Consciousness  

A research team may have figured out its physical origins of consciousness in the brain, after pinpointing a network of three specific regions in a ground-breaking study.

A team of researchers has pinpointed the regions of the brain that may play a role maintaining consciousness. Their findings, which have already garnered multiple awards from the American Academy of Neurology, were published in the journal, Neurology.

"For the first time, we have found a connection between the brainstem region involved in arousal and regions involved in awareness, two prerequisites for consciousness."

“For the first time, we have found a connection between the brainstem region involved in arousal and regions involved in awareness, two prerequisites for consciousness,” said Michael D. Fox, MD, PhD, Director of the Laboratory for Brain Network Imaging and Modulation and the Associate Director of the Berenson-Allen Center for Noninvasive Brain Stimulation at Beth Israel Deaconess Medical Center. “A lot of pieces of evidence all came together to point to this network playing a role in human consciousness.”

Classical neurology holds that arousal and awareness are two critical components of consciousness. Arousal is likely regulated by the brainstem – the portion of the brain, contiguous with the spinal cord, that is responsible for the sleep/wake cycle and cardiac and respiratory rates. Awareness, another critical component of consciousness, has long been thought to reside somewhere in the cortex, the outer layer of the brain responsible for many of its higher functions.

The researchers analyzed 36 patients with brainstem lesions, of which 12 led to coma and 24 did not. Mapping the injuries revealed that a small “coma-specific” area of the brainstem – the rostral dorsolateral pontine tegmentum – was significantly associated with coma. Ten out of the 12 coma-inducing brainstem lesions involved this area, while just one of the 24 control lesions did.

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Prepared with that information, Fox and colleagues used a wiring diagram of the healthy human brain – based on a large, shared data set called the Human Connectome Project– to identify which other parts of the brain were connected to these coma-causing lesions. Their analysis revealed two areas in the cortex of the brain that were significantly connected to the coma-specific region of the brainstem. One sat in the left, ventral, anterior insula (AI), the other in the pregenual anterior cingulate cortex (pACC). Both regions have been implicated previously in arousal and awareness.

“We now have a great map of how the brain is wired up in the Human Connectome,” said Fox, who is also an Assistant Professor of Neurology at Harvard Medical School. “We can look at not just the location of lesions, but also their connectivity. Over the past year, researchers in my lab have used this approach to understand visual and auditory hallucinations, impaired speech, and movement disorders. A collaborative team of neuroscientists and physicians had the insight and unique expertise needed to apply this approach to consciousness.”

Finally, the team investigated whether this brainstem-cortex network was functioning in another subset of patients with disorders of consciousness, including coma. Using a special type of MRI scan, the scientists found that their newly identified “consciousness network” was disrupted in patients with impaired consciousness. The findings – bolstered by data from rodent studies – suggest the network between the brainstem and these two cortical regions plays a role maintaining human consciousness.

“The added value of thinking about coma as a network disorder is it presents possible targets for therapy, such as using brain stimulation to augment recovery,” Boes said.

A next step, Fox notes, may be to investigate other data sets in which patients lost consciousness to find out if the same, different or overlapping neural networks are involved.

“This is most relevant if we can use these networks as a target for brain stimulation for people with disorders of consciousness,” said Fox. “If we zero in on the regions and network involved, can we someday wake someone up who is in a persistent vegetative state? That’s the ultimate question.”

SOURCE  Beth Israel Deaconess Medical Center

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 Neurology  

Scientists have now shown that it's possible to pick out key changes in the genetic code between chimpanzees and humans and visualize their respective contributions to early brain development in mouse embryos. The findings may lend insight what makes the human brain special and why people get some neurological disorders.

Scientists at Duke University have shown that it's possible to pick out key changes in the genetic code between chimpanzees and humans and then visualize their respective contributions to early brain development by using mouse embryos.

The team found that humans are equipped with tiny differences in a particular regulator of gene activity, dubbed HARE5, that when introduced into a mouse embryo, led to a 12% bigger brain than in the embryos treated with the HARE5 sequence from chimpanzees.

The findings, published in Current Biology, may lend insight into not only what makes the human brain special but also why people get some diseases, such as autism and Alzheimer's disease, whereas chimpanzees don't.

"I think we've just scratched the surface, in terms of what we can gain from this sort of study," said Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke University Medical School. "There are some other really compelling candidates

Every genome contains many thousands of short bits of DNA called 'enhancers,' whose role is to control the activity of genes. Some of these are unique to humans. Some are active in specific tissues. But none of the human-specific enhancers previously had been shown to influence brain anatomy directly.

Silver discusses her work in a recent interview on NPR:

In the new study, researchers mined databases of genomic data from humans and chimpanzees, to find enhancers expressed primarily in the brain tissue and early in development. They prioritized enhancers that differed markedly between the two species.

The group's initial screen turned up 106 candidates, six of them near genes that are believed to be involved in brain development. The group named these 'human-accelerated regulatory enhancers,' HARE1 through HARE6.

The strongest candidate was HARE5 for its chromosomal location near a gene called Frizzled 8, which is part of a well-known molecular pathway implicated in brain development and disease. The group decided to focus on HARE5 and then showed that it was likely to be an enhancer for Frizzled8 because the two DNA sequences made physical contact in brain tissue.

"What we found is a piece of the genetic basis for why we have a bigger brain. It really shows in sharp relief just how complicated those changes must have been. This is probably only one piece—a little piece."

The human HARE5 and the chimpanzee HARE5 sequences differ by only 16 letters in their genetic code. Yet, in mouse embryos the researchers found that the human enhancer was active earlier in development and more active in general than the chimpanzee enhancer.

"What's really exciting about this was that the activity differences were detected at a critical time in brain development: when neural progenitor cells are proliferating and expanding in number, just prior to producing neurons," Silver said.

The researchers found that in the mouse embryos equipped with Frizzled8 under control of human HARE5, progenitor cells destined to become neurons proliferated faster compared with the chimp HARE5 mice, ultimately leading to more neurons.

As the mouse embryos neared the end of gestation, their brain size differences became noticeable to the naked eye. Graduate student Lomax Boyd started dissecting the brains and looking at them under a microscope.

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"After he started taking pictures, we took a ruler to the monitor. Although we were blind to what the genotype was, we started noticing a trend," Silver said.

All told, human HARE5 mice had brains 12% larger in area compared with chimpanzee HARE5 mice. The neocortex, involved in higher-level function such as language and reasoning, was the region of the brain affected.

Producing a short list of strong candidates was in itself a feat, accomplished by applying the right filters to analysis of human and chimpanzee genomes, said co-author Gregory Wray, professor of biology and director of the Duke Center for Genomic and Computational Biology.

"Many others have tried this and failed," Wray said. "We've known other people who have looked at genes involved in brain size evolution, tested them out and done the same kinds of experiments we've done and come up dry."

The Duke team plans to study the human HARE5 and chimp HARE5 mice into adulthood, for possible differences in brain structure and behavior. The group also hopes to explore the role of the other HARE sequences in brain development.

"What we found is a piece of the genetic basis for why we have a bigger brain," Wray said. "It really shows in sharp relief just how complicated those changes must have been. This is probably only one piece—a little piece."

Could the research be used to uplift animals to human-level intelligence?

"One can never say never, but I think it's a pretty long-shot, far-fetched type concern," says Ruth Faden, who directs the Johns Hopkins Berman Institute of Bioethics tells NPR.

An experiment like this recent one is not going to create mice that talk and think like people, Faden says. But it could be more ethically worrisome to try to genetically enhance the brains of nonhuman primates or other reasonably intelligent animals — like pigs.

That's something our own species might prefer to avoid, says Faden. "The prospect of, sort of, tearing down the barriers between humans and other nonhuman species in ways that really threaten our sense of ourselves as special is disturbing," she points out.


SOURCE  Duke University via EurekAlert

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 Sleep  

Using mice, researchers showed for the first time that the space between brain cells may increase during sleep, allowing the brain to flush out toxins that build up during waking hours. These results suggest a new role for sleep in health and disease.

A good night’s rest may literally clear the mind. Using mice, researchers showed for the first time that the space between brain cells may increase during sleep, allowing the brain to flush out toxins that build up during waking hours. These results suggest a new role for sleep in health and disease. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH.

“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center in New York, and a leader of the study.

For centuries, scientists and philosophers have wondered why people sleep and how it affects the brain. Only recently have scientists shown that sleep is important for storing memories. In this study, Dr. Nedergaard and her colleagues unexpectedly found that sleep may be also be the period when the brain cleanses itself of toxic molecules.

Their results, published in Science, show that during sleep a “plumbing” system, called the glymphatic system, may open, letting fluid flow rapidly through brain. Dr. Nedergaard’s lab recently discovered the glymphatic system helps control whether cerebrospinal fluid (CSF), a clear liquid surrounding the brain and spinal cord, flows through the brain.

“It’s as if Dr. Nedergaard and her colleagues have uncovered a network of hidden caves and these exciting results highlight the potential importance of the network in normal brain function,” said Roderick Corriveau, Ph.D., a program director at NINDS.

Initially the researchers studied the system by injecting dye into the CSF of mice and watching it flow through their brains while simultaneously monitoring electrical brain activity. The dye flowed rapidly when the mice were unconscious, either asleep or anesthetized. In contrast, the dye barely flowed when the same mice were awake.

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“We were surprised by how little flow there was into the brain when the mice were awake,” said Dr. Nedergaard. “It suggested that the space between brain cells changed greatly between conscious and unconscious states.”

To test this idea, the researchers inserted electrodes into the brain to directly measure the space between brain cells. They found that the space inside the brains increased by 60 percent when the mice were asleep or anesthetized.

“These are some dramatic changes in extracellular space,” said Charles Nicholson, Ph.D., a professor at New York University’s Langone Medical Center and an expert in measuring the dynamics of brain fluid flow and how it influences nerve cell communication.

Certain brain cells, called glia, control flow through the glymphatic system by shrinking or swelling. Noradrenaline is an arousing hormone that is also known to control cell volume. Treating awake mice with drugs that block noradrenaline induced sleep and increased brain fluid flow and the space between cells, further supporting the link between the glymphatic system and sleep.

Previous studies suggest that toxic molecules involved in neurodegenerative disorders accumulate in the space between brain cells. In this study, the researchers tested whether the glymphatic system controls this by injecting mice with radiolabeled beta-amyloid, a protein associated with Alzheimer’s disease, and measuring how long it lasted in their brains when they were asleep or awake. Beta-amyloid disappeared faster in mice brains when the mice were asleep, suggesting sleep normally clears toxic molecules from the brain.

“These results may have broad implications for multiple neurological disorders,” said Jim Koenig, Ph.D., a program director at NINDS. “This means the cells regulating the glymphatic system may be new targets for treating a range of disorders.”

The results may also highlight the importance of sleep.

“We need sleep. It cleans up the brain,” said Dr. Nedergaard.



SOURCE  NIH

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 Brain Research  

Scientists in Austria have grown a three-dimensional, self-organizing model of a developing human brain in the lab using stem cells. The mini-brain may help research brain diseases and treatments more effectively.

Researchers at the Institute of Molecular Biotechnology in Vienna, Austria, have grown a three-dimensional, self-organizing model of a developing human brain in the lab using stem cells.

The system could be used to model neurological diseases and test treatments in an actual human brain, instead of an animal model that may not develop in exactly the same way, or in human patients.

The cerebral organoid, as the researchers have called it, resembles the early developing regions of a human brain, with distinct regions like the dorsal cortex, the ventral forebrain and even an immature retina.

This is the most complex in vitro human brain tissue created so far. It has the beginning signs of cortical layers, though it can't develop the full complexity of a six-layer human cortex.

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The scientists were able to grow their organoids from both embryonic stem cells and the less-controversial induced pluripotent stem cells, which can be derived from the skin or blood cells of adult humans. Most of the organoids grew to about 3 or 4 millimeters, about the size of an embryonic human brain at roughly nine weeks, and could survive up to a year in a spinning bioreactor (to circulate nutrients and oxygen).

Though it looks very similar to early-development brain tissue and has active neurons, the organization isn't quite the same as in naturally developing tissue.

Using imaging techniques, the researchers were even able to detect neural activity (see video, above), although this doesn't mean the brain is conscious in anyway.

"The parts are correctly organized, but not put together," Jürgen Knoblich who coordinated the study, explained in a press conference. He describes it as "a car where you have an engine, you have the wheels--but the engine is on the roof…that car would never drive, but you could still take that car and analyze how an engine works."

The stem-cell-derived organoid (right) compared to a developing mouse brain (left)
 Image Source: Marko Repic and Madeline A. Lancaster) 

Scientists have been able to grow other organ tissue in the lab with stem cells, like livers and heart tissue. Unlike with other lab-grown tissue, though, synthetic brain transplants or patches aren't really on the horizon here. The brain is just too complex, for one, and the lack of circulatory system makes it difficult to get enough nutrients and oxygen to the organoid tissue to grow it any larger than 4 millimeters.

Even though they're not exactly put together like human brains, cerebral organoids could be used to analyze diseases like microcephaly, a neurodevelopmental disorder that results in severely small brains.

"Recent work has shown development of human brain is very fundamentally different from the development of the mouse brain," Knoblich said, and certain diseases like microcephaly have been hard to replicate in mice. "Our system is very useful for us as developmental biologists. It allows us to study the human-specific features of brain development." Eventually he would like to be able to model disorders like schizophrenia or autism.



SOURCE  New Scientist

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 Neuroscience  

Researchers have discovered a new form of communication between neurons and neighboring of a specific type of glial cells involving a transfer of protein and genetic information, protecting neurons from stressful growth conditions.

Scientists at Johannes Gutenberg University Mainz (JGU) have discovered a new form of communication between different cell types in the brain.

Nerve cells interact with neighboring glial cells, which results in a transfer of protein and genetic information. Nerve cells are thus protected against stressful growth conditions. The study undertaken by the Mainz-based cell biologists shows how reciprocal communication between the different cell types contributes to neuronal integrity. Their results have been recently published in the journal PLOS Biology.

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Brain function is determined by the communication between electrically excitable neurons and the surrounding glial cells, which perform many tasks in the brain. Oligodendrocytes are a type of glial cell and these form an insulating myelin sheath around the axons of neurons. In addition to providing this protective insulation, oligodendrocytes also help sustain neurons in other ways that are not yet fully understood.

If this support becomes unavailable, axons can die off. This is what happens in many forms of myelin disorders, such as multiple sclerosis, and it results in a permanent loss of neuron impulse transmission.

Like other types of cells, oligodendrocytes also secrete small vesicles. In addition to lipids and proteins, these membrane-enclosed transport packages also contain ribonucleic acids, in other words, genetic information.

In their study, Carsten Frühbeis, Dominik Fröhlich, and Wen Ping Kuo of the Institute of Molecular Cell Biology at Johannes Gutenberg University Mainz found that oligodendrocytes release nano-vesicles known as 'exosomes' in response to neuronal signals.

These exosomes are taken up by the neurons and their cargo can then be used for neuronal metabolism. "This works on a kind of ‘delivery on call’ principle," explained Dr. Eva-Maria Krämer-Albers, who is leading the current study. "We believe that what are being delivered are 'care packages' that are sent by the oligodendrocytes to neurons."

Krämer-Albers, summarizing the results. "Exosomes are thus similar to viruses in certain respects, with the major difference that they do not inflict damage on the target cells but are instead beneficial." In the future, the researchers hope to develop exosomes as possible 'cure' packages that could be used in the treatment of nerve disorders.



SOURCE  Johannes Gutenberg University Mainz

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