How Neuroscience Will Fight Five Age-Old Afflictions

SEIZURES

A device delivers targeted drugs to calm overactive neurons

For years, large clinical trials have treated people with epilepsy using so-called deep-brain stimulation: surgically implanted electrodes that can detect a seizure and stop it with an electrical jolt. The technology leads to a 69 percent reduction in seizures after five years, according to the latest results.

Tracy Cui, a biomedical engineer at the University of Pittsburgh, hopes to improve upon that statistic. Her group has designed an electrode that would deliver both an electrical pulse and antiseizure medication. “We know where we want to apply the drug,” Cui says, “so you would not need a lot of it.”

To build the device, Cui’s team immersed a metal electrode in a solution containing two key ingredients: a molecule called a monomer and the drug CNQX. Zapping the solution with electricity causes the monomers to link together and form a long chain called a polymer. Because the polymer is positively charged, it attracts the negatively charged CNQX, leaving the engineers with their target product: an electrode coated in a film that’s infused with the drug.

The researchers then placed the electrodes in a petri dish with rat neurons. Another zap of electricity disrupted the electrostatic attraction in the film, causing the polymer to release its pharmacological payload—and nearby cells to quiet their erratic firing patterns. Cui says her team has successfully repeated the experiment in living rats. Next, she’d like to test the electrodes in epileptic rats and then begin the long process of regulatory approval for human use.

The body’s blood-brain barrier protects the organ from everything but the smallest molecules, rendering most drugs ineffective. As a result, this drug-​delivery mechanism could treat other brain disorders, Cui says. The electrodes can be loaded with any kind of small drug—like dopamine or painkillers—making it useful for treating Parkinson’s disease, chronic pain, or even drug addiction.

DEMENTIA

Electrode arrays stimulate mental processing

Dementia is one of the most well-known and frustrating brain afflictions. It damages many of the fundamental cognitive functions that make us human: working memory, decision-making, language, and logical reasoning. Alzheimer’s, Huntington’s, and Parkinson’s diseases all lead to dementia, and it’s also sometimes associated with multiple sclerosis, AIDS, and the normal process of aging.

Theodore Berger, a biomedical engineer at the University of Southern California, hopes to help people stave off the symptoms of dementia with a device implanted in the brain’s prefrontal cortex, a region crucial for sophisticated cognition. He and colleagues at Wake Forest Baptist Medical Center tested the device in a study involving five monkeys and a memory game.

First the team implanted an electrode array so that it could record from layers 2/3 and 5 of the prefrontal cortex and stimulate layer 5. The neural signals that jet back and forth between these areas relate to attention and decision-making. The team then trained the monkeys to play a computer game in which they saw a cartoon picture—such as a truck, lion, or paint palette—and had to select the same image from a panel of pictures 90 seconds later.

The scientists initially analyzed the electrical signals sent between the two cortical layers when the monkeys made a correct match. In later experiments, the team caused the array to emit the same signal just before the monkey made its decision. The animals’ accuracy improved by about 10 percent. That effect may be even more profound in an impaired brain. When the monkeys played the same game after receiving a hit of cocaine, their performance dropped by about 20 percent. But electrical stimulation restored their accuracy to normal levels.

Dementia involves far more complicated circuitry than these two layers of the brain. But once scientists better understand exactly how dementia works, it may be possible to combine several implants to each target a specific region.

BLINDNESS

Gene therapy converts cells into photoreceptors, restoring eyesight

Millions of people lose their eyesight when disease damages the photoreceptor cells in their retinas. These cells, called rods and cones, play a pivotal role in vision: They convert incoming light into electrical impulses that the brain interprets as an image.

In recent years, a handful of companies have developed electrode-array implants that bypass the damaged cells. A microprocessor translates information from a video camera into electric pulses that stimulate the retina; as a result, blind subjects in clinical trials have been able to distinguish objects and even read very large type. But the implanted arrays have one big drawback: They stimulate only a small number of retinal cells—about 60 out of 100,000—which ultimately limits a person’s visual resolution.

A gene therapy being developed by Michigan-based RetroSense could replace thousands of damaged retinal cells. The company’s technology targets the layer of the retina containing ganglion cells. Normally, ganglion cells transmit the electric signal from the rods and cones to the brain. But RetroSense inserts a gene that makes the ganglion cells sensitive to light; they take over the job of the photoreceptors. So far, scientists have successfully tested the technology on rodents and monkeys. In rat studies, the gene therapy allowed the animals to see well enough to detect the edge of a platform as they neared it.

The company plans to launch the first clinical trial of the technology next year, with nine subjects blinded by a disease called retinitis pigmentosa. Unlike the surgeries to implant electrode arrays, the procedure to inject gene therapy will take just minutes and requires only local anesthesia. “The visual signal that comes from the ganglion cells may not be encoded in exactly the fashion that they’re used to,” says Peter Francis, chief medical officer of RetroSense. “But what is likely to happen is that their brain is going to adapt.”

PARALYSIS

A brain-machine interface controls limbs while sensing what they touch

Last year, clinical trials involving brain implants gave great hope to people with severe spinal cord injuries. Two paralyzed subjects imagined picking up a cup of coffee. Electrode arrays decoded those neural instructions in real time and sent them to a robotic arm, which brought the coffee to their lips.

But to move limbs with any real precision, the brain also requires tactile feedback. Miguel Nicolelis, a biomedical engineer at Duke University, has now demonstrated that brain-machine interfaces can simultaneously control motion and relay a sense of touch—at least in virtual reality.

For the experiment, Nicolelis’s team inserted electrodes in two brain areas in monkeys: the motor cortex, which controls movement, and the nearby somatosensory cortex, which interprets touch signals from the outside world. Then the monkeys played a computer game in which they controlled a virtual arm—first by using a joystick and eventually by simply imagining the movement. The arm could touch three identical-looking gray circles. But each circle had a different virtual “texture” that sent a distinct electrical pattern to the monkeys’ somatosensory cortex. The monkeys learned to select the texture that produced a treat, proving that the implant was both sending and receiving neural messages.

This year, a study in Brazil will test the ability of 10 to 20 patients with spinal cord injuries to control an exoskeleton using the implant. Nicolelis, an ardent fan of Brazilian soccer, has set a strict timetable for his team: A nonprofit consortium he created, the Walk Again Project, plans to outfit a paraplegic man with a robotic exoskeleton and take him to the 2014 World Cup in São Paulo, where he will deliver the opening kick.

DEAFNESS

Stem cells repair a damaged auditory nerve, improving hearing

Over the past 25 years, more than 30,000 people with hearing loss have received an electronic implant that replaces the cochlea, the snail-shaped organ in the inner ear whose cells transform sound waves into electrical signals. The device acts as a microphone, picking up sounds from the environment and transmitting them to the auditory nerve, which carries them on to the brain.

But a cochlear implant won’t help the 10 percent of people whose profound hearing loss is caused by damage to the auditory nerve. Fortunately for this group, a team of British scientists has found a way to restore that nerve using stem cells.

The researchers exposed human embryonic stem cells to growth factors, substances that cause them to differentiate into the precursors of auditory neurons. Then they injected some 50,000 of these cells into the cochleas of gerbils whose auditory nerves had been damaged. (Gerbils are often used as models of deafness because their range of hearing is similar to that of people.) Three months after the transplant, about one third of the original number of auditory neurons had been restored; some appeared to form projections that connected to the brain stem. The animals’ hearing improved, on average, by 46 percent.

It will be years before the technique is tested in humans. Once it is, researchers say, it has the potential to help not only those with nerve damage but also people with more widespread impairment whose auditory nerve must be repaired in order to receive a cochlear implant.

Japan to field test rehabilitation robots

Ten hospitals in Japan are set to begin testing the use of a robot known as “Robot Suit HAL” starting next month. The purpose of the test will be to determine whether use of the robot is beneficial to patients needing physical therapy to regain normal use of their legs.

When people experience nerve or muscle damage to their lower backs or legs due to illness, stroke or injury, the normal course of treatment involves undergoing physical therapy. Doing so causes the body to slowly repair the damage that has been done. In order for it to work however, the parts of the body that work properly have to coax the parts that do not into action, a laborious and quite often painful process. For this reason, professional physical therapists assist patients with the process to ensure that all of the body parts are exercised and to offer emotional support. But such experts can only help so much, and for that reason, robots have been developed to help. The thinking is that because they are sensor based and lack emotional involvement in the process, robots are likely to do a better job.

The Robot Suit HAL (Hybrid Assistive Limb) has been designed and built by Cyberdyne Inc. with assistance from researchers around the country. It’s described by its makers as a cyborg-type robot meant to supplement human muscles or to assist in their rehabilitation. Its part handrail, part sensor and part hydraulically controlled machinery. A patient stands between two handrails, holding on, while sensors are affixed to the skin of the legs. The sensors pick up nerve signals which are sent to an onboard computer. Those signals are then converted to action by small motors and power units that cause the muscle to be worked in the same way it would be were the person’s body able to move it on their own. The end result is a direct connection between nerve signals and movement, which the researchers believe, will result in faster and perhaps better recovery for the patient.

Initial testing will involve 30 volunteer patients. Representatives for Cyberdyne have also announced that the company is in the process of making arrangements for testing the robot in hospitals in Europe as well.

Neil Harbisson Is A Cyborg Who Hears More Of The World Than We See

What would your world be like if you couldn’t see color? For artist Neil Harbisson, a rare condition known as achromatopsia that made him completely color blind rendered that question meaningless. Not being able to see color at all meant that there was no blue in the sky or green in grass, and these descriptions were merely something to be taken on faith or memorized to get the correct answers in school.

But Neil’s life would change drastically when he met computer scientist Adam Montandon and with help from a few others, they developed the eyeborg, an electronic eye that transforms colors into sounds. Colors became meaningful for Neil in an experiential way, but one that was fundamentally different than how others described them.

This augmentation device wasn’t like a set of headphones that he could put on when he wanted to “listen” to the world around him, but became a permanent part of who he was. Though he had to memorize how the sounds corresponded to certain colors, in time the sounds became part of his perception and the way he “sees” the world. He even started to expand the range of what he could “see”, so that wavelengths of light outside of the visible range could be perceived.

In other words, he became cybernetic.

Not being readily accepted into society prompted the birth of a mission, as he explains in the phenomenal short film “Cyborg Foundation” that has won the Grand Jury Prize in GE’s $200,000 Focus Forward Filmmaker competition.

Neil recently gave a fascinating talk at TEDGlobal2012 describing how his life is different, including how he can “eat my favorite song: I can compose music with food” and “before I used to dress in a way that it looked good — now I dress in a way that it sounds good.” The foundation he co-launched aims to advocate the development and adoption of cybernetics into society. “Life will be much more exciting when we stop creating applications for mobile phones and start creating them for our body.”

Cellular renewal process may underlie benefits of omega fatty acids

A search for genes that change their levels of expression in response to nutrient deprivation has uncovered potential clues to the mechanism underlying the health benefits of omega fatty acids. In the Feb. 15 issue of Genes & Development, Massachusetts General Hospital (MGH) researchers describe finding that feeding omega-6 fatty acids to C. elegans roundworms or adding them to cultured human cells activates a cellular renewal process called autophagy, which may be deficient in several important diseases of aging. A process by which defective or worn-out cellular components and molecules are broken down for removal or recycling, autophagy is also activated in metabolically stressful situations, allowing cells to survive by self-digesting nonessential components.

"Enhanced autophagy implies improved clearance of old or damaged cellular components and a more efficient immune response," says Eyleen O’Rourke, PhD, of MGH Molecular Biology, lead author of the report. "It has been suggested that autophagy can extend lifespan by maintaining cellular function, and in humans a breakdown in autophagic function may involved in diseases including inflammatory bowel disease, Parkinson’s disease, and in a more complex way in cancer and metabolic syndrome."

O’Rourke is a research fellow in the laboratory of MGH investigator Gary Ruvkun, PhD, whose team investigates the development, longevity and metabolism of C.elegans. Ruvkun and other researchers have discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans and that similar mutations in the corresponding mammalian pathways also regulate lifespan. Many of these mutations also make animals resistant to starvation, suggesting that common molecular mechanisms may underlie both response to nutrient deprivation and the regulation of lifespan.

To find these mechanisms O’Rourke searched genomic databases covering many types of animals for shared genes that respond to fasting by changing their expression. She found that expression of the C. elegans gene lipl-4 increases up to seven times in worms not given access to nutrients. A transgenic strain that constantly expresses elevated levels of lipl-4, even when given full access to food, was found to have increased levels of arachidonic acid (AA), an omega-6, and eicosapentanoic acid (EPA), an omega-3 fatty acid and to resist the effects of starvation.

(Image: The Herman Lab, Kansas State University)

Chimpanzees have faster working memory than humans

Chimpanzees have a faster working memory than humans according to a remarkable study showing that it takes them a fraction of a second to remember something that it would take several seconds for humans to memorise.

A Japanese scientist has demonstrated the prowess of chimps in remembering in less than half a second the precise position and correct sequence of up to nine numbers on a computer screen.

The numbers are shown together randomly distributed on a computer screen and as soon as the chimps press the number “one” the rest of the numerals are masked. However, they can almost invariably remember where each number was.

It is impossible for people to do the same cognitive task that quickly, said Tetsuro Matsuzawa, a primatologist at Kyoto University. “They have a better working memory than us,” he told the American Association for the Advancment of Science meeting in Boston.

Professor Matsuzawa had carried out the memory experiments on a female chimp called Ai, which means “love” in Japanese, and Ayumu, her son who was born in 2000 and has shown even better memory skills, he said.

Professor Matsuzawa suggested that chimps have developed this part of their memory because they live in the “here and now” whereas humans are thinking more about the past and planning for the future.

Hypothalamic control of energy balance: insights into the role of synaptic plasticity

The past 20 years witnessed an enormous leap in understanding of the central regulation of whole-body energy metabolism. Genetic tools have enabled identification of the region-specific expression of peripheral metabolic hormone receptors and have identified neuronal circuits that mediate the action of these hormones on behavior and peripheral tissue functions. One of the surprising findings of recent years is the observation that brain circuits involved in metabolism regulation remain plastic through adulthood. In this review, we discuss these findings and focus on the role of neurons and glial cells in the dynamic process of plasticity, which is fundamental to the regulation of physiological and pathological metabolic events.

Threat bias interacts with combat, gene to boost PTSD risk

Soldiers preoccupied with threat at the time of enlistment or with avoiding it just before deployment were more likely to develop post-traumatic stress disorder (PTSD), in a study of Israeli infantrymen. Such pre-deployment threat vigilance and avoidance, interacting with combat experience and an emotion-related gene, accounted for more than a third of PTSD symptoms that emerged later, say National Institutes of Health scientists, who conducted the study in collaboration with American and Israeli colleagues.

“Since biased attention predicted future risk for PTSD, computerized training that helps modify such attention biases might help protect soldiers from the disorder,” said Daniel Pine, M.D., of the NIH’s National Institute of Mental Health (NIMH).

Pine, Yair Bar-Haim, Ph.D., of Tel Aviv University, and colleagues, report their findings, Feb.  13, 2013, in the journal JAMA Psychiatry.

Parkinson’s patients advised to seek Deep Brain Stimulation treatment in early stages

People with Parkinson’s disease who receive Deep Brain Stimulation (DBS) therapy in the early stages of the condition will benefit from a significant increase in quality of life, a revolutionary study from The New England Journal of Medicine has found.

World-leading neurologist and lead clinician Professor Peter Silburn from the Asia-Pacific Centre for Neuromodulation (APCN), a joint initiative of The University of Queensland (UQ) and St Andrew’s Hospital, said the results published today in the medical journal would transform the way we treat people with Parkinson’s disease.

“Before the release of this study, a typical patient with Parkinson’s disease would need to wait around 10 years or until their motor complications could no longer be treated successfully with medicine alone, before DBS surgery was considered an option,” Professor Silburn said.

“This study has confirmed the best medical practice for a person with Parkinson’s disease is to perform DBS surgery around 4 to 7 years into the condition, as opposed to waiting until the medications stop working.”

Sticky Cells: Cyclic Mechanical Reinforcement Extends Longevity of Bonds Between Cells

Research carried out by scientists at the Georgia Institute of Technology and The University of Manchester has revealed new insights into how cells stick to each other and to other bodily structures, an essential function in the formation of tissue structures and organs. It’s thought that abnormalities in their ability to do so play an important role in a broad range of disorders, including cardiovascular disease and cancer.

The study’s findings are outlined in the journal Molecular Cell and describe a surprising new aspect of cell adhesion involving the family of cell adhesion molecules known as integrins, which are found on the surfaces of most cells. The research uncovered a phenomenon termed “cyclic mechanical reinforcement,” in which the length of time during which bonds exist is extended with repeated pulling and release between the integrins and ligands that are part of the extracellular matrix to which the cells attach.

Professor Martin Humphries, dean of the faculty of life sciences at the University of Manchester and one of the paper’s co-authors, says the study suggests some new capabilities for cells: “This paper identifies a new kind of bond that is strengthened by cyclical applications of force, and which appears to be mediated by complex shape changes in integrin receptors. The findings also shed light on a possible mechanism used by cells to sense extracellular topography and to aggregate information through ‘remembering’ multiple interaction events.”

The cyclic mechanical reinforcement allows force to prolong the lifetimes of bonds, demonstrating a mechanical regulation of receptor-ligand interactions and identifying a molecular mechanism for strengthening cell adhesion through cyclical forces.

“Many cell functions such as differentiation, growth and the expression of particular genes depend on cell interaction with the ligands of the intracellular matrix,” said Cheng Zhu, a professor in the Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and the study’s corresponding author. “The cells respond to their environment, which includes many mechanical aspects. This study has extended our understanding of how connections are made and how mechanical forces regulate interactions.”

The research was published online by the journal on February 14th. The work was supported by the National Institutes of Health (NIH) and the Wellcome Trust.