Tag Archives: circuits

Electrical and computer engineering Professor Barry Van Veen wears an electrode net used to monitor brain activity via EEG signals. His research could help untangle what happens in the brain during sleep and dreaming.

Photo Credit: Nick Berard/UW-Madison

Stanford scientists seek to map origins of mental illness and develop noninvasive treatment

An interdisciplinary team of scientists has convened to map the origins of mental illnesses in the brain and develop noninvasive technologies to treat the conditions. The collaboration could lead to improved treatments for depression, anxiety and post-traumatic stress disorder.

BY AMY ADAMS


Over the years imaging technologies have revealed a lot about what’s happening in our brains, including which parts are active in people with conditions like depression, anxiety or post-traumatic stress disorder. But here’s the secret Amit Etkin wants the world to know about those tantalizing images: they show the result of a brain state, not what caused it.

This is important because until we know how groups of neurons, called circuits, are causing these conditions – not just which are active later – scientists will never be able to treat them in a targeted way.

“You see things activated in brain images but you can’t tell just by watching what is cause and what is effect,” said Amit Etkin, an assistant professor of psychiatry and behavioral sciences. Etkin is co-leader of a new interdisciplinary initiative to understand what brain circuits underlie mental health conditions and then direct noninvasive treatments to those locations.

“Right now, if a patient with a mental illness goes to see their doctor they would likely be given a medication that goes all over the brain and body,” Etkin said. “While medications can work well, they do so for only a portion of people and often only partially.” Medications don’t specifically act on the brain circuits critically affected in that illness or individual.

The Big Idea: treat roots of mental illness

The new initiative, called NeuroCircuit, has the goal of finding the brain circuits that are responsible for mental health conditions and then developing ways of remotely stimulating those circuits and, the team hopes, potentially treating those conditions.

The initiative is part of the Stanford Neurosciences Institute‘s Big Ideas, which bring together teams of researchers from across disciplines to solve major problems in neuroscience and society. Stephen Baccus, an associate professor of neurobiology who co-leads the initiative with Etkin, said that what makes NeuroCircuit a big idea is the merging of teams trying to map circuits responsible for mental health conditions and teams developing new technologies to remotely access those circuits.

“Many psychiatric disorders, especially disorders of mood, probably involve malfunction within specific brain circuits that regulate emotion and motivation, yet our current pharmaceutical treatments affect circuits all over the brain,” said William Newsome, director of the Stanford Neurosciences Institute. “The ultimate goal of NeuroCircuit is more precise treatments, with minimal side effects, for specific psychiatric disorders.”

“The connection between the people who develop the technology and carry out research with the clinical goal, that’s what’s really come out of the Big Ideas,” Baccus said.

Brain control

Etkin has been working with a technology called transcranial magnetic stimulation, or TMS, to map and remotely stimulate parts of the brain. The device, which looks like a pair of doughnuts on a stick, generates a strong magnetic current that stimulates circuits near the surface of the brain.

TMS is currently used as a way of treating depression and anxiety, but Etkin said the brain regions being targeted are the ones available to TMS, not necessarily the ones most likely to treat a person’s condition. They are also not personalized for the individual.

Pairing TMS with another technology that shows which brain regions are active, Etkin and his team can stimulate one part of the brain with TMS and look for a reaction elsewhere. These studies can eventually help map the relationships between brain circuits and identify the circuits that underlie mental health conditions.

In parallel, the team is working to improve TMS to make it more useful as a therapy. TMS currently only reaches the surface of the brain and is not very focused. The goal is to improve the technology so that it can reach structures deeper in the brain in a more targeted way. “Right now they are hitting the only accessible target,” he said. “The parts we really want to hit for depression, anxiety or PTSD are likely deeper in the brain.”

Technology of the future

In parallel with the TMS work, Baccus and a team of engineers, radiologists and physiologists have been developing a way of using ultrasound to stimulate the brain. Ultrasound is widely used to image the body, most famously for producing images of developing babies in the womb. But in recent years scientists have learned that at the right frequency and focus, ultrasound can also stimulate nerves to fire.

In his lab, Baccus has been using ultrasound to stimulate nerve cells of the retina – the light-sensing structure at the back of the eye – as part of an effort to develop a prosthetic retina. He is also teaming up with colleagues to understand how ultrasound might be triggering that stimulation. It appears to compress the nerve cells in a way that could lead to activation, but the connection is far from clear.

Other members of the team are modifying existing ultrasound technology to direct it deep within the brain at a frequency that can stimulate nerves without harming them. If the team is successful, ultrasound could be a more targeted and focused tool than TMS for remotely stimulating circuits that underlie mental health conditions.

The group has been working together for about five years, and in 2012 got funding from Bio-X NeuroVentures, which eventually gave rise to the Stanford Neurosciences Institute, to pursue this technology. Baccus said that before merging with Etkin’s team they had been focusing on the technology without specific brain diseases in mind. “This merger really gives a target and a focus to the technology,” he said.

Etkin and Baccus said that if they are successful, they hope to have both a better understanding of how the brain functions and new tools for treating disabling mental health conditions.

Source: Stanford News

Electrical and computer engineering Professor Barry Van Veen wears an electrode net used to monitor brain activity via EEG signals. His research could help untangle what happens in the brain during sleep and dreaming.

Photo Credit: Nick Berard/UW-Madison

Imagination, reality flow in opposite directions in the brain

By Scott Gordon


As real as that daydream may seem, its path through your brain runs opposite reality.

Aiming to discern discrete neural circuits, researchers at the University of Wisconsin–Madison have tracked electrical activity in the brains of people who alternately imagined scenes or watched videos.

“A really important problem in brain research is understanding how different parts of the brain are functionally connected. What areas are interacting? What is the direction of communication?” says Barry Van Veen, a UW-Madison professor of electrical and computer engineering. “We know that the brain does not function as a set of independent areas, but as a network of specialized areas that collaborate.”

Van Veen, along with Giulio Tononi, a UW-Madison psychiatry professor and neuroscientist, Daniela Dentico, a scientist at UW–Madison’s Waisman Center, and collaborators from the University of Liege in Belgium, published results recently in the journalNeuroImage. Their work could lead to the development of new tools to help Tononi untangle what happens in the brain during sleep and dreaming, while Van Veen hopes to apply the study’s new methods to understand how the brain uses networks to encode short-term memory.

During imagination, the researchers found an increase in the flow of information from the parietal lobe of the brain to the occipital lobe — from a higher-order region that combines inputs from several of the senses out to a lower-order region.

Electrical and computer engineering Professor Barry Van Veen wears an electrode net used to monitor brain activity via EEG signals. His research could help untangle what happens in the brain during sleep and dreaming. Photo Credit: Nick Berard/UW-Madison
Electrical and computer engineering Professor Barry Van Veen wears an electrode net used to monitor brain activity via EEG signals. His research could help untangle what happens in the brain during sleep and dreaming.
Photo Credit: Nick Berard/UW-Madison

In contrast, visual information taken in by the eyes tends to flow from the occipital lobe — which makes up much of the brain’s visual cortex — “up” to the parietal lobe.

“There seems to be a lot in our brains and animal brains that is directional, that neural signals move in a particular direction, then stop, and start somewhere else,” says. “I think this is really a new theme that had not been explored.”

The researchers approached the study as an opportunity to test the power of electroencephalography (EEG) — which uses sensors on the scalp to measure underlying electrical activity — to discriminate between different parts of the brain’s network.

Brains are rarely quiet, though, and EEG tends to record plenty of activity not necessarily related to a particular process researchers want to study.

To zero in on a set of target circuits, the researchers asked their subjects to watch short video clips before trying to replay the action from memory in their heads. Others were asked to imagine traveling on a magic bicycle — focusing on the details of shapes, colors and textures — before watching a short video of silent nature scenes.

Using an algorithm Van Veen developed to parse the detailed EEG data, the researchers were able to compile strong evidence of the directional flow of information.

“We were very interested in seeing if our signal-processing methods were sensitive enough to discriminate between these conditions,” says Van Veen, whose work is supported by the National Institute of Biomedical Imaging and Bioengineering. “These types of demonstrations are important for gaining confidence in new tools.”

Source: UW-Madison News

Neuroscientists reverse memories’ emotional associations

MIT study also identifies the brain circuit that links feelings to memories.

By Anne Trafton

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.

 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). Credits Image courtesy of the researchers/MIT

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).
Credits: Image courtesy of the researchers/MIT

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 miceby 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.

The research was funded by the RIKEN Brain Science Institute, Howard Hughes Medical Institute, and the JPB Foundation.