Fabian Streit

City living and urban upbringing affect neural social stress processing in humans

More than half of the world’s population now lives in cities, making the creation of a healthy urban environment a major policy priority. Cities have both health risks and benefits, but mental health is negatively affected: mood and anxiety disorders are more prevalent in city dwellers and the incidence of schizophrenia is strongly increased in people born and raised in cities. Although these findings have been widely attributed to the urban social environment, the neural processes that could mediate such associations are unknown. Here we show, using functional magnetic resonance imaging in three independent experiments, that urban upbringing and city living have dissociable impacts on social evaluative stress processing in humans. Current city living was associated with increased amygdala activity, whereas urban upbringing affected the perigenual anterior cingulate cortex, a key region for regulation of amygdala activity, negative affect and stress. These findings were regionally and behaviourally specific, as no other brain structures were affected and no urbanicity effect was seen during control experiments invoking cognitive processing without stress. Our results identify distinct neural mechanisms for an established environmental risk factor, link the urban environment for the first time to social stress processing, suggest that brain regions differ in vulnerability to this risk factor across the lifespan, and indicate that experimental interrogation of epidemiological associations is a promising strategy in social neuroscience.

Neuroimaging Evidence for a Role of Neural Social Stress Processing in Ethnic Minority-Associated Environmental Risk

IMPORTANCE Relative risk for the brain disorder schizophrenia is more than doubled in ethnic minorities, an effect that is evident across countries and linked to socially relevant cues such as skin color, making ethnic minority status a well-established social environmental risk factor. Pathoepidemiological models propose a role for chronic social stress and perceived discrimination for mental health risk in ethnic minorities, but the neurobiology is unexplored. OBJECTIVE To study neural social stress processing, using functional magnetic resonance imaging, and associations with perceived discrimination in ethnic minority individuals. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional design in a university setting using 3 validated paradigms to challenge neural social stress processing and, to probe for specificity, emotional and cognitive brain functions. Healthy participants included those with German lineage (n = 40) and those of ethnic minority (n = 40) from different ethnic backgrounds matched for sociodemographic, psychological, and task performance characteristics. Control comparisons examined stress processing with matched ethnic background of investigators (23 Turkish vs 23 German participants) and basic emotional and cognitive tasks (24 Turkish vs 24 German participants). MAIN OUTCOMES AND MEASURES Blood oxygenation level-dependent response, functional connectivity, and psychological and physiological measures. RESULTS There were significant increases in heart rate (P < .001), subjective emotional response (self-related emotions, P < .001; subjective anxiety, P = .006), and salivary cortisol level (P = .004) during functional magnetic resonance imaging stress induction. Ethnic minority individuals had significantly higher perceived chronic stress levels (P = .02) as well as increased activation (family-wise error-corrected [FWE] P = .005, region of interest corrected) and increased functional connectivity (PFWE = .01, region of interest corrected) of perigenual anterior cingulate cortex (ACC). The effects were specific to stress and not explained by a social distance effect. Ethnic minority individuals had significant correlations between perceived group discrimination and activation in perigenual ACC (PFWE = .001, region of interest corrected) and ventral striatum (PFWE = .02, whole brain corrected) and mediation of the relationship between perceived discrimination and perigenual ACC-dorsal ACC connectivity by chronic stress (P < .05). CONCLUSIONS AND RELEVANCE Epidemiologists proposed a causal role of social-evaluative stress, but the neural processes that could mediate this susceptibility effect were unknown. Our data demonstrate the potential of investigating associations from epidemiology with neuroimaging, suggest brain effects of social marginalization, and highlight a neural system in which environmental and genetic risk factors for mental illness may converge.

Brain Structure Correlates of Urban Upbringing, an Environmental Risk Factor for Schizophrenia

Urban upbringing has consistently been associated with schizophrenia, but which specific environmental exposures are reflected by this epidemiological observation and how they impact the developing brain to increase risk is largely unknown. On the basis of prior observations of abnormal functional brain processing of social stress in urban-born humans and preclinical evidence for enduring structural brain effects of early social stress, we investigated a possible morphological correlate of urban upbringing in human brain. In a sample of 110 healthy subjects studied with voxel-based morphometry, we detected a strong inverse correlation between early-life urbanicity and gray matter (GM) volume in the right dorsolateral prefrontal cortex (DLPFC, Brodmann area 9). Furthermore, we detected a negative correlation of early-life urbanicity and GM volumes in the perigenual anterior cingulate cortex (pACC) in men only. Previous work has linked volume reductions in the DLPFC to the exposure to psychosocial stress, including stressful experiences in early life. Besides, anatomical and functional alterations of this region have been identified in schizophrenic patients and high-risk populations. Previous data linking functional hyperactivation of pACC during social stress to urban upbringing suggest that the present interaction effect in brain structure might contribute to an increased risk for schizophrenia in males brought up in cities. Taken together, our results suggest a neural mechanism by which early-life urbanicity could impact brain architecture to increase the risk for schizophrenia.

Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance

Hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (GR, NR3C1). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression.

Sexual dysfunction during treatment with serotonergic and noradrenergic antidepressants: Clinical description and the role of the 5-HTTLPR

Abstract Objectives. Sexual dysfunction (SD) is a frequently reported side-effect of antidepressant treatment, particularly of selective serotonin reuptake inhibitors (SSRIs). In the multicentre clinical and pharmacogenetic GENDEP study (Genome-based Therapeutic Drugs for Depression), the effect of the serotonin transporter gene promoter polymorphism 5-HTTLPR on sexual function was investigated during treatment with escitalopram (SSRI) and nortriptyline (tricyclic antidepressant). Methods. A total of 494 subjects with an episode of DSM-IV major depression were randomly assigned to treatment with escitalopram or nortriptyline. Over 12 weeks, depressive symptoms and SD were measured weekly with the Montgomery–Asberg Depression Rating Scale, the Antidepressant Side-Effect Checklist, the UKU Side Effect Rating Scale, and the Sexual Functioning Questionnaire. Results. The incidence of reported SD after 12 weeks of treatment was relatively low, and did not differ significantly between antidepressants (14.9% escitalopram, 19.7% nortriptyline). There was no significant interaction between the 5-HTTLPR and antidepressant on SD. Improvement in depressive symptoms and younger age were both associated with lower SD. The effect of age on SD may have been moderated by the 5-HTTLPR. Conclusions. In GENDEP, rates of reported SD during treatment were lower than those described in previous reports. There was no apparent effect of the 5-HTTLPR on the observed decline in SD.

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.

Perceived stress and hair cortisol: Differences in bipolar disorder and schizophrenia

INTRODUCTION Bipolar disorder (BD) and schizophrenia (SCZ) are psychiatric disorders with shared and distinct clinical and genetic features. In both disorders, stress increases the risk for onset or relapse and dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has been reported. The latter is frequently investigated by measuring changes in the hormonal end product of the HPA axis, i.e., the glucocorticoid cortisol, whose concentration exhibits diurnal variation. The analysis of hair cortisol concentration (HCC) is a new method, which allows assessment of cumulative cortisol secretion over the preceding three months. AIMS To explore whether perceived stress and HCC: (i) differ between BD patients, SCZ patients, and controls; (ii) change over disease course; and iii) are associated with an increased genetic risk for BD or SCZ. METHODS 159 SCZ patients, 61 BD patients and 82 controls were included. Assessment included psychopathology, perceived stress, and HCC. Inpatients with an acute episode (38 BD and 77 SCZ) were assessed shortly after admission to hospital and at 3 and 6 months follow-up. Outpatients in remission and controls were assessed at one time point only. Polygenic risk scores for BD and SCZ were calculated based on results of the Psychiatric Genomic Consortium. RESULTS (i) Perceived stress was higher in BD and SCZ patients compared to controls (p<0.02), and was lower in outpatients in remission compared to inpatients on admission. HCC was higher in BD patients compared to SCZ patients and controls (p<0.02), and higher in inpatients on admission than in outpatients in remission (p=0.0012). In BD patients (r=0.29; p=0.033) and SCZ patients (r=0.20; p=0.024) manic symptoms were correlated with HCC. (ii) In both BD and SCZ inpatients, perceived stress decreased over the 6 month study period (p=0.048), while HCC did not change significantly over the 6 month study period. (iii) In controls, but not in the patient groups, the genetic risk score for BD was associated with HCC (r=0.28, p=0.023). CONCLUSIONS While our results are consistent with previous reports of increased perceived stress in BD and SCZ, they suggest differential involvement of the HPA axis in the two disorders. The genetic study supports this latter finding, and suggests that this effect is present below the threshold of manifest disorder.

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala

Abstract We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor “urbanicity” to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus-pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene × environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing.

Genetic effects influencing risk for major depressive disorder in China and Europe

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30–40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.