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Abstract Background Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders, and involves high relapse rates in which persistent negative thinking and rumination (i.e., perseverative cognition [PC]) play an important role. Positive fantasizing and mindfulness are common evidence-based psychological interventions that have been shown to effectively reduce PC and subsequent depressive relapse. How the interventions cause changes in PC over time, is unknown, but likely differ between the two. Whereas fantasizing may change the valence of thought content, mindfulness may operate through disengaging from automatic thought patterns. Comparing mechanisms of both interventions in a clinical sample and a non-clinical sample can give insight into the effectivity of interventions for different individuals. The current study aims to 1) test whether momentary psychological and psychophysiological indices of PC are differentially affected by positive fantasizing versus mindfulness-based interventions, 2) test whether the mechanisms of change by which fantasizing and mindfulness affect PC differ between remitted MDD versus never-depressed (ND) individuals, and 3) explore potential moderators of the main effects of the two interventions (i.e., what works for whom). Methods In this cross-over trial of fantasizing versus mindfulness interventions, we will include 50 remitted MDD and 50 ND individuals. Before the start of the measurements, participants complete several individual characteristics. Daily-life diary measures of thoughts and feelings (using an experience sampling method), behavioural measures of spontaneous thoughts (using the Sustained Attention to Response Task), actigraphy, physiological measures (impedance cardiography, electrocardiography, and electroencephalogram), and measures of depressive mood (self-report questionnaires) are performed during the week before (pre-) the interventions and the week during (peri-) the interventions. After a wash-out of at least one month, pre- and peri-intervention measures for the second intervention are repeated. Discussion This is the first study integrating self-reports, behavioural-, and physiological measures capturing dynamics at multiple time scales to examine the differential mechanisms of change in PC by psychological interventions in individuals remitted from multiple MDD episodes and ND individuals. Unravelling how therapeutic techniques affect PC in remitted individuals might generate insights that allows development of personalised targeted relapse prevention interventions. Trial registration ClinicalTrials.gov: NCT06145984, November 16, 2023.

Measurement(s) Blood Oxygen Level-Dependent Functional MRI • brain • Emotion Technology Type(s) functional magnetic resonance imaging • Magnetic Resonance Imaging • Emotion regulation task Factor Type(s) valence • emotion regulation condition Sample Characteristic - Organism Homo sapiens Sample Characteristic - Environment laboratory environment Sample Characteristic - Location Mexico

Changes to structural and functional connectivity can give rise to neurodegeneration and neurodevelopmental diseases. Here the authors investigate molecular and connectomic patterns in 13 different neurological, psychiatric and neurodevelopmental diseases from the ENIGMA consortium.

BackgroundWorldwide, insomnia remains a highly prevalent public health problem. eHealth presents a novel opportunity to deliver effective, accessible, and affordable insomnia treatments on a population-wide scale. However, there is no quantitative integration of evidence regarding the effectiveness of eHealth-based psychosocial interventions on insomnia. ObjectiveWe aimed to evaluate the effectiveness of eHealth-based psychosocial interventions for insomnia and investigate the influence of specific study characteristics and intervention features on these effects. MethodsWe searched PubMed, Embase, Web of Science, PsycINFO, and the Cochrane Central Register of Controlled Trials from database inception to February 16, 2021, for publications investigating eHealth-based psychosocial interventions targeting insomnia and updated the search of PubMed to December 6, 2021. We also screened gray literature for unpublished data. Eligible studies were randomized controlled trials of eHealth-based psychosocial interventions targeting adults with insomnia. Random-effects meta-analysis models were used to assess primary and secondary outcomes. Primary outcomes were insomnia severity and sleep quality. Meta-analyses were performed by pooling the effects of eHealth-based psychosocial interventions on insomnia compared with inactive and in-person conditions. We performed subgroup analyses and metaregressions to explore specific factors that affected the effectiveness. Secondary outcomes included sleep diary parameters and mental health–related outcomes. ResultsOf the 19,980 identified records, 37 randomized controlled trials (13,227 participants) were included. eHealth-based psychosocial interventions significantly reduced insomnia severity (Hedges g=−1.01, 95% CI −1.12 to −0.89; P

BackgroundsDecision-making deficits have been reported as trans-diagnostic characteristics of vulnerability to suicidal behaviors, independent of co-existing psychiatric disorders. Individuals with suicidal behaviors often regret their decision to attempt suicide and may have impairments in future-oriented processing. However, it is not clear how people with suicidal dispositions use future-oriented cognition and past experience of regret to guide decision-making. Here, we examined the processes of regret anticipation and experience in subclinical youth with and without suicidal ideation during value-based decision-making.MethodsIn total, 80 young adults with suicidal ideation and 79 healthy controls completed a computational counterfactual thinking task and self-reported measures of suicidal behaviors, depression, anxiety, impulsivity, rumination, hopelessness, and childhood maltreatment.ResultsIndividuals with suicidal ideation showed a reduced ability to anticipate regret compared to healthy controls. Specifically, suicidal ideators’ experience of regret/relief was significantly different from that of healthy controls upon obtained outcomes, while their disappointment/pleasure experience was not significantly different from healthy controls.ConclusionThese findings suggest that young adults with suicidal ideation have difficulty predicting the consequences or the future value of their behavior. Individuals with suicidal ideation showed impairments in value comparison and flat affect to retrospective rewards, whereas individuals with high suicidality showed blunted affect to immediate rewards. Identifying the counterfactual decision-making characteristics of at-risk suicidal individuals may help to elucidate measurable markers of suicidal vulnerability and identify future intervention targets.

Abstract Everyday cognitive functioning is characterized by constant alternations between different modes of information processing, driven by constant fluctuations in environmental demands. At the neural level, this is realized through corresponding dynamic shifts in functional activation and network connectivity. A distinction is often made between resting and task processing and between task-negative and task-positive functional networks. The Default Mode Network (DMN) is classically considered as a resting state (i.e. task-negative) network, upregulated in the absence of cognitive demands. In contrast, task-positive networks have been labelled the Extrinsic Mode Network (EMN). We investigated changes in brain activation and functional network connectivity in an experimental situation of repeated alterations between levels of cognitive effort, following a block-design. Using fMRI and a classic Stroop paradigm, participants switched back and forth between periods of no effort (resting), low effort (word reading, i.e. automatic processing based on learned internal representations and rules) and high effort (color naming, i.e. cognitively controlled perceptual processing of specific features of external stimuli). Results showed an expected EMN-activation for task versus resting contrasts, and DMN-activation for rest versus task contrasts. The DMN was in addition more strongly activated during periods of low effort contrasted with high effort, suggesting a gradual up- and down-regulation of the DMN network, depending on the level of demand and the type of processing required. The often reported “anti-correlation” between DMN and EMN was strongest during periods of low effort, indicating intermittent contributions of both networks. Taken together, these results challenge the traditional view of the DMN as solely a task-negative network. Instead, both the EMN and DMN may contribute to low-effort cognitive processing. In contrast, periods of resting and high effort are dominated by the DMN and EMN, respectively.

Abstract Abnormal function and connectivity of the fronto-parietal network (FPN) have been documented in patients with schizophrenia, but studies are correlational. We applied repetitive transcranial magnetic stimulation (rTMS) to the dorso-lateral prefrontal cortex (DLPFC) and observed causal connectivity to the inferior parietal lobe (IPL). We hypothesized that patients with schizophrenia would have lower activation and slower reaction in the IPL following DLPFC stimulation. Thirteen patients with schizophrenia (SZ) and fourteen healthy controls subjects (HC) underwent rTMS at 10 Hz to the right DLPFC. Simultaneously, we measured brain activation in the IPL, represented as oxygenized hemoglobin (HbO) levels, using functional near-infrared spectroscopy (fNIRS). rTMS consisted of 20 trains of impulses at 10 Hz for 3 seconds, and 60 seconds waiting time. Using NIRSLab software, GLM was applied to estimate both hemodynamic response function (HRF) and its derivative. Following TMS to the DLPFC, SZ showed a smaller decrease in HbO levels in the bilateral IPL than HC (p = 0.05). Timecourse analysis revealed an immediate decrease in parietal HbO levels in HC, but not in SZ. This difference was significant (at a threshold level of p ≤ 0.05, with Bonferroni correction) for several time segments and channels in both rights and left IPL. Our findings suggest abnormal fronto-temporal connectivity in patients with schizophrenia, beyond a mere decrease or slowing of information processing. This is in line with the hypothesis of reduced fronto-parietal inhibition in schizophrenia.

Abstract Transcranial temporal interference stimulation (tTIS) is a novel non-invasive brain stimulation technique for electrical stimulation of neurons at depth. Deep brain regions are generally small in size, making precise targeting a necessity. The variability of electric fields across individual subjects resulting from the same tTIS montages is unknown so far and may be of major concern for precise tTIS targeting. Therefore, the aim of the current study is to investigate the variability of the electric fields due to tTIS across 25 subjects. To this end, the electric fields of different electrode montages consisting of two electrode pairs with different center frequencies were simulated in order to target selected regions-of-interest (ROIs) with tTIS. Moreover, we set out to compare the electric fields of tTIS with the electric fields of conventional tACS. The latter were also based on two electrode pairs, which, however, were driven in phase at a common frequency. Our results showed that the electric field strengths inside the ROIs (left hippocampus, left motor area and thalamus) during tTIS are variable on single subject level. In addition, tTIS stimulates more focally as compared to tACS with much weaker co-stimulation of cortical areas close to the stimulation electrodes. Electric fields inside the ROI were, however, comparable for both methods. Overall, our results emphasize the potential benefits of tTIS for the stimulation of deep targets, over conventional tACS. However, they also indicate a need for individualized stimulation montages to leverage the method to its fullest potential.

Background Memory function is at the core of the psychopathology of dissociative identity disorder (DID), but little is known about its psychobiological correlates. Aims This study aims to investigate whether memory function in DID differs between dissociative identity states Method Behavioural data and neural activation patterns were assessed in 92 sessions during an n-back working memory task. Participants were people with genuine diagnosed DID (n = 14), DID-simulating controls (n = 16) and a paired control group (post-traumatic stress disorder (n = 16), healthy controls (n = 16)). Both DID groups participated as authentic or simulated neutral and trauma-related identity states. Reaction times and errors of omission were analysed with repeated measures ANOVA. Working memory neural activation (main working memory and linear load) was investigated for effects of identity state, participant group and their interaction. Results Identity state-dependent behavioural performance and neural activation was found. DID simulators made fewer errors of omission than those with genuine DID. Regarding the prefrontal parietal network, main working memory in the left frontal pole and ventrolateral prefrontal cortex (Brodmann area 44) was activated in all three simulated neutral states, and in trauma-related identity states of DID simulators, but not those with genuine DID or post-traumatic stress disorder; for linear load, trauma-related identity states of those with genuine DID did not engage the parietal regions. Conclusions Behavioural performance and neural activation patterns related to working memory in DID are dependent on the dissociative identities involved. The narrowed consciousness of trauma-related identity states, with a proneness to re-experiencing traumatising events, may relate to poorer working memory functioning.

BackgroundIndividuals with a psychotic disorder are at an increased risk of victimization, but evidenced-based interventions are lacking.AimsA body-oriented resilience therapy ('BEATVIC') aimed at preventing victimization was developed and its effectiveness was assessed in a multicenter randomized controlled trial.Methods105 people with a psychotic disorder were recruited from six mental health centers. Participants were randomly allocated to 20 BEATVIC group sessions (n = 53) or befriending group sessions (n = 52). Short term effects on risk factors for victimization (e.g. social cognitive deficits, inadequate interpersonal behavior, low self-esteem, internalized stigma, aggression regulation problems), physical fitness and secondary outcomes were expected. At six-month follow-up, the effect on victimization (either a 50% reduction or an absence of victimization incidents) was examined.ResultsIntervention-dropout was 28.30% for BEATVIC and 39.62% for befriending. In both conditions the majority of participants (60.5% BEATVIC vs 62.9% befriending) showed a reduction or absence of victimization incidents at six months follow-up, which was not significantly different according to condition. Multilevel analyses revealed no main effect of time and no significant time x group interaction on other outcome measures. Per protocol analyses (participants attending ≥ 75% of the sessions) did not change these results.ConclusionsAlthough a reduction or absence of victimization was found at short term follow-up for the majority of participants, BEATVIC was not more effective than the active control condition. No short-term additional effects on risk factors of victimization were found. Analysis of the data at 2-year follow-up is warranted to investigate possible effects in the long-term.Trial registration numberCurrent Controlled Trials: ISRCTN21423535.

The recurrent nature of Major Depressive Disorder (MDD) necessitates a better understanding of mechanisms facilitating relapse. MDD has often been associated with abnormal emotion regulation, underpinned by aberrant interactions between the prefrontal cortex and subcortical areas. We assessed whether neural regulation abnormalities remain after remission and relate to emotion regulation problems in daily life.At the baseline measurement of a randomized controlled trial, an emotion regulation task was performed during fMRI scanning by 46 remitted recurrent (rrMDD) patients and 24 healthy controls. We assessed both fMRI peak activity and the temporal dynamics of the neural response during passive attendance and explicit regulation of positive and negative emotions. Furthermore, we assessed regulation strategy use in daily life using questionnaires, and attentional biases using a modified attentional dot-probe task.RrMDD patients showed lower activation and different temporal dynamics in occipital, parietal, and prefrontal brain regions during passive attendance of emotional material compared to healthy controls. During explicit downregulation of negative emotions, no group differences were found. However, during explicit upregulation of positive emotions, rrMDD patients showed a different neural response over time in the insula. Behaviourally, rrMDD patients were characterized by dysfunctional regulation strategies in daily life. Within rrMDD patients, rumination was associated with activation within a limbic- prefrontal network.After remission, immediate emotional processing seems unaffected, but regulatory abnormalities remain, especially uninstructed and in daily life. Abnormal insula activation during positive upregulation suggests decreased monitoring of positive emotions. The relation between inadequate rumination and brain activity during emotion regulation suggests that regulation of both positive and negative affect is important in understanding neurocognitive underpinnings of resilience.

Abstract Background Major Depressive Disorder (MDD) is a psychiatric disorder with a highly recurrent character, making prevention of relapse an important clinical goal. Preventive Cognitive Therapy (PCT) has been proven effective in preventing relapse, though not for every patient. A better understanding of relapse vulnerability and working mechanisms of preventive treatment may inform effective personalized intervention strategies. Neurocognitive models of MDD suggest that abnormalities in prefrontal control over limbic emotion-processing areas during emotional processing and regulation are important in understanding relapse vulnerability. Whether changes in these neurocognitive abnormalities are induced by PCT and thus play an important role in mediating the risk for recurrent depression, is currently unclear. In the Neurocognitive Working Mechanisms of the Prevention of Relapse In Depression (NEWPRIDE) study, we aim to 1) study neurocognitive factors underpinning the vulnerability for relapse, 2) understand the neurocognitive working mechanisms of PCT, 3) predict longitudinal treatment effects based on pre-treatment neurocognitive characteristics, and 4) validate the pupil dilation response as a marker for prefrontal activity, reflecting emotion regulation capacity and therapy success. Methods In this randomized controlled trial, 75 remitted recurrent MDD (rrMDD) patients will be included. Detailed clinical and cognitive measurements, fMRI scanning and pupillometry will be performed at baseline and three-month follow-up. In the interval, 50 rrMDD patients will be randomized to eight sessions of PCT and 25 rrMDD patients to a waiting list. At baseline, 25 healthy control participants will be additionally included to objectify cross-sectional residual neurocognitive abnormalities in rrMDD. After 18 months, clinical assessments of relapse status are performed to investigate which therapy induced changes predict relapse in the 50 patients allocated to PCT. Discussion The present trial is the first to study the neurocognitive vulnerability factors underlying relapse and mediating relapse prevention, their value for predicting PCT success and whether pupil dilation acts as a valuable marker in this regard. Ultimately, a deeper understanding of relapse prevention could contribute to the development of better targeted preventive interventions. Trial registration Trial registration: Netherlands Trial Register, August 18, 2015, trial number NL5219.

A wide homology between human and macaque striatum is often assumed as in both the striatum is involved in cognition, emotion and executive functions. However, differences in functional and structural organization between human and macaque striatum may reveal evolutionary divergence and shed light on human vulnerability to neuropsychiatric diseases. For instance, dopaminergic dysfunction of the human striatum is considered to be a pathophysiological underpinning of different disorders, such as Parkinson's disease (PD) and schizophrenia (SCZ). Previous investigations have found a wide similarity in structural connectivity of the striatum between human and macaque, leaving the cross-species comparison of its functional organization unknown. In this study, resting-state functional connectivity (RSFC) derived striatal parcels were compared based on their homologous cortico-striatal connectivity. The goal here was to identify striatal parcels whose connectivity is human-specific compared to macaque parcels. Functional parcellation revealed that the human striatum was split into dorsal, dorsomedial, and rostral caudate and ventral, central, and caudal putamen, while the macaque striatum was divided into dorsal, and rostral caudate and rostral, and caudal putamen. Cross-species comparison indicated dissimilar cortico-striatal RSFC of the topographically similar dorsal caudate. We probed clinical relevance of the striatal clusters by examining differences in their cortico-striatal RSFC and gray matter (GM) volume between patients (with PD and SCZ) and healthy controls. We found abnormal RSFC not only between dorsal caudate, but also between rostral caudate, ventral, central and caudal putamen and widespread cortical regions for both PD and SCZ patients. Also, we observed significant structural atrophy in rostral caudate, ventral and central putamen for both PD and SCZ while atrophy in the dorsal caudate was specific to PD. Taken together, our cross-species comparative results revealed shared and human-specific RSFC of different striatal clusters reinforcing the complex organization and function of the striatum. In addition, we provided a testable hypothesis that abnormalities in a region with human-specific connectivity, i.e., dorsal caudate, might be associated with neuropsychiatric disorders.

Abstract Background The cognitive-functional composite (CFC) was designed to improve the measurement of clinically relevant changes in predementia and early dementia stages. We have previously demonstrated its good test-retest reliability and feasibility of use. The current study aimed to evaluate several quality aspects of the CFC, including construct validity, clinical relevance, and suitability for the target population. Methods Baseline data of the Capturing Changes in Cognition study was used: an international, prospective cohort study including participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD) dementia, and dementia with Lewy bodies (DLB). The CFC comprises seven existing cognitive tests focusing on memory and executive functions (EF) and the informant-based Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). Construct validity and clinical relevance were assessed by (1) confirmatory factor analyses (CFA) using all CFC subtests and (2) linear regression analyses relating the CFC score (independent) to reference measures of disease severity (dependent), correcting for age, sex, and education. To assess the suitability for the target population, we compared score distributions of the CFC to those of traditional tests (Alzheimer’s Disease Assessment Scale–Cognitive subscale, Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale, and Clinical Dementia Rating scale). Results A total of 184 participants were included (age 71.8 ± 8.4; 42% female; n = 14 SCD, n = 80 MCI, n = 78 AD, and n = 12 DLB). CFA showed that the hypothesized three-factor model (memory, EF, and IADL) had adequate fit (CFI = .931, RMSEA = .091, SRMR = .06). Moreover, worse CFC performance was associated with more cognitive decline as reported by the informant (β = .61, p

Abstract Background People with a psychotic disorder have an increased risk of becoming the victim of a crime. To prevent victimization a body-oriented resilience therapy using kickboxing exercises was developed. This study aims to explore the feasibility of the therapy, to improve the therapy protocol and to explore suitable outcomes for a RCT. Methods Twenty-four adults with a psychotic disorder received 20 weekly group sessions in which potential risk factors for victimization and strategies for dealing with them were addressed. Sessions were evaluated weekly. During pre and post assessment participants completed questionnaires on, among other, victimization, aggression regulation and social functioning. Results The short recruitment period indicates the interest in such an intervention and the willingness of clients to participate. Mean attendance was 85.3 and 88% of the participants completed fifteen or more sessions. The therapy protocol was assessed as adequate and exercises as relevant with some small improvements to be made. The victimization and aggression regulation questionnaires were found to be suitable outcome measurements for a subsequent RCT. Conclusion The results support the feasibility of the BEATVIC therapy. Participants subjectively evaluated the intervention as helpful in their attempt to gain more self-esteem and assertiveness. With some minor changes in the protocol the effects of BEATVIC can be tested in a RCT. Trial registration The trial registration number (TRN) is 35949 (date submitted 09/11/2018). Retrospectively registered.

Hallucinations and illusions are two instances of perceptual experiences illustrating how perception might diverge from external sensory stimulations and be generated or altered based on internal brain states. The occurrence of these phenomena is not constrained to patient populations. Similar experiences can be elicited in healthy subjects by means of suitable experimental procedures. Studying the neural mechanisms underlying these experiences not only has the potential to expand our understanding of the brain’s perceptual machinery but also of how it might get impaired. In the current study, we employed an auditory signal detection task to induce auditory illusions by presenting speech snippets at near detection threshold intensity embedded in noise. We investigated the neural correlates of auditory false perceptions by examining the EEG activity preceding the responses in speech absent (false alarm, FA) trials and comparing them to speech present (hit) trials. The results of the comparison of event-related potentials (ERPs) in the activation period vs. baseline revealed the presence of an early negativity (EN) and a late positivity (LP) similar in both hits and FAs, which were absent in misses, correct rejections (CR) and control button presses (BPs). We postulate that the EN and the LP might represent the auditory awareness negativity (AAN) and centro-parietal positivity (CPP) or P300, respectively. The event-related spectral perturbations (ERSPs) exhibited a common power enhancement in low frequencies (

Introduction: With aging comes a reduction of cognitive flexibility, which has been related to the development of late-life depression and progression of general cognitive decline. Several factors have been linked to attenuating such decline in cognitive flexibility, such as education, physical exercise and stimulating leisure activities. Speaking two or more languages has recently received abundant attention as another factor that may build up cognitive reserve, thereby limiting the functional implications of compromised cognition that accompany old age. With the number of older adults reaching record levels, it is important to attenuate the development of old-age disorders. Learning to speak a foreign language might offer a powerful tool in promoting healthy aging, but up to date effect studies are sparse. Here, the protocol that forms the foundation of the current study is presented. The present study aims to: (1) examine the effects of a foreign language training on cognitive flexibility and its neural underpinnings, and on mental health; and (2) assess the unique role of foreign language training vs. other cognitive or social programs.Method: One-hundred and ninety-eight Dutch elderly participants reporting subjective cognitive decline are included and randomized to either a language intervention, a music intervention, or a social control intervention. During 3 to 6 months, the language group learns English, the music group learns to play the guitar and the social group participates in social meetings where art workshops are offered. At baseline, at a 3-month follow-up, and at 6 months after termination of the training program, clinical, cognitive and brain activity measurements (combined EEG and fNIRS methods) are taken to assess cognitive flexibility and mental health.Discussion: This is the first trial addressing combined effects of language learning in elderly on cognition, language proficiency, socio-affective measures, and brain activity in the context of a randomized controlled trial. If successful, this study can provide insights into how foreign language training can contribute to more cognitively and mentally healthy years in older adulthood.Clinical Trial Registration: The trial is registered at the Netherlands Trial Register, July 2, 2018, trial number NL7137. https://www.trialregister.nl/trial/7137.

In our daily lives, we continuously evaluate feedback information, update our knowledge, and adapt our behavior in order to reach desired goals. This ability to learn from feedback information, however, declines with age. Previous research has indicated that certain higher-level learning processes, such as feedback evaluation, integration of feedback information, and updating of knowledge, seem to be affected by age, and recent studies have shown how the adaption of choice behavior following feedback can differ with age. The neural mechanisms underlying this age-related change in choice behavior during learning, however, remain unclear. The aim of this study is therefore to investigate the relation between learning-related neural processes and choice behavior during feedback learning in two age groups. Behavioral and fMRI data were collected, while a group of young (age 18–30) and older (age 60–75) adults performed a probabilistic learning task consisting of 10 blocks of 20 trials each. On each trial, the participants chose between a house and a face, after which they received visual feedback (loss vs. gain). In each block, either the house or the face image had a higher probability of yielding a reward (62.5 vs. 37.5%). Participants were instructed to try to maximize their gains. Our results showed that less successful learning in older adults, as indicated by a lower learning rate, corresponded with a higher tendency to switch to the other stimulus option, and with a reduced adaptation of this switch choice behavior following positive feedback. At the neural level, activation following positive and negative feedback was found to be less distinctive in the older adults, due to a smaller feedback-evaluation response to positive feedback in this group. Furthermore, whereas young adults displayed increased levels of knowledge updating prior to adapting choice behavior, we did not find this effect in older adults. Together, our results suggest that diminished learning performance with age corresponds with diminished evaluation of positive feedback and reduced knowledge updating related to changes in choice behavior, indicating how such differences in feedback processing at the trial level in older adults might lead to reduced learning performance across trials.

Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer’s Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p

Formal thought disorder (FTD) is a core symptom cluster of schizophrenia, but its neurobiological substrates remain poorly understood. Here we collected resting-state fMRI data from 276 subjects at seven sites and employed machine-learning to investigate the neurobiological correlates of FTD along positive and negative symptom dimensions in schizophrenia. Three a priori, meta-analytically defined FTD-related brain regions were used as seeds to generate whole-brain resting-state functional connectivity (rsFC) maps, which were then compared between schizophrenia patients and controls. A repeated cross-validation procedure was realized within the patient group to identify clusters whose rsFC patterns to the seeds were repeatedly observed as significantly associated with specific FTD dimensions. These repeatedly identified clusters (i.e., robust clusters) were functionally characterized and the rsFC patterns were used for predictive modeling to investigate predictive capacities for individual FTD dimensional-scores. Compared with controls, differential rsFC was found in patients in fronto-temporo-thalamic regions. Our cross-validation procedure revealed significant clusters only when assessing the seed-to-whole-brain rsFC patterns associated with positive-FTD. RsFC patterns of three fronto-temporal clusters, associated with higher-order cognitive processes (e.g., executive functions), specifically predicted individual positive-FTD scores (p = 0.005), but not other positive symptoms, and the PANSS general psychopathology subscale (p > 0.05). The prediction of positive-FTD was moreover generalized to an independent dataset (p = 0.013). Our study has identified neurobiological correlates of positive FTD in schizophrenia in a network associated with higher-order cognitive functions, suggesting a dysexecutive contribution to FTD in schizophrenia. We regard our findings as robust, as they allow a prediction of individual-level symptom severity.

Background: Cognitive insight is defined as the ability to reflect upon oneself (i.e. self-reflectiveness), and to not be overly confident of one's own (incorrect) beliefs (i.e. self-certainty). These abilities are impaired in several disorders, while they are essential for the evaluation and regulation of one's behavior. We hypothesized that cognitive insight is a dynamic process, and therefore examined how it relates to temporal dynamics of resting state functional connectivity (FC) and underlying structural network characteristics in 58 healthy individuals. Methods: Cognitive insight was measured with the Beck Cognitive Insight Scale. FC characteristics were calculated after obtaining four FC states with leading eigenvector dynamics analysis. Gray matter (GM) and DTI connectomes were based on GM similarity and probabilistic tractography. Structural graph characteristics, such as path length, clustering coefficient, and small-world coefficient, were calculated with the Brain Connectivity Toolbox. FC and structural graph characteristics were correlated with cognitive insight. Results: Individuals with lower cognitive insight switched more and spent less time in a globally synchronized state. Additionally, individuals with lower self-reflectiveness spent more time in, had a higher probability of, and had a higher chance of switching to a state entailing default mode network (DMN) areas. With lower self-reflectiveness, DTI-connectomes were segregated less (i.e. lower global clustering coefficient) with lower embeddedness of the left angular gyrus specifically (i.e. lower local clustering coefficient). Conclusions: Our results suggest less stable functional and structural networks in individuals with poorer cognitive insight, specifically self-reflectiveness. An overly present DMN appears to play a key role in poorer self-reflectiveness.

Anxious individuals tend to make pessimistic judgments in decision making under uncertainty. While this phenomenon is commonly attributed to risk aversion, loss aversion is a critical but often overlooked factor. In this study, we simultaneously examined risk aversion and loss aversion during decision making in high and low trait anxious individuals in a variable gain/loss gambling task during functional magnetic resonance imaging. Although high relative to low anxious individuals showed significant increased risk aversive behavior reflected by decreased overall gamble decisions, there was no group difference in subjective aversion to risk. Instead, loss aversion rather than risk aversion dominantly contributed to predict behavioral decisions, which was associated with attenuated functional connectivity between the amygdala-based emotional system and the prefrontal control regions. Our findings suggest a dominant role of loss aversion in maladaptive risk assessment of anxious individuals, underpinned by disorganization of emotion-related and cognitive-control-related brain networks.

Abstract Introduction In an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive‐Functional Composite (CFC). We investigated the CFC's sensitivity to decline in comparison to traditional clinical endpoints. Methods This longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment, or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6, and 12 months. Sensitivity to change was investigated using linear mixed models and r2 effect sizes. Results CFC scores declined over time (β = −.16, P

Humans experience a sense of self, which is proposed to emerge from the integration of intrinsic and extrinsic self-processing through the propagation of information across brain systems. Using a novel functional magnetic resonance imaging (fMRI) paradigm, we tested this hypothesis in a non-clinical sample by modulating the intrinsic and extrinsic self-relatedness of auditory action consequences in terms of identity and agency, respectively. In addition, the relevance of individual traits associated with altered self-experiences (e.g., psychosis-like experiences) was examined. The task-evoked fMRI results showed distinctive associations between the neural coding of identity and negative affect traits, and between agency and psychosis-like experiences. Most importantly, regarding the functional connectivity analysis, graph theoretical measures demonstrated that the simultaneous processing of identity and agency relies on the functional integration and segregation of default mode, sensorimotor, language, and executive brain networks. Finally, cross-network interactions mediated by executive and sensorimotor regions were negatively associated with psychosis-like experiences when the intrinsic and extrinsic self-relatedness of action consequences conflicted. These findings provide evidence that the self is a multidimensional phenomenon rooted in the functional interactions between large-scale neuronal networks. Such interactions may have particular relevance for self-experience alterations.

Background: Insight is impaired in the majority of schizophrenia patients. The exact neural correlates of impaired insight remain unclear. We assume that the ability to regulate emotions contributes to having good clinical insight, as patients should be able to regulate their emotional state in such a way that they can adapt adequately in order to cope with impaired functioning and negative stigma associated with a diagnosis of schizophrenia. Numerous studies have shown emotional dysregulation in schizophrenia. We investigated the association between insight and brain activation and connectivity during emotion regulation. Methods: Brain activation during emotion regulation was measured with functional MRI in 30 individuals with schizophrenia. Two emotion regulation strategies were examined: cognitive reappraisal and expressive suppression. Clinical insight was measured with the Schedule for the Assessment of Insight – Expanded, and cognitive insight was measured with the Beck Cognitive Insight Scale. Whole brain random effects multiple regression analyses were conducted to assess the relation between brain activation during emotion regulation and insight. Generalized psychophysiological interaction (gPPI) was used to investigate the relation between task-related connectivity and insight. Results: No significant associations were found between insight and neural correlates of cognitive reappraisal. For clinical insight and suppression, significant positive associations were found between symptom relabeling and activation in the left striatum, thalamus and insula, right insula and caudate, right pre- and postcentral gyrus, left superior occipital gyrus and cuneus and right middle and superior occipital gyrus and cuneus. Furthermore, reduced clinical insight was associated with more connectivity between midline medial frontal gyrus and right middle occipital gyrus. For cognitive insight and suppression, significant positive associations were found between self-reflectiveness and activation in pre- and postcentral gyrus and left middle cingulate gyrus. Conclusions: Our results suggest an association between the capacity to relabel symptoms and activation of brain systems involved in cognitive-emotional control and visual processing of negative stimuli. Furthermore, poorer self-reflectiveness may be associated with brain systems subserving control and execution. Keywords: Insight, Cognitive reappraisal, Expressive suppression, fMRI, gPPI, Emotion regulation

The various models proposed for the mediation of auditory verbal hallucinations (AVH) implicate a considerable number of brain areas and mechanisms. To establish which of those mechanisms are actually involved in the mediation of AVH, we developed a novel method to analyze functional MRI data, which allows for the detection of the full network of mutually interacting brain states, and the identification of those states that are relevant to the mediation of AVH, while applying a minimum number of preconceived assumptions. This method is comparable to the draining of a pond to lay bare the full ecosystem that affects the presence of a particular fish species. We used this model to analyze the fMRI data of 85 psychotic patients experiencing AVH. The data were decomposed into 98 independent components (ICs) representing all major functions active in the brain during scanning. ICs involved in mediating AVH were identified by associating their time series with the hallucination time series as provided by subjects within the scanner. Using graph theory, a network of interacting ICs was created, which was clustered into IC modules. We used causal reasoning software to determine the direction of links in this network, and discover the chain of events that leads to the conscious experience of hallucinations. Hallucinatory activity was linked to three of the seven IC clusters and 11 of the 98 ICs. ICs with the most influential roles in producing AVH-related activity were those within the so-called salience network (comprising the anterior cingulate gyrus, right insula, Broca's homologue, premotor cortex, and supramarginal gyrus). Broca's area and the cerebellar regions were significantly, but more distantly involved in the mediation of AVH. These results support the notion that AVH are largely mediated by the salience network. We therefore propose that the mediation of AVH in the context of schizophrenia spectrum disorders involves the attribution of an excess of negative salience by anterior-cingulate areas to linguistic input from Broca's right homologue, followed by subsequent processing errors in areas further ‘downstream’ the causal chain of events. We provide a detailed account of the origin of AVH for this patient group, and make suggestions for selective interventions directed at the most relevant brain areas. Keywords: Schizophrenia, Functional MRI, Graph analysis, Effective connectivity, Systems biology

Abstract Human behaviour can be externally driven, e.g. catching a falling glass, or self-initiated and goal-directed, e.g. drinking a cup of coffee when one deems it is time for a break. Apathy refers to a reduction of self-initiated goal-directed or motivated behaviour, frequently present in neurological and psychiatric disorders. The amount of undertaken goal-directed behaviour varies considerably in clinical as well as healthy populations. In the present study, we investigated behavioural and neural correlates of self-initiated action in a student sample (N = 39) with minimal to high levels of apathy. We replicated activation of fronto-parieto-striatal regions during self-initiation. The neural correlates of self-initiated action did not explain varying levels of apathy in our sample, neither when mass-univariate analysis was used, nor when multivariate patterns of brain activation were considered. Other hypotheses, e.g. regarding a putative role of deficits in reward anticipation, effort expenditure or executive difficulties, deserve investigation in future studies.

AIMS:Theory of Mind (ToM) is often impaired in early and chronic phases of psychosis and it is often suggested that poor ToM is a trait vulnerability for psychosis. The aim of this study was to examine in an adolescent sample whether childhood ToM abilities can predict psychotic experiences over a period of six years and whether this is mediated by social functioning. To examine whether ToM is a specific predictor for psychosis, symptoms of depression and anxiety were also examined. MATERIALS AND METHODS:A baseline case-control sample (T0: age 7-8 years) with and without auditory vocal hallucinations (AVH) in the general population was assessed after five years (T1: age 12-13 years) on ToM ability (ToM Storybook Frank), and after eleven years (T2: age 18-19 years) on psychotic experiences (Community Assessment of Psychic Experiences; CAPE), depressive and anxiety symptoms (Depression Anxiety and Stress Scale; DASS-21), and social functioning (Groningen Questionnaire on Social Behaviour; GSVG-45). Analyses were conducted on a subsample of 157 adolescents aged 18-19 years (T2) who had data available on ToM ability at T1. RESULTS:ToM at T1 was not predictive of psychotic experiences after six years (from age 12-13 to age 18-19) and social functioning was also not a mediator. ToM was not associated with psychopathology in general (depressive and anxiety symptoms) over six years (from age 12-13 to age 18-19). CONCLUSIONS:The current study found no evidence for a longitudinal association between ToM ability and psychotic experiences, social functioning, and symptoms of depression and anxiety, in adolescence.

IntroductionAlthough people with a psychotic disorder are approximately four to six times more often victimized than the general population, victimization is not routinely assessed in mental healthcare. This study investigates prevalence, context and risk factors of victimization in patients with a psychotic disorder in the Northern, relatively rural region of the Netherlands. Moreover, disclosure rates and awareness of psychiatrists are examined.MethodInformation on personal crime (threats, assaults and sexual violence), property and other forms of crime, the context of victimization and disclosure was routinely assessed in 353 patients with a psychotic disorder who received care at a mental health facility. In addition, involved psychiatrists reported on last year's victimization incidents in their patients.ResultsOne third of the patients reported victimization in the previous year. More than half of the crimes were committed by someone acquainted and took place in the victim's own home or a place familiar to the victim. Younger age, having a comorbid disorder, drug use and perpetration of a crime were all positively associated with victimization. Approximately half of the reported personal crimes were disclosed to a health care professional but only in 16% of the cases the involved psychiatrist report to know about the incident.ConclusionThis study confirms that people with a history of psychosis have an increased risk of becoming the victim of a crime. Although our results suggest that in fifty percent of cases the patients did share the information with professionals, a substantial proportion of incidents appear to go still unnoticed.

In schizophrenia (SCZ), dysfunction of the dorsolateral prefrontal cortex (DLPFC) has been linked to the deficits in executive functions and attention. It has been suggested that, instead of considering the right DLPFC as a cohesive functional entity, it can be divided into two parts (anterior and posterior) based on its whole-brain connectivity patterns. Given these two subregions' differential association with cognitive processes, we investigated the functional connectivity (FC) profile of both subregions through resting-state data to determine whether they are differentially affected in SCZ. Resting-state magnetic resonance imaging (MRI) scans were obtained from 120 patients and 172 healthy controls (HC) at 6 different MRI sites. The results showed differential FC patterns for the anterior and posterior parts of the right executive control-related DLPFC in SCZ with the parietal, the temporal and the cerebellar regions, along with a convergent reduction of connectivity with the striatum and the occipital cortex. An increased psychopathology level was linked to a higher difference in posterior vs. anterior FC for the left IFG/anterior insula, regions involved in higher-order cognitive processes. In sum, the current analysis demonstrated that even between two neighboring clusters connectivity could be differentially disrupted in SCZ. Lacking the necessary anatomical specificity, such notions may in fact be detrimental to a proper understanding of SCZ pathophysiology.

Apathy is a common symptom in patients with amnestic mild cognitive impairment (aMCI) and is associated with an increased risk of progression to Alzheimer’s disease (AD). The neural substrates underlying apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo-parietal region. Here we investigated neurometabolites in brain regions that may underlie apathy in aMCI patients using proton magnetic resonance spectroscopy (1H-MRS). Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls underwent 1H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Apathy was measured with the Apathy Evaluation Scale (AES). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additionally, analyses of covariance (ANCOVA) were performed to determine whether metabolite changes differed between patients with or without clinically-diagnosed apathy. The degree of apathy was found to be negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetylaspartate (NAA)/mI ratio was reduced in aMCI without clinical apathy but not in aMCI with clinical apathy. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group compared to controls and reduced in association with depression scores. In conclusion, apathy in aMCI patients was associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. Findings also indicated that in a clinically-diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy.

The neural substrate of cognitive reappraisal has been well-mapped. Individuals who successfully downregulate negative affect (NA) by reshaping their thoughts about a potentially emotional situation show augmented activity in the prefrontal cortex (PFC), with attenuated activity in the amygdala. We performed functional neuroimaging with experience sampling to determine whether individual differences in brain activation correspond to differences in real-life NA. While being scanned, 69 female students (aged 18-25 years) were asked to perform a cognitive reappraisal task. In addition, repeated assessments (5/day, 14 days) of affect and minor events in real-life were conducted. Individual t-maps were created for an instructed downregulation contrast (downregulate negative-attend negative) and an uninstructed regulation contrast (attend negative-attend neutral). Mean beta values were extracted from a priori defined regions of interest in the bilateral amygdala and PFC and were correlated with three daily life NA measures: baseline (mean) NA, NA variability, and NA reactivity to negative events. Only one out of twelve correlations for the amygdalae was nominally significant, which did not survive correction for multiple comparisons. PFC activation in the instructed and uninstructed regulation contrasts explained approximately 10% of the variance in NA reactivity; stronger recruitment during the attend-negative condition was correlated with lower reactivity levels. The degree to which individuals spontaneously engage frontal clusters may be a critical aspect of real-life emotional reactivity. The findings of this study provide a partial external validation of the cognitive reappraisal task, suggesting that frontal brain activation during implicit task conditions may have the strongest connection with real-life behaviors.

Objectives: Reflecting on the self and on others activates specific brain areas and contributes to metacognition and social cognition. The aim of the current study is to investigate brain activation during self- and other-reflection in patients with bipolar disorder (BD). In addition, we examined whether potential abnormal brain activation in BD patients could distinguish BD from patients with schizophrenia (SZ). Methods: During functional magnetic resonance imaging (fMRI), 17 BD patients, 17 SZ patients and 21 healthy controls (HCs) performed a self-reflection task. The task consisted of sentences divided into three conditions: self-reflection, other-reflection and semantic control. Results: BD patients showed less activation in the posterior cingulate cortex (PCC) extending to the precuneus during other-reflection compared to HCs (p = 0.028 FWE corrected on cluster-level within the regions of interest). In SZ patients, the level of activation in this area was in between BD patients and HCs, with no significant differences between patients with SZ and BD. There were no group differences in brain activation during self-reflection. Moreover, there was a positive correlation between the PCC/precuneus activation during other-reflection and cognitive insight in SZ patients, but not in BD patients. Conclusions: BD patients showed less activation in the PCC/precuneus during other-reflection. This may support an account of impaired integration of emotion and memory (evaluation of past and current other-related information) in BD patients. Correlation differences of the PCC/precuneus activation with the cognitive insight in patients with BD and SZ might reflect an important difference between these disorders, which may help to further explore potentially distinguishing markers.

Introduction: Auditory verbal hallucinations (AVH) in schizophrenia (SZ) have been proposed to result from abnormal local, interregional and interhemispheric integration of brain signals in regions involved in language production and perception. This abnormal functional integration may find its base in morphological abnormalities. Structurally, AVHs have been frequently linked to abnormal morphology of the superior temporal gyrus (STG), but only a few studies investigated the relation of hallucination presence with both whole-brain gray matter (GM) and white matter (WM) morphometry. Methods: Using a unified voxel-based morphometry–DARTEL approach, we investigated correlates of AVH presence in 51 schizophrenia patients (20 non-hallucinating [SZ−], 31 hallucinating [SZ+]), and included 51 age and sex matched healthy participants. Effects are reported at p

Research suggests a two factor structure for negative symptoms in patients with psychotic disorders: social amotivation (SA) and expressive deficits (ED). Applying this two-factor structure in clinical settings may provide valuable information with regard to outcomes and to target treatments. We aimed to investigate 1) whether the factor structure is also supported in chronically ill patients with a psychotic disorder and 2) what the relationship is between these factors and functioning (overall functioning and living situation), depressive symptoms and quality of life. 1157 Patients with a psychotic disorder and a duration of illness of 5 years or more were included in the analysis (data selected from the Pharmacotherapy Monitoring Outcome Survey; PHAMOUS). A confirmatory factor analysis was performed using items of the Positive and Negative Syndrome Scale that were previously identified to reflect negative symptoms (N1-4, N6, G5, G7, G13, G16). Subsequently, regression analysis was performed on outcomes. The results confirmed the distinction between SA (N2, N4, G16) and ED (N1, N3, N6, G5, G7, G13) in chronically ill patients. Both factors were related to worse overall functioning as measured with the Health of the Nation Outcome Scales, ED was uniquely associated with residential living status. Higher scores for SA were associated with more depressive symptoms and worse quality of life. Thus, SA is most strongly related to level of social-emotional functioning, while ED are more related to living situation and thereby are indicative of level of everyday functioning. This subdivision may be useful for research purposes and be a valuable additional tool in clinical practice and treatment development.

Although deficits in facial affect processing have been reported in schizophrenia as well as in borderline personality disorder (BPD), these disorders have not yet been directly compared on facial affect labeling. Using degraded stimuli portraying neutral, angry, fearful and angry facial expressions, we hypothesized more errors in labeling negative facial expressions in patients with schizophrenia compared to healthy controls. Patients with BPD were expected to have difficulty in labeling neutral expressions and to display a bias towards a negative attribution when wrongly labeling neutral faces. Patients with schizophrenia (N = 57) and patients with BPD (N = 30) were compared to patients with somatoform disorder (SoD, a psychiatric control group; N = 25) and healthy control participants (N = 41) on facial affect labeling accuracy and type of misattributions. Patients with schizophrenia showed deficits in labeling angry and fearful expressions compared to the healthy control group and patients with BPD showed deficits in labeling neutral expressions compared to the healthy control group. Schizophrenia and BPD patients did not differ significantly from each other when labeling any of the facial expressions. Compared to SoD patients, schizophrenia patients showed deficits on fearful expressions, but BPD did not significantly differ from SoD patients on any of the facial expressions. With respect to the type of misattributions, BPD patients mistook neutral expressions more often for fearful expressions compared to schizophrenia patients and healthy controls, and less often for happy compared to schizophrenia patients. These findings suggest that although schizophrenia and BPD patients demonstrate different as well as similar facial affect labeling deficits, BPD may be associated with a tendency to detect negative affect in neutral expressions.

Low levels of insulin-like growth factor-1 (IGF-1), an essential neurotrophic factor, have been associated with worse cognitive function in older adults. However, few studies have assessed the prospective association of serum IGF-1 with cognitive function. We aimed to determine the association between serum IGF-1 on concurrent and prospective cognitive function in a population sample of men aged 40-80 years. Blood samples were assessed for IGF-1 levels at baseline and neuropsychological assessments were performed at baseline (n = 400) and at follow-up after a mean duration of 8.3 years (n = 286). Linear regression analyses were carried out to determine the associations between quintiles of IGF-1 and cognitive function at the baseline and follow-up visits. Results showed that those in the top quintile of IGF-1 had lower processing capacity and global cognition scores at follow-up after controlling for cognitive function at baseline and other confounding factors. Additional analyses exploring associations with IGF-1 separately in middle-aged and older participants, and with quartiles of IGF-1 produced similar results. In those older than 60 years, high IGF-1 levels were also associated with lower baseline processing capacity. These results suggest that high IGF-1 levels are associated with worse long-term cognition in men. Together with past studies, we suggest that both, high and low levels of IGF-1 may be associated with poor cognitive function and that optimum levels of IGF-1 (quintile 2 and 3 in current study) may be associated with better cognitive function.

This study aims to compare the suicide risk over the past decade following recent onset psychosis to findings from the eighties and nineties in the same catchment area and to identify predictors of suicide in the context of the Psychosis Recent Onset Groningen-Survey (PROGR-S). A medical file search was carried out to determine the current status of all patients admitted between 2000 and 2009. The suicide rate was compared with a study executed in 1973-1988 in the same catchment area. Predictors of suicide were investigated using Cox regression. The status of 424 of the 614 patients was known in July 2014. Suicide occurred in 2.4% of patients with psychosis disorders (n = 10; mean follow-up 5.6 years); 6 out of 10 suicides took place within two years. Within two decades, the suicide rate dropped from 11% (follow-up 15 years, 8.5% after 5 years) to 2.4%. The Standardized Mortality Rate (SMR) of suicides compared with the general population was 41.6. A higher age was the only significant predictor for suicide. Neuroticism, living situation, disorganized and negative symptoms, and passive coping style all showed a trend for significance. A significant reduction in the suicide rate was found for people with psychosis over the past decades. Given the high SMR, suicide research should be given the highest priority. Identifying predictors may contribute to further reduction of suicide among patients with psychosis.

Alexithymia is a personality construct denoting emotion processing problems. It has been suggested to encompass two dimensions: a cognitive and affective dimension. The cognitive dimension is characterized by difficulties in identifying, verbalizing and analyzing emotions, while the affective dimension reflects the level of emotional arousal and imagination. Alexithymia has been previously proposed as a risk factor for developing psychosis. More specifically, the two alexithymia dimensions might be differentially related to the vulnerability for psychosis. Therefore, we examined the two dimensions of alexithymia, measured with the BVAQ in 94 siblings of patients with schizophrenia, 52 subjects at ultra-high risk (UHR) for developing psychosis, 38 patients with schizophrenia and 109 healthy controls. The results revealed that siblings and patients had higher levels of cognitive alexithymia compared to controls. In addition, subjects at UHR for psychosis had even higher levels of cognitive alexithymia compared to the siblings. The levels of affective alexithymia in siblings and patients were equal to controls. However, UHR individuals had significantly lower levels of affective alexithymia (i.e. higher levels of emotional arousal and fantasizing) compared to controls. Alexithymia was further related to subclinical levels of negative and depressive symptoms. These findings indicate that alexithymia varies parametrically with the degree of risk for psychosis. More specifically, a type-II alexithymia pattern, with high levels of cognitive alexithymia and normal or low levels of affective alexithymia, might be a vulnerability factor for psychosis.

BACKGROUND: Patients with schizophrenia often experience problems regulating their emotions. Non-affected relatives show similar difficulties, although to a lesser extent, and the neural basis of such difficulties remains to be elucidated. In the current paper we investigated whether schizophrenia patients, non-affected siblings and healthy controls (HC) exhibit differences in brain activation during emotion regulation. METHODS: All subjects (n = 20 per group) performed an emotion regulation task while they were in an fMRI scanner. The task contained two experimental conditions for the down-regulation of emotions (reappraise and suppress), in which IAPS pictures were used to generate a negative affect. We also assessed whether the groups differed in emotion regulation strategies used in daily life by means of the emotion regulation questionnaire (ERQ). RESULTS: Though the overall negative affect was higher for patients as well as for siblings compared to HC for all conditions, all groups reported decreased negative affect after both regulation conditions. Nonetheless, neuroimaging results showed hypoactivation relative to HC in VLPFC, insula, middle temporal gyrus, caudate and thalamus for patients when reappraising negative pictures. In siblings, the same pattern was evident as in patients, but only in cortical areas. CONCLUSIONS: Given that all groups performed similarly on the emotion regulation task, but differed in overall negative affect ratings and brain activation, our findings suggest reduced levels of emotion regulation processing in neural circuits in patients with schizophrenia. Notably, this also holds for siblings, albeit to a lesser extent, indicating that it may be part and parcel of a vulnerability for psychosis.

BACKGROUND: Repetitive transcranial magnetic stimulation of the left temporo-parietal junction area has been studied as a treatment option for auditory verbal hallucinations. Although the right temporo-parietal junction area has also shown involvement in the genesis of auditory verbal hallucinations, no studies have used bilateral stimulation. Moreover, little is known about durability effects. We studied the short and long term effects of 1 Hz treatment of the left temporo-parietal junction area in schizophrenia patients with persistent auditory verbal hallucinations, compared to sham stimulation, and added an extra treatment arm of bilateral TPJ area stimulation. METHODS: In this randomized controlled trial, 51 patients diagnosed with schizophrenia and persistent auditory verbal hallucinations were randomly allocated to treatment of the left or bilateral temporo-parietal junction area or sham treatment. Patients were treated for six days, twice daily for 20 minutes. Short term efficacy was measured with the Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucinations Rating Scale (AHRS), and the Positive and Negative Affect Scale (PANAS). We included follow-up measures with the AHRS and PANAS at four weeks and three months. RESULTS: The interaction between time and treatment for Hallucination item P3 of the PANSS showed a trend for significance, caused by a small reduction of scores in the left group. Although self-reported hallucination scores, as measured with the AHRS and PANAS, decreased significantly during the trial period, there were no differences between the three treatment groups. CONCLUSION: We did not find convincing evidence for the efficacy of left-sided rTMS, compared to sham rTMS. Moreover, bilateral rTMS was not superior over left rTMS or sham in improving AVH. Optimizing treatment parameters may result in stronger evidence for the efficacy of rTMS treatment of AVH. Moreover, future research should consider investigating factors predicting individual response. TRIAL REGISTRATION: Dutch Trial Register NTR1813.

Neuroticism is a robust personality trait that constitutes a risk factor for psychopathology, especially anxiety disorders and depression. High neurotic individuals tend to be more self-critical and are overly sensitive to criticism by others. Hence, we used a novel resting-state paradigm to investigate the effect of criticism on functional brain connectivity and associations with neuroticism. Forty-eight participants completed the NEO Personality Inventory Revised (NEO-PI-R) to assess neuroticism. Next, we recorded resting state functional magnetic resonance imaging (rsfMRI) during two sessions. We manipulated the second session before scanning by presenting three standardized critical remarks through headphones, in which the subject was urged to please lie still in the scanner. A seed-based functional connectivity method and subsequent clustering were used to analyse the resting state data. Based on the reviewed literature related to criticism, we selected brain regions associated with self-reflective processing and stress-regulation as regions of interest. The findings showed enhanced functional connectivity between the clustered seed regions and brain areas involved in emotion processing and social cognition during the processing of criticism. Concurrently, functional connectivity was reduced between these clusters and brain structures related to the default mode network and higher-order cognitive control. Furthermore, individuals scoring higher on neuroticism showed altered functional connectivity between the clustered seed regions and brain areas involved in the appraisal, expression and regulation of negative emotions. These results may suggest that the criticized person is attempting to understand the beliefs, perceptions and feelings of the critic in order to facilitate flexible and adaptive social behavior. Furthermore, multiple aspects of emotion processing were found to be affected in individuals scoring higher on neuroticism during the processing of criticism, which may increase their sensitivity to negative social-evaluation.

Impaired Theory of Mind (ToM) has been repeatedly reported as a feature of psychotic disorders. ToM is crucial in social interactions and for the development of social behavior. It has been suggested that reasoning about the belief of others, requires inhibition of the self-perspective. We investigated the neural correlates of self-inhibition in nineteen low psychosis prone (PP) and eighteen high PP subjects presenting with subclinical features. High PP subjects have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. Brain activation was measured with functional Magnetic Resonance Imaging during a ToM task differentiating between self-perspective inhibition and belief reasoning. Furthermore, to test underlying inhibitory mechanisms, we included a stop-signal task. We predicted worse behavioral performance for high compared to low PP subjects on both tasks. Moreover, based on previous neuroimaging results, different activation patterns were expected in the inferior frontal gyrus (IFG) in high versus low PP subjects in self-perspective inhibition and simple response inhibition. Results showed increased activation in left IFG during self-perspective inhibition, but not during simple response inhibition, for high PP subjects as compared to low PP subjects. High and low PP subjects showed equal behavioral performance. The results suggest that at a neural level, high PP subjects need more resources for inhibiting the self-perspective, but not for simple motor response inhibition, to equal the performance of low PP subjects. This may reflect a compensatory mechanism, which may no longer be available for patients with schizophrenia-spectrum disorders resulting in ToM impairments.

Depression in myocardial infarction patients is often a first episode with a late age of onset. Two studies that compared depressed myocardial infarction patients to psychiatric patients found similar levels of somatic symptoms, and one study reported lower levels of cognitive/affective symptoms in myocardial infarction patients. We hypothesized that myocardial infarction patients with first depression onset at a late age would experience fewer cognitive/affective symptoms than depressed patients without cardiovascular disease. Combined data from two large multicenter depression studies resulted in a sample of 734 depressed individuals (194 myocardial infarction, 214 primary care, and 326 mental health care patients). A structured clinical interview provided information about depression diagnosis. Summed cognitive/affective and somatic symptom levels were compared between groups using analysis of covariance, with and without adjusting for the effects of recurrence and age of onset. Depressed myocardial infarction and primary care patients reported significantly lower cognitive/affective symptom levels than mental health care patients (F (2,682) = 6.043, p = 0.003). Additional analyses showed that the difference between myocardial infarction and mental health care patients disappeared after adjusting for age of onset but not recurrence of depression. These group differences were also supported by data-driven latent class analyses. There were no significant group differences in somatic symptom levels. Depression after myocardial infarction appears to have a different phenomenology than depression observed in mental health care. Future studies should investigate the etiological factors predictive of symptom dimensions in myocardial infarction and late-onset depression patients.

Major depressive disorder (MDD) has been associated with abnormal prefrontal-limbic interactions and altered catecholaminergic neurotransmission. The val158met polymorphism on the catechol-O-methyltransferase (COMT) gene has been shown to influence prefrontal cortex (PFC) activation during both emotional processing and working memory (WM). Although COMT-genotype is not directly associated with MDD, it may affect MDD pathology by altering PFC activation, an endophenotype associated with both COMT and MDD. 125 participants, including healthy controls (HC, n=28) and MDD patients were genotyped for the COMT val158met polymorphism and underwent functional magnetic resonance imaging (fMRI-neuroimaging) during emotion processing (viewing of emotional facial expressions) and a WM task (visuospatial planning). Within HC, we observed a positive correlation between the number of met-alleles and right inferior frontal gyrus activation during emotional processing, whereas within patients the number of met-alleles was not correlated with PFC activation. During WM a negative correlation between the number of met-alleles and middle frontal gyrus activation was present in the total sample. In addition, during emotional processing there was an effect of genotype in a cluster including the amygdala and hippocampus. These results demonstrate that COMT genotype is associated with relevant endophenotypes for MDD. In addition, presence of MDD only interacts with genotype during emotional processing and not working memory.

UNLABELLED: The 'complex neural pulse'(TM) (CNP) is a neuromodulation protocol employing weak pulsed electromagnetic fields (PEMF). A pioneering paper reported an analgesic effect in healthy humans after 30 minutes of CNP-stimulation using three nested whole head coils. We aimed to devise and validate a stimulator with a novel design entailing a multitude of small coils at known anatomical positions on a head cap, to improve applicability. The main hypothesis was that CNP delivery with this novel device would also increase heat pain thresholds. Twenty healthy volunteers were enrolled in this double-blind, sham-controlled, crossover study. Thirty minutes of PEMF (CNP) or sham was applied to the head. After one week the other treatment was given. Before and after each treatment, primary and secondary outcomes were measured. Primary outcome was heat pain threshold (HPT) measured with thermal quantitative sensory testing. Other outcomes were warmth detection threshold, and aspects of cognition, emotion and motor performance. As hypothesized heat pain threshold was significantly increased after the PEMF stimulation. All other outcomes were unaltered by the PEMF but there was a trend level reduction of cognitive performance after PEMF stimulation as measured by the digit-symbol substitution task. Results from this pilot study suggest that our device is able to stimulate the brain and to modulate its function. This is in agreement with previous studies that used similar magnetic field strengths to stimulate the brain. Specifically, pain control may be achieved with PEMF and for this analgesic effect, coil design does not appear to play a dominant role. In addition, the flexible configuration with small coils on a head cap improves clinical applicability. TRIAL REGISTRATION: Dutch Cochrane Centre NTR1093.

Major depressive disorder (MDD) has been associated with biased memory formation for mood-congruent information, which may be related to altered monoamine levels. The piccolo (PCLO) gene, involved in monoaminergic neurotransmission, has previously been linked to depression in a genome-wide association study. Here, we investigated the role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 MDD patients (64 PCLO risk allele carriers) and 29 healthy controls (18 PCLO risk allele carriers). During negative word encoding, risk allele carriers showed significant lower activity relative to non-risk allele carriers in the insula, and trend-wise in the anterior cingulate cortex and inferior frontal gyrus. Moreover, depressed risk allele carriers showed significant lower activity relative to non-risk allele carriers in the striatum, an effect which was absent in healthy controls. Finally, amygdalar response during processing new positive words vs. known words was blunted in healthy PCLO+ carriers and in MDD patients irrespective of genotype, which may indicate that signalling of salient novel information does not occur to the same extent in PCLO+ carriers and MDD patients. The PCLO risk allele may increase vulnerability for MDD by modulating local brain function with regard to responsiveness to salient stimuli (i.e. insula) and processing novel negative information. Also, depression-specific effects of PCLO on dorsal striatal activation during negative word encoding and the absence of amygdalar salience signalling for novel positive information further suggest a role of PCLO in symptom maintenance in MDD.