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Baby Blues

Mother and foetus

Studies of environmental risk factors, and the specific timing of these insults, is beginning to provide a better understanding of why schizophrenia develops in some individuals and not others.

By Desiree Dickerson

A mother’s immune response to influenza and other infections during pregnancy increases the risk of schizophrenia in her unborn child.

Schizophrenia is a chronic and disabling mental illness characterised by disrupted thoughts, emotions and behaviours. While affecting approximately 1% of the population, it also places a significant burden on family and friends, and commandeers a disproportionate share of mental health services.

While it’s commonly known for its more florid symptoms – the hallucinations and delusions – often the more debilitating aspects of schizophrenia include difficulty in common cognitive functioning such as poor perception, attention, memory and motivation. These difficulties remain more persistent across time, and carry with them the poorest prognosis. Cognitive deficits, their causes and their treatment remain the least understood of the melee of symptoms that make up this mental illness.

Considerable research effort has been directed at understanding the causes of schizophrenia. It is now commonly accepted that there is a significant, albeit elusive, causal role for genes and heritability in this disorder. It has also become clear, however, that environmental factors, and the way they interact with the genetic component, play a critical role. The study of environmental risk factors, and the specific timing of these insults, is beginning to provide a better understanding of why the disorder develops in some individuals and not others.

Several environmental factors increase the risk of individuals developing schizophrenia. Typically these factors have the most impact while the brain is still developing during the critical prenatal and early postnatal stages of life. These factors include exposure to viral infection or other intrauterine hazards that activate the mother’s immune response system.

Maternal infection, such as influenza during pregnancy, is one such risk factor. Mednick and colleagues followed a population of children born following the 1957 influenza epidemic in Finland. They found that there was a two- or threefold increased risk of schizophrenia in the offspring of women who were in mid-gestation during the epidemic. This finding helps explain the seasonal increase in schizophrenia of individuals born in spring and summer months due to their mothers’ increased exposure to colds and flu during the winter and autumn seasons while pregnant.

Obviously these population-wide studies make it difficult to decipher whether those who developed schizophrenia in adulthood were actually exposed to infection. However, maternal sera studies are able to determine a mother’s exposure to infection by identifying antibodies to specific infectious agents in her blood during pregnancy.

In 2004, Brown and colleagues from the New York State Psychiatric Institute and Columbia University conducted a breakthrough study that compared blood samples from the mothers of children who later developed schizophrenia with blood samples from mothers whose children did not. These researchers were able to show that there was a three- to sevenfold increase in the likelihood of children going on to develop schizophrenia if their mothers had elevated levels of influenza antibodies during the first and second trimester.

While this is a notable increase, it is important to understand that this simply represents an increase in risk. Approximately 97% of offspring whose mothers are exposed to the flu do not go on to develop schizophrenia as adults.

Due to its prevalence in the general population, influenza has been the most widely studied pathogen. Other studies have, however, revealed that less prevalent infections and viruses including polio, herpes simplex virus and broncho­pneumonia are also associated with an increased risk for schizophrenia in the offspring of those infected.

This commonality in increased risk across various infections suggests that the risk of schizophrenia is not increased by a specific infection or virus per se. Rather, it appears that the mother’s immune response to the infectious agent plays a key role.

During a maternal response to infection, the body produces a number of signalling molecules called cytokines that are critically involved in the immune response. These cytokines are able to enter the placenta, and are capable of permeating the blood–brain barrier. These same cytokines are also critical signalling molecules, normally involved in brain development, but it appears that when levels are elevated they may trigger aberrant processes that alter the development of the brain during this critical stage of life.

So how does this early disruption in brain development result in the diverse array of symptoms observed in schizophrenia, and why do these symptoms often not become apparent until early adulthood?

Some evidence suggests that a disruption to normal brain development in utero results in the abnormal development of not only brain cells but the connectivity between populations of cells as well. These disruptions lead to changes in brain structure, and we believe they lead to a subsequent breakdown in communication within and between several different brain regions. This disruption in communication is likely to have considerable impact on brain function and may underlie many of the symptoms of schizophrenia.

These early changes have significant flow-on effects, upsetting not only initial brain development but also the subsequent neurodevelopmental trajectory of these cell populations. As a result, many of the effects of these changes do not become apparent until adolescence, when another marked rewiring of brain connectivity occurs. The further disruption in connectivity that occurs during this rewiring process may explain the typical post-pubertal onset of schizophrenia and underlie many of the symptoms.

One prominent hypothesis seeks to explain how a disruption in communication between cell populations underlies the diversity of symptoms seen in schizophrenia. In a recent review of the research, Peter Uhlhaas and Wolf Singer of the Max Planck Institute for Brain Research explained that the breakdown in communication could be specifically tied to the mechanisms by which neurons in the brain can synchronise with each other over long distances.

We know that effective communication between brain regions is necessary for the integration and binding of related information that is being processed in different regions of the brain. This integration is thought to occur through the coordinated firing of cells across widespread brain regions.

Synchrony of firing in the brain can be likened to what happens when a crowd performs a Mexican wave at a football game. In order for the wave to occur, the individuals in the crowd need to act in a coordinated manner, all standing up and sitting down at the appropriate time. In an analogous manner, cells in the brain need to coordinate their activity in order to produce a meaningful response.

In the brains of individuals with schizophrenia, however, the coordination of neural activity is disrupted. Here, the neurons behave like a crowd where every individual is trying to perform a Mexican wave independently and with poor timing. As a result, the wave doesn’t form and no coherent message is conveyed.

So, what evidence do we have that disrupted synchrony underlies the variety of symptoms that people with schizophrenia experience? Well, a number of the cognitive deficits observed in schizophrenia have been associated with disrupted synchrony. These include changes in perception, memory and cognitive control.

One example is illustrated by Peter Uhlhaas and colleagues work on the perception of Mooney faces. These degraded, two-tone pictures of human faces are only perceived as faces when the different components of the image are linked to form a coherent representation of the face. The moment of recognition is associated with a rapid increase in synchrony observed in the EEG of healthy individuals. This reflects the onset of synchronous, coordinated neural firing and may explain why normal perception of the face often comes about suddenly as an “ah-ha” experience.

However, individuals with schizophrenia have difficulty perceiving Mooney faces, suggesting that the neural binding of the various components of the image is dysfunctional. To further support this notion, this deficit in perception is correlated with reduced EEG synchronisation.

Interestingly, while some of the negative and cognitive symptoms of this brain disorder may be associated with reductions in synchrony, transient abnormal increases in synchrony may possibly underlie some of the reality distortions experienced by schizophrenics, such as hallucination and delusions.

The evidence suggesting there is a disruption in both local and long-range synchronisation in people with schizophrenia has been replicated by several research teams working with different patient populations. In these studies, the disruptions are observed by recording EEG activity from outside of the skull. However, the spatial resolution of these methods is relatively poor, making it difficult to know exactly what is different about the functioning of these brains at a cellular level.

In order to determine what neural mechanisms underlie this disorder we need to be able to look at brain function with a higher spatial and temporal resolution. To do this, researchers commonly turn to animal models of the disorder.

Alongside Prof David Bilkey and fellow PhD candidate Amy Wolff in the Department of Psychology at the University of Otago, New Zealand, we recently sought to explore these disruptions in synchrony in rats using prenatal immune activation as the triggering factor. We initiated a single immune response in rat mothers during pregnancy, and then investigated the development and behaviour of the offspring with a specific focus on synchrony between brain regions.

We found that a marked breakdown in synchronised activity occurs in adult offspring in response to exposure to a single maternal immune response in utero. Our findings showed a significant impairment in the ability of two key brain regions, the hippocampus and prefrontal cortex, to coordinate their firing compared with rats that were not exposed to the mothers’ immune response.

What is startling is that this single immune response in the mother, which has immediate effects that seem localised to a period of just 24–48 hours, had profound effects on brain development, function and behaviour of the offspring. These results now provide us with a platform from which we can explore the neural mechanisms that underlie disrupted synchrony, and the role that prenatal infection plays.

So, what does a schizophrenic rat look like, and is it relevant to the human condition? While descriptions of hallucinations and delusions require that the subject has a verbal capacity and are therefore difficult to study in an animal model, cognitive deficits play a significant role in schizophrenia and remain one of the most poorly understood and subsequently poorly treated aspects of the disorder.

Several research teams have demonstrated that prenatal exposure to the maternal immune response in rodents results in changes in cognitive processing that mirror what we see in human individuals with the disorder. These cognitive changes include deficits in working memory, behavioural and cognitive inflexibility, and changes in social interactions. The model also reproduces other changes that characterise the disorder, such as changes in neurotransmitter systems and structural changes such as enlarged ventricles.

Being able to mimic these effects in animals allows us to explore the neural changes that underlie the pervasive symptoms of this disorder. In doing so we hope to better guide the elusive search for interventions that would prove effective in the treatment of this disorder, and ultimately identify measures that may prevent or alleviate the onset of symptoms in the first place.

Desiree Dickerson is a PhD candidate in the Department of Psychology at the University of Otago, New Zealand.