Parkinson’s Disease Brain Rhythms Detected

A team of scientists and clinicians at UC San Francisco has discovered how to detect abnormal brain rhythms associated with Parkinson’s by implanting electrodes within the brains of people with the disease.

The work may lead to developing the next generation of brain stimulation devices to alleviate symptoms for people with the disease.

Described this week in the journal Proceedings of the National Academy of Sciences (PNAS), the work sheds light on how Parkinson’s disease affects the brain, and is the first time anyone has been able to measure a quantitative signal from the disease within the cerebral cortex – the outermost layers of the brain that helps govern memory, physical movement and consciousness.

“Normally the individual cells of the brain are functioning independently much of the time, working together only for specific tasks,” said neurosurgeon Philip Starr, MD, PhD, a professor of neurological surgery at UCSF and senior author of the paper. But in Parkinson’s disease, he said, many brain cells display “excessive synchronization,” firing together inappropriately most of the time.

“They are locked into playing the same note as everyone else without exploring their own music,” Starr explained. This excessive synchronization leads to movement problems and other symptoms characteristic of the disease.

The new work also shows how deep brain stimulation (DBS), which electrifies regions deeper in the brain, below the cortex, can affect the cortex, itself. This discovery may change how DBS is used to treat Parkinson’s and other neurologically based movement disorders, and it may help refine the technique for other types of treatment.

Has evolution given humans unique brain structures?

Humans have at least two functional networks in their cerebral cortex not found in rhesus monkeys. This means that new brain networks were likely added in the course of evolution from primate ancestor to human. These findings, based on an analysis of functional brain scans, were published in a study by neurophysiologist Wim Vanduffel (KU Leuven and Harvard Medical School) in collaboration with a team of Italian and American researchers.

Our ancestors evolutionarily split from those of rhesus monkeys about 25 million years ago. Since then, brain areas have been added, have disappeared or have changed in function. This raises the question, ‘Has evolution given humans unique brain structures?’. Scientists have entertained the idea before but conclusive evidence was lacking. By combining different research methods, we now have a first piece of evidence that could prove that humans have unique cortical brain networks.

Professor Vanduffel explains: “We did functional brain scans in humans and rhesus monkeys at rest and while watching a movie to compare both the place and the function of cortical brain networks. Even at rest, the brain is very active. Different brain areas that are active simultaneously during rest form so-called ‘resting state’ networks. For the most part, these resting state networks in humans and monkeys are surprisingly similar, but we found two networks unique to humans and one unique network in the monkey.”

“When watching a movie, the cortex processes an enormous amount of visual and auditory information. The human-specific resting state networks react to this stimulation in a totally different way than any part of the monkey brain. This means that they also have a different function than any of the resting state networks found in the monkey. In other words, brain structures that are unique in humans are anatomically absent in the monkey and there no other brain structures in the monkey that have an analogous function. Our unique brain areas are primarily located high at the back and at the front of the cortex and are probably related to specific human cognitive abilities, such as human-specific intelligence.”

The study used fMRI (functional Magnetic Resonance Imaging) scans to visualise brain activity. fMRI scans map functional activity in the brain by detecting changes in blood flow. The oxygen content and the amount of blood in a given brain area vary according to a particular task, thus allowing activity to be tracked.

Genome-wide Atlas of Gene Enhancers in the Brain On-line

Future research into the underlying causes of neurological disorders such as autism, epilepsy and schizophrenia, should greatly benefit from a first-of-its-kind atlas of gene-enhancers in the cerebrum (telencephalon). This new atlas, developed by a team led by researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) is a publicly accessible Web-based collection of data that identifies and locates thousands of gene-regulating elements in a region of the brain that is of critical importance for cognition, motor functions and emotion.

“Understanding how the brain develops and functions, and how it malfunctions in neurological disorders, remains one of the most daunting challenges in contemporary science,” says Axel Visel, a geneticist with Berkeley Lab’s Genomics Division. “We’ve created a genome-wide digital atlas of gene enhancers in the human brain – the switches that tell genes when and where they need to be switched on or off. This enhancer atlas will enable other scientists to study in more detail how individual genes are regulated during development of the brain, and how genetic mutations may impact human neurological disorders.”

Visel is the corresponding author of a paper in the journal Cell that describes this work. The paper is titled “A High-Resolution Enhancer Atlas of the Developing Telencephalon.”

Temple scientists find cancer-causing virus in the brain, potential connection to epilepsy

Researchers at Shriner’s Hospital Pediatric Research Center at the Temple University School of Medicine, and the University of Pennsylvania have evidence linking the human papillomavirus 16 (HPV16) – the most common cause of cervical cancer – to a common form of childhood epilepsy. They have shown for the first time that HPV16 may be present in the human brain, and found that when they added a viral protein to the brains of fetal mice, the mice all demonstrated the same developmental problems in the cerebral cortex associated with this type of epilepsy, called focal cortical dysplasia type IIB (FCDIIB). The findings suggest that the virus could play a role in the development of epilepsy.

The results also mean that doctors may have to re-think their approach to treating this type of epilepsy, and perhaps consider other therapeutic options related to HPV, an infectious disease.

"This is a novel mechanism, and it fills a gap in our understanding about the development of congenital brain malformations," said Peter Crino, MD, PhD, Professor of Neurology at Temple University School of Medicine, and a member of Shriner’s Hospital Pediatric Research Center, and the senior author of a recent report in the Annals of Neurology.

"If our data are correct, future treatment of cortical dysplasia could include targeted therapy against HPV16 infection, with the goal of halting seizures. Identifying an infectious agent as part of the pathogenesis of brain malformations could open up an array of new therapeutic approaches against various forms of epilepsy."

(Image: ASME.org)

Study findings have potential to prevent, reverse serious disabilities affecting children born prematurely

Physician-scientists at Oregon Health & Science University Doernbecher Children’s Hospital are challenging the way pediatric neurologists think about brain injury in the pre-term infant. In a study published online in the Jan. 16 issue of Science Translational Medicine, the OHSU Doernbecher researchers report for the first time that low blood and oxygen flow to the developing brain does not, as previously thought, cause an irreversible loss of brain cells, but rather disrupts the cells’ ability to fully mature. This discovery opens up new avenues for potential therapies to promote regeneration and repair of the premature brain.

“As neurologists, we thought ischemia killed the neurons and that they were irreversibly lost from the brain. But this new data challenges that notion by showing that ischemia, or low blood flow to the brain, can alter the maturation of the neurons without causing the death of these cells. As a result, we can focus greater attention on developing the right interventions, at the right time early in development, to promote neurons to more fully mature and reduce the often serious impact of preterm birth. We now have a much more hopeful scenario,” said Stephen Back, M.D., Ph.D., lead investigator and professor of pediatrics and neurology in the Papé Family Pediatric Research Institute at OHSU Doernbecher Children’s Hospital.

Researchers at OHSU Doernbecher have conducted a number of studies in preterm fetal sheep to define how disturbances in brain blood flow lead to injury in the developing brain. Their findings have led to important advances in the care of critically ill newborn infants.

For this study, Back and colleagues used pioneering new MRI studies that allow injury to the developing brain to be identified much earlier than previously feasible. They looked at the cerebral cortex, or “thinking” part of the brain, which controls the complex tasks involved with learning, attention and social behaviors that are frequently impaired in children who survive preterm birth. Specifically, they observed how brain injury in the cerebral cortex of fetal sheep evolved over one month and found no evidence that cells were dying or being lost. They did notice, however, that more brain cells were packed into a smaller volume of brain tissue, which led to, upon further examination, the discovery that the brain cells weren’t fully mature.

In a related study published in the same online issue of Science Translational Medicine, investigators at The Hospital for Sick Children and the University of Toronto studied 95 premature infants using MRI and found that impaired growth of the infants was the strongest predictor of the MRI abnormalities, suggesting that interventions to improve infant nutrition and growth may lead to improved cortical development.

“I believe these studies provide hope for the future for preterm babies with brain injury, because our findings suggest that neurons are not being permanently lost from the human cerebral cortex due to ischemia. This raises the possibility that neurodevelopmental enrichment — or perhaps improved early infant nutrition — as suggested by the companion paper, might make a difference in terms of improved cognitive outcome,” Back said.

“Together, these studies challenge the conventional wisdom that preterm birth is associated with a loss of cortical neurons. This finding may change the way neurologists think about diagnosing and treating children born prematurely,” said Jill Morris, Ph.D., a program director at the National Institute’s of Health’s National Institute Neurological Disorders and Stroke.

New research finds slower growth of preterm infants linked to altered brain development

Preterm infants who grow more slowly as they approached what would have been their due dates also have slower development in an area of the brain called the cerebral cortex, report Canadian researchers in a new study published in Science Translational Medicine.

The cerebral cortex is a two to four millimetre layer of cells that envelopes the top part of the brain and is involved in cognitive, behavioural, and motor processes.

Researchers analyzed MRI brain scans of 95 preterm infants born eight to 16 weeks too early at BC Women’s Hospital & Health Centre between 2006 and 2009. Infants were scanned soon after birth and a second time close to what would have been their due date, the ninth month of pregnancy. These MRI scans allowed researchers to measure the pattern of water movement inside the brain, which normally changes between scans as the brain matures. The researchers also assessed the babies’ weight, length, and head size. They found that preterm infants with slower growth had delayed development in the cerebral cortex compared to those infants who grew more quickly between scans.

“These results are an exciting first step because understanding the importance of growth in relation to the brain in these small babies may eventually lead to new discoveries that will help us optimize their brain development,” says Dr. Steven Miller, the study’s co‐lead. Dr. Miller is head of neurology at The Hospital for Sick Children (SickKids), the Bloorview Children’s Hospital Chair in Paediatric Neuroscience, professor in the department of Paediatrics at the University of Toronto, affiliate professor in the department of Pediatrics at the University of British Columbia (UBC), and affiliate investigator at the Child & Family Research Institute (CFRI) at BC Children’s Hospital. He led the study with Dr. Ruth Grunau, a professor in the UBC Department of Pediatrics and CFRI senior scientist.

“More research needs to be done to understand what is the optimal growth rate for the brain development of these babies,” says Jillian Vinall, the study’s first author and a UBC PhD student cosupervised by Dr. Grunau and Dr. Miller.

We’re especially grateful to the families for their generous and ongoing participation in this study,” says Dr. Miller. The researchers are following the babies through childhood to understand how preterm brain development is associated with their neurodevelopment outcomes.

Lack of Protein Sp2 Disrupts Neuron Creation in Brain

A protein known as Sp2 is key to the proper creation of neurons from stem cells, according to researchers at North Carolina State University. Understanding how this protein works could enable scientists to “program” stem cells for regeneration, which has implications for neural therapies.

Troy Ghashghaei and Jon Horowitz, both faculty in NC State’s Department of Molecular Biomedical Sciences and researchers in the Center for Comparative Medicine and Translational Research, wanted to know more about the function of Sp2, a cell cycle regulator that helps control how cells divide. Previous research from Horowitz had shown that too much Sp2 in skin-producing stem cells resulted in tumors in experimental mice. Excessive amounts of Sp2 prevented the stem cells from creating normal cell “offspring,” or skin cells. Instead, the stem cells just kept producing more stem cells, which led to tumor formation.

“We believe that Sp2 must play a fundamental role in the lives of normal stem cells,” Horowitz says. “Trouble ensues when the mechanisms that regulate its activity are overwhelmed due to its excess abundance.”

Ghashghaei and his team – led by doctoral candidate Huixuan Liang – took the opposite approach. Using genetic tools, they got rid of Sp2 in certain neural stem cells in mice, specifically those that produce the major neurons of the brain’s cerebral cortex. They found that a lack of Sp2 disrupted normal cell formation in these stem cells, and one important result was similar to Horowitz’s: the abnormal stem cells were unable to produce normal cell “offspring,” or neurons. Instead, the abnormal stem cells just created copies of themselves, which were also abnormal.

“It’s interesting that both an overabundance of this protein and a total lack of it result in similar disruptions in how stem cells divide,” Ghashghaei says. “So while this work confirms that Sp2 is absolutely necessary for stem cell function, a lot of questions still remain about what exactly it is regulating, and whether it is present in all stem cells or just a few. We also need to find out if Sp2 deletion or overabundance can produce brain tumors in our mice as in the skin.

“Finally, we are very interested in understanding how Sp2 regulates a very important decision a stem cell has to make: whether to produce more of itself or to produce offspring that can become neurons or skin cells,” Ghashghaei adds. “We hope to address those questions in our future research, because these cellular mechanisms have implications for cancer research, neurodevelopmental diseases and regenerative medicine.”

The results appear online in Development. NC State graduate students Guanxi Xiao, and Haifeng Yin, as well as Dr. Simon Hippenmeyer, a collaborator with the Ghashghaei lab from Austria’s Institute of Science and Technology, contributed to the work. The work was funded by the National Institutes of Health and the American Federation for Aging Research.

Protein identified that can disrupt embryonic brain development and neuron migration

Interneurons – nerve cells that function as ‘dimmers’ – play an important role in the brain. Their formation and migration to the cerebral cortex during the embryonic stage of development is crucial to normal brain functioning. Abnormal interneuron development and migration can eventually lead to a range of disorders and diseases, from epilepsy to Alzheimer’s. New research by Dr. Eve Seuntjens and Dr. Veronique van den Berghe of the Department of Development and Regeneration (Danny Huylebroeck laboratory, Faculty of Medicine) has identified two proteins, Sip1 and Unc5b, that play an important role in the development and migration of interneurons to the cerebral cortex – a breakthrough in our understanding of early brain development.

Two types of nerve cells are crucial to healthy brain functioning. Projection neurons, the more widely known of the two, make connections between different areas of the brain. Interneurons, a second type, work as dimmers that regulate the signalling processes of projection neurons. A shortage or irregular functioning of interneurons can cause short circuits in the nervous system. This can lead to seizures, a common symptom of many brain disorders. Interneuron dysfunction even appears to play a role in schizophrenia, autism and neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS.

Trailblazers

Researchers have only recently understood how different kinds of neuron are formed during embryonic development. During early brain development, stem cells form projection neurons in the cerebral cortex. Interneurons are made elsewhere in the brain. These interneurons then migrate to the cortex to mix with the projection neurons. Dr. Eve Seuntjens of the Celgen laboratory led by Professor Danny Huylebroeck explains: “The journey of interneurons is very complex: their environment changes constantly during growth and there are no existing structures — such as nerve pathways — available for them to follow.”

The question is how young interneurons receive their ‘directions’ to the cerebral cortex. Several proteins play a role, says Dr. Seuntjens. “We changed the gene containing the production code for the protein Sip1 in mice so that this protein was no longer produced during brain development.  In those mice, the interneurons never made it to the cerebral cortex — they couldn’t find the way.

That has to do with the guidance signals – substances that repel or attract interneurons and thus point them in the right direction – encountered by the interneurons on their way to the cerebral cortex. Without Sip1 production, interneurons see things through an overly sharp lens, so to speak. They see too many stop signs and become blocked. That overly sharp lens is Unc5b, a protein. Unc5b is deactivated by Sip1 in healthy mice. There are several known factors that influence the migration of interneurons, but Unc5b is the first protein we’ve isolated that we now know must be switched off in order for interneuron migration to move ahead smoothly.”

The next step is to study this process in the neurons of humans. “Now that there are techniques to create stem cells from skin cells, we can mimic the development of stem cells into interneurons and study what can go wrong. From there, we can test whether certain drugs can reverse the damage. That’s all still on the horizon, but you can see that the focus of research on many brain disorders and diseases is increasingly shifting to early child development because that just might be where a cause can be found.”

Does Einstein’s brain hold the secret to his genius?

Albert Einstein’s brain fascinates scientists and the general public alike, because it may provide clues to the neurological basis of his extraordinary intellectual abilities. The latest study of the great physicist’s grey matter was published last month. The researchers analyzed previously unpublished photographs of the great physicist’s cerebral cortex, and claim to have identified unusual, and hitherto unknown, features. But some are sceptical about how the findings have been interpreted.

Shortly after Einstein’s death on 18th April, 1955, pathologist Thomas Harvey removed his brain and dissected it into 240 blocks, taking dozens of photographs while he did so. He then sent some of the tissue samples and photographs to a handful of researchers, and eventually, a small number of studies emerged. The early ones showed that Einstein’s brain was, in fact, slightly smaller, and weighed about 200 grams less, than average, but subsequent investigations revealed several unusual features, which were, it was claimed, somehow related to his visuo-spatial skills.

For the new study, anthropologist Dean Falk of Florida State University and her colleagues analyzed 14 of the’s photographs from the museum collection, which together reveal the entire surface of Einstein’s cerebral cortex for the first time, enabling the researchers to examine the pattern of grooves and ridges and in detail and compare them to those seen in other brains.

"The new photographs reveal parts of Einstein’s brain that have not previously been seen in published images," says Falk. "We have identified most of the external details of his cerebral cortex, [and] the complexity and pattern of convolutions on certain parts of Einstein’s cerebral cortex is striking and unusual in comparison to brains from normal individuals."

"This is especially noticeable in the prefrontal cortex, which is important for advanced cognition, the parietal lobes, which are important for spatial and arithmetic reasoning, and the visual cortex. The primary sensory and motor cortices are also extraordinarily expanded in certain parts."

Some argue that any conclusions drawn from such findings could be meaningless. “Studying Einstein’s brain is like studying the writings of Nostradamus,” says Chris Chambers, a cognitive neuroscientist at Cardiff University. “You can read them backwards, forward, or even sideways, and draw whatever conclusions you like.”

"We inevitably end up committing logical fallacies of reverse inference and faulty generalisation: that certain parts of Einstein’s brain may look a bit different to other brains, and that this explains his abilities. But the differences might have no functional importance whatsoever, and this makes any kind of conclusion extremely weak."

Chambers adds that there is enormous variability in human brain structure, and that this poses another problem when trying to interpret such findings. “We’re dealing with just one brain and this makes it impossible to draw any firm conclusions about the population at large. Human brains come in all shapes and sizes and there is no known relationship to cognition. Very few people have the ‘normal’ brain we see in textbooks, and neither did Einstein.”

Clinical neurologist Frederick Lepore, a co-author of the new study, made similar arguments in 2001, and in an interview published online earlier this month, he is quoted as saying that the new study confirms Einstein’s brain “was very different,” but that “we face an insurmountable explanatory gap if we attempt to use our neuroanatomical findings to account for the mind that envisioned the curvature of the universe.”

He goes on to say that the next logical step would be to try to generate Einstein’s connectome, a comprehensive map of the connections in his brain, and that a comparison of the brain to those of other geniuses is another possible avenue of research.

Falk believes that the photographs could help researchers to map Einstein’s connectome. “[We have published]… the ‘roadmap’ that provides a key between these areas and recently emerged histological slides of Einstein’s brain, which may allow scientists to study its internal connectivity. These photographs should become more meaningful in the future, as more is learned about the functions of various regions.”

Helping the nose know: Researcher answers 100-year-old question about how olfactory feedback mechanism works

More than a century after it was first identified, Harvard scientists are shedding new light on a little-understood neural feedback mechanism that may play a key role in how the olfactory system works in the brain.

As described in a December 19 paper in Neuron by Venkatesh Murthy, Professor of Molecular and Cellular Biology, researchers have, for the first time, described how that feedback mechanism works by identifying where the signals go, and which type of neurons receive them. Three scientists from the Murthy lab were involved in the work: Foivos Markopoulos, Dan Rokni and David Gire.

"The image of the brain as a linear processor is a convenient one, but almost all brains, and certainly mammalian brains, do not rely on that kind of pure feed-forward system," Murthy explained. "On the contrary, it now appears that the higher regions of the brain which are responsible for interpreting olfactory information are communicating with lower parts of the brain on a near-constant basis."

Though researchers have known about the feedback system for decades, key questions about its precise workings, such as which neurons in the olfactory bulb receive the feedback signals, remained a mystery, partly because scientists simply didn’t have the technological tools needed to activate individual neurons and individual pathways.

"One of the challenges with this type of research is that these feedback neurons are not the only neurons that come back to the olfactory bulb," Murthy explained. "The challenge has always been that there’s no easy way to pick out just one type of neuron to activate."

To do it, Murthy and his team turned to a technique called optogenetics.

Using a virus that has been genetically-modified to produce a light-sensitive protein, Murthy and his team marked specific neurons, which become active when hit with laser light. Researchers were then able to trace the feedback mechanism from the brain’s processing centers back to the olfactory bulb.

Reaching that level of precision was critical, Murthy explained, because while olfactory bulb contains many “principal” neurons which are responsible for sending signals on to other parts of the brain, it is also packed with interneurons, which appear to play a role in formatting olfactory information as it comes into the brain.

(Image: BigStock)