What Happens in the Brain to Make Music Rewarding?

What Happens in the Brain to Make Music Rewarding?

  7:57:00 AM    Science Lover

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A new study reveals what happens in our brain when we decide to purchase a piece of music when we hear it for the first time. The study, conducted at the Montreal Neurological Institute and Hospital -- The Neuro, McGill University and published in the journal Science on April 12, pinpoints the specific brain activity that makes new music rewarding and predicts the decision to purchase music.

A new study reveals what happens in our brain when we decide to purchase a piece of music when we hear it for the first time. (Credit: © Warren Goldswain / Fotolia)

Participants in the study listened to 60 previously unheard music excerpts while undergoing functional resonance imaging (fMRI) scanning, providing bids of how much they were willing to spend for each item in an auction paradigm. "When people listen to a piece of music they have never heard before, activity in one brain region can reliably and consistently predict whether they will like or buy it, this is the nucleus accumbens which is involved in forming expectations that may be rewarding," says lead investigator Dr. Valorie Salimpoor, who conducted the research in Dr. Robert Zatorre's lab at The Neuro and is now at Baycrest Health Sciences' Rotman Research Institute. "What makes music so emotionally powerful is the creation of expectations. Activity in the nucleus accumbens is an indicator that expectations were met or surpassed, and in our study we found that the more activity we see in this brain area while people are listening to music, the more money they are willing to spend."

The second important finding is that the nucleus accumbens doesn't work alone, but interacts with the auditory cortex, an area of the brain that stores information about the sounds and music we have been exposed to. The more a given piece was rewarding, the greater the cross-talk between these regions. Similar interactions were also seen between the nucleus accumbens and other brain areas, involved in high-level sequencing, complex pattern recognition and areas involved in assigning emotional and reward value to stimuli.

In other words, the brain assigns value to music through the interaction of ancient dopaminergic reward circuitry, involved in reinforcing behaviours that are absolutely necessary for our survival such as eating and sex, with some of the most evolved regions of the brain, involved in advanced cognitive processes that are unique to humans.

"This is interesting because music consists of a series of sounds that when considered alone have no inherent value, but when arranged together through patterns over time can act as a reward, says Dr. Robert Zatorre, researcher at The Neuro and co-director of the International Laboratory for Brain, Music and Sound Research. "The integrated activity of brain circuits involved in pattern recognition, prediction, and emotion allow us to experience music as an aesthetic or intellectual reward."

"The brain activity in each participant was the same when they were listening to music that they ended up purchasing, although the pieces they chose to buy were all different," adds Dr. Salimpoor. "These results help us to see why people like different music -- each person has their own uniquely shaped auditory cortex, which is formed based on all the sounds and music heard throughout our lives. Also, the sound templates we store are likely to have previous emotional associations."

An innovative aspect of this study is how closely it mimics real-life music-listening experiences. Researchers used a similar interface and prices as iTunes. To replicate a real life scenario as much as possible and to assess reward value objectively, individuals could purchase music with their own money, as an indication that they wanted to hear it again. Since musical preferences are influenced by past associations, only novel music excerpts were selected (to minimize explicit predictions) using music recommendation software (such as Pandora, Last.fm) to reflect individual preferences.

The interactions between nucleus accumbens and the auditory cortex suggest that we create expectations of how musical sounds should unfold based on what is learned and stored in our auditory cortex, and our emotions result from the violation or fulfillment of these expectations. We are constantly making reward-related predictions to survive, and this study provides neurobiological evidence that we also make predictions when listening to an abstract stimulus, music, even if we have never heard the music before. Pattern recognition and prediction of an otherwise simple set of stimuli, when arranged together become so powerful as to make us happy or bring us to tears, as well as communicate and experience some of the most intense, complex emotions and thoughts.

Listen to the music excerpts used in the study: http://www.zlab.mcgill.ca/science2013/

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Diabetes Drug Makes Brain Cells Grow

Diabetes Drug Makes Brain Cells Grow

  2:00:00 PM    Science Lover

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The widely used diabetes drug metformin comes with a rather unexpected and alluring side effect: it encourages the growth of new neurons in the brain. The study reported in the July 6th issue of Cell Stem Cell, a Cell Press publication, also finds that those neural effects of the drug also make mice smarter.

New research finds that the widely used diabetes drug 
metformin comes with a rather unexpected and alluring 
side effect: it encourages the growth of new neurons in 
the brain. (Credit: iStockphoto/Guido Vrola)

The discovery is an important step toward therapies that aim to repair the brain not by introducing new stem cells but rather by spurring those that are already present into action, says the study's lead author Freda Miller of the University of Toronto-affiliated Hospital for Sick Children. The fact that it's a drug that is so widely used and so safe makes the news all that much better.

Earlier work by Miller's team highlighted a pathway known as aPKC-CBP for its essential role in telling neural stem cells where and when to differentiate into mature neurons. As it happened, others had found before them that the same pathway is important for the metabolic effects of the drug metformin, but in liver cells.

"We put two and two together," Miller says. If metformin activates the CBP pathway in the liver, they thought, maybe it could also do that in neural stem cells of the brain to encourage brain repair.

The new evidence lends support to that promising idea in both mouse brains and human cells. Mice taking metformin not only showed an increase in the birth of new neurons, but they were also better able to learn the location of a hidden platform in a standard maze test of spatial learning.

While it remains to be seen whether the very popular diabetes drug might already be serving as a brain booster for those who are now taking it, there are already some early hints that it may have cognitive benefits for people with Alzheimer's disease. It had been thought those improvements were the result of better diabetes control, Miller says, but it now appears that metformin may improve Alzheimer's symptoms by enhancing brain repair.

Miller says they now hope to test whether metformin might help repair the brains of those who have suffered brain injury due to trauma or radiation therapies for cancer.

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New Energy Source for Future Medical Implants: Sugar

New Energy Source for Future Medical Implants: Sugar

  7:50:00 PM    Science Lover

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MIT engineers have developed a fuel cell that runs on the same sugar that powers human cells: glucose. This glucose fuel cell could be used to drive highly efficient brain implants of the future, which could help paralyzed patients move their arms and legs again.

This silicon wafer consists of glucose fuel cells of varying sizes; 
the largest is 64 by 64 mm. Image: (Credit: Sarpeshkar Lab)

The fuel cell, described in the June 12 edition of the journal PLoS ONE, strips electrons from glucose molecules to create a small electric current. The researchers, led by Rahul Sarpeshkar, an associate professor of electrical engineering and computer science at MIT, fabricated the fuel cell on a silicon chip, allowing it to be integrated with other circuits that would be needed for a brain implant.

The idea of a glucose fuel cell is not new: In the 1970s, scientists showed they could power a pacemaker with a glucose fuel cell, but the idea was abandoned in favor of lithium-ion batteries, which could provide significantly more power per unit area than glucose fuel cells. These glucose fuel cells also utilized enzymes that proved to be impractical for long-term implantation in the body, since they eventually ceased to function efficiently.

The new twist to the MIT fuel cell described in PLoS ONE is that it is fabricated from silicon, using the same technology used to make semiconductor electronic chips. The fuel cell has no biological components: It consists of a platinum catalyst that strips electrons from glucose, mimicking the activity of cellular enzymes that break down glucose to generate ATP, the cell's energy currency. (Platinum has a proven record of long-term biocompatibility within the body.) So far, the fuel cell can generate up to hundreds of microwatts -- enough to power an ultra-low-power and clinically useful neural implant.

"It will be a few more years into the future before you see people with spinal-cord injuries receive such implantable systems in the context of standard medical care, but those are the sorts of devices you could envision powering from a glucose-based fuel cell," says Benjamin Rapoport, a former graduate student in the Sarpeshkar lab and the first author on the new MIT study.

Rapoport calculated that in theory, the glucose fuel cell could get all the sugar it needs from the cerebrospinal fluid (CSF) that bathes the brain and protects it from banging into the skull. There are very few cells in the CSF, so it's highly unlikely that an implant located there would provoke an immune response. There is also significant glucose in the CSF, which does not generally get used by the body. Since only a small fraction of the available power is utilized by the glucose fuel cell, the impact on the brain's function would likely be small.

Karim Oweiss, an associate professor of electrical engineering, computer science and neuroscience at Michigan State University, says the work is a good step toward developing implantable medical devices that don't require external power sources.

"It's a proof of concept that they can generate enough power to meet the requirements," says Oweiss, adding that the next step will be to demonstrate that it can work in a living animal.

A team of researchers at Brown University, Massachusetts General Hospital and other institutions recently demonstrated that paralyzed patients could use a brain-machine interface to move a robotic arm; those implants have to be plugged into a wall outlet.

Mimicking biology with microelectronics

Sarpeshkar's group is a leader in the field of ultra-low-power electronics, having pioneered such designs for cochlear implants and brain implants. "The glucose fuel cell, when combined with such ultra-low-power electronics, can enable brain implants or other implants to be completely self-powered," says Sarpeshkar, author of the book "Ultra Low Power Bioelectronics." This book discusses how the combination of ultra-low-power and energy-harvesting design can enable self-powered devices for medical, bio-inspired and portable applications.

Sarpeshkar's group has worked on all aspects of implantable brain-machine interfaces and neural prosthetics, including recording from nerves, stimulating nerves, decoding nerve signals and communicating wirelessly with implants. One such neural prosthetic is designed to record electrical activity from hundreds of neurons in the brain's motor cortex, which is responsible for controlling movement. That data is amplified and converted into a digital signal so that computers -- or in the Sarpeshkar team's work, brain-implanted microchips -- can analyze it and determine which patterns of brain activity produce movement.

The fabrication of the glucose fuel cell was done in collaboration with Jakub Kedzierski at MIT's Lincoln Laboratory. "This collaboration with Lincoln Lab helped make a long-term goal of mine -- to create glucose-powered bioelectronics -- a reality," Sarpeshkar says. Although he has just begun working on bringing ultra-low-power and medical technology to market, he cautions that glucose-powered implantable medical devices are still many years away.

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Brain Imaging Study Finds Evidence of Basis for Caregiving Impulse

Brain Imaging Study Finds Evidence of Basis for Caregiving Impulse

  7:17:00 PM    Science Lover

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Distinct patterns of activity -- which may indicate a predisposition to care for infants-- appear in the brains of adults who view an image of an infant face -- even when the child is not theirs, according to a study by researchers at the National Institutes of Health and in Germany, Italy, and Japan.

Researchers have found that distinct patterns of activity --
which may indicate a predisposition to care for infants --
appear in the brains of adults who view an image of an
infant face -- even when the child is not theirs.
(Credit: © Jamey Ekins / Fotolia)

Seeing images of infant faces appeared to activate in the adult's brains circuits that reflect preparation for movement and speech as well as feelings of reward.

The findings raise the possibility that studying this activity will yield insights into care giving behavior, but also in cases of child neglect or abuse.

"These adults have no children of their own. Yet images of a baby's face triggered what we think might be a deeply embedded response to reach out and care for that child," said senior author Marc H. Bornstein, Ph.D., head of the Child and Family Research Section of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH institute that collaborated on the study.

While the researchers recorded participants' brain activity, the participants did not speak or move. Yet their brain activity was typical of patterns preceding such actions as picking up or talking to an infant, the researchers explained. The activity pattern could represent a biological impulse that governs adults' interactions with small children.

From their study results, the researchers concluded that this pattern is specific to seeing human infants. The pattern did not appear when the participants looked at photos of adults or of animals -- even baby animals.

Along with Dr. Bornstein, the research was carried out by first author Andrea Caria, Ph.D., of the University of Tuebingen, in Germany; Paola Venuti of the Department of Cognitive Science of University of Trento in Italy; Gianluca Esposito of the RIKEN Brain Science Institute in Saitama, Japan; researchers from the Max Planck Institute for Biological Cybernetics and Eberhard Karls University, in Tuebingen, Germany.

Their findings appear in the journal NeuroImage.

To collect the data, the researchers showed seven men and nine women a series of images while recording their brain activity with a functional magnetic resonance imaging scanner. In the scanner, participants viewed images of puppy and kitten faces, full-grown dogs and cats, human infants and adults.

When the researchers compared the areas and strength of brain activity in response to each kind of image, they found that infant images evoked more activity than any of the other images in brain areas associated with three main functions:

• Premotor and preverbal activity -- The researchers documented increased activity in the premotor cortex and the supplemental motor area, which are regions of the brain directly under the crown of the head. These regions orchestrate brain impulses preceding speech and movement but before movement takes place.
• Facial recognition -- Activity in the fusiform gyrus -- on each side of the brain, about where the ears are -- is associated with processing of information about faces. Activity the researchers detected in the fusiform gyrus may indicate heightened attention to the movement and expressions on an infant's face, the researchers said.
• Emotion and reward -- Activity deep in the brain areas known as the insula and the cingulate cortex indicated emotional arousal, empathy, attachment and feelings linked to motivation and reward, the researchers said. Other studies have documented a similar pattern of activity in the brains of parents responding to their own infants.

Participants also rated how they felt when viewing adult and infant faces. They reported feeling more willing to approach, smile at, and communicate with an infant than an adult. They also recorded feeling happier when viewing images of infants.

Taken together, the researchers contend, the findings suggest a readiness to interact with infants that previously has been only inferred, and only from parents. Such brain activity in nonparents could indicate that the biological makeup of humans includes a mechanism to ensure that infants survive and receive the care they need to grow and develop.

However, signs of readiness to care for a child that appear in the brains of some or even most adults do not necessarily mean the same patterns will appear in the brains of all adults, Dr. Bornstein said. "It's equally important to investigate what's happening in the brains of those who have neglected or abused children," he said. "Additional studies could help us confirm and understand what appears to be a parenting instinct in adults, both when the instinct functions and when it fails to function."

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Stem Cells: Nearing Goal of Using Patient's Own Cells to Make Stem Cells to Replace Lost or Diseased Tissue

Stem Cells: Nearing Goal of Using Patient's Own Cells to Make Stem Cells to Replace Lost or Diseased Tissue

  1:27:00 AM    Science Lover

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Scientists at the Salk Institute for Biological Studies have developed an improved technique for generating large numbers of blood cells from a patient's own cells. The new technique will be immediately useful in further stem cell studies, and when perfected, could be used in stem cell therapies for a wide variety of conditions including cancers and immune ailments.

Round hematopoietic (blood) cells emerge from 
differentiating human pluripotent stem cells. 
(Credit: Courtesy of Aaron Parker, Salk Institute 
for Biological Studies)

"There are further improvements that we need to make, but this takes us a significant step closer to the ultimate goal, which is to be able to take ordinary cells from a patient, induce them to become stem cells, and then use those stem cells to rebuild lost or diseased tissues, for example the patient's bone marrow," says Inder M. Verma, PhD, Irwin and Joan Jacobs Chair in Exemplary Life Science and American Cancer Society Professor of Molecular Biology at the Salk Institute Laboratory of Genetics. Verma is senior author of the report, which is published in the July edition of the journal Stem Cells.

Stem cell researchers have been racing towards this goal since 2006, when techniques for turning ordinary skin cells into induced pluripotential stem cells (iPSCs) were first reported. In principle, iPSCs mimic the embryonic stem cells (ESCs) from which organisms develop. Researchers now want to find the precise mixes and sequences of chemical compounds needed to coax iPSCs to mature into the tissue-specific stem cells of their choice. The latter are self-renewing, and can be transplanted into the body to produce the 'progenitor' cells that multiply locally and produce mature tissue cells.

However, researchers don't know yet how to induce iPSCs to become tissue-specific stem cells or mature tissue cells with high efficiency. "We've been producing these cells in quantities that are too low to enable them to be studied easily, much less used for therapies," says Aaron Parker, PhD, a former graduate student and now a postdoctoral researcher in Verma's lab. Parker is a co-lead-author of the paper, with Niels-Bjarne Woods, PhD, who was a postdoctoral researcher in the Verma lab at the outset of the project, and is now an assistant professor at Lund University in Sweden.

Like many other stem cell research laboratories, the Verma lab has been trying to find more efficient ways to turn iPSCs into blood-forming 'hematopoietic' stem cells (HSCs). These may be more valuable medically than any other tissue-specific stem cell, because they can supply not only oxygen-carrying red blood cells but also all the white blood cells of the immune system. "There would be an almost unlimited number of usages for true HSCs," says Verma.

For the present study, the research team sought to do a better job of mimicking the changing conditions that naturally direct ESCs to become HSCs in the womb. "We took seven lines of human ESCs and iPSCs, and experimented with different combinations and sequences of growth factors and other chemical compounds that are known to be present as ESCs move to the HSC state in a developing human," says Parker.



Applying cocktails of these factors, Parker and Woods and their colleagues induced the iPSCs and ESCs to form colonies of cells that bore the distinctive molecular markers of blood cells. With their best such cocktail they were able to detect blood-specific markers on 84% of their cells after three weeks. "That's a big jump in efficiency from what we saw in the field just a few years ago," says Parker.

The technique still has room for improvement. The researchers detected progenitor cells and mature cells from only one category or lineage: myeloid cells, which include red blood cells and primitive immune cells such as macrophages. "We didn't see any cells from the lymphoid lineage, meaning T-cells and B-cells," Parker says.

Another drawback was that the blood cell population they produced from ESCs and iPSCs contained short-lived progenitors and mature blood cells but no indefinitely renewing, transplantable HSCs. Their cocktail, they believed, either pushed the cells past the HSC state to the progenitor state too quickly, or made the maturing cells skip the HSC state entirely.

From this and other labs' results, the team hypothesized the existence of an intermediate, pre-hematopoietic type of stem cell, produced by ESCs and iPSCs and in turn producing HSCs. "We know that HSCs appear in a particular region of mammals during embryonic development, and our idea is that these pre-hematopoietic stem cells are there and are somehow made to mature into HSCs," says Parker. "So our lab is now going to focus on finding the precise maturation signals provided by that embryonic region to produce these true, transplantable HSCs."

Once that is done, researchers will need to make a number of further refinements to improve the safety of HSCs intended for human patients. "But we're now tantalizingly close to our ultimate goal," says Verma.

The other authors who contributed to the work were Roksana Moraghebi, of Lund University's Stem Cell Center; Margaret K. Lutz, Amy L. Firth, Kristen J. Brennand, W. Travis Berggren and Fred H. Gage of the Salk Institute Laboratory for Genetics; Juan Carlos Izpisúa Belmonte of the Salk Institute Gene Expression Laboratory; and Angel Raya of the Center of Regenerative Medicine in Barcelona, Spain.

Funding for this research was provided by the National Institutes for Health, the California Institute for Regenerative Medicine, the Leducq Foundation, the Merieux Foundation, the Ellison Medical Foundation, Ipsen/Biomeasure, Sanofi Aventis, the Prostate Cancer Foundation, the H.N. and Frances C. Berger Foundation, The Royal Physiographic Society of Sweden, the Lund University Medical Faculty, and the Lars Hierta Memorial Foundation, and the H.A. and Mary K. Chapman Charitable Trust.

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Biomarker for Autism Discovered

Biomarker for Autism Discovered

  8:42:00 PM    Science Lover

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Siblings of people with autism show a similar pattern of brain activity to that seen in people with autism when looking at emotional facial expressions. Researchers at the University of Cambridge identified the reduced activity in a part of the brain associated with empathy and argue it may be a 'biomarker' for a familial risk of autism.

Researchers have identified the reduced activity in a 
part of the brain associated with empathy and argue 
it may be a 'biomarker' for a familial risk of autism. 
(Credit: Michael Spencer)

Dr Michael Spencer, who led the study from the University's Autism Research Centre, said: "The findings provide a springboard to investigate what specific genes are associated with this biomarker. The brain's response to facial emotion could be a fundamental building block in causing autism and its associated difficulties."

The Medical Research Council funded study is published on the 12th of July, in the journal Translational Psychiatry.

Previous research has found that people with autism often struggle to read people's emotions and that their brains process emotional facial expressions differently to people without autism. However, this is the first time scientists have found siblings of individuals with autism have a similar reduction in brain activity when viewing others' emotions.

In one of the largest functional MRI (fMRI) studies of autism ever conducted, the researchers studied 40 families who had both a teenager with autism and a sibling without autism. Additionally, they recruited 40 teenagers with no family history of autism. The 120 participants were given fMRI scans while viewing a series of photographs of faces which were either neutral or expressing an emotion such as happiness. By comparing the brain's activity when viewing a happy verses a neutral face, the scientists were able to observe the areas within the brain that respond to this emotion.



Despite the fact that the siblings of those with autism did not have a diagnosis of autism or Asperger syndrome, they had decreased activity in various areas of the brain (including those associated with empathy, understanding others' emotions and processing information from faces) compared to those with no family history of autism. The scans of those with autism revealed that the same areas of the brain as their siblings were also underactive, but to a greater degree. (These brain regions included the temporal poles, the superior temporal sulcus, the superior frontal gyrus, the dorsomedial prefrontal cortex and the fusiform face area.)

Because the siblings without autism and the controls differed only in terms of the siblings having a family history of autism, the brain activity differences can be attributed to the same genes that give the sibling their genetic risk for autism.

Explaining why only one of the siblings might develop autism when both have the same biomarker, Dr Spencer said: "It is likely that in the sibling who develops autism additional as yet unknown steps -- such as further genetic, brain structure or function differences -- take place to cause autism."

It is known that in a family where one child already has autism, the chances of a subsequent child developing autism are at least 20 times higher than in the general population. The reason for the enhanced risk, and the reason why two siblings can be so differently affected, are key unresolved questions in the field of autism research, and Dr Spencer's group's findings begin to shed light on these fundamental questions.

Professor Chris Kennard, chairman of the Medical Research Council funding board for the research, said: "This is the first time that a brain response to different human facial emotions has been shown to have similarities in people with autism and their unaffected brothers and sisters. Innovative research like this improves our fundamental understanding of how autism is passed through generations affecting some and not others. This is an important contribution to the Medical Research Council's strategy to use sophisticated techniques to uncover underpinning brain processes, to understand predispositions for disease, and to target treatments to the subtypes of complex disorders such as autism."

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Brain Co-Opts the Body to Promote Moral Behavior, Study Finds

Brain Co-Opts the Body to Promote Moral Behavior, Study Finds

  8:19:00 PM    Science Lover

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The human brain may simulate physical sensations to prompt introspection, capitalizing on moments of high emotion to promote moral behavior, according to a USC researcher.

Girl being reflective. Researchers found that individuals who were told stories designed to evoke compassion and admiration for virtue sometimes reported that they felt a physical sensation in response. (Credit: © Paul Hill / Fotolia)

Mary Helen Immordino-Yang of the USC Brain and Creativity Institute and the USC Rossier School of Education found that individuals who were told stories designed to evoke compassion and admiration for virtue sometimes reported that they felt a physical sensation in response. These psycho-physical "pangs" of emotion are very real -- they're detectable with brain scans -- and may be evidence that pro-social behavior is part of human survival.

Immordino-Yang's hypothesis, borne out thus far by her research, is that the feeling or emotional reactions in the body may sometimes prompt introspection, and can ultimately promote moral choices and motivation to help or emulate others.

"These emotions are foundational for morality and social learning. They have the power to change the course of your very life," Immordino-Yang said.

Her article appears in the July issue of Emotion Review.

In one instance cited in the article, a participant responded to a story of a little boy's selflessness toward his mother by reporting that he felt like there was a "balloon or something under my sternum, inflating and moving up and out." While pondering this physical sensation, the participant paused for a moment and considered his own relationship with his parents. Ultimately, he voiced a promise to express more gratitude toward them.



Researchers noted similar reactions to varying degrees in the test's other participants. Immordino-Yang's team has performed about 50 of these qualitative analyses in Beijing and at USC. The researchers provide the emotional story, then record the participant's reaction, and also use brain scans to record the physiological response.

"It's a systematic but naturalistic way to induce these emotions." Immordino-Yang said. After being told an emotional true story during a private, taped interview, the participant is simply asked to describe how he or she feels.

Immordino-Yang said she isn't surprised at the findings, though she is excited by them.

"We are an intensely social species," she said. "Our very biology is a social one. For centuries poets have described so-called gut feelings during social emotions. Now we are uncovering the biological evidence."

Future analysis of the data her team has gathered will focus on discovering to what degree culture and individual styles and experiences influence these reactions, as well as how they develop in children and how they can be promoted by education.

This research was supported by the Brain and Creativity Institute, the USC Provost's grant for Advancing Scholarship in the Humanities and Social Sciences, and the Rossier School of Education.

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Alzheimer's: 'Cleansing' Brain of Plaques

Alzheimer's: 'Cleansing' Brain of Plaques

  8:08:00 PM    Science Lover

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New molecular tools developed at the University of Michigan show promise for "cleansing" the brain of amyloid plaques, implicated in Alzheimer's disease.

Small Molecules for Metal-Amyloid Species in the Brain. 
(Credit: Mi Hee Lim and Joseph J. Braymer)

A hallmark of Alzheimer's disease -- a neurodegenerative disease with no cure -- is the aggregation of protein-like bits known as amyloid-beta peptides into clumps in the brain called plaques. These plaques and their intermediate messes can cause cell death, leading to the disease's devastating symptoms of memory loss and other mental difficulties.

The mechanisms responsible for the formation of these misfolded proteins and their associations with Alzheimer's disease are not entirely understood, but it's thought that copper and zinc ions are somehow involved.

The research, led by assistant professor Mi Hee Lim, was published online Dec. 3 in the Proceedings of the National Academy of Science.
 
In earlier work, Lim and her team developed dual-purpose molecular tools that both grab metal ions and interact with amyloid-beta. The researchers went on to show that in solutions with or without living cells, the molecules were able to regulate copper-induced amyloid-beta aggregation, not only disrupting the formation of clumps, but also breaking up clumps that already had formed.

Building upon that first generation of compounds, Lim and lab members Jung-Suk Choi and Joseph Braymer now report a second generation of compounds that are more stable in biological environments. The researchers tested one of those compounds, described in the PNAS paper, in homogenized brain tissue samples from Alzheimer's disease patients.

"We found that our compound is capable of disassembling the misfolded amyloid clumps to form smaller amyloid pieces, which might be 'cleansed' from the brain more easily, demonstrating a therapeutic application of our compound," said Lim, who has joint appointments in the Life Sciences Institute and the Department of Chemistry. In addition, preliminary tests show that the bi-functional small molecules have a strong potential to cross the blood-brain barrier, the barricade of cells that separates brain tissue from circulating blood, protecting the brain from harmful substances in the bloodstream.

"Crossing this barrier is essential for any treatment like this to be successful," Lim said.

Next steps include more intensive testing of the new compounds for diagnostic and therapeutic properties.

Lim and her team collaborated with Ayyalusamy Ramamoorthy, professor of chemistry and biophysics on this work, with funding from the U-M Horace H. Rackham School of Graduate Studies, the Alzheimer's Art Quilt Initiative, and the National Institutes of Health.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.

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Brains Wiring: More Like the Internet Than a Pyramid?

Brains Wiring: More Like the Internet Than a Pyramid?

  10:51:00 AM    Science Lover

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The brain has been mapped to the smallest fold for at least a century, but still no one knows how all the parts talk to each other.

New research suggests that the distributed network 
of the Internet may be a better model for the human 
brain than a top-down hierarchy. 
(Credit: iStockphoto/Henrik Jonsson)

A study in Proceedings of the National Academy of Sciences answers that question for a small area of the rat brain and in so doing takes a big step toward revealing the brain's wiring.

The network of brain connections was thought too complex to describe, but molecular biology and computing methods have improved to the point that the National Institutes of Health have announced a $30 million plan to map the human "connectome."

The study shows the power of a new method for tracing brain circuits.

USC College neuroscientists Richard H. Thompson and Larry W. Swanson used the method to trace circuits running through a "hedonic hot spot" related to food enjoyment.

The circuits showed up as patterns of circular loops, suggesting that at least in this part of the rat brain, the wiring diagram looks like a distributed network.

Neuroscientists are split between a traditional view that the brain is organized as a hierarchy, with most regions feeding into the "higher" centers of conscious thought, and a more recent model of the brain as a flat network similar to the Internet.

"We started in one place and looked at the connections. It led into a very complicated series of loops and circuits. It's not an organizational chart. There's no top and bottom to it," said Swanson, a member of the National Academy of Sciences and the Milo Don and Lucille Appleman Professor of Biological Sciences at USC College.

The circuit tracing method allows the study of incoming and outgoing signals from any two brain centers. It was invented and refined by Thompson over eight years. Thompson is a research assistant professor of biological sciences at the College.

Most other tracing studies at present focus only on one signal, in one direction, at one location.

"[We] can look at up to four links in a circuit, in the same animal at the same time. That was our technical innovation," Swanson said.

The Internet model would explain the brain's ability to overcome much local damage, Swanson said.

"You can knock out almost any single part of the Internet and the rest of it works."

Likewise, Swanson said, "There are usually alternate pathways through the nervous system. It's very hard to say that any one part is absolutely essential."

Swanson first argued for the distributed model of the brain in his acclaimed book Brain Architecture: Understanding the Basic Plan (Oxford University Press, 2003).

The PNAS study appears to support his view.

"There is an alternate model. It's not proven, but let's rethink the traditional way of regarding how the brain works," he said.

"The part of the brain you think with, the cortex, is very important, but it's certainly not the only part of the nervous system that determines our behavior."

The research described in the PNAS study was supported by the National Institute of Neurological Disorders and Stroke in the National Institutes of Health.

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Nanoparticles: Golden Bullet for Cancer?

Nanoparticles: Golden Bullet for Cancer?

  10:03:00 AM    Science Lover

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In a lecture he delivered in 1906, the German physician Paul Ehrlich coined the term Zuberkugel, or "magic bullet," as shorthand for a highly targeted medical treatment.

Infrared images made while tumors were irradiated with a laser show that in nanocage-injected mice (left), the surface of the tumor quickly became hot enough to kill cells. In buffer-injected mice (right), the temperature barely budged. This specificity is what makes photothermal therapy so attractive as a cancer therapy. (Credit: WUSTL)

Magic bullets, also called silver bullets, because of the folkloric belief that only silver bullets can kill supernatural creatures, remain the goal of drug development efforts today.

A team of scientists at Washington University in St. Louis is currently working on a magic bullet for cancer, a disease whose treatments are notoriously indiscriminate and nonspecific. But their bullets are gold rather than silver. Literally.

The gold bullets are gold nanocages that, when injected, selectively accumulate in tumors. When the tumors are later bathed in laser light, the surrounding tissue is barely warmed, but the nanocages convert light to heat, killing the malignant cells.

In an article just published in the journal Small, the team describes the successful photothermal treatment of tumors in mice.

The team includes Younan Xia, Ph.D., the James M. McKelvey Professor of Biomedical Engineering in the School of Engineering and Applied Science, Michael J. Welch, Ph.D., professor of radiology and developmental biology in the School of Medicine, Jingyi Chen, Ph.D., research assistant professor of biomedical engineering and Charles Glaus, Ph.D., a postdoctoral research associate in the Department of Radiology.

"We saw significant changes in tumor metabolism and histology," says Welch, "which is remarkable given that the work was exploratory, the laser 'dose' had not been maximized, and the tumors were 'passively' rather than 'actively' targeted."

Why the nanocages get hot

The nanocages themselves are harmless. "Gold salts and gold colloids have been used to treat arthritis for more than 100 years," says Welch. "People know what gold does in the body and it's inert, so we hope this is going to be a nontoxic approach."

"The key to photothermal therapy," says Xia, "is the cages' ability to efficiently absorb light and convert it to heat. "

Suspensions of the gold nanocages, which are roughly the same size as a virus particle, are not always yellow, as one would expect, but instead can be any color in the rainbow.

They are colored by something called a surface plasmon resonance. Some of the electrons in the gold are not anchored to individual atoms but instead form a free-floating electron gas, Xia explains. Light falling on these electrons can drive them to oscillate as one. This collective oscillation, the surface plasmon, picks a particular wavelength, or color, out of the incident light, and this determines the color we see.

Medieval artisans made ruby-red stained glass by mixing gold chloride into molten glass, a process that left tiny gold particles suspended in the glass, says Xia.

The resonance -- and the color -- can be tuned over a wide range of wavelengths by altering the thickness of the cages' walls. For biomedical applications, Xia's lab tunes the cages to 800 nanometers, a wavelength that falls in a window of tissue transparency that lies between 750 and 900 nanometers, in the near-infrared part of the spectrum.

Light in this sweet spot can penetrate as deep as several inches in the body (either from the skin or the interior of the gastrointestinal tract or other organ systems).

The conversion of light to heat arises from the same physical effect as the color. The resonance has two parts. At the resonant frequency, light is typically both scattered off the cages and absorbed by them.

By controlling the cages' size, Xia's lab tailors them to achieve maximum absorption.

Passive targeting

"If we put bare nanoparticles into your body," says Xia, "proteins would deposit on the particles, and they would be captured by the immune system and dragged out of the bloodstream into the liver or spleen."

To prevent this, the lab coated the nanocages with a layer of PEG, a nontoxic chemical most people have encountered in the form of the laxatives GoLyTELY or MiraLAX. PEG resists the adsorption of proteins, in effect disguising the nanoparticles so that the immune system cannot recognize them.

Instead of being swept from the bloodstream, the disguised particles circulate long enough to accumulate in tumors.

A growing tumor must develop its own blood supply to prevent its core from being starved of oxygen and nutrients. But tumor vessels are as aberrant as tumor cells. They have irregular diameters and abnormal branching patterns, but most importantly, they have thin, leaky walls.

The cells that line a tumor's blood vessel, normally packed so tightly they form a waterproof barrier, are disorganized and irregularly shaped, and there are gaps between them.

The nanocages infiltrate through those gaps efficiently enough that they turn the surface of the normally pinkish tumor black.

A trial run

In Welch's lab, mice bearing tumors on both flanks were randomly divided into two groups. The mice in one group were injected with the PEG-coated nanocages and those in the other with buffer solution. Several days later the right tumor of each animal was exposed to a diode laser for 10 minutes.

The team employed several different noninvasive imaging techniques to follow the effects of the therapy. (Welch is head of the oncologic imaging research program at the Siteman Cancer Center of Washington University School of Medicine and Barnes-Jewish Hospital and has worked on imaging agents and techniques for many years.)

During irradiation, thermal images of the mice were made with an infrared camera. As is true of cells in other animals that automatically regulate their body temperature, mouse cells function optimally only if the mouse's body temperature remains between 36.5 and 37.5 degrees Celsius (98 to 101 degrees Fahrenheit).

At temperatures above 42 degrees Celsius (107 degrees Fahrenheit) the cells begin to die as the proteins whose proper functioning maintains them begin to unfold.

In the nanocage-injected mice, the skin surface temperature increased rapidly from 32 degrees Celsius to 54 degrees C (129 degrees F).

In the buffer-injected mice, however, the surface temperature remained below 37 degrees Celsius (98.6 degrees Fahrenheit).

To see what effect this heating had on the tumors, the mice were injected with a radioactive tracer incorporated in a molecule similar to glucose, the main energy source in the body. Positron emission and computerized tomography (PET and CT) scans were used to record the concentration of the glucose lookalike in body tissues; the higher the glucose uptake, the greater the metabolic activity.

The tumors of nanocage-injected mice were significantly fainter on the PET scans than those of buffer-injected mice, indicating that many tumor cells were no longer functioning.

The tumors in the nanocage-treated mice were later found to have marked histological signs of cellular damage.

Active targeting

The scientists have just received a five-year, $2,129,873 grant from the National Cancer Institute to continue their work with photothermal therapy.

Despite their results, Xia is dissatisfied with passive targeting. Although the tumors took up enough gold nanocages to give them a black cast, only 6 percent of the injected particles accumulated at the tumor site.

Xia would like that number to be closer to 40 percent so that fewer particles would have to be injected. He plans to attach tailor-made ligands to the nanocages that recognize and lock onto receptors on the surface of the tumor cells.

In addition to designing nanocages that actively target the tumor cells, the team is considering loading the hollow particles with a cancer-fighting drug, so that the tumor would be attacked on two fronts.

But the important achievement, from the point of view of cancer patients, is that any nanocage treatment would be narrowly targeted and thus avoid the side effects patients dread.

The TV and radio character the Lone Ranger used only silver bullets, allegedly to remind himself that life was precious and not to be lightly thrown away. If he still rode today, he might consider swapping silver for gold.

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