Neuroscience
Month
The idea that females are more resilient than males in responding to stress is a popular view, and now University at Buffalo researchers have found a scientific explanation. The paper describing their embargoed study will be published July 9 online, in the high-impact journal, Molecular Psychiatry.
“We have examined the molecular mechanism underlying gender-specific effects of stress,” says senior author Zhen Yan, PhD, a professor in the Department of Physiology and Biophysics in the UB School of Medicine and Biomedical Sciences. “Previous studies have found that females are more resilient to chronic stress and now our research has found the reason why.”
The research shows that in rats exposed to repeated episodes of stress, females respond better than males because of the protective effect of estrogen.
In the UB study, young female rats exposed to one week of periodic physical restraint stress showed no impairment in their ability to remember and recognize objects they had previously been shown. In contrast, young males exposed to the same stress were impaired in their short-term memory.
An impairment in the ability to correctly remember a familiar object signifies some disturbance in the signaling ability of the glutamate receptor in the prefrontal cortex, the brain region that controls working memory, attention, decision-making, emotion and other high-level “executive” processes.
Last year, Yan and UB colleagues published in Neuron a paper showing that repeated stress results in loss of the glutamate receptor in the prefrontal cortex of young males.
The current paper shows that the glutamate receptor in the prefrontal cortex of stressed females is intact. The findings provide more support for a growing body of research demonstrating that the glutamate receptor is the molecular target of stress, which mediates the stress response.
The stressors used in the experiments mimic challenging and stressful, but not dangerous, experiences that humans face, such as those causing frustration and feelings of being under pressure, Yan says.
By manipulating the amount of estrogen produced in the brain, the UB researchers were able to make the males respond to stress more like females and the females respond more like males.
“When estrogen signaling in the brains of females was blocked, stress exhibited detrimental effects on them,” explains Yan. “When estrogen signaling was activated in males, the detrimental effects of stress were blocked.
“We still found the protective effect of estrogen in female rats whose ovaries were removed,” says Yan. “It suggests that it might be estrogen produced in the brain that protects against the detrimental effects of stress.”
In the current study, Yan and her colleagues found that the enzyme aromatase, which produces estradiol, an estrogen hormone, in the brain, is responsible for female stress resilience. They found that aromatase levels are significantly higher in the prefrontal cortex of female rats.
“If we could find compounds similar to estrogen that could be administered without causing hormonal side effects, they could prove to be a very effective treatment for stress-related problems in males,” she says.
She notes that while stress itself is not a psychiatric disorder, it can be a trigger for the development of psychiatric disorders in vulnerable individuals.
Several human and animal studies have shown a relationship between a preference for highly sweet tastes and alcohol use disorders. Furthermore, the brain mechanisms of sweet-taste responses may share common neural pathways with responses to alcohol and other drugs. A new study using functional magnetic resonance imaging (fMRI) has found that recent drinking is related to the orbitofrontal-region brain response to an intensely sweet stimulus, a brain response that may serve as an important phenotype, or observable characteristic, of alcoholism risk.
Results will be published in the December 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"It has long-been known that animals bred to prefer alcohol also drink considerably greater quantities of sweetened water than do animals without this selective breeding for alcohol preference," explained David A. Kareken, deputy director of the Indiana Alcohol Research Center, a professor in the department of neurology at Indiana University School of Medicine, and corresponding author for the study. "More recently, it has become clear that animals bred to prefer the artificial sweetener, saccharin, also drink more alcohol. Although the data in humans are somewhat more variable, some studies do show that alcoholics, or even non-alcoholics with a family history of alcoholism, have a preference for unusually sweet tastes. Thus, while the precise reasons remain unclear, there does seem to be significant evidence suggesting some link between the rewarding properties of both sweet tastes and alcohol."
Kareken added that this is the first study to examine the extent to which regions of the brain’s reward system, as they respond to an intensely sweet taste, are related to human drinking patterns.
Kareken and his colleagues recruited 16 (12 males, 4 females) right-handed, non-treatment seeking, healthy volunteers with a mean age of 26 years from the community. All participants underwent a taste test using a range of sucrose concentrations, and their blood oxygen dependent (BOLD) activation was measured during an fMRI scan while receiving small squirts of either water or an intensely sweet mixture of sugar in water. All were asked about their drinking patterns.
"Our study was designed to determine which brain areas responded to sweet taste – as compared to plain water – and the extent to which these brain responses were related to subjects’ binge-drinking patterns, the number of alcoholic drinks subjects consumed per day when drinking," explained Kareken.
"In addition to ‘activating’ the brain’s gustatory or taste circuits, the sugared water also activated key elements of what neuroscientists consider to be part of the brain’s reward system, including the ventral striatum, amygdala, and parts of the orbitofrontal cortex – the inferior frontal lobe surface just above the eyes – that respond to ingested rewards," Kareken said. "We refer to these as ‘primary’ rewards, being distinct from secondary rewards, like money, which can be used to obtain primary rewards."
What the researchers found was that the response to this intensely sweet taste in the left orbitofrontal area correlated significantly with subjects’ drinking patterns.
"Specifically, the trend was such that those who drank more alcohol on drinking days had stronger left orbitofrontal responses to the intensely sweet water," said Kareken. "Subjects’ subjectively rated liking of the sweetened water also contributed to this relationship, so that both the brain response itself, as well as liking of the sugared water, collectively correlated with drinking behavior."
While previous human and animal research has noted this association between preferences for both sweet tastes and alcohol intoxication, Kareken believes that this is the first study to examine the human brain mechanism behind this association.
"While much more research needs to be done to truly understand the commonalities between sweet-liking and alcoholism, and while alcoholism itself is likely the product of several mechanisms, our findings may implicate a particular brain region that is more generally involved in coding for the value of ‘primary’ rewards such as pleasures," he said. "In a more practical sense, the findings are compelling evidence that the brain response to an intensely sweet taste may be used in future research to test for differences in the reward circuits of those at risk for alcoholism. This may be particularly useful since alcohol itself is not an easy drug to work with in this kind of human imaging, and since alcohol exposure is not ethically appropriate for use in all at-risk subjects, or in subjects trying to abstain from drinking."
A recent 3D-comparative analysis confirms the status of Homo floresiensis as a fossil human species
Ever since the discovery of the remains in 2003, scientists have been debating whether Homo floresiensis represents a distinct Homo species, possibly originating from a dwarfed island Homo erectus population, or a pathological modern human. The small size of its brain has been argued to result from a number of diseases, most importantly from the condition known as microcephaly.
Based on the analysis of 3-D landmark data from skull surfaces, scientists from Stony Brook University New York, the Senckenberg Center for Human Evolution and Palaeoenvironment, Eberhard-Karls Universität Tübingen, and the University of Minnesota provide compelling support for the hypothesis that Homo floresiensis was a distinct Homo species.
The study, titled “Homo floresiensis contextualized: a geometric morphometric comparative analysis of fossil and pathological human samples,” is published in the July 10 edition of PLOS ONE.
The ancestry of the Homo floresiensis remains is much disputed.
The critical questions are: Did it represent an extinct hominin species? Could it be a Homo erectus population, whose small stature was caused by island dwarfism?
Or, did the LB1 skull belong to a modern human with a disorder that resulted in an abnormally small brain and skull? Proposed possible explanations include microcephaly, Laron Syndrome or endemic hypothyroidism (“cretinism”).
The scientists applied the powerful methods of 3-D geometric morphometrics to compare the shape of the LB1 cranium (the skull minus the lower jaw) to many fossil humans, as well as a large sample of modern human crania suffering from microcephaly and other pathological conditions. Geometric morphometrics methods use 3D coordinates of cranial surface anatomical landmarks, computer imaging, and statistics to achieve a detailed analysis of shape.
This was the most comprehensive study to date to simultaneously evaluate the two competing hypotheses about the status of Homo floresiensis.
The study found that the LB1 cranium shows greater affinities to the fossil human sample than it does to pathological modern humans. Although some superficial similarities were found between fossil, LB1, and pathological modern human crania, additional features linked LB1exclusively with fossil Homo. The team could therefore refute the hypothesis of pathology.
“Our findings provide the most comprehensive evidence to date linking the Homo floresiensis skull with extinct fossil human species rather than with pathological modern humans. Our study therefore refutes the hypothesis that this specimen represents a modern human with a pathological condition, such as microcephaly,” stated the scientists.
In the constant cross talk between our brain and our gut, two gut hormones are already known to tell the brain when we have had enough to eat. New research suggests that boosting levels of these hormones simultaneously may be an effective new weapon in the fight against obesity.
Dr Shu Lin, Dr Yan-Chuan Shi and Professor Herbert Herzog, from Sydney’s Garvan Institute of Medical Research, have shown that when mice are injected with PYY3-36 and PP, they eat less, gain less fat, and tend not to develop insulin-resistance, a precursor to diabetes. At the same time, the researchers have shown that the hormones stimulate different nerve pathways, ultimately, however, affecting complementary brain regions. Their findings are now published online in the journal Obesity.
While the double-barreled approach may seem like a no-brainer, the strongly enhanced effect seen was by no means inevitable. In the complex world of neuroscience, two plus two does not always make four.
Drug companies are in the process of conducting pre-clinical trials to examine the separate effects of boosting the hormones PYY3-36 and PP. Until now, there is no research to indicate the detailed molecular interactions that might occur when they are boosted in tandem.
When used together, the hormones independently, yet with combined force, reduce the amount of neuropeptide Y (NPY) produced by the brain, a powerful neurotransmitter that affects a variety of things including appetite, mood, heart rate, temperature and energy levels.
Each hormone also communicates with a different part of the arcuate nucleus in the hypothalamus, a region of the brain where signals can cross the normally impermeable blood / brain barrier. The stimulated regions then produce other neuronal signals deep within the hypothalamus, bringing about a powerful combined effect.
“There are many factors that influence appetite control – and we now realise that there won’t be a single molecular target, or a single drug, that will be effective,” said Dr Yan-Chuan Shi.
“It will be important for drug companies to try different combinations of targets, to see which combinations are most potent, and at the same time have no side effects, or at least minimal side effects.”
“At the moment, the only effective tool against obesity is surgery. Drug companies have so far failed to produce an effective drug without unacceptable side effects, such as mood disorders, nausea or cardiovascular problems.”
Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease that rapidly atrophies the muscles, leading to complete paralysis. Despite its high profile — established when it afflicted the New York Yankees’ Lou Gehrig — ALS remains a disease that scientists are unable to predict, prevent, or cure.
Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.
Now, using samples of stem cells derived from the bone marrow of non-genetic ALS patients, Prof. Miguel Weil of Tel Aviv University’s Laboratory for Neurodegenerative Diseases and Personalized Medicine in the Department of Cell Research and Immunology and his team of researchers have uncovered four different biomarkers that characterize the non-genetic form of the disease. Each sample shows similar biological abnormalities to four specific genes, and further research could reveal additional commonalities. “Because these genes and their functions are already known, they give us a specific direction for research into non-genetic ALS diagnostics and therapeutics,” Prof. Weil says. His initial findings were reported in the journal Disease Markers.
Giving in to stress
To hunt for these biomarkers, Prof. Weil and his colleagues turned to samples of bone marrow collected from ALS patients. Though more difficult to collect than blood, bone marrow’s stem cells are easy to isolate and grow in a consistent manner. In the lab, he used these cells as cellular models for the disease. He ultimately discovered that cells from different ALS patients shared the same abnormal characteristics of four different genes that may act as biomarkers of the disease. And because the characteristics appear in tissues that are related to ALS — including in muscle, brain, and spinal cord tissues in mouse models of genetic ALS — they may well be connected to the degenerative process of the disease in humans, he believes.
Searching for the biological significance of these abnormalities, Prof. Weil put the cells under stress, applying toxins to induce the cells’ defense mechanisms. Healthy cells will try to fight off threats and often prove quite resilient, but ALS cells were found to be overwhelmingly sensitive to stress, with the vast majority choosing to die rather than fight. Because this is such an ingrained response, it can be used as a feature for drug screening for the disease, he adds.
The hunt for therapeutics
Whether these biomarkers are a cause or consequence of ALS is still unknown. However, this finding remains an important step towards uncovering the mechanisms of the disease. Because these genes have already been identified, it gives scientists a clear direction for future research. In addition, these biomarkers could lead to earlier and more accurate diagnostics.
Next, Prof. Weil plans to use his lab’s high-throughput screening facility — which can test thousands of compounds’ effects on diseased cells every day — to search for drug candidates with the potential to affect the abnormal expression of these genes or the stress response of ALS cells. A compound that has an impact on these indicators of ALS could be meaningful for treating the disease, he says.
Prof. Weil is the director of the new Cell Screening Facility for Personalized Medicine at TAU. The facility is dedicated to finding potential drugs for rare and Jewish hereditary diseases.
Finding has implications for alcoholism and other patterns of addictive behavior
Research from the National Institutes of Health has identified neural circuits in mice that are involved in the ability to learn and alter behaviors. The findings help to explain the brain processes that govern choice and the ability to adapt behavior based on the end results.
Researchers think this might provide insight into patterns of compulsive behavior such as alcoholism and other addictions.
“Much remains to be understood about exactly how the brain strikes the balance between learning a behavioral response that is consistently rewarded, versus retaining the flexibility to switch to a new, better response,” said Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism. “These findings give new insight into the process and how it can go awry.”
The study, published online in Nature Neuroscience, indicates that specific circuits in the forebrain play a critical role in choice and adaptive learning.
Like other addictions, alcoholism is a disease in which voluntary control of behavior progressively diminishes and unwanted actions eventually become compulsive. It is thought that the normal brain processes involved in completing everyday activities become redirected toward finding and abusing alcohol.
The research, conducted by investigators from NIAAA, with support from the National Institute of Mental Health and the University of Cambridge, England, used a variety of approaches to study choice.
Researchers used a simple choice task in which mice viewed images on a computer touchscreen and learned to touch a specific image with their nose to get a food reward. Using various techniques to visualize and record neural activity, researchers found that as the mice learned to consistently make a choice, the brain’s dorsal striatum was activated. The dorsal striatum is thought to play an important role in motivation, decision-making, and reward.
Conversely, when the mice later had to shift to a new choice to receive a reward, the dorsal striatum quieted while regions in the prefrontal cortex, an area involved in decision-making and complex cognitive processes, became active.
Building upon these findings, the authors next deleted or pharmacologically blocked a component of nerve cells which normally binds the neurochemical glutamate (specifically, the GluN2B subunit of the NMDA receptor) within two different areas of the brain, the striatum and the frontal cortex. Previous studies have shown that GluN2B plays a role in memory, spatial reference, and attention. Researchers found that making dorsal striatal GluN2B inactive markedly slowed learning, while shutting down GluN2B in the prefrontal cortex made the mice less able to relearn the touchscreen reward task after the reward image was changed.
“These data add to what we understand about the neural control of behavioral flexibility and striatal learning by identifying GluN2B as a critical molecular substrate to both processes,” said the study’s senior author, Andrew Holmes, Ph.D., Laboratory Chief and Principal Investigator of the NIAAA Laboratory of Behavioral and Genomic Neuroscience.
“This is particularly intriguing for future studies because NMDA receptors are a major target for alcohol and contribute to important features of alcoholism, such as withdrawal. These new findings suggest that GluN2B in corticostriatal circuits may also play a key role in driving the transition from controlled drinking to compulsive abuse that characterizes alcoholism.”
A hallmark of neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s is that by the time symptoms appear, significant brain damage has already occurred—and currently there are no treatments that can reverse it. A team of SRI International researchers has demonstrated that measurements of electrical activity in the brains of mouse models of Huntington’s disease could indicate the presence of disease before the onset of major symptoms. The findings, “Longitudinal Analysis of the Electroencephalogram and Sleep Phenotype in the R6/2 Mouse Model of Huntington’s Disease,” are published in the July 2013 issue of the neurology journal Brain, published by Oxford University Press.
SRI researchers led by Stephen Morairty, Ph.D., a director in the Center for Neuroscience in SRI Biosciences, and Simon Fisher, Ph.D., a postdoctoral fellow at SRI, used electroencephalography (EEG), a noninvasive method commonly used in humans, to measure changes in neuronal electrical activity in a mouse model of Huntington’s disease. Identification of significant changes in the EEG prior to the onset of symptoms would add to evidence that the EEG can be used to identify biomarkers to screen for the presence of a neurodegenerative disease. Further research on such potential biomarkers might one day enable the tracking of disease progression in clinical trials and could facilitate drug development.
“EEG signals are composed of different frequency bands such as delta, theta and gamma, much as light is composed of different frequencies that result in the colors we call red, green and blue,” explained Thomas Kilduff, Ph.D., senior director, Center for Neuroscience, SRI Biosciences. “Our research identified abnormalities in all three of these bands in Huntington’s disease mice. Importantly, the activity in the theta and gamma bands slowed as the disease progressed, indicating that we may be tracking the underlying disease process.”
EEG has shown promise as an indicator of underlying brain dysfunction in neurodegenerative diseases, which otherwise occurs surreptitiously until symptoms appear. Until now, most investigations of EEG in patients with neurodegenerative diseases and in animal models of neurodegenerative diseases have shown significant changes in EEG patterns only after disease symptoms occurred.
“Our breakthrough is that we have found an EEG signature that appears to be a biomarker for the presence of disease in this mouse model of Huntington’s disease that can identify early changes in the brain prior to the onset of behavioral symptoms,” said Morairty, the paper’s senior author. “While the current study focused on Huntington’s disease, many neurodegenerative diseases produce changes in the EEG that are associated with the degenerative process. This is the first step in being able to use the EEG to predict both the presence and progression of neurodegenerative diseases.”
Although previous studies have shown there are distinct and extensive changes in EEG patterns in Alzheimer’s and Huntington’s disease patients, researchers are looking for changes that may occur decades before disease onset.
Huntington’s disease is an inherited disorder that causes certain nerve cells in the brain to die, resulting in motor dysfunction, cognitive decline and psychiatric symptoms. It is the only major neurodegenerative disease where the cause is known with certainty: a genetic mutation that produces a change in a protein that is toxic to neurons.
Latest advances in capturing data on brain activity and eye movement are being combined to open up a host of ‘mindreading’ possibilities for the future. These include the potential development of a system that can detect when drivers are in danger of falling asleep at the wheel.
The research has been undertaken at the University of Leicester with funding from the Engineering and Physical Sciences Research Council (EPSRC), and in collaboration with the University of Buenos Aires in Argentina.
The breakthrough involves bringing two recent developments in the world of technology together: high-speed eye tracking that records eye movements in unprecedented detail using cutting-edge infra-red cameras*; and high-density electroencephalograph** (EEG) technology that measures electrical brain activity with millisecond precision through electrodes placed on the scalp.
The research has overcome previous technological challenges which made it difficult to monitor eye movement and brain activity simultaneously. The team has done this by developing novel signal processing techniques.
This could be the first step towards a system that combines brain and eye monitoring to automatically alert drivers who are showing signs of drowsiness. The system would be built into the vehicle and connected unobtrusively to the driver, with the EEG looking out for brain signals that only occur in the early stages of sleepiness. The eye tracker would reinforce this by looking for erratic gaze patterns symptomatic of someone starting to feel drowsy and different from those characteristic of someone driving who is constantly looking out for hazards. Fatigue has been estimated to account for around 20 per cent of traffic accidents on the UK’s motorways.***
The breakthrough achieved by the University of Leicester could also ultimately be built on to deliver many other everyday applications in the years ahead. For example:
A new combination of tissue engineering techniques could reduce the need for nerve grafts, according to new research by The Open University. Regeneration of nerves is challenging when the damaged area is extensive, and surgeons currently have to take a nerve graft from elsewhere in the body, leaving a second site of damage. Nerve grafts contain aligned tissue structures and Schwann cells that support and guide neuron growth through the damaged area, encouraging function to be restored. The research, published in Biomaterials, reported a way to manufacture artificial nerve tissue with the potential to be used as an alternative to nerve grafts.
Pieces of Engineered Neural Tissue (EngNT) are formed by controlling natural Schwann cell behaviour in a three-dimensional collagen gel so that the cells elongate and align, then a stabilisation process removes excess fluid to leave robust artificial tissues. These living biomaterials contain aligned Schwann cells in an aligned collagen environment, recreating key features of normal nerve tissue.
Incorrect orientation of regenerating nerve cells can lead to delays in repair, scarring and poor restoration of nerve function. Much research has taken place into how support cells (Schwann cells) can be combined with materials to guide nerve regeneration. The new technology from The Open University avoids the use of synthetic materials by building neural tissue from collagen, a protein that is abundant in normal nerve tissue. Building the artificial tissue from natural proteins and directing the cellular alignment using normal cell-material interactions means the EngNT can integrate effectively at the repair site.
Dr James Phillips, Lecturer in Health Sciences at The Open University, said: “We previously reported how self-alignment of Schwann cells could be achieved by using a tethered collagen hydrogel, which exploited cells’ natural ability to orientate in the appropriate direction by using their internal contraction forces. Our current research shows that cell-alignment in the hydrogel can be stabilised using plastic compression. The compression removes fluid from the gels, leaving a strong and stable aligned structure that has many features in common with nerve tissue.”
The team incorporated Schwann cells within the aligned material to form artificial neural tissue that could potentially be used in peripheral nerve repair. The technique could be applied to other regenerative medicine scenarios, where a stable artificial tissue containing aligned cellular architecture would be of benefit.
Major depressive disorder is associated with a dysregulation of brain regions including the prefrontal cortex and limbic system. The relationship between structural and functional abnormalities in these brain regions in depressed patients is far from clear. However, both types of changes are assumed to underlie the symptoms of this disorder.
This lack of understanding prompted Dr. Bart de Kwaasteniet at the Academic Medical Center in Amsterdam and his colleagues to use a multimodal neuroimaging approach to further investigate this relationship.
The researchers, led by Professor Damiaan Denys, recruited 18 patients with major depressive disorder and 24 healthy individuals, all of whom underwent multiple neuroimaging scans. They specifically focused on the structural and functional connectivity between the subgenual anterior cingulate cortex (ACC) and the medial temporal lobe, two regions that are connected by a white matter tract called the uncinate fasciculus. These regions are known to be involved in the regulation of emotion and memory.
de Kwaasteniet explained their findings: “We identified decreased structural integrity of the uncinate fasciculus connecting the medial temporal lobe and the subgenual ACC. Furthermore, we identified an increased functional connection between these regions in major depression relative to controls. Importantly, we identified a negative correlation between the integrity of this white matter tract and the functional connection between the subgenual ACC and bilateral hippocampus in major depression.”
These results suggest that structural disturbances in the uncinate fasciculus contribute to abnormally high functional interactions among brain circuits associated with the symptoms of depression. “This leads to the hypothesis that abnormalities in brain structure lead to differences in connectivity between brain areas in depressive disorder,” added de Kwaasteniet.
However, they also hypothesized that the reverse may be true as well. In other words, that the increased functional connectivity among these brain regions leads to structural changes in the brain’s white matter fibers by means of an abnormally increased signal transduction. This hypothesis is supported by recent studies in schizophrenia which suggest that circuit hyperactivity may be a predictor of subsequent cortical atrophy.
"This interesting study suggests that abnormalities in the structural connections between brain regions, the white matter, are associated with abnormal activity within a brain circuit implicated in the symptoms of depression. This observation raises an important question about the implications of treating the circuit functional abnormalities without fixing the underlying brain structure," commented Dr. John Krystal, Editor of Biological Psychiatry. “Perhaps the structural abnormalities contribute to the risk for the relapse of depression among individuals whose brain circuit activity has responded to antidepressant medications.”
More research will be necessary to test the theories generated from the findings of this study.
Some 165 million Europeans are likely to experience some form of brain-related disease during their life. As the population ages, Alzheimer’s and other neurodegenerative or age-related mental disorders are affecting more people and contributing to higher health costs. Finding better ways of preventing and treating brain diseases is therefore becoming urgent, and understanding how our brains work is important to keep our economies at the forefront of new information technologies and services. EU-funded research is answering these challenges.
As mentioned in the first part of this article, this May the European Commission announced EUR 150 million of funding for 20 new ICT research projects expected to deliver new insights and innovations relating to traumatic brain injury, mental disorders, pain, epilepsy and paediatric conduct disorders.
The European Commissioner for Research, Innovation and Science, Máire Geoghegan-Quinn has said, ”Treating those affected (by brain-related disease) is already costing us EUR 1.5 million every minute […] Brain research could help alleviate the suffering of millions of patients and those that care for them. Unlocking the secrets of how the brain works could also open up a whole new universe of services and products for our economies.”
Treating neurological diseases
Stroke is the most common neurological disease to afflict people, causing cognitive problems - such as difficulties with attention, memory or language - or severe physical disability. The incidence increases with age, making it the most frequent cause of life-long impairment in adulthood.
These effects tend to increase patients” dependence on other people, and this lost autonomy can then lead to depression. The CONTRAST project seeks to bridge the gap between institutional rehabilitation and monitoring of the patient at home.
The project is developing an adaptive ”human-computer interface” (HCI) to improve cognitive functioning, offering training modules that improve the recovery of attention and memory. Patients will be able to go through an individually tailored rehabilitation process at home at the computer, while their doctor provides home-based training and monitors their progress from the clinic.
A third of stroke patients will experience long-term physiological or cognitive disabilities - preventing them from maintaining independent lives. COGWATCH aims to enhance the rehabilitation of stroke patients with symptoms of ”apraxia and action disorganisation syndrome” (AADS). Such patients retain their motor capabilities but commit cognitive errors during every-day goal-oriented tasks.
The project is developing intelligent tools and objects, portable and wearable devices, and ambient systems to provide personalised cognitive rehabilitation at home for stroke patients with AADS symptoms. By providing persistent feedback, the system will help to re-train patients on how to carry out the everyday activities they need to be independent.
Parkinson’s disease is another neurodegenerative disorder that is growing in incidence as our population ages - it particularly affects areas of the brain that are involved in movement control. The CUPID project aims to develop innovative, personalised rehabilitation at home for people with Parkinson”s disease, based on the patient”s needs.
The CUPID service will employ wearable sensors, audio biofeedback, virtual reality and external cueing to provide intensive motivating training that is suited to the patient and monitored remotely - decreasing the need for travel to a rehabilitation centre.
By the end of its first year, in December 2012, the project had designed the rehabilitation exercises and developed prototype virtual games for these exercises, as well as the telemedicine infrastructure needed for remote supervision.
Epilepsy is another common neurological disorder that, despite progress in treatment, is still incurable. Nowadays, pharmaceutical treatment can reduce or remove the symptoms, but this needs life-long continuous adjustment in order to be effective. The condition therefore requires monitoring of multiple parameters for accurate diagnosis, prediction, alerting and prevention, as well as treatment follow-up and presurgical evaluation.
The ARMOR project is designing a more holistic, personalised, medically efficient and economical monitoring system to analyse brain and body data from epilepsy patients. This portable system will provide more accurate diagnosis for individual patients, and allow better understanding and prediction of the time and type of their seizures - helping to give a warning and ensure the availability of medical assistance and advice if necessary.
Amputation of a limb is not just a traumatic physical experience. It can also lead to sensations - usually accompanied by pain - that seem to come from the missing body part, called a ”phantom limb”. The TIME project is developing an alternative treatment for phantom limb pain based on a new ”human-machine interface” (HMI) and selective, electrical stimulation of the peripheral nerves.
Using an implantable electrode placed inside the nerve, and electrical stimulators placed outside the body, the system will provide electrical micro stimulation to help reduce painful sensations - and may even have applications such as enabling amputees to sense virtual environments by touch.
Seeing things
The potential of such techniques doesn’t stop at monitoring, diagnosis and managing chronic conditions. The OPTONEURO project could ultimately help return functional sight to blind people.
”Optogenetics” is an exciting new gene therapy technique that makes nerve cells sensitive to particular colours of light. Simple pulses of intense light cause these photosensitised nerve cells to fire ”action potentials”, the carriers of information in the nervous system. To activate the nerve cells, however, the new therapy depends on high illumination densities - bright light shining on very small areas.
The OPTONEURO project therefore aims to develop the complementary optoelectronics needed to stimulate these photosensitised neurons. The system would be scalable for applications both in basic neuroscience research and in ”neuroprosthesis”. In particular, the optoelectronics should be used in a future optogenetic-optoelectronic retinal prosthesis - an artificial eye - for those blinded by the ”retinitis pigmentosa” disease.
The project requires a team of specialists in photonics, micro-optics and neurobiology to develop an array of ultra-bright electronically controlled micro-LEDs, which could also provide a new research tool for the neuroscience and neurotechnology community.
The SEEBETTER project is also looking to develop artificial vision prosthetics for the blind. Conventional image sensors have severe limitations, but ”silicon retina” vision sensors aim to mimic the biological retina”s information processing - computing both spatial and temporal aspects of the visual input. To date, these silicon retinas suffer from low quantum efficiency - meaning low light sensitivity - and an inability to combine both spatial and temporal processing on the same chip.
SEEBETTER’s team of experts - from biology and biophysics, as well as biomedical, electrical and semiconductor engineering - aim to use genetic and physiological techniques to understand better the function of the retina and model the retina’s vision processing. They will then design and build the first high-performance silicon retina, implemented on a single silicon wafer, specialised for both spatial and temporal visual processing.
Understand the neurobiological principles of seeing - beyond the functioning of the retina alone - may help us to replicate the success of human vision for computers and robots. The RENVISION project aims to achieve a comprehensive understanding of how the retina encodes visual information through the different cellular layers and to use such insights to develop a retina-inspired computational approach to computer vision.
Using high-resolution 3D microscopy will allow the researchers to make images of the inner retinal layers at near-cellular resolution. This new knowledge on retinal processing will help develop advanced pattern recognition and machine-learning technologies. The project could therefore solve some of the most difficult tasks in computer vision - such as automated scene categorisation and human action recognition - so that robots and computers can see and perceive what is happening in the images they receive.
These are just some of the EU-funded ICT projects using electronics and computing technologies to understand, augment and improve the human brain and its functioning. The results have the potential to reduce the impact of disability and disease, and improve our computing power, IT infrastructure and economy.
Pitt multidisciplinary research team proposes mathematical model that examines multiple walking patterns and movements in adults older than 65
Older adults diagnosed with brain disorders such as Parkinson’s disease often feel a loss of independence because of their lack of mobility and difficulty walking. To better understand and improve these mobility issues—and detect them sooner—a University of Pittsburgh multidisciplinary research team is working toward building a more advanced motion test that addresses a wider range of walking patterns and movements.
In a recent issue of IEEE Transactions on Neural Systems and Rehabilitation Engineering, researchers from Pitt’s Swanson School of Engineering, School of Health and Rehabilitation Sciences, and School of Medicine propose a mathematical model that can examine multiple walking, or gait-related, features in healthy and clinical populations. To date, no study has brought together such a team to examine such a high number of movement features comparing healthy and clinical older adults. Previous studies have typically only measured one or two types of movement features in just one population.
“Right away, you can tell whether an older individual has difficulties walking by conducting a simple gait test,” said Ervin Sejdic, lead author of the paper and an assistant professor of engineering in the Swanson School. “But can we quantify these changes and document them earlier? That’s the biggest issue here and what we’re trying to model.”
Thirty-five adults older than 65 were recruited for the study, including 14 healthy participants, 10 individuals with Parkinson’s disease, and 11 adults who had impaired feeling in their legs owing to peripheral neuropathy (nerve damage). Walking trials were performed using a computer-controlled treadmill, and participants wore an accelerometer—a small box attached with a belt—and a set of reflective markers on their lower body that allowed for tracking of the participants’ movements through a camera-based, motion-analysis system. These two systems allowed the team to examine the torso and lower body movements of patients as they walked. Participants completed three walking trials on the treadmill—one at a usual walking pace, another while walking slowly, and another that included working on a task while walking (i.e. pushing a button in response to a sound).
The accelerometer signals were used to examine three aspects of movement: participants moving forward and backward, side to side, and up and down. The researchers then used advanced mathematical computations to extract data from these signals.
The results—integrated into the mathematical models—showed significant differences between the healthy and clinical populations. These metrics were able to discriminate between the three groups, identifying critical features in how the participants walked.
The Pitt team is now looking to conduct this type of study on a larger scale—evaluating the gait patterns of older adults residing within independent living facilities.
“Our results indicate that we can potentially develop these mathematical models as biomarkers to predict changes in walking due to diseases like Parkinson’s disease,” said Sejdic. “Now, we want to take it further. We’re especially hoping to help those individuals in independent living facilities by predicting the declines in their walking even earlier.”
“What also makes this study unique is the multidisciplinary team approach we used,” said Jennifer S. Brach (SHRS ’94G, ’00G) coprincipal investigator of the study and associate professor in Pitt’s Department of Physical Therapy. “Here we brought together a research team that included engineers, physical therapists, and experts in geriatrics to work on an important problem in older adults—changes in mobility.”
It is now possible to identify the meaning of words with multiple meanings, without using their semantic context
Two Brazilian physicists have now devised a method to automatically elucidate the meaning of words with several senses, based solely on their patterns of connectivity with nearby words in a given sentence – and not on semantics. Thiago Silva and Diego Amancio from the University of São Paulo, Brazil, reveal, in a paper about to be published in EPJ B, how they modelled classics texts as complex networks in order to derive their meaning. This type of model plays a key role in several natural processing language tasks such as machine translation, information retrieval, content analysis and text processing.
In this study, the authors chose a set of ten so-called polysemous words—words with multiple meanings—such as bear, jam, just, rock or present. They then verified their patterns of connectivity with nearby words in the text of literary classics such as Jane Austen’s Pride and Prejudice. Specifically, they established a model that consisted of a set of nodes representing words connected by their “edges,” if they are adjacent in a text.
The authors then compared the results of their disambiguation exercise with the traditional semantic-based approach. They observed significant accuracy rates in identifying the suitable meanings when using both techniques. The approach described in this study, based on a so-called deterministic tourist walk characterisation, can therefore be considered a complementary methodology for distinguishing between word senses.In future works, the authors are planning to devise new measures to connect not only adjacent words, but also words within a given interval in order to enhance the ability of the model to grasp semantic factors. This approach is supported by another recent study by the same authors, showing that traditional complex network measures mainly depend on the syntax.
Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of disease progression. Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer’s, Parkinson’s and other related neurodegenerative diseases.
Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson’s disease patients, can exist in at least two different structural shapes, or “strains,” when it clumps into fibrils, despite having precisely the same chemical composition.
These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer’s disease.
Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of “seeded” fibril formation in test tubes.
The findings appear in the July 3rd issue of Cell.
Morphed Misfolding Proteins Found In Overlapping Neurodegenerative Diseases
Tau and alpha-synuclein protein clumps are hallmarks of separate diseases – Alzheimer’s and Parkinson’s, respectively. Yet these two proteins are often found entangled in diseased brains of patients who may manifest symptoms of both disorders.
One possible explanation for this convergence of Alzheimer’s and Parkinson’s disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation “Strain A,” and the evolved conformation, “Strain B.”
To figure out how A and B differ, Guo showed that the two strains folded into different shapes, as indicated by their differential reactivity to antibodies and sensitivity to protein-degrading enzymes. The two strains also differed in their ability to promote tau fibrillization and pathology in mouse brains, mimicking the results from cultured cells. When analyzing post-mortem brains of Parkinson’s patients, the team found at least two distinct forms of pathological alpha-synuclein.
Lee and her team speculate that in humans, alpha-synuclein aggregates may shift their shapes as they pass from cell to cell (much like a cube of silly putty being re-shaped to form a sphere), possibly developing the ability to entangle other proteins such as tau along the way. That process, in turn, could theoretically yield distinct types of alpha-synuclein pathologies that are observed in different brain regions of Parkinson’s disease patients.
While further research is needed to confirm and extend these findings, they have potentially significant implications for patients afflicted with Parkinson’s and other neurodegenerative diseases. For example, Lee explains, they could account for some of the heterogeneity observed in Parkinson’s disease. Different strains of pathological alpha-synuclein may promote formation of distinct types of alpha-synuclein aggregates that may or may not induce tau pathology in different brain regions and in different patients. That, in turn, could explain why some Parkinson’s patients, for example, experience only motor impairments while others ultimately develop cognitive impairments.
The findings also have potential therapeutic implications, Lee says. By recognizing that pathological alpha-synuclein can exist in different forms that are linked with different impairments, researchers can now selectively target one or the other, or both, for instance with strain-selective antibodies.
“What we’ve found opens up new areas for developing therapies, and particularly immunotherapies, for Parkinson’s and other neurodegenerative diseases,” Lee says.
In a study that could change the way scientists view the process of protein production in humans, University of Chicago researchers have found a single gene that encodes two separate proteins from the same sequence of messenger RNA.
Published online July 3 in Cell, their finding elucidates a previously unknown mechanism in human gene expression and opens the door for new therapeutic strategies against a thus-far untreatable neurological disease.
"This is the first example of a mechanism in a higher organism in which one gene creates two proteins from the same mRNA transcript, simultaneously," said Christopher Gomez, MD, PhD, professor and chairman of the Department of Neurology at the University of Chicago, who led the study. "It represents a paradigm shift in our understanding of how genes ultimately encode proteins."
The human genome contains a similar number of protein-coding genes as the nematode worm (roughly 20,000). This disparity between biological complexity and gene count partially can be explained by the fact that individual genes can encode multiple protein variants via the production of different sequences of messenger RNA (mRNA) — short, mass-produced copies of genetic code that guide the creation of myriad cellular machinery.
Gomez and his team, which included first author Xiaofei Du, MD, discovered a new layer of complexity in this process of gene expression as they studied spinocerebellar ataxia type-6 (SCA6), a neurodegenerative disease that causes patients to slowly lose coordination of their muscles and eventually their ability to speak and stand. Human genetic studies identified its cause as a mutation in CACNA1A — a gene that encodes a calcium channel protein important for nerve cell function — resulting in extra copies of the amino acid glutamine.
However, although the gene, mutation and dysfunction are known, attempts to find the biological mechanism of the disease proved inconclusive. Calcium channel proteins with the mutation still seemed to function normally.
Suspecting another factor at play, Gomez and his team instead focused on α1ACT, a poorly understood, free-floating fragment of the CACNA1A calcium channel protein known to express extra copies of glutamine in SCA6 cells. The researchers first looked at its origin and found that, to their surprise, α1ACT was generated from the same mRNA sequence as the CACNA1A calcium channel.
For the first time, they had evidence of a human gene that coded one strand of mRNA that coded two separate, structurally distinct proteins. This occurred due to the presence of a special sequence in the mRNA known as an internal ribosomal entry site (IRES). Normally found at the beginning of an mRNA sequence, this IRES site sat in the middle, creating a second location for ribosomes, the cellular machines that read mRNA, to begin the process of protein production.
Looking at function, Gomez and his team found that normal α1ACT acted as a transcription factor and enhanced the growth of specific brain cells. Importantly, mutated α1ACT appeared to be toxic to nerve cells in a petri dish, and caused SCA6-like symptoms in an animal model.
The team hopes to discover other examples of human genes with similar IRES sites to better understand the implications of this new class of “bifunctional” genes on our basic biology. For now, they are focused on leveraging their findings toward helping SCA6 patients and already are working on ways to silence mutated α1ACT.
"We discovered this genetic phenomenon in the pursuit of a disease cause and, in finding it, immediately have a potential strategy for developing preclinical tools to treat that disease," Gomez said. "If we can target the IRES and inhibit production of this mutant form of α1ACT in SCA6, we may be able to stop the progression of the disease."
In the first study to compare all available IVF treatments and the risk of neurodevelopmental disorders in children, researchers find that IVF treatments for the most severe forms of male infertility are associated with an increased risk of intellectual disability and autism in children.
Autism and intellectual disability remain a rare outcome of IVF, and whilst some of the risk is associated with the risk of multiple births, the study provides important evidence for parents and clinicians on the relative risks of modern IVF treatments.
Published in JAMA today, the study is the largest of its kind and was led by researchers at King’s College London (UK), Karolinska Institutet (Sweden) and Mount Sinai School of Medicine in New York (USA).
By using anonymous data from the Swedish national registers, researchers analysed more than 2.5 million birth records from 1982 and 2007 and followed-up whether children had a clinical diagnosis of autism or intellectual disability (defined as having an IQ below 70) up until 2009. Of the 2.5m children, 1.2% (30,959) were born following IVF. Of the 6,959 diagnosed with autism, 103 were born after IVF; of the 15,830 with intellectual disability, 180 were born after IVF. Multiple pregnancies are a known risk factor for pre-term birth and some neurodevelopmental disorders, so the researchers also compared single to multiple births.
Sven Sandin, co-author of the study from King’s College London’s Institute of Psychiatry says: “IVF treatments are vastly different in terms of their complexity. When we looked at IVF treatments combined, we found there was no overall increased risk for autism, but a small increased risk of intellectual disability. When we separated the different IVF treatments, we found that ‘traditional’ IVF is safe, but that IVF involving ICSI, which is specifically recommended for paternal infertility is associated with an increased risk of both intellectual disability and autism in children.”
Compared to spontaneous conception, children born from any IVF treatment were not at an increased risk of autism, but were at a small increased risk of intellectual disability (18% increase – from 39.8 to 46.3 per 100,000 person years). However, the risk increase disappeared when multiple births were taken into account.
Secondly, the researchers compared all 6 different types of IVF procedures available in Sweden – whether fresh or frozen embryos were used; if intracytoplasmic sperm injection (ICSI) was used, and if so, whether sperm was ejaculated or surgically extracted. Developed in 1992, ICSI is recommended for male infertility and is now used in about half of all IVF treatments. The procedure involves injecting a single sperm directly into an egg, rather than fertilization happening in a dish, as in standard IVF.
Children born after IVF treatments with ICSI (with either fresh or frozen embryos) were at an increased risk of intellectual disability (51% increase – 62 to 93 per 100,000). This association was even higher when a preterm birth also occurred (73% increase – 96 to 167 per 100,000). Even when multiple and pre-term births were taken into account, IVF treatment with ICSI and fresh embryos was associated with an increased risk of intellectual disability (66% increase for singleton birth, term birth following ICSI with fresh embryos– 48 to 76 per 100,000).
Children born after IVF with ICSI using surgically extracted sperm and fresh embryos were at an increased risk of autism (360% increase - 29 to 136 per 100,000) but the association disappeared when multiple births were taken into account.
An existing FDA-approved drug improves cognitive function in a mouse model of Down syndrome, according to a new study by researchers at the Stanford University School of Medicine.
The drug, an asthma medication called formoterol, strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories, the study said. It also improved contextual learning, in which the brain integrates spatial and sensory information.
Both hippocampal function and contextual learning, which are impaired in Down syndrome, depend on the brain having a good supply of the neurotransmitter norepinephrine. This neurotransmitter sends its signal via several types of receptors on the neurons, including a group called beta-2 adrenergic receptors.
“This study provides the initial proof-of-concept that targeting beta-2 adrenergic receptors for treatment of cognitive dysfunction in Down syndrome could be an effective strategy,” said Ahmad Salehi, MD, PhD, the study’s senior author and a clinical associate professor of psychiatry and behavioral sciences. The study was published online July 2 in Biological Psychiatry.
Down syndrome, which is caused by an extra copy of chromosome 21, results in both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function. As a result, children with Down syndrome fall behind their peers’ cognitive development. In addition, adults with Down syndrome develop Alzheimer’s-type pathology in their brains by age 40. Down syndrome affects about 400,000 people in the United States and 6 million worldwide.
In prior Down syndrome research, scientists have seen deterioration of the brain center that manufactures norepinephrine in both people with Down syndrome and its mouse model. Earlier work by Salehi’s team found that giving a norepinephrine precursor could improve cognitive function in a mouse model genetically engineered to mimic Down syndrome.
Studies have shown that children with autism often struggle socially and now new research suggests that a corresponding lack of motor skills – including catching and throwing – may further contribute to that social awkwardness.
The findings, published in the July issue of Adapted Physical Activity Quarterly, add to the growing body of research highlighting the link between autism and motor skill deficits.
Lead author Megan MacDonald is an assistant professor in the College of Public Health and Human Sciences at Oregon State University. She is an expert on the movement skills of children with autism spectrum disorder.
In the study, researchers looked a group of young people ages 6 to 15 diagnosed with autism spectrum disorder. All 35 of the students were considered high-functioning and attended typical classrooms. The researchers looked at two types of motor skills – “object-control” motor skills, which involve more precise action such as catching or throwing – and “locomotion” skills, such as running or walking. Students who struggled with object-control motor skills were more likely to have more severe social and communication skills than those who tested higher on the motor skills test.
“So much of the focus on autism has been on developing social skills, and that is very crucial,” MacDonald said. “Yet we also know there is a link between motor skills and autism, and how deficits in these physical skills play into this larger picture is not clearly understood.”
Developing motor skills can be crucial for children because students often “mask” their inability to participate in basic physical activities. A student with autism may not be participating on the playground because of a lack of social skills, but the child may also be unsure of his or her physical ability to play in these activities.
“Something which seems as simple as learning to ride a bike can be crucial for a child with autism,” MacDonald said. “Being able to ride a bike means more independence and autonomy. They can ride to the corner store or ride to a friend’s house. Those kind of small victories are huge.”
She said the ability to run, jump, throw and catch isn’t just for athletic kids – physical activity is linked not only to health, but to social skills and mental well-being.
“I often show people photos of what I like to do in my spare time – canoeing, hiking, snowshoeing, and then point out that these require relatively proficient motor skills,” she said. “But that is not why I do those things. I’m doing it because I’m with my friends and having fun.”
MacDonald said the positive news for parents and educators is that motor skills can be taught.
“We have programs and interventions that we know work, and have measurable impact on motor skill development,” MacDonald said. “We need to make sure we identify the issue and get a child help as early as possible.”