̽��ֱ�� of Cambridge - ̽��ֱ�� College London

̽��ֱ��future’s uncertain – but noradrenaline can help us adapt

jg533 — Fri, 13 Nov 2020 16:00:00 +0000

̽��ֱ��COVID-19 pandemic has plunged us all into a state of uncertainty. In a rapidly changing situation where it is hard to know what will happen next, making decisions can be difficult. Researchers at the ̽��ֱ�� of Cambridge and ̽��ֱ�� College London created a simplistic model of this uncertain situation in the lab, to understand how our brain responds.

They found that when situations seem stable, we tend to rely on our on previous experiences to help us anticipate what will happen in the future. But when the world is volatile, our brain can let go of these expectations and allow rapid learning. ̽��ֱ��balance between the two approaches is moderated by the brain chemical noradrenaline. ̽��ֱ��study is published today in the journal Current Biology.

“Adapting to uncertain situations helps us to survive. When something unexpected happens, we have to decide whether it’s a one-off and ignore it, or whether it’s going to keep happening – in which case we might benefit by doing things differently,” said Dr Rebecca Lawson, a researcher in the ̽��ֱ�� of Cambridge’s Department of Psychology and lead author of the study.

̽��ֱ��study tested the effects of Propranolol - a drug used to reduce anxiety and blood pressure - on how people responded to stable situations and to changeable ones. Propranolol blocks the action of noradrenaline.

Participants in the experiment - who were not suffering with anxiety - heard a sound and were then shown an image of either a house of a face. They quickly learned to predict the image they would see depending on the sound they heard before it appeared. ̽��ֱ��association between particular sounds and images was then changed at random intervals, increasing uncertainty and requiring participants to quickly learn new associations.

̽��ֱ��reaction times of participants who received a placebo drug slowed down as the associations became more unexpected. Those who received Propranolol relied on the sound to a greater extent when uncertainty was high. This suggests that the drug makes people more likely to rely on their expectations, based on prior experience, in the face of uncertainty – which could be how it works to reduce feelings of anxiety.

Using a computational model, the researchers showed that the Propranolol group were slower than the placebo group at learning to use new information to adjust their expectations of what might come next, when a situation is very uncertain.

“We found that a brain chemical called noradrenaline plays a role in our inability to predict the future when the state of the world is volatile,” said Lawson.

When a situation is stable - represented in the experiment by a fixed link between sounds and images – our past experiences can be relied upon as a good guide to what will happen next. But when a situation is changing, we need to be more receptive to new information to try and work out what is happening and how to respond.

“In the face of uncertainty, people taking the anti-anxiety drug Propranolol showed an increased reliance on past experience to inform their behaviour – they were less influenced by changes in their environment that contradicted that experience,” said Lawson.

Difficulty in balancing expectations against new information is thought to underlie many conditions including autism and anxiety. ̽��ֱ��team plans to extend their research to try and understand how people with these conditions learn under uncertainty. In the longer term, this could help those with autism and anxiety to recognise the source of their anxiety and manage it better.

This research was funded by Wellcome. Dr Lawson is a Fellow of the Lister Institute and an Autistica Future Leaders Fellow.

Reference
Lawson, R.P. et al: ‘ ̽��ֱ��computational, pharmacological, and physiological determinants of sensory learning under uncertainty.’ Current Biology, November 2020. DOI: 10.1016/j.cub.2020.10.043

A brain chemical called noradrenaline is responsible for our responses to uncertain situations - helping us to learn quickly and adapt our behaviour, a new study has found.

We found that a brain chemical called noradrenaline plays a role in our inability to predict the future when the state of the world is volatile.

Rebecca Lawson

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Faulty brain processing of new information underlies psychotic delusions, finds new research

jg533 — Wed, 24 Jun 2020 00:00:00 +0000

̽��ֱ��results, published today in the journal Molecular Psychiatry, describe how a chemical messenger in the brain called dopamine ‘tunes’ the brain to the level of novelty in a situation, and helps us to respond appropriately - by either updating our model of reality or discarding the information as unimportant.

̽��ֱ��researchers found that a brain region called the superior frontal cortex is important for signaling the correct degree of learning required, depending on the novelty of a situation. Patients with psychosis have faulty brain activation in this region during learning, which could lead them to believe things that are not real.

“Novelty and uncertainty signals in the brain are very important for learning and forming beliefs. When these signals are faulty, they can lead people to form mistaken beliefs, which in time can become delusions,” said Dr Graham Murray from the ̽��ֱ�� of Cambridge’s Department of Psychiatry, who jointly led the research.

In novel situations, our brain compares what we know with the new information it receives, and the difference between these is called the ‘prediction error’. ̽��ֱ��brain updates beliefs according to the size of this prediction error: large errors signal that the brain’s model of the world is inaccurate, thereby increasing the amount that is learned from new information.

Psychosis is a condition where people have difficulty distinguishing between what is real and what is not. It involves abnormalities in a brain chemical messenger called dopamine, but how this relates to patient experiences of delusions and hallucinations has until now remained a mystery.

̽��ֱ��new study involved 20 patients who were already unwell with psychosis, 24 patients with milder symptoms that put them at risk of the condition, and 89 healthy volunteers.

Participants were put into a brain scanning machine called a functional MRI and asked to play a computer game. This allowed the researchers to record activity in the participants’ brains as they engaged in situations with a potential variety of outcomes.

In a second part of the study, 59 of the healthy volunteers had their brains scanned after taking medications that act on the signaling of dopamine in the brain. These medications changed the way that the superior frontal cortex prediction error responses were tuned to the degree of uncertainty.

“Normally, the activity of the superior frontal cortex is finely tuned to signal the level of uncertainty during learning. But by altering dopamine signaling with medication, we can change the reactivity of this region. When we integrate this finding with the results from patients with psychosis, it points to new treatment development pathways,” said Dr Kelly Diederen from the Institute of Psychiatry, Psychology & Neuroscience at King’s College London, who jointly led the study with Dr Murray.

In addition to studying brain activation, the researchers developed mathematical models of the choices made by participants in the computer game, to better understand the strategies of how people learn. They found that patients with psychosis did not take into account the level of uncertainty during learning, which may be a good strategy in some circumstances but could lead to problems in others. Learning problems were related to alterations in brain activation in the superior frontal cortex, with patients with severe symptoms of psychosis showing more significant alterations.

“While these kind of abnormal brain responses were predicted several years ago, this is the first time the changes have actually been shown to be present. ̽��ֱ��results give us confidence that our theoretical models of psychosis are correct,” said Dr Joost Haarsma from ̽��ֱ�� College London, first author of the study.

This research was funded by the Wellcome Trust.

Reference
Haarsma, J. et al: ‘Precision-weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.’ Molecular Psychiatry, June 2020. DOI: 10.1038/s41380-020-0803-8

Problems in how the brain recognizes and processes novel information lie at the root of psychosis, researchers from the ̽��ֱ�� of Cambridge and King’s College London have found. Their discovery that defective brain signals in patients with psychosis could be altered with medication paves the way for new treatments for the disease.

Novelty and uncertainty signals in the brain are very important for learning and forming beliefs. When these signals are faulty, they can lead people to form mistaken beliefs, which in time can become delusions.

Graham Murray

Pixabay

Yes

Targeting hard-to-treat cancers

sc604 — Wed, 17 Oct 2018 09:06:34 +0000

While the survival rate for most cancers has doubled over the past 40 years, some cancers such as those of the pancreas, brain, lung and oesophagus still have low survival rates.

Such cancers are now the target of an Interdisciplinary Research Collaboration (IRC) led by the ̽��ֱ�� of Cambridge and involving researchers from Imperial College London, ̽��ֱ�� College London and the Universities of Glasgow and Birmingham.

“Some cancers are difficult to remove by surgery and highly invasive, and they are also hard to treat because drugs often cannot reach them at high enough concentration,” explains George Malliaras, Prince Philip Professor of Technology in Cambridge’s Department of Engineering, who leads the IRC. “Pancreatic tumour cells, for instance, are protected by dense stromal tissue, and tumours of the central nervous system by the blood-brain barrier.”

̽��ֱ��aim of the project, which is funded for six years by the Engineering and Physical Sciences Research Council, is to develop an array of new delivery technologies that can deliver almost any drug to any tumour in a large enough concentration to kill the cancerous cells.

Chemists, engineers, material scientists and pharmacologists will focus on developing particles, injectable gels and implantable devices to deliver the drugs. Cancer scientists and clinicians from the Cancer Research UK Cambridge Centre and partner sites will devise and carry out clinical trials. Experts in innovative manufacturing technologies will ensure the devices are able to be manufactured and robust enough to withstand surgical manipulation.

One technology the team will examine is the ability of advanced materials to self-assemble and entrap drugs inside metal-organic frameworks. These structures can carry enormous amounts of drugs, and be tuned both to target the tumour and to release the drug at an optimal rate.

“We are going to pierce through the body’s natural barriers,” says Malliaras, “and deliver anti-cancer drugs to the heart of the tumour.”

Cambridge leads a £10 million interdisciplinary collaboration to target the most challenging of cancers.

We are going to pierce through the body’s natural barriers and deliver anti-cancer drugs to the heart of the tumour.

George Malliaras

David Fairen-Jimenez

Crystalline metal–organic framework

Yes

Mental health disorders: risks and resilience in adolescence

lw355 — Wed, 10 Oct 2018 08:25:17 +0000

When Charly Cox was diagnosed in her teenage years with depression and other mental health disorders, what lay ahead for her was “a long and painful ordeal of trial and error, guesswork and delay. I felt loss and frustration more times than I was ever gifted hope, knowledge or effective treatment.”

For Flo Sharman, who suffered from mental illness from the age of eight: “I lost my childhood to the stigma surrounding mental health.”

James Downs recovered from disordered eating and extreme emotions, but he describes the process as being “like an experimental DIY project rather than something with clear oversight and a plan.”

One in four of us experience the debilitating, isolating and traumatic effects of mental health disorders. Around 75% of adult mental health problems begin before the age of 18, disrupting education and social interactions, affecting relationships with family and friends and future job opportunities, and in some cases, costing lives.

Charly, Flo and James are among those who have lent their support – and their stories – to the mental health charity MQ to help work towards a future in which adolescents no longer face the life-altering challenge of living with these disorders.

Dr Anne-Laura van Harmelen from Cambridge’s Department of Psychiatry leads a project funded by MQ, called HOPES, and shares this vision: “Our brains undergo complex neural development during the teenage years to prepare us to take care of ourselves. However, some of these changes may be linked to a vulnerability to mental health disorders. If we can better understand what these vulnerabilities are, we can identify those at risk and treat them early, before the disorders emerge.”

But, until recently, remarkably little has been known about what’s going on inside a teenager’s head. Unravelling some of the complexity has required the combined input of psychiatrists, neuroscientists, psychologists, social scientists, computational biologists and statisticians – and the brains of hundreds of healthy teenage volunteers. ̽��ֱ��teenagers were scanned as part of the NeuroScience in Psychiatry Network (NSPN), set up in 2012 by Professor Ian Goodyer from the Department of Psychiatry with funding from the Wellcome Trust.

So far, 2,300 healthy volunteers aged 14 to 24 years have been recruited by the ̽��ֱ�� of Cambridge and ̽��ֱ�� College London for analysis through behavioural questionnaires, cognitive tests, and medical and socio-economic history. Some 300 adolescents have also had their brain anatomy and activity scanned millimetre by millimetre using MRI, a method that can reveal connections between brain activity centres.

̽��ֱ��result is one of the most comprehensive ‘circuit diagrams’ of the teenage brain ever attempted. “ ̽��ֱ��project has been a big step forward in looking inside the black box of the teenage brain,” explains Professor Ed Bullmore, who leads the NSPN. “We found that there were distinctive patterns of developmental change in brain structure and function during adolescence that could help to explain why mental health disorders often arise during late adolescence.”

For instance, Bullmore’s colleagues Dr Kirstie Whitaker and Dr Petra Vértes discovered that the outer region of the brain, known as cortical grey matter, shrinks, becoming thinner during adolescence. As this happens, the levels of myelin – the sheath that ‘insulates’ nerve fibres, allowing the fibres to communicate efficiently in the white matter – increase.

In a separate study, Dr František Váša designed a method to combine all of the scans of the structural changes in the brain through a ‘sliding window’ – as if viewing the changes in the brain network of an ‘average’ adolescent as they mature from 14 to 24 years of age. It sounds simple enough but this innovation was so complex that it took several years of statistical and computational analysis to perfect.

“We saw that the changes are greatest in the most connected ‘hub’ parts of the brain. Our interpretation is that when the brain develops it builds too many connections; then, during the teenage years, those that are used frequently are strengthened and others are ‘pruned’,” says Váša, whose PhD studies were funded by the Gates Cambridge Trust.

What makes this especially interesting is that Vértes and Whitaker also discovered that the brain areas undergoing the greatest structural changes during adolescence are those in which genes linked to risk of mental health disorders are most strongly expressed.

One of the disorders is schizophrenia, which affects 1% of the population and often starts in adolescence or early adult life. Vértes has recently been funded by MQ to search for unique patterns of brain connectivity among those who develop symptoms of schizophrenia, and to cross-reference them with patterns of gene expression across the brain. “Not only is this knowledge important for identifying new treatments that are more effective for a greater number of patients at an earlier stage, but it could also help in predicting those who are at risk,” she explains.

Another area where there has been little improvement in predicting behaviours is that of suicide – the second leading cause of death among the young.

“Around 16% of teens think about suicide and 8% report making an attempt, yet there has been little improvement in our ability to predict suicidal behaviours in 50 years,” says van Harmelen, who is a Royal Society Dorothy Hodgkin fellow. ̽��ֱ��HOPES project she leads aims to develop a model to predict who is at risk of suicide by analysing brain scans and data on suicidal behaviour of young people from across the world to identify specific, universal risk factors.

“These risk factors may be connected with traumatic and stressful events early in their lives,” she adds. “In fact, we know that about a third of all mental health problems are attributable to events such as bullying, abuse and neglect. Much of my work has been to understand the impact of these factors on the developing brain.”

She discovered that childhood adversity is related to an altering of the structure and function of parts of the brain, and that this increases vulnerability to mental health problems. Intriguingly, some adolescents with traumatic early life experiences fared a lot better than would be predicted. This ‘resilience’ was enhanced by receiving the right kind of support at the right time. She calls this ‘social buffering’ and finds that for 14-year-olds it most often comes from family members, and for 19-year-olds from friendships.

With funding from the Royal Society, she is now starting to look for biological factors that underpin resilient functioning – for instance, how does the immune system interact with the brain during periods of psychosocial stress in resilient adolescents? Are there biomarkers that can be used to predict resilience after childhood adversity?

“We are diving deeper into the factors and mechanisms that might help,” says van Harmelen. “We know there are lots of social, emotional and behavioural factors that help to build resilience, and that these factors are amenable to intervention by therapists – but which are the most important, or is it a specific combination of these factors?

“If you speak to anyone who has had a mental health problem, you will know the effect it’s had on them and their families,” she adds. “Even a minor contribution to lowering this effect through early diagnosis and treatment is worth a lot of effort.”

Video: In this video you can see the regions of the brain coloured by how much they change between 14 and 24 years of age. ̽��ֱ��darker the colour the more the myelin changes. ̽��ֱ��size of the 'nodes' of the network represents 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'. Data taken from 'Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome' by Whitaker, Vertes et al. published in PNAS in July 2016. DOI: 10.1073/pnas.1601745113 Link: http://dx.doi.org/10.1073/pnas.160174.

Read a profile of Dr František Váša on the Gates Cambridge website.

Deeper understanding of the wiring and rewiring of the adolescent brain is helping scientists pinpoint why young people are especially vulnerable to mental health problems – and why some are resilient.

If you speak to anyone who has had a mental health problem, you will know the effect it’s had on them and their families. Even a minor contribution to lowering this effect through early diagnosis and treatment is worth a lot of effort

Anne-Laura van Harmelen

Photo by Jon Tyson on Unsplash

Yes