Neuroscience
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Researchers at the University of Minnesota’s Center for Magnetic Resonance Research (CMRR) have found a small population of neurons that is involved in measuring time, which is a process that has traditionally been difficult to study in the lab.
In the study, which is published October 30 in the open access journal PLOS Biology, the researchers developed a task in which monkeys could only rely on their internal sense of the passage of time. Their task design eliminated all external cues which could have served as “clocks”.
The monkeys were trained to move their eyes consistently at regular time intervals without any external cues or immediate expectation of reward. Researchers found that despite the lack of sensory information, the monkeys were remarkably precise and consistent in their timed behaviors. This consistency could be explained by activity in a specific region of the brain called the lateral intraparietal area (LIP). Interestingly, the researchers found that LIP activity during their task was different from activity in previous studies that had failed to eliminate external cues or expectation of reward.
"In contrast to previous studies that observed a build-up of activity associated with the passage of time, we found that LIP activity decreased at a constant rate between timed movements," said lead researcher Geoffrey Ghose, Ph.D., associate professor of neuroscience at the University of Minnesota. "Importantly, the animals’ timing varied after these neurons were more, or less, active. It’s as if the activity of these neurons was serving as an internal hourglass."
By developing a model to help explain the differences in timing signals they see relative to previous studies, their study also suggests that there is no “central clock” in the brain that is relied upon for all tasks involving timing. Instead, it appears as though each of the brain’s circuits responsible for different actions are capable of independently producing an accurate timing signal.
One important direction for future research is to explore how such precise timing signals arise as a consequence of practice and learning, and whether, when the signals are altered, there are clear effects on behavior.
In the largest prospective study to date of children with early and later manifestation of autism spectrum disorders (ASD) compared to children without ASD, researchers found two distinct patterns of language, social and motor development in the children with ASD. Published in the journal Child Development, the study found that early in development, children who display early signs of ASD show greater initial delay across multiple aspects of development compared to children whose ASD symptoms emerge later. However at 36 months of age, the early differences between these groups are no longer obvious. By the third birthday, the level of impairment between these symptom onset groups of children with ASD is comparable. Additionally, researchers uncovered a preclinical phase of ASD in which the signs of delay are not easily detected with existing clinical tests.
Previous research by Kennedy Krieger Institute researchers found that approximately half of all children with ASD can be diagnosed around the first birthday, while the remaining half do not show diagnostic indicators until later. The current study builds upon these findings by further evaluating motor and language development in a wider age span of children diagnosed with ASD (6 to 36 months), and examining how development unfolds differently in each group.
“Regardless of diagnosis, the development of children with and without ASD appears similar at six months of age on clinical tests,” says Dr. Rebecca Landa, lead author and director of Kennedy Krieger’s Center for Autism and Related Disorders. “However, for those children who went on to develop autism, the earliest signs of atypical development were non-specific to autism, such as general communication or motor delay.”
Why does shock therapy beat back depression? New experiments show how such a blunt treatment can have such positive effects.
Ian Reid, a psychiatrist at the Royal Cornhill Hospital in the Scottish city of Aberdeen, has treated people with severe depression for 25 years. “It’s a very nasty illness, depression,” he says. “I have worked with people who have cancer and depression, and more than one of them has said, ‘If I had to choose one of those two diseases, I’d go for the cancer.’ ”
When patients come to Royal Cornhill with major depression, they’re first treated with psychotherapy and antidepressants. Only about 40 percent respond to their first medication. Sometimes a different one will do the trick, but in Reid’s experience, about 10 to 20 percent of depressed people respond to no drug at all. In those cases, Reid regularly shifts to a third option. It’s officially called electroconvulsive therapy, or ECT—better known by its unofficial name, shock therapy.
Reid is an expert on ECT, and over the years he has received plenty of grief for it. “There are people on the Internet who describe me as a Nazi, as a barbarian,” he says. “And there’s one person who suggested I should get ECT so I know what I’m doing.”
Reid is not surprised by the reactions. For many people, the sum of their knowledge about ECT comes from the 1975 movie One Flew Over the Cuckoo’s Nest. Jack Nicholson plays Randle McMurphy, a criminal hoping to escape hard labor by spending his term in a mental institution. But McMurphy gets more than he bargained for, including a harrowing session of ECT. The hospital staff straps him down, puts a piece of rubber in his mouth so he won’t bite off his own tongue, and delivers a blast of electricity to his temples. He writhes in agony and then slumps back, his body limp.
That scene bears no resemblance to what Reid does for his patients. For one thing, he gives them anesthesia and muscle relaxants so they don’t experience any flailing. But most crucially, ECT works. “You can watch someone going from being unresponsive and soiling themselves to being completely transformed,” Reid says.
In Scotland, a country of 5 million, 400 people receive the treatment each year. And for about 75 percent of them, it brings relief. “ECT outperforms psychotherapeutic treatments and antidepressant drugs,” Reid notes. Yet its effectiveness is a mystery. “It doesn’t sound intuitive at all,” he admits. “Making someone have a seizure, giving them an electric shock, and making something as complex as depression better just seems crazy.”
There is a long history of research on impaired eye movements associated with schizophrenia. Using a series of simple viewing tests, researchers of a new paper in Biological Psychiatry explored the ability of these eye movement tests to distinguish people with and without the diagnosis of schizophrenia.
Using their complete dataset, they were able to develop a model that could discriminate all schizophrenia cases from healthy control subjects with an impressive 98.3% accuracy.
Drs. Philip Benson and David St. Clair, lead authors on the paper, agreed that their findings were remarkable: “It has been known for over a hundred years that individuals with psychotic illnesses have a variety of eye movement abnormalities, but until our study, using a novel battery of tests, no one thought the abnormalities were sensitive enough to be used as potential clinical diagnostic biomarkers.”
Their battery of tests included smooth pursuit, free-viewing, and gaze fixation tasks. In smooth pursuit, people with schizophrenia have well-documented deficits in the ability to track slow-moving objects smoothly with their eyes. Their eye movements tend to fall behind the moving object and then catch-up with the moving object using a rapid eye movement, called a saccade.. A picture is displayed in the free-viewing test, and where most individuals follow a typical pattern with their gaze as they scan the picture, those with schizophrenia follow an abnormal pattern. In a fixation task, the instruction is to keep a steady gaze on a single unmoving target, which tends to be difficult for individuals with schizophrenia.
As expected, the researchers found that the performance of individuals with schizophrenia was abnormal compared to the healthy volunteer group on each of the eye tests. At right is an example of the differences, with the eye tracking of a schizophrenia case in red and a healthy control in blue.
The researchers then used several methods to model the data. The accuracy of each of the created algorithms was then tested by using eye test data from another group of cases and controls. Combining all the data, one of the models achieved 98.3% accuracy.
"It is encouraging to see the high sensitivity of this model for the diagnosis of schizophrenia. It will be interesting to see the extent to which this approach enables clinical investigators to distinguish people with schizophrenia from individuals with other psychiatric disorders," commented Dr. John Krystal, Editor of Biological Psychiatry.
Benson and St Clair have already started that work, stating, “We now have exciting unpublished data showing that patterns of eye movement abnormalities are specific to different psychiatric subgroups, another key requirement for diagnostic biomarkers. The next thing we want to know is when the abnormalities are first detectable and can they be used as disease markers for early intervention studies in major mental illness?”
"We are also keen to explore how best our findings can be developed for use in routine clinical practice," they added. Typical neuropsychological assessments are time-consuming, expensive, and require highly trained individuals to administer. In comparison, these eye tests are simple, cheap, and take only minutes to conduct. This means that a predictive model with such precision could potentially be incorporated in clinics and hospitals to aid physicians by augmenting traditional symptom-based diagnostic criteria.
Scientists at Freie Universität, Universität Hohenheim, and Katholieke Universiteit Leuven Breed Fruit Flies for First Time without the Neurobeachin Protein and Facilitate Study of Nervous Diseases in Humans
In experiments on the brain of the fruit fly Drosophila, scientists at Freie Universität Berlin have advanced the research on brain function and diseases in humans. Neuroscientists in the Emmy Noether Junior Research Group “Biological Memory Systems” headed by Dr. Martin Schwärzel and based at Freie Universität succeeded in breeding fruit flies without the neurobeachin protein. Among other things, BEACH proteins affect the development and function of the brain in animals and humans. The results were published in the most recent issue of The Journal of Neuroscience. In the future such animal models could be of particular importance for the understanding of certain diseases in humans, such as autism. Scientists from the University of Hohenheim and the Belgian Katholieke Universiteit Leuven were also involved.
Up to now there were no animal models suitable for understanding the significance of neurobeachin proteins in the functioning of the nervous system, for example in memory formation. Mice that are lacking the neurobeachin protein die shortly after birth. Fruit flies, on the other hand, can be alive and well without neurobeachin. The scientists also found in experiments on the flies that neurobeachin has a function in learning as the flies exhibit characteristic learning disabilities due to the absence of the protein.
The flies were also found to have a number of other abnormalities with regard to the development and function of the nervous system. Through a “genetic rescue experiment,” the researchers were able to localize the distribution of these defects in the brain. The function of the lacking neurobeachin gene was reintroduced in certain areas of the nervous system. With this procedure, the researchers were able to show, among other things, that certain features of the neurobeachin protein in flies and mice are identical.
Amyotrophic lateral sclerosis, also called Lou Gehrig’s disease, is a devastatingly cruel neurodegenerative disorder that robs sufferers of the ability to move, speak and, finally, breathe. Now researchers at the Stanford University School of Medicine and San Francisco’s Gladstone Institutes have used baker’s yeast — a tiny, one-celled organism — to identify a chink in the armor of the currently incurable disease that may eventually lead to new therapies for human patients.
“Even though yeast and humans are separated by a billion years of evolution, we were able to use the power of yeast genetics to identify an unexpected potential drug target for ALS,” said Aaron Gitler, PhD, an associate professor of genetics at Stanford. “Many neurodegenerative disorders such as ALS, Parkinson’s and Alzheimer’s exhibit protein clumping or misfolding within the neurons that is thought to either cause or contribute to the conditions. We are trying to figure out why these proteins aggregate in neurons in the brain and spinal cord, and what happens when they do.”
In 2008, Gitler received a New Innovator award from the National Institutes of Health to use yeast as a model for understanding human neurodegenerative diseases and as a way to identify new targets for drug development.
Vulnerability to major depression is linked with how satisfied we are with our lives. This association is largely due to genes.
This is the main finding of a new twin study from the Norwegian Institute of Public Health in collaboration with the University of Oslo. The researchers compared longitudinal information from identical and fraternal twins to determine how vulnerability to major depression is associated with dispositional (overall) lifetime satisfaction.
Previous studies have systematically shown that life satisfaction is considerably stable over time. People who are satisfied at any one point in life are often also satisfied at other times in their lives. This stability—the dispositional life satisfaction—is often said to reflect an underlying positive mood or a positive disposition. Previous studies have also shown that people with such a positive disposition are less depressed, but very few studies have examined the mechanisms behind this relationship.
Results
• Both men and women who met the criteria for lifetime major depression (15.8% and 11.1% respectively) reported lower life satisfaction.
• 74% of the relationship between major depression and life satisfaction could be explained by genes.
• The remaining association (26%) could be explained by unique environmental factors.
• The researchers also calculated the heritability of dispositional life satisfaction and major depression separately. The heritability of dispositional life satisfaction, which has not previously been reported, was estimated to be 72%. In other words, it is largely genes that explain why we differ in our tendency to be satisfied and content with our lives.
• Major depression had a heritability of 34%, which is highly consistent with previous studies.
“The stable tendency to see the bright side of life is associated with lower risk of major depression because some genetic factors influence both conditions”, says researcher Ragnhild Bang Nes from the Division of Mental Health. Genes involved in satisfaction and positivity thus give protection against major depression. Nes is the main author of the study that was recently published in the Journal of Affective Disorders.
Susceptibility to both depression and overall life satisfaction is partly influenced by the same set of genes, but is also influenced by genes that are unique to each.
“The heritability figures mean that 72% of the individual differences in overall satisfaction, and 34% of the differences in depression, are caused by genes. These figures do not provide information on the importance of specific genes for an individual’s life satisfaction or risk of major depression. Traits and propensities like dispositional life satisfaction and vulnerability to major depression are not heritable in themselves. Heritability refers to the importance of genes for explaining the differences between people and the estimates may vary across time and place”, explains Nes.
Although the heritability of major depression was lower than that of life satisfaction, this does not necessarily mean that life satisfaction is far more heritable than depression. The researchers used questionnaire data from two time points to measure dispositional life satisfaction, and a single clinical interview to measure the prevalence of lifetime major depression. The use of only a single assessment to measure depression may partly explain why the heritability of depression is so much lower than life satisfaction.
Can we prevent depression by promoting life satisfaction?
“We found that depression and life satisfaction did not share as many environmental factors as genetic factors. This means that environmental factors of importance to life satisfaction (for example, activities and interventions that make you happy and content) only to a small extent protect against depression”, says Nes.
“Although our underlying disposition to life satisfaction and positivity appears to be relatively stable, small actions in our daily lives may provide temporary pleasures, and these are also important. How we spend our time is tremendously important for our happiness and well-being. It is therefore important to encourage and follow up on activities that make us happy”.
Nes adds:
“To some extent, positive experiences may also accumulate over time and create favorable conditions for our quality of life”.
I suddenly noticed I could move my pinkie. I was cruising towards the highway when this old guy tried to cross the 4-lane road really fast. He hit me and I ejected over to the opposite lane. Luckily someone found me before the traffic got to me.
Paralysis may no longer mean life in a wheelchair. A man who is paralysed from the trunk down has recovered the ability to stand and move his legs unaided thanks to training with an electrical implant.
Andrew Meas of Louisville, Kentucky, says it has changed his life. The stimulus provided by the implant is thought to have either strengthened persistent “silent” connections across his damaged spinal cord or even created new ones, allowing him to move even when the implant is switched off.
The results are potentially revolutionary, as they indicate that the spinal cord is able to recover its function years after becoming damaged.
Previous studies in animals with lower limb paralysis have shown that continuous electrical stimulation of the spinal cord below the area of damage allows an animal to stand and perform locomotion-like movements. That’s because the stimulation allows information about proprioception – the perception of body position and muscle effort – to be received from the lower limbs by the spinal cord. The spinal cord, in turn, allows lower limb muscles to react and support the body without any information being received from the brain (Journal of Neuroscience, doi.org/czq67d).
Last year, Susan Harkema and Claudia Angeli at the Frazier Rehab Institute and University of Louisville in Kentucky and colleagues tested what had been learned on animals in a man who was paralysed after being hit by a car in 2006. He was diagnosed with a “motor complete” spinal lesion in his neck, which means that no motor activity can be recorded below the lesion.
Wouldn’t it be amazing if our bodies prepared us for future events that could be very important to us, even if there’s no clue about what those events will be?
Presentiment without any external clues may, in fact, exist, according to new Northwestern University research that analyzes the results of 26 studies published between 1978 and 2010.
Researchers already know that our subconscious minds sometimes know more than our conscious minds. Physiological measures of subconscious arousal, for instance, tend to show up before conscious awareness that a deck of cards is stacked against us.
"What hasn’t been clear is whether humans have the ability to predict future important events even without any clues as to what might happen," said Julia Mossbridge, lead author of the study and research associate in the Visual Perception, Cognition and Neuroscience Laboratory at Northwestern.
A person playing a video game at work while wearing headphones, for example, can’t hear when his or her boss is coming around the corner.
"But our analysis suggests that if you were tuned into your body, you might be able to detect these anticipatory changes between two and 10 seconds beforehand and close your video game," Mossbridge said. "You might even have a chance to open that spreadsheet you were supposed to be working on. And if you were lucky, you could do all this before your boss entered the room."
This phenomenon is sometimes called “presentiment,” as in “sensing the future,” but Mossbridge said she and other researchers are not sure whether people are really sensing the future.
"I like to call the phenomenon ‘anomalous anticipatory activity,’" she said. "The phenomenon is anomalous, some scientists argue, because we can’t explain it using present-day understanding about how biology works; though explanations related to recent quantum biological findings could potentially make sense. It’s anticipatory because it seems to predict future physiological changes in response to an important event without any known clues, and it’s an activity because it consists of changes in the cardiopulmonary, skin and nervous systems."
The Early Start Denver Model (ESDM), a comprehensive behavioral early intervention program that is appropriate for children with autism spectrum disorder (ASD) as young as 12 months, has been found to be effective in improving social skills and brain responses to social cues in a randomized controlled study published online today in the Journal of the American Academy of Child & Adolescent Psychiatry.
“So much of a toddler’s learning involves social interaction, and early intervention that promotes attention to people and social cues may pay dividends in promoting the normal development of the brain and behavior,” said Geraldine Dawson, Ph.D., Autism Speaks chief science officer and the study’s lead author. This is the first controlled study of an intensive early intervention that demonstrates both improvement of social skills and brain responses to social stimuli resulting from intensive early intervention. Given that the American Academy of Pediatrics recommends that all 18- and 24-month-old children be screened for autism, “it is vital that we have effective therapies available for young children as soon as they are diagnosed,” continued Dr. Dawson.
“This may be the first demonstration that a behavioral intervention for autism is associated with changes in brain function as well as positive changes in behavior,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health. “By studying changes in the neural response to faces, Dawson and her colleagues have identified a new target and a potential biomarker that can guide treatment development.”
ESDM, which combines applied behavioral analysis (ABA) teaching methods with developmental ‘relationship-based’ approaches, was previously demonstrated to achieve significant gains in cognitive, language and daily living skills compared to children with ASD who received commonly available community interventions. On average, the preschoolers receiving ESDM for two years improved 17.5 standard score points compared to 7.0 points in the community intervention comparison group.
Introducing a light-sensitive protein in transgenic nerve cells… transplanting nerve cells into the brains of laboratory animals… inserting an optic fibre in the brain and using it to light up the nerve cells and stimulate them into releasing more dopamine to combat Parkinson’s disease… These events may sound like science fiction but they are soon to become a reality in a research laboratory at Lund University in Sweden.
For the time being, this is basic research but the long term objective is to find new ways of treating Parkinson’s disease. This increasingly common disease is caused by degeneration of the brain cells producing signal substance dopamine.
Many experiments have been conducted on both animals and humans, transplanting healthy nerve cells to make up for the lack of dopamine, but it is difficult to study what happens to the transplant.
“We don’t know how the new nerve cells behave once they have been transplanted into the brain. Do they connect to the surrounding cells as they should, and can they function normally and produce dopamine as they should? Can we use light to reinforce dopamine production? These are the issues we want to investigate with optogenetics”, says Professor Merab Kokaia.
Optogenetics allows scientists to control certain cells in the brain using light, leaving other cells unaffected. In order to do this, the relevant cells are equipped with genes for a special light-sensitive protein. The protein makes the cells react when they are illuminated with light from a thin optic fibre which is also implanted in the brain. The cells can then be “switched on” when they are illuminated.
“If we get signals as a response to light from the host brain, we know that they come from the transplanted cells since they are the only ones to carry the light-sensitive protein. This gives us a much more specific way of studying the brain’s reactions than inserting an electrode, which is the current method. With an electrode, we do not know whether the electric signals that are detected come from “new” or “old” brain cells”, explains Merab Kokaia.
The work will be conducted on laboratory rats modelling Parkinson’s disease. The transplanted cells will be derived from skin from an adult human and will have been “reprogrammed” as nerve cells. Merab Kokaia will be collaborating with neuro-researchers Malin Parmar and Olle Lindvall on the project.
The three Lund researchers have received a grant of USD 75 000 from the Michael J. Fox Foundation, started by actor Michael J. Fox and dedicated to Parkinson’s research.
The light-sensitive protein is obtained from a bacterium, which uses light to gain energy. Since it is not a human protein, the safety checks will be extra strict if the method is to be used on humans.
”We know that this is long term research. But the methodology is interesting and it will be exciting to see what we can come up with,” says Merab Kokaia.
New research presented in October at the 6th Neurodegenerative Conditions Research and Development Conference in San Francisco demonstrates the role of the investigational compound IRX4204 in alleviating cognitive decline in animal models of Alzheimer’s disease (AD). The presentation entitled “Investigation of the RXR-specific agonist IRX4204 as a Disease Modifying Agent of Alzheimer’s Disease Neuropathology and Cognitive Impairment” was made by lead researcher Giulio Maria Pasinetti, MD, PhD, of the Mount Sinai School of Medicine in New York City.
IRX4204 is a retinoid X receptor (RXR) agonist, meaning it stimulates the retinoid receptor in the brain.The data demonstrates attenuation of AD including prevention of plaque deposits associated with cognitive deterioration in an IRX4204-treated mouse model genetically determined to develop AD. IRX4204 also prevents neuropathological features associated with abnormal tau processing, another form of abnormal protein also found in a form of Parkinson’s disease associated with dementia.
"The treatment of AD remains a serious unmet medical need which IRX4204 may be able to address," Dr. Pasinetti said "Our research show that IRX4204 and other RXR agonists have potential for slowing, and possibly reversing pathology and cognitive deficits in Alzheimer’s disease patients."
Ongoing translational studies in subjects with Alzheimer’s disease and Parkinson’s disease with dementia are currently being developed.
Alzheimer’s disease currently afflicts more than 5 million Americans and may triple in prevalence to more than 16 million Americans by 2050, according to data from The Alzheimer’s Association.