Neuroscience

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Posts tagged hippocampus

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The effects of very early Alzheimer’s disease on the characteristics of writing by a renowned author

Iris Murdoch (I.M.) was among the most celebrated British writers of the post-war era. Her final novel, however, received a less than enthusiastic critical response on its publication in 1995. Not long afterwards, I.M. began to show signs of insidious cognitive decline, and received a diagnosis of Alzheimer’s disease, which was confirmed histologically after her death in 1999. Anecdotal evidence, as well as the natural history of the condition, would suggest that the changes of Alzheimer’s disease were already established in I.M. while she was writing her final work. The end product was unlikely, however, to have been influenced by the compensatory use of dictionaries or thesauri, let alone by later editorial interference. These facts present a unique opportunity to examine the effects of the early stages of Alzheimer’s disease on spontaneous written output from an individual with exceptional expertise in this area. Techniques of automated textual analysis were used to obtain detailed comparisons among three of her novels: her first published work, a work written during the prime of her creative life and the final novel. Whilst there were few disparities at the levels of overall structure and syntax, measures of lexical diversity and the lexical characteristics of these three texts varied markedly and in a consistent fashion. This unique set of findings is discussed in the context of the debate as to whether syntax and semantics decline separately or in parallel in patients with Alzheimer’s disease.

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Filed under Iris Murdoch alzheimer's disease cognitive decline hippocampus semantics syntax neuroscience science

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Neuroscientists watch imagination happening in the brain
“You may say I’m a dreamer, but I’m not the only one,” sang John Lennon in his 1971 song Imagine.
And thanks to the dreams of a BYU student, we now know more about where and how imagination happens in our brains.
Stefania Ashby and her faculty mentor devised experiments using MRI technology that would help them distinguish pure imagination from related processes like remembering.
“I was thinking a lot about planning for my own future and imagining myself in the future, and I started wondering how memory and imagination work together,” Ashby said. “I wondered if they were separate or if imagination is just taking past memories and combining them in different ways to form something I’ve never experienced before.”
There’s a bit of scientific debate over whether memory and imagination truly are distinct processes. So Ashby and her faculty mentor devised MRI experiments to put it to the test.
They asked study participants to provide 60 personal photographs for the “remember” section of the experiment. Participants also filled out a questionnaire beforehand to determine which scenarios would be unfamiliar to them and thus a better fit for the “imagine” section.
The researchers then showed people their own photographs during an MRI session to elicit brain activity that is strictly memory-based. A statistical analysis revealed distinctive patterns for memory and imagination.
“We were able to see the distinctions even in those small regions of the hippocampus,” Ashby said. “It’s really neat that we can see the difference between those two tasks in that small of a brain region.”
Ashby co-authored the study with BYU psychology and neuroscience professor Brock Kirwan for the journal Cognitive Neuroscience. Kirwan studies memory at Brigham Young University, and Ashby is one of many students that he has mentored.
“Stefania came in really excited about this project, she pitched it to me, and basically sold it to me right there,” Kirwan said. “It was really cool because it gave me a chance to become more immersed and really broaden my horizons.”
Stefania graduated in 2011 and is currently working as a research associate at UC Davis, where she uses neuroimaging to study individuals at risk of psychotic disorders such as schizophrenia. Her plan is to earn a Ph.D. in neuroscience and continue researching.

Neuroscientists watch imagination happening in the brain

“You may say I’m a dreamer, but I’m not the only one,” sang John Lennon in his 1971 song Imagine.

And thanks to the dreams of a BYU student, we now know more about where and how imagination happens in our brains.

Stefania Ashby and her faculty mentor devised experiments using MRI technology that would help them distinguish pure imagination from related processes like remembering.

“I was thinking a lot about planning for my own future and imagining myself in the future, and I started wondering how memory and imagination work together,” Ashby said. “I wondered if they were separate or if imagination is just taking past memories and combining them in different ways to form something I’ve never experienced before.”

There’s a bit of scientific debate over whether memory and imagination truly are distinct processes. So Ashby and her faculty mentor devised MRI experiments to put it to the test.

They asked study participants to provide 60 personal photographs for the “remember” section of the experiment. Participants also filled out a questionnaire beforehand to determine which scenarios would be unfamiliar to them and thus a better fit for the “imagine” section.

The researchers then showed people their own photographs during an MRI session to elicit brain activity that is strictly memory-based. A statistical analysis revealed distinctive patterns for memory and imagination.

“We were able to see the distinctions even in those small regions of the hippocampus,” Ashby said. “It’s really neat that we can see the difference between those two tasks in that small of a brain region.”

Ashby co-authored the study with BYU psychology and neuroscience professor Brock Kirwan for the journal Cognitive Neuroscience. Kirwan studies memory at Brigham Young University, and Ashby is one of many students that he has mentored.

“Stefania came in really excited about this project, she pitched it to me, and basically sold it to me right there,” Kirwan said. “It was really cool because it gave me a chance to become more immersed and really broaden my horizons.”

Stefania graduated in 2011 and is currently working as a research associate at UC Davis, where she uses neuroimaging to study individuals at risk of psychotic disorders such as schizophrenia. Her plan is to earn a Ph.D. in neuroscience and continue researching.

Filed under imagination memory hippocampus neuroimaging brain activity neuroscience science

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Electric Current to Brain Boosts Memory
Stimulating a particular region in the brain via non-invasive delivery of electrical current using magnetic pulses, called Transcranial Magnetic Stimulation, improves memory, reports a new Northwestern Medicine® study.
The discovery opens a new field of possibilities for treating memory impairments caused by conditions such as stroke, early-stage Alzheimer’s disease, traumatic brain injury, cardiac arrest and the memory problems that occur in healthy aging.
“We show for the first time that you can specifically change memory functions of the brain in adults without surgery or drugs, which have not proven effective,” said senior author Joel Voss, assistant professor of medical social sciences at Northwestern University Feinberg School of Medicine. “This noninvasive stimulation improves the ability to learn new things. It has tremendous potential for treating memory disorders.”
The study was published August 29 in Science.
The study also is the first to demonstrate that remembering events requires a collection of many brain regions to work in concert with a key memory structure called the hippocampus – similar to a symphony orchestra. The electrical stimulation is like giving the brain regions a more talented conductor so they play in closer synchrony. 
“It’s like we replaced their normal conductor with Muti,” Voss said, referring to Riccardo Muti, the music director of the renowned Chicago Symphony Orchestra. “The brain regions played together better after the stimulation.”
The approach also has potential for treating mental disorders such as schizophrenia in which these brain regions and the hippocampus are out of sync with each other, affecting memory and cognition.    
TMS Boosts Memory 
The Northwestern study is the first to show TMS improves memory long after treatment. In the past, TMS has been used in a limited way to temporarily change brain function to improve performance during a test, for example, making someone push a button slightly faster while the brain is being stimulated. The study shows that TMS can be used to improve memory for events at least 24 hours after the stimulation is given.
Finding the Sweet Spot
It isn’t possible to directly stimulate the hippocampus with TMS because it’s too deep in the brain for the magnetic fields to penetrate. So, using an MRI scan, Voss and colleagues identified a superficial brain region a mere centimeter from the surface of the skull with high connectivity to the hippocampus. He wanted to see if directing the stimulation to this spot would in turn stimulate the hippocampus. It did.
“I was astonished to see that it worked so specifically,” Voss said.
When TMS was used to stimulate this spot, regions in the brain involved with the hippocampus became more synchronized with each other, as indicated by data taken while subjects were inside an MRI machine, which records the blood flow in the brain as an indirect measure of neuronal activity.
The more those regions worked together due to the stimulation, the better people were able to learn new information.
How the Study Worked
Scientists recruited 16 healthy adults ages 21 to 40. Each had a detailed anatomical image taken of his or her brain as well as 10 minutes of recording brain activity while lying quietly inside an MRI scanner. Doing this allowed the researchers to identify each person’s network of brain structures that are involved in memory and well connected to the hippocampus. The structures are slightly different in each person and may vary in location by as much as a few centimeters.
“To properly target the stimulation, we had to identify the structures in each person’s brain space because everyone’s brain is different,” Voss said. 
Each participant then underwent a memory test, consisting of a set of arbitrary associations between faces and words that they were asked to learn and remember. After establishing their baseline ability to perform on this memory task, participants received brain stimulation 20 minutes a day for five consecutive days. 
During the week they also received additional MRI scans and tests of their ability to remember new sets of arbitrary word and face parings to see how their memory changed as a result of the stimulation. Then, at least 24 hours after the final stimulation, they were tested again.
At least one week later, the same experiment was repeated but with a fake placebo stimulation. The order of real stimulation and placebo portions of the study was reversed for half of the participants, and they weren’t told which was which.
Both groups performed better on memory tests as a result of the brain stimulation. It took three days of stimulation before they improved.
“They remembered more face-word pairings after the stimulation than before, which means their learning ability improved,” Voss said. “That didn’t happen for the placebo condition or in another control experiment with additional subjects.”
In addition, the MRI showed the stimulation caused the brain regions to become more synchronized with each other and the hippocampus. The greater the improvement in the synchronicity or connectivity between specific parts of the network, the better the performance on the memory test. “The more certain brain regions worked together because of the stimulation, the more people were able to learn face-word pairings, “ Voss said.
Using TMS to stimulate memory has multiple advantages, noted first author Jane Wang, a postdoctoral fellow in Voss’s lab at Feinberg. “No medication could be as specific as TMS for these memory networks,” Wang said. “There are a lot of different targets and it’s not easy to come up with any one receptor that’s involved in memory.”
The Future 
“This opens up a whole new area for treatment studies where we will try to see if we can improve function in people who really need it,“ Voss said.
His current study was with people who had normal memory, in whom he wouldn’t expect to see a big improvement because their brains are already working effectively.
“But for a person with brain damage or a memory disorder, those networks are disrupted so even a small change could translate into gains in their function,” Voss said.
In an upcoming trial, Voss will study the electrical stimulation’s effect on people with early-stage memory loss.
Voss cautioned that years of research are needed to determine whether this approach is safe or effective for patients with Alzheimer’s disease or similar disorders of memory.

Electric Current to Brain Boosts Memory

Stimulating a particular region in the brain via non-invasive delivery of electrical current using magnetic pulses, called Transcranial Magnetic Stimulation, improves memory, reports a new Northwestern Medicine® study.

The discovery opens a new field of possibilities for treating memory impairments caused by conditions such as stroke, early-stage Alzheimer’s disease, traumatic brain injury, cardiac arrest and the memory problems that occur in healthy aging.

“We show for the first time that you can specifically change memory functions of the brain in adults without surgery or drugs, which have not proven effective,” said senior author Joel Voss, assistant professor of medical social sciences at Northwestern University Feinberg School of Medicine. “This noninvasive stimulation improves the ability to learn new things. It has tremendous potential for treating memory disorders.”

The study was published August 29 in Science.

The study also is the first to demonstrate that remembering events requires a collection of many brain regions to work in concert with a key memory structure called the hippocampus – similar to a symphony orchestra. The electrical stimulation is like giving the brain regions a more talented conductor so they play in closer synchrony. 

“It’s like we replaced their normal conductor with Muti,” Voss said, referring to Riccardo Muti, the music director of the renowned Chicago Symphony Orchestra. “The brain regions played together better after the stimulation.”

The approach also has potential for treating mental disorders such as schizophrenia in which these brain regions and the hippocampus are out of sync with each other, affecting memory and cognition.    

TMS Boosts Memory 

The Northwestern study is the first to show TMS improves memory long after treatment. In the past, TMS has been used in a limited way to temporarily change brain function to improve performance during a test, for example, making someone push a button slightly faster while the brain is being stimulated. The study shows that TMS can be used to improve memory for events at least 24 hours after the stimulation is given.

Finding the Sweet Spot

It isn’t possible to directly stimulate the hippocampus with TMS because it’s too deep in the brain for the magnetic fields to penetrate. So, using an MRI scan, Voss and colleagues identified a superficial brain region a mere centimeter from the surface of the skull with high connectivity to the hippocampus. He wanted to see if directing the stimulation to this spot would in turn stimulate the hippocampus. It did.

“I was astonished to see that it worked so specifically,” Voss said.

When TMS was used to stimulate this spot, regions in the brain involved with the hippocampus became more synchronized with each other, as indicated by data taken while subjects were inside an MRI machine, which records the blood flow in the brain as an indirect measure of neuronal activity.

The more those regions worked together due to the stimulation, the better people were able to learn new information.

How the Study Worked

Scientists recruited 16 healthy adults ages 21 to 40. Each had a detailed anatomical image taken of his or her brain as well as 10 minutes of recording brain activity while lying quietly inside an MRI scanner. Doing this allowed the researchers to identify each person’s network of brain structures that are involved in memory and well connected to the hippocampus. The structures are slightly different in each person and may vary in location by as much as a few centimeters.

“To properly target the stimulation, we had to identify the structures in each person’s brain space because everyone’s brain is different,” Voss said. 

Each participant then underwent a memory test, consisting of a set of arbitrary associations between faces and words that they were asked to learn and remember. After establishing their baseline ability to perform on this memory task, participants received brain stimulation 20 minutes a day for five consecutive days. 

During the week they also received additional MRI scans and tests of their ability to remember new sets of arbitrary word and face parings to see how their memory changed as a result of the stimulation. Then, at least 24 hours after the final stimulation, they were tested again.

At least one week later, the same experiment was repeated but with a fake placebo stimulation. The order of real stimulation and placebo portions of the study was reversed for half of the participants, and they weren’t told which was which.

Both groups performed better on memory tests as a result of the brain stimulation. It took three days of stimulation before they improved.

“They remembered more face-word pairings after the stimulation than before, which means their learning ability improved,” Voss said. “That didn’t happen for the placebo condition or in another control experiment with additional subjects.”

In addition, the MRI showed the stimulation caused the brain regions to become more synchronized with each other and the hippocampus. The greater the improvement in the synchronicity or connectivity between specific parts of the network, the better the performance on the memory test. “The more certain brain regions worked together because of the stimulation, the more people were able to learn face-word pairings, “ Voss said.

Using TMS to stimulate memory has multiple advantages, noted first author Jane Wang, a postdoctoral fellow in Voss’s lab at Feinberg. “No medication could be as specific as TMS for these memory networks,” Wang said. “There are a lot of different targets and it’s not easy to come up with any one receptor that’s involved in memory.”

The Future 

“This opens up a whole new area for treatment studies where we will try to see if we can improve function in people who really need it,“ Voss said.

His current study was with people who had normal memory, in whom he wouldn’t expect to see a big improvement because their brains are already working effectively.

“But for a person with brain damage or a memory disorder, those networks are disrupted so even a small change could translate into gains in their function,” Voss said.

In an upcoming trial, Voss will study the electrical stimulation’s effect on people with early-stage memory loss.

Voss cautioned that years of research are needed to determine whether this approach is safe or effective for patients with Alzheimer’s disease or similar disorders of memory.

Filed under memory transcranial magnetic stimulation hippocampus brain stimulation brain activity neuroscience science

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(Image caption: This image depicts the injection sites and the expression of the viral constructs in the two areas of the brain studied: the Dentate Gyrus of the hippocampus (middle) and the Basolateral Amygdala (bottom corners). Image courtesy of the researchers)
Neuroscientists reverse memories’ emotional associations
Most memories have some kind of emotion associated with them: Recalling the week you just spent at the beach probably makes you feel happy, while reflecting on being bullied provokes more negative feelings.
A new study from MIT neuroscientists reveals the brain circuit that controls how memories become linked with positive or negative emotions. Furthermore, the researchers found that they could reverse the emotional association of specific memories by manipulating brain cells with optogenetics — a technique that uses light to control neuron activity.
The findings, described in the Aug. 27 issue of Nature, demonstrated that a neuronal circuit connecting the hippocampus and the amygdala plays a critical role in associating emotion with memory. This circuit could offer a target for new drugs to help treat conditions such as post-traumatic stress disorder, the researchers say.
“In the future, one may be able to develop methods that help people to remember positive memories more strongly than negative ones,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, director of the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory, and senior author of the paper.
The paper’s lead authors are Roger Redondo, a Howard Hughes Medical Institute postdoc at MIT, and Joshua Kim, a graduate student in MIT’s Department of Biology.
Shifting memories
Memories are made of many elements, which are stored in different parts of the brain. A memory’s context, including information about the location where the event took place, is stored in cells of the hippocampus, while emotions linked to that memory are found in the amygdala.
Previous research has shown that many aspects of memory, including emotional associations, are malleable. Psychotherapists have taken advantage of this to help patients suffering from depression and post-traumatic stress disorder, but the neural circuitry underlying such malleability is not known.
In this study, the researchers set out to explore that malleability with an experimental technique they recently devised that allows them to tag neurons that encode a specific memory, or engram. To achieve this, they label hippocampal cells that are turned on during memory formation with a light-sensitive protein called channelrhodopsin. From that point on, any time those cells are activated with light, the mice recall the memory encoded by that group of cells.
Last year, Tonegawa’s lab used this technique to implant, or “incept,” false memories in mice by reactivating engrams while the mice were undergoing a different experience. In the new study, the researchers wanted to investigate how the context of a memory becomes linked to a particular emotion. First, they used their engram-labeling protocol to tag neurons associated with either a rewarding experience (for male mice, socializing with a female mouse) or an unpleasant experience (a mild electrical shock). In this first set of experiments, the researchers labeled memory cells in a part of the hippocampus called the dentate gyrus.
Two days later, the mice were placed into a large rectangular arena. For three minutes, the researchers recorded which half of the arena the mice naturally preferred. Then, for mice that had received the fear conditioning, the researchers stimulated the labeled cells in the dentate gyrus with light whenever the mice went into the preferred side. The mice soon began avoiding that area, showing that the reactivation of the fear memory had been successful.
The reward memory could also be reactivated: For mice that were reward-conditioned, the researchers stimulated them with light whenever they went into the less-preferred side, and they soon began to spend more time there, recalling the pleasant memory.
A couple of days later, the researchers tried to reverse the mice’s emotional responses. For male mice that had originally received the fear conditioning, they activated the memory cells involved in the fear memory with light for 12 minutes while the mice spent time with female mice. For mice that had initially received the reward conditioning, memory cells were activated while they received mild electric shocks.
Next, the researchers again put the mice in the large two-zone arena. This time, the mice that had originally been conditioned with fear and had avoided the side of the chamber where their hippocampal cells were activated by the laser now began to spend more time in that side when their hippocampal cells were activated, showing that a pleasant association had replaced the fearful one. This reversal also took place in mice that went from reward to fear conditioning.
Altered connections
The researchers then performed the same set of experiments but labeled memory cells in the basolateral amygdala, a region involved in processing emotions. This time, they could not induce a switch by reactivating those cells — the mice continued to behave as they had been conditioned when the memory cells were first labeled.
This suggests that emotional associations, also called valences, are encoded somewhere in the neural circuitry that connects the dentate gyrus to the amygdala, the researchers say. A fearful experience strengthens the connections between the hippocampal engram and fear-encoding cells in the amygdala, but that connection can be weakened later on as new connections are formed between the hippocampus and amygdala cells that encode positive associations.
“That plasticity of the connection between the hippocampus and the amygdala plays a crucial role in the switching of the valence of the memory,” Tonegawa says.
These results indicate that while dentate gyrus cells are neutral with respect to emotion, individual amygdala cells are precommitted to encode fear or reward memory. The researchers are now trying to discover molecular signatures of these two types of amygdala cells. They are also investigating whether reactivating pleasant memories has any effect on depression, in hopes of identifying new targets for drugs to treat depression and post-traumatic stress disorder.
David Anderson, a professor of biology at the California Institute of Technology, says the study makes an important contribution to neuroscientists’ fundamental understanding of the brain and also has potential implications for treating mental illness.
“This is a tour de force of modern molecular-biology-based methods for analyzing processes, such as learning and memory, at the neural-circuitry level. It’s one of the most sophisticated studies of this type that I’ve seen,” he says.

(Image caption: This image depicts the injection sites and the expression of the viral constructs in the two areas of the brain studied: the Dentate Gyrus of the hippocampus (middle) and the Basolateral Amygdala (bottom corners). Image courtesy of the researchers)

Neuroscientists reverse memories’ emotional associations

Most memories have some kind of emotion associated with them: Recalling the week you just spent at the beach probably makes you feel happy, while reflecting on being bullied provokes more negative feelings.

A new study from MIT neuroscientists reveals the brain circuit that controls how memories become linked with positive or negative emotions. Furthermore, the researchers found that they could reverse the emotional association of specific memories by manipulating brain cells with optogenetics — a technique that uses light to control neuron activity.

The findings, described in the Aug. 27 issue of Nature, demonstrated that a neuronal circuit connecting the hippocampus and the amygdala plays a critical role in associating emotion with memory. This circuit could offer a target for new drugs to help treat conditions such as post-traumatic stress disorder, the researchers say.

“In the future, one may be able to develop methods that help people to remember positive memories more strongly than negative ones,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, director of the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory, and senior author of the paper.

The paper’s lead authors are Roger Redondo, a Howard Hughes Medical Institute postdoc at MIT, and Joshua Kim, a graduate student in MIT’s Department of Biology.

Shifting memories

Memories are made of many elements, which are stored in different parts of the brain. A memory’s context, including information about the location where the event took place, is stored in cells of the hippocampus, while emotions linked to that memory are found in the amygdala.

Previous research has shown that many aspects of memory, including emotional associations, are malleable. Psychotherapists have taken advantage of this to help patients suffering from depression and post-traumatic stress disorder, but the neural circuitry underlying such malleability is not known.

In this study, the researchers set out to explore that malleability with an experimental technique they recently devised that allows them to tag neurons that encode a specific memory, or engram. To achieve this, they label hippocampal cells that are turned on during memory formation with a light-sensitive protein called channelrhodopsin. From that point on, any time those cells are activated with light, the mice recall the memory encoded by that group of cells.

Last year, Tonegawa’s lab used this technique to implant, or “incept,” false memories in mice by reactivating engrams while the mice were undergoing a different experience. In the new study, the researchers wanted to investigate how the context of a memory becomes linked to a particular emotion. First, they used their engram-labeling protocol to tag neurons associated with either a rewarding experience (for male mice, socializing with a female mouse) or an unpleasant experience (a mild electrical shock). In this first set of experiments, the researchers labeled memory cells in a part of the hippocampus called the dentate gyrus.

Two days later, the mice were placed into a large rectangular arena. For three minutes, the researchers recorded which half of the arena the mice naturally preferred. Then, for mice that had received the fear conditioning, the researchers stimulated the labeled cells in the dentate gyrus with light whenever the mice went into the preferred side. The mice soon began avoiding that area, showing that the reactivation of the fear memory had been successful.

The reward memory could also be reactivated: For mice that were reward-conditioned, the researchers stimulated them with light whenever they went into the less-preferred side, and they soon began to spend more time there, recalling the pleasant memory.

A couple of days later, the researchers tried to reverse the mice’s emotional responses. For male mice that had originally received the fear conditioning, they activated the memory cells involved in the fear memory with light for 12 minutes while the mice spent time with female mice. For mice that had initially received the reward conditioning, memory cells were activated while they received mild electric shocks.

Next, the researchers again put the mice in the large two-zone arena. This time, the mice that had originally been conditioned with fear and had avoided the side of the chamber where their hippocampal cells were activated by the laser now began to spend more time in that side when their hippocampal cells were activated, showing that a pleasant association had replaced the fearful one. This reversal also took place in mice that went from reward to fear conditioning.

Altered connections

The researchers then performed the same set of experiments but labeled memory cells in the basolateral amygdala, a region involved in processing emotions. This time, they could not induce a switch by reactivating those cells — the mice continued to behave as they had been conditioned when the memory cells were first labeled.

This suggests that emotional associations, also called valences, are encoded somewhere in the neural circuitry that connects the dentate gyrus to the amygdala, the researchers say. A fearful experience strengthens the connections between the hippocampal engram and fear-encoding cells in the amygdala, but that connection can be weakened later on as new connections are formed between the hippocampus and amygdala cells that encode positive associations.

“That plasticity of the connection between the hippocampus and the amygdala plays a crucial role in the switching of the valence of the memory,” Tonegawa says.

These results indicate that while dentate gyrus cells are neutral with respect to emotion, individual amygdala cells are precommitted to encode fear or reward memory. The researchers are now trying to discover molecular signatures of these two types of amygdala cells. They are also investigating whether reactivating pleasant memories has any effect on depression, in hopes of identifying new targets for drugs to treat depression and post-traumatic stress disorder.

David Anderson, a professor of biology at the California Institute of Technology, says the study makes an important contribution to neuroscientists’ fundamental understanding of the brain and also has potential implications for treating mental illness.

“This is a tour de force of modern molecular-biology-based methods for analyzing processes, such as learning and memory, at the neural-circuitry level. It’s one of the most sophisticated studies of this type that I’ve seen,” he says.

Filed under optogenetics hippocampus memory emotions amygdala dentate gyrus neuroscience science

240 notes

How the Brain Makes Sense of Spaces, Large and Small







When an animal encounters a new environment, the neurons in its brain that are responsible for mapping out the space are ready for anything. So says a new study in which scientists at the Howard Hughes Medical Institute’s Janelia Research Campus examined neuronal activity in rats as they explored an unusually large maze for the first time.
The researchers found that neurons in the brain’s hippocampus, where information about people, places, and events is stored, each contribute to an animal’s mental map at their own rate. Some neurons begin to associate themselves with the new space immediately, while others hold back, contributing only if the space expands beyond a size that can be represented by the first-line neurons. Similar mechanisms may be at play as the human brain records a new experience, says Janelia group leader Albert Lee, who led the study. Lee, graduate student Dylan Rich, and Hua Peng-Liaw, a technician in Lee’s lab, published their findings in the August 15, 2014, issue of the journal Science.
“The hippocampus has to represent arbitrary things,” Lee says. “When a new experience begins, we don’t know how long it’s going to last, and the brain has to form a new representation on the fly. This mechanism means that the hippocampus doesn’t have to adjust its representation if an environment is larger than predicted, or if an experience goes on longer than expected.”
As an animal explores a new environment, cells in its hippocampus fire to mark new places that it encounters. The cells, called place cells, fire randomly, but become associated with the shapes, smells, and other sensory cues present in that location. In humans, analogous cells store memories of people, places, facts, and events.
In rodents, about a third of the cells in the region of the hippocampus devoted to spatial learning participate in mapping a typical laboratory-sized maze. Different mazes are represented by different but overlapping sets of neurons. The differences between those sets allow the brain to distinguish between memories of different environments.
But what happens when an animal finds itself in an environment larger than a five-meter laboratory maze? In the wild, rats can traverse territories as long as 50 meters. Lee wanted to know how the hippocampus kept track of environments that placed greater demands on its neurons.
If cells continued to mark off space at the rate that scientists had observed in more confined environments, the animal’s mental map would quickly lose its uniqueness. “If every cell is active in the representation of a single space, then you can’t use this mechanism to distinguish memories of different things,” Lee points out. 
So Lee and his team stocked up on supplies from the hardware store and built their own maze, far larger than any that had been used previously to track place cell activity. The 48-meter maze wouldn’t fit inside Lee’s lab, so Lee, Rich, and Liaw set it up in a large cage-cleaning room at Janelia.
The room was busy during the week, so the team did their experiments on weekends. For multiple weekends over the course of about two years, Janelia’s vivarium staff would clear the room for them, and then the team would reassemble the maze and set up video cameras and electrophysiology equipment. The team recorded the activity of individual cells in the hippocampus as rats explored the maze for the first time. They first introduced the animals to a small portion of the maze, then gradually increased the territory to which the rats had access, monitoring how the brain added new information to its spatial map.
When the scientists analyzed their data, they discovered that from the time the rats entered the maze, their brains were ready to represent an environment of any size. “Instead of the hippocampus having to adjust in time as the animal notices that the maze gets larger, it anticipates all different sizes of mazes from the beginning,” Lee says. “It does this by dividing up its population of neurons so that certain ones are ready to represent smaller mazes, others are ready to represent medium-size mazes, and others, large ones.”
All of the neurons acted independently, firing randomly to mark off places in the maze. But some neurons had a greater propensity to mark off space than others, Lee explains. Some neurons mark space quickly and become associated with many places in the maze, whereas others are less likely to fire. These, Lee says, are reserved for mapping larger spaces.
In small environments, a subset of the cells that are most likely to mark off space – those that have a chance to fire while the animal explores – form the map on their own. In larger mazes, all of the neurons with a high propensity to mark space are recruited to the mapping effort, meaning they cannot be used to distinguish the representation of one large maze from another. That’s when the neurons with a lower tendency to fire step in, randomly marking space in a distinct, identifying set.
“There’s always a set of neurons that is just at the edge, where they are equally likely to represent any given environment versus not, regardless of what its size is,” Lee says. “Those are the neurons the brain can actually use to distinguish which environment its in.”
The system means the brain never has to adjust its representation of an environment as it is being created, Lee says. “All neurons are marking space at their own preferred rate, so there doesn’t have to be a mechanism to say, ‘you should fire because this maze is large or this maze is small.’ The hippocampus is ready for anything at any moment.”
Cells in the human brain may record events in a similar way, marking off time as an event unfolds without knowing how long it will continue, Lee says.

How the Brain Makes Sense of Spaces, Large and Small

When an animal encounters a new environment, the neurons in its brain that are responsible for mapping out the space are ready for anything. So says a new study in which scientists at the Howard Hughes Medical Institute’s Janelia Research Campus examined neuronal activity in rats as they explored an unusually large maze for the first time.

The researchers found that neurons in the brain’s hippocampus, where information about people, places, and events is stored, each contribute to an animal’s mental map at their own rate. Some neurons begin to associate themselves with the new space immediately, while others hold back, contributing only if the space expands beyond a size that can be represented by the first-line neurons. Similar mechanisms may be at play as the human brain records a new experience, says Janelia group leader Albert Lee, who led the study. Lee, graduate student Dylan Rich, and Hua Peng-Liaw, a technician in Lee’s lab, published their findings in the August 15, 2014, issue of the journal Science.

“The hippocampus has to represent arbitrary things,” Lee says. “When a new experience begins, we don’t know how long it’s going to last, and the brain has to form a new representation on the fly. This mechanism means that the hippocampus doesn’t have to adjust its representation if an environment is larger than predicted, or if an experience goes on longer than expected.”

As an animal explores a new environment, cells in its hippocampus fire to mark new places that it encounters. The cells, called place cells, fire randomly, but become associated with the shapes, smells, and other sensory cues present in that location. In humans, analogous cells store memories of people, places, facts, and events.

In rodents, about a third of the cells in the region of the hippocampus devoted to spatial learning participate in mapping a typical laboratory-sized maze. Different mazes are represented by different but overlapping sets of neurons. The differences between those sets allow the brain to distinguish between memories of different environments.

But what happens when an animal finds itself in an environment larger than a five-meter laboratory maze? In the wild, rats can traverse territories as long as 50 meters. Lee wanted to know how the hippocampus kept track of environments that placed greater demands on its neurons.

If cells continued to mark off space at the rate that scientists had observed in more confined environments, the animal’s mental map would quickly lose its uniqueness. “If every cell is active in the representation of a single space, then you can’t use this mechanism to distinguish memories of different things,” Lee points out. 

So Lee and his team stocked up on supplies from the hardware store and built their own maze, far larger than any that had been used previously to track place cell activity. The 48-meter maze wouldn’t fit inside Lee’s lab, so Lee, Rich, and Liaw set it up in a large cage-cleaning room at Janelia.

The room was busy during the week, so the team did their experiments on weekends. For multiple weekends over the course of about two years, Janelia’s vivarium staff would clear the room for them, and then the team would reassemble the maze and set up video cameras and electrophysiology equipment. The team recorded the activity of individual cells in the hippocampus as rats explored the maze for the first time. They first introduced the animals to a small portion of the maze, then gradually increased the territory to which the rats had access, monitoring how the brain added new information to its spatial map.

When the scientists analyzed their data, they discovered that from the time the rats entered the maze, their brains were ready to represent an environment of any size. “Instead of the hippocampus having to adjust in time as the animal notices that the maze gets larger, it anticipates all different sizes of mazes from the beginning,” Lee says. “It does this by dividing up its population of neurons so that certain ones are ready to represent smaller mazes, others are ready to represent medium-size mazes, and others, large ones.”

All of the neurons acted independently, firing randomly to mark off places in the maze. But some neurons had a greater propensity to mark off space than others, Lee explains. Some neurons mark space quickly and become associated with many places in the maze, whereas others are less likely to fire. These, Lee says, are reserved for mapping larger spaces.

In small environments, a subset of the cells that are most likely to mark off space – those that have a chance to fire while the animal explores – form the map on their own. In larger mazes, all of the neurons with a high propensity to mark space are recruited to the mapping effort, meaning they cannot be used to distinguish the representation of one large maze from another. That’s when the neurons with a lower tendency to fire step in, randomly marking space in a distinct, identifying set.

“There’s always a set of neurons that is just at the edge, where they are equally likely to represent any given environment versus not, regardless of what its size is,” Lee says. “Those are the neurons the brain can actually use to distinguish which environment its in.”

The system means the brain never has to adjust its representation of an environment as it is being created, Lee says. “All neurons are marking space at their own preferred rate, so there doesn’t have to be a mechanism to say, ‘you should fire because this maze is large or this maze is small.’ The hippocampus is ready for anything at any moment.”

Cells in the human brain may record events in a similar way, marking off time as an event unfolds without knowing how long it will continue, Lee says.

Filed under hippocampus neural activity place cells neurons memory neuroscience science

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Can We Reconcile the Declarative Memory and Spatial Navigation Views on Hippocampal Function?
Some argue that hippocampus supports declarative memory, our capacity to recall facts and events, whereas others view the hippocampus as part of a system dedicated to calculating routes through space, and these two contrasting views are pursued largely independently in current research. Here we offer a perspective on where these views can and cannot be reconciled and update a bridging framework that will improve our understanding of hippocampal function.
Full Article

Can We Reconcile the Declarative Memory and Spatial Navigation Views on Hippocampal Function?

Some argue that hippocampus supports declarative memory, our capacity to recall facts and events, whereas others view the hippocampus as part of a system dedicated to calculating routes through space, and these two contrasting views are pursued largely independently in current research. Here we offer a perspective on where these views can and cannot be reconciled and update a bridging framework that will improve our understanding of hippocampal function.

Full Article

Filed under hippocampus memory spatial navigation neuroscience science

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Our connection to content
Using neuroscience tools, Innerscope Research explores the connections between consumers and media.
It’s often said that humans are wired to connect: The neural wiring that helps us read the emotions and actions of other people may be a foundation for human empathy.
But for the past eight years, MIT Media Lab spinout Innerscope Research has been using neuroscience technologies that gauge subconscious emotions by monitoring brain and body activity to show just how powerfully we also connect to media and marketing communications.
“We are wired to connect, but that connection system is not very discriminating. So while we connect with each other in powerful ways, we also connect with characters on screens and in books, and, we found, we also connect with brands, products, and services,” says Innerscope’s chief science officer, Carl Marci, a social neuroscientist and former Media Lab researcher.
With this core philosophy, Innerscope — co-founded at MIT by Marci and Brian Levine MBA ’05 — aims to offer market research that’s more advanced than traditional methods, such as surveys and focus groups, to help content-makers shape authentic relationships with their target consumers.
“There’s so much out there, it’s hard to make something people will notice or connect to,” Levine says. “In a way, we aim to be the good matchmaker between content and people.”
Read more

Our connection to content

Using neuroscience tools, Innerscope Research explores the connections between consumers and media.

It’s often said that humans are wired to connect: The neural wiring that helps us read the emotions and actions of other people may be a foundation for human empathy.

But for the past eight years, MIT Media Lab spinout Innerscope Research has been using neuroscience technologies that gauge subconscious emotions by monitoring brain and body activity to show just how powerfully we also connect to media and marketing communications.

“We are wired to connect, but that connection system is not very discriminating. So while we connect with each other in powerful ways, we also connect with characters on screens and in books, and, we found, we also connect with brands, products, and services,” says Innerscope’s chief science officer, Carl Marci, a social neuroscientist and former Media Lab researcher.

With this core philosophy, Innerscope — co-founded at MIT by Marci and Brian Levine MBA ’05 — aims to offer market research that’s more advanced than traditional methods, such as surveys and focus groups, to help content-makers shape authentic relationships with their target consumers.

“There’s so much out there, it’s hard to make something people will notice or connect to,” Levine says. “In a way, we aim to be the good matchmaker between content and people.”

Read more

Filed under advertising neuroimaging hippocampus amygdala prefrontal cortex precuneus empathy neuroscience science

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Our genes determine the traces that stress leaves behind on our brains

Our individual genetic make-up determines the effect that stress has on our emotional centres. These are the findings of a group of researchers from the MedUni Vienna. Not every individual reacts in the same way to life events that produce the same degree of stress. Some grow as a result of the crisis, whereas others break down and fall ill, for example with depression. The outcome is determined by a complex interaction between depression gene versions and environmental factors.

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The Vienna research group, together with international cooperation partners, have demonstrated that there are interactions between stressful life events and certain risk gene variants that subsequently change the volume of the hippocampus forever.

The hippocampus is a switching station in the processing of emotions and acts like a central interface when dealing with stress. It is known to react very sensitively to stress. In situations of stress that are interpreted as a physical danger (‘distress’), it shrinks in size, which is a phenomenon observed commonly in patients with depression and one which is responsible for some of their clinical symptoms. By contrast, positive stress (‘eustress’), of the kind that can occur in emotionally exciting social situations can actually cause the hippocampus to increase in size.

According to the results of the study, just how stressful life events impact on the size of the hippocampus depends on more than just environmental factors. There are genes that determine whether the same life event causes an increase or decrease in the volume of the hippocampus, and which therefore defines whether the stress is good or bad for our brain. The more risk genes an individual has, the more negative an impact the “life events” have on the size of the hippocampus. Where there are no or only a few risk genes, this life event can actually have a positive effect.

Examining life crises
As part of the study, carried out at the University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team obtained quantitative information from healthy test subjects about stressful life events, such as deaths in the family, divorce, unemployment, financial losses, relocations, serious illnesses or accidents.

A high-resolution anatomical magnetic resonance scan was also carried out (at the High-Field MR Centre of Excellence, Department of MR Physics, led by Ewald Moser). The University Department of Laboratory Medicine (Harald Esterbauer and colleagues) carried out the gene analyses (COMT Val158Met, BDNF Val66Met, 5-HTTLPR). At the University Department of Psychiatry and Psychotherapy, primary author Ulrich Rabl measured the volume of the test subjects’ hippocampi using computer-assisted techniques and analysed the results in the context of the genetic and environmental data.
"People with the three gene versions believed to encourage depression had a smaller hippocampus than those with fewer or none of these gene versions, even though they had the same number of stressful life events," says study leader Lukas Pezawas, describing the results. People with only one or even none of the risk genes, on the other hand, had an enlarged hippocampus with similar life events.

The study highlights the importance of gene and environment interaction as a determining factor for the volume of the hippocampus. “These results are important for understanding neurobiological processes in stress-associated illnesses such as depression or post-traumatic stress disorder. It is ultimately our genes that determine whether stress makes us psychologically unwell or whether it encourages our mental health,” explains Pezawas.

The study, published in the highly respected “Journal of Neuroscience”, was funded by a special research project of the FWF (Austrian Science Fund) (SFB-35, led by Harald Sitte) and presented as a highlight at the international conference on “Organization for Human Brain Mapping”.

(Source: meduniwien.ac.at)

Filed under stress hippocampus genes environment genetics neuroscience science

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New research sheds light on how children’s brains memorize facts


As children learn basic arithmetic, they gradually switch from solving problems by counting on their fingers to pulling facts from memory. The shift comes more easily for some kids than for others, but no one knows why.
Now, new brain-imaging research gives the first evidence drawn from a longitudinal study to explain how the brain reorganizes itself as children learn math facts. A precisely orchestrated group of brain changes, many involving the memory center known as the hippocampus, are essential to the transformation, according to a study from the Stanford University School of Medicine.
The results, published online Aug. 17 in Nature Neuroscience, explain brain reorganization during normal development of cognitive skills and will serve as a point of comparison for future studies of what goes awry in the brains of children with learning disabilities.
“We wanted to understand how children acquire new knowledge, and determine why some children learn to retrieve facts from memory better than others,” said Vinod Menon, PhD, the Rachael L. and Walter F. Nichols, MD, Professor and  professor of psychiatry and behavioral sciences, and the senior author of the study. “This work provides insight into the dynamic changes that occur over the course of cognitive development in each child.”




The study also adds to prior research into the differences between how children’s and adults’ brains solve math problems. Children use certain brain regions, including the hippocampus and the prefrontal cortex, very differently from adults when the two groups are solving the same types of math problems, the study showed.
“It was surprising to us that the hippocampal and prefrontal contributions to memory-based problem-solving during childhood don’t look anything like what we would have expected for the adult brain,” said postdoctoral scholar Shaozheng Qin, PhD, who is the paper’s lead author.
Charting the shifting strategy
In the study, 28 children solved simple math problems while receiving two functional magnetic resonance imaging brain scans; the scans were done about 1.2 years apart. The researchers also scanned 20 adolescents and 20 adults at a single time point. At the start of the study, the children were ages 7-9. The adolescents were 14-17 and the adults were 19-22. The participants had normal IQs. Because the study examined normal math learning, potential participants with math-related learning disabilities and attention deficit hyperactivity disorder were excluded. The children and adolescents were studying math in school; the researchers did not provide any math instruction.
During the study, as the children aged from an average of 8.2 to 9.4 years, they became faster and more accurate at solving math problems, and relied more on retrieving math facts from memory and less on counting. As these shifts in strategy took place, the researchers saw several changes in the children’s brains. The hippocampus, a region with many roles in shaping new memories, was activated more in children’s brains after one year. Regions involved in counting, including parts of the prefrontal and parietal cortex, were activated less.


The scientists also saw changes in the degree to which the hippocampus was connected to other parts of children’s brains, with several parts of the prefrontal, anterior temporal cortex and parietal cortex more strongly connected to the hippocampus after one year. Crucially, the stronger these connections, the greater was each individual child’s ability to retrieve math facts from memory, a finding that suggests a starting point for future studies of math-learning disabilities.
Although children were using their hippocampus more after a year, adolescents and adults made minimal use of their hippocampus while solving math problems. Instead, they pulled math facts from well-developed information stores in the neocortex.
Memory scaffold
“What this means is that the hippocampus is providing a scaffold for learning and consolidating facts into long-term memory in children,” said Menon, who is also the Rachel L. and Walter F. Nichols, MD, Professor at the medical school. Children’s brains are building a schema for mathematical knowledge. The hippocampus helps support other parts of the brain as adultlike neural connections for solving math problems are being constructed. “In adults this scaffold is not needed because memory for math facts has most likely been consolidated into the neocortex,” he said. Interestingly, the research also showed that, although the adult hippocampus is not as strongly engaged as in children, it seems to keep a backup copy of the math information that adults usually draw from the neocortex.
The researchers compared the level of variation in patterns of brain activity as children, adolescents and adults correctly solved math problems. The brain’s activity patterns were more stable in adolescents and adults than in children, suggesting that as the brain gets better at solving math problems its activity becomes more consistent.
The next step, Menon said, is to compare the new findings about normal math learning to what happens in children with math-learning disabilities.
“In children with math-learning disabilities, we know that the ability to retrieve facts fluently is a basic problem, and remains a bottleneck for them in high school and college,” he said. “Is it that the hippocampus can’t provide a reliable scaffold to build good representations of math facts in other parts of the brain during the early stages of learning, and so the child continues to use inefficient strategies to solve math problems? We want to test this.”

New research sheds light on how children’s brains memorize facts

As children learn basic arithmetic, they gradually switch from solving problems by counting on their fingers to pulling facts from memory. The shift comes more easily for some kids than for others, but no one knows why.

Now, new brain-imaging research gives the first evidence drawn from a longitudinal study to explain how the brain reorganizes itself as children learn math facts. A precisely orchestrated group of brain changes, many involving the memory center known as the hippocampus, are essential to the transformation, according to a study from the Stanford University School of Medicine.

The results, published online Aug. 17 in Nature Neuroscience, explain brain reorganization during normal development of cognitive skills and will serve as a point of comparison for future studies of what goes awry in the brains of children with learning disabilities.

“We wanted to understand how children acquire new knowledge, and determine why some children learn to retrieve facts from memory better than others,” said Vinod Menon, PhD, the Rachael L. and Walter F. Nichols, MD, Professor and  professor of psychiatry and behavioral sciences, and the senior author of the study. “This work provides insight into the dynamic changes that occur over the course of cognitive development in each child.”

The study also adds to prior research into the differences between how children’s and adults’ brains solve math problems. Children use certain brain regions, including the hippocampus and the prefrontal cortex, very differently from adults when the two groups are solving the same types of math problems, the study showed.

“It was surprising to us that the hippocampal and prefrontal contributions to memory-based problem-solving during childhood don’t look anything like what we would have expected for the adult brain,” said postdoctoral scholar Shaozheng Qin, PhD, who is the paper’s lead author.

Charting the shifting strategy

In the study, 28 children solved simple math problems while receiving two functional magnetic resonance imaging brain scans; the scans were done about 1.2 years apart. The researchers also scanned 20 adolescents and 20 adults at a single time point. At the start of the study, the children were ages 7-9. The adolescents were 14-17 and the adults were 19-22. The participants had normal IQs. Because the study examined normal math learning, potential participants with math-related learning disabilities and attention deficit hyperactivity disorder were excluded. The children and adolescents were studying math in school; the researchers did not provide any math instruction.

During the study, as the children aged from an average of 8.2 to 9.4 years, they became faster and more accurate at solving math problems, and relied more on retrieving math facts from memory and less on counting. As these shifts in strategy took place, the researchers saw several changes in the children’s brains. The hippocampus, a region with many roles in shaping new memories, was activated more in children’s brains after one year. Regions involved in counting, including parts of the prefrontal and parietal cortex, were activated less.

The scientists also saw changes in the degree to which the hippocampus was connected to other parts of children’s brains, with several parts of the prefrontal, anterior temporal cortex and parietal cortex more strongly connected to the hippocampus after one year. Crucially, the stronger these connections, the greater was each individual child’s ability to retrieve math facts from memory, a finding that suggests a starting point for future studies of math-learning disabilities.

Although children were using their hippocampus more after a year, adolescents and adults made minimal use of their hippocampus while solving math problems. Instead, they pulled math facts from well-developed information stores in the neocortex.

Memory scaffold

“What this means is that the hippocampus is providing a scaffold for learning and consolidating facts into long-term memory in children,” said Menon, who is also the Rachel L. and Walter F. Nichols, MD, Professor at the medical school. Children’s brains are building a schema for mathematical knowledge. The hippocampus helps support other parts of the brain as adultlike neural connections for solving math problems are being constructed. “In adults this scaffold is not needed because memory for math facts has most likely been consolidated into the neocortex,” he said. Interestingly, the research also showed that, although the adult hippocampus is not as strongly engaged as in children, it seems to keep a backup copy of the math information that adults usually draw from the neocortex.

The researchers compared the level of variation in patterns of brain activity as children, adolescents and adults correctly solved math problems. The brain’s activity patterns were more stable in adolescents and adults than in children, suggesting that as the brain gets better at solving math problems its activity becomes more consistent.

The next step, Menon said, is to compare the new findings about normal math learning to what happens in children with math-learning disabilities.

“In children with math-learning disabilities, we know that the ability to retrieve facts fluently is a basic problem, and remains a bottleneck for them in high school and college,” he said. “Is it that the hippocampus can’t provide a reliable scaffold to build good representations of math facts in other parts of the brain during the early stages of learning, and so the child continues to use inefficient strategies to solve math problems? We want to test this.”

Filed under learning hippocampus memory neuroimaging child development cognitive development mathematics neuroscience science

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New Non-Invasive Technique Controls the Size of Molecules Penetrating the Blood-Brain Barrier

A new technique developed by Elisa Konofagou, professor of biomedical engineering and radiology at Columbia Engineering, has demonstrated for the first time that the size of molecules penetrating the blood-brain barrier (BBB) can be controlled using acoustic pressure—the pressure of an ultrasound beam—to let specific molecules through. The study was published in the July issue of the Journal of Cerebral Blood Flow & Metabolism.

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“This is an important breakthrough in getting drugs delivered to specific parts of the brain precisely, non-invasively, and safely, and may help in the treatment of central nervous system diseases like Parkinson’s and Alzheimer’s,” says Konofagou, whose National Institutes of Health Research Project Grant (R01) funding was just renewed for another four years for an additional $2.22 million. The award is for research to determine the role of the microbubble in controlling both the efficacy and safety of drug safety through the BBB with a specific application for treating Parkinson’s disease.

Most small—and all large—molecule drugs do not currently penetrate the blood-brain barrier that sits between the vascular bed and the brain tissue. “As a result,” Konofagou explains, “all central nervous system diseases remain undertreated at best. For example, we know that Parkinson’s disease would benefit by delivery of therapeutic molecules to the neurons so as to impede their slow death. But because of the virtually impermeable barrier, these drugs can only reach the brain through direct injection and that requires anesthesia and drilling the skull while also increasing the risk of infection and limiting the number of sites of injection. And transcranial injections rarely work—only about one in ten is successful.”

Focused ultrasound in conjunction with microbubbles—gas-filled bubbles coated by protein or lipid shells—continues to be the only technique that can permeate the BBB safely and non-invasively. When microbubbles are hit by an ultrasound beam, they start oscillating and, depending on the magnitude of the pressure, continue oscillating or collapse. While researchers have found that focused ultrasound in combination with microbubble cavitation can be successfully used in the delivery of therapeutic drugs across the BBB, almost all earlier studies have been limited to one specific-sized agent that is commercially available and widely used clinically as ultrasound contrast agents. Konofagou and her team were convinced there was a way to induce a size-controllable BBB opening, enabling a more effective method to improve localized brain drug delivery.

Konofagou targeted the hippocampus, the memory center of the brain, and administered different-sized sugar molecules (Dextran). She found that higher acoustic pressures led to larger molecules accumulating into the hippocampus as confirmed by fluorescence imaging. This demonstrated that the pressure of the ultrasound beam can be adjusted depending on the size of the drug that needs to be delivered to the brain: all molecules of variant sizes were able to penetrate the opened barrier but at distinct pressures, i.e., small molecules at lower pressures and larger molecules at higher pressures.

“Through this study, we’ve been able to show, for the first time, that we can control the BBB opening size through the use of acoustic pressure,” says Konofagou. “We’ve also learned much more about the physical mechanisms associated with the trans-BBB delivery of different-sized agents, and understanding the BBB mechanisms will help us to develop agent size-specific focused ultrasound treatment protocols.”

Konofagou and her Ultrasound Elasticity Imaging Laboratory team plan to continue to work on the treatment of Alzheimer’s and Parkinson’s in a range of models, and hope to test their technique in clinical trials within the next five years.

“It is frightening to think that in the 21st century we still have no idea how to treat most brain diseases,” Konofagou adds. “But we’re really excited because we now have a tool that could potentially change the current dire predictions that come with a neurological disorder diagnosis.”

(Source: engineering.columbia.edu)

Filed under blood–brain barrier hippocampus neurodegenerative diseases drug delivery neuroscience science

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