Schizophrenia Research Forum - A Catalyst for Creative Thinking

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; 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

View all comments by John McGrathComment 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 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

View all comments by Elizabeth Cantor-GraaeComment 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 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

View all comments by James KirkbrideComment 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 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.

View all comments by Wim VelingComment 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

Comments on Related News


Related News: Urban Schizophrenia Risk: A Family Affair?

Comment by:  Patricia Estani
Submitted 13 June 2006
Posted 13 June 2006
  I recommend the Primary Papers

Related News: Urban Schizophrenia Risk: A Family Affair?

Comment by:  Ella Matthews
Submitted 16 June 2006
Posted 5 July 2006

Questions on the different rates of occurrence of the schizophrenia spectrum of brain disorders between northern (developed) and southern underdeveloped countries, between urban and rural, as well as the birth order within the family of those suffering from schizophrenia are important ones.

However, when thinking about family exposure to environmental factors, I think that there is much to learn from social science. Say that a 1970s family moved from the country to the city just at the time when the birth control pill had been developed and began to be widely available in urban industrialized areas: Estrogen levels on the early formulations of the "pill" were too high, causing women to search for other legal birth control methods which they could tolerate more easily. About the only other things that doctors could offer women back then were the highly touted IUDs.

Say also that a woman tried the birth control pill but, because her taking of the pill was spotty, she became pregnant with her first child. After delivering their first children, many 1970s women then turned to IUDs, which did not cause bloating or the other nasty physical side effects of the pill. What IUDs did have was a hidden wicking string. Those strings were ladders for infection moving into the uterus. So when thinking of environmental factors at the level of the family, one has to ask broad-spectrum socioeconomic questions about what families were actually up against in the 1970s.

Birth control methods could also add insight into why schizophrenia was identified in the late 1800s, a time when women were moving into paid labor outside the home. It had been common knowledge since ancient times that any foreign object inserted into the uterus (IUD) would interfere with pregnancy. Working women had to limit the number of children they had. There was information-sharing among female coworkers.

Think about the implications of IUD use in Catholic countries such as Ireland, which has a high rate of schizophrenia. Catholic mothers of schizophrenics would be loath to discuss birth control methods used prior to or during the birth of a child born with schizophrenia. Moreover, during the Dalkon Shield scandal and IUD birth defect lawsuits of the 1970s and 1980s, the schizophrenias did not get any coverage because children born with these disorders hadn't reached the age of onset yet.

I am a parent of a second-born adult daughter suffering from schizophrenia. Families, especially mothers, do not want to go back to the days when it was said that bad mothering caused schizophrenia. Yet, we who carried these children to term have to ask ourselves what was different going into and throughout these pregnancies?

Skilled researchers need to formulate and ask probing questions about what the mother was exposed to prior to and during these pregnancies.

View all comments by Ella Matthews

Related News: How Nature and Nurture Form an Anxious Temperament

Comment by:  Jenni BlackfordStephan Heckers (SRF Advisor)
Submitted 21 September 2010
Posted 21 September 2010
  I recommend the Primary Papers

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

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View all comments by Stephan Heckers

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  John McGrath, SRF Advisor
Submitted 5 November 2010
Posted 5 November 2010

The large study from Nuevo and colleagues is very thought provoking. There was substantial between-site variation in response to various psychosis-screening items. Assuming that endorsement of these items is a mix of: 1) "true" psychotic-like experiences, 2) "true" responses that are understandable from the perspective of local cultures and beliefs, and 3) innocent misinterpretations of the questions, why is there such marked variation? For example, why do 46 percent of respondents from Nepal endorse at least one psychotic-like experience and a third report auditory hallucinations?

It seems self-evident that populations with strong religious and/or cultural beliefs related to psychotic-like experiences might endorse psychosis-screening items more readily (type 2 in the above list). But could it be feasible that these same populations might also “kindle” psychotic experiences in vulnerable people? This notion is pure speculation, but we should remain mindful that dopaminergic pathways related to psychosis are vulnerable to the process of endogenous sensitization (Laruelle, 2000).

What does it mean to be a member of a cultural group that is more “prone” to psychotic-like experiences? Tanya Luhrmann, an anthropologist based at Stanford University, has examined individuals attending evangelical churches who “hear” the voice of God during prayer (Luhrmann et al., 2010). The vignettes suggest that some individuals reported more “hearing the voice of God” after improving their prayer skills. Practice makes perfect, but could it also kindle pathways related to schizophrenia?

Regardless of the underlying mechanisms, understanding variations in these symptoms is a fascinating topic worthy of more multidisciplinary research.

References:

Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev. 2000;31(2-3):371-84. Abstract

Luhrmann TM, Nusbaum H, Thisted R. The absorption hypothesis: learning to hear God in evangelical Christianity. American Anthropologist. 2010;112 (1):66-78.

View all comments by John McGrath

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Tanya Luhrmann
Submitted 12 November 2010
Posted 12 November 2010

It seems to me that there may be two different patterns that show up in these large epidemiological studies: the psychotic continuum and phenomena associated with absorption. Absorption is basically a capacity for/interest in being caught up in your imagination. It is associated with hypnotizability and dissociation, but not identical to them (Tellegen and Atkinson, 1974).

In my own work on evangelical Christianity, I identify a pattern in which people report hallucination-like phenomena that are rare, brief, and not distressing (as opposed to the pattern associated with psychotic disorder, in which the hallucinations are often frequent, extended, and distressing). Those who report hearing God’s voice audibly or seeing the wing of an angel are also more likely to score highly on the Tellegen absorption scale (Luhrmann et al., 2010). This relationship between unusual experiences and absorption also shows up in a significant relationship between absorption and the Posey-Loesch hearing voices scale when these scales are given to undergraduates. Among undergraduates, the rates for hallucination-like phenomena are also consistently far higher than the Nuevo paper reports, perhaps because neither the absorption scale nor the Posey-Loesch scale seems to probe for pathology (Luhrmann, forthcoming).

I am not the only one to have found a significant association between unusual sensory experiences and absorption. Aleman and Laroi (2008) report that a handful of other researchers have also found significant correlations between hallucination scales and the absorption scale. As a result of this work, I think that there may be different pathways to hallucination-like phenomena—some pathological, others less so.

Yet, I also wonder whether there is indeed something like “priming” psychosis, as John suggested. This would arise if there were some looseness in the relationship between psychosis and dissociation, which there appears to be. At least that's the way I interpret some of the phenomena that Romme and Escher (1993) report. If there is some kind of loose relationship, it would suggest that someone could have an absorption/dissociation response to trauma that would look psychotic; it might also suggest that an intensely absorbing negative imaginative experience (being pursued by demons, e.g.) might contribute to a vulnerable person exhibiting more psychotic-like symptoms.

How would we begin to pull this apart?

References:

Aleman A, Laroi F. Hallucinations: The science of idiosyncratic perception. Washington, DC: American Psychological Association, 2008.

Luhrmann TM. When God speaks back. New York: Knopf, forthcoming.

Luhrmann TM, Nusbaum H, Thisted R. The absorption hypothesis: learning to hear God in evangelical Christianity. American Anthropologist. 2010;112 (1):66-78.

Romme M, Escher S. Accepting voices. London: Mind, 1993.

Tellegen A, Atkinson G. Openness to absorbing and self-altering experiences (“absorption”): a trait related to hypnotic susceptibility. J Abnorm Psychol. 1974;83(3):268-77. Abstract

View all comments by Tanya Luhrmann

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Mary Cannon
Submitted 15 November 2010
Posted 15 November 2010

This beautifully written piece serves to excite interest in the fascinating epidemiology of schizophrenia. In our search for the “missing heritability” of schizophrenia, we don’t have to look too far for clues. There are many contained in this piece. It just requires some Sherlock Holmes-type deductive reasoning to put them all together now!

The realization that psychotic symptoms (or psychotic-like experiences) can be used as a proxy for schizophrenia risk has opened up new vistas for exploration (Kelleher and Cannon, 2010). For instance, the paper by Nuevo and colleagues will provide a fertile ground for testing ecological hypotheses on the etiology of schizophrenia—such as examining cross-national vitamin D levels (McGrath et al.) or fish oil consumption. Geneticists have yet to appreciate the potential value of studying such symptoms. Ian Kelleher, Jack Jenner, and I have argued in a recent editorial that the non-clinical psychosis phenotype provides us with a population in which to test hypotheses about the evolutionary benefit of psychosis genes (Kelleher et al., 2010; see also Nesse, 2004). This non-clinical psychosis phenotype gives rise to the possibility of moving beyond just-so stories into the realm of testable hypotheses.

References:

Kelleher I, Cannon M. Psychotic-like experiences in the general population: characterizing a high-risk group for psychosis. Psychol Med. 2010 May 19:1-6. Abstract

Kelleher I, Jenner JA, Cannon M. Psychotic symptoms in the general population - an evolutionary perspective. Br J Psychiatry. 2010 Sep;197(3):167-9.

Nesse RM. Cliff-edged fitness functions and the persistence of schizophrenia. Behav Brain Sci. 2004;27:862-3.

View all comments by Mary Cannon

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Jean-Paul Selten
Submitted 17 November 2010
Posted 17 November 2010
  I recommend the Primary Papers

With interest, I read Victoria Wilcox's summary of some thought-provoking papers published this year. It seems that schizophrenia, like cancer, has many different causes. I would like to point out that three of the studies (Zammit et al., 2010; Wicks et al., 2010; Schofield et al., 2010) support the idea that social defeat and/or social exclusion increase risk. The paper by Zammit et al. showed this in an elegant way: being different from the mainstream, no matter on what account, increased the subject's risk. The next step is to show that social exclusion has an impact on an individual's dopamine function. My group is examining this in young adults with an acquired hearing impairment, using SPECT.

References:

Zammit S, Lewis G, Rasbash J, Dalman C, Gustafsson J-E, Allebeck P. Individuals, schools, and neighborhood: a multilevel longitudinal study of variation in incidence of psychotic disorders. Arch Gen Psychiatry. 2010 Sep;67(9):914-22. Abstract

Wicks S, Hjern A, Dalman C. Social risk or genetic liability for psychosis? A study of children born in Sweden and reared by adoptive parents. Am J Psychiatry. 2010 Oct;167(10):1240-6. Epub 2010 Aug 4. Abstract

Schofield P, Ashworth M, Jones R. Ethnic isolation and psychosis: re-examining the ethnic density effect. Psychol Med. 2010 Sep 22:1-7. Abstract

View all comments by Jean-Paul Selten

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Chris Carter
Submitted 26 November 2010
Posted 26 November 2010
  I recommend the Primary Papers

I have been collecting diverse references for environmental risk factors in schizophrenia at Schizophrenia Risk Factors. These include many prenatal influences due to maternal infection, usually with some sort of virus, or immune activation with fever. Several animal studies have shown that infection or immune activation in mice can produce schizophrenia-like symptoms in the offspring. Toxoplasmosis has often been cited as a risk factor in adulthood.

Many of the genes implicated in schizophrenia are also involved in the life cycles of these pathogens, and interactions between genes and risk factors can together contribute to endophenotypes; for example, MICB and Herpes simplex infection have single and combined effects on grey matter volume in the prefrontal cortex.

Over 600 genes have been associated with schizophrenia. When these were pumped through a Kegg pathway analysis, the usual suspects (neuregulin, dopamine, and glutamate pathways, among others) figure highly in the list of pathways. Immune-related pathways are also highly represented, as are many pathogen entry pathways, including that for toxoplasmosis, which heads the list. Some of the more exotic pathways, for example, Chaga’s disease, should be considered as generic, as well as specific.

These Kegg-generated data suggest that there are strong relationships between genes and risk factors. Perhaps stratification of GWAS data in relation to infection could take this into account.

References:

Bortolato M, Godar SC. Animal models of virus-induced neurobehavioral sequelae: recent advances, methodological issues, and future prospects. Interdiscip Perspect Infect Dis . 2010 Jan 1 ; 2010():380456. Abstract

Carter CJ. Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. Schizophr Bull . 2009 Nov 1 ; 35(6):1163-82. Abstract

Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, Shier A, Sheikh S, Bailey K. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry . 1999 Mar 1 ; 4(2):145-54. Abstract

Fatemi SH, Pearce DA, Brooks AI, Sidwell RW. Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism. Synapse . 2005 Aug 1 ; 57(2):91-9. Abstractx

Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry . 2006 Mar 15 ; 59(6):546-54. Abstract

Prasad KM, Bamne MN, Shirts BH, Goradia D, Mannali V, Pancholi KM, Xue B, McClain L, Yolken RH, Keshavan MS, Nimgaonkar VL. Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia. Schizophr Res . 2010 May 1 ; 118(1-3):232-9. Abstract

Yolken RH, Torrey EF. Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry . 2008 May 1 ; 13(5):470-9. Abstract

Zuckerman L, Weiner I. Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res . 2005 May 1 ; 39(3):311-23. Abstract

View all comments by Chris Carter

Related News: What Can Hearing Loss Tell Us About Social Defeat, Dopamine Sensitization, and Schizophrenia?

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 13 October 2014
Posted 13 October 2014

This is a study in a cohort of hearing impaired subjects thought to be at risk for psychosis, compared to healthy volunteers. There are two findings of interest: 1) increased amphetamine-induced dopamine (DA) release, and 2) lack of a relationship between DA release and the reported increase in psychotic-like symptoms after amphetamine, although the nature of these symptoms and their magnitude are not clear, and whether they qualify as psychotic is also unclear.

Nevertheless, if we assume that patients indeed exhibited psychosis after amphetamine, the paradox of measuring increased DA, psychosis, and yet no relationship between these two measures is worth discussing. The authors suggest factors that may have prevented detection of this relationship, including a selection bias resulting in a cohort with minor impairment, limited sensitivity of the scale used, or lack of power.

We (Abi-Dargham et al., 2003) and others (Volkow et al., 1999) have previously shown that higher levels of DA release in healthy volunteers who do not exhibit psychosis correlate strongly with the subjective effects of stimulants. In these subjects, larger DA release does not translate into psychosis. We also have shown that lower DA release per se does not protect against psychosis, as patients who are comorbid for schizophrenia and addiction showed a psychotic response associated with the magnitude of amphetamine-induced DA release despite lower levels of DA release than those measured in controls (Thompson et al., 2013). These data suggest a complicated picture that goes beyond DA levels, where absolute levels of DA per se are not psychotogenic; rather, the interaction between D2 and DA is psychotogenic, and raises the possibility that a state of "supersensitivity" or "altered sensitivity" of D2 receptors to DA is a necessary requirement for psychosis, and this sensitivity relates to the emergence or exacerbation of psychosis.

We do not fully understand the cellular or circuit level effects of D2 stimulation that lead to psychosis, although it is clear now that excess striatal D2 stimulation during development can alter connectivity (Cazorla et al., 2014) as well as reward and cognitive functions (Simpson et al., 2010), and that D2 signaling plays a major role in long-term potentiation and synaptic plasticity in the frontal cortex (Xu and Yao, 2010). Recent genomewide association studies (GWAS) analyses have confirmed the relevance of the D2 receptor (Schizophrenia Working Group of the Psychiatric Genomics, 2014). It is important that we elucidate the intermediate steps leading from altered D2 function to the final phenotype of psychosis or schizophrenia, and its association with dysregulated dopamine.

References:

Abi-Dargham A, Kegeles LS, Martinez D, Innis RB, Laruelle M. Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naïve healthy volunteers: results from a large cohort. Eur Neuropsychopharmacol . 2003 Dec ; 13(6):459-68. Abstract

Cazorla M, de Carvalho FD, Chohan MO, Shegda M, Chuhma N, Rayport S, Ahmari SE, Moore H, Kellendonk C. Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron . 2014 Jan 8 ; 81(1):153-64. Abstract

Schizophrenia Working Group of the Psychiatric Genomics. Biological insights from 108 schizophrenia-associated genetic loci. Nature . 2014 Jul 24 ; 511(7510):421-7. Abstract

Simpson EH, Kellendonk C, Kandel E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron . 2010 Mar 11 ; 65(5):585-96. Abstract

Thompson JL, Urban N, Slifstein M, Xu X, Kegeles LS, Girgis RR, Beckerman Y, Harkavy-Friedman JM, Gil R, Abi-Dargham A. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry . 2013 Aug ; 18(8):909-15. Abstract

Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Wong C, Hitzemann R, Pappas NR. Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther . 1999 Oct ; 291(1):409-15. Abstract

Xu TX, Yao WD. D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex. Proc Natl Acad Sci U S A . 2010 Sep 14 ; 107(37):16366-71. Abstract

View all comments by Anissa Abi-Dargham

Related News: What Can Hearing Loss Tell Us About Social Defeat, Dopamine Sensitization, and Schizophrenia?

Comment by:  Ceren AkdenizAndreas Meyer-Lindenberg
Submitted 15 October 2014
Posted 15 October 2014
  I recommend the Primary Papers

Social defeat is defined as an "outsider status" (Selten and Cantor-Graae, 2005), or the experience of being excluded which is characterized by a subordinate position, stress, and isolation (Selten et al., 2013). Selten and coworkers have proposed that social defeat underlies several environmental risk factors for psychosis such as urbanicity and migration, and contributes to the impact of drug abuse and low intelligence (Selten et al., 2013). Even though the individual risk and resilience equation is complex and involves multiple levels on both the biological (such as genetics and epigenetics) and social environmental aspects (such as family and social network characteristics) (van Os et al., 2008; Akdeniz et al., 2014), perceived social threat, perceived discrimination, and low social status may plausibly result in a status of social defeat. This may lead to psychosis through dopaminergic hyperactivity in the corticolimbic system, which was previously shown in animal models of schizophrenia (Selten and Cantor-Graae, 2005; Selten et al., 2013; Tidey and Miczek, 1996). Yet before this paper, experimental evidence of dopamine sensitization in a socially excluded group of people was scarce.

The study by Martin Gevonden and colleagues addresses this by investigating the relationship between endogenous dopamine release after exposure to dexamphetamine sulfate and social exclusion in minorities (Gevonden et al., 2014). In their study, they selected a group of participants with severe hearing impairment (SHI) as "socially excluded minorities." Hearing impairment is a risk factor for psychotic experiences (Stefanis et al., 2006; van der Werf et al., 2010; Fors et al., 2013), which could be explained due to feelings of social exclusion and social defeat (Selten et al., 2013; Gevonden et al., 2014). They used single-photon emission computed tomography (SPECT) to examine the link between the dopaminergic activity, social exclusion, and amphetamine-induced psychotic symptoms. As they hypothesized, the participants with severe hearing impairment reported higher levels of loneliness and social defeat, and showed higher amphetamine-induced striatal dopamine release, along with stronger emotional responses to amphetamine. Even though the researchers did not find a relationship among social exclusion scores, changes in psychotic symptoms, and dopamine release per se, their findings offer a substantial step forward in being one of the first experimental studies showing a sensitized dopamine system in a population with increased risk for psychosis.

This observation fits well with experimental data on the neural processing of social stress in at-risk populations (Lederbogen et al., 2011; Akdeniz et al., 2014). These studies indicate that healthy individuals living in urban environments, as well as ethnic minorities with no history of psychiatric disorders, exhibit an alteration in neural functioning of the anterior cingulate cortex (ACC) during social stress (Lederbogen et al., 2011; Akdeniz et al., 2014). Taken together, these studies begin to establish a framework for a final common pathway for the development of psychosis related to environmental risk (Akdeniz et al., 2014). In this theoretical framework, schizophrenia risk resulting from an interaction of early stress and genetic risk factors may ultimately yield sensitization in the dopaminergic system and increased subcortical dopamine release through dysregulation of stress-sensitive regions of the cortex such as ACC.

Of course, much work remains to be done. In humans, it is hard to prove a causal relationship among social exclusion/social defeat, dopamine functioning, and increased risk for psychosis. Nevertheless, the work of Gevonden and colleagues elegantly shows that the study of high-risk populations such as minorities using experimental paradigms in order to investigate the neural underpinnings of the development of psychosis is highly promising.

References:

Selten JP, Cantor-Graae E. Social defeat: risk factor for schizophrenia? The British journal of psychiatry: the journal of mental science Aug 2005;187:101-102. Abstract

Selten JP, van der Ven E, Rutten BP, Cantor-Graae E. The social defeat hypothesis of schizophrenia: an update. Schizophrenia bulletin Nov 2013;39(6):1180-1186. Abstract

van Os J, Rutten BP, Poulton R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophrenia bulletin Nov 2008;34(6):1066-1082. Abstract

Akdeniz C, Tost H, Meyer-Lindenberg A. The neurobiology of social environmental risk for schizophrenia: an evolving research field. Social psychiatry and psychiatric epidemiology Apr 2014;49(4):507-517. Abstract

Tidey JW, Miczek KA. Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study. Brain research May 20 1996;721(1-2):140-149. Abstract

Gevonden M, Booij J, van den Brink W, Heijtel D, van Os J, Selten JP. Increased Release of Dopamine in the Striata of Young Adults With Hearing Impairment and Its Relevance for the Social Defeat Hypothesis of Schizophrenia. JAMA psychiatry Oct 1 2014. Abstract

Stefanis N, Thewissen V, Bakoula C, van Os J, Myin-Germeys I. Hearing impairment and psychosis: a replication in a cohort of young adults. Schizophrenia research Jul 2006;85(1-3):266-272. Abstract

van der Werf M, van Winkel R, van Boxtel M, van Os J. Evidence that the impact of hearing impairment on psychosis risk is moderated by the level of complexity of the social environment. Schizophrenia research Sep 2010;122(1-3):193-198. Abstract

Fors A, Abel KM, Wicks S, Magnusson C, Dalman C. Hearing and speech impairment at age 4 and risk of later non-affective psychosis. Psychol Med Oct 2013;43(10):2067-2076. Abstract

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 Jun 23 ; 474(7352):498-501. Abstract

Akdeniz C, Tost H, Streit F, Haddad L, Wüst S, Schäfer A, Schneider M, Rietschel M, Kirsch P, Meyer-Lindenberg A. Neuroimaging evidence for a role of neural social stress processing in ethnic minority-associated environmental risk. JAMA Psychiatry . 2014 Jun ; 71(6):672-80. Abstract

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