̽��ֱ�� of Cambridge - schizophrenia

New approach to drug discovery could lead to personalised treatment of neuropsychiatric disorders

erh68 — Wed, 08 May 2019 18:00:00 +0000

Mental health disorders are the leading cause of disability worldwide, accounting for 31% of total years lived with disability. While our understanding of the biology behind these disorders has increased, no new neuropsychiatric drugs with improved treatment effects have been developed in the last few decades, and most existing treatments were found through luck.

This is mainly because doctors can’t take brain tissue samples from patients in the same way that they are able to do a biopsy on a cancer tumour elsewhere in the body for example, so it’s difficult for researchers to understand exactly what to target when designing new neuropsychiatric drugs.

Now, a team of scientists led by the ̽��ֱ�� of Cambridge have shown that live blood cells from patients with mental health disorders can be used to identify potential targets for drug discovery research. Their results are reported in the journal Science Advances.

Human blood cells contain many receptors and proteins involved in signalling that are also found in our central nervous system and have been shown to be linked to neuropsychiatric disorders. Previous research has shown that there is a strong link between cells in our blood and the way our central nervous system operates, for example patients suffering from bacterial infections often show depressive-like symptoms.

This makes blood cells an ideal environment in which to test potential new drugs. There is also significant evidence that using primary cells from patients in drug development leads to a higher success rate for effective drug discovery.

“Psychiatric disorders are increasingly recognised as disorders of the whole body,” said Professor Sabine Bahn from Cambridge’s Department of Chemical Engineering and Biotechnology, who leads the research group behind the work. “This study proposes a shift in the field to directly explore live cellular function as a model for disease.”

Using a high-content single-cell screening process, the researchers analysed cells from 42 schizophrenia patients and screened thousands of potential compounds for new drugs. ̽��ֱ��team have focused on discovering new psychiatric uses for drugs which are routinely prescribed for other conditions, such as high blood pressure.

This drug ‘repurposing’ strategy can reduce the time and cost it takes to bring a new drug to the clinic tenfold. With an average drug development cost of $2-3 billion over 12 years, this represents an efficient alternative to deliver new potential treatments to patients in considerably less time. ̽��ֱ��approach could also lead to a reduction in animal testing.

They can also test existing psychiatric treatments on patient blood cells and may be able to predict how effective those treatments will be for each individual. This overcomes a major hurdle in clinical psychiatry as many patients do not respond to first-line treatments. To accomplish this, the team tested rare blood samples from schizophrenia patients before and after clinical treatment, collected via a network of international collaborators.

As a final step, the team confirmed that the activity of new drugs was shared between blood cells and brain cells, by testing those drug compounds on human nerve cells.

“This is the most in-depth, functional exploration of primary psychiatric patient tissue to date and has the potential to substantially accelerate drug discovery and personalised medicine for neuropsychiatric disorders and other human diseases,” said lead author Dr Santiago Lago, who developed the technology with Dr Jakub Tomasik.

̽��ֱ��research was funded in part by the Stanley Medical Research Institute, the Engineering and Physical Sciences Research Council and the European Union.

Reference:
Santiago G. Lago et al. ‘Drug discovery for psychiatric disorders using high-content single-cell screening of signalling network responses ex vivo.’ Science Advances (2019). DOI: 10.1126/sciadv.aau9093

Researchers have developed a method that could drastically accelerate the search for new drugs to treat mental health disorders such as schizophrenia.

Psychiatric disorders are increasingly recognised as disorders of the whole body

Sabine Bahn

Santiago Lago

Drug target in neurons

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Scientists identify mechanism that helps us inhibit unwanted thoughts

cjb250 — Fri, 03 Nov 2017 09:13:20 +0000

We are sometimes confronted with reminders of unwanted thoughts — thoughts about unpleasant memories, images or worries. When this happens, the thought may be retrieved, making us think about it again even though we prefer not to. While being reminded in this way may not be a problem when our thoughts are positive, if the topic was unpleasant or traumatic, our thoughts may be very negative, worrying or ruminating about what happened, taking us back to the event.

“Our ability to control our thoughts is fundamental to our wellbeing,” explains Professor Michael Anderson from the Medical Research Council Cognition and Brain Sciences Unit, which recently transferred to the ̽��ֱ�� of Cambridge. “When this capacity breaks down, it causes some of the most debilitating symptoms of psychiatric diseases: intrusive memories, images, hallucinations, ruminations, and pathological and persistent worries. These are all key symptoms of mental illnesses such as PTSD, schizophrenia, depression, and anxiety.”

Professor Anderson likens our ability to intervene and stop ourselves retrieving particular memories and thoughts to stopping a physical action. “We wouldn’t be able to survive without controlling our actions,” he says. “We have lots of quick reflexes that are often useful, but we sometimes need to control these actions and stop them from happening. There must be a similar mechanism for helping us stop unwanted thoughts from occurring.”

A region at the front of the brain known as the prefrontal cortex is known to play a key role in controlling our actions and has more recently been shown to play a similarly important role in stopping our thoughts. ̽��ֱ��prefrontal cortex acts as a master regulator, controlling other brain regions – the motor cortex for actions and the hippocampus for memories.

In research published today in the journal Nature Communications, a team of scientists led by Dr Taylor Schmitz and Professor Anderson used a task known as the ‘Think/No-Think’ procedure to identify a significant new brain process that enables the prefrontal cortex to successfully inhibit our thoughts.

In the task, participants learn to associate a series of words with a paired, but otherwise unconnected, word, for example ordeal/roach and moss/north. In the next stage, participants are asked to recall the associated word if the cue is green or to suppress it if the cue is red; in other words, when shown ‘ordeal’ in red, they are asked to stare at the word but to stop themselves thinking about the associated thought ‘roach’.

Using a combination of functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy, the researchers were able to observe what was happening within key regions of the brain as the participants tried to inhibit their thoughts. Spectroscopy enabled the researchers to measure brain chemistry, and not just brain activity, as is usually done in imaging studies.

Professor Anderson, Dr Schmitz and colleagues showed that the ability to inhibit unwanted thoughts relies on a neurotransmitter – a chemical within the brain that allows messages to pass between nerve cells – known as GABA. GABA is the main ‘inhibitory’ neurotransmitter in the brain, and its release by one nerve cell can suppress activity in other cells to which it is connected. Anderson and colleagues discovered that GABA concentrations within the hippocampus – a key area of the brain involved in memory – predict people’s ability to block the retrieval process and prevent thoughts and memories from returning.

“What’s exciting about this is that now we’re getting very specific,” he explains. “Before, we could only say ‘this part of the brain acts on that part’, but now we can say which neurotransmitters are likely important – and as a result, infer the role of inhibitory neurons – in enabling us to stop unwanted thoughts.”

“Where previous research has focused on the prefrontal cortex – the command centre – we’ve shown that this is an incomplete picture. Inhibiting unwanted thoughts is as much about the cells within the hippocampus – the ‘boots on the ground’ that receive commands from the prefrontal cortex. If an army’s foot-soldiers are poorly equipped, then its commanders’ orders cannot be implemented well.”

̽��ֱ��researchers found that even within his sample of healthy young adults, people with less hippocampal GABA (less effective ‘foot-soldiers’) were less able to suppress hippocampal activity by the prefrontal cortex—and as a result much worse at inhibiting unwanted thoughts.

̽��ֱ��discovery may answer one of the long-standing questions about schizophrenia. Research has shown that people affected by schizophrenia have ‘hyperactive’ hippocampi, which correlates with intrusive symptoms such as hallucinations. Post-mortem studies have revealed that the inhibitory neurons (which use GABA) in the hippocampi of these individuals are compromised, possibly making it harder for the prefrontal cortex to regulate activity in this structure. This suggests that the hippocampus is failing to inhibit errant thoughts and memories, which may be manifest as hallucinations.

According to Dr Schmitz: “ ̽��ֱ��environmental and genetic influences that give rise to hyperactivity in the hippocampus might underlie a range of disorders with intrusive thoughts as a common symptom.”

In fact, studies have shown that elevated activity in the hippocampus is seen in a broad range of conditions such as PTSD, anxiety and chronic depression, all of which include a pathological inability to control thoughts – such as excessive worrying or rumination.

While the study does not examine any immediate treatments, Professor Anderson believes it could offer a new approach to tackling intrusive thoughts in these disorders. “Most of the focus has been on improving functioning of the prefrontal cortex,” he says, “but our study suggests that if you could improve GABA activity within the hippocampus, this may help people to stop unwanted and intrusive thoughts.”

̽��ֱ��research was funded by the Medical Research Council.

Reference
Schmitz, TW et al. Hippocampal GABA enables inhibitory control over unwanted thoughts. Nature Communications; 3 Nov 2017; DOI: 10.1038/s41467-017-00956-z

Scientists have identified a key chemical within the ‘memory’ region of the brain that allows us to suppress unwanted thoughts, helping explain why people who suffer from disorders such as anxiety, post-traumatic stress disorder (PTSD), depression, and schizophrenia often experience persistent intrusive thoughts when these circuits go awry.

Our ability to control our thoughts is fundamental to our wellbeing. When this capacity breaks down, it causes some of the most debilitating symptoms of psychiatric diseases

Michael Anderson

Jacob Bøtter

Thinking RFIP

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Opinion: How mapping teenagers’ brains has helped us understand more about schizophrenia

ljm67 — Wed, 15 Mar 2017 10:47:28 +0000

When I was studying for my PhD at the ̽��ֱ�� of California at Berkeley, I spent an awful lot of my weekends asking teenagers to lie still in a magnetic resonance imaging (MRI) scanner. While they were lying as still as they could they also had to answer questions they saw on the screen.

We were interested in which parts of the brain these young people were using when they completed an analogical reasoning task. They saw three pictures and were asked to choose the fourth picture to complete the relationships, for example dress is to wardrobe, as milk is to fridge.

We found that association cortex – the parts of the brain that bring together information from many other regions – was used to answer these questions and, importantly, that these regions are activated more and more as you get older. ̽��ֱ��study was recently published in Developmental Science.

A question teenagers answered during a functional MRI scan. Association cortex was activated during this task (top right, orange) and regions in prefrontal cortex were more active as participants got older (bottom right, red). Kirstie Whitaker

Fast forward a few years and I’m now a member of the Neuroscience in Psychiatry Network (NSPN), a collaboration between the ̽��ֱ�� of Cambridge and ̽��ֱ�� College London, funded by the Wellcome Trust.

NSPN aims to better understand the biological mechanisms that lead to young people developing a variety of mental health disorders. ̽��ֱ��network includes experts in epidemiology, adolescent psychopathology, cognition and brain development who are investigating the question of adolescent mental health from multiple angles.

Beautiful brains

I’m in the MRI team, which has collected brain scans from 300 young people between the ages of 14 and 24. This time, instead of asking them to complete questions while they were lying in the scanner, we took structural MRI scans. These are different to the brain scans we use to assess what the brain is doing (“functional MRI”) and they look really beautiful.

A vertical slice through the author’s head using a structural MRI. Cortical thickness (the distance between the red and yellow lines) decreases during the teenage years as adolescents refine their brain networks. Kirstie Whitaker

One of the measures we extract is “cortical thickness” – the depth of the outside layer of the brain (the cortex) that contains synapses. A synapse is where two brain cells (neurons) join together and transmit messages. We have around 100 billion neurons but 100 trillion synapses in our brains. It is the complexity of these connections that allows humans to generate and understand complex thoughts and feelings, including being able to solve analogies in the real world.

Changing minds

In work published in the Proceedings of the National Academy of Science in 2016 the NSPN consortium showed that the cortex got thinner between the ages of 14 and 24. In particular, association cortex – the same regions that are used for complex thought and reasoning – showed the greatest amount of change.

This finding may seem counter-intuitive – at first glance you’d imagine that getting better at something would mean having more brain cells working on the project. In fact, you are born with more neurons than you’ll ever have again, and one of the most important developmental processes is “synaptic refinement” – pruning away some of the connections to ensure your brain is working efficiently.

We also looked at the brain as a network. You can imagine an airline network with connections going around the world between different airports. ̽��ֱ��really important locations are network “hubs” – they have lots of flights in and out every day. In the brain, we found that these hubs are located in association cortex. It makes sense that the brain regions that are important for complex thought need information to liaise with many other different parts of the brain.

̽��ֱ��brain as a network: different brain regions (nodes) are connected by edges. These regions show prolonged development during adolescence and are important for complex thought.

We found that the hubs of the brain’s structural network change most during adolescence. This is likely to reflect prolonged development for these regions – the other parts of the brain are closer to their adult structure and have slowed down by the age of 14. If you think back to my descriptions of synapses being pruned away, it makes sense to keep as many as you need for a long time, until you’re sure of which connections are going to allow you to best reason in the complex world around you.

I made a big deal earlier about the fact that we can not see the actual cells and connections in the brain using MRI. However, innovative work by Petra Vértes and data shared by the Allen Institute for Brain Science gives us some clues as to what is going on at the cellular level in these brain regions.

̽��ֱ��Allen Institute has measured the expression of 20,000 genes at 500 locations around the brains of six brains donated to research after their owner died. Vértes showed that the brain regions in association cortex – the same ones that change structurally the most during the teenage years – have greater expression of genes related to synaptic plasticity. This means that genes controlling how our brain cells adapt their connections based on our experiences are more active in these regions.

These regions are also related to genes associated with schizophrenia – a psychiatric disorder that is most likely to emerge during the late teenage years. Our work provides evidence for a mechanism as to why people with a genetic risk for schizophrenia may not experience symptoms until they are around 20-years-old. ̽��ֱ��affected brain regions are still developing and it may take these many years before the differences in brain structure are big enough to cause the hallucinations and delusions associated with this mental health disorder.

There is still a long way to go in our search to understand the biological underpinnings of mental health disorders. We will continue to work together, both within the Neuroscience in Psychiatry Network and with other researchers around the world, to find treatments for mental health disorders, and, if possible, to find ways to prevent the symptoms from emerging all together.

̽��ֱ��author is appearing on March 21 as part of the Cambridge Science Festival.

Kirstie Whitaker, Research Associate, Department of Psychiatry, ̽��ֱ�� of Cambridge

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

Teenage years can be difficult enough, but for people affected by schizophrenia, this is when symptoms first tend to arise. Dr Kirstie Whitaker (Department of Psychiatry), who is speaking at this year's Cambridge Science Festival, explains in ̽��ֱ��Conversation how her work may shed light on why this is the case.

Kirstie Whitaker

̽��ֱ��brain’s structural network. ̽��ֱ��hubs of this network continue to develop during adolescence.

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Facebook updates could provide a window to understanding – and treating – mental health disorders

cjb250 — Thu, 27 Oct 2016 23:02:16 +0000

Over a billion people worldwide use Facebook daily – one in seven of the global population – and social media use is increasing at three times the rate of other internet use. Evidence suggests that 92% of adolescents use the site daily and disclose considerably more about themselves online than offline.

Writing in today’s edition of Lancet Psychiatry, researchers from the ̽��ֱ�� of Cambridge discuss how social networking sites might be harnessed to provide data to help further our understanding of the onset and early years of mental illness.

“Facebook is hugely popular and could provide us with a wealth of data to improve our knowledge of mental health disorders such as depression and schizophrenia,” says Dr Becky Inkster, the study’s lead-author, from the Department of Psychiatry. “Its reach is particularly broad, too, stretching across the digital divide to traditionally hard-to-reach groups including homeless youth, immigrants, people with mental health problems, and seniors.”

Dr Inkster and her colleagues argue that Facebook might be used to help improve the detection of mental health factors. Dr Michal Kosinski, co-author from Stanford Graduate Business School, adds that Facebook data tends to be more reliable than offline self-reported information, while still reflecting an individual’s offline behaviours. It also enables researchers to measure content that is difficult to assess offline, such as conversation intensity, and to reach sample sizes previously unobtainable.

Status updates, shares and likes can provide a wealth of information about users, they say. A previous study of 200 US college students over the age of 18 years found that one in four posted status updates showing depressive-like symptoms. By analysing the language, emotions and topics used in status updates, the researchers say that it may be possible to look for symptoms or early signs of mental illness. Even photographs might provide new insights; Facebook is the world’s largest photo sharing website, with some 350 million photos uploaded daily, and automated picture analysis of emotional facial expressions might offer unique representations of offline behaviours.

Studies have shown that social networks can have both positive and negative effects on user’s emotions. Being ‘unfriended’ can elicit negative emotions, but even an individuals’ News Feed, which reports what their friends are up to, can affect their mood: one study found that a reduction of the amount of positive content displayed by friends led to an increase in negative status updates by users, and vice-versa. Other research has shown that some people with mental health disorders report positive experiences of social media, suggesting that Facebook might be harnessed to offer people support. People with schizophrenia and psychosis, for example, have reported that social networking sites helped them socialise and did not worsen their symptoms.

̽��ֱ��researchers suggest that the use of therapies based on users’ Facebook pictures and timelines could be trialled as possible ways to use online social networks to support individuals. This might assist with accessing autobiographical memories, which can be impaired in conditions such as depression, and for improving cognition and mood with older patients, similar to offline therapies for early dementia.

“Facebook relationships may help those with reduced self-esteem and provide companionship for individuals who are socially isolated,” says Dr Becky Inkster. “We know that socially isolated adolescents are more likely to suffer from depression and suicidal thoughts, so these online stepping stones could encourage patients to reform offline social connections.”

These online – potentially leading to offline – social connections can provide support for vulnerable individuals such as homeless youth, a population at increased risk of mental health problems. Research has shown that this support is associated with a reduction in their alcohol intake and a decrease in depression-like symptoms. Unlike virtual patient communities, an advantage of using social networking sites, especially Facebook, is that people naturally use them in their daily lives, which addresses concerns about the limited duration of participation in virtual communities.

Early detection of digital warning signs could enhance mental health service contact and improve service provision, the researchers say. Facebook already allows users who are worried about a friend’s risk of suicide to report the post, for example. However, the use of social networking sites in the context of mental health and young people raises potential ethical issues. Vulnerable individuals will need to fully understand what participation in psychiatry research and mental health-care practice involves and that consent is monitored throughout the various stages of their illness.

“People are uneasy at the idea of having their social media monitored and their privacy infringed upon, so this is something that will need to be handled carefully,” says co-author Dr David Stillwell from the Cambridge Judge Business School. “To see this, we only have to look at the recent furore that led to the abrupt suspension of the Samaritans’ Radar Twitter app, which with the best of intentions enabled users to monitor their friends’ Twitter activity for suicidal messages.”

Much of this research is still in its infancy and evidence is often anecdotal or insufficient, argue the team. Several issues need addressing, such as whether using social media might interfere with certain illnesses or symptoms more than others – such as digital surveillance-based paranoid themes – and to ensure confidentiality and data protection rights for vulnerable people. But they are optimistic about its potential uses.

“Although it isn’t clear yet how social networking sites might best be used to improve mental health care, they hold considerable promise for having profound implications that could revolutionise mental healthcare,” says Dr Inkster.

Reference
Becky Inkster, David Stillwell, Michal Kosinski, Peter Jones. A decade into Facebook: where is psychiatry in the digital age? Lancet Psychiatry; 27 Oct 2016; DOI: 10.1016/S2215-0366(16)30041-4

Our Facebook status updates, ‘likes’ and even photos could help researchers better understand mental health disorders with the right ethical safeguards, argue researchers from the ̽��ֱ�� of Cambridge, who suggest that social networks may even be used in future to provide support and interventions, particularly among young people.

Facebook is hugely popular and could provide us with a wealth of data to improve our knowledge of mental health disorders such as depression and schizophrenia

Becky Inkster

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Changes in brain structure during teenage years provide clues to onset of mental health problems

cjb250 — Mon, 25 Jul 2016 19:00:37 +0000

In a study published today in the Proceedings of the National Academy of Sciences, researchers from the ̽��ֱ�� of Cambridge and ̽��ֱ�� College London (UCL) used magnetic resonance imaging (MRI) to study the brain structure of almost 300 individuals aged 14-24 years old.

By comparing the brain structure of teenagers of different ages, they found that during this important period of development, the outer regions of the brain, known as the cortex, shrink in size, becoming thinner. However, as this happens, levels of myelin – the sheath that ‘insulates’ nerve fibres, allowing them to communicate efficiently – increase within the cortex.

Previously, myelin was thought mainly to reside in the so-called ‘white matter’, the brain tissue that connects areas of the brain and allows for information to be communicated between brain regions. However, in this new study, the researchers show that it can also be found within the cortex, the ‘grey matter’ of the brain, and that levels increase during teenage years. In particular, the myelin increase occurs in the ‘association cortical areas’, regions of the brain that act as hubs, the major connection points between different regions of the brain network.

Dr Kirstie Whitaker from the Department of Psychiatry at the ̽��ֱ�� of Cambridge, the study’s joint first author, says: “During our teenage years, our brains continue to develop. When we’re still children, these changes may be more dramatic, but in adolescence we see that the changes refine the detail. ̽��ֱ��hubs that connect different regions are becoming set in place as the most important connections strengthen. We believe this is where we are seeing myelin increasing in adolescence.”

̽��ֱ��researchers compared these MRI measures to the Allen Brain Atlas, which maps regions of the brain by gene expression – the genes that are ‘switched on’ in particular regions. They found that those brain regions that exhibited the greatest MRI changes during the teenage years were those in which genes linked to schizophrenia risk were most strongly expressed.

Dr Petra Vértes, the other first author, also from the Department of Psychiatry explains: "A lot of information already exists on the function of various genes: which parts of the cell they are important for, what biological processes they are involved in and which diseases they are associated with. Matching up MRI brain maps with the Allen Brain Atlas allows us to make connections between large-scale brain changes observed through MRI – such as thinning of the cortex – and the microscopic biological processes that are likely to underpin these changes and which may be compromised in certain disorders."

“Adolescence can be a difficult transitional period and it’s when we typically see the first signs of mental health disorders such as schizophrenia and depression,” explains Professor Ed Bullmore, Head of Psychiatry at Cambridge. “This study gives us a clue why this is the case: it’s during these teenage years that those brain regions that have the strongest link to the schizophrenia risk genes are developing most rapidly.

“As these regions are important hubs that control how regions of our brain communicate with each other, it shouldn’t be too surprising that when something goes wrong there, it will affect how smoothly our brains work. If one imagines these major hubs of the brain network to be like international airports in the airline network, then we can see that disrupting the development of brain hubs could have as big an impact on communication of information across the brain network as disruption of a major airport, like Heathrow, will have on flow of passenger traffic across the airline network.”

̽��ֱ��researchers are confident about the robustness of their findings as they divided their participants into a ‘discovery cohort’ of 100 young people and a ‘validation cohort’ of almost 200 young people to ensure the results could be replicated.

̽��ֱ��study was funded by a Strategic Award from the Wellcome Trust to the Neuroscience in Psychiatry Network (NSPN) Consortium.

Dr Raliza Stoyanova in the Neuroscience and Mental Health team at Wellcome, which funded the study, comments: “A number of mental health conditions first manifest during adolescence. Although we know that the adolescent brain undergoes dramatic structural changes, the precise nature of those changes and how they may be linked to disease is not understood.

“This study sheds much needed light on brain development in this crucial time period, and will hopefully spark further research in this area, and tell us more about the origins of serious mental health conditions such as schizophrenia.”

Video
Nodes of the adolescent brain's structural network coloured by how much they change between 14 and 24 years of age. ̽��ֱ��size of the nodes represent how well connected they are and halfway through the movie the smallest nodes are removed and only the hubs remain. ̽��ֱ��edges that are added in are the strongest connections between these hub regions and represent the brain's rich club. Credit: Kirstie Whitaker

Reference
Whitaker, KJ, Vertes, PE et al. Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome. PNAS; 25 July 2016; DOI: 10.1073/pnas.1601745113

Scientists have mapped the structural changes that occur in teenagers’ brains as they develop, showing how these changes may help explain why the first signs of mental health problems often arise during late adolescence.

̽��ֱ��hubs that connect different regions are becoming set in place as the most important connections strengthen. We believe this is where we are seeing myelin increasing in adolescence

Kirstie Whitaker

Nodes and Edges: NSPN_WhitakerVertes_PNAS2016

Bob Bradburn

Teenager

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Psychotic disorders in minority groups: the high price of being an ‘outsider’

amb206 — Fri, 01 Apr 2016 12:00:00 +0000

In 1932 a psychiatrist called Ornulv Odegaard published a paper in which he reported that Norwegian immigrants in Minnesota had a much higher incidence of mental health problems than Norwegians back in their home country of Norway. ̽��ֱ��percentage of people in the Norwegian immigrant population experiencing such disorders was also much higher than it was among other minority groups in America.

“We’ve known for a long time that immigrant populations experience a greater frequency of psychotic disorders than the host population – and that it’s higher in immigrant groups than in the populations of the countries they have left,” says Hannah Jongsma, a PhD candidate in the Department of Psychiatry.

“Odegaard’s study is striking because he was the first researcher to carry out an academically robust study showing these variations. His findings were frequently interpreted to suggest a ‘selective migration’ hypothesis – and that those who migrated were somehow innately at a higher risk of developing psychotic disorders. This hypothesis has since been thoroughly tested and found to be false.”

Jongsma’s doctoral research draws on data gathered by an ambitious in-depth study of schizophrenia and other psychotic disorders in six countries. The data she uses was gathered by a project known as EU-GEI which sought to identify the interactive genetic, clinical and environmental determinants, involved in the development, severity and outcome of schizophrenia, right across the population of a number of countries.

Next week (2-6 April 2016) Jongsma will present her first findings from the EU-GEI study at the 5th Biennial Schizophrenia International Research Society Conference in Florence, Italy. Her presentation will give an overview of the incidence rates of psychotic disorders (the number of new cases per head of the population) and look at variations between the different study settings.

“My research looks specifically at the experiences of minority communities – for example British citizens with Trinidadian heritage,” says Jongsma. “ ̽��ֱ��data I’m using is from the case-control arm of the EU-GEI study and based on six-hour interviews and assessments with individuals who experienced a first episode of psychosis, their siblings and healthy controls. As far as I know, it is the most ambitious study of its kind to date, combining a rich set of socio-demographic, clinical and cognitive variables with a very large sample size – more than 2,000 people across the three groups.”

Although she has a background in public health, Jongsma’s undergraduate degree was in liberal arts and she holds a masters in philosophy. “As someone without a medical training, I was thrilled to be offered this PhD position in the Department of Psychiatry,” she says. “What I bring to my work on psychosis in minority communities is an ability to look at things from different points of view – a skill you develop when you study philosophy. I find the ability to think at different levels of abstraction has really helped my understanding of psychosis. I’m able to relate societal level variables, such as racial discrimination, to an individual’s chance of developing a psychotic disorder.”

It’s estimated that, in the UK, one in four people experience a mental health problem each year, and one in hundred will experience a psychotic disorder. Psychosis is a catch-all term that covers disorders of thought and perception that may have organic causes (such as a brain lesion or abuse of alcohol or other drugs) as well as a range of genetic components and environmental triggers. ̽��ֱ��World Health Organisation divides psychosis into affective and non-affective disorders. Affective disorders are dominated by their effects on mood and include depression and bipolar disorder. Non-affective disorders are not dominated by their effects on mood and include schizophrenia and delusional disorders.

“It’s likely that psychosis often develops as a consequence of a cluster of factors which have a cumulative effect and stack up to have a negative effect on psychological well-being. ̽��ֱ��factors that interest me most are the cultural and societal ones,” says Jongsma. “One of the great strengths of a university as broad as Cambridge is that it encourages dialogues between, for instance, neuroscientists, geneticists and epidemiologists. For the researcher, this provides valuable opportunities to exchange and develop ideas.”

̽��ֱ��EU-GEI data on which Jongsma is basing her research was gathered in Brazil, England, France, Italy, the Netherlands and Spain. It confirms that psychosis often presents in late adolescence and peaks in adulthood – and that men are more vulnerable. “Our data also shows that psychosis is more prevalent in urban compared to rural areas. Rural Spain showed the lowest incidence and south-east London the highest,” says Jongsma.

Research has shown that the high incidence of psychosis in minority communities is not limited to first-generation immigrants who might have experienced stress and upheaval in moving countries and finding their feet in a new culture.

“Second and subsequent generations are similarly vulnerable to higher levels of psychosis than the majority population around them. Second generation immigrants may struggle with finding a clear identity and experience a conflict in their affiliations and loyalties – on the one hand with the culture of their parents and on the other with the culture of the wider community,” suggests Jongsma. “Interestingly the density of an immigrant community sometimes seems to have a protective effect – in other words, the denser the immigrant community, the lower the level of psychosis – while sometimes the opposite is apparent.”

When a particular, and easily identifiable, community is seen to have raised levels of mental illness, there is a real danger of stereotyping. “In the UK, it is well known that psychotic disorders are particularly prevalent among Afro-Caribbeans who represent one of the largest groups of immigrants,” says Jongsma. “But, in the Netherlands, where I come from, psychosis is most common among Moroccan immigrants. To me, this suggests we need to look at the role these groups hold in society. Both minority groups suffer from deep-seated prejudices and discrimination.”

One possible reason for raised levels of psychotic disorders in minority groups is their lack of economic and social status. ‘Social defeat’ is a term coined by Professor Jean-Paul Selten (Maastricht ̽��ֱ��) and colleagues to describe the persistent negative experience of being excluded from the majority population. “This idea makes an interesting starting point for trying to understand the root causes of psychotic disorders,” says Jongsma. “Being at the lowest rung of the ladder has been shown to be stressful in primates and is likely to have the same effect on humans.”

̽��ֱ��freedom to express cultural identity is important to mental health. “Identities are formed and maintained on the basis of complex interactions with, and imitations of, those around us – and this social aspect of identity is crucial. Empathy with others and seeing them as fellow citizens, for example, comes from shared identity. It might be the case that minorities are excluded from the group of people regarded as fellow citizens,” says Jongsma.

With so many factors in the mix, unravelling the cause and effect of psychotic disorders will continue to present a challenge. For example, does an individual become mentally unwell as a consequence of being isolated – or does he or she withdraw as a result of being unwell? Genetic factors play a part as do environmental factors such as childhood trauma, cannabis use and deprivation.

“One of the arguments I find very interesting to explore is that psychosocial disempowerment could be seen as an explanatory framework. Over a long period, the feeling that you’re not in control of your life, and that you’re stuck in a hopeless situation that’s unlikely to improve, has been shown to increase mortality and the chance of developing physical illnesses such as heart attacks. I think it is important to look at this in the context of mental illness too,” says Jongsma.

“Poor health is strongly linked to deprivation and inequality – and all that comes with disadvantage. This is as true for heart disease and diabetes as it is for mental illness. In order to improve public mental health, we will have to look not just at the individuals who develop psychotic disorders, but at society more broadly.”

Hannah Jongsma is attending the 5th Biennial Schizophrenia International Research Society Conference with a travel grant awarded by the organisers.

Immigrant groups experience a high incidence of mental illness. Hannah Jongsma (Department of Psychiatry) is looking at data from an international study of the distribution of psychotic disorders. She suggests that ‘psychosocial disempowerment’ might be a powerful contributing factor to raised levels in minority communities.

Identities are formed and maintained on the basis of complex interactions with, and imitations of, those around us – and this social aspect of identity is crucial.

Hannah Jongsma

Robert Swier (Flickr Creative Commons)

Still, In a Crowd

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Schizophrenia and the teenage brain: how can imaging help?

lw355 — Wed, 17 Feb 2016 11:02:18 +0000

Restless, disordered, uncertain, impulsive, emotional – the teenage brain can be a confused fury of neural firings and misfirings.

For most 14- to 24-year-olds – the “risky age” as Professor Ed Bullmore describes it – the maelstrom eventually subsides. For some, episodes of depression, low self-esteem, self-harm or paranoia may intensify and become more frequent. For around 1 in 100, the change in mental state is so marked that it will become difficult for them to distinguish their delusions and hallucinations from reality – one of the hallmarks of schizophrenia.

“Schizophrenia is a particularly feared diagnosis,” says Bullmore. “People tend to think it means a chronic lifelong dependency on medication and therapy. It can mean this, but it can also last only a few years. ̽��ֱ��main thing that patients and their families want to know is what does the future hold – am I likely to be able to resume my life, get a job, and so on?”

Bullmore is co-chair of Cambridge Neuroscience, an initiative to enhance multidisciplinary research across the ̽��ֱ��, and leads the Department of Psychiatry, where he and colleagues have been developing imaging techniques that are revealing where and over what timescale abnormalities in the brain develop in people with mental health problems.

This is no easy task. Even being able to show a neural abnormality has been a major and relatively recent advance for understanding a condition that, Bullmore says, has in the past been regarded with prejudice and assumptions. “Demonstrating neural change moves us away from what might be regarded as a blaming approach where someone is made to feel personally responsible for the fact these symptoms exist. Imaging shows you that’s not the case – there is a biological basis.”

̽��ֱ��task is made difficult because there is no single event or area of the brain that underlies schizophrenia. It has only been from the collation of results from imaging studies worldwide that it has become apparent that when it comes to mental health disorders the scientists need to look at the big picture – the changes happening in wiring circuits across the whole brain.

Imaging techniques such as magnetic resonance imaging (MRI) are helping to map the brain in unprecedented detail. Structural MRI follows the movement of water as it diffuses along the pathways forged by neurons – showing the network of connections spread across the brain. Functional MRI measures slow rhythmic activity in the brain; if two areas of the brain show activity at the same time the chances are they are functionally connected. Bullmore and colleagues have developed mathematical methods to calculate the probability of there being such a connection.

“Neuroscience is no longer just about neurons,” he explains. “We can also now talk in terms of hubs, networks and connectomes. If the brain is thought of as a computer, with ‘processors’ in the outer grey matter and ‘wires’ that connect them in the inner white matter, some hub regions are more highly connected than others.”

In schizophrenia, connectivity in the wiring diagram goes awry and highly connected hubs are especially affected – “you could call it a hubopathy,” says Bullmore. His team’s research has demonstrated that those who have suffered decades of schizophrenia have large-scale network abnormalities compared with a healthy brain, which goes some way to explaining the diversity and severity of symptoms experienced in schizophrenia. ̽��ֱ��question is: can imaging be used to chart this progression?

Bullmore and his colleagues believe so: “Roughly a third of patients recover, a third have intermittent symptoms and a third will be affected for decades by schizophrenia. At diagnosis we can’t currently tell which of these outcomes lies in store. But we think one day we will be able to correlate the pattern of network activity with future outcome.”

It’s not only what happens to patients post-diagnosis that interests Bullmore, but also what has happened neurologically in the years before diagnosis.

“For me, one of the most exciting aspects of psychiatry is that we can use imaging to study the ‘risky age’ of brain development to understand how the connectome grows or matures in healthy brains. We can then start to pinpoint which genetic and environmental factors might favour healthy adolescent brain network development and which factors might predispose to abnormal network development, leading to chronic disability or distress.”

In 2012, Bullmore and colleagues Professor Ian Goodyer and Professor Peter Jones in Cambridge’s Department of Psychiatry (in collaboration with Professor Ray Dolan and Professor Peter Fonagy from ̽��ֱ�� College London) launched the NeuroScience in Psychiatry Network, funded by the Wellcome Trust. They have been recruiting a panel of 2,000 healthy volunteers aged 14–24 years, 300 of whom have had brain scans to contribute to one of the most comprehensive ‘circuit diagrams’ of the teenage brain ever attempted.

“Remarkably little is known about how brain networks grow during the crucial transition from childhood dependence to life as independent adults,” adds Bullmore. “ ̽��ֱ��adolescent brain is still a bit of a black box. But it is a big step forward that we can now see healthy human brain development much more clearly, especially with the next-generation brain scanners coming to Cambridge soon [see panel]. It’s very exciting to think that we should then be able to understand and predict the pathways of brain network development that lead to schizophrenia.”

Adolescence is a dangerous time for the onset of mental health problems. Advances in brain imaging are helping to picture how neural changes in these crucial years can lead to chronic debilitating mental illness.

Neuroscience is no longer just about neurons. We can also now talk in terms of hubs, networks and connectomes.

Ed Bullmore

̽��ֱ��District

Scientists are looking at the 'bigger picture' of mental health

Opening the black box

̽��ֱ��arrival of two state-of-the-art MRI machines in Cambridge, thanks to funding from the Medical Research Council (MRC), will revolutionise the study of the brain.

“A brain scan is much more than an image,” contends Ed Bullmore. “It’s really a very large collection of numbers. With the best scanners and some high-performance computing, you can start to think not only about disease mechanisms but also about identifying early risk factors and preventative action.”

Two of the newest scanners in the UK will arrive at the Cambridge Biomedical Campus in 2016, and a new high-speed secure link will be created through to the recently opened £20 million West Cambridge Data Centre, which will analyse the data.

One scanner, a new 7-Tesla ‘ultrahigh-field’ MRI machine, will help researchers see how the human brain works as a whole, yet also with the precision of a grain of sand a fraction of a millimetre across. It will further the study of dementia, brain injury, obesity, addiction, mental health disorders, pain and stroke.

‘7T’ is a collaboration between the ̽��ֱ�� and the MRC’s Cognition and Brain Sciences Unit (CBSU). Professor James Rowe, from the Department of Clinical Neurosciences and the CBSU, explains: “ ̽��ֱ��new scanner is a major advance to study the details of the human brain not only in health but also the effects of age and the origins of brain diseases. ̽��ֱ��unprecedented detail and sensitivity at 7T is essential in the national effort towards a cure for dementia and mental illness.”

Joining the 7T scanner will be a positron emission tomography (PET)–MRI machine, which shows changes in the brain down to the level of individual molecules. Until now only two PET–MRI scanners existed in the UK, but MRC Dementias Platform UK has invested in five more nationally, creating what is thought to be the first nationally coordinated MRI–PET network anywhere in the world.

“Beating dementia is a long-term goal,” adds Rowe. “These scanners will make a very significant contribution to this eventual success and to the lives of patients and their families.”

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

Yes

Hallucinations linked to differences in brain structure

cjb250 — Tue, 17 Nov 2015 10:00:15 +0000

̽��ֱ��study, led by the ̽��ֱ�� of Cambridge in collaboration with Durham ̽��ֱ��, Macquarie ̽��ֱ��, and Trinity College Dublin, found that reductions in the length of the paracingulate sulcus (PCS), a fold towards the front of the brain, were associated with increased risk of hallucinations in people diagnosed with schizophrenia.

̽��ֱ��PCS is one of the last structural folds to develop in the brain before birth, and varies in size between individuals. In a previous study, a team of researchers led by Dr Jon Simons from the Department of Psychology at the ̽��ֱ�� of Cambridge, found that variation in the length of the PCS in healthy individuals was linked to the ability to distinguish real from imagined information, a process known as ‘reality monitoring’.

In this new study, published today in the journal Nature Communications, Dr Simons and his colleagues analysed 153 structural MRI scans of people diagnosed with schizophrenia and matched control participants, measuring the length of the PCS in each participant’s brain. As difficulty distinguishing self-generated information from that perceived in the outside world may be responsible for many kinds of hallucinations, the researchers wanted to assess whether there was a link between length of the PCS and propensity to hallucinate.

̽��ֱ��researchers found that in people diagnosed with schizophrenia, a 1 cm reduction in the fold’s length increased the likelihood of hallucinations by nearly 20%. ̽��ֱ��effect was observed regardless of whether hallucinations were auditory or visual in nature, consistent with a reality monitoring explanation.

“Schizophrenia is a complex spectrum of conditions that is associated with many differences throughout the brain, so it can be difficult to make specific links between brain areas and the symptoms that are often observed,” says Dr Simons. “By comparing brain structure in a large number of people diagnosed with schizophrenia with and without the experience of hallucinations, we have been able to identify a particular brain region that seems to be associated with a key symptom of the disorder.”

̽��ֱ��researchers believe that changes in other areas of the brain are likely also important in generating the complex phenomena of hallucinations, possibly including regions that process visual and auditory perceptual information. In people who experience hallucinations, these areas may produce altered perceptions which, due to differences in reality monitoring processes supported by regions around the PCS, may be misattributed as being real. For example, a person may vividly imagine a voice but judge that it arises from the outside world, experiencing the voice as a hallucination.

“We think that the PCS is involved in brain networks that help us recognise information that has been generated ourselves,” adds Dr Jane Garrison, first author of the study, “People with a shorter PCS seem less able to distinguish the origin of such information, and appear more likely to experience it as having been generated externally.

“Hallucinations are very complex phenomena that are a hallmark of mental illness and, in different forms, are also quite common across the general population. There is likely to be more than one explanation for why they arise, but this finding seems to help explain why some people experience things that are not actually real.”

̽��ֱ��research was primarily supported by the ̽��ֱ�� of Cambridge Behavioural and Clinical Neuroscience Institute, funded by a joint award from the UK Medical Research Council and the Wellcome Trust.

Reference
Garrison, J.R., Fernyhough, C., McCarthy-Jones, S., Haggard, M., ̽��ֱ��Australian Schizophrenia Research Bank, & Simons, J.S. (2015). Paracingulate sulcus morphology is associated with hallucinations in the human brain. Nature Communications, 6, 8956.

People diagnosed with schizophrenia who are prone to hallucinations are likely to have structural differences in a key region of the brain compared to both healthy individuals and people diagnosed with schizophrenia who do not hallucinate, according to research published today.

Hallucinations are very complex phenomena that are a hallmark of mental illness and, in different forms, are also quite common across the general population. There is likely to be more than one explanation for why they arise

Jane Garrison

Prof. Dr. Mario Markus

HALLUZINATION

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