Neuroscience
Month
Researchers at King’s College London have for the first time identified a defective gene at the root of Vici syndrome, a rare inherited disorder which affects infants from birth, leading to impaired development of the brain, eyes and skin, and progressive failure of the heart, skeletal muscles and the immune system.
Published in the journal Nature Genetics, the study identified a defect in the EPG-5 gene, indicating a genetic cause of the condition which was previously unknown. Researchers at King’s and Guy’s & St Thomas’ NHS Foundation Trust, part of King’s Health Partners, analysed the DNA of 18 infants with Vici syndrome and identified the inactivity of EPG-5 as a major cause of the condition.
Infants born with Vici syndrome inherit two copies of the defective gene, one from each parent. Although there are only around 50 known cases of the disorder across the world, researchers believe the precise incidence is unknown due to lack of awareness of this condition. Dr Heinz Jungbluth, from the Children’s Neuroscience Centre at St Thomas’ Hospital, who led the study along with Professor Mathias Gautel from the Cardiovascular Division at King’s, said: ‘Vici syndrome is likely to be under-diagnosed as there is potential for misdiagnosis, particularly when you consider the many different organ systems affected by Vici and the significant overlap with other, more common disorders.’
The study also highlighted the ‘autophagy’ process and the role of EPG-5 in causing this mechanism to fail. Autophagy is a highly regulated cellular process that removes damaged or unwanted components, which is crucial for the health of all cell types, including those involved in muscles, the immune system and brain development. Abnormalities in this process have been implicated previously in neurodegenerative conditions, but defects causing disorders of normal development such as Vici syndrome have rarely been reported. The researchers suggest that autophagy could play a key role in causing a range of disorders, offering the potential for treatment of other conditions. Dr Jungbluth said: ‘Although the condition is very rare, it is likely that insights provided by research into Vici syndrome will also be transferable to the diagnosis and therapy of neurodegenerative and neurodevelopmental disorders, and a wider range of primary muscle conditions.’
Professor Gautel added: ‘Having identified where this genetic defect occurs we are now able to explore potential interventions. For instance, there is the possibility of enhancing other pathways unaffected by the EPG-5 gene, or by preventing use of the defective pathway in the first place.’
As the defective gene is inherited from both the mother and father, there is also the possibility of screening families with a known history of Vici syndrome. Professor Gautel said: ‘Mothers could be offered preimplantation diagnosis, which involves removing a cell from an embryo when it is around three days old and testing it for genetic disorders, so that an unaffected embryo can be implanted into the mother’s womb, if necessary.’
Alzheimer’s disease is the most common form of dementia, affecting over 35 million people worldwide. It is generally assumed that the clumping of beta-amyloid (Aß) protein causes neuronal loss in patients. Medication focuses on reducing Aß42, one of the most common proteins and the most harmful. University of Twente PhD student Annelies Vandersteen is refining the current approach. She explains: “The results of my research provide a broader understanding of the processes that lead to Alzheimer’s disease and in this way may help to bring about new medication”.
The Aß protein occurs in the body in various lengths, ranging from 33 to 49 amino acids. The shorter varieties are regarded as ‘safe’, unlike the longer ones – Aß42 and longer – which are highly aggregating. Current therapeutic strategy tries to reduce the clumping of Aß42, and its harmful effects, by limiting the release of Aß42. Reducing Aß42 production at the same time results in a rise in Aß38 levels. Vandersteen comments: “One of the findings of my research is that small amounts of Aß38 can in fact increase or temper the clumping and toxic effects of longer Aß proteins. The processes that result in Alzheimer’s disease are determined by the whole spectrum of Aß proteins. So the picture is far less black and white than has been assumed so far, and less common forms of Aß are far less harmless than we thought.”
The study
Vandersteen examined the protein mixtures in a laboratory situation. She devised a series of experiments based on a computer-calculated hypothesis. The behaviour of the various Aß proteins and mixtures was studied in detail and described using various biophysical techniques. The influence of the various Aß proteins and mixtures on neurons was then studied in a cell culture.
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.