Beyond DNA code: epigenetics

Why is it that if you keep an active mental life by playing complicated board games or learning a language, or if you keep physically fit, you are less likely to succumb to dementia? A/Prof John Kwok is addressing this question by looking at how lifestyle can alter the function of genes related to dementia.

A/Prof John Kwok

A/Prof John Kwok

To do this, he is engaging with the burgeoning field of epigenetics. Genes have to be expressed (i.e. switched on or off) in a tightly regulated manner for our bodies to function correctly. For example, genes get switched on and off when we are born, or when we hit puberty, in response to hormones or tissue growth. While there are parts of our DNA that control how genes are switched on, there are also epigenetic factors, outside our DNA, that can do this. These factors act like a dimmer switch that changes the brightness of a light.

Diet, exercise, and mental activity can ‘dim the brightness’ of genes that might lead to illness, or enhance genes that promote brain health. Not only do these lifestyle factors change gene expression, but their effect might be inherited by the next generation, even if the relevant gene’s DNA sequence itself is not inherited. Understanding the mechanisms of how this happens is a focus of many areas of NeuRA’s work. The study of epigenetics is important in exploring new possibilities for health care.

What about resilience and wellbeing? The flipside of mental illness

Dr Justine Gatt is an NHMRC Research Fellow who has recently joined the NeuRA team. Her research focuses on understanding the flipside of mental illness: why some people are more resilient to stress than others. It is hoped that these characteristics can be promoted in people who may be less resilient.

Dr Justine Gatt

Dr Justine Gatt

In Australia, nearly half of the population experience a mental disorder at some point in their lifetime, with the most common disorders being anxiety or depression. These disorders can occur in anyone, at any age, but adolescents and young adults are particularly vulnerable as their brain is still undergoing the final stages of development. Exposure to trauma or adversity during childhood or adulthood can often trigger symptoms of these disorders. On the other hand, the presence of certain protective factors may make an individual more resilient to the effects of stress and adversity. Notably, the absence of mental illness does not necessarily imply the presence of optimal mental health, and only a small proportion of people who have no mental illness symptoms are actually functioning optimally and are resilient.

Most psychiatric research has focused on understanding mechanisms of risk for different mental disorders and ways to diagnose and treat them. In comparison, there are very few studies that try to understand the mechanisms of resilience. Our research program aims to understand mental health using a new framework. This includes defining the neural underpinnings of resilience using techniques such as magnetic resonance imaging (MRI) and electroencephalography (EEG) measures of brain function. We also examine the genetics of resilience using saliva samples for DNA analysis.

I am currently analysing data from over 1,600 healthy adult twins who participated in the TWIN-E Study of Emotional Wellbeing. Our team has developed a new questionnaire called COMPAS-W to measure wellbeing. It measures qualities, such as composure, positivity, self-worth and mastery over one’s environment, that are self-reported by study subjects. The questionnaire has been validated against objective psychological tests for symptoms of depression and anxiety. Using measures from this broad source base is helpful when linking biological variables like genetics and brain function, and allows us to explore how innate and environmental factors may moderate our wellbeing, with twin heritability estimates at 48%. The good news is that this means that wellbeing is malleable and can be promoted with intervention.

Comparing between twins allows us to determine the relative contribution of genetics and environment to changes in the volume of grey matter in different parts of the brain. Changes are highlighted in colour. (Gatt et al 2012, Twin Research and Human Genetics)

Comparing identical and non-identical twins allows us to determine the relative contribution of genetics and environment to differences in the volume of grey matter in different parts of the brain. Differences are highlighted in colour. (Gatt et al 2012, Twin Research and Human Genetics)

Another aspect of our research tests how interventions work to promote resilience. We are working with industry partners to test different e-health tools. One of these tools, called MyBrainSolutions, provides targeted, personalised emotional and cognitive solutions over the Internet. To measure resilience, we are testing games that promote positivity (e.g., gratitude training and positive affirmations) and stress management (e.g., the negative thought challenger and MyCalmBeat), as well as executive control games that aim to boost working memory, attention, and goal setting.

Understanding the biology of resilience is the first step towards personalised health solutions. It provides the foundation of features that could be nurtured in low-resilient individuals in order to prevent psychiatric illness. This ‘resilience bio-signature’ could be used as a diagnostic tool for predicting risk for developing mental illness following trauma. At-risk children or adults could then be provided with simple tools to train them to better adapt to life stressors and make them more resilient for the future.

Justine was recently awarded a competitive National Health and Medical Research Council (NHMRC) Career Development Fellowship to conduct this research program. As evidence of innovation and research excellence, Justine was lucky enough to receive the Commonwealth Health Minister’s Award for Excellence in Health and Medical Research in June 2014. The TWIN-E study was a collaborative study with Prof Leanne Williams (Stanford University, previously University of Sydney) as Chief Investigator and co-investigators Prof Peter Schofield (NeuRA), A/Prof Anthony Harris (University of Sydney), Prof Richard Clark (Flinders University), and Dr Justine Gatt (previously as ARC APDI postdoctoral research fellow, University of Sydney) and supported by an Australian Research Council Linkage (LP 0883621) grant with Brain Resource as industry partner.

 

 

Contracture: understanding mechanisms and testing treatments

As part of a new National Health and Medical Research Council Program Grant on motor impairment, Prof Rob Herbert aims to advance the transfer of new understanding of physiology and pathophysiology in motor impairment toward the clinical outcome of improved motor function.

Prof Rob Herbert

Prof Rob Herbert

Motor impairment is a common consequence of a number of illnesses and injuries. One type of motor impairment that is an important cause of physical disability is muscle contracture. A contracture is a stiffening of the muscles that limits normal joint movement, and severe contractures cause deformities that are the most visible manifestation of brain damage. Contractures arise when brain lesions, including those that arise from stroke or traumatic brain injury, cause paralysis or spasticity. Paralysis and spasticity change the mechanical environment of muscles – that is, they cause muscles to experience different patterns of activity, different changes in length and different forces than would normally be experienced. The muscles adapt in response to their altered mechanical environment by becoming stiffer, causing joints to become less mobile.

Contracture is a common problem. In a recent study, my colleagues and I monitored 200 consecutive people admitted to a Sydney hospital with the diagnosis of stroke. Six months after admission, half of all those people had developed at least one contracture. Contractures are also common in people with many other sorts of brain lesions. For example, contractures are prevalent in people who have had a traumatic brain injury, or who have multiple sclerosis or cerebral palsy.

Contractures prevent joint movement, so they cause physical disability. For example, many people who have had a stroke or traumatic brain injury develop contractures of the calf muscles. Calf muscle contractures impede ankle motion, making it difficult to stand up from a chair or walk normally. In the same way, contractures of shoulder muscles can impair the ability to reach and contractures of wrist and finger muscles can impair grasp. Severe muscle contractures can cause the limb to adopt a fixed position. For many people, contractures become a much greater impediment to normal movement than the paralysis or spasticity that initially caused the contracture to develop.

There has been surprisingly little research into the mechanisms of contracture. As a result, the mechanisms are poorly understood. Studies on animals have shown that it is possible to make muscles become short or stiff with a number of experimental procedures. For example, leg muscles can be made short by immobilising the leg in a plaster cast, and diaphragm muscles can be made short by inducing emphysema (a lung disease). These studies show that the stiffening of muscles can occur either because of changes in the muscle tissue (the muscle “fibres” or “fascicles”), or because of changes in the tendons that join muscle fascicles to bones. But studies on animal muscles can’t tell us about the mechanisms of contractures seen in human populations. Surprisingly, it is still not clear whether contractures in people who have had a stroke or traumatic brain injury are due to changes in the muscle fascicles or tendons.

There is just as much uncertainty about how to prevent and treat contracture. For the last half-century, physiotherapists and nurses have applied stretches to muscles, or passively moved limbs, or applied splints or casts to stretch the limb, with the aim of preventing or treating contractures. But recent research suggests these interventions have little effect. For example, in one study, 63 volunteers who had experienced a stroke were randomly allocated to receive either a wrist splint or no splint. Two months later there was no discernable difference in the stiffness of the wrist of people who had or had not been splinted. There have now been over 35 studies like these, and they quite consistently show little or no effect of stretch or movement-based interventions. For now at least, there are no treatments that have been clearly shown to prevent or reverse contracture.

Eventually, scientific research will provide answers, both about the mechanisms of contracture, and about how to prevent and treat contracture. The first steps have been made in identifying the abnormalities of gene expression that are ultimately expressed as contracture. New ideas for treatments are being generated by basic research, for subsequent testing in clinical trials. Our motor impairment program will study human volunteers and patients to learn more about normal motor function and the mechanisms of motor impairment, and to test the clinical efficacy and mechanisms of novel treatment interventions. The development of new techniques for imaging and measuring the internal architecture of muscles using MRI provides one promising advance. One study will look at how muscle tendons and fascicles are recruited during movement, which will inform subsequent clinical studies in people in whom contracture is common, such as people with stroke, spinal cord injury and multiple sclerosis.

Hopefully, the next decade will see major advances in both our understanding of the mechanisms of contracture and how to treat them.

An example of one of the unique muscle images generated by Prof Herbert's team. In the centre is a human leg muscle. The blue lines show the course of muscle cells in six locations in the muscle. The insets provide information about how the cells terminate on the tendinous sheets that cover the upper and lower surfaces of the muscle.

An example of one of the unique muscle images generated by Prof Herbert’s team. In the centre is a human leg muscle. The blue lines show the course of muscle cells in six locations in the muscle. The insets provide information about how the cells terminate on the tendinous sheets that cover the upper and lower surfaces of the muscle.

An international approach to tackling Parkinson’s disease

Dr Nic Dzamko and Prof Glenda Halliday have put together an international team dedicated to researching the causes of Parkinson’s disease. They will be the first in the world to use valuable early clinical samples to identify the genetic and molecular underpinnings of this brain illness.

Parkinson’s disease is a debilitating neurodegenerative disorder with no current cure. 1 in every 30 Australians is diagnosed with Parkinson’s disease, and these numbers are predicted to rise. Over the last 10-15 years, it has emerged that genes play an important role in the risk of developing Parkinson’s disease. Approximately 16 genes have now been identified that increase the risk of developing Parkinson’s disease. Understanding what these genes do in the healthy brain, and how their functionality might go wrong, has become a major focus in the search for clues about the cause of this disease.

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Dr Nic Dzamko in the laboratory

One of these genes, called LRRK2, has received considerable attention. The LRRK2 gene encodes a protein that belongs to a class of enzymes called kinases, which is interesting to researchers because many anti-cancer drugs developed by the pharmaceutical industry also act by blocking kinases. In the past few years, more than 20 drugs that can block the kinase LRRK2 have been patented. While it is hoped that these drugs may be beneficial for the treatment of Parkinson’s disease, more work needs to be done to understand exactly what LRRK2 does, and therefore whether drugs that block its action will be safe and therapeutically useful. To better understand the function of LRRK2, our team at NeuRA has initiated two new projects in collaboration with scientists from around the world.

The first project involves us leading a group of scientists from London, Tokyo, California and the Netherlands. Using 400 samples that have been sent to us from these locations, and that cover a range of brain regions at different disease stages, we will determine if, when and where the expression of the LRRK2 enzyme goes wrong in the Parkinson’s brain.

The second project aims to investigate the idea that inflammation is linked with Parkinson’s disease, in collaboration with researchers in the US and Europe. This project is particularly exciting, as it may identify much-needed markers of early disease. By working with the worldwide LRRK2 Cohort Consortium, established by the Michael J Fox Foundation for Parkinson’s Research, we have access to more and better samples to ultimately obtain more meaningful data. We will measure a range of biological markers associated with inflammation in serum and cerebrospinal fluid. By comparing the extent and type of inflammation in people who do and do not have certain genetic mutations, and between people with Parkinson’s disease and healthy controls, we will identify whether inflammation is an early sign of Parkinson’s disease. This world-first access to blood samples from people with a large genetic risk of getting Parkinson’s, but who do not yet have the disease symptoms, is a chance to try and identify potential treatments for the early stages of this illness.

These projects have taken about a year and over 300 emails to come together. Although meetings are often scheduled in the very early hours of the morning to accommodate time zones, working together as an international team to leverage skills and resources is an important step toward solving the problem of Parkinson’s disease. Of course, our work would not be possible without the funding we have received for these projects from the Michael J Fox Foundation and the Shake it Up Australia Foundation.

The life of an early career researcher

An early career researcher is an interesting creature – focussed, driven and often self-critical. Outgoing Chair of the Early Career Committee (ECC) at NeuRA, Kirsten Coupland, explains what it is like being a young scientist and the role the committee plays in supporting careers.

Early career researchers are those working in science who have completed their PhD less than six years previously or who are under the age of 40; whether studying or employed, involved in academia, or industry. There are around 120 early career researchers currently at NeuRA but this number fluctuates as people take exciting steps in their careers. These researchers are just discovering what a career in research entails. They are finding that a scientific career is not as structured as one in the corporate world; skills are learnt on the job and successful outcomes to experiments often initially elude them. Young researchers learn at the deep end. The work of the ECC, of which I am the outgoing Chair, is important for young researchers at NeuRA. We provide events and seminars that develop the skills and professional attributes young researchers need to cultivate a successful career in science.

What it takes to be a scientist

The world of research is extremely competitive and many of the things that set one scientist apart from the crowd are less tangible than research results. Being a good scientist requires the ability to communicate, have a strong network, a comprehensive knowledge base and confidence.

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Kirsten Coupland in the laboratory

What we do 

NeuRA’s ECC aims to give young researchers the ability to cultivate these assets and enjoy themselves at the same time. Events the ECC orchestrates encourage young researchers to interact with new people from different research groups. In doing so, they not only become confident at communicating their research to scientists from other fields, but they also start developing a network they will use throughout their career. Initiatives include regular seminars featuring speakers from around the country who discuss topics such as ethics, social media, and where to source funding.

Panel discussions of post-docs or non-academic science careers have helped get early career researchers thinking about what they will do with their scientific knowledge. Informal coffee meet-ups allow students to discuss their research with a mixed audience and interact with people they may not know at NeuRA. Early career researchers are the future generation of scientific research. It is important they have the skills and attributes necessary to carry out creative and exciting science that will revolutionise the way we understand the human body.    

Cannabidiol – a glimmer of hope for Alzheimer’s disease?

Alzheimer’s disease is the most common form of dementia, which affects around 330,000 Australians. In 2009 – 2010, the healthcare cost of dementia was over 4.9 billion dollars in Australia. Both of these figures are on the rise, given that our life expectancy is increasing.

People living with Alzheimer’s disease experience a range of symptoms that include social withdrawal and problems with remembering places, objects and people, and these symptoms become progressively worse with time. In the brain, aside from the increasingly well-recognised amyloid plaques and tangles, imaging and post-mortem analyses have also found extensive neuronal degeneration, inflammation, toxicity and oxidative stress, and these processes are likely to contribute to the development of Alzheimer’s disease.

Current treatments are unable to stop the disease progression, and the quest to find a viable treatment for Alzheimer’s disease continues. Many treatments have been designed to target single brain systems that are affected in Alzheimer’s disease. However, this approach is not sufficient for two reasons: 1) more than just one system is affected in the disease, and 2) it may be too late to administer these treatments once the disease has been diagnosed. Research now suggests it may be more beneficial for patients if treatments targeted a range of systems that are altered in Alzheimer’s disease and could be administered early, perhaps even before disease symptoms are prominent, as a method of prevention.

So where does one find a treatment that can exert neuroprotective, anti-oxidant and anti-inflammatory effects all at once? Well, the answer might lie in a compound known as cannabidiol. Cannabidiol has been shown to have all the above properties, which could be relevant for Alzheimer’s disease. However, there have been only a few studies that have followed up on this link, perhaps because many people might be eager to dismiss cannabidiol as a treatment due to concerns that it may exhibit the psychoactive properties of other compounds obtained from the cannabis plant. But in fact, cannabidiol is behaviourally inactive in humans when taken over long periods of time, including in people with schizophrenia and Huntington’s disease. Cannabidiol also prevents the memory-impairing effects of THC, the main psychoactive compound of cannabis. And, in promising news for Alzheimer’s research, cannabidiol has also been shown to reduce amyloid production and increase neurogenesis in brain cells. With this in mind, it is only logical that cannabidiol should be tested for its potential to benefit those with Alzheimer’s disease, as it might counter some of the main biological changes that are occurring.

David Cheng has just completed his PhD at NeuRA under the supervision of Dr Tim Karl.

David Cheng has just completed his PhD at NeuRA under the supervision of Dr Tim Karl.

My study, published in the journal Psychopharmacology, was the first to investigate the effect of cannabidiol treatment in a transgenic mouse model of Alzheimer’s disease. This mouse model carries two genetic mutations that are associated with familial Alzheimer’s disease, and the mice show behaviours that are relevant to Alzheimer’s symptoms, such as social recognition and spatial memory deficits. Since normal mice have a tendency to explore either new things or other mice, we compared how well transgenic mice fared in a test called the social preference test, which measures the amount of time that the test mouse spends exploring either a familiar or a new (never before seen) mouse. I discovered that the Alzheimer’s model mice spent the same amount of time exploring both the new and familiar mice, showing that they were unable to tell the difference between the two. Excitingly, daily cannabidiol treatment given over 3 weeks restored the social recognition memory of the transgenic mice.

In a separate study, soon to be published in the Journal of Alzheimer’s disease, cannabidiol was given to the transgenic mice every day, beginning at a very early age, to test whether it can be administered early as a prevention against the social recognition memory deficits. Promisingly, the development of recognition deficits in the disease model mice was prevented by the cannabidiol treatment. Using various biochemical techniques, I also found evidence to suggest that this effect might be mediated by the anti-inflammatory properties of cannabidiol.

These findings are extremely interesting as they show cannabidiol might have behavioural and biological effects that could benefit people with Alzheimer’s disease. Of course, we know that mice are not exactly like humans, but mouse models give researchers a great amount of insight into the effects of Alzheimer’s disease genetic mutations on both behaviour and biology. For example, links can be drawn between the social recognition deficits displayed by the Alzheimer’s disease model mice and the inability to recognise familiar faces in people with Alzheimer’s disease. Imagine what it would mean for people with Alzheimer’s disease and their friends and relatives if they could still recognise their loved ones! With more research, it will be possible to gain a better understanding of the exact mechanisms behind the beneficial effect that cannabidiol has already shown in this mouse model, paving the way for possible clinical trials in the future.

Building blocks for a fresh understanding of schizophrenia

Dr Dipesh Joshi received this year’s Leslie Kiloh paper award for his work into the understanding of schizophrenia. Since then, he has published new work linking problematic neurons to a genetic abnormality associated with schizophrenia.

He explains how his work has created a greater understanding of this disease…

Genes are a precious gift that every generation passes on to the following one since the existence of mankind. Abnormal functioning of some of these genes may lead to abnormal functioning of the brain cells leading to development of brain disorders. NRG1 and ErbB4 are two such genes that have been identified as ‘schizophrenia risk genes’.

Altered functioning or signaling of these genes contributes to the development of schizophrenia. Research shows that there are physical differences in the brains of people with schizophrenia compared with those of healthy people. To identify how genetic abnormalities lead to such physical differences remains a significant challenge. If this was known, we would be closer to understanding exactly what happens in the brain to cause the symptoms of schizophrenia, such as social withdrawal, difficulty with memory and planning, and even hallucinations, all of which can be very distressing to an individual with the illness.

What drug treatments are available now?

These days, the available antipsychotic treatments are relevant only for positive symptoms such as hearing voices, suspiciousness, feeling as though you are under constant surveillance, delusions, or making up words without a meaning, but not for negative symptoms which might include social withdrawal, cognitive deficits, difficulty in expressing emotion and an inability to feel pleasure. This highlights the urgency of having new antipsychotic drugs that have beneficial effects in treating negative symptoms and cognitive deficits in people with schizophrenia.

What are the risk genes doing in schizophrenia?

Dr Dipesh Joshi is a postdoctoral research officer at NeuRA

Dr Dipesh Joshi is a postdoctoral research officer at NeuRA

Our recent research work has been able to link schizophrenia risk genes (NRG1 and ErbB4) with a type of brain cell which maintains the inhibitory-excitatory balance in a normal brain. In schizophrenia, this particular brain cell-type, called inhibitory interneuron has been found to be reduced compared to healthy individuals. Research conducted in our laboratory is completely unique as it shows how an increase in the risk gene (ErbB4) is linked with a reduction in inhibitory brain cells. Increased levels of ErbB4 gene contributes to the inhibitory-excitatory imbalance resulting in development of schizophrenia.

These findings are crucial for brain researchers to understand how schizophrenia ‘risk genes’ adversely affect brain cells resulting in brain abnormalities found in people with schizophrenia. Our findings are a step forward in identifying new therapeutic targets for a new generation of antipsychotics that will have beneficial effects that extend beyond positive symptoms in people with schizophrenia and for us that is a very exciting prospect.

 

Are you a healthy control?

How about becoming a healthy volunteer for research and helping us Discover ~ Conquer ~ Cure? 

Do you have spare time and want to make a difference to people’s lives? Perhaps you’re willing to give up your time and participate in studies right here in Randwick?

I’m Connie Severino and my job at NeuRA is to maintain our healthy volunteer database that provides researchers with an easy way to recruit people for their studies.

We are always looking to recruit healthy volunteers because we want to make a difference to the lives of many who have suffered or are currently suffering neurological illnesses.

Healthy volunteers play an important part in supporting our research programs.

Each group within NeuRA covers a different area of research ranging from Alzheimer’s disease, chronic pain, falls and balance, Frontotemporal dementia, Parkinson’s disease, sleep apnoea, stroke, and many more. We recruit healthy volunteers for all of these areas.

We use data we collect from our healthy volunteers and compare it with the data we have from those affected with a particular neurological condition.

A healthy volunteer, often referred to as a ‘control’ or who sits within a ‘control group’, is simply a standard of comparison for checking or verifying the results of an experiment. Controls are the standard against which experimental observations are evaluated.

Becoming a volunteer does not cost you anything, however we do ask for your time and patience. Initially we ask you to complete a questionnaire and, from there, if you meet the control criteria, we register you on our Healthy Volunteer Registry that allows you to be selected up to three times a year.

What do I need to know? 

Often researchers will ask for clear specifications in controls such as age, gender, right or left handedness or walking ability. Once you are selected for a study, the researchers are notified and will contact you and ask you to participate.

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Jacqui Zheng with a volunteer for a falls and balance study at NeuRA

Each group’s tasks and activities vary but, rest assured, you will be well informed as to the specific tasks required of you before the trial begins. We endeavor to accommodate all your needs from travel arrangements, pick up and parking depending on your location and, at all times, keep you comfortable and informed.

We look for participants housed all over the country, particularly in NSW and the ACT. That said, due to most testing taking place here in Randwick, we typically invite volunteers from the Sydney metro and surrounding areas to join us, for ease of travel.

How do I get involved? 

Once you become a registered volunteer, you are not obliged to accept every invitation you are offered and you are of course free to withdraw from being on the registry at any given time.

Our registry has been active for approximately four years and has been beneficial for 30 studies to date. Some of our volunteers have returned to us multiple times as they enjoy the process and the ability to contribute to medical science in this way.

If you are interested in contributing your time, please see our website for further details or contact me directly on (02) 9399 1155. I am happy to answer any questions you might have.

It’s my belief that ‘A problem shared is a problem halved’… we thank all those who have helped in the past and who continue to volunteer.

The pain – brain relationship

Exactly how does educating patients about pain lead to better outcomes? PhD student at NeuRA, Hopin Lee, is seeking to answer that question.. 

Most of us know, through personal experience or having heard about someone else’s experience, that back pain can be troublesome. For many it’s just a niggle that can be kept under control with simple analgesics and a bit of reassurance that there is nothing sinister happening in their back. However, for some, back pain can cause major disruptions to life. While there may be some periods when symptoms ease, they often recur and eventually a longer period of persistent pain and disability ensues.

There is no doubt that in clinical practice a large number of patients present with back pain, yet it is often the most difficult condition to treat. Clinicians are often faced with a choice of assorted treatment options, ranging from localised injections to generalised physical exercise and psychological interventions. Despite the plethora of available treatments, research suggests that their effectiveness is often modest with short lived benefits.

The black box 

Most research investigating back pain treatments has focused on answering whether the treatment is successful or not. This is the so-called ‘black box’ approach where little or no attention is paid to how the treatment exerts its effect on the outcomes that we strive to improve. A limitation of this approach is that we are left without any knowledge about whether the underlying theories behind these treatments are valid. Without understanding the mechanisms that underpin treatments, we naturally return to the black box approach and move on to test a new set of treatments, without thinking about how we can improve existing ones. However, if we are able to verify or refute the underlying mechanisms of our treatments, we may be able to refine and modify existing treatments to develop better treatments informed by evidence.

Although theories and speculations about treatment mechanisms are bountiful, there has been little attempt to test theories with appropriately designed studies. A way of testing these mechanisms is to design studies so that mediation analysis can be applied. Born out of psychology, mediation analysis is considered to be an efficient method of investigating relationships between variables. This method of analysis will be the central focus of my PhD thesis – to explain how a treatment for lower back pain may have its effects on the outcomes of interest.

A Journey of understanding.. 

PhD student Hopin Lee

PhD student Hopin Lee

Our group (Moseley group) at NeuRA is conducting a NHMRC funded randomised controlled trial (PREVENT) to evaluate the effectiveness of an educational intervention for patients with acute low back pain. My PhD will investigate the theories that underpin this intervention to see if they are valid and supported by the data.

PREVENT tests, in a randomised controlled trial, whether patient education that focuses on reconceptualising how a patient thinks about pain during the acute stages can prevent their low back pain from becoming persistent. The patient education provides patients with the understanding that pain is a protective output of the brain, rather than a direct measure of tissue damage. Conveying these messages in relation to their existing beliefs and attitudes towards pain may modulate their painful experience, which may lead to better outcomes. These are some of the theories I will test in my PhD.

So how might educating patients about pain lead to better outcomes? For example one of my hypotheses is that if patients are taught to think about their pain as a protective response of the brain rather than a signal of harm to their back, this might reduce catastrophising thoughts (having a negative outlook, thinking the worst will happen). This is a plausible theory, considering that catastrophising thoughts are related to pain intensity and disability. Patients who catastrophise about the prognosis of their back pain tend to have higher levels of pain and disability which coincide with slower recovery rates. The challenge is to decipher whether PREVENT can change these mediating variables (e.g. catastrophising, beliefs and attitudes about pain) and whether this then leads to better outcomes for patients.

My vision for the future is that we seek to open the mysterious black box and peek into some of the complex mechanisms that are at work. This may allow us to move forward to logically refine our treatments based on scientific theory and reason. I think most of us would agree that a clear box provides better insight as opposed to an opaque black box… don’t you?

We are currently recruiting participants to this study. If you are you currently suffering an acute (less than 4 weeks) episode of low back pain, live in Sydney and would like to join the study please email us at prevent@neura.edu.au

 

 

The Social Brain

Dr Muireann Irish uncovers the part of the brain that underpins social cognitive deficits in semantic dementia, further unraveling mysteries behind the disease.

It may sound like the subject matter of a science fiction movie, but mind-reading is a process in which we regularly engage. On a daily basis, whenever we interact in social scenarios, we go beyond our own perspective to infer the thoughts, beliefs, and feelings of other people. This innate skill to appreciate perspectives distinct from our own allows us to function effectively within the social world. For example, we can instinctively understand how a colleague may feel when their latest publication is rejected, or we can intuitively place ourselves in a friend’s shoes when they experience a joyous event like the birth of a first child.

Theory of Mind

My latest study sheds light on the brain regions that need to be functional in order to support this ability to empathise with others. The study, published in the journal Brain, reveals that structures in the right hemisphere of the brain are essential to enable us to read the minds of others and to consider their beliefs and feelings. ‘theory of mind’ is the term used to refer to our uniquely human ability to make these inferences and is crucial for our successful functioning in the social world.

By understanding that other people think and feel in ways that are distinct from our own perspective, we can appreciate differences between individuals. This capacity to infer the mental state of others confers immense flexibility in our approach to various social scenarios. Without this ability, we would appear rigid, egocentric, and unfeeling towards others.

While appreciating the mental state of others may come relatively easy to us, the capacity for theory of mind relies upon a complex network of structures in the brain. Research on healthy individuals has revealed that when we successfully consider another person’s psychological perspective, regions in the frontal, temporal and parietal lobes of the brain activate. Such widespread brain activation reveals how complex this function truly is.

It follows that damage to any one of these brain regions will block the capacity to take another person’s perspective. Theory of mind abilities are disrupted across a number of clinical conditions such as traumatic brain injury, autism, and dementia.

Semantic dementia

In frontotemporal dementia, it is commonly reported that patients are unable to understand how their actions affect other people, or to consider that the reactions of others may differ from their own. However, up until recently, we knew relatively little regarding the capacity for theory of mind in the syndrome of semantic dementia. My recently published research reveals, for the first time, that individuals with semantic dementia experience severe difficulties in considering the mental states of others, and that such deficits are attributable to atrophy of structures in the right hemisphere of the brain.

Semantic dementia is a subtype of frontotemporal dementia, characterised by the progressive loss of general knowledge about the world. It is conceptualised as a language disorder whereby patients experience a profound loss of the meaning of words and concepts. The patient is unable to recall the names of objects, places, people, and experiences difficulties in correctly labeling popular musical tunes, or basic emotional expressions. While the predominant complaint of the patient is that of language disruption, carers of patients with semantic dementia report alterations in social functioning and interpersonal behaviour.

The Protocol

Images taken from Lough et al. (2006) Neuropsychologia,

Images taken from Lough et al. (2006) Neuropsychologia,

I used a new task to explore if patients with semantic dementia could infer the thoughts, beliefs, and feelings of the main characters in humorous cartoon scenarios. Patients were asked to describe why a selection of cartoon scenes were funny and their descriptions were analysed for language that reflected consideration of different mental states, for example “he thinks”, or “she feels”. In the cartoon scene to the left, a correct answer would be something like, “The gentleman thinks he is being held up. The lady is not aware that she is frightening the man.”

A patient with semantic dementia tended to respond as follows, “The woman is hitting the man in the back. He is putting his hands in the air”. These responses indicated that the ability to spontaneously consider the mental state of others was disrupted in semantic dementia. Importantly, I demonstrated that the failure to successfully appreciate the viewpoints of others was not a result of the language difficulties that are typically found in semantic dementia.

Using neuroimaging analysis of structural MRIs, I found that shrinkage of the right temporal lobe of the brain underpinned the theory of mind deficits in semantic dementia. This finding is surprising, as these patients are typified by damage to the left side of the brain. As the disease progresses however, pathology spreads from the left to the right hand side of the brain. The semantic dementia patient displays impairments across multiple domains, beginning with language disruption and gradually progressing to include social dysfunction.

Why is this important?

The findings of this study are unique as they reveal, for the first time, that degeneration of right temporal regions in the brain is associated with social dysfunction in semantic dementia. The right temporal lobes have been consistently implicated in studies of social functioning in healthy individuals.

Our study illuminates the complexity of social cognition and how we achieve sophisticated acts of social inference in our everyday lives. By incorporating brain mapping techniques with new experimental tasks, we can continue to unravel the mystery of mind-reading and build a coherent picture of how humans navigate within the social world.