Neuroscience

Phase 1 trial safely resets patients’ immune systems, reduces attack on myelin protein

A phase 1 clinical trial for the first treatment to reset the immune system of multiple sclerosis (MS) patients showed the therapy was safe and dramatically reduced patients’ immune systems’ reactivity to myelin by 50 to 75 percent, according to new Northwestern Medicine research.

In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness.

“The therapy stops autoimmune responses that are already activated and prevents the activation of new autoimmune cells,” said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “Our approach leaves the function of the normal immune system intact. That’s the holy grail.”

Miller is the co-senior author of a paper on the study, which was published June 5 in the journal Science Translational Medicine. The study is a collaboration between Northwestern’s Feinberg School, University Hospital Zurich in Switzerland and University Medical Center Hamburg-Eppendorf in Germany. 

The human trial is the translation of more than 30 years of preclinical research in Miller’s lab.   

In the trial, the MS patients’ own specially processed white blood cells were used to stealthily deliver billions of myelin antigens into their bodies so their immune systems would recognize them as harmless and develop tolerance to them.    

Current therapies for MS suppress the entire immune system, making patients more susceptible to everyday infections and higher rates of cancer.

While the trial’s nine patients — who were treated in Hamburg, Germany — were too few to statistically determine the treatment’s ability to prevent the progression of MS, the study did show patients who received the highest dose of white blood cells had the greatest reduction in myelin reactivity. 

The primary aim of the study was to demonstrate the treatment’s safety and tolerability. It showed the intravenous injection of up to 3 billion white blood cells with myelin antigens caused no adverse affects in MS patients. Most importantly, it did not reactivate the patients’ disease and did not affect their healthy immunity to real pathogens.

As part of the study, researchers tested patients’ immunity to tetanus because all had received tetanus shots in their lifetime. One month after the treatment, their immune responses to tetanus remained strong, showing the treatment’s immune effect was specific only to myelin.   

The human safety study sets the stage for a phase 2 trial to see if the new treatment can prevent the progression of MS in humans. Scientists are currently trying to raise $1.5 million to launch the trial, which has already been approved in Switzerland. Miller’s preclinical research demonstrated the treatment stopped the progression of relapsing-remitting MS in mice.

“In the phase 2 trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage.” Miller said. “Once the myelin is destroyed, it’s hard to repair that.”

In the trial, patients’ white blood cells were filtered out, specially processed and coupled with myelin antigens by a complex GMP manufacturing process developed by the study co-senior authors, Roland Martin, Mireia Sospedra, and Andreas Lutterotti and their team at the University Medical Center Hamburg-Eppendorf. Then billions of these dead cells secretly carrying the myelin antigens were injected intravenously into the patients. The cells entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. During this process, the immune cells start to recognize myelin as a harmless and immune tolerance quickly develops. This was confirmed in the patients by immune assays developed and carried out by the research team in Hamburg.  

This therapy, with further testing, may be useful for treating not only MS but also a host of other autoimmune and allergic diseases simply by switching the antigens attached to the cells. Previously published preclinical research by Miller showed the therapy’s effectiveness for type 1 diabetes and airway allergy (asthma) and peanut allergy.

The MS human trial relates directly to Miller’s recently published research in mice in which he used nanoparticles — rather than a patient’s white blood cells — to deliver the myelin antigen. Using a patient’s white blood cells is a costly and labor-intensive procedure. Miller’s study showed the nanoparticles, which are potentially cheaper and more accessible to a general population, could be as effective as the white blood cells as delivery vehicles. This nanoparticle technology has been licensed to Cour Pharmaceutical Development Company and is in preclinical development.

Miller’s research represents several pillars of Northwestern’s Strategic Plan by discovering new ways to treat disease in the biomedical sciences and translating those discoveries into ideas and products that make the world a better place for everyone.

The presence of Lewy bodies in nerve cells, formed by intracellular deposits of the protein α-synuclein, is a characteristic pathologic feature of Parkinson’s Disease (PD). In the quest for an animal model of PD that mimics motor and non-motor symptoms of human PD, scientists have developed strains of mice that overexpress α-synuclein. By studying a strain of mice bred to overexpress α-synuclein via the Thy-1 promoter, scientists have found these mice develop many of the age-related progressive motor symptoms of PD and demonstrate changes in sleep and anxiety. Their results are published in the latest issue of Journal of Parkinson’s Disease.

PD is the second most common neurodegenerative disorder in the United States, affecting approximately one million Americans and five million people worldwide. Its prevalence is projected to double by 2030. The most obvious symptoms are movement-related, such as involuntary shaking and muscle stiffness; non-motor symptoms, such as increases in anxiety and sleep disturbances, can appear prior to the onset of motor symptoms. Although the drug levodopa can relieve some symptoms, there is no cure – intensifying the pressure to find an animal model that can help clarify the pathological processes underlying human PD and find new medications to treat the pathology and/or relieve symptoms. 

Investigators at the National Institute on Aging compared wild type mice with specially bred mice that were transgenic for the A53T mutation of the human α-synuclein (SNCA) gene under the control of a human thymus cell antigen 1, theta (THY-1) promoter. As the mice aged, their motor performance on a rotarod test (which measures how long the mouse can remain on a rotating rod) became impaired and the length of their strides were significantly shorter than the wild type control mice.

The study also found that SNCA mice displayed fragmented nighttime activity patterns compared to wild type controls and appeared to have a reduced overall sleep time. “Despite the prevalence of abnormal sleep patterns in PD, very few studies to date have outlined sleep disturbances in animal models of PD,” says Sarah M. Rothman, PhD, a researcher with the National Institute on Aging, in Baltimore, MD.

Many PD patients typically show an increase in anxiety and depression, and in this respect the SNCA mouse model did not replicate the human condition. SNCA mice displayed an early and significant decrease in anxiety-like behavior that persisted throughout their lifespan, as shown by both open field and elevated plus maze tests (in which mice have the choice of spending time in open or closed arms of a maze). Other rodent models that utilize changes in expression of α-synuclein have also reported lower anxiety levels. The authors suggest that higher levels of serotonin found in the hypothalamus of the SNCA mice may be associated with the reduced anxiety observed.

The authors say it is important to remember that the SNCA “model utilizes the presence of a mutation that only occurs very rarely in PD. While all PD patients display α-synuclein pathology, they do not all express the mutated form of the protein,” says Dr. Rothman.

Researchers in Spain have found that a drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. They believe that their findings may be relevant to other neurodegenerative diseases.  A Phase II trial will be starting shortly. The research is published simultaneously on line in the journal Brain.

A drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. This is an important step along the road to the development of a therapy for the human disease for which current treatment options are scarce and only partially effective, the annual conference of the European Society of Human Genetics will hear tomorrow (Sunday).

Professor Aurora Pujol, a research professor for the Catalan Government Research Body ICREA, working as Director of the Neurometabolic Diseases Laboratory at IDIBELL, Barcelona, Spain, investigated the role of mitochondria, the power plant of the cell, in adrenoleukodystrophy, a disease caused by the inactivation of the ABCD1 transporter of fatty acids in peroxisomes.  This inactivation leads to the accumulation of fatty acids in organs and blood plasma, and causes spinal cord degeneration.

“ABCD1 is a protein located in the peroxisomes, compartments of the cell that detoxify chemicals and lipids, and thus the implication of mitochondria in such a disease was not obvious.  But we knew from recent research that oxidative stress – where there is increased production of chemically active oxygen-containing molecules, and also significant decrease in the effectiveness of the body’s antioxidant defences – was involved.  We also knew that bioenergetic failure appeared before disease symptoms.  We therefore decided to investigate the role of the mitochondria”, Professor Pujol will say.

The group of diseases known as leukodystrophies are characterised by progressive loss of the myelin sheath, the fatty covering that acts as an insulator around nerve fibres.  Damage to the myelin sheath impairs the conduction of signals in the affected nerves and leads to locomotor problems. 

“We knew that early oxidative damage and bioenergetic dysfunction underlay the late onset degeneration of nerve fibres observed in the mouse model of X-linked adrenoleukodystrophy (X-ALD), the most frequently inherited leukodystrophy, so we looked at mitochondria for further clues.  We found that the X-ALD mice showed a loss of mitochondria at 12 months of age, prior to disease symptoms, so this could not be a consequence of the disease, but rather a contributing factor.  We also knew that the pathway involved in the mitochondrial loss could be treated by the use of the diabetes drug pioglitazone, so we decided to test its effect in the mice”, Professor Pujol will say.

Pioglitazone halted the nerve fibre degeneration by preventing the loss of mitochondria, and inhibiting metabolic failure and oxidative stress in the treated mice, and hence also halted locomotor disabilities.   The researchers were able to prove this both through analysis of spinal cords post mortem, and in vivo by putting the mice through a number of physical tests.

Although X-ALD is a relatively rare disease  with a minimum incidence of 1 in 17 000 males, there are other neurodegenerative disorders caused by myelin sheath degeneration, for example multiple sclerosis, and many others where impaired bioenergetics combined with oxidative stress and degeneration of axons are known to be involved.  The latter category of disease includes Parkinson’s, Huntington’s, and Alzheimer’s.  “It is possible that our findings may be relevant to these conditions as well,” says Professor Pujol.

“Following on from these promising results, together with Professor Patrick Aubourg from the Hôpital Bicêtre, Paris, we will shortly be starting a multi-centre phase II clinical trial of pioglitazone in adult patients suffering from a late onset variant of adrenoleukodystrophy.   Our research has shown that it will be feasible to monitor the biological effects of the drug by looking for biomarkers of oxidative damage in blood cells or plasma.  We are happy to have made a contribution to finding a simple and effective treatment to a group of devastating diseases”, she will conclude.

A gene linked to autism spectrum disorders that was manipulated in two lines of transgenic mice produced mature adults with irreversible deficits affecting either learning or social interaction.

The findings, published in the May 29 issue of the Journal of Neuroscience, have implications for potential gene therapies but they also suggest that there may be narrow windows of opportunity to be effective, says principal investigator Philip Washbourne, a professor of biology and member of the University of Oregon’s Institute of Neuroscience.

The research, reported by an 11-member team from three universities, targeted the impacts of alterations in the gene neuroligin 1 — one of many genes implicated in human autism spectrum disorders — to neuronal synapses in the altered mice during postnatal development and as they entered adulthood. One group over-expressed the normal gene, the other a mutated version.

Mice with higher-than-normal levels of the normal gene after a month had skewed synapses at maturity. Many were larger, appearing more mature, than normal. In these mice, Washbourne said, there were clear cognitive problems. “Behavior was just not normal. They didn’t learn very well, and they were slower to learn, but their social behavior was not impacted.”

Mice over-producing a mutated version of the gene reached adulthood with structurally immature synapses. “They were held back in development and behavior — the way they behave in terms of learning and memory, in terms of social interaction,” he said. “These were adult mice, three months old, but they behaved like normal mice at four weeks old. We saw arrested development. Learning is a little bit better, they are more flexible just like young mice, they learn faster, but their social interaction is off. To us, this looked more like Asperger’s syndrome.

"So with the same gene, doing two different manipulations — overexpressing the normal form or overexpressing a mutated form — we’ve gone to two different ends of the autism spectrum," said Washbourne, whose lab focuses on basic synapse formation and what goes wrong in relationship to autism. Work has been done in both mice and zebra fish.

"We made these mice so that we can turn the genes on and off as we want," Washbourne said. "Using an antibiotic, doxycycline, it turns off these altered genes that we inserted into their chromosomes. While on doxycycline, the mice are absolutely normal.”

However, if the inserted gene was turned off after the completion of development, mice still showed altered synapses and behavior. This result suggests that any kind of gene therapy may have to be applied to individuals with autism early on.

Effects seen in the social behavior of mice with the mutated gene, he said, are not unlike observations reported by parents of many autistic children. While normal mice prefer to engage with new mice entering their world rather than familiar others, or even a new inanimate object, these mice split their time equally. “It’s not a deficit in memory regarding which mouse is which, it’s more a weighting of their interaction. Does that mean they are autistic? I don’t know, but if you talk to parents of autistic children, one of the frustrating things they report is that their children treat complete strangers in exactly the same way that they treat them.”

While the findings provide new insights, Washbourne said, any translation into treatment could be decades away. “A problem with autism is there are many different genes potentially involved. It could be that some day, if you are diagnosed with autism, a mouth swab might allow for the identification of the exact gene that is mutated and allow for targeted therapy,” he said. “Genome sequencing already has turned up subtle mutations in lots of genes. Autism might be like cancer, with hundreds of potential combinations of faulty genes.”

A protein profile of people with restless leg syndrome (RLS), identifies factors behind disrupted sleep, cardiovascular dysfunction and pain finds research in BioMed Central’s open access journal Fluids and Barriers of the CNS. The research gives insights into the disorder, and could be useful in the development of new treatments.

It is not completely clear what causes RLS, also known as Willis Ekbom disease (WED), but in some people it is associated with iron deficiency in the brain, kidney failure, or low levels of the ‘pleasure’ neurotransmitter dopamine. It can also occur during pregnancy. It affects between 5 and 10% of the population and symptoms, which can range in severity, including sleep deprivation and decreased ability to work can lead to a reduction in quality of life. It is also a risk factor for cardiovascular disease.

Comparing the cerebral spinal fluid (CSF) of women with and without RLS, researchers from the US and Korea discovered  there was a significantly altered level of six specific proteins with RLS. Dr Stephanie Patton from Penn State University who led this study explained, “Our results reveal a protein profile in the RLS/WED CSF that is consistent with iron deficiency, dopamine dysregulation and inflammation.”

These proteins include a protein which transports vitamin D into cells and is involved in the regulation of dopamine levels, cystatin C – a biomarker for pain found in people with sciatica and during labor, and a neuromodulator (PTGDS) known to be involved in sleep disturbances. Levels of apolipoprotein (Apo) A1 were lower with RLS and may be related to the increased risk of cardiovascular disease.

The importance of iron’s role in RLS is highlighted by the presence of B-hemoglobin in the CSF of women with RLS, while levels of a glycoprotein (AGP) were reduced. AGP is involved in response to inflammatory damage and requires the presence of iron for it to be protective.

Dr Stephanie Patton continued, “Although a small study, this CSF protein profile is consistent with observed neuropathological findings and supports existing hypotheses about the biology behind RLS/WED, which could prove clinically important in developing new treatments.”

Unborn babies ‘practise’ facial expressions of pain in the womb, according to a study published today.

The researchers from Durham and Lancaster Universities suggest that fetuses’ ability to show a “pain” facial expression is a developmental process which could potentially give doctors another index of the health of a fetus.

The study is published in the prestigious academic journal, PLOS ONE, and was part funded by the Economic and Social Research Council (ESRC) and Durham University.

The study extends the findings of previous work demonstrating that the facial expressions of healthy fetuses develop and become more complex during pregnancy resulting in fetuses being able to show recognisable facial expressions.

The 4D scans of 15 healthy fetuses showed that they develop from making very simple one-dimensional expressions at 24 weeks, such as moving their lips in order to form a “smile”, to complex multi-dimensional expressions which can be recognised as “pain” expressions, by the time the mother is 36 weeks into her pregnancy.

The researchers suggest this is an adaptive process which enables the unborn baby to prepare themselves for life after birth when they have to communicate, for example if they feel hungry or uncomfortable, by making grimaces or crying. 

The researchers used the video footage of 4D scans, observing repeatedly the facial expressions of eight female and seven male fetuses from the second to third trimester (24 to 36 weeks) of pregnancy.

Fetuses observed at 24 weeks gestation rarely showed a combination of facial movements which make up a ‘pain face’, such as lowering the eyebrows, wrinkling the nose and stretching the mouth. However, by 36 weeks gestation, a combination of at least four movements was seen rather more frequently, giving the impression that these older fetuses were capable of making a pain face.

Lead researcher Dr Nadja Reissland, of Durham University’s Department of Psychology, said: “It is vital for infants to be able to show pain as soon as they are born so that they can communicate any distress or pain they might feel to their carers and our results show that healthy fetuses ‘learn’ to combine the necessary facial movements before they are born.

“This suggests that we can determine the normal development of facial movements and potentially identify abnormal development too. This could then provide a further medical indication of the health of the unborn baby.

“It is not yet clear whether fetuses can actually feel pain, nor do we know whether facial expressions relate to how they feel. Our research indicates that the expression of fetal facial movements is a developmental process which seems to be related to brain maturation rather than being linked to feelings.”

Professor of Social Statistics at Lancaster University Brian Francis said: “Modern methods of data analysis enable the development of fetal pain faces to be clearly detected, with the complexity of facial movements making up a pain face increasing in the third trimester”.

Despite the advances in medical science, we still do not know very much about health indicators of fetal development or any warning signs of delayed or abnormal progress in the womb.

It is hoped that further research will test whether the development of facial expressions is delayed if fetuses experience unhealthy conditions in the womb, such as effects of smoking or alcohol, or where the fetus is undergoing invasive procedures.

From the neurons that enable thought to the keratinocytes that make toenails grow-a complex canopy of sugar molecules, commonly known as glycans, envelop every living cell in the human body.

These complex carbohydrate chains perform a host of vital functions, providing the necessary machinery for cells to communicate, replicate and survive. It stands to reason, then, that when something goes wrong with a person’s glycans, something goes wrong with them.

Now, researchers at the University of Georgia are learning how changes in normal glycan behavior are related to a rare but fatal lysosomal disease known as Niemann-Pick type C (NPC), a genetic disorder that prevents the body from metabolizing cholesterol properly. The findings were published recently in the PNAS Early Edition.

"We are learning that the problems associated with cholesterol trafficking in the cell lead to problems with glycans on the cell’s surface, and that causes a multitude of negative effects," said Geert-Jan Boons, professor of chemistry in the Franklin College of Arts and Sciences and researcher at UGA’s Complex Carbohydrate Research Center. "Now, for the first time, we can see what these problems are, which we hope will lead to a new understanding of diseases like NPC."

Because NPC patients are unable to metabolize cholesterol, the waxy substance begins to accumulate in the brain. This can lead to a host of serious problems, including neurodegeneration, which the researchers hypothesize may be caused by improper recycling of glycans on the surface of an NPC patient’s cells.

Glycans normally undergo a kind of recycling process when they enter the cell only to be returned to the surface recharged and ready to work. The researchers discovered that glycans in NPC cells do not do this.

"One of the secondary effects of NPC is the disruption of traffic pathways within the cell, and this can lead to altered recycling of glycans," said Richard Steet, associate professor of biochemistry and molecular biology and CCRC researcher. "The glycans come into the cell, but they won’t recycle back up to the cell’s surface where they must exist to function as receptors or ion channels."

"Basically, the machinery gets clogged up," Boons said.

Like downed phone lines and flooded roads in a thunderstorm, glycans get stuck inside the cell making communication and travel for these cells difficult or impossible. Without these basic abilities, the body’s motor, sensory and cognitive functions begin to suffer. This might explain why NPC patients suffer from such a wide variety of neurological and psychiatric disorders, such as uncoordinated limb movements, slurred speech, epilepsy, paralysis, psychosis, dementia and hallucinations.

The researchers made these observations in fibroblasts taken from diseased patients. These cells are most commonly found in connective tissues, and they play a vital role in wound healing. However, they hope to continue their investigation into the effects of NPC by studying glycan behavior in neural cells, which make up the human brain.

While they caution that much more work must be done, they hope that an improved understanding of the roles that glycans play in neural cells will lead to new therapeutics for NPC and other diseases like it.

"It is exciting to work on projects like these, because we believe glycobiology is the next frontier, the next level of complexity," Boons said. "The time is right for new discovery."

A new brain imaging study of dyslexia shows that differences in the visual system do not cause the disorder, but instead are likely a consequence. The findings, published today in the journal Neuron, provide important insights into the cause of this common reading disorder and address a long-standing debate about the role of visual symptoms observed in developmental dyslexia.

Dyslexia is the most prevalent of all learning disabilities, affecting about 12 percent of the U.S. population. Beyond the primarily observed reading deficits, individuals with dyslexia often also exhibit subtle weaknesses in processing visual stimuli. Scientists have speculated whether these deficits represent the primary cause of dyslexia, with visual dysfunction directly impacting the ability to learn to read. The current study demonstrates that they do not.

“Our results do not discount the presence of this specific type of visual deficit,” says senior author Guinevere Eden, PhD, director for the Center for the Study of Learning at Georgetown University Medical Center (GUMC) and past-president of the International Dyslexia Association. “In fact our results confirm that differences do exist in the visual system of children with dyslexia, but these differences are the end-product of less reading, when compared with typical readers, and are not the cause of their struggles with reading.”

The current study follows a report published by Eden and colleagues in the journal Nature in 1996, the first study of dyslexia to employ functional Magnetic Resonance Imaging (fMRI). As in that study, the new study also shows less activity in a portion of the visual system that processes moving visual information in the dyslexics compared with typical readers of the same age.

This time, however, the research team also studied younger children without dyslexia, matched to the dyslexics on their reading level. “This group looked similar to the dyslexics in terms of brain activity, providing the first clue that the observed difference in the dyslexics relative to their peers may have more to do with reading ability than dyslexia per se,” Eden explains.

Next, the children with dyslexia received a reading intervention. Intensive tutoring of phonological and orthographic skills was provided, addressing the core deficit in dyslexia, which is widely believed to be a weakness in the phonological component of language. As expected, the children made significant gains in reading. In addition, activity in the visual system increased, suggesting it was mobilized by reading.

The researchers point out that these findings could have important implications for practice. “Early identification and treatment of dyslexia should not revolve around these deficits in visual processing,” says Olumide Olulade, PhD, the study’s lead author and post-doctoral fellow at GUMC. “While our study showed that there is a strong correlation between people’s reading ability and brain activity in the visual system, it does not mean that training the visual system will result in better reading. We think it is the other way around. Reading is a culturally imposed skill, and neuroscience research has shown that its acquisition results in a range of anatomical and functional changes in the brain.”

The researchers add that their research can be applied more broadly to other disorders. “Our study has important implications in understanding the etiology of dyslexia, but it also is relevant to other conditions where cause and consequence are difficult to pull apart because the brain changes in response to experience,” explains Eden.

Despite decades of research, little is known about the function of REM sleep, or the dreams that often accompany it. Rapid eye movements occur in most mammals, with a few exceptions like echidnas and dolphins. In humans, they be become common by the seventh month of pregnancy, and persist throughout life even in the congenitally blind. Researchers have developed techniques to perform a full electrical sleep analysis on subjects while they are simultaneously scanned inside an MRI machine. A new study in PNAS now reports that REM sleep can be distinguished from other states of consciousness by virtue of rhythmic correlations, and anticorrelations, between different areas of the brain.

Polysomnography is a comprehensive biophysical analysis used to gauge sleep state. Most of the recorded variables, like EEG, eye movements and heart rate, are electrical in nature. In addition, many other kinds of measurements are often included like body temperature, breathing rate, or blood oxygenation. Although these variables together paint a fairly reliable picture of depth of sleep, they have little to say about what might be going on in the brain during different states of consciousness.

To address this problem, the researchers in the PNAS study used blood-oxygen level dependent (BOLD) MRI to assess functional connectivity between different regions of the brain. Their main finding was that the BOLD signal time series during REM sleep showed strong correlation between the thalamus and the visual cortex, and strong anticorrelation between the thalamus a region of the brain known as the posterior cingulate gyrus. Furthermore, these relations showed clear rhythmic behavior with a relatively constant period of several seconds. This temporal scale corresponds roughly to many other phasic phenomena that are seen during REM sleep.

Some of the common electrically-recorded features of REM sleep have earned names for themselves by virtue of there uniqueness. The so-called sleep spindles and k-complexes have been associated with the cessation of emg activity, and the onset of the disconnection of the brain from the musculature. At the level specific neural systems, it has long been accepted that the major monoaminergic transmitter systems of the brain take a break during REM, while the cholinergic systems become tonically active. Monoamines are those amino-acid derived transmitters that have a single amine group like noradrenaline, serotonin or histamine.

The researchers sought to partition the brain into various sensorimotor regions, and other association areas they call the default mode network (DMN). The posterior cingulate area, together with the prefrontal cortex and inferior parietal areas are said to make up this DMN. Opposite the posterior cingulate area, on the external surface of the cortex in the inferior parietal lobe, is the angular gyrus. Lying at the top of the primary fold in the brain, this area may be said to be at the convex cusp of connectivity. In other words, axons projecting from this area have more immediate short range connectivity options available to them than perhaps anywhere else in the brain. Stroke this area out, and our most fine-grained functions—mathematical, verbal and ideological—are immediately lobotomized.

As BOLD signals change relatively slowly, and can only be measured relatively slowly, they are ultimately of limited value. Uncovering the mysteries of REM sleep, and why we dream, will require much more attention to anecdote and detail. For example, it is known binocular eye movements during REM sleep can be far from conjugate in both the vertical and horizontal planes. Those creatures that show reduced levels of REM sleep have also been shown to have a smaller corpus callosum, or frequently none at all. Something about the bilateral-binocular nature of the brain seems to feature strongly in REM sleep.

At the level of dreams, it is hard to escape the idea that they have some evolved purpose, though this is not yet within the realm of fact. Many among us have dreamt of waves or waterfalls only to awake with a crushing need to visit the bathroom. Other times we teeter at the edge of a cliff, obviously standing-in for the edge of the bed, or struggle to raise a limb to defend ourself against an imaginary foe, while in reality the limb has become hypoxic under our girth. Further removed from this base physiology, our dreams may reassemble our fears and struggles, and simultaneously exaggerate and trivialize emotional events with quizzically open-ended probes.

The synchrony and interconnection of the thalamus, only accessed at low resolution in the present study, remains of central importance in the study of conscious state. Closer inspection of sensorimotor and association areas within the thalamus itself, may continue to shed more light on these issues.

If people are unable to perceive their own errors as they complete a routine, simple task, their skill will decline over time, Johns Hopkins researchers have found — but not for the reasons scientists assumed. The researchers report that the human brain does not passively forget our good techniques, but chooses to put aside what it has learned.

The term “motor memories” may conjure images of childhood road trips, but in fact it refers to the reason why we’re able to smoothly perform everyday physical tasks. The amount of force needed to lift an empty glass versus a full one, to shut a car door or pick up a box, even to move a limb accurately from one place to another — all of these are motor memories.

In a report published May 1 in the The Journal of Neuroscience, the Johns Hopkins researchers describe their latest efforts to study how motor memories are formed and lost by focusing on one well-known experimental phenomenon: When people learn to do a task well, but are asked to keep doing it while receiving deliberately misleading feedback indicating that their performance is perfect every time, their actual performance will gradually get worse.

It had been assumed that the decline was due to the decay of memories in the absence of reinforcement, says Reza Shadmehr, Ph.D., a professor in the Department of Biomedical Engineering at the Johns Hopkins University School of Medicine.

But when Shadmehr and graduate student Pavan Vaswani asked volunteers to learn a simple task with a few twists designed to deliberately manipulate the brain’s motor control system, they learned otherwise.

The volunteers were told to push a joystick quickly toward a red dot on a computer screen. But the volunteers’ hands were placed under the screen, where they couldn’t see them, and their starting point was shown on the screen as a blue dot. In addition, as the volunteers moved the joystick toward the red dot, a force within the contraption would suddenly push the joystick to the left. So the volunteers practiced until they could move the blue dot straight to and past the red dot by compensating for the leftward push with pressure toward the right.

Once the volunteers had mastered the task, Shadmehr and Vaswani changed it up without their knowing. For one group of 24 volunteers, they added a stiff spring to the joystick device that would guide the user straight to the target, but would also measure the amount of rightward force the volunteers were applying. To the volunteers, it looked as though they were now doing the task perfectly every time, and, as in previous experiments, they gradually stopped pushing to the right, apparently “forgetting” what they had learned.

For a different group of 19 volunteers, though, the researchers not only added the spring, but also changed the feedback on the screen not to reflect what was actually happening during each task, but to show feedback similar to reruns of earlier efforts. The volunteers weren’t seeing the errors they were actually making, but feedback that looked convincingly like errors they might have made. This group continued to do the task as they’d learned, applying the right amount of force to the joystick hundreds of times.

This shows that decline in technique “isn’t just a process of forgetting,” says Vaswani. “Your brain notices that you are doing this task perfectly, and you see what you can do differently.”

Adds Shadmehr, “Our results correct a component of knowledge we thought we understood. Neuroscientists thought decay was intrinsic to motor memories, but in fact it’s not decay — it’s selection.”

For many older adults, the aging process seems to go hand-in-hand with an annoying increase in clumsiness — difficulties dialing a phone, fumbling with keys in a lock or knocking over the occasional wine glass while reaching for a salt shaker.

While it’s easy to see these failings as a normal consequence of age-related breakdowns in agility, vision and other physical abilities, new research from Washington University in St. Louis suggests that some of these day-to-day reaching-and-grasping difficulties may be be caused by changes in the mental frame of reference that older adults use to visualize nearby objects.

“Reference frames help determine what in our environment we will pay attention to and they can affect how we interact with objects, such as controls for a car or dishes on a table,” said study co-author Richard Abrams, PhD, professor of psychology in Arts & Sciences.

“Our study shows that in addition to physical and perceptual changes, difficulties in interaction may also be caused by changes in how older adults mentally represent the objects near them.”

The study, published in the journal Psychological Science, is co-authored by two recent graduates of the psychology graduate program at Washington University. The lead author, Emily K. Bloesch, PhD, is now a postdoctoral teaching associate at Central Michigan University. The third co-author, Christopher C. Davoli, PhD, is a postdoctoral psychology researcher at the University of Notre Dame.

When tested on a series of simple tasks involving hand movements, young people in this study adopted an attentional reference frame centered on the hand, while older study participants adopted a reference frame centered on the body.

Young adults, the researchers explain, have been shown to use an “action-centered” reference frame that is sensitive to the movements they are making. So, when young people move their hands to pick up an object, they remain aware of and sensitive to potential obstacles along the movement path. Older adults, on the other hand, tend to devote more attention to objects that are closer to their bodies — whether they are on the action path or not.

“We showed in our paper that older adults do not use an “action centered” reference frame. Instead they use a “body centered” one,” Bloesch said. “As a result, they might be less able to effectively adjust their reaching movements to avoid obstacles — and that’s why they might knock over the wine glass after reaching for the salt shaker.”

These findings mesh well with other research that has documented age-related physical declines in several areas of the brain that are responsible for hand-eye coordination. Older adults exhibit volumetric declines in the parietal cortex and intraparietal sulcus, as well as white-matter loss in the parietal lobe and precuneus. These declines may make the use of an action-centered reference frame difficult or impossible.

“These three areas are highly involved in visually guided hand actions like reaching and grasping and in creating attentional reference frames that are used to guide such actions. These neurological changes in older adults suggest that their representations of the space around them may be compromised relative to those of young adults and that, consequently, young and older adults might encode and attend to near-body space in fundamentally different ways,” the study finds.

As the U.S. population ages, research on these issues is becoming increasingly important. An estimated 60-to-70 percent of the elderly population reports difficulty with activities of daily living, such as eating and bathing and many show deficiencies in performing goal-directed hand movements. Knowing more about these aging-related changes in spatial representation, the researchers suggest, may eventually inspire options for skills training and other therapies to help seniors compensate for the cognitive declines that influence hand-eye coordination

Highly educated individuals with mild cognitive impairment that later progressed to Alzheimer’s disease cope better with the disease than individuals with a lower level of education in the same situation, according to research published in the June issue of The Journal of Nuclear Medicine. In the study “Metabolic Networks Underlying Cognitive Reserve in Prodromal Alzheimer Disease: A European Alzheimer Disease Consortium Project,”neural reserve and neural compensation were both shown to play a role in determining cognitive reserve, as evidenced by positron emission tomography (PET).

Cognitive reserve refers to the hypothesized capacity of an adult brain to cope with brain damage in order to maintain a relatively preserved functional level. Understanding the brain adaptation mechanisms underlying this process remains a critical question, and researchers of this study sought to investigate the metabolic basis of cognitive reserve in individuals with higher (more than 12 years) and lower (less than 12 years) levels of education who had mild cognitive impairment that progressed to Alzheimer’s disease, also known as prodromal Alzheimer’s disease.

“This study provides new insight into the functional mechanisms that mediate the cognitive reserve phenomenon in the early stages of Alzheimer’s disease,” said Silvia Morbelli, MD, lead author of the study.  “A crucial role of the dorso-lateral prefrontal cortex was highlighted by demonstrating that this region is involved in a wide fronto-temporal and limbic functional network in patients with Alzheimer’s disease and high education, but not in poorly educated Alzheimer’s disease patients.”

In the study, 64 patients with prodromal Alzheimer’s disease and 90 control subjects—coming from the brain PET project (chaired by Flavio Nobili, MD, in Genoa, Italy) of the European Alzheimer Disease Consortium—underwentbrain ¹⁸F-FDG PET scans. Individuals were divided into a subgroup with a low level of education (42 controls and 36 prodromal Alzheimer’s disease patients) and a highly educated subgroup (40 controls and 28 prodromal Alzheimer’s disease patients). Brain metabolism was compared between education-matched groups of patients and controls, and then between highly and poorly educated prodromal Alzheimer’s disease patients.

Higher metabolic activity was shown in the dorso-lateral prefrontal cortex for prodromal Alzheimer’s disease patients. More extended and significant correlations of metabolism within the right dorso-lateral prefrontal cortex and other brain regions were found with highly educated than less educated prodromal Alzheimer’s disease patients or even highly educated controls.

This result suggests that neural reserve and neural compensation are activated in highly educated prodromal Alzheimer’s disease patients. Researchers concluded that evaluation of the implication of metabolic connectivity in cognitive reserve further confirms that adding a comprehensive evaluation of resting ¹⁸F-FDG PET brain distribution to standard inspection may allow a more complete comprehension of Alzheimer’s disease pathophysiology and possibly may increase ¹⁸F-FDG PET diagnostic sensitivity.

“This work supports the notion that employing the brain in complex tasks and developing our own education may help in forming stronger ‘defenses’ against cognitive deterioration once Alzheimer knocks at our door,” noted Morbelli.“It’s possible that, in the future, a combined approach evaluating resting metabolic connectivity and cognitive performance can be used on an individual basis to better predict cognitive decline or response to disease-modifying therapy.”

A multi-institutional team of researchers have pinpointed the genetic traits of the cells that give rise to gliomas – the most common form of malignant brain cancer. The findings, which appear in the journal Cell Reports, provide scientists with rich new potential set of targets to treat the disease.

“This study identifies a core set of genes and pathways that are dysregulated during both the early and late stages of tumor progression,” said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., the senior author of the study and co-director of the Center for Translational Neuromedicine. “By virtue of their marked difference from normal cells, these genes appear to comprise a promising set of targets for therapeutic intervention.”

As its name implies, gliomas arise from a cell type found in the central nervous system called the glial cell. Gliomas progress in severity over time and ultimately become highly invasive tumors known as glioblastomas, which are difficult to treat and almost invariably fatal. Current treatments, which include surgery, radiation therapy, and chemotherapy, can delay disease progression, but ultimately prove ineffective. 

Cancer research has been transformed over the past several years by new concepts arising from stem cell biology. Scientists now appreciate that many cancers are the result of rogue stem cells or their offspring, known as progenitor cells. Traditional cancer therapies often do not prevent a recurrence of the disease since they may not effectively target and destroy the cancer-causing stem cells that lie at the heart of the tumors.

Gliomas are one such example. The source of the cancer is a cell found in the brain called the glial progenitor cell. The cells, which arise from and maintain characteristics of stem cells, comprise about three percent of the cell population of the human brain. When these cells become cancerous they are transformed into glioma stem cells, essentially glial progenitor cells whose molecular machinery has gone awry, resulting in uncontrolled cell division.

Goldman and his team have long studied normal glial progenitor cells. These cells produce glia, a category that includes both astrocytes – cells that support the function of neurons – and oligodendrocytes – cells that produces myelin, the fatty insulation that allows the long-distance conduction of neural impulses.

While Goldman’s group’s work has primarily focused on ways to use glial progenitor cells to treat neurological disorders such as multiple sclerosis, their understanding of the biology of these cells and mastery of the techniques required to sort, identify, and isolate these cells has also enabled them to explore the molecular and genetic changes that transform these cells into cancers.

Using human tissue samples representing the three principal stages of the cancer, the researchers were able to identify and isolate the cancer-inducing stem cells. Working with Goldman, lead authors Romane Auvergne, Ph.D. and Fraser Sim, Ph.D. then compared the gene expression profiles of these cancer stem cells to those of normal glial progenitor cells. The objective was to both pinpoint the earliest genetic changes associated with cancer formation and identify those genes that were unique to the cancer stem cells and were expressed at every stage of disease progression.

Out of a pool over 44,000 tested genes and sequences, the scientists identified a small set of genes in the cancerous glioma progenitor cells that were over-expressed at all stages of malignancy. These genes formed a unique “signature” that identified the tumor progenitor cells and enabled the scientists to define a corresponding set of potential therapeutic targets present throughout all stages of the cancer.

“One of the key things you are looking for in drug development in cancer is a protein or gene that is over-expressed, so that you can attempt to achieve therapeutic benefit by inhibiting it,” said Goldman. 

The researchers chose to test this hypothesis by targeting one such gene, called SIX1, which was highly overexpressed in the glioma progenitor cells. While this particular gene is active in the early development of the nervous system, it had not been observed in the adult brain before. However, SIX1 signaling has been associated with breast and ovarian cancer, raising the possibility of its contribution to brain cancer as well. This turned out to indeed be the case. When the researchers blocked – or knocked down – the expression of this gene, the tumor cells ceased growing, and implanted tumors shrank. 

“This study gives us a blueprint to develop new therapies,” said Goldman. “We can now devise a strategy to systematically and rationally analyze – and eliminate – glioma stem and progenitor cells using compounds that may selectively target these cells, relative to the normal glial progenitors from which they derive. By targeting genes like SIX1 that are expressed at all stages of glioma progression, we hope to be able to effectively treat gliomas regardless of their stage of malignancy.  And by targeting the glioma-initiating cells in particular, we hope to lessen the likelihood of recurrence of these tumors, regardless of the stage at which we initiate treatment.”

Measuring blood flow in the brain may be an easy, noninvasive way to predict stroke or hemorrhage in children receiving cardiac or respiratory support through a machine called ECMO, according to a new study by researchers at Nationwide Children’s Hospital. Early detection would allow physicians to alter treatment and take steps to prevent these complications—the leading cause of death for patients on ECMO.

Short for extracorporeal membrane oxygenation, ECMO is used when a patient is unable to sustain enough oxygen in the blood supply due to heart failure, septic shock, or other life-threatening condition, said Nicole O’Brien, MD, a physician and scientist in critical care medicine at Nationwide Children’s and lead author of the study, which appears in a recent issue of the journal Pediatric Critical Care Medicine. The patient is connected to ECMO with tubes that carry the patient’s blood from a vein through the machine, where it is oxygenated and funneled back to the patient via an artery or vein that then distributes the oxygen-rich blood to vital organs and tissues.

The disease processes that lead someone to need ECMO are different, O’Brien noted, but it is used only after traditional therapies, such as a ventilator, fail. One of the biggest risks of ECMO is bleeding in the brain. Only 36 percent of children who suffer this complication survive, many left with permanent neurologic injury.

“Most of these patients are critically ill before they go on ECMO and often have low oxygen levels, low blood pressure and poor heart function, all of which can certainly lead to strokes,” said O’Brien, also an associate professor of clinical medicine at The Ohio State University College of Medicine. “Still, some patients develop problems and others don’t and we don’t understand why.”

To better understand the cause for these brain bleeds, O’Brien launched a pilot study to monitor cerebral blood flow using a transcranial doplar ultrasound machine, a portable, noninvasive technology that uses sound waves to measure the amount and speed of blood flowing through the brain. All patients on ECMO experience a change in cranial blood flow, but O’Brien wanted to see if those variations offered any hint as to why some patients had complications while others didn’t.

She measured cranial blood flow in 18 ECMO patients, taking the first reading within the patient’s first 24 hours on the machine, then again each day they received the treatment and one more time after ECMO therapy ended.

When she compared these measurements to normal cerebral blood flow rates for children in the same age group, she found significant differences. Thirteen of the children in the study developed no neurologic complications while on ECMO. In these children, cerebral blood flow was 40 percent to 50 percent lower than normal. But in the five patients who had either a stroke or brain hemorrhage while on ECMO, cerebral blood flow was 100 percent higher than normal.

The age of the child, length of time on ECMO or the underlying illness didn’t seem to matter. The only difference was that cerebral blood flow was dramatically increased in patients who ultimately had problems. While O’Brien found that interesting, the most intriguing finding was that the increase in blood flow occurred as long as two to six days before the patient began bleeding in the brain.

“That could give us a lot of lead time to prevent the brain bleeds or hemorrhages,” said O’Brien.

Physicians may decide to try to wean a patient off ECMO a little more quickly or change the dosage of anti-coagulant medication that all ECMO patients take.

Although O’Brien is excited about the results, she is careful to note that the findings are preliminary. She is planning a multi-center trial to see if the outcome will be the same in a larger study population.

“We still need to understand why these kids bleed and why they stroke,” said O’Brien. “This little piece of information is the very tip of the iceberg in terms of why that happens.”

Protein modification may help control Alzheimer’s and epilepsy, TAU researchers find

In the brain, cell-to-cell communication is dependent on neurotransmitters, chemicals that aid the transfer of information between neurons. Several proteins have the ability to modify the production of these chemicals by either increasing or decreasing their amount, or promoting or preventing their secretion. One example is tomosyn, which hinders the secretion of neurotransmitters in abnormal amounts.

Dr. Boaz Barak of Tel Aviv University’s Sagol School of Neuroscience, in collaboration with Prof. Uri Ashery, used a method for modifying the levels of this protein in the mouse hippocampus — the region of the brain associated with learning and memory. It had a significant impact on the brain’s activity: Over-production of the protein led to a sharp decline in the ability to learn and memorize information, the researchers reported in the journal NeuroMolecular Medicine.

"This study demonstrates that it is possible to manipulate various processes and neural circuits in the brain," says Dr. Barak, a finding which may aid in the development of therapeutic procedures for epilepsy and neurodegenerative diseases such as Alzheimer’s. Slowing the transmission rate of information when the brain is overactive during epileptic seizures could have a beneficial effect, and readjusting the levels of tomosyn in an Alzheimer’s patient may help increase cognition and combat memory loss.

A maze of memory loss

The researchers teamed up with a laboratory at the National Institutes of Health (NIH) in Baltimore to create a virus which produces the tomosyn protein. In the lab, the virus was injected into the hippocampus region in mice. Then, in order to test the consequences, they performed a series of behavioral tests designed to measure functions like memory, cognitive ability, and motor skills.

In one experiment, called the Morris Water Maze, mice had to learn to navigate to, and remember, the location of a hidden platform placed inside a pool with opaque water. During the first five days of testing, researchers found that the test group with an over-production of tomosyn had a significant problem in learning and memorizing the location of the platform, compared to a control group that received a placebo injection. And when the platform was removed from the maze, the test group spent less time swimming around the area where the platform once was, indicating that they had no memory of its existence. In comparison, the control group of mice searched for the missing platform in its previous location for two or even three days after its removal, notes Dr. Barak.

These findings were further verified by measuring electrical activity in the brains of both the test group and the control group. In the test group, researchers found decreased levels of transmissions between neurons in the hippocampus, a physiological finding that may explain the results of the behavioral tests.

Correcting neuronal processes

In the future, Dr. Barak believes that the ability to modify proteins directly in the brain will allow for more control over brain activities and the correction of neurodegenerative processes, such as providing stricter regulation in neuronal activity for epileptic patients or stimulating neurotransmitters to help with learning and memory loss in Alzheimer’s patients. Indeed, a separate study conducted by the researchers demonstrates that mouse models for Alzheimer’s disease do have an over-production of tomosyn in the hippocampus region, so countering the production of this protein could have a beneficial effect.

Now Dr. Barak and Prof. Ashery are working towards a method for artificially decreasing levels of the protein, which they believe will have the opposite effect on the cognitive ability of the mice. “We hypothesize that with an under-production in tomosyn, the mice will show a marked improvement in their performance in behavioral testing,” he says.