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Introduction: Studies of brain-damaged patients revealed that amygdala lesions cause deficits in the processing and recognition of emotional faces. Patients with autism spectrum disorders (ASD) have similar deficits also related to dysfunctions of the limbic system including the amygdala.Methods: We investigated a male patient who had been diagnosed with Asperger's syndrome. He also presented with a lesion of the right mesial temporal cortex, including the amygdala. We used functional magnetic resonance imaging (fMRI) to investigate neuronal processing during a passive viewing task of implicit and explicit emotional faces. Clinical assessment included a facial emotion recognition task.Results: There was no amygdala activation on both sides during the presentation of masked emotional faces compared to the no-face control condition. Presentation of unmasked happy and angry faces activated the left amygdala compared to the no-face control condition. There was no amygdala activation in response to unmasked fearful faces on both sides. In the facial emotion recognition task, the patient biased positive and neutral expressions as negative.Conclusions: This case report describes a male patient with right amygdala damage and an ASD. He displayed a non-response of the amygdala to fearful faces and tended to misinterpret fearful expressions. Moreover, a non-reactivity of both amygdalae to emotional facial expressions at an implicit processing level was revealed. It is discussed whether the deficient implicit processing of facial emotional information and abnormalities in fear processing could contribute and aggravate the patient's impairments in social behavior and interaction.

Structural gray matter (GM) volume reductions in patients with schizophrenia have rarely been replicated across two different sites, the impact of culture and clinical characteristics remains unresolved. Hence, we assessed GM volume reductions in patients with schizophrenia using 3 T magnetic resonace imaging to replicate results across two independent and culturally different backgrounds (Germany, Japan), and to investigate the impact of brain volume reductions on clinical characteristics. In total, 163 German (80 patients) and 203 Japanese (83 patients) participants were included in the analysis. Voxel-based morphometry (VBM) was used to investigate structural differences between the groups and across the two sites, comparing local GM volumes. Clinical variables were used to analyze effects unrelated to the socio-cultural background. Across both data sets, widespread GM reductions in frontal and temporal cortical parts were found between patients and controls, indicating strong effects of diagnosis and only small effects of site. The investigation of clinical characteristics revealed the strongest effects for chlorpromazine equivalents on GM volume reductions primarily in the Japanese sample. Although the effects of site are small, several brain regions do not overlap between the two groups. Thus, GM may be affected differently at the two sites in patients with schizophrenia.

Background: There is increasing evidence that people with attention-deficit/hyperactivity disorder (ADHD) are impaired in emotion regulation, but psychophysiological and functional MRI data on emotion processing in adult patients with ADHD are scarce. We investigated the neural correlates of reappraisal as one of the most efficient emotion-regulation strategies. Methods: We included 30 adult patients with ADHD and 35 healthy controls in our study. We applied a well-established reappraisal paradigm in functional MRI and assessed behavioural emotion-regulation strategies with standardized questionnaires. We hypothesized that patients with ADHD would demonstrate impaired reappraisal related to reduced activations in the frontoparietal cognitive control network. Results: Despite our hypothesis, we found no significant activation differences in the neural reappraisal network between patients with ADHD and controls. As well, both groups revealed similar reappraisal success on the immediate behavioural ratings in the scanner. Interestingly, patients with ADHD revealed significantly increased activations in the dorsal and ventral anterior cingulate cortex (ACC) compared with controls when viewing negative > neutral pictures. These ACC activations were significantly correlated with the prevalence of habitual use of reappraisal in patients with ADHD only. Limitations: Patients withdrew medication only 24 hours before the experiment; we investigated negative, but not positive, emotion processing and regulation. Conclusion: Although emotion dysregulation is regarded as a core symptom of ADHD, explicit reappraisal does not seem to be impaired in adult patients. However, increased activation of the ACC implies stronger implicit emotion regulation induced by negative stimuli. This might be explained by emotional hyperresponsivity in patients with ADHD compared with controls.

Objective Emotional dysregulation has emerged as a core symptom domain in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the pathophysiological underpinnings remain poorly understood. This study investigated attentional biases to positive and negative emotional words as possible contributing mechanisms. Methods Event-related potentials (ERPSs) and behavioral attention bias indices were recorded from 39 adult patients with ADHD and 41 healthy controls during a verbal dot-probe task with positive-neutral, negative-neutral, and neutral-neutral word pairs. Results Cue-locked N2pc amplitudes indicated a significant attentional bias towards emotional words in patients with ADHD and healthy controls. In healthy controls, the bias was only significant in positive trials. In patients, the bias was associated with ADHD severity and self-reported poor emotion regulation skills. ADHD patients also exhibited reduced target-locked P1 amplitudes and inferior behavioral performance compared with healthy controls. Conclusions Our findings provide evidence of an attention bias to positive and negative emotional stimuli in adult patients with ADHD and adverse effects of emotional stimuli on task performance. Significance An attentional bias to emotional stimuli might contribute to emotional reactivity and dysregulation in adult patients with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is closely linked to the dysregulation of dopaminergic and noradrenergic neurotransmission in the fronto-striatal neural network, including the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). Additionally, increasing evidence supports the involvement of the glutamatergic system in the pathophysiology of ADHD. Impulsivity, a core symptom in patients with ADHD, has been repeatedly associated with glutamatergic neurotransmission, and pharmacological treatment of ADHD has been shown to reduce glutamate levels in the prefrontal cortex.We investigated glutamate levels in the ACC and the DLPFC in 30 adults with ADHD and 30 healthy controls using single-voxel proton magnetic resonance spectroscopy on a 3T scanner.The ADHD group showed a significant increase in glutamate in the ACC compared to controls, no significant differences in metabolites were observed in the DLPFC. Overall, glutamate levels in the ACC were positively correlated with ADHD symptomatology, especially hyperactivity and impulsivity symptoms.Increased levels of glutamate in the ACC, which were positively correlated with hyperactivity and impulsivity, support the hypothesis that dysfunctional glutamatergic neurotransmission is at least partially responsible for ADHD symptomatology. Modulation of glutamatergic neurotransmission might therefore be a promising avenue for future pharmacological interventions.

ObjectiveaaEarly neuroimaging studies have demonstrated amygdala hypoactivation in schizophrenia but more recent research based on paradigms with minimal cognitive loads or examining automatic processing has observed amygdala hyperactivation. Hyperactivation was found to be related to affective flattening. In this study, amygdala responsivity to threat-related facial expression was investigat ed in patients as a function of automatic versus controlled processing and patients’ flat affect. MethodsaaFunctional magnetic resonance imaging was used to measure amygdala activation in 36 patients with schizophrenia and 42 healthy controls. During scanning, a viewing task with masked and unmasked fearful and neutral faces was presented. ResultsaaPatients exhibited increased amygdala response to unmasked fearful faces. With respect to masked fearful faces, no betweengroup differences emerged for the sample as a whole but a subsample of patients with flat affect showed heightened amygdala activation. The amygdala response to masked fearful faces was positively correlated with the degree of flat affect. Conversely, amygdala response to unmasked fearful faces was negatively correlated to the severity of affective flattening. In patients, amygdala responses to masked and unmasked fearful faces showed an inverse correlation. ConclusionaaOur findings suggest that amygdala hyperresponsivity to unmasked fearful faces might be a functional characteristic of schizophrenia. Amygdala hyperresponsivity to masked fearful faces might be a specific characteristic of patients with affective flattening. A model of flat affect as a response mechanism to emotional overload is proposed.

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene ( NPSR1 ) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected ( p =.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5 min after injection ( p =.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.

Emotional dysregulation (ED) is being increasingly recognized as a core feature of attention-deficit/hyperactivity disorder (ADHD), but the pathophysiological underpinnings remain unclear. In this study, we provide meaningful electrophysiological evidence of ED in adult patients with ADHD (n = 39) compared to healthy controls (n = 40) by exploring the electrophysiological correlates of the emotion regulation strategies reappraisal, distraction, and expressive suppression. Event-related potentials (ERPs) were recorded during passive viewing of neutral and negative images, as well as during emotion regulation. The patients with ADHD exhibited increased frontal late positive potential (LPP) amplitudes during passive viewing of the aversive images and during emotion regulation. Compared with the healthy controls, a subgroup of medication-naive patients with ADHD (n = 25) also exhibited larger centroparietal LPP amplitudes and provided more negative ratings of the aversive and neutral images. Both the frontal and centroparietal LPP amplitudes were associated with ADHD symptom severity. However, no significant deficit in LPP modulation during emotion regulation was found. These findings strongly support the clinical observation of increased emotional responsivity toward negative stimuli and difficulty during the implementation of emotion regulation strategies and thus encourage the implementation of emotion regulation modules in the treatment of adult patients with ADHD.

Dysfunction of dopamine D3 receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D3 receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D3 receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02–0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.

According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic–pituitary–adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p

Affective priming refers to the phenomenon that subliminal presentation of facial emotion biases subsequent evaluation of a neutral object in the direction of the prime. The aim of the present study was to specify the neural correlates of evaluative shifts elicited by facial emotion shown below the threshold of conscious perception. We tested the hypotheses whether the amygdala is involved in negative priming, whereas the nucleus accumbens participates in positive priming. In addition, exploratory whole brain correlation analyses were conducted. During 3T fMRI scanning, pictures of sad, happy, and neutral facial expression masked by neutral faces were presented to 110 healthy adults who had to judge valence of masks on a four-point scale. There was evidence for significant negative priming based on sad faces. A correlation was observed between amygdala activation and negative priming. Activation in medial, middle, and superior frontal and middle temporo-occipital areas, and insula was also associated with negative priming. No significant priming based on happy faces was found. However, nucleus accumbens activation to happy faces correlated with the positive priming score. The present findings confirm that the amygdala but also other brain regions, especially the medial frontal cortex, appear involved in automatically elicited negative evaluative shifts.

Objective: Smooth pursuit eye movements are compromised in patients with schizophrenia and their first-degree relatives. Although research has demonstrated that the motor components of smooth pursuit eye movements are intact, motion perception has been shown to be impaired. In particular, studies have consistently revealed deficits in performance on tasks specific to the high-order motion area V5 (middle temporal area, MT) in patients with schizophrenia. In contrast, data from low-level motion detectors in the primary visual cortex (V1) have been inconsistent. Method: To differentiate between low-level and high-level visual motion processing, we applied a temporal-order judgment task for motion events and a motion-defined figure-ground segregation task using patients with schizophrenia and healthy controls. Successful judgments in both tasks rely on the same low-level motion detectors in the V1; however, the first task is further processed in the higher-order motion area MT in the magnocellular (dorsal) pathway, whereas the second task requires subsequent computations in the parvocellular (ventral) pathway in visual area V4 and the inferotemporal cortex (IT). These latter structures are supposed to be intact in schizophrenia. Results: Patients with schizophrenia revealed a significantly impaired temporal resolution on the motion-based temporal-order judgment task but only mild impairment in the motion-based segregation task. Conclusions: These results imply that low-level motion detection in V1 is not, or is only slightly, compromised; furthermore, our data restrain the locus of the well-known deficit in motion detection to areas beyond the primary visual cortex. (PsycINFO Database Record (c) 2013 APA, all rights reserved). Language: en

Background and objectives Patients with schizophrenia reveal impaired decision-making strategies causing social, financial and health care problems. The extent to which deficits in decision-making reflect intentional risky choices in schizophrenia is still under debate. Based on previous studies we expected patients with schizophrenia to reveal a riskier performance on the GDT and to make more disadvantageous decisions on the IGT. Methods In the present study, we investigated 38 patients with schizophrenia and 38 matched healthy control subjects with two competing paradigms regarding feedback: (1) The Game of Dice Task (GDT), in which the probabilities of winning or losing are stable and explicitly disclosed to the subject, to assess decision-making under risk and (2) the Iowa Gambling Task (IGT), which requires subjects to infer the probabilities of winning or losing from feedback, to investigate decision-making under ambiguity. Results Patients with schizophrenia revealed an overall riskier performance on the GDT; although they adjusted their strategy over the course of the GDT, they still made significantly more disadvantageous choices than controls. More positive symptoms in patients with schizophrenia indicated by higher PANSS positive scores were associated with riskier choices and less use of negative feedback. Compared to healthy controls, they were not impaired in net score but chose more disadvantageous cards than controls on the first block of the IGT. Limitations Effects of medication at the time of testing cannot be ruled out. Conclusions Our findings suggest that patients with schizophrenia make riskier decisions and are less able to regulate their decision-making to implement advantageous strategies, even when the probabilities of winning or losing are explicitly disclosed. The dissociation between performance on the GDT and IGT suggests a pronounced impairment of executive functions related to the dorsolateral prefrontal cortex.

Objectives Memory and executive deficits are important cognitive markers of Alzheimer's disease (AD). Moreover, in the past decade, cerebrospinal fluid (CSF) biomarkers have been increasingly utilized in clinical practice. Both cognitive and CSF markers can be used to differentiate between AD patients and healthy seniors with high diagnostic accuracy. However, the extent to which performance on specific mnemonic or executive tasks enables reliable estimations of the concentrations of different CSF markers and their ratios remains unclear. Methods To address the above issues, we examined the association between neuropsychological data and CSF biomarkers in 51 AD patients using hierarchical multiple regression analyses. In the first step of these analyses, age, education and sex were entered as predictors to control for possible confounding effects. In the second step, data from a neuropsychological test battery assessing episodic memory, semantic memory and executive functioning were included to determine whether these variables significantly increased (compared to step 1) the explained variance in Aβ 42 concentration, p-tau concentration, t-tau concentration, Aβ 42 /t-tau ratio, and Aβ 42 /Aβ 40 ratio. Results The different models explained 52% of the variance in Aβ 42 /t-tau ratio, 27% of the variance in Aβ 42 concentration, and 28% of the variance in t-tau concentration. In particular, Aβ 42 /t-tau ratio was associated with verbal recognition and code shifting, with Aβ 42 being related to verbal recognition and t-tau being related to code shifting. By contrast, the inclusion of neuropsychological data did not allow reliable estimations of Aβ 42 /Aβ 40 ratio or p-tau concentration. Conclusion Our results showed that strong associations exist between the cognitive key symptoms of AD and the concentrations and ratios of specific CSF markers. In addition, we revealed a specific combination of neuropsychological tests that may facilitate reliable estimations of CSF concentrations, thereby providing important diagnostic information for non-invasive early AD detection.

Bipolar disorders rank among the most debilitating psychiatric diseases. Bipolar depression is often misdiagnosed as unipolar depression, leading to suboptimal therapy and poor outcomes. Discriminating unipolar and bipolar depression at earlier stages of illness could therefore help to facilitate efficient and specific treatment. In the present study, the neurobiological underpinnings of emotion processing were investigated in a sample of unipolar and bipolar depressed patients matched for age, gender, and depression severity by means of fMRI. A pattern-classification approach was employed to discriminate the two samples. The pattern classification yielded up to 90 % accuracy rates discriminating the two groups. According to the feature weights of the multivariate maps, medial prefrontal and orbitofrontal regions contributed to classifications specific to unipolar depression, whereas stronger feature weights in dorsolateral prefrontal areas contribute to classifications as bipolar. Strong feature weights were observed in the amygdala for the negative faces condition, which were specific to unipolar depression, whereas higher amygdala features weights during the positive faces condition were observed, specific to bipolar subjects. Standard univariate fMRI analysis supports an interpretation, where this might be related to a higher responsiveness, by yielding a significant emotion × group interaction within the bilateral amygdala. We conclude that pattern-classification techniques could be a promising tool to classify acutely depressed subjects as unipolar or bipolar. However, since the present approach deals with small sample sizes, it should be considered as a proof-of-concept study. Hence, results have to be confirmed in larger samples preferably of unmedicated subjects.

Background Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. Methods One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). Results We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. Conclusions Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.

Theory of mind (ToM) functioning develops during certain phases of childhood. Factors such as language development and educational style seem to influence its development. Some studies that have focused on transcultural aspects of ToM development have found differences between Asian and Western cultures. To date, however, little is known about transcultural differences in neural activation patterns as they relate to ToM functioning.The aim of our study was to observe ToM functioning and differences in brain activation patterns, as assessed by functional magnetic resonance imaging (fMRI). This study included a sample of 18 healthy Japanese and 15 healthy Caucasian subjects living in Japan. We presented a ToM task depicting geometrical shapes moving in social patterns. We also administered questionnaires to examine empathy abilities and cultural background factors.Behavioral data showed no significant group differences in the subjects' post-scan descriptions of the movies. The imaging results displayed stronger activation in the medial prefrontal cortex (MPFC) in the Caucasian sample during the presentation of ToM videos. Furthermore, the task-associated activation of the MPFC was positively correlated with autistic and alexithymic features in the Japanese sample.In summary, our results showed evidence of culturally dependent sociobehavioral trait patterns, which suggests that they have an impact on brain activation patterns during information processing involving ToM.

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n = 71) and control (n = 59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of similar to 50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms. Molecular Psychiatry (2012) 17, 494-502; doi:10.1038/mp.2011.42; published online 12 April 2011

The present work represents the first study to investigate the relationship between adult attachment avoidance and anxiety and automatic affective responses to basic facial emotions. Subliminal affective priming methods allowed for the assessment of unconscious affective reactions. An affective priming task using masked sad and happy faces, both of which are approach-related facial expressions, was administered to 30 healthy volunteers. Participants also completed the Relationship Scales Questionnaire and measures of anxiety and depression. Attachment avoidance was negatively associated with affective priming due to sad (but not happy) facial expressions. This association occurred independently of attachment anxiety, depressivity, and trait anxiety. Attachment anxiety was not correlated with priming due to sad or happy facial expressions. The present results are consistent with the assumption that attachment avoidance moderates automatic affective reaction to sad faces. Our data indicate that avo...

A functional polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to modulate amygdala responsiveness to negative environmental cues. However, it remains unclear whether 5-HTTLPR modulates amygdala responses specifically to negative stimuli or rather to emotionally salient stimuli in general. In 44 healthy subjects, amygdala responses to subliminally presented happy and sad facial expressions were assessed by means of fMRI at 3 Tesla. All subjects were genotyped for 5-HTTLPR and the recently discovered 5-HTT rs25531. We observed a robust emotion by genotype group interaction in the right amygdala. Risk allele carriers (S or LG) showed similar amygdala responses to happy faces compared to homozygous LALA carriers but increased amygdala responses to sad faces. The right amygdala was the only anatomical region across the whole brain demonstrating this interaction at a reasonable threshold. It appears that whereas 5-HTT gene variation modulates automatic amygdala responsiveness to sad faces, no such association was found for happy faces. We conclude that 5-HTTLPR genotype predominantly impacts the central processing predominantly of negative environmental cues but not of emotionally salient stimuli in general.

Background: Although there is considerable evidence that patients with schizophrenia have impaired executive functions, the neural mechanisms underlying these deficits are unclear. Generation and selection is one of the basic mechanisms of executive functioning. We investigated the neural correlates of this mechanism by means of functional magnetic resonance imaging (fMRI) in patients with schizophrenia and healthy controls. Methods: We used the Wisconsin Card Sorting Test (WCST) in an event-related fMRI study to ana lyze neural activation patterns during the distinct components of the WCST in 36 patients with schizophrenia and 28 controls. We fo cused our analyses on the process of set-shifting. After participants received negative feedback, they had to generate and decide on a new sorting rule. Results: A widespread activation pattern encompassing the inferior and middle frontal gyrus, parietal, temporal and oc cipital cortices, anterior cingulate cortex (ACC), supplementary motor area, insula, caudate, thalamus and brainstem was observed in patients with schizophrenia after negative versus positive feedback, whereas in healthy controls, significant activation clusters were more confined to the cortical areas. Significantly increased activation in the rostral ACC after negative feedback and in the dorsal ACC during matching after negative feedback were observed in schizophrenia patients compared with controls. Controls showed activation in the bilateral dorsolateral prefrontal cortex (Brodmann area 46), whereas schizophrenia patients showed activation in the right dorsolateral pre frontal cortex only. Limitations: All patients were taking neuroleptic medication, which has an impact on cognitive function as well as on dopaminergic and serotonergic prefrontal metabolism. Conclusion: Our data suggest that, in patients with schizophrenia, set-shifting is associated with increased activation in the rostral and dorsal ACC, reflecting higher emotional and cognitive demands, respectively.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn 107 Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case–control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli. Molecular Psychiatry (2011) 16, 938–948; doi:10.1038/mp.2010.81; published online 6 July 2010

Background: Several studies have shown that female and male subjects process emotions differently. As women appear to be especially sensitive and responsive to negative and threatening stimuli, gender-specific emotional processing might be an important factor contributing to the increased likelihood of women compared to men to develop anxiety disorders, e.g. panic disorder (PD). Methods: In this study, gender-specific neural activation during facial emotion processing was investigated in 20 PD patients (12 women, 8 men) by functional magnetic resonance imaging. Results: Overall, significantly stronger activation, encompassing the amygdala, prefrontal, temporal, and occipital cortical areas, basal ganglia, and thalamus, was observed in women than in men during the processing of angry, fearful, or neutral but not happy facial expressions. Additionally, functional connectivity between the amygdala and prefrontal cortical areas and thalamus during the processing of angry facial expressions was significantly stronger in women than in men. Conclusions: These results emphasize gender as an important variable in neural activation patterns of emotional processing and may help to further elucidate the biological substrate of gender-specific susceptibility for PD. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc.

Alexithymia is considered a dimensional personality trait that refers to a cluster of deficits in the recognition, differentiation, and verbalization of emotions. Research on the neurobiology of alexithymia has focused hitherto on impairments in the controlled processing of emotional information. In the present study automatic brain reactivity to facial emotion was investigated as a function of alexithymia (as assessed by the 20-Item Toronto Alexithymia Scale - TAS-20). During 3T fMRI scanning, pictures of sad, happy, and neutral facial expression masked by neutral faces were presented to 33 healthy women. A priori regions of interest in the whole brain analysis were cerebral structures that are known to be crucially involved in the emotion perception from the face. Independently from trait anxiety and depression TAS-20 alexithymia was negatively correlated with activation to masked sad and happy faces in several regions of interest (in particular, insula, superior temporal gyrus, middle occipital and parahippocampal gyrus). In addition, the TAS-20 score was negatively correlated with response of the left amygdala to masked sad faces. A reduced automatic reactivity of the amygdala and visual occipito-temporal areas could implicate less automated engagement in the encoding of emotional stimuli in high alexithymia. In addition, a low spontaneous insular and amygdalar responsivity in high alexithymia individuals could be related to an attenuation of basic emotional experiences which may contribute to problems in identifying and differentiating one's feelings.

Background Cognitive theories of depression predict mood-congruent negative biases already at automatic stages of processing, although several behavioral studies seem to contradict this notion. That is, depression should potentiate emotional reactivity to negative emotional cues, whereas it should reduce reactivity in response to positive emotional stimuli. Assessing neurobiological substrates of automatic emotion processing might be a more sensitive challenge for automatic negative bias in depression than behavioral measures. Methods In 30 acutely depressed inpatients and 26 healthy control subjects, automatic amygdala responses to happy and sad facial expressions were assessed by means of functional magnetic resonance imaging (fMRI) at 3 Tesla. To examine automatic responses, a presentation paradigm using subliminal, backward-masked stimuli was employed. A detection task was administered to assess participants' awareness of the masked emotional faces presented in the fMRI experiment. Results Detection performance was at chance level for both patients and healthy control subjects, suggesting that the neurobiological reactions took place in absence of conscious awareness of the emotional stimuli. A robust emotion by group interaction was observed in the right amygdala. Whereas healthy control subjects demonstrated stronger responses to happy faces, depressed patients showed the opposite. Furthermore, amygdala responsiveness to happy facial expression was negatively correlated with current depression severity. Conclusions Depressed patients exhibit potentiated amygdala reactivity to masked negative stimuli along with a reduced responsiveness to masked positive stimuli compared with healthy individuals. Thus, depression is characterized by mood-congruent processing of emotional stimuli in the amygdala already at an automatic level of processing.

The objective of this study was to compare psychiatric morbidity and the course of posttraumatic stress, depression, and anxiety in two groups with severe complications during pregnancy, women after termination of late pregnancy (TOP) due to fetal anomalies and women after preterm birth (PRE). As control group women after the delivery of a healthy child were assessed. A consecutive sample of women who experienced a) termination of late pregnancy in the 2nd or 3rd-trimester (N = 62), or b) preterm birth (N = 43), or c) birth of a healthy child (N = 65) was investigated 14 days (T1), 6 months (T2), and 14 months (T3) after the event. At T1, 22.4% of the women after TOP were diagnosed with a psychiatric disorder compared to 18.5% women after PRE, and 6.2% in the control group. The corresponding values at T3 were 16.7%, 7.1%, and 0%. Shortly after the event, a broad spectrum of diagnoses was found; however, 14 months later only affective and anxiety disorders were diagnosed. Posttraumatic stress and clinician-rated depressive symptoms were highest in women after TOP. The short-term emotional reactions to TOP in late pregnancy due to fetal anomaly appear to be more intense than those to preterm birth. Both events can lead to severe psychiatric morbidity with a lasting psychological impact.

Astrocyte activation indicated by increased S100B is considered a potential pathogenic factor for schizophrenia. To investigate the relationship between astrocyte activation and cognitive performance, S100B serum concentration, memory performance, and psychopathology were assessed in 40 first-episode and 35 chronic schizophrenia patients upon admission and after four weeks of treatment. Chronic schizophrenia patients with high S100B were impaired concerning verbal memory performance (AVLT, Auditory Verbal Learning Test) compared to chronic and first-episode patients with low S100B levels. The findings support the hypothesis that astrocyte activation might contribute to the development of cognitive dysfunction in schizophrenia.

The endocannabinoid system has been implicated in the pathogenesis of depression and anxiety, the mediation of antidepressant drug effects in animal models and the neurobiology of emotion processing in healthy volunteers. Therefore, the impact of cannabinoid receptor 1 gene (CNR1) variants rs1049353 and rs12720071 on antidepressant treatment response was evaluated in 256 Caucasian patients with Major Depression. A subsample of 33 depressed patients was additionally scanned by fMRI under visual presentation of emotional faces. The CNR1 rs1049353 G allele conferred an increased risk of antidepressant treatment resistance, particularly in female patients with high comorbid anxiety. CNR1 rs1049353 G allele carriers also demonstrated weaker bilateral amygdala, putamen and pallidum activity as well as left lateralized caudate and thalamus activity in response to masked happy faces. This analysis provides preliminary support for a role of CNR1 gene variation in depression and anxiety, potentially mediated by subcortical hypo-responsiveness to social reward stimuli.

This study examines the neurobiology of semantic retrieval and describes the influence of gender, menstrual cycle, and sex hormones on semantic networks. Healthy right-handed subjects (12 men, 12 women) were investigated with 3T-fMRI during synonym generation. Behavioral performance and sex hormone levels were assessed. Women were examined during the early follicular and midluteal cycle phase. The activation pattern in all groups involved left frontal and temporal as well as bilateral medial frontal, cingulate, occipital, basal ganglia, and cerebellar regions. Men showed greater left frontal activation than women in both menstrual cycle phases. Women yielded high correlations of left prefrontal activation with estradiol in the midluteal phase and with progesterone in both phases. Testosterone levels correlated highly with left prefrontal activation in all three groups. In all, we describe a cerebral network involved in semantic processing and demonstrate that it is significantly affected by gender and sex steroid hormones.

A high prevalence of deficits in explicit learning has been reported for schizophrenic patients, but it is less clear whether these patients are impaired in implicit learning. Deficits in implicit learning indicative of a fronto-striatal dysfunction have been reported using a serial reaction-time task (SRT), but the impact of typical neuroleptic medication and chronicity remains controversial. The present study compared 37 patients with first-episode schizophrenia treated with atypical neuroleptics and 37 healthy matched control participants on two sequence learning tasks: a modified SRT for implicit sequence learning and a serial generation task (SGT) for explicit sequence learning. The two tasks were designed to be procedurally equivalent, in order to provide better comparability between implicit and explicit performance. Although unaffected in global cognitive functioning, schizophrenic patients were significantly impaired in implicit and explicit sequence learning. Deficient sequence learning in schizophrenic patients was neither related to psychopathology nor to chlorpromazine equivalent daily dosage. As performance was impaired even though patients were exclusively treated with atypical neuroleptics, the present findings concur with converging evidence of a sequence learning deficit inherent in schizophrenia. This deficit would be consistent with a fronto-striatal dysfunction and might constitute a crucial factor for the acquisition of new information.

Involvement of the prefrontal cortex in schizophrenia has been implicated by neuropsychological, as well as neuropathological and imaging studies. Reductions of N-acetylaspartate (NAA), an in vivo marker of neuronal integrity, have repeatedly been detected in the frontal lobes of patients with schizophrenia by proton magnetic resonance spectroscopy (1H-MRS). In chronic medicated patients, a positive correlation between NAA levels of the prefrontal cortex and cognitive functioning has been observed, but to date, there have been no studies in first-episode neuroleptic-naive patients. In this study, single-voxel 1H-MRS was used to investigate neuronal function of the dorsolateral prefrontal cortex in 15 first-episode and 20 chronic schizophrenic patients. Outcomes were compared to 20 age-matched healthy controls to assess the relationship between prefrontal metabolism and neuropsychological performance. Patients with chronic schizophrenia had significant reductions of NAA, glutamate/glutamine, and choline levels compared to first-episode patients and healthy controls. Furthermore, creatine and phosphocreatine were significantly reduced in both patient groups compared to healthy controls. In the neuropsychological tests, chronic schizophrenic patients performed significantly poorer in the Auditory Verbal Learning Task (AVLT) compared to first-episode patients. In both patient groups, NAA levels of the left frontal lobe significantly correlated with performances in verbal learning and memory. These results corroborate data from recent structural and spectroscopic imaging studies of the frontal lobes in schizophrenia, in which cortical gray matter reductions after onset of symptoms as well as reduced levels of NAA in chronic, but not in first-episode schizophrenic patients have been reported.

Repression designates coping strategies that aim to shield the organism from distressing stimuli by disregarding their aversive characteristics. In contrast, sensitization comprises coping strategies that are employed to reduce situational uncertainty such as analyzing the environment. Functional magnetic resonance imaging was used to study neural correlates of coping styles during the perception of threatening and nonthreatening socially relevant information. Pictures of human faces bearing fearful (ambiguously threatening), angry (unambiguously threatening), happy (nonthreatening), and neutral expressions were presented masked and unmasked. Two groups of subjects were examined who were defined as consistent repressors versus consistent sensitizers with the Mainz Coping Inventory. Sensitizers tended to exhibit stronger neural responses in the amygdala to unmasked fearful faces compared with repressors. Overall, repressors were cortically more responsive to fearful (ambiguously threatening) and happy (nonthreatening) facial expressions than sensitizers, whereas sensitizers presented an enhanced responsivity to angry faces in several prefrontal areas, that is, unambiguously threatening expressions. Results from time series analyses suggest that sensitizers could exhibit less top-down cortical regulation of the amygdala than repressors in the processing of fearful faces. An increased responsivity of the amygdala to ambiguously threatening stimuli may represent a biological determinant of sensitizers' feelings of uncertainty.

The amygdala is a key structure in a limbic circuit involved in the rapid and unconscious processing of facial emotions. In the present study, the role of the amygdala in automatic, involuntary appraisal processes, which are believed to be a crucial component of emotion processing, was investigated in 23 healthy subjects. Amygdala activity was recorded in response to masked displays of angry, sad, and happy facial expressions using functional magnetic resonance imaging (fMRI). In a subsequent experiment, the subjects performed a masked affective priming task that characterizes automatic emotion processing by investigating the biasing effect of subliminally presented emotional faces on evaluative ratings to subsequently presented neutral stimuli. In the affective priming task, significant valence-congruent evaluation manipulation was observed. Subjects rated neutral targets more positively if they were primed by happy faces. Significant correlations were found between amygdala responses to masked negative facial expressions and negative evaluation shifts elicited by the corresponding emotion quality in the affective priming task. Spontaneous amygdala reactivity to facial emotions appears to be a determinant of automatic negative evaluative response tendencies. This finding might shed some light on how amygdala hyperresponsivity contributes to negative cognitive biases commonly observed in affective disorders.

Background: Oxytocin has received much attention as a prosocial and anxiolytic neuropeptide. In human studies, the G-allele of a common variant ( rs53576 ) in the oxytocin receptor gene ( OXTR ) has been associated with protective properties such as reduced stress response and higher receptiveness for social support. In contrast, recent studies suggest a detrimental role of the rs53576 G-allele in the context of childhood maltreatment. To further elucidate the role of OXTR, gene by maltreatment interactions on brain structure and function were investigated. Methods: Three hundred nine healthy participants genotyped for OXTR rs53576 underwent structural as well as functional magnetic resonance imaging during a common emotional face-matching task. Childhood maltreatment was assessed with the Childhood Trauma Questionnaire ( CTQ ). Gray matter volumes were investigated by means of voxel-based morphometry across the entire brain. Results: Structural magnetic resonance imaging data revealed a strong interaction of rs53576 genotype and CTQ scores, mapping specifically to the bilateral ventral striatum. GG homozygotes but not A-allele carriers showed strong gray matter reduction with increasing CTQ scores. In turn, lower ventral striatum gray matter volumes were associated with lower reward dependence, a prosocial trait. Furthermore, the G-allele was associated with increased amygdala responsiveness to emotional facial expressions. Conclusions: The findings suggest that the G-allele constitutes a vulnerability factor for specific alterations of limbic brain structure in individuals with adverse childhood experiences, complemented by increased limbic responsiveness to emotional interpersonal stimuli. While oxytocinergic signaling facilitates attachment and bonding in supportive social environments, this attunement for social cues may turn disadvantageous under early adverse conditions.

Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.

Objective Little is known about the underlying mechanisms of poor working memory (WM) performance of adults with attention deficit hyperactivity disorder (ADHD). This study investigates interference and load effects during WM updating by use of event-related potentials. Method Forty ADHD patients and 41 controls performed verbal n -back tasks under conditions of low and high WM load. Intrusion probes, i.e., lures, were implemented to challenge interference control abilities during WM processing. Results Stimulus-dependent N200 amplitude modulation and behavioral performance in lure trials were reduced in adults with ADHD compared to healthy controls. Also, P300 amplitudes tended to be less sensitive to WM load in patients with ADHD. Conclusion Our findings provide electrophysiological evidence for inaccurate discrimination of stimulus categories. Particularly, deficient interference control may lead to overt WM deficits in adult subjects with ADHD. Significance The current findings contribute to a deeper understanding of the neural substrates of executive dysfunction in adult ADHD, focusing on the domain of WM.

It has been argued that critical functions of the human amygdala are to modulate the moment-to-moment vigilance level and to enhance the processing and the consolidation of memories of emotionally arousing material. In this functional magnetic resonance study, pictures of human faces bearing fearful, angry, and happy expressions were presented to nine healthy volunteers using a backward masking procedure based on neutral facial expression. Activation of the left and right amygdala in response to the masked fearful faces (compared to neutral faces) was significantly correlated with the number of fearful faces detected. In addition, right but not left amygdala activation in response to the masked angry faces was significantly related to the number of angry faces detected. The present findings underscore the role of the amygdala in the detection and consolidation of memory for marginally perceptible threatening facial expression.

Visual backward masking deficits have been postulated as potential vulnerability markers for schizophrenia. This study investigated the diagnostic specificity of a location and an identification variant of the backward masking task for schizophrenia and analyzed masking performance during the course of the tasks. The influence of schizophrenia patients' intellectual decline on masking performance was also examined. Twenty-eight schizophrenia patients were compared to 28 patients with unipolar depression and 28 healthy controls on a letter location task and a letter identification task applying a low spatial frequency mask. Schizophrenia patients made significantly more detection errors on the location task than depressives at an interstimulus interval (ISI) of 50 ms and healthy controls at ISIs of 16.7, 33.3, 50, and 66.7 ms. Thus, the location masking dysfunction of schizophrenia patients was distinctive at a rather long interstimulus interval (50 ms). On the identification task the performance of schizophrenia patients did not differ from that of the two control groups. Identification but not location masking performance improved during the course of the task for all groups. Intellectual deterioration of schizophrenia patients was not correlated with location or identification masking performance. Schizophrenia patients are characterized by specific impairments in spatial visual processing which appear to be independent of intellectual decline. Potential explanations of the location masking deficit found in schizophrenia are discussed.

Based upon pharmacological challenge and postmortem studies, schizophrenia has been hypothesized to be caused by decreased glutamatergic neurotransmission. We investigated the glutamatergic neuronal metabolism of the dorsolateral prefrontal cortex with localized 1H magnetic resonance spectroscopy in 18 first-episode patients, 21 chronic patients with schizophrenia, and 21 age-matched controls. Chronic patients had significantly lower levels of glutamate/glutamine (Glx) and N-acetylaspartate (NAA) compared to healthy controls and first-episode patients. Reduced metabolite levels were not correlated with duration of illness or medication. Our results indicate glutamatergic dysfunction in chronic schizophrenia that could be evidence of a progressive brain disorder.

Prior research suggests that anorexic patients show a memory bias for fattening foods when they are processed in depth or with reference to the self. The present study examined whether anorexic subjects exhibit a bias for fattening foods when these are presented as task-irrelevant distractor stimuli. It also investigated whether anorexic patients pay less attention to emotion stimuli. A sequential word-word evaluation task was administered to 11 inpatients with anorexia nervosa and 11 non-dieting normal subjects. There were four types of distractor words: high caloric foods, positive, negative, and neutral. Anorexic patients recalled no more food words but fewer neutral and positive words than normal subjects. The present data suggest that, compared to healthy young women, anorexic patients show no memory bias for fattening foods when these data are presented as peripheral environmental information. Anorexic patients are perceptually no less sensitive to negative emotional information than normal subjects.

Objective For parents, the premature birth of a child represents a traumatic event for which they are poorly prepared. To date, the focus of scientific interest has been on maternal psychological stress responses, such as anxiety and depression, or on appropriate coping mechanisms, whereas only scant attention has been paid to the traumatic aspect of the maternal experience after very low-birth-weight (VLBW) birth. The present study is the first to investigate the posttraumatic stress response of mothers after the birth of a VLBW infant in a prospective longitudinal study. Methods Fifty mothers of VLBW infants were examined at four measuring time points (1–3 days pp, 14 days pp and 6 and 14 months pp) with respect to posttraumatic symptoms [Impact of Event Scale (IES-R)], psychiatric diagnosis (SKID I for DSM-IV) and the extent of depression [Beck Depression Inventory (BDI) and Montgomery Asberg Depression Scale (MADRS)] and anxiety [State–Trait Anxiety Inventory (STAI) and Hamilton Anxiety Scale (HAMA)]. The control group comprised a group of 30 mothers after the uncomplicated spontaneous birth of a healthy child. Results At all four measuring timepoints (except 6 months pp), the mothers of the premature infants recorded significantly higher values for traumatic experience and depressive symptoms and anxiety compared with the controls. In contrast to the mothers in the control group, the mothers of the premature infants displayed no significant reduction in posttraumatic symptoms (IES-total), even 14 months after birth. Conclusion The results indicate that the situation of a mother who has given birth to a VLBW infant is a complex, with long-term traumatic event necessitating ongoing emotional support extending beyond the period immediately after the birth.

The aim of this study was to investigate the relationship between cognitive impairment and cerebral metabolites in patients with anorexia nervosa (AN). N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), choline-containing compounds, glutamate/glutamine (Glx) and myoinositol were measured by proton magnetic resonance spectroscopy ('H-MRS) of the left prefrontal cortex. Compared with healthy controls, AN patients displayed a significantly poorer performance in verbal learning and in attentional and executive tasks. Performance in the divided attention task was correlated with NAA and Cr in the dorsolateral prefrontal cortex, while executive functioning and depressive symptomatology were associated with Glx levels in the anterior cingulate. Our results provide evidence for cognitive impairment in AN patients which is associated with cerebral metabolism in the prefrontal cortex.

Termination of pregnancy for fetal malformation is a traumatic event which any woman finds hard to withstand and which entails the risk of severe and complicated grieving. This paper presents three cases illustrating the trauma and coping mechanisms. Grieving continued for over 6 months in all cases and included pathological anxiety and depression. We offer advice and counselling to such women.

Scientific investigations show that the course of a grieving process may have a substantial impact on the mental and physical wellbeing of those concerned. An international survey of measuring instruments designed to register grief shows little conformity with respect to the key symptoms of grieving. Only few instruments are derived from scientific theory, the majority have been developed on the basis of clinical observations and only some of the instruments are psychometrically designed. Some instruments display correlations with other constructs such as depression and anxiety, with the question of whether the symptoms are grief-specific or autonomous remaining unanswered. Only few instruments serve to differentiate between normal and pathologic grief. The fact that only two German-language instruments for registering grief are available to date also indicates that this subject matter has attracted only scant attention despite its clinical significance. In conclusion, the demands to be made on an instrument to be developed in the future are outlined.