Category: Neuroscience

An Indiana University study has provided preliminary evidence that by measuring brain activity through the use of neuroimaging, researchers can predict who is likely to have an easier time getting off drugs and alcohol, and who will need extra help.

"We can also see how brain activity changes as people recover from their addictions," said Joshua Brown, assistant professor in the Department of Psychological and Brain Sciences at Indiana University Bloomington, part of the College of Arts and Sciences.

The chronic occurrence of relapse underscores the need for improved methods of treatment and relapse prevention. One potential cause for relapse is deficient self-regulatory control over behavior and decision-making. Specifically this lack of self-regulatory ability in substance dependent individuals has been associated with dysfunction of a mesolimbic-frontal brain network. Reduced activity within this self-regulatory brain network has previously been implicated in relapse, but the specific relationship between this network, self-regulatory ability and recovery is yet to be determined.

The current study explores neurophysiological and cognitive indicators of self-regulatory ability in a community-based sample of substance dependent individuals during the first three months of addiction treatment. The study tests participants' risk-taking inclinations through what is called a Balloon Analog Risk Task, a game in which the participants can decide whether to add increasing amounts of air to a balloon, gaining rewards until it pops. Those who took greater risks were shown to have reduced brain activity. By the same token, those who took less risk showed greater brain activity. By three months those who were successful in treatment also demonstrated a pattern of brain activation that coincided with the risk level of cues during the balloon risk task decision-making. In individuals who relapsed, risk-related activation was limited to certain brain regions, possibly signaling the anticipated reward rather than the risk of negative outcome.

 A study by researchers from Emory University and Indiana University found that the beneficial effects daily exercise can have on the regeneration of nerves also require androgens such as testosterone in both males and females. It is the first report of both androgen-dependence of exercise on nerve regeneration and of an androgenic effect of exercise in females.

"The findings will provide a basis for the development of future treatment strategies for patients suffering peripheral nerve injuries," said Dale Sengelaub, professor in the Department of Psychological and Brain Sciences at IU. "And they underscore the need to tailor those treatments differently for men and women."

The researchers discussed the study on Monday at the Neuroscience 2012 scientific meeting in New Orleans.

Injuries to peripheral nerves are common. Hundreds of thousands of Americans are victims of traumatic injuries each year, and non-traumatic injuries, such as carpal tunnel syndrome, are found in even higher numbers. The researchers previously showed that two weeks of moderate daily exercise substantially improves regeneration of cut nerves and leads to functional recovery in mice, though different types of exercise are required to produce the effect in males and females. They now report that these beneficial effects of exercise require androgens such as testosterone in both males and females.

In the study they conducted, they exercised three groups of male and female mice. Nerves of the three groups were cut and surgically repaired. Once group received the drug flutamide, which blocks the androgen receptor. A second group received a placebo treatment. The third group was unexercised. Regenerating nerve fibers in the placebo group grew to more than twice the length of those in unexercised mice in both males and females. In flutamide-treated mice, the effects of exercise were blocked completely in both sexes.

The study, "Enhancement of peripheral axon regeneration by exercise requires androgen receptor signaling in both male and female mice," will be discussed from 11 a.m. to noon on Monday in Hall F-J. Co-authors are Arthur W. English and Nancy Thompson, both from Emory University.

The Society of Neuroscience is promoting the study to media covering the conference as a "Hot Topic."

Children who undergo brain radiation therapy run a significant risk of suffering from permanent neurocognitive adverse effects. These adverse effects are due to the fact that the radiation often encounters healthy tissue. This reduces the formation of new cells, particularly in the hippocampus — the part of the brain involved in memory and learning.

Researchers at the University of Gothenburg's Sahlgrenska Academy have used a model study to test newer radiation therapy techniques which could reduce these harmful adverse effects. The researchers based their study on a number of paediatric patients who had undergone conventional radiation treatment for medulloblastoma, a form of brain tumour that almost exclusively affects children, and simulated treatment plans using proton therapy techniques and newer photon therapy techniques.

Each treatment plan was personalised by physician Malin Blomstrand, physicist Patrik Brodin and their colleagues. The results show that the risk of neurocognitive adverse effects can be reduced significantly using the new radiation treatment techniques, particularly proton therapy.

"This could mean a better quality of life for children who are forced to undergo brain radiation therapy," says Malin Blomstrand.

NewsPsychology (Oct. 15, 2012) — When learning a new language, we automatically organize words into sentences that will be both clearly understood and efficient (quick) to communicate. That’s the finding of a new study reported today in the Proceedings of the National Academy of Sciences (PNAS) which challenges opposing theories on why and how languages come to be organized the way they are.

With more than 5000 languages in the world, it would be easy to assume all vary endlessly, but, in fact, there is great commonality: languages follow only a few recurrent patterns. These commonalities are called “language universals,” a notion suggested in the 1960’s by Noam Chomsky and Joseph Greenberg. A team of researchers from the University of Rochester and Georgetown University Medical Center set out to investigate how these language universals come to be.

Linguists and cognitive scientists have opposing ideas on how a language is developed and shaped. Some believe that languages all derived from a common ancestor; others think that languages vary quite widely and universals do not exist at all. Some have suggested that language universals are an arbitrary evolutionary outcome. The position of the Rochester-Georgetown team is that the human mind shapes a language, even while learning it, based on the need for robust and effective information transfer.

“The thousands of natural languages in our world only have a couple of formats in which they appear, and we are good at understanding and learning languages that have just these formats. Otherwise we could never succeed in learning something so complicated as human languages,” says one of the study’s authors, Elissa L. Newport, Ph.D., a professor in the department of neurology at Georgetown University Medical Center.

A member of the National Academy of Sciences, Newport is also director of the Center for Brain Plasticity and Recovery, a joint program of Georgetown University and MedStar National Rehabilitation Network.

The study was conducted by Rochester graduate researcher Maryia Fedzechkina in a collaboration with Newport and T. Florian Jaeger, Ph.D., Wilmot Assistant Professor of the Sciences in the department of brain and cognitive sciences at Rochester.

According to Jaeger, the question that motivated their study is “whether subtle biases towards language codes that facilitate efficient information transfer operate during language acquisition, causing learners to deviate from the input they receive, slowly changing languages over generations.”

For the study, participants were taught a miniature artificial language made of nonsensical words including 8 verbs and 15 nouns (e.g. kliedum, slergin, zub and zamper). The volunteers were shown videos while hearing sentences from the language, and spent several days learning the language. But the language they were exposed to was organized unlike any natural language. While many languages have prefixes or suffixes on nouns to indicate subject or object — a property called case-marking — their artificial languages contained case marking on only about 60 percent of the nouns, and this sprinkling of case markers did not follow any of the principles that appear in real languages regarding when a case marker would be most likely or most helpful.

The researchers wanted to know if the participants would “fix” the language on their own.

“English, as well as a lot of other languages, use subject-verb-object word order to indicate roles, such as ‘the boy kicked the wall’,” Fedzechkina explains. “Other languages use case markings on nouns. Of particular interest is that some languages such as Korean and Japanese use case markings precisely when the sentence would be easily misunderstood without them.”

The participants in this study spoke only English — they were not familiar with other languages that use case markings. Yet after days of training in the made-up language, when participants were asked to speak new sentences to describe a video in which one person is doing something to another, they deviated from what was taught. They added case markings to nouns precisely when it made the sentence clearer in determining the object and subject.

“They fixed the sentence structure,” Newport says.

“The study’s results support the idea that we apply a ‘language universal’ that services clear yet efficient communication,” Newport says. She adds, what makes this study stronger is what the volunteers didn’t do.

“They could have removed all the inconsistent words and produced a language with none of the case markings,” she explains. “They could have reproduced what we gave them, keeping the meaning of the markers and sentences uncertain. Or they could have added a case marker in every sentence, to mark every object, which would have made the sentences clear but also long and inefficient.”

But they didn’t.

“What they did was add the case marker only in cases where the meaning would have otherwise been ambiguous and confusing.” Newport concludes, “We found that when you make up languages that violate universals, people will change the language, moving it toward universal principles.”

The study was supported by National Science Foundation grants (BCS-0845059 and IIS-1150028) and a Sloan Research Fellowship to Jaeger, and National Institutes of Health grants (DC00167 and HD037082) to Newport. The authors report having no personal financial interests related to the study.

---

Story Source:

The above story is reprinted from materials provided by Georgetown University Medical Center.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

NewsPsychology (Oct. 15, 2012) — For decades, patients with Parkinson’s disease (PD) have had the same experience. Their hands start to shake uncontrollably, their limbs become rigid and they lose their balance. Years before those movement problems set in, many begin struggling with fainting, incontinence, sexual dysfunction, anxiety and depression. Most patients are still treated with a 42-year-old drug called L-DOPA, which temporarily staves off symptoms but can itself cause heart arrhythmias, stomach bleeding and hallucinations.

This punishing experience may explain in part why patients with PD die at twice the rate of those without the disease in the years after their diagnosis. In this light, it’s best to tread carefully when talking about early study results that promise something better. That said, a team of researchers at the University of Alabama at Birmingham is excited.

The team has identified a set of experimental drugs called LRRK2 inhibitors that may go beyond symptom relief to directly counter the inflammation and nerve cell death at the root of Parkinson’s. At least, these effects have been suggested in mouse and cell culture studies meant to approximate human disease. UAB researchers reported on these findings today in a presentation at Neuroscience 2012, the annual meeting of the Society for Neuroscience in New Orleans.

“We don’t yet know what percentage of patients might benefit from LRKK2 inhibitors, but LRRK2 is without a doubt the most exciting target for neuroprotection to have ever been identified in Parkinson’s disease,” says Andrew West, Ph.D., associate professor in the Department of Neurology within the UAB School of Medicine, who gave the presentation at Neuroscience 2012. “We will repeat our experiments many times before drawing final conclusions, but our ultimate goal is see our compound or something like it enter toxicology studies, and ultimately, clinical trials as soon as is prudent.”

While West’s compounds are promising, they still face many crucial tests that will decide whether or not they reach human trials. But the field is excited, because this is the first time such a drug target has been found for any neurodegenerative disease. Along with evidence that LRRK2 plays a crucial role in the mechanisms of Parkinson’s disease, it is a protein kinase, the same kind of enzyme (although not the same one) that has been safely and potently targeted by existing treatments for other diseases, including the cancer drugs Herceptin, Tarceva and Erbitux.

Why LRRK2?

LRRK2 stands for leucine-rich repeat kinase 2. Kinases are enzymes that attach molecules called phosphates to other molecules to start, stop or adjust cellular processes. Past studies found that the most common LRRK2 mutation, called G2019S, makes LRRK2 slightly over-active. The idea is to dial LRRK2 back with drugs.

Whether it’s a bad version of a gene, an unlucky flu infection, a head injury or just age, something makes a protein called alpha-synuclein build up in the nerve cells of Parkinson’s patients, contributing to their self-destruction. Unfortunately, alpha-synuclein and proteins like it are not part of a traditional set of “drug-able” targets. Once alpha-synuclein builds up, the question becomes whether the brain will handle it well or amplify the disease.

LRRK2, to West’s mind, is a critical decision-maker in the body’s answer to that question. He thinks it operates at the intersection between alpha-synuclein, neurotransmission and immune responses, which fight infectious diseases but also create disease-related inflammation when unleashed at the wrong moment, or in the wrong place or amount. Not everyone who has a LRRK2 mutation develops the disease, but West’s team thinks it becomes important when combined with other factors.

Past studies have shown that alpha-synuclein build-up in nerve cells activates nearby immune cells of the brain called microglia, and that these microglia express high levels of LRRK2. Recent cell studies in West’s lab suggest that mutated, overactive LRRK2 strengthens inflammatory responses in microglia and that inhibiting LRRK2 reduces them. Preliminary data also suggests LRRK2-driven inflammation raises the rate of nerve cell death. It’s worth noting, however, that neither these mechanisms nor their relationships with each other and Parkinson’s disease have been fully confirmed.

“The beauty is that we don’t necessarily need to confirm an exact mechanism to move drugs into clinical trials,” says West. “One could argue that human PD is too complex to fully model in other animals. Many predict that we will not know if we understand Parkinson’s disease until we get safe, potent, specific drugs into human studies and until one of them halts or reverses the disease process.”

Toward a new treatment

In West’s view, the perfect drug would get past the barrier that keeps toxins (and many drugs) in the bloodstream from entering the brain, and then past the proteins that pump toxins out of the brain if they slip through the first barrier. This ideal drug would have its effect and then clear out of the body in a reasonable timeframe to avoid building up in any one organ. It also would dial down the activity of LRRK2 alone, and only enough to reduce its signaling to normal.

West’s presentation at the meeting described how his team’s lead compound has achieved these goals in some preclinical disease models. Specifically, the team has identified potent inhibitors that affect only LRRK2 in a test involving more than 300 kinases. The researchers have increased the potency of candidate compounds that show good solubility, stability and brain penetration. Moving forward, they will re-test their best compound in the best rodent model, conduct toxicology studies, and then — should all go well — seek permission from the U.S. Food and Drug Administration to start a clinical trial.

While West leads the ongoing UAB effort, Robert Galemmo Jr., Ph.D., leads a group of collaborators at Birmingham’s Southern Research Institute, together with Joseph Maddry, Ph.D., director of the Medicinal Chemistry Department there. Making this research possible have been UAB- and SRI-related entities like the Alabama Drug Discovery Alliance and the Center for Clinical and Translational Science, which supported West’s LRRK2 work with an early pilot grant. The partnerships have allowed UAB researchers to move drugs closer to clinical trials by taking on roles once shouldered exclusively by pharmaceutical companies.

The research also has been funded by private philanthropists within the Birmingham community who are dedicated to advancing new drugs to treat PD. West is the John A. and Ruth R. Jurenko Scholar at UAB, which reflects the Jurenko family’s vital support of this work.

---

Story Source:

The above story is reprinted from materials provided by University of Alabama at Birmingham. The original article was written by Greg Williams.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

UC Irvine and Brown University researchers have created a new fruit fly model of inherited epilepsy that's providing insights into the mechanisms underlying temperature-dependent seizures while establishing a platform from which to develop therapies for these disorders.

In the Oct. 10 issue of The Journal of Neuroscience, Diane O'Dowd of UCI, Robert Reenan of Brown and colleagues report their method for placing a gene mutation that causes human fever-induced seizures into drosophila fruit flies. As a result, the mutant flies experience heat-induced seizures.

This represents the first time a human genetic disease mutation has been "knocked in" to the equivalent location in the fruit fly genome. The drosophila knock-in model provides a rapid and low-cost basis for defining the neural mechanisms contributing to inherited seizure disorders.

"We can also use this genetic model of human epilepsy in fruit flies to look for new treatments for the disease," said O'Dowd, professor and chair of developmental & cell biology at UCI.

Fever-induced, or febrile, seizures are most commonly seen in children. Only about one in 100 children with febrile seizures develops epilepsy, and most outgrow them by age 5. In contrast, individuals who have the inherited disorder — termed GEFS+ — have febrile seizures that persist beyond childhood and also often develop seizures in the absence of fever.

Reenan, a biology professor at Brown, and Brown undergraduate Jeff Gilligan used a genetic-exchange research method called "homologous recombination" to insert a mutation into the gene in fruit flies that's a direct parallel of the GEFS+ mutation in the human SCN1A sodium channel gene that causes febrile seizures in people.

When placed in tubes that were put in warm water, most of the mutant fruit flies began to experience seizures within 20 to 30 seconds. They would fall over, and their wings would flap and their legs twitch for about two minutes while the flies were kept at a high temperature. The researchers found that seizure susceptibility was dose-dependent: Ninety-five percent of the flies with two copies of the mutant gene had seizures, as opposed to 60 percent of those with just one copy. Unaltered control flies did not have temperature-dependent seizures.

To determine the neurological causes of the seizures, O'Dowd, her postdoctoral fellow and lead study author Lei Sun, and UCI colleagues examined neurons in the brains of both mutant and control flies to monitor activity and see how they behaved as the brains were heated. In the mutant flies, they discovered flaws in the functioning of sodium channels.

"What happens is the mutant channels don't open and close properly," O'Dowd said. "This effect is amplified at high temperature, and this changes the ability of neurons to generate the appropriate electrical signals, leading to hyperactivity in the brain circuits."

"With this knowledge, the next step is to use this model to look for drugs that might reduce or eliminate heat-induced seizures," she added.

In addition to providing insight into the neurology of febrile seizures, the study establishes a new fruit fly model as a viable genetic platform for the study of epilepsy and validates the use of homologous recombination in flies to explore mechanisms underlying other genetically linked diseases.

Ryan Schutte and Vivian Nguyen of UCI and Cynthia Staber of Brown also contributed to the study, which was funded by the National Institutes of Health, Howard Hughes Medical Institute and the Ellison Medical Foundation.

An abstract presented Oct. 19, at the American Academy of Pediatrics (AAP) National Conference and Exhibition in New Orleans highlights the risky behavior of child pedestrians who are struck by cars — including darting into the street, crossing in the middle of the block, and crossing while using an electronic device.

For the abstract, "Risky Behaviors of Pediatric Pedestrians Who are Struck by Motor Vehicles," researchers collected data on all pedestrians who were injured by a motor vehicle and presented to a Level I trauma center in New York City between 2008 and 2011.

Of the 1,075 patients, 145 (13 percent) were under age 18. When compared with adults, children were more likely to be male (65 percent versus. 53 percent), have head injuries (82 percent versus 73 percent), and discharged without admission (70 percent versus 67 percent).

Children age 6 and younger were most often injured when darting into the street (44 percent) or crossing in the middle of the street (36 percent). For children ages 7 to 12, unsupervised activity accounted for 53 percent of the accidents, followed by mid-block crossing (47 percent) and darting into the street (25 percent). Among teens ages 13 to 17, 88 percent were struck by a motor vehicle while unsupervised, 32 percent while crossing mid-block, 18 percent while using an electronic device and 14 percent when darting into the street. Just 4 percent of the teen accidents involved alcohol use.

In comparison, 18 percent of the adult accidents were due to pedestrians crossing in the middle of the street, 15 percent to alcohol use and 9 percent to electronic device use.

"While most other research on this type of population looked only at discharge data of those admitted to hospitals, one of the strengths of this study is that it looks at all patients presented to the emergency department," said study author Nina E. Glass, MD. "While most of the young children in our study were supervised by a parent or guardian, these children still exhibited a lot of risky behaviors in terms of mid-block crossing and crossing against the signal."

In older children, there was a much higher incidence of using electronic devices,and listening to cellphones or music, than researchers saw in the adult population(18 percent of teens versus 9 percent of adults).

Dr. Glass said that greater parental supervision, and safety tip reminders by pediatricians, could play an important role in preventing child pedestrian accidents.