Neuroscience

July 27, 2012 

(Medical Xpress) — Johns Hopkins scientists have discovered a “scaffolding” protein that holds together multiple elements in a complex system responsible for regulating pain, mental illnesses and other complex neurological problems.

Preso1 (green) and mGluR5 (red) appear in the same location inside a neuron.

The finding, published in the May 6 issue of Nature Neuroscience, could give researchers a new target for drugs to treat these often-intractable conditions.

The discovery, detailed in a study led by neuroscience professor Paul Worley, M.D., of the Johns Hopkins University School of Medicine, focuses on a family of proteins called group 1 metabotropic glutamate receptors (mGluRs) that lie on the surfaces of nerve cells. When these receptors lock in glutamate, a chemical that neurons use to communicate, it encourages neurons to fire.

Without a way to turn off these receptors, neurons would remain active indefinitely, keeping pain and other responses going long after they’re useful. Previous research suggested that these mGluRs need to bind to another protein called Homer to shut down, and that this binding is stronger after other molecules called protein kinases modify the receptors. However, Worley explains, thus far it’s been unclear exactly how all these different players come together.

Seeking the mechanism behind this phenomenon, Worley and his colleagues started with a series of experiments to see what other proteins the mGluRs and Homer were binding with in rat brains. Their search turned up a third protein called Preso1, which bound to both mGluRs and Homer. A search in genetic databases shows that the gene responsible for making Preso1 is present in animals ranging from fruit flies to people, highlighting its importance in a wide variety of creatures.

To figure out what Preso1 does, the researchers performed another series of experiments to examine behavior of neurons that produced both mGluRs and Homer. They found that when these neurons also expressed Preso1, the mGluRs bound Homer more efficiently, suggesting that Preso1 might somehow increase modification by protein kinases.

Worley’s team received another clue when they found that protein kinases also bind to Preso1.

Genetically modifying mice so that they don’t make any Preso1, the researchers found that binding between mGluRs and Homer in these animals’ neurons was greatly reduced compared to normal mice.

Additionally, when the researchers injected the modified mice with a chemical that causes pain and inflammation, the animals had a significantly greater and longer-lasting response compared to regular mice. A final experiment showed that neurons taken from the modified animals were significantly more responsive to the neurotransmitter glutamate. When the researchers added Preso1 to the cell cultures, this increased activity disappeared, suggesting that Preso1 is pivotal for mGluRs to signal properly.

Taken together, Worley explains, the findings suggest that Preso1 appears to gather all the important elements in this system — Homer, protein kinases and mGluRs — bringing them all together to coordinate the activation and deactivation of the mGluRs.

With Preso1 so pivotal for regulating group 1 mGluR activity, it could prove a useful new target for drugs to treat a variety of health problems in which these receptors are thought to play a role, including chronic pain, schizophrenia, Alzheimer’s disease, and fragile X syndrome, Worley says.

"Because mGluRs play so many important roles in the brain for so many different mental and neurological health conditions, knowledge of their regulatory mechanisms is extremely important. But we really don’t know how they work in great detail," he says. "You need to know all the players before you can understand the system. Here, we’ve identified an important player that no one had previously known had existed. Preso1 and Homer appear essential for desensitization of mGluR signaling, much like beta-adrenergic receptor kinase and arrestin are important for desensitization of adrenergic and opiate receptors."

Provided by Johns Hopkins University

Source: medicalxpress.com

July 27, 2012

Anyone that has ever had trouble sleeping can attest to the difficulties at work the following day. Experts recommend eight hours of sleep per night for ideal health and productivity, but what if five to six hours of sleep is your norm? Is your work still negatively affected? A team of researchers at Brigham and Women’s Hospital (BWH) have discovered that regardless of how tired you perceive yourself to be, that lack of sleep can influence the way you perform certain tasks.

This finding is published in the July 26, 2012 online edition of The Journal of Vision.

"Our team decided to look at how sleep might affect complex visual search tasks, because they are common in safety-sensitive activities, such as air-traffic control, baggage screening, and monitoring power plant operations," explained Jeanne F. Duffy, PhD, MBA, senior author on this study and associate neuroscientist at BWH. "These types of jobs involve processes that require repeated, quick memory encoding and retrieval of visual information, in combination with decision making about the information."

Researchers collected and analyzed data from visual search tasks from 12 participants over a one month study. In the first week, all participants were scheduled to sleep 10-12 hours per night to make sure they were well-rested. For the following three weeks, the participants were scheduled to sleep the equivalent of 5.6 hours per night, and also had their sleep times scheduled on a 28-hour cycle, mirroring chronic jet lag. The research team gave the participants computer tests that involved visual search tasks and recorded how quickly the participants could find important information, and also how accurate they were in identifying it. The researchers report that the longer the participants were awake, the more slowly they identified the important information in the test. Additionally, during the biological night time, 12 a.m. -6 a.m., participants (who were unaware of the time throughout the study) also performed the tasks more slowly than they did during the daytime.

"This research provides valuable information for workers, and their employers, who perform these types of visual search tasks during the night shift, because they will do it much more slowly than when they are working during the day," said Duffy. "The longer someone is awake, the more the ability to perform a task, in this case a visual search, is hindered, and this impact of being awake is even stronger at night."

While the accuracy of the participants stayed the fairly constant, they were slower to identify the relevant information as the weeks went on. The self-ratings of sleepiness only got slightly worse during the second and third weeks on the study schedule, yet the data show that they were performing the visual search tasks significantly slower than in the first week. This finding suggests that someone’s perceptions of how tired they are do not always match their performance ability, explains Duffy.

Provided by Brigham and Women’s Hospital

Source: medicalxpress.com

July 26, 2012 By Mark Wheeler

UCLA researchers say blocking this molecule may improve and speed recovery

FINDINGS:

Researchers at UCLA have identified a novel molecule in the brain that, after stroke, blocks the formation of new connections between neurons. As a result, it limits the brain’s recovery. In a mouse model, the researchers showed that blocking this molecule—called ephrin-A5—induces axonal sprouting, that is, the growth of new connections between the brain’s neurons, or cells, and as a result promotes functional recovery.

IMPACT:

If duplicated in humans, the identification of this molecule could pave the way for a more rapid recovery from stroke and may allow a synergy with existing treatments, such as physical therapy.

UCLA AUTHOR:

Dr. S. Thomas Carmichael, professor of neurology, and colleagues

JOURNAL:       

The research appears online this week in the journal PNAS.

MORE:

Stroke is the leading cause of adult disability because of the brain’s limited capacity for repair. An important process in recovery after stroke may be in the formation of new connections, termed axonal sprouting. The adult brain inhibits axonal sprouting and the formation of these connections. In previous work the researchers found, paradoxically, that the brain sends mixed signals after a stroke—activating molecules that both stimulate and inhibit axonal sprouting. In this present work, the researchers have identified the effect of one molecule that inhibits axonal sprouting and determined the new connections in the brain that are necessary to form for recovery.

The researchers also developed a new tissue bioengineering approach for delivering drugs to the brain after stroke. This approach uses a biopolymer hydrogel, or a gel of naturally occurring brain proteins, to release neural repair molecules directly to the target region for recovery in stroke—the tissue adjacent  to the center of the stroke.

Last, the paper also shows that the more behavioral activity after stroke, such as the amount an impaired limb is used, the more new connections are directly stimulated to form in the injured brain.  This direct link between movement patterns, like those that occur in neurorehabilitation, and the formation of new brain connections, provides a biological mechanism for the effects of some forms of physical therapy after stroke.

Source: UCLA

July 26, 2012

Excitation of neurons depends on the selected influx of certain ions, namely sodium, calcium and potassium through specific channels. Obviously, these channels were crucial for the evolution of nervous systems in animals. How such channels could have evolved their selectivity has been a puzzle until now. Yehu Moran and Ulrich Technau from the University of Vienna together with Scientists from Tel Aviv University and the Woods Hole Oceanographic Institution (USA) have now revealed that voltage-gated sodium channels, which are responsible for neuronal signaling in the nerves of animals, evolved twice in higher and lower animals. These results were published in Cell Reports.

Close-up of nervous system of a transgenic polyp of the sea anemone Nematostella vectensis, in which a red fluorescent reporter gene (mCherry) is driven by the regulatory sequence of the neuronal ELAV gene. The picture shows the diffuse structure of the nervous system, but also reveals the accumulation of longitudinal axonal tracts along the eight gastric tissue folds (mesenteries). Credit: Copyright: U. Technau

The opening and closing of ion channels enable flow of ions that constitute the electrical signaling in all nervous systems. Every thought we have or every move we make is the result of the highly accurate opening and closing of numerous ion channels. Whereas the channels of most lower animals and their unicellular relatives cannot discern between sodium and calcium ions, those of higher animals are highly specific for sodium, a characteristic that is important for fast and accurate signaling in complex nervous system.

Surprising results in sea anemones and jellyfish

However, the researchers found that a group of basal animals with simple nerve nets including sea anemones and jellyfish also possess voltage-gated sodium channels, which differ from those found in higher animals, yet show the same selectivity for sodium. Since cnidarians separated from the rest of the animals more than 600 million years ago, these findings suggest that the channels of both cnidarians and higher animals originated independently twice, from ancient non-selective channels which also transmit calcium.

Since many other processes of internal cell signaling are highly dependent on calcium ions, the use of non-selective ion channels in neurons would accidently trigger various signaling systems inside the cells and will cause damage. The evolution of selectivity for sodium ions is therefore considered as an important step in the evolution of nervous systems with fast transmission. This study shows that different parts of the channel changed in a convergent manner during the evolution of cnidarians and higher animals in order to perform the same task, namely to select for sodium ions.

This demonstrates that important components for the functional nervous systems evolved twice in basal and higher animals, which suggests that more complex nervous systems that rely on such ion-selective channels could have also evolved twice independently.

Source: PHYS.ORG

ScienceDaily (July 26, 2012) — In one of the first studies to look at transcranial magnetic stimulation (TMS) in real-world clinical practice settings, researchers at Butler Hospital, along with colleagues across the U.S., confirmed that TMS is an effective treatment for patients with depression who are unable to find symptom relief through antidepressant medications. The study findings are published online in the June 11, 2012 edition of Depression and Anxiety in the Wiley Online Library.

(Credit: Butler Hospital)

Previous analysis of the efficacy of TMS has been provided through more than 30 published trials, yielding generally consistent results supporting the use of TMS to treat depression when medications aren’t sufficient. “Those previous studies were key in laying the groundwork for the FDA to approve the first device for delivery of TMS as a treatment for depression in 2008,” said Linda Carpenter, MD, lead author of the report and chief of the Mood Disorders Program and the Neuromodulation Clinic at Butler Hospital. “Naturalistic studies like ours, which provide scrutiny of real-life patient outcomes when TMS therapy is given in actual clinical practice settings, are the next step in further understanding the effectiveness of TMS. They are also important for informing healthcare policy, particularly in an era when difficult decisions must be made about allocation of scarce resources.”

Carpenter explains that naturalistic studies differ from controlled clinical trials because they permit the inclusion of subjects with a wider range of symptomatology and comorbidity, whereas controlled clinical trials typically have more rigid criteria for inclusion. “As a multisite study collecting naturalistic outcomes from patients in clinics in various regions in the U.S., we were also able to capture effects that might arise from introducing a novel psychiatric treatment modality like TMS in non-research settings,” said Carpenter. In all, the study confirms how well TMS works in diverse settings where TMS is administered to a real-life population of patients with depression that have not found relief through many other available treatments.

The published report summarized data collected from 42 clinical TMS practice sites in the US, and included outcomes from 307 patients with Major Depressive Disorder (MDD) who had persistent symptoms despite the use of antidepressant medication. Change during TMS was assessed using both clinicians’ ratings of overall depression severity and scores on patient self-report depression scales, which require the patient to rate the severity of each symptom on the same standardized scale at the end of each 2-week period. Rates for “response” and “remission” to TMS were calculated based on the same cut-off scores and conventions used for other clinical trials of antidepressant treatments. Fifty-eight percent positive response rate to TMS and 37 percent remission rate were observed.

"The patient outcomes we found in this study demonstrated a response rate similar to controlled clinical trial populations," said Dr. Carpenter, explaining that this new data validates TMS efficacy in treating depression for those who have failed to benefit from antidepressant medications. "Continued research and confirmation of the effectiveness of TMS is important for understanding its place in everyday psychiatric care and to support advocacy for insurance coverage of the treatment." Thanks in part to the advocacy efforts of Dr. Carpenter, TMS was recently approved for coverage by Medicare in New England, and it is also now covered by BCBSRI. "Next steps for TMS research involve enhancing our understanding of how to maintain positive response to TMS over time after the course of therapy ends and learning how to customize the treatment for patients using newer technologies, so TMS can help even more patients."

Source: Science Daily

ScienceDaily (July 26, 2012) — Researchers reporting online on July 26 in Current Biology, a Cell Press publication, have for the first time shown that they can control the behavior of monkeys by using pulses of blue light to very specifically activate particular brain cells. The findings represent a key advance for optogenetics, a state-of-the-art method for making causal connections between brain activity and behavior. Based on the discovery, the researchers say that similar light-based mind control could likely also be made to work in humans for therapeutic ends.

(Credit: © Eric Isselée / Fotolia)

"We are the first to show that optogenetics can alter the behavior of monkeys," says Wim Vanduffel of Massachusetts General Hospital and KU Leuven Medical School. "This opens the door to use of optogenetics at a large scale in primate research and to start developing optogenetic-based therapies for humans."

In optogenetics, neurons are made to respond to light through the insertion of light-sensitive genes derived from particular microbial organisms. Earlier studies had primarily validated this method for use in invertebrates and rodents, with only a few studies showing that optogenetics can alter activity in monkey brains on a fine scale.

In the new study, the researchers focused on neurons that control particular eye movements. Using optogenetics together with functional magnetic resonance imaging (fMRI), they showed that they could use light to activate these neurons, generating brain activity and subtle changes in eye-movement behavior.

The researchers also found that optogenetic stimulation of their focal brain region produced changes in the activity of specific neural networks located at some distance from the primary site of light activation.

The findings not only pave the way for a much more detailed understanding of how different parts of the brain control behavior, but they may also have important clinical applications in treating Parkinson’s disease, addiction, depression, obsessive-compulsive disorder, and other neurological conditions.

"Several neurological disorders can be attributed to the malfunctioning of specific cell types in very specific brain regions," Vanduffel says. "As already suggested by one of the leading researchers in optogenetics, Karl Deisseroth from Stanford University, it is important to identify the underlying neuronal circuits and the precise nature of the aberrations that lead to the neurological disorders and potentially to manipulate those malfunctioning circuits with high precision to restore them. The beauty of optogenetics is that, unlike any other method, one can affect the activity of very specific cell types, leaving others untouched."

Source: Science Daily

ScienceDaily (July 25, 2012) — A team of University of California, Berkeley, scientists in collaboration with researchers at the University of Munich and University of Washington, in Seattle, has discovered a chemical that temporarily restores some vision to blind mice, and is working on an improved compound that may someday allow people with degenerative blindness to see again.

Mice with a genetic disease that causes blindness regained some sight after injection with a chemical “photoswitch.” The eye of the untreated mouse on the left shows no response to light, while the pupil of the mouse on the right, which was injected with the chemical, contracts in light. (Credit: Image courtesy of University of California - Berkeley)

The approach could eventually help those with retinitis pigmentosa, a genetic disease that is the most common inherited form of blindness, as well as age-related macular degeneration, the most common cause of acquired blindness in the developed world. In both diseases, the light sensitive cells in the retina — the rods and cones — die, leaving the eye without functional photoreceptors.

The chemical, called AAQ, acts by making the remaining, normally “blind” cells in the retina sensitive to light, said lead researcher Richard Kramer, UC Berkeley professor of molecular and cell biology. AAQ is a photoswitch that binds to protein ion channels on the surface of retinal cells. When switched on by light, AAQ alters the flow of ions through the channels and activates these neurons much the way rods and cones are activated by light.

"This is similar to the way local anesthetics work: they embed themselves in ion channels and stick around for a long time, so that you stay numb for a long time," Kramer said. "Our molecule is different in that it’s light sensitive, so you can turn it on and off and turn on or off neural activity."

Because the chemical eventually wears off, it may offer a safer alternative to other experimental approaches for restoring sight, such as gene or stem cell therapies, which permanently change the retina. It is also less invasive than implanting light-sensitive electronic chips in the eye.

"The advantage of this approach is that it is a simple chemical, which means that you can change the dosage, you can use it in combination with other therapies, or you can discontinue the therapy if you don’t like the results. As improved chemicals become available, you could offer them to patients. You can’t do that when you surgically implant a chip or after you genetically modify somebody," Kramer said.

"This is a major advance in the field of vision restoration," said co-author Dr. Russell Van Gelder, an ophthalmologist and chair of the Department of Ophthalmology at the University of Washington, Seattle.

Kramer, Van Gelder, chemist Dirk Trauner and their colleagues at UC Berkeley, the University of Washington, Seattle, and the University of Munich will publish their findings on July 26, in the journal Neuron.

The blind mice in the experiment had genetic mutations that made their rods and cones die within months of birth and inactivated other photopigments in the eye. After injecting very small amounts of AAQ into the eyes of the blind mice, Kramer and his colleagues confirmed that they had restored light sensitivity because the mice’s pupils contracted in bright light, and the mice showed light avoidance, a typical rodent behavior impossible without the animals being able to see some light. Kramer is hoping to conduct more sophisticated vision tests in rodents injected with the next generation of the compound.

"The photoswitch approach offers real hope to patients with retinal degeneration," Van Gelder said. "We still need to show that these compounds are safe and will work in people the way they work in mice, but these results demonstrate that this class of compound restores light sensitivity to retinas blind from genetic disease."

From optogenetics to implanted chips

The current technologies being evaluated for restoring sight to people whose rods and cones have died include injection of stem cells to regenerate the rods and cones; “optogenetics,” that is, gene therapy to insert a photoreceptor gene into blind neurons to make them sensitive to light; and installation of electronic prosthetic devices, such as a small light-sensitive retinal chip with electrodes that stimulate blind neurons. Several dozen people already have retinal implants and have had rudimentary, low vision restored, Kramer said.

Eight years ago, Kramer, Trauner, a former UC Berkeley chemist now at the University of Munich, and their colleagues developed an optogenetic technique to chemically alter potassium ion channels in blind neurons so that a photoswitch could latch on. Potassium channels normally open to turn a cell off, but with the attached photoswitch, they were opened when hit by ultraviolet light and closed when hit by green light, thereby activating and deactivating the neurons.

Subsequently, Trauner synthesized AAQ (acrylamide-azobenzene-quaternary ammonium), a photoswitch that attaches to potassium channels without the need to genetically modify the channel. Tests of this compound are reported in the current Neuron paper.

New versions of AAQ now being tested are better, Kramer said. They activate neurons for days rather than hours using blue-green light of moderate intensity, and these photoswitches naturally deactivate in darkness, so that a second color of light is not needed to switch them off.

"This is what we are really excited about," he said.

Source: Science Daily

ScienceDaily (July 25, 2012) — A new gene therapy approach can reverse hearing loss caused by a genetic defect in a mouse model of congenital deafness, according to a preclinical study published by Cell Press in the July 26 issue of the journal Neuron. The findings present a promising therapeutic avenue for potentially treating individuals who are born deaf.

(Credit: © Vasiliy Koval / Fotolia)

"This is the first time that an inherited, genetic hearing loss has been successfully treated in laboratory mice, and as such represents an important milestone for treating genetic deafness in humans," says senior study author Lawrence Lustig of the University of California, San Francisco.

Hearing loss is one of the most common human sensory deficits, and it results from damage to hair cells in the inner ear. About half of the cases of congenital hearing loss are caused by genetic defects. However, the current treatment options — hearing amplification devices and cochlear implants — do not restore hearing to normal levels. Correcting the underlying genetic defects has the potential to fully restore hearing, but previous attempts to reverse hearing loss caused by genetic mutations have not been successful.

Addressing this challenge in the new study, Lustig and his team used mice with hereditary deafness caused by a mutation in a gene coding for a protein called vesicular glutamate transporter-3 (VGLUT3). This protein is crucial for inner hair cells to send signals that enable hearing. Two weeks after the researchers delivered the VGLUT3 gene into the inner ear through an injection, hearing was restored in all of the mice. This improvement lasted between seven weeks and one and a half years when adult mice were treated, and at least nine months when newborn mice received the treatment.

The therapy did not damage the inner ear, and it even corrected some structural defects in the inner hair cells. Because the specific gene delivery method used is safe and effective in animals, the findings hold promise for future human studies. “For years, scientists have been hinting at the possibility of gene therapy as a potential cure for deafness,” Lustig says. “In this study, we now provide a very real and big step towards that goal.”

Source: Science Daily

July 25, 2012

Raising levels of the neurotransmitter dopamine in the frontal cortex of the brain significantly decreased impulsivity in healthy adults, in a study conducted by researchers at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco.

"Impulsivity is a risk factor for addiction to many substances, and it has been suggested that people with lower dopamine levels in the frontal cortex tend to be more impulsive," said lead author Andrew Kayser, PhD, an investigator at Gallo and an assistant professor of neurology at UCSF. "We wanted to see if we could decrease impulsivity by raising dopamine, and it seems as if we can."

The study was published on July 4 in the Journal of Neuroscience.

In a double-blinded, placebo-controlled study, 23 adult research participants were given either tolcapone, a medication approved by the Food and Drug Administration (FDA) that inhibits a dopamine-degrading enzyme, or a placebo. The researchers then gave the participants a task that measured impulsivity, asking them to make a hypothetical choice between receiving a smaller amount of money immediately (“smaller sooner”) or a larger amount at a later time (“larger later”). Each participant was tested twice, once with tolcapone and once with placebo.

Participants – especially those who were more impulsive at baseline – were more likely to choose the less impulsive “larger later” option after taking tolcapone than they were after taking the placebo.

Magnetic resonance imaging conducted while the participants were taking the test confirmed that regions of the frontal cortex associated with decision-making were more active in the presence of tolcapone than in the presence of placebo.

"To our knowledge, this is the first study to use tolcapone to look for an effect on impulsivity," said Kayser.

The study was not designed to investigate the reasons that reduced dopamine is linked with impulsivity. However, explained Kayser, scientists believe that impulsivity is associated with an imbalance in dopamine between the frontal cortex, which governs executive functions such as cognitive control and self-regulation, and the striatum, which is thought to be involved in the planning and modification of more habitual behaviors.

"Most, if not all, drugs of abuse, such as cocaine and amphetamine, directly or indirectly involve the dopamine system," said Kayser. "They tend to increase dopamine in the striatum, which in turn may reward impulsive behavior. In a very simplistic fashion, the striatum is saying ‘go,’ and the frontal cortex is saying ‘stop.’ If you take cocaine, you’re increasing the ‘go’ signal, and the ‘stop’ signal is not adequate to counteract it."

Kayser and his research team plan a follow-up study of the effects of tolcapone on drinking behavior. “Once we determine whether drinkers can safely tolerate this medication, we will see if it has any effect on how much they drink while they’re taking it,” said Kayser.

Tolcapone is approved as a medication for Parkinson’s disease, in which a chronic deficit of dopamine inhibits movement.

Provided by University of California, San Francisco

Source: medicalxpress.com

July 25, 2012

Cognition psychologists at the Ruhr-Universität together with colleagues from the University Hospital Bergmannsheil (Prof. Dr. Martin Tegenthoff) have discovered why stressed persons are more likely to lapse back into habits than to behave goal-directed. The team of PD Dr. Lars Schwabe and Prof. Dr. Oliver Wolf from the Institute for Cognitive Neuroscience have mimicked a stress situation in the body using drugs. They then examined the brain activity using functional MRI scanning. The researchers have now reported in the Journal of Neuroscience that the interaction of the stress hormones hydrocortisone and noradrenaline shut down the activity of brain regions for goal-directed behaviour. The brain regions responsible for habitual behaviour remained unaffected.

In order to test the different stress hormones, the cognition psychologists used three substances - a placebo, the stress hormone hydrocortisone and yohimbine, which ensures that the stress hormone noradrenaline stays active longer. Part of the volunteers received hydrocortisone alone or just yohimbine, others both substances. A fourth group were administered a placebo. Altogether, the data of 69 volunteers was included in the study.

In the experiment, all participants - both male and female - learned that they would receive cocoa or orange juice as a reward if they chose certain symbols on the computer. After this learning phase, volunteers were allowed to eat as many oranges or as much chocolate pudding as they liked. “That weakens the value of the reward”, explained Schwabe. “Whoever eats chocolate pudding will lose the attraction to cocoa. Whoever is satiated with oranges, has less appetite for orange juice.” In this context, goal-directed behaviour means: Whoever has previously eaten the chocolate pudding, chooses the symbols leading to cocoa reward less frequently. Whoever is satiated with oranges, selects less frequently the symbols associated with orange juice. Based on previous results, the scientists assumed that only the combination of yohimbine and hydrocortisone attenuates goal-directed behaviour. They have now confirmed this hypothesis.

As expected, volunteers who took yohimbine and hydrocortisone did not behave goal-directed but according to habit. In other words, satiation with oranges or chocolate pudding had no effect. Persons who had taken a placebo or only one medication, on the other hand, behaved goal-directed and showed a satiating effect. The brain data revealed: The combination of yohimbine and hydrocortisone reduced the activity in the forebrain – in the so-called orbitofrontal and medial prefrontal cortex. These areas have been already previously associated with goal-directed behaviour. The brain regions which are important for habitual learning, on the other hand, were similarly active for all volunteers.

Provided by Ruhr-Universitaet-Bochum

Source: medicalxpress.com

July 25, 2012

(Medical Xpress) — New understanding of how the brain processes information from inner ear offers hope for sufferers of vertigo.

If you have ever looked over the edge of a cliff and felt dizzy, you understand the challenges faced by people who suffer from symptoms of vestibular dysfunction such as vertigo and dizziness. There are over 70 million of them in North America. For people with vestibular loss, performing basic daily living activities that we take for granted (e.g. dressing, eating, getting in and out of bed, getting around inside as well as outside the home) becomes difficult since even small head movements are accompanied by dizziness and the risk of falling.

We’ve known for a while that a sensory system in the inner ear (the vestibular system) is responsible for helping us keep our balance by giving us a stable visual field as we move around. And while researchers have already developed a basic understanding of how the brain constructs our perceptions of ourselves in motion, until now no one has understood the crucial step by which the neurons in the brain select the information needed to keep us in balance.

The way that the brain takes in and decodes information sent by neurons in the inner ear is complex. The peripheral vestibular sensory neurons in the inner ear take in the time varying acceleration and velocity stimuli caused by our movement in the outside world (such as those experienced while riding in a car that moves from a stationary position to 50 km per hour). These neurons transmit detailed information about these stimuli to the brain (i.e. information that allows one to reconstruct how these stimuli vary over time) in the form of nerve impulses.

Scientists had previously believed that the brain decoded this information linearly and therefore actually attempted to reconstruct the time course of velocity and acceleration stimuli. But by combining electrophysiological and computational approaches, Kathleen Cullen and Maurice Chacron, two professors in McGill University’s Department of Physiology, have been able to show for the first time that the neurons in the vestibular nuclei in the brain instead decode incoming information nonlinearly as they respond preferentially to unexpected, sudden changes in stimuli.

It is known that representations of the outside world change at each stage in this sensory pathway. For example, in the visual system neurons located closer to the periphery of the sensory system (e.g. ganglion cells in the retina) tend to respond to a wide range of sensory stimuli (a “dense” code), whereas central neurons (e.g. in the primary visual cortex at the back of the head tend to respond much more selectively (a “sparse” code). Chacron and Cullen have discovered that the selective transmission of vestibular information they were able to document for the first time occurs as early as the first synapse in the brain. “We were able to show that the brain has developed this very sophisticated computational strategy to represent sudden changes in movement in order to generate quick accurate responses and maintain balance,” explained Prof. Cullen. “I keep describing it as elegant, because that’s really how it strikes me.”

This kind of selectivity in response is important for everyday life, since it enhances the brain’s perception of sudden changes in body posture. So that if you step off an unseen curb, within milliseconds, your brain has both received the essential information and performed the sophisticated computation needed to help you readjust your position. This discovery is expected to apply to other sensory systems and eventually to the development of better treatments for patients who suffer from vertigo, dizziness, and disorientation during their daily activities. It should also lead to treatments that will help alleviate the symptoms that accompany motion and/or space sickness produced in more challenging environments.

Provided by McGill University

Source: medicalxpress.com

July 25, 2012

(HealthDay) — Shortened telomere length (TL) is associated with risks for dementia and mortality in a population of older adults, according to a study published online July 23 in the Archives of Neurology.

Lawrence S. Honig, M.D., Ph.D., from the Columbia University College of Physicians and Surgeons in New York City, and colleagues used real-time polymerase chain reaction analysis to determine TL in stored leukocyte DNA from 1,983 participants in a community-based study of aging. Participants were 65 years or older and blood was drawn at a mean age of 78.3 years. Participants were followed for a median of 9.3 years for mortality, and 9.6 percent developed incident dementia.

The researchers found that TL correlated inversely with age and was shorter in men than women. TL was significantly shorter in persons dying during follow-up compared with survivors, even after adjusting for age, sex, education, and apolipoprotein E genotype. TL was significantly shorter in the participants with incident and prevalent dementia, compared with those who remained dementia-free. Shorter TL correlated with earlier onset of dementia but this association was significant in women only.

"Our results show an association between shortened TL and mortality, and more specifically an association of shortened TL with Alzheimer’s disease, and are consistent with but not indicative of the possibility that TL may be a factor indicative of biological age," the authors conclude.

Source: medicalxpress.com

July 25, 2012

(Medical Xpress) — Many people, whether they know it or not, are philosophical dualists. That is, they believe that the brain and the mind are two separate entities. Despite the fact dualist beliefs are found in virtually all human cultures, surprisingly little is known about the impact of these beliefs on how we think and behave in everyday life.

But a new research article forthcoming in Psychological Science, a journal of the Association for Psychological Science, suggests that espousing a dualist philosophy can have important real-life consequences.

Across five related studies, researchers Matthias Forstmann, Pascal Burgmer, and Thomas Mussweiler of the University of Cologne, Germany, found that people primed with dualist beliefs had more reckless attitudes toward health and exercise, and also preferred (and ate) a less healthy diet than those who were primed with physicalist beliefs.

Furthermore, they found that the relationship also worked in the other direction. People who were primed with unhealthy behaviors – such as pictures of unhealthy food – reported a stronger dualistic belief than participants who were primed with healthy behaviors.

Overall, the findings from the five studies provide converging evidence demonstrating that mind-body dualism has a noticeable impact on people’s health-related attitudes and behaviors. Specifically, these findings suggest that dualistic beliefs decrease the likelihood of engaging in healthy behavior.

These findings support the researchers’ original hypothesis that the more people perceive their minds and bodies to be distinct entities, the less likely they will be to engage in behaviors that protect their bodies. Bodies are ultimately viewed as a disposable vessel that helps the mind interact with the physical world.

Evidence of a bidirectional relationship further suggests that metaphysical beliefs, such as beliefs in mind-body dualism, may serve as cognitive tools for coping with threatening or harmful situations.

The fact that the simple priming procedures used in the studies had an immediate impact on health-related attitudes and behavior suggests that these procedures may eventually have profound implications for real-life problems. Interventions that reduce dualistic beliefs through priming could be one way to help promote healthier – or less self-damaging – behaviors in at-risk populations.

Provided by Association for Psychological Science

Source: medicalxpress.com

New research suggests that patients whose mobility has been limited by stroke may one day use their imagination and a computer link to move their hands.

Leuthardt

In patients, scientists at Washington University School of Medicine in St. Louis have shown they can detect the brain simply thinking about moving a partially or completely paralyzed hand. The half of the brain that normally thinks such thoughts and moves the hand can no longer do so because of stroke damage. Instead, the signal comes from the undamaged half of the brain.

The new study suggests it may be possible to harness these signals to restore a fuller range of movement in the patient’s limbs.

“We’ve known for some time that the brain can reroute or otherwise adapt its circuits to cope with an injury,” says senior author Eric Leuthardt, MD, associate professor of neurosurgery, of biomedical engineering and of neurobiology. “Now we have proof-of-principle that we can use technology to aid that process.”

To demonstrate the potential to help restore movement, scientists connected brain signals detected by an electrode-studded cap to the movements of a cursor on a computer screen. In 30 minutes or less, patients learned to control the movement of the cursor with thoughts of moving their impaired hand. Researchers are now working on a motorized glove that will make the imagined movements a reality.

The results are available online in The Journal of Neural Engineering.

Leuthardt, who is director of Washington University’s Center for Innovation in Neuroscience and Technology, is a pioneer in the field of brain-computer interfaces, or devices that allow the brain to communicate directly with computers to restore abilities lost to injury or disease.

Much of Leuthardt’s research has focused on patients with epilepsy who are undergoing surgery to remove the part of the brain where their seizures originate. He uses the electrode grids temporarily implanted on the surface of the brain to pinpoint areas where the seizures begin. With the patients’ permissions, Leuthardt also uses the implants to gather and analyze detailed information on brain activity for future use in brain-computer interfaces. This approach laid the foundations for the technique now being applied to the stroke population. 

In the new research, first author David Bundy, a graduate student, worked with four patients who had suffered strokes that caused extensive damage on one side of the brain. All were experiencing paralysis or significant difficulty moving the hand on the opposite side of the body.

The brain signals that control movement are low-frequency signals, which makes them relatively easy to detect with electrodes on the outside of the skull. Researchers fitted patients with an electrode-studded cap connected to a computer, and asked them to perform a finger-tapping activity. Depending on a cue flashed on a screen in front of them, the patients either tapped the fingers of their unimpaired hand or imagined tapping the fingers of the impaired hand. Scientists used the cap to identify signals in healthy part of the brain that accompanied the imaginary movements.

The researchers are now developing motorized braces that can be controlled by similar signals, with the goal of restoring full movement in weak or paralyzed limbs.

“This is an exciting development that opens up new opportunities to help even more patients overcome limitations imposed by brain damage or degeneration,” Leuthardt says.

Source: Washington University in St. Louis

July 24, 2012

A new class of drug developed at Northwestern University Feinberg School of Medicine shows early promise of being a one-size-fits-all therapy for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and traumatic brain injury by reducing inflammation in the brain.

Northwestern has recently been issued patents to cover this new drug class and has licensed the commercial development to a biotech company that has recently completed the first human Phase 1 clinical trial for the drug.

The drugs in this class target a particular type of brain inflammation, which is a common denominator in these neurological diseases and in traumatic brain injury and stroke. This brain inflammation, also called neuroinflammation, is increasingly believed to play a major role in the progressive damage characteristic of these chronic diseases and brain injuries.

By addressing brain inflammation, the new class of drugs — represented by MW151 and MW189 — offers an entirely different therapeutic approach to Alzheimer’s than current ones being tested to prevent the development of beta amyloid plaques in the brain. The plaques are an indicator of the disease but not a proven cause.

A new preclinical study published today in the Journal of Neuroscience, reports that when one of the new Northwestern drugs is given to a mouse genetically engineered to develop Alzheimer’s, it prevents the development of the full-blown disease. The study, from Northwestern’s Feinberg School and the University of Kentucky, identifies the optimal therapeutic time window for administering the drug, which is taken orally and easily crosses the blood-brain barrier.

"This could become part of a collection of drugs you could use to prevent the development of Alzheimer’s," said D. Martin Watterson, a professor of molecular pharmacology and biological chemistry at the Feinberg School, whose lab developed the drug. He is a coauthor of the study.

In previous animal studies, the same drug reduced the neurological damage caused by closed-head traumatic brain injury and inhibited the development of a multiple sclerosis-like disease. In these diseases as well as in Alzheimer’s, the studies show the therapy time window is critical.

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ScienceDaily (July 24, 2012) — A study, performed in mice and utilizing post-mortem samples of brains from patients with Alzheimer’s disease, found that a single event of a moderate-to-severe traumatic brain injury (TBI) can disrupt proteins that regulate an enzyme associated with Alzheimer’s. The paper, published in The Journal of Neuroscience, identifies the complex mechanisms that result in a rapid and robust post-injury elevation of the enzyme, BACE1, in the brain. These results may lead to the development of a drug treatment that targets this mechanism to slow the progression of Alzheimer’s disease.

"A moderate-to-severe TBI, or head trauma, is one of the strongest environmental risk factors for Alzheimer’s disease. A serious TBI can lead to a dysfunction in the regulation of the enzyme BACE1. Elevations of this enzyme cause elevated levels of amyloid-beta, the key component of brain plaques associated with senility and Alzheimer’s disease," said first author Kendall Walker, PhD, postdoctoral associate in the department of neuroscience at Tufts University School of Medicine (TUSM).

Building on her previous work, neuroscientist Giuseppina Tesco, MD, PhD, of Tufts University School of Medicine (TUSM), led a research team that first used an in vivo model to determine how a single episode of TBI could alter the brain. In the acute phase (first two days) following injury, levels of two intracellular trafficking proteins (GGA1 and GGA3) were reduced, and an elevation of BACE1 enzyme level was observed.

Next, in an analysis of post-mortem brain samples from patients with Alzheimer’s disease, the researchers found that GGA1 and GGA3 levels were reduced while BACE1 levels were elevated in the brains of Alzheimer’s disease patients compared to the brains of people without Alzheimer’s disease, suggesting a possible inverse association.

In an additional experiment using a mouse strain genetically modified to express the reduced level of GGA3 that was observed in the brains of Alzheimer’s disease patients, the team found that one week following traumatic brain injury, BACE1 and amyloid-beta levels remained elevated even when GGA1 levels had returned to normal. The research suggests that reduced levels of GGA3 were solely responsible for the increase in BACE 1 levels and therefore the sustained amyloid-beta production observed in the sub-acute phase, or seven days, after injury.

"When the proteins are at normal levels, they work as a clean-up crew for the brain by regulating the removal of BACE1 enzymes and facilitating their transport to lysosomes within brain cells, an area of the cell that breaks down and removes excess cellular material. BACE1 enzyme levels may be stabilized when levels of the two proteins are low, likely caused by an interruption in the natural disposal process of the enzyme," said Tesco, assistant professor of neuroscience at Tufts School of Medicine and member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

"We found that GGA1 and GGA3 act synergistically to regulate BACE1 post-injury. The identification of this interaction may provide a drug target to therapeutically regulate the BACE1 enzyme and reduce the deposition of amyloid-beta in Alzheimer’s patients," she continued. "Our next steps are to confirm these findings in post-mortem brain samples from patients with moderate-to-severe traumatic brain injuries."

Moderate-to-severe TBIs are caused most often by traumas, such as severe falls or motor vehicle accidents, that result in a loss of consciousness. Not all traumas to the head result in a TBI. According to the Centers for Disease Control and Prevention, each year 1.7 million people sustain a TBI. Concussions, the mildest form of a TBI, account for about 75% of all TBIs. Studies have linked repeated head trauma to brain disease and some previous studies have linked single events of brain trauma to brain disease, such as Alzheimer’s. Alzheimer’s disease currently affects as many as 5.1 million Americans and is the most common cause of dementia in adults age 65 and over.

Source: Science Daily

July 24, 2012

Einstein’s famous theory of relativity proposed that matter can distort space and time. Now a new study recently published in the journal Neurology suggests that chronic pain can have the same effect.

Neuroscientists from the University of South Australia, Neuroscience Research Australia and the University of Milano Bicocca in Italy, studied people with chronic back pain, the most common painful condition which costs western countries billions of dollars in lost productivity every year.

They presented identical vibration stimuli to the painful area and a non-painful area and noted that the stimuli were processed more slowly by the brain if they came from the painful area.

The most striking finding, however, was that the same effect occurred if the stimuli were delivered to a healthy body part being held near the painful area.

Lead author of the study, Professor Lorimer Moseley from the University of South Australia, says it was not altogether surprising that, in people with chronic pain, there are changes in the way the brain processes information from and about the painful body part.

“But what is remarkable is that the problem affects the space around the body as well as the body itself,” Prof Moseley says.

Experiments showed that if a hand was held near the painful area of the back, the brain would almost ‘neglect’ that hand.

“The potential similarity between our findings and the time-space distortion predicted by the relativity theory is definitely intriguing,” Prof Moseley says.

“Obviously, here it is not external space that is distorted but the ability of the brain to represent that space within its neural circuitry.

“This finding opens up a whole new area of research into the way the brain allows us to interact with the world and how this can be disrupted in chronic pain.”

Provided by University of South Australia

Source: medicalxpress.com

ScienceDaily (July 24, 2012) — Neuroscientists from Wayne State University and the Massachusetts Institute of Technology (MIT) are taking a deeper look into how the brain mechanisms for memory retrieval differ between adults and children. While the memory systems are the same in many ways, the researchers have learned that crucial functions with relevance to learning and education differ.

The team’s findings were published on July 17, 2012, in the Journal of Neuroscience.

According to lead author Noa Ofen, Ph.D., assistant professor in WSU’s Institute of Gerontology and Department of Pediatrics, cognitive ability, including the ability to learn and remember new information, dramatically changes between childhood and adulthood. This ability parallels with dramatic changes that occur in the structure and function of the brain during these periods.

In the study, “The Development of Brain Systems Associated with Successful Memory Retrieval of Scenes,” Ofen and her collaborative team tested the development of neural underpinnings of memory from childhood to young adulthood. The team of researchers exposed participants to pictures of scenes and then showed them the same scenes mixed with new ones and asked them to judge whether each picture was presented earlier. Participants made retrieval judgments while researchers collected images of their brains with magnetic resonance imaging (MRI).

Using this method, the researchers were able to see how the brain remembers. “Our results suggest that cortical regions related to attentional or strategic control show the greatest developmental changes for memory retrieval,” said Ofen.

The researchers said that older participants used the cortical regions more than younger participants when correctly retrieving past experiences.

"We were interested to see whether there are changes in the connectivity of regions in the brain that support memory retrieval," Ofen added. "We found changes in connectivity of memory-related regions. In particular, the developmental change in connectivity between regions was profound even without a developmental change in the recruitment of those regions, suggesting that functional brain connectivity is an important aspect of developmental changes in the brain."

This study marks the first time that the development of connectivity within memory systems in the brain has been tested, and the results suggest that the brain continues to rearrange connections to achieve adult-like performance during development.

Ofen and her research team plan to continue research in this area, focused on modeling brain network connectivity, and applying these methods to study abnormal brain development.

Source: Science Daily

July 23, 2012

Mice appear to have a specialized system for detecting and at least initially processing instinctually important smells such as those that denote predators. The finding raises a question about whether their response to those smells is hardwired.

A separate subsystem for the smell of fear. Experiments in mice suggest neurons that detect odors associated with an instinctive response — like fleeing when an approaching predator is detected — are configured differently than other olfactory neurons. Further research could determine whether this system automatically triggers flight or other primal behaviors.Credit: Mike Cohea/Brown University

PROVIDENCE, R.I. [Brown University] — A new study finds that mice have a distinct neural subsystem that links the nose to the brain and is associated with instinctually important smells such as those emitted by predators. That insight, published online this week in Proceedings of the National Academy of Sciences, prompts the question whether mice and other mammals have specially hardwired neural circuitry to trigger instinctive behavior in response to certain smells.

In the series of experiments and observations described in the paper, the authors found that nerve cells in the nose that express members of the gene family of trace amine-associated receptors (TAAR) have several key biological differences from the much more common and diverse neurons that express members of the olfactory receptor gene family. Those other nerve cells detect a much broader range of smells, said corresponding author Gilad Barnea, the Robert and Nancy Carney Assistant Professor of Neuroscience at Brown University.

The differences between TAAR neurons and olfactory receptor neurons led Barnea and his co-authors to conclude that they form an independent subsystem for certain smells.

“Our observations suggest that the TAAR-expressing sensory neurons constitute a distinct olfactory subsystem that extracts specific environmental cues that then elicit innate responses,” Barnea said.

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ScienceDaily (July 23, 2012) — Stroboscopic training, performing a physical activity while using eyewear that simulates a strobe-like experience, has been found to increase visual short-term memory retention, and the effects lasted 24 hours.

(Credit: Image courtesy of Duke University)

Participants completed a memory test that required them to note the identity of eight letters of the alphabet that were briefly displayed on a computer screen. After a variable delay, participants were asked to recall one of the eight letters. On easy-level trials, the recall prompt came immediately after the letters disappeared, but on more difficult trials, the prompt came as late as 2.5 seconds following the display. Because participants did not know which letter they would be asked to recall, they had to retain all of the items in memory.

"Humans have a memory buffer in their brain that keeps information alive for a certain short-lived period," said Greg Appelbaum, assistant professor of psychiatry at Duke University and first author of the study. "Wearing the strobe eyewear during the physical training seemed to boost the ability to retain information in this buffer."

The strobe eyewear disrupts vision by only allowing the user to see glimpses of the world. The user must adjust their visual processing in order to perform normally, and this adjustment produces a lingering benefit; once participants removed the strobe eyewear, there was an observed boost in their visual memory retention, which was found to last 24 hours.

Earlier work by Appelbaum and the project’s senior researcher, Stephen Mitroff, had shown that stroboscopic training improves visual perception, including the ability to detect subtle motion cues and the processing of briefly presented visual information. Yet the earlier study had not determined how long the benefits might last.

"Our earlier work on stroboscopic training showed that it can improve perceptual abilities, but we don’t know exactly how," says Mitroff, associate professor of psychology & neuroscience and member of the Duke Institute for Brain Sciences. "This project takes a big step by showing that these improved perceptual abilities are driven, at least in part, by improvements in visual memory."

"Improving human cognition is an important goal with so many benefits," said Appelbaum, also a member of the Duke Institute for Brain Sciences. "Interestingly, our findings demonstrate one way in which visual experience has the capacity to improve cognition."

Source: Science Daily

ScienceDaily (July 23, 2012) — Snack consumption and BMI are linked to both brain activity and self-control, new research has found.

Snack consumption and BMI are linked to both brain activity and self-control, new research has found. (Credit: © farbkombinat / Fotolia)

The research, carried out by academics from the Universities of Exeter, Cardiff, Bristol, and Bangor, discovered that an individual’s brain ‘reward centre’ response to pictures of food predicted how much they subsequently ate. This had a greater effect on the amount they ate than their conscious feelings of hunger or how much they wanted the food,

A strong brain response was also associated with increased weight (BMI), but only in individuals reporting low levels of self-control on a questionnaire. For those reporting high levels of self-control a stronger brain response to food was actually related to a lower BMI.

This study, which is now published in the journal NeuroImage, adds to mounting evidence that overeating and increased weight are linked, in part, to a region of the brain associated with motivation and reward, called the nucleus accumbens. Responses in this brain region have been shown to predict weight gain in healthy weight and obese individuals, but only now have academics discovered that this is independent of conscious feelings of hunger, and that self-control also plays a key role.

Following these results, academics at the University of Exeter and Cardiff have begun testing ‘brain training’ techniques designed to reduce the influence of food cues on individuals who report low levels of self-control. Similar tests are being used to assist those with gambling or alcohol addiction.

Dr Natalia Lawrence of Psychology at the University of Exeter, lead researcher in both the original research and the new studies, said: “Our research suggests why some individuals are more likely to overeat and put on weight than others when confronted with frequent images of snacks and treats. Food images, such as those used in advertising, cause direct increases in activity in brain ‘reward areas’ in some individuals but not in others. If those sensitive individuals also struggle with self-control, which may be partly innate, they are more likely to be overweight. We are now developing computer programs that we hope will counteract the effects of this high sensitivity to food cues by training the brain to respond less positively to these cues.”

Twenty-five young, healthy females with BMIs ranging from 17-30 were involved in the study. Female participants were chosen because research shows females typically exhibit stronger responses to food-related cues. The hormonal changes during the menstrual cycle affect this reaction, so all participants were taking the monophasic combined oral contraceptive pill. Participants had not eaten for at least six hours to ensure they were hungry at the time of the scan and were given a bowl containing 150 g (four and a half packets) of potato chips to eat at the end of the study; they were informed that potato chip intake had been measured afterwards.

Researchers used MRI scanning to detect the participants’ brain activity while they were shown images of household objects, and food that varied in desirability and calorific content. After scanning, participants rated the food images for desirability and rated their levels of hunger and food craving. Results showed that participants’ brain responses to food (relative to objects) in the nucleus accumbens predicted how many potato chips they ate after the scan. However, participants’ own ratings of hunger and how much they liked and wanted the foods, including potato chips, were unrelated to their potato chip intake.

This study was funded by the Wales Institute of Cognitive Neuroscience.

What this study shows:

• Brain responses to food images vary considerably between individuals.
• Brain responses to food images but not conscious feelings of hunger or desire to eat predict subsequent potato chip consumption.
• Individuals’ reported levels of self-control influence whether this brain response is associated with a higher or lower BMI.

What this study does NOT show:

• Brain responses to food cues cause overeating.
• The associations reported here are true in everyone — only healthy young women were included.
• Whether our brain response and levels of self-control are learned or innate.

Source: Science Daily

JUL 23, 2012

A new and powerful class of antioxidants could one day be a potent treatment for Parkinson’s disease, researchers report.

Dr. Bobby Thomas

A class of antioxidants called synthetic triterpenoids blocked development of Parkinson’s in an animal model that develops the disease in a handful of days, said Dr. Bobby Thomas, neuroscientist at the Medical College of Georgia at Georgia Health Sciences University and corresponding author of the study in the journal Antioxidants & Redox Signaling.

Thomas and his colleagues were able to block the death of dopamine-producing brain cells that occurs in Parkinson’s by using the drugs to bolster Nrf2, a natural antioxidant and inflammation fighter.

Stressors from head trauma to insecticide exposure to simple aging increase oxidative stress and the body responds with inflammation, part of its natural repair process. “This creates an environment in your brain that is not conducive for normal function,” Thomas said. “You can see the signs of oxidative damage in the brain long before the neurons actually degenerate in Parkinson’s.”

Nrf2, the master regulator of oxidative stress and inflammation, is – inexplicably – significantly decreased early in Parkinson’s. In fact, Nrf2 activity declines normally with age.

“In Parkinson’s patients you can clearly see a significant overload of oxidative stress, which is why we chose this target,” Thomas said. “We used drugs to selectively activate Nrf2.”

They parsed a number of antioxidants already under study for a wide range of diseases from kidney failure to heart disease and diabetes, and found triterpenoids the most effective on Nrf2. Co-author Dr. Michael Sporn, Professor of Pharmacology, Toxicology and Medicine at Dartmouth Medical School, chemically modified the agents so they could permeate the protective blood-brain barrier.

Both in human neuroblastoma and mouse brain cells they were able to document an increase in Nrf2 in response to the synthetic triterpenoids. Human dopaminergic cells are not available for research so the scientists used the human neuroblastoma cells, which are actually cancer cells that have some properties similar to neurons.

Their preliminary evidence indicates the synthetic triterpenoids also increase Nrf2 activity in astrocytes, a brain cell type which nourishes neurons and hauls off some of their garbage. The drugs didn’t protect brain cells in an animal where the Nrf2 gene was deleted, more proof that that Nrf2 is the drugs’ target.

The researchers used the powerful neurotoxin MPTP to mimic Parkinson’s-like brain cell damage in a matter of days. They are now looking at the impact of synthetic triterpenoids in an animal model genetically programmed to acquire the disease more slowly, as humans do. Collaborators at Johns Hopkins School of Medicine also will be providing induced pluripotent stem cells, adult stem cells that can be coaxed into forming dopaminergic neurons, for additional drug testing.

Other collaborators include scientists at Weill Medical College of Cornell University, Johns Hopkins School of Public Health, Moscow State University, Tohoku University and the University of Pittsburgh.

Source: EarthSky