Neuroscience

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.

To handle large amounts of data from detailed brain models, IBM, EPFL, and ETH Zürich are collaborating on a new hybrid memory strategy for supercomputers. This will help the Blue Brain Project and the Human Brain Project achieve their goals.

Motivated by extraordinary requirements for neuroscience, IBM Research, EPFL, and ETH Zürich through the Swiss National Supercomputing Center CSCS, are exploring how to combine different types of memory – DRAM, which is standard for computer memory, and flash memory that is akin to USB sticks – for less expensive and optimal supercomputing performance.

The Blue Brain Project, for example, is building detailed models of the rodent brain based on vast amounts of information – incorporating experimental data and a large number of parameters – to describe each and every neuron and how they connect to each other. The building blocks of the simulation consist of realistic representations of individual neurons, including characteristics like shape, size, and electrical behavior.

Given the roughly 70 million neurons in the brain of a mouse, a huge amount of data needs to be accessed for the simulation to run efficiently.

“Data-intensive research has supercomputer requirements that go well beyond high computational power,” says EPFL professor Felix Schürmann of the Blue Brain Project in Lausanne. “Here, we investigate different types of memory and how it is used, which is crucial to build detailed models of the brain. But the applications for this technology are much broader.”

70 Million Neurons for the New IBM Blue Gene/Q

The Blue Brain Project has acquired a new IBM Blue Gene/Q supercomputer to be installed at CSCS in Lugano, Switzerland. This machine has four times the memory of the supercomputer used by the Blue Brain Project up to now, but this still may not be enough to model the mouse brain at the desired level of detail.

The challenge for scientists is to modify the supercomputer so that it can model not only more neurons—as many as the 70 million in the mouse brain—but with even more detail while using fewer resources. The researchers aspire to do just that by engineering different types of memory. The Blue Gene/Q comes equipped with 64 terabytes of DRAM memory. But this type of memory, which is ubiquitous in personal computers, loses data almost instantaneously when the power is turned off.

The scientists plan to boost the supercomputer’s capacity by combining DRAM with another type of memory that has made its way into everyday devices, from cameras to mobile phones: flash memory. Unlike DRAM, flash memory can retain information, even without power, and is much more affordable. The Blue Brain Project’s new supercomputer efficiently integrates 128 terabytes of flash memory with the 64 terabytes of DRAM memory.

“These technological advancements will not only help scientists model the brain, but they will also contribute to future evidence-based systems,” says IBM Research computational scientist Alessandro Curioni, who is based in Zurich.

To take full advantage of this novel mix of memory, IBM has been developing a scalable memory system architecture, while EPFL and ETH Zürich researchers are working on high-level software to optimize this hybrid memory for large-scale simulations and interactive supercomputing.

“The resulting machine may not necessarily be the fastest supercomputer in the world, but it will certainly open up new avenues for data-intensive science,” says ETH Zürich professor and CSCS director Thomas Schulthess. “The results of this collaboration will support scientific investigations across all types of data intensive applications including astronomy, geosciences and healthcare.”

Towards the Human Brain

The Blue Brain Project has recently become the core of an even more ambitious project, the European Flagship Human Brain Project, also coordinated by EPFL. The Human Brain Project faces the daunting task of providing the technical tools to integrate as much data as possible into detailed models of the human brain by 2023. Estimated at 90 billion neurons, the human brain compared to that of a mouse contains roughly a thousand times more neurons. The new strategy to use hybrid memory is an important step towards helping the Human Brain Project meet its 10-year goal.

As it goes with research and innovation, a scientific pursuit is pushing the boundaries of technology, leading to new and more powerful tools. The Blue Brain and Human Brain Projects have brought into perspective the need to deal with complex and unusual calculations, requiring supercomputer technology where speed is simply not enough.

A 350-year-old mathematical mystery could lead toward a better understanding of medical conditions like epilepsy or even the behavior of predator-prey systems in the wild, University of Pittsburgh researchers report. 

The mystery dates back to 1665, when Dutch mathematician, astronomer, and physicist Christiaan Huygens, inventor of the pendulum clock, first observed that two pendulum clocks mounted together could swing in opposite directions. The cause was tiny vibrations in the beam caused by both clocks, affecting their motions. 

The effect, now referred to by scientists as “indirect coupling,” was not mathematically analyzed until nearly 350 years later, and deriving a formula that explains it remains a challenge to mathematicians still. Now, Pitt professors apply this principle to measure the interaction of “units”—such as neurons, for example—that turn “off” and “on” repeatedly. Their findings are highlighted in the latest issue of Physical Review Letters. 

“We have developed a mathematical approach to better understanding the ‘ingredients’ in a system that affect synchrony in a number of medical and ecological conditions,” said Jonathan E. Rubin, coauthor of the study and professor in Pitt’s Department of Mathematics within the Kenneth P. Dietrich School of Arts and Sciences. “Researchers can use our ideas to generate predictions that can be tested through experiments.”

More specifically, the researchers believe the formula could lead toward a better understanding of conditions like epilepsy, in which neurons become overly active and fail to turn off, ultimately leading to seizures. Likewise, it could have applications in other areas of biology, such as understanding how bacteria use external cues to synchronize growth. 

Together with G. Bard Ermentrout, University Professor of Computational Biology and professor in Pitt’s Department of Mathematics, and Jonathan J. Rubin, an undergraduate mathematics major, Jonathan E. Rubin examined these forms of indirect communication  that are not typically included in most mathematical studies owing to their complicated elements. In addition to studying neurons, the Pitt researchers applied their methods to a model of artificial gene networks in bacteria, which are used by experimentalists to better understand how genes function.

“In the model we studied, the genes turn off and on rhythmically. While on, they lead to production of proteins and a substance called an autoinducer, which promotes the genes turning on,” said Jonathan E. Rubin. “Past research claimed that this rhythm would occur simultaneously in all the cells. But we show that, depending on the speed of communication, the cells will either go together or become completely out of synch with each another.”

To apply their formula to an epilepsy model, the team assumed that neurons oscillate, or turn off and on in a regular fashion. Ermentrout compares this to Southeast Asian fireflies that flash rhythmically, encouraging synchronization.

“For neurons, we have shown that the slow nature of these interactions encouraged ‘asynchrony,’ or firing at different parts of the cycle,” Ermentrout said. “In these seizure-like states, the slow dynamics that couple the neurons together are such that they encourage the neurons to fire all out of phase with each other.” 

The Pitt researchers believe this approach may extend beyond medical applications into ecology—for example, a situation in which two independent animal groups in a common environment communicate indirectly. Jonathan E. Rubin illustrates the idea by using a predator-prey system, such as rabbits and foxes. 

“With an increase in rabbits will come an increase in foxes, as they’ll have plenty of prey,” said Jonathan E. Rubin. “More rabbits will get eaten, but eventually the foxes won’t have enough to eat and will die off, allowing the rabbit numbers to surge again. Voila, it’s an oscillation. So, if we have a fox-rabbit oscillation and a wolf-sheep oscillation in the same field, the two oscillations could affect each other indirectly because now rabbits and sheep are both competing for the same grass to eat.”

There is growing evidence that a gene variant that reduces the plasticity of the nervous system also modulates responses to treatments for mood and anxiety disorders. In this case, patients with posttraumatic stress disorder, or PTSD, with a less functional variant of the gene coding for brain-derived neurotrophic factor (BDNF), responded less well to exposure therapy.

This gene has been implicated previously in treatment response. Basic science studies have convincingly shown that BDNF levels are an important modifier of the therapeutic effects of antidepressants in animal models. Other researchers have made similar findings in a small group of depressed patients treated with the rapid-acting antidepressant ketamine. Low BDNF plasma levels also have been linked to poorer effects of cognitive rehabilitation in schizophrenia. BDNF infused directly into the infralimbic prefrontal cortex in rats was found to extinguish conditioned fear, and BDNF levels were found to modulate the amount of fear extinction.

"Findings are accumulating to suggest that BDNF is an important modifier of the responses to a number of clinical interventions, presumably because BDNF is such an important regulator of neuroplasticity, i.e., the ability of the brain to adapt," said Dr. John Krystal, Editor of Biological Psychiatry.

In this study, researchers from Australia and Puerto Rico teamed up to investigate the influence of the BDNF Val66Met genotype on response to exposure therapy in patients with PTSD. They recruited 55 patients, all of whom participated in an 8-week exposure-based cognitive behavior therapy program.

Exposure therapy is currently the most effective treatment for PTSD, although it does not work for everyone. This type of therapy is delivered over multiple one-on-one sessions with a trained therapist, with a goal of reducing patients’ fear and anxiety.

They found that patients with the Met-66 allele of BDNF, compared with patients with the Val/Val allele, showed poorer response to exposure therapy.

"This paper reflects an important and significant advance, in translating recent ground-breaking findings in animal and human neuroscience into clinically anxious populations," said first author Dr. Kim Felmingham.

She added, “Findings from this study support a widely held, but largely untested, hypothesis that extinction is necessary for exposure therapy. It also provides evidence that genotypes influence response to cognitive behavior therapy.”

This finding supports prior evidence and highlights the importance of considering genotypes as potential predictor variables in clinical trials of exposure therapy.

Study is the first to show association between mother’s chemical exposure and fetal motor activity and heart rate

A study led by researchers at the Johns Hopkins Bloomberg School of Public Health has for the first time found that a mother’s higher exposure to some common environmental contaminants was associated with more frequent and vigorous fetal motor activity. Some chemicals were also associated with fewer changes in fetal heart rate, which normally parallel fetal movements. The study of 50 pregnant women found detectable levels of organochlorines in all of the women participating in the study—including DDT, PCBs and other pesticides that have been banned from use for more than 30 years. The study is available online in advance of publication in the Journal of Exposure Science and Environmental Epidemiology.

“Both fetal motor activity and heart rate reveal how the fetus is maturing and give us a way to evaluate how exposures may be affecting the developing nervous system. Most studies of environmental contaminants and child development wait until children are much older to evaluate effects of things the mother may have been exposed to during pregnancy; here we have observed effects in utero,” said Janet A. DiPietro, PhD, lead author of the study and Associate Dean for Research at the Bloomberg School of Public Health.

For the study, DiPietro and her colleagues followed a sample of 50 high- and low- income pregnant women living in and around Baltimore, Md. At 36 weeks of pregnancy, blood samples were collected from the mothers and measurements were taken of fetal heart rate and motor activity. The blood samples were tested for levels of 11 pesticides and 36 polychlorinated biphenyl (PCB) compounds.

According to the findings, all participants had detectable concentrations of at least one-quarter of the analyzed chemicals, despite the fact that they have been banned for more than three decades. Fetal heart rate effects were not consistently observed across all of the compounds analyzed; when effects were seen, higher chemical exposures were associated with reductions in fetal heart rate accelerations, an indicator of fetal wellbeing. However, associations with fetal motor activity measures were more consistent and robust: higher concentrations of 7 of 10 organochlorine compounds were positively associated with one of more measures of more frequent and more vigorous fetal motor activity. These chemicals included hexachlorobenzene, DDT, and several PCB congeners. Women of higher socioeconomic status in the study had a greater concentration of chemicals compared to the women of lower socioeconomic status

“There is tremendous interest in how the prenatal period sets the stage for later child development.  These results show that the developing fetus is susceptible to environmental exposures and that we can detect this by measuring fetal neurobehavior. This is yet more evidence for the need to protect the vulnerable developing brain from effects of environmental contaminants both before and after birth,” said DiPietro.

“Fetal heart rate and motor activity associations with maternal organochlorine levels: results of an exploratory study” was written by Janet A. DiPietro, Meghan F. Davis, Kathleen A. Costigan, and Dana Boyd Barr.

Low baseline diastolic blood pressure (DBP) appears to be associated with brain atrophy in patients with arterial disease, whenever declining levels of blood pressure (BP) over time among patients who had a higher baseline BP were associated with less progression of atrophy, according to a report published Online First by JAMA Neurology, a JAMA Network publication.

(Image: Wikimedia Commons)

“Studies have shown that both high and low blood pressure (BP) may play a role in the etiology of brain atrophy. High BP in midlife has been associated with more brain atrophy later in life, whereas studies in older populations have shown a relation between low BP and more brain atrophy. Yet, prospective evidence is limited, and the relation remains unclear in patients with manifest arterial disease,” according to the study.

Hadassa M. Jochemsen, M.D., of University Medical Center Utrecht, the Netherlands, and colleagues examined the association of baseline BP and change in BP over time with the progression of brain atrophy in 663 patients (average age 57 years; 81 percent male). The patients had coronary artery disease, cerebrovascular disease, peripheral artery disease or abdominal aortic aneurysm.

According to the results, patients with lower baseline DBP or mean arterial pressure (MAP) had more progression of subcortical (the area beneath the cortex of the brain) atrophy. In patients with higher BP (DBP, MAP or systolic BP), those with declining BP levels over time had less progression of subcortical atrophy compared with those with rising BP levels.

“This could imply that BP lowering is beneficial in patients with higher BP levels, but one should be cautious with further BP lowering in patients who already have low BP,” the study authors conclude.

Over 100 years ago psychologist Carl Gustav Jung penned his theory of ‘complexes’ where he explained how unconscious psychological issues can be triggered by people, events, or Jung believed, through word association tests.

New research in the Journal of Analytical Psychology is the first to reveal how modern brain function technology allows us to see inside the mind as a ‘hot button’ word triggers a state of internal conflict between the left and right parts of the brain.

The study revealed that some words trigger a subconscious internal conflict between our sense of selves and downloaded brain programs referring to “other” beings.

Analysis showed how this conflict takes place between the left and the right brain over three seconds, after which the left brain takes over to ensure ‘hot buttons’ will continue to be active.

"We found that when a complex is activated, brain circuits involved in how we sense ourselves, but also other people, get activated," said Dr. Leon Petchkovsky. "However, as there is no external person, the ‘other’ circuits really refer to internalized programs about how an ‘other’ person might respond. When a hot button gets pressed, ‘internal self’ and ‘internal other’ get into an argument."

"If we can manage to stay with the conflict rather than pseudo-resolve it prematurely, it may be possible to move beyond it," said Petchkovsky. "We can do this in psychotherapy, or by developing ‘mindfulness’ meditation skills. This makes for fewer ‘hot-buttons’ and a happier life."

Further research into this technology may help to develop an office-based test for condtions such as schizophrenia. Jung noticed that when schizophrenic patients responded to the word association test, their complexes tended to predominate for a much longer time and they would often get a burst of auditory hallucinations when they hit complexed responses.

In Dr Petchkovsky’s research with two schizophrenic patients found that their right brain activity persists for much longer than other patients and they reported an increase in auditory hallucination activity when complexes are struck.

Findings may have implications for treating compulsive behavior associated with psychiatric disease and eating disorders

What started as an experiment to probe brain circuits involved in compulsive behavior has revealed a surprising connection with obesity.

The University of Iowa-led researchers bred mice missing a gene known to cause obesity, and suspected to also be involved in compulsive behavior, with a genetic mouse model of compulsive grooming. The unexpected result was offspring that were neither compulsive groomers nor obese.

The study, published the week of June 10 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), suggests that the brain circuits that control obsessive-compulsive behavior are intertwined with circuits that control food intake and body weight. The findings have implications for treating compulsive behavior, which is associated with many forms of psychiatric disease, including obsessive-compulsive disorder (OCD), Tourette syndrome, and eating disorders.

UI neuro-psychiatrists Michael Lutter, M.D., Ph.D. and Andrew Pieper, M.D., Ph.D. led the study. The team also included researchers from Stanford University School of Medicine, University of Texas Southwestern Medical Center, Beth Israel Deaconess Medical Center, and Harvard Medical School.

Lutter, an assistant professor of psychiatry, and Pieper, an associate professor of psychiatry and neurology at the UI Carver College of Medicine, both recently arrived at the UI and use mouse models in their laboratories to study human disorders and conditions.

Pieper is interested in compulsive behavior. His mouse model of compulsivity lacks a brain protein called SAPAP3. These mice groom themselves excessively to the point of lesioning their skin, and their compulsive behavior can be effectively treated by fluoxetine, a drug that is commonly used to treat OCD in people.

Lutter works with a mouse that genetically mimics an inherited form of human obesity. This mouse lacks a brain protein known a MC4R. Mutations in the MC4R gene are the most common single-gene cause of morbid obesity and over-eating in people.

“I study MC4R signaling pathways and their involvement in the development of obesity,” Lutter explains. “I’m also interested in how these same molecules affect mood and anxiety and reward, because it’s known that there is a connection between depression and anxiety and development of obesity.”

An old study hinted that in addition to its role in food intake and obesity, MC4R might also play a role in compulsive behavior, which got Lutter and Pieper thinking of ways to test the possible interaction.

"We knew in one mouse you could stimulate excessive grooming through this MC4R pathway and in another mouse a different pathway (SAPAP3) caused compulsive grooming," Lutter says. "So, we decided to breed the two mice together to see if it would have an effect on compulsive grooming."

The experiment proved their original hypothesis—knocking out the MC4R protein in the OCD mouse normalized grooming behavior in the animals. In addition, chemically blocking MC4R in the OCD mice also eliminated compulsive grooming. The rescued behavior is mirrored by normalization of a particular pattern of brain cell communication linked to compulsive behavior.

However, the breeding experiment revealed another totally unexpected result. Loss of the SAPAP3 protein from the mice that were obese due to lack of MC4R produced mice of normal weight.

"We had this other, completely shocking finding—we completely rescued body weight and food intake in the double null mouse," Lutter says. "So, not only were we affecting the brain regions involved in grooming and behavior, but we also affected the brain regions involved in food intake and body weight."

Although obesity and obsessive-compulsive behavior may seem unrelated, Lutter suggests that the connection may be rooted in the evolutionary need to eat safe, clean food in times of a food abundance, and to lessen this drive when food is scarce.

"Food safety has been an issue through the entire course of human evolution—refrigeration is a relatively recent invention," he says. "Obsessive behavior, or fear of contamination, may be an evolutionary protection against eating rotten food."

Oils and fats have lots of calories and nutrients but they also spoil much more easily than less nutrient- and calorie-dense foods like potatoes, onions, or apples.

"I think this circuit that we have uncovered is probably involved in determining whether or not people should eat calorically dense foods," he says.

Lutter suggests that slight perturbations in this system might lead, on one hand, to disorders that link anxiety and obsessive behavior to limited food selection or intake, such as anorexia nervosa, Tourette syndrome, or OCD, and on the other hand, to obesity, where people over-consume high-fat foods and may have decreased obsessive behavior and anxiety.

“The next step will be to determine how these two pathways communicate with one another, in hopes of identifying new ways to develop drugs to treat either of these disorders,” says Pieper.

An interesting new report of animal research published in Biological Psychiatry suggests that common antidepressant medications may impair a form of learning that is important clinically.

(Photo: ALAMY)

Selective serotonin reuptake inhibitors, commonly called SSRIs, are a class of antidepressant widely used to treat depression, as well as a range of anxiety disorders, but the effects of these drugs on learning and memory are poorly understood.

In a previous study, Nesha Burghardt, then a graduate student at New York University, and her colleagues demonstrated that long-term SSRI treatment impairs fear conditioning in rats. As a follow-up, they have now tested the effects of antidepressant treatment on extinction learning in rats using auditory fear conditioning, a model of fear learning that involves the amygdala. The amygdala is a region of the brain vitally important for processing memory and emotion.

They found that long-term, but not short-term, SSRI treatment impairs extinction learning, which is the ability to learn that a conditioned stimulus no longer predicts an aversive event.

"This impairment may have important consequences clinically, since extinction-based exposure therapy is often used to treat anxiety disorders and antidepressants are often administered simultaneously," said Dr. Burghardt. "Based on our work, medication-induced impairments in extinction learning may actually disrupt the beneficial effects of exposure-therapy."

This finding is consistent with the results of several clinical studies showing that combined treatment can impede the benefits of exposure therapy or even natural resilience to the impact of traumatic stress at long-term follow-up.

The authors also suggest a mechanism for this effect on fear learning. They reported that the antidepressants decreased the levels of one of the subunits of the NMDA receptor (NR2B) in the amygdala. The NMDA receptor is critically involved in fear-related learning, so these reductions are believed to contribute to the observed effects.

Dr. John Krystal, Editor of Biological Psychiatry, commented, “We know that antidepressants play important roles in the treatment of depression and anxiety disorders. However, it is important to understand the limitations of these medications so that we can improve the effectiveness of the treatment for these disorders.”

New findings provide vital step towards exploring pain medications that may lower risks of prescription drug abuse and side effects of painkillers

For patients managing cancer and other chronic health issues, painkillers such as morphine and Vicodin are often essential for pain relief. The body’s natural tendency to develop tolerance to these medications, however, often requires patients to take higher doses – increasing risks of harmful side effects and dependency.

Now, new research from the University of Michigan Health System and a major pharmaceutical company has identified a novel approach to moderate and severe pain therapy that paves the way for lower dosage painkillers. The findings appear in Proceedings of the National Academy of Sciences of the United States of America.

Drugs such as hydrocodone (the main ingredient of Vicodin) and oxycodone (Oxycontin) are often the best options for the treatment of moderate to severe pain for patients facing medical conditions ranging from a wisdom tooth extraction to cancer. The drugs bind to specific molecules (opioid receptors) on nerve cells in the brain and spinal cord to prevent the feeling of pain.

“We have for the first time discovered compounds that bind to an alternative site on the nerve opioid receptors and that have significant potential to enhance the drug’s positive impact without increasing negative side effects,” says co-author John Traynor, Ph.D., professor of pharmacology at the U-M Medical School.

“We are still in the very early stages of this research with a long way to go, but we believe identifying these compounds is a key step in revolutionizing the treatment of pain. This opens the door to developing pain relief medications that require lower doses to be effective, helping address the serious issues of tolerance and dependence that we see with conventional pain therapy.”

Conventional drug treatments for pain work by targeting the so-called orthosteric site of the opioid receptor that provides pain relief. Targeting this site, however, is a double-edged sword because it is also responsible for all of the drug’s unwanted side effects, such as constipation and respiratory depression. Tolerance also limits chronic use of the drugs because higher doses are required to maintain the same effect.

Using cell systems and mouse brain membranes, researchers have identified compounds that bind to a physically distinct and previously unknown “allosteric” site on the opioid receptor- a site that fine-tunes the activity of the receptor. Not only do these compounds act at a location that hasn’t been studied as a drug target before but they bind to the receptor in a new way to enhance the actions of morphine – which means lower doses can have the same impact.

“The newly-discovered compounds bind to the same receptor as morphine but appear to act at a separate novel site on the receptor and therefore can produce different effects. What’s particularly exciting is that these compounds could potentially work with the body’s own natural painkillers to manage pain,” Traynor says.

“We know that conventional strong pain medications ultimately increase the risk of withdrawal symptoms and addiction, which is an especially serious issue with the current prescription drug abuse epidemic in our country. The implications of this work, if it translates to animal studies and then to humans, are highly significant to this area of study.”

In 2010, China had more people living with Alzheimer’s disease than any other country in the world – and twice as many cases of Alzheimer’s and other kinds of dementia as the World Health Organization thought.

Cases of all kinds of age-related dementia in the country rose from 3.7 million in 1990 to 9.2 million in 2010. This is the finding of the first comprehensive analysis of Chinese epidemiological research, made possible by the recent digitisation of Chinese-language research papers. Previous estimates, based on English-language papers, seem to have under-reported the number of cases by half.

"We are now only beginning to comprehend the enormous value in this ‘parallel universe’ of information," says Igor Rutan of the University of Edinburgh, UK, who was part of the team that carried out the research.

The figures are bad news for a country where 90 per cent of the elderly must be cared for by their families – old people who still have family members living are not allowed to be admitted to a nursing home – even as widespread migration to cities has disrupted the traditional family structure.

Population bulge

The findings are a reflection of China’s ageing population, and its policies.

As countries modernise, death rates fall, and later on birth rates fall as more people take up birth control. Between the two events, though, there is a “bulge” of births, the source of the modern world’s population explosion. Eventually birth and death rates roughly equalise, but the birth bulge remains as an age bulge in the population.

This reached an extreme in China, where a surge in births in the 1950s and 1960s was followed by plummeting birth rates in the 1970s, later reinforced by China’s one-child policy. “Family planning policy means China is becoming an ageing country much faster than other middle-income countries such as India,” says co-author Wei Wang of Edith Cowan University in Perth, Australia.

In its youth, the bulge underpinned China’s economic development. But by 2033, it is predicted that working-age people will be outnumbered by dependents, mostly the elderly.

The new research shows that they will need more care than China was expecting. Dementia rises in an ageing population: cases increased from 4.9 to 6.3 million in the greying European Union between 2004 and 2010.

Unhealthy lifestyle

"The rates in China are similar or even higher than rates in Europe and the US," says Wang.

And they are rising. In 1990, the team estimates, 1.8 per cent of Chinese aged 65 to 69, and 42.1 per cent aged 95 to 99, had dementia. In 2010 those figures were 2.6 and 60.5 per cent, respectively. If similar rates hold in other middle-income countries, there might be 20 per cent more cases of Alzheimer’s worldwide – five million more – than now estimated, the authors calculate.

The increase in China might reflect better diagnosis, but an urbanising lifestyle could also be causing more dementia. “Obesity, diabetes and suboptimal health contribute,” says Wang.

Martin Prince of King’s College London, who is organising another survey for dementia in China, says that if midlife obesity is a risk factor for dementia, then future rates in China could be 20 per cent higher than estimated.

Expert Panel of Physicians and Neuroscientists Announce International Guidance on Using Neurostimulation to Significantly Reduce the Need for Opioids in Chronic Pain

Recognizing that treatment of chronic pain can be confounding, the Neuromodulation Appropriateness Consensus Committee (NACC), an international group of more than 60 leading pain specialists, has created the first consensus guidelines for the use of neurostimulation in chronic pain.

Neurostimulation is an established and growing area of pain therapy that treats nerves with electrical stimulation rather than drugs. The NACC findings, announced at the International Neuromodulation Society (INS) 11th World Congress, address provider training, patient screening, and treatment recommendations.

While the extent and suffering of chronic pain is becoming better recognized, the danger of opioids for addiction, diversion or misuse is well known. Long-term opioid use can lead to the need for escalating doses to bring relief, and raises the risk of physical dependence, overdose, weight gain, depression, and immune and hormone system dysfunction.

“Many studies contain insufficient evidence to prove the safety or effectiveness of any long-term opioid regimen for chronic pain,” said study lead author Dr. Timothy Deer, INS president-elect and director of the Center for Pain Relief in Charleston, W. Va. “Indeed, many patients discontinue long-term opioid therapy due to insufficient pain relief or adverse events.”

Neurostimulation has been shown in clinical studies to be safe and effective for properly selected patients, and is approved by the FDA to treat chronic pain of the trunk and limbs. It belongs to a family of therapies known as neuromodulation because they modulate, or alter, the function of nerves, such as nerves that may have become hypersensitized or damaged, or are otherwise sending pain signals long past the initial injury. Since the components of neurostimulators bear some resemblance to heart pacemakers, they are sometimes called pain pacemakers.

The NACC recommends neurostimulation be used earlier in the treatment of some kinds of chronic pain, such as failed back surgery syndrome and complex regional pain syndrome. A study being presented at the world congress shows neurostimulation effectiveness correlates with early use in those conditions, with the added benefit of shortening the time patients spend trying other methods and containing long-term costs of managing chronic pain.

The most common form of neurostimulation, spinal cord stimulation (SCS), was introduced in 1967 and is now implanted in some 4,000 patients annually in the United States. With SCS, appropriately selected patients who have had back and/or leg pain longer than six months often find their symptoms relieved by 50 percent or more. The therapy uses slender electrical leads placed beneath the skin along the spinal cord and connected to a compact pulse generator, about the size of a pocket watch, that sends mild current along the leads to elicit a natural biological response and limit pain messages sent to the brain. Patients try the minimally invasive technique to see if it works for them before receiving a permanent implant.

“The lessons learned over the last few decades of clinical practice have influenced neurostimulator design, placement, and programming – and added new insights into spinal anatomy and pain physiology,” said INS President Dr. Simon Thomson, consultant in in pain medicine and neuromodulation at Basildon and Thurrock University NHS Trust in the United Kingdom.

Although neurostimulation devices may seem novel at first, using electrical current to limit pain dates back to antiquity, when standing on an electric fish was one remedy. Use of modern neurostimulation devices is likely to expand as the aging populace lives longer with chronic conditions, while technological refinements and clinical evidence continue to accumulate.

“A reduction in opioid use among patients treated with spinal cord stimulation was shown in a several studies, notably a 2005 randomized controlled clinical trial led by Dr. Richard North under the auspices of the Johns Hopkins University School of Medicine,” commented INS Secretary and study co-author Dr. Marc Russo, director of the Hunter Pain Clinic in New South Wales, Australia. “Broad-based studies show that within two years, using spinal cord stimulation rather than repeat back surgery is not only a more cost-effective use of health resources, it also is correlated with higher rates of return to work.”

Consensus committee authors believe that when appropriately applied, neurostimulation to target treatment directly to nerves can improve productivity and quality of life for chronic pain patients, offering a potentially less costly and risky option than repeat surgery or long-term painkiller use. They recommend:

• Neuromodulation providers receive at least 12 hours of continuing medical education per year directly related to improving outcomes with neuromodulation, with additional mentoring by a credentialed provider at a hospital officially accredited by the Joint Commission on Accreditation of Healthcare Organizations or its equivalent.

• Spinal cord stimulation should be used early in the treatment of failed back surgery syndrome as long as there is no progression of a neurological condition requiring semi-urgent intervention.

• Patient selection decisions should be made with any clinicians who are treating co-existing conditions, who may include the patient’s primary care provider, cardiologist, or neurologist.

• Due to the emotional impact of the experience of pain, an assessment of a psychologist or psychiatrist is recommended within the first year of implant.

• Spinal cord stimulation and peripheral nerve stimulation should be considered earlier, when possible, and are recommended to be trialed in the first two years of chronic pain.

• Peripheral nerve stimulation (beyond the spine) should be reserved for patients in whom the pain distribution is primarily in a named nerve that is known to connect the area of pain. Temporary relief of the patients’ pain by an injection of local anesthetic in the nerve distribution should be seen as an encouraging sign for the use of this therapy.

• To cover an area that is not located in the distribution of a named peripheral nerve, stimulation of a peripheral nerve field with electrodes placed in the subcutaneous area just beneath the skin may give relief if stimulation from SCS does not reach this area. In many cases a hybrid of two or more of these methods may present the best chance of an acceptable outcome.

• SCS should be used as an early intervention in patients with Raynaud’s syndrome and other painful ischemic vascular disorders, which involve insufficient blood supply to part of the body. If ischemic symptoms persist despite initial surgical or reasonable medical treatment, SCS should be trialed.

• In the use of spinal cord stimulation to treat painful diabetic peripheral neuropathy, decision-making should be performed on an individualized basis, considering current diagnoses and other factors. A type of SCS that stimulates a structure at the edge of the spinal column, the dorsal root ganglion, may be most suited for this disorder.