A graph neural network framework for causal inference in brain networks.

A central question in neuroscience is how self-organizing dynamic interactions in the brain emerge on their relatively static structural backbone. Due to the complexity of spatial and temporal dependencies between different brain areas, fully comprehending the interplay between structure and function is still challenging and an area of intense research. In this paper we present a graph neural network (GNN) framework, to describe functional interactions based on the structural anatomical layout. A GNN allows us to process graph-structured spatio-temporal signals, providing a possibility to combine structural information derived from diffusion tensor imaging (DTI) with temporal neural activity profiles, like that observed in functional magnetic resonance imaging (fMRI). Moreover, dynamic interactions between different brain regions discovered by this data-driven approach can provide a multi-modal measure of causal connectivity strength. We assess the proposed model's accuracy by evaluating its capabilities to replicate empirically observed neural activation profiles, and compare the performance to those of a vector auto regression (VAR), like that typically used in Granger causality. We show that GNNs are able to capture long-term dependencies in data and also computationally scale up to the analysis of large-scale networks. Finally we confirm that features learned by a GNN can generalize across MRI scanner types and acquisition protocols, by demonstrating that the performance on small datasets can be improved by pre-training the GNN on data from an earlier study. We conclude that the proposed multi-modal GNN framework can provide a novel perspective on the structure-function relationship in the brain. Accordingly this approach appears to be promising for the characterization of the information flow in brain networks.

Effect of grain size and microporosity on the in vivo behaviour of ß-tricalcium phosphate scaffolds.

Defining the most adequate architecture of a bone substitute scaffold is a topic that has received much attention over the last 40 years. However, contradictory results exist on the effect of grain size and microporosity. Therefore, the aim of this study was to determine the effect of these two factors on the in vivo behaviour of ß-tricalcium phosphate (ß-TCP) scaffolds. For that purpose, ß-TCP scaffolds were produced with roughly the same macropore size (≈ 150 µm), and porosity (≈ 80 %), but two levels of microporosity (low: 10 % / high: ≈ 25 %) and grain size (small: 1.3 µm /large: ≈ 3.3 µm). The sample architecture was characterised extensively using materialography, Hg porosimetry, micro-computed tomography (µCT), and nitrogen adsorption. The scaffolds were implanted for 2, 4 and 8 weeks in a cylindrical 5-wall cancellous bone defect in sheep. The histological, histomorphometrical and µCT analysis of the samples revealed that all four scaffold types were almost completely resorbed within 8 weeks and replaced by new bone. Despite the three-fold difference in microporosity and grain size, very few biological differences were observed. The only significant effect at p < 0.01 was a slightly faster resorption rate and soft tissue formation between 4 and 8 weeks of implantation when microporosity was increased. Past and present results suggest that the biological response of this particular defect is not very sensitive towards physico-chemical differences of resorbable bone graft substitutes. As bone formed not only in the macropores but also in the micropores, a closer study at the microscopic and localised effects is necessary.

The psychiatric vulnerability gene CACNA1C and its sex-specific relationship with personality traits, resilience factors and depressive symptoms in the general population.

Genome-wide association studies have reported an association between the A-allele of rs1006737 within CACNA1C and affective disorders and schizophrenia. The aim of the present study was to investigate the relationship between rs1006737 and established and potential endophenotypes for these disorders in a population-based cohort of 3793 subjects, using an analytical method designed to assess a previously reported sex-specific effect of CACNA1C. The investigated endophenotypes included personality traits and resilience factors. At 10-year follow-up, subjects were screened for depressive symptoms. All subjects were genotyped for rs1006737. The direction of the effect and mode of inheritance of rs1006737 differed between the sexes. In men, the A-allele was associated with higher emotional lability and lower resilience, that is, lower sense of coherence (P=0.021), lower perceived social support (P=0.018), lower dispositional optimism (P=0.032) and more depressive symptoms at follow-up (P=0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is, higher sense of coherence (P=0.00028), higher perceived social support (P=0.010), lower neuroticism (P=0.022) and fewer depressive symptoms at follow-up (P=0.035). After conservative Bonferroni correction for 32 tests, results only remained significant for sense of coherence in women (P=0.009). These results suggest that CACNA1C is involved in the genetic architecture of endophenotypes for affective disorders and schizophrenia, and that it shows a distinct sex-specific effect. Comprehensive phenotype characterization in case-control samples and the general population, as well as an adequate modeling of sex-specific genetic effects, may be warranted to elucidate the pathogenetic mechanisms conferred by robustly identified susceptibility genes.

Working memory performance is associated with common glucocorticoid receptor gene polymorphisms.

Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9 beta A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex x genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9 beta G allele displayed faster reaction times than the other genotype groups, 9 beta G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders.

Glucocorticoid receptor gene polymorphisms and glucocorticoid sensitivity of subdermal blood vessels and leukocytes.

A considerable variability in the sensitivity to glucocorticoids (GCs) exists between individuals and these differences have been implicated in the etiology of psychiatric diseases such as depression. Glucocorticoid receptor (GR) gene polymorphisms might account in part for variability in GC responsiveness. We assessed the association between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and markers of glucocorticoid sensitivity in two target tissues (subdermal blood vessels, peripheral leukocytes) in 206 healthy individuals. The BclI GG genotype group showed the least degree of skin blanching, reflecting a lower GC sensitivity of subdermal blood vessels (p=.01). No association between GR genotype and GC sensitivity of peripheral leukocytes was observed. In the same subjects we previously observed an association between GR genotype and GC sensitivity of the pituitary. Polymorphism of the GR gene might constitute a vulnerability or protection factor for stress related disorders and altered GC sensitivity.

Cortisol and ACTH responses to psychosocial stress are modulated by corticosteroid binding globulin levels.

The hypothalamus-pituitary-adrenal (HPA) axis is vital for an organisms' response to physiological and psychological stress. Cortisol, secreted upon activation of the HPA axis, impacts on physiological systems throughout the organism. Responses to cortisol are influenced and modified by a number of factors, including corticosteroid binding globulin (CBG) levels. A major part of circulating cortisol is bound to CBG and only the unbound fraction is thought to be biologically active. The aim of the present study was to examine the modulating effect of CBG levels on hormonal responses following psychosocial stress in women using oral contraceptives (n=115) and in medication-free men (n=93). In women, CBG levels were negatively associated with ACTH and salivary cortisol and positively with total cortisol levels following the TSST. In men, positive associations were observed between CBG and ACTH and total cortisol levels following the TSST. CBG is an important regulatory element of HPA axis response patterns; therefore, CBG levels have to be taken into account as a potential modifier of ACTH and cortisol responses to psychosocial and pharmacological stimulation. Investigations of the consequences of long-lasting OC intake on the neuroendocrine stress regulation in women might be warranted.

Genetic factors, perceived chronic stress, and the free cortisol response to awakening.

Recent studies have demonstrated that the free cortisol response to awakening can serve as a useful index of hypothalamus-pituitary-adrenal axis (HPA) activity. This endocrine marker is rather consistent, shows good intraindividual stability across time and appears to be able to uncover subtle changes in HPA regulation. The present twin study investigated genetic factors as sources of the interindividual variation of the cortisol awakening response. Furthermore, the relationship between psychological variables and morning cortisol levels was studied. On two consecutive days saliva samples were collected 0, 30, 45 and 60 minutes after awakening in 52 monozygotic and 52 dizygotic twin pairs. Moreover, samples were obtained at 0800, 1100, 1500 and 2000 h. ('short day-time profile'). Additionally, the participants filled out questionnaires assessing chronic stress load, self-esteem and self-efficacy.Heritability estimates of h(2)=0.40 for the mean increase and of h(2)=0.48 for the area under the response curve indicate a significant impact of genetic factors on cortisol levels after awakening. However, no genetic influence on the short day-time profile could be observed. Furthermore, several aspects of perceived chronic stress, namely 'worries', 'social stress' and 'lack of social recognition' were significantly associated with the awakening cortisol response. The evidence for a medium-sized, yet distinct genetic influence on cortisol levels after awakening is discussed with regard to a potential clinical relevance of genetic determinants of HPA (re)activity. In line with several recent studies, the present findings further support the view that the cortisol awakening responses is consistently enhanced under chronic stress conditions.

Fluorescence in situ hybridization with chromosome paint probes: a novel approach to assess aneuploidy in human sperm nuclei.

PURPOSE: Fluorescence in situ hybridization (FISH) using whole-chromosome paint probes was performed to evaluate disomy and diploidy frequency for chromosomes 1, 18, 19, and 22 in human sperm nuclei. METHODS: Ten subjects of proven fertility and normal spermatic parameters were included in the study. A dual-color FISH method was carried out. RESULTS: A total of 157,896 spermatozoa was scored. The mean frequencies of disomic sperm for chromosomes 1, 18, 19, and 22 were 0.22% (range, 0.19 to 0.28%), 0.24% (range, 0.14 to 0.37%), 0.22% (range, 0.17 to 0.30%), and 0.25% (range, 0.21 to 0.29%), respectively. The mean frequency of diploidy was 0.14% (range, 0.09 to 0.18%). No interindividual and interchromosomal variations in the aneuploidy frequency were observed between the different subjects. CONCLUSIONS: FISH with whole-chromosome paint probes provides a novel and efficient approach for disomy assessment in human sperm nuclei.

Computer-based training for the treatment of partial blindness.

Partial blindness after brain injury has been considered non-treatable. To evaluate whether patients with visual-field defects can profit from computer-based visual restitution training (VRT), two independent clinical trials were conducted using patients with optic nerve (n = 19) or post-chiasmatic brain injury (n = 19). In post-chiasma patients, VRT led to a significant improvement (29.4%) over baseline in the ability to detect visual stimuli; in optic nerve patients, the effects were even more pronounced (73.6% improvement). Visual-field enlargements were confirmed by the observation of a visual-field expansion of 4.9 degrees-5.8 degrees of visual angle and improved acuity in optic nerve patients. Ninety five percent of the VRT-treated patients showed improvements, 72.2% confirmed visual improvements subjectively. Patients receiving a placebo training did not show comparable improvements. In conclusion, VRT with a computer program improves vision in patients with visual-field defects and offers a new, cost-effective therapy for partial blindness.

Determination of atrazine in rainfall and surface water by enzyme immunoassay.

Rainwater and surface water from four sites in Germany (Bavaria and Lower Saxony) were analyzed for atrazine by enzyme immunoassay from June 1990 until October 1992. The limit of quantification of the immunoassay was 0.02 µg/L with a middle of the test at 0.2 µg/L. About 60 % of the samples contained measurable amounts of atrazine. Seasonal trends were observed, with the highest concentration in the summer months of up to 4 µg/L for rainwater and up to 15 µg/L for surface waters. The highest concentrations were found in agricultural areas, while in the investigated national parks up to 0.56 µg/L could be detected in rain water. This points to long-range atmospheric transport from agricultural areas to pristine national parks. Samples from forest stands usually showed higher atrazine concentrations than samples from open fields. Deposition rates of 10 - 50 µg/m(2) · yr were observed in the national parks and 10-180 µg/m(2) · yr at the agricultural sites. Comparison of results obtained by enzyme immunoassay and GC/MS showed a good correlation of r = 0.95.

Heritability of cortisol responses to human corticotropin-releasing hormone, ergometry, and psychological stress in humans.

The present study investigated cortisol responses to three different stimulation procedures, with a focus on the contribution of genetic factors. Thirteen monozygotic (MZ) twin pairs and 11 dizygotic (DZ) twin pairs performed bicycle ergometry until exhaustion and were exposed to the psychological stress of public speaking and mental arithmetic in front of an audience. Furthermore, 9 MZ pairs and 10 DZ pairs were injected with 100 micrograms synthetic human CRH (hCRH). The adrenocortical response to these challenges was monitored by determination of cortisol in saliva. Significant intraindividual stability of baseline cortisol levels was found in females, but was less in males. Maximum cortisol responses to all three stimulation procedures were significantly intercorrelated in males, but in females only the cortisol responses to hCRH and ergometer exercise showed a significant correlation. While a decided influence of genetic factors was observed for all three baseline cortisol levels as well as for the response to hCRH, heredity appeared to be play a minor role in the adrenocortical response to psychological stress. Cortisol changes after bicycle ergometry revealed no impact of genetic factors on the secretion of cortisol in response to strenuous physical exercise.

Consistent sex differences in cortisol responses to psychological stress.

In four independent studies, sex differences in cortisol responses to psychological stress were investigated in healthy adolescents and adults (total n = 153). Public speaking and mental arithmetic in front of an audience (Studies 1-3) reliably induced increases in free cortisol levels in both sexes with 2- to 4-fold increases above baseline levels. Mean cortisol responses were 1.5- to 2-fold higher in men compared with women. In Study 3, cortisol profiles were additionally investigated after human corticotropin-releasing hormone (h-CRH) and bicycle ergometry until exhaustion. Here, both sexes showed very similar adrenocortical responses. Furthermore, men showed elevated cortisol levels in anticipation of the psychological stress situation without actually having to perform the tasks (Study 4). Under this condition cortisol concentration was unchanged or decreased in women. From these data we conclude that the observed sex difference does not reflect an overall lower responsiveness of the female adrenal cortex. Although these studies do not provide conclusive data, we suggest sex differences in cognitive and/or emotional responses to distressing psychosocial situations which in turn may influence cortisol secretion.

'Normal' cigarette smoking increases free cortisol in habitual smokers.

In habitual smokers salivary cortisol responses to cigarette smoking were investigated. In the first study, 31 adults assigned to two experimental groups smoked either one or two cigarettes of their preferred brand. Mean salivary cortisol levels were significantly elevated after smoking of two cigarettes. In the second study, 10 smokers and 10 nonsmokers provided saliva samples at 20 min intervals over a 12-hr period. While environmental stimuli were paralleled in both groups overall cortisol output was significantly elevated in the smokers. These data suggest that 'normal' cigarette smoking can increase free cortisol levels.