NeuRA Magazine #26

Feature story

SCHIZOPHRENIA BREAKTHROUGH

Professor Cyndi Shannon Weickert has been on a quest to determine the causes of schizophrenia for over 30 years. She has made a series of breakthrough discoveries that will have a global impact in the way we conceptualise the biological basis of this major mental illness.

Importantly, her recent work is poised to transform the treatment of those with schizophrenia. Her latest discovery has identified immune cells from the blood found at increased levels in the brains of a substantial subset of those with schizophrenia. These cells were not known to be in proximity to neurons and the identification of these culprit cells suggest they may play a role in disease development or decline associated with schizophrenia that was never previously considered.

The discovery will transform global schizophrenia research and open new avenues for developing targeted therapies.

Professor Shannon Weickert says researchers have long thought there were three main cellular types that could contribute to the mystery of what caused schizophrenia with the primary pathology residing in the neuron, the glia, or even the endothelial cells. Her research at NeuRA has identified a fourth player – the macrophage, a type of white blood cell, which was seen in the brain tissue of people with schizophrenia who had high levels of inflammation.

“What we believe is the glial cells are ‘angry’ and are emitting distress signals and changing the surface of the endothelial cells so that these can catch and reel in monocytes, a type of white blood cell, from the bloodstream and into the brain tissue,” says Professor Shannon Weickert.

These monocytes then transform into macrophages once inside the human brain. The macrophage, which means ‘big eaters’ in Greek, can be thought to be good as these cells digest cellular debris and microbes. However, these cells have a dark side as they can destroy healthy tissue when they go rogue.

“Through the microscope I saw massive amounts of these clusters of small brown-coloured cells packed along the blood vessels in the brain tissue, close to the neurons,” Professor Shannon Weickert says.

“Before we thought it was primarily the cells that resided in the brain that were causing schizophrenia and for over a century people have been focusing on neurons and glial cells, but we’re the first to show these immune cells are in the brain, in proximity to the neurons and positioned to do damage.”

The presence of immune cells in the brain tissue can produce inflammatory factors to further drive the neuronal damage in schizophrenia. Immune cells would only enter the brain to conduct immune surveillance, then may die out or re-enter the bloodstream. In schizophrenia, they may over-react and cause collateral damage.

Professor Shannon Weickert said these findings suggest schizophrenia researchers should be working with immunologists to develop treatments which target the immune system.

One in every 100 Australians lives with schizophrenia. No single cause for schizophrenia has been identified, and this has prevented the development of a cure. The current treatments for schizophrenia are designed to suppress these symptoms and do not target the cause of the disorder. These drugs only partially relieve symptoms and can produce unwanted side-effects.

“This opens whole new avenues for therapy. We may be able to find a way to block entry of these immune cells into the brain to see if that’s going to seriously thwart symptoms and improve brain function for people with schizophrenia,” says Professor Shannon Weickert. The inflammation observed in 40 per cent of the study sample, indicates future therapies could benefit a large portion of the community.

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FEEL THE BUZZ IN THE AIR? US TOO.

Exploring the electrophysiology and heritability of wellbeing and resilience

The majority of adults without a mental illness still experience poor mental health, indicating a need for a better understanding of what separates mental wellness from mental illness. One way of exploring what separates those with good mental health from those with poor mental health is to use electroencephalography (EEG) to explore differences in brain activity within the healthy population. Previous research has shown that EEG measures differ between clinical groups and healthy participants, suggesting that these measures are useful indicators of mental functioning. Miranda Chilver’s current project aims to examine how different EEG measures relate to each other and to test if they can be used to predict mental wellbeing. Furthermore, she hopes to distinguish between EEG markers of symptoms including depression and anxiety, and markers of positive symptoms of wellbeing to better understand how wellbeing can exist independently of mental illness. This will be done by obtaining measures of wellbeing and depression and anxiety symptoms using the COMPAS-W and DASS-42 questionnaires, respectively. Because EEG measures and mental wellbeing are both impacted by genetics as well as the environment, Miranda will also be testing whether the links found between EEG activity and Wellbeing are driven primarily by heritable or by environmental factors. This information will inform the development of future interventions that will aim to improve wellbeing in the general population. To achieve these goals, the project will assess the relationship between EEG activity and wellbeing, and between EEG and depression and anxiety symptoms to first test whether there is an association between EEG and mental health. Second, the heritability of the EEG, wellbeing, depression, and anxiety will be assessed to determine the extent to which these variables are explained through heritable or environmental factors. Finally, a model assessing the overlap between the heritable versus environmental contributions to each measure will be developed to assess whether genetics or environment drive the relationship between EEG and mental health. This project is based on a sample of over 400 healthy adult twins from the Australian TWIN-E study of resilience led by Dr Justine Gatt. This research will pave the way for improved mental health interventions based on individual needs.
PROJECT