Farsighted engineer invents bionic eye to help the blind

For UCLA bioengineering professor Wentai Liu, more than two decades of visionary research burst into the headlines last month when the FDA approved what it called “the first bionic eye for the blind.”

The Argus II Retinal Prosthesis System — developed by a team of physicians and engineers from around the country — aids adults who have lost their eyesight due to retinitis pigmentosa (RP), age-related macular degeneration or other eye diseases that destroy the retina’s light-sensitive photoreceptors.

At the heart of the device is a tiny yet powerful computer chip developed by Liu that, when implanted in the retina, effectively sidesteps the damaged photoreceptors to “trick” the eye into seeing. The Argus II operates with a miniature video camera mounted on a pair of eyeglasses that sends information about images it detects to a microprocessor worn on the user’s waistband. The microprocessor wirelessly transmits electronic signals to the computer chip, a fingernail-size grid made up of 60 circuits. These chips stimulate the retina’s nerve cells with electronic impulses which head up the optic nerve to the brain’s visual cortex. There, the brain assembles them into a composite image.

Recipients of the retinal implant can read oversized letters of the alphabet, discern objects and movement, and even see the outlines and some details of faces. And while the picture is far from perfect — the healthy human eye sees at a much higher resolution — it’s a breakthrough for people like the first patient, a man in his 70s who was blinded at age 20 by RP, to receive the implant in clinical trials. “It was the first time he’d seen light in a half-century,” said Liu, adding that “it feels good as the engineer” to have helped make this possible.

Liu joined the Artificial Retina Project in 1988 as a professor of computer and electrical engineering at North Carolina State University. The multidisciplinary research project was funded by the U.S. Department of Energy’s Office of Science because it envisioned a potential pandemic of eyesight loss in America’s aging population. Leading the project was Duke University ophthalmologist and neurosurgeon Dr. Mark Humayun, now on faculty at USC. He tapped Liu to engineer the artificial retina.

“I thought it was a great idea,” Liu said. “But I asked, ‘What can I do?’ because I didn’t know much about biology.” Humayun handed him a six-inch-thick medical manual on the retina. “The learning curve was very steep,” Liu recalled with a laugh.

However, Liu’s fellow engineers questioned his sanity. “I was working on integrated chip design and had just gotten tenure when I signed on to this project. They said, ‘You’re crazy!’ But I’m glad I made that choice, getting into this new field.”

How the bionic eye works

Neuronal Morphology Goes Digital: A Research Hub for Cellular and System Neuroscience

The importance of neuronal morphology in brain function has been recognized for over a century. The broad applicability of ‘‘digital reconstructions’’ of neuron morphology across neuroscience subdisciplines has stimulated the rapid development of numerous synergistic tools for data acquisition, anatomical analysis, three-dimensional rendering, electrophysiological simulation, growth models, and data sharing. Here we discuss the processes of histological labeling, microscopic imaging, and semiautomated tracing. Moreover, we provide an annotated compilation of currently available resources in this rich research ‘‘ecosystem’’ as a central reference for experimental and computational neuroscience.

Links Between Physical And Emotional Pain Relief

We often regard relief as the dissipation of pain, discomfort or stress. However, the specific emotion associated with the sense of relief really isn’t fully understood. It is for this reason a team of researchers from the Association for Psychological Science undertook a study in which they aimed to explore and understand more fully the psychological mechanisms at work responsible for providing us with the idea of relief.

To experts in the field, the term for relief after the removal of pain is called the pain offset relief.

The team states their research recognizes the concept of relief, and the mechanisms behind it, are nearly identical for both healthy individuals and those with a history of self-harm. They claim the identical nature of pain offset relief in both of these groups suggests it is a natural mechanism useful in regulating our emotions. Prior to the laboratory portion of the experiment, the researchers assessed participants for emotion dysregulation and reactivity, self-injurious behavior, and various psychiatric disorders.

When an individual is experiencing the sensation of pain or discomfort, the likelihood they will experience a negative emotion is significantly increased. The team wanted to learn specifically if pain offset relief led to more positive emotions being experienced or if it only aided in alleviation of negative emotions.

Lead author Joseph Franklin, along with his colleagues working on the study, employed the use of electrodes intended to measure the participants’ negative emotions and positive emotions when the participants were subjected to loud noises. The loud noise was sometimes presented on its own. At other times, the participants would have received a low- or high-intensity shock at either a 3.5, 6 or 14 second interval preceding the loud noise.

Participants in the study showed an increase in positive emotion in combination with decreased negative emotion after pain offset. They learned the greatest increase in positive emotion occurred almost simultaneously with the culmination of the high-intensity shocks. Alternately, the greatest decrease in negative emotion was associated with the culmination of a low-intensity shock.

The team has published their findings, which they claim will shed light on the emotional nature of pain offset relief, in the journal Psychological Science, as well as the journal Clinical Psychological Science. Additionally, they feel their study might be useful in gaining a better understanding into why some people would seek the sensation of relief by engaging in self-harm behaviors.

It is important to note the results of this study do not support the hypothesis that heightened pain offset relief is a risk factor for engaging in self-harm behaviors. In fact, the team speculates the biggest risk factors for nonsuicidal self-injury may concern how some people overcome the instinctive barriers that keep most people from inflicting self-harm.

Nanotools for neuroscience and brain activity mapping

The ambitious and controversial Brain Activity Map (BAM), initiative instituted by a small group of researchers last year, has been steadily gaining momentum. Earlier this week, a proof-of-principle Zebrafish BAM was demonstrated with astounding clarity by a pair of researchers at the Howard Hughes Medical Institute.

Following on the heels of that work, an exhaustive 17-page compendium of current and soon-to-be brain mapping tools was published yesterday in ACS Nano by a rapidly snowballing list of disciples.

The BAM roster has been a carefully manicured player list from the beginning, and the role it has as ship wheel to this diffuse effort should not be underestimated. With the ranks now swelling to 27, each contributor to the paper has, in word or in spirit, contributed notably to the 185 referenced technologies on the paper. What we have here is not a research release, this is a textbook for the new neuroscience, and the journal choice, though not publicly accessible, hints at the desire to draw even more nanoscale researchers into the effort.

Media attention has channeled formative criticism to the effort in a way we have not seen before. Those sentiments on the cautionary take at least, might be summarized by likening the BAM scientists to cavemen having just discovered fire. Now sitting in the sand, they appear to be chartering a course to the internal combustion engine as they scribe on the ground with blunt bone instruments. The problem is that having just fleshed out how the brain’s wiring, the connectome, might be extracted, the community elites just leapfrogged to the full activity map, or at least one for some of the lesser animals.

The most extravagant technology proposed is undoubtedly the DNA tickertape. It appears to have been developed initially, at least in part, by Northwestern University’s Konrad Kording. Some of the earlier BAM papers show however that George Church, of human genome project fame, actually holds a patent that might cover some aspects of Kording’s idea. In particular, Church seems responsible for the wickedly unique concept of engineering DNA polymerases to produce predictable errors that would in effect record conditions within the cell or device onto DNA tapes. Fortunately Church, having entered neuroscience some time ago, is also a BAM founding father. His “nucleic acid memory device” could be the means by which the spike activity of each neuron would be recorded.

Among the other wild exotica hinted at in the ACS Nano paper is the DNA barcode proposed by Anthony Zador, from the Cold Spring Harbor Lab. This device would use a genetically modified rabies virus to infiltrate the nervous system, and record every connection in the process, web-crawl style. While Zador is not an author on this or the previous BAM papers, his techniques would not only provide a way to deliver a connectome of a complex brain, they potentially could do it non-destructively. Furthermore, the barcode mechanism would perhaps be the ideal way to propagate the Kording-Church tickertape machinery from cell to cell, bundling topology and activity together.

Many of the neurotools mentioned in the ACSNano paper are logical extensions of current technologies, just slightly smaller and a little higher in resolution. Recording cell activity with voltage-sensitive or calcium-imaging dyes, as was done in the Zebrafish map, may or may not be the process used ten years from now. Other ideas, like accessing neurons through fiber optic probes threaded through the vasculature to the capillaries, were re-invigorated, as were new sensors altogether like nanodiamond and nanogold devices.

Glaringly absent from this paper however, is a clear consensus of what exactly is to be done with these tools. The Zebrafish calcium map, for example, does not discriminate between neuron bodies, axons, dendrites, or synapses. The question of what level of detail is to be the goal of new studies still needs to be asked. This is a tough question because an activity map, like the connectome that would couch it, is rewritten on scales beneath our direct perception—not only is it a moving target, its trajectory is largely unknown. A long-term project such as this based in a set of technologies, as opposed to hypothesis-driven scientific inquiry, needs to balance fluidity with credibility.

Imagining what you would want to do if you were making a BAM of your own brain may emerge as the best way to set the project’s goals. In that case, the researchers may not be going for the whole BAM right away—just the things they would want to know in enough detail to get some answers in the least destructive way possible. If they plow through a bunch of animal studies generating terabytes of data, but cannot then use those methods used to learn about our brains, they will not have been successful. Priority then is to be the nondestructive BAM, focused on those high-interest, highly accessible areas with the highest density of observables wherein the observation risks are low. How to do this is the question of the next BAM installment.

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Alterations in brain activity in children at risk of schizophrenia predate onset of symptoms

Research from the University of North Carolina has shown that children at risk of developing schizophrenia have brains that function differently than those not at risk.

Brain scans of children who have parents or siblings with the illness reveal a neural circuitry that is hyperactivated or stressed by tasks that peers with no family history of the illness seem to handle with ease.

Because these differences in brain functioning appear before neuropsychiatric symptoms such as trouble focusing, paranoid beliefs, or hallucinations, the scientists believe that the finding could point to early warning signs or “vulnerability markers” for schizophrenia.

“The downside is saying that anyone with a first degree relative with schizophrenia is doomed. Instead, we want to use our findings to identify those individuals with differences in brain function that indicate they are particularly vulnerable, so we can intervene to minimize that risk,” said senior study author Aysenil Belger, PhD, associate professor of psychiatry at the UNC School of Medicine.

The UNC study, published online on March 6, 2013, in the journal Psychiatry Research: Neuroimaging, is one of the first to look for alterations in brain activity associated with mental illness in individuals as young as nine years of age.

Individuals who have a first degree family member with schizophrenia have an 8-fold to 12-fold increased risk of developing the disease. However, there is no way of knowing for certain who will become schizophrenic until symptoms arise and a diagnosis is reached. Some of the earliest signs of schizophrenia are a decline in verbal memory, IQ, and other mental functions, which researchers believe stem from an inefficiency in cortical processing – the brain’s waning ability to tackle complex tasks.

In this study, Belger and her colleagues sought to identify what if any functional changes occur in the brains of adolescents at high risk of developing schizophrenia. She performed functional magnetic resonance imaging (fMRI) on 42 children and adolescents ages 9 to 18, half of which had relatives with schizophrenia and half of which did not. Study participants each spent an hour and a half playing a game where they had to identify a specific image – a simple circle – out of a lineup of emotionally evocative images, such as cute or scary animals. At the same time, the MRI machine scanned for changes in brain activity associated with each target detection task.

Belger found that the circuitry involved in emotion and higher order decision making was hyperactivated in individuals with a family history of schizophrenia, suggesting that the task was stressing out these areas of the brain in the study subjects.

“This finding shows that these regions are not activating normally,” she says. “We think that this hyperactivation eventually damages these specific areas in the brain to the point that they become hypoactivated in patients, meaning that when the brain is asked to go into high gear it no longer can.”

Belger is currently exploring what kind of role stress plays in the changing mental capacity of adolescents at high risk of developing schizophrenia. Though only a fraction of these individuals will be diagnosed with schizophrenia, Belger thinks it is important to pinpoint the most vulnerable people early to explore interventions that may stave off the mental illness.

“It may be as simple as understanding that people are different in how they cope with stress,” says Belger. “Teaching strategies to handle stress could make these individuals less vulnerable to not just schizophrenia but also other neuropsychiatric disorders.”

Low-Cost ‘Cooling Cure’ Could Avert Brain Damage in Oxygen-Starved Babies

When babies are deprived of oxygen before birth, brain damage and disorders such as cerebral palsy can occur. Extended cooling can prevent brain injuries, but this treatment is not always available in developing nations where advanced medical care is scarce. To address this need, Johns Hopkins undergraduates have devised a low-tech $40 unit to provide protective cooling in the absence of modern hospital equipment that can cost $12,000.

The device, called the Cooling Cure, aims to lower a newborn’s temperature by about 6 degrees F for three days, a treatment that has been shown to protect the child from brain damage if administered shortly after a loss of oxygen has occurred. Common causes of this deficiency are knotting of the umbilical cord or a problem with the mother’s placenta during a difficult birth. In developing regions, untrained delivery, anemia and malnutrition during pregnancy can also contribute to oxygen deprivation.

In a recent issue of the journal Medical Devices: Evidence and Research, the biomedical engineering student inventors and their medical advisors reported successful animal testing of the Cooling Cure prototype. The device is made of a clay pot, a plastic-lined burlap basket, sand, instant ice-pack powder, temperature sensors, a microprocessor and two AAA batteries. To activate it, just add water.

The device could help curtail a serious health problem called hypoxic ischemic encephalopathy, which is triggered by oxygen deficiency in the brain. Globally, more than half of the newborns with a severe form of this condition die, and many of the survivors are diagnosed with cerebral palsy or other brain disorders. The problem is particularly acute in impoverished regions where pregnant women do not have easy access to medical specialists or high-tech hospital equipment. The inventors say Cooling Cure could address this issue.

“The students came up with a neat device that’s easy for non-medical people to use. It’s inexpensive and user-friendly,” said Michael V. Johnston, a Johns Hopkins School of Medicine pediatric neurology professor who advised the undergraduate team. Johnston also is chief medical officer and executive vice president of the Kennedy Krieger Institute, an internationally recognized center in Baltimore that helps children and adolescents with disorders of the brain, spinal cord and musculoskeletal systems.

First neutron scattering experiments on brain tissue reveal weaknesses in formaldehyde preservation, reducing reliability of post-mortem analysis

These results are the first step in a project to push back the limits of  existing dMRI imaging technology, to improve diagnosis and investigate potential treatments for brain diseases.

The first analysis of biological processes within brain tissue using neutrons at the Institut Laue-Langevin has revealed that the common application of formaldehyde preservatives changes, rather than maintains, fundamental properties such as rates of water diffusion. The mapping of cellular water in the brain is a key factor in the post-mortem analysis of several brain pathologies (including tumours and multiple sclerosis), with a view to earlier diagnosis and potential treatment. These results suggest the need for a review of existing research in this area.

The results are the first stage in the team’s own pioneering application of neutrons to understand in unprecedented detail the movement of cellular water within brain tissue. The analysis of this movement is generally performed by diffusion magnetic resonance imaging (dMRI), and provides the basis for diagnosing several brain diseases. These first results clearly demonstrate neutrons’ ability to ‘see’ the effects of these biological processes on a scale 10,000 times smaller than dMRI. In future ILL’s neutrons will analyse with unprecedented resolution cellular water dynamics in ex-vivo pathology-bearing brain tissue samples, thus helping doctors spot the early signs of these diseases and investigate potential treatments.

Cellular water is the major constituent of our body and its content may vary in brain regions depending on their specific composition. Water plays a key role in cell regulation, and its distribution and movement is an accurate indicator of cellular structure; this is because it interacts with different tissue components such as membranes and nerve fibres.

dMRI and other imaging techniques use water diffusion as a contrast method for revealing and characterising several brain pathologies (i.e. ischemia, tumours and, recently, inherited prion disease) on the micron scale 100 times thinner than a human hair. At this scale, however, the contribution of the macromolecular components cannot be separated and have to be averaged out instead.

As the standard imaging techniques used to detect the early signs of brain pathologies are limited in resolution, the use of preservation techniques to investigate pathological conditions in ex-vivo specimens has increased. However, there are concerns over the impact of these preservation processes on our tissues’ fundamental structural and compositional properties, and this has undermined confidence in this line of research.

To address these concerns Dr Francesca Natali from the Italian CNR (Consiglio Nazionale delle Ricerche), in collaboration with Dr Yuri Gerelli, a scientist from the Institut Laue-Langevin, the world’s flagship centre for neutron science, Prof. J. Peters from France’s Joseph Fourier University in Grenoble (UJF), and Dr Calogero Stelletta from the University of Padova in Italy compared the behaviour of cellular water in ex-vivo bovine tissue preserved using two common preservation techniques: chemical fixation, using formaldehyde solutions, and cryo-preservation, where cells or whole tissues are cooled to sub-zero temperatures.

The researchers obtained fresh post-mortem bovine brains from an Italian slaughter-house and applied the different preservation techniques. These samples were then investigated using incoherent quasi-elastic neutron scattering (QENS) on the high-resolution IN5 spectrometer at the Institut Laue-Langevin (ILL).

Neutrons are an ideal probe for the investigation of biological materials at the atomic scale. As they produce no damaging radiation effects, they can accurately map any change in the samples over time.

From this analysis Dr Francesca Natali and her colleagues identified a significant reduction of water movement as a result of the introduction of the formaldehyde-based preservation solutions (potentially due to the formation of cross-links between proteins, within which free water may become trapped, reducing its mobility). This effect was not seen in the samples that underwent cryo-preservation.

As well as these findings, the results of this study also demonstrate for the first time the power of neutrons to model cellular water diffusion within brain tissue; this new modeling technique could help dMRI specialists push back the limits of existing imaging technology, to improve their diagnoses and investigate potential treatments for brain pathologies.

In a separate study, the same team are investigating how the movement and distribution of cellular water in brain tissue is affected by myelin, an electrical insulator that forms protective layers known as sheaths around brain cell axons. Myelin is responsible for speeding up electrical impulses as they travel along tissue fibres. Many neurodegenerative autoimmune diseases, including multiple sclerosis, are caused by the degradation of myelin over time. The neutron scattering team’s new understanding of the impact on research results of preservation techniques will enhance its atomic-scale investigations into the conditions underlying autoimmune diseases and the potential for treatment.

Mapping blank spots in the cheeseboard maze

IST Austria Professor Jozsef Csicsvari together with collaborators succeeds in uncovering processes in which the formation of spatial memory is manifested in a map representation • Researchers investigate timescale of map formation • Inhibitory interneurons possibly involved in selection of map

During learning, novel information is transformed into memory through the processing and encoding of information in neural circuits. In a recent publication in Neuron, IST Austria Professor Jozsef Csicsvari, together with his collaborator David Dupret at the University of Oxford, and Joseph O’Neill, postdoc in Csicsvari’s group, uncovered a novel role for inhibitory interneurons in the rat hippocampus during the formation of spatial memory.

During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using the cheeseboard maze apparatus. This apparatus contains many holes, some of which are selected to hide food in order to test spatial memory. During learning trials, animals learn where the rewards are located, and after a period sleep, the researchers test whether the animal can recall these reward locations. In previous work, they and others have shown that memory of space is encoded in the hippocampus through changes in the firing of excitatory pyramidal cells, the so-called “place cells”. A place cell fires when the animal arrives at a particular location. Normally, place cells always fire at the same place in an environment; however, during spatial learning the place of their firing can change to encode where the reward is found, forming memory maps.

In their new publication, the researchers investigated the timescale of map formation, showing that during spatial learning, pyramidal neuron maps representing previous and new reward locations “flicker”, with both firing patterns occurring. At first, old maps and new maps fluctuate, as the animal is unsure whether the location change is transient or long-lasting. At a later stage, the new map and so the relevant new information dominates.

The scientists also investigated the contribution of inhibitory interneuron circuits to learning. They show that these interneurons, which are extensively interconnected with pyramidal cells, change their firing rates during map formation and flickering: some interneurons fire more often when the new pyramidal map fires, while others fire less often with the new map. These changes in interneuron firing were only observed during learning, not during sleep or recall. The scientists also show that the changes in firing rate are due to map-specific changes in the connections between pyramidal cells and interneurons. When a pyramidal cell is part of a new map, the strengthening of a connection with an interneuron causes an increase in the firing of this interneuron. Conversely, when a pyramidal cell is not part of a new map, the weakening of the connection with the interneuron causes a decrease in interneuron firing rate. Both, the increase and the decrease in firing rate can be beneficial for learning, allowing the regulation of plasticity between pyramidal cells and controlling the timing in their firing.

The new research therefore shows that not only excitatory neurons modify their behaviour and exhibit plastic connection changes during learning, but also the inhibitory interneuron circuits. The researchers suggest that inhibitory interneurons could be involved in map selection – helping one map dominate and take over during learning, so that the relevant information is encoded.

Intuition results from training

A game of Japanese chess reveals how experts develop their capacity for rapid problem-solving

The superior capability of experts to rapidly solve problems depends largely on their intuition, and it has long been known that this is related to experience and training. Although many psychological models relating to the development of intuition have been proposed to explain this phenomenon, none have been validated, and the underlying neural mechanisms remain a mystery.

Keiji Tanaka and colleagues from the Cognitive Brain Mapping Laboratory and Support Unit for Functional Magnetic Resonance Imaging at the RIKEN Brain Science Institute have now shown that activity in the basal ganglia of the brain, which is related to the automatic, rapid information processing or intuition characteristic of experts, develops during the course of training. The work provides a first insight into the neural response of the brain to extended training and hints at ways to improve the efficiency of training experts in industry.

In earlier work, another research team led by Tanaka showed that amateur players of the Japanese chess-like game of shogi plotted their best next-moves consciously using the human brain’s highly developed cerebral cortex. In contrast, they found that in professional players an important part of this process was unconscious or intuitive and had shifted to the head of the caudate nucleus in the basal ganglia, a much older part of the brain. This would leave the cortex free for higher-level strategy, the researchers suggested. Yet it remained unclear as to whether this shift of neural activity was entirely due to training, or dependent to some extent on pre-existing ability.

Tanaka’s most recent experiments involved training 20 novices for 15 weeks in mini-shogi, a simplified version of shogi. After about two weeks and again at the end of the 15-week program, the intuition of the volunteers was tested through their ability to come up with the best next-move to end-phase patterns of mini-shogi games. To ensure the answers were intuitive, each problem was presented for just two seconds and participants had to respond within three seconds. During this process, brain activity was recorded using functional magnetic resonance imaging (fMRI). The researchers found that activity in the caudate nucleus developed over the training period, whereas activity in the cortex remained unchanged.

“This work should open a fruitful interaction between the cognitive psychology of expertise development and biological studies of the basal ganglia,” says Tanaka. “We now would like to elucidate what computations the caudate nucleus conducts in generating the best next-move.”