May 7, 2013 — Scientists at the Virginia Tech Carilion Research Institute have discovered how the predominant class of Alzheimer's pharmaceuticals might sharpen the brain's performance
17One factor even more important than the size of a television screen is the quality of the signal it displays. Having a life-sized projection of Harry Potter dodging a Bludger in a Quidditch match is of little use if the details are lost to pixilation.
The importance of transmitting clear signals, however, is not relegated to the airwaves. The same creed applies to the electrical impulses navigating a human brain. Now, new research has shown that one of the few drugs approved for the treatment of Alzheimer's disease helps patients by clearing up the signals coming in from the outside world.
The discovery was made by a team of researchers led by Rosalyn Moran, an assistant professor at the Virginia Tech Carilion Research Institute. Her study indicates that cholinesterase inhibitors -- a class of drugs that stop the breakdown of the neurotransmitter acetylcholine -- allow signals to enter the brain with more precision and less background noise.
"Increasing the levels of acetylcholine appears to turn your fuzzy, old analog TV signal into a shiny, new, high-definition one," said Moran, who holds an appointment as an assistant professor in the Virginia Tech College of Engineering. "And the drug does this in the sensory cortices. These are the workhorses of the brain, the gatekeepers, not the more sophisticated processing regions -- such as the prefrontal cortex -- where one may have expected the drugs to have their most prominent effect."
Alzheimer's disease affects more than 35 million people worldwide -- a number expected to double every 20 years, leading to more than 115 million cases by 2050. Of the five pharmaceuticals approved to treat the disease by the U.S. Food and Drug Administration, four are cholinesterase inhibitors. Although it is clear that the drugs increase the amount of acetylcholine in the brain, why this improves Alzheimer's symptoms has been unknown. If scientists understood the mechanisms and pathways responsible for improvement, they might be able to tailor better drugs to combat the disease, which costs more than $200 billion annually in the United States alone.
In the new study, Moran recruited 13 healthy young adults and gave them doses of galantamine, one of the cholinesterase inhibitors commonly prescribed to Alzheimer's patients. Two electroencephalographs were taken -- one with the drugs and one without -- as the participants listened to a series of modulating tones while focusing on a simple concentration task.
The researchers were looking for differences in neural activity between the two drug states in response to surprising changes in the sound patterns that the participants were hearing.
The scientists compared the results with computer models built on a Bayesian brain theory, known as the Free Energy Principle, which is a leading theory that describes the basic rules of neuronal communication and explains the creation of complex networks.
The theory hypothesizes that neurons seek to reduce uncertainty, which can be modeled and calculated using free energy molecular dynamics. Connecting tens of thousands of neurons behaving in this manner produces the probability machine that we call a brain.
Moran and her colleagues compiled 10 computer simulations based on the different effects that the drugs could have on the brain. The model that best fit the results revealed that the low-level wheels of the brain early on in the neural networking process were the ones benefitting from the drugs and creating clearer, more precise signals.
"When people take these drugs you can imagine the brain bathed in them," Moran said. "But what we found is that the drugs don't have broad-stroke impacts on brain activity. Instead, they are working very specifically at the cortex's entry points, gating the signals coming into the network in the first place."
Wednesday, May 8, 2013
Tuesday, April 9, 2013
Distorted Thinking in Gambling Addiction: What Are the Cognitive and Neural Mechanisms?
Apr. 8, 2013 — Fascinating new studies into brain activity and behavioural responses have highlighted the overlap between pathological gambling and drug addiction. The research, which is presented at the British Neuroscience Association Festival of Neuroscience (BNA2013) has implications for both the treatment and prevention of problem gambling.
Dr Luke Clark, a senior lecturer at the University of Cambridge (UK), told the meeting that neurocognitive tests of impulsivity and compulsivity, and also positron emission tomography (PET) imaging of the brain have started to show how gambling becomes addictive in pathological gamblers -- people whose gambling habit has spiralled out of control and become a problem.
"Around 70% of the British population will gamble occasionally, but for some of these people, it will become a problem," he said. "Our work has been seeking to understand the changes in decision-making that happen in people with gambling problems. It represents the first large scale study of individuals seeking treatment for gambling problems in the UK, at a time when this disorder is being re-classified alongside drug addiction as the first 'behavioural addiction'. Given the unique legislation around gambling from country to country, it is vital that we understand gambling at a national level. For example, 40% of the problem gamblers at the National Problem Gambling Clinic report that the game they have a problem with is roulette on Fixed Odds Betting Terminals; this kind of gambling machine is peculiar to the British gambling landscape."
In collaboration between the University of Cambridge and Dr Henrietta Bowden-Jones, director of the UK's only specialist gambling clinic in the Central and North West London NHS Trust, Dr Clark and his colleagues compared the brains and behaviours of 86 male, pathological gamblers with those of 45 healthy men without a gambling problem.
"We approach gambling within the framework of addiction, where we think that problematic gambling arises from a combination of individual risk factors, such as genetics, and features of the games themselves. To study individual factors, we have been testing gamblers at the National Problem Gambling Clinic on neurocognitive tests of impulsivity and compulsivity, and we have also measured their dopamine levels using PET imaging," said Dr Clark.
The tests showed that problem gamblers had increased impulsivity, similar to people with alcohol and drug addictions, but there was less evidence of compulsivity. Levels of dopamine -- a neurotransmitter involved in signalling between nerve cells and which is implicated in drug addiction -- showed differences in the more impulsive gamblers.
"Previous PET research has shown that people with drug addiction have reduced dopamine receptors. We predicted the same effect in pathological gamblers, but we did not see any group differences between the pathological gamblers and healthy men. Nevertheless, the problem gamblers do show some individual differences in their dopamine function, related to their levels of impulsivity: more impulsive gamblers showed fewer dopamine receptors," said Dr Clark. "These studies highlight the overlap between pathological gambling and drug addiction.
"To study the properties of the games themselves and how they relate to problem gambling, we have focussed on two psychological distortions that occur across many forms of gambling: 'near-miss' outcomes (where a loss looks similar or 'close' to a jackpot win) and the 'gambler's fallacy' (for example, believing that a run of heads means that a tail is 'due', in a game of chance). In one important discovery, we were the first lab to show that gambling 'near-misses' recruit brain regions that overlap with those recruited in gambling 'wins'. These responses may cause 'near-misses' to maintain gambling play despite their objective status as losses."
Dr Clark said that these findings had implications for both prevention and treatment. "Gambling distortions like the 'near-miss' effect may be amenable to both psychological therapies for problem gambling, and also by drug treatments that may act on the underlying brain systems. By understanding the styles of thinking that characterise the problem gambler, we may also be able to improve education about gambling in teenagers and young adults, to reduce the number of people developing a gambling problem."
The researchers also found a striking demonstration of the underlying brain regions that are involved in gambling when they studied the gambling behaviour of patients who had experienced brain injury due to a tumour or stroke.
"We have seen that two gambling distortions -- the 'gambler's fallacy' and the 'near-miss' effect -- that are evident in the general population, and which appear to be increased in problem gamblers, are actually abolished in patients with damage to the insula region of the brain," he said. "This suggests that in the healthy brain, the insula may be a critical area in generating these distorted expectancies during gambling play, and that interventions to reduce insula activity may have treatment potential.
"The insula is quite a mysterious part of the brain, tucked deep inside the lateral fissure. It is important in processing pain and, more broadly, in representing the state of the body in the brain, and it is striking that gambling is a very visceral, exciting activity. Our ongoing neuroimaging work will look at the relationship between responses in the insula and the body during our gambling tests."
Future work will investigate the styles of thinking that are in evidence when the problem gamblers at the National Problem Gambling Clinic play the simplified games the researchers have developed. "This is the first study to directly look at whether these biases are more pronounced in problem gamblers. We are also starting to recruit the siblings of problem gamblers (those who do not have a gambling problem themselves) in order to look at underlying vulnerability factors," concluded Dr Clark.
This research is funded by grants from the UK's Medical Research Council, and involves further collaboration with researchers at Imperial College London and the University of Oxford.
Dr Luke Clark, a senior lecturer at the University of Cambridge (UK), told the meeting that neurocognitive tests of impulsivity and compulsivity, and also positron emission tomography (PET) imaging of the brain have started to show how gambling becomes addictive in pathological gamblers -- people whose gambling habit has spiralled out of control and become a problem.
"Around 70% of the British population will gamble occasionally, but for some of these people, it will become a problem," he said. "Our work has been seeking to understand the changes in decision-making that happen in people with gambling problems. It represents the first large scale study of individuals seeking treatment for gambling problems in the UK, at a time when this disorder is being re-classified alongside drug addiction as the first 'behavioural addiction'. Given the unique legislation around gambling from country to country, it is vital that we understand gambling at a national level. For example, 40% of the problem gamblers at the National Problem Gambling Clinic report that the game they have a problem with is roulette on Fixed Odds Betting Terminals; this kind of gambling machine is peculiar to the British gambling landscape."
In collaboration between the University of Cambridge and Dr Henrietta Bowden-Jones, director of the UK's only specialist gambling clinic in the Central and North West London NHS Trust, Dr Clark and his colleagues compared the brains and behaviours of 86 male, pathological gamblers with those of 45 healthy men without a gambling problem.
"We approach gambling within the framework of addiction, where we think that problematic gambling arises from a combination of individual risk factors, such as genetics, and features of the games themselves. To study individual factors, we have been testing gamblers at the National Problem Gambling Clinic on neurocognitive tests of impulsivity and compulsivity, and we have also measured their dopamine levels using PET imaging," said Dr Clark.
The tests showed that problem gamblers had increased impulsivity, similar to people with alcohol and drug addictions, but there was less evidence of compulsivity. Levels of dopamine -- a neurotransmitter involved in signalling between nerve cells and which is implicated in drug addiction -- showed differences in the more impulsive gamblers.
"Previous PET research has shown that people with drug addiction have reduced dopamine receptors. We predicted the same effect in pathological gamblers, but we did not see any group differences between the pathological gamblers and healthy men. Nevertheless, the problem gamblers do show some individual differences in their dopamine function, related to their levels of impulsivity: more impulsive gamblers showed fewer dopamine receptors," said Dr Clark. "These studies highlight the overlap between pathological gambling and drug addiction.
"To study the properties of the games themselves and how they relate to problem gambling, we have focussed on two psychological distortions that occur across many forms of gambling: 'near-miss' outcomes (where a loss looks similar or 'close' to a jackpot win) and the 'gambler's fallacy' (for example, believing that a run of heads means that a tail is 'due', in a game of chance). In one important discovery, we were the first lab to show that gambling 'near-misses' recruit brain regions that overlap with those recruited in gambling 'wins'. These responses may cause 'near-misses' to maintain gambling play despite their objective status as losses."
Dr Clark said that these findings had implications for both prevention and treatment. "Gambling distortions like the 'near-miss' effect may be amenable to both psychological therapies for problem gambling, and also by drug treatments that may act on the underlying brain systems. By understanding the styles of thinking that characterise the problem gambler, we may also be able to improve education about gambling in teenagers and young adults, to reduce the number of people developing a gambling problem."
The researchers also found a striking demonstration of the underlying brain regions that are involved in gambling when they studied the gambling behaviour of patients who had experienced brain injury due to a tumour or stroke.
"We have seen that two gambling distortions -- the 'gambler's fallacy' and the 'near-miss' effect -- that are evident in the general population, and which appear to be increased in problem gamblers, are actually abolished in patients with damage to the insula region of the brain," he said. "This suggests that in the healthy brain, the insula may be a critical area in generating these distorted expectancies during gambling play, and that interventions to reduce insula activity may have treatment potential.
"The insula is quite a mysterious part of the brain, tucked deep inside the lateral fissure. It is important in processing pain and, more broadly, in representing the state of the body in the brain, and it is striking that gambling is a very visceral, exciting activity. Our ongoing neuroimaging work will look at the relationship between responses in the insula and the body during our gambling tests."
Future work will investigate the styles of thinking that are in evidence when the problem gamblers at the National Problem Gambling Clinic play the simplified games the researchers have developed. "This is the first study to directly look at whether these biases are more pronounced in problem gamblers. We are also starting to recruit the siblings of problem gamblers (those who do not have a gambling problem themselves) in order to look at underlying vulnerability factors," concluded Dr Clark.
This research is funded by grants from the UK's Medical Research Council, and involves further collaboration with researchers at Imperial College London and the University of Oxford.
Non-Invasive Mapping Helps to Localize Language Centers Before Brain Surgery
Apr. 8, 2013 — A new functional magnetic resonance imaging (fMRI) technique may provide neurosurgeons with a non-invasive tool to help in mapping critical areas of the brain before surgery, reports a study in the April issue of Neurosurgery, official journal of the Congress of Neurological Surgeons.
Evaluating brain fMRI responses to a "single, short auditory language task" can reliably localize critical language areas of the brain -- in healthy people as well as patients requiring brain surgery for epilepsy or tumors, according to the new research by Melanie Genetti, PhD, and colleagues of Geneva University Hospitals, Switzerland.
Brief fMRI Task for Functional Brain Mapping
The researchers designed and evaluated a quick and simple fMRI task for use in functional brain mapping. Functional MRI can show brain activity in response to stimuli (in contrast to conventional brain MRI, which shows anatomy only). Before neurosurgery for severe epilepsy or brain tumors, functional brain mapping provides essential information on the location of critical brain areas governing speech and other functions.
The standard approach to brain mapping is direct electrocortical stimulation (ECS) -- recording brain activity from electrodes placed on the brain surface. However, this requires several hours of testing and may not be applicable in all patients. Previous studies have compared fMRI techniques with ECS, but mainly for determining the side of language function (lateralization) rather than the precise location (localization).
The new fMRI task was developed and evaluated in 28 healthy volunteers and in 35 patients undergoing surgery for brain tumors or epilepsy. The test used a brief (eight minutes) auditory language stimulus in which the patients heard a series of sense and nonsense sentences.
Functional MRI scans were obtained to localize the brain areas activated by the language task -- activated areas would "light up," reflecting increased oxygenation. A subgroup of patients also underwent ECS, the results of which were compared to fMRI.
Non-invasive Test Accurately Localizes Critical Brain Areas
Based on responses to the language stimulus, fMRI showed activation of the anterior and posterior (front and rear) language areas of the brain in about 90 percent of subjects -- neurosurgery patients as well as healthy volunteers. Functional MRI activation was weaker and the language centers more spread-out in the patient group. These differences may have reflected brain adaptations to slow-growing tumors or longstanding epilepsy.
Five of the epilepsy patients also underwent ECS using brain electrodes, the results of which agreed well with the fMRI findings. Two patients had temporary problems with language function after surgery. In both cases, the deficits were related to surgery or complications (bleeding) in the language area identified by fMRI.
Functional brain mapping is important for planning for complex neurosurgery procedures. It provides a guide for the neurosurgeon to navigate safely to the tumor or other diseased area, while avoiding damage to critical areas of the brain. An accurate, non-invasive approach to brain mapping would provide a valuable alternative to the time-consuming ECS procedure.
"The proposed fast fMRI language protocol reliably localized the most relevant language areas in individual subjects," Dr. Genetti and colleagues conclude. In its current state, the new test probably isn't suitable as the only approach to planning surgery -- too many areas "light up" with fMRI, which may limit the surgeon's ability to perform more extensive surgery with necessary confidence. The researchers add, "Rather than a substitute, our current fMRI protocol can be considered as a valuable complementary tool that can reliably guide ECS in the surgical planning of epileptogenic foci and of brain tumors."
Evaluating brain fMRI responses to a "single, short auditory language task" can reliably localize critical language areas of the brain -- in healthy people as well as patients requiring brain surgery for epilepsy or tumors, according to the new research by Melanie Genetti, PhD, and colleagues of Geneva University Hospitals, Switzerland.
Brief fMRI Task for Functional Brain Mapping
The researchers designed and evaluated a quick and simple fMRI task for use in functional brain mapping. Functional MRI can show brain activity in response to stimuli (in contrast to conventional brain MRI, which shows anatomy only). Before neurosurgery for severe epilepsy or brain tumors, functional brain mapping provides essential information on the location of critical brain areas governing speech and other functions.
The standard approach to brain mapping is direct electrocortical stimulation (ECS) -- recording brain activity from electrodes placed on the brain surface. However, this requires several hours of testing and may not be applicable in all patients. Previous studies have compared fMRI techniques with ECS, but mainly for determining the side of language function (lateralization) rather than the precise location (localization).
The new fMRI task was developed and evaluated in 28 healthy volunteers and in 35 patients undergoing surgery for brain tumors or epilepsy. The test used a brief (eight minutes) auditory language stimulus in which the patients heard a series of sense and nonsense sentences.
Functional MRI scans were obtained to localize the brain areas activated by the language task -- activated areas would "light up," reflecting increased oxygenation. A subgroup of patients also underwent ECS, the results of which were compared to fMRI.
Non-invasive Test Accurately Localizes Critical Brain Areas
Based on responses to the language stimulus, fMRI showed activation of the anterior and posterior (front and rear) language areas of the brain in about 90 percent of subjects -- neurosurgery patients as well as healthy volunteers. Functional MRI activation was weaker and the language centers more spread-out in the patient group. These differences may have reflected brain adaptations to slow-growing tumors or longstanding epilepsy.
Five of the epilepsy patients also underwent ECS using brain electrodes, the results of which agreed well with the fMRI findings. Two patients had temporary problems with language function after surgery. In both cases, the deficits were related to surgery or complications (bleeding) in the language area identified by fMRI.
Functional brain mapping is important for planning for complex neurosurgery procedures. It provides a guide for the neurosurgeon to navigate safely to the tumor or other diseased area, while avoiding damage to critical areas of the brain. An accurate, non-invasive approach to brain mapping would provide a valuable alternative to the time-consuming ECS procedure.
"The proposed fast fMRI language protocol reliably localized the most relevant language areas in individual subjects," Dr. Genetti and colleagues conclude. In its current state, the new test probably isn't suitable as the only approach to planning surgery -- too many areas "light up" with fMRI, which may limit the surgeon's ability to perform more extensive surgery with necessary confidence. The researchers add, "Rather than a substitute, our current fMRI protocol can be considered as a valuable complementary tool that can reliably guide ECS in the surgical planning of epileptogenic foci and of brain tumors."
Monday, March 25, 2013
Spatial Memory: Mapping Blank Spots in the Cheeseboard Maze
Mar. 21, 2013 — IST Austria Professor Jozsef Csicsvari together with collaborators has succeeded in uncovering processes in which the formation of spatial memory is manifested in a map representation.
During learning, novel information is transformed into memory through the processing and encoding of information in neural circuits. In a recent publication in Neuron, IST Austria Professor Jozsef Csicsvari, together with his collaborator David Dupret at the University of Oxford, and Joseph O'Neill, postdoc in Csicsvari's group, uncovered a novel role for inhibitory interneurons in the rat hippocampus during the formation of spatial memory.
During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using the cheeseboard maze apparatus. This apparatus contains many holes, some of which are selected to hide food in order to test spatial memory. During learning trials, animals learn where the rewards are located, and after a period sleep, the researchers test whether the animal can recall these reward locations. In previous work, they and others have shown that memory of space is encoded in the hippocampus through changes in the firing of excitatory pyramidal cells, the so-called "place cells."
A place cell fires when the animal arrives at a particular location. Normally, place cells always fire at the same place in an environment; however, during spatial learning the place of their firing can change to encode where the reward is found, forming memory maps.
In their new publication, the researchers investigated the timescale of map formation, showing that during spatial learning, pyramidal neuron maps representing previous and new reward locations "flicker," with both firing patterns occurring. At first, old maps and new maps fluctuate, as the animal is unsure whether the location change is transient or long-lasting. At a later stage, the new map and so the relevant new information dominates.
The scientists also investigated the contribution of inhibitory interneuron circuits to learning. They show that these interneurons, which are extensively interconnected with pyramidal cells, change their firing rates during map formation and flickering: some interneurons fire more often when the new pyramidal map fires, while others fire less often with the new map. These changes in interneuron firing were only observed during learning, not during sleep or recall. The scientists also show that the changes in firing rate are due to map-specific changes in the connections between pyramidal cells and interneurons. When a pyramidal cell is part of a new map, the strengthening of a connection with an interneuron causes an increase in the firing of this interneuron. Conversely, when a pyramidal cell is not part of a new map, the weakening of the connection with the interneuron causes a decrease in interneuron firing rate. Both, the increase and the decrease in firing rate can be beneficial for learning, allowing the regulation of plasticity between pyramidal cells and controlling the timing in their firing.
The new research therefore shows that not only excitatory neurons modify their behaviour and exhibit plastic connection changes during learning, but also the inhibitory interneuron circuits. The researchers suggest that inhibitory interneurons could be involved in map selection -- helping one map dominate and take over during learning, so that the relevant information is encoded.
Sunday, March 3, 2013
Changes in Patterns of Brain Activity Predict Fear Memory Formation
Science News-Mar. 1, 2013 — Psychologists at the University of Amsterdam (UvA) have discovered that changes in patterns of brain activity during fearful experiences predict whether a long-term fear memory is formed. The research results have recently been published in the scientific journal Nature Neuroscience.
Researchers Renee Visser MSc, Dr Steven Scholte, Tinka Beemsterboer MSc and Prof. Merel Kindt discovered that they can predict future fear memories by looking at patterns of brain activity during fearful experiences. Up until now, there was no way of predicting fear memory. It was also, above all, unclear whether the selection of information to be stored in the long-term memory occurred at the time of fear learning or after the event.
Picture predicts pain stimulus
During magnetic resonance brain imaging (MRI), participants saw neutral pictures of faces and houses, some of which were followed by a small electric shock. In this way, the participants formed fear memories. They showed fear responses when the pictures were shown that were paired with shocks. This fear response can be measured in the brain, but is also evident from increased pupil dilation when someone sees the picture. After a few weeks, the participants returned to the lab and were shown the same images. Brain activity and pupil diameter were once again measured. The extent to which the pupil dilated when seeing the images that were previously followed by a shock, was considered an expression of the previously formed fear memory.
Pattern Analysis
In order to analyse the fMRI data, (spatial) patterns of brain activity (Multi-Voxel Pattern Analysis, or MVPA) were analysed. By correlating patterns of various stimulus presentations with each other, it is possible to measure the extent to which the representation of two stimuli is the same. It appears that images that have nothing in common, such as houses and faces, lead to increasing neural pattern similarity when they predict danger. This does not occur when they do not predict danger. This leads to the formation of stronger fear responses. The extent to which this occurs is an indication of fear memory formation: the stronger the response during learning, the stronger the fear response will be in the long term.
These findings may lead to greater insights into the formation of emotional memory. As a result, it is possible to conduct experimental research into the mechanisms that strengthen, weaken or even erase fear memory in a more direct fashion, without having to wait until the fear memory is expressed.
The research is part of the Vici project of Prof. Merel Kindt, which is funded by the Netherlands Organisation for Scientific Research (NWO).
Researchers Renee Visser MSc, Dr Steven Scholte, Tinka Beemsterboer MSc and Prof. Merel Kindt discovered that they can predict future fear memories by looking at patterns of brain activity during fearful experiences. Up until now, there was no way of predicting fear memory. It was also, above all, unclear whether the selection of information to be stored in the long-term memory occurred at the time of fear learning or after the event.
Picture predicts pain stimulus
During magnetic resonance brain imaging (MRI), participants saw neutral pictures of faces and houses, some of which were followed by a small electric shock. In this way, the participants formed fear memories. They showed fear responses when the pictures were shown that were paired with shocks. This fear response can be measured in the brain, but is also evident from increased pupil dilation when someone sees the picture. After a few weeks, the participants returned to the lab and were shown the same images. Brain activity and pupil diameter were once again measured. The extent to which the pupil dilated when seeing the images that were previously followed by a shock, was considered an expression of the previously formed fear memory.
Pattern Analysis
In order to analyse the fMRI data, (spatial) patterns of brain activity (Multi-Voxel Pattern Analysis, or MVPA) were analysed. By correlating patterns of various stimulus presentations with each other, it is possible to measure the extent to which the representation of two stimuli is the same. It appears that images that have nothing in common, such as houses and faces, lead to increasing neural pattern similarity when they predict danger. This does not occur when they do not predict danger. This leads to the formation of stronger fear responses. The extent to which this occurs is an indication of fear memory formation: the stronger the response during learning, the stronger the fear response will be in the long term.
These findings may lead to greater insights into the formation of emotional memory. As a result, it is possible to conduct experimental research into the mechanisms that strengthen, weaken or even erase fear memory in a more direct fashion, without having to wait until the fear memory is expressed.
The research is part of the Vici project of Prof. Merel Kindt, which is funded by the Netherlands Organisation for Scientific Research (NWO).
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