In a look at how major stressors during childhood can change a person's biological risk for psychiatric disorders, researchers at Butler Hospital have discovered a genetic alteration at the root of the association. The research, published online in PLoS ONE on January 25, 2012, suggests that childhood adversity may lead to epigenetic changes in the human glucocorticoid receptor gene, an important regulator of the biological stress response that may increase risk for psychiatric disorders.
The association between childhood adversity, including parental loss and childhood maltreatment, and risk for psychiatric disorders such as depression and anxiety has been established in multiple studies. However, researchers have yet to define how and why this association exists in humans. "We need to understand the biology of this effect in order to develop better treatment and prevention programs," said Audrey Tyrka, MD, PhD, director of the Laboratory for Clinical and Translational Neuroscience at Butler Hospital and associate professor of Psychiatry and Human Behavior at Brown University. "Our research group turned to the field of epigenetics to determine how environmental conditions in childhood can influence the biological stress response."
Epigenetics is the study of changes to the genome that do not alter the DNA sequence, but influence whether genes will be expressed, or "turned on," versus whether they will be silenced. Knowing that the connection between childhood maltreatment and psychiatric disorders has been linked to the hormone system that coordinates biological stress responses, the researchers sought to identify the root cause at a genetic level.
The glucocorticoid receptor is an important regulator of the stress response, and methylation is a particularly stable type of epigenetic modification. "We knew that epigenetic changes to this gene could be affected by childhood parenting experiences because previous animal research showed that rodents with low levels of maternal care had increased methylation of this gene, and consequently, as adults these animals had greater stress sensitivity and fear in stressful situations," said Tyrka.
The researchers looked at 99 healthy adults, some of whom had a history of parental loss or childhood maltreatment. DNA was extracted from each of the participants using a blood sample, then analyzed to identify epigenetic changes to the glucocorticoid receptor. The researchers then performed a standardized hormone provocation test to measure the stress hormone, cortisol.
The researchers found that adults with a history of childhood adversity—maltreatment or parental loss—had increased methylation of the glucocorticoid receptor (GR) gene, which is thought to change the way this gene is expressed on a long-term basis. They also found that greater methylation was linked to blunted cortisol responses to the hormone provocation test. "Our results suggest that exposure to stressful experiences during childhood may actually alter the programming of an individual's genome. This concept may have broad public health implications, as it could be a mechanism for the association of childhood trauma with poor health outcomes, including psychiatric disorders as well as medical conditions such as cardiovascular disease," said Tyrka.
In early studies of animals, researchers have identified drugs that can reverse methylation effects. "More research is needed to better understand the epigenetic mechanism behind this association," said Tyrka, noting a larger scale study currently underway at Butler and a study of this association in children. "This line of research may allow us to better understand who is most at risk and why, and may allow for the development of treatments that could reverse epigenetic effects of childhood adversity."
An inflated cortical surface of the human brain reconstructed from MRI scans and viewed from the front. Areas of the prefrontal cortex where increased grey matter volume correlated with more extraordinary metacognitive ability are shown in hot colours. Credit: Dr Steve Fleming.
At New York University, Sir Henry Wellcome, Postdoctoral Fellow Dr Steve Fleming, is exploring the neural basis of metacognition: how we think about thinking and assess the accuracy of our decisions, judgements and other mental performance.
Metacognition is an important-sounding word for a very everyday process. We are 'metacognitive' when reflecting on our thinking process and knowledge.
We do it on a moment-to-moment basis, according to Dr. Steve Fleming at New York University. "We reflect on our thoughts, feelings, judgements and decisions, assessing their accuracy and validity all day long," he says.
This kind of introspection is crucial for making good decisions. Do I really want that bar of chocolate? Do I want to go out tonight? Will I enjoy myself? Am I aiming at the right target? Is my aim accurate? Will I hit it? How sure am I that I'm right? Is that really the correct answer?
If we ask ourselves these questions as a kind of faint, ongoing, almost intuitive commentary in the back of our minds, we will progress smoothly through life.
Although we all do it, we're not equally good at it. An example Steve likes to use is the gameshow 'Who Wants to be a Millionaire?' When asked the killer question, 'Is that your final answer?', contestants with good metacognitive skills will assess how confident they are in their knowledge.
If sure (I know that I know), they'll answer 'yes'. If unsure (I don't know that I know), they'll phone a friend or ask the audience. Contestants who are less metacognitively gifted may have too much confidence in their knowledge and give the wrong answer - or have too little faith and waste their lifelines.
Metacognition is also fundamental to our sense of self: to know who we are. Perhaps we only really know anyone when we understand how and what they think - and the same applies to learning ourselves. How reliable are our thought processes? Are they an accurate reflection of reality? How real is our knowledge of a particular subject?
Last year, Steve won a prestigious Sir Henry Wellcome Postdoctoral Fellowship to explore the neural basis of metacognitive behaviour: what happens in the brain when we think about our thoughts and decisions or assess how well we know something?
Killer questions
One of the challenges for neuroscientists interested in metacognition has been the fact that - unlike in learning or decision-making, where we can measure how much a person improves at a task or how accurate their decision is - there are no outward indicators of introspective thought, so it's hard to quantify.
As part of his PhD at University College London, Steve joined a research team led by Wellcome Trust Senior Fellow Professor Geraint Rees and helped devise an experiment that could objectively measure a person's performance on a task and how accurately they judged their own performance.
Thirty-two volunteers were asked to look at a series of similar black and grey pictures on a screen and say which one contained a brighter patch.
"We adjusted the brightness or contrast of the patches so that everyone was performing at a similar level," says Steve. "And we made it difficult to see which patch was brighter, so no one was entirely sure whether their answer was correct; they were all in a similar zone of uncertainty."
They then asked the 'killer' metacognitive question: How sure are you of your answer, on a scale from one to six?
Comparing people's answers to their actual performance revealed that although all the volunteers performed equally well on the primary task of identifying the brighter patches, there was a lot of variation between individuals regarding how accurately they assessed their own performance - or how well they knew their own minds.
Magnetic resonance imaging (MRI) scans of the volunteers' brains further revealed that those who most accurately assessed their own performance had more grey matter (the tissue containing the cell bodies of our neurons) in a part of the brain located at the very front, called the anterior prefrontal cortex. In addition, a white-matter tract (a pathway enabling brain regions to communicate) connected to the prefrontal cortex showed greater integrity in individuals with better metacognitive accuracy.
The findings, published in Science in September 2010, linked the complex high-level process of metacognition to a small part of the brain. The study was the first to show that physical brain differences between people are linked to their level of self-awareness or metacognition.
Intriguingly, the anterior prefrontal cortex is also one of the few parts of the brain with anatomical properties unique to humans and fundamentally different from our closest relatives, the great apes. It seems introspection might be unique to humans.
"At this stage, we don't know whether this area develops as we get better at reflecting on our thoughts, or whether people are better at introspection if their prefrontal cortex is more developed in the first place," says Steve.
I believe I do
Although this research and research from other labs points to candidate brain regions or networks for metacognition located in the prefrontal cortex, it needs to explain why they are involved. Steve plans to use his fellowship to address that question by investigating the neural mechanisms that generate metacognitive reports.
He's approaching the question by attempting to separate the different kinds of information (or variables) people use to monitor their mental and physical performance.
He cites playing a tennis shot as an example. "If I ask you whether you just played a good tennis shot, you can introspect whether you aimed correctly and how well you carried out your shot. These two variables might combine to make up your overall confidence in the shot."
To evaluate how confident we are in each variable (aim and shot) we need to weigh up different sets of perceptual information. To assess our aim, we consider the speed and direction of the ball and the position of our opponent across the net. To judge how well we carried out the actual shot, we would think about the position of our feet and hips, how we pivoted, and how we swung and followed through.
There may have been some discrepancy between the shot we wanted to achieve and the shot we actually made. This is a crucial distinction for scientists exploring decision-making. "Psychologists tend to think of beliefs, 'what I should do', as separate from actions," explains Steve.
"When choosing between two chocolate bars, you might decide on a Mars bar - that's what you believe you should have, what you want and value. But when you actually carry out the action of reaching for a bar, you might reach for a Twix instead. There's sometimes a difference between what you should do and what you actually do, and that's a crucial distinction for metacognition. My initial experiments are going to try to tease apart these variables."
Research into decision-making has identified specific brain regions where beliefs about one choice option (one chocolate bar or one tennis shot) being preferable to another are encoded. However, Steve says, "what we don't know is how this type of information [about values and beliefs] relates to metacognition about your decision making. How does the brain allow humans to reflect on its computations?"
He aims to connect the finely detailed picture of decision-making given to us by neuroscience to the vague notion we have of self-reflection or metacognition.
New York, New York
Steve is working with researchers at New York University who are leaders in task design and building models of decision making, "trying to implement in a laboratory setting exactly the kind of question we might ask the tennis player."
They are designing a perceptual task, in which people will have to choose a target to hit based on whether a patch of dots is moving to the left or right. In other words, people need to decide which target they should hit (based on their belief about its direction of motion), and then they have to hit it accurately (action).
"We can use various techniques to manipulate the task's difficulty. If we make the target very small, people will obviously be more uncertain about whether they will be able to hit it. So we can separately manipulate the difficulty of deciding what you should do, and the difficulty of actually doing it."
Once the task is up and running, they will ask the volunteers to make confidence judgements - or even bets - about various aspects of their performance: how likely they thought they chose the right target, or hit it correctly. Comparing their answers with their actual performance will objectively measure the accuracy of their beliefs (metacognition) about their performance.
Drilling down
Such a task will mean Steve and his colleagues can start to decouple the perceptual information that gives people information about what they should do (which target to hit) from the perceptual data that enables them to assess the difficulty of actually carrying out the action (hitting the target).
And that will make it possible to start uncoupling various aspects of metacognition - about beliefs and about actions or responses - from one another. "I want to drill down into the basics, the variables that come together to make up metacognition, and ask the question: how fine-grained is introspection?"
He'll then use various neuroscience techniques, including brain scanning and intervention techniques such as transcranial magnetic stimulation (to briefly switch off metacognitive activity in the brain), to understand how different brain regions encode information relevant for metacognition. "Armed with our new task, we can ask questions such as: is belief- and action-related information encoded separately in the brain? Is the prefrontal cortex integrating metacognitive information? How does this integration occur? Answers to these questions will allow us to start understanding how the system works."
Since metacognition is so fundamental to making successful decisions and knowing ourselves - it's important to understand more about it. Steve's research may also have practical uses in the clinic. Metacognition is linked to the concept of 'insight', which in psychiatry refers to whether someone is aware of having a particular disorder. As many as 50 per cent of patients with schizophrenia have profoundly impaired insight and, unsurprisingly, this is a good indicator of whether they will fail to take their medication.
"If we have a nice task to study metacognition in healthy individuals that can quantify the different components of awareness of beliefs, and awareness of responses and actions, we hope to translate that task into patient populations to understand the deficits of metacognition they might have." With that in mind, Steve plans to collaborate with researchers at the University of Oxford and the Institute of Psychiatry in London when he returns to finish his fellowship in the UK.
The science of metacognition also has implications for concepts of responsibility and self-control. Our society places great weight on self-awareness: think of a time when you excused your behaviour with 'I just wasn't thinking'. Therefore, understanding the boundaries of self-reflection is central to how we ascribe blame and punishment, approach psychiatric disorders, and view human nature.
More information: Fleming S. Relating introspective accuracy to individual differences in brain structure. Science 2010;329(5998):1541-3.
Provided by Wellcome Trust
"Metacognition: I know (or don't know) that I know." February 27th, 2012. http://medicalxpress.com/news/2012-02-metacognition-dont.html
(Medical Xpress) -- Researchers from the Institute of Psychiatry at King’s College London have found a relationship between molecular tags on our DNA and the weight of a particular region of the human brain called the cerebellum. The findings may provide important clues for understanding the causes of schizophrenia and autism.
The researchers focussed on a gene called Insulin-like Growth Factor 2 (IGF2) as its activity is known to be controlled by a specific process called DNA methylation. The IGF2 gene is important in regulating growth and development, principally by controlling the size of the placenta which affects the flow of nutrients from mother to foetus.
Previous studies have examined patterns of DNA methylation on the IGF2 gene in animals and human placenta samples. However, the new study, published in Epigenetics is the first time that researchers have taken a detailed look at IGF2 methylation in human brain tissue. Changes in cerebellum weight are important as the size of the cerebellum is altered in some psychiatric disorders, including autism and schizophrenia.
Ruth Pidsley, from the IoP at King’s who led the research, says: ‘DNA methylation can be thought of as a molecular switch, helping to control the activity of genes in different parts of our bodies. New techniques allow us to accurately measure DNA methylation and investigate how it relates to measurable traits. Using these techniques we have shown that variation in DNA methylation at IGF2 is associated with cerebellum weight.’
People inherit two copies of almost every gene: one from the mother and one from the father. The activity, or expression, of a gene is controlled by DNA methylation, and in most cases this activity comes from both copies. However, in the case of IGF2, the copy we inherit from our father is methylated, and gene expression is silenced.
Using this information the researchers found that genetic sequence changes in the IGF2 gene showed a different association with cerebellum weight depending on whether the copy was maternally- or paternally-inherited. The average difference in cerebellum weight between individuals who inherited the genetic variant from just their mother and those who inherited it just from their father was considerable at 30g, roughly the weight of a kiwi fruit!
Dr Jonathan Mill, Head of the Psychiatric Epigenetics group at the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre adds: ‘Given the link between structural brain abnormalities and neuropsychiatric disease, an understanding of the factors influencing brain morphology provides important clues about the etiology of disorders such as schizophrenia and autism.’
Postmortem brain tissue was donated by the UK Medical Research Council (MRC) London Neurodegenerative Diseases Brain Bank and the Stanley Medical Research Institute. The research was supported by grants from the US National Institutes of Health and funds from the London University Central Research Fund.
More information: Pidsley, R. et al. ‘Epigenetic and genetic variation at the IGF2/H19 imprinting control region on 11p15.5 is associated with cerebellum weight’ Epigenetics (Feb 2012) doi: 10.4161/epi.7.2.18910
