Neuroscience

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Posts tagged neuroimaging

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The brain is alive, will new MRI diffusion techniques let us see it move and shake?

Pioneering experiments back in 1982 by Tasaki and Iwasa at the NIH revealed that action potentials in neurons are more than just the electrical blips that physiologists readily amplify and record. These so-called “spikes” are in fact multi-modal signalling packages that include mechanical and thermal disturbances propagating down the axon at their own rates. Nobel Laureate Francis Crick published a paper that same year, in which he postulated potential mechanisms that would explain twitching in dendritic spines, adding to an emerging picture of a brain more vibrant and motile than had been previously imagined. More recently, researchers have developed diffusion-based MRI methods, like diffusion tensor imaging (DTI), to trace the trajectories of axons, and perhaps more intriguingly, determine their directional polarity. Working at the EPFL in Switzerland, Denis Le Bihan and his co-workers have been using diffusional MRI in slightly different way. They now appear to be able to directly measure neuronal activity from the subtle movements of membranes, the water within them, and in the extracellular space around them. Their work, just published in PNAS, provides a much needed conceptual shift away from currently established, but typically nebulous, ideas regarding neurovascular coupling of brain activity to blood flow.

image

Present-day imaging methods, like blood oxygen level-dependent (BOLD) MRI, are only indirectly and remotely related to the cortical activity they often claim to measure. In 2006, Le Bihan reported a water “phase transition” response that preceded the neurovascular response normally detected by functional MRI. He attributed the changes in water diffusion to previously established effects involving membrane expansion and cell swelling secondary to activity. At the biophysical level, interpreting action potentials as phase transitions is a little off the beaten path from traditional neurobiology, but it can be an informative approach when to trying to understand what might be going on when cells fire.

As biophysicist Gerald Pollack has previously pointed out, spikes may involve the propagation of the line of transition of water from the ordered phase, (as patterned by hydrophic interactions nucleated at the surfaces of membranes and proteins) to a disordered phase.
Traditionally, the so-called bound surface water only extends out a only a couple of molecules from the surface of nondiffusable features. That idea may need to be revisited in light of more recent understanding when attempting to account for the diffusion of water in axons. A decrease in water diffusion as measured by MRI may be in part explained by a decrease in extracellular space, and that has been suggested from experiments measuring intrinsic optical effects. The larger picture of water diffusion, however, is likely a bit more complicated than this.

In his new study, Le Bihan stimulated the forepaw of a rat and looked at responses in the somatosensory cortex. The key experiment was to infuse nitroprusside in attempt to inhibit neurovascular coupling. It is a tricky alteration because nitroprusside apparently has many diffuse effects. It can induce potent vasodilation, particularly on the vascular end (mainly the smaller venules), after it breaks down to produce nitric oxide. It is also a diamagnetic molecule, and each molecule releases five cyanide ions, which are presumably detoxified by the mitochondrial enzyme rhodanese. The experiments were done under isoflurane anesthesia, which also introduces a few uncertainties, particularly with regard to responses to different frequencies of forepaw stimulation.

If nitroprusside is indeed a realistic experimental proxy for neurovascular uncoupling, then the results of Le Bihan appear to show that the diffusion response is not of vascular origin, and that it is closely linked to neural activation. He found that the standard BOLD MRI responses were completely quenched under nitroprusside, whereas the diffusion MRI responses were only slightly suppressed. Local field potentials were also simultaneously measured and suggested at least, that the neuronal responses were also intact.

The work of Le Bihan indicates that diffusion-based MRI can be used to infer neural activity directly from the structural changes that affect the molecular displacements of water. The ability to use shape changes in neurons, astrocytes, or even spines, raises the question of whether these kinds of techniques might eventually be of use in creating larger scale, and more detailed, Brain Activity Maps (BAMs). I asked Konrad Kording, author on the recent theoretical paper which discussed the theoretical limits to MRI and other activity recording methods, whether methods that probe water movements might be applied to this end.

Kording observed that the spatial resolution of standard MRI is ultimately limited by the diffusion of water, but more importantly perhaps, the temporal resolution of all known MRI methods is nowhere near that required to create spike maps. None-the-less, detecting mechanical responses in the brain could provide many unique insights into function. For example, experiments using agents that dissolve the extracellular matrix, like the clot-busting drug TPA, result in more twitching, or vibration if you will, in dendritic spines. Other studies have shown that the greater the electrical drive on a spine, the less it tends to twitch or change size, particularly during periods of rapid development.

Similarly, sensory deprivations appear to increase these kinds of movements as neurons grow and reorganize connections. While these effects are far below that which could be detected by any large external method of MRI, new tools may permit us to access these newly-revealed activities. Diffusional MRI in particular, can be done with a little modification of the standard MRI procedure. For example, to determine directional diffusion parameters, or diffusion tensors, typically six gradients are used to measure three directional vectors. As these capabilities become more common, hopefully the results of Le Bihan can be further explored and verified.

Filed under brain activity blood flow neuroimaging diffusion tensor imaging cortical activity neuroscience science

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Visualizing a memory trace Whole brain imaging of zebrafish reveals neuronal networks involved in retrieving long-term memories during decision making In mammals, a neural pathway called the cortico-basal ganglia circuit is thought to play an important role in the choice of behaviors. However, where and how behavioral programs are written, stored and read out as a memory within this circuit remains unclear. A research team led by Hitoshi Okamoto and Tazu Aoki of the RIKEN Brain Science Institute has for the first time visualized in zebrafish the neuronal activity associated with the retrieval of long-term memories during decision making. The team performed experiments on genetically engineered zebrafish expressing a fluorescent protein that changes its intensity when it binds to calcium ions in neurons and thereby acts as an indicator of neuronal activity. “Neurons in the fish cortical region form a neural circuit similar to the mammalian cortico-basal ganglia circuit,” says Okamoto. The fish were trained on an avoidance task by placing individual fish into a two-compartment tank and shining a red light for several seconds into the compartment containing the fish. If the fish did not move into the other compartment in response to the light, it was ‘punished’ with a mild electric shock. After several repetitions, the fish learned to avoid the shock by switching compartments as soon as the light came on.  The researchers then examined the neuronal activity of the fish under the microscope in response to exposure to red light. One day after the learning task, the fish showed specific activity in a discrete region of the telencephalon, which corresponds to the cerebral cortex in mammals, when presented with the red light. However, just 30 minutes after the learning task no activity was observed in this part of the brain. The results suggest that this telencephalonic area encodes the long-term memory for the learned avoidance behavior. Confirming this, removing this part of the telencephalon abolished the long-term memory but did not affect learning or short-term storage of the memory.  In humans, the ability to choose the correct behavioral programs in response to environmental changes is indispensable for everyday life, and the ability to do so is thought to be impaired in various psychiatric conditions such as depression and schizophrenia.  “Combining the neural imaging technique with genetics, we will be able to investigate how neurons in the cortico-basal ganglia circuit choose the most suitable behavior in any given situation,” says Okamoto. “Our findings open the way to investigate and understand how these symptoms appear in human psychiatric disorders.”

Visualizing a memory trace

Whole brain imaging of zebrafish reveals neuronal networks involved in retrieving long-term memories during decision making

In mammals, a neural pathway called the cortico-basal ganglia circuit is thought to play an important role in the choice of behaviors. However, where and how behavioral programs are written, stored and read out as a memory within this circuit remains unclear. A research team led by Hitoshi Okamoto and Tazu Aoki of the RIKEN Brain Science Institute has for the first time visualized in zebrafish the neuronal activity associated with the retrieval of long-term memories during decision making.

The team performed experiments on genetically engineered zebrafish expressing a fluorescent protein that changes its intensity when it binds to calcium ions in neurons and thereby acts as an indicator of neuronal activity. “Neurons in the fish cortical region form a neural circuit similar to the mammalian cortico-basal ganglia circuit,” says Okamoto.

The fish were trained on an avoidance task by placing individual fish into a two-compartment tank and shining a red light for several seconds into the compartment containing the fish. If the fish did not move into the other compartment in response to the light, it was ‘punished’ with a mild electric shock. After several repetitions, the fish learned to avoid the shock by switching compartments as soon as the light came on. 

The researchers then examined the neuronal activity of the fish under the microscope in response to exposure to red light. One day after the learning task, the fish showed specific activity in a discrete region of the telencephalon, which corresponds to the cerebral cortex in mammals, when presented with the red light. However, just 30 minutes after the learning task no activity was observed in this part of the brain. The results suggest that this telencephalonic area encodes the long-term memory for the learned avoidance behavior. Confirming this, removing this part of the telencephalon abolished the long-term memory but did not affect learning or short-term storage of the memory. 

In humans, the ability to choose the correct behavioral programs in response to environmental changes is indispensable for everyday life, and the ability to do so is thought to be impaired in various psychiatric conditions such as depression and schizophrenia. 

“Combining the neural imaging technique with genetics, we will be able to investigate how neurons in the cortico-basal ganglia circuit choose the most suitable behavior in any given situation,” says Okamoto. “Our findings open the way to investigate and understand how these symptoms appear in human psychiatric disorders.”

Filed under zebrafish brain activity telencephalon memory LTM neuroimaging neurons neuroscience science

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A fundamental problem for brain mapping Recent findings force scientists to rethink the rules of neuroimaging Is there a brain area for mind-wandering? For religious experience? For reorienting attention? A recent study casts serious doubt on the evidence for these ideas, and rewrites the rules for neuroimaging. Brain mapping experiments attempt to identify the cognitive functions associated with discrete cortical regions. They generally rely on a method known as “cognitive subtraction.” However, recent research reveals a basic assumption underlying this approach—that brain activation is due to the additional processes triggered by the experimental task—is wrong “It is such a basic assumption that few researchers have even thought to question it,” said Anthony Jack, assistant professor of cognitive science at Case Western Reserve University. “Yet study after study has produced evidence it is false.” Brain mapping experiments all share a basic logic. In the simplest type of experiment, researchers compare brain activity while participants perform an experimental task and a control task. The experimental task might involve showing participants a noun, such as the word “cake,” and asking them to say aloud a verb that goes with that noun, for instance “eat.” The control task might involve asking participants to simply say the word they see aloud. “The idea here is that the control task involves some of the same cognitive processes as the experimental task, in this case perceptual and articulatory processes,” Jack explained. “But there is at least one process that is different—the act of selecting a semantically appropriate word from a different lexical category.” By subtracting activity recorded during the control task from the experimental task, researchers try to isolate distinct cognitive processes and map them onto specific brain areas. Jack and former Case Western Reserve student Benjamin Kubit, now at the University of California Davis, challenge a key assumption of the subtraction method and several tenets of Ventral Attention Network theory, one of the longest established theories in cognitive neuroscience and which relies on cognitive subtraction. In a paper published today in Frontiers in Human Neuroscience, they highlight a new and additional problem that casts doubt on papers from well-established laboratories published in top journals. Jack’s previous research shows that that two opposing networks in the brain prevent people from being empathetic and analytic at the same time. If participants are engaged in a non-social task, they suppress activity in a network known as the default mode network, or DMN. The moment that task is over, activity in the DMN bounces back up again. On the other hand, if participants are engaged in a social task, they suppress brain activity in a second network, known as the task positive network, or TPN. The moment that task is over, activity in the TPN bounces back up again. Work by another group even shows activity in a network bounces higher the more it has been suppressed, rather like releasing a compressed spring. “It’s clear these increases in activity are not due to additional task-related processes,” Jack said. “Instead of cognitive subtraction, what we are seeing here is cognitive addition—parts of the brain do more the less the task demands.” Kubit and Jack caution that researchers must consider whether an increase in activity in a suppressed region is due to task-related processing, or the release of suppression, if they want to accurately interpret their data. In the paper, they lay out data from other studies, meta-analysis and resting connectivity that all suggest activation of a particular brain area, the right temporoparietal junction (rTPJ), in attention reorienting tasks can be most simply explained by the release of suppression. Based on that, “We haven’t shown that Ventral Attention Network theory is false,” Jack said, “but we have raised a big question mark over the theory and the evidence that has been taken to support it.” The working hypothesis for more than a decade has been that the basic function of the rTPJ is attention reorienting. But, upon considering the possibility of cognitive addition as well as cognitive subtraction, the evidence supporting this view looks slim, the researchers assert. “The evidence is compelling that there are two distinct areas near rTPJ - regions which are not only involved in distinct functions but which also tend to suppress each other,” Jack said. “There is no easy way to square this with the Ventral Attention Network account of rTPJ.” A number of broad challenges to brain imaging have been raised in the past by psychologists and philosophers, and in the recent book Brainwashed: The Seductive Appeal of Mindless Neuroscience, by Sally Satel and Scott Lilienfeld. One of the most popular objections has been to liken brain mapping to phrenology. “There was some truth to that, particularly in the early days” Jack said. Brain mapping can run afoul because the psychological category it assigns to a region don’t represent basic functions. For instance, the claim that there is a “God spot” in the brain doesn’t reflect a mature understanding of the science, he continued. Researchers recognize that individual brain regions have more general functions, and that specific cognitive processes, like religious experiences, are realized by interactions between distributed networks of regions. “Just because a brain region is involved in a cognitive process, for example that the rTPJ is involved in out-of-body experiences, doesn’t mean that out-of-body experiences are the basic function of the rTPJ,” Jack explained. “You need to look at all the cognitive processes that engage a region to get a truer idea of its basic function.” Kubit and Jack go beyond the existing critiques that apply to naïve brain mapping. The researchers point out that, even when an experimental task creates more activity in a brain region than a control task, it still isn’t safe to assume that the brain area is involved in the additional cognitive processes engaged by the experimental task. “Another possibility is that the control task was suppressing the region more than the experimental task,” Jack said. For example, Malia Mason et al’s widely cited 2007 publication that appeared in the journal Science used the logic of cognitive subtraction to reach the conclusion that the function of a large area of cortex, known as the default mode network (DMN), is mind-wandering or spontaneous cognition. “At this point, we can safely rule out that interpretation,” Jack said. “The DMN is activated above resting levels for social tasks that engage empathy. So, unless tasks that engage empathetic social cognition involve more mind-wandering than—well—being at rest and letting your mind wander, then that interpretation can’t possibly be right. The right way to interpret those findings is that tasks that engage analytic thinking positively suppress empathy. Unsurprisingly, when your mind wanders from those tasks, you get less suppression.” The pair believes one reason researchers have felt safe with the assumptions underlying cognitive subtraction is that they have assumed the brain will not expend any more energy than is needed to perform the task at hand. “Yet the brain clearly does expend more energy than is needed to guide ongoing behavior,” Jack said. “The influential neurologist Marcus Raichle has shown that task-related activity represents the tip of the iceberg, in terms of neural and metabolic activity. The brain is constantly active and restless, even when the person is entirely ‘at rest’ —that is, even when they aren’t given any task to do.” Jack said their critique won’t hurt brain imaging as a discipline. “Quite the reverse, understanding the full implications of the suppressive relationship between brain networks will move the discipline forward.” “One of the best known theories in psychology is dual-process theory,” he continued. “But the opposing-networks findings suggest a quite different picture from the account favored by psychologists.” Dual process theory is outlined in the recent book Thinking Fast and Slow by the Nobel prize-winner Daniel Kahneman. Classic dual-process theory postulates a fight between deliberate reasoning and primitive automatic processes. But the fight that is most obvious in the brain is between two types of deliberate and evolutionarily advanced reasoning – one for empathetic, the other for analytic thought, the researchers say. The two theories are compatible. “But, it looks like a number of phenomena will be better explained by the opposing networks research,” Jack said. Jack warned that to conclude this critique of cognitive subtraction and Ventral Attention Network theory shows that brain imaging is fundamentally flawed would be like claiming that critiques of Darwin’s theory show evolution is false. Brain mapping, Jack believes, was just the first phase of this science. “What we are talking about here is refining the science,” he said. “It should be no surprise that that journey involves some course corrections. The key point is that we are moving from brain mapping to identifying neural constraints on cognition that behavioral psychologists have missed.” (Image: Saad Faruque, Flickr)

A fundamental problem for brain mapping

Recent findings force scientists to rethink the rules of neuroimaging

Is there a brain area for mind-wandering? For religious experience? For reorienting attention? A recent study casts serious doubt on the evidence for these ideas, and rewrites the rules for neuroimaging.

Brain mapping experiments attempt to identify the cognitive functions associated with discrete cortical regions. They generally rely on a method known as “cognitive subtraction.” However, recent research reveals a basic assumption underlying this approach—that brain activation is due to the additional processes triggered by the experimental task—is wrong

“It is such a basic assumption that few researchers have even thought to question it,” said Anthony Jack, assistant professor of cognitive science at Case Western Reserve University. “Yet study after study has produced evidence it is false.”

Brain mapping experiments all share a basic logic. In the simplest type of experiment, researchers compare brain activity while participants perform an experimental task and a control task. The experimental task might involve showing participants a noun, such as the word “cake,” and asking them to say aloud a verb that goes with that noun, for instance “eat.” The control task might involve asking participants to simply say the word they see aloud.

“The idea here is that the control task involves some of the same cognitive processes as the experimental task, in this case perceptual and articulatory processes,” Jack explained. “But there is at least one process that is different—the act of selecting a semantically appropriate word from a different lexical category.”

By subtracting activity recorded during the control task from the experimental task, researchers try to isolate distinct cognitive processes and map them onto specific brain areas.

Jack and former Case Western Reserve student Benjamin Kubit, now at the University of California Davis, challenge a key assumption of the subtraction method and several tenets of Ventral Attention Network theory, one of the longest established theories in cognitive neuroscience and which relies on cognitive subtraction. In a paper published today in Frontiers in Human Neuroscience, they highlight a new and additional problem that casts doubt on papers from well-established laboratories published in top journals.

Jack’s previous research shows that that two opposing networks in the brain prevent people from being empathetic and analytic at the same time. If participants are engaged in a non-social task, they suppress activity in a network known as the default mode network, or DMN. The moment that task is over, activity in the DMN bounces back up again. On the other hand, if participants are engaged in a social task, they suppress brain activity in a second network, known as the task positive network, or TPN. The moment that task is over, activity in the TPN bounces back up again.

Work by another group even shows activity in a network bounces higher the more it has been suppressed, rather like releasing a compressed spring.

“It’s clear these increases in activity are not due to additional task-related processes,” Jack said. “Instead of cognitive subtraction, what we are seeing here is cognitive addition—parts of the brain do more the less the task demands.”

Kubit and Jack caution that researchers must consider whether an increase in activity in a suppressed region is due to task-related processing, or the release of suppression, if they want to accurately interpret their data. In the paper, they lay out data from other studies, meta-analysis and resting connectivity that all suggest activation of a particular brain area, the right temporoparietal junction (rTPJ), in attention reorienting tasks can be most simply explained by the release of suppression.

Based on that, “We haven’t shown that Ventral Attention Network theory is false,” Jack said, “but we have raised a big question mark over the theory and the evidence that has been taken to support it.”

The working hypothesis for more than a decade has been that the basic function of the rTPJ is attention reorienting. But, upon considering the possibility of cognitive addition as well as cognitive subtraction, the evidence supporting this view looks slim, the researchers assert. “The evidence is compelling that there are two distinct areas near rTPJ - regions which are not only involved in distinct functions but which also tend to suppress each other,” Jack said. “There is no easy way to square this with the Ventral Attention Network account of rTPJ.”

A number of broad challenges to brain imaging have been raised in the past by psychologists and philosophers, and in the recent book Brainwashed: The Seductive Appeal of Mindless Neuroscience, by Sally Satel and Scott Lilienfeld. One of the most popular objections has been to liken brain mapping to phrenology.

“There was some truth to that, particularly in the early days” Jack said. Brain mapping can run afoul because the psychological category it assigns to a region don’t represent basic functions.

For instance, the claim that there is a “God spot” in the brain doesn’t reflect a mature understanding of the science, he continued. Researchers recognize that individual brain regions have more general functions, and that specific cognitive processes, like religious experiences, are realized by interactions between distributed networks of regions.

“Just because a brain region is involved in a cognitive process, for example that the rTPJ is involved in out-of-body experiences, doesn’t mean that out-of-body experiences are the basic function of the rTPJ,” Jack explained. “You need to look at all the cognitive processes that engage a region to get a truer idea of its basic function.”

Kubit and Jack go beyond the existing critiques that apply to naïve brain mapping. The researchers point out that, even when an experimental task creates more activity in a brain region than a control task, it still isn’t safe to assume that the brain area is involved in the additional cognitive processes engaged by the experimental task. “Another possibility is that the control task was suppressing the region more than the experimental task,” Jack said.

For example, Malia Mason et al’s widely cited 2007 publication that appeared in the journal Science used the logic of cognitive subtraction to reach the conclusion that the function of a large area of cortex, known as the default mode network (DMN), is mind-wandering or spontaneous cognition.

“At this point, we can safely rule out that interpretation,” Jack said. “The DMN is activated above resting levels for social tasks that engage empathy. So, unless tasks that engage empathetic social cognition involve more mind-wandering than—well—being at rest and letting your mind wander, then that interpretation can’t possibly be right. The right way to interpret those findings is that tasks that engage analytic thinking positively suppress empathy. Unsurprisingly, when your mind wanders from those tasks, you get less suppression.”

The pair believes one reason researchers have felt safe with the assumptions underlying cognitive subtraction is that they have assumed the brain will not expend any more energy than is needed to perform the task at hand.

“Yet the brain clearly does expend more energy than is needed to guide ongoing behavior,” Jack said. “The influential neurologist Marcus Raichle has shown that task-related activity represents the tip of the iceberg, in terms of neural and metabolic activity. The brain is constantly active and restless, even when the person is entirely ‘at rest’ —that is, even when they aren’t given any task to do.”

Jack said their critique won’t hurt brain imaging as a discipline. “Quite the reverse, understanding the full implications of the suppressive relationship between brain networks will move the discipline forward.”

“One of the best known theories in psychology is dual-process theory,” he continued. “But the opposing-networks findings suggest a quite different picture from the account favored by psychologists.”

Dual process theory is outlined in the recent book Thinking Fast and Slow by the Nobel prize-winner Daniel Kahneman. Classic dual-process theory postulates a fight between deliberate reasoning and primitive automatic processes. But the fight that is most obvious in the brain is between two types of deliberate and evolutionarily advanced reasoning – one for empathetic, the other for analytic thought, the researchers say.

The two theories are compatible. “But, it looks like a number of phenomena will be better explained by the opposing networks research,” Jack said.

Jack warned that to conclude this critique of cognitive subtraction and Ventral Attention Network theory shows that brain imaging is fundamentally flawed would be like claiming that critiques of Darwin’s theory show evolution is false.

Brain mapping, Jack believes, was just the first phase of this science. “What we are talking about here is refining the science,” he said. “It should be no surprise that that journey involves some course corrections. The key point is that we are moving from brain mapping to identifying neural constraints on cognition that behavioral psychologists have missed.”

(Image: Saad Faruque, Flickr)

Filed under brain mapping neuroimaging brain activity cognitive subtraction neuroscience science

134 notes

Breakthrough Study Reveals Biological Basis for Sensory Processing Disorders in Kids Sensory processing disorders (SPD) are more prevalent in children than autism and as common as attention deficit hyperactivity disorder, yet it receives far less attention partly because it’s never been recognized as a distinct disease. In a groundbreaking new study from UC San Francisco, researchers have found that children affected with SPD have quantifiable differences in brain structure, for the first time showing a biological basis for the disease that sets it apart from other neurodevelopmental disorders. One of the reasons SPD has been overlooked until now is that it often occurs in children who also have ADHD or autism, and the disorders have not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists. “Until now, SPD hasn’t had a known biological underpinning,” said senior author Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging and bioengineering at UCSF. “Our findings point the way to establishing a biological basis for the disease that can be easily measured and used as a diagnostic tool,” Mukherjee said. The work is published in the open access online journal NeuroImage:Clinical. ‘Out of Sync’ Kids Sensory processing disorders affect 5 to 16 percent of school-aged children. Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with social interaction. Furthermore, a sound that one day is an irritant can the next day be sought out.  The disease can be baffling for parents and has been a source of much controversy for clinicians, according to the researchers. “Most people don’t know how to support these kids because they don’t fall into a traditional clinical group,” said Elysa Marco, MD, who led the study along with postdoctoral fellow Julia Owen, PhD. Marco is a cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital, ranked among the nation’s best and one of California’s top-ranked centers for neurology and other specialties, according to the 2013-2014 U.S. News & World Report Best Children’s Hospitals survey. “Sometimes they are called the ‘out of sync’ kids. Their language is good, but they seem to have trouble with just about everything else, especially emotional regulation and distraction. In the real world, they’re just less able to process information efficiently, and they get left out and bullied,” said Marco, who treats affected children in her cognitive and behavioral neurology clinic. “If we can better understand these kids who are falling through the cracks, we will not only help a whole lot of families, but we will better understand sensory processing in general. This work is laying the foundation for expanding our research and clinical evaluation of children with a wide range of neurodevelopmental challenges – stretching beyond autism and ADHD,” she said. Imaging the Brain’s White Matter In the study, researchers used an advanced form of MRI called diffusion tensor imaging (DTI), which measures the microscopic movement of water molecules within the brain in order to give information about the brain’s white matter tracts. DTI shows the direction of the white matter fibers and the integrity of the white matter. The brain’s white matter is essential for perceiving, thinking and learning. The study examined 16 boys, between the ages of eight and 11, with SPD but without a diagnosis of autism or prematurity, and compared the results with 24 typically developing boys who were matched for age, gender, right- or left-handedness and IQ. The patients’ and control subjects’ behaviors were first characterized using a parent report measure of sensory behavior called the Sensory Profile.  The imaging detected abnormal white matter tracts in the SPD subjects, primarily involving areas in the back of the brain, that serve as connections for the auditory, visual and somatosensory (tactile) systems involved in sensory processing, including their connections between the left and right halves of the brain.  “These are tracts that are emblematic of someone with problems with sensory processing,” said Mukherjee. “More frontal anterior white matter tracts are typically involved in children with only ADHD or autistic spectrum disorders. The abnormalities we found are focused in a different region of the brain, indicating SPD may be neuroanatomically distinct.”  The researchers found a strong correlation between the micro-structural abnormalities in the white matter of the posterior cerebral tracts focused on sensory processing and the auditory, multisensory and inattention scores reported by parents in the Sensory Profile. The strongest correlation was for auditory processing, with other correlations observed for multi-sensory integration, vision, tactile and inattention. The abnormal microstructure of sensory white matter tracts shown by DTI in kids with SPD likely alters the timing of sensory transmission so that processing of sensory stimuli and integrating information across multiple senses becomes difficult or impossible. “We are just at the beginning, because people didn’t believe this existed,” said Marco. “This is absolutely the first structural imaging comparison of kids with research diagnosed sensory processing disorder and typically developing kids. It shows it is a brain-based disorder and gives us a way to evaluate them in clinic.” Future studies need to be done, she said, to research the many children affected by sensory processing differences who have a known genetic disorder or brain injury related to prematurity.

Breakthrough Study Reveals Biological Basis for Sensory Processing Disorders in Kids

Sensory processing disorders (SPD) are more prevalent in children than autism and as common as attention deficit hyperactivity disorder, yet it receives far less attention partly because it’s never been recognized as a distinct disease.

In a groundbreaking new study from UC San Francisco, researchers have found that children affected with SPD have quantifiable differences in brain structure, for the first time showing a biological basis for the disease that sets it apart from other neurodevelopmental disorders.

One of the reasons SPD has been overlooked until now is that it often occurs in children who also have ADHD or autism, and the disorders have not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists.

“Until now, SPD hasn’t had a known biological underpinning,” said senior author Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging and bioengineering at UCSF. “Our findings point the way to establishing a biological basis for the disease that can be easily measured and used as a diagnostic tool,” Mukherjee said.

The work is published in the open access online journal NeuroImage:Clinical.

‘Out of Sync’ Kids

Sensory processing disorders affect 5 to 16 percent of school-aged children.

Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with social interaction. Furthermore, a sound that one day is an irritant can the next day be sought out.  The disease can be baffling for parents and has been a source of much controversy for clinicians, according to the researchers.

“Most people don’t know how to support these kids because they don’t fall into a traditional clinical group,” said Elysa Marco, MD, who led the study along with postdoctoral fellow Julia Owen, PhD. Marco is a cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital, ranked among the nation’s best and one of California’s top-ranked centers for neurology and other specialties, according to the 2013-2014 U.S. News & World Report Best Children’s Hospitals survey.

“Sometimes they are called the ‘out of sync’ kids. Their language is good, but they seem to have trouble with just about everything else, especially emotional regulation and distraction. In the real world, they’re just less able to process information efficiently, and they get left out and bullied,” said Marco, who treats affected children in her cognitive and behavioral neurology clinic.

“If we can better understand these kids who are falling through the cracks, we will not only help a whole lot of families, but we will better understand sensory processing in general. This work is laying the foundation for expanding our research and clinical evaluation of children with a wide range of neurodevelopmental challenges – stretching beyond autism and ADHD,” she said.

Imaging the Brain’s White Matter

In the study, researchers used an advanced form of MRI called diffusion tensor imaging (DTI), which measures the microscopic movement of water molecules within the brain in order to give information about the brain’s white matter tracts. DTI shows the direction of the white matter fibers and the integrity of the white matter. The brain’s white matter is essential for perceiving, thinking and learning.

The study examined 16 boys, between the ages of eight and 11, with SPD but without a diagnosis of autism or prematurity, and compared the results with 24 typically developing boys who were matched for age, gender, right- or left-handedness and IQ. The patients’ and control subjects’ behaviors were first characterized using a parent report measure of sensory behavior called the Sensory Profile. 

The imaging detected abnormal white matter tracts in the SPD subjects, primarily involving areas in the back of the brain, that serve as connections for the auditory, visual and somatosensory (tactile) systems involved in sensory processing, including their connections between the left and right halves of the brain. 

“These are tracts that are emblematic of someone with problems with sensory processing,” said Mukherjee. “More frontal anterior white matter tracts are typically involved in children with only ADHD or autistic spectrum disorders. The abnormalities we found are focused in a different region of the brain, indicating SPD may be neuroanatomically distinct.” 

The researchers found a strong correlation between the micro-structural abnormalities in the white matter of the posterior cerebral tracts focused on sensory processing and the auditory, multisensory and inattention scores reported by parents in the Sensory Profile. The strongest correlation was for auditory processing, with other correlations observed for multi-sensory integration, vision, tactile and inattention.

The abnormal microstructure of sensory white matter tracts shown by DTI in kids with SPD likely alters the timing of sensory transmission so that processing of sensory stimuli and integrating information across multiple senses becomes difficult or impossible.

“We are just at the beginning, because people didn’t believe this existed,” said Marco. “This is absolutely the first structural imaging comparison of kids with research diagnosed sensory processing disorder and typically developing kids. It shows it is a brain-based disorder and gives us a way to evaluate them in clinic.”

Future studies need to be done, she said, to research the many children affected by sensory processing differences who have a known genetic disorder or brain injury related to prematurity.

Filed under autism ADHD neurodevelopmental disorders white matter neuroimaging neuroscience science

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Irreversible tissue loss seen within 40 days of spinal cord injury The rate and extent of damage to the spinal cord and brain following spinal cord injury have long been a mystery. Now, a joint research effort between the University of Zurich, University Hospital Balgrist and colleagues from University College London have found evidence that patients already have irreversible tissue loss in the spinal cord within 40 days of injury. Using a new imaging measurement technique the impact of therapeutic treatments and rehabilitative interventions can be now determined more quickly and directly than before. A spinal cord injury changes the functional state and structure of the spinal cord and the brain. For example, the patients’ ability to walk or move their hands can become restricted. How quickly such degenerative changes develop, however, has remained a mystery until now. The assumption was that it took years for patients with a spinal cord injury to also display anatomical changes in the spinal cord and brain above the injury site. For the first time, researchers from the University of Zurich and the Uniklinik Balgrist, along with English colleagues from University College London (UCL), now demonstrate that these changes already occur within 40 days of acute spinal cord injury. Spinal cord depletes rapidly The scientists studied 13 patients with acute spinal cord injuries every three months for a year using novel MRI (magnetic resonance imaging) protocols. They discovered that the diameter of the spinal cord had rapidly decreased and was already seven percent smaller after twelve months. A lesser volume decline was also evident in the corticospinal tract, a tract indispensable for motor control, and nerve cells in the sensorimotor cortex. The extent of the degenerative changes coincided with the clinical outcome. “Patients with a greater tissue loss above the injury site recovered less effectively than those with less changes,” explains Patrick Freund, the investigator responsible for the study at the Paraplegic Center Balgrist. Gaining insights into effect of therapies Treatments targeting the injured spinal cord have entered clinical trials. Gaining insights into mechanisms of repair and recovery within the first year are crucial. Thanks to the use of the new neuroimaging protocols, Freund says, we now have the possibility of displaying the effect of therapeutic treatments on the central nervous system and of rehabilitative measures more quickly. Consequently, the effect of new therapies can also be recorded more rapidly. “This study is an excellent example of the value of combining the complementary expertise of the two universities,” says UCL’s Dean of Brain Sciences, Professor Alan Thompson, who is one of the senior authors of the study. “It provides exciting new insights into the complications of spinal cord trauma and gives us the possibility of identifying both imaging biomarkers and therapeutic targets.” The findings are the result of a new three-year neuroscience partnership between the Neuroscience Centre Zurich (ZNZ) and UCL. Literature: Patrick Freund, Nikolaus Weiskopf, John Ashburner, Katharina Wolf, Reto Sutter, Daniel R Altmann, Karl Friston, Alan Thompson, Armin Curt. MRI investigation of the sensorimotor cortex and corticospinal tract after acute spinal cord injury: a prospective longitudinal study. The Lancet Neurology. July 2, 2013.

Irreversible tissue loss seen within 40 days of spinal cord injury

The rate and extent of damage to the spinal cord and brain following spinal cord injury have long been a mystery. Now, a joint research effort between the University of Zurich, University Hospital Balgrist and colleagues from University College London have found evidence that patients already have irreversible tissue loss in the spinal cord within 40 days of injury. Using a new imaging measurement technique the impact of therapeutic treatments and rehabilitative interventions can be now determined more quickly and directly than before.

A spinal cord injury changes the functional state and structure of the spinal cord and the brain. For example, the patients’ ability to walk or move their hands can become restricted. How quickly such degenerative changes develop, however, has remained a mystery until now. The assumption was that it took years for patients with a spinal cord injury to also display anatomical changes in the spinal cord and brain above the injury site. For the first time, researchers from the University of Zurich and the Uniklinik Balgrist, along with English colleagues from University College London (UCL), now demonstrate that these changes already occur within 40 days of acute spinal cord injury.

Spinal cord depletes rapidly

The scientists studied 13 patients with acute spinal cord injuries every three months for a year using novel MRI (magnetic resonance imaging) protocols. They discovered that the diameter of the spinal cord had rapidly decreased and was already seven percent smaller after twelve months. A lesser volume decline was also evident in the corticospinal tract, a tract indispensable for motor control, and nerve cells in the sensorimotor cortex. The extent of the degenerative changes coincided with the clinical outcome. “Patients with a greater tissue loss above the injury site recovered less effectively than those with less changes,” explains Patrick Freund, the investigator responsible for the study at the Paraplegic Center Balgrist.

Gaining insights into effect of therapies

Treatments targeting the injured spinal cord have entered clinical trials. Gaining insights into mechanisms of repair and recovery within the first year are crucial. Thanks to the use of the new neuroimaging protocols, Freund says, we now have the possibility of displaying the effect of therapeutic treatments on the central nervous system and of rehabilitative measures more quickly. Consequently, the effect of new therapies can also be recorded more rapidly.

“This study is an excellent example of the value of combining the complementary expertise of the two universities,” says UCL’s Dean of Brain Sciences, Professor Alan Thompson, who is one of the senior authors of the study. “It provides exciting new insights into the complications of spinal cord trauma and gives us the possibility of identifying both imaging biomarkers and therapeutic targets.”

The findings are the result of a new three-year neuroscience partnership between the Neuroscience Centre Zurich (ZNZ) and UCL.

Literature:

Patrick Freund, Nikolaus Weiskopf, John Ashburner, Katharina Wolf, Reto Sutter, Daniel R Altmann, Karl Friston, Alan Thompson, Armin Curt. MRI investigation of the sensorimotor cortex and corticospinal tract after acute spinal cord injury: a prospective longitudinal study. The Lancet Neurology. July 2, 2013.

Filed under spinal cord spinal cord injury neuroimaging corticospinal tract sensorimotor cortex tissue neuroscience science

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A look inside children’s minds University of Iowa study shows how 3- and 4-year-olds retain what they see around them When young children gaze intently at something or furrow their brows in concentration, you know their minds are busily at work. But you’re never entirely sure what they’re thinking. Now you can get an inside look. Psychologists led by the University of Iowa for the first time have peered inside the brain with optical neuroimaging to quantify how much 3- and 4-year-old children are grasping when they survey what’s around them and to learn what areas of the brain are in play. The study looks at “visual working memory,” a core cognitive function in which we stitch together what we see at any given point in time to help focus attention. In a series of object-matching tests, the researchers found that 3-year-olds can hold a maximum of 1.3 objects in visual working memory, while 4-year-olds reach capacity at 1.8 objects. By comparison, adults max out at 3 to 4 objects, according to prior studies. “This is literally the first look into a 3 and 4-year-old’s brain in action in this particular working memory task,” says John Spencer, psychology professor at the UI and corresponding author of the paper, which appears in the journal NeuroImage. The research is important, because visual working memory performance has been linked to a variety of childhood disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, developmental coordination disorder as well as affecting children born prematurely. The goal is to use the new brain imaging technique to detect these disorders before they manifest themselves in children’s behavior later on. “At a young age, children may behave the same,” notes Spencer, who’s also affiliated with the Delta Center and whose department is part of the College of Liberal Arts and Sciences, “but if you can distinguish these problems in the brain, then it’s possible to intervene early and get children on a more standard trajectory.” Plenty of research has gone into better understanding visual working memory in children and adults. Those prior studies divined neural networks in action using function magnetic resonance imaging (fMRI). That worked great for adults, but not so much with children,­ especially young ones, whose jerky movements threw the machine’s readings off kilter. So, Spencer and his team turned to functional near-infrared spectroscopy (fNIRS), which has been around since the 1960s but has never been used to look at working memory in children as young as three years of age. “It’s not a scary environment,” says Spencer of the fNIRS. “No tube, no loud noises. You just have to wear a cap.” Like fMRI, fNIRS records neural activity by measuring the difference in oxygenated blood concentrations anywhere in the brain. You’ve likely seen similar technology when a nurse puts your finger in a clip to check your circulation. In the brain, when a region is activated, neurons fire like mad, gobbling up oxygen provided in the blood. Those neurons need another shipment of oxygen-rich blood to arrive to keep going. The fNIRS measures the contrast between oxygen-rich and oxygen-deprived blood to gauge which area of the brain is going full tilt at a point in time. The researchers outfitted the youngsters with colorful, comfortable ski hats in which fiber optic wires had been woven. The children played a computer game in which they were shown a card with one to three objects of different shapes for two seconds. After a pause of a second, the children were shown a card with either the same or different shapes. They responded whether they had seen a match. The tests revealed novel insights. First, neural activity in the right frontal cortex was an important barometer of higher visual working memory capacity in both age groups. This could help clinicians evaluate children’s visual working memory at a younger age than before, and work with those whose capacity falls below the norm, the researchers say. Secondly, 4-year olds showed a greater use than 3-year olds of the parietal cortex, located in both hemispheres below the crown of the head and which is believed to guide spatial attention. "This suggests that improvements in performance are accompanied by increases in the neural response," adds Aaron Buss, a UI graduate student in psychology and the first author on the paper. "Further work will be needed to explain exactly how the neural response increases—either through changes in local tuning, or through changes in long range connectivity, or some combination."

A look inside children’s minds

University of Iowa study shows how 3- and 4-year-olds retain what they see around them

When young children gaze intently at something or furrow their brows in concentration, you know their minds are busily at work. But you’re never entirely sure what they’re thinking.

Now you can get an inside look. Psychologists led by the University of Iowa for the first time have peered inside the brain with optical neuroimaging to quantify how much 3- and 4-year-old children are grasping when they survey what’s around them and to learn what areas of the brain are in play. The study looks at “visual working memory,” a core cognitive function in which we stitch together what we see at any given point in time to help focus attention. In a series of object-matching tests, the researchers found that 3-year-olds can hold a maximum of 1.3 objects in visual working memory, while 4-year-olds reach capacity at 1.8 objects. By comparison, adults max out at 3 to 4 objects, according to prior studies.

“This is literally the first look into a 3 and 4-year-old’s brain in action in this particular working memory task,” says John Spencer, psychology professor at the UI and corresponding author of the paper, which appears in the journal NeuroImage.

The research is important, because visual working memory performance has been linked to a variety of childhood disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, developmental coordination disorder as well as affecting children born prematurely. The goal is to use the new brain imaging technique to detect these disorders before they manifest themselves in children’s behavior later on.

“At a young age, children may behave the same,” notes Spencer, who’s also affiliated with the Delta Center and whose department is part of the College of Liberal Arts and Sciences, “but if you can distinguish these problems in the brain, then it’s possible to intervene early and get children on a more standard trajectory.”

Plenty of research has gone into better understanding visual working memory in children and adults. Those prior studies divined neural networks in action using function magnetic resonance imaging (fMRI). That worked great for adults, but not so much with children,­ especially young ones, whose jerky movements threw the machine’s readings off kilter. So, Spencer and his team turned to functional near-infrared spectroscopy (fNIRS), which has been around since the 1960s but has never been used to look at working memory in children as young as three years of age.

“It’s not a scary environment,” says Spencer of the fNIRS. “No tube, no loud noises. You just have to wear a cap.”

Like fMRI, fNIRS records neural activity by measuring the difference in oxygenated blood concentrations anywhere in the brain. You’ve likely seen similar technology when a nurse puts your finger in a clip to check your circulation. In the brain, when a region is activated, neurons fire like mad, gobbling up oxygen provided in the blood. Those neurons need another shipment of oxygen-rich blood to arrive to keep going. The fNIRS measures the contrast between oxygen-rich and oxygen-deprived blood to gauge which area of the brain is going full tilt at a point in time.

The researchers outfitted the youngsters with colorful, comfortable ski hats in which fiber optic wires had been woven. The children played a computer game in which they were shown a card with one to three objects of different shapes for two seconds. After a pause of a second, the children were shown a card with either the same or different shapes. They responded whether they had seen a match.

The tests revealed novel insights. First, neural activity in the right frontal cortex was an important barometer of higher visual working memory capacity in both age groups. This could help clinicians evaluate children’s visual working memory at a younger age than before, and work with those whose capacity falls below the norm, the researchers say.

Secondly, 4-year olds showed a greater use than 3-year olds of the parietal cortex, located in both hemispheres below the crown of the head and which is believed to guide spatial attention.

"This suggests that improvements in performance are accompanied by increases in the neural response," adds Aaron Buss, a UI graduate student in psychology and the first author on the paper. "Further work will be needed to explain exactly how the neural response increases—either through changes in local tuning, or through changes in long range connectivity, or some combination."

Filed under memory working memory learning parietal cortex neuroimaging frontal cortex neuroscience science

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How visual attention affects the brain

New work at the University of California, Davis, shows for the first time how visual attention affects activity in specific brain cells. The paper, published June 26 in the journal Nature, shows that attention increases the efficiency of signaling into the brain’s cerebral cortex and boosts the ratio of signal over noise.

image

It’s the first time neuroscientists have been able to look at the behavior of synaptic circuits at such a fine-grained level of resolution while measuring the effects of attention, said Professor Ron Mangun, dean of social sciences at UC Davis and a researcher at the UC Davis Center for Mind and Brain.

Our brains recreate an internal map of the world we see through our eyes, mapping our visual field onto specific brain cells. Humans and our primate relatives have the ability to pay attention to objects in the visual scene without looking at them directly, Mangun said.

"Essentially, we ‘see out of the corner of our eyes,’ as the old saying goes. This ability helps us detect threats, and react quickly to avoid them, as when a car running a red light at high speed is approach from our side," he said.

Postdoctoral scholar Farran Briggs worked with Mangun and Professor Martin Usrey at the UC Davis Center for Neuroscience to measure signaling through single nerve connections, or synapses, in monkeys while they performed a standard cognitive test for attention: pressing a joystick in response to seeing a stimulus appear in their field of view.

By taking measurements on each side of a synapse leading into the cerebral cortex, the team could measure when neurons were firing, the strength of the signal and the signal-to-noise ratio.

The researchers found that when the animals were paying attention to an area within their field of view, the signal strength through corresponding synapses leading into the cortex became more effective, and the signal was boosted relative to background noise.

Combining established cognitive psychology with advanced neuroscience, the technique opens up new possibilities for research.

"There are a lot of questions about attention that we can now investigate, such as which brain mechanisms are disordered in diseases that affect attention," Usrey said.

The method could be used, for example, to probe the cholinergic nervous system, which is impacted by Alzheimer’s disease. It could also help to better understand developmental disorders that involve defects in attention, such as attention deficit hyperactivity disorder and autism.

"It’s going to turn out to be important for understanding and treating all kinds of diseases," Mangun predicted.

(Source: news.ucdavis.edu)

Filed under neuroimaging cerebral cortex neurons synapses visual attention psychology neuroscience science

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Past Brain Activation Revealed in Scans Weizmann Institute scientists discover that spontaneously emerging brain activity patterns preserve traces of previous cognitive activity What if experts could dig into the brain, like archaeologists, and uncover the history of past experiences? This ability might reveal what makes each of us a unique individual, and it could enable the objective diagnosis of a wide range of neuropsychological diseases. New research at the Weizmann Institute hints that such a scenario is within the realm of possibility: It shows that spontaneous waves of neuronal activity in the brain bear the imprints of earlier events for at least 24 hours after the experience has taken place. The new research stems from earlier findings in the lab of Prof. Rafi Malach of the Institute’s Neurobiology Department and others that the brain never rests, even when its owner is resting. When a person is resting with closed eyes – that is, no visual stimulus is entering the brain – the normal bursts of nerve cell activity associated with incoming information are replaced by ultra-slow patterns of neuronal activity. Such spontaneous or “resting” waves travel in a highly organized and reproducible manner through the brain’s outer layer – the cortex – and the patterns they create are complex, yet periodic and symmetrical. Like hieroglyphics, it seemed that these patterns might have some meaning, and research student Tal Harmelech, under the guidance of Malach and Dr. Son Preminger, set out to uncover their significance. Their idea was that the patterns of resting brain waves may constitute “archives” for earlier experiences. As we add new experiences, the activation of our brain’s networks lead to long-term changes in the links between brain cells, a facility referred to as plasticity. As our experiences become embedded in these connections, they create “expectations” that come into play before we perform any type of mental task, enabling us to anticipate the result. The researchers hypothesized that information about earlier experiences would thus be incorporated into the links between networks of nerve cells in the cortex, and these would show up in the brain’s spontaneously emerging wave patterns. In the experiment, the researchers had volunteers undertake a training exercise that would strongly activate a well-defined network of nerve cells in the frontal lobes. While undergoing scans of their brain activity in the Institute’s functional magnetic resonance imaging (fMRI) scanner, the subjects were asked to imagine a situation in which they had to make rapid decisions. The subjects received auditory feedback in real time, based on the information obtained directly from their frontal lobe, which indicated the level of neuronal activity in the trained network. This “neurofeedback” strategy proved highly successful in activating the frontal network – a part of the brain that is notoriously difficult to activate under controlled conditions. To test whether the connections created in the brain during this exercise would leave their traces in the patterns formed by the resting brain waves, the researchers performed fMRI scans on the resting subjects before the exercise, immediately afterward, and 24 hours later. Their findings, which appeared in the Journal of Neuroscience, showed that the activation of the specific areas in the cortex did indeed remodel the resting brain wave patterns. Surprisingly, the new patterns not only remained the next day, they were significantly strengthened. These observations fit in with the classic learning principles proposed by Donald Hebb in the mid-20th century, in which the co-activation of two linked nerve cells leads to long term strengthening of their link, while activity that is not coordinated weakens this link. The fMRI images of the resting brain waves showed that brain areas that were activated together during the training sessions exhibited an increase in their functional link a day after the training, while those areas that were deactivated by the training showed a weakened functional connectivity. This research suggests a number of future possibilities for exploring the brain. For example, spontaneously emerging brain patterns could be used as a “mapping tool” for unearthing cognitive events from an individual’s recent past. Or, on a wider scale, each person’s unique spontaneously emerging activity patterns might eventually reveal a sort of personal profile – highlighting each individual’s abilities, shortcomings, biases, learning skills, etc. “Today, we are discovering more and more of the common principles of brain activity, but we have not been able to account for the differences between individuals,” says Malach. “In the future, spontaneous brain patterns could be the key to obtaining unbiased individual profiles.” Such profiles could be especially useful in diagnosing or learning the brain pathologies associated with a wide array of cognitive disabilities.

Past Brain Activation Revealed in Scans

Weizmann Institute scientists discover that spontaneously emerging brain activity patterns preserve traces of previous cognitive activity

What if experts could dig into the brain, like archaeologists, and uncover the history of past experiences? This ability might reveal what makes each of us a unique individual, and it could enable the objective diagnosis of a wide range of neuropsychological diseases. New research at the Weizmann Institute hints that such a scenario is within the realm of possibility: It shows that spontaneous waves of neuronal activity in the brain bear the imprints of earlier events for at least 24 hours after the experience has taken place.

The new research stems from earlier findings in the lab of Prof. Rafi Malach of the Institute’s Neurobiology Department and others that the brain never rests, even when its owner is resting. When a person is resting with closed eyes – that is, no visual stimulus is entering the brain – the normal bursts of nerve cell activity associated with incoming information are replaced by ultra-slow patterns of neuronal activity. Such spontaneous or “resting” waves travel in a highly organized and reproducible manner through the brain’s outer layer – the cortex – and the patterns they create are complex, yet periodic and symmetrical.

Like hieroglyphics, it seemed that these patterns might have some meaning, and research student Tal Harmelech, under the guidance of Malach and Dr. Son Preminger, set out to uncover their significance. Their idea was that the patterns of resting brain waves may constitute “archives” for earlier experiences. As we add new experiences, the activation of our brain’s networks lead to long-term changes in the links between brain cells, a facility referred to as plasticity. As our experiences become embedded in these connections, they create “expectations” that come into play before we perform any type of mental task, enabling us to anticipate the result. The researchers hypothesized that information about earlier experiences would thus be incorporated into the links between networks of nerve cells in the cortex, and these would show up in the brain’s spontaneously emerging wave patterns.

In the experiment, the researchers had volunteers undertake a training exercise that would strongly activate a well-defined network of nerve cells in the frontal lobes. While undergoing scans of their brain activity in the Institute’s functional magnetic resonance imaging (fMRI) scanner, the subjects were asked to imagine a situation in which they had to make rapid decisions. The subjects received auditory feedback in real time, based on the information obtained directly from their frontal lobe, which indicated the level of neuronal activity in the trained network. This “neurofeedback” strategy proved highly successful in activating the frontal network – a part of the brain that is notoriously difficult to activate under controlled conditions.

To test whether the connections created in the brain during this exercise would leave their traces in the patterns formed by the resting brain waves, the researchers performed fMRI scans on the resting subjects before the exercise, immediately afterward, and 24 hours later. Their findings, which appeared in the Journal of Neuroscience, showed that the activation of the specific areas in the cortex did indeed remodel the resting brain wave patterns. Surprisingly, the new patterns not only remained the next day, they were significantly strengthened. These observations fit in with the classic learning principles proposed by Donald Hebb in the mid-20th century, in which the co-activation of two linked nerve cells leads to long term strengthening of their link, while activity that is not coordinated weakens this link. The fMRI images of the resting brain waves showed that brain areas that were activated together during the training sessions exhibited an increase in their functional link a day after the training, while those areas that were deactivated by the training showed a weakened functional connectivity.

This research suggests a number of future possibilities for exploring the brain. For example, spontaneously emerging brain patterns could be used as a “mapping tool” for unearthing cognitive events from an individual’s recent past. Or, on a wider scale, each person’s unique spontaneously emerging activity patterns might eventually reveal a sort of personal profile – highlighting each individual’s abilities, shortcomings, biases, learning skills, etc. “Today, we are discovering more and more of the common principles of brain activity, but we have not been able to account for the differences between individuals,” says Malach. “In the future, spontaneous brain patterns could be the key to obtaining unbiased individual profiles.” Such profiles could be especially useful in diagnosing or learning the brain pathologies associated with a wide array of cognitive disabilities.

Filed under brain mapping brain activity cognitive function Hebbian learning neuroimaging plasticity neuroscience science

50 notes

NMR advance brings proteins into the open A key protein interaction, common across all forms of life, had eluded scientists’ observation until a team of researchers cracked the case by combining data from four different techniques of nuclear magnetic resonance spectroscopy. When working a cold case, smart investigators try something new. By taking a novel approach to nuclear magnetic resonance spectroscopy — a blending of four techniques — scientists have been able to resolve a key interaction between two proteins that could never be observed before. They report on their findings the week of June 24, 2013, in Proceedings of the National Academy of Sciences (PNAS). The interaction, which the team first described, is nearly universal across all of life. A protein machine called a chaperone takes hold of a disordered smaller protein to help it find its proper folded conformation. In this case, the team set up test-tube experiments where they hoped to watch the capsule-shaped bacterial chaperone GroEL capture a disordered amyloid β (Aβ) protein, a molecule that in humans is central in Alzheimer’s disease. The two proteins are well studied, but the motions they go through when they first meet — when the open GroEL capsule captures its target — have been invisible to scientists. Electron microscopy and X-ray crystallography are only good for taking snapshots of easily frozen moments in time. NMR is capable of sensing the interactions and kinetics of protein handshakes as they occur, but in some cases any single technique can provide only hints and whispers of what’s going on. Brown University biologist Nicolas Fawzi, who was a postdoctoral researcher in the group of Marius Clore at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH), worked with co-authors and NIDDK researchers David Libich, Jinfa Yang and Marius Clore to piece together the story of the proteins by combining four different NMR techniques. They figured out what each one could tell them about the interaction and built the case presented in PNAS. “None of the four techniques alone gave us sufficient information,” said Fawzi, assistant professor of medical science in Brown’s Department of Molecular Pharmacology, Physiology, and Biotechnology. “Only by using them all together would we be able to figure out the structure and motions of Aβ when it was bound to GroEL. By having four indirect measurements together, that was able to give us a complete picture.” The researchers acted like a team of detectives working on a case in which no single witness saw everything. Instead they found three witnesses, each with something different to contribute, and then one more that could corroborate some of what the others revealed and rule out other possibilities. The NMR techniques they used were lifetime line broadening, Carr-Purcell-Meinboom-Gill (CPMG) relaxation dispersion spectroscopy, and exchange-induced chemical shifts. “The fourth technique we employed was Dark-state Exchange Saturation Transfer (DEST) spectroscopy, which we had developed in my lab at the NIH in 2011,” said Clore, also the paper’s corresponding author. “We were able to more effectively conduct our research by using that tool to corroborate and extend the information afforded by the other three measurements.” Bouncing with the chaperone The mystery debated among molecular biologists was what the GroEL chaperone requires of its captives at the moment they engage. Does it force them into a particular conformation? Does it hold on tightly while it closes its capsule lid around the smaller protein, or does the captive stay in motion at all? What the team observed is that the GroEL is a permissive captor. It bound Aβ at just two “hydrophobic” sites, leaving the smaller protein to otherwise dangle in a variety of conformations. It also didn’t keep it bound the entire time, letting it instead detach and re-bind. Essentially Aβ would bounce off and on within GroEL’s binding cavity. “By using these four techniques together we were able to extract information about the structure of the protein while it binds as well as how fast it comes on and off and what it’s doing at each position,” Fawzi said. “Instead of forming more particular structure upon binding it appears to retain great conformational heterogeneity.” The lifetime line broadening technique, for example, told them that the Aβ was interacting with something big (GroEL), while the CPMG and chemical shift observations combined to show the length of time Aβ spent on GroEL before unbinding, as well as the structural details of Aβ when it was bound to GroEL. DEST provided information that could confirm much of the story of the other techniques. Fawzi said GroEL’s laid-back approach could be a matter of being able to bind many different proteins in disordered conformations, but also of saving energy. Forcing proteins into a specific conformation just to make and sustain the initial capture would require more energy than it’s worth. Eventually, in moments after those the team resolved in this study, GroEL closes its lid and encapsulates its target proteins fully, Fawzi said. That’s when it invests in forcing them to fold the right way. For molecular and structural biologists, the newly proven blend of NMR techniques could open a number of other cold cases of elusive interactions. “We can now look at how these big machines can do their job while they are working,” Fawzi said. “This is not just limited to this GroEL machine.”

NMR advance brings proteins into the open

A key protein interaction, common across all forms of life, had eluded scientists’ observation until a team of researchers cracked the case by combining data from four different techniques of nuclear magnetic resonance spectroscopy.

When working a cold case, smart investigators try something new. By taking a novel approach to nuclear magnetic resonance spectroscopy — a blending of four techniques — scientists have been able to resolve a key interaction between two proteins that could never be observed before. They report on their findings the week of June 24, 2013, in Proceedings of the National Academy of Sciences (PNAS).

The interaction, which the team first described, is nearly universal across all of life. A protein machine called a chaperone takes hold of a disordered smaller protein to help it find its proper folded conformation. In this case, the team set up test-tube experiments where they hoped to watch the capsule-shaped bacterial chaperone GroEL capture a disordered amyloid β (Aβ) protein, a molecule that in humans is central in Alzheimer’s disease.

The two proteins are well studied, but the motions they go through when they first meet — when the open GroEL capsule captures its target — have been invisible to scientists. Electron microscopy and X-ray crystallography are only good for taking snapshots of easily frozen moments in time. NMR is capable of sensing the interactions and kinetics of protein handshakes as they occur, but in some cases any single technique can provide only hints and whispers of what’s going on.

Brown University biologist Nicolas Fawzi, who was a postdoctoral researcher in the group of Marius Clore at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH), worked with co-authors and NIDDK researchers David Libich, Jinfa Yang and Marius Clore to piece together the story of the proteins by combining four different NMR techniques. They figured out what each one could tell them about the interaction and built the case presented in PNAS.

“None of the four techniques alone gave us sufficient information,” said Fawzi, assistant professor of medical science in Brown’s Department of Molecular Pharmacology, Physiology, and Biotechnology. “Only by using them all together would we be able to figure out the structure and motions of Aβ when it was bound to GroEL. By having four indirect measurements together, that was able to give us a complete picture.”

The researchers acted like a team of detectives working on a case in which no single witness saw everything. Instead they found three witnesses, each with something different to contribute, and then one more that could corroborate some of what the others revealed and rule out other possibilities. The NMR techniques they used were lifetime line broadening, Carr-Purcell-Meinboom-Gill (CPMG) relaxation dispersion spectroscopy, and exchange-induced chemical shifts.

“The fourth technique we employed was Dark-state Exchange Saturation Transfer (DEST) spectroscopy, which we had developed in my lab at the NIH in 2011,” said Clore, also the paper’s corresponding author. “We were able to more effectively conduct our research by using that tool to corroborate and extend the information afforded by the other three measurements.”

Bouncing with the chaperone

The mystery debated among molecular biologists was what the GroEL chaperone requires of its captives at the moment they engage. Does it force them into a particular conformation? Does it hold on tightly while it closes its capsule lid around the smaller protein, or does the captive stay in motion at all?

What the team observed is that the GroEL is a permissive captor. It bound Aβ at just two “hydrophobic” sites, leaving the smaller protein to otherwise dangle in a variety of conformations. It also didn’t keep it bound the entire time, letting it instead detach and re-bind. Essentially Aβ would bounce off and on within GroEL’s binding cavity.

“By using these four techniques together we were able to extract information about the structure of the protein while it binds as well as how fast it comes on and off and what it’s doing at each position,” Fawzi said. “Instead of forming more particular structure upon binding it appears to retain great conformational heterogeneity.”

The lifetime line broadening technique, for example, told them that the Aβ was interacting with something big (GroEL), while the CPMG and chemical shift observations combined to show the length of time Aβ spent on GroEL before unbinding, as well as the structural details of Aβ when it was bound to GroEL. DEST provided information that could confirm much of the story of the other techniques.

Fawzi said GroEL’s laid-back approach could be a matter of being able to bind many different proteins in disordered conformations, but also of saving energy. Forcing proteins into a specific conformation just to make and sustain the initial capture would require more energy than it’s worth.

Eventually, in moments after those the team resolved in this study, GroEL closes its lid and encapsulates its target proteins fully, Fawzi said. That’s when it invests in forcing them to fold the right way.

For molecular and structural biologists, the newly proven blend of NMR techniques could open a number of other cold cases of elusive interactions.

“We can now look at how these big machines can do their job while they are working,” Fawzi said. “This is not just limited to this GroEL machine.”

Filed under alzheimer's disease neuroimaging NMR beta amyloid crystallography electron microscopy neuroscience science

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"BigBrain" Study Provides Most Detailed 3-D Map of the Brain Yet A landmark three-dimensional digital reconstruction of a complete human brain, called the BigBrain, shows the brain anatomy in microscopic detail at a spatial resolution of 20 micrometers—smaller than the size of one fine strand of hair. The reconstruction, published in the 21 June issue of the journal Science, exceeds the resolution of all existing reference brains presently in the public domain, and will be made freely available to the broader scientific community. The fine-grained anatomical resolution of the BigBrain will allow scientists who use it to gain insights into the neurobiological basis of cognition, language, emotions and other processes, according to the study. The anatomical tool yielded by the researchers will serve as an atlas for neurosurgery and provide a framework for research in many directions, including enhanced understanding of brain diseases, such as Alzheimer’s disease. "It is a common basis for scientific discussions because everybody can work with this brain model," said Science co-author Karl Zilles, senior professor of the Jülich Aachen Research Alliance. The new reference brain, which is part of the European Human Brain Project, “redefines traditional maps from the beginning of the 20th century,” explained lead author Katrin Amunts from the Research Centre Jülich. Amunts serves as director of the Cecile and Oskar Vogt Institute for Brain Research at the Heinrich Heine University Düsseldorf in Germany. "The authors pushed the limits of current technology," said Science Senior Editor Peter Stern. Existing reference brains do not probe further than the macroscopic, or visible, components of the brain. The BigBrain provides a resolution much finer than the typical 1 millimeter resolution from MRI studies. "The spatial resolution the researchers achieved exceeds that of presently available reference brains by a factor of 50," said Stern. "Of course, we would love to have spatial resolution going down to 1 micrometer," said Amunts in a 19 June press teleconference. However, "there are simply no computers at this moment which would be capable to process such data, to visualize this or to analyze it." To create the detailed brain atlas, Amunts and colleagues took advantage of new advances in computing capacities and image analysis. Using a special tool called a microtome, they carefully cut the paraffin-covered brain of a 65-year-old female into 20 micrometer-thick sections. The project was “a tour-de-force to assemble images of over 7400 individual histological sections, each with its own distortions, rips and tears, into a coherent 3-D volume,” said Science co-author Alan Evans, a professor at the Montreal Neurological Institute at McGill University in Montreal, Canada. The sections were mounted on slides, stained to detect cell structures and finally digitized with a high-resolution flatbed scanner so researchers could reconstruct the high-resolution 3-D brain model. It took approximately 1000 hours to collect the data. The researchers’ future plans for using the map include extracting measurements of cortical thickness to gain insights into aging and neurodegenerative disorders. Eventually, Amunts and colleagues hope to build a brain model at the resolution of 1 micron to capture details of single cell morphology. Detailed brain maps can aid researchers who are exploring the full set of neural connections and real-time brain activity, as scientists discussed recently in a Capitol Hill briefing sponsored by AAAS. The creation of such a detailed brain map, offering a gateway to unprecedented insights into the brain’s anatomy and organization, was long in the works. “It was a dream for almost 20 years,” Amunts said. “The dream came true because of an interdisciplinary and intercontinental collaboration spanning from Europe to Canada and from neuroanatomy to supercomputing .” Though not directly related to the BRAIN Initiative announced by President Barack Obama earlier this year, the work by Amunts and colleagues supports the Initiative’s goal of giving scientists the best possible tools with which to obtain a dynamic picture of the brain.

"BigBrain" Study Provides Most Detailed 3-D Map of the Brain Yet

A landmark three-dimensional digital reconstruction of a complete human brain, called the BigBrain, shows the brain anatomy in microscopic detail at a spatial resolution of 20 micrometers—smaller than the size of one fine strand of hair.

The reconstruction, published in the 21 June issue of the journal Science, exceeds the resolution of all existing reference brains presently in the public domain, and will be made freely available to the broader scientific community.

The fine-grained anatomical resolution of the BigBrain will allow scientists who use it to gain insights into the neurobiological basis of cognition, language, emotions and other processes, according to the study. The anatomical tool yielded by the researchers will serve as an atlas for neurosurgery and provide a framework for research in many directions, including enhanced understanding of brain diseases, such as Alzheimer’s disease.

"It is a common basis for scientific discussions because everybody can work with this brain model," said Science co-author Karl Zilles, senior professor of the Jülich Aachen Research Alliance.

The new reference brain, which is part of the European Human Brain Project, “redefines traditional maps from the beginning of the 20th century,” explained lead author Katrin Amunts from the Research Centre Jülich. Amunts serves as director of the Cecile and Oskar Vogt Institute for Brain Research at the Heinrich Heine University Düsseldorf in Germany.

"The authors pushed the limits of current technology," said Science Senior Editor Peter Stern. Existing reference brains do not probe further than the macroscopic, or visible, components of the brain. The BigBrain provides a resolution much finer than the typical 1 millimeter resolution from MRI studies. "The spatial resolution the researchers achieved exceeds that of presently available reference brains by a factor of 50," said Stern.

"Of course, we would love to have spatial resolution going down to 1 micrometer," said Amunts in a 19 June press teleconference. However, "there are simply no computers at this moment which would be capable to process such data, to visualize this or to analyze it."

To create the detailed brain atlas, Amunts and colleagues took advantage of new advances in computing capacities and image analysis. Using a special tool called a microtome, they carefully cut the paraffin-covered brain of a 65-year-old female into 20 micrometer-thick sections.

The project was “a tour-de-force to assemble images of over 7400 individual histological sections, each with its own distortions, rips and tears, into a coherent 3-D volume,” said Science co-author Alan Evans, a professor at the Montreal Neurological Institute at McGill University in Montreal, Canada.

The sections were mounted on slides, stained to detect cell structures and finally digitized with a high-resolution flatbed scanner so researchers could reconstruct the high-resolution 3-D brain model. It took approximately 1000 hours to collect the data.

The researchers’ future plans for using the map include extracting measurements of cortical thickness to gain insights into aging and neurodegenerative disorders. Eventually, Amunts and colleagues hope to build a brain model at the resolution of 1 micron to capture details of single cell morphology. Detailed brain maps can aid researchers who are exploring the full set of neural connections and real-time brain activity, as scientists discussed recently in a Capitol Hill briefing sponsored by AAAS.

The creation of such a detailed brain map, offering a gateway to unprecedented insights into the brain’s anatomy and organization, was long in the works. “It was a dream for almost 20 years,” Amunts said. “The dream came true because of an interdisciplinary and intercontinental collaboration spanning from Europe to Canada and from neuroanatomy to supercomputing .”

Though not directly related to the BRAIN Initiative announced by President Barack Obama earlier this year, the work by Amunts and colleagues supports the Initiative’s goal of giving scientists the best possible tools with which to obtain a dynamic picture of the brain.

Filed under BigBrain brain mapping 3-D brain map neuroimaging BRAIN initiative Human Brain Project neuroscience science

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