The gradient model of brain organization in decisions involving "empathy for pain".

Influential models of cortical organization propose a close relationship between heteromodal association areas and highly connected hubs in the default mode network. The "gradient model" of cortical organization proposes a close relationship between these areas and highly connected hubs in the default mode network, a set of cortical areas deactivated by demanding tasks. Here, we used a decision-making task and representational similarity analysis with classic "empathy for pain" stimuli to probe the relationship between high-level representations of imminent pain in others and these areas. High-level representations were colocalized with task deactivations or the transitions from activations to deactivations. These loci belonged to 2 groups: those that loaded on the high end of the principal cortical gradient and were associated by meta-analytic decoding with the default mode network, and those that appeared to accompany functional repurposing of somatosensory cortex in the presence of visual stimuli. These findings suggest that task deactivations may set out cortical areas that host high-level representations. We anticipate that an increased understanding of the cortical correlates of high-level representations may improve neurobiological models of social interactions and psychopathology.

Segregation, connectivity, and gradients of deactivation in neural correlates of evidence in social decision making.

Functional imaging studies of sensory decision making have detected a signal associated with evidence for decisions that is consistent with data from single-cell recordings in laboratory animals. However, the generality of this finding and its implications on our understanding of the organization of the fMRI signal are not clear. In the present functional imaging study, we investigated decisions in an elementary social cognition domain to identify the neural correlates of evidence, their segregation, connectivity, and their relationship to task deactivations. Besides providing data in support of an evidence-related signal in a social cognition task, we were interested in embedding these neural correlates in models of supramodal associative cortex placed at the top of a hierarchy of processing areas. Participants were asked to decide which of two depicted individuals was saddest based on information rich in sensory features (facial expressions) or through contextual cues suggesting the mental state of others (stylized drawings of mourning individuals). The signal associated with evidence for the decision was located in two distinct networks differentially recruited depending on the information type. Using the largest peaks of the signal associated with evidence as seeds in a database of connectivity data, these two networks were retrieved. Furthermore, the hubs of these networks were located near or along a ribbon of cortex located between task activations and deactivations between areas affected by perceptual priming and the deactivated areas of the default network system. In associative cortex, these findings suggest gradients of progressive relative deactivation as a possible neural correlate of the cortical organization envisaged by structural models of cortical organization and by predictive coding theories of cortical function.

Accelerated 3D-GRASE imaging improves quantitative multiple post labeling delay arterial spin labeling.

PURPOSE: To investigate the impact of accelerated, single-shot 3D-GRASE acquisition on quantitative arterial spin labeling (ASL) with multiple and single post-labeling delay (PLD) in terms of perfusion-weighted SNR per unit scan time (TSNRPW ) and quantification accuracy. METHODS: Five subjects were scanned on a 3T MRI scanner using the pseudo-continuous arterial spin labeling (PCASL) technique with a 3D-GRASE imaging sequence capable of parallel imaging acceleration. A 3-inversion pulse background suppression was simulated and implemented in the sequence. Three time-matched single PLD measurements, a segmented one without acceleration, 1 with conventional GRAPPA, and 1 with CAIPIRINHA sampling, were used to compare TSNRPW . Three time-matched multiple PLD measurements with the identical imaging parameters were additionally evaluated (no acceleration vs. CAIPIRINHA sampling vs. CAIPIRINHA sampling with doubled number of PLDs). Cerebral blood flow and arterial transit time fit uncertainties were compared and used as a quality measure. RESULTS: The single PLD measurements show an 11% TSNRPW increase using CAIPIRINHA sampling instead of GRAPPA sampling, while the non-accelerated scan exhibits 35% higher TSNRPW compared to the GRAPPA scan. However, taking advantage of the increased number of averages for multiple PLD acquisitions, a 14%/16% (gray matter) and 34%/36% (white matter) reduction of CBF fit uncertainty is observed with CAIPIRINHA sampling (6 PLDs/12 PLDs) compared to no acceleration. CONCLUSION: Accelerated single-shot 3D-GRASE with PCASL allows for smaller quantification uncertainties than time-matched segmented acquisitions. Corresponding single-shot acquisitions with acceptable blurring and no intra-volume motion render state-of-the-art ASL methods in a clinically feasible time possible.

Adaptation of the Scrambled-Sentences Task to Assess "Shattered Assumptions:" Construction of the Test and Investigation of Neural Substrates in an fMRI Study.

BACKGROUND: Increasing recognition is being given to the importance of cognitions observed in posttraumatic conditions. These cognitions may reflect the activation of negative schemas. The aim of this work was to evaluate the feasibility of the scrambled-sentences task (SST) to assess individual differences in attributions commonly observed after traumas. Originally developed to assess the tendency to activate negative cognitions in individuals predisposed to depression, the SST is a laboratory task the outcome of which has been shown to predict depression relapse and is associated with depressiveness. SAMPLING AND METHODS: We used content from self-rating scales for assessment of the activation of trauma-related schemas to develop a trauma-related SST and evaluated its performance in a behavioral study (n = 43) and a functional neuroimaging study (n = 20). RESULTS: In the healthy sample in which we tested it, the trauma-related SST was strongly associated with individual differences in negative affect (scores in depressiveness and neuroticism scales) as well as with the scores on trauma-related cognition scales. However, we failed to detect a clear specificity of trauma-related cognitions in correlations with scores on the trauma-related scales in the healthy participants. The neuroimaging data demonstrated activation of a ventral network of areas that included the perisylvian/temporal cortex and the peri-cingular cortex in handling trauma-related relative to neutral material, replicating previous neuroimaging studies of the SST. CONCLUSION: The shattered-assumptions SST demonstrated strong associations with individual differences in all of the rating scales used in the study, suggesting its usefulness in capturing aspects of affective psychopathology. The neuroimaging study confirmed the capacity of this task to elicit specific activations. In future studies, evaluation of the conditions in which these neural substrates are active may shed light on the mechanism of schema selection.

Multimodal FLAIR/MPRAGE segmentation of cerebral cortex and cortical myelin.

The MR signal from gray matter has been long known to present small differences in intensity that have been attributed to variations in cortical myelin content. Previous studies have shown that the T1-, T2-weighted signal and their ratio are sensitive to these variations. Here, we investigated different combinations of signal from MPRAGE and FLAIR images in multimodal segmentation with parametric models of signal intensity to identify a procedure for the identification of contrast in cortical gray matter and the segmentation of different cortical components at 3T. We show that a three-modal combination of these signals delivers a stable segmentation of the cortical mantle in which two distinct components are reliably identified. The resulting intensity maps correspond well to known regional myeloarchitectural differences between cortical regions. These results confirm that widely available MR sequences contain signal that may be used to reliably detect subtle differences in the composition of gray matter with a segmentation approach.

Changing views of emotion regulation and neurobiological models of the mechanism of action of psychotherapy.

Influential neurobiological models of the mechanism of action of psychotherapy attribute its success to increases of activity in prefrontal areas and decreases in limbic areas, interpreted as the successful and adaptive recruitment of controlled processes to achieve emotion regulation. In this article, we review the behavioral and neuroscientific evidence in support of this model and its applicability to explain the mechanism of action of psychotherapy. Neuroimaging studies of explicit emotion regulation, evidence on the neurobiological substrates of implicit emotion regulation, and meta-analyses of neuroimaging studies of the effect of psychotherapy consistently suggest that areas implicated in coding semantic representations play an important role in emotion regulation not covered by existing models based on controlled processes. We discuss the findings that implicate these same areas in supporting working memory, in encoding preferences and the prospective outcome of actions taken in rewarding or aversive contingencies, and show how these functions may be integrated into process models of emotion regulation that depend on elaborate semantic representations for their effectiveness. These alternative models also appear to be more consistent with internal accounts in the psychotherapeutic literature of how psychotherapy works.

Use of magnetic resonance imaging in pharmacogenomics.

Because of the large variation in the response to psychoactive medication, many studies have attempted to uncover genetic factors that determine response. While considerable knowledge exists on the large effects of genetic polymorphisms on pharmacokinetics and plasma concentrations of drugs, effects of the concentration at the target site and pharmacodynamic effects on brain functions in disease are much less known. This article reviews the role of magnetic resonance imaging (MRI) to visualize response to medication in brain behaviour circuits in vivo in humans and assess the influence of pharmacogenetic factors. Two types of studies have been used to characterize effects of medication and genetic variation. In task-related activation studies the focus is on changes in the activity of a neural circuit associated with a specific psychological process. The second type of study investigates resting state perfusion. These studies provide an assessment of vascular changes associated with bioavailability of drugs in the brain, but may also assess changes in neural activity after binding of centrally active agents. Task-related pharmacogenetic studies of cognitive function have characterized the effects in the prefrontal cortex of genetic polymorphisms of dopamine receptors (DRD2), metabolic enzymes (COMT) and in the post-synaptic signalling cascade under the administration of dopamine agonists and antagonists. In contrast, pharmacogenetic imaging with resting state perfusion is still in its infancy. However, the quantitative nature of perfusion imaging, its non-invasive character and its repeatability might be crucial assets in visualizing the effects of medication in vivo in man during therapy.

Phenotypic Models of Drug-Drug-Gene Interactions Mediated by Cytochrome Drug-Metabolizing Enzymes.

Genetic polymorphisms in drug metabolizing enzymes and drug-drug interactions are major sources of inadequate drug exposure and ensuing adverse effects or insufficient responses. The current challenge in assessing drug-drug gene interactions (DDGIs) for the development of precise dose adjustment recommendation systems is to take into account both simultaneously. Here, we analyze the static models of DDGI from in vivo data and focus on the concept of phenoconversion to model inhibition and genetic polymorphisms jointly. These models are applicable to datasets where pharmacokinetic information is missing and are being used in clinical support systems and consensus dose adjustment guidelines. We show that all such models can be handled by the same formal framework, and that models that differ at first sight are all versions of the same linear phenoconversion model. This model includes the linear pharmacogenetic and inhibition models as special cases. We highlight present challenges in this endeavor and the open issues for future research in developing DDGI models for recommendation systems.

The dark side of personality functioning: associations between antisocial cognitions, personality functioning (AMPD), empathy and mentalisation.

Introduction: With the introduction of the new psychiatric diagnostic manuals, personality functioning has gained new prominence. Several studies have reported consistent findings that individual showing high levels of antisocial features are associated with alterations in interpersonal functioning domains such as empathy and mentalisation. The focus of the current study (N = 198) is to examine antisocial cognitions, as measured by the Scrambled Sentences Task (SST), and to what extent this approach can help to better understand the relationship between antisocial traits and personality functioning/empathy. Method: We implemented a hypothesis-driven approach using logistic regression and a data-driven approach using machine learning to examine distinct but related measures of personality functioning as predictors of antisocial cognitions. Results: Antisocial cognitions were associated with low interpersonal functioning as expected, but only when not adjusting for antisocial traits, which accounted for almost all the association. The data-driven analysis revealed that individual items assessing empathic concern in personality functioning scales (as opposed to the whole scores) explained low antisocial cognitions even when adjusting for antisocial traits. Discussion: Antisocial cognitions appear to be associated to two distinct traits, the antisocial and a specific type of personality functioning. This finding is discussed in terms of the possible distinction between two motivational forces: to harm others/prioritize one's advantage, and to help suffering others.

Effect of paroxetine and bupropion on human resting brain perfusion: an arterial spin labeling study.

Due to the physiological coupling with metabolism, brain perfusion is a potential aid in understanding the effects of medication on neural activity in vivo. In this study, arterial spin labeling (ASL) was used to quantify the effect of seven days of administration of paroxetine (20 mg), bupropion (150 mg) on cerebral blood flow levels at rest in a double-blind, placebo-controlled crossover design in N=21 healthy participants. Paroxetine administration was associated with diffuse cortical perfusion decrements, more marked in the prefrontal region, and with decrements in the striatum, caudate and the basal forebrain. The effect of bupropion on the cortex was similar but less conspicuous. In the brainstem, there was suggestive evidence of perfusion decrements in the main serotonergic and noradrenergic nuclei. These results demonstrate the existence of effects on rest perfusion of antidepressant medication of potential use in monitoring its action. The observed perfusion reductions may be related to compensatory decrements of monoaminergic neural activity in the initial phases of treatment that are observed under both drugs following the increase in extracellular concentration of transmitters.

Genetic variation in CYP2D6 impacts neural activation during cognitive tasks in humans.

The drug metabolizing cytochrome P450 2D6 enzyme (CYP2D6) is highly expressed in brain and potentially involved in neurotransmitter biotransformation. Here, we report the effect of the CYP2D6 genotype on brain activation during a working memory and an emotional face matching task measured with fMRI. Subjects were taken from an ongoing large scale multicenter imaging genetic study. CYP2D6 genotyping of the alleles *2, *3, *4, *5, *6, *9, *10, *17, *35, *41 and the duplication was performed in N=114 healthy drug free individuals. All individuals had completed two tasks in functional brain imaging: an n-back working memory task and an implicit emotional face matching task. Contrast images were analyzed in second-level random effects models with CYP2D6 enzyme activity levels as regressor of interest and age, sex and scanning site as covariates. In the working memory task, a significant effect of CYP2D6 genotype was found in the fusiform gyrus and the precuneus. In the emotional face matching task, an effect was detected in the cuneus. No significant activation results were found in the thalamus. A conjunction analysis confirmed a significant joint effect of the CYP2D6 association in both regions. In both tasks activation increased with increasing CYP2D6 activity. In conclusion, we confirmed a central nervous system effect of CYP2D6 activity in a large independent sample using a different imaging modality, and provide evidence that basic cognitive processes related to such as alertness may be impacted.

Pharmacogenetic Dose Modeling Based on CYP2C19 Allelic Phenotypes.

Pharmacogenetic variability in drug metabolism leads to patient vulnerability to side effects and to therapeutic failure. Our purpose was to introduce a systematic statistical methodology to estimate quantitative dose adjustments based on pharmacokinetic differences in pharmacogenetic subgroups, addressing the concerns of sparse data, incomplete information on phenotypic groups, and heterogeneity of study design. Data on psychotropic drugs metabolized by the cytochrome P450 enzyme CYP2C19 were used as a case study. CYP2C19 activity scores were estimated, while statistically assessing the influence of methodological differences between studies, and used to estimate dose adjustments in genotypic groups. Modeling effects of activity scores in each substance as a population led to prudential predictions of adjustments when few data were available ('shrinkage'). The best results were obtained with the regularized horseshoe, an innovative Bayesian approach to estimate coefficients viewed as a sample from two populations. This approach was compared to modeling the population of substance as normally distributed, to a more traditional "fixed effects" approach, and to dose adjustments based on weighted means, as in current practice. Modeling strategies were able to assess the influence of study parameters and deliver adjustment levels when necessary, extrapolated to all phenotype groups, as well as their level of uncertainty. In addition, the horseshoe reacted sensitively to small study sizes, and provided conservative estimates of required adjustments.

A Short Functional Neuroimaging Assay Using Attachment Scenes to Recruit Neural Correlates of Social Cognition-A Replication Study.

Attachment theory provides a conceptual framework to understand the impact of early child-caregiver experiences, such as loss or separation, on adult functioning and psychopathology. In the current study, scenes from the Adult Attachment Projective Picture System (AAP), a validated, commonly used standardized diagnostic instrument to assess adult attachment representations, were used to develop a short fMRI assay eliciting the neural correlates of encoding of potentially hurtful and threatening social situations such as social losses, rejections or loneliness. Data from healthy participants (N = 19) showed activations in brain areas associated with social cognition and semantic knowledge during exposure to attachment-related scenes compared to control scenes. Extensive activation of the temporal poles was observed, suggesting the use of semantic knowledge for generating social concepts and scripts. This knowledge may underlie our ability to explain and predict social interactions, a specific aspect of theory of mind or mentalization. In this replication study, we verified the effectiveness of a modified fMRI assay to assess the external validity of a previously used imaging paradigm to investigate the processing of emotionally negatively valenced and painful social interactions. Our data confirm the recruitment of brain areas associated with social cognition with our very short neuroimaging assay.

The interplay of Criterion A of the Alternative Model for Personality Disorders, mentalization and resilience during the COVID-19 pandemic.

Background and aims: The COVID-19 pandemic has been accompanied by a worsening of mental health levels in some, while others manage to adapt or recover relatively quickly. Transdiagnostic factors such as personality functioning are thought to be involved in determining mental health outcomes. The present study focused on two constructs of personality functioning, Criterion A of the Alternative Model for Personality Disorders (AMPD, DSM-5) and mentalization, as predictors of depressive symptoms and life satisfaction during the COVID-19 pandemic. A second focus of the study was to examine whether this relationship was mediated by resilience. Methods: Linear regression analyses were used to examine the relationship between personality functioning measured by Criterion A (AMPD, DSM-5) and mentalizing abilities as predictors, and depression and life satisfaction as mental health outcomes. To assess the hypothesis that this relationship is mediated by resilience a structural equation modeling approach was conducted. Data from N = 316 individuals from the general population were collected. Results: Linear regression models revealed highly significant associations between Criterion A/mentalization and both outcome measures. Structural equation models showed a significant partial mediation by resilience of these relationships. Conclusion: Our results support the hypothesis that mentalizing serves as a protective function by promoting resilience to the impact of stress and threats. Criterion A and mentalization performed similarly as predictors of mental health outcomes, providing empirically overlapping operationalizations of personality functioning. This finding emphasizes the importance of personality functioning in positive and negative mental health outcomes. Furthermore, our results are consistent with a mediating role of resilience.

Effects of large-scale nonstationarity on parametric maps. A study of rest perfusion CASL data.

This study investigates the emergence of characteristic patterns in clusters thresholded at uncorrected significance levels, using as a case study rest perfusion images obtained with the continuous arterial spin labelling technique (CASL). The origin of these patterns is traced back to the existence of large-scale spatial covariance, a violation of the stationarity assumption on the spatial distribution of residual errors. It is shown that in the presence of large-scale covariance, several principles or intuitions common among experimenters when evaluating the inferential strength of their analyses are not applicable. Thresholded maps and clusters are confounded by the spatial patterns of large-scale covariance, irrespective of the existence of a true effect, as shown in t maps constructed by resampling groups at random from a large pool of volumes. Filtering clusters according to their size made the problem worse, and corrections on cluster size based on random field theory models of smoothness had only a minor impact on their tendency to appear in characteristic locations. A formal analysis shows that the large-scale covariance at the origin of these problems is retained in the parametric map irrespective of sample size. Therefore, neither sample independence nor sample size protect from replications of effects being confounded by replications of the spatial covariance of residual errors. In contrast, cluster peaks were not affected by large-scale covariance but only by local differences in smoothness levels, as predicted by random field theory for the distribution of maxima, highlighting the different inferential robustness of cluster-based and maxima-based statistics. A framework is provided to generalize these results to mixed effects models with nested random effects, applicable also to activation studies. Large-scale nonstationarity is most problematic when the variance source at the origin of the characteristic patterns is not specific to a function or variable involved in the inferential process, as typically in observational studies of individual differences. These results raise the question of the existence and impact of large-scale nonstationarity in studies with data obtained with other techniques.

Neurobiological models of emotion regulation: a meta-analysis of neuroimaging studies of acceptance as an emotion regulation strategy.

Emotional acceptance is an important emotion regulation strategy promoted by most psychotherapy approaches. We adopted the Activation Likelihood Estimation technique to obtain a quantitative summary of previous fMRI (functional Magnetic Resonance Imaging) studies of acceptance and test different hypotheses on its mechanisms of action. The main meta-analysis included 13 experiments contrasting acceptance to control conditions, yielding a total of 422 subjects and 170 foci of brain activity. Additionally, subgroups of studies with different control conditions (react naturally or focus on emotions) were identified and analysed separately. Our results showed executive areas to be affected by acceptance only in the subgroup of studies in which acceptance was compared to natural reactions. In contrast, a cluster of decreased brain activity located in the posterior cingulate cortex (PCC)/precuneus was associated with acceptance regardless of the control condition. These findings suggest that high-level executive cortical processes are not a distinctive feature of acceptance, whereas functional deactivations in the PCC/precuneus constitute its specific neural substrate. The neuroimaging of emotional acceptance calls into question a key tenet of current neurobiological models of emotion regulation consisting in the necessary involvement of high-level executive processes to actively modify emotional states, suggesting a complementary role for limbic portions of the default system.

Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain.

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N = 608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.

Effort-Reward-Imbalance, Burnout, and Depression Among Psychiatrists 2006 and 2016-Changes After a Legislative Intervention.

Background: Physicians, especially psychiatrists, have a high risk of job-related stress, and mental impairment. In our study we examined changes in private and occupational stress factors and mental health within a decade. The legislative reduction of physicians' working hours in Germany during this period made it possible to investigate the impact of working hours in particular. Methods: Questionnaires were administered at two psychiatrist meetings (2006 and 2016) about job and family situation, depressiveness, burnout and effort-reward imbalance. A total of N = 1,797 datasets were analyzed. Results: Working hours and free weekends were associated with mental health indices. Correlation analyses showed that a reduction in weekly working hours and working days at weekends was related to reduced scores for effort-reward-imbalance, burnout and depression. Conclusions: Our data show changes in workplace stress and mental health in psychiatrists in a decade in which a reduction in working hours has been required by law. These results can provide indications of effective prevention strategies in the professional context of physicians working in psychiatry.

Unbiased ROI selection in neuroimaging studies of individual differences.

Individual differences studies are those that investigate the interaction between a subject level covariate, such as sex, age, or performance, and the effect of an experimental task. Commonly, a brain region is selected on the basis of the task effect, and the signal in this region correlated with individual covariates. It is shown here that, provided that data are identically and independently distributed between subjects, the selection of the region on the basis of the task effect is unbiased in two cases: when selection is based on a one-sample t test of the task effect, or when the subject level covariate is centered. This result is meant to contribute to clarifying when using the same data for ROI selection and testing leads to valid tests in studies of individual differences.

Components of acquisition-to-acquisition variance in continuous arterial spin labelling (CASL) imaging.

BACKGROUND: Images of perfusion estimates obtained with the continuous arterial spin labelling technique are characterized by variation between single acquisitions. Little is known about the spatial determinants of this variation during the acquisition process and their impact on voxel-by-voxel estimates of effects. RESULTS: We show here that the spatial patterns of covariance between voxels arising during the acquisition of these images uncover distinct mechanisms through which this variance arises: through variation in global perfusion levels; through the action of large vessels and other, less well characterized, large anatomical structures; and through the effect of noisy areas such as the edges of the brain. CONCLUSIONS: Knowledge of these covariance patterns is important to experimenters for a correct interpretation of findings, especially for studies where relatively few acquisitions are made.