Brain structural correlates of upward social mobility in ethnic minority individuals.

PURPOSE: Perigenual anterior cingulate cortex (pACC) is a neural convergence site for social stress-related risk factors for mental health, including ethnic minority status. Current social status, a strong predictor of mental and somatic health, has been related to gray matter volume in this region, but the effects of social mobility over the lifespan are unknown and may differ in minorities. Recent studies suggest a diminished health return of upward social mobility for ethnic minority individuals, potentially due to sustained stress-associated experiences and subsequent activation of the neural stress response system. METHODS: To address this issue, we studied an ethnic minority sample with strong upward social mobility. In a cross-sectional design, we examined 64 young adult native German and 76 ethnic minority individuals with comparable sociodemographic attributes using whole-brain structural magnetic resonance imaging. RESULTS: Results showed a significant group-dependent interaction between perceived upward social mobility and pACC gray matter volume, with a significant negative association in the ethnic minority individuals. Post-hoc analysis showed a significant mediation of the relationship between perceived upward social mobility and pACC volume by perceived chronic stress, a variable that was significantly correlated with perceived discrimination in our ethnic minority group. CONCLUSION: Our findings extend prior work by pointing to a biological signature of the "allostatic costs" of socioeconomic attainment in socially disadvantaged upwardly mobile individuals in a key neural node implicated in the regulation of stress and negative affect.

A neural mechanism for affective well-being: Subgenual cingulate cortex mediates real-life effects of nonexercise activity on energy.

Physical activity substantially improves well-being and mental health, but the underlying brain processes remain unclear. Most research concerns exercise, although the majority of everyday human behaviors, such as walking or stair climbing, are nonexercise activities. Combining neuroimaging with ecological assessment of activity and GPS-triggered smartphone diaries, we show a specific association of nonexercise activity with energy in two independent samples mediated by the subgenual part of the anterior cingulate cortex (sgACC), a key emotion regulatory site. Furthermore, energy predicted a range of mental health metrics. sgACC volume moderated humans' emotional gain from nonexercise activity in real life: Individuals with low sgACC volume, a risk factor for depression, felt less energized when inactive but benefited more from periods of high nonexercise activity. This suggests an everyday life mechanism affecting affective well-being in the general population and, if substantiated in patient samples, a risk and resilience process for mood disorders.

Sex-Dependent Association of Perigenual Anterior Cingulate Cortex Volume and Migration Background, an Environmental Risk Factor for Schizophrenia.

Migration status is one of the best-established risk factors for schizophrenia. An increase in risk is observed in both first- and second-generation immigrants, with a varying magnitude depending on the ethnic background of the individuals. The underlying mechanisms for the increased risk are only recently coming into focus. A causal role for social stress has been widely proposed, and recent work indicated altered neural stress processing in the perigenual anterior cingulate cortex (pACC) in migrants. Since previous work shows that social stress may lead to enduring changes in the gray matter volume of vulnerable brain regions, we investigated the impact of migration background on brain structure. We studied healthy young adults (N = 124), native Germans and second-generation migrants, using whole-brain structural magnetic resonance imaging. Groups were matched for a broad range of sociodemographic characteristics including age, gender, urban exposure, and education. We found a significant group by sex interaction effect in pACC gray matter volume, which was reduced in males with migration background only. This mirrors previous findings in urban upbringing, another risk factor for schizophrenia. Our results provide convergent evidence for an impact of environmental risk factors linked to schizophrenia on gray matter volume and extend prior data by highlighting the possibility that the pACC structure may be particularly sensitive to the convergent risk factors linked to schizophrenia.

Sex-specific association between functional neuropeptide S receptor gene (NPSR1) variants and cortisol and central stress responses.

The brain neuropeptide S (NPS) system has recently generated substantial interest and may be of major relevance for central stress regulation. The NPS receptor (NPSR1) is highly expressed in the limbic system, exogenous NPS exerts pronounced anxiolytic and fear-attenuating effects in rodents and extensive close crosstalk between the NPS system and the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated. In humans, associations between NPSR1 variants and anxiety and panic disorder, as well as amygdala responsiveness to fear- relevant faces and prefrontal cortex activity in a fear conditioning paradigm have been reported. Moreover, a NPSR1 sequence variant was found to be associated with cortisol stress responses in males. Here, we performed a haplotype-based analysis covering three functional NPSR1 single nucleotide polymorphisms in the promoter (rs2530547), in exon 3 (rs324981) and exon 6 (rs727162) in 277 healthy subjects who were exposed to the Trier Social Stress Test (TSST). A significant sex-specific association with salivary cortisol responses to acute psychosocial stress was detected for the common TTC haplotype 2 (frequency of about 20%). In an additional study using an imaging genetics approach, 65 healthy subjects were exposed to a stress paradigm for scanner environments ("ScanSTRESS"). We found a significant and, again, sex-specific interaction between rs324981 (whose minor T-allele is harbored by haplotype 2) and the neural stress response in a cluster close to the parahippocampal gyrus (whole brain corrected). Moreover, as in the TSST sample, NPSR1 variation was associated with salivary cortisol responses (on a trend level) in a sex-specific way. In summary, our preliminary findings in two independent cohorts exposed to different stress paradigms suggest that the NPS system significantly influences acute stress responses and that sequence variation in NPSR1 may contribute to sex differences in stress regulation.

Information flow between interacting human brains: Identification, validation, and relationship to social expertise.

Social interactions are fundamental for human behavior, but the quantification of their neural underpinnings remains challenging. Here, we used hyperscanning functional MRI (fMRI) to study information flow between brains of human dyads during real-time social interaction in a joint attention paradigm. In a hardware setup enabling immersive audiovisual interaction of subjects in linked fMRI scanners, we characterize cross-brain connectivity components that are unique to interacting individuals, identifying information flow between the sender's and receiver's temporoparietal junction. We replicate these findings in an independent sample and validate our methods by demonstrating that cross-brain connectivity relates to a key real-world measure of social behavior. Together, our findings support a central role of human-specific cortical areas in the brain dynamics of dyadic interactions and provide an approach for the noninvasive examination of the neural basis of healthy and disturbed human social behavior with minimal a priori assumptions.

Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations.

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.

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

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.

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.

The neurobiology of social environmental risk for schizophrenia: an evolving research field.

INTRODUCTION: Schizophrenia is a severe and complex brain disorder that usually manifests in early adulthood and disturbs a wide range of human functions. More than 100 years after its initial description, the pathophysiology of the disorder is still incompletely understood. Many epidemiological studies strongly suggest a complex interaction between genetic and environmental risk factors for the development of the disorder. While there is considerable evidence for a social environmental component of this risk, the links between adverse social factors and altered brain function have just come into focus. METHODS: In the present review, we first summarize epidemiological evidence for the significance of social environmental risk factors, outline the role of altered social stress processing in mental illness, and review the latest experimental evidence for the neural correlates of social environmental risk for schizophrenia. CONCLUSIONS: The studies we have discussed in this review provide a selection of the current work in the field. We suggest that many of the social environmental risk factors may impact on perceived social stress and engage neural circuits in the brain whose functional and structural architecture undergoes detrimental change in response to prolonged exposure. We conclude that multidisciplinary approaches involving various fields and thoroughly constructed longitudinal designs are necessary to capture complex structure of social environmental risks.