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Background: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition., Method: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS)., Results: On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex., Conclusions: This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region's involvement in cognitive control, particularly the 'regulative' component of this., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 -5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Auditory verbal hallucinations (AVH) are a key symptom of schizophrenia (SZ) defined by anomalous perception of speech. Anomalies of processing external speech stimuli have also been reported in people with AVH, but it is unexplored which specific dimensions of language are processed differently. Using a speech perception task (passive listening), we here targeted the processing of deixis, a key dimension of language governing the contextual anchoring of speech in interpersonal context. We designed naturalistic speech stimuli that were either non-personal and fact-reporting ('low-deixis' condition), or else involved rich deictic devices such as the grammatical first and second persons, direct questions, and vocatives ('high-deixis'). We asked whether neural correlates of deixis obtained with fMRI would distinguish patients with and without frequent hallucinations (AVH + vs AVH-) from controls and each other. Results showed that high-deixis relative to low-deixis was associated with clusters of increased activation in the bilateral middle temporal gyri extending into the temporal poles and the inferior parietal cortex, in all groups. The AVH + and AVH- groups did not differ. When unifying them, the SZ group as a whole showed altered activity in the precuneus, midline regions and inferior parietal cortex. These results fail to confirm deictic processing anomalies specific to patients with AVH, but reveal such anomalies across SZ. Hypoactivation of this network may relate to a cognitive mechanism for attributing and anchoring thought and referential speech content in context., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Previous imaging studies in patients with borderline personality disorder (BPD) have detected functional brain dysfunctions. Mindfulness training may improve the symptoms of BPD, although the neural mechanisms involved remain poorly understood. This study had several key aims: a) to investigate the role of right anterior insula (rAI) functional connectivity in modulating baseline emotional status in BPD, b) to compare differences in connectivity changes after mindfulness training versus interpersonal effectiveness intervention, and c) to explore the correlation between longitudinal changes in imaging data and clinical indicators., Methods: Thirty-eight patients with BPD underwent resting-state functional magnetic resonance imaging. Participants completed self-report clinical scales and participated in a dialectical-behavioral therapy (mindfulness versus interpersonal effectiveness modules). Changes in clinical and imaging variables were evaluated longitudinally after completion of the first 10-week sessions of psychotherapeutic intervention., Results: At baseline, the rAI was strongly connected with the other salience network nodes and anticorrelated with most core nodes of the default mode network (p < .05, corrected). The functional connectivity of the rAI correlated with emotional dysregulation and deficits in mindfulness capacities (p < .05, corrected). After completion of psychotherapeutic intervention, both groups (mindfulness and interpersonal effectiveness) showed divergent posttherapy functional connectivity changes, which were in turn associated with the clinical response., Conclusions: The functional connectivity of the rAI seems to play an important role in emotion dysregulation and deficits in mindfulness capacities in individuals with BPD. Psychotherapy seems to modulate this functional connectivity, leading to beneficial changes in clinical variables., (Copyright © 2021 by the American Psychosomatic Society.)

Background: Individuals with schizophrenia exhibit greater inter-patient variability in functional brain activity during neurocognitive task performance. Some studies have shown associations of age and illness duration with brain function; however, the association of these variables with variability in brain function activity is not known. In order to better understand the progressive effects of age and illness duration across disorders, we examined the relationship with individual variability in brain activity., Methods: Neuroimaging and behavioural data were extracted from harmonized datasets collectively including 212 control participants, 107 individuals with bipolar disorder, and 232 individuals with schizophrenia (total n = 551). Functional activity in response to an N-back working memory task (2-back vs 1-back) was examined. Individual variability was quantified via the correlational distance of fMRI activity between participants; mean correlational distance of one participant in relation to all others was defined as a 'variability score'., Results: Greater individual variability was found in the schizophrenia group compared to the bipolar disorder and control groups (p = 1.52e-09). Individual variability was significantly associated with aging (p = 0.027), however, this relationship was not different across diagnostic groups. In contrast, in the schizophrenia sample only, a longer illness duration was associated with increased variability (p = 0.027)., Conclusion: An increase in variability was observed in the schizophrenia group related to illness duration, beyond the effects of normal aging, implying illness-related deterioration of cognitive networks. This has clinical implications for considering long-term trajectories in schizophrenia and progressive neural and cognitive decline which may be amiable to novel treatments., 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 © 2022. Published by Elsevier Inc.)

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Sex differences influence the clinical characteristics and course of illness of bipolar disorder (BD)., Objective: Therefore, the aim of the present study was to examine the role of sex differences in neurocognitive performance and psychosocial functioning in a large sample of euthymic patients suffering from BD., Methods: The sample included 462 individuals, 347 patients with BD (148 males and 199 females) and 115 healthy controls (HC) (45 males and 70 females). Performance on a comprehensive neuropsychological battery assessing six cognitive domains and psychosocial functioning was compared between groups using linear mixed models, with sex and group as main effects, group by sex interactions and center as a random effect., Results: Males performed better than females in working memory (p < 0.001), whereas females outperformed males in the verbal learning (p = 0.03) and memory recognition (p = 0.03) tasks. No significant group by sex interactions were detected in cognitive performance. There were no overall sex differences or group by sex interactions in psychosocial functioning., Limitations: Lack of assessment of visuo-spatial working memory., Conclusions: There were no overall sex differences in neurocognition and psychosocial functioning. However, small sex differences in some measures of working memory and verbal memory were found. Individual differences of each patient, including sex perspective, should be considered in order to perform a tailored intervention plan adjusted to specific needs in the context of personalized treatment., (Copyright © 2021. Published by Elsevier B.V.)

The Stroop task, which examines an aspect of executive function/cognitive control, the ability to inhibit prepotent responses, has been relatively little examined in schizophrenia, and the findings have been inconsistent. Whether performance of this task is associated with failure of de-activation in the disorder is also uncertain. We examined 42 schizophrenic patients and 61 healthy controls during performance of an fMRI-adapted version of the Stroop task, the counting Stroop task. Task-related activations (incongruent > congruent condition) and de-activations (baseline > incongruent) were examined using whole-brain, voxel-based methods. In the healthy controls, task performance was found to be associated with activations in the left dorsolateral prefrontal cortex and the dorsal anterior cingulate cortex, among other regions. De-activations were seen in the medial frontal cortex, the middle and posterior cingulate gyrus and cuneus, the parahippocampal gyrus and the hippocampus. The schizophrenic patients did not show reduced activation compared to the healthy controls. They did, however, show failure of de-activation in the medial frontal cortex. Our negative finding with respect to hypoactivation during performance of a task requiring inhibition of prepotent responses suggests that brain functional abnormality in schizophrenia may not affect all aspects of executive function/cognitive control. The finding of medial frontal cortex failure of de-activation adds to existing findings of default mode network dysfunction in the disorder., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression., (© 2021. The Author(s).)

Although previous imaging studies in borderline personality disorder (BPD) have found brain abnormalities, the results have been inconsistent. This study aimed to investigate structural brain abnormalities using voxel-based morphometry (VBM) and cortical thickness (Cth) analyses in a large sample of patients with BPD. Additionally, we aimed to determine the correlation between structural abnormalities and clinical severity and to assess its potential value at predicting psychotherapeutic response. Sixty-one individuals with BPD and 19 healthy controls underwent magnetic resonance imaging. Participants with BPD completed several self-report clinical scales, received dialectical-behavioral therapy skills training and post-therapy changes in clinical scores were also recorded. Gray matter volume (GMV) and Cth differences between groups were compared. Within the BPD group, we further characterized the structural brain correlates of clinical severity and investigated the relationship between pre-therapy structural abnormalities and therapeutic response. As potential confounders we included age, sex, educational level, and total intracranial volume (the latter only in VBM analyses). Compared to controls, the BPD group showed a reduced GMV/Cth in prefrontal areas but increased GMV in the limbic structures (amygdala and parahippocampal regions). Prefrontal abnormalities correlated with higher baseline scores on impulsivity and general BPD severity. Increased GMV in the parahippocampal area correlated with a greater emotion dysregulation. Importantly, several baseline structural abnormalities correlated with worse response to psychotherapy. Patients with BPD showed a reduced GMV in the prefrontal areas but a greater GMV in the limbic structures. Several structural abnormalities (i.e. middle and inferior prefrontal areas, anterior insula, or parahippocampal area) correlated with clinical severity and could potentially be used as imaging biological correlates biomarkers to predict psychotherapy response., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

In spite of extensive work, inconsistent findings and lack of specificity in most neuroimaging techniques used to examine age- and gender-related patterns in brain tissue microstructure indicate the need for additional research. Here, we performed the largest Multi-component T 2 relaxometry cross-sectional study to date in healthy adults (N = 145, 18-60 years). Five quantitative microstructure parameters derived from various segments of the estimated T 2 spectra were evaluated, allowing a more specific interpretation of results in terms of tissue microstructure. We found similar age-related myelin water fraction (MWF) patterns in men and women but we also observed differential male related results including increased MWF content in a few white matter tracts, a faster decline with age of the intra- and extra-cellular water fraction and its T 2 relaxation time (i.e. steeper age related negative slopes) and a faster increase in the free and quasi-free water fraction, spanning the whole grey matter. Such results point to a sexual dimorphism in brain tissue microstructure and suggest a lesser vulnerability to age-related changes in women., (Copyright © 2021. Published by Elsevier Inc.)

Background: One hypothesis proposed to underlie formal thought disorder (FTD), the incoherent speech is seen in some patients with schizophrenia, is that it reflects impairment in frontal/executive function. While this proposal has received support in neuropsychological studies, it has been relatively little tested using functional imaging. This study aimed to examine brain activations associated with FTD, and its two main factor-analytically derived subsyndromes, during the performance of a working memory task., Methods: Seventy patients with schizophrenia showing a full range of FTD scores and 70 matched healthy controls underwent fMRI during the performance of the 2-back version of the n-back task. Whole-brain corrected, voxel-based correlations with FTD scores were examined in the patient group., Results: During 2-back performance the patients showed clusters of significant inverse correlation with FTD scores in the inferior frontal cortex and dorsolateral prefrontal cortex bilaterally, the left temporal cortex and subcortically in the basal ganglia and thalamus. Further analysis revealed that these correlations reflected an association only with 'alogia' (poverty of speech, poverty of content of speech and perseveration) and not with the 'fluent disorganization' component of FTD., Conclusions: This study provides functional imaging support for the view that FTD in schizophrenia may involve impaired executive/frontal function. However, the relationship appears to be exclusively with alogia and not with the variables contributing to fluent disorganization.

The Computerised Multiple Elements Test (CMET) is a novel executive task to assess goal management and maintenance suitable for use within the fMRI environment. Unlike classical executive paradigms, it resembles neuropsychological multi-elements tests that capture goal management in a more ecological way, by requiring the participant to switch between four simple games within a specified time period. The present study aims to evaluate an fMRI version of the CMET and examine its brain correlates. Thirty-one healthy participants performed the task during fMRI scanning. During each block, they were required to play four simple games, with the transition between games being made either voluntarily (executive condition) or automatically (control condition). The executive condition was associated with increased activity in fronto-parietal and cingulo-opercular regions, with anterior insula activity linked to better task performance. In an additional analysis, the activated regions showed to form functional networks during resting-state and to overlap the executive fronto-parietal and cingulo-opercular networks identified in resting-state with independently defined seeds. These results show the ability of the CMET to elicit activity in well-known executive networks, becoming a potential tool for the study of executive impairment in neurological and neuropsychiatric populations in a more ecological way than classical paradigms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Auditory verbal hallucinations (AVH, 'hearing voices') are an important symptom of schizophrenia but their biological basis is not well understood. One longstanding approach proposes that they are perceptual in nature, specifically that they reflect spontaneous abnormal neuronal activity in the auditory cortex, perhaps with additional 'top down' cognitive influences. Functional imaging studies employing the symptom capture technique-where activity when patients experience AVH is compared to times when they do not-have had mixed findings as to whether the auditory cortex is activated. Here, using a novel variant of the symptom capture technique, we show that the experience of AVH does not induce auditory cortex activation, even while real speech does, something that effectively rules out all theories that propose a perceptual component to AVH. Instead, we find that the experience of AVH activates language regions and/or regions that are engaged during verbal short-term memory., (© 2021. The Author(s).)

Schizophrenia is a complex psychiatric disorder that displays an outstanding interindividual variability in clinical manifestation and neurobiological substrates. A better characterization and quantification of this heterogeneity could guide the search for both common abnormalities (linked to lower intersubject variability) and the presence of biological subtypes (leading to a greater heterogeneity across subjects). In the current study, we address interindividual variability in functional connectome by means of resting-state fMRI in a large sample of patients with schizophrenia and healthy controls. Among the different metrics of distance/dissimilarity used to assess variability, geodesic distance showed robust results to head motion. The main findings of the current study point to (i) a higher between subject heterogeneity in the functional connectome of patients, (ii) variable levels of heterogeneity throughout the cortex, with greater variability in frontoparietal and default mode networks, and lower variability in the salience network, and (iii) an association of whole-brain variability with levels of clinical symptom severity and with topological properties of brain networks, suggesting that the average functional connectome overrepresents those patients with lower functional integration and with more severe clinical symptoms. Moreover, after performing a graph theoretical analysis of brain networks, we found that patients with more severe clinical symptoms had decreased connectivity at both whole-brain level and within the salience network, and that patients with higher negative symptoms had large-scale functional integration deficits., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates., (© 2020. The Author(s).)

Background: The coronavirus disease 2019 (COVID-19) pandemic and lockdown might increase anxiety and depressive symptoms in most individuals. Health bodies recommend several coping behaviors to protect against such symptoms, but evidence on the relationship between these behaviors and symptoms mostly comes from cross-sectional studies in convenience samples. We will conduct a prospective longitudinal study of the associations between coping behaviors and subsequent anxiety and depressive symptoms during the COVID-19 pandemic in a representative sample of the Spanish general adult population. Methods: We will recruit 1,000 adult participants from all autonomous communities of Spain and with sex, age, and urbanicity distributions similar to those of their populations and assess anxiety and depressive symptoms and coping behaviors using fortnightly questionnaires and real-time methods (ecological momentary assessments) for 1 year. The fortnightly questionnaires will inquire about anxiety and depressive symptoms [General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9)] and the frequency of 10 potential coping behaviors (e.g., follow a routine) during the past 2 weeks. In addition, we will collect several variables that could confound or moderate these associations. These will include subjective well-being [International Positive and Negative Affect Schedule Short Form (I-PANAS-SF) and Satisfaction with Life Scale (SWLS)], obsessive-compulsive symptoms [Obsessive Compulsive Inventory-Revised (OCI-R)], personality and emotional intelligence [International Personality Item Pool (IPIP) and Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF)], sociodemographic factors (e.g., work status, housing-built environment), and COVID-19 pandemic-related variables (e.g., hospitalizations or limitations in social gatherings). Finally, to analyze the primary relationship between coping behaviors and subsequent anxiety and depressive symptoms, we will use autoregressive moving average (ARMA) models. Discussion: Based on the study results, we will develop evidence-based, clear, and specific recommendations on coping behaviors during the COVID-19 pandemic and lockdown. Such suggestions might eventually help health bodies or individuals to manage current or future pandemics., Competing Interests: IG has received grants and served as consultant, advisor, or CME speaker for the following identities: Angelini, AstraZeneca, CasenRecordati, Ferrer, Janssen Cilag, and Lundbeck, Lundbeck-Otsuka, SEI Healthcare, FEDER. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. 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., (Copyright © 2021 Fortea, Solanes, Pomarol-Clotet, Garcia-Leon, Fortea, Torrent, Varo, Bonnin, Montejo, Alonso, Carmona, Soldevila-Matías, Alustiza, Arbós, Hidalgo-Mazzei, Grande, Vieta, Fullana and Radua.)

Reward prediction error, the difference between the expected and obtained reward, is known to act as a reinforcement learning neural signal. In the current study, we propose a model fitting approach that combines behavioral and neural data to fit computational models of reinforcement learning. Briefly, we penalized subject-specific fitted parameters that moved away too far from the group median, except when that deviation led to an improvement in the model's fit to neural responses. By means of a probabilistic monetary learning task and fMRI, we compared our approach with standard model fitting methods. Q-learning outperformed actor-critic at both behavioral and neural level, although the inclusion of neuroimaging data into model fitting improved the fit of actor-critic models. We observed both action-value and state-value prediction error signals in the striatum, while standard model fitting approaches failed to capture state-value signals. Finally, left ventral striatum correlated with reward prediction error while right ventral striatum with fictive prediction error, suggesting a functional hemispheric asymmetry regarding prediction-error driven learning.

Aim: To investigate DDR1  methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1 b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

Multi-component T 2 relaxometry allows probing tissue microstructure by assessing compartment-specific T 2 relaxation times and water fractions, including the myelin water fraction. Non-negative least squares (NNLS) with zero-order Tikhonov regularization is the conventional method for estimating smooth T 2 distributions. Despite the improved estimation provided by this method compared to non-regularized NNLS, the solution is still sensitive to the underlying noise and the regularization weight. This is especially relevant for clinically achievable signal-to-noise ratios. In the literature of inverse problems, various well-established approaches to promote smooth solutions, including first-order and second-order Tikhonov regularization, and different criteria for estimating the regularization weight have been proposed, such as L-curve, Generalized Cross-Validation, and Chi-square residual fitting. However, quantitative comparisons between the available reconstruction methods for computing the T 2 distribution, and between different approaches for selecting the optimal regularization weight, are lacking. In this study, we implemented and evaluated ten reconstruction algorithms, resulting from the individual combinations of three penalty terms with three criteria to estimate the regularization weight, plus non-regularized NNLS. Their performance was evaluated both in simulated data and real brain MRI data acquired from healthy volunteers through a scan-rescan repeatability analysis. Our findings demonstrate the need for regularization. As a result of this work, we provide a list of recommendations for selecting the optimal reconstruction algorithms based on the acquired data. Moreover, the implemented methods were packaged in a freely distributed toolbox to promote reproducible research, and to facilitate further research and the use of this promising quantitative technique in clinical practice., Competing Interests: Declaration of Competing Interest Gian Franco Piredda, Tom Hilbert, and Tobias Kober are employed by Siemens Healthcare AG. Switzerland., (Copyright © 2021. Published by Elsevier B.V.)

The ability of attributing mental states to oneself and to the others (theory of mind, ToM) is impaired in schizophrenia. ToM is not a monolithic function, it includes different capacities: some implies the decoding of affective states, others the reasoning about mental states. We have developed the BAT, a Battery to Assess Theory of mind abilities in adult psychotic subjects in an ecological audiovisual format. The performance on the BAT and three other test of social cognition was compared in a sample of schizophrenic patients with a control group. The samples were matched in terms of age and premorbid IQ. The BAT was sensitive to detect the ToM impairments in schizophrenia, showed good internal consistency and concurrent validity. The area under the ROC curves established a cutoff point that would correctly classify controls and patients in a 96.6% of cases. The factorial analysis isolated two factors: empathy and reasoning, with a good adjustment. Our results showed that the BAT could be a valid, ecological and usable tool to assess ToM in psychotic patients, with good psychometric properties, that would allow obtaining a more complete profile of their impairment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Previous studies have shown that the gene encoding the adhesion G protein-coupled receptor L3 (ADGRL3; formerly latrophilin 3, LPHN3) is associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Conversely, no studies have investigated the anatomical or functional brain substrates of ADGRL3 risk variants. We examined here whether individuals with different ADGRL3 haplotypes, including both patients with ADHD and healthy controls, showed differences in brain anatomy and function. We recruited and genotyped adult patients with combined type ADHD and healthy controls to achieve a sample balanced for age, sex, premorbid IQ, and three ADGRL3 haplotype groups (risk, protective, and others). The final sample (n = 128) underwent structural and functional brain imaging (voxel-based morphometry and n-back working memory fMRI). We analyzed the brain structural and functional effects of ADHD, haplotypes, and their interaction, covarying for age, sex, and medication. Individuals (patients or controls) with the protective haplotype showed strong, widespread hypo-activation in the frontal cortex extending to inferior temporal and fusiform gyri. Individuals (patients or controls) with the risk haplotype also showed hypo-activation, more focused in the right temporal cortex. Patients showed parietal hyper-activation. Disorder-haplotype interactions, as well as structural findings, were not statistically significant. To sum up, both protective and risk ADGRL3 haplotypes are associated with substantial brain hypo-activation during working memory tasks, stressing this gene's relevance in cognitive brain function. Conversely, we did not find brain effects of the interactions between adult ADHD and ADGRL3 haplotypes.

Deficits in emotion processing are a core feature of schizophrenia, but their neurobiological bases are poorly understood. Previous research, mainly focused on emotional face processing and emotion recognition deficits, has shown controverted results. Furthermore, the use of faces has been questioned for not entailing an appropriate stimulus to study emotional processing. This highlights the importance of investigating emotional processing abnormalities using evocative stimuli. For the first time, we have studied the brain responses to scenic stimuli in patients with schizophrenia. We selected scenes from the IAPS that elicit fear, disgust, happiness, and sadness. Twenty-six patients with schizophrenia and thirty age-, sex- and premorbid IQ-matched healthy controls were included. Behavioral task results show that patients tended to misclassify disgust and sadness as fear. Brain responses in patients were different from controls in images eliciting disgust and fear. In response to disgust images, patients hyperactivated the right temporal cortex, which was not activated by the controls. With fear images, hyperactivation was observed in brain regions involved in fear processing, including midline regions from the medial frontal cortex to the anterior cingulate cortex, the superior frontal gyrus, inferior and superior temporal cortex, and visual areas. These results suggest that schizophrenia is characterized by hyper-responsivity to stimuli evoking high-arousal, negative emotions, and a bias towards fear in emotion recognition., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The brain functional correlates of autobiographical recall are well established, but have been little studied in schizophrenia. Additionally, autobiographical memory is one of a small number of cognitive tasks that activates rather than de-activates the default mode network, which has been found to be dysfunctional in this disorder., Methods: Twenty-seven schizophrenic patients and 30 healthy controls underwent functional magnetic resonance imaging while viewing cue words that evoked autobiographical memories. Control conditions included both non-memory-evoking cues and a low level baseline (cross fixation)., Results: Compared to both non-memory evoking cues and low level baseline, autobiographical recall was associated with activation in default mode network regions in the controls including the medial frontal cortex, the posterior cingulate cortex and the hippocampus, as well as other areas. Clusters of de-activation were seen outside the default mode network. There were no activation differences between the schizophrenic patients and the controls, but the patients showed clusters of failure of de-activation in non-default mode network regions., Conclusions: According to this study, patients with schizophrenia show intact activation of the default mode network and other regions associated with recall of autobiographical memories. The finding of failure of de-activation outside the network suggests that schizophrenia may be associated with a general difficulty in de-activation rather than dysfunction of the default mode network per se.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., Design, Setting, and Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., Main Outcomes and Measures: Interregional profiles of group difference in cortical thickness between cases and controls., Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., Conclusions and Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Functional connectivity analyses are typically based on matrices containing bivariate measures of covariability, such as correlations. Although this has been a fruitful approach, it may not be the optimal strategy to fully explore the complex associations underlying brain activity. Here, we propose extending connectivity to multivariate functions relating to the temporal dynamics of a region with the rest of the brain. The main technical challenges of such an approach are multidimensionality and its associated risk of overfitting or even the non-uniqueness of model solutions. To minimize these risks, and as an alternative to the more common dimensionality reduction methods, we propose using two regularized multivariate connectivity models. On the one hand, simple linear functions of all brain nodes were fitted with ridge regression. On the other hand, a more flexible approach to avoid linearity and additivity assumptions was implemented through random forest regression. Similarities and differences between both methods and with simple averages of bivariate correlations (i.e., weighted global brain connectivity) were evaluated on a resting state sample of N = 173 healthy subjects. Results revealed distinct connectivity patterns from the two proposed methods, which were especially relevant in the age-related analyses where both ridge and random forest regressions showed significant patterns of age-related disconnection, almost completely absent from the much less sensitive global brain connectivity maps. On the other hand, the greater flexibility provided by the random forest algorithm allowed detecting sex-specific differences. The generic framework of multivariate connectivity implemented here may be easily extended to other types of regularized models., Competing Interests: EdV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behavior Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the EU Horizon 2020, and the Stanley Medical Research Institute. 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., (Copyright © 2020 Salvador, Verdolini, Garcia-Ruiz, Jiménez, Sarró, Vilella, Vieta, Canales-Rodríguez, Pomarol-Clotet and Voineskos.)

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47-67.00, ROC-AUC = 71.49%, 95% CI = 69.39-73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70-60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen's Kappa = 0.83, 95% CI = 0.829-0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

Background: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample., Method: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls., Results: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression., Conclusion: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning)., Competing Interests: Declaration of competing interest AB has consulting fees from Biogen and lecture fees from Lundbeck, Otsuka and Janssen. AP has served as a consultant for Boehringer Ingelheim. AS: Advisory board (DSP), Research grants (CynK, DSP, MTPC, and Ono). CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. CH is faculty member, Lundbeck Psychiatric Institute. CP is on an advisory board for Lundbeck, Australia Pty Ltd and also received honoraria for talks presented at educational meetings organized by Lundbeck. CSW is on an advisory board for Lundbeck, Australia Pty Ltd and in collaboration with Astellas Pharma Inc., Japan. DJS has received research grants or consultancy honoraria from Lundbeck and Sun. EV has received grants and served as a consultant, advisor or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. IN has no conflicts of interest to declare. RTS has received consulting fees from Genentech and Roche. SL has received consulting fees and speaking honoraria from Roche, Novartis, Biogen and Merck., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) has been found to be effective in treatment resistant neurological and psychiatric disorders. So far there has been only one completed trial in schizophrenia, in which seven treatment resistant patients received DBS in the subgenual anterior cingulate cortex (sgACC, N = 4) or the nucleus accumbens (NAc, N = 3); four met symptomatic response criteria over the trial period. Six patients underwent 18 F-FDG PET at baseline and after at least 6 months of stimulation. Individual patient analysis indicated that DBS to both the sgACC and NAc was associated with local and distant changes in glucose metabolism. Increments and decrements of brain activity were observed in regions that included the medial prefrontal cortex, the dorsolateral prefrontal cortex, the anterior cingulate cortex, the caudate nucleus, the NAc, the hippocampus and the thalamus. Increased activity appeared to be associated with clinical improvement. These preliminary findings suggest that DBS acts by modulating cerebral activity in the cortico-basal-thalamic-cortical circuit in patients with schizophrenia who show improvement in psychotic symptoms., Competing Interests: Declaration of competing interest All authors report no biomedical financial interest or potential conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Although executive and other cognitive deficits have been found in patients with borderline personality disorder (BPD), whether these have brain functional correlates has been little studied. This study aimed to examine patterns of task-related activation and de-activation during the performance of a working memory task in patients with the disorder., Methods: Sixty-seven DSM-IV BPD patients and 67 healthy controls underwent fMRI during the performance of the n-back task. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups., Results: On corrected whole-brain analysis, there were no activation differences between the BPD patients and the healthy controls during the main 2-back v. baseline contrast, but reduced activation was seen in the precentral cortex bilaterally and the left inferior parietal cortex in the 2-back v. 1-back contrast. The patients showed failure of de-activation affecting the medial frontal cortex and the precuneus, plus in other areas. The changes did not appear to be attributable to previous history of depression, which was present in nearly half the sample., Conclusions: In this study, there was some, though limited, evidence for lateral frontal hypoactivation in BPD during the performance of an executive task. BPD also appears to be associated with failure of de-activation in key regions of the default mode network.

BACKGROUND: The excess of mortality in people with severe mental illness is due to unnatural causes such as accidents or suicides and natural causes such as metabolic syndrome. The presence of modifiable risk factors like tobacco consumption increases cardiovascular and metabolic risk. AIMS: The purpose of this study was to identify the prevalence of metabolic syndrome and other cardiovascular risk factors in people with severe mental illness. This study also aimed to identify the prevalence of patients receiving treatment for any metabolic syndrome risk factor. METHOD: A cross-sectional descriptive study was performed. A total of 125 participants from two community mental health centers in Spain were recruited. RESULTS: More than half of the participants (58.4%) were active smokers. The prevalence of metabolic syndrome was 60%. A total of 16.8% received previous treatment for hypertension, 17.6% for hypertriglyceridemia, and 11.2% for diabetes. No differences were found between centers (22.7% vs. 18.7%, p = .9). CONCLUSIONS: The findings underscore the importance of monitoring the physical health of patients on antipsychotic therapy. The identification and management of cardiovascular and metabolic risks factors is an essential part of nursing care for people with severe mental illness. Mental health nurses are ideally positioned to carry out this task by performing physical health screening, health education, and lifestyle interventions.

Huntington's disease (HD) is a neurodegenerative disease causing motor symptoms along with cognitive and affective problems. Recent evidence suggests that HD also affects language across core levels of linguistic organization, including at stages of the disease when standardized neuropsychological test profiles are still normal and motor symptoms do not yet reach clinical thresholds ('pre-manifest HD'). The present study aimed to subject spontaneous speech to a more fine-grained linguistic analysis in a sample of 20 identified HD gene-carriers, 10 with pre-manifest and 10 with early manifest HD. We further explored how language performance related to non-linguistic cognitive impairment, using standardized neuropsychological measures. A distinctive pattern of linguistic impairments marked off participants with both pre-manifest and manifest HD from healthy controls and each other. Fluency patterns in premanifest HD were marked by prolongations, filled pauses, and repetitions, which shifted to a pattern marked by empty (unfilled) pauses, re-phrasings, and truncations in manifest HD. Both HD groups also significantly differed from controls and each other in how they grammatically connected clauses and used noun phrases referentially. Functional deficits in language occurred in pre-manifest HD in the absence of any non-linguistic neuropsychological impairment and did largely not correlate with standardized neuropsychological measures in manifest HD. These results further corroborate that language can act as a fine-grained clinical marker in HD, which can track disease progression from the pre-manifest stage, define critical remediation targets, and inform the role of the basal ganglia in language processing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: An alteration in self/other differentiation has been proposed as a basis for several symptoms in schizophrenia, including delusions of reference and social functioning deficits. Dysfunction of the right temporo-parietal junction (TPJ), a region linked with social cognition, has been proposed as the basis of this alteration. However, imaging studies of self- and other-processing in schizophrenia have shown, so far, inconsistent results., Methods: Patients with schizophrenia and healthy controls underwent fMRI scanning while performing a task with three conditions: self-reflection, other-reflection and semantic processing., Results: Both groups activated similar brain regions for self- and other-reflection compared to semantic processing, including the medial prefrontal cortex, the precuneus and the TPJ. Compared to healthy subjects, patients hyperactivated the left lateral frontal cortex during self- and other-reflection. In other-reflection, compared to self-reflection, patients failed to increase right TPJ activity., Conclusions: Altered activity in the right TPJ supports a disturbance in self/other differentiation in schizophrenia, which could be linked with psychotic symptoms and affect social functioning in patients. Hyperactivity of the lateral frontal cortex for self- and other-reflection suggests the presence of greater cognitive demand to perform the task in the patient group., Competing Interests: Declaration of Competing Interest None, (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The profiles of cortical abnormalities in schizophrenia and bipolar disorder, and how far they resemble each other, have only been studied to a limited extent. The aim of this study was to identify and compare the changes in cortical morphology associated with these pathologies., Methods: A total of 384 subjects, including 128 patients with schizophrenia, 128 patients with bipolar disorder and 127 sex-age-matched healthy subjects, were examined using cortical surface-based morphology. Four cortical structural measures were studied: cortical volume (CV), cortical thickness (CT), surface area (SA) and gyrification index (GI). Group comparisons for each separate cortical measure were conducted., Results: At a threshold of P = 0.05 corrected, both patient groups showed significant widespread CV and CT reductions in similar areas compared to healthy subjects. However, the changes in schizophrenia were more pronounced. While CV decrease in bipolar disorder was exclusively explained by cortical thinning, in schizophrenia it was driven by changes in CT and partially by SA. Reduced GI was only found in schizophrenia. The direct comparison between both disorders showed significant reductions in all measures in patients with schizophrenia., Conclusions: Cortical volume and cortical thickness deficits are shared between patients with schizophrenia and bipolar disorder, suggesting that both pathologies may be affected by similar environmental and neurodegenerative factors. However, the exclusive alteration in schizophrenia of metrics related to the geometry and curvature of the brain cortical surface (SA, GI) suggests that this group is influenced by additional neurodevelopmental and genetic factors., Competing Interests: Declaration of Competing of Interest All authors declare that they have no conflicts of interest., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly., Methods: Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed)., Findings: One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively)., Interpretation: These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The development of metabolic syndrome negatively affects the quality of life of people with serious mental illness. Experts agree on the need to evaluate the physical health of patients and intervene in modifiable risk factors, with emphasis on the promotion of healthy lifestyles. Interventions should include nutritional counselling and physical activity. This 24-week randomized trial evaluated the effects of a community-based nurse-led lifestyle-modification intervention in people with serious mental illness meeting metabolic syndrome criteria, and its impact on health-related quality of life and physical activity. Sixty-one participants from two community mental health centres were randomly assigned to the intervention or control group. The intervention consisted of weekly group sessions, with 20 min of theoretical content and 60 min of nurse-led physical activity. Postintervention results between groups showed no differences in weight, waist circumference, fasting glucose, and systolic blood pressure. Differences in body mass index, triglyceride concentrations, and diastolic blood pressure were found to be significant (P = 0.010, P = 0.038, and P = 0.017). Participants who performed the intervention reported an increase in physical activity, which did not occur in the control group (P = 0.035), and also reported better health status (P < 0.001). Our intervention showed positive effects reducing participants' cardiovascular and metabolic risks and improving their physical activity and quality of life. To our knowledge, this is the first clinical trial led and carried out by mental health nurses in community mental health centres which takes into account the effects of a lifestyle intervention on every metabolic syndrome criterion, health-related quality of life, and physical activity., (© 2019 Australian College of Mental Health Nurses Inc.)

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R 2  = 0.041, P corr  < 0.001) and cingulum (right: R 2  = 0.041, left: R 2  = 0.040, P corr  < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Magnetic resonance imaging (MRI) has been proposed as a source of information for automatic prediction of individual diagnosis in schizophrenia. Optimal integration of data from different MRI modalities is an active area of research aimed at increasing diagnostic accuracy. Based on a sample of 96 patients with schizophrenia and a matched sample of 115 healthy controls that had undergone a single multimodal MRI session, we generated individual brain maps of gray matter vbm, 1back, and 2back levels of activation ( n back fMRI), maps of amplitude of low-frequency fluctuations (resting-state fMRI), and maps of weighted global brain connectivity (resting-state fMRI). Four unimodal classifiers (Ridge, Lasso, Random Forests, and Gradient boosting) were applied to these maps to evaluate their classification accuracies. Based on the assignments made by the algorithms on test individuals, we quantified the amount of predictive information shared between maps (what we call redundancy analysis). Finally, we explored the added accuracy provided by a set of multimodal strategies that included post-classification integration based on probabilities, two-step sequential integration, and voxel-level multimodal integration through one-dimensional-convolutional neural networks (1D-CNNs). All four unimodal classifiers showed the highest test accuracies with the 2back maps (80% on average) achieving a maximum of 84% with the Lasso. Redundancy levels between brain maps were generally low (overall mean redundancy score of 0.14 in a 0-1 range), indicating that each brain map contained differential predictive information. The highest multimodal accuracy was delivered by the two-step Ridge classifier (87%) followed by the Ridge maximum and mean probability classifiers (both with 85% accuracy) and by the 1D-CNN, which achieved the same accuracy as the best unimodal classifier (84%). From these results, we conclude that from all MRI modalities evaluated task-based fMRI may be the best unimodal diagnostic option in schizophrenia. Low redundancy values point to ample potential for accuracy improvements through multimodal integration, with the two-step Ridge emerging as a suitable strategy., (Copyright © 2019 Salvador, Canales-Rodríguez, Guerrero-Pedraza, Sarró, Tordesillas-Gutiérrez, Maristany, Crespo-Facorro, McKenna and Pomarol-Clotet.)

Patients with borderline personality disorder (BPD) present dysfunctions of the default mode network (DMN). Mindfulness training has proven effective to improve the symptoms of BPD. The present study examines the effect of mindfulness training on BPD symptomatology and DMN activity during the performance of a working memory task in patients with BPD. Sixty-five individuals with BPD were randomized to receive psychotherapy with either the mindfulness module of dialectical behavioural therapy (DBT-M) or with interpersonal effectiveness module (DBT-IE). The impact of treatments was evaluated with clinical and mindfulness variables as well as with functional magnetic resonance imaging during performance of the task. Both groups showed improvement in BPD symptoms and other clinical variables after treatment. Unexpectedly, there were no between-group differences in DMN activation or deactivation. However, activation of the left anterior insula increased in both groups after the intervention. Compared with the control group, participants in the DBT-M group presented higher deactivation in a cluster extending bilaterally from the calcarine to the cuneus and superior occipital gyri., (© 2019 John Wiley & Sons, Ltd.)

Objectives: While widespread cortical and subcortical brain functional abnormalities have been found in bipolar disorder, the changes that take place between illness phases and recovery are less clearly documented. Only a small number of longitudinal studies of manic patients, in particular, have been carried out., Methods: Twenty-six bipolar patients underwent fMRI during performance of the n-back working memory task when manic and again after recovery. Twenty-six matched healthy controls were also scanned on two occasions. Task-related activations and de-activations were examined., Results: When manic, the patients showed clusters of significantly reduced activation in the left dorsolateral prefrontal cortex (DLPFC)/precentral cortex and the parietal cortex/superior precuneus bilaterally. They also showed failure of de-activation in the ventromedial frontal cortex (vmPFC). After recovery, activation in the left DLPFC/precentral cortex and in the bilateral parietal cortex/superior precuneus clusters increased significantly. However, failure of de-activation remained present in the vmPFC., Conclusions: Recovery from mania is associated with normalization of DLPFC and parietal hypoactivation, but not with vmPFC failure of de-activation, which accordingly appears to represent a trait abnormality in the disorder., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Research shows that personnel working in mental health facilities may share some of the societal prejudices towards mental illness. This might result in stigmatizing behaviours towards people suffering from mental disorders, undermining the quality of their care., Aims: To describe and compare attitudes towards mental illness across a sample of professionals working in a wide range of mental health facilities in Spain, Portugal and Italy., Method: We administered a survey to personnel including two questionnaires related to stigmatizing attitudes: The Community Attitudes toward the Mentally Ill (CAMI) and the Attribution Questionnaire (AQ-27). Data were compared according to professional category, work setting and country., Results: 34.06% (1525) professionals of the surveyed population responded adequately. Psychologists and social therapists had the most positive attitudes, and nursing assistants the most negative, on most factors of CAMI and AQ-27. Community staff had more positive attitudes than hospital-based professionals in most factors on CAMI and in discriminatory responses on AQ-27., Conclusions: Globally, mental health professionals showed a positive attitude towards mental illness, but also a relative support to coercive treatments. There are differences in attitudes modulated by professional category and setting. Results can guide preventive strategies, particularly for the hospital-based and nursing staff.

Very few studies have investigated the formal linguistic aspects of auditory verbal hallucinations (AVHs), though speech is a defining aspect of AVHs. Hallucinated speech heard by 19 patients with schizophrenia and highly frequent voices was obtained online, as and when they spoke, and annotated for pre-selected linguistic variables. Results showed that, consistently across the sample, (i) the grammatical first Person was significantly less represented than both second and third person, and often absent altogether; (ii) overwhelmingly, isolated clauses with no grammatical connectivity (parataxis) were produced, as compared with subordinations, coordinations, and adjunctions; (iii) in all participants except one, virtually no noun phrases (NPs) were anaphoric ones, back-referring to previous NPs, illustrating again a lack of connectivity across utterances. (vi) Sentence-level content was largely personal rather than impersonal, and in impersonal utterances, it was generally vague. (v) Formal syntactic errors were consistently nearly absent, as were semantic level errors such as paraphasias. Voice talk was not generally stereotyped. These results indicate that, despite a certain amount of individual variation, there is a distinctive linguistic profile to voice speech, which constrains theories of AVHs and their neurocognitive basis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Brain structural and functional changes in bipolar disorder (BD) are well-established findings, but it is uncertain whether these changes are already present in first episode mania (FEM)., Methods: We compared 31 FEM subjects, with 31 healthy individuals matched for age, sex, and premorbid IQ. Whole-brain voxel-wise morphometry, functional magnetic resonance imaging during the n-back task, and a functional connectivity analysis were performed., Results: There were no volumetric differences between the 2 groups. During the 2-back task, FEM patients did not perform differently from controls and activated similar regions, but they showed less deactivation in the ventromedial prefrontal cortex (vmPFC), the anterior hub of the default mode network (DMN). They showed preserved functional connectivity between the vmPFC and other regions of the DMN, but increased connectivity with the superior frontal gyrus., Conclusions: The absence of volumetric changes in FEM patients suggests that these changes could be related to progression of the illness. On the other hand, the failure of deactivation of the anterior hub of the DMN is present from the onset of the illness and may represent a core pathophysiological feature of BD., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)