Friday, January 12, 2007
Early to Bed, Early to Rise: Scientists Determine How Gene Behind Sleep Cycle Works
Early to Bed, Early to Rise: Scientists Determine How Gene Behind Sleep Cycle Works
A single amino acid in a particular protein can get you up long before dawn and into bed well before prime time.
By Nikhil Swaminathan
Scientific American
In 2000 scientists at the University of Utah discovered a family of early risers who typically slept from around five at night to two in the morning. The condition, dubbed familial advanced sleep phase syndrome (FASPS), has allowed researchers studying circadian rhythms to understand how the human body clock works, which could pave the way for future therapies aimed at seasonal affective disorder, jet lag and insomnia.
Now, a new study by a team out of the University of California, San Francisco, which includes members of the group that initially identified FASPS, has determined the operational mechanism by which the gene Per2 is implicated in adjusting the body clock's response to light. Their findings, published in this week's issue of Cell, state that the replacement of one amino acid from among hundreds found in a protein can result in irregular sleep patterns.
"A single amino acid change from serine to glycine, that's enough for all these people who have this mutation to have FASPS," says neurologist and study co-author Ying-Hui Fu. Based on lab tests of cells from the Utah family, the researchers believe that a single point mutation in Per2 results in the replacement of serine with glycine during transcription. This substitution then prevents a still unknown enzyme from adding a phosphate molecule onto the absent serine, which kicks off a domino effect resulting in lower overall transcription from DNA to mRNA (messenger RNA). This decreased mRNA, in turn, leads to lower amounts of protein when RNA is translated. "The message of this gene doesn't get transmitted appropriately," explains Fu," and therefore the protein level is low."
Previous studies had hinted that Per2's effect on circadian rhythm was an issue of protein stability, a defect that would have been caused during or after translation. "The biggest surprise in this [study] was the change in messenger RNA as opposed to protein stability," notes University of Utah cancer and circadian rhythm specialist David Virshup, who adds that the new paper conflicts with the results of a study published late last year in Genes & Development. Choogon Lee, a biomedical scientist at Florida State University, believes that post-translational effects are d efinitely not absent based on the raw data. He notes that the decrease in messenger RNA is only 30 percent in the Cell study, but that this results in a protein decrease of 80 to 90 percent. "So, it's not just the transcription decrease," he says. "There must be some protein-stability effect, too."
The San Francisco team, with the aid of University of Utah neurologist Christopher Jones, also studied the effects of Per2 mutation in mice. The scientists added a mutated copy of the Per2 gene to mice that would change the 662nd amino acid in the PER2 protein from a serine to glycine. This triggered a shift in the animals' circadian period, causing the mice to go to sleep nearly two hours earlier than before. When the researchers deleted the natural Per2 genes before inserting the mutated gene, the mice slept and woke nearly four hours earlier than before. "The mutation has a dominant effect over the endogenous Per2, so without endogenous Per2, interference, the phenotype is worse," Fu says. When the researchers inserted a copy of the gene that mimicked the presence of serine, the circadian period lengthened, which, Fu says, "really tells you that this amino acid plays a really critical role. It's almost like a dial in your cell that can turn your [period] short or long."
David Weaver, a neurobiologist at the University of Massachusetts Medical School says he found the new study's findings to be quite surprising. "While the authors can't completely exclude a contribution of post-translational effects on PER2 protein levels," he explains, "their data indicate it has quite an important effect on Per2 transcript levels that I would not have anticipated." He also points out that "while the population affected by FASPS is relatively small, the lessons learned and the mouse models generated will likely be useful in developing methods for resetting the circadian clock."
Fu says that her group is working to develop therapies for modulating the human body clock, irregularities of which are associated with everything from insomnia to seasonal affective disorder and cancer. "We can use our mouse model to screen compounds to see which one can regulate period," Fu says, "to make it normal again."
Why a Quick Look Can Be Better than a Deep Study
Why a Quick Look Can Be Better than a Deep Study
When searching for an object in a field of many others, often the first place we look is where it is
By Nikhil Swaminathan
Scientific American
Perhaps all the time spent furiously hunting for the red- and white-stripe-wearing hider Waldo could have been avoided if his eventual spotter just glanced and pointed to the page. At least that is what is indicated by the findings of a new study conducted by researchers at University College London, which appears in the January 9 issue of Current Biology.
MIND'S EYE: British researchers determine that certain tasks--like picking a unique object out of many other objects--can be completed more accurately by inpection with solely a cursory glance, avoiding higher level visual processing that can confound perception Perhaps all the time spent furiously hunting for the red- and white-stripe-wearing hider Waldo could have been avoided if his eventual spotter just glanced and pointed to the page. At least that is what is indicated by the findings of a new study conducted by researchers at University College London,
which appears in the January 9 issue of Current Biology.
Psychologist Zhaoping Li presented 10 subjects with a matrix of more than 650 lines leaning at a 45-degree angle, like slashes, with one object somewhere in the array reversed, like a backslash. The participants had to determine within seconds whether "the odd one out" resided on the left- or right-hand side of the screen in front of them. The subjects chose most accurately when they had little to no time to scrutinize the matrix.
"This finding seems counterintuitive," Li says. "You would expect people to make more accurate decisions when given the time to look properly. Instead they performed better when given almost no time to think."
Li and her colleague Nathalie Guyader used eye-tracking technology to follow the subjects' gazes as the their eyes darted around the array before them. In one trial, as soon as a participant's eye wandered onto the nonconforming line, the researchers hid the array and then prompted the viewer for an answer. Li says that most participants thought they were just blindly guessing which of the sides the backward line appeared in but they were nearly 95 percent accurate in choosing the correct region. On the other hand, when the researchers gave them more than 500 milliseconds to peruse the picture, allowing them to turn on higher level mental functions, the subjects' accuracy dropped to about 70 percent.
"A lot of times the eye darting around is actually the lower level function," Li explains. "Before your gaze actually lands on the target, you're seeing the target in your peripheral vision, and with your peripheral vision it hasn't really engaged your full attention y et and that's why you were darting around looking for it." Once a person's gaze lands on the target his or her brain begins to try to determine if it is the actual one. "Obviously the extra scrutiny, which is the extra mental recruitment," she notes, "is bad for them."
To our conscious minds, a rotated object is the same as the original object.
Li expounds on the dilemma of involving higher order brain functions in some tasks, such as copying a portrait with a pen and paper. "It's better that you don't think that it's somebody's face," she says. "If you think, 'Oh the nose should curve this way and the jaw should curve that way,' that actually interferes with you trying to reproduce the shade of a patch or curves. The contours and the shadings are actually lower level tasks that do not require you to recognize the shape of something." She also notes that this processing paradigm may be the reason why supermarket cashiers are asked to turn the signature on a credit card upside down when comparing it with the signature on a bill.
Wieske van Zoest, a researcher at the Brain and Attention Research Lab at the University of British Columbia, notes that Li's findings are similar to work she has done on the processing of simple features." We have shown that when people are intentionally looking for something salient, the obvious benefit of a salient target does not exist when people take a long time to respond," she says.
Jeremy Wolfe, head of the Visual Attention Lab at Harvard's Brigham and Women's Hospital, says Li's study reminds him of the brainteasers that appear in children's magazines and on IQ tests in which a shape is hidden within a picture. "I think that what this paper really shows is that very early on in processing you've got access to that information that then gets hidden by that larger context," he explains. "It points toward different stages in [the] visual process where different bits of information become available at different times."
Thursday, December 28, 2006
How the brain decides what to focus conscious attention on
How the brain decides what to focus conscious attention on
By Andreas K. Engel, Stefan Debener and Cornelia Kranczioch
As cognitive neuroscientists, we would like to know what is behind such phenomena: What happens in our brains when we deliberately concentrate on something? Does some mechanism inside our heads decide which information reaches our consciousness--and which does not? And do our intentions, needs and expectations influence what we perceive? Recent research offers some fascinating insights.
Homing in on Attention
Psychologists began seeking answers to such questions as long ago as 1890, when American philosopher and psychologist William James wrote about important characteristics of attention in The Principles of Psychology. James concluded that the capacity of consciousness is limited, which is why we cannot pay attention to everything at once. Attention is much more selective: it impels consciousness to concentrate on certain stimuli to process them especially effectively. James and others also distinguished between types of attention. Some of them are "self-created": a penetrating odor, a loud siren, a woman in a bright red dress amid people clad in black. (Many researchers now call this process "bottom-up," because the stimuli battle their way into our consciousness automatically because they are so striking.) Alternatively, we can actively and deliberately control our focus (called "top-down," because higher brain regions are involved at the outset). For example, at a noisy party, we can tune out background noise to listen to the conversation at the next table.
Neuroscience did not take up this topic until much later. In 1985 a research team led by Robert Desimone at the National Institute of Mental Health was first to observe how single neurons in the visual cortex of rhesus monkeys changed their activity depending on what the primates were looking at. Desimone and his collaborator Jeffrey Moran discovered that certain neurons in the V4 area of the visual cortex--an area important for the perception of color--fired more frequently when the test animal gazed fixedly at a colored target. The same nerve cells exhibited much weaker activity when the ape noticed the target but did not look right at it. Other researchers later discovered that active attention was not only reflected in the higher levels of visual processing, such as in the V4 area, but could also be traced down to stimulus processing in the lowest levels in the cortical hierarchy.
Synchronous Firing All these studies linked attention to an increase in the firing rate, or activity, of neurons. Now the latest neurobiological research points to another significant factor in attention: huge numbers of neurons synchronize their activity. Many neuroscientists believe that study of this phenomenon will provide the answer to one of the biggest riddles of attention research, the so-called binding problem.
Imagine that a grasshopper suddenly lands on the table in front of you. Before the insect can arrive in your consciousness as a fully realized, three-dimensional entity, several different areas of the brain must be active. One processes the insect's color, another its size, yet another its location, and so on. How does the brain bind all these individual characteristics together into a single impression of a green grasshopper?
Twenty years ago Christoph von der Malsburg, a computer scientist and brain theorist, now at the Ruhr University in Bochum, Germany, suggested a solution. By synchronizing their activities, nerve cells could join into effectively cooperating units--so-called assemblies. Subsequently, a number of research teams, among them the group at Wolf Singer's laboratory at the Max Planck Institute for Brain Research in Frankfurt, have demonstrated that this "ballet of neurons" in fact exists. Peter Koenig, Singer and one of us (Engel) carried out an especially decisive experiment at the end of the 1980s. We presented a cat with various targets to observe. When we showed it a single object, neurons in its visual system responsible for analyzing characteristics synchronized their activities in a pronounced way. When we gave the animal two separate objects to look at, however, the common rhythm broke down. The synchronization changed to a pattern of rapid oscillatory fluctuations at characteristic frequencies between 30 and 100 hertz, a region that brain researchers call the gamma band.
Then, in the early 1990s, Nobel laureate Francis Crick (who died in 2004) and computational neuroscientist Christof Koch of the California Institute of Technology expanded on Malsburg's hypothesis with a then provocative idea. The two scientists posited that only signals from "teams" of neurons that cooperated especially well possessed enough strength to reach the consciousness.
Recent findings lend empirical support to the Crick-Koch hypothesis. Between 1995 and 1998, Pascal Fries--now at the F. C. Donders Center for Cognitive Neuroimaging in Nijmegen, the Netherlands--and Singer, Engel and others at Max Planck carried out some of these experiments. The investigators took advantage of an effect called binocular rivalry: if the right eye and the left eye are equipped with special glasses that let each see only one of two very different images, the subject cannot meld them into a single perception. The brain resolves this dichotomy by favoring input from one eye and suppressing input from the other. As a result, the volunteers always saw just one of the pictures at a time. First they would see one image and then, a few seconds later, the other.
Two Eyes Vying How is binocular rivalry waged at the neuronal level? We compared two groups of nerve cells in the visual cortices of cats: one group dealt with the characteristics of the left image, the other with those of the right. From an animal's behavior we could tell which image it was looking at during any given moment. Whichever side occupied the feline's attention showed superior neuronal synchronization. In contrast, when we then compared the neurons' firing rates, we observed no difference. This result demonstrated that the degree of neuronal synchronization decisively influences which incoming signals are further processed and thus becomes relevant to the consciousness's perception.
What happens in our brains when we deliberately concentrate on something?
Fries also showed that active, intentional control of attention can influence gamma synchroniza-tion. He worked in Desimone's lab with macaques that had learned to direct their attention to a particular spot on the monitor screen in response to a signal; a stimulus would appear at that location after a short delay. If this stimulus appeared at the expected location, the gamma oscillations were clearly stronger. Synchronization immediately weakened, however, as soon as the research animals switched their attention to other stimuli.
For humans, such experiments using implanted electrodes are possible only during brain surgery. As a result we usually measure gamma activity by means of electroencephalography (EEG). We recently carried out an attention experiment in which subjects read letters that flashed briefly on a computer monitor. Most of the letters were black, but now and again we inserted a few green letters, which we asked the subjects to count. Analysis of the EEG signals taken during the tests showed that only the unexpected appearance of green letters produced an increase in the high-frequency part of the gamma band.
Expectant Neurons
The effect of expectation reveals itself especially clearly in an experiment using acoustic stimuli. We asked listeners to pay particular attention to high tones in a series of more or less similar tones. When they heard the target tone, a high-frequency gamma-band activity appeared in the brain; in contrast, unexpected loud noises, which automatically call attention to themselves, did not elicit this effect.
Regardless of which sensory system is -involved, the reinforced rhythmic synchronization in the gamma band that we measured seems to be a good indicator of active attention. When a person deliberately directs attention to a stimulus, not only do the firing rates of individual neurons in the brain change, but the synchronization also improves for all the neurons taking part in the coding for the same stimulus. We liken the effect to a symphony orchestra that soon arrives at a common tempo after the individual instruments begin playing.
In what ways might intentions and needs influence attention? With the help of functional magnetic resonance imaging (fMRI), we wanted to locate brain regions involved in conscious perception of a target stimulus. To do so, we needed a research technique to compare two conditions: one that led from active attention to conscious awareness of a stimulus, and a second, in which the same stimulus did not penetrate the consciousness. We used a phenomenon called attention blink. In the experiment we once again displayed a series of letters to subjects while we observed them with fMRI. This time, however, only a single green letter appeared among rapidly changing black letters, and the subject had to tell us, at the end of the test run, whether or not it was a vowel. At the same time, the subject was to look for a black X that popped up at different times after the green -letter.
During the experiment, the attention of our subjects showed clear gaps--the "blinks"--as a result of their intentional, conscious focus on the task. If the black X appeared very soon--within a third of a second--after the green letter, about half the time the participants did not notice it. If there was a longer period after the first stimulus, their recognition rate improved.
At the end of the experiment, we compared the fMRI values for each run-through in which the subjects perceived the X with those in which it was shown but not noticed. We saw clear differences in activity in a few brain regions, all in the frontal and the parietal cortices. Scientists have been aware of these regions' importance in controlling attention for a long time: for example, some patients who suffer damage to certain parts of their parietal cortex from a stroke can no longer pay attention to any stimuli in certain areas of their visual fields, which means they cannot consciously perceive them. We were surprised, however, when we found a difference in the limbic system--in the amygdala, to be precise, which is normally involved in processing emotional reactions. The state of our emotional system probably influences the control of attention and which sensory signals are allowed to reach consciousness.
The experiments we describe provide another puzzle for researchers who are seeking the neuronal basis of consciousness: the gamma oscillation that is closely associated with conscious perception does not just depend on external stimuli but also on the flexible inner dynamic of the brain. We theorize that neurons are constantly and actively predicting where the visual stimuli they expect will appear. Fries and other researchers have in fact measured the synchronization effect in the visual area of animals even before they were presented with an expected stimulus. Probably, brain regions such as the frontal cortex or the limbic system exercise influence over synchronization in the sensory areas.
All incoming stimuli set their own temporal coupling patterns in motion. If these stimuli correspond to those that the expectation has created, the incoming signals are reinforced by a resonance effect and conducted onward. If the expectations are not met, however, the brain suppresses the incoming neuronal messages. This process was at work in the gorilla experiment. The subjects were not looking for a person in a gorilla suit. Their brains were engaged in tracking the moving players in white. Any information about an ape that hit their retinas was out of sync with neuronal expectations, found no resonance and went unnoticed.
Neuronal synchronization brings order to the chaotic mental world. In fact, cognitive deficits and disordered thoughts among schizophrenic patients appear to be connected to disturbed gamma-band coupling. The healthy brain is, however, anything but a passive receiver of news from the environment. It is an active system, one that controls itself via a complex internal dynamic. Our experiences, intentions, expectations and needs affect this dynamic and thus determine how we perceive and interpret our environment.
ANDREAS K. ENGEL is director of the Institute for Neurophysiology and Pathophysiology at the University of Hamburg in Germany. STEFAN DEBENER is senior scientist at the MRC Institute of Hearing Research in Southampton, England. CORNELIA KRANCZIOCH is a clinical neuropsychologist in the Epilepsy Center of Saxony in Radeberg, Germany.
Tuesday, December 19, 2006
Happiness: Good for Creativity, Bad for Single-Minded Focus
Happiness: Good for Creativity, Bad for Single-Minded Focus
Happy people are open to all sorts of ideas, some of which can be distracting
by JR Minkel December 18, 2006
Despite those who romanticize depression as the wellspring of artistic genius, studies find that people are most creative when they are in a good mood, and now researchers may have explained why: For better or worse, happy people have a harder time focusing.
In one test, participants in a happy mood were better able to come up with a word that unified three other seemingly disparate words, such as "mower," "atomic" and "foreign." Solving the puzzle required participants to think creatively, moving beyond the normal word associations--"lawn," "bomb" and "currency"--to come up with the more remote answer: "power."
Interestingly, induced happiness made the subjects worse at the second task, which required them to ignore distractions and focus on a single piece of information. Participants had to identify a letter flashed on a computer screen flanked by either the same letter, as in the string "N N N N N," or a different letter, as in "H H N H H." When the surrounding letters didn't match, the happy participants were slower to recognize the target letter in the middle, indicating that the ringers distracted them.
The results suggest that an upbeat mood makes people more receptive to information of all kinds, says psychologist Adam Anderson, co-author of the study published online by Proceedings of the National Academy of Sciences USA. "With positive mood, you actually get more access to things you would normally ignore," he says. "Instead of looking through a porthole, you have a landscape or panoramic view of the world."
Researchers have long proposed that negative emotions give people a kind of tunnel vision or filter on their attention,
As for the myth of the depressed but brilliant artist,
A HAPPY THOUGHT: People in a happy mood perform better than others on a task that requires them to be creative, but do worse when asked to cut through distractions and focus on one thing.