Complex brain function depends on flexibility

Over the past few decades, neuroscientists have made much progress in mapping the brain by deciphering the functions of individual neurons that perform very specific tasks, such as recognizing the location or color of an object.

However, there are many neurons, especially in brain regions that perform sophisticated functions such as thinking and planning, that don’t fit into this pattern. Instead of responding exclusively to one stimulus or task, these neurons react in different ways to a wide variety of things. MIT neuroscientist Earl Miller first noticed these unusual activity patterns about 20 years ago, while recording the electrical activity of neurons in animals that were trained to perform complex tasks.

“We started noticing early on that there are a whole bunch of neurons in the prefrontal cortex that can’t be classified in the traditional way of one message per neuron,” recalls Miller, the Picower Professor of Neuroscience at MIT and a member of MIT’s Picower Institute for Learning and Memory.

In a paper appearing in Nature on May 19, Miller and colleagues at Columbia University report that these neurons are essential for complex cognitive tasks, such as learning new behavior. The Columbia team, led by the study’s senior author, Stefano Fusi, developed a computer model showing that without these neurons, the brain can learn only a handful of behavioral tasks.

“You need a significant proportion of these neurons,” says Fusi, an associate professor of neuroscience at Columbia. “That gives the brain a huge computational advantage.”

Lead author of the paper is Mattia Rigotti, a former grad student in Fusi’s lab.

Multitasking neurons

Miller and other neuroscientists who first identified this neuronal activity observed that while the patterns were difficult to predict, they were not random. “In the same context, the neurons always behave the same way. It’s just that they may convey one message in one task, and a totally different message in another task,” Miller says.

For example, a neuron might distinguish between colors during one task, but issue a motor command under different conditions.

Miller and colleagues proposed that this type of neuronal flexibility is key to cognitive flexibility, including the brain’s ability to learn so many new things on the fly. “You have a bunch of neurons that can be recruited for a whole bunch of different things, and what they do just changes depending on the task demands,” he says.

At first, that theory encountered resistance “because it runs against the traditional idea that you can figure out the clockwork of the brain by figuring out the one thing each neuron does,” Miller says.

For the new Nature study, Fusi and colleagues at Columbia created a computer model to determine more precisely what role these flexible neurons play in cognition, using experimental data gathered by Miller and his former grad student, Melissa Warden. That data came from one of the most complex tasks that Miller has ever trained a monkey to perform: The animals looked at a sequence of two pictures and had to remember the pictures and the order in which they appeared.

During this task, the flexible neurons, known as “mixed selectivity neurons,” exhibited a great deal of nonlinear activity — meaning that their responses to a combination of factors cannot be predicted based on their response to each individual factor (such as one image).

Expanding capacity

Fusi’s computer model revealed that these mixed selectivity neurons are critical to building a brain that can perform many complex tasks. When the computer model includes only neurons that perform one function, the brain can only learn very simple tasks. However, when the flexible neurons are added to the model, “everything becomes so much easier and you can create a neural system that can perform very complex tasks,” Fusi says.

The flexible neurons also greatly expand the brain’s capacity to perform tasks. In the computer model, neural networks without mixed selectivity neurons could learn about 100 tasks before running out of capacity. That capacity greatly expanded to tens of millions of tasks as mixed selectivity neurons were added to the model. When mixed selectivity neurons reached about 30 percent of the total, the network’s capacity became “virtually unlimited,” Miller says — just like a human brain.

Mixed selectivity neurons are especially dominant in the prefrontal cortex, where most thought, learning and planning takes place. This study demonstrates how these mixed selectivity neurons greatly increase the number of tasks that this kind of neural network can perform, says John Duncan, a professor of neuroscience at Cambridge University.

“Especially for higher-order regions, the data that have often been taken as a complicating nuisance may be critical in allowing the system actually to work,” says Duncan, who was not part of the research team.

Miller is now trying to figure out how the brain sorts through all of this activity to create coherent messages. There is some evidence suggesting that these neurons communicate with the correct targets by synchronizing their activity with oscillations of a particular brainwave frequency.

“The idea is that neurons can send different messages to different targets by virtue of which other neurons they are synchronized with,” Miller says. “It provides a way of essentially opening up these special channels of communications so the preferred message gets to the preferred neurons and doesn’t go to neurons that don’t need to hear it.”

Scientists identify molecular trigger for Alzheimer’s disease

Researchers have pinpointed a catalytic trigger for the onset of Alzheimer’s disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons in the brain.

For the first time, scientists at Cambridge’s Department of Chemistry, led by Dr Tuomas Knowles, Professor Michele Vendruscolo and Professor Chris Dobson working with Professor Sara Linse and colleagues at Lund University in Sweden have been able to map in detail the pathway that generates “aberrant” forms of proteins which are at the root of neurodegenerative conditions such as Alzheimer’s.

They believe the breakthrough is a vital step closer to increased capabilities for earlier diagnosis of neurological disorders such as Alzheimer’s and Parkinson’s, and opens up possibilities for a new generation of targeted drugs, as scientists say they have uncovered the earliest stages of the development of Alzheimer’s that drugs could possibly target.

The study, published today in the Proceedings of the US National Academy of Sciences, is a milestone in the long-term research established in Cambridge by Professor Christopher Dobson and his colleagues, following the realisation by Dobson of the underlying nature of protein ‘misfolding’ and its connection with disease over 15 years ago.

The research is likely to have a central role to play in diagnostic and drug development for dementia-related diseases, which are increasingly prevalent and damaging as populations live longer.

In 2010, the Alzheimer’s Research UK showed that dementia costs the UK economy over £23 billion, more than cancer and heart disease combined. Just last week, PM David Cameron urged scientists and clinicians to work together to “improve treatments and find scientific breakthroughs” to address “one of the biggest social and healthcare challenges we face.”

The neurodegenerative process giving rise to diseases such as Alzheimer’s is triggered when the normal structures of protein molecules within cells become corrupted.

Protein molecules are made in cellular ‘assembly lines’ that join together chemical building blocks called amino acids in an order encoded in our DNA. New proteins emerge as long, thin chains that normally need to be folded into compact and intricate structures to carry out their biological function.

Under some conditions, however, proteins can ‘misfold’ and snag surrounding normal proteins, which then tangle and stick together in clumps which build to masses, frequently millions, of malfunctioning molecules that shape themselves into unwieldy protein tendrils.

The abnormal tendril structures, called ‘amyloid fibrils’, grow outwards around the location where the focal point, or ‘nucleation’ of these abnormal “species” occurs.

Amyloid fibrils can form the foundations of huge protein deposits – or plaques – long-seen in the brains of Alzheimer’s sufferers, and once believed to be the cause of the disease, before the discovery of ‘toxic oligomers’ by Dobson and others a decade or so ago.

A plaque’s size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer’s disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery.

The new work, in large part carried out by researcher Samuel Cohen, shows that once a small but critical level of malfunctioning protein ‘clumps’ have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through ‘nucleation’.

It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the ‘toxic oligomers’ that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.

“There are no disease modifying therapies for Alzheimer’s and dementia at the moment, only limited treatment for symptoms. We have to solve what happens at the molecular level before we can progress and have real impact,” said Dr Tuomas Knowles from Cambridge’s Department of Chemistry, lead author of the study and long-time collaborator of Professor Dobson and Professor Michele Vendruscolo.

“We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene – the molecular catalyst that underlies the pathology.”

The researchers brought together kinetic experiments with a theoretical framework based on master equations, tools commonly used in other areas of chemistry and physics but had not been exploited to their full potential in the study of protein malfunction before.

The latest research follows hard on the heels of another ground breaking study, published in April of this year again in PNAS, in which the Cambridge group, in Collaboration with Colleagues in London and at MIT, worked out the first atomic structure of one of the damaging amyloid fibril protein tendrils. They say the years spent developing research techniques are really paying off now, and they are starting to solve “some of the key mysteries” of these neurodegenerative diseases.

“We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease,” explained Knowles.

“Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results. With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.”

The Fractal Nature of the Brain: EEG Data Suggests That the Brain Functions as a “Quantum Computer” in 5-8 Dimensions

The brain has been traditionally viewed as a deterministic machine where certain inputs give rise to certain outputs. However, there is a growing body of work that suggests this is not the case. The high importance of initial inputs suggests that the brain may be working in the realms of chaos, with small changes in initial inputs leading to the production of strange attractors. This may also be reflected in the physical structure of the brain which may also be fractal. EEG data is a good place to look for the underlying patterns of chaos in the brain since it samples many millions of neurons simultaneously. Several studies have arrived at a fractal dimension of between 5 and 8 for human EEG data. This suggests that the brain operates in a higher dimension than the 4 of traditional space-time. These extra dimensions suggest that quantum gravity may play a role in generating consciousness.

(Image courtesy: Kookmin University)

What are stem cells?

In a paper published in Cell yesterday, scientists from the US and Thailand have, for the first time, successfully produced embryonic stem cells from human skin cells.

That sounds interesting, but what are stem cells and where do they come from?

If you take a limb from a rose tree, and put it in soil, it will grow into a thriving bush.

But you might say: “Plants are special. This won’t work with animals.” Or will it? If you cut off a lizard’s tail, a new tail may grow. A lobster can grow back a lost claw.

There is a special type of flatworm that can be cut in half, again and again hundreds of times, and each half grows back into a full worm.

Similarly, if you cut out half a human liver, it will grow back. The story of Prometheus, whose liver was eaten away by eagles and regrew each day, suggests that the Greeks of ancient times knew about regeneration of organs.

This sort of regeneration is attributed to special cells called “stem cells”.

Reprogramming the workers

Most of our cells are like many professional workers – they are hardened in their ways and can’t manage career changes.

Blood cells carry oxygen or fight disease, muscle cells expand and contract to move us around, nerve cells carry signals, skin cells form a protective layer over our bodies, and structures made up of kidney cells filter our blood.

The cells of most organs or tissues are referred to as “terminally differentiated” cells. They have specialised, and many won’t divide again. If they are damaged or die they will disappear. This is very important.

Although we feel like we grow a lot after we are born, we really only double in size two or three times and most of our cells don’t divide much.

If they did we would be at great risk from cancer – the uncontrolled doubling of cells at the wrong time.

We have a lot of cells and it is important that none of them run out of control.

But some cells can double to renew themselves and can also differentiate and give rise to specialised progeny.

These are the stem cells. We need them to produce new skin to replace damaged skin cells. Similarly, we need them in our guts to replace damaged cells on the surface of our intestines.

Our blood cells also get worn out as they race around our bodies so we have blood stem cells that divide and replace themselves. They also differentiate to form the different types of white and red blood cells we need.

Australian researchers identified stem cells in the breast that can proliferate and form a complete functioning breast. There are also stem cells in the brain and in the heart.

While stem cells tend to be very rare, they exist in many of our organs.

Types of stem cells

The ultimate stem cells are embryonic stem cells.

These cells are found in the inner cell mass of the early embryo and are referred to as “totipotent” since they have the ability to form every cell that is needed in the growing embryo.

They can be extracted from the early embryo and grown in culture dishes.

They can also be genetically modified by the addition of DNA, then injected back into other embryos or into adult animals where find their way into localities that suit them and replace themselves by duplication or differentiate into other cell types that may be needed. For a long time this type of work had been done primarily in laboratory mice.

The techniques in yesterday’s Cell paper involved injecting the nucleus from a human skin cell into a human egg (the nucleus of which has been destroyed) then growing the resulting embryo until the inner cell mass cells could be harvested.

The method may still be controversial because it uses unfertilised eggs, but many people will regard it as preferable to using human embryos. And there are other interesting methods for making stem cells.

Somatic cells to stem cells

It is also possible to convert skin cells, and indeed many different terminally differentiated cells, back into what are called “induced pluripotent stem cells” or iPS cells.

One uses the “magic four” or “OKSM” set of DNA-binding proteins that govern normal stem cell biology:

• Octamer-binding transcription factor 4 (OCT4)
• Kruppel-like factor 4 (KLF4)
• SRY (sex determining region Y)-box 2 (SOX2)
• cellular myelocytomatosis virus-like gene (MYC)

In 2012 Shinya Yamanaka won the Nobel Prize for discovering how to convert normal cells into iPS cells using the OKSM regulators to turn on and off the right genes and convert skin cells into stem cells.

Researchers are continuing to investigate whether iPS cells have the same therapeutic potential as embryo derived stem cells.

It is hoped that stem cells may provide therapies for people suffering from degenerative diseases.

Skin cells could be taken from a patient, converted to stem cells, and then these could be injected back into the damaged organ.

Ideally, they would repopulate the damaged organ with new cells.

So why doesn’t this happen in normal biology? Why aren’t our own heart stem cells busy trying to repair broken hearts?

They may be but our natural supply of stem cells is limited and presumably insufficient to tackle severe disease.

So why don’t we just have more stem cells in our bodies?

The down side of having too many stem cells may be cancer.

Stem cells share a number of features with cancer cells – both are able to self-renew and double without limit.

One theory about cancer holds that the disease most often originates not from terminally differentiated cells but from one of the small number of stem cells in the relevant tissues.

The obvious concern about using stem cells for therapy is that injecting too many could increase the chances that some of these cells would proliferate beyond control, and ultimately give rise to cancer.

Stem cell therapy for regenerative medicine is an exciting idea.

Every day we are learning more about stem cells – how to purify or make them, and how to grow them in culture and direct them down particular pathways to repopulate different organs.

Future research will assess the risks and how effective they can be in experimental systems and ultimately in human patients.

Suicidal behaviour is a disease, psychiatrists argue

As suicide rates climb steeply in the US a growing number of psychiatrists are arguing that suicidal behaviour should be considered as a disease in its own right, rather than as a behaviour resulting from a mood disorder.

They base their argument on mounting evidence showing that the brains of people who have committed suicide have striking similarities, quite distinct from what is seen in the brains of people who have similar mood disorders but who died of natural causes.

Suicide also tends to be more common in some families, suggesting there may be genetic and other biological factors in play. What’s more, most people with mood disorders never attempt to kill themselves, and about 10 per cent of suicides have no history of mental disease.

The idea of classifying suicidal tendencies as a disease is being taken seriously. The team behind the fifth edition of the Diagnostic Standards Manual (DSM-5) – the newest version of psychiatry’s “bible”, released at the American Psychiatric Association’s meeting in San Francisco this week – considered a proposal to have “suicide behaviour disorder” listed as a distinct diagnosis. It was ultimately put on probation: put into a list of topics deemed to require further research for possible inclusion in future DSM revisions.

Another argument for linking suicidal people together under a single diagnosis is that it could spur research into the neurological and genetic factors they have in common. This could allow psychiatrists to better predict someone’s suicide risk, and even lead to treatments that stop suicidal feelings.

Signs in the brain

Until the 1980s, the accepted view in psychiatry was that people who committed suicide were, by definition, depressed. But that view began to change when autopsies revealed distinctive features in the brains of people who had committed suicide, including structural changes in the prefrontal cortex – which controls high-level decision-making – and altered levels of the neurochemical serotonin. These characteristics appeared regardless of whether the people had suffered from depression, schizophrenia, bipolar disorder, or no disorder at all (Brain Research).

But there is no single neurological cause of suicide, says Gustavo Turecki of McGill University in Montreal. What is more likely, he says, is that environmental factors trigger a series of changes in the brains of people who are already genetically prone to suicide, contributing to a constellation of factors that ultimately increase risk. These factors include a history of abuse as a child, post-traumatic stress disorder, long periods of anxiety, or sleep deprivation.

The search for more of these factors is complicated by the rarity of brain samples from suicide victims and the lack of an animal model – humans are unique in their wilful ability to end their lives. But some studies are yielding insights. For example, when people with bipolar disorder who have previously attempted suicide begin taking lithium, they tend to stop attempting suicide even if the drug has no effect on their other symptoms. This suggests that the drug may be acting on neural pathways that specifically influence suicidal tendencies (Annual Review of Pharmacology and Toxicology).

In the genes?

There is also growing evidence that genetics plays a role. For example, according to one study, identical twins share suicidal tendencies 15 per cent of the time, compared with 1 per cent in non-identical twins (Journal of Affective Disorders). And a study of adopted people who had committed suicide found that their biological relatives were six times more likely to commit suicide than members of the family that adopted them (American Journal of Medical Genetics).

A number of individual genes have been linked to suicide, such as those involved in the brain’s response to mood-lifting serotonin, and a signalling molecule called brain-derived neurotrophic factor (BDNF), which regulates the brain’s response to stress. Both tend to be suppressed in the brains of people who committed suicide, regardless of what mental disorder they had. Other studies of post-mortem brains have found that people who commit suicide after a bout of depression have different brain chemistry from depressed people who die of natural causes.

A study by Turecki, published this month, compared the brains of 46 people who had committed suicide with those of 16 people who died of natural causes. In the first group, 366 genes, mostly related to learning and memory, had a different set of epigenetic markers – chemical switches that turn genes on and off (American Journal of Psychiatry). The results are complicated by the fact that many of the people who committed suicide suffered from mental disorders, but Turecki says that suicide, rather than having a mental disorder, was the only significant predictor for these specific epigenetic changes.

No one yet knows the mechanism through which environmental factors would alter these genes, although stress hormones such as cortisol may be playing a role.

Understanding risk

Ultimately, biological and genetic markers might allow psychiatrists to better predict which patients are most at risk of suicide. But David Brent of the University of Pittsburgh, Pennsylvania, cautions that even if we can one day use biomarkers to predict if someone will make a suicide attempt, they do not tell us when. “If clinicians are keeping an eye on a patient, they need to know if there’s imminent risk,” he says.

However, knowing someone’s long-term suicide risk may have important implications for how a doctor chooses to treat that person, says Jan Fawcett of the University of New Mexico in Albuquerque.

For instance, a doctor may decide not to prescribe certain antidepressants to a patient with these biomarkers, as many drugs are thought to increase suicide risk. Another question would be whether to commit a person to a mental hospital – a major decision, he says, as people are most likely to commit suicide right after being released from hospital (Archives of General Psychiatry).

David Shaffer of Columbia University in New York, who was a member of the DSM-V working group, says that suicide behaviour disorder is “very much in the spirit” of the new Research Domain Criteria system that the US National Institute of Mental Health proposed as an alternative diagnosis standard to DSM-V. Rather than diagnosing people with depression or bipolar disorder, for example, the NIMH wants mental disorders to be diagnosed and treated more objectively using patients’ behaviour, genetics and neurobiology.

Ultimately, says Nader Perroud of the University of Geneva in Switzerland, if suicidal behaviour is considered as a disease in its own right, it will become possible to conduct more focused, evidence-based research on it and medications that treat it effectively. “We might be able to find a proper treatment for suicidal behaviour.”

(Image: GETTY)