Neuroscience

Ache, agony, distress and pain draw more attention than non-pain related words when it comes to people who suffer from chronic pain, a York University research using state-of-the-art eye-tracking technology has found.

(Image credit)

“People suffering from chronic pain pay more frequent and longer attention to pain-related words than individuals who are pain-free,” says Samantha Fashler, a PhD candidate in the Faculty of Health and the lead author of the study. “Our eye movements — the things we look at — generally reflect what we attend to, and knowing how and what people pay attention to can be helpful in determining who develops chronic pain.”

Chronic pain currently affects about 20 per cent of the population in Canada.

The current study, “More than meets the eye: visual attention biases in individuals reporting chronic pain”, published in the Journal of Pain Research, incorporated an eye-tracker, which is a more sophisticated measuring tool to test reaction time than the previously used dot-probe task in similar studies.

“The use of an eye-tracker opens up a number of previously unavailable avenues for research to more directly tap what people with chronic pain attend to and how this attention may influence the presence of pain,” says Professor Joel Katz, Canada Research Chair in Health Psychology, the co-author of the study.

The researchers recorded both reaction time and eye movements of chronic pain (51) and pain-free (62) participants. Both groups viewed neutral and sensory pain-related words on a dot-probe task. They found reaction time did not indicate attention, but “the eye-tracking technology captured eye gaze patterns with millimetre precision,” according to Fashler. She points out that this helped researchers to determine how frequently and how long individuals looked at sensory pain words.

“We now know that people with and without chronic pain differ in terms of how, where and when they attend to pain-related words. This is a first step in identifying whether the attentional bias is involved in making pain more intense or more salient to the person in pain,” says Katz.

Scientists studying two genes that are mutated in an early-onset form of Parkinson’s disease have deciphered how normal versions of these genes collaborate to help rid cells of damaged mitochondria. Mitochondria are the cell’s primary energy source, and maintaining their health is critical for cellular function. Mitochondrial dysfunction may underlie multiple neurodegenerative diseases, including Parkinson’s.

(Image caption: PARKIN (green) is localized on damaged mitochondria. Image: Harper Lab)

In their analysis published in Molecular Cell, Harvard Medical School researchers used powerful quantitative mass spectrometry and live-cell imaging approaches to elucidate a multistep mechanism by which the two proteins mutated in Parkinson’s disease—PINK1 and PARKIN—mark mitochondria as damaged by attaching chains of a small protein called ubiquitin. This work paves the way for a deeper understanding of what molecular steps are defective when these proteins are mutated in patients with Parkinson’s disease.

“The PINK1-PARKIN pathway has been studied for many years, yet its mechanisms weren’t clearly defined,” said Wade Harper, Bert and Natalie Vallee Professor of Molecular Pathology in the Department of Cell Biology at HMS and senior author of the paper. “Combining imaging and advanced mass spectrometry approaches has allowed us for the first time to determine with molecular precision the biochemical output of the PINK1-PARKIN pathway in living cells.”

One hypothesis about the origin of Parkinson’s disease suggests that neurons place high energy demands on their mitochondria. When mitochondria become damaged and their energy production falls, they must be cleared away; if not, cell death results when the damaged mitochondria create harmful chemicals called reactive oxygen species.

People who have certain early-onset mutations in PINK1 or PARKIN genes may live normal lives until they enter their 30s when movement disorders begin to appear, reflecting the loss of neurons that make the neurotransmitter dopamine. These neurons seem to be the cells that are the most sensitive to an inability to remove damaged mitochondria.

Only in the last few years have scientists understood that the enzymes PARKIN and PINK1 work together to remove damaged mitochondria. The PINK1 kinase, an enzyme that transfers phosphate to other proteins, is activated specifically on damaged mitochondria where it then functions to promote accumulation of PARKIN on the mitochondrial surface. Once there, PARKIN—a ubiquitin ligase— marks numerous proteins on the surface of the mitochondria with chains of ubiquitin, which in turn target the damaged mitochondria for removal from the cell.

In their new work, Harper’s team identifies a multistep “feed-forward” mechanism that involves intertwined ubiquitylation and phosphorylation in a sequence of reactions that successively build on one another. To the authors’ knowledge, this is the first report of a feed-forward mechanism of this type.

The team, led by postdoctoral fellow Alban Ordureau, found that PINK1 actually has two functions in a multistep pathway. First, PINK1 phosphorylates PARKIN, greatly stimulating its ability to attach ubiquitin to mitochondrial substrates. Second, PINK1 phosphorylates ubiquitin chains that PARKIN has just built. Unexpectedly, these phosphorylated ubiquitin chains then bind tightly to activated PARKIN, thereby facilitating its retention on the mitochondrial surface and furthering ubiquitin chain assembly through a feed-forward mechanism. Eventually these chains become so dense that the damaged mitochondria are marked for degradation. 

“Our finding that PARKIN binds phosphorylated-ubiquitin chains as its mechanism of retention on damaged mitochondria was completely unexpected,” Harper said. “Ubiquitin has been studied for almost 40 years, but only recently has regulation of ubiquitin by phosphorylation emerged as a major focus for the field.”

Methods employed in this study have their origins in prior work of Steven Gygi, HMS professor of cell biology and a co-author of the paper, who developed ways to quantify ubiquitin chains more than a decade ago. Harper says there is “enormous potential in the application of these approaches to understand how defects in the ubiquitin system lead to disease.”

The team also included Brenda Schulman, a Howard Hughes Medical Institute investigator, the co-director of the Cancer Genetics, Biochemistry and Cell Biology Program at St. Jude Children’s Research Hospital and a leading expert on ubiquitin biochemistry.

“This is a very intricate pathway,” Ordureau said. “We were surprised by our findings at every step.”

Johnny Depp has an unforgettable face. Tony Angelotti, his stunt double in “Pirates of the Caribbean,” does not. So why is it that when they’re swashbuckling on screen, audiences worldwide see them both as the same person? UC Berkeley scientists have cracked that mystery.

Researchers have pinpointed the brain mechanism by which we latch on to a particular face even when it changes. While it may seem as though our brain is tricking us into morphing, say, an actor with his stunt double, this “perceptual pull” is actually a survival mechanism, giving us a sense of stability, familiarity and continuity in what would otherwise be a visually chaotic world, researchers point out.

“If we didn’t have this bias of seeing a face as the same from one moment to the next, our perception of people would be very confusing. For example, a friend or relative would look like a completely different person with each turn of the head or change in light and shade,” said Alina Liberman, a doctoral student in neuroscience at UC Berkeley and lead author of the study published Thursday, Oct. 2 in the online edition of the journal, Current Biology.

In searching for an exact match to a “target” face on a computer screen, study participants consistently identified a face that was not the target face, but a composite of the faces they had seen over the past few seconds. Moreover, participants judged the match to be more similar to the target face than it really was. The results help explain how humans process visual information from moment to moment to stabilize their environment.

“Our visual system loses sensitivity to stunt doubles in movies, but that’s a small price to pay for perceiving our spouse’s identity as stable,” said David Whitney,  a professor of psychology at UC Berkeley and senior author of the study.

Previous research in Whitney’s lab established the existence of a “Continuity Field” in which we visually meld similar objects seen within a 15-second time frame. For example, that study helped explain why we miss movie-mistake jump cuts, such as Harry Potter’s T-shirt abruptly changing from a crewneck into a henley shirt in the “Order of the Phoenix.”

This latest study builds on that by testing how a Continuity Field applies to our observation and recognition of faces, arguably one of the most important human social and perceptual functions, researchers said.

“Without the extraordinary ability to recognize faces, many social functions would be lost.Imagine picking up your child at school and not being able to recognize which kid is yours,” Whitney said. “Fortunately, this type of face blindness is rare. What is common, however, are changes in viewpoint, noise, blur, and lighting changes that could cause faces to appear very different from moment to moment. Our results suggest that the visual system is biased against such wavering perception in favor of continuity.”

To test this phenomenon, study participants viewed dozens of faces that varied in similarity. Each six seconds, a “target face” flashed on the computer screen for less than a second, followed by a series of faces that morphed with each click of an arrow key from one to the next. Participants clicked through the faces until they found the one that most closely matched the “target face.” Time and again, the face they picked was a combination of the two most recently seen target faces.

“Regardless of whether study participants cycled through many faces until they found a match or quickly named which face they saw, perception of a face was always pulled towards face identities they saw within the last 10 seconds,” Liberman said. “Importantly, if the faces that participants recently saw all looked very distinct, the visual system did not merge these identities together, indicating that this perceptual pull does depend on the similarity of recently seen faces.”

In a follow up experiment, the faces were viewed from different angles instead of frontal views to ensure that study participants were not latching on to a particular feature, say, bushy eyebrows or a distinct shadow across a cheekbone, but actually recognizing the entire visage.

“Sequential faces that are somewhat similar will display a much more striking family resemblance than is actually present, simply because of this Continuity Field for faces,” Liberman said.

A mini-stroke may not cause lasting physical damage, but it could increase your risk of developing post-traumatic stress disorder (PTSD), a small, new study suggests.

Almost one-third of patients who suffered a mini-stroke — known as a transient ischemic attack (TIA) — developed symptoms of PTSD, including depression, anxiety and reduced quality of life, the researchers said.

"At the moment, a TIA is seen by doctors as a fairly benign disorder," said study co-author Kathrin Utz, a researcher in the department of neurology at the University of Erlangen-Nuremberg in Germany.

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New insights into botulinum neurotoxins and their interactions with cells are moving scientists ever closer to safer forms of Botox and a better understanding of the dangerous disease known as botulism. By comparing all known structures of botulinum neurotoxins, researchers writing in the Cell Press journal Trends in Biochemical Sciences on October 1st suggest new ways to improve the safety and efficacy of Botox injections.

"If we know from high-resolution structures how botulinum neurotoxins interact with their receptors, we can design inhibitors or specific antibodies directed at the binding interface to prevent the interaction," said Richard Kammerer of the Paul Scherrer Insititute in Switzerland. "Furthermore, it may be possible to engineer safer toxins for medical and cosmetic applications."

In addition to its popular cosmetic use, the neurotoxin is used for the treatment of muscle conditions related to cerebral palsy, multiple sclerosis, stroke, Parkinson’s disease, and more.

The bacterium known as Clostridium botulinum, classically found as a contaminant in home-canned food, produces the neurotoxins, which pass the intestine and enter the bloodstream when ingested, Kammerer explained. When the neurotoxins reach neurons, they bind to receptors at the cell surface. Through a series of events, a portion of the toxin is released inside the cell. Once inside, that light-chain portion acts as a protease to specifically cleave a protein important for the release of acetylcholine, a neurotransmitter important for signaling from nerve to muscle. The result is paralysis, which can be fatal if the muscles required for breathing are affected.

Kammerer and his colleagues offer a comprehensive review of high-resolution structures of botulinum neurotoxins and their complexes with cell-surface receptors, many of which have become available only recently. While many questions remain, the new picture of BoNT/A and its interactions offers considerable hope for less-risky clinical use of Botox in the future.

"The wide range of BoNT/A dosage used in medical or cosmetic applications bears the substantial risk of accidental BoNT/A overdosage," the researchers write. "The BoNT/A-SV2C complex crystal structure provides a strong platform for the rational design of BoNT/A variants with attenuated SV2C binding properties. Such variants are promising candidate proteins for safer applications of the toxin."

For older adults, being unable to identify scents is a strong predictor of death within five years, according to a study published October 1, 2014, in the journal PLOS ONE. Thirty-nine percent of study subjects who failed a simple smelling test died during that period, compared to 19 percent of those with moderate smell loss and just 10 percent of those with a healthy sense of smell.

The hazards of smell loss were “strikingly robust,” the researchers note, above and beyond most chronic diseases. Olfactory dysfunction was better at predicting mortality than a diagnosis of heart failure, cancer or lung disease. Only severe liver damage was a more powerful predictor of death. For those already at high risk, lacking a sense of smell more than doubled the probability of death.

"We think loss of the sense of smell is like the canary in the coal mine," said the study’s lead author Jayant M. Pinto, MD, an associate professor of surgery at the University of Chicago who specializes in the genetics and treatment of olfactory and sinus disease. "It doesn’t directly cause death, but it’s a harbinger, an early warning that something has gone badly wrong, that damage has been done. Our findings could provide a useful clinical test, a quick and inexpensive way to identify patients most at risk."

The study was part of the National Social Life, Health and Aging Project (NSHAP), the first in-home study of social relationships and health in a large, nationally representative sample of men and women ages 57 to 85.

In the first wave of NSHAP, conducted in 2005-06, professional survey teams from the independent research organization NORC at the University of Chicago used a well-validated test — adapted by Martha K. McClintock, PhD, the study’s senior author — for this field survey of 3,005 participants. It measured their ability to identify five distinct common odors.

The modified smell tests used “Sniffin’Sticks,” odor-dispensing devices that resemble a felt-tip pen but are loaded with aromas rather than ink. Subjects were asked to identify each smell, one at a time, from a set of four choices. The five odors, in order of increasing difficulty, were peppermint, fish, orange, rose and leather.

Measuring smell with this test, they learned that:

• Almost 78 percent of those tested were classified as “normosmic,” having normal smelling; 45.5 percent correctly identified five out of five odors and 29 percent identified four out of five.
• Almost 20 percent were considered “hyposmic.” They got two or three out of five correct.
• The remaining 3.5 percent were labelled “anosmic.” They could identify just one of the five scents (2.4%), or none (1.1%).

The interviewers also assessed participants’ age, physical and mental health, social and financial resources, education, and alcohol or substance abuse through structured interviews, testing and questionnaires. As expected, performance on the scent test declined steadily with age; 64 percent of 57-year-olds correctly identified all five smells. That fell to 25 percent of 85-year-olds.

In the second wave, during 2010-11, the survey team carefully confirmed which participants were still alive. During that five-year gap, 430 (12.5%) of the original 3005 study subjects had died; 2,565 were still alive.

When the researchers adjusted for demographic variables such as age, gender, socioeconomic status (as measured by education or assets), overall health, and race, those with greater smell loss when first tested were substantially more likely to have died five years later. Even mild smell loss was associated with greater risk.

"This evolutionarily ancient special sense may signal a key mechanism that affects human longevity," noted McClintock, the David Lee Shillinglaw Distinguished Service Professor of Psychology, who has studied olfactory and pheromonal communication throughout her career.

Age-related smell loss can have a substantial impact on lifestyle and wellbeing, according to Pinto, a member of the university’s otolaryngology-head and neck surgery team. “Smells impact how foods taste. Many people with smell deficits lose the joy of eating. They make poor food choices, get less nutrition. They can’t tell when foods have spoiled or detect odors that signal danger, like a gas leak or smoke. They may not notice lapses in personal hygiene.”

"Of all human senses," Pinto said, "smell is the most undervalued and underappreciated — until it’s gone."

Precisely how smell loss contributes to mortality is unclear. “Obviously, people don’t die just because their olfactory system is damaged,” McClintock said.

The research team, which includes biopsychologists, physicians, sociologists and statisticians, is considering several hypotheses. The olfactory nerve, the only cranial nerve directly exposed to the environment, may serve as a conduit, they suggest, exposing the central nervous system to pollution, airborne toxins, pathogens or particulate matter.

McClintock noted that the olfactory system also has stem cells which self-regenerate, so “a decrease in the ability to smell may signal a decrease in the body’s ability to rebuild key components that are declining with age and lead to all-cause mortality.”

Every day, organ transplant patients around the world take a drug called rapamycin to keep their immune systems from rejecting their new kidneys and hearts. New research suggests that the same drug could help brain tumor patients by boosting the effect of new immune-based therapies.

In experiments in animals, researchers from the University of Michigan Medical School showed that adding rapamycin to an immunotherapy approach strengthened the immune response against brain tumor cells.

What’s more, the drug also increased the immune system’s “memory” cells so that they could attack the tumor if it ever reared its head again. The mice and rats in the study that received rapamycin lived longer than those that didn’t.

Now, the U-M team plans to add rapamycin to clinical gene therapy and immunotherapy trials to improve the treatment of brain tumors. They currently have a trial under way at the U-M Health System which tests a two-part gene therapy approach in patients with brain tumors called gliomas in an effort to get the immune system to attack the tumor. In future clinical trials, adding rapamycin could increase the therapeutic response.

The new findings, published online in the journal Molecular Cancer Therapeutics, show that combining rapamycin with a gene therapy approach enhanced the animals’ ability to summon immune cells called CD8+ T cells to kill tumor cells directly. Due to this cytotoxic effect, the tumors shrank and the animals lived longer.

But the addition of rapamycin to immunotherapy even for a short while also allowed the rodents to develop tumor-specific memory CD8+ T cells that remember the specific “signature” of the glioma tumor cells and attacked them swiftly when a tumor was introduced into the brain again.

“We had some indication that rapamycin would enhance the cytotoxic T cell effect, from previous experiments in both animals and humans showing that the drug produced modest effects by itself,” says Maria Castro, Ph.D., senior author of the new paper. Past clinical trials of rapamycin in brain tumors have failed.

“But in combination with immunotherapy, it became a dramatic effect, and enhanced the efficacy of memory T cells too. This highlights the versatility of the immunotherapy approach to glioma,” says Castro, who is the R.C. Schneider Collegiate Professor in the Department of Neurosurgery and a professor of cell and developmental biology at U-M.

Rapamycin is an FDA-approved drug that produces few side effects in transplant patients and others who take it to modify their immune response. So in the future, Castro and her colleagues plan to propose new clinical trials that will add rapamycin to immune gene therapy trials like those already ongoing at UMHS.

She notes that other researchers currently studying immunotherapies for glioma and other brain tumors should also consider doing the same. “This could be a universal mechanism for enhancing efficacy of immunotherapies in glioma,” she says.

Rapamycin inhibits a specific molecule in cells, called mTOR. As part of the research, Castro and her colleagues determined that brain tumor cells use the mTOR pathway to hamper the immune response of patients.

This allows the tumor to trick the immune system, so it can continue growing without alerting the body’s T cells that a foreign entity is present. Inhibiting mTOR with rapamycin, then, uncloaks the cells and makes them vulnerable to attack.

Castro notes that if the drug proves useful in human patients, it could also be used for long-term prevention of recurrence in patients who have had the bulk of their tumor removed. “This tumor always comes back,” she says.

Medical imaging is at the forefront of diagnostics today, with imaging techniques like MRI (magnetic resonance imaging), CT (computerized tomography), scanning, and NMR (nuclear magnetic resonance) increasing steeply over the last two decades. However, persisting problems of image resolution and quality still limit these techniques because of the nature of living tissue. A solution is hyperpolarization, which involves injecting the patient with substances that can increase imaging quality by following the distribution and fate of specific molecules in the body but that can be harmful or potentially toxic to the patient. A team of scientists from EPFL, CNRS, ENS and CPE Lyon and ETH Zürich has developed a new generation of hyperpolarization agents that can be used to dramatically enhance the signal intensity of imaged body tissues without presenting any danger to the patient. Their work is published in PNAS.

The team of scientists coordinated by Lyndon Emsley – who is currently Professor at EPFL and ENS Lyon – has developed a new generation of hyperpolarizing agents that are both effective and safe for the patient. The substances, called HYPSOs, were developed by the teams of Christophe Copéret at ETH Zurich and Chloé Thieuleux at CPE-Lyon. The HYPSOs come in the form of a fine, white, porous powder that contains the “tracking” molecules to be hyperpolarized. The HYPSO powder is made up of mesoporous silica (silicon dioxide), which is the major component of sand and is commonly used in nanotechnology.

The silica powder used for the HYPSOs consists of particles, containing pore channels. It has been designed in such a way that the surface of each pore channel can be evenly covered with molecules known as ‘organic radicals’. The radicals are homogeneously distributed, and are able to induce polarization around them. “Controlling the radical distribution was a ‘tour de force’ never achieved in the past, which made the HYPSO materials ideal for this application,” says Christophe Copéret. The pore channels are then filled with a solution of the “tracking” molecules to be hyperpolarized, which act as markers for the imaging – e.g. pyruvate, which is important in the production of energy in cells.

Using novel instruments and methods developed by Sami Jannin at EPFL, the HYPSO sample is hyperpolarized with microwaves in a magnetic field at a very low temperature. The magnetic moments of the atoms are forced to align through a process called “dynamic nuclear polarization”, which transfers the spin energy of the free radicals’ electrons to the markers’ nuclei. The electronic spin magnetism of the hyperpolarizing agent acts on the marker molecule, aligning, or “polarizing”, the nuclei of its atoms.

Hot water is then used to melt and flush the substrate out of the powder. Because of the equipment and conditions needed, the process generally takes place in a room adjacent to the imaging facility. The substrate is then ready to be injected through a long tube into the patient inside the medical imaging device. The entire process only lasts about ten seconds.

Two scans are performed, one with and one without the hyperpolarized agent. When the two images are compared, it is possible to observe the distribution of the hyperpolarized marker in the patient’s body, which, depending on the medical context, can be indicative of disease. For example, accumulation of pyruvate in the prostate could be an early indication of prostate cancer.

The researchers have tested the efficiency of the HYPSOs method on several imaging markers, including pyruvate, acetate, fumarate, pure water, and a simple peptide. Because the HYPSOs is physically retained during dissolution, the technique yields pure solutions of hyperpolarized markers, free of any contaminant. The protocol is therefore simpler and potentially safer for the patient, while its dramatic efficiency on signal quality forecasts the use of this new generation of hyperpolarized agents with a broad range of molecules. As Sami Jannin points out: “We have now received queries of scientists from abroad who are eager to boost their research with this new technology. Amongst other plans, we are very excited about testing these materials in vivo”.

Scientists at The Scripps Research Institute (TSRI) have discovered that a gene mutation linked to hereditary spastic paraplegia, a disabling neurological disorder, interferes with the normal breakdown of triglyceride fat molecules in the brain. The TSRI researchers found large droplets of triglycerides within the neurons of mice modeling the disease.

The findings, reported this week online ahead of print by the journal Proceedings of the National Academy of Sciences, point the way to potential therapies and showcase an investigative strategy that should be useful in determining the biochemical causes of other genetic illnesses. Scientists in recent decades have linked thousands of gene mutations to human diseases, yet many of the genes in question code for proteins of unknown function.

“We often need to understand the protein function that is disrupted by a gene mutation, if we’re going to understand the mechanistic basis for the disease and move towards developing a therapy, and that is what we’ve tried to do here,” said Benjamin F. Cravatt, professor and chair of TSRI’s Department of Chemical Physiology.

There is currently no treatment for hereditary spastic paraplegia (HSP), a set of genetic illnesses whose symptoms include muscle weakness and stiffness, and in some cases cognitive impairments. About 100,000 people worldwide live with HSP.

Uncovering Clues

In the new study, Cravatt and members of his laboratory, including graduate student Jordon Inloes and postdoctoral fellow Ku-Lung Hsu, focused on DDHD2, an enzyme of unclear function whose gene is mutated in a subset of HSP cases. “These cases involving DDHD2 disruption feature cognitive defects as well as spasticity and muscle wasting, so they’re among the more devastating forms of this illness,” said Cravatt.

To start, the researchers created a mouse model of DDHD2-related HSP, in which a targeted deletion from the DDHD2 gene eliminated the expression of the DDHD2 protein. “These mice showed symptoms similar to those of HSP patients, including abnormal gait and lower performance on tests of movement and cognition,” said Inloes.

Prior research had suggested that the DDHD2 enzyme is expressed in the brain and is involved somehow in lipid metabolism. One study reported elevated levels of an unknown fat molecule in the brains of DDHD2-mutant HSP patients. Cravatt’s team compared the tissues of the no-DDHD2 mice to the tissues of mice with normal versions of the gene, and also found that the mutant mice had much higher levels of a type of fat molecule, principally in the brain.

Using a set of sophisticated “lipidomics” tests to analyze the accumulating fat molecules, they identified them as triglycerides—a major component of stored fat in the body, and a risk factor for obesity, atherosclerosis and type 2 diabetes.

“We were able to show as well, using both light microscopy and electron microscopy, that droplets of triglyceride-rich fat are present in the neurons of DDHD2-knockout mice, in several brain regions, but are not present in normal mice,” said Inloes.

For the next phase of the study, Cravatt’s team developed a complementary tool for studying DDHD2’s function: a specific inhibitor of the DDHD2 enzyme, one of a set of powerful enzyme-blocking compounds they had identified in a study reported last year. “After four days of treatment with this inhibitor, normal mice showed an increase in brain triglycerides,” said Inloes. “This suggests that DDHD2 normally breaks down triglycerides, and its inactivity allows triglycerides to build up.”

Finally the team confirmed DDHD2’s role in triglyceride metabolism by showing that triglycerides are rapidly broken down into smaller fatty acids in its presence.
“These findings give us some insight, at least, into the biochemical basis of the HSP syndrome,” said Cravatt.

Looking Ahead

Future projects in this line of inquiry, he adds, include a study of how triglyceride droplets in neurons lead to impairments of movement and cognition, and research on potential therapies to counter these effects, including the possible use of diacylglycerol transferase (DGAT) inhibitors, which reduce the natural production of triglycerides.

Cravatt also notes that the same approach used in this study can be applied to other enzymes in DDHD2’s class (serine hydrolases), whose dysfunctions cause human neurological disorders.

The idea of mapping the brain is not new. Researchers have known for years that the key to treating, curing, and even preventing brain disorders such as Alzheimer’s disease, epilepsy, and traumatic brain injury, is to understand how the brain records, processes, stores, and retrieves information.

New Tel Aviv University research published in PLOS Computational Biology makes a major contribution to efforts to navigate the brain. The study, by Prof. Eshel Ben-Jacob and Dr. Paolo Bonifazi of TAU’s School of Physics and Astronomy and Sagol School of Neuroscience, and Prof. Alessandro Torcini and Dr. Stefano Luccioli of the Instituto dei Sistemi Complessi, under the auspices of TAU’s Joint Italian-Israeli Laboratory on Integrative Network Neuroscience, offers a precise model of the organization of developing neuronal circuits.

In an earlier study of the hippocampi of newborn mice, Dr. Bonifazi discovered that a few “hub neurons” orchestrated the behavior of entire circuits. In the new study, the researchers harnessed cutting-edge technology to reproduce these findings in a computer-simulated model of neuronal circuits. “If we are able to identify the cellular type of hub neurons, we could try to reproduce them in vitro out of stem cells and transplant these into aged or damaged brain circuitries in order to recover functionality,” said Dr. Bonifazi.

Flight dynamics and brain neurons

"Imagine that only a few airports in the world are responsible for all flight dynamics on the planet," said Dr. Bonifazi. "We found this to be true of hub neurons in their orchestration of circuits’ synchronizations during development. We have reproduced these findings in a new computer model."

According to this model, one stimulated hub neuron impacts an entire circuit dynamic; similarly, just one muted neuron suppresses all coordinated activity of the circuit. “We are contributing to efforts to identify which neurons are more important to specific neuronal circuits,” said Dr. Bonifazi. “If we can identify which cells play a major role in controlling circuit dynamics, we know how to communicate with an entire circuit, as in the case of the communication between the brain and prosthetic devices.”

Conducting the orchestra of the brain

In the course of their research, the team found that the timely activation of cells is fundamental for the proper operation of hub neurons, which, in turn, orchestrate the entire network dynamic. In other words, a clique of hubs works in a kind of temporally-organized fashion, according to which “everyone has to be active at the right time,” according to Dr. Bonifazi.

Coordinated activation impacts the entire network. Just by alternating the timing of the activity of one neuron, researchers were able to affect the operation of a small clique of neurons, and finally that of the entire network.

"Our study fits within framework of the ‘complex network theory,’ an emerging discipline that explores similar trends and properties among all kinds of networks — i.e., social networks, biological networks, even power plants," said Dr. Bonifazi. "This theoretical approach offers key insights into many systems, including the neuronal circuit network in our brains."

Parallel to their theoretical study, the researchers are conducting experiments on in vitro cultured systems to better identify electrophysiological and chemical properties of hub neurons. The joint Italy-Israel laboratory is also involved in a European project aimed at linking biological and artificial neuronal circuitries to restore lost brain functions.

Findings could help guide clinicians in selecting stimulation sites and improve treatment for neurological and psychiatric disorders

Over the past several decades, brain stimulation has become an increasingly important treatment option for a number of psychiatric and neurological conditions.

Divided into two broad approaches, invasive and noninvasive, brain stimulation works by targeting specific sites to adjust brain activity. The most widely known invasive technique, deep brain stimulation (DBS), requires brain surgery to insert an electrode and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Parkinson’s disease and essential tremor. Noninvasive techniques, including transcranial magnetic stimulation (TMS), can be administered from outside the head and are currently approved for the treatment of depression. Brain stimulation can result in dramatic benefit to patients with these disorders, motivating researchers to test whether it can also help patients with other diseases.

But, in many cases, the ideal sites to administer stimulation have remained ambiguous. Exactly where in the brain is the best spot to stimulate to treat a given patient or a given disease?

Now a new study in the Proceedings of the National Academy of Sciences (PNAS) helps answer this question. Led by investigators at Beth Israel Deaconess Medical Center (BIDMC), the findings suggest that brain networks – the interconnected pathways that link brain circuits to one another— can help guide site selection for brain stimulation therapies.

"Although different types of brain stimulation are currently applied in different locations, we found that the targets used to treat the same disease are nodes in the same connected brain network," says first author Michael D. Fox, MD, PhD, an investigator in the Berenson-Allen Center for Noninvasive Brain Stimulation and in the Parkinson’s Disease and Movement Disorders Center at BIDMC.

"This may have implications for how we administer brain stimulation to treat disease. If you want to treat Parkinson’s disease or tremor with brain stimulation, you can insert an electrode deep in the brain and get a great effect. However, getting this same benefit with noninvasive stimulation is difficult, as you can’t directly stimulate the same site deep in the brain from outside the head," explains Fox, an Assistant Professor of Neurology at Harvard Medical School (HMS). "But, by looking at the brain’s own network connectivity, we can identify sites on the surface of the brain that connect with this deep site, and stimulate those sites noninvasively."

Brain networks consist of interconnected pathways linking brain circuits or loops, similar to a college campus in which paved sidewalks connect a wide variety of buildings.

In this paper, Fox led a team that first conducted a large-scale literature search to identify all neurological and psychiatric diseases where improvement had been seen with both invasive and noninvasive brain stimulation. Their analysis revealed 14 conditions: addiction, Alzheimer’s disease, anorexia, depression, dystonia, epilepsy, essential tremor, gait dysfunction, Huntington’s disease, minimally conscious state, obsessive compulsive disorder, pain, Parkinson disease and Tourette syndrome. They next listed the stimulation sites, either deep in the brain or on the surface of the brain, thought to be effective for the treatment of each of the 14 diseases.

"We wanted to test the hypothesis that these various stimulation sites are actually different spots within the same brain network," explains Fox. "To examine the connectivity from any one site to other brain regions, we used a data base of functional MRI images and a technique that enables you to see correlations in spontaneous brain activity." From these correlations, the investigators were able to create a map of connections from deep brain stimulation sites to the surface of the brain. When they compared this map to sites on the brain surface that work for noninvasive brain stimulation, the two matched.

"These results suggest that brain networks might be used to help us better understand why brain stimulation works and to improve therapy by identifying the best place to stimulate the brain for each individual patient and given disease," says senior author Alvaro Pascual-Leone, MD, PhD, the Director of the Berenson-Allen Center for Noninvasive Brain Stimulation at BIDMC and Professor of Neurology at HMS. "This study illustrates the potential of gaining fundamental insights into brain function while helping patients with debilitating diseases, and provides us with a powerful way of selecting targets based on their connectivity to other regions that can be widely applied to help guide brain stimulation therapy across multiple neurological and psychiatric disorders."

"As we’re trying different types of brain stimulation for different diseases, the question comes up, ‘How does one relate to the other?’" notes Fox. "In other words, can we use the success in one to help design a trial or inform how we apply a new type of brain stimulation? Our new findings suggest that resting-state functional connectivity may be useful for translating therapy between treatment modalities, optimizing treatment and identifying new stimulation targets."

Researchers at the Gladstone Institutes have shown that low levels of the protein progranulin in the brain can increase the formation of amyloid-beta plaques (a hallmark of Alzheimer’s disease), cause neuroinflammation, and worsen memory deficits in a mouse model of this condition. Conversely, by using a gene therapy approach to elevate progranulin levels, scientists were able to prevent these abnormalities and block cell death in this model.

Progranulin deficiency is known to cause another neurodegenerative disorder, frontotemporal dementia (FTD), but its role in Alzheimer’s disease was previously unclear. Although the two conditions are similar, FTD is associated with greater injury to cells in the frontal cortex, causing behavioral and personality changes, whereas Alzheimer’s disease predominantly affects memory centers in the hippocampus and temporal cortex.

Earlier research showed that progranulin levels were elevated near plaques in the brains of patients with Alzheimer’s disease, but it was unknown whether this effect counteracted or exacerbated neurodegeneration. The new evidence, published today in Nature Medicine, shows that a reduction of the protein can severely aggravate symptoms, while increases in progranulin may be the brain’s attempt at fighting the inflammation associated with the disease.

According to first author S. Sakura Minami, PhD, a postdoctoral fellow at the Gladstone Institutes, “This is the first study providing evidence for a protective role of progranulin in Alzheimer’s disease. Prior research had shown a link between Alzheimer’s and progranulin, but the nature of the association was unclear. Our study demonstrates that progranulin deficiency may promote Alzheimer’s disease, with decreased levels rendering the brain vulnerable to amyloid-beta toxicity.”

In the study, the researchers manipulated several different mouse models of Alzheimer’s disease, genetically raising or lowering their progranulin levels. Reducing progranulin markedly increased amyloid-beta plaque deposits in the brain as well as memory impairments. Progranulin deficiency also triggered an over-active immune response in the brain, which can contribute to neurological disorders. In contrast, increasing progranulin levels via gene therapy effectively lowered amyloid beta levels, protecting against cell toxicity and reversing the cognitive deficits typically seen in these Alzheimer’s models.

These effects appear to be linked to progranulin’s involvement in phagocytosis, a type of cellular house-keeping whereby cells “eat” other dead cells, debris, and large molecules. Low levels of progranulin can impair this process, leading to increased amyloid beta deposition. Conversely, increasing progranulin levels enhanced phagocytosis, decreasing the plaque load and preventing neuron death.

“The profound protective effects of progranulin against both amyloid-beta deposits and cell toxicity have important therapeutic implications,” said senior author Li Gan, PhD, an associate investigator at Gladstone and associate professor of neurology at the University of California, San Francisco. “The next step will be to develop progranulin-enhancing approaches that can be used as potential novel treatments, not only for frontotemporal dementia, but also for Alzheimer’s disease.”

How the brain ages is still largely an open question – in part because this organ is mostly insulated from direct contact with other systems in the body, including the blood and immune systems. In research that was recently published in Science, Weizmann Institute researchers Prof. Michal Schwartz of the Neurobiology Department and Dr. Ido Amit of Immunology Department found evidence of a unique “signature” that may be the “missing link” between cognitive decline and aging. The scientists believe that this discovery may lead, in the future, to treatments that can slow or reverse cognitive decline in older people.

(Image caption: Immunofluorescence microscope image of the choroid plexus. Epithelial cells are in green and chemokine proteins (CXCL10) are in red)

Until a decade ago, scientific dogma held that the blood-brain barrier prevents the blood-borne immune cells from attacking and destroying brain tissue. Yet in a long series of studies, Schwartz’s group had shown that the immune system actually plays an important role both in healing the brain after injury and in maintaining the brain’s normal functioning. They have found that this brain-immune interaction occurs across a barrier that is actually a unique interface within the brain’s territory.

This interface, known as the choroid plexus, is found in each of the brain’s four ventricles, and it separates the blood from the cerebrospinal fluid. Schwartz: “The choroid plexus acts as a ‘remote control’ for the immune system to affect brain activity. Biochemical ‘danger’ signals released from the brain are sensed through this interface; in turn, blood-borne immune cells assist by communicating with the choroid plexus. This cross-talk is important for preserving cognitive abilities and promoting the generation of new brain cells.”

This finding led Schwartz and her group to suggest that cognitive decline over the years may be connected not only to one’s “chronological age” but also to one’s “immunological age,” that is, changes in immune function over time might contribute to changes in brain function – not necessarily in step with the count of one’s years.

To test this theory, Schwartz and research students Kuti Baruch and Aleksandra Deczkowska teamed up with Amit and his research group in the Immunology Department. The researchers used next-generation sequencing technology to map changes in gene expression in 11 different organs, including the choroid plexus, in both young and aged mice, to identify and compare pathways involved in the aging process.

That is how they identified a strikingly unique “signature of aging” that exists solely in the choroid plexus – not in the other organs. They discovered that one of the main elements of this signature was interferon beta – a protein that the body normally produces to fight viral infection. This protein appears to have a negative effect on the brain: When the researchers injected an antibody that blocks interferon beta activity into the cerebrospinal fluid of the older mice, their cognitive abilities were restored, as was their ability to form new brain cells. The scientists were also able to identify this unique signature in elderly human brains. The scientists hope that this finding may, in the future, help prevent or reverse cognitive decline in old age, by finding ways to rejuvenate the “immunological age” of the brain.

RMIT University researchers have brought ultra-fast, nano-scale data storage within striking reach, using technology that mimics the human brain.

The researchers have built a novel nano-structure that offers a new platform for the development of highly stable and reliable nanoscale memory devices. 

The pioneering work will feature on a forthcoming cover of prestigious materials science journal Advanced Functional Materials (11 November). 

Project leader Dr Sharath Sriram, co-leader of the RMIT Functional Materials and Microsystems Research Group, said the nanometer-thin stacked structure was created using thin film, a functional oxide material more than 10,000 times thinner than a human hair. 

“The thin film is specifically designed to have defects in its chemistry to demonstrate a ‘memristive’ effect – where the memory element’s behaviour is dependent on its past experiences,” Dr Sriram said.

“With flash memory rapidly approaching fundamental scaling limits, we need novel materials and architectures for creating the next generation of non-volatile memory. 

“The structure we developed could be used for a range of electronic applications – from ultrafast memory devices that can be shrunk down to a few nanometers, to computer logic architectures that replicate the versatility and response time of a biological neural network.

“While more investigation needs to be done, our work advances the search for next generation memory technology can replicate the complex functions of human neural system – bringing us one step closer to the bionic brain.”

The research relies on memristors, touted as a transformational replacement for current hard drive technologies such as Flash, SSD and DRAM. Memristors have potential to be fashioned into non-volatile solid-state memory and offer building blocks for computing that could be trained to mimic synaptic interfaces in the human brain.