Posts tagged science
Articles and news from the latest research reports.
The anatomy of fear: Understanding the biological underpinnings of anxiety, phobias and PTSD
Fear in a mouse brain looks much the same as fear in a human brain.
When a frightening stimulus is encountered, the thalamus shoots a message to the amygdala — the primitive part of the brain — even before it informs the parts responsible for higher cognition. The amygdala then goes into its hard-wired fight-or-flight response, triggering a host of predictable symptoms, including racing heart, heavy breathing, startle response, and sweating.
The similarities of fear response in the brains of mice and men have allowed scientists to understand the neural circuitry and molecular processes of fear and fear behaviors perhaps better than any other response. That understanding has spurred breakthroughs in treatments for psychiatric disorders that are underpinned by fear.
Anxiety disorders are one of the most common mental illnesses in the country, with nearly one-third of Americans experiencing symptoms at least once during their lives. There are generalized anxiety disorders and fear-related disorders, which include panic disorders, phobias, and post-traumatic stress disorder (PTSD).
Emory psychiatrist and researcher Kerry Ressler is on the front lines of fear-disorder research. In his lab at Yerkes National Primate Research Center, he studies the molecular and cellular mechanisms of fear learning and extinction in mouse models. At Grady Memorial Hospital, he investigates the psychology, genetics, and biology of PTSD. And through the Grady Trauma Project, he works to draw attention to the problem of inner city intergenerational violence.
"If you look at Kerry’s work, it can seem like it’s all over the place — he’s got so many studies going on, and he collaborates with so many other scientists," says Barbara Rothbaum, associate vice chair of clinical research in psychiatry and director of the Trauma and Anxiety Recovery Program at Emory. "But they are all pieces to the same puzzle. All his work, from molecular to clinical to policy, fits together and starts telling a story." A Howard Hughes Medical Institute investigator, Ressler was recently elected to the Institute of Medicine — one of the highest honors in the fields of health and medicine. He was named a member of a new national PTSD consortium led by Draper Laboratory. And he recently appeared on the Charlie Rose show’s brain series.
Panic attacks seem to tie the fear-related disorders together, he explained on Charlie Rose. Everyone experiences fear, which evolved as a survival mechanism, but it only rises to a clinical level when people are unable to function normally in the face of it. For instance, PTSD includes not only intrusive thoughts, memories, nightmares, and startle responses, but also the concept of avoidance, which may extend to other areas of the individual’s life.
"There’s a patient I’ve seen who was attacked in a dark alley," Ressler shared on the show. "Initially it just felt dangerous to go out at night, but after a while she grew afraid of men and couldn’t go to that part of town. Then she couldn’t leave her house, and finally, her bedroom. The world got more and more dangerous."
Alzheimer’s disease drug-development pipeline: few candidates, frequent failures
Introduction
Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.
Methods
We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.
Results
During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).
Conclusions
The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.
(Image: Shutterstock)
What’s Lost as Handwriting Fades
Does handwriting matter?
Not very much, according to many educators. The Common Core standards, which have been adopted in most states, call for teaching legible writing, but only in kindergarten and first grade. After that, the emphasis quickly shifts to proficiency on the keyboard.
But psychologists and neuroscientists say it is far too soon to declare handwriting a relic of the past. New evidence suggests that the links between handwriting and broader educational development run deep.
Children not only learn to read more quickly when they first learn to write by hand, but they also remain better able to generate ideas and retain information. In other words, it’s not just what we write that matters — but how.
Enlarging the scope: grasping brain complexity
To further advance our understanding of the brain, new concepts and theories are needed. In particular, the ability of the brain to create information flows must be reconciled with its propensity for synchronization and mass action. The theoretical and empirical framework of Coordination Dynamics, a key aspect of which is metastability, are presented as a starting point to study the interplay of integrative and segregative tendencies that are expressed in space and time during the normal course of brain and behavioral function. Some recent shifts in perspective are emphasized, that may ultimately lead to a better understanding of brain complexity.
Hypnosis: The day my mind was ‘possessed’
I am lying on my back and trapped in a gleaming white tunnel, the surface barely six inches from my nose. There is a strange mechanical rumbling in the background, and I hear footsteps padding around the room beyond. In my mounting claustrophobia, I ask myself why I am here – but there is no way out now. A few moments later, the light dims, and as the man speaks, my thoughts begin to fade.
“The engineer has developed a way of taking control of your thoughts from the inside. He does this because he is fascinated by mind control, and wants to apply the most direct method of controlling your thoughts. He is doing this to advance his research into mind control. You will soon be aware of the engineer inserting his thoughts.”
A strange serenity descends as I realise that soon, my will won’t be my own. Then the experiment begins. I am about to be possessed.
Watching TV and Food Intake: The Role of Content
Obesity is a serious and growing health concern worldwide. Watching television (TV) represents a condition during which many habitually eat, irrespective of hunger level. However, as of yet, little is known about how the content of television programs being watched differentially impacts concurrent eating behavior. In this study, eighteen normal-weight female students participated in three counter-balanced experimental conditions, including a ‘Boring’ TV condition (art lecture), an ‘Engaging’ TV condition (Swedish TV comedy series), and a no TV control condition during which participants read (a text on insects living in Sweden). Throughout each condition participants had access to both high-calorie (M&Ms) and low-calorie (grapes) snacks. We found that, relative to the Engaging TV condition, Boring TV encouraged excessive eating (+52% g, P = 0.009). Additionally, the Engaging TV condition actually resulted in significantly less concurrent intake relative to the control ‘Text’ condition (−35% g, P = 0.05). This intake was driven almost entirely by the healthy snack, grapes; however, this interaction did not reach significance (P = 0.07). Finally, there was a significant correlation between how bored participants were across all conditions, and their concurrent food intake (beta = 0.317, P = 0.02). Intake as measured by kcals was similarly patterned but did not reach significance. These results suggest that, for women, different TV programs elicit different levels of concurrent food intake, and that the degree to which a program is engaging (or alternately, boring) is related to that intake. Additionally, they suggest that emotional content (e.g. boring vs. engaging) may be more associated than modality (e.g. TV vs. text) with concurrent intake.
(Image: ThinkStock)
Neuroscientists study our love for deep bass sounds
Have you ever wondered why bass-range instruments tend to lay down musical rhythms, while instruments with a higher pitch often handle the melody?
According to new research from Laurel Trainor and colleagues at the McMaster Institute for Music and The Mind, this is no accident, but rather a result of the physiology of hearing.
In other words, when the bass is loud and rock solid, we have an easier time following along to the rhythm of a song.
Could boosting brain cells’ appetites fight disease? New research shows promise
Deep inside the brains of people with dementia and Lou Gehrig’s disease, globs of abnormal protein gum up the inner workings of brain cells – dooming them to an early death.
But boosting those cells’ natural ability to clean up those clogs might hold the key to better treatment for such conditions.
That’s the key finding of new research from a University of Michigan Medical School physician scientist and his colleagues in California and the United Kingdom. They reported their latest findings this week in the journal Nature Chemical Biology.
Though the team showed the effect worked in animals and human neurons from stem cells, not patients, their discoveries point the way to find new medicines that boost the protein-clearing cleanup process.
The work also shows how an innovative microscope technique can help researchers see what’s going on inside brain cells, as they labor to clear out the protein buildup.
The researchers focused on a crucial cell-cleaning process called autophagy – a hot topic in basic medical research these days, as scientists discover its important role in many conditions. In autophagy, cells bundle unwanted materials up, break them down and push the waste products out.
In the newly published research, the team showed how the self-cleaning capacity of some brain cells gets overwhelmed if the cells make too much of an abnormal protein called TDP43. They found that cells vary greatly in how quickly their autophagy capacity gets swamped.
In brain cells that were made from stem cells derived from ALS patients, treatment with two drugs that stimulate autophagy led to longer cell survival (middle two lines).
But they also showed how three drugs that boost autophagy – speeding up the clean-out process – could keep the brain cells alive longer.
Longer-living, TDP43-clearing brain cells are theoretically what people with Lou Gehrig’s disease (amyotrophic lateral sclerosis or ALS) and certain forms of dementia (called frontotemporal) need. But only further research will show for sure.
Sami Barmada, M.D., Ph.D., the U-M neurologist and scientist who is first author of the new study, says the new findings are encouraging – and so is the success of a microscope technique used in the research. His new lab, in the U-M Department of Neurology, is continuing to refine ways to view the inner workings of nerve cells.
“Using this new visualization technique, we could truly see how the protein was being cleared, and therefore which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells,” he says. “This allowed us to see that increased autophagy was directly related to improved cell survival.”
Barmada worked on the team at the Gladstone Institutes and the University of California San Francisco headed by Steven Finkbeiner, M.D., Ph.D., that published the new findings. The team used stem cells derived from the cells of people who have ALS to grow neurons and astrocytes – the two types of brain cell most crucial to normal brain function.
Because he both sees patients in clinic and studies neurological disease in the laboratory, Barmada brings a special perspective to the research.
At U-M, he specializes in treating patients who have neurological diseases that affect both thinking and muscle control. About a third of ALS patients develop signs of frontotemporal dementia, also called FTD – and about 10 percent of people with FTD also have a motor neuron disease that affects their brain’s ability to control muscle movement.
One of the drugs tested in the study, an antipsychotic drug developed in the 1960s to treat people with schizophrenia, had actually shown some anti-dementia promise in human ALS patients, but comes with many side effects. Barmada notes that Finkbeiner’s team at the Gladstone Institute is already working to identify other compounds that could produce the effect with fewer side effects.
Interestingly, small studies have suggested that people with schizophrenia who take antipsychotic drugs are much less likely to develop ALS.
Barmada’s work at U-M now focuses on the connection between brain cells’ ability to clear abnormal proteins. He also studies the cells’ regulation of RNA molecules created as part of expressing protein-encoding genes. Looking further upstream in the protein-producing process could yield further clues to why disease develops and what can be done about it, he says.
(Source: uofmhealth.org)
Glitch in garbage removal enhances risk
An international team of researchers identified a pathogenic mechanism that is common to several neurodegenerative diseases. The findings suggest that it may be possible to slow the progression of dementia even after the onset of symptoms.
The relentless increase in the incidence of dementia in aging societies poses an enormous challenge to health-care systems. An international team of researchers led by Professor Christian Haass and Gernot Kleinberger at the LMU‘s Adolf-Butenandt-Institute and the German Center for Neurodegenerative Diseases (DZNE), has now elucidated the mode of action of a genetic defect that contributes to the development of several different dementia syndromes.
Neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases or frontotemporal dementia display a number of common features. They are all characterized by the appearance in the brains of affected patients of abnormally high levels of insoluble protein deposits, which are associated with massive loss of nerve cells. In order to minimize further damage to nerve cells in the vicinity of such deposits, dead cells and the proteinaceous aggregates released from them must be efficiently degraded and disposed of. This task is performed by specialized phagocytic cells – the so-called microglia – which act as “sanitary inspectors” in the brain to ensure the prompt removal of debris that presents a danger to the health of nearby cells. Microglia are found only in the central nervous system, but functionally they represent a division of the body’s innate immune system.
As Haass and his colleagues now report in the latest issue of the journal Science Translational Medicine, specific mutations in the gene for a protein called TREM2, which regulates the uptake of waste products by microglia, lead to its absence from the cell surface. TREM2 is normally inserted into the plasma membrane of microglial cells such that part of it extends through the membrane as an extracellular domain. This exposed portion of TREM2 is responsible for the recognition of waste products left behind by dead cells. “We believe that the genetic defect disrupts the folding of the protein chain soon during its synthesis in the cell, so that it is degraded before it can reach the surface of the microglia,” says Kleinberger. As a result, the amount of debris that the microglia can cope with is significantly reduced. Consequently, the toxic protein deposits, as well as whole dead cells, cannot be efficiently removed and continue to accumulate in the brain. This is expected to trigger inflammatory reactions that may promote further nerve-cell loss.
The new study thus pinpoints a mechanism that influences the course of several different brain diseases. “In addition, our findings may perhaps point to ways of slowing the rate of progression of these illnesses even after the manifestation of overt signs of dementia, which has not been possible so far,” says Haass. “That this may indeed be feasible is suggested by the initial results of an experiment in which we were able to stimulate the phagocytic activity of microglia by pharmacological means.”
(Source: en.uni-muenchen.de)
Do not disturb! How the brain filters out distractions
You know the feeling? You are trying to dial a phone number from memory… you have to concentrate…. then someone starts shouting out other numbers nearby. In a situation like that, your brain must ignore the distraction as best it can so as not to lose vital information from its working memory. A new paper published in Neuron by a team of neurobiologists led by Professor Andreas Nieder at the University of Tübingen gives insight into just how the brain manages this problem.
The researchers put rhesus monkey in a similar situation. The monkeys had to remember the number of dots in an image and reproduce the knowledge a moment later. While they were taking in the information, a distraction was introduced, showing a different number of dots. And even though the monkeys were mostly able to ignore the distraction, their concentration was disturbed and their memory performance suffered.
Measurements of the electrical activity of nerve cells in two key areas of the brain showed a surprising result: nerve cells in the prefrontal cortex signaled the distraction while it was being presented, but immediately restored the remembered information (the number of dots) once the distraction was switched off. In contrast, nerve cells in the parietal cortex were unimpressed by the distraction and reliably transmitted the information about the correct number of dots.
These findings provide important clues about the strategies and division of labor among different parts of the brain when it comes to using the working memory. “Different parts of the brain appear to use different strategies to filter out distractions,” says Dr. Simon Jacob, who carried out research in Tübingen before switching to the Psychiatric Clinic at the Charité hospitals in Berlin. “Nerve cells in the parietal cortex simply suppress the distraction, while nerve cells in the prefrontal cortex allow themselves to be momentarily distracted – only to return immediately to the truly important memory content.”
The researchers were surprised by the two brain areas’ difference in sensitivity to distraction. “We had assumed that the prefrontal cortex is able to filter out all kinds of distractions, while the parietal cortex was considered more vulnerable to disturbances,” says Professor Nieder. “We will have to rethink that. The memory-storage tasks and the strategies of each brain area are distributed differently from what we expected.”