ICOSR 2009—Brain Structure Changes With Psychosis
As part of our ongoing coverage of the 2009 International Congress on Schizophrenia Research (ICOSR), 28 March to 1 April 2009, in San Diego, California, we bring you a meeting missive from researcher C. Anthony Altar, NeuroDrug Consulting.
13 May 2009. Way back in time, during the 1999 ICOSR in Santa Fe, New Mexico, poster reports of small decreases in brain area volumes and ventricular enlargement in schizophrenia were an eye-opener for this author and other attendees. That made for an exciting meeting as neurology and psychiatry collided. Five International Congresses and 10 years later, the 30 March 2009 symposium, "New Perspectives on Progression of Brain Abnormalities in Psychosis," reinforced these findings and elaborated upon brain loss in a number of dimensions, such as decreases in cortical thickness and gray and white matter losses, which are age-dependent and at least twice as great in schizophrenia patients as in control subjects.
Robert McCarley, Harvard University, described post-onset progression of brain abnormalities 1.5 years after the first schizophrenia episode. Remarkably, 7-10 percent increases in CSF/ventricular volume developed in this brief period. That period must be disproportionately severe for ventricular swelling, which might represent a sensitive biomarker, or an etiologic clue, for schizophrenia.
Interestingly, bipolar patients showed a 4 percent increase in neocortical gray matter slightly after disease onset. This increase may be due to medication, since patients who partially took their meds showed only a 2.5 percent increase, and gray matter loss was slightly greater in medication-non-compliant schizophrenia patients. So why not give valproate or other mood stabilizers to all psychotic patients? As McCarley described, the lack of correlation between the Brief Psychiatric Rating Scale (BPRS) and the 5 to 15 percent range of gray matter losses does not predict a clinical benefit from lessening gray matter loss.
The subgenual subdivision of the anterior cingulate cortex was the brain area most consistently atrophied in bipolar disease, while in schizophrenia, atrophy occurred throughout the anterior cingulate, both in subdivisions considered "affective" and "cognitive."
An 8-9 percent loss in gray matter over 1.5 years was found in the left temporal gyri in schizophrenia, with cortical atrophy predominant in the inferior and middle frontal gyri, the superior temporal gyrus (STG), left cingulate cortex, and the insula. Changes in the 30-item Mini-Mental Status Examination (MMSE) were most strongly correlated (+0.53) with changes in the left or right middle and inferior frontal gyrus. Decreases in volumes of bilateral Heschlís gyri were correlated with worsening of hallucinatory behavior (r = +0.6; p <0.001), and also with thinking disturbance and unusual thought content. Negative symptoms evaluated with BPRS were correlated with atrophy in left and right inferior frontal gyrus and in the insula (r = +0.8).
Many of the atrophied regions are hyperactive during hallucinations, McCarley said, possibly consistent with excessive glutamate signaling and a longer-term neurotoxic mechanism that produces atrophy.
Similar to McCarley, Hilleke Hulshoff Pol, University Medical Center, Utrecht, showed that the frontal and temporal cerebral cortices suffer the biggest decreases in schizophrenia. Similar volume losses do occur after about age 35 in healthy subjects, but in schizophrenia, Pol reported that these regions have been atrophying since age 25 and at a rate of about 2.5 ml/year. Gray matter losses accelerate to about 5 ml/year by age 70 in schizophrenia, and less in controls. White matter increases occur until midlife in schizophrenia, and then decrease. These losses exceeded those of healthy controls, but their etiology remains unknown.
High-resolution spatial measures of cortical thickness showed decreases over time in schizophrenia that were up to 10 times as great as in control subjects. The greatest losses were in the lateral neocortex, such as the temporal pole, occipital gyrus, left central gyrus, inferior frontal sulcus, post middle temporal gyrus, cuneus, and lingual sulcus. As McCarley had found, the poorer the functioning of the patients, the bigger were the losses over time.
Like the above-mentioned benefit of drugs in bipolar disease, Pol found that the higher the atypical dose, the smaller the loss in cortical thickness. This was also shown in a sub-analysis study for clozapine alone. However, the higher clinical doses of typical antipsychotics were associated with the greatest losses in cortical thickness. It was not clear how differences in socio-economic status, nutrition, or related health factors account for differences between those getting the inexpensive typical agents versus the more costly atypicals.
These results are in good agreement with a meta-analysis Pol conducted of six postmortem studies, in which patients showed a 0.5 percent brain mass loss/year, compared to only 0.2 percent brain loss/year for controls, resulting in 3 percent (70 ml) loss after 20 years for patients versus 1.5 percent (35 ml) for controls.
It appears that the shrinking superior temporal gyrus (STG) is a hot spot for converting to schizophrenia. Christos Pantelis, University of Melbourne, looked at the earliest stages of schizophrenia with a focus on the frontal cortex and STG. Losses here may have a relationship with disorders of language, hallucinations, and delusions, but no studies have examined the STG in non-psychotic individuals. Among individuals at "ultra high risk" for schizophrenia (UHR), 41 percent converted to psychosis by age ~20 years. They showed decreases in STG after the onset of illness but not at first examination, and these decreases correlated with the extent of delusions. Those who did not convert did not show decreases in STG mass. That was impressive.
In summary, these three presentations added considerable support for the enhanced and early loss in the frontal and superior temporal gyri, the anterior cingulate, and Heschlís gyri in schizophrenia.
A retraction of gray matter away from the skull was apparent during a four-year longitudinal study of normal adults (Sun et al., 2008). Pantelis showed with a subtraction image that enhanced shrinking is prominent in the frontal lobes in schizophrenia, and that this enhanced shrinking occurs along much of the rostral half of the cortex.
The STG is divided into areas most prone to atrophy in schizophrenia: Heschlís gyrus, which is primary auditory cortex; planum temporale (PT), part of the secondary auditory cortex; and the temporal pole, the most anterior portion of STG. It is likely that auditory hallucinations may result from this atrophy of important auditory areas of the brain, according to Pantelis.
Nitin Gogtay of NIMH published the highly impressive fMRI study on the cortical thinning that occurs from age four to 21 in humans (Gogtay et al., 2004). He discussed progressive gray and white matter abnormalities in childhood-onset schizophrenia (COS; before age 12). COS is, fortunately, rare (one in 40,000). Between ages 12 and 16, these children have a profound (p <0.001 to p = 0.00002) gray matter loss. By age 16, losses are greatest relative to normals, and are most prominent in parietal and temporal, prefrontal, and occipital areas, up to 10-fold more than in normal development.
In his presentation, Gogtay asked, and answered, five questions:
1. Does cortical thinning in COS continue with age? Answer: It clearly cannot do so in a constant manner. Greenstein et al., 2006, found that by the time COS children are 24 years old, further gray matter loss is limited to prefrontal and temporal regions after considerable losses have occurred in superior parietal areas.
2. What is the contribution of the heavy medication status of these children? Answer: Probably little, since patients with the alternative diagnosis of childhood psychosis/not otherwise specified (NOS) also get lots of medications from an early age, but do not go on to develop schizophrenia, and show very little—maybe even less—gray matter loss than healthy controls. Gogtay and colleagues found that a group of 32 COS children on clozapine had thinner cortices than 12 on olanzapine; the rate of loss from age 12 to 23 did not differ (same slope of decreases).
3. Is cortical atrophy genetically influenced? Answer: Maybe. The COMT gene val allele is associated with greater COMT enzyme stability, lower IQ, and poorer cognition. Healthy subjects with the val-val allele have more gray matter thickness decreases over time than val-met or met-met Gogtay et al., 2007. A study that Gogtay et al. conducted with the Weinberger/Straub group at NIMH also showed a positive, pairwise association between COS and three SNPs in the 5' upstream region of GAD1 (GAD67) and an association with increased frontal gray matter loss (Addington et al., 2005). This writer wonders whether patients with COMT-val-val and the GAD1 SNPs show the greatest neocortical atrophy.
4. Are trajectory differences limited to the cortex? Answer: No. COS patients show significantly steeper slopes of loss in all subregions of the cerebellum versus healthy controls.
5. Could the gray matter loss be due to white matter encroachment? Answer:
No. Both white and gray matter growth are highly compromised, based on analysis of 12 COS subjects (studied between ages 12-18). The annual growth rate of cortical white matter was less in COS subjects versus controls.
Our own International Congress on Schizophrenia Research organizer, Carol Tamminga, University of Texas, Southwestern, showed with fMRI that regional cerebral blood flow (rCBF) is increased in the anterior hippocampus of schizophrenia patients off medication, and that antipsychotic drugs reduce perfusion to normal levels in the hippocampus. Tamminga's group has found that hippocampal activation in response to novel pictures is markedly lower in untreated patients versus controls, but reaches normal levels with medication. A new method employing a contrast agent provided remarkably high-resolution MRI images; one had the feeling of looking at a brain tissue section rather than an MRI image. This additional method, in two schizophrenia subjects, showed an increased fMRI signal in CA3, and normalization with antipsychotic drugs.
The model that Tamminga and colleagues propose is that in schizophrenia, there is lower dentate granule neuron communication with the CA3 subfield of the anterior hippocampus. This elevates metabolic activity of the terminal areas innervated by the dentate neurons. This is consistent with decreases in metabolic gene expression in the dentate granule neurons of schizophrenia cases (Altar et al., 2005).—C. Anthony Altar.
Comments on Related News
Related News: A Tale of Two City Exposures and the BrainComment 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.
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
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Related News: A Tale of Two City Exposures and the Brain
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 Lederbogenís findings have implications for migrant research, the ďmigrant effectĒ 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).
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-Graae
Related News: A Tale of Two City Exposures and the Brain
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 Dunhamís 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, Mannheimís 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.
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
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Related News: A Tale of Two City Exposures and the Brain
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 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 individualís 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 userís 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.
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 Veling
Related News: A Tale of Two City Exposures and the Brain
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.
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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