22 June 2011. A new study of healthy subjects offers clues to the ways in which city living may get on one’s nerves and perhaps even help foster schizophrenia. In a paper published in Nature on June 23, Andreas Meyer-Lindenberg, University of Heidelberg, Mannheim, Germany, and colleagues found differences in the brain’s responses to social stress depending upon where people lived or had grown up. In particular, subjects who grew up in an urban setting showed heightened stress responses in the anterior cingulate cortex, while those who were living in urban areas at the time of the study displayed ramped-up responses in the amygdala. The findings tie the urban experience to the processing of social stress and suggest that differently timed environmental exposures leave their mark on different brain regions. In addition, the study points to the potential benefits of epidemiology-inspired neuroscience.
The perks of city life may come with a mental health price tag. A recent meta-analysis of quality studies found a 38 percent higher prevalence of psychiatric disorders and a 39 percent higher prevalence of mood disorders in subjects born or raised in urban areas (Peen et al., 2010). A literature review on schizophrenia found a stream of evidence connecting urban birth, upbringing, or residence to increased risk of the disorder (Kelly et al., 2010; also see SRF related news story). Importantly, the associations between urbanicity and psychiatric illness remain after adjustment for possible confounding variables; however, whether the associations occur worldwide remains unknown.
Complementing the urban-rural findings, a related body of work highlights the social milieu as an indicator of schizophrenia risk (see SRF live discussion; also see SRF related news story). Some research suggests, for instance, that residents of socially fragmented areas have an increased risk of psychosis (Allardyce et al., 2005; Kirkbride et al., 2007; also see SRF related news story). Furthermore, chronic social defeat—that is, the perception that one is an outsider or in a subordinate position—plays a key role in at least one account of how schizophrenia develops (Selten and Cantor-Graae, 2005; Selten and Cantor-Graae, 2007). The supposition is that this form of social stress may, over time, change brain structures or circuits (e.g., the mesolimbic system) and hence increase vulnerability to schizophrenia.
Connecting the dots from urbanicity to social factors, the new Nature study examined whether urban living and upbringing change the brain’s processing of social stress. The researchers—including lead authors Florian Lederbogen, Peter Kirsch, and Leila Haddad, all of the University of Heidelberg, Mannheim, Germany—conducted a series of experiments to address this issue. In each experiment, healthy volunteers performed a task while functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent signals recorded their brain activity.
The when and where
The first experiment exposed 32 subjects, ages 18 and over, to the stress of negative social evaluation. It did so by tasking them with performing mental math and pressuring them to do it quickly and correctly; in addition, an experimenter criticized their performance after each test segment. This approach produced the desired effect in that subjects’ stress ratings went up during the task, as did their heart rate, blood pressure, and cortisol levels.
To assess urban versus rural exposures, the researchers assigned a code of 3 to cities with over 100,000 inhabitants, 2 to smaller towns with a population of over 10,000, and 1 to rural areas. They quantified urban upbringing by multiplying the code for each place the subject lived by the number of years in residence there until age 15, and summed the result across residences.
Data analyses revealed greater task-related activation of the amygdala, which processes emotion-related information, in current city dwellers (see SRF related news story). Indeed, Lederbogen and colleagues found evidence of a “dose-response” relationship—the least amygdalar activity in rural residents and the most in city dwellers, with small-town folk in between. The results for urban upbringing echoed those for current urban living, except in one key aspect: the brain region involved. This time, another part of the limbic system, the perigenual anterior cingulate cortex, showed an amplified stress response that correlated with urbanicity. Again, the evidence favored a dose-response gradient in which subjects with the most time spent in urban settings during their upbringing showed the most activity in this region, and those who grew up only in rural areas showed the least activity. Neither demographic nor clinical variables explained the stress-and-the-city associations, which arose only in the two limbic regions.
Checking it thrice
Concerned that the findings might be specific to the sample or the task used, the researchers measured the brain activity of 23 new volunteers, mostly college students. The subjects performed a modified set of mental arithmetic and mental rotation tasks, under a barrage of disparaging comments about their performance. The results mirrored those from the first experiment, and the replication held even after the researchers offset the preponderance of city folks with additional people from towns and rural areas.
Thus far, the tasks combined social stress with cognitive performance, making it difficult to disentangle the two. To make sure that the findings reflected social stress rather than the cognitive tasks used, the research team asked 80 additional subjects to complete a working memory task and an emotional face-matching task. This group encountered no mean experimenter or other trumped-up social threat, and showed none of the urbanicity-related stress responses in the amygdala or the anterior cingulate cortex. This convinced Lederbogen and colleagues that social stress played a role in the urban-rural differences seen earlier.
The brain on city life
In hindsight, the researchers thought that the study’s findings made sense given what is known about the amygdala and the anterior cingulate cortex. The former processes information about environmental threats, whereas the perigenual anterior cingulate cortex helps regulate the amygdala (for a primer on the amygdala, see LeDoux, 2007). Both structures govern the response of the hypothalamic-pituitary-adrenocortical axis to stress (Herman et al., 2005).
The cingulate may be particularly sensitive to urban hardships encountered in early life, Lederbogen and colleagues suggest. They reported that functional connectivity between these regions correlated inversely with early urban roots (Spearman’s Rho = -0.39, P = 0.01), but not at all with subsequent urban living.
Although this study only included healthy subjects, its findings might help researchers explain the high rates of mental illness in cities. Limbic dysfunction is thought to play a role in many psychiatric conditions, including mood disorders and schizophrenia (see SRF related news story; SRF news story). In fact, studies have found gray matter shrinkage in the anterior cingulate cortex in schizophrenia (see SRF related news story; SRF news story). Perhaps additional research at the junction of neuroscience and epidemiology will clarify whether the processing of social stress plays a causal role in schizophrenia.—Victoria L. Wilcox.
Lederbogen F, Kirsch P, Haddad L, Streit F, Tost H, Schuch P, Wüst S, Pruessner JC, Rietschel M, Deuschle M, Meyer-Lindenberg A. City living and urban upbringing affect neural social stress processing in humans. Nature. 2011 June 23; 474(7352):498-501.