June 27th, 2012

Researchers from the Huck Institutes’ Center for Cellular Dynamics, led by Center director Melissa Rolls, have found that a neuroprotective pathway initiated in response to injured or stressed neural axons serves to stabilize and protect the nerve cell against further degeneration.

Neurons, or nerve cells, typically have a single axon that transmits signals to other neurons or to output cells such as muscle tissue, and as these axons extend for long distances within the cell, they are thus at risk for injury.

Furthermore, if an axon is damaged, its parent neuron can no longer function; and since many animals develop only one set of neurons, those neurons will mount major responses to axon injury.

“Neurons are quite remarkable cells,” says Dr. Rolls. “Most of them need to survive and function for your entire lifetime. Maybe then it shouldn’t be a surprise that they do not give up easily when damaged or stressed, but it is amazing to be able to watch them fight back and stabilize themselves.”

Neurons expressing a toxic form of spinocerebellar ataxia type 3 (SCA3) with protective pathway enabled (left) and blocked (right). Image adapted from Penn State press release image with credit to Melissa Rolls. Click for larger view and original image from Penn State.

Dissecting Drosophila

Dr. Rolls and her team set out to understand these cellular responses to axon injury by observing the effects of severing fruit fly axons with a laser.

What they found was that the neurons responded to the injury by increasing production of microtubules — cytoskeletal components responsible for maintaining cell structure and providing platforms for intracellular transport — in order to stabilize the neural dendrites, which are the branched structures responsible for transmitting signals to the nerve cell body.

In addition to acute injury response, the team also investigated neurons’ response to long-term axon stress — and found similar results.

Accumulation of misfolded proteins or protein aggregates — responsible for neurodegenerative diseases such as Huntington’s disease and spinocerebellar ataxia — induced the same type of cytoskeletal changes as acute axon injury.

Dr. Rolls elaborates: “The assays that we use are all in vivo, so we can literally watch what the neurons do in different scenarios, including cutting of their axon. Being able to observe the cellular responses gave us some ideas we would not have come up with otherwise. For example, it is not intuitive that expressing a protein that causes degeneration would trigger the cell to turn on a pathway that delays degeneration.”

The neuroprotective pathway

The video below shows the difference in microtubule dynamics between cells expressing a non-toxic form of the huntingtin protein (left) and cells expressing a disease-causing form (right).

[Video: Axon injury and stress trigger a microtubule-based neuroprotective pathway]
Credit: Melissa Rolls, Director, Center for Cellular Dynamics

Conclusions and implications

Based on their observations, the authors suggest that this pathway represents an endogenous neuroprotective response to axon stress — and could potentially be developed into a diagnostic tool for the detection of early stages of neurodegenerative disease, or even utilized in novel therapies for such illnesses.

“We don’t yet know if all types of neurodegenerative disease trigger this type of stabilization pathway; but if there are some diseases in which it is off, then it may be beneficial to try to turn it on to help the neurons resist degeneration,” says Dr. Rolls.

The results of the study have been published in Proceedings of the National Academy of Sciences.

Source: Neuroscience News

ScienceDaily (June 27, 2012) — Scientists at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have gained important insights for stem cell research which are also applicable to human tumours and could lead to the development of new treatments. As Rolf Kemler’s research group discovered, a molecular link exists between the telomerase that determines the length of the telomeres and a signalling pathway known as the Wnt/β-signalling pathway.

Telomeres are the end caps of chromosomes that play a very important role in the stability of the genome. Telomeres in stem cells are long and become shorter during differentiation or with age, but lengthen again in tumour cells.

The Wnt/β-catenin signalling pathway controls numerous processes in embryonic development, such as the formation of the body axis and of organ primordia, and is particularly active in embryonic and adult stem cells. The β-catenin protein plays a key role in this signalling pathway. The incorrect regulation or mutation of β-catenin leads to the development of tumours.

Rolf Kemler’s research group has now shown that β-catenin regulates the telomerase gene directly, and has explained the molecular mechanism at work here. Embryonic stem cells with mutated β-catenin generate more telomerase and have extended telomeres, while cells without β-catenin have low levels of telomerase and have shortened telomeres.

This regulation mechanism can also be found in human cancer cells. These discoveries could lead to the development of a new approach to the treatment of human tumours.

Source: Science Daily

ScienceDaily (June 27, 2012) — A new study shows significant differences in brain development in high-risk infants who develop autism starting as early as age 6 months. The findings published in the American Journal of Psychiatry reveal that this abnormal brain development may be detected before the appearance of autism symptoms in an infant’s first year of life. Autism is typically diagnosed around the age of 2 or 3.

The study offers new clues for early diagnosis, which is key, as research suggests that the symptoms of autism — problems with communication, social interaction and behavior — can improve with early intervention. “For the first time, we have an encouraging finding that enables the possibility of developing autism risk biomarkers prior to the appearance of symptoms, and in advance of our current ability to diagnose autism,” says co-investigator Dr. Alan Evans at the Montreal Neurological Institute and Hospital — the Neuro, McGill University, which is the Data Coordinating Centre for the study.

"Infancy is a time when the brain is being organized and connections are developing rapidly," says Dr. Evans. "Our international research team was able to detect differences in the wiring by six months of age in those children who went on to develop autism. The difference between high-risk infants that developed autism and those that did not was specifically in white matter tract development — fibre pathways that connect brain regions." The study followed 92 infants from 6 months to age 2. All were considered at high-risk for autism, as they had older siblings with the developmental disorder. Each infant had a special type of MRI scan, known as diffusion tensor imaging, at 6 months and a behavioral assessment at 24 months. The majority also had additional scans at either or both 12 and 24 months.

At 24 months, 30% of infants in the study were diagnosed with autism. White matter tract development for 12 of the 15 tracts examined differed significantly between the infants that developed autism and those who did not. Researchers evaluated fractional anisotropy (FA), a measure of white matter organization based on the movement of water through tissue. Differences in FA values were greatest at 6 and 24 months. Early in the study, infants who developed autism showed elevated FA values along these tracts, which decreased over time, so that by 24 months autistic infants had lower FA values than infants without autism.

The study characterizes the dynamic age-related brain and behavior changes underlying autism — vital for developing tools to aid autistic children and their families. This is the latest finding from the on-going Infant Brain Imaging Study (IBIS), which is funded by the National Institutes of Health (NIH) and brings together the expertise of a network of researchers from institutes across North America. The IBIS study is headquartered at the University of North Carolina, and The Neuro is the Data Coordinating Centre where all IBIS data is centralized.

Source: Science Daily

June 26, 2012

Researchers at the University of Michigan have found that the Apple iPad 2 can interfere with settings of magnetically programmable shunt devices, which are often used to treat children with hydrocephalus. The iPad 2 contains magnets that can change valve settings in the shunt if the tablet computer is held too close to the valve (within 2 inches). Such a change may result in shunt malfunction until the problem is recognized and the valve adjusted to the proper setting. Patients and their caregivers should monitor use of the tablet computer to ensure that no change is made to the valve settings. The results of this study can be found in the article “Programmable shunt valve affected by exposure to a tablet computer. Laboratory investigation,” by Strahle and colleagues, published in the August 2012 issue of the Journal of Neurosurgery: Pediatrics and available online today.

The researchers first thought of performing this study because a tablet computer seemed to affect a programmable shunt in one of their patients, a 4-month-old girl with hydrocephalus. Three weeks after the baby had received the shunt, she was examined for shunt malfunction due to a changed setting in the magnetically programmable valve that regulates the flow of cerebrospinal fluid. The baby’s mother stated that she had held an iPad 2 while holding the infant. Programmable shunt valve settings can be altered by exposure to magnetic fields. Indeed, specialized magnets are used by physicians to adjust the settings on these valves. Since in this case no other environmental factor could be identified that would have led to a shift in the valve settings, the authors decided to test whether the iPad 2 might be implicated because, unlike the initial iPad, the iPad 2 contains several magnets and is often used with an Apple Smart Cover, which contains additional magnets.

The researchers tested 10 programmable shunt valves with a variety of settings. They exposed the valves to an iPad 2 with and without the Smart Cover at different distances: less than 1 centimeter (cm), 1 to 2.5 cm, 2.5 to 5 cm, 5 to 10 cm, and greater than 10 cm. Each exposure lasted 10 seconds. Overall, the valves were tested 100 times for each of the five distances during exposures to the iPad 2 with the Smart Cover closed and 30 times for distances less than 1 cm for the tablet computer without the cover.

After exposure of the programmable valves to the iPad 2 and Smart Cover at distances between 0 and 1 cm, the researchers found that the settings had changed in 58 percent of the valves. After exposure at distances between 1 and 2.5 cm the settings had changed in 5 percent of valves, and after exposure at distances between 2.5 and 5 cm the settings had changed in only 1 percent of valves. No changes in valve settings were identified after exposures at higher distances.

After exposure of programmable valves to the iPad 2 without a cover, which was only tested at distances between 0 and 1 cm, the researchers found that the settings had changed in 67 percent of the valves.

Although no change in setting was found past a distance of 5 cm (2 inches), the authors caution that patients and caregivers should be made aware of the potential for a change in the settings of a magnetically programmable shunt valve if an iPad 2 is placed very near. This is not to say that the iPad 2 cannot be safely used in the vicinity of patients with programmable shunts. A variety of magnets can be found in households today, and the authors state that the magnetic field strength of the iPad 2 lies within the range of these everyday magnets. Therefore, patients and caregivers should regard precautions surrounding the use of the iPad 2 to be the same as those taken with other household magnets. Cormac Maher, M.D., a pediatric neurosurgeon and lead author of the report, said that he hopes to raise awareness of this potential interaction through publication of this study.

Provided by Journal of Neurosurgery Publishing Group

Source: medicalxpress.com

ScienceDaily (June 26, 2012) — In the brains of humans and non-human primates, over 100 billion nerve cells build up complicated neural circuits and produce higher brain functions. When an attempt is made to perform gene therapy for neurological diseases like Parkinson’s disease, it is necessary to specify a responsible neural circuit out of many complicated circuits. Until now, however, it was difficult to introduce a target gene into this particular circuit selectively.

The collaborative research group consisting of Professor Masahiko Takada from Primate Research Institute, Kyoto University, Professor Atsushi Nambu from National Institute for Physiological Sciences, National Institutes of Natural Sciences, and Professor Kazuto KOBAYASHI from Fukushima Medical University School of Medicine have now developed a gene transfer technique that can “eliminate”a specific neural circuit in non-human primates for the first time.

They applied this technique to the basal ganglia, the brain region that is affected in movement disorders such as Parkinson’s disease, and successfully eliminated a particular circuit selectively to elucidate its functional role. This technique can be applied to gene therapy for various neurological diseases in humans. This research achievement was supported by the Strategic Research Program of Brain Sciences by MEXT of Japan.

The research group developed a special viral vector, NeuRet-IL-2R alpha-GFP viral vector, expressing human interleukin type 2 alpha receptor, which the cell death inducer immunotoxin binds. Nerve cells transfected with this viral vector cause cell death by immunotoxin. First, the research group injected the viral vector into the subthalamic nucleus that is a component of the basal ganglia. Then, they injected immunotoxin into the motor cortex, an area of the cerebral cortex that controls movement, and succeed in selective elimination of the “hyperdirect pathway” that is one of the major circuits connecting the motor cortex to the basal ganglia. As a result, they have discovered that neuronal excitation observed at the early stage occurs through this hyperdirect pathway when motor information derived from the cortex enters the basal ganglia.

Professors Takada and Nambu expect that this gene transfer technique enables us to elucidate higher brain functions in primates and to develop primate models of various psychiatric/neurological disorders and their potential treatments including gene therapy. They think that this should provide novel advances in the field of neuroscience research that originate from Japan.

Source: Science Daily

ScienceDaily (June 26, 2012) — Magnetic fields generated by microscopic devices implanted into the brain may be able to modulate brain-cell activity and reduce symptoms of several neurological disorders. Micromagnetic stimulation appears to generate the kind of neural activity currently elicited with electrical impulses for deep brain stimulation (DBS) — a therapy that can reduce symptoms of Parkinson’s disease, other movement disorders, multiple sclerosis and chronic pain — and should avoid several common problems associated with DBS, report Massachusetts General Hospital investigators.

"We have shown that fields generated by magnetic coils small enough to be implanted into the central nervous system can be used to modulate the activity of neurons, potentially leading to a new generation of neural prosthetics that are safer and possibly more effective than conventional electrical stimulation devices," says Giorgio Bonmassar, PhD, of the Martinos Center for Biomedical Imaging at MGH, co-lead author of the report in the online journal Nature Communications.

DBS involves implantation of small electrodes called leads into structures deep within the brain. The leads, connected to a battery-operated power source implanted into the abdomen, generate electrical signals that modulate neural activity at sites that vary depending on the condition being treated. DBS has successfully alleviated symptoms in patients not helped by other therapies, but it does have limitations. Magnetic resonance imaging (MRI) can cause metallic DBS implants to heat up and damage adjacent brain tissue, which limits the use of MRI in these patients. In addition, the presence of DBS implants typically elicits an immune system response, leading to scarring around the implant that can block the electrical signal.

Magnetic stimulation has been used to diagnose and treat neurological disorders for two decades, but until now it has required the use of large hand-held coils that generate fields from outside the skull, limiting the brain structures that can be stimulated and the accuracy with which a signal can be delivered. The current study was designed to investigate the potential of much smaller magnetic coils to generate the kind of neural activity produced by DBS, exploring a concept first developed by Bonmassar. The investigators first developed a computational simulation that verified that magnetic coils 1 millimeter long and .5 mm in diameter would generate magnetic and electrical fields that should stimulate neuronal activity.

The research team then tested whether a commercially available coil of that size, coated with a plastic material, would activate neurons in retinal tissue. Positioned right above retinal tissue and either parallel or perpendicular to the tissue surface, the coil generated fields that successfully elicited neuronal signals in retinal cells. How the coil was positioned relative to the retinal surface produced significant differences in the physiologic responses. When the coil was oriented parallel to the retina, the induced field appeared to activate retinal bipolar cells, which transmit signals from the light-sensing photoreceptors to retinal ganglion cells. A coil oriented perpendicular to the retina produced responses indicative of ganglion cell activation.

"These differences suggest that, by modifying the geometry of the coil, we may be able to selectively target populations of neurons and minimize the effects on non-targeted cells," says Shelley Fried, PhD, of the MGH Department of Neurosurgery, corresponding author of the Nature Communications report. “By sizing and orienting the coil appropriately to any given population of central nervous system neurons, we should be able to either activate or avoid activation of that population.

"This study provides a proof of concept that small coils can activate neurons, and much work still needs to be done," he adds. "We need to explore how to optimize coil properties and then evaluate the devices in animal models. We also hope to explore the use of these coils in non-DBS applications, including cardiovascular procedures such as heart muscle pacing." Fried is an instructor in Surgery and Bonmassar an assistant professor of Radiology at Harvard Medical School.

Source: Science Daily

ScienceDaily (June 26, 2012) — Scientists from the University of Barcelona (UB) in collaboration with a multidisciplinary team from the Spanish National Research Council (CSIC) has discovered a mechanism that prevents alterations in neurogenesis, the process of neuronal formation, during the development of the nervous system in vertebrates. The study, published in the journal Development, relates these distortions to the natural presence of a molecule that inhibits the neuronal formation at the regions adjacent to the tissue suitable for neurogenesis.

Left: altered neurogenic wavefront in the absence of Delta. Right: normal neurogenic wavefront. (Credit: Image courtesy of Universidad de Barcelona)

Through a theoretical and computational analysis of the retina, scientists have found that lateral inhibition, a process that regulates the generation of neurons in the central nervous system, undergoes alterations at the neurogenic wavefront (i.e. the edge between the regions that generate neurons and the adjacent areas, where neurogenesis has not yet begun).

"The study shows that the absence of the Delta molecule at the adjacent regions reduces the robustness of the neurogenic process, often resulting in an increased production of neurons or in the presence of morphological alterations of the wavefront. These alterations could be catastrophic for the proper development of the nervous system," explains José María Frade, researcher from the CSIC, at the Cajal Institute.

Lateral inhibition during embryonic development aims to control the amount of neurons that are formed. It consists in cells that inhibit other neighbouring cells, promoting neuronal differentiation. “Neuronal precursor cells expressing high levels of Delta induce inhibitory signals in neighbouring cells. These inhibitory signals reduce the capacity of these cells to express Delta itself and, in turn, facilitate the differentiation of the high Delta-expressing precursors. Thus, the massive generation of neurons is avoided and the orderly production of different types of neurons necessary for brain function is facilitated,” explains researcher from the CSIC Saúl Ares, who works at the Spanish National Biotechnology Centre.

Previous theoretical studies suggested that the lateral inhibition process can be altered at the neurogenic edges. “However, the importance of this inhibition process had not been appropriately acknowledged. Our study demonstrates the relevance of Delta expression ahead of the neurogenic wavefront, provides predictions and explains developmental alterations resulting from the absence of Delta. It also represents a breakthrough in the theoretical field because it formulates a front propagation mechanism based on self-regulatory mechanisms,” points out Marta Ibañes, researcher from the UB.

According to researchers, this study provides a new concept that will attract the attention of neurobiologists who work both in the development of the nervous system and in several pathologies derived from neuronal development.

Source: Science Daily

26 June 12 | By Liat Clark

A UK mathematician has made a public appeal for people to phone a dedicated number so data can be gathered to hone a tool that can diagnose Parkinson’s disease by analysing voice patterns.

Image: Shutterstock

Max Little, a research fellow at the Massachusetts Institute of Technology, made the announcement during the opening of the TEDGlobal conference in Edinburgh, 25 June. While studying at Oxford University, Little developed an algorithm that identifies the unique characteristics present in the voice of a Parkinson’s Disease sufferer. He setup the Parkinson’s Voice Initiative in order to improve upon the machine learning system — the algorithm is built to adapt when new information is introduced and, by widening the pool (it’s hoped, with 10,000 phone calls form the public), it should become a more accurate diagnosis tool, able to identify specific symptoms amid numerous variants of speech.

"This raises a very interesting possibility," Little says in a promotional video. "If we could use the entire existing telephone network then we could scale up the screening of Parkinson’s disease to the entire population, and do it at very minimal cost."

Other than the UK, there are phone numbers on the Parkinson’s Voice Initiative website for people in the US, Brazil, Mexico, Spain, Argentina and Canada. Parkinson’s sufferers and non-sufferers are both encouraged to call in anonymously. The calls should only last around three minutes. By getting non-sufferers to call in, the system can learn to weed out and discard unnecessary voice patterns, such as those brought on by a cold or heavy smoking.

Around 70-90 percent of sufferers report instances of vocal impairment following the onset of the disease. Little’s proposal therefore presents opportunities for widespread remote diagnosis.

He first presented the diagnosis tool’s successful testing in a paper published earlier this year in the IEEE Transactions journal. Little and co-author Athanasios Tsanas explained how 43 candidates were asked to hold one sound frequency for as long as possible. They collected 263 data samples in this way, and from this extracted 132 different vocal impairments. Using only ten of these recorded impairments, the algorithm could diagnose Parkinson’s speech markers accurately 99 percent of the time. The system is trained to identify the anomalies in the speech.

By collating more data in the future, the range of these vocal features could be widened, lessening the margin of error even more.

The paper suggests that in the future, data could be collected using Intel’s At-Home Testing Device, a telemonitoring system. It would then be sent to a clinic where the algorithm processes it and maps out the speech, identifying markers on the Unified Parkinson’s Disease Rating Scale (UPDRS) so that the severity of the illness is known. In this way, the system could not only be used to diagnose, but to monitor the progression of the disease.

Voice recognition could be a cheap and efficient alternative to having patients’ head to their GP for a twenty-minute diagnosis session. There is currently no simple diagnosis tool — no blood test that can identify Parkinson’s — and vocal tremors, breathiness and reduced speech volume are some of the first symptoms recorded in nearly all patients. These can be very subtle at the start, however, and systems such as Little’s could conceivably pick up the slightest abnormal intonation.

Parkinson’s Disease is the second most common neurodegenerative disorder after Alzheimer’s and, since it can only be treated with drugs or surgery and cannot be cured, early diagnosis can massively effect an individual’s quality of life.

Source: wired.co.uk

ScienceDaily (June 26, 2012) — UCLA researchers discovered that a diet enriched with a popular omega-3 fatty acid and an ingredient in curry spice preserved walking ability in rats with spinal-cord injury. Published June 26 in the Journal of Neurosurgery: Spine, the findings suggest that these dietary supplements help repair nerve cells and maintain neurological function after degenerative damage to the neck.

Turmeric. (Credit: © Elzbieta Sekowska / Fotolia)

"Normal aging often narrows the spinal canal, putting pressure on the spinal cord and injuring tissue," explained principal investigator Dr. Langston Holly, associate professor of neurosurgery at the David Geffen School of Medicine at UCLA. "While surgery can relieve the pressure and prevent further injury, it can’t repair damage to the cells and nerve fibers. We wanted to explore whether dietary supplementation could help the spinal cord heal itself."

The UCLA team studied two groups of rats with a condition that simulated cervical myelopathy — a progressive disorder that often occurs in people with spine-weakening conditions like rheumatoid arthritis and osteoporosis. Cervical myelopathy can lead to disabling neurological symptoms, such as difficulty walking, neck and arm pain, hand numbness and weakness of the limbs. It’s the most common cause of spine-related walking problems in people over 55.

The first group of animals was fed rat chow that replicated a Western diet high in saturated fats and sugar. The second group consumed a standard diet supplemented with docosahexaenoic acid, or DHA, and curcumin, a compound in turmeric, an Indian curry spice. A third set of rats received a standard rat diet and served as a control group.

Why these supplements? DHA is an omega-3 fatty acid shown to repair damage to cell membranes. Curcumin is a strong antioxidant that previous studies have linked to tissue repair. Both reduce inflammation.

"The brain and spinal cord work together, and years of research demonstrate that supplements like DHA and curcumin can positively influence the brain," said coauthor Fernando Gomez-Pinilla, professor of neurosurgery. "We suspected that what works in the brain may also work in the spinal cord. When we were unable to find good data to support our hypothesis, we decided to study it ourselves."

The researchers recorded a baseline of the rats walking and re-examined the animals’ gait on a weekly basis. As early as three weeks, the rats eating the Western diet demonstrated measurable walking problems that worsened as the study progressed. Rats fed a diet enriched with DHA and curcumin walked significantly better than the first group even six weeks after the study’s start.

Next, the scientists examined the rats’ spinal cords to evaluate how diet affected their injury on a molecular level. The researchers measured levels of three markers respectively linked to cell-membrane damage, neural repair and cellular communication.

The rats that ate the Western diet showed higher levels of the marker linked to cell-membrane damage. In contrast, the DHA and curcumin appeared to offset the injury’s effect in the second group, which displayed equivalent marker levels to the control group.

Levels of the markers linked to neural repair and cellular communication were significantly lower in the rats raised on the Western diet. Again, levels in the animals fed the supplemented diet appeared similar to those of the control group.

"DHA and curcumin appear to invoke several molecular mechanisms that preserved neurological function in the rats," said Gomez-Pinilla. "This is an exciting first step toward understanding the role that diet plays in protecting the body from degenerative disease."

"Our findings suggest that diet can help minimize disease-related changes and repair damage to the spinal cord," said Holly. "We next want to look at other mechanisms involved in the cascade of events leading up to chronic spinal-cord injury. Our goal is to identify which stages will respond best to medical intervention and identify effective steps for slowing the disease process."

Source: Science Daily