Neuroscience

Month

May 2012

How Illusions Trick the Brain: 'Rotating Snakes' Appear to Dance

ScienceDaily (May 1, 2012) — Barrow Neurological Institute researchers Jorge Otero-Millan, Stephen Macknik, and Susana Martinez-Conde share the recent cover of the Journal of Neuroscience in a compelling study into why illusions trick our brains. Barrow is part of St. Joseph’s Hospital and Medical Center in Phoenix.

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The study, led by Martinez-Conde’s laboratory, explores the neural bases of illusory motion in Akiyoshi Kitaoka’s striking visual illusion, known as the “Rotating Snakes.” Kitaoka is a Japanese psychology professor who specializes in visual illusions of geometric shapes and motion illusions.

The study shows that tiny eye movements and blinking can make a geometric drawing of “snakes” appear to dance. The results help explain the mystery of how the Rotating Snakes illusion tricks the brain.

"Visual illusions demonstrate the ways in which the brain creates a mental representation that differs from the physical world," says Martinez-Conde. "By studying illusions, we can learn the mechanisms by which the brain constructs our conscious experience of the world."

Earlier studies of the “Rotating Snakes” indicated the perception of motion was triggered by the eyes moving slowly across the illusion. But by tracking eye movements in eight volunteers, the vision neuroscientists found a different explanation: fast eye movements called “saccades,” some of which are microscopic and undetectable by the viewer, drive the illusory motion.

Participants lifted a button when the snakes seemed to swirl and pressed down the button when the snakes appeared still. Right before the snakes appeared to move, participants tended to produce blinks, saccades and/or microsaccades, and right before the snakes stopped, participants’ eyes tended to remain stable, Otero-Millan, Macknik, and Martinez-Conde report in the April 25th Journal of Neuroscience cover story.

"Studying the mismatch between perception and reality may lead to a deeper understanding of the mind," says Martinez-Conde. "The findings from our recent study may help us to understand the neural bases of motion perception, both in the normal brain, and in patients with brain lesions that affect the perception of motion. This research could aid in the design of neural prosthetics for patients with brain damage."

Source: Science Daily

May 1, 20123 notes
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Important Mechanism That Affects the Aging Process Identified

ScienceDaily (May 1, 2012) — Scientists at Joslin Diabetes Center have identified a key mechanism of action for the TOR (target of rapamycin) protein kinase, a critical regulator of cell growth which plays a major role in illness and aging. This finding not only illuminates the physiology of aging but could lead to new treatments to increase lifespan and control age-related conditions, such as cancer, type 2 diabetes, and neurodegeneration.

Over the past decade, studies have shown that inhibiting TOR activity, which promotes cell growth by regulating protein synthesis, increases lifespan in a variety of species including flies and mice; in recent years research has focused on uncovering the precise mechanisms underlying this effect. The Joslin study, published in the May 2 issue of Cell Metabolism, reports that TOR has a direct impact on two master gene regulator proteins — SKN-1 and DAF-16 -which control genes that protect against environmental, metabolic and proteotoxic stress. The TOR kinase acts in two signaling pathways, TORC1 and TORC2. When TORC1 is inhibited, SKN-1 and DAF-16 are mobilized, leading to activation of protective genes that increase stress resistance and longevity. This new finding was demonstrated in experiments with C. elegans, a microscopic worm used as a model organism, but activation of protective genes was also observed in mice. Most findings in C. elegans have turned out to be applicable to mice and humans.

"We uncovered a critical mechanism in the relationship between TOR and aging and disease. There is a homeostatic relationship between protein synthesis and stress defenses: when protein synthesis is reduced, stress defenses increase," says lead author T. Keith Blackwell, MD, PhD, co-head of the Joslin Islet Cell & Regenerative Biology Section and Professor of Pathology at Harvard Medical School. The Blackwell lab studies the aging process and how it is influenced by insulin and other metabolic regulatory mechanisms.

TOR activity, which is essential for early development but can lead to age-related decline, is implicated in a variety of chronic diseases, including diabetes, cardiovascular disease, cancer and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. In diabetes, TOR has both positive and negative effects: It promotes beta cell growth and insulin production but inappropriate TORC1 activity leads to insulin resistance and beta cell demise, as well as fat accumulation. At the same time, insufficient TORC2 activity can lead to insulin resistance.

The new results on TOR and SKN-1 suggest that SKN-1 might have a positive effects in Type 2 diabetes: “Turning on this pathway could be important in defending against the effects of high glucose, and promoting beta cell health” says Blackwell.

In the study, TOR activity was inhibited by genetic interference and the TOR-inhibitor rapamycin, a naturally occurring compound which is used as an immunosuppressant in organ transplants, and has been shown to increase lifespan in mice. Using rapamycin or related drugs to treat diseases affected by TOR has been a subject of intense interest among scientists and clinicians. The study found that rapamycin inhibits both TORC1 and TORC2, which will interest scientists investigating rapamycin as a pharmaceutical. “We need to increase understanding of rapamycin and its effects on TOR activity to determine how targeting TOR or processes it controls can help treat diseases that involve TOR and derangement of metabolism. We also need to look at therapies that work on TORC1 and TORC2 independently,” said Blackwell. However, one caveat with TOR inhibition is that the kinase plays such a central role in the basic physiology of growing and dividing cells. The new results suggest that in some situations we might want to bypass TOR itself, and directly harness beneficial processes that are controlled by SKN-1 or DAF-16.

Future research will focus on gaining a deeper understanding of how TOR acts on beneficial defense pathways and affects aging and disease. “In science, we are always looking for ways to interfere with mechanisms that promote aging and disease in ways that are beneficial to people,” says Blackwell.

Source: Science Daily

May 1, 20125 notes
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Computer use and exercise combo may reduce the odds of having memory loss

May 1, 2012

You think your computer has a lot of memory … if you keep using your computer you may, too.

Combining mentally stimulating activities, such as using a computer, with moderate exercise decreases your odds of having memory loss more than computer use or exercise alone, a Mayo Clinic study shows. Previous studies have shown that exercising your body and your mind will help your memory but the new study, published in the May 2012 issue of Mayo Clinic Proceedings, reports a synergistic interaction between computer activities and moderate exercise in “protecting” the brain function in people better than 70 years old.

Researchers studies 926 people in Olmsted County, Minn., ages 70 to 93, who completed self-reported questionnaires on physical exercise, and computer use within one year prior of the date of interview. Moderate physical exercise was defined as brisk walking, hiking, aerobics, strength training, golfing without a golf cart, swimming, doubles tennis, yoga, martial arts, using exercise machines and weightlifting. Mentally stimulating activities included reading, crafts, computer use, playing games, playing music, group and social and artistic activities and watching less television. Of those activities the study singled out computer use because of its popularity, said study author Yonas E. Geda, M.D., MSc, a physician scientist with Mayo Clinic in Arizona.

"The aging of baby boomers is projected to lead to dramatic increases in the prevalence of dementia," Dr. Geda said. "As frequent computer use has becoming increasingly common among all age groups, it is important to examine how it relates to aging and dementia. Our study further adds to this discussion."

The study examined exercise, computer use and the relationship to neurological risks such as mild cognitive impairment, Dr. Geda says. Mild cognitive impairment is the intermediate stage between normal memory loss that comes with aging and early Alzheimer’s disease. Of the study participants who did not exercise and did not use a computer, 20.1 percent were cognitively normal and 37.6 percent showed signs of mild cognitive impairment. Of the participants who both exercise and use a computer, 36 percent were cognitively normal and 18.3 percent showed signs of MCI.

Dr. Geda expects that this study will lead to more research on this topic.

Provided by Mayo Clinic

Source: medicalxpress.com

May 1, 20124 notes
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Technology Eases Migraine Pain in the Deep Brain

ScienceDaily (Apr. 30, 2012) — Migraine pain sits at the upper end of the typical pain scale — an angry-red section often labeled “severe.” At this intensity, pain is debilitating. Yet many sufferers do not get relief from — or cannot tolerate — over-the-counter and commonly prescribed pain medications.

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Migraine Therapy: Computer model of the distribution of electrical current in the brain’s pain network (sub-cortical and brainstem structures) during transcranial direct current stimulation (tDCS). (Credit: Image courtesy of City College of New York)

Recently, a team of researchers that includes Dr. Marom Bikson, associate professor of biomedical engineering in CCNY’s Grove School of Engineering, has shown that a brain stimulation technology can prevent migraine attacks from occurring. Their technique, using transcranial direct current stimulation (tDCS), applies a mild electrical current to the brain from electrodes attached to the scalp.

"We developed this technology and methodology in order to get the currents deep into the brain," said Bikson. The researchers aimed to tap into the so-called pain network, among other areas, a collection of interconnected brain regions involved in perceiving and regulating pain.

Professor Bikson and his colleagues, including Dr. Alexandre DaSilva at the University of Michigan School of Dentistry and Dr. Felipe Fregni at Harvard Medical School, found that the technology seems to reverse ingrained changes in the brain caused by chronic migraine, such as greater sensitivity to headache triggers.

Repeated sessions reduced the duration of attacks and decreased the pain intensity of migraines that did occur on average about 37 percent. The improvements accumulated over four weeks of treatment and they persisted.

In pilot studies, the effects lasted for months. The only side effect subjects reported was a mild tingling sensation during treatment. Professor Bikson expects that a patient could use the system every day to ward off attacks, or periodically, like a booster.

The team’s computational models show that tDCS delivers therapeutic current along the pain network through both upper (cortical) and deep brain structures. They will publish their results in the journal Headache.

Thirty-six million Americans suffer from migraine, according to the Migraine Research Foundation. Of these, 14 million of them experience chronic daily headaches. “The fact that people still suffer from migraines means that the existing treatments using electrical technology or chemistry are not working,” said Professor Bikson.

Existing brain stimulation technologies can help relieve a migraine already underway. But those afflicted with chronic migraine pain may suffer 15 or more attacks a month, making treatment a constant battle.

The other techniques also have drawbacks — from heavy, unwieldy equipment to serious side effects, such as seizures. Some only stimulate the upper layers of the brain. Others reach deep brain regions, but require brain surgery to implant the electrodes. The tDCS technology is safe, easy to use, and portable, Professor Bikson said. “You can walk around with it and keep it in your desk drawer or purse. This is definitely the first technology that operates on just a 9-volt battery and can be applied at home.” He envisions future units as small as an iPod.

The next step will be to scale up clinical trials to a larger study population. A market-ready version of the tDCS is still years away. “There’s something about migraine pain that’s particularly distressing,” noted Professor Bikson. “If it’s possible to help some people get just 30 percent better, that’s a very meaningful improvement in quality of life.”

Source: Science Daily

May 1, 20121 note
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Halting an Enzyme Can Slow Multiple Sclerosis in Mice

ScienceDaily (Apr. 30, 2012) — Researchers studying multiple sclerosis (MS) have long been looking for the specific molecules in the body that cause lesions in myelin, the fatty, insulating cells that sheathe the nerves. Nearly a decade ago, a group at Mayo Clinic found a new enzyme, called Kallikrein 6, that is present in abundance in MS lesions and blood samples and is associated with inflammation and demyelination in other neurodegenerative diseases. In a study published this month in Brain Pathology,the same group found that an antibody that neutralizes Kallikrein 6 is capable of staving off MS in mice.

"We were able to slow the course of disease through early chronic stages, both in the brain and spinal cord," says lead author Isobel Scarisbrick, Ph.D., of the Mayo Clinic Department of Physical Medicine and Rehabilitation.

Researchers looked at mice representing a viral model of MS. The model is based on the theory that infection with viral infection early in life results in an eventual abnormal immune response in the brain and spinal cord. One week after being infected with a virus, the mice showed elevated levels of Kallikrein 6 enzyme in the brain and spinal cord. However, when researchers treated mice to produce an antibody capable of blocking and neutralizing the enzyme, they saw a decrease in diseases effecting the brain and spinal cord, including demyelination. The Kallikrein 6 neutralizing antibody had reduced inflammatory white blood cells and slowed the depletion of myelin basic protein, a key component of the myelin sheath.

The findings in the MS model have implications for other conditions affecting the brain and spinal cord. The group has previously shown that the Kallikrein 6 enzyme, produced by immune cells, is elevated in spinal cord injury, while other studies have shown it to be elevated in animal models of stroke and patients with post-polio syndrome.

"These findings suggest Kallikrein 6 plays a role in the inflammatory and demyelinating processes that accompany many types of neurological conditions," says Dr. Scarisbrick. "In the early chronic stages of some neurological diseases, Kallikrein 6 may represent a good molecule to target with drugs capable of neutralizing its effects."

Source: Science Daily

May 1, 20123 notes
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Molecule Blocks Pathway Leading to Alzheimer's Disease

ScienceDaily (Apr. 30, 2012) — UC Davis researchers have found novel compounds that disrupt the formation of amyloid, the clumps of protein in the brains of people with Alzheimer’s disease believed to be important in causing the disease’s characteristic mental decline. The so-called “spin-labeled fluorene compounds” are an important new target for researchers and physicians focused on diagnosing, treating and studying the disease.

The study was published April 30 in the online journal PLoS ONE.

"We have found these small molecules to have significant beneficial effects on cultured neurons, from protecting against toxic compounds that form in neurons to reducing inflammatory factors," said John C. Voss, professor of biochemistry and molecular medicine at the UC Davis School of Medicine and the principal investigator of the study. "As a result, they have great potential as a therapeutic agent to prevent or delay injury in individuals in the earliest stages of Alzheimer’s disease, before significant damage to the brain occurs."

Amyloid is an accumulation of proteins and peptides that are otherwise found naturally in the body. One component of amyloid − the amyloid beta (Aβ) peptide − is believed to be primarily responsible for destroying neurons in the brain. Fluorene compounds, which are small three-ringed molecules, originally were developed as imaging agents to detect amyloid with PET imaging. In addition to being excellent for detecting amyloid, fluorenes bind and destabilize Aβ peptide and thereby reduce amyloid formation, according to previous findings in mice by Lee-Way Jin, another study author and associate professor in the UC Davis MIND Institute and Department of Medical Pathology and Laboratory Medicine.

The current research studied the effects of fluorene compounds by attaching a special molecule to make their activity evident using electron paramagnetic resonance (EPR) spectroscopy. This technology allows researchers to observe very specific activities of molecules of interest because biological tissues do not emit signals detectable by EPR. Since Voss was interested in the activity of fluorenes, he added a nitroxide “spin label,” a chemical species with a unique signal that can be measured by EPR.

The group found that spin-labeled compounds disrupted Aβ peptide formation even more effectively than did non-labeled fluorenes. In addition, the antioxidant properties of the nitroxide, which scavenge reactive oxygen species known to damage neurons and increase inflammation, significantly contributed to the protective effects on neurons.

"The spin-labeled fluorenes demonstrated a number of extremely important qualities: They are excellent for detecting amyloid in imaging studies, they disrupt Aβ formation, and they reduce inflammation," said Voss. "This makes them potentially useful in the areas of research, diagnostics and treatment of Alzheimer’s disease."

Alzheimer’s disease is the most common form of dementia and affects some 5 million Americans. Current medications used to fight the disease usually have only small and temporary benefits, and commonly have many side effects.

A major obstacle in developing Alzheimer’s disease therapy is that most molecules will not cross the blood-brain barrier, so that potential treatments given orally or injected into the bloodstream cannot enter the brain where they are needed. Fluorene compounds are small molecules that have been shown to penetrate the brain well.

"We have brought together expertise from diverse fields to get to this point, and what was once a side interest has become a major focus," said Voss. "We are very excited and hopeful that these unique compounds can become extremely important."

Voss’ group next plans to study the safety of spin-labeled fluorene compounds as well as their efficacy for treating models of Alzheimer’s disease in small animals.

Source: Science Daily

May 1, 20125 notes
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Bilingualism fine-tunes hearing, enhances attention

April 30, 2012

A Northwestern University study that will be published in the Proceedings of the National Academy of Sciences (PNAS) provides the first biological evidence that bilinguals’ rich experience with language in essence “fine-tunes” their auditory nervous system and helps them juggle linguistic input in ways that enhance attention and working memory.

Northwestern bilingualism expert Viorica Marian teamed up with auditory neuroscientist Nina Kraus to investigate how bilingualism affects the brain. In particular, they looked at subcortical auditory regions that are bathed with input from cognitive brain areas. In extensive research, Kraus has already shown that lifelong music training enhances language processing, and an examination of subcortical auditory regions helped to tell that tale.

"For our first collaborative study, we asked if bilingualism could also promote experience-dependent changes in the fundamental encoding of sound in the brainstem — an evolutionarily ancient part of the brain," said Marian, professor of communication sciences in Northwestern’s School of Communication. The answer, according to their study, is a resounding yes.

The researchers found that the experience of bilingualism changes how the nervous system responds to sound. “People do crossword puzzles and other activities to keep their minds sharp,” Marian said. “But the advantages we’ve discovered in dual language speakers come automatically simply from knowing and using two languages. It seems that the benefits of bilingualism are particularly powerful and broad, and include attention, inhibition and encoding of sound.”

Co-authored by Kraus, Marian and researchers Jennifer Krizman, Anthony Shook and Erika Skoe, “Bilingualism and the Brain: Subcortical Indices of Enhanced Executive Function” underscores the pervasive impact of bilingualism on brain development. The article will appear in the April 30 issue of PNAS.

"Bilingualism serves as enrichment for the brain and has real consequences when it comes to executive function, specifically attention and working memory," said Kraus, Hugh Knowles Professor at Northwestern. In future studies, she and Marian will investigate whether these results can be achieved by learning a language later in life.

In the study, the researchers recorded the brainstem responses to complex sounds (cABR) in 23 bilingual English-and-Spanish-speaking teenagers and 25 English-only-speaking teens as they heard speech sounds in two conditions.

Under a quiet condition, the groups responded similarly. But against a backdrop of background noise, the bilingual brains were significantly better at encoding the fundamental frequency of speech sounds known to underlie pitch perception and grouping of auditory objects. This enhancement was linked with advantages in auditory attention.

"Through experience-related tuning of attention, the bilingual auditory system becomes highly efficient in automatically processing sound," Kraus explained.

"Bilinguals are natural jugglers," said Marian. "The bilingual juggles linguistic input and, it appears, automatically pays greater attention to relevant versus irrelevant sounds. Rather than promoting linguistic confusion, bilingualism promotes improved ‘inhibitory control,’ or the ability to pick out relevant speech sounds and ignore others."

The study provides biological evidence for system-wide neural plasticity in auditory experts that facilitates a tight coupling of sensory and cognitive functions. “The bilingual’s enhanced experience with sound results in an auditory system that is highly efficient, flexible and focused in its automatic sound processing, especially in challenging or novel listening conditions,” Kraus added.

Provided by Northwestern University

Source: medicalxpress.com

May 1, 20129 notes
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Neurodevelopmental Disorders: How Human Cells 'Hold Hands'

ScienceDaily (Apr. 30, 2012) — University of Iowa biologists have advanced the knowledge of human neurodevelopmental disorders by finding that a lack of a particular group of cell adhesion molecules in the cerebral cortex — the outermost layer of the brain where language, thought and other higher functions take place — disrupts the formation of neural circuitry.

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Reconstructions of single wildtype (left) and gamma-protocadherin mutant (right) cortical neurons are superimposed upon a low magnification view of fluorescently-labeled neurons in the corresponding animals. (Credit: Image courtesy of University of Iowa Health Care)

Andrew Garrett, former neuroscience graduate student and current postdoctoral fellow at the Jackson Laboratory, Bar Harbor, Maine; Dietmar Schreiner, former postdoctoral fellow currently at the University of Basel, Switzerland; Mark Lobas, current neuroscience graduate student; and Joshua A. Weiner, associate professor in the UI College of Liberal Arts and Sciences Department of Biology, published their findings in the April 26 issue of the journal Neuron.

Cell adhesion is the way in which cells “hold hands” — how one cell binds itself to another cell using specific molecules that protrude from cell membranes and bind each other together. The process is necessary to form all body tissues. The UI researchers studied a clustered family of 22 genes (gamma-protocadherins) that make such cellular hand-holding possible by encoding cell adhesion molecules.

In their previous work, they found that mice lacking the molecules exhibited death of neurons and loss of synapses in the spinal cord. So, they knew the gamma-protocadherins were important for neurons in the spinal cord, but not whether this was true in the cortex. However, in the current study, they found that an absence of the cell adhesion molecules had a significant and much different effect.

"We found that mice lacking the gamma-protocadherins in the cortex do not exhibit the severe loss of synapses and increased neuronal death that we observed in the spinal cord," says Weiner. "Instead, we found that the cortical neurons had severely reduced development of their dendrites, tree-like branched structures that receive input from other neurons.

"We discovered the reason for this: gamma-protocadherins normally inhibit a key signaling pathway within neurons that acts to reduce dendrite branching. In the absence of the gamma-protocadherins, this signaling pathway was hyperactive, leading to defective branching of cortical neuron dendrites," says Weiner.

In their previous work, the researchers showed that these molecules — the 22 distinct adhesion molecules, the gamma-protocadherins — are critical for the development of the animal, because when all of the genes are deleted from mice, they die shortly after birth with a variety of neurological defects including loss of connections (synapses) and excessive neuronal cell death in the spinal cord — an early-developing part of the nervous system.

Because those mutants die so young, the researchers could not assess a role for the gamma-protocadherins in the cerebral cortex. The reason is that the cortex develops only after birth. They used new genetic technologies to remove the gamma-protocadherins only from the cerebral cortex, which allowed the animals to survive to adulthood.

Weiner says that the latest research findings may help researchers to better understand the causes of various human developmental disorders.

"Human neurodevelopmental disorders such as autism, mental retardation, and schizophrenia all involve dysregulation of dendrite branching and synaptogenesis," he says. "Our identification of a large family of 22 cell adhesion molecules — which we previously showed interact with each other in very complex and specific ways — as new regulators of dendrite branching raises the question of whether specific interactions between distinct neuronal groups during development is important for the spreading of dendritic branches. If so, the gamma-protocadherins and/or the signaling pathways they regulate might be disrupted in a variety of human brain disorders."

Now that the researchers have shown that the gamma-protocadherin family, as a whole, is critical for dendrite branching, they plan to become more focused in their research. Next, they plan to ask whether specific interactions between individual members of the family are important for instructing neurons on the location and size of dendrite growth.

Source: Science Daily

May 1, 20125 notes
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April 2012

A new drug to manage resistant chronic pain

April 30, 2012

Neuropathic pain, caused by nerve or tissue damage, is the culprit behind many cases of chronic pain. It can be the result of an accident or caused by a variety of medical conditions and diseases such as tumors, lupus, and diabetes. Typically resistant to common types of pain management including ibuprofen and even morphine, neuropathic pain can lead to lifelong disability for many sufferers.

Now a drug developed by Tel Aviv University researchers, known as BL-7050, is offering new hope to patients with neuropathic pain. Developed by Prof. Bernard Attali and Dr. Asher Peretz of TAU’s Department of Physiology and Pharmacology at the Sackler Faculty of Medicine, the medication inhibits the transmission of pain signals throughout the body. In both in-vitro and in-vivo experiments measuring electrical activity of neurons, the compound has been shown to prevent the hyper-excitability of neurons — protecting not only against neuropathic pain, but epileptic seizures as well.

The medication has been licensed by Ramot, TAU’s technology transfer company, for development and commercialization by BioLineRx, an Israeli biopharmaceutical development company.

Targeting potassium for pain control

According to Prof. Attali, the medication works by targeting a group of proteins which act as a channel for potassium. Potassium has a crucial role in the excitability of cells, specifically those in the nervous system and the heart. When potassium channels don’t function properly, cells are prone to hyper-excitability, leading to neurological and cardiovascular disorders such as epilepsy and arrhythmias. These are also the channels that convey pain signals caused by nerve or tissue damage, known as neuropathic pain.

With few treatment options available for neuropathic pain, Prof. Attali set out to develop a medication that could bind to and stabilize the body’s potassium channels, controlling their hyper-excitability and preventing the occurrence of pain by keeping the channels open for the outflow of potassium. This novel targeting approach has been recently reported in the journal PNAS.

Inducing calm in the neurons

Understanding the mechanism that controls these channels has been crucial to the development of the drug. By successfully controlling the excitability of the neurons, Prof. Attali believes that BL-7050 could bring relief to hundreds of millions of patients around the world who suffer from neuropathic pain. The medication will reach the first phase of clinical trials in the near future.

In pre-clinical trials, BL-7050 was tested in rats experiencing both epilepsy and neuropathic pain and was found to be efficient in protecting against both when taken as a pill. While on the medication, rats were no longer affected by stimuli that had previously caused pain. Measures in the electrical activities of neurons also revealed that the medication was able to induce “calm” in the neurons, inhibiting pain pathways.

Provided by Tel Aviv University

Source: medicalxpress.com

Apr 30, 20127 notes
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Scientists identify brain circuitry associated with addictive, depressive behaviors

April 30, 2012

(Medical Xpress) — Scientists at the UCSF-affiliated Gladstone Institutes have determined how specific circuitry in the brain controls not only body movement, but also motivation and learning, providing new insight into neurodegenerative disorders such as Parkinson’s disease — and psychiatric disorders such as addiction and depression.

Previously, researchers in the laboratory of Gladstone Investigator Anatol Kreitzer, PhD, discovered how an imbalance in the activity of a specific category of brain cells is linked to Parkinson’s.

Now, in a paper published online today in Nature Neuroscience, Kreitzer, who is also an assistant professor of physiology at UCSF, and his team used animal models to demonstrate that this imbalance may also contribute to psychiatric disorders. These findings also help explain the wide range of Parkinson’s symptoms — and mark an important step in finding new treatments for those who suffer from addiction or depression.

“The physical symptoms that affect people with Parkinson’s — including tremors and rigidity of movement — are caused by an imbalance between two types of medium spiny neurons in the brain,” said Kreitzer, whose lab studies how Parkinson’s disease affects brain functions. “In this paper we showed that psychiatric disorders — specifically addiction and depression —might be caused by this same neural imbalance.”

Normally, two types of medium spiny neurons, or MSNs, coordinate body movements. One type, called direct pathway MSNs (dMSNs), acts like a gas pedal. The other type, known as indirect pathway MSNs (iMSNs), acts as a brake. And while researchers have long known about the link between a chemical in the brain called dopamine and Parkinson’s, Gladstone researchers recently clarified that dopamine maintains the balance between these two MSN types.

But abnormal dopamine levels are implicated not only in Parkinson’s, but also in addiction and depression. Kreitzer and his team hypothesized that the same circuitry that controlled movement might also control the process of learning to repeat pleasurable experiences and avoid unpleasant ones—and that an imbalance in this process could lead to addictive or depressive behaviors.

Kreitzer and his team genetically modified two sets of mice so that they could control which specific type of MSN was activated. They placed mice one at a time in a box with two triggers — one that delivered a laser pulse to stimulate the neurons and one that did nothing. They then monitored which trigger each mouse preferred.

“The mice that had only dMSNs activated gravitated toward the laser trigger, pushing it again and again to get the stimulation — reminiscent of addictive behavior,” said Alexxai Kravitz, PhD, Gladstone postdoctoral fellow and a lead author of the paper. “But the mice that had only iMSNs activated did the opposite. Unlike their dMSN counterparts, the iMSN mice avoided the laser stimulation, which suggests that they found it unpleasant.” These findings reveal a precise relationship between the two MSN types and how behaviors are learned. They also show how an MSN imbalance can throw normal learning processes out of whack, potentially leading to addictive or depressive behavior.

“People with Parkinson’s disease often show signs of depression before the onset of significant movement problems, so it’s likely that the neural imbalance in Parkinson’s is also responsible for some behavioral changes associated with the disease,” said Kreitzer, who is also an assistant professor of physiology at UCSF.. “Future research could discover how MSNs are activated in those suffering from addiction or depression—and whether tweaking them could reduce their symptoms and improve their quality of life.

Graduate student Lynne Tye was also a lead author on this paper. Funding came from a variety of sources, including the W.M. Keck Foundation, the Pew Biomedical Scholars Program, the McKnight Foundation and the National Institutes of Health.

Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Provided by University of California, San Francisco 

Source: medicalxpress.com

Apr 30, 201220 notes
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Overlooked nighttime spikes on EEGs may reflect an underlying brain injury

April 30, 2012

Children with developmental delay or autism may have unrecognized epilepsy-like brain activity during sleep, report researchers at Boston Children’s Hospital. These nighttime electrical spikes, detectable only on EEGs, occur even in some children without known epilepsy and appear to result from early strokes or other early life injuries to the developing brain, the study found. Results were published online April 25 by the journal Neurology.

“Kids can have an almost normal EEG while awake, but may show increased spikes during sleep,” says lead investigator Tobias Loddenkemper, MD, a neurologist in the Epilepsy Center at Boston Children’s. “If nighttime spiking remains undiagnosed and untreated, it may interfere with learning and development. This has been frequently overlooked in the past.”

Based on their findings, the researchers suggest that sleep EEG monitoring should be considered more often in children not meeting developmental milestones, and that bedtime medications to suppress nighttime seizures may be beneficial if heightened brain electrical activity is found. In a preliminary treatment trial, such nighttime dosing before times of greatest spike or seizure activity has been found to be beneficial.

The study involved sleep EEG monitoring in 147 patients who were suspected of having excess brain electrical activity during sleep, based on loss of developmental milestones, and, in some cases, known seizures. All children had at least one brain MRI available for review. The EEGs and MRIs were read by physicians who did not know details of the patients’ history.

Of the 147 patients, seen at Boston Children’s over a 14-year period, 100 had prominent EEG spikes during sleep; the other 47 (controls) did not. Although there was no significant difference between groups in the percentage of patients with recognized seizures (78 percent of the “spike” group versus 64 percent of controls) or on most clinical measures, the “spike” group had significantly more patients with brain lesions on MRI (48 vs. 19 percent).

Children with EEG spikes were especially more likely than controls (14 vs. 2 percent) to have damage in the thalamus, the structure that relays sensory and motor signals to the cortex and regulates sleep and consciousness. The most common type of brain injury was early stroke (found in 14 vs. 0 percent, respectively).

The authors speculate that these early injuries disrupt circuit formation in the developing brain and lead to over-excitability – too much communication that is reflected in the EEG spikes and that may impinge on learning and development. “We know that children lose skills when these spikes appear,” says Loddenkemper. “These children lose out on a critical period of brain development and may never fully catch up later in life.”

Loddenkemper notes that up to 20 percent of children with heightened nighttime brain electrical activity do not have seizures or recognizable epilepsy. “Developmental delay may be the only clinical finding in some children,” he says. “Children at age 2 or 3, and sometimes older, may suddenly lose developmental milestones such as language, walking skills or fine motor movement.”

In the future, Loddenkemper and colleagues hope to conduct a prospective, multicenter trial in which they follow children with known early brain injury and monitor their nighttime EEG activity. They will then try different drugs to suppress nighttime spiking to see how the children’s long-term learning and development are affected.

Provided by Children’s Hospital Boston 

Source: medicalxpress.com

Apr 30, 20123 notes
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Huge study finds brain networks connected to teen drug abuse

April 29, 2012

Why do some teenagers start smoking or experimenting with drugs—while others don’t?

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Newly discovered networks in the brain, shown here in color, go a long way toward explaining why some teenagers are more likely to start experimenting with drugs and alcohol. Diminished activity in some of these networks, discovered by two scientists at the University of Vermont and their European colleagues, makes some teens more impulsive — and less able to inhibit urges to try alcohol, cigarettes and illegal drugs in early adolescence. Credit: Robert Whelan, University of Vermont, Nature Neuroscience, 2012

In the largest imaging study of the human brain ever conducted—involving 1,896 14-year-olds—scientists have discovered a number of previously unknown networks that go a long way toward an answer.

Robert Whelan and Hugh Garavan of the University of Vermont, along with a large group of international colleagues, report that differences in these networks provide strong evidence that some teenagers are at higher risk for drug and alcohol experimentation—simply because their brains work differently, making them more impulsive.

Their findings are presented in the journal Nature Neuroscience, published online April 29, 2012.

This discovery helps answer a long-standing chicken-or-egg question about whether certain brain patterns come before drug use—or are caused by it.

"The differences in these networks seem to precede drug use," says Garavan, Whelan’s colleague in UVM’s psychiatry department, who also served as the principal investigator of the Irish component of a large European research project, called IMAGEN, that gathered the data about the teens in the new study.

In a key finding, diminished activity in a network involving the “orbitofrontal cortex” is associated with experimentation with alcohol, cigarettes and illegal drugs in early adolescence.

"These networks are not working as well for some kids as for others," says Whelan, making them more impulsive.

Faced with a choice about smoking or drinking, the 14-year-old with a less functional impulse-regulating network will be more likely to say, “yeah, gimme, gimme, gimme!” says Garavan, “and this other kid is saying, ‘no, I’m not going to do that.’”

Testing for lower function in this and other brain networks could, perhaps, be used by researchers someday as “a risk factor or biomarker for potential drug use,” Garavan says.

The researchers were also able to show that other newly discovered networks are connected with the symptoms of attention-deficit hyperactivity disorder. These ADHD networks are distinct from those associated with early drug use.

In recent years, there has been controversy and extensive media attention about the possible connection between ADHD and drug abuse. Both ADHD and early drug use are associated with poor inhibitory control—they’re problems that plague impulsive people.

But the new research shows that these seemingly related problems are regulated by different networks in the brain—even though both groups of teens can score poorly on tests of their “stop-signal reaction time,” a standard measure of overall inhibitory control used in this study and other similar ones. This strengthens the idea that risk of ADHD is not necessarily a full-blown risk for drug use as some recent studies suggest.

The impulsivity networks—connected areas of activity in the brain revealed by increased blood flow—begin to paint a more nuanced portrait of the neurobiology underlying the patchwork of attributes and behaviors that psychologists call impulsivity—as well as the capacity to put brakes on these impulses, a set of skills sometimes called inhibitory control.

Edythe London, Professor of Addiction Studies and Director of the UCLA Laboratory of Molecular Pharmacology, who was not part of the new study, described it as “outstanding,” noting that the work by Whelan and others “substantially advances our understanding of the neural circuitry that governs inhibitory control in the adolescent brain.”

Using a complex mathematical approach called factor analysis, Whelan and colleagues were able to fish out seven networks involved when impulses were successfully inhibited and six networks involved when inhibition failed—from the vast and chaotic actions of a teenage brain at work. These networks “light up,” Whelan says, in a functional MRI scanner during trials when the teenagers were asked to perform a repetitive task that involved pushing a button on a keyboard, but then were able to successfully stop—or inhibit—the act of pushing the button in mid-action. Those teens with better inhibitory control were able to succeed at this task faster.

But the underlying networks behind these tasks could not have been detectable in a “typical fMRI study of about 16 or 20 people,” says Whelan. “This study was orders of magnitude bigger, which lets us overcome much of the randomness and noise—and find the brain regions that actually vary together.”

"The take-home message is that impulsivity can be decomposed, broken down into different brain regions," says Garavan, "and the functioning of one region is related to ADHD symptoms, while the functioning of other regions is related to drug use.

The new study draws on the multi-year work of the IMAGEN Consortium, funded by the European Union, and headed by Prof. Gunter Schumann at the Institute of Psychiatry, King’s College London. IMAGEN, lead by a team of scientists across Europe, carried out neuroimaging, genetic and behavioral analyses in 2000 teenage volunteers in Ireland, England, France, and Germany and will be following them for several years, investigating the roots of risk-taking behavior and mental health in teenagers.

That teenagers push against boundaries—and sometimes take risks—is as predictable as the sunrise. It happens in all cultures and even across all mammal species: adolescence is a time to test limits and develop independence.

But death among teenagers in the industrialized world is largely caused by preventable or self-inflicted accidents that are often launched by impulsive risky behaviors, often associated with alcohol and drug use. Additionally, “addiction in the western world is our number one health problem,” says Garavan. “Think about alcohol, cigarettes or harder drugs and all the consequences that has in society for people’s health.” Understanding brain networks that put some teenagers at higher risk for starting to use them could have large implications for public health.

Provided by University of Vermont

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Apr 29, 201219 notes
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Apr 29, 201267 notes
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Fruit Flies Provide New Knowledge About Uninhibited Cell Growth

ScienceDaily (Apr. 27, 2012) — In a new study, scientists at the University of Copenhagen show that a specific type of carbohydrate plays an important role in the intercellular signalling that controls the growth and development of the nervous system. In particular, defects in that carbohydrate may result in the uninhibited cell growth that characterizes the genetic disease neurofibromatosis and certain types of cancer.

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Egghead to the right: Changes in cellular growth. (Credit: Klaus Qvortrup)

The results have just been published in the well-reputed journal PNAS.

Scientists from The Faculty of Health and Medical Sciences at the University of Copenhagen have put a special type of fruit fly under the microscope. The new research results turn the spotlight on a certain group of carbohydrates — the so-called glycolipids — and their influence on the cells’ complicated communication system. In the long term, this model study can shine new light on the disease neurofibromatosis for the benefit of patients the world over.

"The most important thing about our discovery right now is that we document a new function for carbohydrates in the communication between cells. We also show how disturbances in the signalling pathways cause changes in cellular growth. This is knowledge that cancer researchers can develop," says Ole Kjærulff, doctor and associate professor at the Department of Neuroscience and Pharmacology, who has conducted the study together with Dr. Katja Dahlgaard, and Hans Wandall, associate professor at the Copenhagen Center for Glycomics.

Sugar chains control cell growth

Glycolipids are compounds consisting of fats linked to long chains of sugar molecules. They are located in the cell membrane, where they serve various functions, such as protecting the cell or making it recognizable to the immune system.

"In the fruit fly model, if we prevent the sugar chains from lengthening, we can show that carbohydrate plays an important role in controlling the growth of normal cells. When the sugar chains are shortened, the tissue grows dramatically on account of increased cell division. In particular, it appears that the nervous system’s support cells — the glia cells — are influenced," explains Hans Wandall, associate professor.

Neurofibromatosis can cause deformity

The new results also influence our understanding of neurofibromatosis. This is a heritable disorder that results in unsightly tumours — so-called neurofibromas — in the nerves and skin. The disease affects approximately 20 people out of 100,000 and varies from mild to severe cases with decided deformities. The condition also affects the bones and often causes learning problems:

"When you get closer to an understanding of the mechanisms that result in a certain disease, naturally it is easier to influence the disease process in the form of drug development in the longer term. Neurofibromatosis is not a terminal disease, but it very much affects the life quality of the people who have it because the symptoms are so noticeable," explains Ole Kjærulff. Hans Wandall adds that the disease is also associated with certain types of cancer, particularly in the brain.

Source: Science Daily 

Apr 28, 20124 notes
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Maintain your brain: The secrets to aging success

April 27, 2012

Aging may seem unavoidable, but that’s not necessarily so when it comes to the brain. So say researchers in the April 27th issue of the Cell Press journal Trends in Cognitive Sciences explaining that it is what you do in old age that matters more when it comes to maintaining a youthful brain not what you did earlier in life.

"Although some memory functions do tend to decline as we get older, several elderly show well preserved functioning and this is related to a well-preserved, youth-like brain," says Lars Nyberg of Umeå University in Sweden.

Education won’t save your brain — PhDs are as likely as high-school dropouts to experience memory loss with old age, the researchers say. Don’t count on your job either. Those with a complex or demanding career may enjoy a limited advantage, but those benefits quickly dwindle after retirement.

Engagement is the secret to success. Those who are socially, mentally and physically stimulated reliably show better cognitive performance with a brain that appears younger than its years.

"There is quite solid evidence that staying physically and mentally active is a way towards brain maintenance," Nyberg says.

The researchers say this new take on successful aging represents an important shift in focus for the field. Much attention in the past has gone instead to understanding ways in which the brain copes with or compensates for cognitive decline in aging. The research team now argues for the importance of avoiding those age-related brain changes in the first place. Genes play some role, but life choices and other environmental factors, especially in old age, are critical.

Elderly people generally do have more trouble remembering meetings or names, Nyberg says. But those memory losses often happen later than many often think, after the age of 60. Older people also continue to accumulate knowledge and to use what they know effectively, often to very old ages.

"Taken together, a wide range of findings provides converging evidence for marked heterogeneity in brain aging," the scientists write. "Critically, some older adults show little or no brain changes relative to younger adults, along with intact cognitive performance, which supports the notion of brain maintenance. In other words, maintaining a youthful brain, rather than responding to and compensating for changes, may be the key to successful memory aging."

Provided by Cell Press

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Apr 28, 201213 notes
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Childhood socioeconomic status affects brain volume

April 27, 2012

(HealthDay) — Childhood socioeconomic status affects hippocampal volume in older adults, after adjusting for adult socioeconomic status, gender, education, and other factors, according to a study published in the May issue of the Annals of Neurology.

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Childhood socioeconomic status affects hippocampal volume in older adults, after adjusting for adult socioeconomic status, gender, education, and other factors, according to a study published in the May issue of the Annals of Neurology.

Roger T. Staff, Ph.D., of the Aberdeen Royal Infirmary in the United Kingdom, and colleagues used magnetic resonance imaging of the brain to measure whole brain and hippocampal volume in 249 volunteers without dementia who were born in 1936. Childhood socioeconomic status history was recorded and mental ability at age 11 (recorded in 1947) was available for all participants.

After adjusting for mental ability at age 11 years, adult socioeconomic status, gender, and education, the researchers observed a significant association between childhood socioeconomic status and hippocampal volume.

"Early life socioeconomic conditions contribute to hippocampal volume in late adulthood independently of later life circumstances," the authors conclude. "These findings suggest that the capacity to compensate for age-related neuropathology (reserve) may well be established in early life."

More information: Abstract

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Apr 28, 201211 notes
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Novel Regulatory Molecules Called Mirror-microRNAs Control Multiple Aspects of Brain Function

ScienceDaily (Apr. 27, 2012) — Our genes control many aspects of who we are — from the colour of our hair to our vulnerability to certain diseases — but how are the genes, and consequently the proteins they make themselves controlled? Researchers have discovered a new group of molecules which control some of the fundamental processes behind memory function and may hold the key to developing new therapies for treating neurodegenerative diseases.

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The mirror-miRNA (red) is expressed in hippocampal neurons, the nucleus is shown in blue. (Credit: Image courtesy of University of Bristol)

The research, led by academics from the University of Bristol’s Schools of Clinical Sciences, Biochemistry and Physiology & Pharmacology and published in the Journal of Biological Chemistry, has revealed a new group of molecules, called mirror-microRNAs.

MicroRNAs are non-coding genes that often reside within ‘junk DNA’ and regulate the levels and functions of multiple target proteins — responsible for controlling cellular processes in the brain. The study’s findings have shown that two microRNA genes with different functions can be produced from the same piece (sequence) of DNA — one is produced from the top strand and another from the bottom complementary ‘mirror’ strand.

Specifically, the research has shown that a single piece of human DNA gives rise to two fully processed microRNA genes that are expressed in the brain and have different and previously unknown functions. One microRNA is expressed in the parts of nerve cells that are known to control memory function and the other microRNA controls the processes that move protein cargos around nerve cells.

James Uney, Professor of Molecular Neuroscience in the University’s School of Clinical Sciences, said: “These findings are important as they show that very small changes in microRNA genes will have a dramatic effect on brain function and may influence our memory function or likelihood of developing neurodegenerative diseases. These findings also suggest that many more human mirror microRNAs will be found and that they could ultimately be used as treatments for human neurodegenerative diseases such as dementia.”

MicroRNAs can be seen as a novel regulatory layer within the genome, relying on the interaction between different RNA molecules. Through binding to messenger RNA (mRNA), they adjust the levels of proteins. Due to their small size, they are able to regulate many different RNAs. MicroRNAs have already been found throughout the double helix, lying in between genes or in areas of the code for a single gene that would normally be discarded. Such areas that were once considered “junk DNA” are now revealing a more complex and important role. In addition microRNAs can be produced in conjunction with their genes, within which they lie, or be controlled and produced entirely independently.

Helen Scott and Joanna Howarth, the lead authors on the study, added: “We have now found that both sides of the double helix can each produce a microRNA. These two microRNAs are almost a perfect mirror of each other, but due to slight differences in their sequence, they regulate different sets of protein producing RNAs, which will in turn affect different biological functions. Such mirror-miRNAs are likely to represent a new group of microRNAs with complex roles in coordinating gene expression, doubling the capacity of regulation.”

Source: Science Daily

Apr 28, 20128 notes
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New Form of Intellectual Disability Discovered

ScienceDaily (Apr. 27, 2012) — Researchers at the Centre for Addiction and Mental Health (CAMH) led a study discovering a gene for a new form of intellectual disability, as well as how it likely affects cognitive development by disrupting neuron functioning.

CAMH Senior Scientist Dr. John Vincent and his team found a mutation in the gene NSUN2 among three sisters with intellectual disability, a finding to be published in the May issue of the American Journal of Human Genetics.

The discovery was made after mapping genes in a Pakistani family, in which three of seven siblings had intellectual disability as well as muscle weakness and walking difficulties, says Dr. Vincent, who heads the Molecular Neuropsychiatry and Development Laboratory in the Campbell Family Mental Health Research Institute at CAMH.

Intellectual disability is a condition in which individuals have limitations in their mental abilities and in functioning in daily life. It affects one to three per cent of the population, and is often caused by genetic mutations.

Another study in the same journal, submitted together with the CAMH-led research, also identified NSUN2 gene mutations in Iranian and Kurdish families with intellectual disability. As with the Pakistani family, first cousin marriages in these families carrying the mutations increased the likelihood of intellectual disability among their children, and enabled researchers to focus on areas to map genes.

"The combined results from these two studies mean that NSUN2 is among the most common causes of intellectual disability resulting from recessive genes," says Dr. Vincent.

As a recessive disorder, a child must inherit one defective NSUN2 gene from each parent to develop intellectual disability. This gene, located on chromosome 5p, encodes a type of protein called an RNA methyltransferase.

At the cellular level, the researchers found that the mutated protein was prevented from reaching its target area within the nucleus of a cell. As a result, it was unable to perform its normal role in cell division and/or RNA methylation.

Collaborators from the Wellcome Trust Centre for Stem Cell Research in Cambridge, U.K., showed which type of brain cells were likely to be most affected by this mutation. They are called Purkinje cells, a type of neuron that responds to the neurotransmitter GABA. Purkinje cells also control motor coordination, which were affected in the Pakistani family.

"We speculate that the muscle effects may result from the accumulation of the NSUN2 protein outside its target area in the nucleus," says Dr. Vincent.

To date, Dr. Vincent’s lab has identified five genes causing different forms of recessive intellectual disability.

Source: Science Daily

Apr 28, 20123 notes
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Analytic Thinking Can Decrease Religious Belief, Study Shows

ScienceDaily (Apr. 26, 2012) — A new University of British Columbia study finds that analytic thinking can decrease religious belief, even in devout believers.

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The statue “The Thinker,” by Auguste Rodin. (Credit: © Ignatius Wooster / Fotolia)

The study, which is published in the April 27 issue of Science, finds that thinking analytically increases disbelief among believers and skeptics alike, shedding important new light on the psychology of religious belief.

“Our goal was to explore the fundamental question of why people believe in a God to different degrees,” says lead author Will Gervais, a PhD student in UBC’s Dept. of Psychology. “A combination of complex factors influence matters of personal spirituality, and these new findings suggest that the cognitive system related to analytic thoughts is one factor that can influence disbelief.”

Researchers used problem-solving tasks and subtle experimental priming – including showing participants Rodin’s sculpture The Thinker or asking participants to complete questionnaires in hard-to-read fonts – to successfully produce “analytic” thinking. The researchers, who assessed participants’ belief levels using a variety of self-reported measures, found that religious belief decreased when participants engaged in analytic tasks, compared to participants who engaged in tasks that did not involve analytic thinking.

The findings, Gervais says, are based on a longstanding human psychology model of two distinct, but related cognitive systems to process information: an “intuitive” system that relies on mental shortcuts to yield fast and efficient responses, and a more “analytic” system that yields more deliberate, reasoned responses.

“Our study builds on previous research that links religious beliefs to ‘intuitive’ thinking,” says study co-author and Associate Prof. Ara Norenzayan, UBC Dept. of Psychology. “Our findings suggest that activating the ‘analytic’ cognitive system in the brain can undermine the ‘intuitive’ support for religious belief, at least temporarily.”

The study involved more than 650 participants in the U.S. and Canada. Gervais says future studies will explore whether the increase in religious disbelief is temporary or long-lasting, and how the findings apply to non-Western cultures.

Recent figures suggest that the majority of the world’s population believes in a God, however atheists and agnostics number in the hundreds of millions, says Norenzayan, a co-director of UBC’s Centre for Human Evolution, Cognition and Culture. Religious convictions are shaped by psychological and cultural factors and fluctuate across time and situations, he says.

Source: Science Daily

Apr 28, 201224 notes
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Mechanism That Could Contribute to Problems in Alzheimer's Identified

ScienceDaily (Apr. 26, 2012) — Scientists at the Gladstone Institutes have unraveled a process by which depletion of a specific protein in the brain contributes to the memory problems associated with Alzheimer’s disease. These findings provide insights into the disease’s development and may lead to new therapies that could benefit the millions of people worldwide suffering from Alzheimer’s and other devastating neurological disorders.

The study, led by Gladstone Investigator Jorge J. Palop, PhD, revealed that low levels of a protein, called Nav1.1, disrupt the electrical activity between brain cells. Such activity is crucial for healthy brain function and memory. Indeed, the researchers found that restoring Nav1.1 levels in mice that were genetically modified to mimic key aspects of Alzheimer’s disease (AD-mice) improved learning and memory functions and increased their lifespan. Their findings are featured on the cover of the April 27 issue of Cell, available online April 26.

"It is estimated that more than 30 million people worldwide suffer from Alzheimer’s disease and that number is expected to rise dramatically in the near future," said Lennart Mucke, MD, who directs neurological research at Gladstone, an independent and nonprofit biomedical-research organization. "This research improves our understanding of the biological processes that underlie cognitive dysfunction in this disease and could open the door for new therapeutic interventions."

The researchers’ findings suggest that Nav1.1 levels in special regulatory nerve cells called parvalbumin cells, or PV cells, are essential to generate healthy brain-wave activity — and that problems in this process contribute to cognitive decline in AD-mice and possibly in patients with Alzheimer’s.

In the brain, neurons form highly interconnected networks, using chemical and electrical signals to communicate with each other. The researchers investigated whether this communication between neurons is disrupted in AD-mice, and if so, how this may affect the symptoms of Alzheimer’s disease.

To study this, they performed electroencephalogram (EEG) recordings — a technique that detects abnormalities in the brain’s electrical waves such as those found in patients with epilepsy. They found that similar abnormalities emerged during periods of reduced gamma-wave oscillations — a type of brain wave that is crucial to regulating learning and memory.

"Like a conductor in an orchestra, PV cells regulate brain rhythms by precisely controlling excitatory brain activity," said Laure Verret, PhD, postdoctoral fellow and lead author. "We found that PV cells in patients with Alzheimer’s and in AD-mice have low levels of the protein Nav1.1 — likely contributing to PV cell dysfunction. As a consequence, AD-mice had abnormal brain rhythms. By restoring Nav1.1 levels, we were able to re-establish normal brain function."

Indeed, the scientists found that increasing Nav1.1 levels in PV cells improves brain wave activity, learning, memory and survival rates in AD-mice.

"Enhancing Nav1.1 activity, and consequently improving PV cell function, may help in the treatment of Alzheimer’s disease and other neurological disorders associated with gamma-wave alterations and cognitive impairments such as epilepsy, autism and schizophrenia," said Dr. Palop, who is also an assistant professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "These findings may allow us to develop therapies to help patients with these devastating diseases."

Source: Science Daily

Apr 27, 20124 notes
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Clues to Reverse Cognitive Deficits in People With Neurological Disorders

ScienceDaily (Apr. 26, 2012) — The ability to navigate using spatial cues was impaired in mice whose brains were minus a channel that delivers potassium — a finding that may have implications for humans with damage to the hippocampus, a brain structure critical to memory and learning, according to a Baylor University researcher.

Mice missing the channel also showed diminished learning ability in an experiment dealing with fear conditioning, said Joaquin Lugo, Ph.D., the lead author in the study and an assistant professor of psychology and neuroscience in Baylor’s College of Arts & Sciences. “By targeting chemical pathways that alter those potassium channels, we may eventually be able to apply the findings to humans and reverse some of the cognitive deficits in people with epilepsy and other neurological disorders,” Lugo said.

The research was done in Baylor College of Medicine Intellectual and Developmental Disabilities Research Center Mouse Neurobehavior Core in Houston during Lugo’s time as a researcher there.

The findings are published online in the journal Learning & Memory.

The channel, called Kv4.2, delivers potassium, which aids neuron function in the brain’s hippocampus. The hippocampus forms memory for long-term storage in the brain. Potassium also helps to regulate excitability.

Individuals who have epilepsy sometimes exhibit altered or missing Kv.4.2 channels or similar types of channels.

In the experiment investigating navigation, “knockout” mice — those without the channel — were tested in a water maze four feet in diameter and 12 inches deep, with eight trials daily — each lasting about a minute — over four days, he said. Their performance was compared with that of normal mice.

Both groups responded to visual cues — colored symbols — in learning their way around the maze, but the knockout mice did not respond as well as the normal mice in terms of spatial cues — hidden platforms in the water.

"When the mice don’t have this channel, it hurts their ability to learn," Lugo said. In a separate experiment examining fear conditioning, both knockout mice and normal mice were placed in a cage, and researchers sounded a tone before giving the mice a mild electric shock. In repeated trials, both groups began to freeze upon hearing the tone as they anticipated a shock. But the normal mice also reacted to the context — being placed in the cage — while the mice who did not have the Kv4.2 channel reacted only to the tone. The research was funded by the Epilepsy Foundation and the National Institutes of Health.

Source: Science Daily

Apr 27, 20122 notes
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Learning Mechanism of the Adult Brain Revealed

ScienceDaily (Apr. 26, 2012) — They say you can’t teach an old dog new tricks. Fortunately, this is not always true. Researchers at the Netherlands Institute for Neuroscience (NIN-KNAW) have now discovered how the adult brain can adapt to new situations. The Dutch researchers’ findings are published on April 25 in the journal Neuron. Their study may be significant in developing treatments of neurodevelopmental disorders.

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Two inhibitory synapses (yellow) disappear from the process of a nerve-cell (red) during learning. (Credit: Image courtesy of Netherlands Institute for Neuroscience)

Ability to learn

Our brain processes information in complex networks of nerve cells. The cells communicate and excite one another through special connections, called synapses. Young brains are capable of forming many new synapses, and they are consequently better at learning new things. That is why we acquire vital skills — walking, talking, hearing and seeing — early on in life. The adult brain stabilises the synapses so that we can use what we have learned in childhood for the rest of our lives.

Disappearing inhibitors

Earlier research found that approximately one fifth of the synapses in the brain inhibit rather than excite other nerve-cell activity. Neuroscientists have now shown that many of these inhibitory synapses disappear if the adult brain is forced to learn new skills. They reached this conclusion by labelling inhibitory synapses in mouse brains with fluorescent proteins and then tracking them for several weeks using a specialised microscope. They then closed one of the mice’s eyes temporarily to accustom them to seeing through just one eye. After a few days, the area of the brain that processes information from both eyes began to respond more actively to the open eye. At the same time, many of the inhibitory synapses disappeared and were later replaced by new synapses.

Regulating the information network

Inhibitory synapses are vital for the way networks function in the brain. “Think of the excitatory synapses as a road network, with traffic being guided from A to B, and the inhibitory synapses as the matrix signs that regulate the traffic,” explains research leader Christiaan Levelt. “The inhibitory synapses ensure an efficient flow of traffic in the brain. If they don’t, the system becomes overloaded, for example as in epilepsy; if they constantly indicate a speed of 20 kilometres an hour, then everything will grind to a halt, for example when an anaesthetic is administered. If you can move the signs to different locations, you can bring about major changes in traffic flows without having to entirely reroute the road network.”

Hope

Inhibitory synapses play a hugely influential role on learning in the young brain. People who have neurodevelopmental disorders — for example epilepsy, but also autism and schizophrenia — may have trouble forming inhibitory synapses. The discovery that the adult brain is still capable of pruning or forming these synapses offers hope that pharmacological or genetic intervention can be used to enhance or manage this process. This could lead to important guideposts for treating the above-mentioned neurological disorders, but also repairing damaged brain tissue.

Source: Science Daily

Apr 27, 201281 notes
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Learning mechanism of the adult brain revealed

April 26, 2012

They say you can’t teach an old dog new tricks. Fortunately, this is not always true. Researchers at the Netherlands Institute for Neuroscience have now discovered how the adult brain can adapt to new situations. The Dutch researchers’ findings are published on Wednesday in the prestigious journal Neuron. Their study may be significant in the treatment of neurodevelopmental disorders such as epilepsy, autism and schizophrenia.

Our brain processes information in complex networks of nerve cells. The cells communicate and excite one another through special connections, called synapses. Young brains are capable of forming many new synapses, and they are consequently better at learning new things. That is why we acquire vital skills – walking, talking, hearing and seeing – early on in life. The adult brain stabilises the synapses so that we can use what we have learned in childhood for the rest of our lives.

Earlier research found that approximately one fifth of the synapses in the brain inhibit rather than excite other nerve-cell activity. Neuroscientists have now shown that many of these inhibitory synapses disappear if the adult brain is forced to learn new skills. They reached this conclusion by labelling inhibitory synapses in mouse brains with fluorescent proteins and then tracking them for several weeks using a specialised microscope. They then closed one of the mice’s eyes temporarily to accustom them to seeing through just one eye. After a few days, the area of the brain that processes information from both eyes began to respond more actively to the open eye. At the same time, many of the inhibitory synapses disappeared and were later replaced by new synapses.

Inhibitory synapses are vital for the way networks function in the brain. “Think of the excitatory synapses as a road network, with traffic being guided from A to B, and the inhibitory synapses as the matrix signs that regulate the traffic,” explains research leader Christiaan Levelt. “The inhibitory synapses ensure an efficient flow of traffic in the brain. If they don’t, the system becomes overloaded, for example as in epilepsy; if they constantly indicate a speed of 20 kilometres an hour, then everything will grind to a halt, for example when an anaesthetic is administered. If you can move the signs to different locations, you can bring about major changes in traffic flows without having to entirely reroute the road network.”

Inhibitory synapses play a hugely influential role on learning in the young brain. People who have neurodevelopmental disorders – for example epilepsy, but also autism and schizophrenia – may have trouble forming inhibitory synapses. The discovery that the adult brain is still capable of pruning or forming these synapses offers hope that pharmacological or genetic intervention can be used to enhance or manage this process. This could lead to important guideposts for treating the above-mentioned neurological disorders, but also repairing damaged brain tissue.

Provided by Royal Netherlands Academy of Arts and Sciences

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Apr 27, 20122 notes
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Watching neurons learn

April 26, 2012

What happens at the level of individual neurons while we learn? This question intrigued the neuroscientist Daniel Huber, who recently arrived at the Department of Basic Neuroscience at the University of Geneva. During his stay in the United States, he and his team tried to unravel the network mechanisms underlying learning and memory at the level of the cerebral cortex.

What’s the role of individual neurons in behavior? Do they always participate in the same functions? How do their responses evolve during learning?” asks the professor. One way to address these questions is to follow the activity of a large set of neurons while the subject learns a novel task. The goal is to link the behavioral changes with the changes in neuronal representations.

It’s currently impossible to follow the activity of a large number of individual neurons in humans, but the team of researchers quickly realized that mice are excellent subjects for such studies. “We were surprised by capacities of these small rodents. They learn novel associations quickly and are able to focus for hours on complex behavioral tasks. However, it is important to keep them motivated by rewarding them accordingly. They are very similar to us in that way.”

The behavioral task of the mice consisted in sampling the area in front of their snout with their whiskers to search for a small object. The object was presented either within reach and out of reach of their whiskers. Each time the object was detected with the whiskers, the mouse had to respond by licking to a reward spout. The correct choices were rewarded with a drop of liquid. “In this task different sensory and motor circuits have to interact in order to establish a novel association, leading to better and better performance”.

Remained the problem of how to follow the activity of the large number of neurons across many days of learning. The researchers replaced a small part of the bone overlying motor cortex with a tiny glass window. The neurons underneath the window were genetically modified to express a fluorescent marker which changes its intensity according to the activity of the neurons. This window into the brain allowed the researches around Daniel Huber to use two-photon microscopy to record the activity of the same set of 500 neurons during days of learning. 

"We then correlated the activity of the individual neurons with the different actions of the mouse, such as moving the whiskers, touching the object or licking at the right moment. It’s like synchronizing the soundtrack with the images in a movie" adds the neuroscientist. The researchers analyzed this data using a series of computational approaches to establish a link between the neuronal activity and the different sensory and motor features of the task. This allowed them to build algorithmic models that can predict different motor outputs by solely monitoring the neuronal activity. Decoding the neuronal activity allowed the researchers then to construct functional maps of the recorded neurons and quantify each neuron’s link with the different aspects of the behavior.

These functional maps revealed several fundamental findings: “Although the movements of the whiskers became more and more precise and targeted to search for the object during the learning, their relative neuronal representation remained relatively stable. In contrast, the representation of licking to respond and collect the rewards became more and more pronounced”. Taken together, only selected aspects of the learned behavior induced changes it the neuronal representation in the cortex. The scientists also found that different sensory and motor representations are spatially intermingled in the rodent brain.

Other analysis revealed that individual neurons remain stably linked to a given behavioral function, but they have a flexibility to remain silent on a given day. This functional stability despite a flexibility to join (or not) a given representation was actually suggested by different theoretical work on learning.

"If these characteristics are limited to the motor cortex or if these are more general rules that are apply across the cerebral cortex remains open" says Daniel Huber. That in fact this is one of the questions we are currently investigating in my lab in Geneva".

Provided by University of Geneva

Source: medicalxpress.com

Apr 27, 20125 notes
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Seeing is as seeing does: Spatially-structured retinal input in early development of cortical maps

April 26, 2012 by Stuart Mason Dambrot

(Medical Xpress) — Remarkably, cortical maps show that neurons in the primary visual cortex have specific preferences for the location and orientation of a given visual field stimulus – but how these maps develop and what function they play in visual processing remains a mystery. Evidence suggests that the retinotopic map is established by molecular gradients, but little is known about how orientation maps are wired. One hypothesis: at their inception, these orientation maps are seeded by the spatial interference of ON- and OFF-center retinal receptive field mosaics. Recently, scientists in the Departments of Neurobiology and Psychology at the University of California, Los Angeles have shown that this proposed mechanism predicts a link between the layout of orientation preferences around singularities of different signs and the cardinal axes of the retinotopic map, and have confirmed this prediction in the tree shrew primary visual cortex. The researchers say their findings support the idea that spatially structured retinal input may provide a blueprint of sorts for the early development of cortical maps and receptive fields – and that the same may hold true for other senses as well.

image

Moiré interference of retinal mosaics predicts a link between retinotopic and orientation maps. (A) (Upper) Two hexagonal lattices representing ON- (red) and OFF-center (blue) ganglion cell receptive fields/ (Lower) A cortical cell with input dominated by a dipole has a receptive field with side-by-side subregions of opposite sign and can be tuned for orientation. (B) (Upper) The orientation of dipoles in the interference pattern, indicated by the orientation of short line segments, changes over space, generating a blueprint for an orientation map. (Lower) The organization of orientation preferences around negative (Left) and positive (Right) singularities. Image Courtesy PNAS, doi: 10.1073/pnas.1118926109

Professor of Neurobiology and Psychology Dario L. Ringach articulates the primary elements of showing that the hypothesis that orientation maps are initially seeded by the spatial interference of ON- and OFF-center retinal receptive field mosaics corresponds to a mechanism that predicts a link between the layout of orientation preferences around singularities of different signs and the cardinal axes of the retinotopic map. “The cerebral cortex of higher mammals contains diverse maps,” he tells Medical Xpress, “where information about sensory input or motor planning is laid out systematically across the surface of a given cortical area. Some scientists have postulated that these computational maps are key to cortical function. However, we still do not know exactly what role cortical maps play in normal sensory and motor processes.” Their importance, he stresses, is that understanding how cortical maps are wired during development, and what types of pathology may arise from their faulty wiring, are fundamental questions of brain function.

Ringach also notes that neurons in primary visual cortex are selective to the orientation of a stimulus in visual space, and their preference changes systematically across the cortical surface in a periodic fashion. “We know these maps are present at the earliest stages of life,” he continues, “and do not require normal sensory experience to develop – but how do they wire themselves? We’ve postulated that the initial structure of these maps is biased by the spatial organization of the periphery.” In the visual system this is represented by the signals the retina within the eye conveys to the brain.

The researchers’ model postulates that at each location in the visual field, the input from the retina constraints the range of orientation preferences that the cortex can implement at that location. “We show that, given what is known about the organization of retinal signals, that such constraints would be quasi-periodic, thereby potentially providing the blueprint for an orientation map in the cortex.” One prediction of this theory is that groups of neurons preferring the same orientation should be arranged on an approximate hexagonal lattice on the cortical surface – a prediction the researchers confirmed in a previous study1. 

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Apr 27, 201211 notes
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Gauging seizures' severity

April 26, 2012 by Larry Hardesty

In this week’s issue of the journal Neurology, researchers at MIT and two Boston hospitals provide early evidence that a simple, unobtrusive wrist sensor could gauge the severity of epileptic seizures as accurately as electroencephalograms (EEGs) do — but without the ungainly scalp electrodes and electrical leads. The device could make it possible to collect clinically useful data from epilepsy patients as they go about their daily lives, rather than requiring them to come to the hospital for observation. And if early results are borne out, it could even alert patients when their seizures are severe enough that they need to seek immediate medical attention.

Rosalind Picard, a professor of media arts and sciences at MIT, and her group originally designed the sensors to gauge the emotional states of children with autism, whose outward behavior can be at odds with what they’re feeling. The sensor measures the electrical conductance of the skin, an indicator of the state of the sympathetic nervous system, which controls the human fight-or-flight response.

In a study conducted at Children’s Hospital Boston, the research team — Picard, her student Ming-Zher Poh, neurologist Tobias Loddenkemper and four colleagues from MIT, Children’s Hospital and Brigham and Women’s Hospital — discovered that the higher a patient’s skin conductance during a seizure, the longer it took for the patient’s brain to resume the neural oscillations known as brain waves, which EEG measures.

At least one clinical study has shown a correlation between the duration of brain-wave suppression after seizures and the incidence of sudden unexplained death in epilepsy (SUDEP), a condition that claims thousands of lives each year in the United States alone. With SUDEP, death can occur hours after a seizure.

Currently, patients might use a range of criteria to determine whether a seizure is severe enough to warrant immediate medical attention. One of them is duration. But during the study at Children’s Hospital, Picard says, “what we found was that this severity measure had nothing to do with the length of the seizure.” Ultimately, data from wrist sensors could provide crucial information to patients deciding whether to roll over and go back to sleep or get to the emergency room.

Surprising signals

The realization that the wrist sensors might be of use in treating epilepsy was something of a fluke. “We’d been working with kids on the autism spectrum, and I didn’t realize, but a lot of them have seizures,” Picard says. In reviewing data from their autism studies, Picard and her group found that seizures were sometimes preceded by huge spikes in skin conductance. It seemed that their sensors might actually be able to predict the onset of seizures.

At the time, several MIT students were working in Picard’s lab through MIT’s Undergraduate Research Opportunities Program (UROP); one of them happened to be the daughter of Joseph Madsen, director of the Epilepsy Surgery Program at Children’s Hospital. “I decided it was time to meet my UROP’s dad,” Picard says.

In a project that would serve as the basis of Poh’s doctoral dissertation, Madsen agreed to let the MIT researchers test the sensors on patients with severe epilepsy, who were in the hospital for as much as a week of constant EEG monitoring. Poh and Picard considered several off-the-shelf sensors for the project, but “at the time, there was nothing we could buy that did what we needed,” Picard says. “Finally, we just built our own.”

"It’s a big challenge to make a device robust enough to withstand long hours of recording," Poh says. "We were recording days or weeks in a row." In early versions of the sensors, some fairly common gestures could produce false signals. Eliminating the sensors’ susceptibility to such sources of noise was largely a process of trial and error, Picard says.

Blending in

Additionally, Poh says, “I put a lot of thought into how to make it really comfortable and as nonintrusive as possible. So I packaged it all into typical sweatbands.” Since the patients in the study were children, “I allowed them to choose their favorite character on their wristband — for example, Superman, or Dora the Explorer, whatever they like,” Poh says. “To them, they were wearing a wristband. But there was a lot of complicated sensing going on inside the wristband.” Indeed, Picard says, the researchers actually lost five of their homemade sensors because hospital cleaning staff saw what they thought were ratty sweatbands lying around recently vacated rooms and simply threw them out.

Picard is continuing to investigate the possibility that initially intrigued her — that the devices could predict seizures. In the meantime, however, her collaborators at Children’s Hospital are conducting a study that will follow up on the one reported in Neurology, and a similar study is beginning at Brigham and Women’s Hospital. Rather than sweatbands with TV and comic-book characters, however, the new studies will use sensors produced by Affectiva, a company that Picard started in order to commercialize her lab’s work.

Provided by Massachusetts Institute of Technology 

Source: medicalxpress.com

Apr 27, 20122 notes
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Scientists discover a ‘handbrake’ for MS

April 26, 2012

(Medical Xpress) — The progression of the debilitating disease Multiple Sclerosis (MS) could be slowed or even halted by blocking a protein that contributes to nerve damage, according to a new study.

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Professor Claude Bernard and Dr Steven Petratos

In research published today in the journal Brain, scientists from the Monash Immunology and Stem Cell Laboratories (MISCL), the University of Toronto, Yale and the University of Western Australia, have demonstrated the key role played by the collapsin response mediator protein 2 (CRMP-2) in the development of MS.

Led by MISCL’s Dr Steven Petratos, also of RMIT University, and Professor Claude Bernard, the research team found that a modified version of CRMP-2 is present in active MS lesions, which indicate damage to the nervous system, in a laboratory model of MS.

The modified CRMP-2 interacts with another protein to cause nerve fibre damage that can result in numbness, blindness, difficulties with speech and motor skills, and cognitive impairments in sufferers.

When either the modified CRMP-2 or the interaction between the two proteins was blocked, using a method already approved in both the US and Australia, the progression of the disease was halted.

Director of MISCL, Professor Richard Boyd said the discovery could lead to new treatments for MS.

“Blocking the same protein in people with MS could provide a ‘handbrake’ to the progression of the disease,” Professor Boyd said.

Dr Petratos said the method used to block the protein was approved for the treatment of other disease conditions by both the US Food and Drug Administration and Australia’s Therapeutic Goods Administration.

“This should mean that clinical trials – once they start – will be fast tracked as the form of administration has already been approved,” Dr Petratos said.

MS Australia estimates that the disease affects more than 20,000 people in Australia, and up to 2.5 million worldwide. The disease tends to strike early in adulthood, with women three times more likely than men to be diagnosed. The total cost to the Australian community of the disease is estimated at $1 billion annually.

The research received major funding from the National Multiple Sclerosis Society of the United States of America and partial funding from MS Research Australia.

Provided by Monash University

Source: medicalxpress.com

Apr 27, 201212 notes
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Striatal brain volume predicts Huntington disease onset

April 26, 2012

Huntington disease (HD) is an inherited neurodegenerative disorder caused by a defect on chromosome four where, within the Huntingtin gene, a CAG repeat occurs too many times. Most individuals begin experiencing symptoms in their 40s or 50s, but studies have shown that significant brain atrophy occurs several years prior to an official HD diagnosis. As a result, the field has sought a preventive treatment that could be administered prior to the development of actual symptoms that might delay the onset of illness.

Using data from the ongoing PREDICT-HD study and led by Dr. Elizabeth Aylward, author and Associate Director at the Center for Integrative Brain Research, Seattle Children’s Research Institute, researchers examined whether neuroimaging measures can improve the accuracy of prediction of disease onset.

The PREDICT- HD study is an international, multi-site, long-term study of individuals who carry the gene mutation for Huntington disease but entered the study prior to onset of diagnosable motor impairment. Participants underwent structural magnetic resonance imaging (MRI) scans, which allowed for the comparison of individuals who developed HD during the course of the study and those who had not yet been diagnosed with HD.

They found that striatum and white matter volumes in the brain were significantly smaller in individuals diagnosed 1 to 4 years following the initial scan, suggesting that these volumetric measures can assist in determining which individuals are closest to disease onset.

"We believe that the results of this study will be important in designing future clinical trials for individuals who have the Huntington disease gene mutation, but who are not yet showing symptoms. We also believe this group of individuals is well suited for drug intervention studies, as their brain involvement is not as severe as those who have already been diagnosed," said Dr. Aylward.

"Huntington disease can be considered a model neuropsychiatric disorder, since it is caused by a single gene and has such predictable and well-characterized brain changes. It may guide thinking about other disorders with genetic contribution, such as schizophrenia," commented Dr. Christopher A. Ross, co-author and Professor of Psychiatry, Neurology and Neuroscience, Johns Hopkins University. "If we could better understand the natural history of brain changes in schizophrenia, for instance, we may be able to identify genetically vulnerable individuals, and intervene therapeutically, not just to treat symptoms, but to alter the biology and course of the disease."

Dr. John Krystal, Editor of Biological Psychiatry, agreed, noting that “biomarkers of illness progress are critical for all neuropsychiatric disorders.”

For now, these results may enhance the formulas used to calculate age of onset and help aid in the planning of future clinical trials aimed at delaying disease onset.

"Identifying individuals who are close to onset of diagnosable symptoms will allow feasible studies that use onset of symptoms as the primary outcome measure to determine if a drug intervention is effective," Dr. Aylward added. "Although it would be unreasonable to suggest that all potential clinical trial participants receive MRI scans one to four years prior to taking part in a trial, there are many individuals who have participated in pre-HD observational studies who already have such data available."

Perhaps more importantly, Dr. Krystal concluded that “the development of good disease staging using MRI in Huntington disease could assist investigators studying novel treatments and affected individuals and family members anxious to learn about disease progress.”

Provided by Elsevier

Source: medicalxpress.com

Apr 27, 2012
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Action Videogames Change Brains, Improve Visual Attention

ScienceDaily (Apr. 26, 2012) — A team led by psychology professor Ian Spence at the University of Toronto reveals that playing an action videogame, even for a relatively short time, causes differences in brain activity and improvements in visual attention.

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Playing an action videogame, even for a relatively short time, causes differences in brain activity and improvements in visual attention. (Credit: © j0yce / Fotolia)

Previous studies have found differences in brain activity between action videogame players and non-players, but these could have been attributed to pre-existing differences in the brains of those predisposed to playing videogames and those who avoid them. This is the first time research has attributed these differences directly to playing video games.

Twenty-five subjects — who had not previously played videogames — played a game for a total of 10 hours in one to two hour sessions. Sixteen of the subjects played a first-person shooter game and, as a control, nine subjects played a three-dimensional puzzle game.

Before and after playing the games, the subjects’ brain waves were recorded while they tried to detect a target object among other distractions over a wide visual field. Subjects who played the shooter videogame and also showed the greatest improvement on the visual attention task showed significant changes in their brain waves. The remaining subjects — including those who had played the puzzle game — did not.

"After playing the shooter game, the changes in electrical activity were consistent with brain processes that enhance visual attention and suppress distracting information," said Sijing Wu, a PhD student in Spence’s lab in U of T’s Department of Psychology and lead author of the study.

"Studies in different labs, including here at the University of Toronto, have shown that action videogames can improve selective visual attention, such as the ability to quickly detect and identify a target in a cluttered background," said Spence. "But nobody has previously demonstrated that there are differences in brain activity which are a direct result of playing the videogame."

"Superior visual attention is crucial in many important everyday activities," added Spence. "It’s necessary for things such as driving a car, monitoring changes on a computer display, or even avoiding tripping while walking through a room with children’s toys scattered on the floor."

Source: Science Daily

Apr 27, 201218 notes
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Agent Reduces Autism-like Behaviors in Mice

April 25th, 2012

National Institutes of Health researchers have reversed behaviors in mice resembling two of the three core symptoms of autism spectrum disorders (ASD). An experimental compound, called GRN-529, increased social interactions and lessened repetitive self-grooming behavior in a strain of mice that normally display such autism-like behaviors, the researchers say.

GRN-529 is a member of a class of agents that inhibit activity of a subtype of receptor protein on brain cells for the chemical messenger glutamate, which are being tested in patients with an autism-related syndrome. Although mouse brain findings often don’t translate to humans, the fact that these compounds are already in clinical trials for an overlapping condition strengthens the case for relevance, according to the researchers.

“Our findings suggest a strategy for developing a single treatment that could target multiple diagnostic symptoms,” explained Jacqueline Crawley, Ph.D., of the NIH’s National Institute of Mental Health (NIMH). “Many cases of autism are caused by mutations in genes that control an ongoing process – the formation and maturation of synapses, the connections between neurons. If defects in these connections are not hard-wired, the core symptoms of autism may be treatable with medications.”

Crawley, Jill Silverman, Ph.D., and colleagues at NIMH and Pfizer Worldwide Research and Development, Groton, CT, report on their discovery April 25th, 2012 in the journal Science Translational Medicine.

“These new results in mice support NIMH-funded research in humans to create treatments for the core symptoms of autism,” said NIMH director Thomas R. Insel, M.D. “While autism has been often considered only as a disability in need of rehabilitation, we can now address autism as a disorder responding to biomedical treatments.”

(Video: Agent Reduces Repetitive Behavior in Mice)
Autism-like behaviors in mice have been reduced, using an experimental agent being tested in patients for a related disorder. Here, a mouse is absorbed in repetitive self-grooming. The experimental agent reduced this repetitive behavior in a strain of mice that is prone to it, and almost stopped repetitive vertical jumping in another strain of mice. Credit: MuYang, Ph.D., Adam Katz, and Jacqueline Crawley, Ph.D., NIMH Laboratory of Behavioral Neuroscience. 

Crawley’s team followed-up on clues from earlier findings hinting that inhibitors of the receptor, called mGluR5, might reduce ASD symptoms. This class of agents – compounds similar to GRN-529, used in the mouse study – are in clinical trials for patients with the most common form of inherited intellectual and developmental disabilities, Fragile X syndrome, about one third of whom also meet criteria for ASDs.

To test their hunch, the researchers examined effects of GRN-529 in a naturally occurring inbred strain of mice that normally display autism-relevant behaviors. Like children with ASDs, these BTBR mice interact and communicate relatively less with each other and engage in repetitive behaviors – most typically, spending an inordinate amount of time grooming themselves.

Crawley’s team found that BTBR mice injected with GRN-529 showed reduced levels of repetitive self-grooming and spent more time around – and sniffing nose-to-nose with – a strange mouse.

(Video: Agent Boosts Sociability in Mice)
Autism-like behaviors in mice have been reduced, using an experimental agent being tested in patients for a related disorder. Here, a mouse pays a social visit to a strange animal. The experimental agent increased such sociability, which is impaired in autism. Credit: MuYang, Ph.D., and Jacqueline Crawley, Ph.D., NIMH Laboratory of Behavioral Neuroscience.

Moreover, GRN-529 almost completely stopped repetitive jumping in another strain of mice.

“These inbred strains of mice are similar, behaviorally, to individuals with autism for whom the responsible genetic factors are unknown, which accounts for about three fourths of people with the disorders,” noted Crawley. “Given the high costs – monetary and emotional – to families, schools, and health care systems, we are hopeful that this line of studies may help meet the need for medications that treat core symptoms.” 

Source: Neuroscience News  

Apr 27, 20124 notes
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How PCBs Promote Dendrite Growth, May Increase Autism Risk

ScienceDaily (Apr. 25, 2012) — New research from UC Davis and Washington State University shows that PCBs, or polychlorinated biphenyls, launch a cellular chain of events that leads to an overabundance of dendrites — the filament-like projections that conduct electrochemical signals between neurons — and disrupts normal patterns of neuronal connections in the brain.

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New findings underscore the developing brain’s vulnerability to environmental exposures and demonstrate how PCBs could add to autism risk. (Credit: © yalayama / Fotolia)

"Dendrite growth and branching during early development is a finely orchestrated process, and the presence of certain PCBs confuses the conductor of that process," said Pamela Lein, a developmental neurobiologist and professor of molecular biosciences in the UC Davis School of Veterinary Medicine. "Impaired neuronal connectivity is a common feature of a number of conditions, including autism spectrum disorders."

Reported April 24 in two related studies in the journal Environmental Health Perspectives, the findings underscore the developing brain’s vulnerability to environmental exposures and demonstrate how PCBs could add to autism risk.

"We don’t think PCB exposure causes autism," Lein said, "but it may increase the likelihood of autism in children whose genetic makeup already compromises the processes by which neurons form connections."

The senior authors of the studies were Lein and Isaac Pessah, chair of molecular biosciences in the School of Veterinary Medicine and director of the Center for Children’s Environmental Health at UC Davis. Both are researchers with the UC Davis MIND Institute, which is dedicated to finding answers to autism and other neurodevelopmental disorders. The lead author was Gary Wayman of Washington State University’s Program in Neuroscience, who first described the molecular pathway that controls the calcium signaling in the brain that guides normal dendrite growth.

Wayman found that key cellular players, called calcium and calmodulin kinases, are activated by increased calcium levels. Activated calmodulin kinase then turns on the protein known as CREB that regulates genes that produce Wnt2, a potent molecule and the final arbiter of whether and how dendrites grow. Wnt2 directs structural proteins to construct scaffolding that supports dendrite growth and branching.

"Orderly choreography of the calmodulin kinase-to-Wnt2 pathway translates normal increases in calcium levels into normal levels of dendrite production," said Wayman. "The wiring of billions of neurons is dependent on the health of this cellular process and is crucial to proper development of virtually all complex behaviors, learning, memories and language."

For the current studies, the team set out to determine if that pathway was altered by exposure to PCBs, focusing on neurons of the hippocampus — the brain region linked with learning and memory and known to suffer impaired connectivity in many neurodevelopmental disorders.

The scientists also focused on the effects of an understudied PCB subset known as non-dioxin-like PCBs, which have been shown to increase calcium levels in neurons. Both non-dioxin-like PCBs and the more familiar dioxin-like subset were widely used in electrical equipment in the 1950s and 1960s. Banned in the 1970s because of the potential for dioxin-like PCBs to cause cancer, all PCBs are stable compounds that persist throughout the environment today.

One of the current UC Davis studies examined dendrite growth in rat pups born to and nursed by PCB-exposed mothers. Another study analyzed how PCBs affect rat neurons in cell cultures at developmental stages similar to those in the third trimester of pregnancy in humans. In both studies, PCB exposure levels were similar to those found in the human diet and in human tissues, including the placenta and breast milk.

Evaluation of the brains of the rats exposed to PCBs early in life showed significant overproduction of dendrites. The cellular studies showed that PCBs triggered the calcium pathway that led to the aberrant brain architecture, and that dendrite production was normal when that cellular pathway was blocked.

"We are the first to show that non-dioxin-like PCBs alter how the developing brain gets wired by hijacking the calcium signaling pathway and greatly expanding dendrite growth," said Lein.

The experiments also helped identify for the first time the specific trigger for this cellular chain of events as the ryanodine receptor (RyR) calcium channel. Pessah, a recognized leader in calcium-channel dysfunction and neurodevelopment, previously showed that RyR is selectively activated by non-dioxin-like PCBs. The new studies prove that RyR is a necessary component in the pathway that controls dendritic growth.

"These same calcium pathways are implicated in some forms of autism and, while environmental exposures alone do not cause autism, these new findings provide good evidence that PCBs could add to autism risk in genetically predisposed children," said Pessah. "Understanding the fundamental mechanisms by which PCBs alter neural networks sets the stage for research on environmental contaminants that are structurally related to PCBs, including flame retardants, and their risks to susceptible populations."

Source: Science Daily

Apr 26, 201212 notes
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New Embryonic Stem Cell Line Will Aid Research on Nerve Condition

April 25th, 2012

Second U-M stem cell line now publicly available to help researchers find treatments for nerve condition.
Charcot-Marie-Tooth disease line made from a never-frozen donated embryo.

The University of Michigan’s second human embryonic stem cell line has just been placed on the U.S. National Institutes of Health’s registry, making the cells available for federally-funded research. It is the second of the stem cell lines derived at U-M to be placed on the registry.

The line, known as UM11-1PGD, was derived from a cluster of about 30 cells removed from a donated five-day-old embryo roughly the size of the period at the end of this sentence. That embryo was created for reproductive purposes, tested and found to be affected with a genetic disorder, deemed not suitable for implantation, and would therefore have otherwise been discarded when it was donated in 2011.

It carries the gene defect responsible for Charcot-Marie-Tooth disease, a hereditary neurological disorder characterized by a slowly progressive degeneration of the muscles in the foot, lower leg and hand. CMT, as it is known, is one of the most common inherited neurological disorders, affecting one in 2,500 people in the United States. People with CMT usually begin to experience symptoms in adolescence or early adulthood.

The embryo used to create the cell line was never frozen, but rather was transported from another IVF laboratory in the state of Michigan to the U-M in a special container. This may mean that these stem cells will have unique characteristics and utilities in understanding CMT disease progression or screening therapies in comparison to other human embryonic stem cells.

“We are proud to provide this cell line to the scientific community, in hopes that it may aid the search for new treatments and even a cure for CMT,” says Gary Smith, Ph.D., who derived the line and also is co-director of the U-M Consortium for Stem Cell Therapies, part of the A. Alfred Taubman Medical Research Institute. “Once again, the acceptance of these cells to the registry demonstrates our attention to details of proper oversight, consenting, and following of NIH guidelines.”

U-M is one of only four institutions – including two other universities and one private company – to have disease-specific stem cell lines listed in the national registry. U-M has several other disease-specific hESC lines submitted to NIH and awaiting approval, says Smith, who is a professor in the Department of Obstetrics and Gynecology at the University of Michigan Medical School. The first line, a genetically normal one, was accepted to the registry in February.

“Stem cell lines that carry genetic traits linked to specific diseases are a model system to investigate what causes these diseases and come up with treatments,” says Sue O’Shea, Ph.D., professor of Cell and Developmental Biology at the U-M Medical School, and co-director of the Consortium for Stem Cell Therapies.

Each line is the culmination of years of preparation and cooperation between U-M and Genesis Genetics, a Michigan-based genetic diagnostic company. This work was made possible by Michigan voters’ November 2008 approval of a state constitutional amendment permitting scientists to derive embryonic stem cell lines using surplus embryos from fertility clinics or embryos with genetic abnormalities and not suitable for implantation.

The amendment also made possible an unusual collaboration that has blossomed between the University of Michigan and molecular research scientists at Genesis Genetics, a company that has grown in only eight years to become the leading global provider of pre-implantation genetic diagnosis (PGD) testing. PGD is a testing method used to identify days-old embryos carrying the genetic mutations responsible for serious inherited diseases. During a PGD test, a single cell is removed from an eight-celled embryo. The other seven cells continue to multiply and on the fifth day form a cluster of roughly 100 cells known as a blastocyst.

Genesis Genetics performs nearly 7,500 PGD tests annually. Under the arrangement between the company and U-M, patients with embryos that test positive for a genetic disease now have the option of donating those embryos to U-M if they have decided not to use them for reproductive purposes and the embryos would otherwise be discarded.

The agreement was worked out between U-M’s Smith and Mark Hughes, M.D., Ph.D., founder and president of Genesis Genetics and a pioneer in the field of pre-implantation genetic diagnosis. “These are very precious cells, and it would be unconscionable not to take advantage of such an opportunity for medical science and the cure of disease,” Hughes says.

“This is another major step forward for medical science in Michigan. It opens up another avenue for researchers to really begin exploring the causes and progression of those diseases, with the ultimate goal of finding new therapies for patients,” says Eva Feldman, M.D., Ph.D., F.A.A.N., director of the A. Alfred Taubman Medical Research Institute and the Russell N. DeJong professor of neurology at the U-M Medical School. Feldman sees patients with CMT as part of her clinical practice.

Contributors to the A. Alfred Taubman Medical Research Institute’s Consortium for Stem Cell Therapies include the Taubman Institute; the Office of the Executive Vice President for Medical Affairs; the Office of the Medical School Dean; the Comprehensive Cancer Center; the Department of Pediatrics and Communicable Diseases; the Office of the Vice President for Research; the School of Dentistry; the Department of Pathology; the Department of Cell and Developmental Biology; the College of Engineering; the Life Sciences Institute; the Department of Neurology; and U-M’s Michigan Institute for Clinical and Health Research.

A. Alfred Taubman, founder and chair of U-M’s Taubman Institute, called the second registry placement a tremendous step for stem cell research. “I consider stem cells to be a modern medical miracle – the most exciting advance in medicine since antibiotics. The progress we have made throughout the state in stem cell research has been nothing short of remarkable,” he says.

“This new milestone means much to the University and the state of Michigan, but also to the world. It offers another route for researchers to move ahead in studying these horrible diseases. We hope it is the first of many lines that we can contribute to the global efforts to improve human health.”

Written by Kara Gavin

Source: Neuroscience News

Apr 26, 201211 notes
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Strong Support for Once-Marginalized Theory On Parkinson’s Disease

ScienceDaily (Apr. 25, 2012) — University of California, San Diego scientists have used powerful computational tools and laboratory tests to discover new support for a once-marginalized theory about the underlying cause of Parkinson’s disease.

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This image shows a construction of a possible ring oligomer position in the cell membrane after four nanoseconds of molecular dynamics simulations. Image courtesy of Igor Tsigelny, San Diego Supercomputer Center and Department of Neurosciences, UC San Diego. (Credit: Image courtesy of University of California, San Diego)

The new results conflict with an older theory that insoluble intracellular fibrils called amyloids cause Parkinson’s disease and other neurodegenerative diseases. Instead, the new findings provide a step-by-step explanation of how a “protein-run-amok” aggregates within the membranes of neurons and punctures holes in them to cause the symptoms of Parkinson’s disease.

The discovery, published in the March 2012 issue of the FEBS Journal, describes how α-synuclein (a-syn), can turn against us, particularly as we age. Modeling results explain how α-syn monomers penetrate cell membranes, become coiled and aggregate in a matter of nanoseconds into dangerous ring structures that spell trouble for neurons.

"The main point is that we think we can create drugs to give us an anti-Parkinson’s effect by slowing the formation and growth of these ring structures," said Igor Tsigelny, lead author of the study and a research scientist at the San Diego Supercomputer Center and Department of Neurosciences, both at UC San Diego.

Familial Parkinson’s disease is caused in many cases by a limited number of protein mutations. One of the most toxic is A53T. Tsigelny’s team showed that the mutant form of α-syn not only penetrates neuronal membranes faster than normal α-syn, but the mutant protein also accelerates ring formation.

"The most dangerous assault on the neurons of Parkinson’s patients appears to be the relatively small α-syn ring structures themselves," said Tsigelny. "It was once heretical to suggest that these ring structures, rather than long fibrils found in neurons of people having Parkinson’s disease, were responsible for the symptoms of the disease; however, the ring theory is becoming more and more accepted for this neurodegenerative disease and others such as Alzheimer’s disease. Our results support this shift in thinking."

The modeling results also are consistent with the electron microscopy images of neurons in Parkinson’s disease patients; the damaged neurons are riddled with ring structures.

Wasting no time, the modeling discoveries have spawned an intense hunt at UC San Diego for drug candidates that block ring formation in neuron membranes. The sophisticated modeling required involves a complex realm of science at the intersection of chemistry, physics, and statistical probabilities. A kaleidoscope of interacting forces in this realm makes α-syn proteins bump and tremble like they’re in an earthquake, coil and uncoil, and join together in pairs or larger groups of inventive ballroom dancers.

The modeling is creating a much better understanding of the mysterious a-syn protein itself, according to Tsigelny. A few years ago it was shown to accumulate in the central nervous system of patients with Parkinson’s disease and a related disorder called dementia with Lewy bodies.

The new modeling study has revealed precisely how two α-syn proteins insert their molecular toes into the membrane of a neuron, wiggle into it in only a few nanoseconds and immediately join together as a pair. The pair isn’t itself toxic; however, when more α-syn proteins join the dance, a key threshold is eventually crossed; polymerization accelerates into a ring structure that perforates the membrane, damaging the cell.

Tsigelny said many ring structures may be required to actually kill neurons, which are known for their durability. The nerve cells may be able to repair dozens of ring-induced perforations, keeping pace with a-syn assault. But at some point, the rate of perforations surpasses the ability of neurons to repair them. As a result, symptoms of Parkinson’s disease gradually appear and worsen.

"We think we can create a drug that stops the α-syn polymerization at the point of non-propagating dimers," Tsigelny said. "By interrupting the polymerization at this crucial step, we may be able to slow the disease significantly."

Tsigelny’s research team included Yuriy Sharikov, with SDSC and UC San Diego’s Department of Neurosciences; Wolfgang Wrasidlo, with the university’s Moores Cancer Center; and Tania Gonzalez, Paula A. Desplats, Leslie Crews, and Brian Spencer, all with UC San Diego’s Department of Neurosciences. The experimental validation studies were performed by Eliezer Masliah, a professor in the UC San Diego departments of Neurosciences and Pathology, and his associates. They relied on 3-D models of proteins, plus molecular dynamics simulations of the proteins, other modeling techniques and cell-culture experiments.

Given their deeper understanding of α-syn polymerization in neurons, they are now focused on understanding how monomers of α-syn stick to one another. Their search for drug candidates will include molecules that induce different conformations of α-syn proteins that are less inclined to stick together. Tsigelny said this effect, even if small, could reduce symptoms.

This computationally intensive approach includes an examination of the many possible three-dimensional arrangements of α-syn dimers, trimmers and tetramers. Pharmaceutical companies have used versions of the approach to develop drug candidates designed to bind to ‘anchor residues’ or ‘hot spots’ within target proteins. Algorithms assess in virtual experiments the theoretical ability of thousands of candidate drugs to bind to human proteins in the ever-expanding database of known 3-D structures of those proteins.

However, attempts to find drugs this way have generated promising candidates that fail in clinical trials with expensive regularity.

"Out of these failures we’ve come to appreciate that proteins change their shapes so often that what would appear to be a primary drug target may be present one nanosecond, gone the next, or it wasn’t relevant in the first place," said Tsigelny, a physicist-turned-drug-designer.

Tsigelny’s approach takes advantage of classical drug-discovery algorithms, but adds additional analytical techniques to expand the search to include how a target protein’s conformations change in response to the forces operating on the scale of molecules.

"Sometimes, the drug-discovery models, despite being ‘nice looking,’ can be completely wrong," Tsigelny said. "Scientists involved in drug discovery need to know when and to what extent to trust them. Even a slight shift in a cell’s environment can profoundly change the interactions of proteins with neighboring molecules. We think it’s realistically possible to design a drug to treat neurodegenerative diseases such as Parkinson’s disease and other diseases like diabetes with a more fundamental understanding of the proteins involved in those diseases."

Source: Science Daily

Apr 26, 201213 notes
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Your Brain Knows Which Ads Are Winners, Better Than You Do: Study On Smokers' Brains May Mark Dawn of New Age in Advertising

ScienceDaily (Apr. 25, 2012) — Advertisers and public health officials may be able to access hidden wisdom in the brain to more effectively sell their products and promote health and safety, UCLA neuroscientists report in the first study to use brain data to predict how large populations will respond to advertisements.

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The brain, with the medial prefrontal cortex highlighted in green. (Credit: Image courtesy of University of California - Los Angeles)

Thirty smokers who were trying to quit watched television commercials from three advertising campaigns, which all ended by showing the phone number of the National Cancer Institute’s smoking-cessation hotline. They were asked which commercials they thought would be most effective; they responded that advertising campaigns “A” and “B” would be the best and “C” would be the worst.

The UCLA researchers also consulted experts who work in the anti-smoking field and who have been involved in creating anti-smoking advertisements. These experts agreed that campaigns “A” and “B” were the best and “C” was the worst.

While the smokers watched the advertisements, they underwent functional magnetic resonance imaging (fMRI) brain scans at UCLA’s Ahmanson-Lovelace Brain Mapping Center, and the neuroscientists focused on part of the medial prefrontal cortex — located in the front of the brain, between the eyebrows — a region that they have found to be especially important in previous persuasion studies.

The researchers found that activity in the medial prefrontal cortex increased much more during advertising campaign “C” than it did during campaign “A,” and somewhat more than it did during campaign “B.”

"The medial prefrontal cortex predicted ‘C’ would be the best, ‘B’ would be second best and ‘A’ would be the worst — essentially the opposite of what the experts and the participants told us they thought would happen," said the study’s senior author, Matthew Lieberman, a UCLA professor of psychology and of psychiatry and biobehavioral sciences.

"We didn’t expect how radically different people’s predictions would be from the predictions we made based on their brain activity," said Lieberman, one of the founders of social cognitive neuroscience. "We had people telling us one thing and this brain region telling us something diametrically opposed."

Initially, Lieberman and first author Emily Falk, an assistant professor of communication studies and psychology at the University of Michigan-Ann Arbor, were concerned when they saw the results from the medial prefrontal cortex.

"We were hoping the brain data would add something to the self-reports of our participants," Lieberman said. "Given how different they were from one another, we were afraid our brain data might not end up predicting the real-world outcomes at all."

A few months later, after the advertisements had been broadcast, the authors received the call-volume data from the National Cancer Institute’s 1-800-QUIT-NOW hotline. They compared the number of people who called the hotline the month before and the month after each of the advertising campaigns was run. All three advertising campaigns were successful in increasing the number of phone calls to the hotline. Campaign “A” more than doubled the number of calls, “B” increased the number of calls more than ten-fold and “C” boosted the number of calls a remarkable thirty-fold. (The advertisements were shown in Michigan, Massachusetts and Louisiana.)

Activity in the medial prefrontal cortex predicted which ads persuaded more people to call the hotline significantly better than the smokers’ own thoughts about how successful the ads would be.

The research is published this month in the online edition of the journal Psychological Science.

What are the implications for the advertising industry, which often relies, at least partly, on unscientific focus groups?

"If people are making decisions based on what focus groups tell them, here’s an important brain region saying, ‘No, spend your money a different way,’" Lieberman said. "If I were deciding on an advertising campaign, I would want to know which ads are activating this region the most — that is where I would want to spend my money."

This new research represents “the first thing you could call a neural focus group,” Lieberman said.

One reason focus groups can be misleading, he said, is that people often do not know what motivates their own behavior.

"Our brain is built to generate reasons for our actions," Lieberman said, "and we think the reasons we come up with must be true. We believe our own reasons with an intensity that is out of proportion to their accuracy. In this study, we are bypassing people’s self-reports and getting at a form of hidden wisdom in the brain.

"We wanted to determine what kind of brain activity serves as the catalyst between people seeing a message and whether they actually change their behavior," he said. "This is the region we identified. We have tested it multiple times, and each time, it has been successful."

John Wanamaker, a 19th-century U.S. department store pioneer, famously said he wasted half the money he spent on advertising, but “the trouble is I don’t know which half.” Many people since Wanamaker have hoped to predict which advertising campaigns will succeed or fail before committing their advertising dollars.

"We’re too late for Wanamaker, but now we have a method for figuring out which ads will succeed," Lieberman said.

The 30 smokers in the study were between the ages of 28 and 69; half were female.

Brain regions associated with thinking analytically have not been consistently associated with whether people change their behavior in these studies, Lieberman said. The medial prefrontal cortex is associated not with analytical thinking but with self-reflection — thinking about our own identity as well as what we like and do not like.

"Persuasive advertising seems to be about getting to people’s hearts and their identity," Lieberman said. "We are just at the beginning of this line of research. There are many more questions than answers, but the initial results have been promising."

In research Lieberman and Falk published in the Journal of Neuroscience in 2010, greater activity in the same medial prefrontal region was predictive of who would increase their sunscreen usage after seeing persuasive messages about daily sunscreen use.

"We knew from prior studies that this brain region predicted people’s behavior change in response to a persuasive message," Lieberman said.

With the new study, Lieberman and his colleagues wanted to know whether they could predict not only people’s own behavior but use these brain responses to predict how effective advertisements would be throughout the country.

Source: Science Daily

Apr 26, 20126 notes
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Growing up as a neural stem cell: The importance of clinging together and then letting go

April 25, 2012

Can one feel too attached? Does one need to let go to mature? Neural stem cells have this problem, too.

As immature cells, neural stem cells must stick together in a protected environment called a niche in order to divide so they can make all of the cells that populate the nervous system. But when it’s time to mature, or differentiate, the neural stem cells must stop dividing, detach from their neighbors and migrate to where they are needed to form the circuits necessary for humans to think, feel and interact with the world.

Now, stem cell researchers at UCLA have identified new components of the genetic pathway that controls the adhesive properties and proliferation of neural stem cells and the formation of neurons in early development.

The finding by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA could be important because errors in this pathway can lead to a variety of birth defects that affect the structure of the nervous system, as well as more subtle changes that impair cognitive and motor functions associated with disorders such as autism.

The results of the four-year study are published April 26, 2012 in the peer-reviewed journal Neuron.

The UCLA team found that a delicate balance of gene expression enables the pool of neural stem and progenitor cells in early development to initially increase and then quickly stop dividing to form neurons at defined times.

"One of the greatest mysteries in developmental biology is what constitutes the switch between stem cell proliferation and differentiation. In our studies of the formation of motor neurons, the cells that are essential for movement, we were able to uncover what controls the early expansion of neural stem and progenitor cells, and more importantly what stops their proliferation when there are enough precursors built up," said Bennett G. Novitch, an assistant professor of neurobiology, a Broad Stem Cell Research Center scientist and senior author of the study. "If the neurons don’t form at the proper time, it could lead to deficits in their numbers and to catastrophic, potentially fatal neurological defects." 

During the first trimester of development, the neural stem and progenitor cells form a niche, or safe zone, within the nervous system. The neural stem and precursor cells adhere to each other in a way that allows them to expand their numbers and keep from differentiating. A protein called N-cadherin facilitates this adhesion, Novitch said.

When it is time for the neural precursors to become motor neurons, two proteins that repress gene expression, called Foxp2 and Foxp4, become elevated and then silence N-cadherin expression, causing the clustered neural stem and precursor cells to break apart and begin differentiating.

"We have these cells in a dividing state, making more of themselves, and to make neurons that process has to be stopped and those contacts between the cells disassembled," Novitch said. "Until now, it has not been clear how the cells are pulled apart."

Novitch and his team showed that if you eliminate Foxp protein function, motor neurons and other mature cells in the nervous system are not properly formed because the N-cadherin gene is not silenced, confirming the delicate balancing act that must be achieved for normal development of both the stem and precursor cells and their neuronal progeny.

"It’s a fundamental discovery. Most studies have focused on defining what promotes the adhesiveness and self-renewal of neural stem cells, rather than what breaks these contacts," Novitch said. "We were also surprised to see how small changes in the degree of cell adhesion can markedly alter the development and structure of the nervous system. It’s all about balance, if you have too many or too few stem and precursor cells, the result could be disastrous."

Going forward, Novitch and his team will examine whether the functions of Foxp2 and Foxp4 in regulating cell adhesion may be important for the maintenance and differentiation of neural stem cells in the adult brain, and whether the loss of their activity may contribute to the formation and growth of brain tumors. In addition, Novitch’s group plans to examine whether their findings are relevant for investigating the function of Foxp2 and Foxp4 in other aspects of neural development, as mutations in Foxp proteins have previously been associated with a range of intellectual disabilities and speech-language disorders.

"It is tempting to speculate that these loss-of-function phenotypes might result from abnormal cell adhesion associated with dysregulated N-cadherin expression or function," the study states. "If true, these findings could provide a molecular explanation for the association of Foxp mutations with developmental human language and motor disorders, including autism."

Provided by University of California - Los Angeles Health Sciences

Source: medicalxpress.com

Apr 26, 20122 notes
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Taking it all in: Revealing how we sense things

April 25, 2012 By Allison Flynn

McGill physiology research team sheds light on how the brain processes what we sense.

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We rely on our senses in all aspects of our lives. Unfortunately, many people suffer from some kind of impaired sensory function. In Canada alone, 600,000 people are visually impaired while almost three million suffer from partial or total hearing loss. In a paper published this week in The Journal of Neuroscience, researchers from McGill University have demonstrated for the first time that there are specific neurons that respond selectively to first and second order sensory attributes. In the visual system, for example, luminance is a first-order attribute, whereas contrast is second-order. These findings could pave the way to the development of novel therapies and improved prosthetics for those with sensory deficiencies.

The research team, led by physiology student Patrick McGillivray, recorded the responses to stimuli of midbrain electro-sensory neurons in the weakly electric fish. Based on these responses, the researchers were able to demonstrate that there are specific neurons that respond selectively to different attributes at the same time. Moreover, they uncovered the simple and generic neural circuits that enable this selectivity. These findings provide important clues about how the brain processes first and second order sensory attributes in audition (like pitch and timbre) and vision (like luminance and contrast).

"Uncovering these clues relies on identifying the attributes that we use to perceive stimuli, the computations performed by the brain, and the actual neural networks that implement these," explained Dr. Maurice Chacron, lead author and principal investigator at McGill’s Computational Systems Neuroscience Lab. "Stimuli like speech and music are characterized by multiple attributes. For example, when listening to music, we can perceive both frequency (how low or high an instrument is playing), as well as timbre (the type of instrument playing)."

Provided by McGill University

Source: medicalxpress.com

Apr 26, 201213 notes
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How Your Eyes Deceive You

April 24th, 2012

Researchers at the University of Sydney have thrown new light on the tricks the brain plays as it struggles to make sense of the visual and other sensory signals it constantly receives.

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In this tilt illusion, the lines in the centre of the image appear tilted counterclockwise, but they are actually vertical. Image adapted from University of Sydney image.

The research has implications for understanding how the brain interprets the world visually and how the brain itself works.

People rely on their eyes for most tasks – yet the information provided by our visual sensing system is often distorted, unreliable and subject to illusion.

In a just published article in Proceedings of the National Academy of Science, Dr Isabelle Mareschal and Professor Colin Clifford, from the University’s School of Psychology and The Vision Centre, report a series of groundbreaking experiments tracing the origins of the tilt illusion to the cells of the primary visual cortex. This is where the first stage of vision processing takes place before the conscious mind takes over.

“We tend to regard what we see as the real world,” said Dr Mareschal.

“In fact a lot of it is distortion, and it is occurring in the early processing of the brain, before consciousness takes over. Our work shows that the cells of the primary visual cortex create small distortions, which then pass on to the higher levels of the brain, to interpret as best it can.”

A common example of this that is often exploited by artists and designers is known as the tilt illusion where perfectly vertical lines appear tilted because they are placed on an oriented background.

“We wanted to test at what level the illusion occurs in the brain, unconscious or conscious – and also to see if the higher brain is aware of the illusions it is receiving and how it tries to correct for them,” she explains.

“The answer is that the brain seeks more contextual information from the background to try to work out the alignment of the object it is seeing.”

The team subjected volunteers to a complex test in which they indicated the orientation of a vertical line, perceived as constantly tilting from side to side, against a fuzzy background that was also changing.

“These illusions happen very fast, perhaps in milliseconds,” Dr Mareschal says. “And we found that even the higher brain cannot always correct for them, as it doesn’t in fact know they are illusions.”

This is one reason why people’s eyes sometimes mislead them when looking at objects in their visual landscape.

Normally, Dr Mareschal explains, it doesn’t matter all that much – but in the case of a person driving a car fast in traffic, an athlete performing complex acrobatic feats, a pilot landing an aircraft or other high-speed uses of sight, the illusion may be of vital importance by causing them to misinterpret the objects they ‘see’.

The brain uses context, or background, to interpret a host of other visual signals besides the orientation of objects. For example, it uses context to tell colour, motion, texture and contrast. The research will help study how the brain understands these visual cues adding to our overall understanding of brain function.

Source: Neuroscience News

Apr 25, 201214 notes
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Myth, busted: You only use 10 percent of brain

By Brian Alexander

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Good news for all those who ever had a teacher or a parent say “If you would just apply yourself you could learn anything! You’re only using 10 percent of your brain!”

All those people were wrong. If we did use only 10 percent of our brains we’d be close to dead, according to Eric Chudler, director of the Center for Sensorimotor Neural Engineering at the University of Washington, who maintains an entertaining brain science website for kids. “When recordings are made from brain EEGs, or PET scans, or any type of brain scan, there’s no part of the brain just sitting there unused,” he said. 

Larry Squire, a research neuroscientist with the Veterans Administration hospital in San Diego, and at the University of California San Diego, pointed out that “any place the brain is damaged there is a consequence.”

Damaged brains may have been where this myth originated. During the first half of the last century, a pioneering neuroscientist named Karl Lashley experimented on rodents by excising portions of their brains to see what happened. When he put these rodents in mazes they’d been trained to navigate, he found that animals with missing bits of brain often successfully navigated the mazes.

This wound up being transmuted into the idea humans must be wasting vast brain potential. With the rise of the human potential movement in the 1960s, some preached that all sorts of powers, including bending spoons and psychic abilities, were laying dormant in our heads and that all we had to do was get off our duffs and activate them.

“That’s a case of something one often sees, of taking something from the world of psychology and in trying to make the idea concrete, bringing in the mechanisms of biology,” Squire explained. “It’s fair to say we can all do better, and we have room for improvement through practice and developing skills, but that has nothing to do with the idea that we use only 10 percent of our brains.”

The brain, Chudler said, isn’t like a disc drive with some set amount of capacity. It’s a dynamic maze of wiring where new connections can be created in response to new stimuli, or lost with disuse. And much of it is constantly occupied not with intellectual thinking, but running our systems.

“That’s why the brain is such an expensive organ,” he explained. “It requires 20 percent of our blood supply, and it’s a real energy hog.” If we used only 10 percent of it, the brain wouldn’t require such high maintenance.

“Besides,” he pointed out, “why would our brains have gotten bigger through evolution if so much of it were going unused?”

Source: The Body Odd

Apr 25, 201245 notes
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Brain cell changes may cause sleep troubles in aging

April 24, 2012

Older animals show cellular changes in the brain “clock” that sets sleep and wakeful periods, according to new research in the April 25 issue of The Journal of Neuroscience. The findings may help explain why elderly people often experience trouble sleeping at night and are drowsy during the day.

Like humans, mice experience shifts in daily activities and sleep patterns as they age. To find out why, researchers directed by Johanna Meijer, PhD, at the Leiden University Medical Center in the Netherlands studied the electrical activity of cells in the suprachiasmatic nucleus (SCN), an area of the brain responsible for setting sleep-wake cycles.

Consistent with previous studies, the researchers found aged mice showed disrupted sleep behavior and weakened brain network activity in the SCN. But Meijer and colleagues also found changes occurring in individual SCN cells, not just in their networks.

"In fact, the changes at the single-cell level were more severe than the changes at the network level," said Meijer. This represents a shift in understanding of aging’s effects on the brain.

The researchers made electrophysiological recordings from isolated SCN neurons, a difficult experiment given the advanced age of the animals and the small size of this type of neuron. They found aged SCN neurons lack day-night rhythms in some membrane properties. In addition, the team identified age-related reductions of certain potassium currents that are important to the neurons’ rhythmic firing.

Because potassium and other ion channels can be manipulated with drugs, “This work provides a new target for potential therapeutic interventions that can mitigate the age-related decline in the sleep-wake cycle,” said Christopher Colwell, PhD, an expert in circadian clock function at the University of California, Los Angeles, who was not involved in the study.

Provided by Society for Neuroscience

Source: medicalxpress.com

Apr 25, 20123 notes
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Binge eating may lead to addiction-like behaviors

April 24, 2012

A history of binge eating — consuming large amounts of food in a short period of time — may make an individual more likely to show other addiction-like behaviors, including substance abuse, according to Penn State College of Medicine researchers. In the short term, this finding may shed light on the factors that promote substance abuse, addiction, and relapse. In the long term, may help clinicians treat individuals suffering from this devastating disease.

"Drug addiction persists as a major problem in the United States," said Patricia Sue Grigson, Ph.D., professor, Department of Neural and Behavioral Sciences. "Likewise, excessive food intake, like binge eating, has become problematic. Substance-abuse and binge eating are both characterized by a loss of control over consumption. Given the common characteristics of these two types of disorders, it is not surprising that the co-occurrence of eating disorders and substance abuse disorders is high. It is unknown, however, whether loss of control in one disorder predisposes an individual to loss of control in another."

Grigson and her colleagues found a link between bingeing on fat and the development of cocaine-seeking and -taking behaviors in rats, suggesting that conditions promoting excessive behavior toward one substance can increase the probability of excessive behavior toward another. They report their results in Behavioral Neuroscience.

The researchers used rats to test whether a history of binge eating on fat would augment addiction-like behavior toward cocaine by giving four groups of rats four different diets: normal rat chow; continuous ad lib access to an optional source of dietary fat; one hour of access to optional dietary fat daily; and one hour of access to dietary fat on Mondays, Wednesdays, and Fridays. All four groups also had unrestricted access to nutritionally complete chow and water. The researchers then assessed the cocaine-seeking and -taking behaviors.

"Fat bingeing behaviors developed in the rats with access to dietary fat on Mondays, Wednesdays, and Fridays — the group with the most restricted access to the optional fat," Grigson said. 

This group tended to take more cocaine late in training, continued to try to get cocaine when signaled it was not available, and worked harder for cocaine as work requirements increased.

"While the underlying mechanisms are not known, one point is clear from behavioral data: A history of bingeing on fat changed the brain, physiology, or both in a manner that made these rats more likely to seek and take a drug when tested more than a month later," Grigson said. "We must identify these predisposing neurophysiological changes."

While the consumption of fat in and of itself did not increase the likelihood of subsequent addiction-like behavior for cocaine, the irregular binge-type manner in which the fat was eaten proved critical. Rats that had continuous access to fat consumed more fat than any other group, but were three times less likely to exhibit addiction-like behavior for cocaine than the group with access only on Mondays, Wednesdays and Fridays.

"Indeed, while about 20 percent of those rats and humans exposed to cocaine will develop addiction-like behavior for the drug under normal circumstances, in our study, the probability of addiction to cocaine increased to approximately 50 (percent) for subjects with a history of having binged on fat," Grigson said.

Future studies will look more closely at how bingeing can lead to addiction-like behaviors — whether bingeing on sugar or a mixture of sugar and fat also promotes cocaine or heroin addiction, for example, and whether bingeing on a drug, in turn, increases the likelihood of bingeing on fat.

Provided by Pennsylvania State University

Source: medicalxpress.com

Apr 25, 201222 notes
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Anticonvulsant Drug Helps Marijuana Smokers Kick the Habit

ScienceDaily (Apr. 24, 2012) — Scientists at The Scripps Research Institute have found clinical evidence that the drug gabapentin, currently on the market to treat neuropathic pain and epilepsy, helps people to quit smoking marijuana (cannabis). Unlike traditional addiction treatments, gabapentin targets stress systems in the brain that are activated by drug withdrawal.

In a 12-week trial of 50 treatment-seeking cannabis users, those who took gabapentin used less cannabis, experienced fewer withdrawal symptoms such as sleeplessness, and scored higher on tests of attention, impulse-control, and other cognitive skills, compared to patients who received a placebo. If these results are confirmed by ongoing larger trials, gabapentin could become the first FDA-approved pharmaceutical treatment for cannabis dependence.

"A lot of other drugs have been tested for their ability to decrease cannabis use and withdrawal, but this is the first to show these key effects in a controlled treatment study," said Barbara J. Mason, the Pearson Family Chair and Co-Director of the Pearson Center for Alcoholism and Addiction Research at Scripps Research. "The other nice thing about gabapentin is that it is already widely prescribed, so its safety is less likely to be an issue."

Mason led the new gabapentin study, recently published online ahead of print by the journal Neuropsychopharmacology.

Stress Circuits

Addiction researchers have long known that recreational drugs hook users by disrupting the normal tuning of their brains’ reward and motivation circuitry. But as scientists at Scripps Research and other institutions have shown in animal studies, cannabis withdrawal after prolonged heavy use also leads to the long-term activation of basic stress circuits. “In human cannabis users who try to quit, this stress response is reflected in reports of drug craving, sleep disturbances, anxiety, irritability, and dysphoria, any one of which can motivate a person to return to using, because cannabis will quiet these symptoms,” said Mason.

A 2008 study by Pearson Center Co-Director George Koob and his colleagues found that gabapentin, an FDA-approved anticonvulsant drug that resembles the neurotransmitter GABA, can quiet this withdrawal-related activation in stress circuitry in alcohol-dependent rats. That finding motivated Mason to set up a pilot trial of gabapentin in cannabis-dependent individuals, whose withdrawal syndrome features a similar over-activation of stress circuits.

She and her colleagues recruited cannabis users with local newspaper and web ads headlined: “Smoking too much pot? We want to help you stop.” "We needed only 50 subjects, but we quickly got more than 700 queries from cannabis users who were eager to quit," Mason said. "Some people deny that cannabis can be addictive, but surveys show that between 16 and 25 percent of substance use treatment admissions around the world every year involve people with primary cannabis dependence."

Twice as Many Abstinent from Cannabis Use

The trial was based at Mason’s laboratory at The Scripps Research Institute. Half of the 50 recruits were randomly assigned to take 1,200 mg/day of gabapentin; the rest were given identical-looking placebo capsules. Over 12 weeks, Mason and her colleagues, including a medical team from the nearby Scripps Clinic, monitored the subjects with tests. Using standard behavioral therapy techniques, they also counseled the patients to stay off cannabis.

The subjects’ self-reports and more objective urine tests revealed that gabapentin, compared to placebo, significantly reduced their continuing cannabis use. “Urine metabolite readings indicate about twice as many of the gabapentin subjects had no new cannabis use during the entire study, and, in the last four weeks of the study, all of the gabapentin subjects who completed the study stayed abstinent,” Mason said.

Gabapentin also clearly reduced the reported symptoms of withdrawal such as sleep disturbances, drug cravings, and dysphoria. And even though gabapentin normally is thought of as a brain-quieting drug that can cause sleepiness as a side effect, there was some evidence that it sharpened cognition among the cannabis users. Seven gabapentin and ten placebo patients sat for tests of attention, impulse-control, and other executive functions just before the start of the trial and at week four. While the placebo patients tended to score lower after four weeks of attempted abstinence, the gabapentin patients generally scored higher.

Help Resisting Cravings

Addiction researchers now recognize that one of the effects of repeated drug use is the weakening of executive functions — which can happen through the over-activation of reward circuitry as well as by withdrawal-related stress. “That weakening of self-control-related circuits makes it even harder for people to resist drug cravings when they’re trying to quit, but gabapentin may help restore those circuits, by reducing stress and enabling patients to sleep better, so that they function better while awake,” Mason said.

She is now conducting a larger, confirmatory study of gabapentin in cannabis users, as well as a new study of a novel drug that targets the same stress circuitry.

"People in the treatment community have told me that they’re eager for these trial results to come out, because until now nothing has been shown to work against both relapse and withdrawal symptoms," Mason said.

Source: Science Daily

Apr 24, 20128 notes
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Study Points to Potential Treatment for Stroke

ScienceDaily (Apr. 24, 2012) — Stanford University School of Medicine neuroscientists have demonstrated, in a study published online April 24 in Stroke, that a compound mimicking a key activity of a hefty, brain-based protein is capable of increasing the generation of new nerve cells, or neurons, in the brains of mice that have had strokes. The mice also exhibited a speedier recovery of their athletic ability.

These results are promising, because the compound wasn’t administered to the animals until a full three days after they had suffered strokes, said the study’s senior author, Marion Buckwalter, MD, PhD, an assistant professor of neurology and neurological sciences. This means that the compound works not by limiting a stroke’s initial damage to the brain, but by enhancing recovery.

This is of critical significance, said Buckwalter, a practicing clinical neurologist who often treats recently arrived stroke patients in Stanford Hospital’s intensive care unit.

"No existing therapeutic agents today enhance recovery from stroke," Buckwalter said. "The only approved stroke drug, tissue plasminogen activator, can bust up clots that initially caused the stroke but does nothing to stimulate the restoration of brain function later." Furthermore, to be effective, tPA has to be given within four and a half hours after a stroke has occurred, she added. "In real life, many people don’t get to the hospital that quickly. They may live alone or have their stroke while sleeping, or they and the people close to them didn’t recognize the stroke’s symptoms well enough to realize they’d just had one."

Looking for an alternative, Buckwalter chose to focus on a compound called LM22A-4, which had shown promise in previous research. LM22A-4 is a small molecule whose bulk is less than one-seventieth that of the brain protein it mimics: brain-derived neurotrophic factor, a powerful and long-studied nerve growth factor. BDNF is critical during the development of the nervous system and known to be involved in important brain functions including memory and learning.

Stem-cell therapy, while an exciting prospect, is a relatively invasive and expensive way to replace lost or damaged tissue. A drug that could achieve similar results in such a delicate and complex organ as the brain would be a welcome development.

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Apr 24, 20123 notes
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Evaluating the First Drug to Show Improvement in Subtype of Autism

ScienceDaily (Apr. 24, 2012) — In an important test of one of the first drugs to target core symptoms of autism, researchers at Mount Sinai School of Medicine are undertaking a pilot clinical trial to evaluate insulin-like growth factor (IGF-1) in children who have SHANK3 deficiency (also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome), a known cause of autism spectrum disorder (ASD).

This study builds on findings announced by the researchers in 2010, which showed that after two weeks of treatment with IGF-1 in a mouse model, deficits in nerve cell communication were reversed and deficiencies in adaptation of nerve cells to stimulation, a key part of learning and memory, were restored.

"This clinical trial is part of a paradigm shift to develop medications specifically to treat the core symptoms of autism, as opposed to medications that were developed for other purposes but were found to be beneficial for autism patients as well," said Joseph Buxbaum, PhD, Director of the Seaver Autism Center at Mount Sinai. "Our study will evaluate the impact of IGF-1 vs. placebo on autism-specific impairments in socialization and associated symptoms of language and motor disability."

The seven-month study, which begins this month, will be conducted under the leadership of the Seaver Autism Center Clinical Director Alex Kolevzon, MD, and will utilize a double-blind, placebo-controlled crossover design in children ages 5 to 17 years old with SHANK3 deletions or mutations. Patients will receive three months of treatment with active medication or placebo, separated by a four-week washout period. Future trials are planned to explore the utility of IGF-1 in ASD without SHANK3 deficiency.

The primary aim of the study is to target core features of ASD, including social withdrawal and language impairment, which will be measured using both behavioral and objective assessments. If preliminary results are promising, the goal is to expand the studies into larger, multi-centered efforts to include as many children as possible affected by this disorder.

IGF-1 is a US Food and Drug Administration-approved, commercially available compound that is known to promote neuronal cell survival as well as synaptic maturation and plasticity. Side effects of IGF-1 administration include low blood sugar, liver function abnormalities, and increased cholesterol and triglyceride levels. Study subjects will undergo rigorous safety screening before they are enrolled in the trial, and will be carefully monitored every two to four weeks with safety and efficacy assessments.

"We are excited that the researchers at the Seaver Autism Center are undertaking this pilot study to evaluate a possible treatment for SHANK3 deficiency, which may also help everyone with ASD," said Geraldine Bliss, Research Support Chair of the Phelan-McDermid Foundation. "This will be the first clinical trial in Phelan-McDermid Syndrome to emerge from convincing preclinical evidence in a model system."

The cause of autism has been debated for many years. Currently the best scientific evidence indicates that genetic mutations are the most likely culprits, acting either directly or indirectly, in upwards of 80 to 90 percent of individuals with ASDs. In the past few years, gene mutations and gene copy number variations have been identified that cause approximately 15 percent of cases of ASD. However, it is thought that hundreds of genes may be involved in causing autism.

One copy of the q13 portion of chromosome 22 is either missing or otherwise mutated in SHANK3 deficiency, also known as Phelan-McDermid Syndrome or 22q13 Deletion Syndrome (22q13DS). The area in question contains the gene SHANK3, and there is overwhelming evidence that it is the loss of one copy of SHANK3 that produces the neurological and behavioral aspects of the syndrome. The SHANK3 gene is key to the development of the human nervous system, and loss of SHANK3 can impair the ability of neurons to communicate with one another.

Source: Science Daily

Apr 24, 20129 notes
#science #brain #neuroscience #autism
Chronic Fatigue Syndrome Patients Had Reduced Activity in Brain’s 'Reward Center'

ScienceDaily (Apr. 24, 2012) — Chronic fatigue syndrome, a medical disorder characterized by extreme and ongoing fatigue with no other diagnosed cause, remains poorly understood despite decades of scientific study. Although researchers estimate that more than 1 million Americans are affected by this condition, the cause for chronic fatigue syndrome, a definitive way to diagnose it, and even its very existence remain in question. In a new study, researchers have found differing brain responses in people with this condition compared to healthy controls, suggesting an association between a biologic functional response and chronic fatigue syndrome.

The findings show that patients with chronic fatigue syndrome have decreased activation of an area of the brain known as the basal ganglia in response to reward. Additionally, the extent of this lowered activation was associated with each patient’s measured level of fatigue. The basal ganglia are at the base of the brain and are associated with a variety of functions, including motor activity and motivation. Diseases affecting basal ganglia are often associated with fatigue. These results shed more light on this mysterious condition, information that researchers hope may eventually lead to better treatments for chronic fatigue syndrome.

The study was conducted by Elizabeth R. Unger, James F. Jones, and Hao Tian of the Centers for Disease Control and Prevention (CDC), Andrew H. Miller and Daniel F. Drake of Emory University School of Medicine, and Giuseppe Pagnoni of the University of Modena and Reggio Emilia. An abstract of their study entitled, “Decreased Basal Ganglia Activation in Chronic Fatigue Syndrome Subjects is Associated with Increased Fatigue,” will be discussed at the meeting Experimental Biology 2012, being held April 21-25 at the San Diego Convention Center. The abstract is sponsored by the American Society for Investigative Pathology (ASIP), one of six scientific societies sponsoring the conference which last year attracted some 14,000 attendees.

More Fatigue, Less Activation

Dr. Unger says that she and her colleagues became curious about the role of the basal ganglia after previous studies by collaborators at Emory University showed that patients treated with interferon alpha, a common treatment for chronic hepatitis C and several other conditions, often experienced extreme fatigue. Further investigation into this phenomenon showed that basal ganglia activity decreased in patients who received this immune therapy. Since the fatigue induced by interferon alpha shares many characteristics with chronic fatigue syndrome, Unger and her colleagues decided to investigate whether the basal ganglia were also affected in this disorder.

The researchers recruited 18 patients with chronic fatigue syndrome, as well as 41 healthy volunteers with no symptoms of CFS. Each study participant underwent functional magnetic resonance imaging, a brain scan technique that measures activity in various parts of the brain by blood flow, while they played a simple card game meant to stimulate feelings of reward. The participants were each told that they’d win a small amount of money if they correctly guessed whether a preselected card was red or black. After making their choice, they were presented with the card while researchers measured blood flow to the basal ganglia during winning and losing hands.

The researchers showed that patients with chronic fatigue syndrome experienced significantly less change in basal ganglia blood flow between winning and losing than the healthy volunteers. When the researchers looked at scores for the Multidimensional Fatigue Inventory, a survey often used to document fatigue for chronic fatigue syndrome and various other conditions, they also found that the extent of a patient’s fatigue was tightly tied with the change in brain activity between winning and losing. Those with the most fatigue had the smallest change.

Results Suggest Role of Inflammation

Unger notes that the findings add to our understanding of biological factors that may play a role in chronic fatigue syndrome. “Many patients with chronic fatigue syndrome encounter a lot of skepticism about their illness,” she says. “They have difficulty getting their friends, colleagues, coworkers, and even some physicians to understand their illness. These results provide another clue into the biology of chronic fatigue syndrome.”

The study also suggests some areas of further research that could help scientists develop treatments for this condition in the future, she adds. Since the basal ganglia use the chemical dopamine as their major neurotransmitter, dopamine metabolism may play an important role in understanding and changing the course of this illness. Similarly, the difference in basal ganglia activation between the patients and healthy volunteers may be caused by inflammation, a factor now recognized as pivotal in a variety of conditions, ranging from heart disease to cancer.

Estimates from the CDC suggest that annual medical costs associated with chronic fatigue syndrome total about $14 billion in the United States. Annual losses to productivity because of lost work time range between $9 and $37 billion, with costs to individual households ranging between $8,000 and $20,000 per year.

Source: Science Daily

Apr 24, 201212 notes
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Prions in the Brain Eliminated by Homing Molecules

ScienceDaily (Apr. 24, 2012) — Toxic prions in the brain can be detected with self-illuminating polymers. The originators, at Linköping University in Sweden, has now shown that the same molecules can also render the prions harmless, and potentially cure fatal nerve-destroying illnesses.

Linköping researchers and their colleagues at the University Hospital in Zürich tested the luminescent conjugated polymers, or LCPs, on tissue sections from the brains of mice that had been infected with prions. The results show that the number of prions, as well as their toxicity and infectibility, decreased drastically. This is the first time anyone has been able to demonstrate the possibility of treating illnesses such as mad cow disease and Creutzfeldt-Jacobs with LCP molecules.

"When we see this effect on prion infections, we believe the same approach could work on Alzheimer’s disease as well," says Peter Nilsson, researcher in Bioorganic Chemistry funded by ERC, the European Research Council.

Along with professors Per Hammarström and Adriano Aguzzi and others, he is now publishing the results in The Journal of Biological Chemistry.

Prions are diseased forms of normally occurring proteins in the brain. When they clump together in large aggregates, nerve cells in the surrounding area are affected, which leads to serious brain damage and a quick death. Prion illnesses can be inherited, occur spontaneously or through infection, for example through infected meat — as was the case with mad cow disease.

The course of the illness is relentless when the prions fall to pieces and replicate at an exponential rate. When researchers inserted the LCP molecules into their model system, the replication was arrested, possible through stabilizing the prion aggregates.

The variable components in an LCP are various chemical subgroups attached onto the polymer. In the published study, eight different substances were tested, and all of them had significant effect on the toxicity of the prions.

"Based on these results, we can now customise entirely new molecules with potentially even better effect. These are now being tested on animal models," Nilsson says.

Researchers want to go even further and test whether the molecules will function on fruit flies with an Alzheimer’s-like nerve disorder. Alzheimer’s is caused by what is known as amyloid plaque, which has a similar but slower course than prion diseases.

Source: Science Daily

Apr 24, 20122 notes
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Nano-Devices that Cross Blood-Brain Barrier Open Door to Treatment of Cerebral Palsy, Other Neurologic Disorders

April 23rd, 2012

A team of scientists from Johns Hopkins and elsewhere have developed nano-devices that successfully cross the brain-blood barrier and deliver a drug that tames brain-damaging inflammation in rabbits with cerebral palsy.

image

Schematic picture of a dendrimer with multiple branches that are tagged with drug molecules and imaging agents. Image adapted from press release image from Johns Hopkins.

A report on the experiments, conducted at Wayne State University in collaboration with the Perinatology Research Branch of the National Institute of Child Health and Human Development, before the lead and senior investigators moved to Johns Hopkins, is published in the April 18 issue of Science Translational Medicine.

For the study, researchers used tiny, manmade molecules laced with N-acetyl-L-cysteine (NAC), an anti-inflammatory drug used as antidote in acetaminophen poisoning. The researchers precision-targeted brain cells gone awry to halt brain injury. In doing so they improved the animals’ neurologic function and motor skills.

The new approach holds therapeutic potential for a wide variety of neurologic disorders in humans that stem from neuro-inflammation, including Alzheimer’s disease, stroke, autism and multiple sclerosis, the investigators say.

The scientists caution that the findings are a long way from human application, but that the simplicity and versatility of the drug-delivery system make it an ideal candidate for translation into clinical use.

“In crossing the blood-brain barrier and targeting the cells responsible for inflammation and brain injury, we believe we may have opened the door to new therapies for a wide-variety of neurologic disorders that stem from an inflammatory response gone haywire,” says lead investigator Sujatha Kannan, M.D., now a pediatric critical-care specialist at Johns Hopkins Children’s Center.

Cerebral palsy (CP), estimated to occur in three out of 1,000 newborns, is a lifelong, often devastating disorder caused by infection or reduced oxygen to the brain before, during or immediately after birth. Current therapies focus on assuaging symptoms and improving quality of life, but can neither reduce nor reverse neurologic damage and loss of motor function.

Neuro-inflammatory damage occurs when two types of brain cells called microglia and astrocytes — normally deployed to protect the brain during infection and inflammation — actually damage it by going into overdrive and destroying healthy brain cells along with damaged ones.

Directly treating cells in the brain has long proven difficult because of the biological and physiological systems that have evolved to protect the brain from blood-borne infections. The quest to deliver the drug to the brain also involved developing a technique to get past the brain-blood barrier, spare healthy brain cells and deliver the anti-inflammatory drug exclusively inside the rogue cells.

To do all this, the scientists used a globular, tree-like synthetic molecule, known as a dendrimer. Its size — 2,000 times smaller than a red blood cell — renders it fit for travel across the blood-brain barrier. Moreover, the dendrimer’s tree-like structure allowed scientists to attach to it molecules of an anti-inflammatory NAC. The researchers tagged the drug-laced dendrimers with fluorescent tracers to monitor their journey to the brain and injected them into rabbits with cerebral palsy six hours after birth. Another group of newborn rabbits received an injection of NAC only.

Not only did the drug-loaded dendrimers make their way inside the brain but, once there, were rapidly swallowed by the overactive astrocytes and microglia.

“These rampant inflammatory cells, in effect, gobbled up their own poison,” Kannan says.

“The dendrimers not only successfully crossed the blood-brain barrier but, perhaps more importantly, zeroed in on the very cells responsible for neuro-inflammation, releasing the therapeutic drug directly into them,” says senior investigator Rangaramanujam Kannan, Ph.D., of the Center for Nanomedicine at the Johns Hopkins Wilmer Eye Institute.

Animals treated with dendrimer-borne NAC showed marked improvement in motor control and coordination within five days after birth, nearly reaching the motor skill of healthy rabbits. By comparison, rabbits treated with dendrimer-free NAC showed minimal, if any, improvement, even at doses 10 times higher than the dendrimer-borne version. Animals treated with the dendrimer-delivered drug also showed better muscle tone and less stiffness in the hind leg muscles, both hallmarks of CP.

Brain tissue analysis revealed that rabbits treated with dendrimer-borne NAC had notably fewer “bad” microglia — the inflammatory cells responsible for brain damage — as well as markedly lower levels of other inflammation markers. They also had better preserved myelin, the protein that sheaths nerves and is stripped or damaged in CP and other neurologic disorders. And even though CP is marked by neuron death in certain brain centers, animals who received dendrimer-borne NAC had higher number of neurons in the brain regions responsible for coordination and motor control, compared with untreated animals and those treated with NAC only.

The findings suggest that the treatment not only reduces inflammation in the cells, but may also prevent cell damage and cell death, the researchers said. The Kannans, who are married, say they plan to follow some treated animals into adulthood to ensure the improvements are not temporary.

Source: Neuroscience News

Apr 24, 20126 notes
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Protein prevents DNA damage in the developing brain and might serve as a tumor suppressor

April 23, 2012

St. Jude Children’s Research Hospital scientists have rewritten the job description of the protein TopBP1 after demonstrating that it guards early brain cells from DNA damage. Such damage might foreshadow later problems, including cancer.

Researchers showed that cells in the developing brain require TopBP1 to prevent DNA strands from breaking as the molecule is copied prior to cell division. Investigators also reported that stem cells and immature cells known as progenitor cells involved at the beginning of brain development are more sensitive to unrepaired DNA damage than progenitor cells later in the process. Although more developmentally advanced than stem cells, progenitor cells retain the ability to become one of a variety of more specialized neurons.

"Such DNA strand breaks have great potential for creating mutations that push a normal cell toward malignancy," said Peter McKinnon, Ph.D., a St. Jude Department of Genetics member and the paper’s senior author. "When we selectively knocked out TopBP1 in mice, the amount of DNA damage we saw suggests that TopBP1 is likely to be a tumor suppressor. We are exploring that question now."

The work appeared in the April 22 online edition of the scientific journal Nature Neuroscience. The research builds on McKinnon’s interest in DNA repair systems, including the enzymes ATM and ATR, which are associated with a devastating cancer-prone neurodegenerative disease in children called ataxia telangiectasia, and a neurodevelopmental disorder called Seckel syndrome.

TopBP1 was known to activate ATR. Previous laboratory research by other investigators also suggested that activation made TopBP1 indispensable for DNA replication and cell proliferation. This study, however, showed that was not the case. Most progenitor cells in the embryonic mouse brain kept dividing after investigators switched off the TopBP1 gene. 

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Apr 24, 20124 notes
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Gatekeeper of brain steroid signals boosts emotional resilience to stress

April 23, 2012

A cellular protein called HDAC6, newly characterized as a gatekeeper of steroid biology in the brain, may provide a novel target for treating and preventing stress-linked disorders, such as depression and post-traumatic stress disorder (PTSD), according to research from the Perelman School of Medicine at the University of Pennsylvania.

Glucocorticoids are natural steroids secreted by the body during stress. A small amount of these hormones helps with normal brain function, but their excess is a precipitating factor for stress-related disorders.

Glucocorticoids exert their effects on mood by acting on receptors in the nucleus of emotion–regulating neurons, such as those producing the neurotransmitter serotonin. For years, researchers have searched for ways to prevent deleterious effects of stress by blocking glucocorticoids in neurons. However, this has proved difficult to do without simultaneously interfering with other functions of these hormones, such as the regulation of immune function and energy metabolism.

In a recent Journal of Neuroscience paper, the lab of Olivier Berton, PhD, assistant professor of Psychiatry, shows how a regulator of glucocorticoid receptors may provide a path towards resilience to stress by modulating glucocorticoid signaling in the brain. The protein HDAC6, which is particularly enriched in serotonin pathways, as well as in other mood-regulatory regions in both mice and humans, is ideally distributed in the brain to mediate the effect of glucocorticoids on mood and emotions. HDAC6 likely does this by controlling the interactions between glucocorticoid receptors and hormones in these serotonin circuits.

Experiments that first alerted Berton and colleagues to a peculiar role of HDAC6 in stress adaptation came from an approach that reproduces certain clinical features of traumatic stress and depression in mice. The animals are exposed to brief bouts of aggression from trained “bully” mice. In most aggression-exposed mice this experience leads to the development of a lasting form of social aversion that can be treated by chronic administration of antidepressants. 

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Apr 24, 20126 notes
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Brain surgery for epilepsy underutilized: study

April 23, 2012

Ten years ago, a landmark clinical trial in Canada demonstrated the unequivocal effectiveness of brain surgeries for treating uncontrolled epilepsy, but since then the procedure has not been widely adopted—in fact, it is dramatically underutilized according to a new study from the University of California, San Francisco (UCSF).

The study, published this month in the journal Neurology, showed that the number of Americans having the surgery has not changed in the decade since release of the effectiveness study, though surgical treatment is now uniformly encouraged by neurology and neurosurgery professional societies.

The U.S. Centers for Disease Control and Prevention estimates that 2 million Americans have epilepsy. Hundreds of thousands of these men, women and children suffer from uncontrolled seizures, but nationally only a few hundred are treated surgically each year with UCSF performing about 50 of the operations.

Among people who do have the operation, the study found, there are significant disparities by race and insurance status. White patients were more likely to have surgery than racial minorities, and privately insured patients were more likely to undergo surgery than those with Medicaid or Medicare.

"As a medical community, we are not practicing evidence-based medicine with regard to the treatment of patients who have epilepsy," said Edward Chang, MD, chief of adult epilepsy surgery in the UCSF Department of Neurological Surgery and the UCSF Epilepsy Center. "There are a lot of people who are taking medications and continuing to have seizures even though they can potentially be seizure-free."

A MODERN SURGERY FOR AN ANCIENT DISEASE

Epilepsy has been recognized as an important neurological condition since ancient times and its name means “seizures” in Greek. It can be inherited or it can be caused by anything that injures or irritates the brain. Hippocrates, the father of western medicine, described it in detail in his writings some 2,500 years ago, and it is believed to have afflicted many famous people throughout history, including Julius Caesar.

UCSF is one of the world’s leading institutions involved in epilepsy research, with one of the few medical centers that has top-ranking departments in relevant areas: neurology, biomedical imaging, and neurosurgery.

Paul Garcia, MD, director of the clinical epilepsy program and a study co-author, said that most patients referred to UCSF for surgical evaluation have had uncontrolled seizures for many years despite trying several medications. Research has shown that after the first two medicines fail, it is uncommon for patients to gain complete seizure control with medical treatment alone. Without control over their seizures, patients are at risk for physical injuries or even dying. Furthermore, the seizures often interfere with normal life activities such as driving, studying and working.

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Apr 24, 20128 notes
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Omega-3 fatty acids not associated with beneficial effects in multiple sclerosis: study

April 23, 2012

Omega-3 fatty acid supplements were not associated with beneficial effects on disease activity in patients with relapsing-remitting multiple sclerosis, according to a report of a randomized controlled trial published Online First by Archives of Neurology.

Multiple sclerosis is a chronic, incurable disease of the central nervous system that affects about 2.5 million people worldwide. Some patients use, or have tried, omega-3 fatty acids supplementation to control the disease because the essential fatty acids could theoretically have anti-inflammatory and neuroprotective effects in multiple sclerosis, the authors write in their study background.

Øivind Torkildsen, M.D., Ph.D., of Haukeland University Hospital, Bergen, Norway, and colleagues included 92 patients with multiple sclerosis in their double-blind, placebo-controlled trial to examine whether omega-3 fatty acid supplementation as a monotherapy (single therapy) or in combination with subcutaneous (under the skin) interferon beta-1a could reduce disease activity.

Half of the patients (46) were given omega-3 fatty acids – 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily - and the other half (46) were administered placebo. After six months, all patients received interferon beta-1a three times a week for another 18 months. Researchers used magnetic resonance imaging (MRI) to measure disease activity by the number of new T1-weighted gadolinium-enhancing lesions in the brain.

"The results from this study did not show any beneficial effects of ω-3 [omega-3] fatty acid supplementation on disease activity in multiple sclerosis as a monotherapy or in combination with interferon beta," the authors comment. They note their results were in contrast with two other studies reporting a possible positive effect.

The median number of new T1-weighted gadolinium-enhancing lesions was three in the omega-3 fatty acids group and two in the placebo group during the first six months, according to the study results. The results indicate no difference between the two groups in the number of relapses during the first six months of treatment or after 24 months. No differences were detected either in fatigue or quality-of-life scores.

However, the authors comment their data do not suggest that omega-3 fatty acid supplementation was harmful or that it interfered with interferon beta treatment, which they note can reduce disease activity in the relapsing-remitting course of the disease.

"The design of this study allowed us to compare the effect of ω-3 fatty acid supplementation both against placebo alone and in combination with interferon beta. As expected, the MRI disease activity was significantly reduced when interferon beta-1a was introduced," they conclude.

Provided by JAMA and Archives Journals

Source: medicalxpress.com

Apr 24, 20123 notes
#science #neuroscience #psychology #brain
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