"BigBrain" Study Provides Most Detailed 3-D Map of the Brain Yet

A landmark three-dimensional digital reconstruction of a complete human brain, called the BigBrain, shows the brain anatomy in microscopic detail at a spatial resolution of 20 micrometers—smaller than the size of one fine strand of hair.

The reconstruction, published in the 21 June issue of the journal Science, exceeds the resolution of all existing reference brains presently in the public domain, and will be made freely available to the broader scientific community.

The fine-grained anatomical resolution of the BigBrain will allow scientists who use it to gain insights into the neurobiological basis of cognition, language, emotions and other processes, according to the study. The anatomical tool yielded by the researchers will serve as an atlas for neurosurgery and provide a framework for research in many directions, including enhanced understanding of brain diseases, such as Alzheimer’s disease.

"It is a common basis for scientific discussions because everybody can work with this brain model," said Science co-author Karl Zilles, senior professor of the Jülich Aachen Research Alliance.

The new reference brain, which is part of the European Human Brain Project, “redefines traditional maps from the beginning of the 20th century,” explained lead author Katrin Amunts from the Research Centre Jülich. Amunts serves as director of the Cecile and Oskar Vogt Institute for Brain Research at the Heinrich Heine University Düsseldorf in Germany.

"The authors pushed the limits of current technology," said Science Senior Editor Peter Stern. Existing reference brains do not probe further than the macroscopic, or visible, components of the brain. The BigBrain provides a resolution much finer than the typical 1 millimeter resolution from MRI studies. "The spatial resolution the researchers achieved exceeds that of presently available reference brains by a factor of 50," said Stern.

"Of course, we would love to have spatial resolution going down to 1 micrometer," said Amunts in a 19 June press teleconference. However, "there are simply no computers at this moment which would be capable to process such data, to visualize this or to analyze it."

To create the detailed brain atlas, Amunts and colleagues took advantage of new advances in computing capacities and image analysis. Using a special tool called a microtome, they carefully cut the paraffin-covered brain of a 65-year-old female into 20 micrometer-thick sections.

The project was “a tour-de-force to assemble images of over 7400 individual histological sections, each with its own distortions, rips and tears, into a coherent 3-D volume,” said Science co-author Alan Evans, a professor at the Montreal Neurological Institute at McGill University in Montreal, Canada.

The sections were mounted on slides, stained to detect cell structures and finally digitized with a high-resolution flatbed scanner so researchers could reconstruct the high-resolution 3-D brain model. It took approximately 1000 hours to collect the data.

The researchers’ future plans for using the map include extracting measurements of cortical thickness to gain insights into aging and neurodegenerative disorders. Eventually, Amunts and colleagues hope to build a brain model at the resolution of 1 micron to capture details of single cell morphology. Detailed brain maps can aid researchers who are exploring the full set of neural connections and real-time brain activity, as scientists discussed recently in a Capitol Hill briefing sponsored by AAAS.

The creation of such a detailed brain map, offering a gateway to unprecedented insights into the brain’s anatomy and organization, was long in the works. “It was a dream for almost 20 years,” Amunts said. “The dream came true because of an interdisciplinary and intercontinental collaboration spanning from Europe to Canada and from neuroanatomy to supercomputing .”

Though not directly related to the BRAIN Initiative announced by President Barack Obama earlier this year, the work by Amunts and colleagues supports the Initiative’s goal of giving scientists the best possible tools with which to obtain a dynamic picture of the brain.

Scientists Discover Key Signaling Pathway that Makes Young Neurons Connect

Neuroscientists at The Scripps Research Institute (TSRI) have filled in a significant gap in the scientific understanding of how neurons mature, pointing to a better understanding of some developmental brain disorders.

In the new study, the researchers identified a molecular program that controls an essential step in the fast-growing brains of young mammals. The researchers found that this signaling pathway spurs the growth of neuronal output connections by a mechanism called “mitochondrial capture,” which has never been described before.

“Mutations that may affect this signaling pathway already have been found in some autism cases,” said TSRI Professor Franck Polleux, who led the research, published June 20, 2013 in the journal Cell.

Branching Out

Polleux’s laboratory is focused on identifying the signaling pathways that drive neural development, with special attention to the neocortex—a recently evolved structure that handles the “higher” cognitive functions in the mammalian brain and is highly developed in humans.

In a widely cited study published in 2007, Polleux’s team identified a trigger of an early step in the development of the most important class of neocortical neurons. As these neurons develop following asymmetric division of neural stem cells, they migrate to their proper place in the developing brain. Meanwhile they start to sprout a root-like mesh of input branches called dendrites from one end, and, from the other end, a long output stalk called an axon. Polleux and his colleagues found that the kinase LKB1 provides a key signal for the initiation of axon growth in these immature cortical neurons.

In the new study, Polleux’s team followed up this discovery and found that LKB1 also is crucially important for a later stage of these neurons’ development: the branching of the end of the axon onto the dendrites of other neurons.

“In experiments with mice, we knocked the LKB1 gene out of immature cortical neurons that had already begun growing an axon, and the most striking effect was a drastic reduction in terminal branching,” said Julien Courchet, a research associate in the Polleux laboratory who was a lead co-author of the study. “We saw this also in lab dish experiments, and when we overexpressed the LKB1 gene, the result was a dramatic increase in axon branching.”

Further experiments by Courchet showed that LKB1 drives axonal branching by activating another kinase, NUAK1. The next step was to try to understand how this newly identified LKB1-NUAK1 signaling pathway induced the growth of new axon branches.

Stopping the Train in Its Tracks

Following a thin trail of clues, the researchers decided to look at the dynamics of microtubules. These tiny railway-like tracks are laid down within axons for the efficient transport of molecular cargoes and are altered and extended during axonal branching. Although they could find no major change in microtubule dynamics within immature axons lacking LKB1 or NUAK1, the team did discover one striking abnormality in the transport of cargoes along these microtubules. Tiny oxygen-reactors called mitochondria, which are the principal sources of chemical energy in cells, were transported along axons much more actively—and by contrast, became almost immobile when LKB1 and NUAK1 were overexpressed.

But the LKB1-NUAK1 signals weren’t just immobilizing mitochondria randomly. They were effectively inducing their capture at points on the axons where axons form synaptic connections with other neurons. “When we removed LKB1 or NUAK1 in cortical neurons, the mitochondria were no longer captured at these points,” said Tommy Lewis, Jr., a research associate in the Polleux Laboratory who was co-lead author of the study.

“We argue that there must be an active ‘homing factor’ that specifies where these mitochondria stop moving,” said Polleux. “And we think that this is essentially what the LKB1-NAUK1 signaling pathway does here.”

Looking Ahead

Precisely how the capture of mitochondria at nascent synapses promotes axonal branching is the object of a further line of investigation in the Polleux laboratory. “We think that we have uncovered something very interesting about mitochondrial function at synapses,” Polleux said.

In addition to its basic scientific importance, the work is likely to be highly relevant medically. Developmentally related brain disorders such as epilepsy, autism and schizophrenia typically involve abnormalities in neuronal connectivity. Recent genetic surveys have found NUAK1-related gene mutations in some children with autism, for example. “Our study is the first one to identify that NUAK1 plays a crucial role during the establishment of cortical connectivity and therefore suggests why this gene might play a role in autistic disorder,” Polleux says.

He notes, too, that declines in normal mitochondrial transport within axons have been observed in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. “In the light of our findings, we wonder if the decreased mitochondrial mobility observed in these cases might be due not to a transport defect, but instead to a defect in mitochondrial capture in aging neurons,” he said. “We’re eager to start doing experiments to test such possibilities.”

(Image: Shutterstock)

Animal study shows promising path to prevent epilepsy

Duke Medicine researchers have identified a receptor in the nervous system that may be key to preventing epilepsy following a prolonged period of seizures.

Their findings from studies in mice, published online in the journal Neuron on June 20, 2013, provide a molecular target for developing drugs to prevent the onset of epilepsy, not just manage the disease’s symptoms.

"Unfortunately, there are no preventive therapies for any common disorder of the human nervous system – Alzheimer’s, Parkinson’s, schizophrenia, epilepsy – with the exception of blood pressure-lowering drugs to reduce the likelihood of stroke," said study author James O. McNamara, M.D., professor of neurobiology at Duke Medicine.

Epilepsy is a serious neurological disorder marked by recurring seizures. Temporal lobe epilepsy – where seizures occur in the region of the brain where memories are stored and language, emotions and senses are processed – is the most common form, and can be devastating. Because afflicted individuals have seizures that impair their awareness and may have associated behavioral problems, they may have difficulty with everyday activities, including holding a job or obtaining a driver’s license.

Conventional therapies to treat epilepsy address the disease’s symptoms by trying to reduce the likelihood of having a seizure. However, many people with temporal lobe epilepsy still have seizures despite taking these drugs.

"This study opens a promising new avenue of research into treatments that may prevent the development of epilepsy," said Vicky Whittemore, PhD, a program director at the National Institute of Neurological Disorders and Stroke, who oversees the grants that funded this study.

Retrospective studies of people with severe temporal lobe epilepsy reveal that many of them initially have an episode of prolonged seizures, known as status epilepticus. Status epilepticus is often followed by a period of seizure-free recovery before people start to experience recurring temporal lobe seizures.

In animal studies, inducing status epilepticus in an otherwise healthy animal can cause them to become epileptic. The prolonged seizures in status epilepticus are therefore thought to cause or importantly contribute to the development of epilepsy in humans.

"An important goal of this field has been to identify the molecular mechanism by which status epilepticus transforms a brain from normal to epileptic," said McNamara. "Understanding that mechanism in molecular terms would provide a target with which one could intervene pharmacologically, perhaps to prevent an individual from becoming epileptic."

Earlier research in epilepsy flagged a receptor in the nervous system called TrkB as a key player in transforming the brain from normal to epileptic. In the current study, McNamara and his colleagues sought to confirm if TrkB was important for status epilepticus-induced epilepsy.

Using an approach combining chemistry and genetic analyses, the researchers studied normal and genetically altered mice. The genetically altered mice were unique in that a drug, 1NMPP1, inhibited TrkB in their brains. If the drug stopped the genetically altered mice from becoming epileptic, this genetic approach would prove that inhibiting TrkB prevents the onset of epilepsy.

When the researchers caused status epilepticus in the animals, both the normal and genetically modified mice developed epilepsy. However, treatment with 1NMPP1 after the prolonged period of seizures prevented epilepsy in the genetically altered but not the normal mice.

"This demonstrated that it is possible to intervene following status epilepticus and prevent the animal from becoming epileptic," McNamara said.

Importantly, the researchers only administered treatment with 1NMPP1 for two weeks, which was sufficient to prevent epilepsy from developing in the mice when tested many weeks later. The results suggest that a preventive therapy may only need to be given for a limited period of time following the initial bout of prolonged seizures, not an individual’s entire life, which could prevent unnecessary side effects that come with long-term use of drugs.

In future studies, the researchers hope to determine the exact time window in which TrkB signaling needs to be repressed to prevent the onset of epilepsy. Long term, this research provides a molecular target for developing the first drugs to prevent epilepsy.

"This study provides a strong rationale for the development of selective inhibitors of TrkB signaling," said McNamara.

New Alzheimer’s research suggests possible cause: the interaction of proteins in the brain

Research shows interaction of tau and amyloid-beta in the brain may cause cognitive decline

For years, Alzheimer’s researchers have focused on two proteins that accumulate in the brains of people with Alzheimer’s and may contribute to the disease: plaques made up of the protein amyloid-beta, and tangles of another protein, called tau.

But for the first time, an Alzheimer’s researcher has looked closely at not the two proteins independently, but at the interaction of the two proteins with each other — in the brain tissue of post-mortem Alzheimer’s patients and in mouse brains with Alzheimer’s disease. The research found that the interaction between the two proteins might be the key: as these interactions increased, the progression of Alzheimer’s disease worsened.

The research, by Hemachandra Reddy, Ph.D., an associate scientist at the Oregon National Primate Research Center at Oregon Health & Science University, is detailed in the June 2013 edition of the Journal of Alzheimer’s Disease.

Reddy’s paper suggests that when the interaction between the phosphorylated tau and the amyloid-beta — particularly in its toxic form — happens at brain synapses, it can damage those synapses. And that can lead to cognitive decline in Alzheimer’s patients.

"This complex formation between amyloid-beta and tau — it is actually blocking the neural communication," Reddy said. "If we could somehow find a molecule that could inhibit the binding of these two proteins at the synapses, that very well might be the cure to Alzheimer’s disease."

To conduct the research, Reddy and his team studied three different kinds of mice, who had been bred to have some of the brain characteristics of Alzheimer’s disease, including having amyloid-beta and phosphorylated tau in their brains. Reddy also analyzed postmortem brain tissue from people who had Alzheimer’s disease.

Using multiple antibodies that recognize amyloid-beta and phosphorylated tau, Reddy and Maria Manczak, Ph.D., a research associate in Reddy’s laboratory, specifically looked for the evidence of the amyloid-beta and phosphorylated tau interactions. They found amyloid-beta/tau complexes in the human Alzheimer’s brain tissue and in the Alzheimer’s disease mouse brains. The Reddy team also found much more of those amyloid-beta/tau complexes in brains where Alzheimer’s disease had progressed the most.

Reddy found very little or no evidence of the same interaction in the “control” subjects — mice that did not have the Alzheimer’s traits and human brain tissue of people who did not have Alzheimer’s.

"So much Alzheimer’s research has been done to look at amyloid-beta and tau," Reddy said. "But ours is the first paper to strongly demonstrate that yes, there is an amyloid-beta/phosphorylated tau interaction. And that interaction might be causing the synaptic damage and cognitive decline in persons with Alzheimer’s disease."

Reddy and his lab are already working on the next crucial questions. One is to define the binding site or sites and exactly where within the neuron the interaction of amyloid-beta and tau first occurs. The second is to find a way to inhibit that interaction — and thus maybe prevent or slow the progression of Alzheimer’s.

Manczak was a co-author on the Journal of Alzheimer’s Disease article.

(Image: Shutterstock)

Long-term study reports deep brain stimulation effective for most common hereditary dystonia

In what is believed to be the largest follow-up record of patients with the most common form of hereditary dystonia – a movement disorder that can cause crippling muscle contractions – experts in deep brain stimulation report good success rates and lasting benefits.

Michele Tagliati, MD, neurologist, director of the Movement Disorders Program at Cedars-Sinai Medical Center’s Department of Neurology, and Ron L. Alterman, MD, chief of the Division of Neurosurgery at Beth Israel Deaconess Medical Center in Boston, published the study in the July issue of the journal Neurosurgery. The doctors worked together at two New York City hospitals for a decade, until Tagliati joined Cedars-Sinai in 2010.

The study is focused on early-onset generalized dystonia, which in 1997 was found to be caused by a mutation of the DYT1 gene. Less than 1 percent of the overall population carries this mutation, but the frequency is believed to be three to five times higher among people of Ashkenazi Jewish heritage. Thirty percent of people who carry the defect develop dystonia.

“Long-term follow-up of DYT1 patients who have undergone DBS treatment is scarce, with current medical literature including only about 50 patients followed for three or more years,” Tagliati said. This study reviewed medical records of 47 consecutive patients treated with DBS for at least one year over a span of 10 years, 2001 to 2011.

“We found that, on average, symptom severity dropped to less than 20 percent of baseline within two years of device implantation. Sixty-one percent of patients were able to discontinue all their dystonia-related medications, and 91 percent were able to discontinue at least one class of drugs,” Tagliati said. “Although a few earlier studies found that stimulation’s effectiveness might wane after five years, our observations confirmed what other important DBS studies in dystonia are finding. Patients had statistically and clinically significant improvement that was maintained up to eight years.”

Alterman, the article’s senior author and the neurosurgeon who performed the implant surgeries, said the study also confirmed the procedure’s safety. Complications, such as infection and device malfunction, were rare and manageable.

Patient follow-up ranged from one year to eight years after surgery; 41 patients were seen for at least two years, and four completed eight years. The youngest patient at time of surgery was 8 and the oldest was 71, with a median age of 16.

Dystonia’s muscle contractions cause the affected area of the body to twist involuntarily, with symptoms that range from mild to crippling. If drugs – which often have undesirable side effects, especially at higher doses – fail to give relief, neurosurgeons and neurologists may work together to supplement medications with deep brain stimulation, aimed at modulating abnormal nerve signals. Electrical leads are implanted in the brain – one on each side – and an electrical pulse generator is placed near the collarbone. The device is programmed with a remote, hand-held controller. Tagliati is an expert in device programming, which fine-tunes stimulation for individual patients.

How neural stem cells create new and varied neurons

A new study examining the brains of fruit flies reveals a novel stem cell mechanism that may help explain how neurons form in humans. A paper on the study by researchers at the University of Oregon appeared in the online version of the journal Nature in advance of the June 27 publication date.

"The question we confronted was ‘How does a single kind of stem cell, like a neural stem cell, make all different kinds of neurons?’" said Chris Doe, a biology professor and co-author on the paper "Combinatorial temporal patterning in progenitors expands neural diversity."

Researchers have known for some time that stem cells are capable of producing new cells, but the new study shows how a select group of stem cells can create progenitors that then generate numerous subtypes of cells.

"Instead of just making 100 copies of the same neuron to expand the pool, these progenitors make a whole bunch of different neurons in a particular way, a sequence," Doe said. "Not only are you bulking up the numbers but you’re creating more neural diversity."

The study, funded by the Howard Hughes Medical Institute and the NIH National Institute of Child Health and Human Development, builds on previous research from the Doe Lab published in 2008. That study identified a special set of stem cells that generated neural progenitors. These so-called intermediate neural progenitors (INPs) were shown to blow up into dozens of new cells. The research accounted for the number of cells generated, but did not explain the diversity of new cells.

"While it’s been known that individual neural stem cells or progenitors could change over time to make different types of neurons and other types of cells in the nervous system, the full extent of this temporal patterning had not been described for large neural stem cell lineages, which contain several different kinds of neural progenitors," said lead author Omer Bayraktar, a doctoral student in developmental neurobiology who recently defended his dissertation.

The cell types in the study, Bayraktar said, have comparable analogs in the developing human brain and the research has potential applications for human biologists seeking to understand how neurons form.

The Nature paper appears alongside another study on neural diversity by researchers from New York University. Together the two papers provide new insight into the processes involved in producing the wide range of nerve cells found in the brains of flies.

For their study, Bayraktar and Doe zeroed in on the stem cells in drosophila (fruit flies) known as type II neuroblasts. The neuroblasts, which had previously been shown to generate INPs, were shown in this study to be responsible for a more complex patterning of cells. The INPs were shown to sequentially generate distinct neural subtypes. The research accounted for additional neural diversity by revealing a second axis in the mechanism. Instead of making 100 neurons, as had been previously thought, a stem cell may be responsible for generating some 400 or 500 neurons.

The study concludes that neuroblasts and INP patterning act together to generate increased neural diversity within the central complex of the fruit fly and that progenitors in the human cerebral cortex may use similar mechanisms to increase neural diversity in the human brain. One long-term application of the research may be to eventually pinpoint stem cell treatments to target specific diseases and disorders.

"If human biologists understand how the different types of neurons are made, if we can tell them ‘This is the pathway by which x, y and z neurons are made,’ then they may be able to reprogram and redirect stem cells to make these precise neurons," Doe said.

The mechanism described in the paper has its limits. Eventually the process of generating new cells stops. One of the next questions to answer will be what makes the mechanism turn off, Doe said.

"This vital research will no doubt capture the attention of human biologists," said Kimberly Andrews Espy, vice president for research and innovation and dean of the UO graduate school. "Researchers at the University of Oregon continue to further our understanding of the processes that undergird development to improve the health and well-being of people throughout the world."