Neuroscience

For the first time, scientists have transplanted neural cells derived from a monkey’s skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.

Because the cells were derived from adult cells in each monkey’s skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not “foreign” tissue, there were no signs of immune rejection — potentially a major problem with cell transplants. “When you look at the brain, you cannot tell that it is a graft,” says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison. “Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”

Marina Emborg, an associate professor of medical physics at UW-Madison and the lead co-author of the study, says, “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”

The cells were implanted in the monkeys “using a state-of-the-art surgical procedure” guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson’s disease, which afflicts up to 1 million Americans. Parkinson’s is caused by the death of a small number of neurons that make dopamine, a signaling chemical used in the brain.

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.

In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.

Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process. “We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells.”

Another positive sign was the absence of any signs of cancer, says Zhang — a worrisome potential outcome of stem cell transplants. “Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, they become neurons with long axons [conducting fibers], as we’d expect. They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous.”

The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal’s behavior did not improve.

Although promising, the transplant technique is a long way from the clinic, Zhang adds. “Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough… And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem.”

Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg. “By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine.”

The need for treatment is incessant, says Emborg, noting that each year, Parkinson’s is diagnosed in 60,000 patients. “I’m gratified that the Parkinson’s Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease.”

"It’s really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang. "I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."

An iron imbalance caused by prion proteins collecting in the brain is a likely cause of cell death in Creutzfeldt-Jakob disease (CJD), researchers at Case Western Reserve University School of Medicine have found.

The breakthrough follows discoveries that certain proteins found in the brains of Alzheimer’s and Parkinson’s patients also regulate iron. The results suggest that neurotoxicity by the form of iron, called redox-active iron, may be a trait of neurodegenerative conditions in all three diseases, the researchers say.

Further, the role of the normal prion protein known as PrPc in iron metabolism may provide a target for strategies to maintain iron balance and reduce iron-induced neurotoxicity in patients suffering from CJD, a rare degenerative disease for which no cure yet exists.

The researchers report that lack of PrPC hampers iron uptake and storage and more findings are now in the online edition of the Journal of Alzheimer’s Disease.

"There are many skeptics who think iron is a bystander or end-product of neuronal death and has no role to play in neurodegenerative conditions," said Neena Singh, a professor of pathology and neurology at Case Western Reserve and the paper’s senior author. "We’re not saying that iron imbalance is the only cause, but failure to maintain stable levels of iron in the brain appears to contribute significantly to neuronal death."

Prions are misfolded forms of PrPC that are infectious and disease-causing agents of CJD. PrPc is the normal form present in all tissues including the brain. PrPc acts as a ferrireductase, that is, it helps to convert oxidized iron to a form that can be taken up and utilized by the cells, the scientists show.

In their investigation, mouse models that lacked PrPC were iron-deficient. By supplementing their diets with excess inorganic iron, normal levels of iron in the body were restored. When the supplements stopped, the mice returned to being iron-deficient.

Examination of iron metabolism pathways showed that the lack of PrPC impaired iron uptake and storage, and alternate mechanisms of iron uptake failed to compensate for the deficiency.

Cells have a tight regulatory system for iron uptake, storage and release. PrPC is an essential element in this process, and its aggregation in CJD possibly results in an environment of iron imbalance that is damaging to neuronal cells, Singh explained

It is likely that as CJD progresses and PrPC forms insoluble aggregates, loss of ferrireductase function combined with sequestration of iron in prion aggregates leads to insufficiency of iron in diseased brains, creating a potentially toxic environment, as reported earlier by this group and featured in Nature Journal club.

Recently, members of the Singh research team also helped to identify a highly accurate test to confirm the presence of CJD in living sufferers. They found that iron imbalance in the brain is reflected as a specific change in the levels of iron-management proteins other than PrPc in the cerebrospinal fluid. The fluid can be tapped to diagnose the disease with 88.9 percent accuracy, the researchers reported in the journal Antioxidants & Redox Signaling online last month.

Singh’ s team is now investigating how prion protein functions to convert oxidized iron to a usable form. They are also evaluating the role of prion protein in brain iron metabolism, and whether the iron imbalance observed in cases of CJD, Alzheimer’s disease and Parkinson’s disease is reflected in the cerebrospinal fluid. A specific change in the fluid could provide a disease-specific diagnostic test for these disorders.

Gamma-aminobutyric acid (GABA) deficits have been implicated in schizophrenia and depression. In schizophrenia, deficits have been particularly well-described for a subtype of GABA neuron, the parvalbumin fast-spiking interneurons. The activity of these neurons is critical for proper cognitive and emotional functioning.

It now appears that parvalbumin neurons are particularly vulnerable to oxidative stress, a factor that may emerge commonly in development, particularly in the context of psychiatric disorders like schizophrenia or bipolar disorder, where compromised mitochondrial function plays a role. parvalbumin neurons may be protected from this effect by N-acetylcysteine, also known as Mucomyst, a medication commonly prescribed to protect the liver against the toxic effects of acetaminophen (Tylenol) overdose, reports a new study in the current issue of Biological Psychiatry.

Dr. Kim Do and collaborators, from the Center for Psychiatric Neurosciences of Lausanne University in Switzerland, have worked many years on the hypothesis that one of the causes of schizophrenia is related to vulnerability genes/factors leading to oxidative stress. These oxidative stresses can be due to infections, inflammations, traumas or psychosocial stress occurring during typical brain development, meaning that at-risk subjects are particularly exposed during childhood and adolescence, but not once they reach adulthood.

Their study was performed with mice deficient in glutathione, a molecule essential for cellular protection against oxidations, leaving their neurons more exposed to the deleterious effects of oxidative stress. Under those conditions, they found that the parvalbumin neurons were impaired in the brains of mice that were stressed when they were young. These impairments persisted through their life. Interestingly, the same stresses applied to adults had no effect on their parvalbumin neurons.

Most strikingly, mice treated with the antioxidant N-acetylcysteine, from before birth and onwards, were fully protected against these negative consequences on parvalbumin neurons.

“These data highlight the need to develop novel therapeutic approaches based on antioxidant compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects,” said Do. “To give an antioxidant from childhood on to carriers of a genetic vulnerability for schizophrenia could reduce the risk of emergence of the disease.”

“This study raises the possibility that GABA neuronal deficits in psychiatric disorder may be preventable using a drug, N-acetylcysteine, which is quite safe to administer to humans,” added Dr. John Krystal, Editor of Biological Psychiatry.

Newly released findings from Bradley Hospital published in the Journal of the American Academy of Child & Adolescent Psychiatry have found that autism spectrum disorders (ASD) affect the brain activity of children and adults differently.

In the study, titled “Developmental Meta-Analysis of the Functional Neural Correlates of Autism Spectrum Disorders,” Daniel Dickstein, M.D., FAAP, director of the Pediatric Mood, Imaging and Neurodevelopment Program at Bradley Hospital, found that autism-related changes in brain activity continue into adulthood.

"Our study was innovative because we used a new technique to directly compare the brain activity in children with autism versus adults with autism," said Dickstein. "We found that brain activity changes associated with autism do not just happen in childhood, and then stop. Instead, our study suggests that they continue to develop, as we found brain activity differences in children with autism compared to adults with autism. This is the first study to show that."

This new technique, a meta-analysis, which is a study that compiles pre-existing studies, provided researchers with a powerful way to look at potential differences between children and adults with autism.

Dickstein conducted the research through Bradley Hospital’s PediMIND Program. Started in 2007, this program seeks to identify biological and behavioral markers—scans and tests—that will ultimately improve how children and adolescents are diagnosed and treated for psychiatric conditions. Using special computer games and brain scans, including magnetic resonance imaging (MRI), Dickstein hopes to one day make the diagnosis and treatment of autism and other disorders more specific and more effective.

Among autism’s most disabling symptoms is a disruption in social skills, so it is noteworthy that this study found significantly less brain activity in autistic children than autistic adults during social tasks, such as looking at faces. This was true in brain regions including the right hippocampus and superior temporal gyrus—two brain regions associated with memory and other functions.

Dickstein noted, “Brain changes in the hippocampus in children with autism have been found in studies using other types of brain scan, suggesting that this might be an important target for brain-based treatments, including both therapy and medication that might improve how this brain area works.”

Rowland Barrett, Ph.D., chief psychologist at Bradley Hospital and chief-of-service for The Center for Autism and Developmental Disabilities was also part of the team leading the study.

"Autism spectrum disorders, including autistic disorder, Asperger’s disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS), are among the most common and impairing psychiatric conditions affecting children and adolescents today," said Barrett. "If we can identify the shift in the parts of the brain that autism affects as we age, then we can better target treatments for patients with ASD."

Cognitive impairments are disabling for individuals with schizophrenia, and no satisfactory treatments currently exist. These impairments affect a wide range of cognition, including memory, attention, verbal and motor skills, and IQ. They appear in the earliest stages of the disease and disrupt or even prevent normal day-to-day functioning.

Scientists are exploring a variety of strategies to reduce these impairments including “exercising the brain” with specially designed computer games and medications that might improve the function of brain circuits.

In this issue of Biological Psychiatry, Dr. Mera Barr and her colleagues at University of Toronto provide new evidence that stimulating the brain using repetitive transcranial magnetic stimulation (rTMS) may be an effective strategy to improve cognitive function.

“In a randomized controlled trial, we evaluated whether rTMS can improve working memory in schizophrenia,” said Barr and senior author Dr. Zafiris Daskalakis. “Our results showed that rTMS resulted in a significant improvement in working memory performance relative to baseline.”

Transcranial magnetic stimulation is a non-invasive procedure that uses magnetic fields to stimulate nerve cells. It does not require sedation or anesthesia and so patients remain awake, reclined in a chair, while treatment is administered through coils placed near the forehead.

“TMS can have lasting effects on brain circuit function because this approach not only changes the activity of the circuit that is being stimulated, but it also may change the plasticity of that circuit, i.e., the capacity of the circuit to remodel itself functionally and structurally to support cognitive functions,” explained Dr. John Krystal, Editor of Biological Psychiatry.

Previous work has shown that rTMS improves working memory in healthy individuals and a recent open-label trial showed promising findings for verbal memory in schizophrenia patients. This series of findings led this study to determine if high frequency rTMS could improve memory in individuals with schizophrenia.

They recruited medicated schizophrenia patients who completed a working memory task before and after 4 weeks of treatment. Importantly, this was a double-blind study, where neither the patients nor the researchers knew who was receiving real rTMS or a sham treatment that was designed to entirely mimic the procedure without actually delivering brain stimulation.

rTMS not only improved working memory in patients after 4 weeks, but the improvement was to a level comparable to healthy subjects. These findings suggest that rTMS may be a novel, efficacious, and safe treatment for working memory deficits in schizophrenia.

In 2008, rTMS was FDA-approved to treat depression for individuals who don’t respond to pharmacotherapy. The hope is that additional research will replicate these findings and finally provide an approved treatment for cognitive impairments in schizophrenia.

The authors concluded: “Working memory is an important predictor of functional outcome. Developing novel treatments aimed at improving these deficits may ultimately translate into meaningful changes in the lives of patients suffering from this debilitating disorder.”

A research team led by Robert Nagele, PhD, of the New Jersey Institute for Successful Aging (NJISA) at the University of Medicine and Dentistry of New Jersey (UMDNJ)-School of Osteopathic Medicine, has demonstrated that the anti-atherosclerosis drug darapladib can significantly reduce leaks in the blood brain barrier. This finding potentially opens the door to new therapies to prevent the onset or the progression of Alzheimer’s disease. Writing in the Journal of Alzheimer’s Disease (currently in press), the researchers describe findings involving the use of darapladib in animal models that had been induced to develop diabetes mellitus and hypercholesterolemia (DMHC), which are considered to be major risk factors for Alzheimer’s disease.

“Diabetes and hypercholesterolemia are associated with an increased permeability of the blood-brain barrier, and it is becoming increasingly clear that this blood-brain barrier breakdown contributes to neurodegenerative diseases such as Alzheimer’s,” Nagele said. “Darapladib appears to be able to reduce this permeability to levels comparable to those found in normal, non-DMHC controls, and suggests a link between this permeability and the deposition of amyloid peptides in the brain.”

The study involved 28 animal (pig) models that were divided into three groups – DMHC animals treated with a 10 mg/day dose of darapladib; DMHC animals that received no treatment; and non-DMHC controls. Post-mortem analysis of the brains of the darapladib-treated animals showed significant decreases in blood-brain barrier leakage and in the density of amyloid-positive neurons in the cerebral cortices. Interestingly, the amyloid peptides that leaked into the brain tissue were found almost exclusively in the pyramidal neurons of the cerebral cortex, one of the earliest pathologies of the development of Alzheimer’s disease.

“Because our results suggest that these metabolic disorders can trigger neurodegenerative changes through blood-brain barrier compromise, therapies – such as darapladib – that can reduce vascular leaks have great potential for delaying the onset or slowing the progression of diseases like Alzheimer’s,” said the study’s lead author, Nimish Acharya, PhD, of the NJISA and the UMDNJ-Graduate School of Biomedical Sciences. “The clinical, caregiving and financial impact of such an effect cannot be overestimated.”

The British astrophysicist Stephen Hawking is likely to be the world’s most famous person living with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is a progressive disease affecting motor neurons, nerve cells that control muscle function, and nearly always leads to death. Researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna have now identified a completely new mechanism in the onset of motor neuron diseases. Their findings could be the basis for future treatments for these presently incurable diseases.

A new principle on motor neuron death
The IMBA scientists, working with an international team of researchers under the leadership of Josef Penninger and Javier Martinez, discovered a completely new fundamental mechanism that triggers the death of motor neurons. Motor neurons are nerve cells responsible for stimulating muscles. The loss of these motor neurons in mice with a genetic mutation in a gene named CLP11 leads to severe and progressive muscular paralysis and, in some cases, to death.
"We’ve been working on resolving the function of the CLP1 gene in a living organism for a long time. To do that, we developed model mice in which the function of CLP1 was genetically inactivated. To our utter surprise we discovered that deactivating CLP1 increases the sensitivity of cell die when exposed to oxidative stress2. That leads to enhanced activity of the p53 protein3 and then to the permanent destruction of motor neurons," says Toshikatsu Hanada, a postdoctoral researcher working in the lab of Josef Penninger and first author of the study along with Stefan Weitzer.

Stephen Hawking - a most renowned patient
Motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are chronic disorders of the neuromuscular system. These diseases are caused by damage in the motor nerve cells in the brain and spinal cord, and the nerves can no longer stimulate motion in the muscles. The primary symptoms are muscular weakness, muscular dystrophy, and problems swallowing or speaking. Stephen Hawking was diagnosed with ALS 50 years ago. But not all ALS patients live so long with the disease: so far there are no treatments for ALS. Nearly all ALS patients die of paralysis of respiratory muscles within a few years.

Completely new disease mechanism
Javier Martinez, an IMBA team leader and co-author of the study, is a specialist in the field of ribonucleic acid (RNA) research. His research group had discovered the CLP1 gene in an earlier study, published in Nature in 2007. Until now, the exact essential function of CLP1 in RNA biology was unclear. “By deactivating CLP1, we have discovered a previously unknown new species of RNA,” says Javier Martinez about the scientific relevance of the work. “The accumulation of this RNA is a consequence of increased oxidative stress in the cell. We see this as one of the triggers for the loss of motor neurons that occurs in ALS and other neuromuscular diseases. Thus our findings describe a completely new mechanism of motor neuron diseases.”

Seminal findings
Josef Penninger, scientific director at the IMBA and last-author of the study, is excited about the researchers’ findings: “This surprising discovery of a role of CLP1 in the onset of motor neuron diseases is an entirely new principle in how RNA talks to oxidative stress. Nearly all genetic mutations found in ALS patients affect either RNA metabolism or oxidative stress, suggesting a possibly unifying principle for these diseases. Our work may have revealed the ‘missing link’ in how these two biological systems communicate and trigger incurable diseases like ALS.”

Stefan Weitzer sees tremendous potential for these findings: “We’ve discovered a new mechanism that leads to the death of motor neurons. If this holds true for other neuronal disease, our results could be one day used to drive the development of treatments for previously incurable diseases. In our work we also describe how the p53 protein regulates the loss of motor neurons. Removing p53 saves mice with CLP1 mutations from certain death.” If scientists are successful in applying these findings to people, the researchers may have discovered a treatment approach to cure ALS and similar diseases. The authors, however, caution that more studies will be needed to translate their findings to human medicine.

This study was performed in collaboration with research groups from the Medical Universities of Vienna and Innsbruck, the University Medical Center at Hamburg-Eppendorf in Germany, the Harvard Medical School, the Harvard Stem Cell Institute, the Boston Children’s and Massachusetts General Hospitals, the Keio University School of Medicine in Tokyo, Oita University in Japan, and the Weizmann Institute of Science in Rehovot in Israel.

Their work, “CLP1 links tRNA metabolism to progressive motor-neuron loss”, was published on March 10, 2013 in “Nature”, an internationally renowned journal.

People with multiple sclerosis (MS) who have cognitive problems, or problems with memory, attention, and concentration, have more damage to areas of the brain involved in cognitive processes than people with MS who do not have cognitive problems, according to a study published in the March 6, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study used a type of MRI brain scan called diffusion tensor imaging along with regular MRI scans to compare brain measurements in 20 people with MS who had related cognitive problems, 35 people with MS who did not have cognitive problems and 30 healthy participants.

The diffusion tensor images showed that, compared to the healthy control participants, 49 percent of the investigated brain white matter had impaired integrity in those with MS and no cognitive problems, while impaired integrity was evident in 76 percent of the investigated white matter of those with MS and related cognitive problems. In the people with MS-related cognitive problems, the extra white matter dysfunction was particularly seen in areas important for cognitive skills, such as the thalamus.

“This state-of-the-art imaging technology confirms that cognitive symptoms in MS have a biological basis,” said study author Hanneke E. Hulst, MSc, of VU University Medical Center in Amsterdam, the Netherlands. “The consequence of this discovery is that imaging can now be used to capture a wider spectrum of changes in the brains of people with MS, and will therefore help determine more accurately whether new treatments are helping with all aspects of the disease.” Cognitive problems are common in MS, affecting up to 65 percent of people with the disease.

For the first time, an international team of researchers has found that a combination of a particular virus in the mother and a specific gene variant in the child increases the risk of the child developing schizophrenia.

Viruses and genes interact in a way that may increase the risk of developing schizophrenia significantly. This happens already in the developing foetus.

An international team of scientists led by Aarhus University, Denmark, has made this discovery. As the first in the world, they scanned the entire genome of hundreds of sick and healthy people to see if there is an interaction between genes and a very common virus - cytomegalovirus - and to see whether the interaction influences the risk of developing schizophrenia.

And it does.

Women that have been infected by the virus - and around 70% has - will have a statistically significant increased risk of giving birth to a child who later develops schizophrenia if the child also has the aforementioned gene variant. This variant is found in 15 percent. The risk is five times higher than usual, the researchers report in Molecular Psychiatry.

No cause for alarm

People infected with cytomegalovirus most often do not know it, as the infection by the virus, which belongs to the herpes virus family, is usually very mild. But the researchers stress that there is no cause for alarm - even if both risk factors are present in mother and child, there may be a variety of other factors that prevents disease development in the child.

But as schizophrenia affects 1 per cent of the global population, this new knowledge is very important.

"In the longer term, the development of an effective vaccine against cytomegalovirus may help to prevent many cases of schizophrenia," says Professor of Medical Genetics at Aarhus University, Anders Børglum.

"And our discovery emphasizes that mental disorders such as schizophrenia may arise in the context of an interaction between genes and biological environmental factors very early in life."

Every year thousands of people in Europe are paralysed by a spinal cord injury. Many are young adults, facing the rest of their lives confined to a wheelchair. Although no medical cure currently exists, in the future they could be able to walk again thanks to a mind-controlled robotic exoskeleton being developed by EU-funded researchers.

The system, based on innovative ‘Brain-neural-computer interface’ (BNCI) technology - combined with a light-weight exoskeleton attached to users’ legs and a virtual reality environment for training - could also find applications in the rehabilitation of stroke victims and in assisting astronauts rebuild muscle mass after prolonged periods in space.

In the United Kingdom, every eight hours someone suffers a spinal cord injury, often leading to partial or full lower-body paralysis. In the United States, more than 250.000 people are living with paralysis as a result of damage to their spinal cord, usually because of a traffic accident, fall or sporting injury. Many are under the age of 50, and with no known medical cure or way of repairing damaged spinal nerves they face the rest of their lives in a wheelchair.

But by bypassing the spinal cord entirely and routing brain signals to a robotic exoskeleton, they should be able to get back on their feet. That is the ultimate goal of researchers working in the ‘Mind-controlled orthosis and VR-training environment for walk empowering' (Mindwalker) project, a three-year initiative supported by EUR 2.75 million in funding from the European Commission.

'Mindwalker was proposed as a very ambitious project intended to investigate promising approaches to exploit brain signals for the purpose of controlling advanced orthosis, and to design and implement a prototype system demonstrating the potential of related technologies,' explains Michel Ilzkovitz, the project coordinator at Space Applications Services in Belgium.

The team’s approach relies on an advanced BNCI system that converts electroencephalography (EEG) signals from the brain, or electromyography (EMG) signals from shoulder muscles, into electronic commands to control the exoskeleton.

The Laboratory of Neurophysiology and Movement Biomechanics at the Université Libre de Bruxelles (ULB) focused on the exploitation of EEG and EMG signals treated by an artificial neural network, while the Foundation Santa Lucia in Italy developed techniques based on EMG signals modelled by the coupling of neural and biomechanical oscillators.

One approach for controlling the exoskeleton uses so-called ‘steady-state visually evoked potential’, a method that reads flickering visual stimuli produced at different frequencies to induce correlated EEG signals. Detection of these EEG signals is used to trigger commands such as ‘stand’, ‘walk’, ‘faster’ or ‘slower’.

A second approach is based on processing EMG signals generated by the user’s shoulders and exploits the natural arm-leg coordination in human walking: arm-swing patterns can be perceived in this way and converted into control signals commanding the exoskeleton’s legs.

A third approach, ‘ideation’, is also based on EEG-signal processing. It uses the identification and exploitation of EEG Theta cortical signals produced by the natural mental process associated with walking. The approach was investigated by the Mindwalker team but had to be dropped due to the difficulty, and time needed, in turning the results of early experiments into a fully exploitable system.

Regardless of which method is used, the BNCI signals have to be filtered and processed before they can be used to control the exoskeleton. To achieve this, the Mindwalker researchers fed the signals into a ‘Dynamic recurrent neural network’ (DRNN), a processing technique capable of learning and exploiting the dynamic character of the BNCI signals.

'This is appealing for kinematic control and allows a much more natural and fluid way of controlling an exoskeleton,' Mr Ilzkovitz says.

The team adopted a similarly practical approach for collecting EEG signals from the user’s scalp. Most BNCI systems are either invasive, requiring electrodes to be placed directly into brain tissue, or require users to wear a ‘wet’ capon their head, necessitating lengthy fitting procedures and the use of special gels to reduce the electrical resistance at the interface between the skin and the electrodes. While such systems deliver signals of very good quality and signal-to-noise ratio, they are impractical for everyday use.

The Mindwalker team therefore turned to a ‘dry’ technology developed by Berlin-based eemagine Medical Imaging Solutions: a cap covered in electrodes that the user can fit themselves, and which uses innovative electronic components to amplify and optimise signals before sending them to the neural network.

'The dry EEG cap can be placed by the subject on their head by themselves in less than a minute, just like a swimming cap,' Mr Ilzkovitz says.

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According to a 2012 World Health Organization report, over 35 million people worldwide currently have dementia, a number that is expected to double by 2030 (66 million) and triple by 2050 (115 million). Alzheimer’s disease, the most common form of dementia, has no cure and there are currently only a handful of approved treatments that slow, but do not prevent, the progression of symptoms.

New drug development, no matter the disease, is a slow, expensive, and risky process. Thus, innovative techniques to study and assess the possibilities of already-existing drugs for different diseases can be used to alleviate the traditional burdens of cost and time. Detailed in their new article in Biological Psychiatry, researchers from the University of Washington, led by Dr. Brian Kraemer, have developed an exciting new approach to screening potential new treatments for Alzheimer’s disease using C. elegans, a small transparent worm.

Their focus was on tau, a protein involved in maintaining brain cell structure. In Alzheimer’s disease and related disorders, tau protein becomes abnormally modified and forms clumps of protein called aggregates. These aggregates are a hallmark of the dying nerve cells in Alzheimer’s disease and other related disorders. Diseases with abnormal tau are called tauopathies.

Dr. Kraemer’s lab previously developed a worm model for tauopathy by expressing human tau in C. elegans nerve cells. This model has behavioral abnormalities, accumulates abnormal tau protein, and exhibits loss of nerve cells—all of which are general features of Alzheimer’s disease.

Using their worm model for this study, they screened a library of 1,120 drugs approved for human use and tested each at three different concentrations to identify compounds that suppress the effects of abnormal tau aggregation.

“We have identified six compounds capable of reliably alleviating tau induced behavioral abnormalities in our C. elegans model for tauopathy. In a human cultured cell model for abnormal tau protein, we have also seen that azaperone treatment can decrease the amount of abnormal tau,” said Kraemer.

Azaperone, an antipsychotic drug, normally binds to certain dopamine receptors found in nerve cells. They demonstrated that removing those receptors in either C. elegans or human cells has the same effect as azaperone treatment, indicating that azaperone and related drugs should alter abnormal tau accumulation. Other antipsychotic drugs also have a similar effect to azaperone.

Tests of these compounds for anti-tau properties are now underway in existing mouse models of Alzheimer’s disease.

“This study is an exemplary instance of how a simple C. elegans model system may be used to rapidly screen drugs for diseases and evaluate mechanism of action,” said Drs. Sangeetha Iyer and Jonathan Pierce-Shimomura, authors of a commentary that accompanies this article.

Dr. John Krystal, Editor of Biological Psychiatry, agrees and added: “Studying the worm, C. elegans, has already provided us with fundamental insights into how the brain develops. The new approach described by McCormick and colleagues suggests that this animal model may be a powerful new approach to studying novel treatments that prevent its decline.”