Babies’ brains to be mapped in the womb and after birth

UK scientists have embarked on a six-year project to map how nerve connections develop in babies’ brains while still in the womb and after birth.

By the time a baby takes its first breath many of the key pathways between nerves have already been made. And some of these will help determine how a baby thinks or sees the world, and may have a role to play in the development of conditions such as autism, scientists say.

But how this rich neural network assembles in the baby before birth is relatively unchartered territory.

Researchers from Guy’s and St Thomas’ Hospital, King’s College London, Imperial College and Oxford University aim to produce a dynamic wiring diagram of how the brain grows, at a level of detail that they say has been impossible until now.

They hope that by charting the journeys of bundles of nerves in the final three months of pregnancy, doctors will be able to understand more about how they can help in situations when this process goes wrong.

Prof David Edwards, director of the Centre for the Developing Brain, who is leading the research, says: “There is a distressing number of children in our society who grow up with problems because of things that happen to them around the time of birth or just before birth.

"It is very important to be able to scan babies before they are born, because we can capture a period when an awful lot is changing inside the brain, and it is a time when a great many of the things that might be going wrong do seem to be going wrong."

'Neural networks'

The study - known as the Developing Human Connectome Project - hopes to look at more than 1,500 babies, studying many aspects of their neurological development.

By examining the brains of babies while they are still growing in the womb, as well as those born prematurely and at full term, the scientists will try to define baselines of normal development and investigate how these may be affected by problems around birth.

And they plan to share their map with the wider research community.

Central to this project are advanced MRI scanning techniques, which the scientists say are able to pick up on details of the growing brain that have been difficult to capture until now.

While in the womb, foetuses are free to somersault in their amniotic sacs, and this constant movement has so far hindered clear images of growing brains.

But researchers at the Centre for the Developing Brain have found ways to counter the effects of these movements, building up full three-dimensional pictures while the foetus is in motion.

And by placing the MRI machine in the neonatal intensive care unit at Evelina Children’s Hospital in London they are one of the few centres in the world to have a scanner in such close proximity to the babies who often need it most, Prof Edwards says.

This means the same scanning system can be used to find out more about the brains of the sickest and smallest newborn babies, he says.

'Macro level'

Daniel Rueckert, professor of visual information processing at Imperial College London, who is also involved in the research, says: “We are trying to look at brain connectivity in two ways: firstly, from a structural perspective, to find out which parts of the brain are wired to other parts. And secondly we are looking at functional connectivity - how strongly two brain regions are linked across time and activity.”

But Prof Partha Mitra, a neuroscientist at Cold Spring Harbor Laboratory, New York state, says we need to be aware of the limitations of the technology in use.

"It would obviously be a very good thing to know more about the circuits in the developing human brain. Much of what we know hasn’t changed in a hundred years and has come from dissection studies.

"But we need to keep in mind the imaging techniques we have are indirect - we can’t open up a human brain and look at the connections while someone is alive so we rely on these non-invasive methods. But there is a big gap between the real circuits in the brain and what images can show us."

Prof Rueckert acknowledges that this map will provide a “macro-level” view of the developing brain and not be the “final answer”.

But he points to early results from the adult version of this project - the Human Connectome Project, based in the US: “There is so much evidence already from the adult project that there are significant changes in the brain that can be mapped with the technology we have now.

"It will be incredibly useful to be able to do this with the still growing and developing brain - perhaps giving us more time to intervene when things go wrong."

BRAIN Initiative Launched to Unlock Mysteries of Human Mind

Today at the White House, President Barak Obama unveiled the “BRAIN” Initiative — a bold new research effort to revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer’s, schizophrenia, autism, epilepsy, and traumatic brain injury.

The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is part of a new Presidential focus aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a revolutionary new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. Long desired by researchers seeking new ways to treat, cure, and even prevent brain disorders, this picture will fill major gaps in our current knowledge and provide unprecedented opportunities for exploring exactly how the brain enables the human body to record, process, utilize, store, and retrieve vast quantities of information, all at the speed of thought.

Why is the NIH BRAIN Initiative needed?

With nearly 100 billion neurons and 100 trillion connections, the human brain remains one of the greatest mysteries in science and one of the greatest challenges in medicine. Neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, autism, epilepsy, schizophrenia, depression, and traumatic brain injury, exact a tremendous toll on individuals, families, and society. Despite the many advances in neuroscience in recent years, the underlying causes of most of neurological and psychiatric conditions remain largely unknown, due to the vast complexity of the human brain. If we are ever to develop effective ways of helping people suffering from these devastating conditions, researchers will first need a more complete arsenal of tools and information for understanding how the brain functions both in health and disease.

Why is now the right time for the NIH BRAIN Initiative?

In the last decade alone, scientists have made a number of landmark discoveries that now create the opportunity to unlock the mysteries of the brain. We have witnessed the sequencing of the human genome, the development of new tools for mapping neuronal connections, the increasing resolution of imaging technologies, and the explosion of nanoscience. These discoveries have yielded unprecedented opportunities for integration across scientific fields. For instance, by combining advanced genetic and optical techniques, scientists can now use pulses of light in animal models to determine how specific cell activities within the brain affect behavior. What’s more, through the integration of neuroscience and physics, researchers can now use high-resolution imaging technologies to observe how the brain is structurally and functionally connected in living humans.

While these technological innovations have contributed substantially to our expanding knowledge of the brain, significant breakthroughs in how we treat neurological and psychiatric disease will require a new generation of tools to enable researchers to record signals from brain cells in much greater numbers and at even faster speeds. This cannot currently be achieved, but great promise for developing such technologies lies at the intersections of nanoscience, imaging, engineering, informatics, and other rapidly emerging fields of science.

How will the NIH BRAIN Initiative work?

Given the ambitious scope of this pioneering endeavor, it is vital that planning for the NIH BRAIN Initiative be informed by a wide range of expertise and experience. Therefore, NIH is establishing a high level working group of the Advisory Committee to the NIH Director (ACD) to help shape this new initiative. This working group, co-chaired by Dr. Cornelia “Cori” Bargmann (The Rockefeller University) and Dr. William Newsome (Stanford University), is being asked to articulate the scientific goals of the BRAIN initiative and develop a multi-year scientific plan for achieving these goals, including timetables, milestones, and cost estimates.

As part of this planning process, input will be sought broadly from the scientific community, patient advocates, and the general public. The working group will be asked to produce an interim report by fall 2013 that will contain specific recommendations on high priority investments for Fiscal Year (FY) 2014. The final report will be delivered to the NIH Director in June 2014.

How will the NIH BRAIN Initiative be supported?

In total, NIH intends to allocate $40 million in FY14. Given the cross-cutting nature of this project, the NIH Blueprint for Neuroscience Research — an initiative spanning 14 NIH Institutes and Centers — will be the leading NIH contributor to its implementation in FY14. Of course, a goal this audacious will require ideas from the best scientists and engineers across many diverse disciplines and sectors. Therefore, NIH is working in close collaboration with other government agencies, including the Defense Advanced Research Projects Agency (DARPA) and the National Science Foundation (NSF). Strong interest has also been expressed by several private foundations, including the Howard Hughes Medical Institute, the Allen Institute for Brain Science, and The Kavli Foundation, and the Salk Institute for Biological Studies. Private industries have also expressed a high level of interest in participation in this groundbreaking initiative.

Obama proposes $100m to map the human brain

President Barack Obama on Tuesday asked Congress to spend $100 million next year on a new project to map the human brain in hopes of eventually finding cures for disorders like Alzheimer’s, epilepsy and traumatic injuries.

Obama said the so-called BRAIN Initiative could create jobs and eventually lead to answers to ailments including Parkinson’s and autism and help reverse the effect of a stroke. The president told scientists gathered in the White House’s East Room that the research has the potential to improve the lives of billions of people worldwide.

‘‘As humans we can identify galaxies light-years away,’’ Obama said. ‘‘We can study particles smaller than an atom, but we still haven’t unlocked the mystery of the three pounds of matter that sits between our ears.’’

BRAIN stands for Brain Research through Advancing Innovative Neurotechnologies. The idea, which Obama first proposed in his State of the Union address, would require the development of new technology that can record the electrical activity of individual cells and complex neural circuits in the brain ‘‘at the speed of thought,’’ the White House said.

Obama wants the initial $100 million investment to support research at the National Institutes of Health, the Defense Advanced Research Projects Agency and the National Science Foundation. He also wants private companies, universities and philanthropists to partner with the federal agencies in support of the research. And he wants a study of the ethical, legal and societal implications of the research.

The goals of the work are unclear at this point. A working group at NIH, co-chaired by Cornelia ‘‘Cori’’ Bargmann of The Rockefeller University and William Newsome of Stanford University, would work on defining the goals and develop a multi-year plan to achieve them that included cost estimates.

Nanotools for neuroscience and brain activity mapping

The ambitious and controversial Brain Activity Map (BAM), initiative instituted by a small group of researchers last year, has been steadily gaining momentum. Earlier this week, a proof-of-principle Zebrafish BAM was demonstrated with astounding clarity by a pair of researchers at the Howard Hughes Medical Institute.

Following on the heels of that work, an exhaustive 17-page compendium of current and soon-to-be brain mapping tools was published yesterday in ACS Nano by a rapidly snowballing list of disciples.

The BAM roster has been a carefully manicured player list from the beginning, and the role it has as ship wheel to this diffuse effort should not be underestimated. With the ranks now swelling to 27, each contributor to the paper has, in word or in spirit, contributed notably to the 185 referenced technologies on the paper. What we have here is not a research release, this is a textbook for the new neuroscience, and the journal choice, though not publicly accessible, hints at the desire to draw even more nanoscale researchers into the effort.

Media attention has channeled formative criticism to the effort in a way we have not seen before. Those sentiments on the cautionary take at least, might be summarized by likening the BAM scientists to cavemen having just discovered fire. Now sitting in the sand, they appear to be chartering a course to the internal combustion engine as they scribe on the ground with blunt bone instruments. The problem is that having just fleshed out how the brain’s wiring, the connectome, might be extracted, the community elites just leapfrogged to the full activity map, or at least one for some of the lesser animals.

The most extravagant technology proposed is undoubtedly the DNA tickertape. It appears to have been developed initially, at least in part, by Northwestern University’s Konrad Kording. Some of the earlier BAM papers show however that George Church, of human genome project fame, actually holds a patent that might cover some aspects of Kording’s idea. In particular, Church seems responsible for the wickedly unique concept of engineering DNA polymerases to produce predictable errors that would in effect record conditions within the cell or device onto DNA tapes. Fortunately Church, having entered neuroscience some time ago, is also a BAM founding father. His “nucleic acid memory device” could be the means by which the spike activity of each neuron would be recorded.

Among the other wild exotica hinted at in the ACS Nano paper is the DNA barcode proposed by Anthony Zador, from the Cold Spring Harbor Lab. This device would use a genetically modified rabies virus to infiltrate the nervous system, and record every connection in the process, web-crawl style. While Zador is not an author on this or the previous BAM papers, his techniques would not only provide a way to deliver a connectome of a complex brain, they potentially could do it non-destructively. Furthermore, the barcode mechanism would perhaps be the ideal way to propagate the Kording-Church tickertape machinery from cell to cell, bundling topology and activity together.

Many of the neurotools mentioned in the ACSNano paper are logical extensions of current technologies, just slightly smaller and a little higher in resolution. Recording cell activity with voltage-sensitive or calcium-imaging dyes, as was done in the Zebrafish map, may or may not be the process used ten years from now. Other ideas, like accessing neurons through fiber optic probes threaded through the vasculature to the capillaries, were re-invigorated, as were new sensors altogether like nanodiamond and nanogold devices.

Glaringly absent from this paper however, is a clear consensus of what exactly is to be done with these tools. The Zebrafish calcium map, for example, does not discriminate between neuron bodies, axons, dendrites, or synapses. The question of what level of detail is to be the goal of new studies still needs to be asked. This is a tough question because an activity map, like the connectome that would couch it, is rewritten on scales beneath our direct perception—not only is it a moving target, its trajectory is largely unknown. A long-term project such as this based in a set of technologies, as opposed to hypothesis-driven scientific inquiry, needs to balance fluidity with credibility.

Imagining what you would want to do if you were making a BAM of your own brain may emerge as the best way to set the project’s goals. In that case, the researchers may not be going for the whole BAM right away—just the things they would want to know in enough detail to get some answers in the least destructive way possible. If they plow through a bunch of animal studies generating terabytes of data, but cannot then use those methods used to learn about our brains, they will not have been successful. Priority then is to be the nondestructive BAM, focused on those high-interest, highly accessible areas with the highest density of observables wherein the observation risks are low. How to do this is the question of the next BAM installment.

Full Article

First neutron scattering experiments on brain tissue reveal weaknesses in formaldehyde preservation, reducing reliability of post-mortem analysis

These results are the first step in a project to push back the limits of  existing dMRI imaging technology, to improve diagnosis and investigate potential treatments for brain diseases.

The first analysis of biological processes within brain tissue using neutrons at the Institut Laue-Langevin has revealed that the common application of formaldehyde preservatives changes, rather than maintains, fundamental properties such as rates of water diffusion. The mapping of cellular water in the brain is a key factor in the post-mortem analysis of several brain pathologies (including tumours and multiple sclerosis), with a view to earlier diagnosis and potential treatment. These results suggest the need for a review of existing research in this area.

The results are the first stage in the team’s own pioneering application of neutrons to understand in unprecedented detail the movement of cellular water within brain tissue. The analysis of this movement is generally performed by diffusion magnetic resonance imaging (dMRI), and provides the basis for diagnosing several brain diseases. These first results clearly demonstrate neutrons’ ability to ‘see’ the effects of these biological processes on a scale 10,000 times smaller than dMRI. In future ILL’s neutrons will analyse with unprecedented resolution cellular water dynamics in ex-vivo pathology-bearing brain tissue samples, thus helping doctors spot the early signs of these diseases and investigate potential treatments.

Cellular water is the major constituent of our body and its content may vary in brain regions depending on their specific composition. Water plays a key role in cell regulation, and its distribution and movement is an accurate indicator of cellular structure; this is because it interacts with different tissue components such as membranes and nerve fibres.

dMRI and other imaging techniques use water diffusion as a contrast method for revealing and characterising several brain pathologies (i.e. ischemia, tumours and, recently, inherited prion disease) on the micron scale 100 times thinner than a human hair. At this scale, however, the contribution of the macromolecular components cannot be separated and have to be averaged out instead.

As the standard imaging techniques used to detect the early signs of brain pathologies are limited in resolution, the use of preservation techniques to investigate pathological conditions in ex-vivo specimens has increased. However, there are concerns over the impact of these preservation processes on our tissues’ fundamental structural and compositional properties, and this has undermined confidence in this line of research.

To address these concerns Dr Francesca Natali from the Italian CNR (Consiglio Nazionale delle Ricerche), in collaboration with Dr Yuri Gerelli, a scientist from the Institut Laue-Langevin, the world’s flagship centre for neutron science, Prof. J. Peters from France’s Joseph Fourier University in Grenoble (UJF), and Dr Calogero Stelletta from the University of Padova in Italy compared the behaviour of cellular water in ex-vivo bovine tissue preserved using two common preservation techniques: chemical fixation, using formaldehyde solutions, and cryo-preservation, where cells or whole tissues are cooled to sub-zero temperatures.

The researchers obtained fresh post-mortem bovine brains from an Italian slaughter-house and applied the different preservation techniques. These samples were then investigated using incoherent quasi-elastic neutron scattering (QENS) on the high-resolution IN5 spectrometer at the Institut Laue-Langevin (ILL).

Neutrons are an ideal probe for the investigation of biological materials at the atomic scale. As they produce no damaging radiation effects, they can accurately map any change in the samples over time.

From this analysis Dr Francesca Natali and her colleagues identified a significant reduction of water movement as a result of the introduction of the formaldehyde-based preservation solutions (potentially due to the formation of cross-links between proteins, within which free water may become trapped, reducing its mobility). This effect was not seen in the samples that underwent cryo-preservation.

As well as these findings, the results of this study also demonstrate for the first time the power of neutrons to model cellular water diffusion within brain tissue; this new modeling technique could help dMRI specialists push back the limits of existing imaging technology, to improve their diagnoses and investigate potential treatments for brain pathologies.

In a separate study, the same team are investigating how the movement and distribution of cellular water in brain tissue is affected by myelin, an electrical insulator that forms protective layers known as sheaths around brain cell axons. Myelin is responsible for speeding up electrical impulses as they travel along tissue fibres. Many neurodegenerative autoimmune diseases, including multiple sclerosis, are caused by the degradation of myelin over time. The neutron scattering team’s new understanding of the impact on research results of preservation techniques will enhance its atomic-scale investigations into the conditions underlying autoimmune diseases and the potential for treatment.

Brain-mapping increases understanding of alcohol’s effects on college freshmen

A research team that includes several Penn State scientists has completed a first-of-its-kind longitudinal pilot study aimed at better understanding how the neural processes that underlie responses to alcohol-related cues change during students’ first year of college.

Anecdotal evidence abounds attesting to the many negative social and physical effects of the dramatic increase in alcohol use that often comes with many students’ first year of college. The behavioral changes that accompany those effects indicate underlying changes in the brain. Yet in contrast to alcohol’s numerous other effects, its effect on the brain’s continuing development from adolescence into early adulthood — which includes the transition from high school to college — is not well known.

Penn State psychology graduate student Adriene Beltz, with a team of additional researchers, investigated the changes that occurred to alcohol-related neural processes in the brains of a small group of first-year students.

Using functional magnetic resonance imaging (fMRI) and a data analysis technique known as effective connectivity mapping, the researchers collected and analyzed data from 11 students, who participated in a series of three fMRI sessions beginning just before the start of classes and concluding part-way through the second semester.

"We wanted to know if and how brain responses to alcohol cues — pictures of alcoholic beverages in this case — changed across the first year of college," said Beltz, "and how these potential changes related to alcohol use. Moreover, we wanted our analysis approach to take advantage of the richness of fMRI data."

Analysis of the data collected from the study participants revealed signs in their brains’ emotion processing networks of habituation to alcohol-related stimuli, and noticeable alterations in their cognitive control networks.

Recent studies have indicated that young adults’ cognitive development continues through the ages of the mid-20s, particularly in those regions of the brain responsible for decision-making or judgment-related activity — the sort of cognitive “fine tuning” that potentially makes us, in some senses, as much who we are (and will be) as any other stage of our overall development.

Other recent studies suggest that binge drinking during late adolescence may damage the brain in ways that could last into adulthood.

Beltz’s study indicates that connections among brain regions involved in emotion processing and cognitive control may change with increased exposure to alcohol and alcohol-related cues. Those connections also may influence other parts of the brain, such as those still-developing regions responsible for students’ decision-making and judgment abilities.

"The brain is a complex network," Beltz said. "We know that connections among different brain regions are important for behavior, and we know that many of these connections are still developing into early adulthood. Thus, alcohol could have far-reaching consequences on a maturing brain, directly influencing some brain regions and indirectly influencing others by disrupting neural connectivity."

While in an fMRI scanner at the Penn State Social, Life and Engineering Sciences Imaging Center, students participating in the study completed a task: responding as quickly as possible, by pressing a button on a grip device, to an image of either an alcoholic beverage or a non-alcoholic beverage when both types of images were displayed consecutively on a screen. From the resulting data, effective connectivity maps were created for each individual and for the group.

Examining the final maps, the researchers found that brain regions involved in emotion-processing showed less connectivity when the students responded to alcohol cues than when they responded to non-alcohol cues, and that brain regions involved in cognitive control showed the most connectivity during the first semester of college. The findings suggest that the students needed to heavily recruit brain regions involved in cognitive control in order to overcome the alcohol-associated stimuli when instructed to respond to the non-alcohol cues.

"Connectivity among brain regions implicated in cognitive control spiked from the summer before college to the first semester of college," said Beltz. "This was particularly interesting because the spike coincided with increases in the participants’ alcohol use and increases in their exposure to alcohol cues in the college environment. From the first semester to the second semester, levels of alcohol use and cue exposure remained steady, but connectivity among cognitive control brain regions decreased. From this, we concluded that changes in alcohol use and cue exposure — not absolute levels — were reflected by the underlying neural processes."

Although the immediate implications of the pilot study for first-year students are fairly clear, there are still a number of unanswered questions related to alcohol’s longer-term effects on development, for college students after their first year and for those same individuals later in life.

To begin exploring those potential long-term effects, Beltz has planned a follow-up study to track a larger number of participants over a greater length of time.

A Future Without Seizures

Five-year-old Nathan Kalina of Naperville will enter kindergarten this fall after spending the summer in day camp: playing games, enjoying field trips, and romping in the pool. He loves playing with action figures and acting out scenes from his favorite movies.

The scene two years ago was very different. After getting a few reports from daycare about unexplained falls, Nathan’s parents started to notice him having minor seizures. His mother, Megan, wasn’t too concerned at first; both she and her father had had childhood seizures and recovered from them without incident. Then came Nathan’s first tonic-clonic seizure (formerly known as a “grand mal” seizure), a major event involving his whole brain and body. A trip to a local emergency room for basic tests led to an electroencephalogram a few days later. All the while Nathan was having more seizures, large and small.

"We went from zero to crazy in a matter of days," Megan said.

Medication helped some. Nathan’s father David, a teacher in the Naperville schools, devoted his summer to adjusting Nathan’s regimen. But in the fall, the seizures ramped up again. One specialist suggested a high-fat ketogenic diet, which has been shown to help some children with epilepsy — but it didn’t help Nathan. “Feeding a 4-year-old picky eater on meat, cheese and cream was hard on us and started making him sick,” Megan said.

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