With imprecise chips to the artificial brain

Which circuits and chips are suitable for building artificial brains using the least possible amount of power? This is the question that Junior Professor Dr. Elisabetta Chicca from the Center of Excellence Cognitive Interaction Technology (CITEC) has been investigating in collaboration with colleagues from Italy and Switzerland. A surprising finding: Constructions that use not only digital but also analog compact and imprecise circuits are more suitable for building artificial nervous systems, rather than arrangements with only digital or precise but power-demanding analog electronic circuits. The study will be published in the scientific journal ‘Proceedings of the IEEE’. A preview was published online on Thursday, 1 March 2014.

Elisabetta Chicca is the head of the research group ‘Neuromorphic Behaving Systems’. One of the aims of her work is to make robots and other technical systems as autonomous and capable of learning as possible. The artificial brains that she and her team are developing are modelled on the biological nervous systems of humans and animals. ‘Environmental stimuli are processed in the biological nervous systems of humans and animals in a totally different way to modern computers’, says Chicca. ‘Biological nervous systems organise themselves; they adapt and learn. In doing so, they require a relatively small amount of energy in comparison with computers and allow for complex skills such as decision-making, the recognition of associations and of patterns.’

The neuroinformatics researcher is trying to utilise biological principles to build artificial nervous systems. Dr. Chicca and her colleagues have been investigating which type of circuits can simulate synapses electronically. Synapses serve as the ‘bridges’ that transmit signals between nerve cells. Stimuli are communicated through them and they can also save information. Furthermore, the research team have analysed which type of circuit can imitate the so-called plasticity of the biological nerves. Plasticity describes the ability of nerve cells, synapses and cerebral areas to adapt their characteristics according to use. In the brains of athletes, for example, certain cerebral areas are more strongly connected than in non-athletes.

The four researchers also offer solutions for the control of artificial nervous systems. They present software on the basis of which programmes can be written that can control the circuits and chips of an ‘electronic brain’.

Older migraine sufferers may have more silent brain injury

Older migraine sufferers may be more likely to have silent brain injury, according to research published in the American Heart Association’s journal Stroke.

In a new study, people with a history of migraine headaches had double the odds of ischemic silent brain infarction compared to people who said they didn’t have migraines. Silent brain infarction is a brain injury likely caused by a blood clot interrupting blood flow to brain tissue. Sometimes called “silent strokes,” these injuries are symptomless and are a risk factor for future strokes.

Previous studies indicated migraine could be an important stroke risk factor for younger people.

“I do not believe migraine sufferers should worry, as the risk of ischemic stroke in people with migraine is considered small,” said Teshamae Monteith, M.D., lead author of the study and assistant professor of clinical neurology and chief of the Headache Division at the University of Miami Miller School of Medicine. “However, those with migraine and vascular risk factors may want to pay even greater attention to lifestyle changes that can reduce stroke risk, such as exercising and eating a low-fat diet with plenty of fruits and vegetables.”

High blood pressure, another important stroke risk factor, was more common in those with migraine. But the association between migraine and silent brain infarction was also found in participants with normal blood pressure.

Because Hispanics and African-Americans are at increased stroke risk, researchers from the Northern Manhattan Study (NOMAS) – a collaborative investigation between the University of Miami and Columbia University – studied a multi-ethnic group of older adults (41 percent men, average age 71) in New York City. About 65 percent of participants were Hispanic. Comparing magnetic resonance imaging results between 104 people with a history of migraine and 442 without, they found:

• A doubling of silent brain infarctions in those with migraine even after adjusting for other stroke risk factors;
• No increase in the volume of white-matter hyperintensities (small blood vessel abnormalities) that have been associated with migraine in other studies;
• Migraines with aura — changes in vision or other senses preceding the headache — wasn’t common in participants and wasn’t necessary for the association with silent cerebral infarctions.

“While the lesions appeared to be ischemic, based on their radiographic description, further research is needed to confirm our findings,” Monteith said.

The research raises the question of whether preventive treatment to reduce the severity and number of migraines could reduce the risk of stroke or silent cerebral infarction.

“We still don’t know if treatment for migraines will have an impact on stroke risk reduction, but it may be a good idea to seek treatment from a migraine specialist if your headaches are out of control,” Monteith said.

Hope for paraplegic patients

People with severe injuries to their spinal cord currently have no prospect of recovery and remain confined to their wheelchairs. Now, all that could change with a new treatment that stimulates the spinal cord using electric impulses. The hope is that the technique will help paraplegic patients learn to walk again. From June 3 – 5, Fraunhofer researchers will be at the Sensor + Test measurement fair in Nürnberg to showcase the implantable microelectrode sensors they have developed in the course of pre-clinical development work (Hall 12, Booth 12-537).

Thomas T. was just 25 years old when a severe motorcycle accident changed his life in an instant. Doctors diagnosed him with paraplegia following an injury to his spinal cord in the lumbar region. The young man has been confined to a wheelchair ever since. The diagnosis of paraplegia came as a shock, and it was only in the course of a month-long period of rehabilitation that Thomas T. was able to come to terms with his condition. Patients like him currently have no prospect of recovery, as there is still no effective course of treatment available for improving motor function among the severely disabled.

Now a consortium of European research institutions and companies want to get affected patients quite literally back on their feet. In the EU’s NEUWalk project, which has been awarded funding of some nine million euros, researchers are working on a new method of treatment designed to restore motor function in patients who have suffered severe injuries to their spinal cord. The technique relies on electrically stimulating the nerve pathways in the spinal cord. “In the injured area, the nerve cells have been damaged to such an extent that they no longer receive usable information from the brain, so the stimulation needs to be delivered beneath that,” explains Dr. Peter Detemple, head of department at the Fraunhofer Institute for Chemical Technology’s Mainz branch (IMM) and NEUWalk project coordinator. To do this, Detemple and his team are developing flexible, wafer-thin microelectrodes that are implanted within the spinal canal on the spinal cord. These multichannel electrode arrays stimulate the nerve pathways with electric impulses that are generated by the accompanying by microprocessor-controlled neurostimulator. “The various electrodes of the array are located around the nerve roots responsible for locomotion. By delivering a series of pulses, we can trigger those nerve roots in the correct order to provoke motion sequences of movements and support the motor function,” says Detemple.

Researchers from the consortium have already successfully conducted tests on rats in which the spinal cord had not been completely severed. As well as stimulating the spinal cord, the rats were given a combination of medicine and rehabilitation training. Afterwards the animals were able not only to walk but also to run, climb stairs and surmount obstacles. “We were able to trigger specific movements by delivering certain sequences of pulses to the various electrodes implanted on the spinal cord,” says Detemple. The research scientist and his team believe that the same approach could help people to walk again, too. “We hope that we will be able to transfer the results of our animal testing to people. Of course, people who have suffered injuries to their spinal cord will still be limited when it comes to sport or walking long distances. The first priority is to give them a certain level of independence so that they can move around their apartment and look after themselves, for instance, or walk for short distances without requiring assistance,” says Detemple.

Researchers from the NEUWalk project intend to try out their system on two patients this summer. In this case, the patients are not completely paraplegic, which means there is still some limited communication between the brain and the legs. The scientists are currently working on tailored implants for the intervention. “However, even if both trials are a success, it will still be a few years before the system is ready for the general market. First, the method has to undergo clinical studies and demonstrate its effectiveness among a wider group of patients,” says Detemple.

Electric spinal cord stimulation to offer relief for Parkinson’s disease

Patients with Parkinson’s disease could also benefit from the neural prostheses. The most well-known symptoms of the disease are trembling, extreme muscle tremors and a short, stooped gait that has a profound effect on patients’ mobility. Until now this neurodegenerative disorder has mostly been treated with dopamine agonists – drugs that chemically imitate the effects of dopamine but that often lead to severe side effects when taken over a longer period of time. Once the disease has reached an advanced stage, doctors often turn to deep brain stimulation. This involves a complex operation to implant electrodes in specific parts of the brain so that the nerve cells in the region can be stimulated or suppressed as required. In the NEUWalk project, researchers are working on electric spinal cord simulation – an altogether less dangerous intervention that should however ease the symptoms of Parkinson’s disease just as effectively. “Initial animal testing has yielded some very promising results,” says Detemple.

The researchers from Mainz will be at the Sensor + Test 2014 measurement fair in Nürnberg to showcase their neural prostheses. These include implantable microelectrode sensors controlled by microprocessors as well as rigid multi-channel sensors that can be used to record electrophysiological signals and to stimulate neural structures.

No such thing as a ‘universal’ intelligence test. Cultural differences determine results country by country

Researchers at the University of Granada have shown that a universal test of intelligence quotient (IQ) does not exist. Results in this type of test are determined by cultural differences.

Their objective was to study and explain cultural differences in IQ test performance. To do this, scientists from CIMCYC—the University of Granada’s Brain Mind and Behavior Research Center—conducted a study of 54 individuals aged between 18 and 54 years: 27 were Spanish and the other 27 were Moroccans residing in Spain.

The groups were selected to ensure that clear cultural differences existed between them: they spoke different languages (Spanish versus Arabic), professed different religions (Christians versus Muslims), had different traditions, and came from very different geographical contexts (Europe versus Africa).

Both groups underwent different tests of intellectual capacity: for example, a test of non-verbal intelligence, and various neuropsychological tests that measure functions such as visual memory and executive functions.

The same test measures different cognitive functions

Although the two groups were similar in terms of sex, educational level and socio-economic status, the results showed that in the test of non-verbal intelligence, the Spanish group obtained a higher IQ score than the Moroccan group. Moreover, the neuropsychological skills used in each subtest were clearly dependent on the country of origin of each participant. In other words, the same test can measure different cognitive functions in individuals from different cultures.

In the light of the results of this study, the authors suggest that the non-verbal tests cannot be considered culture-free and confirm the importance of validating the tests in their cultural context.

In 2014, this study has been ranked in the top 10 of articles downloaded from Archives of Clinical Neuropsychology.

Herpes-loaded stem cells used to kill brain tumors

Harvard Stem Cell Institute (HSCI) scientists at Massachusetts General Hospital have a potential solution for how to more effectively kill tumor cells using cancer-killing viruses. The investigators report that trapping virus-loaded stem cells in a gel and applying them to tumors significantly improved survival in mice with glioblastoma multiforme, the most common brain tumor in human adults and also the most difficult to treat.

The work, led by Khalid Shah, MS, PhD, an HSCI Principal Faculty member, is published in the Journal of the National Cancer Institute. Shah heads the Molecular Neurotherapy and Imaging Laboratory at Massachusetts General Hospital.

Cancer-killing or oncolytic viruses have been used in numerous phase 1 and 2 clinical trials for brain tumors but with limited success. In preclinical studies, oncolytic herpes simplex viruses seemed especially promising, as they naturally infect dividing brain cells. However, the therapy hasn’t translated as well for human patients. The problem previous researchers couldn’t overcome was how to keep the herpes viruses at the tumor site long enough to work.

Shah and his team turned to mesenchymal stem cells (MSCs)—a type of stem cell that gives rise to bone marrow tissue—which have been very attractive drug delivery vehicles because they trigger a minimal immune response and can be utilized to carry oncolytic viruses. Shah and his team loaded the herpes virus into human MSCs and injected the cells into glioblastoma tumors developed in mice. Using multiple imaging markers, it was possible to watch the virus as it passed from the stem cells to the first layer of brain tumor cells and subsequently into all of the tumor cells.

“So, how do you translate this into the clinic?” asked Shah, who also is an Associate Professor at Harvard Medical School.

“We know that 70-75 percent of glioblastoma patients undergo surgery for tumor debulking, and we have previously shown that MSCs encapsulated in biocompatible gels can be used as therapeutic agents in a mouse model that mimics this debulking,” he continued. “So, we loaded MSCs with oncolytic herpes virus and encapsulated these cells in biocompatible gels and applied the gels directly onto the adjacent tissue after debulking. We then compared the efficacy of virus-loaded, encapsulated MSCs versus direct injection of the virus into the cavity of the debulked tumors.”

Using imaging proteins to watch in real time how the virus combated the cancer, Shah’s team noticed that the gel kept the stem cells alive longer, which allowed the virus to replicate and kill any residual cancer cells that were not cut out during the debulking surgery. This translated into a higher survival rate for mice that received the gel-encapsulated stem cells.

“They survived because the virus doesn’t get washed out by the cerebrospinal fluid that fills the cavity,” Shah said. “Previous studies that have injected the virus directly into the resection cavity did not follow the fate of the virus in the cavity. However, our imaging and side-by-side comparison studies showed that the naked virus rarely infects the residual tumor cells. This could give us insight into why the results from clinical trials with oncolytic viruses alone were modest.”

The study also addressed another weakness of cancer-killing viruses, which is that not all brain tumors are susceptible to the therapy. The researchers’ solution was to engineer oncolytic herpes viruses to express an additional tumor-killing agent, called TRAIL. Again, using mouse models of glioblastoma—this time created from brain tumor cells that were resistant to the herpes virus—the therapy led to increased animal survival.

“Our approach can overcome problems associated with current clinical procedures,” Shah said. “The work will have direct implications for designing clinical trials using oncolytic viruses, not only for brain tumors, but for other solid tumors.”

Further preclinical work will be needed to use the herpes-loaded stem cells for breast, lung and skin cancer tumors that metastasize to the brain. Shah predicts the approach will enter clinical trials within the next two to three years.

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War and Peace (of Mind)
Meditation training may help reduce stress disorders among U.S. military personnel

Researchers from the University of California, San Diego School of Medicine and Naval Health Research Center have found that mindfulness training – a combination of meditation and body awareness exercises – can help U.S. Marine Corps personnel prepare for and recover from stressful combat situations.

The study, published in the May 16, 2014 online issue of the American Journal of Psychiatry, suggests that incorporating meditative practices into pre-deployment training might be a way to help the U.S. military reduce rising rates of stress-related health conditions, including PTSD, depression and anxiety, within its ranks.

“Mindfulness training won’t make combat easier,” said Martin Paulus, MD, professor of psychiatry and senior author. “But we think it can help Marines recover from stress and return to baseline functioning more quickly.”

Scientists describe mindfulness as a mental state characterized by “full attention to the present moment without elaboration, judgment or emotional reactivity.”  Mindfulness training, traditionally practiced through sitting meditation, attempts to cultivate this mental state by quieting the mind of extraneous thoughts.

In the study, Marine infantrymen in four platoons at Marine Corps Base Camp Pendleton took an eight-week course in mindfulness, tailored for individuals operating in highly stressful environments.

The course included classroom instruction on meditation and homework exercises, as well as training on interoception – the ability to help the body regulate its overall physical equilibrium (homeostasis) by becoming aware of bodily sensations, such as tightness in the stomach, heart rate and tingling of the skin.

“If you become aware of tightness in your stomach, your brain will automatically work to correct that tightness,” Paulus explained.

Participating Marines, along with others who had not undergone mindfulness training, then spent a day in mock immersive combat at a 32,000-square-foot training facility staged to resemble a rural Middle Eastern village. During the day’s exercises, Marines patrolled the village, met village leadership and responded to a highly realistic ambush.

The scientists found that the heart and breathing rates of those who had received mindfulness training returned to their normal, baseline levels faster than those who had not received the mindfulness training. Blood levels of a tell-tale neuropeptide suggested that the mindfulness-trained Marines experienced improved immune function, as well.

Subsequent magnetic resonance imaging scans revealed that the mindfulness-trained Marines had reduced activity patterns in regions of the brain responsible for integrating emotional reactivity, cognition and interoception. Lori Haase, a postdoctoral fellow in Paulus’ lab and a co-author of the study, said similar brain activity patterns had been observed in high performance athletes and Navy seals. High-activity levels in these areas of the brain, she noted, are associated with anxiety and mood disorders. The scientists hypothesize that reduced brain activity in the anterior insula and anterior cingulate may be characteristic of elite performers in general.

“That we can re-regulate the activity in these areas with so little training is this study’s most significant finding,” Paulus said. “Mindfulness helps the body optimize its response to stress by helping the body interpret stressful events as bodily sensations. The brain adds less emotional affect to experiences and this helps with stress recovery.”

New headway in battle against neurodegenerative diseases

Conditions which may accelerate the spread of Parkinson’s disease, and a potential means of enhancing naturally-occurring defences against neurodegenerative disorders, have been identified in two new studies.

Two significant breakthroughs which could inform future treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, have been announced by scientists.

The research, published in two separate studies this week, advances understanding of the early development of such disorders and how they might be prevented – in particular by identifying the biological areas and processes that could be pinpointed by future drugs.

Both sets of results have emerged from collaborations between the research groups led by Chris Dobson, Tuomas Knowles and Michele Vendruscolo at the University of Cambridge, who focus on understanding protein “misfolding” diseases. These include Alzheimer’s and Parkinson’s diseases, as well as numerous others.

The first study provides evidence that the early spread of the protein aggregates associated with Parkinson’s appears to happen at an accelerated rate in mildly acidic conditions. This suggests that particular compartments within brain cells, which are slightly more acidic than others, may turn out to be appropriate targets for future treatments fighting the disease.

Meanwhile, researchers behind the second study appear to have identified a way in which the effectiveness of so-called molecular “chaperones”, responsible for limiting the damage caused by misfolded proteins, can be significantly enhanced.

The papers appear in the latest issue of Proceedings of the National Academy of Sciences of the USA.

As the term suggests, protein misfolding diseases stem from the fact that proteins, which need to fold into a particular shape to carry out their assigned function in the body, can sometimes misfold. In certain cases these misfolded proteins then clump together into fibre-like threads, called amyloid fibrils, potentially becoming toxic to other cells.

How this formation begins at a molecular level is still not completely understood, but comprehending the process will be fundamental to the development of future therapies and is the subject of extensive current research.

The first of the new studies builds on research published in 2013, which showed that in Alzheimer’s sufferers, the initial “nucleation” between proteins, which leads to amyloid formation, is followed by an amplification process called secondary nucleation. In these secondary events, the existing amyloid structures facilitate the formation of new aggregates, leading to their exponential increase. This process is likely to be at the heart of the development and spread of the disease in affected brains.

Using the same techniques, the researchers behind the latest study identified a similar process that is relevant in the early stage development of Parkinson’s Disease. Their work focused on a protein called α-synuclein, which is associated with the disorder, and simulated different conditions in which this protein might misfold and form clumps.

As with the previous study on Alzheimer’s, the research identified that Parkinson’s could spread through a series of secondary nucleation events. In addition, however, it showed that in the case of α-synuclein, this happens at a highly accelerated rate only in solutions which are mildly acidic, with a pH below 5.8. The finding is important because certain sub-compartments within cells are more acidic than others, meaning that these may be particularly productive areas for future treatments to target.

Dr Tuomas Knowles, from the Department of Chemistry and a Fellow of St John’s College, Cambridge, said: “This tells us much more about the molecular mechanisms underlying protein aggregation in Parkinson’s and suggests that mildly acidic microenvironments within cells may enhance that process by several orders of magnitude. Not every sub-cellular compartment offers these conditions, so it takes us much closer to understanding how the disease might spread.”

The second study meanwhile suggests a potential route to improving the effectiveness of a particular molecular “chaperone” – a loose classification for proteins which assist in the folding of others, thereby preventing them from causing damage when they misfold.

The researchers focused on a chaperone called α2-macroglobulin (α2M), which is found outside cells themselves. This is important because neurodegenerative diseases often stem from a process which begins with extracellular misfolding. The α2M was tested on a substrate of the amyloid-beta peptide associated with Alzheimer’s Disease.

Typically, the potency of α2M is limited. The new study, however, found that when it comes into contact with the oxidant hypochlorite – the same chemical found in household bleach, which also naturally occurs in our immune systems – its structure is modified in a manner that makes it into a much more dynamic defence.

In their report, the researchers suggest that this increased effectiveness stems from the fact that α2M, which is usually found in a four-part, “tetrameric” form, breaks down into “dimeric”, two-part forms when it comes into contact with hypochlorite.

The chaperone usually plays its role by preventing a misfolded protein from interacting with the membranes that surround and protect cells. Once in its dimeric form, however, receptor binding sites within the α2M are exposed, leading to specific interactions with receptors on the cell itself. If the α2M has already interacted with misfolded proteins, this connection triggers the cell to break the potentially harmful protein down.

“It’s almost like a warning flag for the cell, telling it that something is wrong,” Dr Janet Kumita, from the Department of Chemistry, explained. “It triggers the cell to react in a way that subjects the cargo of misfolded protein to a degradation pathway.”

“Increasing its potency in this way is an exciting prospect. If we could find a way of developing a drug that introduces the same structural alterations, we would have a therapeutic intervention capable of increasing this protective activity in patients with Alzheimer’s Disease.”

Professor Christopher Dobson, from the University’s Department of Chemistry and Master of St John’s College, said: “These studies add very substantially to our detailed understanding of the molecular origins of neurodegenerative diseases, which are now becoming one of the greatest threats to healthcare in the modern world.”

“We are beginning to understand exactly how a single, aberrant event can lead to the proliferation and spreading of toxic species throughout the brain, and the manner in which our sophisticated defence mechanisms do their best to suppress such phenomena. It will undoubtedly provide vital clues to the development in due course of new and effective drugs to combat these debilitating and increasingly common disorders.”

Brain’s response to sexual images linked to number of sexual partners

Like most things, sex requires motivation. An attractive face, a pleasant fragrance, perhaps a sexy image. Yet people differ in their response to sex cues, some react strongly; some don’t. A greater responsiveness to sexual cues might provide greater motivation for a person to act sexually, and risky sexual behaviors typically occur when a person is motivated by particularly potent, sexual reward cues.

Now researchers at UCLA have, for the first time, directly linked brain responses  and real-world sexual behaviors. Specifically, the researchers found that how strongly the brain responded to viewing such images was related to the number of sex partners a person had in the previous year.

Led by Nicole Prause, a research scientist in the department of psychiatry in the UCLA Semel Institute for Neuroscience and Human Behavior, the study was published in the current online edition of the journal Social Cognitive and Affective Neuroscience. Prause and her colleagues used electroencephalogram (EEG) to measure a particular type of electrical activity in the brains of people as they were viewing a variety of images — some romantic, some pornographic, and some having nothing at all to do with sex.

Understanding how the brain responds to sexual images could help scientists create a brain stimulation intervention to reduce sensitivity to sexual reward and thus reduce some people’s proclivity to engage in risky sexual activities.

"These are the first data we know of that link brain responses to actual sexual risk behaviors," said Prause, who directs the Sexual Psychophysiology and Affective Neuroscience Laboratory at UCLA. "If your brain responds very strongly even to very tame pictures of sex, then you seem to be easily sexually excited in the real world, too. If we show very explicit sex pictures, eventually everyone’s brain responds strongly. It is those weaker images, just hinting at sex, that show the difference."

In the study, 40 men and 22 women, ages 18 to 40, completed a questionnaire that included the question, “How many partners have you had sexual intercourse with in the last 12 months?” They then were shown 225 images that included non-sexual, pleasant images (for example, skydiving), neutral images (like portraits) and sexual images ranging from G-rated to explicit scenes.

While viewing the images, participants’ brain activity was measured by EEG. Specifically, the researchers looked at a type of activity called late positive potential, which reacts to images depending on their emotional intensity.

The researchers found that participants who reported having had a higher number of sexual partners in the previous year exhibited similar late positive potential responses to both the graphic and less-graphic sexual images. Those who reported having had fewer intercourse partners in the previous year were different: They showed reduced late positive potential responses to the less explicit sexual images and greater response to the more graphic images.

"This pattern helps tell us why people may choose to pursue new sex partners," Prause said. "For example, some researchers have suggested that people may pursue new partners to experience sexual excitement that they did not experience in their regular lives or with their regular partner. These results, she said, "suggest that new partners actually might be pursued because people have high sexual excitement in response to any potential partner, whether regular or new. This distinction is very important if we want to help people feel in control of their sexual urges."