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.

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.

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.

A Computerized Version of the Scrambled Sentences Test.

The scrambled sentences test (SST), an experimental procedure that involves participants writing down their cognitions, has been used to elicit individual differences in depressiveness and vulnerability to depression. We describe here a modification of the SST to adapt it to computerized administration, with a particular view of its use in large samples and functional neuroimaging applications. In a first study with the computerized version, we reproduce the preponderance of positive cognitions in the healthy and the inverse association of these cognitions with individual measures of depressiveness. We also report a tendency of self-referential cognitions to elicit higher positive cognition rates. In a second study, we describe the patterns of neural activations elicited by emotional and neutral sentences in a functional neuroimaging study, showing that it replicates and extends previous findings obtained with the original version of the SST. During the formation of emotional cognitions, ventral areas such as the ventral anterior cingulus and the supramarginal gyrus were relatively activated. This activation pattern speaks for the recruitment of mechanisms coordinating motivational and associative processes in the formation of value-based decisions.