Katja Koelkebeck

Increased amygdala activation during automatic processing of facial emotion in schizophrenia

Schizophrenia patients show abnormalities in the processing of facial emotion. The amygdala is a central part of a brain network that is involved in the perception of facial emotions. Previous functional neuroimaging studies on the perception of facial emotion in schizophrenia have focused almost exclusively on controlled processing. In the present study, we investigated the automatic responsivity of the amygdala to emotional faces in schizophrenia and its relationship to clinical symptomatology by applying an affective priming task. 3-T fMRI was utilized to examine amygdala responses to sad and happy faces masked by neutral faces in 12 schizophrenia patients and 12 healthy controls. The Positive and Negative Syndrome Scale (PANSS) was administered to assess current symptomatology. Schizophrenia patients exhibited greater automatic amygdala responses to sad and happy faces relative to controls. Amygdala responses to masked sad and happy expressions were positively correlated with the negative subscale of the PANSS. Schizophrenia patients appear to be characterized by amygdalar hyperresponsiveness to negative and positive facial expressions on an automatic processing level. Heightened automatic amygdala responsivity could be involved in the development and maintenance of negative symptoms in schizophrenia.

Memory impairment correlates with increased S100B serum concentrations in patients with chronic schizophrenia.

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.

Neural correlates of set-shifting: decomposing executive functions in schizophrenia.

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 analyze neural activation patterns during the distinct components of the WCST in 36 patients with schizophrenia and 28 controls. We focused 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 occipital 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 prefrontal 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.

Abnormal asymmetry of white matter integrity in schizophrenia revealed by voxelwise diffusion tensor imaging.

A number of magnetic resonance imaging (MRI) studies have revealed morphological cortical asymmetry in the normal human brain, and reduction or inversion of such hemispheric asymmetry has been reported in schizophrenia. On the other hand, diffusion tensor imaging (DTI) studies have reported inconsistent findings concerning abnormal asymmetry of white matter integrity in schizophrenia. Our aim was to confirm whether there is reduced or inverted asymmetry of white matter integrity in the whole brain in schizophrenia. For this study, 26 right‐handed schizophrenia patients, and 32 matched healthy control subjects were investigated. Voxelwise analysis of DTI data was performed using the tract‐based spatial statistics. The fractional anisotropy (FA) images were normalized and projected onto the symmetrical white matter skeleton, and the laterality index (LI) of FA, determined by 2 × (left ‐ right)/(left + right), was calculated. The results reveal that schizophrenia patients and healthy controls showed similar patterns of overall FA asymmetries. In the group comparison, patients showed significant reduction of LI in the external capsule (EC), and posterior limb of the internal capsule (PLIC). The EC cluster revealed increased rightward asymmetry, and the PLIC cluster showed reduced leftward asymmetry. Rightward‐shift of FA in the EC cluster correlated with negative symptom severity. Considering that the EC cluster includes the uncinate and inferior occipitofrontal fasciculi, which have connections to the orbitofrontal cortex, abnormal asymmetry of white matter integrity in schizophrenia may play a crucial role in the pathogenesis of schizophrenia, through the altered connectivity to the orbitofrontal cortex. Hum Brain Mapp, 2011.

Risk Variants in the S100B Gene Predict Elevated S100B Serum Concentrations in Healthy Individuals

Several lines of evidence suggest an important role of the S100B protein and its coding gene in different neuropathological and psychiatric disorders like dementia, bipolar affective disorders and schizophrenia. To clarify whether a direct link exists between gene and gene product, that is, whether S100B variants directly modulate S100B serum concentration, 196 healthy individuals were assessed for S100B serum concentrations and genotyped for five potentially functional S100B SNPs. Functional variants of the serotonergic genes 5‐HT1A and 5‐HTT possibly modulating S100B serum levels were also studied. Further, publicly available human postmortem gene expression data were re‐analyzed to elucidate the impact of S100B, 5‐HT1A and 5‐HTT SNPs on frontal cortex S100B mRNA expression. Several S100B SNPs, particularly rs9722, and the S100B haplotype T‐G‐G‐A (including rs2186358‐rs11542311‐rs2300403‐rs9722) were associated with elevated S100B serum concentrations (Bonferroni corrected P < 0.05). Of these, rs11542311 was also associated with S100B mRNA expression directly (Bonferroni corrected P = 0.05) and within haplotype G‐A‐T‐C (rs11542311‐rs2839356‐rs9984765‐rs881827; P = 0.004), again with the G‐allele increasing S100B expression. Our results suggest an important role of S100B SNPs on S100B serum concentrations and S100B mRNA expression. It hereby links recent evidence for both, the impact of S100B gene variation on various neurological or psychiatric disorders like dementia, bipolar affective disorders and schizophrenia and the strong relation between S100B serum levels and these disorders.

Anterior cingulate cortex activation is related to learning potential on the WCST in schizophrenia patients.

The remediation of executive function in patients with schizophrenia is important in rehabilitation because these skills affect the patients capacity to function in the community. There is evidence that instructional techniques can improve deficits in the Wisconsin Card Sorting Test (WCST) in some schizophrenia patients. We used a standard test/training phase/standard test format of the WCST to classify 36 schizophrenia patients as high-achievers, learners or non-retainers. All healthy controls performed as high-achievers. An event-related fMRI design assessed neural activation patterns during post-training WCST performance. Patients showed a linear trend between set-shifting related activation in the anterior cingulate cortex and learning potential, i.e. increased activation in high-achievers, a trend for increased activation in learners, and no activation in non-retainers compared to controls. In addition, activation in the temporoparietal cortex was highest in patients classified as learners, whereas in non-retainers activation was increased in the inferior frontal gyrus compared to controls and high-achieving patients. These results emphasize the relevance of the ACCs neural integrity in learning set-shifting strategies for patients with schizophrenia. Also, our results support the hypothesis that compensatory neural activation in patients with schizophrenia helps them to catch up with healthy controls on cognitive tasks.

The contribution of cortical thickness and surface area to gray matter asymmetries in the healthy human brain

Human cortical gray matter (GM) is structurally asymmetrical and this asymmetry has been discussed to be partly responsible for functional lateralization of human cognition and behavior. Past studies on brain asymmetry have shown mixed results so far, with some studies focusing on the global shapes of the brains surface, such as gyrification patterns, while others focused on regional brain volumes. In this study, we investigated cortical GM asymmetries in a large sample of right‐handed healthy volunteers (n = 101), using a surface‐based method which allows to analyze brain cortical thickness and surface area separately. As a result, substantially different patterns of symmetry emerged between cortical thickness and surface area measures. In general, asymmetry is more prominent in the measure of surface compared to that of thickness. Such a detailed investigation of structural asymmetries in the normal brain contributes largely to our knowledge of normal brain development and also offers insights into the neurodevelopmental basis of psychiatric disorders, such as schizophrenia. Hum Brain Mapp 35:6011–6022, 2014.

Impact of gray matter reductions on theory of mind abilities in patients with schizophrenia

To identify the brain regions involved in the interpretation of intentional movement by patients with schizophrenia, we investigated the association between cerebral gray matter (GM) volumes and performance on a theory of mind (ToM) task using voxel-based morphometry. Eighteen patients with schizophrenia and thirty healthy controls participated in the study. Participants were given a moving shapes task that employs the interpretation of intentional movement. Verbal descriptions were rated according to intentionality. ToM performance deficits in patients were found to be positively correlated with GM volume reductions in the superior temporal sulcus and medial prefrontal cortex. Our findings confirm that divergent brain regions contribute to mentalizing abilities and that GM volume reductions impact behavioral deficits in patients with schizophrenia.

Benefits of using culturally unfamiliar stimuli in ambiguous emotion identification: A cross-cultural study.

A novel emotion recognition task that employs photos of a Japanese mask representing a highly ambiguous stimulus was evaluated. As non-Asians perceive and/or label emotions differently from Asians, we aimed to identify patterns of task-performance in non-Asian healthy volunteers with a view to future patient studies. The Noh mask test was presented to 42 adult German participants. Reaction times and emotion attribution patterns were recorded. To control for emotion identification abilities, a standard emotion recognition task was used among others. Questionnaires assessed personality traits. Finally, results were compared to age- and gender-matched Japanese volunteers. Compared to other tasks, German participants displayed slowest reaction times on the Noh mask test, indicating higher demands of ambiguous emotion recognition. They assigned more positive emotions to the mask than Japanese volunteers, demonstrating culture-dependent emotion identification patterns. As alexithymic and anxious traits were associated with slower reaction times, personality dimensions impacted on performance, as well. We showed an advantage of ambiguous over conventional emotion recognition tasks. Moreover, we determined emotion identification patterns in Western individuals impacted by personality dimensions, suggesting performance differences in clinical samples. Due to its properties, the Noh mask test represents a promising tool in the differential diagnosis of psychiatric disorders, e.g. schizophrenia.

A case of non-SIADH-induced hyponatremia in depression after treatment with reboxetine

Hyponatremia is a well-known side effect of antidepressant treatment with serotonin reuptake inhibitors (SSRI) or combined serotonin and noradrenaline reuptake inhibitors (SNRI), and is linked to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in most cases. In contrast, only very few data are available on hyponatremia following treatment with selective noradrenalin reuptake inhibitors (NaRI). In this report, we describe the case of a patient who developed severe hyponatremia after treatment with reboxetine. However, extensive laboratory testing did not reveal inappropriate secretion of ADH, suggesting that SIADH did not account for hyponatremia in our case. Proposing further examination of the underlying pathomechanism of hyponatremia as a side effect of NaRIs, we discuss the importance of careful monitoring of serum sodium levels in patients treated with NaRIs.