Neuroscience

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.”

The results of the study may bear significance in the treatment of Alzheimer’s disease and cancer

Dysfunction of the ubiquitin-proteasome system is related to many severe neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, and certain types of cancer. Such dysfunction is also believed to be related to some degenerative muscle diseases.

The proteasome is a large protein complex that maintains cellular protein balance by degrading and destroying damaged or expired proteins. The ubiquitin is a small protein that labels proteins for destruction for the proteasome. If the system does not work effectively enough, expired and damaged proteins accumulate in the cell. If the system is overly active, it destroys necessary proteins in addition to unnecessary ones. In both cases, cell function is disturbed, and the cell may even die.

Proteasome activity is believed to decrease with ageing. However, not much is yet known about how proteasome activity is regulated in an aging multicellular organism. The research team of Academy Research Fellow, Docent Carina Holmberg-Still has discovered an important proteasome regulatory mechanism. The study was published in Cell Reports, a highly esteemed scientific journal.

"We examined whether proteasome activity is affected by insulin/IGF-1 signalling [IIS], which regulates aging in many organisms. The results show that decreased IIS increases proteasome activity," says Holmberg-Still.

Proteasome activity was studied in C. elegans, a free-living roundworm. Decreased IIS increases proteasome activity through the FOXO transcription factor DAF-16 and the UBH-4 enzyme. DAF-16 represses the expression of ubh-4 in certain cell types. The ubh-4 enzyme slows proteasome activity, which means that its repression accelerates proteasome activity.

"Using a cell culture model, we proved that the same mechanism works in human cells," says Holmberg-Still. When the expression of the uchl5 enzyme – the human equivalent of ubh-4 – was decreased, proteasome activity and the degradation of harmful proteins increased.

"Our study shows that the effect of ageing and the related signalling pathway on proteasome activity is tissue-specific. This was a new and interesting discovery that bears great significance in terms of treatment opportunities," says researcher Olli Matilainen, who prepared his dissertation in Holmberg-Still’s research team.

The identification of proteins that regulate proteasome activity and an understanding of the regulatory mechanism offer new opportunities in treating diseases that involve proteasome dysfunction. According to Holmberg-Still, proteins that regulate proteasome activity are particularly interesting in terms of medicine development.

"An ability to accelerate proteasome activity could be beneficial in the treatment of neurodegenerative diseases. Targeted proteasome inhibitors would be useful in the treatment of cancer – general proteasome inhibitors are already used as cancer medication to some extent, but they often have harmful side effects, because they cannot be targeted to a specific tissue."

Holmberg-Still’s team continues to investigate tissue-specific mechanisms that regulate proteasome activity. The team collaborates with clinical researchers to confirm whether its research results can be refined for clinical use.

Researchers at NYU Langone Medical Center have discovered a mechanism that triggers chronic inflammation in Alzheimer’s, atherosclerosis and type-2 diabetes. The results, published today in Nature Immunology, suggest a common biochemical thread to multiple diseases and point the way to a new class of therapies that could treat chronic inflammation in these non-infectious diseases without crippling the immune system. Alzheimer’s, atherosclerosis and type-2 diabetes—diseases associated with aging and inflammation—affect more than 100 million Americans.

When the body encounters a pathogen, it unleashes a rush of chemicals known as cytokines that draws immune cells to the site of infection and causes inflammation. Particulate matter in the body, such as the cholesterol crystals associated with vascular disease and the amyloid plaques that form in the brain in Alzheimer’s disease, can also cause inflammation but the exact mechanism of action remains unclear. Researchers previously thought that these crystals and plaques accumulate outside of cells, and that macrophages—immune cells that scavenge debris in the body—induce inflammation as they attempt to clear them.

“We’ve discovered that the mechanism causing chronic inflammation in these diseases is actually very different,” says Kathryn J. Moore, PhD, senior author of the study and associate professor of medicine and cell biology, Leon H. Charney Division of Cardiology at NYU Langone Medical Center.

The researchers found that particulate matter does not linger on the outside of cells. Instead, a receptor called CD36 present on macrophages draws the soluble forms of these particles inside the cell where they are transformed into substances that trigger an inflammatory response. Says Dr. Moore, “What we found is that CD36 binds soluble cholesterol and protein matter associated with these diseases, pulls them inside the cell, and then transforms them. The resulting insoluble crystals and amyloid damage the macrophage and trigger a powerful cytokine, called interleukin-1B, linked to a chronic inflammatory response.”

These findings hold exciting clinical implications.When the researchers blocked the CD36 receptor in mice with atherosclerosis (in which cholesterol thickens the arteries), the cytokine response declined, fewer cholesterol crystals formed in plaques, and inflammation decreased. Consequently, atherosclerosis also abated.

Other less-targeted strategies to control inflammation may hamper the immune response, but the CD36 strategy spares certain cytokines to fight off pathogens, while blocking CD36’s ability to trigger interleukin-1B.

“Our findings identify CD36 as a central regulator of the immune response in these conditions and suggest that blocking CD36 might be a common therapeutic option for all three diseases,” says Dr. Moore.

Identification of a protein that appears to play an important role in the immune system’s removal of amyloid beta (A-beta) protein from the brain could lead to a new treatment strategy for Alzheimer’s disease. The report from researchers at Massachusetts General Hospital (MGH) has been published online in Nature Communications.

"We identified a receptor protein that mediates clearance from the brain of soluble A-beta by cells of the innate immune system," says Joseph El Khoury, MD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Infectious Diseases, co-corresponding author of the report. "We also found that deficiency of this receptor in a mouse model of Alzheimer’s disease leads to greater A-beta deposition and accelerated death, while upregulating its expression enhanced A-beta clearance from the brain."

The brain’s immune system – which includes cells like microglia, monocytes and macrophages that engulf and remove foreign materials – appears to play a dual role in neurodegenerative disorders like Alzheimer’s disease. At early stages, these cells mount a response against the buildup of A-beta, the primary component of the toxic plaques found in the brains of patients with the devastating neurological disorder. But as the disease progresses and A-beta plaques become larger, not only do these cells lose their ability to take up A-beta, they also release inflammatory chemicals that cause further damage to brain tissue.

In their investigation of factors that may underlie the breakdown of the immune system’s clearance of A-beta, El Khoury’s team with the hypothesis that, in addition to recognizing and binding to the insoluble form of A-beta found in amyloid plaques, the brain’s immune cells might also interact with soluble forms of A-beta that could begin accumulating in the brain before plaques appear. The researchers first examined a group of receptor proteins known to be used by microglia, monocytes and macrophages to interact with insoluble A-beta. Although any role for these proteins in Alzheimer’s disease has not been known, the MGH investigators previously found that their expression in a mouse model of the disease dropped as the animals aged.

After they first identified the involvement of a receptor called Scara1 in the uptake of soluble A-beta by monocytes and macrophages, the researchers then confirmed that Scara1 appears to be the major receptor for recognition and clearance of A-beta by the innate immune system, the body’s first line of defense. In a mouse model of Alzheimer’s, animals that were missing one or both copies of the Scara1 gene died several months earlier than did those with two functioning copies. By the age of 8 months, Alzheimer’s mice with no functioning Scara1 genes had double the A-beta in their brains as did a control group of Alzheimer’s mice, while normal mice had virtually none.

To investigate possible therapeutic application of the role of Scara1 in A-beta clearance, the MGH team treated cultured immune cells with Protollin, a compound that has been used to enhance the immune response to certain vaccines. Application of Protollin to immune cells tripled their expression of Scara1 and also increased levels of a protein that attracts other immune cells. Adding Protollin-stimulated microglia to brain samples from Alzheimer’s mice reduced the size and number of A-beta deposits in the hippocampus, an area particularly damaged by the disease, but that reduction was significantly less when microglia from Scara1-deficient mice were used.

El Khoury notes that previous research showed that Protollin treatment reduced A-beta deposits in Alzheimer’s mice and the current study reveals the probable mechanism behind that finding. “Upregulating Scara1 expression is a promising approach to treating Alzheimer’s disease,” he says. “First we need to duplicate these studies using human cells and identify new classes of molecules that can safely increase Scara1 expression or activity. That could potentially lead to ways of harnessing the immune system to delay the progression of this disease.” El Khoury is an associate professor of Medicine at Harvard Medical School.

A key brain structure that regulates emotions works differently in preschoolers with depression compared with their healthy peers, according to new research at Washington University School of Medicine in St. Louis.

The differences, measured using functional magnetic resonance imaging (fMRI), provide the earliest evidence yet of changes in brain function in young children with depression. The researchers say the findings could lead to ways to identify and treat depressed children earlier in the course of the illness, potentially preventing problems later in life.

“The findings really hammer home that these kids are suffering from a very real disorder that requires treatment,” said lead author Michael S. Gaffrey, PhD. “We believe this study demonstrates that there are differences in the brains of these very young children and that they may mark the beginnings of a lifelong problem.”

The study is published in the July issue of the Journal of the American Academy of Child & Adolescent Psychiatry.

Depressed preschoolers had elevated activity in the brain’s amygdala, an almond-shaped set of neurons important in processing emotions. Earlier imaging studies identified similar changes in the amygdala region in adults, adolescents and older children with depression, but none had looked at preschoolers with depression.

For the new study, scientists from Washington University’s Early Emotional Development Program studied 54 children ages 4 to 6. Before the study began, 23 of those kids had been diagnosed with depression. The other 31 had not. None of the children in the study had taken antidepressant medication.

Although studies using fMRI to measure brain activity by monitoring blood flow have been used for years, this is the first time that such scans have been attempted in children this young with depression. Movements as small as a few millimeters can ruin fMRI data, so Gaffrey and his colleagues had the children participate in mock scans first. After practicing, the children in this study moved less than a millimeter on average during their actual scans.

While they were in the fMRI scanner during the study, the children looked at pictures of people whose facial expressions conveyed particular emotions. There were faces with happy, sad, fearful and neutral expressions.

“The amygdala region showed elevated activity when the depressed children viewed pictures of people’s faces,” said Gaffrey, an assistant professor of psychiatry. “We saw the same elevated activity, regardless of the type of faces the children were shown. So it wasn’t that they reacted only to sad faces or to happy faces, but every face they saw aroused activity in the amygdala.”

Looking at pictures of faces often is used in studies of adults and older children with depression to measure activity in the amygdala. But the observations in the depressed preschoolers were somewhat different than those previously seen in adults, where typically the amygdala responds more to negative expressions of emotion, such as sad or fearful faces, than to faces expressing happiness or no emotion.

In the preschoolers with depression, all facial expressions were associated with greater amygdala activity when compared with their healthy peers.

Gaffrey said it’s possible depression affects the amygdala mainly by exaggerating what, in other children, is a normal amygdala response to both positive and negative facial expressions of emotion. But more research will be needed to prove that. He does believe, however, that the amygdala’s reaction to people’s faces can be seen in a larger context.

“Not only did we find elevated amygdala activity during face viewing in children with depression, but that greater activity in the amygdala also was associated with parents reporting more sadness and emotion regulation difficulties in their children,” Gaffrey said. “Taken together, that suggests we may be seeing an exaggeration of a normal developmental response in the brain and that, hopefully, with proper prevention or treatment, we may be able to get these kids back on track.”

Scientists at Karolinska Institutet have identified the neuronal circuits in the spinal cord of mice that control the ability to produce the alternating movements of the legs during walking. The study, published in the journal Nature, demonstrates that two genetically-defined groups of nerve cells are in control of limb alternation at different speeds of locomotion, and thus that the animals’ gait is disturbed when these cell populations are missing.

Most land animals can walk or run by alternating their left and right legs in different coordinated patterns. Some animals, such as rabbits, move both leg pairs simultaneously to obtain a hopping motion. In the present study, the researchers Adolfo Talpalar and Julien Bouvier together with professor Ole Kiehn and colleagues, have studied the spinal networks that control these movement patterns in mice. By using advanced genetic methods that allow the elimination of discrete groups of neurons from the spinal cord, they were able to remove a type of neurons characterized by the expression of the gene Dbx1.

"It was classically thought that only one group of nerve cells controls left right alternation", says Ole Kiehn who leads the laboratory behind the study at the Department of Neuroscience. "It was then very interesting to find that there are actually two specific neuronal populations involved, and on top of that that they each control different aspect of the limb coordination."

Indeed, the researchers found that the gene Dbx1 is expressed in two different groups of nerve cells, one of which is inhibitory and one that is excitatory. The new study shows that the two cellular populations control different forms of the behaviour. Just like when we change gear to accelerate in a car, one part of the neuronal circuit controls the mouse’s alternating gait at low speeds, while the other population is engaged when the animal moves faster. Accordingly, the study also show that when the two populations are removed altogether in the same animal, the mice were unable to alternate at all, and hopped like rabbits instead.

There are some animals, such as desert mice and kangaroos, which only hop. The researchers behind the study speculate that the locomotive pattern of these animals could be attributable to the lack of the Dbx1 controlled alternating system.

For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small molecules that allow for complete control over a genetic defect responsible for the most common adult onset form of muscular dystrophy. These small molecules will enable scientists to investigate potential new therapies and to study the long-term impact of the disease.

“This is the first example I know of at all where someone can literally turn on and off a disease,” said TSRI Associate Professor Matthew Disney, whose new research was published June 28, 2013, by the journal Nature Communications. “This easy approach is an entirely new way to turn a genetic defect off or on.”

Myotonic dystrophy is an inherited disorder, the most common form of a group of conditions called muscular dystrophies that involve progressive muscle wasting and weakness. Myotonic dystrophy type 1 is caused a type of RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code. In this case, a cytosine-uracil-guanine (CUG) triplet repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities.

To find drug candidates that act against the defect, Disney and his colleagues analyzed the results of a National Institutes of Health (NIH)-sponsored screen of more than 300,000 small molecules that inhibit a critical RNA-protein complex in the disease.

The team divided the NIH hits into three “buckets”—the first group bound RNA, the second bound protein, and a third whose mechanism was unclear. The researchers then studied the compounds by looking at their effect on human muscle tissue both with and without the defect.

Startlingly, diseased muscle tissue treated with RNA-binding compounds caused signs of the disease to go away. In contrast, both healthy and diseased tissue treated with the protein-binding compounds showed the opposite effect—signs of the disease either appeared (in healthy tissue) or became worse.

The new compounds will serve as useful tools to study the disease on a molecular level. “In complex diseases, there are always unanticipated mechanisms,” Disney noted. “Now that we can reverse the disease at will, we can study those aspects of it.”

In addition, Disney said, with the new discovery, scientists will be able to develop a greater understanding of how to control RNA splicing with small molecules. RNA splicing can cause a host of diseases that range from sickle-cell disease to cancer, yet prior to this study, no tools were available to control specific RNA splicing.

Scientists using sophisticated imaging techniques have observed a molecular protein folding process that may help medical researchers understand and treat diseases such as Alzheimer’s, Lou Gehrig’s and cancer.

The study, reported this month in the journal Cell, verifies a process that scientists knew existed but with a mechanism they had never been able to observe, according to Dr. Hays Rye, Texas A&M AgriLife Research biochemist.

“This is a step in the direction of understanding how to modulate systems to prevent diseases like Alzheimer’s. We needed to understand the cell’s folding machines and how they interact with each other in a complicated network,” said Rye, who also is associate professor of biochemistry and biophysics at Texas A&M.

Rye explained that individual amino acids get linked together like beads on a string as a protein is made in the cell.

“But that linear sequence of amino acids is not functional,” he explained. “It’s like an origami structure that has to fold up into a three-dimensional shape to do what it has to do.”

Rye said researchers have been trying to understand this process for more than 50 years, but in a living cell the process is complicated by the presence of many proteins in a concentrated environment.

"The constraints on getting that protein to fold up into a good ‘origami’ structure are a lot more demanding,” he said. “So, there are special protein machines, known as molecular chaperones, in the cell that help proteins fold.”

But how the molecular chaperones help protein fold when it isn’t folding well by itself has been the nagging question for researchers.

“Molecular chaperones are like little machines, because they have levers and gears and power sources. They go through turning over cycles and just sort of buzz along inside a cell, driving a protein folding reaction every few seconds,” Rye said.

The many chemical reactions that are essential to life rely on the exact three-dimensional shape of folded proteins, he said. In the cell, enzymes, for example, are specialized proteins that help speed biological processes along by binding molecules and bringing them together in just the right way.

“They are bound together like a three-dimensional jigsaw puzzle,” Rye explained.  “And the proteins — those little beads on the string that are designed to fold up like origami — are folded to position all these beads in three-dimensional space to perfectly wrap around those molecules and do those chemical reactions.

“If that doesn’t happen — if the protein doesn’t get folded up right – the chemical reaction can’t be done. And if it’s essential, the cell dies because it can’t convert food into power needed to build the other structures in the cell that are needed. Chemical reactions are the structural underpinning of how cells are put together, and all of that depends on the proteins being folded in the right way.”

When a protein doesn’t fold or folds incorrectly it turns into an “aggregate,” which Rye described as “white goo that looks kind of like a mayonnaise, like crud in the test tube.

“You’re dead; the cell dies,” he said.

Over the past 20 years, he said, researchers have linked that aggregation process “pretty convincingly” to the development of diseases — Alzheimer’s disease, Lou Gehrig’s disease, Huntington’s disease, to name a few. There’s evidence that diabetes and cancer also are linked to protein folding disorders.

“One of the main roles for the molecular chaperones is preventing those protein misfolding events that lead to aggregation and not letting a cell get poisoned by badly folded or aggregated proteins,” he said.

Rye’s team focused on a key molecular chaperone — the HSP60.

“They’re called HSP for ‘heat shock protein’ because when the cell is stressed with heat, the proteins get unstable and start to fall apart and unfold,” Rye said. “The cell is built to respond by making more of the chaperones to try and fix the problem.

“This particular chaperone takes unfolded protein and goes through a chemical reaction to bind the unfolded protein and literally puts it inside a little ‘box,’” Rye said.

He added that the mystery had long been how the folding worked because, while researchers could see evidence of that happening, no one had ever seen precisely how it happened.

Rye and the team zeroed in on a chemically modified mutant that in other experiments had seemed to stall at an important step in the process that the “machine” goes through to start the folding action. This clued the researchers that this stalling might make it easier to watch.

They then used cryo-electron microscopy to capture hundreds of thousands of images of the process at very high resolutions which allowed them to reconstruct from two-dimensional flat images a three-dimensional model. A highly sophisticated computer algorithm aligns the images and classifies them in subcategories.

“If you have enough of them you can actually reconstruct and view a structure as a three-dimensional model,” Rye said.

What the team saw was this: The HSP60 chaperone is designed to recognize proteins that are not folded from the ones that are. It binds them and then has a separate co-chaperone that puts a “lid” on top of the box to keep the folding intermediate in the box. They could see the box move, and parts of the molecule moved to peel the chaperone box away from the bound protein — or “gift” in the box. But the bound protein was kept inside the package where it could then initiate a folding reaction. They saw tiny tentacles, “like a little octopus in the bottom of the box rising up and grabbing hold of the substrate protein and helping hold it inside the cavity.”

"The first thing we saw was a large amount of an unfolded protein inside of this cavity,” he said. “Even though we knew from lots and lots of other studies that it had to go in there, nobody had ever seen it like this before. We can also see the non-native protein interacting with parts of the box that no one had ever seen before. It was exciting to see all of this for the first time. I think we got a glimpse of a protein in the process of folding, which we actually can compare to other structures.”

“By understanding the mechanism of these machines, the hope is that one of the things we can learn to do is turn them up or turn them off when we need to, like for a patient who has one of the protein folding diseases,” he said.

A single dose of a commonly-prescribed attention deficit hyperactivity disorder (ADHD) drug helps improve brain function in cocaine addiction, according to an imaging study conducted by researchers from the Icahn School of Medicine at Mount Sinai. Methylphenidate (brand name Ritalin®) modified connectivity in certain brain circuits that underlie self-control and craving among cocaine-addicted individuals. The research is published in the current issue of JAMA Psychiatry, a JAMA network publication.

Previous research has shown that oral methylphenidate improved brain function in cocaine users performing specific cognitive tasks such as ignoring emotionally distracting words and resolving a cognitive conflict. Similar to cocaine, methylphenidate increases dopamine (and norepinephrine) activity in the brain, but, administered orally, takes longer to reach peak effect, consistent with a lower potential for abuse. By extending dopamine’s action, the drug enhances signaling to improve several cognitive functions, including information processing and attention.

“Orally administered methylphenidate increases dopamine in the brain, similar to cocaine, but without the strong addictive properties,” said Rita Goldstein, PhD, Professor of Psychiatry at Mount Sinai, who led the research while at Brookhaven National Laboratory (BNL) in New York. “We wanted to determine whether such substitutive properties, which are helpful in other replacement therapies such as using nicotine gum instead of smoking cigarettes or methadone instead of heroin, would play a role in enhancing brain connectivity between regions of potential importance for intervention in cocaine addiction.”

Anna Konova, a doctoral candidate at Stony Brook University, who was first author on this manuscript, added, ”Using fMRI, we found that methylphenidate did indeed have a beneficial impact on the connectivity between several brain centers associated with addiction.”

Dr. Goldstein and her team recruited 18 cocaine addicted individuals, who were randomized to receive an oral dose of methylphenidate or placebo. The researchers used functional magnetic resonance imaging (fMRI) to measure the strength of connectivity in particular brain circuits known to play a role in addiction before and during peak drug effects. They also assessed each subject’s severity of addiction to see if this had any bearing on the results.

Methylphenidate decreased connectivity between areas of the brain that have been strongly implicated in the formation of habits, including compulsive drug seeking and craving. The scans also showed that methylphenidate strengthened connectivity between several brain regions involved in regulating emotions and exerting control over behaviors—connections previously reported to be disrupted in cocaine addiction.

“The benefits of methylphenidate were present after only one dose, indicating that this drug has significant potential as a treatment add-on for addiction to cocaine and possibly other stimulants,” said Dr. Goldstein. “This is a preliminary study, but the findings are exciting and warrant further exploration, particularly in conjunction with cognitive behavioral therapy or cognitive remediation.”