It’s the way you tell em’: Study discovers how the brain controls accents and impersonations

A study, led by Royal Holloway University researcher Carolyn McGettigan, has identified the brain regions and interactions involved in impersonations and accents.

Using an fMRI scanner, the team asked participants, all non-professional impressionists, to repeatedly recite the opening lines of a familiar nursery rhyme either with their normal voice, by impersonating individuals, or by impersonating regional and foreign accents of English.

They found that when a voice is deliberately changed, it brings the left anterior insula and inferior frontal gyrus (LIFG) of the brain into play. The researchers also discovered that when comparing impersonations against accents, areas in the posterior superior temporal/inferior parietal cortex and in the right middle/anterior superior temporal sulcus showed greater responses.

“The voice is a powerful channel for the expression of our identity – it conveys information such as gender, age and place of birth, but crucially, it also expresses who we want to be,” said lead author Carolyn McGettigan from the Department of Psychology at Royal Holloway.

“Consider the difference between talking to a friend on the phone, talking to a police officer who’s cautioning you for parking violation, or speaking to a young infant. While the words we use might be different across these settings, another dramatic difference is the tone and style with which we deliver the words we say. We wanted to find out more about this process and how the brain controls it.”

While past work has found that listening to voices activates regions of the temporal lobe of the brain, no research had explored the brain regions involved in controlling vocal identity before this study.

“Our aim is to find out more about how the brain controls this very flexible communicative tool, which could potentially lead to new treatments for those looking to recover their own vocal identity following brain injury or a stroke, ” said Carolyn.

Key Protein is Linked to Circadian Clocks, Helps Regulate Metabolism

Inside each of us is our own internal timing device. It drives everything from sleep cycles to metabolism, but the inner-workings of this so-called “circadian clock” are complex, and the molecular processes behind it have long eluded scientists. But now, researchers at the Gladstone Institutes have discovered how one important protein falls under direct instructions from the body’s circadian clock. Furthermore, they uncover how this protein regulates fundamental circadian processes—and how disrupting its normal function can throw this critical system out of sync.

In the latest issue of the Journal of Neuroscience, Gladstone Investigator Katerina Akassoglou, PhD, and her team reveal in animal models how the production of the p75 neurotrophin receptor (p75NTR) protein oscillates in time with the body’s natural circadian clock—and how these rhythmic oscillations help regulate vital metabolic functions. This discovery underscores the widespread importance of p75NTR by offering insight into how the circadian clock helps maintain the body’s overall metabolic health.

Virtually every organism on the planet—from bacteria to humans—has a circadian clock, a biological timing mechanism that oscillates with a period of about 24 hours and is coordinated with the cycle of day and night. And while it runs independent of external cues, it is influenced by the rhythms of light, temperature and food availability. Intriguingly, recent studies have also found a link between circadian clocks and metabolism.

“Important metabolic functions are also heavily influenced by circadian clocks, which is why activities such as chronic night-shift work—which can cause a misalignment of this clock—increase one’s risk for metabolic and autoimmune diseases such as obesity, Type 2 diabetes, cancer and multiple sclerosis,” said Dr. Akassoglou. Dr. Akassoglou is also a professor of neurology at the University of California, San Francisco, (UCSF) with which Gladstone is affiliated. “In this study, we pinpointed p75NTR as an important molecular ‘link’ between circadian clocks and metabolic health.”

Originally, p75NTR was only thought to be active in the nervous system. Later studies found it to be active in many cell types throughout the body, suggesting that it impacts a variety of biological functions. Last year, Gladstone researchers discovered that p75NTR was present in the liver and in fat cells, and that it regulates glucose levels in the blood—an important metabolic process. Since these findings uncovered a link between p75NTR and metabolism, the research team tested—first in a petri dish and then in animal models—whether there was also a link between p75NTR and the circadian clock.

The team focused on two genes called Clock and Bmal1. These so-called “circadian regulator genes,” and others like them, are found throughout the body. Their activity controls the body’s circadian clock. The researchers wanted to see if there was a connection between these circadian genes and p75NTR.

“Our initial experiments revealed such a connection,” recalls Gladstone Postdoctoral Fellow Bernat Baeza-Raja, PhD, the paper’s lead author. “In individual cells, we saw that p75NTR production was controlled by Clock and Bmal1, which bind directly to the gene that codes for the p75NTR and start production of the protein.”

But perhaps even more important than how p75NTR was produced was when. The team found that p75NTR production, like the circadian clock genes themselves, oscillated in a 24-hour cycle—in sync with the cells’ natural circadian rhythm. Experiments in mouse models further supported these findings.

And when the team genetically modified a group of mice so that it lacked the circadian Clock gene, everything else fell out of sync. The circadian oscillation of p75NTR production was disrupted, and p75NTR levels dropped.

However, what was most fascinating, say the researchers, was how a drop in p75NTR levels then affected a variety of circadian clock systems. Specifically, the regular oscillations of other circadian genes in the brain and the liver became disrupted, as well as genes known to regulate glucose and lipid metabolism.

“The finding that a loss of p75NTR affected circadian and metabolic systems is strong evidence that this protein is intricately tied to both,” said Life Sciences Institute Director Alan Saltiel, PhD, who is also a professor at the University of Michigan and was not involved in the study. “It will be fascinating to see what additional insight Dr. Akassoglou and her team will uncover as they continue to examine the role of p75NTR in circadian clocks and metabolic function.”

“While these findings reveal p75NTR to be an important link between circadian clocks and metabolism, the system is complex, and there are likely other factors at play,” said Dr. Akassoglou. “We are currently working to identify the relationship between the circadian clock, metabolism and the immune system, so that one day we could develop therapies to treat diseases influenced by circadian clock disruption—including not only obesity and diabetes, but also potentially multiple sclerosis and even Alzheimer’s disease.”

(Image: Brain Treatment Center)

Study Shows How the Nanog Protein Promotes Growth of Head and Neck Cancer

A new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James) has identified a biochemical pathway in cancer stem cells that is essential for promoting head and neck cancer.

The study shows that a protein called Nanog, which is normally active in embryonic stem cells, promotes the growth of cancer stem cells in head and neck cancer. The findings provide information essential for designing novel targeted drugs that might improve the treatment of head and neck cancer.

Normally, Nanog helps healthy embryonic stem cells maintain their undifferentiated, uncommitted (i.e., pluripotent) state. But recent evidence suggests that Nanog promotes tumor growth by stimulating the proliferation of cancer stem cells.

“This study defines a signaling axis that is essential for head and neck cancer progression, and our findings show that this axis may be disrupted at three key steps,” says principal investigator Quintin Pan, PhD, associate professor of otolaryngology at the OSUCCC – James. “Targeted drugs that are designed to inhibit any or all of these three steps might greatly improve the treatment of head and neck cancer.”

The findings were published in a recent issue of the journal Oncogene.

Specifically, the study shows that an enzyme called “protein kinase C-epsilon” (PKCepsilon) adds energy-packing phosphate groups to the Nanog molecule. This phosphorylation of Nanog stabilizes and activates the molecule.

It also triggers a series of events: Two Nanog molecules bind together, and these are joined by a third “co-activating” molecule called p300. This molecular complex then binds to the promoter region of a gene called Bmi1, an event that increases the expression of the gene. This, in turn, stimulates proliferation of cancer stem cells.

“Our work shows that the PKCepsilon/Nanog/Bmi1 signaling axis is essential to promote head and neck cancer,” Pan says. “And it provides initial evidence that the development of inhibitors that block critical points in this axis might yield a potent collection of targeted anti-cancer therapeutics that could be valuable for the treatment of head and neck cancer.”

(Image: Gray’s Anatomy of the Human Body)

Fiber-optic pen helps see inside brains of children with learning disabilities

For less than $100, University of Washington researchers have designed a computer-interfaced drawing pad that helps scientists see inside the brains of children with learning disabilities while they read and write.

The device and research using it to study the brain patterns of children will be presented June 18 at the Organization for Human Brain Mapping meeting in Seattle. A paper describing the tool, developed by the UW’s Center on Human Development and Disability, was published this spring in Sensors, an online open-access journal. “Scientists needed a tool that allows them to see in real time what a person is writing while the scanning is going on in the brain,” said Thomas Lewis, director of the center’s Instrument Development Laboratory. “We knew that fiber optics were an appropriate tool. The question was, how can you use a fiber-optic device to track handwriting?”

To create the system, Lewis and fellow engineers Frederick Reitz and Kelvin Wu hollowed out a ballpoint pen and inserted two optical fibers that connect to a light-tight box in an adjacent control room where the pen’s movement is recorded. They also created a simple wooden square pad to hold a piece of paper printed with continuously varying color gradients. The custom pen and pad allow researchers to record handwriting during functional magnetic resonance imaging, or fMRI, to assess behavior and brain function at the same time.Other researchers have developed fMRI-compatible writing devices, but “I think it does something similar for a tenth of the cost,” Reitz said of the UW system. By using supplies already found in most labs (such as a computer), the rest of the supplies – pen, fiber optics, wooden pad and printed paper – cost less than $100.The device connects to a computer with software that records every aspect of the handwriting, from stroke order to speed, hesitations and liftoffs. Understanding how these physical patterns correlate with a child’s brain patterns can help scientists understand the neural connections involved.

Researchers studied 11- and 14-year-olds with either dyslexia or dysgraphia, a handwriting and letter-processing disorder, as well as children without learning disabilities. Subjects looked at printed directions on a screen while their heads were inside the fMRI scanner. The pen and pad were on a foam pad on their laps.

Subjects were given four-minute blocks of reading and writing tasks. Then they were asked to simply think about writing an essay (they later wrote the essay when not using the fMRI). Just thinking about writing caused many of the same brain responses as actual writing would.

“If you picture yourself writing a letter, there’s a part of the brain that lights up as if you’re writing the letter,” said Todd Richards, professor of radiology and principal investigator of the UW Integrated Brain Imaging Center. “When you imagine yourself writing, it’s almost as if you’re actually writing, minus the motion problems.”

Richards and his staff are just starting to analyze the data they’ve collected from about three dozen subjects, but they have already found some surprising results.

“There are certain centers and neural pathways that we didn’t necessarily expect” to be activated, Richards said. “There are language pathways that are very well known. Then there are other motor pathways that allow you to move your hands. But how it all connects to the hand and motion is still being understood.”

Besides learning disorders, the inexpensive pen and pad also could help researchers study diseases in adults, especially conditions that cause motor control problems, such as stroke, multiple sclerosis and Parkinson’s disease.

“There are several diseases where you cannot move your hand in a smooth way or you’re completely paralyzed,” Richards said. “The beauty is it’s all getting recorded with every stroke, and this device would help us to study these neurological diseases.”

Not all reading disabilities are dyslexia

A common reading disorder goes undiagnosed until it becomes problematic, according to the results of five years of study by researchers at Vanderbilt’s Peabody College of education and human development in collaboration with the Kennedy Krieger Institute/Johns Hopkins School of Medicine. Results of the study were recently published online by the National Institutes of Health.

Dyslexia, a reading disorder in which a child confuses letters and struggles with sounding out words, has been the focus of much reading research.

But that’s not the case with the lesser known disorder Specific Reading Comprehension Deficits or S-RCD, in which a child reads successfully but does not sufficiently comprehend the meaning of the words, according to lead investigator Laurie Cutting, Patricia and Rodes Hart Chair at Peabody.

“S-RCD is like this: I can read Spanish, because I know what sounds the letters make and how the words are pronounced, but I couldn’t tell you what the words actually mean,” Cutting said. “When a child is a good reader, it’s assumed their comprehension is on track. But 3 to 10 percent of those children don’t understand most of what they’re reading. By the time the problem is recognized, often closer to third or fourth grade, the disorder is disrupting their learning process.”

Researchers have been able to pinpoint brain activity and understand its role in dyslexia, but no functional magnetic resonance imaging or fMRI studies, until now, have examined the neurobiological profile of those who exhibit poor reading comprehension despite intact word-level abilities.

Neuroimaging of children showed that the brain function of those with S-RCD while reading is quite different and distinct from those with dyslexia. Those with dyslexia exhibited abnormalities in a specific region in the occipital-temporal cortex, a part of the brain that is associated with successfully recognizing words on a page.

But those with S-RCD did not show abnormalities in this region, instead showing specific abnormalities in regions typically associated with memory.

“It may be that these individuals have a whole different neurobiological signature associated with how they read that is not efficient for supporting comprehension,” Cutting said. “We want to understand the different systems that support reading and see which ones help different types of difficulties, and how we can target the cognitive systems that support those skills.”

The study, an ongoing 10-year effort supported by National Institutes of Health grant No. M01-RR000052, has enrolled more than 300 children to date.

The discerning fruit fly: Linking brain-cell activity and behavior in smell recognition

Behind the common expression “you can’t compare apples to oranges” lies a fundamental question of neuroscience: How does the brain recognize that apples and oranges are different? A group of neuroscientists at Cold Spring Harbor Laboratory (CSHL) has published new research that provides some answers.

In the fruit fly, the ability to distinguish smells lies in a region of the brain called the mushroom body (MB). Prior research has demonstrated that the MB is associated with learning and memory, especially in relation to the sense of smell, also known as olfaction.

CSHL Associate Professor Glenn Turner and colleagues have now mapped the activity of brain cells in the MB, in flies conditioned to have Pavlovian behavioral responses to different odors. Their results, outlined in a paper published today by the Journal of Neuroscience, suggest that the activity of a remarkably small number of neurons — as few as 25 — is required to be able to distinguish between different odors.

They also found that a similarly small number of nerve cells are involved in grouping alike odors. This means, for instance, that “if you’ve learned that oranges are good, the smell of a tangerine will also get you thinking about food,” says Robert Campbell, a postdoctoral researcher in the Turner lab and lead author on the new study.

These intriguing new findings are part of a broad effort in contemporary neuroscience to determine how the brain, easily the most complex organ in any animal, manages to make a mass of raw sensory data intelligible to the individual — whether a person or a fly — in order to serve as a basis for making vital decisions.

Looking closely at Kenyon cells

The neurons in the fly MB are known as Kenyon cells, named after their discoverer, the neuroscientist Frederick Kenyon, who was the first person to stain and visualize individual neurons in the insect brain. Kenyon cells receive sensory inputs from organs that perceive smell, taste, sight and sound. This confluence of sensory input in the MB is important for memory formation, which comes about through a linking of different types of information.

Kenyon cells make up only about 4% of the entire fly brain and are extremely sensitive to inputs triggered by odors, in which only two connections between neurons, called synapses, separate them from the receptor cells at the “front end” of the olfactory system.

But in contrast to other regions of the brain, such as the vertebrate hippocampus, the sensory responses in the MB are few in number and relatively weak. It is the sparseness of the signals in the Kenyon cell neurons that makes studying memory formation in flies so promising to Turner and his team. “We set out to learn if these signals were really informative to the animal’s learning and memory with regard to smell,” Turner says.

In particular, Turner’s group wanted to see if they could link these signals with actual behavior in flies. The team used an imaging technique that allowed them to view the responses of over 100 Kenyon cells at a time and, importantly, quantify their results. They found that even the very sparse responses in these cells that are triggered by odors provide a large amount of information about odor identity. Turner suspects the very selectiveness of the response helps in the accurate formation and recall of memories.

When the researchers used two odors blended together in a series of increasingly similar concentrations, they found that two very similar smells could be distinguished as a result of the activity of as few as 25 Kenyon cells. This correlated well with the behavior of the flies: when brain activity suggested the flies had difficulty discerning the odors, their behavior also showed they could not choose between them.

The activity of these cells also accounts for flies’ ability to discern novel odors and group them together. This was determined in a “generalization” test, in which the degree to which flies learned a generalized aversion to unfamiliar test odors could be predicted based upon the relatively similar activity patterns of Kenyon cells that the odors induced.

“Being able to do this type of ‘mind-reading’ means we really understand what signals these activity patterns are sending,” says Turner. Ultimately, he and colleagues hope to be able to relate their findings in the fly brain with the operation of the brain in mammals.