Of squiggly lines and schizophrenia

Dr Jason Bruggemann is investigating new ways of identifying children at risk of developing schizophrenia.

I am relatively new to schizophrenia research, so I was surprised by the sheer diversity of people I have met who have schizophrenia – men and women from a wide variety of backgrounds with distinct personalities who don’t conform to any particular stereotype. While the disease affects them in different ways, however, they have all described the significant challenges that schizophrenia has posed for them and their families.

Schizophrenia is a neurodevelopmental disorder that typically begins during late adolescence or early adulthood. Healthy development during adolescence involves large-scale reorganisation and restructuring of the brain, including changes to the delicate excitatory/inhibitory balance of the brain’s neurotransmitter systems and underlying brain structure. This process seems to go awry for people with schizophrenia. Environmental factors like stress also appear to contribute to the onset of the disease.

Dr Jason Bruggemann

Dr Jason Bruggemann holds an EEG ‘net’, made up of wires and electrodes.

We know that early diagnosis and treatment can significantly improve long-term outcomes and help minimise the damaging effects of schizophrenia. Hence, current research is focused on potential ways of identifying children at risk of developing schizophrenia. Our colleague Dr Kristin Laurens and her team from Kings College London are currently evaluating a combination of factors as potential early markers, including subtle peculiarities of speech and movement, lower IQ and poorer academic achievement, disturbances in social, emotional, and behavioural functioning, and subclinical psychotic-like experiences such as occasionally hearing voices that nobody else can hear.

At NeuRA, we are conducting research into another potential marker of schizophrenia risk called the mismatch negativity (MMN). The MMN is an index of the brain’s electrical response to changing patterns of sounds. It’s derived from a measure of the electrical activity of the brain called the electroencephalograph (EEG), more commonly known as ‘brainwaves’. The raw EEG signal may look like just a bunch of squiggly lines running across the computer screen but, once analysed, the resulting data can help us better understand patterns of normal and abnormal brain function.

An example of a raw EEG

The squiggly lines of a raw EEG read out.

In adults with schizophrenia, the size of the MMN has been related to disease severity, ability to function in the wider-community (functional outcome), and grey matter volume loss in the frontal and temporal brain regions. The MMN is usually smaller in adults with chronic schizophrenia compared with typical individuals. In light of this, we recently investigated whether a group of children who may be at increased risk of schizophrenia (based on having some of the risk factors described above or having a first-degree relative with schizophrenia) also have a smaller MMN relative to typically developing children.

Our results showed that although the MMN exhibited by the children at risk of schizophrenia was unlike that of their typically developing peers, it also differed from the smaller MMN observed in adults with schizophrenia. In fact, we found a relative increase in the MMN over the frontal brain region, rather than a decrease!

“If we can reliably identify at-risk children then perhaps we can reduce the burden of schizophrenia for future generations.”

It was difficult for us to interpret this result in the context of what we know about MMN in adults with chronic schizophrenia. We looked at MRI data from an overlapping sample of children, which revealed differences in grey and white matter volume in the same brain regions that produce the electrical activity seen in the MMN. Also, the developmental literature indicates that the MMN tends to be larger in young children compared to adults. This has led us to speculate that perhaps the ‘at-risk’ children are on a different developmental trajectory than their peers. It is possible that this unusual MMN result may reflect the complex interplay between developmental changes and the factors placing these children at higher risk of developing schizophrenia.

It’s essential to conduct long-term follow-up of these potentially at-risk children to establish who goes on to develop schizophrenia and how their MMN changes as they mature. This follow-up work, being completed by our colleague Dr Kristen Laurens, will tell us whether the increased MMN we found in this study may indeed be a useful way of identifying children at risk of developing schizophrenia.

The unique people with schizophrenia that I have met currently live their lives as best they can despite the challenges raised by this condition. If we can reliably identify at-risk children then, with appropriate early treatment, perhaps we can reduce the burden of schizophrenia for future generations.

Is high cholesterol putting your brain at risk?

If you want to reduce your risk of Alzheimer’s disease, says Dr Scott Kim, be mindful of your cholesterol levels.

Notwithstanding the recent debate in the media, most of us understand that high cholesterol is harmful to your health because it can negatively affect your heart and arteries.

What you may not know, however, is that high cholesterol can also affect your brain; specifically, there’s growing evidence leading neuroscientists like me to suspect that high cholesterol may increase your risk of developing Alzheimer’s disease.

NeuRA's Dr Scott Kim is investigating the role of cholesterol in Alzheimer's disease

NeuRA’s Dr Scott Kim is investigating the role of cholesterol in Alzheimer’s disease

The growing evidence

Why do we suspect this? Firstly, we know that factors that increase your risk of developing heart disease – specifically, high blood cholesterol levels but also high blood pressure and a history of stroke and diabetes – also increase your risk of developing Alzheimer’s disease. Furthermore, there’s evidence that taking cholesterol-lowering drugs, called statins, decreases your likelihood of developing Alzheimer’s disease.

Another red flag is data from several animal studies suggesting a link between cholesterol and the production of amyloid-beta, the protein that accumulates abnormally in the brains of people with Alzheimer’s disease.

So how is it that high cholesterol increases your risk of Alzheimer’s disease? At NeuRA, we are trying to answer that question.

Cholesterol in the brain

Cholesterol is abundant in our brains; although the brain makes up only two per cent of body’s weight, it contains nearly a quarter of all the body’s cholesterol stores. Cholesterol has important jobs in the brain such as storing energy, acting as a structural component of the cell membrane and acting as a signalling (communication) molecule.

Cholesterol is transported out of cells by transporter proteins, and it’s these proteins – known as ABC transporters – that are the main focus of our research.

Our work has shown that ABC transporters are key regulators of how much cholesterol is inside brain cells. Just recently, we demonstrated that deleting a specific ABC transporter, called ABCA7, in a mouse model of Alzheimer’s disease caused significant increases in amyloid-beta levels. We suspect that the ABCA7 transporter facilitates the clearing of amyloid-beta from the brain. This is direct evidence that ABCA7 is crucial in the development of Alzheimer’s disease.

It’s important to understand what’s happening at a molecular level in Alzheimer’s disease so that we can discover new targets for drug treatments. By understanding the role of ABCA7, we may be able to learn how to inhibit the build-up of amyloid-beta protein and therefore provide potential therapeutic avenues for the treatment of Alzheimer’s disease.

In the meantime…

In the meantime, what can you do in terms of cholesterol to decrease your risk of developing Alzheimer’s disease?

Although controlling cholesterol levels in the brain by altering what you eat is generally very difficult, you can lead a healthy lifestyle and reduce foods in your diet that contain high levels of saturated fat. This will help to reduce the risk factors associated with Alzheimer’s disease that I mentioned earlier on.

Apart from healthy eating and regular exercise, keeping your brain active is also helpful. If playing games, writing a letter or simply interacting with others sounds easy (and it is!), then don’t delay – as the saying goes, ‘use it or lose it’!

The sensitive topic of brain donation

Brain donor program coordinator Lauren Bartley says while it can be difficult to talk to people about brain donation, it’s for a very important cause.

When I first began recruiting to the brain donor program at NeuRA and the Sydney Brain Bank, I found it difficult to broach such a sensitive topic with the participant and their family members. After all, how do you ask someone you have met just briefly if you can have access to their brain tissue after they pass away?

This is a discussion I’ve had to have with all our research participants – and one that I no longer shy away from. I know that every brain is valuable and have seen firsthand that every donation brings us closer to understanding more about dementia.

Sometimes there can be confusion over whether the tissue we collect will be transplanted into another human (which it’s not); other times, I’ve found that participants think their brains won’t be useful because of their cognitive impairments.

Lauren Bartley is a brain donor program coordinator at NeuRA.

It’s actually brain tissue from people with these very impairments that is helping scientists at NeuRA understand why proteins that cause dementia begin to deposit in some people’s brains and not others, and how this occurs.

In some cases, it’s difficult for a neurologist to determine if the patient is suffering from early onset Alzheimer’s disease (AD) or frontotemporal dementia (FTD). While clinically these dementia syndromes can appear similar, the brain tissue pathology is quite different. Looking at brain tissue has been essential for understanding the differences in pathology between AD and FTD.

Thanks to people who have donated their brain tissue in the past, we now know that the brain tissue of people with Alzheimer’s disease is marked with plaques formed by the beta-amyloid protein and tangled accumulations of the tau protein.

The tau protein also accumulates in frontotemporal dementia, depositing not in tangles but as inclusions inside brain cells called Pick bodies (FTD is also known as Pick’s disease). Some people with FTD also have pathological inclusions of other proteins such as TDP-43 or FUS.

“This is at the heart of what’s driving our research: we need to come up with new ways of accurately diagnosing dementia while a person is still living.”

Because of the heterogeneity of pathology in FTD, it’s impossible to predict which protein is responsible for the illness with the clinical tools we currently have at our disposal.

I can recall many times when participants were only found to have evidence of motor neurone disease (in addition to their dementia) during the autopsy process. There have been instances where we found participants who had been diagnosed with FTD actually had Alzheimer’s disease pathology and vice versa.

If we had known the true cause of their illness during life, they may have been able to access therapies or medicine to reduce the impact of their symptoms. This will become increasingly important as new therapies for dementia syndromes become available.

This is at the heart of what’s driving our research: we need to come up with new ways of accurately diagnosing dementia while a person is still living.

Helping us improve diagnosis during life is one of the reasons why brain donation is invaluable, and it’s why I’d like to thank each and every brain donor who I’ve had the privilege of working with at NeuRA.

 

More information about brain donation

While I am not able to accept brain donations from the general public, we do accept brain donations for AD and FTD research from people who have participated in research at our clinic. There are also circumstances where people who we have not seen in our clinic but have had a diagnosis from a neurologist/geriatrician and previous brain imaging (preferably MRI) can also be enrolled.

After the Sydney Brain Bank at NeuRA has finalised the report identifying the protein that caused the dementia, I send this report to the families and clinicians. The tissue donation is then used in ethically approved projects performed by medical researchers across Australia and the world.

If you are interested in finding out more about brain donation for medical research into AD and FTD, please contact me at frontierbiomarkers@neura.edu.au

Restraining children in cars: moving in the right direction

NeuRA’s Dr Julie Brown has looked at the impact of the 2010 NSW child restraint legislation – and has good news.

I am so happy that we finally have some good news to share with parents, carers and those advocating for change to reduce child injury – it seems there have been positive changes in the way children are travelling in cars since the introduction of new laws requiring appropriate restraints for children up to at least age seven.

Australian parents have always been really good at getting their children into restraints. The old ‘What about me?’ and ‘Click Clack Front and Back’ media campaigns that were everywhere in NSW a few decades ago really seem to have got the message through. By the late 1990’s we had one of the highest rates of restraint use anywhere in the world, with more than 98% of children using a restraint whenever they travelled in a car. While this high restraint use worked to reduce rates of injury in children in car crashes significantly through the 80’s and 90’s, in 2003 we were still seeing alarming numbers of children killed and injured in crashes – despite the use of restraints.

NeuRA’s Dr Julie Brown (right) and PhD student Lauren Meredith (left) with their crash lab research equipment.

My colleague Lynne Bilston and I began studying in detail crashes where restrained children had been injured and we soon realised that most of the serious injury was happening when children were using restraints designed for older children and adults, or were not using their restraints in the right way. We then went out and looked at what people who weren’t in crashes were doing – observing and surveying more than 500 children across the state. And we found we had a big problem. Only about a quarter of the children we saw were what we would call optimally restrained. That is, they were in the right sort of restraint for their age (appropriately restrained) and using the restraint in the right way (correctly restrained).

If we just looked at the type of restraints they were in, we saw that about half of all children were in the right sort of restraint for their age (appropriately restrained). And if we looked at how they were using the restraint (ignoring whether they were appropriately restrained), we saw that about half were using the restraint in the right way (correctly restrained).

We also did a lot of other research to try and understand the barriers parents were facing in getting their child restraint practices right. I was struck by the fact that although parents really wanted to keep their children safe, especially in cars, there was just so much confusion out there about how best to do this. I think the new legislation and accompanying media campaigns helped reduce this confusion because they spelled out exactly what sort of restraint a child should use depending on the child’s age.

“This is really good news… we will now have less serious injury among children in crashes.”

Working with our colleagues at the George Institute for Global Health, we had the opportunity to go back out in the field and observe children in cars across western Sydney about 3 months after the introduction of the legislation. We were really excited to see that among preschool aged children, appropriate restraint use had increase by 20%, and that in our post legislation sample, children were more than twice as likely to have been in an appropriate restraint than the children in our pre-legislation sample. This is really good news because this sort of increase in appropriate restraint use will likely mean that we will now have less serious injury among children in crashes.

There is obviously still more work to do – to get appropriate restraint use up as high as possible, and also to revisit the design of child restraint systems to make them easier to use correctly. Having said that, these latest results are encouraging, and tell us we are moving in the right direction.

For information about our research into keeping children safe in cars visit us here.

Books For Brains

The NeuRA Foundation is looking to raise funds to support brain research via ‘Books for Brains’, which kicks off in October.

Sometimes an idea just ‘feels right’, and so it was when we conceived the idea for NeuRA’s Books for Brains event.

From the outset, it was clear to us that people who enjoy reading intuitively know that reading is good for their brains. And so the idea that people in book clubs would take a lively interest in the frontiers of knowledge about the brain, and how it works, was not a stretch.

Books for Brains is a NeuRA initiative calling on book clubs around Australia to put their heads together in the month of October and read a book with a focus on the brain and mind.

NeuRA’s Judy Dixon

The concept has received praise from a number of bestselling authors.

Norman Doidge, author of this year’s featured book, The Brain that Changes Itself, says:

“At this moment, while Australian neuroscience researchers are ‘punching well above their weight’ and making huge breakthroughs, so many Australians display an open-minded wonder about the brain. That’s why NeuRA’s initiative, Books for Brains, is such a wonderful idea. What could be more enlivening than digesting the meaning of new findings, which can so illuminate our lives, by getting together and discussing them within your book club – with the helpful, up-to-date comments on offer through Books for Brains from leading Australian researchers at NeuRA.

Ruby Wax, comedian and author of 2013’s bestseller, Sane New World, a story about what is it like to live with depression, says:

“The problem is in us; in our brains. The conflict is within ourselves. It’s those voices battering us and we project it out on the world. Inside our heads there is always war. I totally support NeuRA’s Books for Brains – unless we learn what’s in our heads, we will never resolve our own issues and the world’s.”

Peter FitzSimons, much-loved Australian author and social commentator, says:

 ”Books for Brains is a wonderful initiative to raise awareness about an issue growing in importance with every passing year. Once, while playing rugby in France, I was so badly eye-gouged I actually saw my own brain, and was satisfied it was big. But as time has gone on, I have become aware that none of us can take brain health for granted, and I fully support all efforts to make Australians aware of that very fact.”

Through NeuRA’s Books for Brains, we hope to encourage your book club to think about the importance of brain research. We want to encourage you to discuss one of our suggested books and hope that you find it stimulating, uplifting, funny or even moving.

To register and access this year’s book list, visit us here.

Can pain change our brain ‘maps’?

NeuRA researcher Flavia Di Pietro is investigating the maps in our brain and the role they might play in the pain experience.

There is a region of the cortex – the outer layer of your brain – that contains a precise and organised map of your entire body. Here, every part of your body surface is represented by a network or ‘column’ of neurons that is activated when that body part is touched or stimulated in some way.

This region, known popularly as the sensory homunculus and to scientists as the primary somatosensory cortex (S1), is a key site of research in the chronic pain disorder known as Complex Regional Pain Syndrome. CRPS is the focus of my research at NeuRA.

Flavia di Pietro is investigating the brain’s role in chronic pain – specifically Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is a disorder, usually of the hand or wrist, characterised by ongoing pain and dysfunction across several body systems. We don’t know what causes CRPS but the most common predisposing injury is a wrist fracture. Some of the signs and symptoms are altered sensitivity, muscle weakness, and changes in hair and nail growth. Intriguingly, patients with CRPS can also have altered perceptions of their affected limb, for instance they often neglect it (that is, they feel it is no longer theirs) or sometimes they perceive it to be bigger than it is in reality.

Using many different neuroimaging technologies, researchers around the world are currently investigating the brain’s role in CRPS. S1 is one of the regions most talked about, given what we know about its role in body representation and perception. Studies have investigated the function of S1 – or more specifically, the representation of the CRPS-affected hand in S1 – by stimulating the painful hand (e.g. with light touch or electrical stimulation) and then looking at the S1 activation that results, i.e. the coloured ‘blob’ on the brain scan.

Past studies have demonstrated that the S1 area representing the painful part re-organises; in fact the ‘blob’ has been shown to shrink in size. These findings are compelling given the interesting perceptual problems that a lot of CRPS patients have. These findings have contributed to innovative and non-invasive therapies for CRPS.

“Intriguingly, patients with CRPS can have altered perceptions of their affected limb.”

That S1 reorganises with pain, and the S1 representation of the CRPS-affected hand is smaller, is widely assumed and accepted. We wanted to know the true state of the evidence; had all the studies come to the same conclusion? We embarked on a systematic review. This involves trawling through the literature to find all the studies that have addressed this question of S1 function in CRPS, pooling their findings and also assessing these studies for their quality. In research this is a great way to get a definitive answer to a specific question.

What did we find? We found consistent evidence that the representation of the CRPS-affected hand in S1 is smaller than that of the unaffected hand, and that of healthy pain-free controls. But the evidence isn’t as strong we thought it would be: we were surprised to find so few studies, recruiting a low total number of subjects, and also a high risk of bias in their findings (namely in the ways they did their statistical analyses and reported their findings).

Our review is important because now we know what’s been investigated and what still needs to be done. We’re not sure what the shrunken hand representation in S1 might mean. We’re not sure if it causes pain or the other way around, or neither of these. But in light of the clinical integration of new therapies that theoretically target this reorganisation in the brain, it’s important that we better understand the brain’s role in CRPS. Here at NeuRA we are currently doing our own investigation into S1 function in CRPS, and the methods we are using have been informed by the findings of our systematic review.

Lost and forgotten: improving our diagnosis of dementia

Accurately diagnosing conditions of the brain such as dementia can be very challenging; there are no easy blood tests or scans that tell us without a doubt what a patient is suffering from. Diagnosis involves observing the patient’s symptoms and performing a number of clinical tests such as testing memory function, and depends on a good understanding of what symptoms differentiate it from other similar diseases.

Sicong Tu uses magnetic resonance imaging to detect tissue loss in the brains of people with dementia.

Alzheimer’s disease is the most common form of dementia. While most people are familiar with the name if not the symptoms associated with the disease, there is a common misconception that the memory problems seen in the early stages of Alzheimer’s disease are exclusive to this type of dementia. As mentioned in a previous post, however, there is increasing evidence to suggest memory is also affected in the early stages of a different form of dementia called frontotemporal dementia. Since memory impairment is not exclusive to one disease, this poses a problem for the diagnosis of dementia conditions.

The clinical research group at NeuRA that I work with, called FRONTIER, is trying to solve this problem. FRONTIER is an internationally recognised research program investigating younger onset dementias (under 65 years of age). FRONTIER applies a multidisciplinary approach combining clinical, behavioural and cognitive investigations to better understand the symptoms, behaviours and brain pathology that characterise different types of dementia. For those of you who have encountered Alzheimer’s disease, it is clear that while deterioration in memory is present, it is also accompanied by many other changes such as disorientation and confusion about time and place. In some cases, where the disease has progressed to a moderate severity, they may show a different perception of time such as preparing to depart after just arriving at an appointment or even becoming lost within their own home.

In a recent study by our group, we conducted an in depth examination of clinical memory and orientation performance in Alzheimer’s disease and frontotemporal dementia. We found that memory is indeed impaired in both Alzheimer’s disease and frontotemporal dementia, reconfirming that of an earlier study. Interestingly, however, orientation was intact in frontotemporal dementia patients but impaired in Alzheimer’s disease patients.

We also looked at the brain structures underlying memory and orientation using magnetic resonance imaging (MRI). We found that memory performance could be attributed to brain tissue loss in the anterior (front) regions of the hippocampus in both Alzheimer’s disease and frontotemporal dementia. Excitingly, we identified loss of brain tissue responsible for impaired orientation in the posterior (rear) region of the hippocampus, specific to Alzheimer’s disease. While there is a long history of research implicating the hippocampus in memory, it is becoming increasingly clear that different areas along the structure are responsible for different mental processes.

The scan on the right highlights the region of the hippocampus responsible for memory; the scan on the left highlights the region responsible for orientation. Tissue loss is this area is unique to Alzheimer’s disease.

Our findings have important clinical implications, namely that clinicians should consider measures of orientation in combination with memory to help distinguish Alzheimer’s disease from other dementia conditions. Our next step will be to develop novel assessments that can provide a more in-depth assessment of orientation. In this vein, we are currently piloting a new computer-based task that will hopefully allow clinicians to perform a quick and reliable assessment of orientation. Watch this space!