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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.

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.

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.

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

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