̽��ֱ�� of Cambridge - Graham Murray

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

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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

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ADHD

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Antipsychotic drugs linked to slight decrease in brain volume

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

As we age, our brains naturally lose some of their volume – in other words, brain cells and connections. This process, known as atrophy, typically begins in our thirties and continues into old age. Researchers have known for some time that patients with schizophrenia lose brain volume at a faster rate than healthy individuals, though the reason why is unclear.

Now, in a study published in the open access journal PLOS ONE, a team of researchers from the ̽��ֱ�� of Oulu, Finland, and the ̽��ֱ�� of Cambridge has identified the rate of decrease in both healthy individuals and patients with schizophrenia. They also documented where in the brain schizophrenia patients have more atrophy, and have examined links between atrophy and antipsychotic medication.

By comparing brain scans of 33 patients with schizophrenia with 71 control subjects over a period of 9 years – from age 34 to 43 – the researchers were able to show that schizophrenia patients lost brain volume at a rate of 0.7% each year. ̽��ֱ��control participants lost brain volume at a rate of 0.5% per year.

Scientists have previously speculated that antipsychotic medication used to treat schizophrenia may be linked to this decrease in brain volume. Today’s research confirms this association, showing that the rate of decrease in volume was greater when the dose of medication was higher. However, the mechanisms behind this – and whether it was in fact the medication that was causing this greater loss of tissue – are not clear. Some researchers have previously argued that whilst older antipsychotic medications might cause brain volume decreases, newer antipsychotic medications may protect against these decreases. However, today’s research suggests that both classes of antipsychotic medication are associated with similar declines in brain volume.

̽��ֱ��researchers also looked at whether there was any link between the volume of brain lost and the severity of symptoms or loss of cognitive function, but found no effect.

Professor Juha Veijola from the Department of Psychiatry at the ̽��ֱ�� of Oulu, Finland says: “We all lose some brain tissue as we get older, but people with schizophrenia lose it at a faster rate. We’ve shown that this loss seems to be linked to the antipsychotic medication people are taking. Research like this where patients are studied for many years can help to develop guidelines about when clinicians can reduce the dosage of antipsychotic medication in the long term treatment of people with schizophrenia.”

“It’s important to stress that the loss of brain volume doesn’t appear to have any effect on people over the nine year follow-up we conducted, and patients should not stop their medication on the basis of this research, ” adds Dr Graham Murray from the Behavioural and Clinical Neuroscience Institute and the Department of Psychiatry at ̽��ֱ�� of Cambridge. “A key question in future will be to examine whether there is any effect of this loss of brain volume later in life. We need more research in larger studies with longer follow-ups to evaluate the significance of these brain changes.”

̽��ֱ��research was supported by the Academy of Finland, Medical Research Council, Sigrid Jusélius Foundation, and the Brain and Behavior Research Foundation.

A study published today has confirmed a link between antipsychotic medication and a slight, but measureable, decrease in brain volume in patients with schizophrenia. For the first time, researchers have been able to examine whether this decrease is harmful for patients’ cognitive function and symptoms, and noted that over a nine year follow-up, this decrease did not appear to have any effect.

̽��ֱ��loss of brain volume doesn’t appear to have any effect on people, and patients should not stop their medication on the basis of this research

Graham Murray

Adrian Cousins, Wellcome Images

Schizophrenia - hearing voices (Artist's illustration)

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