The personality trait self-directedness predicts the amygdala's reaction to appetizing cues in fMRI.

Personality and neural response to food cues in various mesolimbic brain structures have been linked to eating disorders. We investigated the question of whether personality traits in healthy individuals correlate with the brain activation induced on confrontation with appetizing visual stimuli. Personality was assessed in 27 normal-weight participants (14 women, mean age=26.0, SD=3.3 years) with the Temperament and Character Inventory (TCI). After an overnight fast, participants viewed blocks of pictures, half containing appetizing food and the other half showing scrambled pictures as control. After each block, participants rated their appetite. Brain activation was measured using a 3T MR scanner. Food compared to control stimuli elicited a significantly higher appetite rating, as well as strong activation in the ventral and dorsal visual stream, the fusiform gyrus and consecutive limbic centres such as the parahippocampal gyrus, the amygdala, the thalamus, the insula, the ventral striatum and the orbitofrontal cortex. In a region-of-interest analysis, the TCI trait self-directedness was negatively correlated with mean blood oxygenation level dependent (BOLD) signal change in the right amygdala (r=-.43, p=.025). Ultimately, amygdala reactivity might provide a risk factor for the development of eating disorders.

Integrating digital pathology and mathematical modelling to predict spatial biomarker dynamics in cancer immunotherapy.

In oncology clinical trials, on-treatment biopsy samples are taken to confirm the mode of action of new molecules, among other reasons. Yet, the time point of sample collection is typically scheduled according to 'Expert Best Guess'. We have developed an approach integrating digital pathology and mathematical modelling to provide clinical teams with quantitative information to support this decision. Using digitised biopsies from an ongoing clinical trial as the input to an agent-based mathematical model, we have quantitatively optimised and validated the model demonstrating that it accurately recapitulates observed biopsy samples. Furthermore, the validated model can be used to predict the dynamics of simulated biopsies, with applications from protocol design for phase 1-2 studies to the conception of combination therapies, to personalised healthcare.

Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination.

Recent studies suggest that the antidepressant effects of the psychedelic 5-HT2A receptor agonist psilocybin are mediated through its modulatory properties on prefrontal and limbic brain regions including the amygdala. To further investigate the effects of psilocybin on emotion processing networks, we studied for the first-time psilocybin's acute effects on amygdala seed-to-voxel connectivity in an event-related face discrimination task in 18 healthy volunteers who received psilocybin and placebo in a double-blind balanced cross-over design. The amygdala has been implicated as a salience detector especially involved in the immediate response to emotional face content. We used beta-series amygdala seed-to-voxel connectivity during an emotional face discrimination task to elucidate the connectivity pattern of the amygdala over the entire brain. When we compared psilocybin to placebo, an increase in reaction time for all three categories of affective stimuli was found. Psilocybin decreased the connectivity between amygdala and the striatum during angry face discrimination. During happy face discrimination, the connectivity between the amygdala and the frontal pole was decreased. No effect was seen during discrimination of fearful faces. Thus, we show psilocybin's effect as a modulator of major connectivity hubs of the amygdala. Psilocybin decreases the connectivity between important nodes linked to emotion processing like the frontal pole or the striatum. Future studies are needed to clarify whether connectivity changes predict therapeutic effects in psychiatric patients.

The effect of 5-HTTLPR and a serotonergic multi-marker score on amygdala, prefrontal and anterior cingulate cortex reactivity and habituation in a large, healthy fMRI cohort.

Major depressive disorder (MDD) is characterized by low mood for at least two weeks. Impaired emotion regulation has been suggested to be the consequence of dysfunctional serotonergic regulation of limbic and prefrontal regions, especially the amygdala, the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC). The impact of genetic variation on brain function can be investigated with intermediate phenotypes. A suggested intermediate phenotype of MDD is emotion recognition: The 5-HTTLPR polymorphism of SLC6A4 as well as other serotonergic genes have been associated with amygdala and prefrontal function during emotion recognition. Previously, it has been suggested that habituation is a more reliable index of emotion recognition than functional activation. We examined the relationship of genes involved in serotonergic signaling with amygdala as well as prefrontal functional activation and habituation during an emotion recognition task in 171 healthy subjects. While effects of 5-HTTLPR and of a serotonergic multi-marker score (5-HTTLPR, TPH1(rs1800532), TPH2(rs4570625), HTR1A(rs6295) and HTR2A(rs6311)) on amygdala activation did not withstand correction for multiple regions of interest, we observed a strong correlation of the multi-marker score and habituation in the amygdala, DLPFC, and ACC. We replicated a well-studied intermediate phenotype for association with 5-HTTLPR and provided additional evidence for polygenic involvement. Furthermore, we showed that task habituation may be influenced by genetic variation in serotonergic signaling, particularly by a serotonergic multi-marker score. We provided preliminary evidence that PFC activation is an important intermediate phenotype of MDD. Future studies are needed to corroborate the results in larger samples.

Functional neuroimaging effects of recently discovered genetic risk loci for schizophrenia and polygenic risk profile in five RDoC subdomains.

Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10-4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.

Species-conserved reconfigurations of brain network topology induced by ketamine.

Species-conserved (intermediate) phenotypes that can be quantified and compared across species offer important advantages for translational research and drug discovery. Here, we investigate the utility of network science methods to assess the pharmacological alterations of the large-scale architecture of brain networks in rats and humans. In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species. As these alterations are opposed to those commonly observed in patients suffering from depression, they might indicate systems-level correlates of the antidepressant effect of ketamine.

5-HTTLPR/rs25531 polymorphism and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus.

The s/s-genotype of the 5-HTTLPR polymorphism and the personality trait of neuroticism have both been associated with experiences of negative affect, anxiety and mood disorders, as well as an emotional processing bias towards negative facial emotions. On a neural level, this bias can be characterized by altered amygdala and fusiform gyrus (FFG) activity during perception of negative facial expressions. Using resting-state functional magnetic resonance imaging in a multi-center-sample of 178 healthy subjects of European descent, this study investigated the association of 5-HTTLPR (short s- and long l-allele) including the genotype of the single nucleotide polymorphism (SNP) rs25531 (A/G) within this region polymorphism, and trait neuroticism on resting-state functional connectivity (rs-FC) between amygdala and the FFG. Moreover, we aimed to identify additional brain regions with associations of 5-HTTLPR/rs25531 (combined according to its expression; low: s/s; high: l(A)/l(A); intermediate: s/l(A), s/l(G), l(G)/l(G), l(A)/l(G)) and trait neuroticism to amygdala rs-FC. Separate analyses for 5-HTTLPR/rs25531 and neuroticism (controlling for age, gender, handedness, and research site) revealed that s/s-homozygotes and individuals high in neuroticism obtained altered amygdala rs-FC in the right occipital face area, which is considered to be a "core component" of the face processing system. Importantly, effects of neuroticism were replicated across three independent research sites. Additionally, associations of 5-HTTLPR/rs25531 genotype and amygdala rs-FC were observed in the anterior and posterior cingulate cortex, whereas neuroticism was not related to rs-FC in these areas. The presented data implies that 5-HTTLPR/rs25531 variants and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus and suggests that variants of 5-HTTLPR/rs25531 genotype and different levels of neuroticism may partly account for altered processing of negative facial emotions.

Mutational analysis of the neuronal cadherin gene CELSR1 and exclusion as a candidate for catatonic schizophrenia in a large family.

The cadherin gene CELSR1 is specifically expressed in the brain and located on chromosome 22q13.33, a region that has recently been shown to be involved in the etiopathogenesis of familial catatonic schizophrenia. The gene is a strong positional candidate and was considered for mutational analysis. A total of 17 allelic variants of CELSR1 was found by sequencing all 35 exons, intron-exon junctions, and the putative promoter region by screening two patients from a large family mainly supporting this locus, and three control subjects in a first step. No variant exclusively co-segregates with the disease in the large pedigree, providing evidence that CELSR1 is not causative for the pathogenesis of catatonic schizophrenia in this family.

[Fatal child neglect in East Germany 1 January 1985 to 2 October 1990. Results of a multicenter study]. / Tödliche Kindesvernachlässigung in der DDR im Zeitraum 1.1.1985 bis 2.10.1990. Ergebnisse einer multizentrischen Studie.

UNLABELLED: No reliable data are available on cases of lethal child neglect in the area of the former German Democratic Republic. In a multicenter study we therefore examined the police and court records for such cases occurring in the period 1 January 1985 to 2 October 1990 in the entire area of the former German Democratic Republic. RESULTS: A total of 9 cases were reported to the study center. This does not include undetected cases, whose number, though indeterminate, is probably small due to the general obligation to perform autopsies on all children dying before their 16 birthday. Just over half of all victims were less than one year old, the oldest was 3 1/2 years old. Starvation and severe dehydration were by far the most common causes of death; in half of cases these occurred in combination with hypothermia. Most often mother killed their children by neglect, either alone or together with the victim's father. In the majority of cases no close bond existed between the parents and the child. Seventy percent of the perpetrators were chronic alcoholics. All 10 of the perpetrators were sentenced to imprisonment for periods ranging from one year to life long. Mitigating circumstances were presented at the sentencing phase of the trial on behalf of 20% of those convicted. The experience of legal medical and pathological institutes in the former German Democratic Republic underscores the need to perform an autopsy on all deceased infants and young children. Only this can ensure that no cases of lethal child neglect are overlooked.

[Lethal child abuse (through the use of physical force) in the German Democratic Republic during the period 1 January 1985 to 2 October 1990. Results of a multicenter study]. / Tödliche Kindesmisshandlung (durch physische Gewalteinwirkung) in der DDR im Zeitraum 1.1.1985 bis 2.10.1990.

UNLABELLED: No reliable data are available on cases of lethal child abuse (by active force) in the area of the former German Democratic Republic. In a multicenter study we therefore examined the police and court records for such cases occurring in the period 1 January 1985 to 2 October 1990 in the entire area of the former German Democratic Republic. RESULTS: The study center received information on 39 cases of lethal child abuse which correspond to approximately 7 cases per year. However, a low percentage of undetected crimes which cannot be determined more precisely has to be taken into consideration. Almost 40% of the victims were younger than 1 year, 73% of the victims showed indications of repeated ill-treatment. The effects caused by using direct blunt forces, against the head in particular, were by far the most frequent causes of death. The male contact person (the victim's father, brother or stepfather as well as the life companion of the child's mother in particular) killed the child in most of the cases. As far as it is known, 37% of the male/female offenders suffered from chronic alcoholism; 32% of the male/female offenders were under the influence of alcohol when the crime happened. 83% of the male/female offenders who were found guilty made a confession shortly after the crime had happened or during the interrogations. Almost all the male/female offenders were sentenced to prison (the duration of the imprisonment varied between one year and for life). Due to the considerably lower section rate compared to the one in the German Democratic Republic, it is to fear that each second fatal child abuse is not detected in the new federal states.

Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding.

Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the 'missing heritability' of complex phenotypes.

Functional impact of a recently identified quantitative trait locus for hippocampal volume with genome-wide support.

In a large brain-imaging study, a multinational consortium has recently identified a common genetic variation in rs7294919 being associated with hippocampal volume. Here, we explored whether this quantitative trait locus also affects hippocampal function using a previously established reliable neuroimaging paradigm. We observed a significant effect of rs7294919 variation in the right hippocampus showing that hippocampal activation increased with the number of risk alleles. Furthermore, the risk allele was associated with decreased performance in a verbal learning and memory task. By showing that this single-nucleotide polymorphism also relates to behavioral difference and underlying brain activation in memory, our findings support the idea that rs7294919 may affect the individual capacity to resist disease in terms of diminishing or boosting hippocampal resources.

Reduced striatal activation during reward anticipation due to appetite-provoking cues in chronic schizophrenia: a fMRI study.

The occurrence of weight gain in schizophrenia (SZ) has profound clinical impact and interacts with antipsychotic medication, life style and disease severity. The functional neuroanatomy underlying altered nutritional behavior is unraveled, but dysregulated reward anticipation might be one of the involved neuronal mechanisms. The striatum, a core region of the reward network and salience attribution, was previously shown to regulate appetite perception and eating behavior. We studied patients suffering from chronic schizophrenia with a stable medication in comparison to age and gender matched healthy adults. Every subject had to undergo a 6h fasting period before a newly developed, appetite-provoking fMRI task was applied. Subjects saw visual stimuli of appetitive food items in a 3Tesla scanner. In healthy controls food images elicited stronger activation in the striatum compared to SZ patients. When adjusting a ROI-based striatal activation for medication and weight, the group difference remained still significant. This points an effect of illness independent of antipsychotic medication. These data underscore the involvement of the striatum into salience attribution, reward anticipation and the neuronal pathways leading to altered eating behavior and weight gain in schizophrenia.

[One decade of functional imaging in schizophrenia research. From visualisation of basic information processing steps to molecular-genetic oriented imaging]. / Zehn Jahre funktionelle Magnetresonanztomographie in der Schizophrenieforschung. Von der Abbildung einfacher Informationsverarbeitungsprozesse zur molekulargenetisch orientierten Bildgebung.

Modern neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have contributed tremendously to our current understanding of psychiatric disorders in the context of functional, biochemical and microstructural alterations of the brain. Since the mid-nineties, functional MRI has provided major insights into the neurobiological correlates of signs and symptoms in schizophrenia. The current paper reviews important fMRI studies of the past decade in the domains of motor, visual, auditory, attentional and working memory function. Special emphasis is given to new methodological approaches, such as the visualisation of medication effects and the functional characterisation of risk genes.

[The cadherin hypothesis of schizophrenia]. / Die Bedeutung der Cadherine bei der Pathogenese schizophrener Erkrankungen.

Disturbance of prenatal brain development and/or postnatal brain maturation in the context of the etiology and pathophysiology of schizophrenic psychoses is increasingly recognized as the developmental hypothesis of schizophrenia. This hypothesis is based on findings in neuroimaging and neuroanatomical findings in schizophrenic disorders. Cell adhesion molecules, such as the cadherins, are of critical importance for morphogenesis in the CNS during embryonic development. Recent investigations of the genomic organization and chromosomal localization of cadherins show a remarkable association with linkage results in affected multiplex pedigrees. Taken together, these findings should lead to an investigation of the role of cadherins in complex psychiatric disorders.

[Computer-assisted identification and comparative studies of the human skull]. / Computergestützte Identifizierung und Vergleichsuntersuchungen menschlicher Schädel.

The comparison of reconstructed skull profiles with photographic or other patterns for identification up to the reply to questions for sex, age, and race by the help of image analysis represents a relatively new development in forensic medicine. Using a Robotron image analyzing system 20 human skulls of different races were analysed morphometrically. Standardized profile functions, which were put through a morphometric analysis, showed characteristic individual features. By the help of the computerbased identification method mathematic differences between skulls of varions races became veritable.