Neurological correlates of environmental factors have been less studied than genetic make-up. But we have now established that the link between urbanisation and schizophrenia is associated with differences in brain structure and function. Such research and its implications are explored in an in-depth feature on the Lundbeck Institute Campus.
People who spend their early life in a city are 2-3 times more likely to develop schizophrenia than those born in the countryside.1 Can this consistent epidemiological observation be linked to measurable neurological features?
In an important example of “social neuroscience”, functional magnetic resonance imaging (fMRI) was used to investigate potential differences in social stress processing between urban and rural inhabitants.2
Growing up in a city had a significant impact on activity in the perigenual anterior cingulate cortex, a region important in regulating the activity of the amygdala and the processing of negative affect. Other parts of the brain seemed unaffected by urban versus rural background, and differences in function were specific to cognitive processing involving stress.
Differences in brain function and structure may relate to city dwellers’ greater risk of schizophrenia.
In a second study, differences in brain structure were found when city dwellers were compared with others.3 Neuroimaging found an inverse correlation between being born or raised in an urban environment and grey matter volume in the right dorsolateral prefrontal cortex and perigenual anterior cingulate cortex. These findings are particularly interesting since research has associated altered structure in the prefrontal cortex with early life stress and, in later life, with schizophrenia.
Insights into prevention
Given that humanity worldwide is flocking to live in cities, the psychiatric implications of such structural and functional differences could be profound.
Psychiatric and neurological disorders cause enormous distress to the millions who suffer from them, and to the millions more who love and care for those directly affected. For wider society, the burden is primarily economic: in Europe alone, the cost of brain diseases has been estimated at 800 billion euros per year. Whether we consider the problem in terms of personal suffering or economics, there is a pressing need for interventions to reduce its impact. These should encompass prevention as well as treatment, and consider genes, environment, and their interaction.4
Environment alters the brain
One approach to prevention is to investigate what environmental risk factors look like at the level of the brain. We are familiar with imaging studies that investigate the correlates of genetic risk factors. Conceptually, this approach is equally valid as a means of helping us understand how the effects of social isolation or urban environments or migration are mediated.
Imaging reveals the effects of genes on brain structure and function. It can equally well show the effects of urbanisation or low socio-economic status.
In one important fMRI study, healthy men and women who perceived themselves as having a low social status compared to their peers had significantly less grey matter volume in the anterior cingulate cortex even after data had been adjusted for demographic factors.5
Being from a migratory background has also been linked to altered brain function on fMRI, especially when people are processing information to do with social status or stress, such as feeling they are being discriminated against.6 It is not surprising that the perigenual anterior cingulate cortex was again involved. Intriguingly, this study suggests the impact of being from a migratory background is more evident in the brain function of men than of women.
Interplay of genes and environment
Now we can sequence the entire genome for a thousand dollars, the temptation to focus on genetic factors underlying mental illness is especially strong. But we should not be seduced into thinking that a small number of easily identifiable genetic variants will unlock the secrets of schizophrenia or major depression. A few rare variants have high impact, but the common variants are low in impact.
Furthermore, the influence of genes is probably modulated by intermediate events that affect downstream risk, rather than by direct contribution to pathogenesis. And the genetic heterogeneity between individuals is vast.
When thinking about prevention, the difficulty is in unravelling the relative contributions of heredity and environment. These are likely to differ according to the nature and severity of the disease. Do genetic factors play a greater part in schizophrenia or bipolar disorder than in depression? Within major depression, does the genetic component become more pronounced with increasing severity of disease?
Although we speak of nature versus nurture, the reality is that we have an interplay of these two influences. There are genetic factors that increase susceptibility to certain environmental events. And epigenetics teaches us that environmental factors modulate gene expression. So it should be no surprise that there are strong environmental influences in highly heritable disorders – even though at first sight that seems paradoxical.4
