BRAIN initiative is underway, funding new ways to map cells, circuits

Scientists will aim to capture the workings of the human brain in comprehensive recordings, to watch the brain while in motion and to reimagine the world’s most complex biological organism as a buzzing network of interlocking circuits with the award of $46 million in study grants announced Tuesday.

The announcement marks the first concrete steps taken under the Obama administration’s BRAIN Initiative, short for Brain Research Through Advancing Innovative Neurotechnologies. Unveiled in April 2013, the initiative is a planned 12-year effort to spur new understanding of the brain in sickness and in health by improving technologies used to map, record, probe and stimulate its workings.

President Obama has sought $110 million for the BRAIN initiative in 2014 and $200 million for the 2015 fiscal year, which begins on Wednesday, with future years’ funding to be worked out. He has likened the initiative to the Human Genome Project, which has dramatically deepened understanding of the roles played by nearly 25,000 genes that make up human DNA, and has advanced medicine along a wide front.

On Tuesday, Obama administration officials revealed which researchers and universities will carry out the first federally funded projects under the initiative’s banner, naming more than 100 investigators in 15 states and several countries.

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Discovery of new pathways controlling the serotonergic system

With the aid of new methods, a research team at Karolinska Institutet have developed a detailed map of the networks of the brain that control the neurotransmitter serotonin. The study, published in the scientific journal Neuron, may lead to new knowledge on a number of psychiatric conditions and the development of new pharmaceuticals.

The neurotransmitter serotonin controls impulsivity, mood and our cognitive functions, among other things, and comes from the serotonergic neurons – the neurons that produce serotonin. So that we have good mental health and normal behaviour, it is important that there is correctly regulated activity among these neurons. The activity is governed by other neurons from different regions of the brain via direct links, known as synapses, on the serotonergic neurons. Imbalance in the serotonergic system can lead to depression, Parkinson’s disease, schizophrenia and autism, among other things.

So far it has been impossible to study in detail how different types of nerve cells are interlinked and how the brain’s networks control behaviour. Consequently, there has also been a lack of knowledge of which nerve cells control the activity of the serotonergic neurons. But with the help of new methods, researchers at Karolinska Institutet can now investigate how the various networks of the brain are organised and how they work. The research team, led by Konstantinos Meletis of the Department of Neuroscience, has established which networks of the brain control the serotonergic neurons.

“We have been able to create a new type of map of the neurons’ contacts and discovered new pathways that control the serotonergic system. These networks were previously unknown and are very interesting in terms of how they help us to understand how the serotonergic system works, which could also help us to understand certain mental illnesses,” Konstantinos Meletis explains.

In order to map out which neurons have direct contact with serotonergic neurons, the researchers established a method in which these cells were marked with a rabies virus which produced a fluorescent marker. Via genetic manipulation, the rabies virus was then spread to all of the neurons directly linked to the serotonergic neurons. The researchers thereby gained a very detailed, three-dimensional image of the networks of the brain that control serotonin. Using optogenetics, a method in which light is used to control the activity of neurons, the researchers were then able to manipulate select networks and thus study their effect on the serotonergic neurons.

Via mapping, the researchers discovered a network in the frontal lobe which is associated with cognition and well-being and which controls the serotonergic neurons. Researchers also found that serotonin can be controlled from new types of neurons in the basal ganglia, an area of the cerebrum which among other things controls movement, well-being and decision-making; a discovery which may have significance for conditions such as Parkinson’s disease.

“We are very optimistic that the revolution we are now seeing in brain research could also lead to entirely new and effective medicine in the field of psychiatry,” Konstantinos Meletis explains.

For neurons in the brain, identity can be used to predict location

Throughout the world, there are many different types of people, and their identity can tell a lot about where they live. The type of job they work, the kind of car they drive, and the foods they eat can all be used to predict the country, the state, or maybe even the city a person lives in.

The brain is no different. There are many types of neurons, defined largely by the patterns of genes they use, and they “live” in numerous distinct brain regions. But researchers do not yet have a comprehensive understanding of these neuronal types and how they are distributed in the brain. Today, a team of scientists at Cold Spring Harbor Laboratory (CSHL) led by Professor Partha Mitra describes a new mathematical model that combines large data sets to predict where different types of cells are located within the brain, based on their molecular identity.

Scientists at the Allen Institute for Brain Science in Seattle are using microscopy to directly observe gene activity, one at a time, in razor-thin slices of mouse brain tissue. This approach yields brain maps that are collectively known as the Allen Mouse Brain Atlas. Each individual map shows where a single gene is expressed in the brain. When multiple maps are overlaid, patterns begin to emerge that show how different regions of the brain activate specific and often discrete complements of genes. These patterns are known as “co-expression” profiles.

Elsewhere, other research groups have taken a complementary approach, harvesting a single type of neuron from the brain and profiling all of the genes that are expressed by that cell. But this data lacks the spatial component of the atlas assembled by the Allen Brain Institute.

Mitra and postdoctoral fellow Pascal Grange, Ph.D., set out to integrate these two kinds of datasets. They devised a mathematical model that does just this. “Our model is simple,” says Mitra, “but it has predictive power. If the gene expression profile of a neuronal type is measured, then the model predicts where in the brain that type of neuron can be found.”

The significance of the new model, according to Grange, is that “it enables us to now have a biological understanding of the patterns, the co-expression profiles, seen in the Allen Gene Expression Atlas of the Mouse Brain.”

As scientists continue to generate larger datasets of gene activation for neurons, this model will allow them to draw an increasingly accurate map of their distribution in the brain. The eventual goal is to gain a better understanding of how signaling between different types of neurons controls memory and cognition.

(Image caption: Illustration of the mirror neuron system in the human brain. Credit: Jan Brascamp)

Brain mapping confirms patients with schizophrenia have impaired ability to imitate

According to George Bernard Shaw, “Imitation is not just the sincerest form of flattery – it’s the sincerest form of learning.” According to psychologists, imitation is something that we all do whenever we learn a new skill, whether it is dancing or how to behave in specific social situations.

Now, the results of a brain-mapping experiment conducted by a team of neuroscientists at Vanderbilt University strengthen the theory that an impaired ability to imitate may underlie the profound and enduring difficulty with social interactions that characterize schizophrenia. In a paper published online on Mar. 14 by the American Journal of Psychiatry, the researchers report that when patients with schizophrenia were asked to imitate simple hand movements, their brains exhibited abnormal brain activity in areas associated with the ability to imitate.

“The fact that patients with schizophrenia show abnormal brain activity when they imitate simple hand gestures is important because action imitation is a primary building block of social abilities,” said first author Katharine Thakkar, who conducted much of the research while completing her doctoral program at Vanderbilt and is now a post-doctoral fellow at the University Medical Center in Utrecht. “The ability to imitate is present early in life and is crucial for learning how to navigate the social world. According to current theory, covert imitation is also the most fundamental way that we understand the intentions and feelings of other people.”

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Study first to offer detailed map of mouse’s cerebral cortex

The mammalian cerebral cortex, long thought to be a dense single interrelated tangle of neural networks, actually has a “logical” underlying organizational principle, according to a study appearing in the journal Cell.

Researchers have identified eight distinct neural subnetworks that together form the connectivity infrastructure of the mammalian cortex — the part of the brain involved in higher-order functions such as cognition, emotion and consciousness.

“This study is the first comprehensive mapping of the most developed region of the mammalian brain: the cerebral cortex. The cortex is highly complex and made up of many densely interconnected structures, but when you strip it down, is organized into a small number of subnetworks,” said senior author Hongwei Dong of the USC Institute for Neuroimaging and Informatics (INI).

The cerebral cortex is the outermost layer of neural tissue in the brain and is one of the most extensively studied brain structures in the field of neuroscience. However, before this study, its underlying organizational principle was still largely unclear.

“Think about it: The brain is built for logic, so it’s organization must be logical. The brain’s architectural organization is arranged such that all of its substructures most efficiently work in conjunction to produce appropriate behaviors,” said Dong, associate professor of neurology at the Keck School of Medicine of USC. “We want to find the code to how the brain is structurally organized.”

The study is also a reminder that while there is more data than ever, the quality and reliability of information still matters. In contrast to past patchwork attempts, Dong and his team undertook an effort to directly develop a whole-brain mouse atlas of brain pathways. Across the cortex, they injected fluorescent molecules. These molecules were then transported along the brain’s “cellular highways” — the neuronal pathways — and meticulously tracked using a high-resolution microscope.

The uniformity and completeness of the scientists’ effort across the entire cortex provided for a searchable image database of cortical connections, which the researchers are making open-access and publicly available.

It also allowed them to reliably see patterns: the seemingly inscrutable mass of connections in the cerebral cortex is highly organized, consisting of eight distinct subnetworks that are relatively segregated.

“The systematic and comprehensive manner in which the data were collected lent itself to a detailed analysis through which these subnetworks emerged,” explained co-lead author Houri Hintiryan of the USC Laboratory of Neuro Imaging.

So that scientists around the world may continue to look for fundamental structural insights, the full, interactive imaging dataset is viewable at Mouse Connectome Project, providing a resource for researchers interested in studying the anatomy and function of cortical networks throughout the brain.

“It really is quite tedious,” Dong said of collecting the data, “and labor-intensive, and it requires highly specialized skills and technology. But think of the Human Genome Project and how much it accelerated the process of discovery and the whole field when infrastructures existed for people to share and compare. That was our motivation.”

How these subnetworks interact will provide a crucial baseline from which to better understand diseases of “disconnection” such as autism and Alzheimer’s disease, in which the manifestations of symptoms are potentially a result of disordered or damaged connections.

The researchers’ map of the mouse cerebral cortex can be compared to data on disease-affected brains, brains in development and genetic information. It will also offer necessary context for humans, who behaved just like other mammals only a few thousand years ago and who still share most underlying basic behavioral characteristics such as hunger and pain.

“The fundamental logic of mammalian brains is the same, particularly when it comes to basic behaviors such as eating, sleeping and social behaviors” said Dong, who noted that similar studies in humans have thus far not gotten to the cellular level. “There are lots of organizing principles to brain structures that we are just beginning to understand.”

The researchers identified the brain subnetworks based on their high degree of interconnectivity — though relatively independent, several structures provide communication routes through which the subnetworks interact. Combined with behavioral data from past research and information about subcortical targets, these interconnections imply remarkable functional significance for the subnetworks.

Four of the eight identified subnetworks in the mouse cortex relate to sensation and movement of the body — what the researchers dub somatic sensorimotor. In particular, the researchers identified separate subnetworks for movements in the face, upper limbs, lower limbs and trunk, and whiskers. Together, these networks facilitate motor behaviors such as eating and drinking, reaching and grabbing, locomotion and exploration of the environment.

Two other subnetworks are comprised of structures located along the midline of the cerebral cortex. These medial subnetworks seem devoted to the integration of visual, auditory and somatic sensory information, according to the study. Several other structures located along the side of the brain form two lateral subnetworks, one of which potentially serves to regulate the internal status of the body (i.e., taste, hunger, visceral information) and the other as a “mega-integration” subnetwork that allows the interaction of information from nearly the entire cortex.

Mapping objects in the brain

The ability to recognize objects in the environment is mediated by the brain’s ability to integrate and process massive amounts of visual information. A research group led by Takayuki Sato and Manabu Tanifuji from the RIKEN Brain Science Institute has now discovered that in macaque monkeys, this remarkable ability is supported by mosaic-like structures in the anterior inferior temporal (IT) cortex, where localized clusters of neurons encode different visual features in an organized hierarchy. 

Two competing models have been proposed to explain the functional organization of brain regions that underlies object recognition in primates. One model states that discrete brain ‘modules’ process stimuli from particular categories, such as faces, with object recognition arising from communication among the modules. The other model postulates that the visual cortex extracts generic features, which are then composited to recognize specific objects. Since both models are based on measurements of functional signals produced by metabolic changes associated with neural activity rather than measurements of the neuronal activity itself, the precise underlying mechanism responsible for object recognition has remained unclear.

To resolve this debate, the researchers undertook dense electrophysiological mapping of neural activity in anesthetized macaque monkeys exposed to a series of color images from different object categories: faces, hands, bodies, food and various other objects. Sato and his colleagues directly recorded neuronal activity from multiple locations within the anterior IT cortex, which allowed them to track the location of neurons that responded to a particular object category.

The team found that some regions responded best to faces and others to monkey bodies. While there were also regions that responded worst to faces, none appeared to respond preferentially to hands, food or manufactured items.

Interestingly, small neuron clusters within a region appeared to be selective to different facial features, responding differently to human and monkey faces and to scrambled and normal faces. This indicates that a region in the anterior IT cortex that is selective for an object category consists of smaller-scale neuron clusters that are selective for particular visual features.

“The cortical mosaics that encode visual information seem to be efficient functional structures where object-category information and information about constituent features are represented within the limited space of the brain,” explains Sato. “This could also be the way that the brain organizes information in other sensory modalities, such as hearing.” If the results are also found to extend to humans, they may offer insight into the visual recognition of objects and the development of language.

Focusing on Faces

Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals.

"We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team’s findings. “We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally.”

The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD.

By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown.

"It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment."

"We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs.

To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs.

"At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says.

Connections in the brains of young children strengthen during sleep

While young children sleep, connections between the left and the right hemispheres of their brain strengthen, which may help brain functions mature, according to a new study by the University of Colorado Boulder.

The research team—led by Salome Kurth, a postdoctoral researcher, and Monique LeBourgeois, assistant professor in integrative physiology—used electroencephalograms, or EEGs, to measure the brain activity of eight sleeping children multiple times at the ages of 2, 3 and 5 years.

“Interestingly, during a night of sleep, connections weakened within hemispheres but strengthened between hemispheres,” Kurth said.

Scientists have known that the brain changes drastically during early childhood: New connections are formed, others are removed and a fatty layer called “myelin” forms around nerve fibers in the brain. The growth of myelin strengthens the connections by speeding up the transfer of information.

Maturation of nerve fibers leads to improvement in skills such as language, attention and impulse control. But it is still not clear what role sleep plays in the development of such brain connections.

In the new study, appearing online in the journal Brain Sciences, the researchers looked at differences in brain activity during sleep as the children got older and differences in brain activity of each child over a night’s sleep. They found that connections in the brain generally became stronger during sleep as the children aged. They also found that the strength of the connections between the left and right hemispheres increased by as much as 20 percent over a night’s sleep.

“There are strong indications that sleep and brain maturation are closely related, but at this time, it is not known how sleep leads to changes in brain structure,” Kurth said.

Future studies will be aimed at determining how sleep disruption during childhood may affect brain development and behavior.

“I believe inadequate sleep in childhood may affect the maturation of the brain related to the emergence of developmental or mood disorders,” Kurth said.

Researchers Discover Idling Brain Activity in Severely Brain Injured Patients Who “Wake Up” After Using a Sleep Drug

George Melendez has been called a medical miracle. After a near drowning deprived his brain of oxygen, Melendez remained in a fitful, minimally conscious state until his mother, in 2002, decided to give him the sleep aid drug Ambien to quiet his moaning and writhing. The next thing she knew, her son was quietly looking at her and trying to talk. He has been using the drug ever since to maintain awareness, but no one could understand why Ambien led to such an awakening.

Now, a team of scientists led by Weill Cornell Medical College has discovered a signature of brain activity in Melendez and two other similarly “awakened” patients they say explain why he and others regain some consciousness after using Ambien or other drugs or treatments. The pattern of activity, reported Nov. 19 in the journal eLife, was identified by analyzing the common electroencephalography (EEG) test, which tracks brain waves.

"We found a surprisingly consistent picture of electrical activity in all three patients before they receive the drug. Most interesting is that their specific pattern of activity suggests a particular process occurring in the brain cells of the cerebral cortex and also supports the role of a crucial brain circuit," says the study’s senior investigator, Dr. Nicholas Schiff, the Jerold B. Katz Professor of Neurology and Neuroscience and professor of public health at Weill Cornell. "These findings may help predict other patients who might similarly harbor reserve capacity, whether they are able to respond to Ambien or other approaches." Dr. Schiff is also on the faculty of the Feil Family Brain and Mind Research Institute at Weill Cornell and is a neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"We are focused on finding ways to identify patients who have a functional reserve of cognitive capacities that can be rescued and how to achieve this result," Dr. Schiff adds. "These findings give us a very important lead to follow, and we will now rigorously test their implications in other patients."

Although it is not precisely known how many Americans are diagnosed as severely brain injured with disorders of consciousness, by one estimate there are nearly 300,000 patients trapped in a minimally conscious state who may retain some awareness, according to Dr. Schiff.

Riding a Wave of Excitation

The three patients in the study suffered brain damage in different ways. One fell and the other had a brain aneurysm that led to multiple strokes. Melendez was in a car accident that led to his nearly drowning. All three patients — two men and a woman — become aware when Ambien was used, a rare response that has been documented in fewer than 15 brain-injured patients.

The research team, which included scientists from Memorial Sloan-Kettering Cancer Center, Boston University School of Medicine, and the University Hospital of Liège in Belgium, used EEG to measure electrical activity in the patients’ brains before and after they were given the drug.

Although each patient’s brain was damaged in different ways, all showed the same unique features of low frequency waves in their EEG readings. These low frequency oscillations are most prominent over the frontal cortex, a region strongly dependent for its activity on other brain structures, particularly the central thalamus and the striatum, which together support short-term memory, reward, motivation, attention, alertness and sleep, among other functions.

In this setting of an idling brain, the investigators propose that Ambien works like any anesthesia drug, in that it briefly triggers a fast wave of excitation in brain cells before producing sleep — a phenomenon known as paradoxical excitation. Instead of going on to produce sedation and sleep, as it does in healthy people who use the drug, zolpidem further activates the brain after it’s affected the idling cells, allowing the patients to become more awake than at baseline. “What we think is happening in these patients is that the initial excitation produced by Ambien turns on a specific circuit. The drug creates the opportunity for the brain to effectively catch a ride on this initial wave of excitation, and turn itself back on,” Dr. Schiff says.

This proposed “mesocircuit” links the cortical regions of the brain to the central thalamus and striatum. Neurons in the central thalamus are highly connected to other parts of the brain, “so damage in one part of the brain or another will affect the thalamus, which is key to consciousness,” Dr. Schiff says. Neurons in the striatum “will only fire if there is a lot of electrical input coming to them quickly,” he says.

"We believe the switch that Ambien turns on is at the level of the joint connections between these three brain structures," Dr. Schiff says.

The pattern of brain activity seen in the EEG on Ambien was also the same in all the patients in the study. But the circuit turns off again when the effects of the drug diminish. Using the drug regularly at mealtimes, Melendez can speak fluently, and read and write simple phrases. His tremors and spasticity are significantly reduced on Ambien and he can use objects, such as a spoon, and is alert and can communicate. The first patient in the study can reliably move from minimally conscious to “the mid-range of what is called a confusional state — a more alert status, but not full consciousness,” Dr. Schiff says. “Use of Ambien offers a step in the right direction, but certainly not a cure.”

Different Ways to Kick-Start the Brain

The resting EEG pattern the researchers saw in the patients indicates they have a “recruitable reserve” of function in these critical brain areas that Ambien can harness to turn the brain on, even if only temporarily. “The idea is that hopefully we can screen other patients with EEG to find out if they also have such a reserve,” Dr. Schiff says.

And while some of these patients may not respond to Ambien — as the drug works at a very specific brain receptor and individuals can vary considerably in having enough of it in the key components of the proposed circuit — other drugs may target the same structures and potentially produce similar effects, he says. For example, two drugs (amantadine and L-Dopa) that provide extra dopamine, a brain chemical that fuels the part of the brain damaged in the study’s patients, have been shown to have similar effects on restoring function in patients with severe brain injuries, as has electrical brain stimulation of the central thalamus.

"Now that we have uncovered important insight into fundamental mechanisms underlying the dramatic and rare response of some severely brain-injured patients to Ambien, we hope to systematically explore ways to achieve such kick-starts in other patients — that is our goal," Dr. Schiff says.

(Image credit)