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A Tale of Two City Exposures and the Brain

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.

Reference:
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.

 
Comments on News and Primary Papers
Comment by:  John McGrath, SRF Advisor
Submitted 22 June 2011 Posted 22 June 2011

The findings from Lederbogen et al. are very thought provoking. The dissociation between the fMRI correlates of current versus early life urbanicity is unexpected. The authors have replicated their finding in an independent sample, reducing the chance that the finding was a type 1 error.

It is heartening to see important clues from epidemiology influencing fMRI research design. With respect to schizophrenia, the findings provide much-needed clues to the neurobiological correlates of urban birth (Pedersen and Mortensen, 2001; Pedersen and Mortensen, 2006; Pedersen and Mortensen, 2006). Somewhat to the embarrassment of the epidemiology research community, the link between urban birth and risk of schizophrenia has been an area of research where the strength of the empirical evidence has been much stronger than hypotheses proposed to explain the findings (McGrath and Scott, 2006;   Read more


View all comments by John McGrath

Comment by:  Elizabeth Cantor-Graae
Submitted 23 June 2011 Posted 23 June 2011

The study by Lederbogen et al. linking neural processes to epidemiology opens up an exciting avenue of inquiry, It suggests that exposure to urban upbringing could modify brain activity. Whether that could lead to schizophrenia per se remains to be seen.

Still, one might want to keep in mind that there is no evidence that urban-rural differences in schizophrenia risk are causally related to individual exposure. Pedersen and Mortensen (2006) showed that the association between urban upbringing and the development of schizophrenia is attributable both to familial-level factors as well as individual-level factors. Thus, the link between urbanicity and schizophrenia may be mediated by genetic factors, and if so, the social stressors shown by Lederbogen may in turn be related to those same genes.

Although it might be tempting to speculate whether Lederbogen’s findings have implications for migrant research, the “migrant effect” does not seem neatly explained by urban birth/upbringing. To the contrary, our findings show that the...  Read more


View all comments by Elizabeth Cantor-Graae

Comment by:  James Kirkbride
Submitted 27 June 2011 Posted 27 June 2011

Mannheim, Germany, has long played a pivotal role in unearthing links between the environment and schizophrenia (Hafner et al., 1969). Using administrative incidence data from Mannheim in 1965, Hafner and colleagues were amongst the first groups to independently verify Faris and Dunham’s seminal work from Chicago in the 1920s, which showed that hospitalized admission rates of schizophrenia were higher in progressively more urban areas of the city (Faris and Dunham, 1939). Now, almost 50 years later, Mannheim’s historical pedigree in this area looks set to endure, following the publication of the landmark study by Lederbogen et al. in Nature, which reported for the first time associations of urban living and upbringing with increased brain activity amongst healthy volunteers in two brain regions involved in determining environmental threat and processing stress responses.

Tantalizingly, their work bridges epidemiology and neuroscience, and provides some of the first empirical data to directly implicate functional neural alterations in stress processing associated with...  Read more


View all comments by James Kirkbride

Comment by:  Wim Veling
Submitted 5 July 2011 Posted 5 July 2011

This publication is interesting and important, as it is one of the first efforts to connect epidemiological findings to neuroscience. Both fields of research have made great progress over the last decades, but results were limited because epidemiologists and neuroscientists rarely joined forces.

Several risk factors that implicate preconceptional, prenatal, or early childhood exposures have been consistently related to schizophrenia in epidemiological studies, including paternal age at conception, early prenatal famine, urban birth, childhood trauma, and migration (Van Os et al., 2010). While some of these associations are likely to be causal, the mechanisms by which they are linked to schizophrenia are still largely unknown. A next phase of studies is required, the methods and measures of which link social environment to psychosis, brain function, and genes. The study by Lederbogen and colleagues is a fine example of such an innovative research design. Their findings are consistent with hypotheses of social stress mediating...  Read more


View all comments by Wim Veling

Comment by:  Dana March
Submitted 7 July 2011 Posted 7 July 2011

The paper by Lederbogen and colleagues represents a critical step in elucidating the mechanisms underlying the consistent association between urban upbringing and adult schizophrenia. As John McGrath rightly points out, the urbanicity findings have long been in search of hypotheses. We understand little about what the effects of place on psychosis might actually be (March et al., 2008). What it is about place that matters for neurodevelopment and for schizophrenia in particular can be greatly enriched by a translational approach linking epidemiological findings to clinical and experimental science (Weissman et al., 2011), which will in turn help us formulate and refine our hypotheses about why place matters. Lederbogen and colleagues have opened the door in Mannheim. Where we go from here will require creativity, persistence, and collaboration.

References:

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, Susser E. Psychosis and place. Epidemiol Rev . 2008 Jan 1 ; 30:84-100. Abstract

Weissman MM, Brown AS, Talati A. Translational epidemiology in psychiatry: linking population to clinical and basic sciences. Arch Gen Psychiatry . 2011 Jun 1 ; 68(6):600-8. Abstract

View all comments by Dana March

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