Neuroscience

Your brain’s ability to instantly link what you see with what you do is down to a dedicated information ‘highway’, suggests new UCL-led research.

For the first time, researchers from UCL and Cambridge University have found evidence of a specialised mechanism for spatial self-awareness that combines visual cues with body motion.

Standard visual processing is prone to distractions, as it requires us to pay attention to objects of interest and filter out others. The new study has shown that our brains have separate ‘hard-wired’ systems to visually track our own bodies, even if we are not paying attention to them. In fact, the newly-discovered network triggers reactions even before the conscious brain has time to process them.

The researchers discovered the new mechanism by testing 52 healthy adults in a series of three experiments. In all experiments, participants used robotic arms to control cursors on two-dimensional displays, where cursor motion was directly linked to hand movement. Their eyes were kept fixed on a mark at the centre of the screen, confirmed with eye tracking.

In the first experiment, participants controlled two separate cursors with their left and right hands, both equally close to the centre. The goal was to guide each cursor to a corresponding target at the top of the screen. Occasionally the cursor or target on one side would jump left or right, requiring participants to take corrective action. Each jump was ‘cued’ with a flash on one side, but this was random so did not always correspond to the side about to change.

Unsurprisingly, people reacted faster to target jumps when their attention was drawn to the ‘correct’ side by the cue. However, reactions to cursor jumps were fast regardless of cuing, suggesting that a separate mechanism independent of attention is responsible for tracking our own movements.

“The first experiment showed us that we react very quickly to changes relating to objects directly under our own control, even when we are not paying attention to them,” explains Dr Alexandra Reichenbach of the UCL Institute of Cognitive Neuroscience, lead author of the study. “This provides strong evidence for a dedicated neural pathway linking motor control to visual information, independently of the standard visual systems that are dependent on attention.”

The second experiment was similar to the first, but also introduced changes in brightness to demonstrate the attention effect on the visual perception system. In the third experiment, participants had to guide one cursor to its target in the presence of up to four dummy targets and cursors, ‘distractors’, alongside the real ones. In this experiment, responses to cursor jumps were less affected by distractors than responses to target jumps. Reactions to cursor jumps remained vigorous with one or two distractors, but were significantly decreased when there were four.

“These results provide further evidence of a dedicated ‘visuomotor binding’ mechanism that is less prone to distractions than standard visual processing,’ says Dr Reichenbach. “It looks like the specialised system has a higher tolerance for distractions, but in the end it is still affected. Exactly why we evolved a separate mechanism remains to be seen, but the need to react rapidly to different visual cues about ourselves and the environment may have been enough to necessitate a specialised pathway.”

The newly-discovered system could explain why some schizophrenia patients feel like their actions are controlled by someone else.

“Schizophrenia often manifests as delusion of control, and a dysfunction in the visuomotor mechanism identified in this study might be a cause for this symptom,” explains Dr Reichenbach. “If someone does not automatically link corresponding visual cues with body motion, then they might have the feeling that they are not controlling their movements. We would need further research to confirm this, and it would be fascinating to see how schizophrenia patients perform in these experiments.”

These findings could also explain why people with even the most advanced prosthetic limbs can have trouble coordinating movements.

“People often describe their prosthetic limbs as feeling ‘other’, not a true extension of their body,’ says Dr Reichenbach. “Even on the best prosthetic hands, if the observed movement of the fingers is not exactly what you would expect, then it will not feel like you are in direct control. These small details might have a big effect on how people perceive prostheses.”

People who try to quit smoking often say that kicking the habit makes the voice inside telling them to light up even louder, but why people succumb to those cravings so often has never been fully understood.  Now, a new brain imaging study in this week’s JAMA Psychiatry from scientists in Penn Medicine and the National Institute on Drug Abuse (NIDA) Intramural Research Program shows how smokers suffering from nicotine withdrawal may have more trouble shifting from a key brain network—known as default mode, when people are in a so-called “introspective” or “self-referential” state— and into a control network, the so-called executive control network, that could help exert more conscious, self-control over cravings and to focus on quitting for good.

The findings help validate a neurobiological basis behind why so many people trying to quit end up relapsing—up to 80 percent, depending on the type of treatment—and may lead to new ways to identify smokers at high risk for relapse who need more intensive smoking cessation therapy.  

The brain imaging study was led by researchers at University of Pennsylvania’s new Brain and Behavior Change Program, led by Caryn Lerman, PhD, who is also the deputy director of Penn’s Abramson Cancer Center, and Elliot Stein, PhD, and collaborators at NIDA. They found that smokers who abstained from cigarettes showed weakened interconnectivity between certain large-scale networks in their brains: the default mode network, the executive control network, and the salience network. They posit that this weakened connectivity reduces smokers’ ability to shift into or maintain greater influence from the executive control network, which may ultimately help maintain their quitting attempt.

“What we believe this means is that smokers who just quit have a more difficult time shifting gears from inward thoughts about how they feel to an outward focus on the tasks at hand,” said Lerman, who also serves as the Mary W. Calkins professor in the Department of Psychiatry. “It’s very important for people who are trying to quit to be able to maintain activity within the control network— to be able to shift from thinking about yourself and your inner state to focus on your more immediate goals and plan.”

Prior studies have looked at the effects of nicotine on brain interconnectivity in the resting state, that is, in the absence of any specific goal directed activity. This is the first study, however, to compare resting brain connectivity in an abstinent state and when people are smoking as usual, and then relate those changes to symptoms of craving and mental performance.

For the study, researchers conducted brain scans on 37 healthy smokers (those who smoke more than 10 cigarettes a day) ages 19 to 61 using functional magnetic resonance imaging (fMRI) in two different sessions: 24 hours after biochemically confirmed abstinence and after smoking as usual.

Imaging showed a significantly weaker connectivity between the salience network and default mode network during abstinence, compared with their sated state. Also, weakened connectivity during abstinence was linked with increases in smoking urges, negative mood, and withdrawal symptoms, suggesting that this weaker internetwork connectivity may make it more difficult for people to quit.

Establishing the strength of the connectivity between these large-scale brain networks will be important in predicting people’s ability to quit and stay quit, the authors write. Also, such connectivity could serve as a clinical biomarker to identify smokers who are most likely to respond to a particular treatment.

“Symptoms of withdrawal are related to changes in smokers’ brains, as they adjust to being off of nicotine, and this study validates those experiences as having a biological basis,” said Lerman. “The next step will be to identify in advance those smokers who will have more difficultly quitting and target more intensive treatments, based on brain activity and network connectivity.”

Research from McGill University reveals that the brain’s motor network helps people remember and recognize music that they have performed in the past better than music they have only heard. A recent study by Prof. Caroline Palmer of the Department of Psychology sheds new light on how humans perceive and produce sounds, and may pave the way for investigations into whether motor learning could improve or protect memory or cognitive impairment in aging populations. The research is published in the journal Cerebral Cortex.

“The memory benefit that comes from performing a melody rather than just listening to it, or saying a word out loud rather than just hearing or reading it, is known as the ’production effect’ on memory”, says Prof. Palmer, a Canada Research Chair in Cognitive Neuroscience of Performance. “Scientists have debated whether the production effect is due to motor memories, such as knowing the feel of a particular sequence of finger movements on piano keys, or simply due to strengthened auditory memories, such as knowing how the melody tones should sound. Our paper provides new evidence that motor memories play a role in improving listeners’ recognition of tones they have previously performed.”

For the study, researchers recruited twenty skilled pianists from Lyon, France. The group was asked to learn simple melodies by either hearing them several times or performing them several times on a piano. Pianists then heard all of the melodies they had learned, some of which contained wrong notes, while their brain electric signals were measured using electroencephalography (EEG). 

“We found that pianists were better at recognizing pitch changes in melodies they had performed earlier,” said the study’s first author, Brian Mathias, a McGill PhD student who conducted the work at the Lyon Neuroscience Research Centre in France with additional collaborators Drs. Barbara Tillmann and Fabien Perrin.

The team found that EEG measurements revealed larger changes in brain waves and increased motor activity for previously performed melodies than for heard melodies about 200 milliseconds after the wrong notes. This reveals that the brain quickly compares incoming auditory information with motor information stored in memory, allowing us to recognize whether a sound is familiar.

“This paper helps us understand ‘experiential learning’, or ‘learning by doing’, and offers pedagogical and clinical implications,” said Mathias, “The role of the motor system in recognizing music, and perhaps also speech, could inform education theory by providing strategies for memory enhancement for students and teachers.”

Alzheimer’s disease is the most widespread degenerative neurological disorder in the world. Over five million Americans live with it, and one in three senior citizens will die with the disease or a similar form of dementia. While memory loss is a common symptom of Alzheimer’s, other behavioral manifestations — depression, loss of inhibition, delusions, agitation, anxiety, and aggression — can be even more challenging for victims and their families to live with.

Now Prof. Daniel Offen and Dr. Adi Shruster of Tel Aviv University’s Sackler School of Medicine have discovered that by reestablishing a population of new cells in the part of the brain associated with behavior, some symptoms of Alzheimer’s disease significantly decreased or were reversed altogether.

The research, published in the journal Behavioural Brain Research, was conducted on mouse models; it provides a promising target for Alzheimer’s symptoms in human beings as well.

"Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you aged or as the result of injury or disease," said Prof. Offen, who also serves as Chief Scientific Officer at BrainStorm, a biotech company at the forefront of innovative stem cell research. "We now know that stem cells can be used to regenerate areas of the brain."

Speeding up recovery

After introducing stem cells in brain tissue in the laboratory and seeing promising results, Prof. Offen leveraged the study to mice with Alzheimer’s disease-like symptoms. The gene (Wnt3a) was introduced in the part of the mouse brain that controls behavior, specifically fear and anxiety, in the hope that it would contribute to the formation of genes that produce new brain cells.

According to Prof. Offen, untreated Alzheimer’s mice would run heedlessly into an unfamiliar and dangerous area of their habitats instead of assessing potential threats, as healthy mice do. Once treated with the gene that increased new neuron population, however, the mice reverted to assessing their new surroundings first, as usual.

"Normal mice will recognize the danger and avoid it. Mice with the disease, just like human patients, lose their sense of space and reality," said Prof. Offen. "We first succeeded in showing that new neuronal cells were produced in the areas injected with the gene. Then we succeeded in showing diminished symptoms as a result of this neuron repopulation."

"The loss of inhibition is a cause of great embarrassment for most patients and relatives of patients with Alzheimer’s," said Prof. Offen. "Often, patients take off their pants in public, having no sense of their surroundings. We saw parallel behavior in animal models with Alzheimer’s."

Next: Memory

After concluding that increased stem cell production in a certain area of the brain had a positive effect on behavioral deficits of Alzheimer’s, Prof. Offen has moved to research into the area of the brain that controls memory. He and his team are currently exploring it in the laboratory and are confident that the results of the new study will be similar.

"Although there are many questions to answer before this research produces practical therapies, we are very optimistic about the results and feel this is a promising direction for Alzheimer’s research," said Prof. Offen.

New research from Karolinska Institutet and Umeå University in Sweden demonstrates for the first time that there is a close relationship between body perception and the ability to remember. For us to be able to store new memories from our lives, we need to feel that we are in our own body. According to researchers, the results could be of major importance in understanding the memory problems that psychiatric patients often exhibit.

The memories of what happened on the first day of school are an example of an episodic memory. How these memories are created and how the role that the perception of one’s own body has when storing memories has long been inconclusive. Swedish researchers can now demonstrate that volunteers who experience an exciting event whilst perceiving an illusion of being outside their own body exhibit a form of memory loss.

“It is already evident that people who have suffered psychiatric conditions in which they felt that they were not in their own body have fragmentary memories of what actually occurred”, says Loretxu Bergouignan, principal author of the current study. “We wanted to see how this manifests itself in healthy subjects.”

The study, which is published in the scientific journal PNAS, involved a total of 84 students reading about and undergoing four oral questioning sessions. To make these sessions extra memorable, an actor (Peter Bergared) took up the role of examiner – a (fictional) very eccentric professor at Karolinska Institutet. Two of the interrogations were perceived from a first person perspective from their own bodies in the usual way, while the participants in the other two sessions experienced a created illusion of being outside their own body. In both cases, the participants wore virtual reality goggles and earphones. One week later, they either underwent memory testing where they had to recall the events and provide details about what had happened, in which order, and what they felt, or they had to try to remember the events while they underwent brain imaging with functional magnetic resonance imaging (fMRI).

It then turned out that the participants remembered the ‘out-of-body’ interrogations significantly worse than those experienced from the normal ‘In body’ perspective. This was the case despite the fact that they responded equally well to the questions from each situation and also indicated that they experienced the same level of emotion. The fMRI scans further revealed a crucial difference in activity in the portion of the temporal lobe – the hippocampus – that is known to be central for episodic memories.

“When they tried to remember what happened during the interrogations experienced out-of-body, activity in the hippocampus was eliminated, unlike when they remembered the other situations. However, we could see activity in the frontal lobe cortex, so they were really making an effort to remember”, says professor Henrik Ehrsson, the research group leader behind the study. 

The researchers’ interpretation of the results is that there is a close relationship between body experience and memory. Our brain constantly creates the experience of one’s own body in space by combining information from multiple senses: sight, hearing, touch, and more. When a memory is created, it is the task of the hippocampus to link all the information found in the cerebral cortex into a unified memory for further long-term storage. During the experience of being outside one’s body, this memory storage process is disturbed, whereupon the brain creates fragmentary memories instead.

“We believe that this new knowledge may be important for future research on memory disorders in a number of psychiatric conditions such as post-traumatic stress disorder, borderline personality disorder and certain psychoses where patients have dissociative experiences,” says Loretxu Bergouignan.

Researchers at the School of Medicine have identified a subset of nerve cells that mediates a form of chronic, touch-evoked pain called tactile allodynia, a condition that is resistant to conventional pain medication.

The discovery could point researchers to more fruitful efforts to develop effective drugs for the condition.

Touch-evoked pain occurs as part of a larger neuropathic pain condition arising from damage or disruption of nerve-cell circuits or signals caused by disorders such as alcoholism, diabetes, shingles and AIDS, or procedures such as spine surgery and chemotherapy. For patients with tactile allodynia, the slightest touch — a gentle caress or the brush of shirt against skin — can cause excruciating pain because changes in nerve-cell signals or networks trick the brain into mistaking touch for pain.

The study, published online Feb. 27 in Neuron, found that these “touch” neurons are different from the usual “pain” neurons that respond to stimuli such as cuts or bruises.

Unlike pain caused by such wounds, neuropathic pain is difficult to manage because little can be done to repair nerve damage. Managing it may require strong painkillers or combinations of treatments.

Common painkillers such as morphine have little effect on touch-evoked pain, possibly because they don’t target the touch neurons, the authors say. Morphine binds to specific protein-binding sites on pain neurons called mu opioid receptors, or MORs, and cuts off the their signals so that the brain can no longer sense pain.

However, the touch neurons do not carry MORs, which is why morphine cannot bind to them and block the pain. Instead, they carry delta opioid receptors, or DORs, whose role in pain control has been unclear until recently.

"That’s been the problem so far; any type of severe pain you have, you go into the clinic and very likely you will be treated with morphine-like opioids," said Gregory Scherrer, PharmD, PhD, the senior author of the study and an assistant professor of anesthesia. "You can give some of these patients as much morphine as you want; it won’t work if the mu opioid receptor is not present on the neurons that underlie that type of pain."

There are currently no Food and Drug Administration-approved pain-control drugs that target DORs. Previous attempts at developing DOR-targeting drugs haven’t succeeded because researchers didn’t know what type of pain such drugs would be useful for, Scherrer said.

Two DOR-binding drugs developed for knee pain by Adolor Corp., a biotechnology firm, for instance, probably failed because there is no compelling evidence that DOR was present or involved. AstraZeneca, another pharmaceutical firm, also had a DOR program but recently stopped its research efforts, Scherrer added.

"Now that we have provided a rationale and mechanism supporting the utility of DOR agonists for cutaneous pain and tactile allodynia, these companies will be able to design trials more carefully to evaluate specifically the drugs’ efficacy against touch-evoked pain," he said.

Earlier studies by Scherrer and others hinted at the presence of special nerve fibers on the skin that might contribute to touch-evoked pain.

In the current study, Scherrer and colleagues used fluorescent mouse models to isolate these neurons and identify how they control touch-evoked pain. They found that DOR can play an inhibitory role in these neurons: When proteins bind to DOR, they cut off communication to the spinal cord, through which sensory signals travel to the brain.
DOR-carrying “touch” neurons pervade the skin and could easily be targeted by drugs in the form of skin patches or topical creams, Scherrer suggested.

"By contrast, most MOR-carrying neurons penetrate internal organs," he said. "That’s why morphine is effective in treating post-surgery pain, for example."

Scherrer and fellow researchers tested two different DOR-binding compounds individually on mice and found that both reduced the mice’s sensitivity to touch-evoked pain.

Preliminary studies also indicate that DOR-targeting drugs might not cause dramatic side effects like morphine does, especially if they can be used topically, Scherrer said.

"Morphine and other MOR-targeting drugs have myriad deleterious side effects — including addiction, respiratory depression, constipation, nausea and vomiting — that further limits their utility for chronic pain management," he said.

The next step is to determine whether DOR could be a target for other types of pain, such as arthritis pain, pain from bone cancer and muscle pain, Scherrer added.

The findings also suggest that the body’s opioid system — normally associated with pain and addiction — may also respond to other stimuli such as touch.

"We may have underestimated the importance of the opioid system and what can be achieved with drugs targeting other subtypes of opioid receptors," Scherrer said.

By examining the sense of touch in stroke patients, a University of Delaware cognitive psychologist has found evidence that the brains of these individuals may be highly plastic even years after being damaged.

The research is published in the March 6 edition of the journal Current Biology, in an article written by Jared Medina, assistant professor of psychology at UD, and Brenda Rapp of Johns Hopkins University’s Department of Cognitive Science. The findings, which are focused on patients who lost the sense of touch in their hands after a stroke, also have potential implications for other impairments caused by brain damage, Medina said.

“Our lab is interested in how the brain represents the body, not just in the sense of touch,” he said. “That involves a lot of different areas of the brain.”

For decades, scientists have been mapping the brain to determine which areas control certain functions, from movement to emotion to memory. In terms of representing the sense of touch, researchers know which specific parts of the brain are associated with representing specific parts of the body, Medina said.

Those scientists also know that, following the brain damage a stroke causes, patients often regain some of what they initially lost due to that damage.

“Even if every neuron has been killed in the part of the brain that represents touch on the hand, that doesn’t mean that you’re never going to feel anything on your hand again,” Medina said. “We’ve known that isn’t the case because the map can reorganize. The brain can change due to injury.”

But what the new research by Medina and Rapp found is that the brains of those stroke patients may change much more easily than the undamaged brains of healthy people — what they call “hyper-lability.”

The researchers worked with people who had had strokes in the past that affected their ability to localize touch. Each research participant, without being able to see his hand, was touched on the wrist and then on the fingertips. When asked to pinpoint the second touch, the stroke patients reported sensing the touch farther down their finger, toward the wrist, rather than in its actual location. 

Medina says that likely occurs because the neural map in the brain is shifting based on the earlier wrist touch — a phenomenon termed “experience-dependent plasticity.”

“Now what’s interesting about this is that when you and I [who haven’t had a stroke] are touched on the wrist, then the fingertips, we don’t have these changes that the brain-damaged individuals do,” he said. “This provides the counterintuitive finding that the maps in brain-damaged individuals are actually much more plastic than in you and me.”

Hyper-plasticity has positive and negative implications, he said.

“On the positive side, this plasticity may potentially be harnessed in rehabilitation to improve function” after a stroke or various other types of brain injury, Medina said. But, he added, the brain may also be so plastic in those cases that changes aren’t stable, creating additional problems.

That’s what he expects additional research to address.

“Now that we’ve found that these maps are more plastic than we thought, can certain strategies help the map become more stable and more accurate again? That’s one of the next questions, and we can only answer it by continuing to learn more about how the mind works.”

It may seem normal: As we age, we misplace car keys, or can’t remember a name we just learned or a meal we just ordered. But University of Florida researchers say memory trouble doesn’t have to be inevitable, and they’ve found a drug therapy that could potentially reverse this type of memory decline.

The drug can’t yet be used in humans, but the researchers are pursuing compounds that could someday help the population of aging adults who don’t have Alzheimer’s or other dementias but still have trouble remembering day-to-day items. Their findings will be published in today’s (March 5) issue of the Journal of Neuroscience.

The kind of memory responsible for holding information in the mind for short periods of time is called “working memory.” Working memory relies on a balance of chemicals in the brain. The UF study shows this chemical balance tips in older adults, and working memory declines. The reason? It could be because their brains are producing too much of a chemical that slows neural activity.

“Graduate student Cristina Banuelos’ work suggests that cells that normally provide the brake on neural activity are in overdrive in the aged prefrontal cortex,” said researcher Jennifer Bizon, Ph.D., an associate professor in the department of neuroscience and a member of UF’s Evelyn F. & William L. McKnight Brain Institute.

This chemical, an inhibitory brain neurotransmitter called GABA, is essential. Without it, brain cells can become too active, similar to what happens in the brains of people with schizophrenia and epilepsy. A normal level of GABA helps maintain the optimal levels of cell activation, said collaborator Barry Setlow, Ph.D., an associate professor in UF’s departments of psychiatry and neuroscience.

Working memory underlies many mental abilities and is sometimes referred to as the brain’s mental sketchpad, Bizon said. For example, Bizon said, you use your working memory in many everyday activities such as calculating your final bill at the end of dining at a restaurant. Most people can calculate a 15 percent tip and add it to the cost of their meal without pencil and paper. Central to this process is the ability to keep multiple pieces of information in mind for a short duration — such as remembering the cost of your dinner while calculating the amount needed for the tip.

“Almost all higher cognitive processes depend on this fundamental operation,” Bizon said.

To determine the culprit behind working memory decline, the researchers tested the memory of young and aged rats in a “Skinner box.” In the Skinner box, rats had to remember the location of a lever for short periods of up to 30 seconds. The scientists found that while both young and old rats could remember the location of the lever for brief periods of time, as those time periods lengthened, old rats had more difficulty remembering the location of the lever than young rats.

But not all older rats did poorly on the memory test, just as not all older adults have memory problems. The study shows the older brains of some people or rats with no memory problems might compensate for the overactive inhibitory system — they are able to produce fewer GABA receptors and therefore bind less of the inhibitory chemical.

Older rats with memory problems had more GABA receptors. The drug the researchers tested blocked GABA receptors, mimicking the lower number of those receptors that some older rats had naturally and restoring working memory in aged rats to the level of younger rats.

“Modern medicine has done a terrific job of keeping us alive for longer, and now we have to keep up and determine how to maximize the quality of life for seniors,” Bizon said. “A key aspect of that is going to be developing strategies and therapies that can maintain and improve cognitive health.”

Veterans exposed to explosions who do not report symptoms of traumatic brain injury (TBI) may still have damage to the brain’s white matter comparable to veterans with TBI, according to researchers at Duke Medicine and the U.S. Department of Veterans Affairs.

The findings, published in the Journal of Head Trauma Rehabilitation on March 3, 2014, suggest that a lack of clear TBI symptoms following an explosion may not accurately reflect the extent of brain injury.

Veterans of recent military conflicts in Iraq and Afghanistan often have a history of exposure to explosive forces from bombs, grenades and other devices, although relatively little is known about whether this injures the brain. However, evidence is building – particularly among professional athletes – that subconcussive events have an effect on the brain.

"Similar to sports injuries, people near an explosion assume that if they don’t have clear symptoms – losing consciousness, blurred vision, headaches – they haven’t had injury to the brain,” said senior author Rajendra A. Morey, M.D., associate professor of psychiatry and behavioral sciences at Duke University School of Medicine and a psychiatrist at the Durham Veterans Affairs Medical Center. “Our findings are important because they’re showing that even if you don’t have symptoms, there may still be damage.”

Researchers in the Mid-Atlantic Mental Illness Research, Education and Clinical Center at the W.G. (Bill) Hefner Veterans Affairs Medical Center in Salisbury, N.C., evaluated 45 U.S. veterans who volunteered to participate in the study. The veterans, who served since September 2001, were split into three groups: veterans with a history of blast exposure with symptoms of TBI; veterans with a history of blast exposure without symptoms of TBI; and veterans without blast exposure. The study focused on veterans with primary blast exposure, or blast exposure without external injuries, and did not include those with brain injury from direct hits to the head.

To measure injury to the brain, the researchers used a type of MRI called Diffusion Tensor Imaging (DTI). DTI can detect injury to the brain’s white matter by measuring the flow of fluid in the brain. In healthy white matter, fluid moves in a directional manner, suggesting that the white matter fibers are intact. Injured fibers allow the fluid to diffuse.

White matter is the connective wiring that links different areas of the brain. Since most cognitive processes involve multiple parts of the brain working together, injury to white matter can impair the brain’s communication network and may result in cognitive problems.

Both groups of veterans who were near an explosion, regardless of whether they had TBI symptoms, showed a significant amount of injury compared to the veterans not exposed to a blast. The injury was not isolated to one area of the brain, and each individual had a different pattern of injury.

Using neuropsychological testing to assess cognitive performance, the researchers found a relationship between the amount of white matter injury and changes in reaction time and the ability to switch between mental tasks. However, brain injury was not linked to performance on other cognitive tests, including decision-making and organization.

“We expected the group that reported few symptoms at the time of primary blast exposure to be similar to the group without exposure. It was a surprise to find relatively similar DTI changes in both groups exposed to primary blast,” said Katherine H. Taber, Ph.D., a research health scientist at the W.G. (Bill) Hefner Veterans Affairs Medical Center and the study’s lead author. “We are not sure whether this indicates differences among individuals in symptoms-reporting or subconcussive effects of primary blast. It is clear there is more we need to know about the functional consequences of blast exposures.”

Given the study’s findings, the researchers said clinicians treating veterans should take into consideration a person’s exposure to explosive forces, even among those who did not initially show symptoms of TBI. In the future, they may use brain imaging to support clinical tests.

“Imaging could potentially augment the existing approaches that clinicians use to evaluate brain injury by looking below the surface for TBI pathology,” Morey said.

The researchers noted that the results are preliminary, and should be replicated in a larger study.

TAU researchers discover a link between sharp vision and the brain’s processing speed

Middle-aged adults who suddenly need reading glasses, patients with traumatic brain injuries, and people with visual disorders such as “lazy eye” may have one thing in common — “visual crowding,” an inability to recognize individual items surrounded by multiple objects. Visual crowding makes it impossible to read, as single letters within words are rendered illegible. And basic cognitive functions such as facial recognition can also be significantly hampered. Scientists and clinicians currently attribute crowding to a disorder in peripheral vision.

Now Prof. Uri Polat, Maria Lev, and Dr. Oren Yehezkel of Tel Aviv University’s Goldschleger Eye Research Instituteat the Sackler Faculty of Medicine have discovered new evidence that correlates crowding in the fovea — a small part of the retina responsible for sharp vision — and the brain’s processing speed. These findings, published in Nature’s Scientific Reports, could greatly alter earlier models of visual crowding, which emphasized peripheral impairment exclusively. And for many adults lost without their reading glasses, this could improve their vision significantly.

"Current theories strongly stress that visual crowding does not exist in the fovea, that it’s a phenomenon that exists only in peripheral visual fields," said Prof. Polat. "But our study points to another part of the eye altogether — the fovea — and contributes to a unified model for how the brain integrates visual information."

A trained eye

According to Prof. Polat, vision is dynamic and changes rapidly, but it takes time for the brain to process this visual information. Rapidly moving tickers on TV, or traffic signs seen as the driver speeds past, are difficult for anyone to read. However, given enough time, someone with excellent vision can fully recognize the words. Those with slower processing speeds — usually the result of poor perceptive development or age — may not be able to decipher the tickers or the traffic signs. In the study, Prof. Polat employed his expertise in improving vision by retraining the brain and the foveal part of the eye, using exercises in which speed is a key element.

"Training adults to reduce foveal crowding leads to improved vision. A similar training we conducted two years ago allowed adults to eliminate their use of reading glasses altogether, using a technology provided by the GlassesOff company. Other patients who had lost sharp vision for whatever reason were also able to benefit from the same training and improve their processing speed and visual capabilities," said Prof. Polat.

Maria Lev, who performed the study as a part of her doctoral thesis, said one young subject had experienced significant limitations in school for years and had been unable to obtain a driver’s license due to severe visual impairment from foveal crowding. After undergoing training that emphasized a foveal rather than a peripheral focus, he was able to overcome the handicap.

"He finally managed to learn to read properly and found his way forward," said Lev. "I’m proud to say that today he is not only eligible for a driver’s license, he’s also been able to earn his master’s degree."

Prof. Polat and his team are currently exploring how visual integration and foveal crowding develop in various clinical cases.

New research from the University of Virginia School of Medicine has revealed the dramatic effect the immune system has on the brain development of young children. The findings suggest new and better ways to prevent developmental impairment in children in developing countries, helping to free them from a cycle of poverty and disease, and to attain their full potential.

U.Va. researchers working in Bangladesh determined that the more days infants suffered fever, the worse they performed on developmental tests at 12 and 24 months. They also found that elevated levels of inflammation-causing proteins in the blood were associated with worse performance, while higher levels of inflammation-fighting proteins were associated with improved performance.

“The problem we sought to address was why millions of young children in low- and middle-income countries are not attaining their full developmental potential,” said lead author Nona Jiang, who performed the research while an undergraduate student in the laboratory of Dr. William Petri Jr. “Early childhood is an absolutely critical time of brain development, and it’s also a time when these children are suffering from recurrent infections. Therefore, we asked whether these infections are contributing to the impaired development we observe in children growing up in adversity.”

Their findings offer a potential explanation for the developmental impairment seen in children living in poverty. They also offer important direction for doctors attempting to combat the problem: By preventing inflammation, physicians may be able to enhance children’s mental ability for a lifetime.

“We are interested in examining factors that predict healthy child development around the world,” said researcher Dr. Rebecca Scharf of U.Va.’s Department of Pediatrics. “By studying which early childhood influences are associated with hindrances to growth and learning, we will know better where to target interventions for the critical period of early childhood.”

In addition, the finding illuminates the complex relationship between the immune system and cognitive development, an increasingly important area of research that U.Va. has helped pioneer.

“This is a very interesting study, showing, probably for the first time, the link between peripheral cytokine levels and improved cognitive development in humans,” said Jonathan Kipnis, a professor of neuroscience and director of U.Va.’s Center for Brain Immunology & Glia. “What is of the most interest and of a great novelty is the fact that [inflammation-fighting cytokines] have positive correlation with cognitive function. My lab published results showing that these IL-4 cytokines are required for proper brain function in mice, and this work from Dr. Petri’s lab completely independently shows similar correlation in humans.

“I hope the scientific community will appreciate how dramatic the effects of the immune system are on the central nervous system and will invest more efforts in studying and better understanding these complex and intriguing interactions between the body’s two major systems.”

Johns Hopkins researchers report that people with chronic insomnia show more plasticity and activity than good sleepers in the part of the brain that controls movement.

"Insomnia is not a nighttime disorder," says study leader Rachel E. Salas, M.D., an assistant professor of neurology at the Johns Hopkins University School of Medicine. "It’s a 24-hour brain condition, like a light switch that is always on. Our research adds information about differences in the brain associated with it."

Salas and her team, reporting in the March issue of the journal Sleep, found that the motor cortex in those with chronic insomnia was more adaptable to change - more plastic - than in a group of good sleepers. They also found more “excitability” among neurons in the same region of the brain among those with chronic insomnia, adding evidence to the notion that insomniacs are in a constant state of heightened information processing that may interfere with sleep.

Researchers say they hope their study opens the door to better diagnosis and treatment of the most common and often intractable sleep disorder that affects an estimated 15 percent of the United States population.

To conduct the study, Salas and her colleagues from the Department of Psychiatry and Behavioral Sciences and the Department of Physical Medicine and Rehabilitation used transcranial magnetic stimulation (TMS), which painlessly and noninvasively delivers electromagnetic currents to precise locations in the brain and can temporarily and safely disrupt the function of the targeted area. TMS is approved by the U.S. Food and Drug Administration to treat some patients with depression by stimulating nerve cells in the region of the brain involved in mood control.

The study included 28 adult participants - 18 who suffered from insomnia for a year or more and 10 considered good sleepers with no reports of trouble sleeping. Each participant was outfitted with electrodes on their dominant thumb as well as an accelerometer to measure the speed and direction of the thumb.

The researchers then gave each subject 65 electrical pulses using TMS, stimulating areas of the motor cortex and watching for involuntary thumb movements linked to the stimulation. Subsequently, the researchers trained each participant for 30 minutes, teaching them to move their thumb in the opposite direction of the original involuntary movement. They then introduced the electrical pulses once again.

The idea was to measure the extent to which participants’ brains could learn to move their thumbs involuntarily in the newly trained direction. The more the thumb was able to move in the new direction, the more likely their motor cortexes could be identified as more plastic.

Because lack of sleep at night has been linked to decreased memory and concentration during the day, Salas and her colleagues suspected that the brains of good sleepers could be more easily retrained. The results, however, were the opposite. The researchers found much more plasticity in the brains of those with chronic insomnia.

Salas says the origins of increased plasticity in insomniacs are unclear, and it is not known whether the increase is the cause of insomnia. It is also unknown whether this increased plasticity is beneficial, the source of the problem or part of a compensatory mechanism to address the consequences of sleep deprivation associated with chronic insomnia. Patients with chronic phantom pain after limb amputation and with dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements, also have increased brain plasticity in the motor cortex, but to detrimental effect.

Salas says it is possible that the dysregulation of arousal described in chronic insomnia - increased metabolism, increased cortisol levels, constant worrying - might be linked to increased plasticity in some way. Diagnosing insomnia is solely based on what the patient reports to the provider; there is no objective test. Neither is there a single treatment that works for all people with insomnia. Treatment can be a hit or miss in many patients, Salas says.

She says this study shows that TMS may be able to play a role in diagnosing insomnia, and more importantly, she says, potentially prove to be a treatment for insomnia, perhaps through reducing excitability.

So why do neurons respond in this remarkable way? A new study by Professor Jeff Bowers and colleagues at the University of Bristol argues that highly selective neural representations are well suited to co-activating multiple things, such as words, objects and faces, at the same time in short-term memory. 

The researchers trained an artificial neural network to remember words in short-term memory. Like a brain, the network was composed of a set of interconnected units that activated in response to inputs; the network ‘learnt’ by changing the strength of connections between units. The researchers then recorded the activation of the units in response to a number of different words.

When the network was trained to store one word at a time in short-term memory, it learned highly distributed codes such that each unit responded to many different words. However, when it was trained to store multiple words at the same time in short-term memory it learned highly selective (‘grandmother cell’) units – that is, after training, single units responded to one word but not any other. This is much like the neurons in the cortex that respond to one face amongst many.

Why did the network learn such highly specific representations when trained to co-activate multiple words at the same time? Professor Bowers and colleagues argue that the non-selective representations can support memory for a single word, given that a pattern of activation across many non-selective units can uniquely represent a specific word. However, when multiple patterns are mixed together, the resulting blend pattern is often ambiguous (the so-called ‘superposition catastrophe’).

This ambiguity is easily avoided, however, when the network learns to represent words in a highly selective manner, for example, if one unit codes for the word RACHEL, another for MONICA, and yet another JOEY, there is no ambiguity when the three units are co-activated.

Professor Bowers said: “Our research provides a possible explanation for the discovery that single neurons in the cortex respond to information in a highly selective manner. It’s possible that the cortex learns highly selective codes in order to support short-term memory.”

The study is published in Psychological Review.

Schizophrenia is one of the most disabling of all psychiatric illnesses. Sadly, it is not uncommon and it strikes early in life.

Many studies have looked into causes and potential interventions, and it has been long known that genetic factors play a role in determining the risk of developing schizophrenia. However, recent work has shown that there will be no simple answers as to why some people get schizophrenia: No single gene or small number of genes explains much of the risk for illness. Instead, future studies must focus on larger numbers of interacting genes.

In a new paper published in PLOS ONE, researchers led by Bruce Cohen of Harvard Medical School and McLean Hospital report promising evidence on what one of those important groups of genes may be.

Previous studies of schizophrenia have shown abnormalities in the brain’s white matter—its wiring and insulation—but these studies could not definitively separate inherited from environmental causes. For this study, researchers used previously discovered anomalies to select likely assortments of genes that, as a group, might be highly determinative of the risk for schizophrenia. The choice of genes was based on convergent results of past studies conducted locally and around the world, and included genes that control the insulation of the nerve cells in the brain.

The results of this study strongly suggest that the abnormalities of wiring and insulation are substantially determined by genes.

“There is abundant evidence from our center and from other laboratories that this insulation is compromised in schizophrenia,” said Cohen, HMS Robertson-Steele Professor of Psychiatry and director of the Shervert Frazier Research Institute at McLean Hospital. “Based on this lead, we tested whether the genes required for the activities of the cells that make this insulation (oligodendrocytes) were associated with schizophrenia. In a primary analysis, followed by three separate means of confirmatory analysis, we found strong evidence that genes for oligodendrocytes, as a group, were indeed associated with schizophrenia.”

The findings suggest a concrete reason why insulation is disrupted in the brain in schizophrenia. This disruption in turn may explain why thinking is altered in schizophrenia: Nerve cells are unable to pass exact messages if they lack proper insulation.

Further, the findings show that the abnormality in insulation is at least in part genetically determined, rather than solely due to environmental factors such as years of treatment, different life activities or exposure to toxins.

Finally, the results identify a specific cell-level abnormality, in oligodendrocytes, in schizophrenia.

Similar findings, using different techniques, were recently reported by an independent group of investigators, working separately but contemporaneously with the authors of this study.

“Knowing that one of the pathways of risk for schizophrenia is in this set of genes and in these cells may help identify who is at risk and in what way they are at risk,” said Cohen. “The cells themselves will next be studied to define the problem and seek methods to prevent or reverse it. Thus, the findings can point us towards new ways to reduce the risk and burden of schizophrenia.”

Additional researchers from HMS, Harvard School of Public Health, McLean Hospital, Massachusetts General Hospital, The Broad Institute of MIT and Harvard, and the Cardiff University School of Medicine in Wales contributed to the study.

A new study led by Weill Cornell Medical College scientists shows that the most common genetic form of mental retardation and autism occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a drug that blocks this silencing mechanism can prevent fragile X syndrome — suggesting similar therapy is possible for 20 other diseases that range from mental retardation to multisystem failure.

(Image caption: A key brain signaling protein, seen here in green, that is normally lost in Fragile X syndrome neurons is restored by an experimental drug. Image: Dilek Colak)

Fragile X syndrome occurs mostly in boys, causing intellectual disability as well as telltale physical, behavioral and emotional traits. While researchers have known for more than two decades that the culprit behind the disease is an unusual mutation characterized by the excess repetition of a particular segment of the genetic code, they weren’t sure why the presence of a large number of these repetitions — 200 or more — sets the disease process in motion.

Using stem cells from donated human embryos that tested positive for fragile X syndrome, the scientists discovered that early on in fetal development, messenger RNA — a template for protein production — begins sticking itself onto the fragile X syndrome gene’s DNA. This binding appears to gum up the gene, making it inactive and unable to produce a protein crucial to the transmission of signals between brain cells.

"Until 11 weeks of gestation, the fragile X syndrome gene is active — it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient’s lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off," says senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. "We discovered that the messenger RNA can jam up one strand of the gene’s DNA, shutting down the gene — which was not known before.

"This is new biology — an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease," Dr. Jaffrey says. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel — and very exciting."

The malfunction occurs suddenly — before the end of the first trimester in humans and after 50 days in laboratory embryonic stem cells. At that point, the messenger RNA produced by the fragile X syndrome gene makes what the researchers call an RNA-DNA duplex — a particular arrangement of molecules in which the messenger RNA is stuck onto its DNA complement. (DNA produces two complementary strands of the genetic code responsible for human development and function. The four nucleic acids in the genomic code — A, C, G, T — have specific complements. In the case of fragile X syndrome, the repeat sequence in question is CGG. Therefore, RNA binds to its GCC complement on one strand of DNA.)

The RNA-DNA duplex then shuts down production of the fragile X syndrome gene, causing the loss of a protein needed for communication between brain cells. The gene then remains inactive for life. A normal fragile X gene — one with fewer than 200 CGG repeats — stays active in a person without the disorder, and produces the necessary protein. However, the mutant fragile X gene contains more than 200 CGG repeats, resulting in fragile X syndrome. Fragile X occurs in about 1 in 4,000 males and 1 in 8,000 females.

"Because the fragile X syndrome mutation is a repeat sequence, it is very easy for just a small portion of this sequence in the messenger RNA to find a matching repeat sequence on the DNA," Dr. Jaffrey says. "This is a unique feature of repeat sequences. When there are 200 or more repeats, the RNA-DNA interaction locks into place."

Hope for treatment — and other disorders

Dr. Jaffrey and his team, which includes researchers from The Scripps Research Institute in Florida and Albert Einstein College of Medicine in the Bronx, sought to find out why the disease is switched on when the CGG repeat is present in 200 to as many as 1,000 copies.

"Utilizing traditional ways to solve this puzzle has been impossible," he says. "Human fragile X syndrome genes introduced into mice and cells in the laboratory never turn off, no matter how many CGG repeats the genes have."

So the scientists turned to human embryonic stem cells. Co-authors Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College, and Dr. Nikica Zaninovic, assistant professor of reproductive medicine, generated stem cell lines from donated embryos that tested positive for fragile X syndrome. “These stem cells were critical to the success of this research, because they alone allowed us to mimic what happens to the fragile X gene during embryonic development,” says Dr. Dilek Colak, a postdoctoral scientist in Dr. Jaffrey’s laboratory and the first author of the study.

The stem cells were coaxed to become brain neurons, and at about 50 days, they differentiated in the same way that an embryo’s brain is developing at 11-plus weeks when the fragile X syndrome gene is switched off.

The researchers then used a drug developed by co-author Dr. Matthew Disney of the Scripps Research Institute that binds to CGG in the fragile X gene’s RNA before and after the 50-day switch. Strikingly, the gene never stopped producing its beneficial protein.

That suggests a potential prevention or treatment strategy for fragile X syndrome, Dr. Jaffrey says. “If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation. This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients,” he says.

The researchers are now looking for similar RNA-DNA duplexes in other trinucleotide repeat diseases, including Huntington’s disease (a degenerative brain disease), myotonic dystrophy 1 and 2 (a multisystem progressive disease), Friedrich’s ataxia (a progressive nervous system disorder), Jacobsen syndrome (an intellectual disorder), and familial amyotrophic lateral sclerosis (a motor neuron disease), among others.

"This completely new mechanism by which RNAs can direct gene silencing may be involved in a lot of other diseases," Dr. Jaffrey says. "Our hope is that we can find drugs that interfere with this new type of disease process."