̽��ֱ�� of Cambridge - functional magnetic resonance imaging (fMRI)

Opinion: Brain scanners allow scientists to ‘read minds’ – could they now enable a ‘Big Brother’ future?

ljm67 — Mon, 13 Feb 2017 12:58:19 +0000

Are you lying? Do you have a racial bias? Is your moral compass intact? To find out what you think or feel, we usually have to take your word for it. But questionnaires and other explicit measures to reveal what’s on your mind are imperfect: you may choose to hide your true beliefs or you may not even be aware of them.

But now there is a technology that enables us to “read the mind” with growing accuracy: functional magnetic resonance imaging (fMRI). It measures brain activity indirectly by tracking changes in blood flow – making it possible for neuroscientists to observe the brain in action. Because the technology is safe and effective, fMRI has revolutionised our understanding of the human brain. It has shed light on areas important for speech, movement, memory and many other processes.

More recently, researchers have used fMRI for more elaborate purposes. One of the most remarkable studies comes from Jack Gallant’s lab at the ̽��ֱ�� of California. His team showed movie trailers to their volunteers and managed to reconstruct these video clips based on the subjects’ brain activity, using a machine learning algorithm.

In this approach, the computer developed a model based on the subject’s brain activity rather than being fed a pre-programmed solution by the researchers. ̽��ֱ��model improved with practice and after having access to enough data, it was able to decode brain activity. ̽��ֱ��reconstructed clips were blurry and the experiment involved extended training periods. But for the first time, brain activity was decoded well enough to reconstruct such complex stimuli with impressive detail.

Enormous potential

So what could fMRI do in the future? This is a topic we explore in our new book Sex, Lies, and Brain Scans: How fMRI Reveals What Really Goes on in our Minds. One exciting area is lie detection. While early studies were mostly interested in finding the brain areas involved in telling a lie, more recent research tried to actually use the technology as a lie detector.

As a subject in these studies, you would typically have to answer a series of questions. Some of your answers would be truthful, some would be lies. ̽��ֱ��computer model is told which ones are which in the beginning so it gets to know your “brain signature of lying” – the specific areas in your brain that light up when you lie, but not when you are telling the truth.

Afterwards, the model has to classify new answers as truth or lies. ̽��ֱ��typical accuracy reported in the literature is around 90%, meaning that nine out of ten times, the computer correctly classified answers as lies or truths. This is far better than traditional measures such as the polygraph, which is thought to be only about 70% accurate. Some companies have now licensed the lie detection algorithms. Their next big goal: getting fMRI-based lie detection admitted as evidence in court.

They have tried several times now, but the judges have ruled that the technology is not ready for the legal setting – 90% accuracy sounds impressive, but would we want to send somebody to prison if there is a chance that they are innocent? Even if we can make the technology more accurate, fMRI will never be error proof. One particularly problematic topic is the one of false memories. ̽��ֱ��scans can only reflect your beliefs, not necessarily reality. If you falsely believe that you have committed a crime, fMRI can only confirm this belief. We might be tempted to see brain scans as hard evidence, but they are only as good as your own memories: ultimately flawed.

fMRI scanner. wikipedia

Still, this raises some chilling questions about the possibility for a “Big Brother” future where our innermost thoughts can be routinely monitored. But for now fMRI cannot be used covertly. You cannot walk through an airport scanner and be asked to step into an interrogation room, because your thoughts were alarming to the security personnel.

Undergoing fMRI involves lying still in a big noise tube for long periods of time. ̽��ֱ��computer model needs to get to know you and your characteristic brain activity before it can make any deductions. In many studies, this means that subjects were being scanned for hours or in several sessions. There’s obviously no chance of doing this without your knowledge – or even against your will. If you did not want your brain activity to be read, you could simply move in the scanner. Even the slightest movements can make fMRI scans useless.

Although there is no immediate danger of undercover scans, fMRI can still be used unethically. It could be used in commercial settings without appropriate guidelines. If academic researchers want to start an fMRI study, they need to go through a thorough process, explaining the potential risks and benefits to an ethics committee. No such guidelines exist in commercial settings. Companies are free to buy fMRI scanners and conduct experiments with any design. They could show you traumatising scenes. Or they might uncover thoughts that you wanted to keep to yourself. And if your scan shows any medical abnormalities, they are not forced to tell you about it.

Mapping the brain in great detail enables us to observe sophisticated processes. Researchers are beginning to unravel the brain circuits involved in self control and morality. Some of us may want to use this knowledge to screen for criminals or detect racial biases. But we must keep in mind that fMRI has many limitations. It is not a crystal ball. We might be able to detect an implicit racial bias in you, but this cannot predict your behaviour in the real world.

fMRI has a long way to go before we can use it to fire or incarcerate somebody. But neuroscience is a rapidly evolving field. With advances in clever technological and analytical developments such as machine learning, fMRI might be ready for these futuristic applications sooner than we think. Therefore, we need to have a public discussion about these technologies now. Should we screen for terrorists at the airport or hire only teachers and judges who do not show evidence of a racial bias? Which applications are useful and beneficial for our society, which ones are a step too far? It is time to make up our minds.

Julia Gottwald, PhD candidate in Psychiatry, ̽��ֱ�� of Cambridge and Barbara Sahakian, Professor of Clinical Neuropsychology, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

Brain imaging can reveal a great deal about who we are and what is going inside our heads. But how far can – and should – this research take us? Julia Gottwald and Barbara Sahakian, authors of Sex, Lies, and Brain Scans: How fMRI Reveals What Really Goes on in our Minds, investigate for ̽��ֱ��Conversation.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Differences in brain structure and memory suggest adolescents may not ‘grow out of’ ADHD

cjb250 — Thu, 27 Aug 2015 10:37:33 +0000

̽��ֱ��findings, published today in the journal European Child Adolescent Psychiatry, suggest that aspects of ADHD may persist into adulthood, even when current diagnostic criteria fail to identify the disorder.

ADHD is a disorder characterised by short attention span, restlessness and impulsivity, and is usually diagnosed in childhood or adolescence. Estimates suggest that more than three in every 100 boys and just under one in every 100 girls has ADHD. Less is known about the extent to which the disorder persists into adulthood, with estimates suggesting that between 10-50% of children still have ADHD in adulthood. Diagnosis in adulthood is currently reliant on meeting symptom checklists (such as the American Psychiatric Association’s Diagnostic and Statistical Manual).

Some have speculated that as the brain develops in adulthood, children may grow out of ADHD, but until now there has been little rigorous evidence to support this. So far, most of the research that has followed up children and adolescents with ADHD into adulthood has focused on interview-based assessments, leaving questions of brain structure and function unanswered.

Now, researchers at Cambridge and Oulu have followed up 49 adolescents diagnosed with ADHD at age 16, to examine their brain structure and memory function in young adulthood, aged between 20-24 years old, compared to a control group of 34 young adults. ̽��ֱ��research was based within the Northern Finland Birth Cohort 1986, which has followed up thousands of children born in 1986 from gestation and birth into adulthood. ̽��ֱ��results showed that the group diagnosed in adolescence still had problems in terms of reduced brain volume and poorer memory function, irrespective of whether or not they still met diagnostic checklist criteria for ADHD.

By analysing the structural magnetic resonance imaging (MRI) brain scans and comparing them to the controls, the researchers found that the adolescents with ADHD had reduced grey matter in a region deep within the brain known as the caudate nucleus, a key brain region that integrates information across different parts of the brain, and supports important cognitive functions, including memory.

To investigate whether or not these grey matter deficits were of any importance, the researchers conducted a functional MRI experiment (fMRI), which measured brain activity whilst 21 of the individuals previously diagnosed with ADHD and 23 of the controls undertook a test of working memory inside the scanner.

One third of the adolescents with ADHD failed the memory test compared to less than one in twenty of the control group (an accuracy of less than 75% was classed as a fail). Even amongst the adolescent ADHD sample who passed the memory test, the scores were on average 6 percentage points less than controls. ̽��ֱ��poor memory scores seemed to relate to a lack of responsiveness in the activity of the caudate nucleus: in the controls, when the memory questions became more difficult, the caudate nucleus became more active, and this appeared to help the control group perform well; in the adolescent ADHD group, the caudate nucleus kept the same level of activity throughout the test.

There were no differences in brain structure or memory test scores between those young adults previously diagnosed with ADHD who still met the diagnostic criteria and those who no longer met them.

Dr Graham Murray from the Department of Psychiatry, ̽��ֱ�� of Cambridge, who led the study, says: “In the controls, when the test got harder, the caudate nucleus went up a gear in its activity, and this is likely to have helped solve the memory problems. But in the group with adolescent ADHD, this region of the brain is smaller and doesn’t seem to be able to respond to increasing memory demands, with the result that memory performance suffers.

“We know that good memory function supports a variety of other mental processes, and memory problems can certainly hold people back in terms of success in education and the workplace. ̽��ֱ��next step in our research will be to examine whether these differences in brain structure and memory function are linked to difficulties in everyday life, and, crucially, see if they respond to treatment.”

̽��ֱ��fact that the study was set in Finland, where medication is rarely used to treat ADHD, meant that only one of the 49 ADHD adolescents had been treated with medication. This meant the researchers could confidently rule out medication as a confounding factor.

To date, ‘recovery’ in ADHD has focused on whether people do or do not continue to meet symptom checklist criteria for diagnosis. However, this research indicates that objective measures of brain structure and function may continue to be abnormal even if diagnostic criteria are no longer met. ̽��ֱ��results therefore emphasize the importance of taking a wider perspective on ADHD outcomes than simply whether or not a particular patient meets diagnostic criteria at any given point in time.

̽��ֱ��research was funded in part by the Medical Research Council, with additional support from the Wellcome Trust and the NIHR Cambridge Biomedical Research Centre.

Reference
Roman-Urrestarazu, A et al. Brain structural deficits and working memory fMRI dysfunction in young adults who were diagnosed with ADHD in adolescence. European Child Adolescent Psychiatry; 27 Aug 2015

Young adults diagnosed with attention deficit/hyperactivity disorder (ADHD) in adolescence show differences in brain structure and perform poorly in memory tests compared to their peers, according to new research from the ̽��ֱ�� of Cambridge, UK, and the ̽��ֱ�� of Oulu, Finland.

Good memory function supports a variety of other mental processes, and memory problems can certainly hold people back in terms of success in education and the workplace

Graham Murray

mararie

ADHD

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Your brain might not be as ‘old’ as you think

cjb250 — Mon, 09 Mar 2015 09:22:10 +0000

How ‘old’ is your brain? Put another way, how ‘aged’ is your brain? ̽��ֱ��standard, scientific answer, suggests that the older you get, the greater the changes in the activity of your neurons. In fact, my colleagues and I have found out that this isn’t necessarily the case: older brains may be more similar to younger brains than we’d previously thought.

In our study, published recently in the journal Human Brain Mapping, we’ve shown that changes in the ageing brain previously observed using functional magnetic resonance imaging (fMRI) – one of the standard ways of measuring brain activity – may be due to changes in our blood vessels, rather than changes in the activity of our nerve cells, our neurons. Given the large number of fMRI studies used to assess the ageing brain, this has important consequences for understanding how the brain changes with age and it challenges current theories of ageing.

̽��ֱ��fundamental problem of fMRI is that it measures the activity of our neurons indirectly through changes in regional blood flow. Without careful correction for age differences in how the blood vessels respond, differences in fMRI signals may be erroneously regarded as differences in our neurons.

An important line of research focuses on controlling for noise in fMRI signals using additional baseline measures of vascular (blood vessel) function, for example involving experimental manipulations of carbon dioxide levels in blood. However, such methods have not been widely used, possibly because they are impractical to implement in studies of ageing.

An alternative way of correcting makes use of the resting state, ’task-free’, fMRI measurement, which is easy to acquire and available in most fMRI experiments. While this method has been difficult to validate in the past, the unique combination of an impressively detailed data set across 335 healthy volunteers over the lifespan, as part of the Cambridge Centre for Ageing and Neuroscience (CamCAN) project, has allowed us to probe the true nature of the effects of ageing on resting state fMRI signal amplitude. This showed that age differences in signal amplitude at rest – in other words, while volunteers perform no task during the scan – originate from our blood vessels, not our nerve cells. We believe we can use this as a robust correction factor to control for vascular differences in fMRI studies of ageing.

A number of research studies have previously found reduced brain activity in the areas of the brain related to our senses and movement during tasks that study these aspects. Using conventional methods, we replicated these findings, but, after correction, we found that it is more likely to be vascular health, not brain function, that accounts for most age-related differences in fMRI signals in sensory areas. In other words, neuroscientists may have been overestimating age differences in brain activity in previous fMRI studies.

Why is this important? We’re an ageing society, with more and more people living into old age, so it’s crucial that we understand how age affects how the brain functions. We clearly need to refine our fMRI experiments, otherwise we risk creating a misleading picture of activity in the brain as we age. Without refinement, such fMRI studies may misinterpret the effect of age as a cognitive phenomenon, when really it has more to do with our blood vessels.

Dr Tsvetanov is funded by the Biotechnology and Biological Sciences Research Council (BBSRC).

Reference

Tsvetanov, KA et al. ̽��ֱ��effect of ageing on fMRI: correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults. Human Brain Mapping; 27 February 2015

Our standard way of measuring brain activity could be giving us a misleading picture of how our brains age, argues Dr Kamen Tsvetanov from the Department of Psychology.

We’re an ageing society, with more and more people living into old age, so it’s crucial that we understand how age affects how the brain functions

Kamen Tsvetanov

Brain areas with rich blood supply lower their vascular reactivity with ageing

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Brain activity in sex addiction mirrors that of drug addiction

cjb250 — Fri, 11 Jul 2014 18:00:00 +0000

Although precise estimates are unknown, previous studies have suggested that as many as one in 25 adults is affected by compulsive sexual behaviour, an obsession with sexual thoughts, feelings or behaviour which they are unable to control. This can have an impact on a person’s personal life and work, leading to significant distress and feelings of shame. Excessive use of pornography is one of the main features identified in many people with compulsive sexual behaviour. However, there is currently no formally accepted definition of diagnosing the condition.

In a study funded by the Wellcome Trust, researchers from the Department of Psychiatry at the ̽��ֱ�� of Cambridge looked at brain activity in nineteen male patients affected by compulsive sexual behaviour and compared them to the same number of healthy volunteers. ̽��ֱ��patients started watching pornography at earlier ages and in higher proportions relative to the healthy volunteers.

“ ̽��ֱ��patients in our trial were all people who had substantial difficulties controlling their sexual behaviour and this was having significant consequences for them, affecting their lives and relationships,” explains Dr Valerie Voon, a Wellcome Trust Intermediate Clinical Fellow at the ̽��ֱ�� of Cambridge. “In many ways, they show similarities in their behaviour to patients with drug addictions. We wanted to see if these similarities were reflected in brain activity, too.”

̽��ֱ��study participants were shown a series of short videos featuring either sexually explicit content or sports whilst their brain activity was monitored using functional magnetic resonance imaging (fMRI), which uses a blood oxygen level dependent (BOLD) signal to measure brain activity.

̽��ֱ��researchers found that three regions in particular were more active in the brains of the people with compulsive sexual behaviour compared with the healthy volunteers. Significantly, these regions – the ventral striatum, dorsal anterior cingulate and amygdala – were regions that are also particularly activated in drug addicts when shown drug stimuli. ̽��ֱ��ventral striatum is involved in processing reward and motivation, whilst the dorsal anterior cingulate is implicated in anticipating rewards and drug craving. ̽��ֱ��amygdala is involved in processing the significance of events and emotions.

̽��ֱ��researchers also asked the participants to rate the level of sexual desire that they felt whilst watching the videos, and how much they liked the videos. Drug addicts are thought to be driven to seek their drug because they want – rather than enjoy – it. This abnormal process is known as incentive motivation, a compelling theory in addiction disorders.

As anticipated, patients with compulsive sexual behaviour showed higher levels of desire towards the sexually explicit videos, but did not necessarily rate them higher on liking scores. In the patients, desire was also correlated with higher interactions between regions within the network identified – with greater cross-talk between the dorsal cingulate, ventral striatum and amygdala – for explicit compared to sports videos.

Dr Voon and colleagues also found a correlation between brain activity and age – the younger the patient, the greater the level of activity in the ventral striatum in response to pornography. Importantly, this association was strongest in individuals with compulsive sexual behaviour. ̽��ֱ��frontal control regions of the brain – essentially, the ‘brakes’ on our compulsivity – continue to develop into the mid-twenties and this imbalance may account for greater impulsivity and risk taking behaviours in younger people. ̽��ֱ��age-related findings in individuals with compulsive sexual behaviours suggest that the ventral striatum may be important in developmental aspects of compulsive sexual behaviours in a similar fashion as it is in drug addictions, although direct testing of this possibility is needed.

“There are clear differences in brain activity between patients who have compulsive sexual behaviour and healthy volunteers. These differences mirror those of drug addicts,” adds Dr Voon. “Whilst these findings are interesting, it’s important to note, however, that they could not be used to diagnose the condition. Nor does our research necessarily provide evidence that these individuals are addicted to porn – or that porn is inherently addictive. Much more research is required to understand this relationship between compulsive sexual behaviour and drug addiction.”

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, says: “Compulsive behaviours, including watching porn to excess, over-eating and gambling, are increasingly common. This study takes us a step further to finding out why we carry on repeating behaviours that we know are potentially damaging to us. Whether we are tackling sex addiction, substance abuse or eating disorders, knowing how best, and when, to intervene in order to break the cycle is an important goal of this research.”

Pornography triggers brain activity in people with compulsive sexual behaviour – known commonly as sex addiction – similar to that triggered by drugs in the brains of drug addicts, according to a ̽��ֱ�� of Cambridge study published in the journal PLOS ONE. However, the researchers caution that this does not necessarily mean that pornography itself is addictive.

There are clear differences in brain activity between patients who have compulsive sexual behaviour and healthy volunteers

Valerie Voon

Nick Olejniczak

Browsing (cropped). Homepage image: Ecstacy by Terminallychll

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Patient in ‘vegetative state’ not just aware, but paying attention

sj387 — Thu, 31 Oct 2013 12:14:31 +0000

A patient in a seemingly vegetative state, unable to move or speak, showed signs of attentive awareness that had not been detected before, a new study reveals. This patient was able to focus on words signalled by the experimenters as auditory targets as successfully as healthy individuals. If this ability can be developed consistently in certain patients who are vegetative, it could open the door to specialised devices in the future and enable them to interact with the outside world.

̽��ֱ��research, by scientists at the Medical Research Council Cognition and Brain Sciences Unit (MRC CBSU) and the ̽��ֱ�� of Cambridge, is published today, 31 October, in the journal Neuroimage: Clinical.

For the study, the researchers used electroencephalography (EEG), which non-invasively measures the electrical activity over the scalp, to test 21 patients diagnosed as vegetative or minimally conscious, and eight healthy volunteers. Participants heard a series of different words - one word a second over 90 seconds at a time - while asked to alternatingly attend to either the word ‘yes’ or the word ‘no’, each of which appeared 15% of the time. (Some examples of the words used include moss, moth, worm and toad.) This was repeated several times over a period of 30 minutes to detect whether the patients were able to attend to the correct target word.

They found that one of the vegetative patients was able to filter out unimportant information and home in on relevant words they were being asked to pay attention to. Using brain imaging (fMRI), the scientists also discovered that this patient could follow simple commands to imagine playing tennis. They also found that three other minimally conscious patients reacted to novel but irrelevant words, but were unable to selectively pay attention to the target word.

These findings suggest that some patients in a vegetative or minimally conscious state might in fact be able to direct attention to the sounds in the world around them.

Dr Srivas Chennu at the ̽��ֱ�� of Cambridge, said: ”Not only did we find the patient had the ability to pay attention, we also found independent evidence of their ability to follow commands – information which could enable the development of future technology to help patients in a vegetative state communicate with the outside world.

“In order to try and assess the true level of brain function and awareness that survives in the vegetative and minimally conscious states, we are progressively building up a fuller picture of the sensory, perceptual and cognitive abilities in patients. This study has added a key piece to that puzzle, and provided a tremendous amount of insight into the ability of these patients to pay attention.”

Dr Tristan Bekinschtein at the MRC Cognition and Brain Sciences Unit said: “Our attention can be drawn to something by its strangeness or novelty, or we can consciously decide to pay attention to it. A lot of cognitive neuroscience research tells us that we have distinct patterns in the brain for both forms of attention, which we can measure even when the individual is unable to speak. These findings mean that, in certain cases of individuals who are vegetative, we might be able to enhance this ability and improve their level of communication with the outside world.”

This study builds on a joint programme of research at the ̽��ֱ�� of Cambridge and MRC CBSU where a team of researchers have been developing a series of diagnostic and prognostic tools based on brain imaging techniques since 1998. Famously, in 2006 the group was able to use fMRI imaging techniques to establish that a patient in a vegetative state could respond to yes or no questions by indicating different, distinct patterns of brain activity.

Research raises possibility of devices in the future to help some patients in a vegetative state interact with the outside world.

These findings mean that, in certain cases of individuals who are vegetative, we might be able to [...] improve their level of communication with the outside world

Dr Tristan Bekinschtein

Clinical Neurosciences

This scan depicts patterns of the vegetative patient's electrical activity over the head when they attended to the designated words, and when they when they were distracted by novel but irrelevant words

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Looking into the brain

bjb42 — Tue, 04 Jan 2011 16:15:11 +0000

Neurosurgeon Professor John Pickard is chairman and clinical director of the centre, which uses state-of-the-art positron emission tomography (PET) and magnetic resonance imaging (MRI). “Nobody else in the world has got the kind of facilities that we have,” he says. “These unique facilities have enabled a number of breakthroughs in research. We now have new insights into what happens in the brain as patients emerge from a coma, as well as which parts of the brain are affected by hydrocephalus (‘water on the brain’).”

Doctors are now able to predict the risk of a stroke and distinguish between different types of dementia. Researchers have also used the MRI equipment in new ways to detect how malignant brain tumours spread through the brain and hence focus radiotherapy more appropriately. Other research breakthroughs include the identification of areas of the brain involved in appetite and recognition of facial emotion, leading to new concepts of how brain malfunction may lead to eating disorders and autism. And knowledge gained at the WBIC has helped researchers design new equipment such as the patented scanner that combines PET with MRI, tackling the key problem of how to localise and resolve in fine detail the distribution of novel chemicals within the living brain.

̽��ֱ��Centre’s mission is to advance the understanding and management of the most challenging and critically ill of patients with disorders of the brain, spinal cord and mind from initial illness through rehabilitation to final outcome.

In the last 20 years, death rates for people with acute brain injury have been almost halved because of good medical care. And that does not mean simply keeping people alive – the proportion of severely disabled patients and those in a vegetative state has fallen too. “We are trying to improve the management of patients with acute brain injury and to explore exciting new drugs,” says Pickard. He believes strongly that society still does not understand the need for urgency in managing patients with all forms of ‘brain attack’ and the need for timely rehabilitation. For example, people should act far more quickly on signs of a minor stroke – like short periods when a person is unable to speak – because so much can be done to help. “One of the problems we have to change is the perception of the general public that once you have had a stroke, there is nothing you can do about it. That is not true. If you have a stroke and have treatment, you can avoid ending up in a nursing home for the next 10 or 20 years.” he says.

www.wbic.cam.ac.uk/

̽��ֱ��Wolfson Brain Imaging Centre is a unique venture that brings together scientists and doctors from Cambridge ̽��ֱ�� and Cambridge’s Addenbrookes Hospital for the development of new treatments for patients with brain disorders.

We are trying to improve the management of patients with acute brain injury and to explore exciting new drugs,

John Pickard

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Sunlight and Shadow

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Obsessive compulsive disorder linked to brain activity

bjb42 — Wed, 16 Jul 2008 00:00:00 +0000

As the current diagnosis of OCD is based on a clinical interview and often does not occur until the disorder has progressed, this could enable earlier more objective detection, and intervention.

̽��ֱ��scientists, funded by the Medical Research Council and Wellcome Trust, have discovered that people with OCD and their close family members show under-activation of brain areas responsible for stopping habitual behaviour. This is the first time that scientists have associated functional changes in the brain with familial risk for the disorder. Their findings are reported in the 18 July edition of Science.

Obsessive compulsive disorder is a debilitating condition that affects 2-3% of the population at some point in life. Patients suffer from recurrent intrusive thoughts (obsessions) that are distressing and hard to suppress. Examples include fears of contamination, or that something terrible will happen to a loved one. They also suffer from repetitive rituals (compulsions), which are often designed to neutralise these thoughts. Examples include hand-washing and checking gas hobs. These symptoms cause distress and can occupy hours during the day, interfering with quality of life and the ability to work.

Although OCD tends to run in families, genetic factors responsible for this heritability are not known. Genes may pose a risk for OCD by influencing how the brain develops.

Dr Samuel Chamberlain at the ̽��ֱ�� of Cambridge's Department of Psychiatry used functional magnetic resonance imaging (fMRI) to measure brain activity in the lateral orbitofrontal cortex (OFC). Located in the frontal lobes the lateral OFC is involved in decision making and behaviour.

Volunteers were asked to look at two pictures on a screen, each image had a house and a face superimposed. ̽��ֱ��volunteers were asked to use trial and error to work out whether the house or face was the correct target. Volunteers pressed a button to indicate which image they believed to be the target and feedback of 'correct' or 'incorrect' was given on the screen. After the correct target had been identified six times in a row it changed so the volunteer had to learn again. fMRI was used to monitor their patterns of brain activity throughout.

Fifteen volunteers without a family history of OCD, 14 people with OCD and 12 immediate relatives of these patients took the picture test. Later comparison of fMRI images of their brain activity throughout showed under-activation in the lateral orbitofrontal cortex and other brain areas in both the OCD patients and their family members.

Dr Chamberlain, who led the study, explains, "Impaired function in brain areas controlling flexible behaviour probably predisposes people to developing the compulsive rigid symptoms that are characteristic of OCD. This study shows that these brain changes run in families and represent a candidate vulnerability factor. ̽��ֱ��current diagnosis of OCD is subjective and improved understanding of the underlying causes of OCD could lead to more accurate diagnosis and improved clinical treatments.

"However, much work is still needed to identify the genes contributing to abnormal brain function in those at risk of OCD. We also need to investigate not only vulnerability factors, but also protective factors that account for why many people at genetic risk of the condition never go on to develop the symptoms."

Cambridge researchers have discovered that measuring activity in a region of the brain could help to identify people at risk of developing obsessive compulsive disorder (OCD).

Impaired function in brain areas controlling flexible behaviour probably predisposes people to developing the compulsive rigid symptoms that are characteristic of OCD.

Dr Samuel Chamberlain

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brain

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Why are we so fat?

bjb42 — Sun, 01 Apr 2007 15:56:04 +0000

One of the most important public health issues of today is obesity. Why do people gain weight? Is it simply about eating too much food and taking too little exercise? Why do some people gain a lot of weight while others stay thin yet share the same environment? Dr Sadaf Farooqi, working with Professor Stephen O’Rahilly in the ̽��ֱ�� Department of Clinical Biochemistry, is helping to answer some of these questions.

Obesity is defined as an excess of body fat that’s large enough to result in adverse consequences for health – the most common being high blood pressure, type 2 diabetes, coronary heart disease and certain cancers. Although calculating exactly how much body fat a person has requires sophisticated techniques, we usually use body mass index or BMI (weight in kilograms/height in metres squared) as a measure of heaviness as it correlates reasonably well with body fat content. Obesity is defined as a BMI greater than 30 kg/m2.

In the UK, current estimates of obesity indicate that 23% of men and 24% of women are obese. ̽��ֱ��World Health Organization has warned that obesity has reached epidemic proportions globally, with more than 1 billion adults overweight and is now ‘a major contributor to the global burden of chronic disease and disability.’

Why is obesity on the increase? We live in an age of increased availability of palatable, energy-dense foods and yet we have a reduced requirement for physical exertion during our working and domestic life. All this contributes to a state of positive energy balance, which over a period of time is enough to shift the mean BMI of a population. Obesity can run in families, which might point to the sharing of a common lifestyle but might also point to a genetic link. In fact, the heritability of body weight and fat mass is very high, at 40–70%, based on studies in twins and adopted children. How can we find the genes that control body weight?

Finding the ‘fat’ genes

Dr Sadaf Farooqi and her colleagues have made progress in uncovering the molecular basis of obesity by focusing on patients who have severe forms of the condition. Many of the patients they study are extremely obese from a young age, with excessive food consumption beyond what is needed for their basic energy requirements – a type of behaviour known as hyperphagia.

̽��ֱ��story began a decade ago, with the finding of two severely obese Pakistani cousins with uncontrollable appetites. Dr Farooqi’s studies revealed that the children had undetectable levels of a protein called leptin in their serum and further analysis showed that they carried homozygous mutations in the leptin gene. ̽��ֱ��story unfolded as other families were identified with mutations either in this gene or in the receptor that binds leptin. When the patients were given daily injections of synthetic leptin in a clinical trial, dramatic beneficial effects were seen: within two weeks, the uncontrollable food-seeking behaviour had normalised, and their body weight and fat mass slowly reduced to normal levels.

To date, the team have identified seven genes that, when defective, result in severe obesity in children. All are part of the leptin–melanocortin system and all are involved in the control of appetite. One of these, the gene encoding the melanocortin receptor MC4R, is turning out to be the commonest single gene disorder causing obesity, with mutations found in 0.1% of the general population, a prevalence higher than for cystic fibrosis. Dr Farooqi and colleagues have studied 2000 severely obese individuals as part of the Genetics of Obesity Study (GOOS), discovering that as many as 5–6% of participants have pathogenic mutations in this gene.

Unfortunately no therapy yet exists for patients with MC4R deficiency, although much has been learnt about how mutations change the structure and function of the receptor and also about the range of associated clinical problems. By studying over 150 patients with MC4R deficiency, Dr Farooqi and colleagues have shown that when MC4R doesn’t work at all, this leads to a more severe form of the disease. This is even reflected in the amount of food eaten. People with a defective MC4R eat much more when given free access to food at a test meal, compared with people in whom the MC4R gene is working at 50%. This shows that MC4R acts as a brake on food intake and suggests that targeting MC4R may be useful as a treatment for obesity.

It’s all in the mind

Eating behaviour results from the innate drive to eat. Although this is genetically determined, it’s also influenced by the hedonic or rewarding properties of food – which can override the biological cues that govern hunger and fullness and result in hyperphagia. Eating behaviour is unique in that some of the key molecular determinants of the drive to eat are being identified. ̽��ֱ��genetic disorders involving the leptin–melanocortin pathway studied by Dr Farooqi affect a signalling pathway that starts with leptin released from fat calls and leads back to the hypothalamus in the brain. Studies in patients with defects in the proteins involved in this pathway should provide the opportunity to find out how the biological pathways link with the reward pathways to influence eating behaviour.

̽��ֱ��drive to eat: what’s next?

Progress towards defining the molecular basis of obesity in some patients has helped not only to suggest treatment strategies but also to highlight that, for many people, theirs is a medical condition. ̽��ֱ��seven disorders found so far are likely to be joined by the identification of many other gene defects that lead to severe obesity. These findings provide insights into the pathways that regulate body weight, which in turn is a starting point for developing treatments that may well be applicable to more common forms of obesity.

Although several groups in the UK have recently identified the first gene, FTO, that increases the risk of common obesity in the population, uncovering the basis of common forms of obesity or more subtle genetic defects will undoubtedly prove harder, and new approaches to assessing obesity are an attractive option. One new avenue of research has been to look directly at what is happening in the brain in response to food. Considerable experience exists in Cambridge in the use of imaging techniques to study brain function and to assess human behaviour in conjunction with biological correlates. Recent advances in these technologies are helping scientists to understand the brain pathways involved in eating behaviour. Dr Farooqi is working with Dr Paul Fletcher in the Department of Psychiatry and Drs Andrew Lawrence and Andy Calder at the Medical Research Council (MRC) Cognition and Brain Sciences Unit on one such technique. They are using functional magnetic resonance imaging (fMRI) to measure patterns of brain activity when people see images of food compared with everyday items such as toys, trees and trains. It is hoped that these studies will shed light on the areas of the brain involved in food reward and explain why some people have uncontrollable urges to eat.

For more information, please contact the author Dr Sadaf Farooqi (isf20@cam.ac.uk) at the Department of Clinical Biochemistry. This research is supported by the Wellcome Trust and the MRC, and the functional imaging studies are supported by an endowment from the WOCO Foundation.

For some people, the urge to eat is uncontrollable. Cambridge scientists have taken us a step closer to understanding the causes of obesity by studying a group of patients for whom overeating is an everyday event.

Dr Sadaf Farooqi

Functional MRI scan

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