Non-Invasive Mapping Helps to Localize Language Centers Before Brain Surgery

A new functional magnetic resonance imaging (fMRI) technique may provide neurosurgeons with a non-invasive tool to help in mapping critical areas of the brain before surgery, reports a study in the April issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

Evaluating brain fMRI responses to a “single, short auditory language task” can reliably localize critical language areas of the brain—in healthy people as well as patients requiring brain surgery for epilepsy or tumors, according to the new research by Melanie Genetti, PhD, and colleagues of Geneva University Hospitals, Switzerland.

Brief fMRI Task for Functional Brain Mapping
The researchers designed and evaluated a quick and simple fMRI task for use in functional brain mapping. Functional MRI can show brain activity in response to stimuli (in contrast to conventional brain MRI, which shows anatomy only). Before neurosurgery for severe epilepsy or brain tumors, functional brain mapping provides essential information on the location of critical brain areas governing speech and other functions.

The standard approach to brain mapping is direct electrocortical stimulation (ECS)—recording brain activity from electrodes placed on the brain surface. However, this requires several hours of testing and may not be applicable in all patients. Previous studies have compared fMRI techniques with ECS, but mainly for determining the side of language function (lateralization) rather than the precise location (localization).

The new fMRI task was developed and evaluated in 28 healthy volunteers and in 35 patients undergoing surgery for brain tumors or epilepsy. The test used a brief (eight minutes) auditory language stimulus in which the patients heard a series of sense and nonsense sentences.

Functional MRI scans were obtained to localize the brain areas activated by the language task—activated areas would “light up,” reflecting increased oxygenation. A subgroup of patients also underwent ECS, the results of which were compared to fMRI.

Non-invasive Test Accurately Localizes Critical Brain Areas
Based on responses to the language stimulus, fMRI showed activation of the anterior and posterior (front and rear) language areas of the brain in about 90 percent of subjects—neurosurgery patients as well as healthy volunteers. Functional MRI activation was weaker and the language centers more spread-out in the patient group. These differences may have reflected brain adaptations to slow-growing tumors or longstanding epilepsy.

Five of the epilepsy patients also underwent ECS using brain electrodes, the results of which agreed well with the fMRI findings. Two patients had temporary problems with language function after surgery. In both cases, the deficits were related to surgery or complications (bleeding) in the language area identified by fMRI.

Functional brain mapping is important for planning for complex neurosurgery procedures. It provides a guide for the neurosurgeon to navigate safely to the tumor or other diseased area, while avoiding damage to critical areas of the brain. An accurate, non-invasive approach to brain mapping would provide a valuable alternative to the time-consuming ECS procedure.

"The proposed fast fMRI language protocol reliably localized the most relevant language areas in individual subjects," Dr. Genetti and colleagues conclude. In its current state, the new test probably isn’t suitable as the only approach to planning surgery—too many areas "light up" with fMRI, which may limit the surgeon’s ability to perform more extensive surgery with necessary confidence. The researchers add, "Rather than a substitute, our current fMRI protocol can be considered as a valuable complementary tool that can reliably guide ECS in the surgical planning of epileptogenic foci and of brain tumors."

Mind over matter? Study led by NUS researcher reveals for the first time that core body temperature can be controlled by the brain

A team of researchers led by Associate Professor Maria Kozhevnikov from the Department of Psychology at the National University of Singapore (NUS) Faculty of Arts and Social Sciences showed, for the first time, that it is possible for core body temperature to be controlled by the brain. The scientists found that core body temperature increases can be achieved using certain meditation techniques (g-tummo) which could help in boosting immunity to fight infectious diseases or immunodeficiency.

Published in science journal PLOS ONE in March 2013, the study documented reliable core body temperature increases for the first time in Tibetan nuns practising g-tummo meditation. Previous studies on g-tummo meditators showed only increases in peripheral body temperature in the fingers and toes. The g-tummo meditative practice controls “inner energy” and is considered by Tibetan practitioners as one of the most sacred spiritual practices in the region. Monasteries maintaining g-tummo traditions are very rare and are mostly located in the remote areas of eastern Tibet.

The researchers collected data during the unique ceremony in Tibet, where nuns were able to raise their core body temperature and dry up wet sheets wrapped around their bodies in the cold Himalayan weather (-25 degree Celsius) while meditating. Using electroencephalography (EEG) recordings and temperature measures, the team observed increases in core body temperature up to 38.3 degree Celsius. A second study was conducted with Western participants who used a breathing technique of the g-tummo meditative practice and they were also able to increase their core body temperature, within limits.

Applications of the research findings

The findings from the study showed that specific aspects of the meditation techniques can be used by non-meditators to regulate their body temperature through breathing and mental imagery. The techniques could potentially allow practitioners to adapt to and function in cold environments, improve resistance to infections, boost cognitive performance by speeding up response time and reduce performance problems associated with decreased body temperature.

The two aspects of g-tummo meditation that lead to temperature increases are “vase breath” and concentrative visualisation. “Vase breath” is a specific breathing technique which causes thermogenesis, which is a process of heat production. The other technique, concentrative visualisation, involves focusing on a mental imagery of flames along the spinal cord in order to prevent heat losses. Both techniques work in conjunction leading to elevated temperatures up to the moderate fever zone.

Assoc Prof Kozhevnikov explained, “Practicing vase breathing alone is a safe technique to regulate core body temperature in a normal range. The participants whom I taught this technique to were able to elevate their body temperature, within limits, and reported feeling more energised and focused. With further research, non-Tibetan meditators could use vase breathing to improve their health and regulate cognitive performance.”

Further research into controlling body temperature

Assoc Prof Kozhevnikov will continue to explore the effects of guided imagery on neurocognitive and physiological aspects. She is currently training a group of people to regulate their body temperature using vase breathing, which has potential applications in the field of medicine. Furthermore, the use of guided mental imagery in conjunction with vase breathing may lead to higher body temperature increases and better health.

Study finds that hot and cold senses interact

A study from the University of North Carolina School of Medicine offers new insights into how the nervous system processes hot and cold temperatures. The research led by neuroscientist Mark J. Zylka, PhD, associate professor of cell biology and physiology, found an interaction between the neural circuits that detect hot and cold stimuli: cold perception is enhanced when nerve circuitry for heat is inactivated.

“This discovery has implications for how we perceive hot and cold temperatures and for why people with certain forms of chronic pain, such as neuropathic pain, or pain arising as  direct consequence of a nervous system injury or disease, experience heightened responses to cold temperatures,” says Zylka, a member of the UNC Neuroscience Center.

The study also has implications for why a promising new class of pain relief drugs known as TRPV1 antagonists (they block a neuron receptor protein) cause many patients to shiver and “feel cold” prior to the onset of hyperthermia, an abnormally elevated body temperature. Enhanced cold followed by hyperthermia is a major side effect that has limited the use of these drugs in patients with chronic pain associated with multiple sclerosis, cancer, and osteoarthritis.

Zylka’s research sheds new light on how the neural circuits that regulate temperature sensation bring about these responses, and could suggest ways of reducing such side-effects associated with TRPV1 antagonists and related drugs.

The research was selected by the journal Neuron as cover story for the April 10, 2013 print edition and was available in the April 4, 2013 advanced online edition.

This new study used cutting edge cell ablation technology to delete the nerve circuit that encodes heat and some forms of itch while preserving the circuitry that sense cold temperatures. This manipulation results in animals  that were practically “blind” to heat, meaning they could no longer detect hot temperatures, Zylka explains. “Just like removing heat from a room makes us feel cold (such as with an air conditioner), removing the circuit that animals use to sense heat made them hypersensitive to cold. Physiological studies indicated that these distinct circuits regulate one another in the spinal cord.”

TRPV1 is a receptor for heat and is found in the primary sensory nerve circuit that Zylka studied. TRPV1 antagonists make patients temporarily blind to heat, which Zylka speculates is analogous to what happened when his lab deleted the animals’ circuit that detects heat: cold hypersensitivity.

Zylka emphasizes that future studies will be needed to confirm that TRPV1 antagonists affect cold responses in a manner similar to what his lab found with nerve circuit deletion.

First trial to investigate magic mushrooms as a treatment for depression delayed by UK and EU regulations

The world’s first clinical trial to explore the use of the hallucinogenic ingredient in magic mushrooms to treat depression is being delayed due to the UK and EU rules on the use of illegal drugs in research.

Professor David Nutt, president of the British Neuroscience Association and Professor of Neuropsychopharmacology at Imperial College London (UK), will tell the BNA’s Festival of Neuroscience today (Sunday) that although the UK’s Medical Research Council has awarded a grant for the trial, the Government’s regulations controlling the licensing of illegal drugs in research and the EU’s guidelines on Good Manufacturing Practice (GMP) have stalled the start of the trial, which was expected to start this year. He is calling for a change to the regulations.

He will tell the meeting at the Barbican in London, that his research has shown that psilocybin, the psychedelic ingredient in magic mushrooms, has the potential to alleviate severe forms of depression in people who have failed to respond fully to other anti-depressant treatments. However, psilocybin is illegal in the UK; the United Nations 1971 Convention on Psychotropic Substances classifies it as a Schedule 1 drug, one that has a high potential for abuse with no recognised medical use, and the UK has classified it as a Class A drug, the classification used for the most dangerous drugs. This means that a special licence has to be obtained to use magic mushrooms in research in the UK, and the manufacture of a synthetic form of psilocybin for use in patients is tightly controlled by EU regulations.

Prof Nutt will say: “The law for the control of drugs like psilocybin as a Schedule 1 Class A drug makes it almost impossible to use them for research and the reason we haven’t started the study is because finding companies who could manufacture the drug and who are prepared to go through the regulatory hoops to get the licence, which can take up to a year and triple the price, is proving very difficult. The whole situation is bedevilled by this primitive, old-fashioned attitude that Schedule 1 drugs could never have therapeutic potential, and so they have to be made impossible to access.”

“The knock-on effect is this profound impairment of research. We are the first people ever to have done a psilocybin study in the UK, but we are still hunting for a company that can manufacture the drug to GMP standards for the clinical trial, even though we’ve been trying for a year to find one. We live in a world of insanity in terms of regulating drugs at present. The whole field is so bogged down by these intransient regulations, so that even if you have a good idea, you may never get it into the clinic.”

He will say that the regulations need to be changed. “Even if I do this study and I show it’s a really useful treatment for some people with depression, there’s only four hospitals in this country that have a licence to hold this drug, so you couldn’t roll out the treatment if it worked because the regulations would make it difficult to use,” he said.

Prof Nutt and his team at Imperial College London (UK) have shown that when healthy volunteers are injected with psilocybin, the drug switched off a front part of the brain called the anterior cingulate cortex, which is known from previous imaging studies to be over-active in depression. “We found that, even in normal people, the more that part of the brain was switched off under the influence of the drug, the better they felt two weeks later. So there was a relationship between that transient switching off of the brain circuit and their subsequent mood,” he will explain. “This is the basis on which we want to run the trial, because this is what you want to do in depression: you want to switch off that over-active part of the brain.

“The other thing we discovered is that the major site of action of the magic mushrooms is to turn down a circuit in the brain called the ‘default mode network’, which the anterior cingulate cortex is part of. The default mode network is a part of the brain between the front and back. It is active when you are thinking about you; it coordinates the thinking and emotional aspects of you.”

The researchers discovered that the ‘default mode network’ had the highest density of 5HT2A receptors in the brain. These are known to be involved in depression and are the targets for a number of existing anti-depressive drugs that aim to improve levels of serotonin – the neurotransmitter [1] that gives people a sense of well-being and happiness. Psilocybin also acts on these receptors.

“We have found that people with depression have over-active default mode networks, and they are continually locked into a mode of thinking about themselves. So they ruminate on themselves, on their incompetencies, on their badness, that they’re worthless, that they’ve failed; these things are not true, and sometimes they reach delusional levels. This negative rumination may be due to a lack of serotonin and what psilocybin is doing is going in and rapidly replacing the missing serotonin, switching them back into a mind state where they are less ruminating and less depressed,” Prof Nutt will say.

The proposed trial will be for patients with depression who have failed two previous treatments for the condition. Thirty patients will be given a synthetic form of psilocybin and 30 patients will be given a placebo. The drug (or placebo) will be given during two, possibly three, carefully controlled and prepared 30-60 minute sessions. The first session will be a low dose to check there are no adverse responses, the second session will give a higher, therapeutic dose, and then patients can have a third, booster dose in a later session if it’s considered necessary. While they are under the influence of the drug, the patients will have guided talking therapy to enable them to explore their negative thinking and issues that are troubling them. The doctors will follow up the patients for at least a year.

“What we are trying to do is to tap into the reservoir of under-researched ‘illegal’ drugs to see if we can find new and beneficial uses for them in people whose lives are often severely affected by illnesses such as depression. The current legislation is stopping the benefits of these drugs being explored and for the last 40 years we have missed really interesting opportunities to help patients.”

Ethical approval for the trial was granted in March and Prof Nutt says he hopes to be able to start the trial within the next six months – so long as he can find a manufacturer for the drug.

(Image: coolchaser.com)

New research shows how our bodies interact with our minds in response to fear and other emotions

New research has shown that the way our minds react to and process emotions such as fear can vary according to what is happening in other parts of our bodies.

In two different presentations today (Monday) at the British Neuroscience Association Festival of Neuroscience (BNA2013) in London, researchers have shown for the first time that the heart’s cycle affects the way we process fear, and that a part of the brain that responds to stimuli, such as touch, felt by other parts of the body also plays a role.

Dr Sarah Garfinkel, a postdoctoral fellow at the Brighton and Sussex Medical School (Brighton, UK), told a news briefing: “Cognitive neuroscience strives to understand how biological processes interact to create and influence the conscious mind. While neural activity in the brain is typically the focus of research, there is a growing appreciation that other bodily organs interact with brain function to shape and influence our perceptions, cognitions and emotions.

“We demonstrate for the first time that the way in which we process fear is different dependent on when we see fearful images in relation to our heart.”

Dr Garfinkel and her colleagues hooked up 20 healthy volunteers to heart monitors, which were linked to computers. Images of fearful faces were shown on the computers and the electrocardiography (ECG) monitors were able to communicate with the computers in order to time the presentation of the faces with specific points in the heart’s cycle.

“Our results show that if we see a fearful face during systole (when the heart is pumping) then we judge this fearful face as more intense than if we see the very same fearful face during diastole (when the heart is relaxed). To look at neural activity underlying this effect, we performed this experiment in an MRI [magnetic resonance imaging] scanner and demonstrated that a part of the brain called the amygdala influences how our heart changes our perception of fear.

“From previous research, we know that if we present images very fast then we have trouble detecting them, but if an image is particularly emotional then it can ‘pop’ out and be seen. In a second experiment, we exploited our cardiac effect on emotion to show that our conscious experience is affected by our heart. We demonstrated that fearful faces are better detected at systole (when they are perceived as more fearful), relative to diastole. Thus our hearts can also affect what we see and what we don’t see – and can guide whether we see fear.

“Lastly, we have demonstrated that the degree to which our hearts can change the way we see and process fear is influenced by how anxious we are. The anxiety level of our individual subjects altered the extent their hearts could change the way they perceived emotional faces and also altered neural circuitry underlying heart modulation of emotion.”

Dr Garfinkel says that her findings might have the potential to help people who suffer from anxiety or other conditions such as post traumatic stress disorder (PTSD).

“We have identified an important mechanism by which the heart and brain ‘speak’ to each other to change our emotions and reduce fear. We hope to explore the therapeutic implications in people with high anxiety. Anxiety disorders can be debilitating and are very prevalent in the UK and elsewhere. We hope that by increasing our understanding about how fear is processed and ways that it could be reduced, we may be able to develop more successful treatments for these people, and also for those, such as war veterans, who may be suffering from PTSD.

“In addition, there is a growing appreciation about how different forms of meditation can have therapeutic consequences. Work that integrates body, brain and mind to understand changes in emotion can help us understand how meditation and mindfulness practices can have calming effects.”

In a second presentation, Dr Alejandra Sel, a postdoctoral researcher in the Department of Psychology at City University (London, UK), investigated a part of the brain called the somatosensory cortex – the area that perceives bodily sensations, such as touch, pain, body temperature and the perception of the body’s place in space, and which is activated when we observe emotional expressions in the faces of other people.

“In order to understand other’s people emotions we need to experience the same observed emotions in our body. Specifically, observing an emotional face, as opposed to a neutral face, is associated with an increased activity in the somatosensory cortex as if we were expressing and experiencing our own emotions. It is also known that people with damage to the somatosensory cortex find it difficult to recognise emotion in other people’s faces,” Dr Sel told the news briefing.

However, until now, it has not been clear whether activity in the somatosensory cortex was simply a by-product of the way we process visual information, or whether it reacts independently to emotions expressed in other people’s faces, actively contributing to how we perceive emotions in others.

In order to discover whether the somatosensory cortex contributes to the processing of emotion independently of any visual processes, Dr Sel and her colleagues tested two situations on volunteers. Using electroencephalography (EEG) to measure the brain response to images, they showed participants either a face showing fear (emotional) or a neutral face. Secondly, they combined the showing of the face with a small tap to an index finger or the left cheek immediately afterwards.

Dr Sel said: “By tapping someone’s cheek or finger you can modify the ‘resting state’ of the somatosensory cortex inducing changes in brain electrical activity in this area. These changes are measureable and observable with EEG and this enables us to pinpoint the brain activity that is specifically related to the somatosensory cortex and its reaction to external stimuli.

“If the ‘resting state’ of the somatosensory cortex when a fearful face is shown has greater electrical activity than when a neutral face is shown, the changes in the activity of the somatosensory cortex induced by the taps and measured by EEG also will be greater when observing fearful as opposed to neutral faces.

“We subtracted results of the first situation (face only) from the second situation (face and tap), and compared changes in the activity related with the tap in the somatosensory cortex when seeing emotional faces versus neutral faces. This way, we could observe responses of the somatosensory cortex to emotional faces independently of visual processes,” she explained.

The researchers found that there was enhanced activity in the somatosensory cortex in response to fearful faces in comparison to neutral faces, independent of any visual processes. Importantly, this activity was focused in the primary and secondary somatosensory areas; the primary area receives sensory information directly from the body, while the secondary area combines sensory information from the body with information related to body movement and other information, such as memories of previous, sensitive experiences.

“Our experimental approach allows us to isolate and show for the first time (as far as we are aware) changes in somatosensory activity when seeing emotional faces after taking away all visual information in the brain. We have shown the crucial role of the somatosensory cortex in the way our minds and bodies perceive human emotions. These findings can serve as starting point for developing interventions tailored for people with problems in recognising other’s emotions, such as autistic children,” said Dr Sel.

The researchers now plan to investigate whether they get similar results when people are shown faces with other expressions such as happy or angry, and whether the timing of the physical stimulus, the tap to the finger or cheek, makes any difference. In this experiment, the tap occurred 105 milliseconds after a face was shown, and Dr Sel wonders about the effect of a longer time interval.

(Image: Shutterstock)

Foetal exposure to excessive stress hormones in the womb linked to adult mood disorders

Exposure of the developing foetus to excessive levels of stress hormones in the womb can cause mood disorders in later life and now, for the first time, researchers have found a mechanism that may underpin this process, according to research presented today (Sunday) at the British Neuroscience Association Festival of Neuroscience (BNA2013) in London.

The concept of foetal programming of adult disease, whereby the environment experienced in the womb can have profound long-lasting consequences on health and risk of disease in later life, is well known; however, the process that drives this is unclear. Professor Megan Holmes, a neuroendocrinologist from the University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science in Scotland (UK), will say: “During our research we have identified the enzyme 11ß-HSD2 which we believe plays a key role in the process of foetal programming.”

Adverse environments experienced while in the womb, such as in cases of stress, bereavement or abuse, will increase levels of glucocorticoids in the mother, which may harm the growing baby. Glucocorticoids are naturally produced hormones and they are also known as stress hormones because of their role in the stress response.

“The stress hormone cortisol may be a key factor in programming the foetus, baby or child to be at risk of disease in later life. Cortisol causes reduced growth and modifies the timing of tissue development as well as having long lasting effects on gene expression,” she will say.

Prof Holmes will describe how her research has identified an enzyme called 11ß-HSD2 (11beta-hydroxysteroid dehydrogenase type 2) that breaks down the stress hormone cortisol to an inactive form, before it can cause any harm to the developing foetus. The enzyme 11ß-HSD2 is present in the placenta and the developing foetal brain where it is thought to act as a shield to protect against the harmful actions of cortisol.

Prof Holmes and her colleagues developed genetically modified mice that lacked 11ß-HSD2 in order to determine the role of the enzyme in the placenta and foetal brain. “In mice lacking the enzyme 11ß-HSD2, foetuses were exposed to high levels of stress hormones and, as a consequence, these mice exhibited reduced foetal growth and went on to show programmed mood disorders in later life. We also found that the placentas from these mice were smaller and did not transport nutrients efficiently across to the developing foetus. This too could contribute to the harmful consequences of increased stress hormone exposure on the foetus and suggests that the placental 11ß-HSD2 shield is the most important barrier.

“However, preliminary new data show that with the loss of the 11ß-HSD2 protective barrier solely in the brain, programming of the developing foetus still occurs, and, therefore, this raises questions about how dominant a role is played by the placental 11ß-HSD2 barrier. This research is currently ongoing and we cannot draw any firm conclusions yet.

“Determining the exact molecular and cellular mechanisms that drive foetal programming will help us identify potential therapeutic targets that can be used to reverse the deleterious consequences on mood disorders. In the future, we hope to explore the potential of these targets in studies in humans,” she will say.

Prof Holmes hopes that her research will make healthcare workers more aware of the fact that children exposed to an adverse environment, be it abuse, malnutrition, or bereavement, are at an increased risk of mood disorders in later life and the children should be carefully monitored and supported to prevent this from happening.

In addition, the potential effects of excessive levels of stress hormones on the developing foetus are also of relevance to individuals involved in antenatal care. Within the past 20 years, the majority of women at risk of premature delivery have been given synthetic glucocorticoids to accelerate foetal lung development to allow the premature babies to survive early birth.

“While this glucocorticoid treatment is essential, the dose, number of treatments and the drug used, have to be carefully monitored to ensure that the minimum effective therapy is used, as it may set the stage for effects later in the child’s life,” Prof Holmes will say.

Puberty is another sensitive time of development and stress experienced at this time can also be involved in programming adult mood disorders. Prof Holmes and her colleagues have found evidence from imaging studies in rats that stress in early teenage years could affect mood and emotional behaviour via changes in the brain’s neural networks associated with emotional processing.

The researchers used fMRI (Functional Magnetic Resonance Imaging) to see which pathways in the brain were affected when stressed, peripubertal rats responded to a specific learned task.

Prof Holmes will say: “We showed that in stressed ‘teenage’ rats, the part of the brain region involved in emotion and fear (known as amygdala) was activated in an exaggerated fashion when compared to controls. The results from this study clearly showed that altered emotional processing occurs in the amygdala in response to stress during this crucial period of development.”

(Image: iStockphoto)

Flies Model a Potential Sweet Treatment for Parkinson’s disease

Researchers from Tel Aviv University describe experiments that could lead to a new approach for treating Parkinson’s disease (PD) using a common sweetener, mannitol. This research is presented today at the Genetics Society of America’s 54th Annual Drosophila Research Conference in Washington D.C., April 3-7, 2013.

Mannitol is a sugar alcohol familiar as a component of sugar-free gum and candies. Originally isolated from flowering ash, mannitol is believed to have been the “manna” that rained down from the heavens in biblical times. Fungi, bacteria, algae, and plants make mannitol, but the human body can’t. For most commercial uses it is extracted from seaweed although chemists can synthesize it. And it can be used for more than just a sweetener.

The Food and Drug Administration approved mannitol as an intravenous diuretic to flush out excess fluid. It also enables drugs to cross the blood-brain barrier (BBB), the tightly linked cells that form the walls of capillaries in the brain. The tight junctions holding together the cells of these tiniest blood vessels come slightly apart five minutes after an infusion of mannitol into the carotid artery, and they stay open for about 30 minutes.

Mannitol has another, less-explored talent: preventing a sticky protein called α-synuclein from gumming up the substantia nigra part of the brains of people with PD and Lewy body dementia (LBD), which has similar symptoms to PD. In the disease state, the proteins first misfold, then form sheets that aggregate and then extend, forming gummy fibrils.

Certain biochemicals, called molecular chaperones, normally stabilize proteins and help them fold into their native three-dimensional forms, which are essential to their functions. Mannitol is a chemical chaperone. So like a delivery person who both opens the door and brings in the pizza, mannitol may be used to treat Parkinson’s disease by getting into the brain and then restoring normal folding to α-synuclein.

Daniel Segal, PhD, and colleagues at Tel Aviv University investigated the effects of mannitol on the brain by feeding it to fruit flies with a form of PD that has highly aggregated α-synuclein.

The researchers used a “locomotion climbing assay” to study fly movement. Normal flies scamper right up the wall of a test tube, but flies whose brains are encumbered with α-synuclein aggregates stay at the bottom, presumably because they can’t move normally. The percentage of flies that climb one centimeter in 18 seconds assesses the effect of mannitol.

An experimental run tested flies daily for 27 days. After that time, 72% of normal flies climbed up, in comparison to 38% of the PD flies. Their lack of ascension up the sides of the test tube indicated “severe motor dysfunction.”

In contrast, were flies bred to harbor the human mutant α-synuclein gene, who as larvae feasted on mannitol that sweetened the medium at the bottoms of their vials. These flies fared much better — 70% of them could climb after 27 days. And slices of their brains revealed a 70% decrease in accumulated misfolded protein compared to the brains of mutant flies raised on the regular medium lacking mannitol.

It’s a long way from helping climbing-impaired flies to a new treatment for people, but the research suggests a possible novel therapeutic direction. Dr. Segal, however, cautioned that people with PD or similar movement disorders should not chew a ton of mannitol-sweetened gum or sweets; that will not help their current condition. The next step for researchers is to demonstrate a rescue effect in mice, similar to improved climbing by flies, in which a rolling drum (“rotarod”) activity assesses mobility.

“Until and if mannitol is proven to be efficient for PD on its own, the more conservative and possibly more immediate use can be the conventional one, using it as a BBB disruptor to facilitate entrance of other approved drugs that have problems passing through the BBB,” Dr. Segal said. A preliminary clinical trial of mannitol on a small number of volunteers might follow if results in mice support those seen in the flies, he added, but that is still many research steps away.

(Image: Wikimedia Commons)

Researchers shine light on how stress circuits learn

Researchers at the University of Calgary’s Hotchkiss Brain Institute have discovered that stress circuits in the brain undergo profound learning early in life. Using a number of cutting edge approaches, including optogenetics, Jaideep Bains, PhD, and colleagues have shown stress circuits are capable of self-tuning following a single stress. These findings demonstrate that the brain uses stress experience during early life to prepare and optimize for subsequent challenges.

The team was able to show the existence of unique time windows following brief stress challenges during which learning is either increased or decreased. By manipulating specific cellular pathways, they uncovered the key players responsible for learning in stress circuits in an animal model. These discoveries culminated in the publication of two back-to-back studies in the April 7 online edition of Nature Neuroscience [1, 2], one of the world’s top neuroscience journals.

"These new findings demonstrate that systems thought to be ‘hardwired’ in the brain, are in fact flexible, particularly early in life," says Bains, a professor in the Department of Physiology and Pharmacology. "Using this information, researchers can now ask questions about the precise cellular and molecular links between early life stress and stress vulnerability or resilience later in life."

Stress vulnerability, or increased sensitivity to stress, has been implicated in numerous health conditions including cardiovascular disease, obesity, diabetes and depression. Although these studies used animal models, similar mechanisms mediate disease progression in humans.

"Our observations provide an important foundation for designing more effective preventative and therapeutic strategies that mitigate the effects of stress and meet society’s health challenges," he says.

Brain Games are Bogus

A decade ago, a young Swedish researcher named Torkel Klingberg made a spectacular discovery. He gave a group of children computer games designed to boost their memory, and, after weeks of play, the kids showed improvements not only in memory but in overall intellectual ability. Spending hours memorizing strings of digits and patterns of circles on a four-by-four grid had made the children smarter. The finding countered decades of psychological research that suggested training in one area (e.g., recalling numbers) could not bring benefits in other, unrelated areas (e.g., reasoning). The Klingberg experiment also hinted that intelligence, which psychologists considered essentially fixed, might be more mutable: that it was less like eye color and more like a muscle.

It seemed like a breakthrough, offering new approaches to education and help for people with A.D.H.D., traumatic brain injuries, and other ailments. In the years since, other, similar experiments yielded positive results, and Klingberg helped found a company, Cogmed, to commercialize the software globally. (Pearson, the British publishing juggernaut, purchased it in 2010.) Brain training has become a multi-million-dollar business, with companies like Lumosity, Jungle Memory, and CogniFit offering their own versions of neuroscience-you-can-use, and providing ambitious parents with new assignments for overworked but otherwise healthy children. The brain-training concept has made Klingberg a star, and he now enjoys a seat on an assembly that helps select the winners of the Nobel Prize in Physiology or Medicine. The field has become a staple of popular writing. Last year, the New York Times Magazine published a glowing profile of the young guns of brain training called “CAN YOU MAKE YOURSELF SMARTER?”

The answer, however, now appears to be a pretty firm no—at least, not through brain training. A pair of scientists in Europe recently gathered all of the best research—twenty-three investigations of memory training by teams around the world—and employed a standard statistical technique (called meta-analysis) to settle this controversial issue. The conclusion: the games may yield improvements in the narrow task being trained, but this does not transfer to broader skills like the ability to read or do arithmetic, or to other measures of intelligence. Playing the games makes you better at the games, in other words, but not at anything anyone might care about in real life.

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Flies with personality

Fruit flies may have more individuality and personality than we imagine.

And it might all be down to a bit of genetic shuffling in nerve cells that makes every fly brain unique, suggest Oxford University scientists.

Their new study has found that small genetic elements called ‘transposons’ are active in neurons in the fly brain. Transposons are also known as 'jumping genes', as these short scraps of DNA have the ability to move, cutting themselves out from one position in the genome and inserting themselves somewhere else.

The inherent randomness of the process is likely to make every fly brain unique, potentially providing behavioural individuality – or ‘fly personality’. So says Professor Scott Waddell, who led the work at the University of Oxford Centre for Neural Circuits and Behaviour: ‘We have known for some time that individual animals that are supposed to be genetically identical behave differently.

'The extensive variation between fly brains that this mechanism could generate might demystify why some behave while others misbehave,' he suggests.

The Oxford researchers, along with US colleagues at the University of Massachusetts Medical School and Howard Hughes Medical Institute, were able to deep-sequence the DNA from small numbers of nerve cells in the brains of Drosophila fruit flies.

They identified many transposons that were inserted in a number of important memory-related genes. Whether this is detrimental or advantageous to the fly remains an open question, the researchers say.

Scott Waddell notes that neural transposition has been described in rodent and human brains, and transposons have historically been considered to be problematic parasites. New insertions of transposons can on occasion disrupt genes (as was found in this study), and transposons have been associated to some human disorders such as schizophrenia.

However, it is also possible that organisms have harnessed transposition to generate variation within cells, and by extension create variation between individual animals that may turn out to be favourable.

Scott Waddell wants next to determine whether neural transposition provides an explanation for variation in fruit fly behaviour by finding ways of halting the process in flies in his lab.