Posts tagged science
Articles and news from the latest research reports.
Altered Activity in the Central Medial Thalamus Precedes Changes in the Neocortex during Transitions into Both Sleep and Propofol Anesthesia
How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing “top-down” inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20–40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1–4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.
Researchers Find Promise in New Treatments for GBM
Glioblastoma multiforme (GBM) is one of the most lethal primary brain tumors, with median survival for these patients only slightly over one year. Researchers at Boston University School of Medicine (BUSM), in collaboration with researchers from the City of Hope, are looking toward novel therapeutic strategies for the treatment of GBM in the form of targeted therapies against a unique receptor, the interleukin-13 receptor α chain variant 2 (IL13Rα2).
In a review paper published in the October issue of Neuro-Oncology, the researchers discuss various targeted therapies against IL13Rα2 and early successes of clinical trials with these therapies in the treatment of GBM. The paper also highlights the need for future trials to improve efficacy and toxicity profiles of targeted therapies in this field.
Targeted therapies, which are drugs that interfere with specific molecules involved in cancer growth, have been successfully used in the treatment of many cancers, including breast and blood cancers. Successful targets for therapies are specific to tumor cells and not found on normal cells. Selectively expressed on GBM and absent on surrounding brain tissue, the interleukin-13 receptor α chain variant 2 (IL13Rα2) was identified as a potential target for therapy for GBM two decades ago. IL13Rα2 also plays an important role in the growth of tumors. In normal physiologic conditions, IL-13 binds to the receptor IL13Rα1 and helps regulate immune responses. In cancer cells, IL-13 binds to the receptor IL13Rα2 and, through a series of steps, prevents cancer cells from undergoing normal cell death. Increased expression of IL13Rα2 promotes the progression of GBM.
Since its discovery, IL13Rα2 has provided a target for therapies in GBM. These therapies have ranged from fusion proteins of IL-13 and bacterial toxins, oncolytic viruses, and immunotherapies. A phase I clinical trial and a phase III clinical trial have been completed for a T-cell based immunotherapy and IL-13/ bacterial toxin fusion protein respectively, both with promising outcomes.
“The field of targeted therapies in gliomas holds a lot of promise, and IL13Rα2 is in an optimal position to materialize these promises,” explained corresponding author Sadhak Sengupta, PhD, assistant professor of neurosurgery at BUSM and principal investigator of the Brain Tumor Lab at Roger Williams. “While early trials are encouraging, we need further research to achieve better targeting of the receptor and improved safety profiles of the treatments.”
Scientists aim to give botox a safer facelift
New insights into botulinum neurotoxins and their interactions with cells are moving scientists ever closer to safer forms of Botox and a better understanding of the dangerous disease known as botulism. By comparing all known structures of botulinum neurotoxins, researchers writing in the Cell Press journal Trends in Biochemical Sciences on October 1st suggest new ways to improve the safety and efficacy of Botox injections.
"If we know from high-resolution structures how botulinum neurotoxins interact with their receptors, we can design inhibitors or specific antibodies directed at the binding interface to prevent the interaction," said Richard Kammerer of the Paul Scherrer Insititute in Switzerland. "Furthermore, it may be possible to engineer safer toxins for medical and cosmetic applications."
In addition to its popular cosmetic use, the neurotoxin is used for the treatment of muscle conditions related to cerebral palsy, multiple sclerosis, stroke, Parkinson’s disease, and more.
The bacterium known as Clostridium botulinum, classically found as a contaminant in home-canned food, produces the neurotoxins, which pass the intestine and enter the bloodstream when ingested, Kammerer explained. When the neurotoxins reach neurons, they bind to receptors at the cell surface. Through a series of events, a portion of the toxin is released inside the cell. Once inside, that light-chain portion acts as a protease to specifically cleave a protein important for the release of acetylcholine, a neurotransmitter important for signaling from nerve to muscle. The result is paralysis, which can be fatal if the muscles required for breathing are affected.
Kammerer and his colleagues offer a comprehensive review of high-resolution structures of botulinum neurotoxins and their complexes with cell-surface receptors, many of which have become available only recently. While many questions remain, the new picture of BoNT/A and its interactions offers considerable hope for less-risky clinical use of Botox in the future.
"The wide range of BoNT/A dosage used in medical or cosmetic applications bears the substantial risk of accidental BoNT/A overdosage," the researchers write. "The BoNT/A-SV2C complex crystal structure provides a strong platform for the rational design of BoNT/A variants with attenuated SV2C binding properties. Such variants are promising candidate proteins for safer applications of the toxin."
(Source: eurekalert.org)
Medical discovery first step on path to new painkillers
A major medical discovery by scientists at The University of Nottingham could lead to the development of an entirely new type of painkiller.
A drug resulting from the research, published in the journal Neurobiology of Disease, would offer new hope to sufferers of chronic pain conditions such as traumatic nerve injury, for which few effective painkillers are currently available.
The work, led by Dr Lucy Donaldson in the University’s School of Life Sciences, in collaboration with David Bates, Professor of Oncology in the University’sCancer Biology Unit, focuses on a signal protein called vascular endothelial growth factor (VEGF).
VEGF controls the re-growth of blood vessels in tissues which have been damaged by injury. It is a widely targeted compound for cancer, eye disease and other illnesses in which abnormal blood vessel growth occurs.
Drugs are used to inhibit the VEGF in cancer, which can otherwise lead to the formation of new blood vessels that provide oxygen and nutrients to tumours.
Professor Bates and colleagues had previously discovered in 2002 that VEGF comes in two forms and acts like a switch — one which turns on the growth of blood vessels and another that blocks growth.
Pain prevention
However, this latest research has shown for the first time that these two forms of VEGF not only act on blood vessels but also differently affect the sensory nerves that control pain.
The academics discovered that the VEGF that promotes blood vessel growth causes pain, while the other, which inhibits blood vessel growth, prevents pain.
The study has centred on understanding how these two types of VEGF work and why the body makes one form rather than the other.
The academics have been able to switch from the pain stimulating form to the pain inhibiting VEGF in animal models in the laboratory and are now investigating compounds to replicate this in humans. It is thought these compounds could form the basis for new drugs to be tested in humans in clinical trials.
Decreased ability to identify odors can predict death
For older adults, being unable to identify scents is a strong predictor of death within five years, according to a study published October 1, 2014, in the journal PLOS ONE. Thirty-nine percent of study subjects who failed a simple smelling test died during that period, compared to 19 percent of those with moderate smell loss and just 10 percent of those with a healthy sense of smell.
The hazards of smell loss were “strikingly robust,” the researchers note, above and beyond most chronic diseases. Olfactory dysfunction was better at predicting mortality than a diagnosis of heart failure, cancer or lung disease. Only severe liver damage was a more powerful predictor of death. For those already at high risk, lacking a sense of smell more than doubled the probability of death.
"We think loss of the sense of smell is like the canary in the coal mine," said the study’s lead author Jayant M. Pinto, MD, an associate professor of surgery at the University of Chicago who specializes in the genetics and treatment of olfactory and sinus disease. "It doesn’t directly cause death, but it’s a harbinger, an early warning that something has gone badly wrong, that damage has been done. Our findings could provide a useful clinical test, a quick and inexpensive way to identify patients most at risk."
The study was part of the National Social Life, Health and Aging Project (NSHAP), the first in-home study of social relationships and health in a large, nationally representative sample of men and women ages 57 to 85.
In the first wave of NSHAP, conducted in 2005-06, professional survey teams from the independent research organization NORC at the University of Chicago used a well-validated test — adapted by Martha K. McClintock, PhD, the study’s senior author — for this field survey of 3,005 participants. It measured their ability to identify five distinct common odors.
The modified smell tests used “Sniffin’Sticks,” odor-dispensing devices that resemble a felt-tip pen but are loaded with aromas rather than ink. Subjects were asked to identify each smell, one at a time, from a set of four choices. The five odors, in order of increasing difficulty, were peppermint, fish, orange, rose and leather.
Measuring smell with this test, they learned that:
- Almost 78 percent of those tested were classified as “normosmic,” having normal smelling; 45.5 percent correctly identified five out of five odors and 29 percent identified four out of five.
- Almost 20 percent were considered “hyposmic.” They got two or three out of five correct.
- The remaining 3.5 percent were labelled “anosmic.” They could identify just one of the five scents (2.4%), or none (1.1%).
The interviewers also assessed participants’ age, physical and mental health, social and financial resources, education, and alcohol or substance abuse through structured interviews, testing and questionnaires. As expected, performance on the scent test declined steadily with age; 64 percent of 57-year-olds correctly identified all five smells. That fell to 25 percent of 85-year-olds.
In the second wave, during 2010-11, the survey team carefully confirmed which participants were still alive. During that five-year gap, 430 (12.5%) of the original 3005 study subjects had died; 2,565 were still alive.
When the researchers adjusted for demographic variables such as age, gender, socioeconomic status (as measured by education or assets), overall health, and race, those with greater smell loss when first tested were substantially more likely to have died five years later. Even mild smell loss was associated with greater risk.
"This evolutionarily ancient special sense may signal a key mechanism that affects human longevity," noted McClintock, the David Lee Shillinglaw Distinguished Service Professor of Psychology, who has studied olfactory and pheromonal communication throughout her career.
Age-related smell loss can have a substantial impact on lifestyle and wellbeing, according to Pinto, a member of the university’s otolaryngology-head and neck surgery team. “Smells impact how foods taste. Many people with smell deficits lose the joy of eating. They make poor food choices, get less nutrition. They can’t tell when foods have spoiled or detect odors that signal danger, like a gas leak or smoke. They may not notice lapses in personal hygiene.”
"Of all human senses," Pinto said, "smell is the most undervalued and underappreciated — until it’s gone."
Precisely how smell loss contributes to mortality is unclear. “Obviously, people don’t die just because their olfactory system is damaged,” McClintock said.
The research team, which includes biopsychologists, physicians, sociologists and statisticians, is considering several hypotheses. The olfactory nerve, the only cranial nerve directly exposed to the environment, may serve as a conduit, they suggest, exposing the central nervous system to pollution, airborne toxins, pathogens or particulate matter.
McClintock noted that the olfactory system also has stem cells which self-regenerate, so “a decrease in the ability to smell may signal a decrease in the body’s ability to rebuild key components that are declining with age and lead to all-cause mortality.”
(Source: uchospitals.edu)
Lift weights, improve your memory
The Georgia Tech research isn’t the first to find that exercise can improve memory. But the study, which was just published in the journal Acta Psychologica, took a few new approaches. While many existing studies have demonstrated that months of aerobic exercises such as running can improve memory, the current study had participants lift weights just once two days before testing them. The Georgia Tech researchers also had participants study events just before the exercise rather than after workout. They did this because of extensive animal research suggesting that the period after learning (or consolidation) is when the arousal or stress caused by exercise is most likely to benefit memory.
The study began with everyone looking at a series of 90 photos on a computer screen. The images were evenly split between positive (i.e. kids on a waterslide), negative (mutilated bodies) and neutral (clocks) pictures. Participants weren’t asked to try and remember the photos. Everyone then sat at a leg extension resistance exercise machine. Half of them extended and contracted each leg at their personal maximum effort 50 times. The control group simply sat in the chair and allowed the machine and the experimenter to move their legs. Throughout the process, each participant’s blood pressure and heart rate were monitored. Every person also contributed saliva samples so the team could detect levels of neurotransmitter markers linked to stress.
The participants returned to the lab 48 hours later and saw a series of 180 pictures – the 90 originals were mixed in with 90 new photos. The control group recalled about 50 percent of the photos from the first session. Those who exercised remembered about 60 percent.
“Our study indicates that people don’t have to dedicate large amounts of time to give their brain a boost,” said Lisa Weinberg, the Georgia Tech graduate student who led the project.
Although the study used weight exercises, Weinberg notes that resistance activities such as squats or knee bends would likely produce the same results. In other words, exercises that don’t require the person to be in good enough to shape to bike, run or participate in prolonged aerobic exercises.
While all participants remembered the positive and negative images better than the neutral images, this pattern was greatest in the exercise participants, who showed the highest physiological responses. The team expected that result, as existing research on memory indicates that people are more likely to remember emotional experiences especially after acute (short-term) stress.
But why does it work? Existing, non-Georgia Tech human research has linked memory enhancements to acute stress responses, usually from psychological stressors such as public speaking. Other studies have also tied specific hormonal and norepinephrine releases in rodent brains to better memory. Interestingly, the current study found that exercise participants had increased saliva measures of alpha amylase, a marker of central norepinephrine.
“Even without doing expensive fMRI scans, our results give us an idea of what areas of the brain might be supporting these exercise-induced memory benefits,” said Audrey Duarte, an associate professor in the School of Psychology. “The findings are encouraging because they are consistent with rodent literature that pinpoints exactly the parts of the brain that play a role in stress-induced memory benefits caused by exercise.”
The collaborative team of psychology and applied physiology faculty and students plans to expand the study in the future, now that the researchers know resistance exercise can enhance episodic memory in healthy young adults.
“We can now try to determine its applicability to other types of memories and the optimal type and amount of resistance exercise in various populations,” said Minoru Shinohara, an associate professor in the School of Applied Physiology. “This includes older adults and individuals with memory impairment.”
Judgment and decision-making: brain activity indicates there is more than meets the eye
Published today in PLOS ONE, the study is the first in the world to show that it is possible to predict abstract judgments from brain waves, even though people were not conscious of making such judgments. The study also increases our understanding of impulsive behaviours and how to regulate it.
It found that researchers could predict from participants’ brain activity how exciting they found a particular image to be, and whether a particular image made them think more about the future or the present. This is true even though the brain activity was recorded before participants knew they were going to be asked to make these judgments.
Lead authors Dr Stefan Bode from the Melbourne School of Psychological Sciences and Dr Carsten Murawski from the University of Melbourne Department of Finance said these findings illustrated there was more information encoded in brain activity than previously assumed.
“We have found that brain activity when looking at images can encode judgments such as time reference, even when the viewer is not aware of making such judgments. Moreover, our results suggest that certain images can prompt a person to think about the present or the future,” they said.
The authors said the results contributed to our understanding of impulsive behaviours, especially where those behaviours were caused by ‘prompts’ in the world around us.
“For instance, consider someone trying to quit gambling who sees a gambling advertisement on TV. Our results suggest that even if this person is trying to ignore the ad, their brain may be unconsciously processing it and making it more likely that they will relapse,” he said.
The researchers used electroencephalography technology (EEG) to measure the electrical activity of people’s brains while they looked at different pictures. The pictures displayed images of food, social scenes or status symbols like cars and money.
After the EEG, researchers showed participants the same pictures again and asked questions about each image, such as how exciting they thought the image was or how strongly the image made them think of either the present or the future.
A statistical ‘decoding’ technique was then used to predict the judgments participants made about each of the pictures from the EEG brain activity that was recorded.
Co-author Daniel Bennett said just as certain prompts might cause impulsive behaviour, images could be used to prompt people to be more patient by regulating impulse control.
“Our results suggest that prompting people with images related to the future might cause processing outside awareness that could make it easier to think about the future. In theory, this could make people less impulsive and more likely to make healthy long-term decisions. These are hypotheses we will try to test in the future,” he said. The research was done in collaboration with the University of Cologne, Germany.
Worry, jealousy, moodiness linked to higher risk of Alzheimer’s in women
Women who are anxious, jealous, or moody and distressed in middle age may be at a higher risk of developing Alzheimer’s disease later in life, according to a nearly 40-year-long study published in the October 1, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.
"Most Alzheimer’s research has been devoted to factors such as education, heart and blood risk factors, head trauma, family history and genetics," said study author Lena Johannsson, PhD, of the University of Gothenburg in Gothenburg, Sweden. "Personality may influence the individual’s risk for dementia through its effect on behavior, lifestyle or reactions to stress."
For the study, 800 women with an average age of 46 were followed for 38 years and given personality tests that looked at their level of neuroticism and extraversion or introversion, along with memory tests. Of those, 19 percent developed dementia.
Neuroticism involves being easily distressed and personality traits such as worrying, jealousy or moodiness. People who are neurotic are more likely to express anger, guilt, envy, anxiety or depression. Introversion is described as shyness and reserve and extraversion is associated with being outgoing.
The women were also asked if they had experienced any period of stress that lasted one month or longer in their work, health, or family situation. Stress referred to feelings of irritability, tension, nervousness, fear, anxiety or sleep disturbances. Responses were categorized as zero to five, with zero representing never experiencing any period of stress, to five, experiencing constant stress during the last five years. Women who chose responses from 3 and 5 were considered to have distress.
The study found that women who scored highest on the tests for neuroticism had double the risk of developing dementia compared to those who scored lowest on the tests. However, the link depended on long-standing stress.
Being either withdrawn or outgoing did not appear to raise dementia risk alone, however, women who were both easily distressed and withdrawn had the highest risk of Alzheimer’s disease in the study. A total of 16 of the 63 women, or 25 percent, who were easily distressed and withdrawn developed Alzheimer’s disease, compared to eight out of the 64 people, or 13 percent, of those who were not easily distressed and were outgoing.
(Image: Corbis)
Why Wet Feels Wet: Understanding the Illusion of Wetness
Human sensitivity to wetness plays a role in many aspects of daily life. Whether feeling humidity, sweat or a damp towel, we often encounter stimuli that feel wet. Though it seems simple, feeling that something is wet is quite a feat because our skin does not have receptors that sense wetness. The concept of wetness, in fact, may be more of a “perceptual illusion” that our brain evokes based on our prior experiences with stimuli that we have learned are wet.
So how would a person know if he has sat on a wet seat or walked through a puddle? Researchers at Loughborough University and Oxylane Research proposed that wetness perception is intertwined with our ability to sense cold temperature and tactile sensations such as pressure and texture. They also observed the role of A-nerve fibers—sensory nerves that carry temperature and tactile information from the skin to the brain—and the effect of reduced nerve activity on wetness perception. Lastly, they hypothesized that because hairy skin is more sensitive to thermal stimuli, it would be more perceptive to wetness than glabrous skin (e.g., palms of the hands, soles of the feet), which is more sensitive to tactile stimuli.
Davide Filingeri et al. exposed 13 healthy male college students to warm, neutral and cold wet stimuli. They tested sites on the subjects’ forearms (hairy skin) and fingertips (glabrous skin). The researchers also performed the wet stimulus test with and without a nerve block. The nerve block was achieved by using an inflatable compression (blood pressure) cuff to attain enough pressure to dampen A-nerve sensitivity.
They found that wet perception increased as temperature decreased, meaning subjects were much more likely to sense cold wet stimuli than warm or neutral wet stimuli. The research team also found that the subjects were less sensitive to wetness when the A-nerve activity was blocked and that hairy skin is more sensitive to wetness than glabrous skin. These results contribute to the understanding of how humans interpret wetness and present a new model for how the brain processes this sensation.
“Based on a concept of perceptual learning and Bayesian perceptual inference, we developed the first neurophysiological model of cutaneous wetness sensitivity centered on the multisensory integration of cold-sensitive and mechanosensitive skin afferents,” the research team wrote. “Our results provide evidence for the existence of a specific information processing model that underpins the neural representation of a typical wet stimulus.”
The article “Why wet feels wet? A neurophysiological model of human cutaneous wetness sensitivity” is published in the Journal of Neurophysiology.
What happens in our brain when we unlock a door?
People who are unable to button up their jacket or who find it difficult to insert a key in lock suffer from a condition known as apraxia. This means that their motor skills have been impaired – as a result of a stroke, for instance. Scientists in Munich have now examined the parts of the brain that are responsible for planning and executing complex actions. They discovered that there is a specific network in the brain for using tools. Their findings have been published in the Journal of Neuroscience.
Researchers from Technische Universität München (TUM) and the Klinikum rechts der Isar hospital have analyzed the brain networks that control the use of tools or other utensils. Their chosen method of functional magnetic resonance imaging (fMRI) shows the areas of the brain that are activated when a person thinks, moves and performs actions.
The use of tools is an essential human skill. “Numerous studies are investigating the neural processes at play when we pick up a tool,” says Prof. Joachim Hermsdörfer from TUM’s Chair of Human Movement Science. “But many of these studies are restricted to test subjects observing an action, miming it, or simply visualizing it.” The aim of this latest study was to analyze the basic neural principles of tool use under the most realistic conditions possible.
In the MRI study, the subjects received ten everyday objects, including a hammer, a bottle-opener, a key, a lighter and a scissors as well as some unfamiliar objects. Their task was to either use the objects or simply lift them up and place them down again, first with the left and then with the right hand. When they analyzed the data, the scientists looked at the planning phase and the actual execution phase separately. In this way, they were able to identify the brain networks that were activated while the subjects planned and used a tool and those that controlled execution.
Tool-specific network in the brain
One important finding was that the left hemisphere was activated when the subjects planned to use a tool – regardless of the hand they held it in. In addition, the researchers recognized a distributed network responsible for both planning and execution. When working with unfamiliar objects, these regions of the brain were less activated.
The “tool network” consists of brain regions of the parietal and frontal lobes as well as regions in the posterior temporal lobe and another area in the lateral occipital lobe. What the researchers found, therefore, was a neural activation pattern that covered all elements of a complex action. This includes recognizing the objects as tools, understanding how they are used, and the motor action to actually use the tool.
“The study also allowed us to confirm that there are different streams of perception in the brain for different tasks,” explains Hermsdörfer. The dorsal stream of perception conducts signals to the posterior parietal lobe and is generally responsible for controlling actions. “It can be divided into two function-specific processing pathways. The dorso-dorsal stream controls basic gripping and movement processes, regardless of whether the person is familiar with the object or not. A second ventro-dorsal stream becomes active when we use tools that are familiar to us.
Armed with knowledge about the localization of these “action modules”, doctors could in future provide a more differentiated diagnosis of apraxia and develop improved therapeutic approaches.