Neuroscience

Researchers have identified a new virus in patients with severe brain infections in Vietnam. Further research is needed to determine whether the virus is responsible for the symptoms of disease.

The virus was found in a total of 28 out of 644 patients with severe brain infections in the study, corresponding to around 4 per cent, but not in any of the 122 patients with non-infectious brain disorders that were tested.

Infections of the brain and central nervous system are often fatal, and patients who survive - often young children and young adults - are left severely disabled. Brain infections can be caused by a range of bacterial, parasitic, fungal and viral agents; however, doctors fail to find the cause of the infection in more than half of all cases, despite extensive diagnostic efforts. Not knowing the causes of these brain infections makes public health and treatment interventions impossible.

Researchers at the Oxford University Clinical Research Unit, the Wellcome Trust South East Asia Major Overseas Programme and the Academic Medical Center at the University of Amsterdam identified the virus, tentatively named CyCV-VN, in the fluid around the brain of two patients with brain infections of unknown cause. The virus was subsequently detected in an additional 26 out of 642 patients with brain infections of known and unknown causes.

Using next-generation gene sequencing techniques, the team sequenced the entire genetic material of the virus, confirming that it represents a new species that has not been isolated before. They found that it belongs to a family of viruses called the Circoviridae, which have previously only been associated with disease in animals, including birds and pigs.

Dr Rogier van Doorn, Head of Emerging Infections at the Wellcome Trust Vietnam Research Programme and Oxford University Clinical Research Unit Hospital for Tropical Diseases in Vietnam, explains: “We don’t yet know whether this virus is responsible for causing the serious brain infections we see in these patients, but finding an infectious agent like this in a normally sterile environment like the fluid around the brain is extremely important. We need to understand the potential threat of this virus to human and animal health.”

The researchers were not able to detect CyCV-VN in blood samples from the patients, but it was present in 8 out of 188 faecal samples from healthy children. The virus was also detected in more than half of faecal samples from chickens and pigs taken from the local area of one of the patients from whom the virus was initially isolated, which may suggest an animal source of infection.

Dr Le Van Tan, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, said: “The evidence so far seems to suggest that CyCV-VN may have crossed into humans from animals, another example of a potential zoonotic infection. However, detecting the virus in human samples is not in itself sufficient evidence to prove that the virus is causing disease, particularly since the virus could also be detected in patients with other known viral or bacterial causes of brain infection.

"While detection of this virus in the fluid around the brain is certainly remarkable, it could still be that it doesn’t cause any harm. Clearly, we need to do more work to understand the role this virus may play in these severe infections."

The researchers are currently trying to grow the virus in the laboratory using cell culture techniques to develop a blood assay to test for antibody responses in patient samples, which would indicate that the patients had mounted an immune response against the virus. Such a test could also be used to study how many people in the population have been exposed to CyCV-VN without showing symptoms of disease.

The team are collaborating with scientists across South-east Asia and in the Netherlands to determine whether CyCV-VN can be detected in patient samples from other countries and better understand its geographical distribution.

Professor Menno de Jong, head of the Department of Medical Microbiology of the Academic Medical Centre in Amsterdam, said: “Our research shows the importance of continuing efforts to find novel causes of important infectious diseases and the strength of current technology in aid of these efforts.”

The distribution of white matter brain abnormalities in some patients after mild traumatic brain injury (MTBI) closely resembles that found in early Alzheimer’s dementia, according to a new study published online in the journal Radiology.

“Findings of MTBI bear a striking resemblance to those seen in early Alzheimer’s dementia,” said the study’s lead author, Saeed Fakhran, M.D., assistant professor of radiology in the Division of Neuroradiology at the University of Pittsburgh School of Medicine. “Additional research may help further elucidate a link between these two disease processes.”

MTBI, or concussion, affects more than 1.7 million people in the United States annually. Despite the name, these injuries are by no means mild, with approximately 15 percent of concussion patients suffering persistent neurological symptoms.

“Sleep-wake disturbances are among the earliest findings of Alzheimer’s patients, and are also seen in a subset of MTBI patients,” Dr. Fakhran said. “Furthermore, after concussion, many patients have difficulty filtering out white noise and concentrating on the important sounds, making it hard for them to understand the world around them. Hearing problems are not only an independent risk factor for developing Alzheimer’s disease, but the same type of hearing problem seen in MTBI patients has been found to predict which patients with memory problems will go on to develop Alzheimer’s disease.”

For the study, Dr. Fakhran and colleagues set out to determine if there was a relationship between white matter injury patterns and severity of post-concussion symptoms in MTBI patients with normal findings on conventional magnetic resonance imaging (MRI) exams. The researchers studied data from imaging exams performed on 64 MTBI patients and 15 control patients, using an advanced MRI technique called diffusion tensor imaging, which identifies microscopic changes in the brain’s white matter.

The brain’s white matter is composed of millions of nerve fibers called axons that act like communication cables connecting various regions of the brain. Diffusion tensor imaging produces a measurement, called fractional anisotropy, of the movement of water molecules along axons. In healthy white matter, the direction of water movement is fairly uniform and measures high in fractional anisotropy. When water movement is more random, fractional anisotropy values decrease.

Of the MTBI patients, 42 (65.6 percent) were men, and the mean age was 17. Sports injury was the reason for concussion in two-thirds of the patients. All patients underwent neurocognitive evaluation with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). The researchers analyzed correlation between fractional anisotropy values, the ImPACT total symptom score, and findings of sleep-wake disturbances.

Sleep-wake disturbances are among the most disabling post-concussive symptoms, directly decreasing quality of life and productivity and magnifying post-concussion memory and social dysfunction.

The results showed a significant correlation between high ImPACT total symptom score and reduced fractional anisotropy at the gray-white junction, most prominently in the auditory cortex. Significantly decreased fractional anisotropy was found in patients with sleep-wake disturbances in the parahippocampal gyri relative to patients without sleep-wake disturbances.

“When we sleep, the brain organizes our experiences into memories, storing them so that we can later find them,” Dr. Fakhran said. “The parahippocampus is important for this process, and involvement of the parahippocampus may, in part, explain the memory problems that occur in many patients after concussion.”

According to Dr. Fakhran, the results suggest that the true problem facing concussion patients may not be the injury itself, but rather the brain’s response to that injury.

“Traditionally, it has been believed that patients with MTBI have symptoms because of abnormalities secondary to direct injury,” he said. “Simply put, they hit their head, damaged their brain at the point of trauma and thus have symptoms from that direct damage. Our preliminary findings suggest that the initial traumatic event that caused the concussion acts as a trigger for a sequence of degenerative changes in the brain that results in patient symptoms and that may be potentially prevented. Furthermore, these neurodegenerative changes are very similar to those seen in early Alzheimer’s dementia.”

The researchers hope that these findings may lead to improved treatments in the future.

“The first step in developing a treatment for any disease is understanding what causes it,” Dr. Fakhran said. “If we can prove a link, or even a common pathway, between MTBI and Alzheimer’s, this could potentially lead to treatment strategies that would be potentially efficacious in treating both diseases.”

Memory improves in older, overweight women after they lose weight by dieting, and their brain activity actually changes in the regions of the brain that are important for memory tasks, a new study finds. The results were presented at The Endocrine Society’s 95th Annual Meeting in San Francisco.

(Image: Corbis)

“Our findings suggest that obesity-associated impairments in memory function are reversible, adding incentive for weight loss,” said lead author Andreas Pettersson, MD, a PhD student at Umea University, Umea, Sweden.

Previous research has shown that obese people have impaired episodic memory, the memory of events that happen throughout one’s life.

Pettersson and co-workers performed their study to determine whether weight loss would improve memory and whether improved memory correlated with changes in relevant brain activity. A special type of brain imaging called functional magnetic resonance imaging (functional MRI) allowed them to see brain activity while the subjects performed a memory test.

The researchers randomly assigned 20 overweight, postmenopausal women (average age, 61) to one of two healthy weight loss diets for six months. Nine women used the Paleolithic diet, also called the Caveman diet, which was composed of 30 percent protein; 30 percent carbohydrates, or “carbs”; and 40 percent unsaturated fats. The other 11 women followed the Nordic Nutrition Recommendations of a diet containing 15 percent protein, 55 percent carbs and 30 percent fats.

Before and after the diet, the investigators measured the women’s body mass index (BMI, a measure of weight and height) and body fat composition. They also tested the subjects’ episodic memory by instructing them to memorize unknown pairs of faces and names presented on a screen during functional MRI. The name for this process of creating new memory is “encoding.” Later, the women again saw the facial images along with three letters. Their memory retrieval task, during functional MRI, was to indicate the correct letter that corresponded to the first letter of the name linked to the face.

Because the two dietary groups did not differ in body measurements and functional MRI data, their data were combined and analyzed as one group. The group’s average BMI decreased from 32.1 before the diet to 29.2 (below the cutoff for obesity) after six months of dieting, and their average weight dropped from 188.9 pounds (85 kilograms) to 171.3 pounds (77.1 kilograms), the authors reported. This study was part of a larger, diet-focused study funded by the Swedish Research Council and the Swedish Heart-Lung Foundation.

Memory performance improved after weight loss, and Pettersson said the brain-activity pattern during memory testing reflected this improvement. After weight loss, brain activity reportedly increased during memory encoding in the brain regions that are important for identification and matching of faces. In addition, brain activity decreased after weight loss in the regions that are associated with retrieval of episodic memories, which Pettersson said indicates more efficient retrieval.

“The altered brain activity after weight loss suggests that the brain becomes more active while storing new memories and therefore needs fewer brain resources to recollect stored information,” he said.

A missing brain enzyme increases concentrations of a protein related to pain-killer addiction, according to an animal study. The results were presented at The Endocrine Society’s 95th Annual Meeting in San Francisco.

Opioids are pain-killing drugs, derived from the opium plant, which block signals of pain between nerves in the body. They are manufactured in prescription medications like morphine and codeine, and also are found in some illegal drugs, like heroin. Both legal and illegal opioids can be highly addictive.

In addition to the synthetic opioids, natural opioids are produced by the body. Most people have heard of the so-called feel-good endorphins, which are opioid-like proteins produced by various organs in the body in response to certain activities, like exercise.

Drug addiction occurs, in part, because opioid-containing drugs alter the brain’s biochemical balance of naturally produced opioids. Nationwide, drug abuse of opioid-containing prescription drugs is skyrocketing, and researchers are trying to identify the risk factors that differentiate people who get addicted from those who do not.

In this particular animal model, researchers eliminated an enzyme called prohormone convertase 2, or PC2, which normally converts pre-hormonal substances into active hormones in certain parts of the brain. Previous research by this team demonstrated that PC2 levels increase after long-term morphine treatment, according to study lead author Theodore C. Friedman, MD, PhD, chairman of the internal medicine department at Charles R. Drew University of Medicine and Science in Los Angeles.

“This raises the possibility that PC2-derived peptides may be involved in some of the addiction parameters related to morphine,” Friedman said.

For this study, Friedman and his co-researchers analyzed the effects of morphine on the brain after knocking out the PC2 enzyme in mice. Morphine normally binds to a protein on cells known as the mu opioid receptor, or MOR. They found that MOR concentrations were higher in mice lacking PC2, compared to other mice.

To analyze the effects of PC2 elimination, the researchers examined MOR levels in specific parts of the brain that are related to pain relief, as well as to behaviors associated with reward and addiction. They measured these levels using a scientific test called immunohistochemistry, which uses specific antibodies to identify the cells in which proteins are expressed.

“In this study, we found that PC2 knockout mice have higher levels of MOR in brain regions related to drug addiction,” Friedman said. “We conclude that PC2 regulates endogenous opioids involved in the addiction response and in its absence, up-regulation of MOR expression occurs in key brain areas related to drug addiction.”

Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the disease. The story of MeCP2 is in many ways a microcosm of human genetics. It has become the showcase gene for many complex epi-genetic phenomena including X-linked inactivation, DNA methylation, and genomic imprinting. These gender-specific bargaining chips provide compatibility in an evolutionary system where sex-chromosome provisioning is inherently assymetric. In two new papers, one in Nature and the the other in Nature Neuroscience, Bird and collaborator Michael Greenberg, show how mutations found in Rett Syndrome affect the interaction of MeCP2 with a key regulatory protein known as NCoR.

Nearly all cases of Rett Syndrome are caused by mutations at various postions in the MeCP2 gene. Bird and Greenberg analyzed the locations of these mutations using the RettBase MeCp2 database, and found they cluster to two primary locations—the well-known methyl-CpG binding domain, and a new hotspot within a transcriptional repressor domain (TRD). When they compared these locations with mutations found in the general population by using the Exome Variant Server, they found no overlap. This suggests the that the MeCP2 and TRD regions are the primary regions involved in Rett’s.

The researchers hypothesized that the newly found TRD region must act through a unknown regulator of MeCP2 function. Using mass spectrometry, they were able to identify several factors which they had purified from Mecp2-EGFP “knock-in” mice. Most of these factors turned out to be subunits of the co-repressor, NCoR, which was previously known to interact with MeCP2. This is the first identified example of a protein-protein interaction known to be disrupted in Rett’s.

In the Nature paper, the researchers further report that activity-dependent phosphorylation of MeCP2 mediates its interaction with NCoR. They used a technique known as phosphotryptic mapping to identify three sites that are directly phosphorylated in MeCP2 as a result of elevation in cAMP or BDNF. More generally, they showed that membrane depolarization, and therefore activity, results in the phosporylation.

One confounding factor in trying to pinpoint the mechanisms underlying Rett Syndrome is that both loss of MeCP2, and overexpression of MeCP2, can lead to the disease. In mouse models of the disease, this could be accounted for by the observation that both loss of NCoR binding, and constitutive binding of NCoR can lead to disease symptoms. While not a complete explanation of the role of MeCP2 in the disease, it provides some clues to help dissect the involvement of the many different kinds of mutations involved.

Despite the rarity of Rett’s syndrome, its impact on our understanding of human genetics and neural development should not be underestimated. As one of the autistic spectrum disorders, research on Rett’s helps connect molecular mechanics to behavior. For example, when MeCP2 is bound to DNA it can cause condensation of the chromatin structure, and also form complexes with histone deacetylaces. In demostrating that neural activity, and subsequent signal tranduction pathways, lead to modifications of MeCP2, the researchers have revealed a path from the environment directly to the genes.

The X-linked inactivation of one copy of the MeCP2 gene in females adds another layer of complexity to the disease. The celluar mosiac formed by the pattern of inactivation, particularly in the brain, needs more study to be undersatood. The fact that Rett’s symptoms can be “rescued” in mice by the expression of MeCP2 in postmitotic neurons is encouraging. In humans, Rett’s is frequently not observed untill the first or second year of life. As MeCP2 activation correlates with this period of rapid neural maturation, Rett’s is generally considered to be neurodevelopmental disease, as opposed to a neurodegenerative disease.

Rett’s is hardly ever observed in males for the simple reason that they fail to thrive long before birth. In those rare cases that a presumably XXY male child is rescued by the additional X chromsome, as in Klinefelder’s disease, rare opportunity to study the disease etiology is afforded. The efforts of these researchers, and the larger Rett’s community, together with the insights afforded by massive data collation have turned a rare disease into a primary source of knowledge about how evolution proceeds through the interplay of the sexes at the genetic and epigenetic levels.

TAU researcher says mannitol could prevent aggregation of toxic proteins in the brain

Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field — it’s approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.

Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University’s Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain — a process that is characteristic of Parkinson’s disease.

These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this artificial sweetener could be a novel therapy for the treatment of Parkinson’s and other neurodegenerative diseases. The research was funded by a grant from the Parkinson’s Disease Foundation and supported in part by the Lord Alliance Family Trust.

Seeing a significant difference

After identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins’ ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.

Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the “climbing assay,” in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.

The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. This time, 70 percent of the mutated flies could climb up the test tube. In addition, the researchers observed a 70 percent reduction in aggregates of α-synuclein in mutated flies that had been fed mannitol, compared to those that had not.

These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.

Delivering therapeutic compounds to the brain

The researchers now plan to re-examine the structure of the mannitol compound and introduce modifications to optimize its effectiveness. Further experiments on animal models, including behavioral testing, whose disease development mimics more closely the development of Parkinson’s in humans is needed, Prof. Segal says.

For the time being, mannitol may be used in combination with other medications that have been developed to treat Parkinson’s but which have proven ineffective in breaking through the blood/brain barrier, says Prof. Segal. These medications may be able to “piggy-back” on mannitol’s ability to open this barrier into the brain.

Although the results look promising, it is still not advisable for Parkinson’s patients to begin ingesting mannitol in large quantities, Prof. Segal cautions. More testing must be done to determine dosages that would be both effective and safe.

The lipidation states (or modifications) in certain proteins in the brain that are related to the development of Alzheimer disease appear to differ depending on genotype and cognitive diseases, and levels of these protein and peptides appear to be influenced by diet, according to a report published Online First by JAMA Neurology, a JAMA Network publication.

Sporadic Alzheimer disease (AD) is caused in part by the accumulation of β-amyloid (Αβ) peptides in the brain. These peptides can be bound to lipids or lipid carrier proteins, such as apolipoprotein E (ApoE), or be free in solution (lipid-depleted [LD] Αβ). Levels of LD Αβ are higher in the plasma of adults with AD, but less is known about these peptides in the cerebrospinal fluid (CSF), the authors write in the study background.

Angela J. Hanson, M.D., Veterans Affairs Puget Sound Health Care System and the University of Washington, Seattle, and colleagues studied 20 older adults with normal cognition (average age 69 years) and 27 older adults with amnestic mild cognitive impairment (average age 67 years).

The patients were randomized to a diet high in saturated fat content (45 percent energy from fat, greater than 25 percent saturated fat) with a high glycemic index or a diet low in saturated fat content (25 percent of energy from fat, less than 7 percent saturated fat) with a low glycemic index. The main outcomes the researchers measured were lipid depleted (LD) Αβ42 and Αβ40 and ApoE in cerebrospinal fluid.

Study results indicate that baseline levels of LD Αβ were greater for adults with mild cognitive impairment compared with adults with normal cognition. The authors also note that these findings were more apparent in adults with mild cognitive impairment and the Ɛ4 allele (a risk factor for AD), who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis. Study results indicate that the diet low in saturated fat tended to decrease LD Αβ levels, whereas the diet high in saturated fat increased these fractions.

The authors note the data from their small pilot study need to be replicated in a larger sample before any firm conclusions can be drawn.

“Overall, these results suggest that the lipidation states of apolipoproteins and amyloid peptides might play a role in AD pathological processes and are influenced by APOE genotype and diet,” the study concludes.

Editorial: Food for Thought

In an editorial, Deborah Blacker, M.D., Sc.D., of the Massachusetts General Hospital/Harvard Medical School, Boston, writes: “The article by Hanson and colleagues makes a serious effort to understand whether dietary factors can affect the biology of Alzheimer disease (AD).”

“Hanson et al argue that the changes observed after their two dietary interventions may underlie some of the epidemiologic findings regarding diabetes and other cardiovascular risk factors and risk for AD. The specifics of their model may not capture the real underlying biological effect of these diets, and it is unclear whether the observed changes in the intermediate outcomes would lead to beneficial changes in oligomers or plaque burden, much less to decreased brain atrophy or improved cognition,” she continues.

“At some level, however, the details of the biological model are not critical; the important lesson from the study is that dietary intervention can change brain amyloid chemistry in largely consistent and apparently meaningful ways – in a short period of time. Does this change clinical practice for those advising patients who want to avoid dementia? Probably not, but it adds another small piece to the growing evidence that taking good care of your heart is probably good for your brain too,” Blacker concludes.

Researchers have discovered a pathway by which the brain controls a molecule critical to forming long-term memories and connected with bipolar disorder and schizophrenia.

The discovery was made by a team of scientists led by Alexei Morozov, an assistant professor at the Virginia Tech Carilion Research Institute.

The mechanism – a protein called Rap1 – controls L-type calcium channels, which participate in the formation of long-term memories. Previous studies have also linked alterations in these ion channels to certain psychiatric disorders. The discovery of the channels’ regulation by Rap1 could help scientists understand the physiological genesis of bipolar disorder and schizophrenia.

"People with genetic mutations affecting L-type calcium channels have higher rates of bipolar disorder and schizophrenia," said Morozov. "This suggests that there might be a relationship between the activation of L-type calcium channels and these psychiatric disorders. Understanding how these ion channels are controlled is the first step to determining how their functioning or malfunctioning affects mental health."

A single neuron in the brain can have thousands of synapses, each of which can grow, strengthen, weaken, and change structurally in response to learning new information. Electric signals traveling from neuron to neuron jump across these synapses through chemical neurotransmitters. The release of these chemicals is caused by the flow of electrically charged atoms through a particular subset of ion channels known as voltage-gated calcium channels.

Previous studies have shown that blocking these ion channels inhibits the formation of long-term memories. Although it was known that L-type calcium channels are activated in response to learning, how they are controlled was a mystery.

In the experiment, Morozov and colleagues knocked out the gene responsible for coding the enzyme Rap1, which he suspected played a role in activating L-type calcium channels. The researchers then used live imaging techniques to monitor the release of neurotransmitters and electron microscopy to visualize L-type channels at synapses. They discovered that, without Rap1, the L-type calcium channels were more active and more abundant at synapses all the time, increasing the release of neurotransmitters. The results showed that Rap1 is responsible for suppressing L-type calcium channels, allowing them to activate only at the proper moments, possibly during long-term memory formation.

"Our next step is to determine whether this new signaling pathway is altered in cases of mental disease," said Morozov. "If so, it could help us gain a better understanding of the molecular underpinnings of channel-related psychiatric disorders, such as bipolar disorder and schizophrenia. Such knowledge would go a long way toward developing new therapeutic methods."

UCLA researchers now have the first evidence that bacteria ingested in food can affect brain function in humans. In an early proof-of-concept study of healthy women, they found that women who regularly consumed beneficial bacteria known as probiotics through yogurt showed altered brain function, both while in a resting state and in response to an emotion-recognition task.

The study, conducted by scientists with the Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, part of the UCLA Division of Digestive Diseases, and the Ahmanson–Lovelace Brain Mapping Center at UCLA, appears in the current online edition of the peer-reviewed journal Gastroenterology.

The discovery that changing the bacterial environment, or microbiota, in the gut can affect the brain carries significant implications for future research that could point the way toward dietary or drug interventions to improve brain function, the researchers said.

"Many of us have a container of yogurt in our refrigerator that we may eat for enjoyment, for calcium or because we think it might help our health in other ways," said Dr. Kirsten Tillisch, an associate professor of medicine in the digestive diseases division at UCLA’s David Geffen School of Medicine and lead author of the study. "Our findings indicate that some of the contents of yogurt may actually change the way our brain responds to the environment. When we consider the implications of this work, the old sayings ‘you are what you eat’ and ‘gut feelings’ take on new meaning."

Researchers have known that the brain sends signals to the gut, which is why stress and other emotions can contribute to gastrointestinal symptoms. This study shows what has been suspected but until now had been proved only in animal studies: that signals travel the opposite way as well.

"Time and time again, we hear from patients that they never felt depressed or anxious until they started experiencing problems with their gut," Tillisch said. "Our study shows that the gut–brain connection is a two-way street."

The small study involved 36 women between the ages of 18 and 55. Researchers divided the women into three groups: one group ate a specific yogurt containing a mix of several probiotics — bacteria thought to have a positive effect on the intestines — twice a day for four weeks; another group consumed a dairy product that looked and tasted like the yogurt but contained no probiotics; and a third group ate no product at all.

Functional magnetic resonance imaging (fMRI) scans conducted both before and after the four-week study period looked at the women’s brains in a state of rest and in response to an emotion-recognition task in which they viewed a series of pictures of people with angry or frightened faces and matched them to other faces showing the same emotions. This task, designed to measure the engagement of affective and cognitive brain regions in response to a visual stimulus, was chosen because previous research in animals had linked changes in gut flora to changes in affective behaviors.

The researchers found that, compared with the women who didn’t consume the probiotic yogurt, those who did showed a decrease in activity in both the insula — which processes and integrates internal body sensations, like those from the gut — and the somatosensory cortex during the emotional reactivity task.

Further, in response to the task, these women had a decrease in the engagement of a widespread network in the brain that includes emotion-, cognition- and sensory-related areas. The women in the other two groups showed a stable or increased activity in this network.

During the resting brain scan, the women consuming probiotics showed greater connectivity between a key brainstem region known as the periaqueductal grey and cognition-associated areas of the prefrontal cortex. The women who ate no product at all, on the other hand, showed greater connectivity of the periaqueductal grey to emotion- and sensation-related regions, while the group consuming the non-probiotic dairy product showed results in between.

The researchers were surprised to find that the brain effects could be seen in many areas, including those involved in sensory processing and not merely those associated with emotion, Tillisch said.

The knowledge that signals are sent from the intestine to the brain and that they can be modulated by a dietary change is likely to lead to an expansion of research aimed at finding new strategies to prevent or treat digestive, mental and neurological disorders, said Dr. Emeran Mayer, a professor of medicine (digestive diseases), physiology and psychiatry at the David Geffen School of Medicine at UCLA and the study’s senior author.

"There are studies showing that what we eat can alter the composition and products of the gut flora — in particular, that people with high-vegetable, fiber-based diets have a different composition of their microbiota, or gut environment, than people who eat the more typical Western diet that is high in fat and carbohydrates," Mayer said. "Now we know that this has an effect not only on the metabolism but also affects brain function."

The UCLA researchers are seeking to pinpoint particular chemicals produced by gut bacteria that may be triggering the signals to the brain. They also plan to study whether people with gastrointestinal symptoms such as bloating, abdominal pain and altered bowel movements have improvements in their digestive symptoms which correlate with changes in brain response.

Meanwhile, Mayer notes that other researchers are studying the potential benefits of certain probiotics in yogurts on mood symptoms such as anxiety. He said that other nutritional strategies may also be found to be beneficial.

By demonstrating the brain effects of probiotics, the study also raises the question of whether repeated courses of antibiotics can affect the brain, as some have speculated. Antibiotics are used extensively in neonatal intensive care units and in childhood respiratory tract infections, and such suppression of the normal microbiota may have long-term consequences on brain development.

Finally, as the complexity of the gut flora and its effect on the brain is better understood, researchers may find ways to manipulate the intestinal contents to treat chronic pain conditions or other brain related diseases, including, potentially, Parkinson’s disease, Alzheimer’s disease and autism.

Answers will be easier to come by in the near future as the declining cost of profiling a person’s microbiota renders such tests more routine, Mayer said.

Support the BRAIN Initiative, but don’t overlook the neurogenomic diagnostics that are already driving breakthroughs in brain and rare neurological disorders.

On April 2^nd, 2013, President Obama proposed a forward-thinking, $100 million research program designed to unlock the mysteries of the human brain. The BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative seeks to identify how brain cells and neural circuits interact in order to inform the development of future treatments for brain disorders, including Alzheimer’s disease, epilepsy, and traumatic brain injury.

This Initiative could favorably contribute to medical practice years from now. It should not, however, overshadow the potential of neurogenomic advances to improve the diagnosis, treatment and management of neurological disorders right now.

Most of my career has focused on neurogenomics. During the Human Genome Project era, I managed a clinical neurogenomics program at the National Institutes of Health to further understanding the genetic underpinnings of neurological disorders to help diagnose, treat, cure, and even prevent disease. Today, I oversee the development of neurodiagnostics for the neurology business of Quest Diagnostics, with an emphasis on rare neurological disorders, autism, and dementias.

Over the years, I’ve come to identify certain obstacles that prevent the translation of neurogenomic science into effective clinical management. These obstacles are surmountable, but they require a fundamental shift in how care is delivered to patients with neurological disorders.

Our current healthcare system groups healthcare professionals into two categories: generalists, such as primary care physicians and internists, and specialists, including neurologists. We assume that the former have the knowledge to reliably refer patients, when appropriate, to the latter. This may have been a fair assumption in the past, but in the age of genomic medicine, is it still valid?

In the case of neurogenomic disorders, such as genetic forms of epilepsy, neuromuscular disorders, dementia, and developmental disabilities overlapping clinical signs and symptoms often present a diagnostic challenge for neurologists, and even more so for generalists. A dearth of clinical information available on rare disorders, and the infrequency with which primary care physicians come in contact with effected patients, makes diagnosis even more difficult.

Dravet syndrome, for example, is a rare and catastrophic form of infantile epilepsy that is associated with a high incidence of developmental delays and even SUDEP (sudden unexplained death in epilepsy). Dravet is caused by a genetic defect in the SCN1A gene-affecting sodium channel. While not curable, the condition can be managed if diagnosed—but only if treating physicians are aware of the disorder, treatment options, and the detrimental effects of certain anticonvulsants.

Through advances in laboratory diagnostics, physicians are increasingly equipped to pinpoint the molecular causes of these diseases—some of which are amenable to treatment. But too often, the only clinicians who know about the tests and treatment options are specialists.

We must work more closely with medical societies and advocacy groups to educate primary care professionals and even patients in the value of, and tools for, diagnosing and treating neurological disorders.

Neurogenomic research is revealing that some rare disorders share similar molecular markers and mechanisms. By categorizing these rare disorders into clinical areas, we potentially reduce an otherwise lengthy diagnostic process for the patient and advance the development of new treatment options. Greater investment in new diagnostics that pinpoint molecular markers for disease will help remove the mystery that clouds the diagnosis of many disorders.

Too few clinicians, including neurologists, can keep on top of the rapid evolution of genomic science and diagnostics. As a result, patients are often referred from physician to physician, and administered test after test, in a protracted process to diagnose and treat. This wastes healthcare dollars. More importantly, it creates terrible anxiety and frustration for patients.

To alleviate this problem, medical societies need to do more to cultivate sub-specialists in neurogenomics—clinicians who have deep specialized expertise in specific neurological diseases, particularly rare disorders. With such experience, these experts can more efficiently and reliably diagnose the patient’s disorder.

While the BRAIN Initiative may yield clinically valuable insights in the future, scientists and physicians can do a great deal now with current technologies to translate genomic knowledge into effective diagnosis, management and, in some cases, treatment. With greater genomics education and collaboration, we can help improve the quality of life for patients with neurological disorders—and that, ultimately, is the most meaningful measurement of success.

New array measures vibrations across the skin, may help engineers design optimal, wearable tactile displays.

In the near future, a buzz in your belt or a pulse from your jacket may give you instructions on how to navigate your surroundings.

Think of it as tactile Morse code: vibrations from a wearable, GPS-linked device that tell you to turn right or left, or stop, depending on the pattern of pulses you feel. Such a device could free drivers from having to look at maps, and could also serve as a tactile guide for the visually and hearing impaired.

Lynette Jones, a senior research scientist in MIT’s Department of Mechanical Engineering, designs wearable tactile displays. Through her work, she’s observed that the skin is a sensitive — though largely untapped — medium for communication.

“If you compare the skin to the retina, you have about the same number of sensory receptors, you just have them over almost two square meters of space, unlike the eye where it’s all concentrated in an extremely small area,” Jones says. “The skin is generally as useful as a very acute area. It’s just that you need to disperse the information that you’re presenting.”

Knowing just how to disperse tactile information across the skin is tricky. For instance, people may be much more sensitive to stimuli on areas like the hand, as opposed to the forearm, and may respond best to certain patterns of vibrations. Such information on skin responsiveness could help designers determine the best configuration of motors in a display, given where on the skin a device would be worn.

Now Jones has built an array that precisely tracks a motor’s vibrations through skin in three dimensions. The array consists of eight miniature accelerometers and a single pancake motor — a type of vibrating motor used in cellphones. She used the array to measure motor vibrations in three locations: the palm of the hand, the forearm and the thigh. From her studies with eight healthy participants, Jones found that a motor’s mechanical vibrations through skin drop off quickly in all three locations, within 8 millimeters from where the vibrations originated.

Jones also gauged participants’ perception of vibrations, fitting them with a 3-by-3 array of pancake motors in these three locations on the body. While skin generally stopped vibrating 8 millimeters from the source, most people continued to perceive the vibrations as far away as 24 millimeters.

When participants were asked to identify specific locations of motors within the array, they were much more sensitive on the palm than on the forearm or thigh. But in all three locations, people were better at picking out vibrations in the four corners of the array, versus the inner motors, leading Jones to posit that perhaps people use the edges of their limbs to localize vibrations and other stimuli.

“For a lot of sensory modalities, you have to work out what it is people can process, as one of the dictates for how you design,” says Jones, whose results will appear in the journal IEEE Transactions on Haptics. “There’s no point in making things much more compact, which may be a desirable feature from an engineering point of view, but from a human-use point of view, doesn’t make a difference.”

Mapping good vibrations

In addition to measuring skin’s sensitivity to vibrations, Jones and co-author Katherine Sofia ’12 found that skin has a strong effect on motor vibrations. The researchers compared a pancake motor’s frequency of vibrations when mounted on a rigid structure or on more compliant skin. They found that in general, skin reduced a motor’s vibrations by 28 percent, with the forearm and thigh having a slightly stronger dampening effect than the palm of the hand.

The skin’s damping of motor vibrations is significant, Jones says, if engineers plan to build tactile displays that incorporate different frequencies of vibrations. For instance, the difference between two motors — one slightly faster than the other — may be indistinguishable in certain parts of the skin. Likewise, two motors spaced a certain distance apart may be differentiable in one area but not another.

“Should I have eight motors, or is four enough that 90 percent of the time, I’ll know that when this one’s on, it’s this one and not that one?” Jones says. “We’re answering those sorts of questions in the context of what information you want to present using a device.”

Roberta Klatzky, a professor of psychology at Carnegie Mellon University, says that measurements taken by Jones’ arrays can be used to set up displays in which the location of a stimulus — for example, a pattern to convey a letter — is important.

“A major challenge is to enable people to tell the difference between patterns applied to the skin as, for example, blind people do when reading Braille,” says Klatzky, who specializes in the study of spatial cognition. “Lynette’s work sets up a methodology and potential guidelines for effective pattern displays.”

Creating a buzz

Jones sees promising applications for wearable tactile displays. In addition to helping drivers navigate, she says tactile stimuli may direct firefighters through burning buildings, or emergency workers through disaster sites. In more mundane scenarios, she says tactile displays may help joggers traverse an unfamiliar city, taking directions from a buzzing wristband, instead of having to look at a smartphone. 

Using data from their mechanical and perceptual experiments, Jones’ group is designing arrays that can be worn across the back and around the wrist, and is investigating various ways to present vibrations. For example, a row of vibrations activated sequentially from left to right may tell a driver to turn right; a single motor that buzzes with increasing frequency may be a warning to slow down.

“There’s a lot of things you can do with these displays that are fairly intuitive in terms of how people respond,” Jones says, “which is important because no one’s going to spend hours and hours in any application, learning what a signal means.”

The sound of small children chattering has always been considered cute – but not particularly sophisticated. However, research by a Newcastle University expert has shown their speech is far more advanced than previously understood.

Dr Cristina Dye, a lecturer in child language development, found that two to three- year-olds are using grammar far sooner than expected.

She studied fifty French speaking youngsters aged between 23 and 37 months, capturing tens of thousands of their utterances.

Dr Dye, who carried out the research while at Cornell University in the United States, found that the children were using ‘little words’ which form the skeleton of sentences such as a, an, can, is, an, far sooner than previously thought.

Dr Dye and her team used advanced recording technology including highly sensitive microphones placed close to the children, to capture the precise sounds the children voiced. They spent years painstakingly analysing every minute sound made by the toddlers and the context in which it was produced.

They found a clear, yet previously undetected, pattern of sounds and puffs of air, which consistently replaced grammatical words in many of the children’s utterances.

Dr Dye said: “Many of the toddlers we studied made a small sound, a soft breath, or a pause, at exactly the place that a grammatical word would normally be uttered.” 

“The fact that this sound was always produced in the correct place in the sentence leads us to believe that young children are knowledgeable of grammatical words. They are far more sophisticated in their grammatical competence than we ever understood.

“Despite the fact the toddlers we studied were acquiring French, our findings are expected to extend to other languages. I believe we should give toddlers more credit – they’re much more amazing than we realised.”

For decades the prevailing view among developmental specialists has been that children’s early word combinations are devoid of grammatical words. On this view, children then undergo a ‘tadpole to frog’ transformation where due to an unknown mechanism, they start to develop grammar in their speech. Dye’s results now challenge the old view.

Dr Dye said: “The research sheds light on a really important part of a child’s development. Language is one of the things that makes us human and understanding how we acquire it shows just how amazing children are.

“There are also implications for understanding language delay in children. When children don’t learn to speak normally it  can lead to serious issues later in life. For example, those who have it are more likely to suffer from mental illness or be unemployed later in life. If we can understand what is ‘normal’ as early as possible then we can intervene sooner to help those children.”

The research was originally published in the Journal of Linguistics.

Researchers at the MedUni Vienna have proved in a so far unique multicenter study that clinical functional magnetic resonance tomography (fMRI), in the area in which the MedUni Vienna has a leading role internationally, is a safe method in brain surgery. With the aid of fMRI imaging can pinpoint to the millimetre where critical nerve fibres (e.g. vital for speech or hand function) lie and which have to be avoided – in operations on brain tumours for example.

"With the assistance of functional magnetic resonance tomography we are, if you like, drawing a red line for the surgeon so he knows where not to make an incision so as to avoid damage," says Roland Beisteiner from the University Department of Neurology at the MedUni Vienna. The neurologist and president of the Austrian Society for fMRI was playing a part in the development of fMRI as early as 1992, initiating its development in Austria. Since then this method has been developed and implemented at the University Department of Neurology and the High Field MRI Center of Excellence.

Now Beisteiner’s team have been able for the first time to demonstrate in a current paper in the top journal “Radiology" that functional magnetic resonance tomography provides diagnostic certainty in operations on the brain – no matter what the equipment is (whether a 7Tesla magnetic resonance tomograph as in Vienna or even only a 1.5Tesla), no matter in which location and also irrespective of who is operating it. The Medical Universities in Innsbruck and Salzburg, the Heinrich Heine University of Düsseldorf and the Stiftungsklinikum Koblenz (Koblenz Hospital Foundation) also took part in the study.

The “Imaging and Cognition Biology” Research Cluster of the MedUni and Vienna University

Likewise, with the help of functional magnetic resonance tomography, the teams of Beisteiner and Tecumseh Fitch (Faculty of Life Sciences of the University of Vienna) are investigating in a joint research cluster belonging to the MedUni Vienna and the University of Vienna whether the structural and syntactic processing of music takes place in similar areas of the brain as does the processing of speech. Says Beisteiner: “It is never exactly the same area of the brain; however, brain activities can overlap when talking or playing an instrument.”

The main focus of the research cluster is to determine precisely the common areas of the brain involved and to develop new treatments by activating them. These could perhaps then be used on people suffering from aphasia, which is a loss of language as the result of brain damage mostly to the left half of the brain.

According to Beisteiner there have been some astonishing results: “People, who could no longer speak because of their aphasia, have been able to sing the words they have learned to the matching tune.” From this one can conclude that it would seem to make sense to also practise music skills during speech therapy.

The “Imaging and Cognition Biology” research cluster is one of six joint clusters at the MedUni Vienna with the University of Vienna, which were set up in 2011. Further information: http://forschungscluster.meduniwien.ac.at/.

Scientists at the University of Massachusetts Medical School have developed a novel transgenic system which allows them to remotely activate individual brain cells in the model organism Drosophila using ambient temperature. This powerful new tool for identifying and characterizing neural circuitry has lead to the identification of a pair of neurons – now called Fdg neurons – in the fruit fly that decide when to eat and initiate the subsequent feeding action. Discovery of these neurons may help neurobiologists better understand how the brain uses memory and stimuli to produce classically conditioned responses, such as those often associated with phobias or drug tolerance. The study appears in the journal Nature.

"For any organism, the decision to eat is a complex integration of internal and external stimuli leading to the activation of an organized sequence of motor patterns," said Motojiro Yoshihara, PhD, assistant professor of neurobiology at the University of Massachusetts Medical School and lead author of the Nature study. “By developing genetic tools to remotely activate individual brain cells in Drosophila, we’ve been able to isolate a pair of neurons that are critical to the act of eating in fruit flies. More importantly, we now have a powerful new tool with which we can answer important questions about the function and composition of neural circuitry.”

To isolate the neurons responsible for sensing food and initiating the complex feeding program in Drosophila, UMMS scientists had to develop a method of studying the behavior of freely moving flies while targeting and manipulating individual neurons. To accomplish this, Dr. Yoshihara expressed temperature activated genes in random neurons in more than 800 Drosophila lines. Placing these genetically modified flies in a small temperature-controlled chamber, he was able to active these genes by increasing and decreasing the ambient temperature. This, in turn, activated the corresponding neurons.

Under wild conditions, when a hungry fly comes in contact with food it ceases motion and executives eight basic motor functions resulting in the consumption of the food. When the temperature in the chamber was increased, Yoshihara and colleagues were able to isolate a single Drosophila line which exhibited these eight motor functions, even in the absence of food or other stimuli. Subsequent experiments revealed that the feeding mechanism initiated by activating the transgenes was being controlled by a single pair of neurons in the fly’s brain. Furthermore, these feeding (Fdg) neurons were responsible for synthesizing cues about available food and hunger, and using them to start the feeding mechanism.

"Our results showed that these neurons become active in the presence of a food source for the fly, but the response was contingent on whether the animal was hungry," said Yoshihara. "This means that these neurons are integrating both internal and external stimuli in order to initiate a complex feeding behavior with multiple motor programs."

Yoshihara believes this discovery will provide researchers with a powerful new tool for isolating, analyzing and characterizing aspects of the brain’s neural circuitry and studying how information is integrated in the brain. In the future, Yoshihara plans to use the Fdg-neurons to study the biological basis of classical or Pavlovian conditioning. Doing so, he hopes to uncover how memory integrates stimuli to illicit a conditioned behavior.

Sleep researchers from University of California campuses in Riverside and San Diego have identified the sleep mechanism that enables the brain to consolidate emotional memory and found that a popular prescription sleep aid heightens the recollection of and response to negative memories.

Their findings have implications for individuals suffering from insomnia related to posttraumatic stress disorder (PTSD) and other anxiety disorders who are prescribed zolpidem (Ambien) to help them sleep.

The study — “Pharmacologically Increasing Sleep Spindles Enhances Recognition for Negative and High-arousal Memories” — appears in the Journal of Cognitive Neuroscience. It was funded by a National Institutes of Health career award to Sara C. Mednick, assistant professor of psychology at UC Riverside, of $651,999 over five years.

Mednick and UC San Diego psychologists Erik J. Kaestner and John T. Wixted determined that a sleep feature known as sleep spindles — bursts of brain activity that last for a second or less during a specific stage of sleep — are important for emotional memory.

Research Mednick published earlier this year demonstrated the critical role that sleep spindles play in consolidating information from short-term to long-term memory in the hippocampus, located in the cerebral cortex of the brain. Zolpidem enhanced the process, a discovery that could lead to new sleep therapies to improve memory for aging adults and those with dementia, Alzheimer’s and schizophrenia. It was the first study to show that sleep can be manipulated with pharmacology to improve memory.

“We know that sleep spindles are involved in declarative memory — explicit information we recall about the world, such as places, people and events, ” she explained.

But until now, researchers had not considered sleep spindles as playing a role in emotional memory , focusing instead on rapid eye movement (REM) sleep.

Using two commonly prescribed sleep aids — zolpidem and sodium oxybate (Xyrem) — Mednick, Kaestner and Wixted were able to tease apart the effects of sleep spindles and rapid eye movement (REM) sleep on the recall of emotional memories. They determined that sleep spindles, not REM, affect emotional memory.

The researchers gave zolpidem, sodium oxybate (Xyrem) and a placebo to 28 men and women between the ages of 18 and 39 who were normal sleepers, allowing several days between doses to allow the pharmaceuticals to leave their bodies. The participants viewed standardized images known to elicit positive and negative responses for one second before and after taking supervised naps. They recalled more images that had negative or highly arousing content after taking zolpidem, a finding that also suggests that the brain may favor consolidation of negative memories, she said.

“I was surprised by the specificity of the results, that the emotional memory improvement was specifically for the negative and high-arousal memories, and the ramifications of these results for people with anxiety disorders and PTSD,” Mednick said. “These are people who already have heightened memory for negative and high-arousal memories. Sleep drugs might be improving their memories for things they don’t want to remember.”

The study may have even broader implications, the researchers said. Clinical guidelines of the U.S. Department of Veterans Affairs and Department of Defense recommend against the routine use of benzodiazepines to treat PTSD, although their use increased among men and women with PTSD between 2003 and 2010. The effects of benzodiazepines on sleep are similar to those of zolpidem.

The U.S. Air Force uses zolpidem as one of the prescribed “no-go pills” to help flight crews calm down after taking stimulants to stay awake during long missions, the researchers noted in the study.

“In light of the present results, it would be worthwhile to investigate whether the administration of benzodiazepine-like drugs may be increasing the retention of highly arousing and negative memories, which would have a countertherapeutic effect,” they wrote. “Further research on the relationship between hypnotics and emotional mood disorders would seem to be in order.”

TAU researcher develops a protein to protect and restore nerve cell communications

A structure called “the microtubule network” is a crucial part of our nervous system. It acts as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s, this network breaks down, hindering motor abilities and cognitive function.

Now Prof. Illana Gozes of Tel Aviv University’s Sackler Faculty of Medicine has developed a new peptide in her lab, called NAP or Davunetide, that has the capacity to both protect and restore microtubule function. The peptide is a compound derived from the protein ADNP, which regulates more than 400 genes and is essential for brain formation, memory, and behavior.

Prof. Gozes and her team of researchers, including Dr. Yan Jouroukhin and graduate student Regin Ostritsky of TAU, observed that in animal models with microtubule damage, NAP was able to maintain or revive the transport of proteins and other materials in cells, ameliorating symptoms associated with neurodegeneration. These findings, which were reported in the journal Neurobiology of Disease, indicate that NAP could be an effective tool in fighting some of the most debilitating effects of neurodegenerative diseases.

Prof. Gozes is the director of TAU’s Adams Super Center for Brain Studies and holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors.

Securing passage through the brain

In their investigation, the researchers used two different animal models with microtubule damage. The first group was made up of normal mice whose microtubule system was broken down through the use of a compound. The second group were genetically-engineered mouse models of ALS, in which the microtubule system was chronically damaged. In both groups, half the mice were given a single NAP injection, while the control half were not.

To determine the impact of NAP on nerve cell communications, the researchers administered the chemical element manganese to all animal models and tracked its movement through the brain using an MRI. In the mice treated with NAP, researchers observed that the manganese was able to travel through the brain normally — the microtubule system had been protected from damage or restored to normal use. Those mice that did not receive the peptide experienced the usual breakdown or continued dysfunction of the microtubule system.

These findings were corroborated by a subsequent study conducted in the UK, published in the journal Molecular Psychiatry, which found that NAP was able to ameliorate damage in fruit fly models of microtubule deficiency, repairing nerve cell dysfunction.

Slowing down cognitive dysfunction

NAP appears to have widespread potential in terms of neuroprotection, says Prof. Gozes, who was recently awarded the Meitner-Humblodt Research Award for her lifelong contribution to the field of brain sciences.

Previous studies on the peptide, conducted through a collaboration between Allon Therapeutics and Ramot, TAU’s technology transfer arm, have shown that patients suffering from cognitive dysfunction — a precursor to Alzheimer’s Disease — showed significant improvements in their cognitive scores when treated with NAP. Additional studies have also shown that NAP has a positive impact on rectifying microtubule deficiencies in schizophrenia patients.

Prof. Gozes notes that more research must be conducted to discover how to optimize the use of NAP as a treatment, including which patients can benefit most from the intervention.

• Genomic research has shown that glioblastoma, the most dangerous type of brain cancer, has four subtypes.

• This study examines two of the subtypes and identifies an abnormal metabolic pathway that drives the aggressive growth of one of them.

• The findings could lead to targeted therapies for treating an aggressive form of glioblastoma.

A study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has identified an abnormal metabolic pathway that drives cancer-cell growth in a particular glioblastoma subtype. The finding might lead to new therapies for a subset of patients with glioblastoma, the most common and lethal form of brain cancer.

The physician scientists sought to identify glioblastoma subtype-specific cancer stem cells. Genetic analyses have shown that high-grade gliomas can be divided into four subtypes: proneural, neural, classic and mesenchymal.

This study shows that the mesenchymal subtype is the most aggressive subtype, that it has the poorest prognosis among affected patients, and that cancer stem cells isolated from the mesenchymal subtype have significantly higher levels of the enzyme ALDH1A3 compared with the proneural subtype.

The findings, published recently in the Proceedings of the National Academy of Sciences, show that high levels of the enzyme drive tumor growth.

“Our study suggests that ALDH1A3 is a potentially functional biomarker for mesenchymal glioma stem cells, and that inhibiting that enzyme might offer a promising therapeutic approach for high-grade gliomas that have a mesenchymal signature,” says principal investigator Ichiro Nakano, MD, PhD, associate professor of neurosurgery at the OSUCCC – James. “This indicates that therapies for high-grade gliomas should be personalized, that is, based on the tumor subtype instead of applying one treatment to all patients,” he says.

The National Cancer Institute estimates that 23,130 Americans will be diagnosed with brain and other nervous system tumors in 2013, and that 14,000 people will die of these malignancies. Glioblastoma accounts for about 15 percent of all brain tumors, is resistant to current therapies and has a survival as short as 15 months after diagnosis.

Little is known, however, about the metabolic pathways that drive the growth of individual glioblastoma subtypes – knowledge that is crucial for developing novel and effective targeted therapies that might improve treatment for these lethal tumors.

For this study, Nakano and his collaborators used cancer cells from 40 patients with high-grade gliomas, focusing on tumor cells with a stem-cell signature. The researchers then used microarray analysis and pre-clinical animal assays to identify two predominant glioblastoma subtypes, proneural and mesenchymal.
 
Key technical findings include:

• Genes involved in glycolysis and gluconeogenesis, particularly ALDH1A3, were significantly up-regulated in mesenchymal glioma stem cells compared to proneural stem cells;
• Mesenchymal glioma stem cells show significantly higher radiation resistance and high expression of DNA-repair genes;
• Radiation induces transformation of proneural glioma stem cells into mesenchymal-like glioma stem cells that are highly resistant to radiation treatment; inhibiting the ALDH1 pathway reverses this resistance.
• Inhibiting ALDH1A3-mediated pathways slows the growth of mesenchymal glioma stem cells and might provide a promising therapeutic approach for glioblastomas with a mesenchymal signature.

“Overall, our data suggest that a novel signaling mechanism underlies the transformation of proneural glioma stem cells to mesenchymal-like cells and their maintenance as stem-like cells,” Nakano says. Currently, their discoveries are in provision patent application, led by the Technology Licensing Office at University of Pittsburgh.

A new University of Florida study suggests a promising brain-imaging technique has the potential to improve diagnoses for the millions of people with movement disorders such as Parkinson’s disease.

Utilizing the diffusion tensor imaging technique, as it is known, could allow clinicians to assess people earlier, leading to improved treatment interventions and therapies for patients.

The three-year study looked at 72 patients, each with a clinically defined movement disorder diagnosis. Using a technique called diffusion tensor imaging, the researchers successfully separated the patients into disorder groups with a high degree of accuracy.

The study is being published in the journal Movement Disorders.

“The purpose of this study is to identify markers in the brain that differentiate movement disorders which have clinical symptoms that overlap, making [the disorders] difficult to distinguish,” said David Vaillancourt, associate professor in the department of applied physiology and kinesiology and the study’s principal investigator.

“No other imaging, cerebrospinal fluid or blood marker has been this successful at differentiating these disorders,” he said. “The results are very promising.”

Movement disorders such as Parkinson’s disease, essential tremor, multiple system atrophy and progressive supranuclear palsy exhibit similar symptoms in the early stages, which can make it challenging to assign a specific diagnosis. Often, the original diagnosis changes as the disease progresses, Vaillancourt said.

Diffusion tensor imaging, known as DTI, is a non-invasive method that examines the diffusion of water molecules within the brain and can identify key areas that have been affected as a result of damage to gray matter and white matter in the brain. Vaillancourt and his team measured areas of the basal ganglia and cerebellum in individuals, and used a statistical approach to predict group classification. By asking different questions within the data and comparing different groups to one another, they were able to show distinct separation among disorders.

“Our goal was to use these measures to accurately predict the original disease classification,” Vaillancourt said. “The idea being that if a new patient came in with an unknown diagnosis, you might be able to apply this algorithm to that individual.

He compared the process to a cholesterol test.

“If you have high cholesterol, it raises your chances of developing heart disease in the future,” he said. “There are tests like those that give a probability or likelihood scenario of a particular disease group. We’re going a step further and trying to utilize information to predict the classification of specific tremor and Parkinsonian diseases.”

A specific MicroRNA, a short set of RNA (ribonuclease) sequences, naturally packaged into minute (50 nanometers) lipid containers called exosomes, are released by stem cells after a stroke and contribute to better neurological recovery according to a new animal study by Henry Ford Hospital researchers.

The important role of a specific microRNA transferred from stem cells to brain cells via the exosomes to enhance functional recovery after a stroke was shown in lab rats. This study provides fundamental new insight into how stem cells affect injured tissue and also offers hope for developing novel treatments for stroke and neurological diseases, the leading cause of long-term disability in adult humans.

The study was published in the journal Stem Cells.

Although most stroke victims recover some ability to voluntarily use their hands and other body parts, nearly half are left with weakness on one side of their body, while a substantial number are permanently disabled.

Currently no treatment exists for improving or restoring this lost motor function in stroke patients, mainly because of mysteries about how the brain and nerves repair themselves.

“This study may have solved one of those mysteries by showing how certain stem cells play a role in the brain’s ability to heal itself to differing degrees after stroke or other trauma,” says study author Michael Chopp, Ph.D., scientific director of the Henry Ford Neuroscience Institute and vice chairman of the department of Neurology at Henry Ford Hospital.

The researchers noted that Henry Ford’s Institutional Animal Care and Use Committee approved all the experimental procedures used in the new study.

The experiment began by isolating mesenchymal stem cells (MSCs) from the bone marrow of lab rats. These MSCs are then genetically altered to release exosomes that contain specific microRNA molecules. The MSCs then become “factories” producing exosomes containing specific microRNAs. These microRNAs act as master switches that regulate biological function.

The new study showed for the first time that a specific microRNA, miR-133b, carried by these exosomes contributes to functional recovery after a stroke.

The researchers genetically raised or lowered the amount of miR-133b in MSCs and, respectively, treated the rats. When these MSCs are injected into the bloodstream 24 hours after stroke, they enter the brain and release their exosomes. When the exosomes were enriched with the miR-133b, they amplified neurological recovery, and when the exosomes were deprived of the miR-133b, the neurological recovery was substantially reduced.

Stroke was induced under anesthesia by inserting a nylon thread up the carotid artery to occlude a major artery in the brain, the middle cerebral artery. MSCs were then injected 24 hours after the induction of stroke in these animals and neurological recovery was measured.

As a measure on neurological recovery, rats were given two types of behavioral tests to measure the normal function of their front legs and paws – a “foot-fault test,” to see how well they could walk on an unevenly spaced grid; and an “adhesive removal test” to measure how long it took them to remove a piece of tape stuck to their front paws.

Researchers then separated the disabled rats into several groups and injected each group with a specific dosage of saline, MSCs and MSCs with increased or decreased miR-133b, respectively. The two behavioral tests were again given to the rats three, seven and 14 days after treatment.

The data demonstrated that the enriched miR-133b exosome package greatly promoted neurological recovery and enhanced axonal plasticity, an aspect of brain rewiring, and the diminished miR-133b exosome package failed to enhance neurological recovery

While the research team was careful to note that this was an animal study, its findings offer hope for new ways to address the single biggest concern of stroke victims as well as those with neural injury such as traumatic brain injury and spinal cord damage – regaining neurological function for a better quality of life.