised anxiety disorder). Comparison of psychiatric comorbidity and general wellbeing between subjects with early and late onset in the general population and an outpatient cohort, demonstrated that among outpatients anxiety comorbidity was more common in early onset agoraphobia, but also that anxiety- as well as mood comorbidity were more common in late onset social phobia. A major limitation was the retrospective assessment of onset. Our results encourage future studies into correlates of early onset of psychiatric disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Psychopathy is a serious psychiatric phenomenon characterized by a pathological constellation of affective (e.g., callous, unemotional), interpersonal (e.g., manipulative, egocentric), and behavioral (e.g., impulsive, irresponsible) personality traits. Though amygdala subregional defects are suggested in psychopathy, the functionality and connectivity of different amygdala subnuclei is typically disregarded in neurocircuit-level analyses of psychopathic personality. Hence, little is known of how amygdala subregional networks may contribute to psychopathy and its underlying trait assemblies in severely antisocial people. We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral (BLA) and centromedial (CMA) amygdala networks in relation to affective, interpersonal, and behavioral traits of psychopathy, in conduct-disordered juveniles with a history of serious delinquency (N = 50, mean age = 16.83 ± 1.32). As predicted, amygdalar connectivity profiles exhibited dissociable relations with different traits of psychopathy. Interpersonal psychopathic traits not only related to increased connectivity of BLA and CMA with a corticostriatal network formation accommodating reward processing, but also predicted stronger CMA connectivity with a network of cortical midline structures supporting sociocognitive processes. In contrast, affective psychopathic traits related to diminished CMA connectivity with a frontolimbic network serving salience processing and affective responding. Finally, behavioral psychopathic traits related to heightened BLA connectivity with a frontoparietal cluster implicated in regulatory executive functioning. We suggest that these trait-specific shifts in amygdalar connectivity could be particularly relevant to the psychopathic phenotype, as they may fuel a self-centered, emotionally cold, and behaviorally disinhibited profile. Hum Brain Mapp 37:4017-4033, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc., (© 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF., (© The Author (2016). Published by Oxford University Press.)

Adolescents with internalizing disorders and adolescents with childhood sexual abuse related post-traumatic stress disorder (CSA-related PTSD) show a large overlap in symptomatology. In addition, brain research indicated hyper-responsiveness and sustained activation instead of habituation of amygdala activation to emotional faces in both groups. Little is known, however, about whether the same patterns of amygdala habituation are present in these two groups. The current study examined habituation patterns of amygdala activity to emotional faces (fearful, happy and neutral) in adolescents with a DSM-IV depressive and/or anxiety disorder (N=25), adolescents with CSA-related PTSD (N=19) and healthy controls (N=26). Behaviourally, the adolescents from the internalizing and CSA-related PTSD group reported more anxiety to fearful and neutral faces than adolescents from the control group and adolescents from the CSA-related PTSD group reacted slower compared to the internalizing group. At the whole brain level, there was a significant interaction between time and group within the left amygdala. Follow-up ROI analysis showed elevated initial activity in the amygdala and rapid habituation in the CSA-related PTSD group compared to the internalizing group. These findings suggest that habituation patterns of amygdala activation provide additional information on problems with emotional face processing. Furthermore, the results suggest there are differences in the underlying neurobiological mechanisms related to emotional face processing for adolescents with internalizing disorders and adolescents with CSA-related PTSD. Possibly CSA-related PTSD is characterized by a stronger primary emotional response driven by the amygdala., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess white matter (WM) and gray matter (GM) magnetization transfer ratio histogram peak heights (MTR-HPHs) in different subsets of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) who have unremarkable findings on 3T magnetic resonance imaging of the brain and to evaluate whether these values could be used to highlight different clinically suspected underlying pathogenic processes or identify the clinical NPSLE status or whether they could be associated with a specific NPSLE syndrome., Methods: Sixty-four SLE patients with neuropsychiatric symptoms were included. The initial NPSLE diagnosis and suspected underlying pathogenic process were established by multidisciplinary evaluation. The final diagnosis was made after also considering the disease course 6-18 months later. Thirty-three patients with central nervous system (CNS) NPSLE and 31 SLE patients with neuropsychiatric symptoms unrelated to SLE (non-SLE-related NP) were included. Twenty SLE patients without neuropsychiatric symptoms and 36 healthy control subjects were included for comparison. Differences in the WM and GM mean MTR-HPHs and between the different NPSLE subgroups (CNS NPSLE diagnosis, NPSLE phenotype [inflammatory or ischemic], and clinical changes after treatment) and the relationship to NPSLE syndromes were evaluated., Results: Patients with inflammatory NPSLE had significantly lower WM MTR-HPHs than did the healthy controls, the SLE patients, and the non-SLE-related NP patients. Cognitive disorder, mood disorder, and psychosis were related to lower WM MTR-HPH values and cerebrovascular symptoms to higher values. Furthermore, the mean MTR-HPHs in the WM increased when the clinical status of the NPSLE patients improved., Conclusion: Measurement of MTR-HPH of the WM has the potential to identify inflammatory NPSLE with CNS involvement. This finding underscores the usefulness of this technique for the detection of cerebral changes in NPSLE patients and for the assessment of clinical changes after treatment., (© 2016, American College of Rheumatology.)

This study seeks to determine whether white matter integrity in the brain differs between adolescents with post-traumatic stress disorder (PTSD) due to childhood sexual abuse (CSA) and matched healthy adolescents and whether there is a relationship between white matter integrity and symptom severity in the patient group. Using 3T diffusion tensor imaging, we examined fractional anisotropy (FA) in a group of adolescents with CSA-related PTSD (n = 20) and matched healthy controls (n = 20), in a region of interest consisting of the bilateral uncinate fasciculus (UF), the genu, splenium and body of the corpus callosum (CC), and the bilateral cingulum. In addition, we performed an exploratory whole brain analysis. Trauma symptomatology was measured with the Trauma Symptom Checklist for Children (TSCC) to enable correlational analyses between FA differences and trauma symptomatology. The PTSD group had significantly lower FA values in the genu, midbody and splenium of the CC in comparison with controls (p < 0.05, tfce corrected). Post hoc analyses of the eigenvalues of the DTI scan showed increased radial and mean diffusivity in the patient group. In addition, we found a significant negative correlation between scores on the anger subscale of the TSCC and FA values in the left body of the CC in patients (p < 0.05). Adolescents with CSA-related PTSD show decreased FA in the CC, with abnormalities in the integrity of the left body of the CC being related to anger symptoms. These findings suggest that early trauma exposure affects the development of the CC, which may play a role in the pathophysiology of PTSD in adolescents.

Unlabelled: The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity., Significance Statement: The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system., (Copyright © 2016 the authors 0270-6474/16/367866-12$15.00/0.)

A substantial proportion of patients with burn injury develop chronic itch, which can severely affect their quality of life. As found in research on chronic pain, different psychophysiological processes may also play a role in chronic itch, of which central sensitization, conditioned modulation, and attentional processes have been studied most frequently. This study aimed to explore psychophysiological processes of chronic post-burn itch by comparing 15 patients with long-term itch due to burn injury with 15 matched healthy controls. Exploratory results indicated tendencies for higher itch sensitivity in patients than in controls, for mechanical stimuli and histamine, but not for electrical stimulation. Results further suggest that the efficacy of itch modulation by an itch- or pain-conditioning stimulus or directing attention towards itch stimuli do not differ between these patients and controls. Further elucidation of the processes underlying post-burn itch may improve the early identification and treatment of burn patients developing chronic itch.

Background: Deficits in empathy are reported in autism spectrum disorders (ASD) and also underlie antisocial behavior of individuals with conduct disorder and callous-unemotional traits (CD/CU+). Many studies suggest that individuals with ASD are typically impaired in cognitive aspects of empathy, and individuals with CD/CU+ typically in affective aspects. In the current study, we compared the neural correlates of cognitive and affective aspects of empathy between youth with ASD and youth with CD/CU+., Methods: Functional magnetic resonance imaging (fMRI) was used to assess boys with ASD (N = 23), boys with CD/CU+ (N = 23), and typically developing (TD) boys (N = 33), aged 15-19 years. Angry and fearful faces were presented and participants were asked to either infer the emotional state from the face (other-task; emotion recognition) or to judge their own emotional response to the face (self-task; emotional resonance)., Results: During emotion recognition, boys with ASD showed reduced responses compared to the other groups in the ventromedial prefrontal cortex (vmPFC). During emotional resonance, the CD/CU+ and ASD groups showed reduced amygdala responses compared to the TD controls, boys with ASD showed reduced responses in bilateral hippocampus, and the CD/CU+ boys showed reduced responses in the inferior frontal gyrus (IFG) and anterior insula (AI)., Conclusion: Results suggest differential abnormal brain responses associated with specific aspects of empathic functioning in ASD and CD/CU+. Decreased amygdala responses in ASD and CD/CU+ might point to impaired emotion processing in both disorders, whereas reduced vmPFC responses suggest problems in processing cognitive aspects of empathy in ASD. Reduced IFG/AI responses, finally, suggest decreased emotional resonance in CD/CU+., (© 2015 Association for Child and Adolescent Mental Health.)

Background: Data from the general population show higher prevalence of different anxiety disorders in women as compared with men. We analysed gender differences in a naturalistic sample of outpatients with anxiety disorders in a mental healthcare setting., Method: Routine outcome monitoring data were collected from 1333 patients (age: 18-65; 63.3% women) fulfilling Diagnostic and Statistical Manual of Mental Disorders IV criteria of current anxiety disorder according to the Mini-International Neuropsychiatric Interview between 2004 through 2006. Data included Comprehensive Psychopathological Rating Scale, Brief Symptom Inventory (BSI), Short Form Health Survey (SF-36), Mood and Anxiety Symptom Questionnaire (MASQ). Chi-squared test and t-test were used to compare women with men for variables with parametric distributions, and Mann-Whitney test for non-parametric distribution. Adjustments for potential confounders (age, level of education, ethnicity and comorbidites) were made by logistic regression models (for discrete variables) or analysis of covariance., Results: The female-to-male ratio (i.e., 844 women, 489 men) for any anxiety disorder was 1.73 : 1 (95% confidence interval [CI]: 1.63-1.83), with the strongest skewness for post-traumatic stress disorder (2.80 : 1) and the smallest one for social phobia (1.18 : 1). Compared with men, women reported more severe self-rating scores on the BSI (on average, the scores were 12.3% higher on 3 of 9 subscales: somatisation, interpersonal sensitivity and anxiety), SF-36 (self-reported generic health status was lower on 5 of 8 subscales: physical functioning, social functioning, physical problems, vitality and bodily pain) and MASQ (on average, the scores were 6.6% higher on 4 of 5 subscales: anxious arousal, general distress, general distress depression, general distress anxiety). On the contrary, no gender difference was found in the severity of anxiety symptoms measured by the Brief Anxiety Scale. Women were more likely to suffer from comorbid depression and bulimia nervosa, and less likely from substance abuse., Conclusions: In a treatment-seeking population the prevalence rate of anxiety disorders was 1.7 times higher in female compared with men. Female outpatients were more severely affected on self-rated but not on observer-rated scales.

Unlabelled: Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations., Significance Statement: Norepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding., (Copyright © 2016 the authors 0270-6474/16/365699-10$15.00/0.)

Research suggests that individuals with conduct disorder (CD) are marked by social impairments, such as difficulties in processing the affective reactions of others. Little is known, though, about how they make decisions during social interactions in response to emotional expressions of others. In this study, we therefore investigated the neural mechanisms underlying fairness decisions in response to communicated emotions of others in aggressive, criminal justice-involved boys with CD (N = 32) compared with typically developing (TD) boys (N = 33), aged 15-19 years. Participants received written emotional responses (angry, disappointed or happy) from peers in response to a previous offer and then had to make fairness decisions in a version of the Dictator Game. Behavioral results showed that CD boys did not make differential fairness decisions in response to the emotions, whereas the TD boys did show a differentiation and also responded more unfair to happy reactions than the CD boys. Neuroimaging results revealed that when receiving happy vs disappointed and angry reactions, the CD boys showed less activation than the TD boys in the temporoparietal junction and supramarginal gyrus, regions involved in perspective taking and attention. These results suggest that boys with CD have difficulties with processing explicit emotional cues from others on behavioral and neural levels., (© The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Objective: Several neuroimaging meta-analyses have summarized structural brain changes in major depression using coordinate-based methods. These methods might be biased toward brain regions where significant differences were found in the original studies. In this study, a novel voxel-based technique is implemented that estimates and meta-analyses between-group differences in grey matter from individual MRI studies, which are then applied to the study of major depression., Methods: A systematic review and meta-analysis of voxel-based morphometry studies were conducted comparing participants with major depression and healthy controls by using statistical parametric maps. Summary effect sizes were computed correcting for multiple comparisons at the voxel level. Publication bias and heterogeneity were also estimated and the excess of heterogeneity was investigated with metaregression analyses., Results: Patients with major depression were characterized by diffuse bilateral grey matter loss in ventrolateral and ventromedial frontal systems extending into temporal gyri compared to healthy controls. Grey matter reduction was also detected in the right parahippocampal and fusiform gyri, hippocampus, and bilateral thalamus. Other areas included parietal lobes and cerebellum. There was no evidence of statistically significant publication bias or heterogeneity., Conclusions: The novel computational meta-analytic approach used in this study identified extensive grey matter loss in key brain regions implicated in emotion generation and regulation. Results are not biased toward the findings of the original studies because they include all available imaging data, irrespective of statistically significant regions, resulting in enhanced detection of additional areas of grey matter loss., (© 2016 Wiley Periodicals, Inc.)

Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets., (© 2016 Wiley Periodicals, Inc.)

Background: Abnormal brain activations during processing of emotional facial expressions in depressed patients have been demonstrated. We investigated the natural course of brain activation in response to emotional faces in depression, indexed by functional magnetic resonance imaging (fMRI) scans preceding and following change in depressive state. We hypothesized a decrease in activation in the amygdala, anterior cingulate cortex (ACC), and insula with a decrease in depressive pathology., Methods: A 2-year longitudinal fMRI study was conducted as part of the Netherlands Study of Depression and Anxiety. We included 32 healthy controls and 49 depressed patients. During the second scan, 27 patients were in remission (remitters), the other 22 were not (nonremitters). All participants viewed faces with emotional expressions during scanning., Results: Rostral ACC activation during processing of happy faces was predictive of a decrease in depressive state (PFWE = .003). In addition, remitters showed decreased activation of the insula over time (PFWE = .016), specifically during happy faces. Nonremitters displayed increased abnormalities in emotion recognition circuitry during the second scan compared to the first. No effect of selective serotonin reuptake inhibitor use was observed., Conclusions: Our results demonstrate that rostral ACC activation may predict changes in depressive state even at 2-year outcome. The association between change in depressed state and change in insula activation provides further evidence for the role of the insula in a network maintaining emotional and motivational states., (© 2015 Wiley Periodicals, Inc.)

Rationale: The specific role of neuromodulator systems in regulating rapid fluctuations of attention is still poorly understood., Objectives: In this study, we examined the effects of clonidine and scopolamine on multiple target detection in a rapid serial visual presentation task to assess the role of the central noradrenergic and cholinergic systems in temporal attention., Method: Eighteen healthy volunteers took part in a crossover double-dummy study in which they received clonidine (150/175 μg), scopolamine (1.2 mg), and placebo by mouth in counterbalanced order. A dual-target attentional blink task was administered at 120 min after scopolamine intake and 180 min after clonidine intake. The electroencephalogram was measured during task performance., Results: Clonidine and scopolamine both impaired detection of the first target (T1). For clonidine, this impairment was accompanied by decreased amplitudes of the P2 and P3 components of the event-related potential. The drugs did not impair second-target (T2) detection, except if T2 was presented immediately after T1. The attentional blink for T2 was not affected, in line with a previous study that found no effect of clonidine on the attentional blink., Conclusions: These and other results suggest that clonidine and scopolamine may impair temporal attention through a decrease in tonic alertness and that this decrease in alertness can be temporarily compensated by a phasic alerting response to a salient stimulus. The comparable behavioral effects of clonidine and scopolamine are consistent with animal studies indicating close interactions between the noradrenergic and cholinergic neuromodulator systems.

Objective: Catatonia is an underdiagnosed syndrome that may occur in severely ill patients. The malignant subtype, consisting of motor symptoms, autonomic instability and fever, is associated with high mortality rates, though exact current mortality rates are unknown. This subtype requires a fast detection and treatment with high doses of a benzodiazepine or electroconvulsive therapy (ECT), preferably in an intensive care unit (ICU) setting., Method: Case series and qualitative literature review., Results: This paper presents four patients admitted to the ICU of an academic hospital diagnosed with malignant catatonia. All patients received ECT after an ineffective trial of high-dose intravenous benzodiazepine treatment. The duration of ECT ranged from 6 to 23 treatments after which the catatonic features partially or fully remitted. In addition, we have reviewed the diagnostic challenges, neurobiology, possible causes, differential diagnosis and treatment options of catatonia, focusing on the treatment with ECT and the importance of detection and multidisciplinary collaboration., Conclusion: Malignant catatonia is an underdiagnosed, potentially life-threatening syndrome that requires fast recognition and prompt treatment, preferably in an ICU setting., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Researchers have proposed several hypotheses about the neuromodulator systems involved in generating P3 components of the ERP. To test some of these hypotheses, we conducted a randomized placebo-controlled crossover study in which we investigated how the late positive ERP response to deviant stimuli is modulated by (a) clonidine, an α2 agonist that attenuates baseline noradrenergic activity; and (b) scopolamine, a muscarinic antagonist of acetylcholine receptors. We collected EEG data from 18 healthy volunteers during the performance of an auditory oddball task with several active and passive task conditions. We then used temporospatial principal component analysis (PCA) to decompose the ERP waveforms. The PCA revealed two distinct late positive ERP components: the classic parietal P300 and the frontal novelty P3. Statistical analysis of the temporospatial factor scores indicated that in most conditions the amplitude of the classic P300 was increased by clonidine and scopolamine. In contrast, the amplitude of the novelty P3 was decreased by both drugs. The similar pattern of results for clonidine and scopolamine probably reflects the strong interactions between the noradrenergic and cholinergic systems. The results, in combination with previous pharmacological studies, suggest a critical role for both neuromodulator systems in the generation of the P300 and the novelty P3., (© 2015 Society for Psychophysiological Research.)

Depression and anxiety disorders are highly comorbid and share neurobiological characteristics. However, this is usually not explicitly addressed in studies on intrinsic brain functioning in these disorders. Contrary to previous resting-state reports on small, monodiagnostic subsets of the current sample, we investigated resting-state functional connectivity (RSFC) in medication-free patients with depression, anxiety, comorbid depression and anxiety, and a healthy control group. RSFC was investigated in 140 medication-free subjects: 37 major depressive disorder patients (MDD), 30 patients with one or more anxiety disorders (ANX), 25 patients with MDD and one or more anxiety disorders (COM), and 48 healthy controls (HC). RSFC networks were calculated using a probabilistic independent component analysis. Using a dual regression approach, individuals׳ timecourses were extracted and regressed to obtain subjects-specific spatial maps, which were used for group comparisons in four networks of interest (limbic, default mode, salience and sensory-motor networks). When compared to HC, the COM group showed increased RSFC of the limbic network with a cluster containing the bilateral precuneus, intracalcarine cortex, lingual gyrus, and posterior cingulate, and with a cluster including the right precentral gyrus, inferior frontal gyrus, and middle frontal gyrus. This effect was specific for comorbid depression and anxiety. No abnormal RSFC of other networks or in the MDD and ANX groups was observed. No association was found between strength of RSFC and symptom severity. These results indicate that altered RSFC of cortical regions with a limbic network could be specific for comorbid depression and anxiety., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Cannabis has been suggested to impair the capacity to recognize discrepancies between expected and executed actions. However, there is a lack of conclusive evidence regarding the acute impact of cannabis on the neural correlates of error monitoring. In order to contribute to the available knowledge, we used a randomized, double-blind, between-groups design to investigate the impact of administration of a low (5.5 mg THC) or high (22 mg THC) dose of vaporized cannabis vs. placebo on the amplitudes of the error-related negativity (ERN) and error positivity (Pe) in the context of the Flanker task, in a group of frequent cannabis users (required to use cannabis minimally 4 times a week, for at least 2 years). Subjects in the high dose group (n=18) demonstrated a significantly diminished ERN in comparison to the placebo condition (n=19), whereas a reduced Pe amplitude was observed in both the high and low dose (n=18) conditions, as compared to placebo. The results suggest that a high dose of cannabis may affect the neural correlates of both the conscious (late), as well as the initial automatic processes involved in error monitoring, while a low dose of cannabis might impact only the conscious (late) processing of errors., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)