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Negative cognitions associated to depressive symptoms have been intensively investigated. In contrast, little is known about the cognitions associated with antisocial personality. We adapted the Scrambled Sentences Task, an instrument from depression research, to document the existence of a different class of negative cognitions that included justifications (external blaming for one’s behavior) and harm to others (based on the notion that some of these individuals enjoy harming or humiliating others) that we hypothesized may be prevalent in antisocial personality. Furthermore, we mapped the prevalence of these cognitions in the dimensional diagnostic system of the Alternative Model of Personality Disorders of the DSM-5 (AMPD). Confirming our hypothesis, these cognitions were associated with ratings in different antisocial personality scales in two non-clinical samples, but not with depressive symptoms or neuroticism. Antisocial personality subscales showed similar levels of antisocial cognitions, but cognitions including harm to others were differentially associated with high sadism. We also uncovered the prevalence of these cognitions in individuals with high detachment scores in the AMPD. These findings suggest that core elements of these cognitions, reflecting a negative view of social interactions, are shared among individuals located in a specific subspace of the AMP dimensional system.

Translational Psychiatry 11(1), 467 (2021). doi:10.1038/s41398-021-01591-5, Published by Nature Publishing Group, London

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.

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.

Recent meta-analytic studies of social cognition and the functional imaging of empathy have exposed the overlap between their neural substrates and heteromodal association areas. 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' visual stimuli to probe the relationship between high-level representations of imminent pain in others and the high end of the gradient of this model. High-level representations were found to co-localize with task deactivations or the transitions from activations to deactivations. These loci belonged to two 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. In contrast to the nonspecific meta-analytic decoding of these loci, low-level representations, such as those of body parts involved in pain or of pain itself, were decoded with matching topics terms. These findings suggest that that task deactivations may set out cortical areas that host high-level representations, but whose functional characterization in terms of simple mappings is unlikely. We anticipate that an increased understanding of the cortical correlates of high-level representations may improve neurobiological models of social interactions and psychopathology.

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.

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.

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.

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.

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 peri­cingular 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.

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.

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.

The cytochrome P450 enzyme 2D6 is involved in the metabolism of 20% of all commonly used drugs, including many psychotropic drugs and CNS-active substances. CYP2D6 is among the CYP enzymes with the highest expression levels in the brain, suggesting a role in the local brain metabolism of psychotropic drugs and the existence of endogenous substrates. The genetic polymorphism of CYP2D6, which causes individual differences in activity levels of the enzyme, has also been characterized functionally in human brain imaging studies. Here we explore the feasibility of predicting CYP2D6 phenotype using component-wise gradient boosting on fMRI resting brain perfusion images. The images belonged to subjects showing a range of genetic CYP2D6 variants. We achieved sensitivity and specificity values between 85% and 87% for the classification of ultrarapid metabolisers, and between 71% and 79% for poor metabolisers. An extension of the boosting algorithm, developed to improve the clinical plausibility of the inherently sparse models, produced enhanced models in agreement with the results of previous studies, showing some brain regions as positively associated with genotypic variation, most prominently in the prefrontal white matter and the corpus callosum. With further development, such a probabilistic method might constitute a valuable, non-invasive alternative to actual genotyping.

Background Current research does not provide a clear explanation for why some patients with Parkinson’s Disease (PD) develop psychotic symptoms. In schizophrenia research the ‘aberrant salience hypothesis’ of psychosis has been influential in explaining the development of psychotic symptoms. The theory proposes that dopaminergic dysregulation leads to inappropriate attribution of salience to otherwise irrelevant or non-informative stimuli, facilitating the formation of hallucinations and delusions, by providing irrational explanations. However, this theory has received very limited attention in the context of PD-psychosis. Methods In the study, we investigated salience processing in 14 PD-patients with psychotic symptoms, 23 PD-patients without psychotic symptoms and 19 healthy controls. All patients received dopaminergic medication. There was no difference in the medication dose between the two patient groups. We examined emotional salience using a visual oddball fMRI paradigm that has been used to investigate early stages of schizophrenia spectrum psychosis, controlling for resting cerebral blood flow (arterial spin labelling fMRI). Furthermore, a subgroup of the two patient groups complete a behavioural ‘jumping to conclusions’ task. Results We found significant differences in brain responses to emotional salience between the two patient groups. PD-patients with psychotic symptoms revealed enhanced brain responses in the striatum, the hippocampus and the amygdala compared to patients without psychotic symptoms. PD-patients with psychotic symptoms showed significant correlations between the levels of dopaminergic drugs they were taking and BOLD signalling, as well as psychotic symptom scores. Furthermore, our data provide first indications for dysfunctional top-down processes, measured in a ‘jumping to conclusions’ bias. Discussion Our study suggests that enhanced signalling in the striatum, hippocampus and amygdala together with deficient top-down cognitive regulations is associated with the development of psychotic symptoms in PD, similarly to that proposed in the ‘aberrant salience hypothesis’ of psychosis in schizophrenia.

Several brain circuits interact in computing the value of choices between options, as when we express our preference between a set of available consumer goods. Here, we used a procedure developed in functional neuroimaging studies of consumer choice to identify the neural substrates activated by choosing between values that, when put into practice, can give meaning to one’s life, such as achievement, community, tradition, or religion, and are unrelated to material needs or financial security. In a first sample (N=18), instead of the neural substrates usually associated with choice between consumer goods, we found activation of the amygdala, a limbic system structure which presides over assignment of values to stimuli according to immediate affective experience and promotes responses according to their association with potential rewards. This unexpected finding was replicated in a second independent sample (N=18). These results are consistent with views arguing for the existential nature of values that give meaning to one’s life here and now, in contrast to maximizing long-term utility.

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., Highlights • Borderline personality (BPD) is characterized by difficulties in social interactions. • BPD patients show enhanced emotional reactivity/contagion, but low mentalization. • BPD showed enhanced recruitment of somatosensory mirror neuron system (MNS). • MNS associated in literature with emotional contagion, but not mentalization. • BPD showed reduced recruitment of inferior frontal gyrus, as in low mentalization.

Highlights • Our study highlights the use of neuroimaging methods to detect and analyze therapy associated side effects, and the main finding of our study is that interferon, known to induce depression as adverse drug effect, leads to selective blunting of appetitive rather than affective stimuli. • Our study shows the utility of sophisticated imaging methods to assess and clarify the nature of subtle drug effects on emotional and cognitive behavior. • We think that the use of neuroimaging methods for the prediction and detection of off-target drug effects on mental health is an important topic in personalized medicine., 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.

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.

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.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.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.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.

The aim of this article is to review the field of clinically relevant pharmacogenetic effects of cytochrome P450 polymorphisms on metabolism, kinetics, and action of selective serotonin reuptake inhibitors (SSRIs).The relevant literature in humans on the implications of genetic variation on SSRI drug exposure, drug safety, and efficacy was systematically evaluated. There is a large amount of evidence on the influences of CYP polymorphisms on the pharmacokinetics of SSRIs. Regulatory agencies have issued warnings or advice considering dose adjustments in the presence of affected metabolic phenotypes for several SSRIs. Evidence-based dose adjustments for drugs dependent on CYP genotype are available to clinicians. However, few data on the relationship between genetically determined elevated plasma concentrations of SSRIs and specific side effects or therapeutic failure are currently available.Genetic polymorphisms in CYP2D6 and CYP2C19 exert large influences on the individual exposure to SSRIs, leading to the aim to achieve similar concentration time courses in different metabolizer phenotypes. The implementation of a stratified approach to medication with SSRIs in different metabolic phenotypes on a rational basis will require new studies assessing the association between clinical outcomes (such as adverse reactions) and genetically determined elevated plasma concentrations.

Aim: The identification of antidepressant drugs (ADs) response biomarkers in depression is of high clinical importance. We explored CHL1 and ITGB3 expression as tentative response biomarkers. Materials & methods: In vitro sensitivity to ADs, as well as gene expression and genetic variants of the candidate genes CHL1, ITGB3 and SLC6A4 were measured in lymphoblastoid cell lines (LCLs) of 58 depressed patients. Results: An association between the clinical remission of depression and the basal expression of CHL1 and ITGB3 was discovered. Individuals whose LCLs expressed higher levels of CHL1 or ITGB3 showed a significantly better remission upon AD treatment. In addition individuals with the CHL1 rs1516338 TT genotype showed a significantly better remission after 5 weeks AD treatment than those carrying a CC genotype. No association between the in vitro sensitivity of LCLs toward AD and the clinical remission could be detected. Conclusion: CHL1 expression in patient-derived LCLs correlated with the clinical outcome. Thus, it could be a valid biomarker to predict the success of an antidepressant therapy. Original submitted 8 December 2014; Revision submitted 2 March 2015

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.