Neuroscience

(Image: Matthias Kulka / Corbis)

The origin of an innate ability the brain has to protect itself from damage that occurs in stroke has been explained for the first time.

The Oxford University researchers hope that harnessing this inbuilt biological mechanism, identified in rats, could help in treating stroke and preventing other neurodegenerative diseases in the future.

'We have shown for the first time that the brain has mechanisms that it can use to protect itself and keep brain cells alive,' says Professor Alastair Buchan, Head of the Medical Sciences Division and Dean of the Medical School at Oxford University, who led the work.

The researchers report their findings in the journal Nature Medicine and were funded by the UK Medical Research Council and National Institute for Health Research.

Stroke is the third most common cause of death in the UK. Every year around 150,000 people in the UK have a stroke.

It occurs when the blood supply to part of the brain is cut off. When this happens, brain cells are deprived of the oxygen and nutrients they need to function properly, and they begin to die.

'Time is brain, and the clock has started immediately after the onset of a stroke. Cells will start to die somewhere from minutes to at most 1 or 2 hours after the stroke,' says Professor Buchan.

This explains why treatment for stroke is so dependent on speed. The faster someone can reach hospital, be scanned and have drugs administered to dissolve any blood clot and get the blood flow re-started, the less damage to brain cells there will be.

It has also motivated a so-far unsuccessful search for ‘neuroprotectants’: drugs that can buy time and help the brain cells, or neurons, cope with damage and recover afterwards.

The Oxford University research group have now identified the first example of the brain having its own built-in form of neuroprotection, so-called ‘endogenous neuroprotection’.

They did this by going back to an observation first made over 85 years ago. It has been known since 1926 that neurons in one area of the hippocampus, the part of the brain that controls memory, are able to survive being starved of oxygen, while others in a different area of the hippocampus die. But what protected that one set of cells from damage had remained a puzzle until now.

'Previous studies have focused on understanding how cells die after being depleted of oxygen and glucose. We considered a more direct approach by investigating the endogenous mechanisms that have evolved to make these cells in the hippocampus resistant,' explains first author Dr Michalis Papadakis, Scientific Director of the Laboratory of Cerebral Ischaemia at Oxford University.

Working in rats, the researchers found that production of a specific protein called hamartin allowed the cells to survive being starved of oxygen and glucose, as would happen after a stroke.

They showed that the neurons die in the other part of the hippocampus because of a lack of the hamartin response.

The team was then able to show that stimulating production of hamartin offered greater protection for the neurons.

Professor Buchan says: ‘This is causally related to cell survival. If we block hamartin, the neurons die when blood flow is stopped. If we put hamartin back, the cells survive once more.’

Finally, the researchers were able to identify the biological pathway through which hamartin acts to enable the nerve cells to cope with damage when starved of energy and oxygen.

The group points out that knowing the natural biological mechanism that leads to neuroprotection opens up the possibility of developing drugs that mimic hamartin’s effect.

Professor Buchan says: ‘There is a great deal of work ahead if this is to be translated into the clinic, but we now have a neuroprotective strategy for the first time. Our next steps will be to see if we can find small molecule drug candidates that mimic what hamartin does and keep brain cells alive.

'While we are focussing on stroke, neuroprotective drugs may also be of interest in other conditions that see early death of brain cells including Alzheimer's and motor neurone disease,' he suggests.

Linguistics and biology researchers propose a new theory on the deep roots of human speech.

“The sounds uttered by birds offer in several respects the nearest analogy to language,” Charles Darwin wrote in “The Descent of Man” (1871), while contemplating how humans learned to speak. Language, he speculated, might have had its origins in singing, which “might have given rise to words expressive of various complex emotions.”

Now researchers from MIT, along with a scholar from the University of Tokyo, say that Darwin was on the right path. The balance of evidence, they believe, suggests that human language is a grafting of two communication forms found elsewhere in the animal kingdom: first, the elaborate songs of birds, and second, the more utilitarian, information-bearing types of expression seen in a diversity of other animals.

“It’s this adventitious combination that triggered human language,” says Shigeru Miyagawa, a professor of linguistics in MIT’s Department of Linguistics and Philosophy, and co-author of a new paper published in the journal Frontiers in Psychology.

The idea builds upon Miyagawa’s conclusion, detailed in his previous work, that there are two “layers” in all human languages: an “expression” layer, which involves the changeable organization of sentences, and a “lexical” layer, which relates to the core content of a sentence. His conclusion is based on earlier work by linguists including Noam Chomsky, Kenneth Hale and Samuel Jay Keyser.

Based on an analysis of animal communication, and using Miyagawa’s framework, the authors say that birdsong closely resembles the expression layer of human sentences — whereas the communicative waggles of bees, or the short, audible messages of primates, are more like the lexical layer. At some point, between 50,000 and 80,000 years ago, humans may have merged these two types of expression into a uniquely sophisticated form of language.

“There were these two pre-existing systems,” Miyagawa says, “like apples and oranges that just happened to be put together.”

These kinds of adaptations of existing structures are common in natural history, notes Robert Berwick, a co-author of the paper, who is a professor of computational linguistics in MIT’s Laboratory for Information and Decision Systems, in the Department of Electrical Engineering and Computer Science.

“When something new evolves, it is often built out of old parts,” Berwick says. “We see this over and over again in evolution. Old structures can change just a little bit, and acquire radically new functions.”

A new chapter in the songbook

The new paper, “The Emergence of Hierarchical Structure in Human Language,” was co-written by Miyagawa, Berwick and Kazuo Okanoya, a biopsychologist at the University of Tokyo who is an expert on animal communication.

To consider the difference between the expression layer and the lexical layer, take a simple sentence: “Todd saw a condor.” We can easily create variations of this, such as, “When did Todd see a condor?” This rearranging of elements takes place in the expression layer and allows us to add complexity and ask questions. But the lexical layer remains the same, since it involves the same core elements: the subject, “Todd,” the verb, “to see,” and the object, “condor.”

Birdsong lacks a lexical structure. Instead, birds sing learned melodies with what Berwick calls a “holistic” structure; the entire song has one meaning, whether about mating, territory or other things. The Bengalese finch, as the authors note, can loop back to parts of previous melodies, allowing for greater variation and communication of more things; a nightingale may be able to recite from 100 to 200 different melodies.

By contrast, other types of animals have bare-bones modes of expression without the same melodic capacity. Bees communicate visually, using precise waggles to indicate sources of foods to their peers; other primates can make a range of sounds, comprising warnings about predators and other messages.

Humans, according to Miyagawa, Berwick and Okanoya, fruitfully combined these systems. We can communicate essential information, like bees or primates — but like birds, we also have a melodic capacity and an ability to recombine parts of our uttered language. For this reason, our finite vocabularies can generate a seemingly infinite string of words. Indeed, the researchers suggest that humans first had the ability to sing, as Darwin conjectured, and then managed to integrate specific lexical elements into those songs.

“It’s not a very long step to say that what got joined together was the ability to construct these complex patterns, like a song, but with words,” Berwick says.

As they note in the paper, some of the “striking parallels” between language acquisition in birds and humans include the phase of life when each is best at picking up languages, and the part of the brain used for language. Another similarity, Berwick notes, relates to an insight of celebrated MIT professor emeritus of linguistics Morris Halle, who, as Berwick puts it, observed that “all human languages have a finite number of stress patterns, a certain number of beat patterns. Well, in birdsong, there is also this limited number of beat patterns.”

Birds and bees

Norbert Hornstein, a professor of linguistics at the University of Maryland, says the paper has been “very well received” among linguists, and “perhaps will be the standard go-to paper for language-birdsong comparison for the next five years.”

Hornstein adds that he would like to see further comparison of birdsong and sound production in human language, as well as more neuroscientific research, pertaining to both birds and humans, to see how brains are structured for making sounds.

The researchers acknowledge that further empirical studies on the subject would be desirable.

“It’s just a hypothesis,” Berwick says. “But it’s a way to make explicit what Darwin was talking about very vaguely, because we know more about language now.”

Miyagawa, for his part, asserts it is a viable idea in part because it could be subject to more scrutiny, as the communication patterns of other species are examined in further detail. “If this is right, then human language has a precursor in nature, in evolution, that we can actually test today,” he says, adding that bees, birds and other primates could all be sources of further research insight.

MIT-based research in linguistics has largely been characterized by the search for universal aspects of all human languages. With this paper, Miyagawa, Berwick and Okanoya hope to spur others to think of the universality of language in evolutionary terms. It is not just a random cultural construct, they say, but based in part on capacities humans share with other species. At the same time, Miyagawa notes, human language is unique, in that two independent systems in nature merged, in our species, to allow us to generate unbounded linguistic possibilities, albeit within a constrained system.

“Human language is not just freeform, but it is rule-based,” Miyagawa says. “If we are right, human language has a very heavy constraint on what it can and cannot do, based on its antecedents in nature.”

Hypnosis has begun to attract renewed interest from neuroscientists interested in using hypnotic suggestion to test predictions about normal cognitive functioning.

To demonstrate the future potential of this growing field, guest editors Professor Peter Halligan from the School of Psychology at Cardiff University and David A. Oakley of University College London, brought together leading researchers from cognitive neuroscience and hypnosis to contribute to this month’s special issue of the international journal, Cortex.

The issue illustrates how methodological and theoretical advances, using hypnotic suggestion, can return novel and experimentally verifiable insights for the neuroscience of consciousness and motor control. The research also includes novel brain imaging studies, which address sceptics’ concerns regarding the subjective reality and comparability of hypnotically suggested phenomena that previously depended on subjects’ largely unverifiable report and behaviour.

Halligan and Oakley also contribute to a new and revealing brain imaging study in the special issue that explores the brain systems involved in hypnotic paralysis. This research follows their earlier pioneering work on hypnotic leg paralysis reported in the Lancet in 2000.

Patients with “functional” or “psychogenic” conversion disorders present symptoms, such as paralyses, are clinically challenging. They comprise between 30 and 40% of patients attending neurology outpatient clinics and place a huge strain on public health services.

Professor Halligan of Cardiff University’s School of Psychology said: “This new study, working with colleagues at the Institute of Psychiatry in London, suggests that hypnosis can provide insights into of the brain systems involved in patients who display symptoms of neurological illness, but without evidence of brain damage. New insights show that symptoms experienced by patients with functional or dissociative conversion disorders (e.g. medically unexplained paralysis) can be simulated using targeted hypnotic suggestion.

"In this study we monitored brain activations of healthy volunteers with hypnosis induction who experienced paralysis-like experiences which could be turned ‘on’ and ‘off’. The suggestion resulted in subjects being unable to move a joystick together with a realistic and compelling experience of being unable to move and control their left hand despite trying.

"When compared to the completed movements, the suggested paralysis condition revealed increased activity in brain regions know to be active during motor planning and intention to move – and also brain areas involved in response selection and inhibition."

Comparing symptoms conveyed by conversion disorder patients and those produced by ‘paralysis’ suggestions in hypnosis, has revealed similar patterns of brain activation associated with attempted movement of the affected limb.

These findings could inform future studies of the brain mechanisms underpinning limb paralysis in patients with conversion disorders. More importantly they could lead to effective treatments.

Electrodes operated into the brain are today used in research and to treat diseases such as Parkinson’s. However, their use has been limited by their size. At Lund University in Sweden, researchers have, for the first time, succeeded in implanting an ultrathin nanowire-based electrode and capturing signals from the nerve cells in the brain of a laboratory animal.

The researchers work at Lund University’s Neuronano Research Centre in an interdisciplinary collaboration between experts in subjects including neurophysiology, biomaterials, electrical measurements and nanotechnology. Their electrode is composed of a group of nanowires, each of which measures only 200 nanometres (billionths of a metre) in diameter.

Such thin electrodes have previously only been used in experiments with cell cultures.

“Carrying out experiments on a living animal is much more difficult. We are pleased that we have succeeded in developing a functioning nano-electrode, getting it into place and capturing signals from nerve cells”, says Professor Jens Schouenborg, who is head of the Neuronano Research Centre.

He sees this as a real breakthrough, but also as only a step on the way. The research group has already worked for several years to develop electrodes that are thin and flexible enough not to disturb the brain tissue, and with material that does not irritate the cells nearby. They now have the first evidence that it is possible to obtain useful nerve signals from nanometre-sized electrodes.

The research will now take a number of directions. The researchers want to try and reduce the size of the base to which the nanowires are attached, improve the connection between the electrode and the electronics that receive the signals from the nerve cells, and experiment with the surface structure of the electrodes to see what produces the best signals without damaging the brain cells.

“In the future, we hope to be able to make electrodes with nanostructured surfaces that are adapted to the various parts of the nerve cells – parts that are no bigger than a few billionths of a metre. Then we could tailor-make each electrode based on where it is going to be placed and what signals it is to capture or emit”, says Jens Schouenborg.

When an electrode is inserted into the brain of a patient or a laboratory animal, it is generally anchored to the skull. This means that it doesn’t move smoothly with the brain, which floats inside the skull, but rather rubs against the surrounding tissue, which in the long term causes the signals to deteriorate. The Lund group’s electrodes will instead be anchored by their surface structure.

“With the right pattern on the surface, they will stay in place yet still move with the body – and the brain – thereby opening up for long-term monitoring of neurones”, explains Jens Schouenborg.

He praises the collaboration between medics, physicists and others at the Neuronano Research Centre, and mentions physicist Dmitry B. Suyatin in particular. He is the principal author of the article which the researchers have now published in the international journal PLOS ONE.

The overall goal of the Neuronano Research Centre is to develop electrodes that can be inserted into the brain to study learning, pain and other mechanisms, and, in the long term, to treat conditions such as chronic pain, depression and Parkinson’s disease.

Study finds fog-like condition related to chemotherapy’s effect on new brain cells and rhythms.

It’s not unusual for cancer patients being treated with chemotherapy to complain about not being able to think clearly, connect thoughts or concentrate on daily tasks. The complaint – often referred to as chemo-brain – is common. The scientific cause, however, has been difficult to pinpoint.

New research by Rutgers University behavioral neuroscientist Tracey Shors offers new clues for this fog-like condition, medically known as chemotherapy-induced cognitive impairment. In a featured article published in the European Journal of Neuroscience, Shors and her colleagues argue that prolonged chemotherapy decreases the development of new brain cells, a process known as neurogenesis, and disrupts ongoing brain rhythms in the part of the brain responsible for making new memories. Both, she says, are affected by learning and in some cases are necessary for learning to occur.

“One of the things that these brain rhythms do is to connect information across brain regions,” says Shors, Professor II in the Department of Psychology and Center for Collaborative Neuroscience at Rutgers. “We are starting to have a better understanding of how these natural rhythms are used in the process of communication and how they change with experience.”

Working in the Shors laboratory, postdoctoral fellow Miriam S. Nokia from the Department of Psychology at the University of Jyvaskyla in Finland and Rutgers neuroscience graduate student Megan Anderson treated rats with a chemotherapy drug – temozolomide (TMZ) – used on individuals with either malignant brain tumors or skin cancer to stop rapidly dividing cells that have gone out of control and resulted in cancer.

In this study, scientists found that the production of new healthy brain cells treated with the TMZ was reduced in the hippocampus by 34 percent after being caught in the crossfire of the drug’s potency. The cell loss, coupled with the interference in brain rhythms, resulted in the animal being unable to learn difficult tasks.

Shors says the rats had great difficulty learning to associate stimulus events if there was a time gap between the activities but could learn simple task if the stimuli were not separated in time.  Interestingly, she says, the drug did not disrupt the memories that were already present when the treatment began.

For cancer patients undergoing long-term chemotherapy this could mean that although they are able to do simple everyday tasks, they find it difficult to do more complicated activities like processing long strings of numbers, remembering recent conversations, following instructions and setting priorities. Studies indicate that while most cancer patients experience short-term memory loss and disordered thinking, about 15 percent of cancer patients suffer more long-lasting cognitive problems as a result of the chemotherapy treatment.

“Chemotherapy is an especially difficult time as patients are learning how to manage their treatment options while still engaging in and appreciating life. The disruptions in brain rhythms and neurogenesis during treatment may explain some of the cognitive problems that can occur during this time. The good news is that these effects are probably not long-lasting,” says Shors.