Neuroscience
Month
The classic theory of the brain is one of connections, in which the brain consists of a network of neurons that interact with each other to allow us to think, see, interpret, and understand the world around us. In this model, called distributed representation, an individual neuron by itself has no inherent meaning, but only contributes to a pattern of neuronal activity that has meaning. For example, a certain pattern of many neurons fires when you think “dog” and another pattern for “cat.”
"The belief in distributed representation theory is that a concept or object is not represented by a single neuron in the brain but by a pattern of activations over a number of neurons," explains Asim Roy, a professor of information systems at Arizona State University, to Medical Xpress . "Thus there is no single neuron in the brain representing a cat or a dog. Proponents of this theory claim that a cat or a dog is represented by its microfeatures such as legs, ears, body, tail, and so on. However, they think that neurons have absolutely no meaning on a stand-alone basis. Therefore, they go further and claim that these microfeatures are at the subsymbolic level, which means that meaning arises only when you consider the pattern of activations as a whole. Therefore, there are no neurons representing legs, ears, body, tail, etc. The representation is at a much lower level."
Roy is among a number of scientists working in the fields of neuroscience and artificial intelligence (AI) who suspect that the brain may not be as connected as distributed representation suggests. The basis of their alternative model, called localist representation, is that a single neuron can represent a dog, a cat, or any other object or concept. These neurons can be considered symbols since they have meaning on a stand-alone basis. However, as Roy explains, this doesn’t necessarily mean only one neuron represents a dog; such “concept cells” are high-level neurons, which fire in response to the firing of an assortment of low-level neurons that represent the legs, ears, body, tail, etc.
"In localist representation, there could be separate neurons for a dog and a cat, and also neurons for legs, ears, body, tail, etc.," he said. "It’s very similar to the model in my paper for word recognition, which is an old model from James McClelland [Chair of the Psychology Department at Stanford University] and [the late pioneering neuroscientist] David Rumelhart. You have low-level neurons that detect letters of the alphabet and then high-level neurons for individual words. So letter neurons and word neurons, they both exist."
The origins of this dispute between localist and distributed representation goes back to the early ’80s, to a dispute between the symbol processing hypothesis of artificial intelligence (AI) and the subsymbolic paradigm of connectionists. In the past 30 years, the debate has only intensified.
A scientist at the University of British Columbia and Vancouver Coastal Health has identified the molecule that controls a scissor-like protein responsible for the production of plaques – the telltale sign of Alzheimer’s disease (AD).
The molecule, known as GSK3-beta, activates a gene that creates a protein, called BACE1. When BACE1 cuts another protein, called APP, the resulting fragment – known as amyloid beta – forms tiny fibers that clump together into plaques in the brain, eventually killing neural cells.
Using an animal model, Dr. Weihong Song, Canada Research Chair in Alzheimer’s Disease and professor of psychiatry, found that disabling GSK3-beta’s effect in mice resulted in less BACE1 and far fewer deposits of amyloid in their brains. Song’s research, published online in the Journal of Clinical Investigation, also found that such mice performed better than untreated mice on memory tests.
Previous research had shown that GSK3-beta spurred the growth of twisted fibers inside neurons, known as tangles – another hallmark of AD. Song says his discovery of the protein’s dual destructiveness makes it a promising target for drug research.
GSK3-beta, however, is a versatile enzyme that controls many vital physiological functions. The drug used to inhibit GSK3-beta in the mice is too indiscriminate, and could cause several serious side effects, including cancer.
“If we can find a way to stop GSK3-beta’s specific reaction with BACE1, and still leave it intact to perform other crucial tasks, we have a much better chance of treating AD and preventing its progression,” says Song, a member of the Brain Research Centre at UBC and the Vancouver Coastal Health Research Institute (VCHRI), and Director of the Townsend Family Laboratories at UBC.
Surgeons may soon be able to regrow patients’ nerves, such as those in damaged spinal cords, using technology adapted from the type of inkjet printer most of us have connected to our computer at home.
The ink has to keep the cells in suspension, as well as having the right chemical composition to keep them alive. It also protects them as they are shot out of the printer at amazing speeds.
The scaffolds act as the base upon which the cells thrive, and contain substances such as growth factor molecules and electrical conduits to enable stimulation to promote cell growth. The aim is to produce structures up to 4 cm long, which can be “patched” into broken or damaged nerves or muscles.
“There’s great interest from the medical world, and we are working closely with clinicians at St Vincents Hospital in Melbourne,” says Prof Gordon Wallace, director of the Materials node of ANFF and ACES. “They’re very interested in the possibilities it raises, and the collaboration is resulting in new ideas almost every week.”
“The support from ANFF and the collaborative, interdisciplinary approach that our facilities bring has attracted the best people in the world to join our teams,” he adds.
A Loyola University Medical Center neurologist is reporting surprising results of a study of patients who experience both epileptic and non-epileptic seizures.
Non-epileptic seizures resemble epileptic seizures, but are not accompanied by abnormal electrical discharges. Rather, these seizures are believed to be brought on by psychological stresses.
Dr. Diane Thomas reported that 15.7 percent of hospital patients who experienced non-epileptic seizures also had epileptic seizures during the same hospital stay. Previous studies found the percentage of such patients experiencing both types of seizures was less than 10 percent.
Thomas reported the findings Dec. 2 at a meeting of the American Epilepsy Society.
The finding is significant because epileptic and non-epileptic seizures are treated differently. Non-epileptic seizures do not respond to epilepsy medications, and typically are treated with psychotherapy, anti-depressants, or both, Thomas said.
Non-epileptic seizures used to be called pseudoseizures. But they are quite real, and the preferred term now is psychogenic non-epileptic seizure. A non-epileptic seizure can resemble the convulsions characteristic of a grand mal epileptic seizure, or the staring-into-space characteristic of a petit mal epileptic seizure. But unlike an epileptic seizure, the brain waves during a non-epileptic seizure are normal.
Non-epileptic seizures can be triggered by stresses such as physical or sexual abuse, incest, job loss, divorce or death of a loved one. In some cases, the traumatic event may be blocked from the patient’s conscious memory.
Non-epileptic seizures often are mistaken for epileptic seizures. While some patients who have both types can distinguish between the two, others find it difficult to distinguish when they are having non-epileptic seizures.
The only way to make a definitive seizure diagnosis is to monitor a patient with an electroencephalogram (EEG) and a video camera. (The EEG can detect abnormal electrical discharges that indicate an epileptic seizure.) The patient is monitored with the camera until a seizure occurs, and the EEG recordings from the event are then analyzed.
Thomas conducted her study at the University of Maryland Medical Center, where she did a fellowship in epilepsy before recently joining Loyola. Thomas and colleagues reviewed 256 patients who had come to the hospital to have their seizures monitored. Seventy of the patients had documented non-epileptic seizures. Of these, 11 patients (15.7 percent) also experienced epileptic seizures during their hospital stays.
Forgive your mind this minor annoyance because it has worked to save your life—or more accurately, the lives of your ancestors. Most likely you have not needed to worry whether the rustling in the underbrush is a rabbit or a leopard, or had to identify the best escape route on a walk by the lake, or to wonder whether the funny pattern in the grass is a snake or dead branch. Yet these were life-or-death decisions to our ancestors. Optimal moment-to-moment readiness requires a brain that is working constantly, an effort that takes a great deal of energy. (To put this in context, the modern human brain is only 2 percent of our body weight, but it uses 20 percent of our resting energy.) Such an energy-hungry brain, one that is constantly seeking clues, connections and mechanisms, is only possible with a mammalian metabolism tuned to a constant high rate.
Constant thinking is what propelled us from being a favorite food on the savanna—and a species that nearly went extinct—to becoming the most accomplished life-form on this planet. Even in the modern world, our mind always churns to find hazards and opportunities in the data we derive from our surroundings, somewhat like a search engine server. Our brain goes one step further, however, by also thinking proactively, a task that takes even more mental processing.
So even though most of us no longer worry about leopards in the grass, we do encounter new dangers and opportunities: employment, interest rates, “70 percent off” sales and swindlers offering $20 million for just a small investment on our part. Our primate heritage brought us another benefit: the ability to navigate a social system. As social animals, we must keep track of who’s on top and who’s not and who might help us and who might hurt us. To learn and understand this information, our mind is constantly calculating “what if?” scenarios. What do I have to do to advance in the workplace or social or financial hierarchy? What is the danger here? The opportunity?
For these reasons, we benefit from having a brain that works around the clock, even if it means dealing with intrusive thoughts from time to time.
Scientists at the Gladstone Institutes have defined for the first time a key underlying process implicated in multiple sclerosis (MS)—a disease that causes progressive and irreversible damage to nerve cells in the brain and spinal cord. This discovery offers new hope for the millions who suffer from this debilitating disease for which there is no cure.
Researchers in the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, have identified in animal models precisely how a protein that seeps from the blood into the brain sets off a response that, over time, causes the nerve cell damage that is a key indicator of MS. These findings, which are reported in the latest issue of Nature Communications, lay the groundwork for much-needed therapies to treat this disease.
Professor José Miguel Soria, a member of the Institute of Biomedical Sciences, Universidad CEU Cardenal Herrera, has co-directed with Professor Manuel Monleón of the Universitat Politècnica de València a study on the compatibility of polymeric biomaterials in the brain and its effectiveness to favour neuroregeneration in areas with some kind of damage or brain injury.
The research carried out has shown that these types of implants, made of a biocompatible synthetic material, are colonized within two months by neural progenitor cells and irrigated by new blood vessels. This allows the generation, within these structures, of new neurons and glia, capable of repairing injured brain tissue caused by trauma, stroke or neurodegenerative disease, among other causes.
The synthetic structures used in this study are made with a porous and biocompatible polymeric material called acrylate copolymer. In the first phase of the project, the structures have been studied in vitro by implanting them into neural tissue, and subsequently also in vivo, when implanted in two areas of the adult rat brain: the cerebral cortex and the subventricular zone, the most important source of generation of adult neural stem cells.
The study has confirmed the high biocompatibility of polymeric materials, such as acrylate copolymer, with brain tissue and opens new possibilities of the effectiveness of the implementation of these structures in the brain, seeking optimum location for developing regenerative strategies of the central nervous system.
Furthermore, the results are particularly relevant when one considers that in the adult brain neuroregeneration capacity is more limited than in younger individuals and that the main impediment for this is the lack of revascularization of damaged tissue, something that the biomaterial studied has shown to favour.
New research suggests that the molecular mechanism leading to schizophrenia may be different in patients who fail to respond to anti-psychotic medication compared to patients who do respond.
The research, from King’s College London’s Institute of Psychiatry may help explain why up to one third of patients with schizophrenia do not respond to traditional anti-psychotic medication.
Schizophrenia is known to be associated with an overactive dopamine system, meaning that the brain processes abnormally high levels of dopamine. Traditional dopamine-blocking anti-psychotic medication attempts to normalise this process. However, approximately one third of patients with schizophrenia do not respond to this treatment, and until now, no study has examined whether dopamine abnormality is present in patients resistant to antipsychotic treatment.
The study was led by Dr Arsime Demjaha, Dr Oliver Howes, Professor Shitij Kapur, Professor Sir Robin Murray and Professor Philip McGuire from King’s Institute of Psychiatry and published in the American Journal of Psychiatry.
Dr Arsime Demjaha and co-authors, say: ‘Despite considerable scientific and therapeutic progress over the last 50 years, we still do not know why some patients with schizophrenia respond to treatment whilst others do not. Treatment resistance in such a disabling condition is one of the greatest clinical and therapeutic challenges to psychiatry, significantly affecting patients, their families and society in general.’
The authors conclude: ‘Our findings suggest that there may be a different molecular mechanism leading to schizophrenia in patients who do not respond to anti-psychotic medication. Identifying the precise molecular pathway particularly in these patients is of utmost importance and will help inform the development of much-needed novel treatments.’
Researchers used PET scan imaging to investigate dopamine synthesis capacity in 12 patients with schizophrenia who did not respond to treatment, 12 who did, and 12 healthy controls. They found that schizophrenia patients whose illness was resistant to antipsychotic treatment have relatively normal levels of dopamine synthesis capacity which would explain why the dopamine blocking anti-psychotic medication was not effective in this group.
However, the authors add that the findings need to be replicated in larger samples before the research can affect clinical practice. They add that future research will need to focus on long-term prospective studies of patients who have never taken anti-psychotics to determine whether presynaptic dopamine synthesis capacity was normal in patients in the treatment-resistant group at the onset of their illness, and predates antipsychotic exposure.
Autism spectrum disorders (ASD) are neurodevelopmental disorders typically characterized by difficulties in social interactions and delayed or abnormal language development. Although ASD reportedly affects 1 in 88 people in the United States, to date there have been no distinctive biomarkers to diagnose the disease. In a special themed issue of Disease Markers, investigators report on the current understanding of ASD genetics and the possibilities of translating genetic research toward biomarker development in ASD.
"Although some individuals with ASD are highly functional, many are severely impaired and require permanent care. The significant level of impairment combined with the fact that no specific therapy is yet available for ASD, make ASD a devastating illness for patients and families, and a heavy financial burden for the healthcare system," says guest editor, Irina Voineagu, MD, PhD, RIKEN Omics Science Center, Yokohama, Japan. "The most effective intervention for ASD has proven to be early behavioral therapy. Thus the identification of biological markers for ASD, allowing very early detection, even before the onset of symptoms, would be of tremendous value."
Five articles comprise this comprehensive issue, providing an overview of ASD genetic models, an exploration of several key emerging concepts in understanding ASD’s molecular basis, and discussion of current biomarker development, focusing on genomic data.
Following an introduction by Voineagu, Yuri Bozzi and colleagues review the phenotype characteristics of currently available mouse models of ASD. Carmen Panaitof then discusses the role of the songbird as an experimental model system for investigating the genetic basis of human language and its ASD-related impairments. Michael Bowers and Genevieve Konopka further explore language deficits and provide new evidence for the role of the FOXP gene to regulate language. Alka Saxena, Dave Tang, and Piero Carninci focus on the functional roles of the gene MECP2, which is mutated in most cases of Rett syndrome, one of the ASDs.
A review rounding out the issue is “Subphenotype-Dependent Disease Markers for Diagnosis and Personalized Treatment of Autism Spectrum Disorders,” by Valerie W. Hu, PhD, The George Washington University, School of Medicine and Health Sciences, Washington, DC, PhD, which discusses current progress toward identifying ASD biomarkers based on genome-wide data.
"Without genetic or molecular markers for screening, individuals with ASD are typically not diagnosed before the age of 2, with milder cases diagnosed much later," writes Dr. Hu. "Because early diagnosis is tantamount to early behavioral intervention, which has been shown to improve individual outcomes, an objective biomarker test that can diagnose at-risk children perinatally is a medical imperative."
Hu demonstrates the possibility and importance of developing ASD subtypes to help identify relevant disease markers, which can ultimately aid in developing specific targeted therapies.
Voineagu concludes, “It is exciting times for genetic research and although the phenotypic and genetic heterogeneity of ASD often seem to be a daunting conundrum, well-defined diagnostic criteria, larger cohort sizes for genetic studies and integrative approaches of genomic and epigenomic data already delineate a promising avenue for elucidating the mechanisms of ASD.”
Scientists at NYU Langone Medical Center have identified two genes involved in establishing the neuronal circuits required for breathing. They report their findings in a study published in the December issue of Nature Neuroscience. The discovery, featured on the journal’s cover, could help advance treatments for spinal cord injuries and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), which gradually kill neurons that control the movement of muscles needed to breathe, move, and eat.
The study identifies a molecular code that distinguishes a group of muscle-controlling nerve cells collectively known as the phrenic motor column (PMC). These cells lie about halfway up the back of the neck, just above the fourth cervical vertebra, and are “probably the most important motor neurons in your body,” says Jeremy Dasen, PhD, assistant professor of physiology and neuroscience and a member of the Howard Hughes Medical Institute, who led the three-year study with Polyxeni Philippidou, PhD, a postdoctoral fellow.
Harming the part of the spinal cord where the PMC resides can instantly shut down breathing. But relatively little is known about what distinguishes PMC neurons from neighboring neurons, and how PMC neurons develop and wire themselves to the diaphragm in the fetus.
The PMC cells relay a constant flow of electrochemical signals down their bundled axons and onto the diaphragm muscles, allowing the lungs to expand and relax in the natural rhythm of breathing. “We now have a set of molecular markers that distinguish those cells from other populations of motor neurons, so that we can study them in detail and look for ways to selectively enhance their survival,” Dr. Dasen says. Degeneration of PMC neurons is the primary cause of death in patients with ALS and spinal cord injuries.
To find out what distinguishes PMC neurons from their spinal neighbors in mice, Dr. Philippidou injected a retrograde fluorescent tracer into the phrenic nerve, which wires the PMC to the diaphragm, and then looked for the spinal neurons that lit up as the tracer worked its way back to the PMC. He used transgenic mice that express green fluorescent protein (GFP) in motor neurons and their axons in order to see the phrenic nerve. After noting the characteristic gene expression pattern of these PMC neurons, Dr. Philippidou began to determine their specific roles. Ultimately, a complicated strain of transgenic mice, based partly on mice supplied by collaborator Lucie Jeannotte, PhD, at the University of Laval in Quebec, revealed two genes, Hoxa5 and Hoxc5, as the prime controllers of proper PMC development. Hox genes (39 are expressed in humans) are well known as master gene regulators of animal development.
When Hoxa5 and Hoxc5 are silenced in embryonic motor neurons in mice, the scientists reported, the PMC fails to form its usual, tightly columnar organization and doesn’t connect correctly to the diaphragm, leaving a newborn animal unable to breathe. “Even if you delete these genes late in fetal development, the PMC neuron population drops and the phrenic nerve doesn’t form enough branches on diaphragm muscles,” Dr. Dasen says.
Dr. Dasen plans to use the findings to help understand the wider circuitry of breathing—including rhythm-generating neurons in the brain stem, which are in turn responsive to carbon dioxide levels, stress, and other environmental factors. “Now that we know something about PMC cells, we can work our way through the broader circuit, to try to figure out how all those connections are established,” he says.
"Once we understand how the respiratory network is wired we can begin to develop novel treatment options for breathing disorders such as sleep apneas," adds Dr. Philippidou.
In late October Dr. Dasen lost many of his transgenic mice when Hurricane Sandy flooded the basement of the Smilow building at NYU Langone Medical Center. But just before the hurricane hit, he sent an important group of these mice back to Dr. Jeannotte in Quebec, “so we didn’t lose everything,” he says.
Borrowing from microfabrication techniques used in the semiconductor industry, MIT and Harvard Medical School (HMS) engineers have developed a simple and inexpensive way to create three-dimensional brain tissues in a lab dish.
The new technique yields tissue constructs that closely mimic the cellular composition of those in the living brain, allowing scientists to study how neurons form connections and to predict how cells from individual patients might respond to different drugs. The work also paves the way for developing bioengineered implants to replace damaged tissue for organ systems, according to the researchers.
"We think that by bringing this kind of control and manipulation into neurobiology, we can investigate many different directions," says Utkan Demirci, an assistant professor in the Harvard-MIT Division of Health Sciences and Technology (HST).
Demirci and Ed Boyden, associate professor of biological engineering and brain and cognitive sciences at MIT’s Media Lab and McGovern Institute, are senior authors of a paper describing the new technique, which appears in the Nov. 27 online edition of the journal Advanced Materials. The paper’s lead author is Umut Gurkan, a postdoc at HST, Harvard Medical School and Brigham and Women’s Hospital.