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 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.

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.

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.

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.

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.

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.

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity.

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

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.

Signals of anticipation of reward and of mean reward rates in the human brain.

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors. While changes in reward expectations activated ventral striatal areas as in previous studies, mean reward rates preferentially modulated the substantia nigra/ventral tegmental area, deep layers of the superior colliculi, and a posterior pontomesencephalic region. These brainstem structures may work together to set motivation and attentional efforts levels according to perceived reward opportunities.

Interferon-beta-induced changes in neuroimaging phenotypes of appetitive motivation and reactivity to emotional salience.

Treatment with interferon (IFN) has been associated with depressive side effects. Previous neuroimaging studies have provided information about changes in brain activation patterns in patients under treatment with IFN-alpha, but the effect of other IFNs, or the role of the underlying disease, has yet to be clarified. In the present fMRI study, we looked at brain changes after 8 days of IFN-beta treatment in N = =17 healthy volunteers, thus avoiding the possible confound of the effects of underlying pathology in studies of IFN-treated patients with neurological or other medical disorders. We followed a symptom dimensional approach by simultaneously investigating two distinct symptom domains of depressiveness: negative affect (amygdala) and appetitive motivation (ventral striatum). In these early phases of IFN treatment we detected a selective change in neural substrates of appetitive motivation, consistent with the predominant symptomatic change recorded in psychopathology ratings. In contrast, the fMRI phenotype of negative affect, which is known to characterize disorders of affect involving anxiety and depressiveness as well as individual vulnerability to depression, was unchanged after treatment. These findings suggest that IFN may induce an affective syndrome through a mechanism involving down-regulation of appetitive motivation.

Mirror neuron activations in encoding of psychic pain in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by pronounced emotional instability in interpersonal relations. Previous studies have shown increased activity in the amygdala, an imaging phenotype of negative affect. However, clinical accounts of BPD have drawn attention to deficits in social cognition and their likely role in engendering emotional instability. BPD patients show enhanced sensitivity to other people's emotions, while being less proficient in reading motives and reasons. In the present functional imaging study, we exposed BPD participants to stylized scenes of individuals affected by loss or separation, an issue to which these patients are particularly sensitive. Previously shown to activate the mirror neuron system, these mourning scenes were here also used to assess differential amygdala activity in stimuli of negative valence, but low arousal. Relative to controls, BPD patients were found to activate sensorimotor areas, a part of the mirror neuron system thought to encode basic aspects of the perception of motoric activity and pain. This contrasted with the activity of areas related to more complex aspects of social cognition, such as the inferior frontal gyrus. The amygdala was more active in patients when viewing these scenes, but this effect also showed a strong association with levels of depressiveness and neuroticism. After adjusting for these covariates, differences in amygdala activation were no longer significant. These findings are consistent with models of social cognition in BPD that attribute emotional sensitivity to emotional contagion through the mirror neuron system, in contrast to areas associated with more sophisticated forms of social cognition. These effects were accompanied by increased amygdala reactivity, consistently with the common occurrence of affective symptoms in these patients.

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.

Repeated fMRI in measuring the activation of the amygdala without habituation when viewing faces displaying negative emotions.

Functional imaging studies of affective disorders have demonstrated abnormal activity in the amygdala in response to emotionally salient stimuli. Since in other studies this response has been shown to habituate during the scanning session, it is not clear if it may be of use in monitoring disease progression or remission, or in monitoring the effects of therapy, as habituation may confound normalisation of response. We investigated here amygdala activation in healthy participants exposed to displays of emotional facial expressions in a sample of N = 31 individuals assessed twice in an interval of three weeks. At this interval no habituation could be detected, suggesting the validity of this imaging assay in repeated assessments of amygdalar reactivity. However, the fusiform gyrus and the inferior frontal lobes showed decreases in activations that may be related to the role of these areas in encoding visual and emotional aspects of the stimuli.

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.

Multimodal MEMPRAGE, FLAIR, and [Formula: see text] Segmentation to Resolve Dura and Vessels from Cortical Gray Matter.

While widely in use in automated segmentation approaches for the detection of group differences or of changes associated with continuous predictors in gray matter volume, T1-weighted images are known to represent dura and cortical vessels with signal intensities similar to those of gray matter. By considering multiple signal sources at once, multimodal segmentation approaches may be able to resolve these different tissue classes and address this potential confound. We explored here the simultaneous use of FLAIR and apparent transverse relaxation rates (a signal related to [Formula: see text] relaxation maps and having similar contrast) with T1-weighted images. Relative to T1-weighted images alone, multimodal segmentation had marked positive effects on 1. the separation of gray matter from dura, 2. the exclusion of vessels from the gray matter compartment, and 3. the contrast with extracerebral connective tissue. While obtainable together with the T1-weighted images without increasing scanning times, apparent transverse relaxation rates were less effective than added FLAIR images in providing the above mentioned advantages. FLAIR images also improved the detection of cortical matter in areas prone to susceptibility artifacts in standard MPRAGE T1-weighted images, while the addition of transverse relaxation maps exacerbated the effect of these artifacts on segmentation. Our results confirm that standard MPRAGE segmentation may overestimate gray matter volume by wrongly assigning vessels and dura to this compartment and show that multimodal approaches may greatly improve the specificity of cortical segmentation. Since multimodal segmentation is easily implemented, these benefits are immediately available to studies focusing on translational applications of structural imaging.

The iconography of mourning and its neural correlates: a functional neuroimaging study.

The present functional neuroimaging study focuses on the iconography of mourning. A culture-specific pattern of body postures of mourning individuals, mostly suggesting withdrawal, emerged from a survey of visual material. When used in different combinations in stylized drawings in our neuroimaging study, this material activated cortical areas commonly seen in studies of social cognition (temporo-parietal junction, superior temporal gyrus, and inferior temporal lobe), empathy for pain (somatosensory cortex), and loss (precuneus, middle/posterior cingular gyrus). This pattern of activation developed over time. While in the early phases of exposure lower association areas, such as the extrastriate body area, were active, in the late phases activation in parietal and temporal association areas and the prefrontal cortex was more prominent. These findings are consistent with the conventional and contextual character of iconographic material, and further differentiate it from emotionally negatively valenced and high-arousing stimuli. In future studies, this neuroimaging assay may be useful in characterizing interpretive appraisal of material of negative emotional valence.

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.