Protein researchers closing in on the mystery of schizophrenia

Seven per cent of the adult population suffer from schizophrenia, and although scientists have tried for centuries to understand the disease, they still do not know what causes the disease or which physiological changes it causes in the body. Doctors cannot make the diagnosis by looking for specific physiological changes in the patient’s blood or tissue, but have to diagnose from behavioral symptoms.

In an attempt to find the physiological signature of schizophrenia, researchers from the University of Southern Denmark have conducted tests on rats, and they now believe that the signature lies in some specific, measurable proteins. Knowing these proteins and comparing their behaviour to proteins in the brains of not-schizophrenic people may make it possible to develop more effective drugs.

It is extremely difficult to study brain activity in schizophrenic people, which is why researchers often use animal models in their strive to understand the mysteries of the schizophrenic brain. Rat brains resemble human brains in so many ways that studying them makes sense if one wants to learn more about the human brain.

Schizophrenic symptoms in rats

The strong hallucinogenic drug phenocyclidine (PCP), also known as “angel’s dust”, provides a range of symptoms in people which are very similar to schizophrenia.

“When we give PCP to rats, the rats become valuable study objects for schizophrenia researchers,” explains Ole Nørregaard Jensen, professor and head of the Department of Biochemistry and Molecular Biology.

Along with Pawel Palmowski, Adelina Rogowska-Wrzesinska and others, he is the author of a scientific paper about the discovery, published in the international Journal of Proteome Research.

Among the symptoms and reactions that can be observed in both humans and rats are changes in movement and reduced cognitive functions such as impaired memory, attention and learning ability.

"Scientists have studied PCP rats for decades, but until now no one really knew what was going on in the rat brains at the molecular level. We now present what we believe to be the largest proteomics data set to date," says Ole Nørregaard Jensen.

PCP is absorbed very quickly by the brain, and it only stays in the brain for a few hours. Therefore, it was important for researchers to examine the rats’ brain cells soon after the rats were injected with the hallucinogenic drug.

"We could see changes in the proteins in the brain already after 15 minutes. And after 240 minutes, it was almost over," says Ole Nørregaard Jensen.

The University of Southern Denmark holds some of the world’s most advanced equipment for studying proteins, and Ole Nørregaard Jensen and his colleagues used the university’s so-called mass spectrometres for their protein studies.

352 proteins cause brain changes

"We found 2604 proteins, and in 352 of them, we saw changes that can be associated with the PCP injections. These 352 proteins will be extremely interesting to study in closer detail to see if they also alter in people with schizophrenia - and if that’s the case, it will of course be interesting to try to develop a drug that can prevent the protein changes that lead to schizophrenia," says Ole Nørregaard Jensen about the discovery and the work that now lies ahead.

The 352 proteins in rat brains responded immediately when the animals were exposed to PCP. Roughly speaking, the drug made proteins turn on or off when they should not turn on and off. This started a chain reaction of other disturbances in the molecular network around the proteins, such as changes in metabolism and calcium balance.

"These 352 proteins are what causes the rats to change their behaviour - and the events are probably comparable to the devastating changes in a schizophrenic brain," explains Ole Nørregaard Jensen.

The protocol for studying rat brain proteins with mass spectrometry, developed by Ole Nørregaard Jensen and his colleagues, is not limited to schizophrenia studies - it can also be used to explore other diseases.

The research was a collaboration between the University of Southern Denmark, the Danish Technological Institute and NeuroSearch A/S.

Details about the experiment
Twelve rats were used for the experiment. Six received an injection with the hallucinogenic drug PCP (10 mg/kg body weight), and six were injected with a saline solution to serve as controls. After 15 minutes, the first two animals in each group were killed and within less than two minutes, samples of their brains (temporal lobes) were taken and quickly frozen in liquid nitrogen.

After 30 and 240 minutes, respectively, the same was done to other rats. All experiments were conducted in accordance with Danish and EU guides for the handling of laboratory animals. The collected tissue samples were then subjected to various mass spectrometric protein analyses. The analyses revealed differences in the phosphorylation of proteins indicating which proteins had been affected by the drug PCP.

Interpretation of the complex protein data set suggest that PCP affects a number of processes in brain cells and leads to changes in calcium balance in the brain cells, changes in the transport of substances into and out of cells, changes in cell metabolism and changes in the structure of the cell’s internal skeleton, the cytoskeleton.

EEG study: Brain infers structure, rules of tasks

A new study documents the brain activity underlying our strong tendency to infer a structure of context and rules when learning new tasks (even when a structure isn’t valid). The findings, which revealed individual differences, shows how we try to apply task knowledge to similar situations and could inform future research on learning disabilities.

In life, many tasks have a context that dictates the right actions, so when people learn to do something new, they’ll often infer cues of context and rules. In a new study, Brown University brain scientists took advantage of that tendency to track the emergence of such rule structures in the frontal cortex — even when such structure was not necessary or even helpful to learn — and to predict from EEG readings how people would apply them to learn new tasks speedily.

Context and rule structures are everywhere. They allow an iPhone user who switches to an Android phone, for example, to reason that dimming the screen would involve finding a “settings” icon that will probably lead to a slider control for “brightness.” But when the context changes, inflexible generalization can lead a person temporarily astray — like a small-town tourist who greets strangers on the streets of New York City. In some developmental learning disabilities, the whole process of inferring abstract structures may be impaired.

“The world tends to be organized, and so we probably develop prior [notions] over time that there is going to be a structure,” said Anne Collins, a postdoctoral scholar in the Department of Cognitive, Linguistic, and Psychological Sciences at Brown and lead author of the study published March 25 in the Journal of Neuroscience. “When the world is organized, you just reduce the size of what you have to learn about by being able to generalize across situations in which the same things usually happen together. It is efficient to generalize if there is structure, and there usually is structure.”

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Researchers Discover Idling Brain Activity in Severely Brain Injured Patients Who “Wake Up” After Using a Sleep Drug

George Melendez has been called a medical miracle. After a near drowning deprived his brain of oxygen, Melendez remained in a fitful, minimally conscious state until his mother, in 2002, decided to give him the sleep aid drug Ambien to quiet his moaning and writhing. The next thing she knew, her son was quietly looking at her and trying to talk. He has been using the drug ever since to maintain awareness, but no one could understand why Ambien led to such an awakening.

Now, a team of scientists led by Weill Cornell Medical College has discovered a signature of brain activity in Melendez and two other similarly “awakened” patients they say explain why he and others regain some consciousness after using Ambien or other drugs or treatments. The pattern of activity, reported Nov. 19 in the journal eLife, was identified by analyzing the common electroencephalography (EEG) test, which tracks brain waves.

"We found a surprisingly consistent picture of electrical activity in all three patients before they receive the drug. Most interesting is that their specific pattern of activity suggests a particular process occurring in the brain cells of the cerebral cortex and also supports the role of a crucial brain circuit," says the study’s senior investigator, Dr. Nicholas Schiff, the Jerold B. Katz Professor of Neurology and Neuroscience and professor of public health at Weill Cornell. "These findings may help predict other patients who might similarly harbor reserve capacity, whether they are able to respond to Ambien or other approaches." Dr. Schiff is also on the faculty of the Feil Family Brain and Mind Research Institute at Weill Cornell and is a neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"We are focused on finding ways to identify patients who have a functional reserve of cognitive capacities that can be rescued and how to achieve this result," Dr. Schiff adds. "These findings give us a very important lead to follow, and we will now rigorously test their implications in other patients."

Although it is not precisely known how many Americans are diagnosed as severely brain injured with disorders of consciousness, by one estimate there are nearly 300,000 patients trapped in a minimally conscious state who may retain some awareness, according to Dr. Schiff.

Riding a Wave of Excitation

The three patients in the study suffered brain damage in different ways. One fell and the other had a brain aneurysm that led to multiple strokes. Melendez was in a car accident that led to his nearly drowning. All three patients — two men and a woman — become aware when Ambien was used, a rare response that has been documented in fewer than 15 brain-injured patients.

The research team, which included scientists from Memorial Sloan-Kettering Cancer Center, Boston University School of Medicine, and the University Hospital of Liège in Belgium, used EEG to measure electrical activity in the patients’ brains before and after they were given the drug.

Although each patient’s brain was damaged in different ways, all showed the same unique features of low frequency waves in their EEG readings. These low frequency oscillations are most prominent over the frontal cortex, a region strongly dependent for its activity on other brain structures, particularly the central thalamus and the striatum, which together support short-term memory, reward, motivation, attention, alertness and sleep, among other functions.

In this setting of an idling brain, the investigators propose that Ambien works like any anesthesia drug, in that it briefly triggers a fast wave of excitation in brain cells before producing sleep — a phenomenon known as paradoxical excitation. Instead of going on to produce sedation and sleep, as it does in healthy people who use the drug, zolpidem further activates the brain after it’s affected the idling cells, allowing the patients to become more awake than at baseline. “What we think is happening in these patients is that the initial excitation produced by Ambien turns on a specific circuit. The drug creates the opportunity for the brain to effectively catch a ride on this initial wave of excitation, and turn itself back on,” Dr. Schiff says.

This proposed “mesocircuit” links the cortical regions of the brain to the central thalamus and striatum. Neurons in the central thalamus are highly connected to other parts of the brain, “so damage in one part of the brain or another will affect the thalamus, which is key to consciousness,” Dr. Schiff says. Neurons in the striatum “will only fire if there is a lot of electrical input coming to them quickly,” he says.

"We believe the switch that Ambien turns on is at the level of the joint connections between these three brain structures," Dr. Schiff says.

The pattern of brain activity seen in the EEG on Ambien was also the same in all the patients in the study. But the circuit turns off again when the effects of the drug diminish. Using the drug regularly at mealtimes, Melendez can speak fluently, and read and write simple phrases. His tremors and spasticity are significantly reduced on Ambien and he can use objects, such as a spoon, and is alert and can communicate. The first patient in the study can reliably move from minimally conscious to “the mid-range of what is called a confusional state — a more alert status, but not full consciousness,” Dr. Schiff says. “Use of Ambien offers a step in the right direction, but certainly not a cure.”

Different Ways to Kick-Start the Brain

The resting EEG pattern the researchers saw in the patients indicates they have a “recruitable reserve” of function in these critical brain areas that Ambien can harness to turn the brain on, even if only temporarily. “The idea is that hopefully we can screen other patients with EEG to find out if they also have such a reserve,” Dr. Schiff says.

And while some of these patients may not respond to Ambien — as the drug works at a very specific brain receptor and individuals can vary considerably in having enough of it in the key components of the proposed circuit — other drugs may target the same structures and potentially produce similar effects, he says. For example, two drugs (amantadine and L-Dopa) that provide extra dopamine, a brain chemical that fuels the part of the brain damaged in the study’s patients, have been shown to have similar effects on restoring function in patients with severe brain injuries, as has electrical brain stimulation of the central thalamus.

"Now that we have uncovered important insight into fundamental mechanisms underlying the dramatic and rare response of some severely brain-injured patients to Ambien, we hope to systematically explore ways to achieve such kick-starts in other patients — that is our goal," Dr. Schiff says.

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Personal reflection triggers increased brain activity during depressive episodes

Research by the University of Liverpool has found that people experiencing depressive episodes display increased brain activity when they think about themselves.

Using functional magnetic resonance imaging (fMRI) brain imaging technologies, scientists found that people experiencing a depressive episode process information about themselves in the brain differently to people who are not depressed.

British Queen

Researchers scanned the brains of people in major depressive episodes and those that weren’t whilst they chose positive, negative and neutral adjectives to describe either themselves or the British Queen -  a figure significantly removed from their daily lives but one that all participants were familiar with.

Professor Peter Kinderman, Head of the University’s Institute of Psychology, Health and Society, said: “We found that participants who were experiencing depressed mood chose significantly fewer positive words and more negative and neutral words to describe themselves, in comparison to participants who were not depressed.

“That’s not too surprising, but the brain scans also revealed significantly greater blood oxygen levels in the medial superior frontal cortex – the area associated with processing self-related information – when the depressed participants were making judgments about themselves.

“This research leads the way for further studies into the psychological and neural processes that accompany depressed mood. Understanding more about how people evaluate themselves when they are depressed, and how neural processes are involved could lead to improved understanding and care.”

Dr May Sarsam, from the Mersey Care NHS Trust, said:  “This study explored the difference in medical and psychological theories of depression.  It showed that brain activity only differed when depressed people thought about themselves, not when they thought about the Queen or when they made other types of judgements, which fits very well with the current psychological theory.

Equally important

“Thought and neurochemistry should be considered as equally important in our understanding of mental health difficulties such as depression.”

Depression is associated with extensive negative feelings and thoughts.  Nearly one-fifth of adults experience anxiety or depression, with the conditions affecting a higher proportion of women than men.

The research, in collaboration with the Mersey Care NHS Trust and the Universities of Manchester, Edinburgh and Lancaster, is published in PLOS One.

Studying the social side of carnivores

The part of the brain that makes humans and primates social creatures may play a similar role in carnivores, according to a growing body of research by a Michigan State University neuroscientist.

In studying spotted hyenas, lions and, most recently, the raccoon family, Sharleen Sakai has found a correlation between the size of the animals’ frontal cortex and their social nature.

In her latest study, Sakai examined the digitally recreated brains of three species in the Procyonid family – the raccoon, the coatimundi and the kinkajou – and found the coatimundi had the largest frontal cortex. The frontal cortex is thought to regulate social interaction, and the coatimundi is by far the most social of the three animals, often living in bands of 20 or more.

The study, funded by the National Science Foundation, is published in the research journal Brain, Behavior and Evolution.

“Most neuroscience research that looks at how brains evolve has focused primarily on primates, so nobody really knows what the frontal cortex in a carnivore does,” said Sakai, professor of psychology. “These findings suggest the frontal cortex is processing social information in carnivores perhaps similar to what we’ve seen in monkeys and humans.”

Sakai did the most recent study in her neuroscience lab with Bradley Arsznov, a former MSU doctoral student who’s now an assistant professor of psychology at Minnesota State University. Sakai is one of myriad MSU faculty members who help make the university’s brain research portfolio one of the most diverse in the nation.

Her latest study was based on the findings from 45 adult Procyonid skulls acquired from university museum collections (17 coatimundis, 14 raccoons and 14 kinkajous). The researchers used computed tomography, or CT scans, and sophisticated software to digitally “fill in” the areas where the brains would have been.

When they analyzed into the findings, they discovered the female coatimundi had the largest anterior cerebrum volume consisting mainly of the frontal cortex, which regulates social activity in primates. This makes sense, Sakai said, since the female coatimundi is highly social while the male coatimundi, once grown, typically lives on its own or with another male. Also known as the Brazilian aardvark, the coatimundi – or coati – is native to Central and South America.

Raccoons, the most solitary of the three animals, had the smallest frontal cortex. However, raccoons had the largest posterior cerebrum, which contains the sensory area related to forepaw sensation and dexterity – and the raccoon’s forepaws are extremely dexterous and highly sensitive.

The rainforest-dwelling kinkajou had the largest cerebellum and brain stem, areas that regulate motor coordination. This skill is crucial for animals like the kinkajou that live in trees.

Brain size variations in this small family of carnivores appear to be related to differences in behavior including social interaction, Sakai said.

Picking up mistakes

Musicians have sharper minds are able to pick up mistakes and fix them quicker than the rest of us, according to new research.

The study, by researchers at the University of St Andrews, suggests that musical activity could protect against decline in mental abilities through age or illness.

The work, published in the journal Neuropsychologia, extends previous findings that mental abilities are positively related to musical skills. The researchers say that the latest findings demonstrate the potential for ‘far reaching benefits’ of musical activity on mental and physical well-being.

The study was led by St Andrews psychologist Dr Ines Jentzsch, who compared the cognitive ability of amateur musicians versus non-musicians in performing simple mental tasks.

The most striking difference she found lay in the musicians’ ability to recognise and correct mistakes. Not only that, but they responded faster than those with little or no musical training, with no loss in accuracy. This is perhaps not surprising since musicians learn to be constantly aware of their performance, but to not be overly affected by mistakes.

Dr Jentzsch, a Reader in the University’s School of Psychology and Neuroscience, commented, “Our study shows that even moderate levels of musical activity can benefit brain functioning.

“Our findings could have important implications as the processes involved are amongst the first to be affected by aging, as well as a number of mental illnesses such as depression. The research suggests that musical activity could be used as an effective intervention to slow, stop or even reverse age- or illness-related decline in mental functioning.”

The study compared groups of amateur musicians with varying levels of time they had spent in practicing their instrument to a non-musician control group. They then measured each group’s behavioural and brain responses to simple mental tests.

The results showed that playing a musical instrument, even at moderate levels, improves the ability to monitor our behavior for errors and adjust subsequent responses more effectively when needed.

Dr Jentzsch, herself a keen pianist, continued, “Musical activity cannot only immensely enrich our lives but the associated benefits for our physical and mental functioning could be even more far-reaching than proposed in our and previous research.

“Music plays an important role in virtually all societies. Nevertheless, in times of economic hardship, funds for music education are often amongst the first to be cut.

“We strongly encourage political decision makers to reconsider funding cuts for arts education and to increase public spending for music tuition.

“In addition, adults who have never played an instrument or felt too old to learn should be encouraged to take up music - it’s never too late.”

In longterm relationships, the brain makes trust a habit

After someone betrays you, do you continue to trust the betrayer? Your answer depends on the length of the relationship, according to research by sociologist Karen Cook of Stanford University and her colleagues. The researchers found that those who have been deceived early in a relationship use regions of the brain associated with controlled, careful decision making when deciding if they should continue to trust the person who deceived them. However, those betrayed later in a relationship use areas of the brain associated with automatic, habitual decision making, increasing the likelihood of forgiveness. The study appears in the Proceedings of the National Academy of Sciences.

Cook and her team wanted to understand why some people choose to reconcile after they’ve become victims of betrayal, but others don’t. They hypothesized that if the relationship formed recently, the victim will engage in conscious, deliberate problem solving when deciding how to respond to the deceit. On the other hand, if the relationship has existed for a long time, the victim will take trustworthy behavior for granted and consider a breach of trust an exception to the rule.

To test their hypothesis, the team performed an online experiment, using subjects recruited through an internet survey provider. Each subject received eight dollars and could either keep the money or give it to an unseen partner. If the subject gave the money away, its value would triple. The partner would then decide whether to keep it all or give half back to the subject.

Unbeknownst to the subject, the partner was really a computer, sometimes programmed to betray the subject early in the game and sometimes programmed to betray the subject later. Cook’s team found that after an early betrayal, the subject would be more likely to keep the money than after a late betrayal.

When the team repeated the experiment in a laboratory, with subjects hooked up to fMRI scanners, the anterior cingulate cortex, associated with conscious learning, planning and problem solving, and the lateral frontal cortex, associated with feelings of uncertainty, became more active after early betrayal. In contrast, the lateral temporal cortex, associated with habituated decision making, became more active after late betrayal.

As with the first experiment, an early betrayal increased the likelihood of the subject holding onto the money in later rounds. Early betrayal also increased the amount of time taken to make a decision, suggesting that victims of early betrayal were putting more conscious thought into their decisions than victims of late betrayal were.

The researchers hope their study will increase understanding of why some victims of deceit continue to forgive those who deceived them.