Neuroscience
Month
A group of researchers at Chalmers University of Technology and the University of Gothenburg are now working on technology that can make MEG far more accessible. The vision is an MEG system that is simple and cheap enough to be available at every hospital, while furthermore providing totally new possibilities for fundamental investigations in brain research.
At the heart of the system is a new class of sensors that, unlike today’s MEG sensors, don’t require cooling to -269 Celsius. Instead, these work at -196 Celsius. This capability provides many advantages:
“One of them is the reduction of insulation between the sensors and the subject’s head,” says Dag Winkler, professor of physics at Chalmers. “The sensors can therefore get much closer to the brain so that one can take a more high-resolution picture of brain activity.”
With today’s technology, you can record activity from a patch of the brain that is roughly the size of a 1€ coin. With “Focal MEG” – MEG with liquid-nitrogen cooled sensors – the precision can be improved such that you’re recording from a patch of the brain that is a fraction of that size.
One example of what that can lead to is diagnosis of autism in children at a younger age – something that would be very meaningful considering how critical it is for these children to get the right help as early as possible.
“Another important advantage with Focal MEG is that the coolant the hardware requires is just liquid nitrogen”, Dag Winkler adds. “Today’s MEG requires liquid helium, which is extremely expensive. Furthermore, one can build the hardware with far more flexibility and less complication when using nitrogen instead of helium.”
The Gothenburg researchers have shown that Focal MEG works for advanced brain investigations. Using two sensors they developed, they have successfully recorded spontaneous brain activity –something that had never been done before with liquid-nitrogen cooled sensors. The ability to record spontaneous brain activity (as opposed to averaged activity from repetitive stimulation) is a solid indication that they can record more complicated brain activity.
“The prevailing assumption among MEG researchers has been that MEG with liquid-nitrogen cooled sensors isn’t feasible,” says Justin Schneiderman, assistant professor in biomedical engineering at the University of Gothenburg and MedTech West. “But now we’ve begun to expose holes in that assumption by demonstrating good sensitivity to two well-known brain waves from well-understood parts of the brain.”
The researchers have furthermore made an unexpected finding. They have recorded an uncharacteristically strong brain wave – the so-called theta rhythm – from the back of the brain. Today’s methods tend to find theta waves only in other parts of the brain.
“This is quite exciting,” says Mikael Elam, professor in clinical neurophysiology at the University of Gothenburg. “It may be an as-yet undetected type of brain signal that can only be found when one measures as close to the head as we do.”
A drug that works through the same brain mechanism as the fast-acting antidepressant ketamine briefly improved treatment-resistant patients’ depression symptoms in minutes, with minimal untoward side effects, in a clinical trial conducted by the National Institutes of Health. The experimental agent, called AZD6765, acts through the brain’s glutamate chemical messenger system.
Existing antidepressants available through prescription, which work through the brain’s serotonin system, take a few weeks to work, imperiling severely depressed patients, who can be at high risk for suicide. Ketamine also works in hours, but its usefulness is limited by its potential for dissociative side-effects, including hallucinations. It is being studied mostly for clues to how it works.
“Our findings serve as a proof of concept that we can tap into an important component of the glutamate pathway to develop a new generation of safe, rapid-acting practical treatments for depression,” said Carlos Zarate, M.D., of the NIH’s National Institute of Mental Health, which conducted the research.
Zarate, and colleagues, reported on their results online Dec. 1, 2012 in the journal Biological Psychiatry.
AZD6765, like ketamine, works by blocking glutamate binding to a protein on the surface of neurons, called the NMDA receptor. It is a less powerful blocker of the NMDA receptor, which may be a reason why it is better tolerated than ketamine.
About 32 percent of 22 treatment-resistant depressed patients infused with ASD6765 showed a clinically meaningful antidepressant response at 80 minutes after infusion that lasted for about half an hour – with residual antidepressant effects lasting two days for some. By contrast, 52 percent of patients receiving ketamine show a comparable response, with effects still detectable at seven days. So a single infusion of ketamine produces more robust and sustained improvement, but most patients continue to experience some symptoms with both drugs.
However, depression rating scores were significantly better among patients who received AZD6765 than in those who received placebos. The researchers deemed this noteworthy, since, on average, these patients had failed to improve in seven past antidepressant trials, and nearly half failed to respond to electroconvulsive therapy (ECT).
The patients reported only minor side effects, such as dizziness and nausea, which were not significantly different from those experienced with the placebo.
Zarate and colleagues say their results warrant further trials with AZD6765, testing whether repeated infusions a few times per week or higher doses might produce longer-lasting results.
A research team composed of University of Kentucky researchers has published a paper which provides the first direct evidence that activated astrocytes could play a harmful role in Alzheimer’s disease. The UK Sanders-Brown Center on Aging has also received significant new National Institutes of Health (NIH) funding to further this line of study.
Chris Norris, an associate professor in the UK College of Medicine Department of Molecular and Biomedical Pharmacology, as well as a member of the faculty at the UK Sanders-Brown Center on Aging, is the senior author on a paper published recently in the Journal of Neuroscience, entitled “Targeting astrocytes to ameliorate neurologic changes in a mouse model of Alzheimer’s disease.” The first author on the article, Jennifer L. Furman, was a graduate student in the Norris laboratory during completion of the study.
The astrocyte is a very abundant non-neuronal cell type that performs absolutely critical functions for maintaining healthy nervous tissue. However, in neurodegenerative diseases, like Alzheimer’s disease, many astrocytes exhibit clear physical changes often referred to as “astrocyte activation.” The appearance of activated astrocytes at very early stages of Alzheimer’s has led to the idea that astrocytes contribute to the emergence and/or maintenance of other pathological markers of the disease, including synaptic dysfunction, neuroinflammation and accumulation of amyloid plaques.
Using an animal model, researchers directly modulated the activation state of hippocampal astrocytes using a form of gene therapy.
Mice received the gene therapy at a very young age, before the development of extensive amyloid plaque pathology, and were assessed 10 months later on a variety of Alzheimer’s biomarkers.
The research team found that inhibition of astrocyte activation blunted the activation of microglia (a cell that mediates neuroinflammation), reduced toxic amyloid levels, improved synaptic function and plasticity, and preserved cognitive function.
Norris and collaborators suggest that similar astrocyte-based approaches could be developed to treat humans suffering from Alzheimer’s disease, or possibly other neurodegenerative diseases. This study provides proof of principle that therapeutically targeting astrocytes can be beneficial.
Functional magnetic resonance imaging offers insights into mental fatigue
We all perhaps know the feeling of mental exhaustion, but what does it mean physiologically to have mental fatigue? A new study carried out using brain scans could help scientists uncover the neurobiological mechanisms underlying mental fatigue.
According to Bui Ha Duc and Xiaoping Li of the National University of Singapore writing in a forthcoming issue of the International Journal Computer Applications in Technology, mental fatigue has become commonplace as many people face increasing mental demands from stressful jobs, longer working hours with less time to relax and increasingly suffer sleep problems. Mental fatigue has received attention from those involved generally in health and well being as well as from the military and transport industry. After all, mental fatigue not only affects the health of individuals but can also have implications for road safety and international security.
The researchers used functional magnetic resonance imaging (fMRI) to monitor activity in the brains of ten student volunteers (male and female aged 19 to 25 years) deprived of sleep for 25 hours and given a simple task repeatedly through that period. They carried out scans at 9am, 2pm, 3am, 9am the following day. All volunteers had to have avoided alcohol and caffeine for the 24 hours prior to the experiment, were all physically and mentally fit prior to participation and none had any sleep problems.
The activation of the left thalamus increases with sleep deprivation, going in an exactly opposite trend to the inferior parietal that (following the circadian rhythm) decreases in activation from 9 am to 3 am next day and then increases in activation. This finding fits with logic as the inferior parietal cortex integrates information from different sensory modalities. As all the information has to go through the thalamus and then is sent by the thalamus to the inferior parietal, when the inferior parietal decreases in activation, the thalamus must increase its activation to get the information sent through.
The team explains that a gradual increase in mental fatigue led to decreased activity in the volunteers’ brains in specific regions: the anterior cingulate gyrus, right inferior frontal, left middle frontal and right superior temporal cortex. The anterior cingulate cortex has been described as an interface between motivation, cognition and action, and has been implicated in using reinforcement information to control behavior. The fMRI scans suggest that decreased activity in this part of the brain is therefore linked to those familiar feelings of mental fatigue including lethargy and slowness of thinking.
"The research provides a neurophysiologic basis for measuring the level of mental fatigue by EEG, as well as for the intervention by non-invasive neural stimulation to maintain wakefulness," the team says. "We have developed devices for both, which will be commercialized by our spinoff company, Newrocare Pte Ltd."
This fall, science writers have made sport of yet another instance of bad neuroscience. The culprit this time is Naomi Wolf; her new book, “Vagina,” has been roundly drubbed for misrepresenting the brain and neurochemicals like dopamine and oxytocin.
Earlier in the year, Chris Mooney raised similar ire with the book “The Republican Brain,” which claims that Republicans are genetically different from — and, many readers deduced, lesser to — Democrats. “If Mooney’s argument sounds familiar to you, it should,” scoffed two science writers. “It’s called ‘eugenics,’ and it was based on the belief that some humans are genetically inferior.”
Sharp words from disapproving science writers are but the tip of the hippocampus: today’s pop neuroscience, coarsened for mass audiences, is under a much larger attack.
Meet the “neuro doubters.” The neuro doubter may like neuroscience but does not like what he or she considers its bastardization by glib, sometimes ill-informed, popularizers.
Neurobiologists from Heidelberg University’s Centre for Organismal Studies (COS) have gained new insights into how different types of nerve cells are formed in the developing animal. Through specialised microscopes, they were able to follow the development of the neural retina in the eye of living zebrafish embryos. Using high-resolution three-dimensional time-lapse images the researchers simultaneously observed the division of retinal nerve cells and changes in gene expression. This enabled them to gain insights into the way in which the two processes are linked during eye development and how the number and proportion of different cell types are regulated.
A central question in developmental and regenerative neurobiology concerns the growth processes in animal organisms: How does a growing animal control the generation of the right number of each type and subtype of nerve cell in the brain and what is the relationship between these cells? The retina consists of many different kinds of nerve cells, which are well characterised and common to all vertebrates. Thus, the retina is a particularly good model for studying neuronal development. The researchers studied such retinal developmental processes in living organisms using zebrafish embryos, which are completely transparent and grow rapidly outside their mother.
All retinal cells, which are either excitatory or inhibitory, arise from a relatively small number of apparently homogeneous progenitor cells. These progenitors are able to generate all the different retinal cell types. “It is a challenge to understand how each progenitor cell contributes to the correct number and subtype of nerve cells that compose the final retinal network. Our work contributes to the understanding of how different genes orchestrate neuronal diversity along a progenitor cell lineage, that is the number of cell divisions and types of neurons generated”, says Heidelberg researcher Dr. Lucia Poggi.
To tackle this challenge, Dr. Poggi’s team used different lines of transgenic zebrafish, in which fluorescent reporter proteins highlight the expression of different genes in dividing cells. Working in close cooperation with Dr. Patricia Jusuf of the Australian Regenerative Medicine Institute at Monash University, the researchers found that some particular kinds of excitatory and inhibitory nerve cells tend to be lineally related, i.e. they derive from a common progenitor cell. For the first time, 4D recordings permitted an in vivo analysis of how the generation of particular inhibitory cells is regulated through coordination of cell division mode and gene expression within individual retinal progenitors of excitatory nerve cells.
This study has established a model of how cell lineage influences neuronal subtype specification and neuronal circuitry formation in the native environment of the vertebrate brain. The results were published in the Journal of Neuroscience.
Chinese researchers have devised a new technique for reprogramming cells from human urine into immature brain cells that can form multiple types of functioning neurons and glial cells. The technique, published in the journal Nature Methods, could prove useful for studying the cellular mechanisms of neurodegenerative conditions such as Alzheimer’s and Parkinson’s and for testing the effects of new drugs that are being developed to treat them.
Stem cells offer the hope of treating these debilitating diseases, but obtaining them from human embryos poses an ethical dilemma. We now know that cells taken from the adult human body can be made to revert to a stem cell-like state and then transformed into virtually any other type of cell. This typically involves using genetically engineered viruses that shuttle control genes into the nucleus and inserts them into the chromosomes, whereupon they activate genes that make them pluripotent, or able to re-differentiate into another type of cell.
In 2008, for example, American researchers took skin cells from an 82-year-old patient with amyotrophic lateral sclerosis and reprogrammed them into motor neurons. Cells obtained in this way could help us gain a better understanding of such diseases. Grafts of patients’ own cells do not elicit an immune response, so this approach may eventually lead to effective cell transplantation therapies. But it also has its problems – it appears that the reprogramming process destabilizes the genome and causes mutations, and that iPSCs may therefore harbour genetic defects that render them useless.
Last year, Duanqing Pei of the Chinese Academy of Sciences and his colleagues reported that human urine contains skin-like cells from the lining of the kidney tubules which can be efficiently reprogrammed, via the pluripotent state, into neurons, glia, liver cells and heart muscle cells. Now they have improved on the approach, making it quicker, more efficient and possibly less prone to errors.
In the new study, they isolated cells from urine samples given by three donors, aged 10, 25 and 37, and converted them directly into neural progenitors. They then grew these cells in Petri dishes and drove them to differentiate into mature neurons that can generate nervous impulses, and also into astrocytes and oligodendrocytes, two types of glial cell found in the human brain. Finally, they transplanted the re-programmed neurons and astrocytes into the brains of newborn rats, and found that the cells had survived when they examined the brains a month later, but it remains to be seen if they can survive for longer, and if they integrate into the existing circuits to be become functional.
This isn’t the first time that one type of cell has been converted into another without going through the pluripotent stage – in 2010, researchers from Stanford converted mouse connective tissue cells directly into neurons. The new technique does have a number of advantages, however.
Instead of using a virus to deliver the reprogramming genes, the researchers used a small circular piece of bacterial DNA which can replicate in the cytoplasm. This not only speeds up the process, but also eliminates the need to integrate the reprogramming genes into the chromosome, which is one potential source of genetic mutation, but it’s still not clear whether these cells contain fewer mutations than those reprogrammed using viruses.
Even so, the technique also makes the procedure of generating iPSCs far easier and non-invasive, as the cells can be obtained from a urine sample instead of a blood sample or biopsy. The next logical step will be to generate neurons from urine samples obtained from patients with Alzheimer’s, Parkinson’s, and other neurodegenerative diseases and to determine the extent to which this new non-viral technique damages the DNA.
Wellcome Trust researchers have discovered how the brain assesses confidence in its decisions. The findings explain why some people have better insight into their choices than others.
Throughout life, we’re constantly evaluating our options and making decisions based on the information we have available. How confident we are in those decisions has clear consequences. For example, investment bankers have to be confident that they’re making the right choice when deciding where to put their clients’ money.
Researchers at the Wellcome Trust Centre for Neuroimaging at UCL led by Professor Ray Dolan have pinpointed the specific areas of the brain that interact to compute both the value of the choices we have in front of us and our confidence in those choices, giving us the ability to know what we want.
The team used functional magnetic resonance imaging (fMRI) to measure activity in the brains of twenty hungry volunteers while they made choices between food items that they would later eat. To determine the subjective value of the snack options, the participants were asked to indicate how much they would be willing to pay for each snack. Then after making their choice, they were asked to report how confident they were that they had made the right decision and selected the best snack.
It has previously been shown that a region at the front of the brain, the ventromedial prefrontal cortex, is important for working out the value of decision options. The new findings reveal that the level of activity in this area is also linked to the level of confidence participants placed on choosing the best option. The study also shows that the interaction between this area of the brain and an adjacent area reflects participants’ ability to access and report their level of confidence in their choices.
Dr Steve Fleming, a Sir Henry Wellcome Postdoctoral Fellow now based at New York University, explains: “We found that people’s confidence varied from decision to decision. While we knew where to look for signals of value computation, it was very interesting to also observe neural signals of confidence in the same brain region.”
Dr Benedetto De Martino, a Sir Henry Wellcome Postdoctoral Fellow at UCL, added: “Overall, we think our results provide an initial account both of how people make choices, and also their insight into the decision process.”