Neuroscience

Nanoparticles often meet a sticky end in the brain. In theory, the tiny structures could deliver therapeutic drugs to a brain tumour, but navigating the narrow, syrupy spaces between brain cells is difficult. A spot of lubrication could help.

Nanoparticles (green) coated with poly(ethylene-glycol) (PEG) (Image: Elizabeth Nance, Graeme Woodworth, Kurt Sailor)

Justin Hanes at Johns Hopkins University in Baltimore, Maryland, was surprised to discover just how impermeable brain tissue is to nanoparticles. “It’s very sticky stuff,” he says, similar in adhesiveness to mucus, which protects parts of the body – such as the respiratory system – by trapping foreign particles.

It was thought that the adhesiveness of brain tissue limited the size of particles that can smoothly spread through the brain. Signalling molecules, nutrients and waste products below 64 nanometres in diameter can pass through the tissue with relative ease, but larger nanoparticles – suitable for delivering a payload of drugs to a specific location in the brain – quickly get stuck.

Now Hanes and his colleagues have doubled that size limit. They coated their nanoparticles with a densely-packed polymer shield, which lubricates their surface by preventing electrostatic and hydrophobic interactions with the surrounding tissue. “A nice hydrated shell around the particle prevents it from adhering to cells,” says Hanes.

Tracking the particles

Using this approach, they were able to observe the diffusion of nanoparticles 114 nanometres in diameter through live mouse brains and dissected human and rat brain tissue. Hanes believes the true upper size limit now lies somewhere between 114 nm and 200 nm. “Things were starting to slow down at 114,” he says.

But further research is needed before the team can progress to clinical trials in humans. “At this scale, it is very important to understand where our nanoparticles go once injected into the body,” says team member Elizabeth Nance, also of Johns Hopkins University. “We will need to show that, when combined with a therapeutic agent, these particles are getting to our site of interest, are having the intended effect and are not causing any side effects or toxicity to healthy normal tissue.”

"The effect of this work should be long-term," says Paul Wilson at the University of Warwick in Coventry, UK. The result represents significant progress in the battle to administer drugs within the brain, he says. "More effective and longer-lasting treatments against brain diseases, such as tumours and strokes, will no doubt soon follow."

Source: NewScientist

ScienceDaily (Aug. 28, 2012) — Deep-brain stimulation (DBS) may stop uncontrollable shaking in patients with Parkinson’s disease and essential tremor by imposing its own rhythm on the brain, according to two studies published recently by University of Alabama at Birmingham researchers in the journal Movement Disorders. An article addressing brain stimulation for essential tremor was published online August 28; a related article on Parkinson’s disease was released May 30.

DBS uses an electrode implanted beneath the skin to deliver electrical pulses into the brain more than 100 times per second. Although this technology was approved by the Food and Drug Administration more than 15 years ago, it remains unclear how it reduces tremor and other symptoms of movement disorders.

With the help of electroencephalography or EEG — electrodes placed on the scalp — study authors used new techniques to suppress the electrical signal associated with the DBS electrode. That enabled the first clear, non-invasive EEG measurements of the underlying brain response during clinically effective, high-frequency brain stimulation in humans.

The results show that nerves in the cerebral cortex, the outer layer of the brain, fire with rapid and precise timing in response to individual stimulus pulses. This suggests that DBS may synchronize the firing of nerve cells and break the abnormal rhythms associated with involuntary movements in Parkinson’s disease and essential tremor.

The newly identified rhythm was captured during effective DBS treatment, so it could represent a new physiological measure of the stimulation dose, say the authors. If validated, such a yardstick could help to guide the fine-tuning of DBS stimulator settings in patients for more lasting relief, fewer side effects and less-frequent battery-replacement surgeries.

"Though it’s clear that more work is needed to better understand these initial observations, we’re very excited by our findings because they may provide a biological marker for improvement in the symptoms of these patients," says Harrison Walker, M.D., assistant professor in the UAB Department of Neurology’s Division of Movement Disorders and lead author of the study.

In current clinical practice, stimulator settings are adjusted by trial and error, requiring careful observation of changes in symptoms over multiple clinic visits. But such immediate, visual feedback may not be available as DBS is applied to neurological or psychiatric conditions such as epilepsy, severe depression or obsessive compulsive disorder. In these diseases, an effective dose measurement could be especially useful in optimizing DBS therapy.

Read More →

Devices could reveal inner workings of neurons and how they communicate with each other.

Automated assistance may soon be available to neuroscientists tackling the brain’s complex circuitry, according to research presented last week at the Aspen Brain Forum in Colorado. Robots that can find and simultaneously record the activity of dozens of neurons in live animals could help researchers to reveal how connected cells interpret signals from one another and transmit information across brain areas — a task that would be impossible using single-neuron studies.

A robot that can access the internal workings of neurons could be scaled up to allow 100 cells to be studied at a time. MIT McGovern Institute/E. Boyden/Sputnik Animation

The robots are designed to perform whole-cell patch-clamping, a difficult but powerful method that allows neuroscientists to access neurons’ internal electrical workings, says Edward Boyden of the Massachusetts Institute of Technology in Cambridge, who is leading the work.

Read More →

ROBOTS developed in the safety of a laboratory can be too slow to react to the dangers of the real world. But software inspired by biology promises to give robots the equivalent of the mammalian amygdala, a part of the brain that responds quickly to threats.

(Image: SuperStock)

STARTLE, developed by Mike Hook and colleagues at Roke Manor Research of Romsey in Hampshire, UK, employs an artificial neural network to look out for abnormal or inconsistent data. Once it has been taught what is out of the ordinary, it can recognise dangers in the environment.

For instance, from data fed by a robotic vehicle’s on-board sensors, STARTLE could notice a pothole and pass a warning to the vehicle’s control system to focus more computing resources on that part of the road.

"If it sees something anomalous then investigative processing is cued; this allows us to use computationally expensive algorithms only when needed for assessing possible threats, rather than responding equally to everything," says Hook.

This design mimics the amygdala, which provides a rapid response to threats. The amygdala helps small animals to deal with complex, fast-changing surroundings, allowing them to ignore most sensory stimuli. “The key is that it’s for spotting anomalous conditions,” says Hook, “not routine ones.”

STARTLE has been tested in both vehicle navigation and robot health monitoring. In the latter, it can be trained to respond to danger signs, such as sudden changes in battery power or temperature. It has also been tested in computer networks, as a way to detect security threats, having been trained to identify the pattern of activity associated with an attack.

"A robot amygdala network could be useful," says neuroscientist Keith Kendrick of the University of Electronic Science and Technology of China in Chengdu. "Such a low-resolution analysis will sometimes make mistakes, and you will avoid something needlessly." But a slower, high-resolution analysis is also carried out, he says, which can override the mistakes.

Hooks says that STARTLE could be useful for any robots in complex environments. For example, a robot vehicle would be able to spot other drivers behaving erratically, a major challenge for conventional computing.

Source: NewScientist

Columbia neurophysiologist David Sulzer took his first piano lessons at the age of 11 and was playing his violin and guitar in bars by age 15. Later he gained a national following as a founder of the Soldier String Quartet and the Thai Elephant Orchestra—an actual orchestra of elephants in northern Thailand—and for playing with the likes of Bo Diddley, the Velvet Underground’s John Cale and the jazz great Tony Williams.

From left, Brad Garton and David Sulzer discuss turning brain waves into music on WHYY/PBS in Philadelphia.

It was only after arriving at Columbia, however, that the musician-turned-research-scientist embarked on perhaps his most exotic musical venture—using a computer to translate the spontaneous patterns of his brain waves into music.

With the help of Brad Garton, director of Columbia’s Computer Music Center, Sulzer has performed his avant-garde brain wave music in solo recitals and with musical ensembles.

Last spring, Sulzer presented a piece entitled Reading Stephen Colbert at a conference in New York City sponsored by Columbia and the Paris-based IRCAM (Institut de Recherche et Coordination Acoustique/Musique), a global center of musical research.

Sulzer, a professor in the departments of Psychiatry, Neurology and Pharmacology, wore electrodes attached to his scalp to measure voltage fluctuations in his brain as he sat in a chair reading a book by the comedian. Those fluctuations were fed into a computer program created by Garton, which transformed them into musical notes.

Read More →

Are you a morning lark or a night owl? Scientists use that simplified categorization to explain that different people have different internal body clocks, commonly called circadian clocks. Sleep-wake cycles, digestive activities, and many other physiological processes are controlled by these clocks. In recent years, researchers have found that internal body clocks can also affect how patients react to drugs. For example, timing a course of chemotherapy to the internal body time of cancer patients can improve treatment efficacy and reduce side effects.

Round the clock. Tracking the levels of 50 hormones and amino acids in blood samples (shown by ribbons) reveals a body’s internal time. Credit: PNAS

But physicians have not been able to exploit these findings because determining internal body time is, well, time consuming. It’s also cumbersome. The most established and reliable method requires taking blood samples from a patient hourly and tracking levels of the hormone melatonin, which previous research has tied closely to internal body time.

Now a Japanese group has come up with an alternative method of determining internal body time by constructing what it calls a molecular timetable based on levels in blood samples of more than 50 metabolites—hormones and amino acids—that result from biological activity. The researchers established a molecular timetable based on samples from three subjects and validated it using the conventional melatonin measurement. They then used that timetable to determine the internal body times of other subjects by checking the levels of the metabolites in just two blood samples from each subject per day.

Having such a timetable could allow doctors to synchronize drug delivery to internal body time, the team reports online today in the Proceedings of the National Academy of Sciences. “Usually personalized medicine is focusing on genetic differences, but there are also temporal differences [among patients]. That will be the next step in personalized medicine,” says systems biologist Hiroki Ueda of the RIKEN Center for Developmental Biology in Kobe, Japan, who heads the research group.

"In principle, the method holds great promise as a way of replacing the cumbersome melatonin assay," says Steven Brown, a molecular biologist at the University of Zurich in Switzerland. "The authors show in a small-scale, well-controlled experiment that they are able to predict internal body time within a precision frame of 3 hours," says Urs Albrecht of the University of Fribourg in Switzerland. Both researchers say further work will be necessary to make the technique more practical and more widely applicable, and Ueda agrees. The experimental subjects were all young men, and different molecular timetables are likely needed for women and for people of different ages. He would also like to improve the precision and make it reliable with just one blood sample per day.

Source: ScienceNOW

ScienceDaily (Aug. 27, 2012) — Muscular dystrophy is a complicated set of genetic diseases in which genetic mutations affect the various proteins that contribute to a complex that is required for a structural bridge between muscle cells and the extracellular matrix (ECM) that provides the physical and chemical environment required for their development and function.

The affects of these genetic mutations in patients vary widely, even when the same gene is affected. In order to develop treatments for this disease, it is important to have an animal model that accurately reflects the course of the disease in humans. In this issue of the Journal of Clinical Investigation, researchers at the University of Iowa report the development of a mouse model of Fukuyama’s muscular dystrophy that copies the pathology seen in the human form of the disease.

By removing the gene fukutin from mouse embryos at various points during development, researchers led by Kevin Campbell were able to determine that fukutin disrupts important modifications of dystrophin that prevent the muscle cells from attaching to the ECM. Disruption of the gene earlier in development led to a more severe form of the disease, suggesting that fukutin is important for muscle maturation. Disruptions in later stages of development caused a less severe form of the disease. In a companion piece, Elizabeth McNally of the University of Chicago discusses the implications of this disease model for the development of new therapies to treat muscular dystrophy.

Source: Science Daily

August 26, 2012

Vitamin B12 is essential to human health. However, some people have inherited conditions that leave them unable to process vitamin B12. As a result they are prone to serious health problems, including developmental delay, psychosis, stroke and dementia. An international research team recently discovered a new genetic disease related to vitamin B12 deficiency by identifying a gene that is vital to the transport of vitamin into the cells of the body. This discovery will help doctors better diagnose this rare genetic disorder and open the door to new treatments. The findings are published in the journal Nature Genetics.

"We found that a second transport protein was involved in the uptake of the vitamin into the cells, thus providing evidence of another cause of hereditary vitamin B12 deficiency", said Dr. David Rosenblatt, one of the study’s co-authors, scientist in medical genetics and genomics at the Research Institute of the McGill University Health Centre (RI MUHC) and Dodd Q. Chu and Family Chair in Medical Genetics and the Chair of the Department of Human Genetics at McGill University. "It is also the first description of a new genetic disease associated with how vitamin B12 is handled by the body".

These results build on previous research by the same team from the RI MUHC and McGill University, with their colleagues in Switzerland, Germany and the United States. In previous work, the researchers discovered that vitamin B12 enters our cells with help from of a specific transport protein. In this study, they were working independently with two patients showing symptoms of the cblF gene defect of vitamin B12 metabolism but without an actual defect in this gene. Their work led to the discovery of a new gene, ABCD4, associated with the transport of B12 and responsible for a new disease called cblJ combined homocystinuria and methylmalonic aciduria (cblJ-Hcy-MMA).

Using next generation sequencing of the patients’ genetic information, the scientists identified two mutations in the same ABCD4 gene, in both patients. “We were also able to compensate for the genetic mutation by adding an intact ABCD4 protein to the patients’ cells, thus allowing the vitamin to be properly integrated into the cells,” explained Dr. Matthias Baumgartner, senior author of the study and a Professor of metabolic diseases at Zurich’s University Children’s Hospital.

Vitamin B12, or cobalamin, is essential for healthy functioning of the human nervous system and red blood cell synthesis. Unable to produce the vitamin itself, the human body has to obtain it from animal-based foods such as milk products, eggs, red meat, chicken, fish, and shellfish – or vitamin supplements. Vitamin B12 is not found in vegetables.

"This discovery will lead to the early diagnosis of this serious genetic disorder and has given us new paths to explore treatment options. It also helps explain how vitamin B12 functions in the body, even for those without the disorder," said Dr. Rosenblatt who is the director of one of only two referral laboratories in the world for patients suspected of having this genetic inability to absorb vitamin B12. Dr. Rosenblatt points out that the study of patients with rare diseases is essential to the advancement of our knowledge of human biology.

Source: medicalxpress.com

26 August 2012 by Mo Costandi

Subjects trained to sniff pleasant smells while asleep retain the conditioning when they wake up.

It sounds like every student’s dream: research published today in Nature Neuroscience shows that we can learn entirely new information while we snooze.

TIPS/Photoshot

Anat Arzi of the Weizmann Institute of Science in Rehovot, Israel, and her colleagues used a simple form of learning called classical conditioning to teach 55 healthy participants to associate odours with sounds as they slept.

They repeatedly exposed the sleeping participants to pleasant odours, such as deodorant and shampoo, and unpleasant odours such as rotting fish and meat, and played a specific sound to accompany each scent.

It is well known that sleep has an important role in strengthening existing memories, and this conditioning was already known to alter sniffing behaviour in people who are awake. The subjects sniff strongly when they hear a tone associated with a pleasant smell, but only weakly in response to a tone associated with an unpleasant one.

But the latest research shows that the sleep conditioning persists even after they wake up, causing them to sniff strongly or weakly on hearing the relevant tone — even if there was no odour. The participants were completely unaware that they had learned the relationship between smells and sounds. The effect was seen regardless of when the conditioning was done during the sleep cycle. However, the sniffing responses were slightly more pronounced in those participants who learned the association during the rapid eye movement (REM) stage, which typically occurs during the second half of a night’s sleep.

Pillow power

Arzi thinks that we could probably learn more complex information while we sleep. “This does not imply that you can place your homework under the pillow and know it in the morning,” she says. “There will be clear limits on what we can learn in sleep, but I speculate that they will be beyond what we have demonstrated.”

In 2009, Tristan Bekinschtein, a neuroscientist at the UK Medical Research Council’s Cognition and Brain Sciences Unit in Cambridge, and his colleagues reported that some patients who are minimally conscious or in a vegetative state can be classically conditioned to blink in response to air puffed into their eyes. Conditioned responses such as these could eventually help clinicians to diagnose these neurological conditions, and to predict which patients might subsequently recover. “It remains to be seen if the neural networks involved in sleep learning are similar to the ones recruited during wakefulness,” says Bekinschtein.

The findings by Arzi and her colleagues might also be useful for these purposes, and could lead to ‘sleep therapies’ that help to alter behaviour in conditions such as phobia.

“We are now trying to implement helpful behavioural modification through sleep-learning,” says Arzi. “We also want to investigate the brain mechanisms involved, and the type of learning we use in other states of altered consciousness, such as vegetative state and coma.”

Source: Nature

The nervous system is a complex collection of nerves and specialized cells known as neurons that transmit signals between different parts of the body. Vertebrates — animals with backbones and spinal columns — have central and peripheral nervous systems.

The central nervous system is made up of the brain, spinal cord and retina. The peripheral nervous system consists of sensory neurons, ganglia (clusters of neurons) and nerves that connect to one another and to the central nervous system.

Credit: iDesign, Shutterstock

Description of the nervous system

The nervous system is essentially the body’s electrical wiring. It is composed of nerves, which are cylindrical bundles of fibers that start at the brain and central cord and branch out to every other part of the body.

Neurons send signals to other cells through thin fibers called axons, which cause chemicals known as neurotransmitters to be released at junctions called synapses. A synapse gives a command to the cell and the entire communication process typically takes only a fraction of a millisecond.

Sensory neurons react to physical stimuli such as light, sound and touch and send feedback to the central nervous system about the body’s surrounding environment. Motor neurons, located in the central nervous system or in peripheral ganglia, transmit signals to activate the muscles or glands.

Glial cells, derived from the Greek word for “glue,” support the neurons and hold them in place. Glial cells also feed nutrients to neurons, destroy pathogens, remove dead neurons and act as traffic cops by directing the axons of neurons to their targets. Specific types of glial cells (oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system) generate layers of a fatty substance called myelin that wraps around axons and provides electrical insulation to enable them to rapidly and efficiently transmit signals.

Read More →