Studies of the biological bases of temperament can provide critical insights into why certain individuals are at increased risk for psychiatric disease. The study by Oler and colleagues makes an important contribution to the field by assessing the heritability of temperament-related brain activity in a large colony of pre-adolescent rhesus monkeys. The authors used a standard human intruder paradigm to elicit the phenotypic behavior and concomitant brain activity associated with anxious temperament. Temperament-related brain activity was first identified by correlating anxious temperament with glucose metabolism, the measure of brain activity. Next, heritability estimates were calculated for each voxel in these brain regions. Activity in both the amygdala and hippocampus were correlated with anxious temperament. The amygdala finding confirms previous studies of increased amygdalar activity in both monkeys and humans with an anxious temperament; however, amygdalar activity was not heritable. Instead, the temperament-associated activation in the anterior hippocampus was...  Read more

Studies of the biological bases of temperament can provide critical insights into why certain individuals are at increased risk for psychiatric disease. The study by Oler and colleagues makes an important contribution to the field by assessing the heritability of temperament-related brain activity in a large colony of pre-adolescent rhesus monkeys. The authors used a standard human intruder paradigm to elicit the phenotypic behavior and concomitant brain activity associated with anxious temperament. Temperament-related brain activity was first identified by correlating anxious temperament with glucose metabolism, the measure of brain activity. Next, heritability estimates were calculated for each voxel in these brain regions. Activity in both the amygdala and hippocampus were correlated with anxious temperament. The amygdala finding confirms previous studies of increased amygdalar activity in both monkeys and humans with an anxious temperament; however, amygdalar activity was not heritable. Instead, the temperament-associated activation in the anterior hippocampus was heritable, providing initial evidence for the hippocampus as a genetically determined neural substrate of anxious temperament.

This hippocampal finding is intriguing and provides a potentially important link among anxious temperament, social anxiety, and schizophrenia. Anxious temperament is a significant risk factor for social anxiety, and social anxiety is very common in individuals with schizophrenia, but a direct link between anxious temperament and schizophrenia has yet to be established. Structural and functional hippocampal deficits are well established in schizophrenia (Heckers et al., 1998; Wright et al., 2000), but most research on anxious temperament and social anxiety has focused on the amygdala, given its role in fight-or-flight fear responses. However, a model of personality proposed by Gray (1982) specifically predicted the septohippocampal system as a neural substrate of the anxiety-related Behavioral Inhibition System—a “system that responds to novel stimuli or stimuli associated with punishment or non-reward by inhibiting ongoing behavior and increasing arousal and attention to the environment.” Kagan’s (1988) temperament trait of Behavioral Inhibition was defined as wary or avoidant responses to novel stimuli and is also associated with risk for social anxiety. Thus, individual differences in temperamental traits related to detection of and response to novelty may be associated with increased risk for social anxiety.

Novel stimuli activate both the hippocampus and amygdala (Blackford et al., 2010), and both regions are involved in emotional memory formation (Phelps, 2004). For individuals with temperament and personality traits associated with increased risk for social anxiety, novelty detection and facial memory may be especially important. Among healthy controls, repeated presentations of a novel face result in increased recognition memory for the face and an associated reduction in amygdala activation (Breiter et al., 1996). Individuals with an anxious temperament fail to show this reduction, but instead have a sustained amygdala response to even familiarized faces (Blackford et al., 2010). Interestingly, individuals with schizophrenia also demonstrate a sustained amygdala response across repeated presentations of faces (Holt et al., 2005). Sustained amygdala activation to even familiarized faces may reflect a deficit in the creation of facial memories, such that the amygdala continues to respond to the faces as though they are new. These empirical findings suggest that dysfunction in a hippocampal-dependent familiarity process may underlie a continuum of social dysfunction ranging from anxious temperament to social anxiety to schizophrenia. This deficit may result in the social anxiety characteristic of both anxious temperament and schizophrenia.

A logical next step is to identify the genes that underlie the temperament-associated hippocampal activation. While much of the discovery in psychiatric genetics has focused on specific disorders, a shift to examining the genes underlying a dimension of social dysfunction may be fruitful.

References:

Blackford JU, Avery SN, Cowan RL, Shelton RC, Zald DH. Sustained amygdala response to both novel and newly familiar faces characterizes inhibited temperament. Soc Cogn Affect Neurosci . 2010 Jul 26. Abstract

Blackford JU, Buckholtz JW, Avery SN, Zald DH. A unique role for the human amygdala in novelty detection. Neuroimage . 2010 Apr 15 ; 50(3):1188-93. Abstract

Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, Strauss MM, Hyman SE, Rosen BR. Response and habituation of the human amygdala during visual processing of facial expression. Neuron . 1996 Nov 1 ; 17(5):875-87. Abstract

Gray JA. The neuropsychology of anxiety. Issues Ment Health Nurs . 1985 Jan 1 ; 7(1-4):201-28.

Heckers S, Rauch SL, Goff D, Savage CR, Schacter DL, Fischman AJ, Alpert NM. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci . 1998 Aug 1 ; 1(4):318-23. Abstract

Holt DJ, Weiss AP, Rauch SL, Wright CI, Zalesak M, Goff DC, Ditman T, Welsh RC, Heckers S. Sustained activation of the hippocampus in response to fearful faces in schizophrenia. Biol Psychiatry . 2005 May 1 ; 57(9):1011-9. Abstract

Kagan J, Reznick JS, Snidman N. Biological bases of childhood shyness. Science . 1988 Apr 8 ; 240(4849):167-71. Abstract

Phelps EA. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr Opin Neurobiol . 2004 Apr 1 ; 14(2):198-202. Abstract

Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry . 2000 Jan 1 ; 157(1):16-25. Abstract

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

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; March et al., 2008). The new findings should trigger more focused research exploring the fMRI correlates in urban- versus rural-born individuals with schizophrenia.

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

McGrath J, Scott J. Urban birth and risk of schizophrenia: a worrying example of epidemiology where the data are stronger than the hypotheses. Epidemiol Psichiatr Soc . 2006 Oct-Dec ; 15(4):243-6. Abstract

Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry . 2001 Nov 1 ; 58(11):1039-46. Abstract

Pedersen CB, Mortensen PB. Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals? Am J Epidemiol . 2006 Jun 1 ; 163(11):971-8. Abstract

Pedersen CB, Mortensen PB. Urbanization and traffic related exposures as risk factors for schizophrenia. BMC Psychiatry . 2006 Jan 1 ; 6():2. Abstract

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

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 dose-response relationship between urbanization and schizophrenia (Pedersen and Mortensen, 2001) could be replicated only among persons born in Denmark whose parents had both been born in Denmark, and not in second-generation immigrants (Cantor-Graae and Pederson, 2007). Second-generation immigrants had an increased risk of developing schizophrenia independently of urban birth/upbringing (Cantor-Graae and Pedersen, 2007).

References:

Pedersen CB, Mortensen PB. Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals? Am J Epidemiol. 2006; 163:971-8. Abstract

Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry. 2001; 58:1039-46. Abstract

Cantor-Graae E, Pedersen CB. Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study. Psychol Med. 2007; 37:485-94. Abstract

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

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 living in urban environments. One important step will now be to discover whether such neural changes (following exposure to urban environments) are associated with clinical phenotypes, such as schizophrenia. This would support long-speculated paradigms of social stress (Selten and Cantor-Graae, 2005) as an important mechanism in a causal pathway between the environment and psychosis, although alternative environmental exposures in urban areas, including viral hypotheses and vitamin D, should not yet be excluded.

The work by Lederbogen et al. opens many avenues for possible study, including replication of their findings in clinical samples (via case-control designs) and using population-based rather than convenience samples. One of the greatest challenges in the social epidemiology of psychiatric disorders is to identify the specific suite of factors that underpin associations between the urban environment and the risk of clinical disorder. While Lederbogen et al. did not provide specific enlightenment on what these factors might be, their work also informs this search, because it suggests that focusing on factors likely to induce (or protect against) social stress would be potentially fruitful. To this end, their work should pave the way for mimetic studies, in both non-clinical and clinical populations, to investigate neural processing in relation to candidate social risk factors for psychiatric illness that were implicated in previous epidemiological studies (Cantor-Graae and Selten, 2005; March et al., 2008). These candidates may include migration or minority group membership (Coid et al., 2008), childhood traumas and other major life events (Kendler et al., 1992; Morgan et al., 2007), neighborhood socioeconomic deprivation (Croudace et al., 2000), income inequality (Boydell et al., 2004), and both individual-level social networks and neighborhood-level social cohesion and ethnic density (Kirkbride et al., 2008); some of these factors may also mitigate the effects of social stress.

The interface between social epidemiology and social neuroscience will also potentially provide new avenues by which to develop public health interventions. Presently, universal prevention strategies that focus on community-based interventions to prevent mental illness are not readily viable (Kirkbride et al., 2010), given both the absolute rarity of psychotic disorder and the relative ubiquity of broadly defined exposures such as urban living (many people live in urban environments, but only a handful of them will ever develop a psychotic illness). However, social neuroscience breakthroughs like those reported here may increase the viability of community-based public health initiatives by making it possible to move the focus of the intervention from preventing the clinical phenotype to preventing the abnormal neural changes associated with social-stress processing. Importantly, such strategies must also consider the possible benefits of enhanced social-stress processing in urban environments, which might be an important adaptation to more threatening environments. Because social stress may be associated with a range of neuropsychiatric and somatic disorders, public health strategies that target reductions in social stress rather than any single disorder may lead to significant improvements in population health across a range of morbidities. Such strategies, if justifiable, may also be cost effective, since a single intervention may prevent a range of disorders.

References:

Hafner H, Reimann H, Immich H, Martini H. Inzidenz seelischer Erkrankungen in Mannheim 1965. Soc Psychiatr. 1969;4:127-35.

Faris REL, Dunham HW. Mental disorders in urban areas. Chicago: University of Chicago Press; 1939.

Selten JP, Cantor-Graae E. Social defeat: risk factor for schizophrenia? Br J Psychiatry. 2005 August 1;187(2):101-2. Abstract

Cantor-Graae E, Selten J-P. Schizophrenia and Migration: A Meta-Analysis and Review. Am J Psychiatry. 2005 January 1;162(1):12-24. Abstract

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

Coid JW, Kirkbride JB, Barker D, Cowden F, Stamps R, Yang M, Jones PB. Raised incidence rates of all psychoses among migrant groups: findings from the East London first episode psychosis study. Arch Gen Psychiatry. 2008;65(11):1250-8. Abstract

Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch Gen Psychiatry. 1992 Feb;49(2):109-16. Abstract

Morgan C, Kirkbride JB, Leff J, Craig T, Hutchinson G, McKenzie K, Morgan K, Dazzan P, Doody GA, Jones P, Murray R, Fearon P. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med. 2007;37(4):495-503. Abstract

Croudace TJ, Kayne R, Jones PB, Harrison GL. Non-linear relationship between an index of social deprivation, psychiatric admission prevalence and the incidence of psychosis. Psychol Med. 2000 Jan;30(1):177-85. Abstract

Boydell J, van Os J, McKenzie K, Murray RM. The association of inequality with the incidence of schizophrenia--an ecological study. Soc Psychiatry Psychiatr Epidemiol. 2004 Aug;39(8):597-9. Abstract

Kirkbride J, Boydell J, Ploubidis G, Morgan C, Dazzan P, McKenzie K, Murray RM, Jones PB. Testing the association between the incidence of schizophrenia and social capital in an urban area. Psychol Med. 2008;38(8):1083-94. Abstract

Kirkbride JB, Coid JW, Morgan C, Fearon P, Dazzan P, Yang M, Lloyd T, Harrison GL, Murray RM, Jones PB. Translating the epidemiology of psychosis into public mental health: evidence, challenges and future prospects. J Public Ment Health. 2010;9(2):4-14. Abstract

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

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 the relationship between environmental factors and schizophrenia. It stimulates further research in this direction.

Two key issues need to be addressed. First, measures of social pathways should be refined (March et al., 2008). Which aspects of the daily social environment contribute to the onset of psychotic symptoms, how do these symptoms develop, and which individual characteristics moderate this outcome? It is extremely difficult to investigate daily social environments, because they are highly complex, cannot be controlled, are never exactly the same, and are strongly influenced by the individual’s behavior. Arguably, the only way to test mechanisms of psychotic responses to the social environment, and the moderators thereof, is to randomize individuals to controlled experimental social risk environments. Virtual reality (VR) technology, that is, substituting sense data from the natural world with sense data about an imaginary world that change in response to the user’s actions in an interactive three-dimensional virtual world, offers the possibility to do so. Freeman pioneered VR in psychosis research, investigating safety and feasibility (Fornells-Ambrojo et al., 2008; Freeman, 2008); however, there are no studies investigating mechanisms of risk environments. Our group recently found in a small pilot study that virtual environments with high population density or low ethnic density appear to elicit more physiological and subjective stress, as well as higher level of paranoia towards avatars (Brinkman et al., 2011). Larger studies and more experiments are needed.

Second, how are early social experiences translated to brain dysfunction? Another recent development has been in the field of epigenetics. Epigenetic mechanisms may mediate the effects of environmental risk factors, as the epigenetic status of the genome can be modified in response to the environment during embryonic growth, and probably also in the early years of life (Heijmans et al., 2009). Preliminary evidence suggests that epigenetic differences may be related to schizophrenia (Mill et al., 2008), but these epigenetic studies have not yet included environmental exposures. Epidemiologic studies may be a tool to detect epigenetic mechanisms in schizophrenia. Environmental exposures such as prenatal famine or migration may be used, as these exposures have been related to schizophrenia, can be measured with sufficient precision, offer homogeneously exposed populations for study, and had plausible biological pathways suggested for them (Veling et al. Environmental studies as a tool for detecting epigenetic mechanisms in schizophrenia. In: Petronis A, Mill J, editors. Epigenetics and Human Health: Brain, Behavior and Epigenetics. Heidelberg: Springer; 2011). Comparing the epigenome of exposed and unexposed schizophrenia cases and controls may help us to understand how gene expression affects disease risk.

As far fetched and futuristic as these research designs perhaps may seem, the publication of Lederbogen and colleagues shows that novel approaches can be very fruitful. If we improve interdisciplinary collaboration and use new technology, we may advance from associations to understanding in etiologic schizophrenia research.

References:

Van Os J, Kenis G, Rutten BPF. The environment and schizophrenia. Nature. 2010;468:203-12. Abstract

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, et al. Psychosis and place. Epidemiological Reviews. 2008;30:84-100. Abstract

Fornells-Ambrojo M, Barker C, Swapp D, Slater M, Antley A, Freeman D. Virtual Reality and persecutory delusions: safety and feasibility. Schizophrenia Research. 2008;104:228-36. Abstract

Freeman D. Studying and treating schizophrenia using Virtual Reality: a new paradigm. Schizophrenia Bulletin. 2008;34:605-10. Abstract

Brinkman WP, Veling W, Dorrestijn E, Sandino G, Vakili V, Van der Gaag M. Virtual reality to study responses to social environmental stressors in individuals with and without psychosis. Studies in Health Technology and Informatics. 2011;167:86-91. Abstract

Heijmans BT, Tobi EW, Lumey LH, Slagboom PE. The epigenome; archive of the prenatal environment. Epigenetics. 2009;4:526-31. Abstract

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. American Journal of Human Genetics. 2008;82:696-711. Abstract

Veling W, Lumey LH, Heijmans BT, Susser E. Environmental studies as a tool for detecting epigenetic mechanisms in schizophrenia. In: Petronis A, Mill J, editors. Epigenetics and Human Health: Brain, Behavior and Epigenetics. Heidelberg: Springer; 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

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