Neuroscience

When minor wounds heal, the fine nerve endings that sense touch, or control sweating, are usually able to regrow. Like many processes in the body, the ability to regenerate new tissues changes throughout the lifecycle, typically diminishing with age. To investigate the molecular details of regeneration, the nervous system of the worm, C. Elegans, is ideal because its entire blueprint—the connectome—is available. The close-knit cadre of researchers who study C. elegans are the true veterinarians of neuroscience in that they command nearly every tool in the field to study this microcosm of biology. Publishing today in Science, a group of these researchers has uncovered a genetic circuit that regulates the regrowth of axons after they are experimentally cut with a laser. While the integrity of these mechanisms insures stability in the adult nervous system, manipulation of them could allow insults to the system to be restored to normal function.

(C. Elegans neuron. Credit: Technion-Israel Institute of Technology)

In order to develop properly in the first place, the expression of the genes controlling tissue construction proceeds in a choreographed rhythm, with each having its proper time and place. Once the organism has developed, many of these genes are decommissioned, or their cycles of expression dephased. Sometimes two components that act together in the larval stage, oppose each other in the adult. Two players in this genetic tit-for-tat, lin-41 and let-7, have previously been found to act as timers during these transitions. The researchers in the study described here, stumbled upon this particular circuit while they were looking at the effect of yet another gene, alg-1, on axon regeneration. Specifically, they had found that worms with a mutant form of alg-1, could regenerate certain axons up to 2.5 times longer than the axons of normal adult worms.

One particular sensory neuron, the AVM (anterior ventral microtubule) neuron, has a clearly defined axon that can regrow in larva, in not in adults. This strangely-named neuron has an even stranger subcellular feature. Its dendrites, in addition to the axon, are filled with a unique kind of microtubule, one that is composed of 15 protofilaments. Most mammals use a microtubule form-factor specifically made from 13 protofilaments, but many invertebrates use anywhere from 10 to 15. The avm neuron is also unique in that is one of just a few neurons that migrates to an asymmetric position in the body of the worm—it has no counterpart on the opposite side.

(Let-7 microRNA. Credit: Wikipedia commons)

The AVM neuron shows clear expression not only the alg-1 gene, but also another factor regulated by alg-1 known as let-7. The researchers were able to show that let-7 is responsible for inhibiting adult regrowth in the AVM neuron. Inhibiting let-7 directly, or alternatively, increasing the level of its reciprocal inhibitor, lin-41, completely restored the regeneration capabilities of the larval axons. From this they conclude that cyclic interactions between let-7 and lin-41 are a general strategy used not only in determining cell fate in development, but also in controlling axon regeneration.

Expression of let-7 was controlled by using a version of the gene which is temperature-sensitive. The particular allele used has normal activity at 15 degrees C, but can be completely turned off at 20 degrees C. The actual product of the let-7 gene is ultimately not a protein, but one of a class of newly-discovered regulators known as microRNAs. The full functionality of microRNAs has yet to be completely defined, but they seem to be able to regulate proteins, DNA, and mRNA.

The researchers were also partial to speculation as to why the organism appears to take pains to inhibit regrowth in the adult. Axotomy by laser may not have been a primary selection criteria during the evolution of the worm, but some ability for tissue repair would be important in the life of a worm. In the greater scheme of things, it would seem that loss of certain capabilities in the adult, may be a small price to pay for the greater stability of connections that may come along with it.

We recently reported on a study in mice, which demonstrated that mature brains continue to remodel their fine structure throughout the entire life of the organism. Mammalian axons have the further complication that while myelination is required to conduct signals over appreciable distances, it can also be an impediment to regrowth. For axons that have been compromised by trauma, or through developmental fault, turning back the clock on a few genes may be only part of the puzzle.

A new Swedish study published in the journal Neurology shows that the risk of developing dementia may have declined over the past 20 years, in direct contrast to what many previously assumed. The result is based on data from SNAC-K, an ongoing study on aging and health that started in 1987.

"We know that cardiovascular disease is an important risk factor for dementia. The suggested decrease in dementia risk coincides with the general reduction in cardiovascular disease over recent decades", says Associate Professor Chengxuan Qiu of the Aging Research Center, established by Karolinska Institutet and Stockholm University. "Health check-ups and cardiovascular disease prevention have improved significantly in Sweden, and we now see results of this improvement reflected in the risk of developing dementia."

Dementia is a constellation of symptoms characterized by impaired memory and other mental functions. After age 75, dementia is commonly due to multiple causes, mainly Alzheimers disease and vascular dementia. In the current study, more than 3000 persons 75 years and older living in the central Stockholm neighborhood of Kungsholmen participated. Of the participants, 523 were diagnosed with some form of dementia. The key members of the research group have been essentially the same since 1987, including the neurologist responsible for the clinical diagnoses of dementia. All study participants were assessed by a nurse, a physician, and a psychologist.

The result shows the prevalence of dementia was stable in both men and women across all age groups after age 75 during the entire study period (1987-1989 and 2001-2004), despite the fact that the survival of persons with dementia increased since the end of the 1980s. This means that the overall risk of developing dementia must have declined during the period, possibly thanks to prevention and better treatment of cardiovascular disease.

"The reduction of dementia risk is a positive phenomenon, but it is important to remember that the number of people with dementia will continue to rise along with the increase in life expectancy and absolute numbers of people over age 75", says Professor Laura Fratiglioni, Director of the Aging Research Center. "This means that the societal burden of dementia and the need for medical and social services will continue to increase. Today there’s no way to cure patients who have dementia. Instead we must continue to improve health care and prevention in this area."

Using a new, stem cell-based, drug-screening technology that could reinvent and greatly reduce the cost of developing pharmaceuticals, researchers at the Harvard Stem Cell Institute (HSCI) have found a compound that is more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) than are two drugs that failed in human clinical trials after large sums were invested in them.

The new screening technique developed by Lee Rubin, a member of HSCI’s executive committee and a professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), had predicted that the two drugs that eventually failed in the third and final stage of human testing would do just that.

“It’s a deep, dark secret of drug discovery that very few drugs have been tested on human-diseased cells before being tested in a live person,” said Rubin, who heads HSCI’s program in translational medicine. “We were interested in the notion that we can use stem cells to correct that situation.”

Rubin’s model is built on an earlier proof of concept developed by HSCI principal faculty member Kevin Eggan, who demonstrated that it was possible to move a neuron-based disease into a laboratory dish using stem cells carrying the genes of patients with the disease.

In a paper published today in the journal Cell Stem Cell, Rubin laid out how he and his colleagues applied their new method of stem cell-based drug discovery to ALS, also known as Lou Gehrig’s disease. The illness is associated with the progressive death of motor neurons, which pass information between the brain and the muscles. As cells die, people with ALS experience weakness in their limbs, followed by rapid paralysis and respiratory failure. The disease typically strikes later in life. Ten percent of cases are genetically predisposed, but for most patients there is no known trigger.

Rubin’s lab began by studying the disease in mice, growing billions of motor neurons from mouse embryonic stem cells, half normal and half with a genetic mutation known to cause ALS. Investigators starved the cells of nutrients and then screened 5,000 druglike molecules to find any that would keep the motor neurons alive.

Several hits were identified, but the molecule that best prolonged the life of both normal and ALS motor neurons was kenpaullone, previously known for blocking the action of an enzyme (GSK-3) that switches on and off several cellular processes, including cell growth and death. “Shockingly, this molecule keeps cells alive better than the standard culture medium that everybody keeps motor neurons in,” Rubin said.

Kenpaullone proved effective in several follow-up experiments that put mouse motor neurons in situations of certain death. Neuron survival increased in the presence of the molecule whether the cells were programmed to die or were placed in a toxic environment.

After further investigation, Rubin’s lab discovered that kenpaullone’s potency came from its ability also to inhibit HGK, an enzyme that sets off a chain of reactions that leads to motor neuron death. This enzyme was not previously known to be important in motor neurons or associated with ALS, marking the discovery of a new drug target for the disease.

“I think that stem cell screens will discover new compounds that have never been discovered before by other methods,” Rubin said. “I’m excited to think that someday one of them might actually be good enough to go into the clinic.”

To find out if kenpaullone worked in diseased human cells, Rubin’s lab exposed patient motor neurons and motor neurons grown from human embryonic stem cells to the molecule, as well as two drugs that did well in mice but failed in phase III human clinical trials for ALS. Once again, kenpaullone increased the rate of neuron survival, while one drug saw little response, and the other drug failed to keep any cells alive.

According to Rubin, before kenpaullone could be used as a drug, it would need a substantial molecular makeover to make it better able to target cells and find its way into the spinal cord so it can access motor neurons.

“This is kind of a proof of principle on the do-ability of the whole thing,” he said. “I think it’s possible to use this method to discover new drug targets and to prevalidate compounds on real human disease cells before putting them in the clinic.”

Rubin’s next steps will be to continue searching for better druglike compounds that can inhibit HGK and thus enhance motor neuron survival. He believes that the new information that comes out of this research will be useful to academia and the pharmaceutical industry.

“These kinds of exploratory screens are hard to fund, so being part of the HSCI” — which provided some of the funding — “has been absolutely essential,” Rubin said.

A bizarre twist on the usual way proteins are made may explain mysterious symptoms in the grandparents of some children with mental disabilities.

The discovery, made by a team of scientists at the University of Michigan Medical School, may lead to better treatments for older adults with a recently discovered genetic condition.

The condition, called Fragile X-associated Tremor Ataxia Syndrome (FXTAS), causes shakiness and balance problems and is often misdiagnosed as Parkinson’s disease. The grandchildren of people with the disease have a separate disorder called Fragile X syndrome, caused by problems in the same gene. The new discovery may also help shine light on that disease, though indirectly.

In a new paper published in the journal Neuron, the U-M-led team presents evidence that a toxic protein they’ve named FMRpolyG contributes to the death of nerve cells in FXTAS – and that this protein is made in a very unusual way.

Normally, DNA is transcribed into RNA, and then a part of the RNA is translated into a protein that performs its function in cells. Where this translation process starts on the RNA is usually determined by a specific sequence called a start codon.

The gene mutation that causes FXTAS is a repeated DNA sequence that is made into RNA but normally is not made into protein because it lacks a start codon. However, the investigators discovered that when this repeat expands, it can trigger protein production by a new mechanism known as RAN translation.

Corresponding author Peter Todd, M.D., Ph.D., notes that this unusual translation process appears to stem from a long chain of repeated DNA “letters” found in the genes of both grandparents and kids with Fragile X mutations. Todd is the Bucky and Patti Harris Professor in the U-M Department of Neurology

"Essentially, we’ve found that a sequence of DNA which shouldn’t be made into protein is being made into protein – and that this causes a toxicity in nerve cells," he explains. "We believe that the protein forms aggregates, and that this is a major contributor to toxicity and symptoms in FXTAS."

The U-M group went on to show how this RAN translation occurs in FXTAS and demonstrated that blocking it prevents the repeat mutation from being toxic, suggesting a new target for future treatments.

Fragile X tremor/ataxia syndrome or FXTAS was only discovered a decade ago. It may affect as many as one in every 3,000 men and one in 20,000 women, who have a repeat mutation in the gene known as FMR1. However, these patients don’t usually develop symptoms until late middle age, allowing them to pass the mutation on to their daughters, who can then have children where the DNA repeat that has grown much longer. In those children, especially in boys, it can cause severe intellectual disability and autism-like symptoms as the FMR1 gene shuts down and none of the normal protein is produced.

In fact, says Todd, it’s often only after a child is diagnosed with Fragile X syndrome through genetic testing that their grandfather or grandmother finds out that their own symptoms stem from FXTAS. Doctors in U-M’s Neurogenetics clinic for adults, and the Pediatric Genetics Clinic at U-M’s C.S. Mott Children’s Hospital, routinely work together to address the needs of Fragile X families.

"We have some treatments for the symptoms that FXTAS patients have, but we do not yet have a cure," says Todd, who regularly sees patients with FXTAS and related disorders. "Better treatments are needed – and this new discovery might help lead to novel strategies for clearing away or preventing the buildup of this toxic protein."

In addition, he says, the discovery that Fragile X ataxia results in part from RAN translation could have significance both for other diseases like amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease) and certain forms of dementia that are caused by DNA repeats. It can also aid our understanding of basic biology. “This may represent a new way in which translational initiation events occur, and may have importance beyond this one disease,” he notes. Further research on how RAN translation occurs, and why, is needed.

The idea that proteins can be created without a “start site” flies in the face of what most students of biology have learned in the last century. “In biology, we’re finding that the rules we once thought were hard and fast have some wiggle room,” Todd says.

TAU reveals the missing link between brain patterns and Alzheimer’s

Evidence indicates that the accumulation of amyloid-beta proteins, which form the plaques found in the brains of Alzheimer’s patients, is critical for the development of Alzheimer’s disease, which impacts 5.4 million Americans. And not just the quantity, but also the quality of amyloid-beta peptides is crucial for Alzheimer’s initiation. The disease is triggered by an imbalance in two different amyloid species — in Alzheimer’s patients, there is a reduction in a relative level of healthy amyloid-beta 40 compared to 42.

Now Dr. Inna Slutsky of Tel Aviv University’s Sackler Faculty of Medicine and the Sagol School of Neuroscience, with postdoctoral fellow Dr. Iftach Dolev and PhD student Hilla Fogel, have uncovered two main features of the brain circuits that impact this crucial balance. The researchers have found that patterns of electrical pulses (called “spikes”) in the form of high-frequency bursts and the filtering properties of synapses are crucial to the regulation of the amyloid-beta 40/42 ratio. Synapses that transfer information in spike bursts improve the amyloid-beta 40/42 ratio.

This represents a major advance in understanding that brain circuits regulate composition of amyloid-beta proteins, showing that the disease is not just driven by genetic mutations, but by physiological mechanisms as well. Their findings were recently reported in the journal Nature Neuroscience.

Tipping the balance

High-frequency bursts in the brain are critical for brain plasticity, information processing, and memory encoding. To check the connection between spike patterns and the regulation of amyloid-beta 40/42 ratio, Dr. Dolev applied electrical pulses to the hippocampus, a brain region involved in learning and memory.

When increasing the rate of single pulses at low frequencies in rat hippocampal slices, levels of both amyloid-beta 42 and 40 grew, but the 40/42 ratio remained the same. However, when the same number of pulses was distributed in high-frequency bursts, researchers discovered an increased amyloid-beta 40 production. In addition, the researchers found that only synapses optimized to transfer encoded by bursts contributed towards tipping the balance in favor of amyloid-beta 40. Further investigations conducted by Fogel revealed that the connection between spiking patterns and the type of amyloid-beta produced could revolve around a protein called presenilin. “We hypothesize that changes in the temporal patterns of spikes in the hippocampus may trigger structural changes in the presenilin, leading to early memory impairments in people with sporadic Alzheimer’s,” explains Dr. Slutsky.

Behind the bursts

According to Dr. Slutsky, different kinds of environmental changes and experiences — including sensory and emotional experience — can modify the properties of synapses and change the spiking patterns in the brain. Previous research has suggested that a stimulant-rich environment could be a contributing factor in preventing the development of Alzheimer’s disease, much as crossword and similar puzzles appear to stimulate the brain and delay the onset of Alzheimer’s. In the recent study, the researchers discovered that changes in sensory experiences also regulate synaptic properties — leading to an increase in amyloid-beta 40.

In the next stage, Dr. Slutsky and her team are aiming to manipulate activity patterns in the specific hippocampal pathways of Alzheimer’s models to test if it can prevent the initiation of cognitive impairment. The ability to monitor dynamics of synaptic activity in humans would be a step forward early diagnosis of sporadic Alzheimer’s.

Information from the senses has an important influence on how we move. For instance, you can see and feel when a mug is filled with hot coffee, and you lift it in a different way than if the mug were empty. Neuroscientist Julian Tramper discovered that the brain uses two forms of old information in order to execute new movements well. This discovery can be useful for the field of robotics. Tramper will receive his doctorate on Thursday 24 April from Radboud University Nijmegen

Every time you move, the brain deals with two problems. First, there is a slight delay in the sensory information needed to execute the movement. Second, the command from the brain directing the muscles to move is not entirely clear, because neuronal signals contain a certain amount of natural static interference. According to Tramper, the brain has a clever way of getting around both problems: It combines the old information from the senses with experience gained through similar movements made in the past. This means that our senses use two forms of old information in order to make new movements.

Computer versus test subject
Understanding the brain processes behind movement can be of great importance to fields like robotics. Therefore Tramper is trying to model his findings so that it will be possible to use them in robots in the future. He has already succeeded in this for certain hand-eye coordination experiments, to the extent that a computer can perform at about the same level as human test subjects. As a post-doctoral researcher within the Donders Institute, Tramper is researching how these types of models can be integrated into bio-inspired robots (robots based on biological principles).

SpaceCog
Tramper is currently working on a project called SpaceCog. The goal of this project is to develop a robot which can independently orient itself in space, something that humans do automatically. This is difficult to achieve, because each time a robot moves, it must reinterpret the information from its cameras and other sensors in order to determine whether the changes to its input are the result of its own movement or an external cause. The researchers involved in SpaceCog want to figure out how our brain has solved this problem. Tramper has three years to come up with a good computer model addressing this issue.

Looking towards the future
Tramper is studying hand-eye coordination by having test subjects play a special computer game. The subjects use a game controller to move a digital right hand and left hand on a screen. They have to move the two hands independently of one another and make them each follow a particular path in order to reach a final destination (see film 1). It turned out that the test subject’s eyes moved ahead of the digital hands. In other words, the eyes looked at a point that the hands would reach in the future (see film 2). This type of eye movement is called smooth pursuit, and before now it had only been detected in the case of external stimuli, when a subject was following an object’s movement. Tramper detected smooth pursuit eye movements at locations the hands had not yet reached, meaning these movements were triggered by internal stimuli.

Smooth pursuit
Tramper explains, ‘We’d previously demonstrated for other types of eye movement that the eye anticipates and moves in advance of external movement  To our surprise, this is also the case with smooth pursuit. It is probable that this is a compromise between where you are at a particular moment and where you want to get to. When moving, you need to keep track of your current location (which is constantly changing) and your target destination. Smooth pursuit eye movements can help you do this by letting your eye “hover” between both locations. If we can teach robots to do something like this, it will help make their movements much more natural. This will increase the number of ways in which robots can be put to work.’

Exosomes are small, virus-like particles that can transport genetic material and signal substances between cells. Researchers at Lund University, Sweden, have made new findings about exosomes released from aggressive brain tumours, gliomas. These exosomes are shown to have an important function in brain tumour development, and could be utilised as biomarkers to assess tumour aggressiveness through a blood test.

“Current wisdom says that cells are closed entities that communicate through the secretion of soluble signalling molecules. Recent findings indicate that cells can exchange more complex information – whole packages of genetic material and signalling proteins. This is an entirely new conception of how cells communicate”, says Dr Mattias Belting, Professor of Oncology at Lund University and senior consultant in oncology at Skåne University Hospital, Lund, Sweden.

Exosomes are small vesicles of only 30–90 nm. They are produced inside cells and act as “transport vehicles” of genetic material that can be transferred to surrounding cells. Since their first discovery, exosomes have been found in blood, saliva, urine, breast milk and other body fluids.

Mattias Belting’s research group has investigated exosomes released from tumour cells of patients with gliomas. The tiny exosome particles are delivered from the tumour to healthy cells of the brain and may prime normal tissue for efficient spreading of the tumour. The researchers in Lund have now shown that the aggressiveness of the tumour is reflected in the exosome molecular profile.

“We have succeeded in developing a method for the isolation of exosomes from brain tumour patients through a relatively simple blood test. Our analyses indicate that the content of exosomes mirrors the aggressiveness of the tumour in a unique manner”, says postdoctoral researcher Paulina Kucharzewska.

Exosomes could thus be utilised as biomarkers, i.e. to provide guidance on how the patient should be treated and to monitor treatment response. This possibility is particularly attractive with brain tumours that are not readily accessible for tissue biopsy. However, analysis of exosomes from the blood may also prove important with other tumour types. The value of conventional tumour biopsies is limited by the heterogeneity of tumour tissue, i.e. the tissue specimen may not be fully representative of the biological characteristics of a particular tumour. Exosomes, however, may offer more comprehensive information, according to the researchers.

The second international meeting on exosomes has just opened in Boston, and Mattias Belting and members of his team are there.

“It is very exciting to be part of the emergence of a novel research field. It can be anticipated that the most influential researchers in this area may one day be awarded the Nobel Prize”, says Dr Belting.

The results are published in Proceedings of the National Academy of Sciences (PNAS).

Researchers at the University Department of Neurology at the MedUni Vienna have identified a gene behind an epilepsy syndrome, which could also play an important role in other idiopathic (genetically caused) epilepsies. With the so-called “next generation sequencing”, with which genetic changes can be identified within a few days, it was ascertained that the CNTN2 gene is defective in this type of epilepsy.

This was investigated by a team led by Elisabeth Stögmann in collaboration with Cairo’s Ain Shams University and the Helmholtz Centre Munich with reference to a particular Egyptian family, in which five sick children have resulted from the marriage of one healthy cousin to his, likewise healthy, second cousin. The children affected suffer from a specific epilepsy syndrome, in which different types of epileptic attacks occur. This constellation has the “advantage”, according to Stögmann, that both alleles of the gene, which is how one designates different forms of the gene, demonstrate this defect: “As a result the defect becomes symptomatic and identifiable.

"20,000 to 25,000 genes, including all the "protein coding" ones, were sequenced for this. When this was done a mutation was found in the CNTN2 gene. CNTN2 undertakes an important function in the anchoring of potassium channels to the synapses. The mutation makes it no longer possible to generate this protein and, as a consequence, the potassium channels no longer remain affixed to the synapses. The researchers suspect that the epilepsy in this family is triggered by the altered function of the potassium channels.

This discovery, which has now been published in the top journal “Brain”, is providing the stimulus for further research to investigate this particular gene in other epilepsy patients as well. Approximately one percent of the population suffers from active epilepsy in which regular epileptic fits occur. The danger of suffering from an epileptic fit once in your life lies at approximately four to five percent. Genetic factors play a major part in the occurrence of epilepsies.

A team led by Dr. Alex Parker, a professor of pathology and cellular biology and a researcher at the University of Montreal Hospital Research Centre (CRCHUM), has identified an important therapeutic target for alleviating the symptoms of Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis (ALS), and other related neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

In a study published in the online version of Neurobiology of Disease, the team both confirmed the importance of this new target as well as a series of compounds that can be used to attenuate the dysregulation of one of the important cellular processes that lead to neuronal dysfunction and ultimately to brain cell death.

Although scientists are unclear about causes of ALS, they have made headway in identifying the cellular process potentially implicated in disease onset and progression. One such process which has attracted researcher interest involves the endoplasmic reticulum (ER), a component of cells that plays an important role in maintaining cell health. In collaboration with Dr. Pierre Drapeau at the University of Montreal and using worm and zebrafish models of ALS, Parker’s team not only confirmed that incapacitated ER leads to the motor neuron death typical of ALS, but also identified a series of compounds that alleviate the fatal consequences of defective ER.

“Since Riluzole, the one approved treatment compound for treating ALS, only has a modest effect on slowing disease progression, we set out to test a number of other compounds, and in so doing we discovered that they work by compensating for defective ER” explains Dr Parker. The compounds in question, Methylene blue, Salubrinal, Guanabenz and Phenazine, were each tested individually and in different combinations.

With the exception of Phenazine, these compounds have known benefits for treating neurodegenerative diseases. Parker and his team showed that each of these compounds reduces paralysis and neurodegeneration and that each acts on different parts of the ER pathway to achieve neuroprotection. More importantly, the researchers found that using these compounds in different combinations can enhance their therapeutic effects.

“These results are quite encouraging,” says Dr Parker, “and have given us a much better understanding of ER’s role in ALS as well as showing the way for improved treatments”. Parker’s team plans to test and confirm these findings with more complex animal models, a necessary step in developing medication that can be of benefit to human beings.

Research has implications for understanding memory and imagination

While studying rats’ ability to navigate familiar territory, Johns Hopkins scientists found that one particular brain structure uses remembered spatial information to imagine routes the rats then follow. Their discovery has implications for understanding why damage to that structure, called the hippocampus, disrupts specific types of memory and learning in people with Alzheimer’s disease and age-related cognitive decline. And because these mental trajectories guide the rats’ behavior, the research model the scientists developed may be useful in future studies on higher-level tasks, such as decision-making.

The details of their work were published online in the journal Nature on April 17.

“For the first time, we believe we have evidence that before a rat returns to an important place, it actually plans out its path,” says David Foster, Ph.D., assistant professor of neuroscience at the Johns Hopkins University School of Medicine. “The rat finds that location in its mind’s eye and knows how to get there.”

Foster and his team found that, at least for the purposes of navigation, the “mind’s eye” is located in the hippocampus, which is composed of two banana-shaped segments under the cerebral cortex on both sides of the brain. It is best known for creating memories. In people with Alzheimer’s, it is one of the first parts of the brain to sustain damage.

The Foster lab experiments focused on a group of neurons in the hippocampus called place cells because they are known to fire when animals are at a given location within a given environment. What was not known, Foster says, was how and when the brain uses that information.

By miniaturizing an existing technology, Foster and a postdoc in his lab, Brad Pfeiffer, Ph.D., were able to implant 20 microwires into each side of the hippocampus of four rats. The tiny wires let them record electrical activity from as many as 250 individual place cells at the same time, more than ever achieved before.

Over a two-week training period, the rats became familiar with the testing area which was surrounded by a variety of objects, so that the rats could tell where they were in relation to the objects outside. The space was 2 meters square with 36 tiny “dishes” placed at regular intervals in a grid. A single dish at a time would be filled with the rats’ reward: liquid chocolate.

The rats’ navigation tests involved as many as 40 sets of alternating “odd” and “even” trials per day. The odd trials required the rats to “forage” through the arena to find a chocolate-filled dish in a random location; the even trials required the rats to return each time to a “home” dish to receive their reward. While the rats fulfilled their tasks, the researchers recorded the firing of their place cells.

They found that as a rat travels randomly through the box without knowing where it needs to go, different combinations of place cells fire at each location along its path. The same set of cells fires every time the rat travels the same spot. These unique combinations of firings “mark” each spot in the rat’s brain and can be reconstructed into what seems like a virtual map, when needed.

When a rat is about to go to a specific location, e.g., “home,” place cells in its hippocampus fire in a sequence that creates a predictive path, which the rat then follows, somewhat like Hansel and Gretel following an imagined bread crumb trail.

Foster says that “unlike a Hansel and Gretel bread crumb trail, which only allows you to leave by the same route by which you entered, the rats’ memories of their surroundings are flexible and can be reconstructed in a way that allows them to ‘picture’ how to quickly get from point A to point B.” In order to do this, he says, the rats must already be familiar with the terrain between point A and point B, but, like a GPS, they don’t have to have previously started at point A with the goal of reaching point B.

Foster says the elderly can get lost easily, and research on aged mice shows that their place cells can fail to distinguish between different environments. His team’s research suggests that defective place cells would also affect a person’s ability to “look ahead” in their imaginations to predict a way home. Similarly, he says, higher-order brain functions, like problem solving, also require people to “look ahead” and imagine themselves in a different scenario.

“The hippocampus seems to be directing the movement of the rats, making decisions for them in real time,” says Foster. “Our model allows us to see this happening in a way that’s not been possible before. Our next question is, what will these place cells do when we put obstacles in the rats’ paths?”

Close family members of people with Alzheimer’s disease are more than twice as likely as those without a family history to develop silent buildup of brain plaques associated with Alzheimer’s disease, according to researchers at Duke Medicine.

The study, published online in the journal PLOS ONE on April 17, 2013, confirms earlier findings on a known genetic variation that increases one’s risk for Alzheimer’s, and raises new questions about other genetic factors involved in the disease that have yet to be identified.

An estimated 25 million people worldwide have Alzheimer’s disease, and the number is expected to triple by 2050. More than 95 percent of these individuals have late-onset Alzheimer’s, which usually occurs after the age of 65. Research has shown that Alzheimer’s begins years to decades before it is diagnosed, with changes to the brain measurable through a variety of tests.

Family history is a known risk factor and predictor of late-onset Alzheimer’s disease, and studies suggest a two- to four-fold greater risk for Alzheimer’s in individuals with a mother, father, brother or sister who develop the disease. These first-degree relatives share roughly 50 percent of their genes with another member of their family. Common genetic variations, including changes to the APOE gene, account for around 50 percent of the heritability of Alzheimer’s, but the disease’s other genetic roots are still unexplained.

“In this study, we sought to understand whether simply having a positive family history, in otherwise normal or mildly forgetful people, was enough to trigger silent buildup of Alzheimer’s plaques and shrinkage of memory centers,” said senior author P. Murali Doraiswamy, professor of psychiatry and medicine at Duke.

Duke neuroscience research trainee Erika J. Lampert, Doraiswamy and colleagues analyzed data from 257 adults, ages 55 to 89, both cognitively healthy and with varying levels of impairment. The participants were part of the Alzheimer’s Disease Neuroimaging Initiative, a national study working to define the progression of Alzheimer’s through biomarkers.

The researchers looked at participants’ age, gender and family history of the disease, with a positive family history defined as having a parent or sibling with Alzheimer’s. This information was compared with cognitive assessments and other biological tests, including APOE genotyping, MRI scans measuring hippocampal volume, and studies of three different pathologic markers (Aβ42, t-tau, and t-tau/Aβ42 ratio) found in cerebrospinal fluid.

As expected, the researchers found that a variation in the APOE gene associated with a greater risk and earlier onset of Alzheimer’s was overrepresented in participants with a family history of the disease. However, other biological differences were also seen in those with a family history, suggesting that unidentified genetic factors may influence the disease’s development before the onset of dementia.

Nearly half of all healthy people with a positive family history would have met the criteria for preclinical Alzheimer’s disease based on measurements of their cerebrospinal fluid, but only about 20 percent of those without a family history would have met such criteria.

“We already knew that family history increases one’s risk for developing Alzheimer’s, but we now are showing that people with a positive family history may also have higher levels of Alzheimer’s pathology earlier, which could be a reason why they experience a faster cognitive decline than those without a family history,” Lampert said.

The findings may influence the design of future studies developing new diagnostic tests for Alzheimer’s, as researchers may choose to exclude those with a positive family history – a group that has historically volunteered to participate in studies to better understand the disease – as healthy controls, given that they are more likely to develop Alzheimer’s pathology.

“Our study shows the power of a simple one-minute questionnaire about family history to predict silent brain changes,” Doraiswamy said. “In the absence of full understanding of all genetic risks for late-onset Alzheimer’s, family history information can serve as a risk stratification tool for prevention research and personalizing care.” He encouraged those with a known positive family history to seek out clinical trials specific to preventing the disease.

Cigarette smoking is the leading cause of preventable deaths globally. Unfortunately smoking cessation is difficult, with more than 90% of attempts to quit resulting in relapse.

(Image: Jupiterimages)

There are a growing number of available methods that can be tried in the effort to reduce smoking, including medications, behavioral therapies, hypnosis, and even acupuncture. All attempt to alter brain function or behavior in some way.

A new study published in Biological Psychiatry now reports that a single 15-minute session of high frequency transcranial magnetic stimulation (TMS) over the prefrontal cortex temporarily reduced cue-induced smoking craving in nicotine-dependent individuals.

Nicotine activates the dopamine system and reward-related regions in the brain. Nicotine withdrawal naturally results in decreased activity of these regions, which has been closely associated with craving, relapse, and continued nicotine consumption.

One of the critical reward-related regions is the dorsolateral prefrontal cortex, which can be targeted using a brain stimulation technology called transcranial magnetic stimulation. Transcranial magnetic stimulation is a non-invasive procedure that uses magnetic fields to stimulate nerve cells. It does not require sedation or anesthesia and so patients remain awake, reclined in a chair, while treatment is administered through coils placed near the forehead.

Dr. Xingbao Li and colleagues at Medical University of South Carolina examined cravings triggered by smoking cues in 16 nicotine-dependent volunteers who received one session each of high frequency or sham repetitive transcranial magnetic stimulation applied over the dorsolateral prefrontal cortex. This design allowed the researchers to ferret out the effects of the real versus the sham stimulation, similar to how placebo pills are used in evaluating the effectiveness and safety of new medications.

They found that craving induced by smoking cues was reduced after participants received real stimulation. They also report that the reduction in cue-induced craving was positively correlated with level of nicotine dependence; in other words, the TMS-induced craving reductions were greater in those with higher levels of nicotine use.

Dr. John Krystal, Editor of Biological Psychiatry, commented, “One of the elegant aspects of this study is that it suggests that specific manipulations of particular brain circuits may help to protect smokers and possibly people with other addictions from relapsing.”

"While this was only a temporary effect, it raises the possibility that repeated TMS sessions might ultimately be used to help smokers quit smoking. TMS as used in this study is safe and is already FDA approved for treating depression. This finding opens the way for further exploration of the use of brain stimulation techniques in smoking cessation treatment," said Li.

University of British Columbia researchers have found a new potential use for the over-the-counter pain drug Tylenol. Typically known to relieve physical pain, the study suggests the drug may also reduce the psychological effects of fear and anxiety over the human condition, or existential dread.

Published in the Association for Psychological Science journal Psychological Science, the study advances our understanding of how the human brain processes different kinds of pain.

“Pain exists in many forms, including the distress that people feel when exposed to thoughts of existential uncertainty and death,” says lead author Daniel Randles, UBC Dept. of Psychology. “Our study suggests these anxieties may be processed as ‘pain’ by the brain – but Tylenol seems to inhibit the signal telling the brain that something is wrong.”

The study builds on recent American research that found acetaminophen – the generic form of Tylenol – can successfully reduce the non-physical pain of being ostracized from friends. The UBC team sought to determine whether the drug had similar effects on other unpleasant experiences – in this case, existential dread.

In the study, participants took acetaminophen or a placebo while performing tasks designed to evoke this kind of anxiety – including writing about death or watching a surreal David Lynch video – and then assign fines to different types of crimes, including public rioting and prostitution.

Compared to a placebo group, the researchers found the people taking acetaminophen were significantly more lenient in judging the acts of the criminals and rioters – and better able to cope with troubling ideas. The results suggest that participants’ existential suffering was “treated” by the headache drug.

“That a drug used primarily to alleviate headaches may also numb people to the worry of thoughts of their deaths, or to the uneasiness of watching a surrealist film – is a surprising and very interesting finding,” says Randles, a PhD candidate who authored the study with Prof. Steve Heine and Nathan Santos.

While the findings suggest that acetaminophen can help to reduce anxiety, the researchers caution that further research – and clinical trials – must occur before acetaminophen should be considered a safe or effective treatment for anxiety.

Brain scans are increasingly able to reveal whether or not you believe you remember some person or event in your life. In a new study presented at a cognitive neuroscience meeting today, researchers used fMRI brain scans to detect whether a person recognized scenes from their own lives, as captured in some 45,000 images by digital cameras. The study is seeking to test the capabilities and limits of brain-based technology for detecting memories, a technique being considered for use in legal settings.

“The advancement and falling costs of fMRI, EEG, and other techniques will one day make it more practical for this type of evidence to show up in court,” says Francis Shen of the University of Minnesota Law School, who is chairing a session on neuroscience and the law at a meeting of the Cognitive Neuroscience Society (CNS) in San Francisco this week. “But technological advancement on its own doesn’t necessarily lead to use in the law.” But as the technology has advanced and as the legal system desires to use more empirical evidence, neuroscience and the law are intersecting more often than in previous decades.

In U.S. courts, neuroscientific evidence has been used largely in cases involving brain injury litigation or questions of impaired ability. In some cases outside the United States, however, courts have used brain-based evidence to check whether a person has memories of legally relevant events, such as a crime. New companies also are claiming to use brain scans to detect lies – although judges have not yet admitted this evidence in U.S. courts. These developments have rallied some in the neuroscience community to take a critical look at the promise and perils of such technology in addressing legal questions – working in partnership with legal scholars through efforts such as the MacArthur Foundation Research Network on Law and Neuroscience.

Recognizing your own memories

What inspired Anthony Wagner, a cognitive neuroscientist at Stanford University, to test fMRI uses for memory detection was a case in June 2008 in Mumbai, India, in which a judge cited EEG evidence as indicating that a murder suspect held knowledge about the crime that only the killer could possess. “It appeared that the brain data held considerable sway,” says Wagner, who points out that the methods used in that case have not been subject to extensive peer review.

Since then, Wagner and colleagues have conducted a number of experiments to test whether brain scans can be used to discriminate between stimuli that people perceive as old or new, as well as more objectively, whether or not they have previously encountered a particular person, place, or thing. To date, Wagner and colleagues have had success in the lab using fMRI-based analyses to determine whether someone recognizes a person or perceives them as unfamiliar, but not in determining whether in fact they have actually seen them before.

In a new study presented today, his team sought to take the experiments out of the lab and into the real world by outfitting participants with digital cameras around their necks that automatically took photos of the participants’ everyday experiences. Over a multi-week period, the cameras yielded 45,000 photos per participant.

Wagner’s team then took brief photo sequences of individual events from the participants’ lives and showed them to the participants in the fMRI scanner, along with photo sequences from other subjects as the control stimuli. The researchers analyzed their brain patterns to determine whether or not the participants were recognizing the sequences as their own. “We did quite well with most subjects, with a mean accuracy of 91% in discriminating between event sequences that the participant recognized as old and those that the participant perceived as unfamiliar, ” Wagner says. “These findings indicate that distributed patterns of brain activity, as measured with fMRI, carry considerable information about an individual’s subjective memory experience – that is, whether or not they are remembering the event.”

In another new study, Wagner and colleagues tested whether people can “beat the technology” by using countermeasures to alter their brain patterns. Back in the lab, the researchers showed participants individual faces and later asked them whether the faces were old or new. “Halfway through the memory test, we stopped and told them ‘What we are actually trying to do is read out from your brain patterns whether or not you are recognizing the face or perceiving it as novel, and we’ve been successful with other subjects in doing this in the past. Now we want you to try to beat the system by altering your neural responses.’” The researchers instructed the participants to think about a familiar person or experience when presented with a new face, and to focus on a novel feature of the face when presented a previously encountered face.

“In the first half of the test, during which participants were just making memory decisions, we were well above chance in decoding from brain patterns whether they recognized face or perceived it as novel. However, in the second half of the test, we were unable to classify whether or not they recognized the face nor whether the face was objectively old or new,” Wagner says. Within a forensic setting, Wagner says, it is conceivable that a suspect could use such measures to try to mask the brain patterns associated with memory.

Wagner says that his work to date suggests that the technology may have some utility in reading out brain patterns in cooperative individuals but that the uses are much more uncertain with uncooperative individuals. However, Wagner stresses that the method currently does not distinguish well between whether a person’s memory reflects true or false recognition. He says that it is premature to consider such evidence in the courts because many additional factors await future testing, including the effects of stress, practice, and time between the experience and the memory test.

Overgeneralizing the adolescent brain

A general challenge to the use of neuroscientific evidence in legal settings, Wagner says, is that most studies are at the group rather than the individual level. “The law cares about a particular individual in a particular situation right in front of them,” he says, and the science often cannot speak to that specificity.

Shen cites the challenge of making individualized inference from group-based data as one of the major ones facing use of neuroscience evidence in the court. “This issue has come up in the context of juvenile justice, where the adolescent brain development data confirms behavioral data that on average 17-year-olds are more impulsive than adults, but does not tell us whether a particular 17-year-old, namely the one on trial, was less able to control his/her actions on the day and in the manner in question,” he says.

Indeed, B.J. Casey of the Weill Medical College of Cornell University says that too often we overgeneralize the lack of self control among adolescents. Although adolescents do show poor self control as a group, some situations and individuals are more prone to this breakdown than others.

“It is not that teens can’t make decisions, they can and they can do so efficiently,” Casey says. “It is when they must make decisions in the heat of the moment – in presence of potential or perceived threats, among peers – that the court should consider diminished responsibility of teens while still holding them accountable for their behavior.” Research suggests that this diminished ability is due to the immature development of circuitry involved in processing of negative or positive cues in the environment in the subcortical limbic regions and then in regulating responses to those cues in the prefrontal cortex.

The body of research to date is at the group-level, however, and is not yet able to comment on the neurobiological maturity of an individual adolescent. To help provide more guidance on this issue in legal settings, Casey and colleagues are working alongside legal scholars on a developmental imaging study, funded by the MacArthur Foundation, that is examining behaviors relevant to juvenile criminal behavior, including impulsivity and peer influence.

Making real-world connections

The same type of work – to connect brain imaging to particular behaviors in the real-world – is ongoing in a number of other areas, including fMRI-based lie detection and linking negligence to specific mental states. “It’s a big leap to go from a laboratory setting, in which impulse control may be measured by one’s ability to not press a button in response to a stimulus, to the real-world, where the question is whether someone had requisite self-control not to tie up an innocent person and throw them off a bridge.” Shen says. “I don’t see neuroscience solving these big problems anytime soon, and so the question for law becomes: What do we do with this uncertainty? I think this is where we’re at right now, and where we’ll be for some time.”

“With a few notable exceptions such as death penalty cases, cases where a juvenile is facing a very stiff sentence, and litigating brain injury claims, ‘law and neuroscience’ is not familiar to most lawyers,” Shen says. “But this might change – and soon.” The ongoing work is vital, he says, for laying a foundation for a future that’s yet to come, and he hopes that more neuroscientists will increasingly collaborate with legal scholars.

A brain-training task that increases the number of items an individual can remember over a short period of time may boost performance in other problem-solving tasks by enhancing communication between different brain areas. The new study being presented this week in San Francisco is one of a growing number of experiments on how working-memory training can measurably improve a range of skills – from multiplying in your head to reading a complex paragraph.

(Image: Nelson Marques)

“Working memory is believed to be a core cognitive function on which many types of high-level cognition rely, including language comprehension and production, problem solving, and decision making,” says Brad Postle of the University of Wisconsin-Madison, who is co-chairing a session on working-memory training at the Cognitive Neuroscience Society (CNS) annual meeting today in San Francisco. Work by various neuroscientists to document the brain’s “plasticity” – changes brought about by experience – along with technical advances in using electromagnetic techniques to stimulate the brain and measure changes, have enabled researchers to explore the potential for working-memory training like never before, he says.

The cornerstone brain-training exercise in this field has been the “n-back” task, a challenging working memory task that requires an individual to mentally juggle several items simultaneously. Participants must remember both the recent stimuli and an increasing number of stimuli before it (e.g., the stimulus “1-back,” “2-back,” etc). These tasks can be adapted to also include an audio component or to remember more than one trait about the stimuli over time – for example, both the color and location of a shape.

Through a number of experiments over the past decade, Susanne Jaeggi of the University of Maryland, College Park, and others have found that participants who train with n-back tasks over the course of approximately a month for about 20 minutes per day not only get better at the n-back task itself, but also experience “transfer” to other cognitive tasks on which they did not train. “The effects generalize to important domains such as attentional control, reasoning, reading, or mathematical skills,” Jaeggi says. “Many of these improvements remain over the course of several months, suggesting that the benefits of the training are long lasting.”

As yet unresolved and controversial, however, has been understanding which factors determine whether working-memory training will generalize to other domains, as well as how the brain changes in response to the training. Work by Postle’s group using a new technique of applying electromagnetic stimulation on the brains of people undergoing working-memory training addresses some of these questions.

Training increases connectivity

Bornali Kundu of the University of Wisconsin-Madison, who works in Postle’s laboratory, used transcranial magnetic stimulation (TMS) with electroencephalography (EEG) to measure activity in specific brain circuits before and after training with an n-back task. “Our main finding was that training on the n-back task increased the number of items an individual could remember over a short period of time,” explains Kundu, who is presenting these new results today. “This increase in short-term memory performance was associated with enhanced communication between distant brain areas, in particular between the parietal and frontal brain areas.”

In the n-back task, Kundu’s team presented stimuli one-at-a-time on a computer screen and asked participants to decide if the current stimulus matched both the color and location of the stimulus presented a certain number of presentations previously. The color varied among seven primary colors, and the location varied among eight possible positions arranged in a square formation. The control task was playing the video game Tetris, which involves moving colored shapes to different locations, but does not require participants to remember anything. Before and after the training, researchers administered a range of cognitive tasks on which subjects did not receive training, and simultaneously delivered TMS while recording EEG, to measure communication between brain areas during task performance.

After practicing the n-back task for 5 hours a day and 5 days per week over 5 weeks, subjects were able to remember more items over short periods of time. Importantly, for those whose working memory improved, communication between the dorsolateral prefrontal cortex (DLPFC) and parietal cortex also improved. “This is in comparison to the control group, who showed no such differences in neural communication after practicing Tetris for 5 weeks,” Kundu says.

Working-memory training also produced improvement on cognitive tasks for which participants were not trained that are also believed to rely on communication between the parietal cortex and DLPFC. For two of these tasks – the ability to detect a change in a briefly presented array of squares, and the ability to detect a red letter “C” embedded in a field of distracting stimuli of rotated red “C”s and blue “C”s – those who had trained in the n-back test also showed a decrease in task-related EEG. The training exercise had registered a similar decrease. “The overall picture seems to be that the extent of transfer of training to untrained tasks depends on the overlap of neural circuits recruited by the two,” Kundu says.

Developing future therapies

Moving forward, many cognitive neuroscientists are working to see how working-memory training may specifically help clinical populations, such as patients with ADHD. “If we can learn the ‘rules’ that govern how, why, and when cognitive training can produce improvements that generalize to untrained tasks, it may be that therapies can be developed for patients suffering from neurological or psychiatric disease,” Postle says.

Both Jaeggi’s team, as well as Torkel Klingberg of the Karolinska Institute in Sweden, who is also presenting at the symposium today in San Francisco, have had success with such training for children with ADHD, decreasing the symptoms of inattention. “Here, the reason working-memory training may transfer to tests of fluid intelligence, as well as to a reduction in ADHD-associated hyperactivity symptoms, may be because both of those complex behaviors use some of the same brain circuits also used in performing the working-memory training tasks,” Kundu says.

“Individual differences in working memory performance have been related to individual differences in numerous real world skills such as reading comprehension, performance on standardized tests, and much more,” she adds. “I would not expect the same sorts of transfer effects that have been seen with working-memory training to happen if an individual practiced a task that used a minimally overlapping network, such as, for example, shooting three-pointers – which presumably uses different brain areas like primary and secondary motor cortex and the cerebellum.”

Jaeggi says that it is important to understand that cognitive abilities are not as unchangeable as some might think. “Even though there is certainly a hereditary component to mental abilities, that does not mean that there are not also components that are malleable and respond to experience and practice,” she says. “Whereas we try to strengthen participants’ working memory skills in our research, there are other routes that are possible as well, such as for example physical or musical training, meditation, nutrition, or even sleep.”

Despite all the promising research, Jaeggi says, researchers still need to understand many aspects of this work, such as “individual differences that influence training and transfer effects, the question of how long the effects last, and whether and how the effects translate into more real-world settings and ultimately, academic achievement.”

Even a mild injury to the brain can have long lasting consequences, including increased risk of cognitive impairment later in life. While it is not yet known how brain injury increases risk for dementia, there are indications that chronic, long-lasting, inflammation in the brain may be important. A new paper by researchers at the University of Kentucky Sanders-Brown Center on Aging (SBCoA), appearing in the Journal of Neuroscience, offers the latest information concerning a “switch” that turns “on” and “off” inflammation in the brain after trauma.

A team of researchers led by Linda Van Eldik, director of SBCoA, used a mouse model to study the role of p38a MAPK in trauma-induced injury responses in the microglia resident immune cell of the brain.

"The p38α MAPK protein is an important switch that drives abnormal inflammatory responses in peripheral tissue inflammatory disorders, including chronic debilitating diseases like rheumatoid arthritis," said Van Eldik.

"However, less is known about the potential importance of p38α MAPK in controlling inflammatory responses in the brain. Our work supports p38α MAPK as a promising clinical target for the treatment of CNS disorders associated with uncontrolled brain inflammation, including trauma, and potentially others like Alzheimer’s disease. We are excited by our findings, and are actively working to develop drugs targeting p38a MAPK designed specifically for diseases of the brain."

Lead author of the paper Adam D. Bachstetter said, “I was surprised when I looked under the microscope at the brain tissue of mice that had a diffuse brain injury. Microglia normally look like a small spider, but after suffering a brain injury the microglia become like angry spiders from a horror movie. In brain-injured mice that lack p38a MAPK there were no angry-looking microglia, only the normal small spider-like cells. When I started the study I never expected the results to be so clear and striking. I believe that the p38a MAPK is a promising clinical target for the treatment of CNS disorders with dysregulated inflammatory responses, but we are still a long way from development of CNS-active p38 inhibitor drugs. “

Making decisions involves a gradual accumulation of facts that support one choice or another. A person choosing a college might weigh factors such as course selection, institutional reputation and the quality of future job prospects.

But if the wrong choice is made, Princeton University researchers have found that it might be the information rather than the brain’s decision-making process that is to blame. The researchers report in the journal Science that erroneous decisions tend to arise from errors, or “noise,” in the information coming into the brain rather than errors in how the brain accumulates information.

These findings address a fundamental question among neuroscientists about whether bad decisions result from noise in the external information — or sensory input — or because the brain made mistakes when tallying that information. In the example of choosing a college, the question might be whether a person made a poor choice because of misleading or confusing course descriptions, or because the brain failed to remember which college had the best ratings.

Previous measurements of brain neurons have indicated that brain functions are inherently noisy. The Princeton research, however, separated sensory inputs from the internal mental process to show that the former can be noisy while the latter is remarkably reliable, said senior investigator Carlos Brody, a Princeton associate professor of molecular biology and the Princeton Neuroscience Institute (PNI), and a Howard Hughes Medical Institute Investigator.

"To our great surprise, the internal mental process was perfectly noiseless. All of the imperfections came from noise in the sensory processes," Brody said. Brody worked with first author Bingni Brunton, now a postdoctoral research associate in the departments of biology and applied mathematics at the University of Washington; and Matthew Botvinick, a Princeton associate professor of psychology and PNI.

The research subjects — four college-age volunteers and 19 laboratory rats — listened to streams of randomly timed clicks coming into both the left ear and the right ear. After listening to a stream, the subjects had to choose the side from which more clicks originated. The rats had been trained to turn their noses in the direction from which more clicks originated.

The test subjects mostly chose the correct side but occasionally made errors. By comparing various patterns of clicks with the volunteers’ responses, researchers found that all of the errors arose when two clicks overlapped, and not from any observable noise in the brain system that tallied the clicks. This was true in experiment after experiment utilizing different click patterns, in humans and rats.

The researchers used the timing of the clicks and the decision-making behavior of the test subjects to create computer models that can be used to indicate what happens in the brain during decision-making. The models provide a clear window into the brain during the “mulling over” period of decision-making, the time when a person is accumulating information but has yet to choose, Brody said.

"Before we conducted this study, we did not have a way of looking at this process without inserting electrodes into the brain," Brody said. "Now thanks to our model, we have an estimation of what is going on at each moment in time during the formation of the decision."

The study suggests that information represented and processed in the brain’s neurons must be robust to noise, Brody said. “In other words, the ‘neural code’ may have a mechanism for inherent error correction,” he said.

"The new work from the Brody lab is important for a few reasons," said Anne Churchland, an assistant professor of biological sciences at Cold Spring Harbor Laboratory who studies decision-making and was not involved in the study. "First, the work was very innovative because the researchers were able to study carefully controlled decision-making behavior in rodents. This is surprising in that one might have guessed rodents were incapable of producing stable, reliable decisions that are based on complex sensory stimuli.

"This work exposed some unexpected features of why animals, including humans, sometimes make incorrect decisions," Churchland said. "Specifically, the researchers found that errors are mostly driven by the inability to accurately encode sensory information. Alternative possibilities, which the authors ruled out, included noise associated with holding the stimulus in mind, or memory noise, and noise associated with a bias toward one alternative or the other."

Scientists at CWRU School of Medicine Discover New Technique that Holds Promise for the Treatment of Multiple Sclerosis and Cerebral Palsy

Researchers at Case Western Reserve School of Medicine have discovered a technique that directly converts skin cells to the type of brain cells destroyed in patients with multiple sclerosis, cerebral palsy and other so-called myelin disorders.

This discovery appears today in the journal Nature Biotechnology.

This breakthrough now enables “on demand” production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced.

The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes, the type of cell responsible for myelinating the neurons of the brain.

“Its ‘cellular alchemy,’” explained Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy.”

In a process termed “cellular reprogramming,” researchers manipulated the levels of three naturally occurring proteins to induce fibroblast cells to become precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).

Tesar’s team, led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, rapidly generated billions of these induced OPCs (called iOPCs). Even more important, they showed that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.

When oligodendrocytes are damaged or become dysfunctional in myelinating diseases, the insulating myelin coating that normally coats nerves is lost. A cure requires the myelin coating to be regenerated by replacement oligodendrocytes.

Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but with limitations.
“The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes,” explained co-author and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine and the university’s vice president for research. “The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells.”

This initial study used mouse cells. The critical next step is to demonstrate feasibility and safety using human cells in a lab setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.
“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” said Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center. “It is a real breakthrough.”

The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.

The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.

Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.

The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.

“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.

The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.

“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”

The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.

Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.

This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.

Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.

Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.

Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.

“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”