Posts tagged fear
Articles and news from the latest research reports.
Missing “brake in the brain” can trigger anxiety states
Fear, at the right level, can increase alertness and protect against dangers. Disproportionate fear, on the other hand, can disrupt the sensory perception, be disabling, reduce happiness and therefore become a danger in itself. Anxiety disorders are therefore a psychiatric condition that should not be underestimated. In these disorders, the fear is so strong that there is tremendous psychological strain and living a normal life appears to be impossible. Researchers at the MedUni Vienna have now found a possible explanation as to how social phobias and fear can be triggered in the brain: a missing inhibitory connection or missing “brake” in the brain.
Inside the brain, the amygdala and the orbitofrontal cortex in the frontal lobe form an important control circuit for regulating the emotions. This control circuit is termed the brain’s emotional control centre. Whereas in healthy subjects, this circuit has “negative feedback” and “calmness” was identified, scientists used functional magnetic resonance imaging (MRI) on people with social phobias and found the opposite to be true: an important inhibitory connection is different in these patients, which may explain why they are unable to control their fears.
In collaboration with the Centre for Medical Physics and Biomedical Technology and the University Department of Psychiatry and Psychotherapy at the MedUni Vienna, the research team lead by Christian Windischberger was also able to discover through its recent study at the MedUni Vienna’s High Field MR Centre of Excellence how the areas of the brain that are involved with processing emotions are able to influence each other.
The study participants were shown a series of “emotional faces” while undergoing functional magnetic resonance imaging. fMRI is a non-invasive method which uses radio waves and magnetic fields to measure changes in the levels of oxygen in the blood and therefore neuronal activity in individual regions of the brain. An analysis method developed at University College London was used to provide new perspectives on the data obtained.
Breaking the circle of fear
When emotional facial expressions were shown - from laughing to crying, from happiness to anger - neuronal activity was triggered in the brain. The result: on a purely external basis, the test subjects looked no different, but the healthy subjects were kept calm thanks to their automatic “brake”, despite the emotional nature of the images. For the social phobics, on the other hand, the photographs put their brains into “overdrive”, triggering very strong neuronal activity. This was demonstrated very clearly using the new analysis method: “We have the opportunity not only to localise brain activity and compare it between groups, but we can now also make statements regarding functional connections within the brain. In psychiatric conditions especially, we can assume that there are not complete failures of these connections going on, but rather imbalances in complex regulatory processes,” says Ronald Sladky, the study’s primary author.
This better understanding of the neuronal mechanisms involved will now be used to develop new approaches to treatment. The aim is to understand what effect medications and psycho-therapeutic support have on the networks involved in order to help patients break out of their circles of fear.
(Source: meduniwien.ac.at)
Biofeedback-based horror game challenges players to deal with fear
While traditional horror video games seek to provide an exciting thrill, Nevermind is a biofeedback-enhanced horror game that has greater ambitions. It requires you to manage your anxiety in alarming scenarios – the more stressed you feel, the harder the game becomes. The aim, says Erin Reynolds, its creator, is for players to learn how to not let their fears get the best of them in nerve-wracking situations and hopefully carry over their gameplay-acquired skills into the real world.
A Garmin cardio chest strap akin to the ones gym-goers use to monitor their workout acts as a sensor, relaying the player’s heart rate information to the game through an ANT+ USB stick. The game calculates the player’s Heart Rate Variability (HRV), measuring the change in the duration between their heartbeats to figure out when their “fight or flight” response has kicked in and adjusts the gameplay accordingly. While Nevermind can’t zero in on specific stressful emotions like frustration or upset, it’s able to detect the intensity of the player’s feelings and gauge how deeply they feel stress at any point during the game.
Instead of having fanged horrors and hordes of zombies jump out from around corners, which might need a learning curve, the game is more subtle in inducing fear and is designed to appeal to non-gamers too. It creates a warped chaotic atmosphere where the creepiness factor is slowly dialed up, with huge screaming heads, blood-spattered doors and thrashing body bags.
Assuming the role of a newly hired Neruroprober at the Neurostalgia Institute, players boldly dive into the troubled minds of traumatized patients who are repressing their most horrific memories. To root out the cause of their suffering, players will need to solve puzzles and be willing to face a host of unimaginable terrors before the patient’s subconscious is ready to release its painful memories.
"This psychological phenomenon is based on how some people cope with severe psychological trauma in real life," Reynolds tells Gizmag. "These are individuals who experienced an event so terrible at some point in their lives that their conscious minds locked all memories of that event away completely. Although the patients can’t recall exactly what, if anything, happened to them, the repressed memories end up festering within their subconscious and create immense challenges in their attempts to live a normal life."
The sensor detects how scared or stressed the player gets as they move through the patient’s subconscious, recovering ten Polaroid photographs that each represent a distressful memory. Once all the photographs have been collected, they’ll have to differentiate the false memories from the five true ones and reconstruct the traumatizing memory. If they start to feel more fear, which the game sets out to trigger, the gameplay becomes perceptibly difficult. While some situations impact players more than others, they are all designed to push the player’s buttons.
For example, in the “car maze” section players follow the guiding sound of a blaring car horn through a twisting cave-like maze of crashed and wrecked cars full of disorienting imagery. As the player’s fear levels rise, the visuals become increasingly distorted until they are barely able to see what’s ahead of them.
"Some players become anxious over the car horn, others over the complexity of the maze, some over the imagery – there are a whole host things in this area that can rile up one’s nerves," says Reynolds. "The player needs to have a good grasp on how to calm down by this point in the game as it’s a nearly impossible challenge to escape the maze while scared or stressed."
In another scenario, the player explores a grotesque kitchen to find an ambiguous writhing mass in an oven and a giant bloodied refrigerator buzzing with flies that offers a puzzle. If the player gets rattled trying to solve the puzzle in this disturbing setting, milk starts flooding the room, pouring in from all over. Sloshing around in the waist-high milk makes it harder to move and the more anxious the player feels, the more milk floods in until it drowns them. If they are able to calm down in time the milk stops pouring in and drains out. If not, they drown and the game pulls them out of the room, returning them to the peaceful surroundings of the Institute until they feel ready again.
Making the game tougher as the player’s fear increases might seem counter-intuitive, but its developers were very clear about designing it that way. “We wanted players to become aware in a very real way of when their anxiety levels were starting to become elevated and reward them for being able to manage that anxiety on the fly,” Reynolds tells us. “We knew making the environment change so significantly that it would impact what the player was doing would get their attention.”
Developed as part of a Master of Fine Arts (MFA) thesis project within the University of Southern California’s Interactive Media and Games Division, Nevermind took about a year to build and presently exists as a “proof of concept game.” It has one level with one patient’s subconscious mind connected to a hub area that’s built to support the minds of 10 more patients. A play through takes about an hour. Reynolds plans to get a Kickstarter project going and launch the game with a variety of disturbed patients in late 2014. The team also plans to conduct thorough studies of the game’s impact on players and explore its use in therapy.
Will playing the game have us reacting to freaky situations with a Yoda-like serene gaze? Its developers hope it will help.
“Nevermind draws players in with the promise of a fun, exciting horror game that uses some spiffy new technology, but I hope it ultimately leaves them better equipped to take on the world more bravely and confidently than ever before,” Reynolds tells us. “In a way, it’s the biggest puzzle in the game – how do you solve your gut, knee-jerk reactions to unpleasant scenarios? If you can figure it out in the game, you’ll find success. If you can figure it out in life, you’ll find success there too.”
What do bullies and sex have in common? Based on work by scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, it seems that the same part of the brain reacts to both. In a study published today in Nature Neuroscience, the researchers found that – at least in mice – different types of fear are processed by different groups of neurons, even if the animals act out those fears in the same way. The findings could have implications for addressing phobias and panic attacks in humans.
“We found that there seems to be a circuit for handling fear of predators – which has been described anatomically as a kind of defence circuit – but fear of members of the same species uses the reproductive circuit instead,” says Bianca Silva, who carried out the work, “and fear of pain goes through yet another part of the brain.”
Working in the lab of Cornelius Gross at EMBL, Silva exposed mice to three threats: another mouse (chosen for being particularly aggressive), a rat (the mouse’s natural predator) or a mild electric shock to the feet. The mice showed the same typical fearful behaviours – running away, freezing – in response to all threats, but their brains painted a different picture. When the scientists mapped the brain activity of mice exposed to the aggressive mouse and the rat, they saw that different parts of a region called the ventromedial hypothalamus (VMH) ‘lit up’ depending on the threat. Fear of the mouse seemed to activate the bottom and sides of the VMH, while fear of the rat seemed to be processed by the VMH’s central and upper areas. This was confirmed when the scientists used drugs to block only the neurons in those ‘rat fear’ areas: mice were no longer afraid of the rat, but were still afraid of the mouse, showing that mice need this brain circuit specifically to process fear of predators.
The human brain has similar circuits, and we too experience different kinds of fear, so the results hint at the possibility of developing more efficient treatments for specific phobias or panic attacks, by targeting only the relevant region of the brain.
For their part, the EMBL scientists plan to probe these fears further.
“What we’re interested in, in the long-run, is if these results represent a kind of mental state,” says Cornelius Gross, who led the work. “If so, mice should be able to be in that state without expressing it in their behaviour – do they re-live that fear, for example? These are not easy questions to ask in the mouse, but we’re looking into them.”
Gross’s lab are also looking at how these different fears – and the neural circuits that process them – may have evolved. Working with Detlev Arendt’s group at EMBL Heidelberg, they have discovered a similar brain region in a marine worm thought to closely resemble our ancestors from 600 million years ago. Now the team is exploring the possibility that this represents an ancestral core fear circuit that those ancestors handed down to us all, from worms to man.
Neuroscientists Determine How Treatment for Anxiety Disorders Silences Fear Neurons
Excessive fear can develop after a traumatic experience, leading to anxiety disorders such as post-traumatic stress disorder and phobias. During exposure therapy, an effective and common treatment for anxiety disorders, the patient confronts a fear or memory of a traumatic event in a safe environment, which leads to a gradual loss of fear. A new study in mice, published online today in Neuron, reports that exposure therapy remodels an inhibitory junction in the amygdala, a brain region important for fear in mice and humans. The findings improve our understanding of how exposure therapy suppresses fear responses and may aid in developing more effective treatments. The study, led by researchers at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts, was partially funded by a New Innovator Award from the Office of the Director at the National Institutes of Health.
A fear-inducing situation activates a small group of neurons in the amygdala. Exposure therapy silences these fear neurons, causing them to be less active. As a result of this reduced activity, fear responses are alleviated. The research team sought to understand how exactly exposure therapy silences fear neurons.
The researchers found that exposure therapy not only silences fear neurons but also induces remodeling of a specific type of inhibitory junction, called the perisomatic synapse. Perisomatic inhibitory synapses are connections between neurons that enable one group of neurons to silence another group of neurons. Exposure therapy increases the number of perisomatic inhibitory synapses around fear neurons in the amygdala. This increase provides an explanation for how exposure therapy silences fear neurons.
“The increase in number of perisomatic inhibitory synapses is a form of remodeling in the brain. Interestingly, this form of remodeling does not seem to erase the memory of the fear-inducing event, but suppresses it,” said senior author, Leon Reijmers, Ph.D., assistant professor of neuroscience at Tufts University School of Medicine and member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.
Reijmers and his team discovered the increase in perisomatic inhibitory synapses by imaging neurons activated by fear in genetically manipulated mice. Connections in the human brain responsible for suppressing fear and storing fear memories are similar to those found in the mouse brain, making the mouse an appropriate model organism for studying fear circuits.
Mice were placed in a box and experienced a fear-inducing situation to create a fear response to the box. One group of mice, the control group, did not receive exposure therapy. Another group of mice, the comparison group, received exposure therapy to alleviate the fear response. For exposure therapy, the comparison group was repeatedly placed in the box without experiencing the fear-inducing situation, which led to a decreased fear response in these mice. This is also referred to as fear extinction.
The researchers found that mice subjected to exposure therapy had more perisomatic inhibitory synapses in the amygdala than mice who did not receive exposure therapy. Interestingly, this increase was found around fear neurons that became silent after exposure therapy.
“We showed that the remodeling of perisomatic inhibitory synapses is closely linked to the activity state of fear neurons. Our findings shed new light on the precise location where mechanisms of fear regulation might act. We hope that this will lead to new drug targets for improving exposure therapy,” said first author, Stéphanie Trouche, Ph.D., a former postdoctoral fellow in Reijmers’ lab at Tufts and now a medical research council investigator scientist at the University of Oxford in the United Kingdom.
“Exposure therapy in humans does not work for every patient, and in patients that do respond to the treatment, it rarely leads to a complete and permanent suppression of fear. For this reason, there is a need for treatments that can make exposure therapy more effective,” Reijmers added.
(Source: now.tufts.edu)
Snakes on the brain: Are primates hard-wired to see snakes?
Was the evolution of high-quality vision in our ancestors driven by the threat of snakes? Work by neuroscientists in Japan and Brazil is supporting the theory originally put forward by Lynne Isbell, professor of anthropology at the University of California, Davis.
In a paper published Oct. 28 in the journal Proceedings of the National Academy of Sciences, Isbell; Hisao Nishijo and Quan Van Le at Toyama University, Japan; and Rafael Maior and Carlos Tomaz at the University of Brasilia, Brazil; and colleagues show that there are specific nerve cells in the brains of rhesus macaque monkeys that respond to images of snakes.
The snake-sensitive neurons were more numerous, and responded more strongly and rapidly, than other nerve cells that fired in response to images of macaque faces or hands, or to geometric shapes. Isbell said she was surprised that more neurons responded to snakes than to faces, given that primates are highly social animals.
"We’re finding results consistent with the idea that snakes have exerted strong selective pressure on primates," Isbell said.
Isbell originally published her hypothesis in 2006, following up with a book, “The Fruit, the Tree and the Serpent” (Harvard University Press, 2009) in which she argued that our primate ancestors evolved good, close-range vision primarily to spot and avoid dangerous snakes.
Modern mammals and snakes big enough to eat them evolved at about the same time, 100 million years ago. Venomous snakes are thought to have appeared about 60 million years ago — “ambush predators” that have shared the trees and grasslands with primates.
Nishijo’s laboratory studies the neural mechanisms responsible for emotion and fear in rhesus macaque monkeys, especially instinctive responses that occur without learning or memory. Previous researchers have used snakes to provoke fear in monkeys, he noted. When Nishijo heard of Isbell’s theory, he thought it might explain why monkeys are so afraid of snakes.
"The results show that the brain has special neural circuits to detect snakes, and this suggests that the neural circuits to detect snakes have been genetically encoded," Nishijo said.
The monkeys tested in the experiment were reared in a walled colony and neither had previously encountered a real snake.
"I don’t see another way to explain the sensitivity of these neurons to snakes except through an evolutionary path," Isbell said.
Isbell said she’s pleased to be able to collaborate with neuroscientists.
"I don’t do neuroscience and they don’t do evolution, but we can put our brains together and I think it brings a wider perspective to neuroscience and new insights for evolution," she said.
(Source: news.ucdavis.edu)
New role for ‘hunger hormone’
About a dozen years ago, scientists discovered that a hormone called ghrelin enhances appetite. Dubbed the “hunger hormone,” ghrelin was quickly targeted by drug companies seeking treatments for obesity — none of which have yet panned out.
MIT neuroscientists have now discovered that ghrelin’s role goes far beyond controlling hunger. The researchers found that ghrelin released during chronic stress makes the brain more vulnerable to traumatic events, suggesting that it may predispose people to posttraumatic stress disorder (PTSD).
Drugs that reduce ghrelin levels, originally developed to try to combat obesity, could help protect people who are at high risk for PTSD, such as soldiers serving in war, says Ki Goosens, an assistant professor of brain and cognitive sciences at MIT, and senior author of a paper describing the findings in the Oct. 15 online edition of Molecular Psychiatry.
“Perhaps we could give people who are going to be deployed into an active combat zone a ghrelin vaccine before they go, so they will have a lower incidence of PTSD. That’s exciting because right now there’s nothing given to people to prevent PTSD,” says Goosens, who is also a member of MIT’s McGovern Institute for Brain Research.
Lead author of the paper is Retsina Meyer, a recent MIT PhD recipient. Other authors are McGovern postdoc Anthony Burgos-Robles, graduate student Elizabeth Liu, and McGovern research scientist Susana Correia.
Stress and fear
Stress is a useful response to dangerous situations because it provokes action to escape or fight back. However, when stress is chronic, it can produce anxiety, depression and other mental illnesses.
At MIT, Goosens discovered that one brain structure that is especially critical for generating fear, the amygdala, has a special response to chronic stress. The amygdala produces large amounts of growth hormone during stress, a change that seems not to occur in other brain regions.
In the new paper, Goosens and her colleagues found that the release of the growth hormone in the amygdala is controlled by ghrelin, which is produced primarily in the stomach and travels throughout the body, including the brain.
Ghrelin levels are elevated by chronic stress. In humans, this might be produced by factors such as unemployment, bullying, or loss of a family member. Ghrelin stimulates the secretion of growth hormone from the brain; the effects of growth hormone from the pituitary gland in organs such as the liver and bones have been extensively studied. However, the role of growth hormone in the brain, particularly the amygdala, is not well known.
The researchers found that when rats were given either a drug to stimulate the ghrelin receptor or gene therapy to overexpress growth hormone over a prolonged period, they became much more susceptible to fear than normal rats. Fear was measured by training all of the rats to fear an innocuous, novel tone. While all rats learned to fear the tone, the rats with prolonged increased activity of the ghrelin receptor or overexpression of growth hormone were the most fearful, assessed by how long they froze after hearing the tone. Blocking the cell receptors that interact with ghrelin or growth hormone reduced fear to normal levels in chronically stressed rats.
When rats were exposed to chronic stress over a prolonged period, their circulating ghrelin and amygdalar growth hormone levels also went up, and fearful memories were encoded more strongly. This is similar to what the researchers believe happens in people who suffer from PTSD.
“When you have people with a history of stress who encounter a traumatic event, they are more likely to develop PTSD because that history of stress has altered something about their biology. They have an excessively strong memory of the traumatic event, and that is one of the things that drives their PTSD symptoms,” Goosens says.
New drugs, new targets
Over the last century, scientists have described the hypothalamic-pituitary-adrenal (HPA) axis, which produces adrenaline, cortisol (corticosterone in rats), and other hormones that stimulate “fight or flight” behavior. Since then, stress research has focused almost exclusively on the HPA axis.
After discovering ghrelin’s role in stress, the MIT researchers suspected that ghrelin was also linked to the HPA axis. However, they were surprised to find that when the rats’ adrenal glands — the source of corticosterone, adrenaline, and noradrenaline — were removed, the animals still became overly fearful when chronically stressed. The authors also showed that repeated ghrelin-receptor stimulation did not trigger release of HPA hormones, and that blockade of the ghrelin receptor did not blunt release of HPA stress hormones. Therefore, the ghrelin-initiated stress pathway appears to act independently of the HPA axis. “That’s important because it gives us a whole new target for stress therapies,” Goosens says.
Pharmaceutical companies have developed at least a dozen possible drug compounds that interfere with ghrelin. Many of these drugs have been found safe for humans, but have not been shown to help people lose weight. The researchers believe these drugs could offer a way to vaccinate people entering stressful situations, or even to treat people who already suffer from PTSD, because ghrelin levels remain high long after the chronic stress ends.
PTSD affects about 7.7 million American adults, including soldiers and victims of crimes, accidents, or natural disasters. About 40 to 50 percent of patients recover within five years, Meyer says, but the rest never get better.
The researchers hypothesize that the persistent elevation of ghrelin following trauma exposure could be one of the factors that maintain PTSD. “So, could you immediately reverse PTSD? Maybe not, but maybe the ghrelin could get damped down and these people could go through cognitive behavioral therapy, and over time, maybe we can reverse it,” Meyer says.
Working with researchers at Massachusetts General Hospital, Goosens’ lab is now planning to study ghrelin levels in human patients suffering from anxiety and fear disorders. They are also planning a clinical trial of a drug that blocks ghrelin to see if it can prevent relapse of depression.
(Source: web.mit.edu)
Robots Strike Fear in the Hearts of Fish
Anxious Zebrafish Help NYU-Poly Researchers Understand How Alcohol Affects Fear
The latest in a series of experiments testing the ability of robots to influence live animals shows that bio-inspired robots can not only elicit fear in zebrafish, but that this reaction can be modulated by alcohol. These findings may pave the way for new methodologies for understanding anxiety and other emotions, as well as substances that alter them.
Maurizio Porfiri, associate professor of mechanical and aerospace engineering at the Polytechnic Institute of New York University (NYU-Poly) and Simone Macrì, a collaborator at the Istituto Superiore di Sanità in Rome, Italy, published their findings in PLOS ONE, an international, peer-reviewed, open-access, online publication.
This latest study expands Porfiri and Macrì’s efforts to determine how bio-inspired robots can be employed as reliable stimuli to elicit reactions from live zebrafish. Previous studies have established that zebrafish show a strong affinity for robotic members designed to swim and appear as one of their own and that this preference can be abolished by exposing the fish to ethanol.
Porfiri and Macri, along with students Valentina Cianca and Tiziana Bartolini, hypothesized that robots could be used to induce fear as well as affinity and designed a robot mimicking the morphology and locomotion pattern of the Indian leaf fish, a natural predator of the zebrafish. In the lab, they simulated a harmless predatory scenario, placing the zebrafish and the robotic Indian leaf fish in separate compartments of a three-section tank. The other compartment was left empty. The control group uniformly avoided the robotic predator, showing a preference for the empty section.
To determine whether alcohol would affect fear responses, the researchers exposed separate groups of fish to different doses of ethanol in water. Ethanol has been shown to influence anxiety-related responses in humans, rodents and some species of fish. The zebrafish exposed to the highest concentrations of ethanol showed remarkable changes in behavior, failing to avoid the predatory robot. Acute administration of ethanol causes no harm and has no lasting effect on zebrafish.
“These results are further evidence that robots may represent an exciting new approach in evaluating and understanding emotional responses and behavior,” said Porfiri. “Robots are ideal replacements as independent variables in tests involving social stimuli—they are fully controllable, stimuli can be reproduced precisely each time, and robots can never be influenced by the behavior of the test subjects.”
To validate their findings and ensure that the zebrafish behavior being modulated was, in fact, a fear-based response, Porfiri and his collaborators conducted two traditional anxiety tests and evaluated whether the results obtained therein were sensitive to ethanol administration.
They placed test subjects in a two-chamber tank with one well-lit side and one darkened side, to establish which conditions were preferable. In a separate tank, they simulated a heron attack from the water’s surface—herons also prey on zebrafish—and measured how quickly and how many fish took shelter from the attack. As expected, the fish strongly avoided the dark compartment, and most sought shelter very quickly from the heron attack. Ethanol exposure significantly modulated these fear responses as well, abolishing the preference for the light compartment and significantly slowing the fishes’ retreat to shelter during the simulated attack.
“We hoped to see a correlation between the robotic Indian leaf fish test results and the results of the other anxiety tests, and the data support that,” Porfiri explained. “The majority of control group fish avoided the robotic predator, preferred the light compartment and sought shelter quickly after the heron attack. Among ethanol-exposed fish, there were many more who were unaffected by the robotic predator, preferred the dark compartment and were slow to swim to shelter when attacked.”
Porfiri and his colleagues believe zebrafish may be a suitable replacement for higher-order animals in tests to evaluate emotional responses. This novel robotic approach would also reduce the number of live test subjects needed for experiments and may inform other areas of inquiry, from collective behavior to animal protection.
The Love Hormone is Two-Faced
Finding shows oxytocin strengthens bad memories and can increase fear and anxiety
It turns out the love hormone oxytocin is two-faced. Oxytocin has long been known as the warm, fuzzy hormone that promotes feelings of love, social bonding and well-being. It’s even being tested as an anti-anxiety drug. But new Northwestern Medicine® research shows oxytocin also can cause emotional pain, an entirely new, darker identity for the hormone.
Oxytocin appears to be the reason stressful social situations, perhaps being bullied at school or tormented by a boss, reverberate long past the event and can trigger fear and anxiety in the future.
That’s because the hormone actually strengthens social memory in one specific region of the brain, Northwestern scientists discovered.
If a social experience is negative or stressful, the hormone activates a part of the brain that intensifies the memory. Oxytocin also increases the susceptibility to feeling fearful and anxious during stressful events going forward.
(Presumably, oxytocin also intensifies positive social memories and, thereby, increases feelings of well being, but that research is ongoing.)
The findings are important because chronic social stress is one of the leading causes of anxiety and depression, while positive social interactions enhance emotional health. The research, which was done in mice, is particularly relevant because oxytocin currently is being tested as an anti-anxiety drug in several clinical trials.
“By understanding the oxytocin system’s dual role in triggering or reducing anxiety, depending on the social context, we can optimize oxytocin treatments that improve well-being instead of triggering negative reactions,” said Jelena Radulovic, the senior author of the study and the Dunbar Professsor of Bipolar Disease at Northwestern University Feinberg School of Medicine. The paper was published July 21 in Nature Neuroscience.
This is the first study to link oxytocin to social stress and its ability to increase anxiety and fear in response to future stress. Northwestern scientists also discovered the brain region responsible for these effects — the lateral septum – and the pathway or route oxytocin uses in this area to amplify fear and anxiety.
The scientists discovered that oxytocin strengthens negative social memory and future anxiety by triggering an important signaling molecule — ERK (extracellular signal regulated kinases) — that becomes activated for six hours after a negative social experience. ERK causes enhanced fear, Radulovic believes, by stimulating the brain’s fear pathways, many of which pass through the lateral septum. The region is involved in emotional and stress responses.
The findings surprised the researchers, who were expecting oxytocin to modulate positive emotions in memory, based on its long association with love and social bonding.
“Oxytocin is usually considered a stress-reducing agent based on decades of research,” said Yomayra Guzman, a doctoral student in Radulovic’s lab and the study’s lead author. “With this novel animal model, we showed how it enhances fear rather than reducing it and where the molecular changes are occurring in our central nervous system.’
The new research follows three recent human studies with oxytocin, all of which are beginning to offer a more complicated view of the hormone’s role in emotions.
All the new experiments were done in the lateral septum. This region has the highest oxytocin levels in the brain and has high levels of oxytocin receptors across all species from mice to humans.
“This is important because the variability of oxytocin receptors in different species is huge,” Radulovic said. “We wanted the research to be relevant for humans, too.”
Experiments with mice in the study established that 1) oxytocin is essential for strengthening the memory of negative social interactions and 2) oxytocin increases fear and anxiety in future stressful situations.
Experiment 1: Oxytocin Strengthens Bad Memories
Three groups of mice were individually placed in cages with aggressive mice and experienced social defeat, a stressful experience for them. One group was missing its oxytocin receptors, essentially the plug by which the hormone accesses brain cells. The lack of receptors means oxytocin couldn’t enter the mice’s brain cells. The second group had an increased number of receptors so their brain cells were flooded with the hormone. The third control group had a normal number of receptors.
Six hours later, the mice were returned to cages with the aggressive mice. The mice that were missing their oxytocin receptors didn’t appear to remember the aggressive mice and show any fear. Conversely, when mice with increased numbers of oxytocin receptors were reintroduced to the aggressive mice, they showed an intense fear reaction and avoided the aggressive mice.
Experiment 2: Oxytocin Increases Fear and Anxiety in Future Stress
Again, the three groups of mice were exposed to the stressful experience of social defeat in the cages of other more aggressive mice. This time, six hours after the social stress, the mice were put in a box in which they received a brief electric shock, which startles them but is not painful. Then 24 hours later, the mice were returned to the same box but did not receive a shock.
The mice missing their oxytocin receptors did not show any enhanced fear when they re-entered the box in which they received the shock. The second group, which had extra oxytocin receptors showed much greater fear in the box. The third control group exhibited an average fear response.
“This experiment shows that after a negative social experience the oxytocin triggers anxiety and fear in a new stressful situation,” Radulovic said.
(Source: northwestern.edu)
Researchers Discover Link Between Fear and Sound Perception
Anyone who’s ever heard a Beethoven sonata or a Beatles song knows how powerfully sound can affect our emotions. But it can work the other way as well – our emotions can actually affect how we hear and process sound. When certain types of sounds become associated in our brains with strong emotions, hearing similar sounds can evoke those same feelings, even far removed from their original context. It’s a phenomenon commonly seen in combat veterans suffering from posttraumatic stress disorder (PTSD), in whom harrowing memories of the battlefield can be triggered by something as common as the sound of thunder. But the brain mechanisms responsible for creating those troubling associations remain unknown. Now, a pair of researchers from the Perelman School of Medicine at the University of Pennsylvania has discovered how fear can actually increase or decrease the ability to discriminate among sounds depending on context, providing new insight into the distorted perceptions of victims of PTSD. Their study is published in Nature Neuroscience.
“Emotions are closely linked to perception and very often our emotional response really helps us deal with reality,” says senior study author Maria N. Geffen, PhD, assistant professor of Otorhinolaryngology: Head and Neck Surgery and Neuroscience at Penn. “For example, a fear response helps you escape potentially dangerous situations and react quickly. But there are also situations where things can go wrong in the way the fear response develops. That’s what happens in anxiety and also in PTSD — the emotional response to the events is generalized to the point where the fear response starts getting developed to a very broad range of stimuli.”
Geffen and the first author of the study, Mark Aizenberg, PhD, a postdoctoral researcher in her laboratory, used emotional conditioning in mice to investigate how hearing acuity (the ability to distinguish between tones of different frequencies) can change following a traumatic event, known as emotional learning. In these experiments, which are based on classical (Pavlovian) conditioning, animals learn to distinguish between potentially dangerous and safe sounds — called “emotional discrimination learning.” This type of conditioning tends to result in relatively poor learning, but Aizenberg and Geffen designed a series of learning tasks intended to create progressively greater emotional discrimination in the mice, varying the difficulty of the task. What really interested them was how different levels of emotional discrimination would affect hearing acuity – in other words, how emotional responses affect perception and discrimination of sounds. This study established the link between emotions and perception of the world – something that has not been understood before.
The researchers found that, as expected, fine emotional learning tasks produced greater learning specificity than tests in which the tones were farther apart in frequency. As Geffen explains, “The animals presented with sounds that were very far apart generalize the fear that they developed to the danger tone over a whole range of frequencies, whereas the animals presented with the two sounds that were very similar exhibited specialization of their emotional response. Following the fine conditioning task, they figured out that it’s a very narrow range of pitches that are potentially dangerous.”
When pitch discrimination abilities were measured in the animals, the mice with more specific responses displayed much finer auditory acuity than the mice who were frightened by a broader range of frequencies. “There was a relationship between how much their emotional response generalized and how well they could tell different tones apart,” says Geffen. “In the animals that specialized their emotional response, pitch discrimination actually became sharper. They could discriminate two tones that they previously could not tell apart.”
Another interesting finding of this study is that the effects of emotional learning on hearing perception were mediated by a specific brain region, the auditory cortex. The auditory cortex has been known as an important area responsible for auditory plasticity. Surprisingly, Aizenberg and Geffen found that the auditory cortex did not play a role in emotional learning. Likely, the specificity of emotional learning is controlled by the amygdala and sub-cortical auditory areas. “We know the auditory cortex is involved, we know that the emotional response is important so the amygdala is involved, but how do the amygdala and cortex interact together?” says Geffen. “Our hypothesis is that the amygdala and cortex are modifying subcortical auditory processing areas. The sensory cortex is responsible for the changes in frequency discrimination, but it’s not necessary for developing specialized or generalized emotional responses. So it’s kind of a puzzle.”
Solving that puzzle promises new insight into the causes and possible treatment of PTSD, and the question of why some individuals develop it and others subjected to the same events do not. “We think there’s a strong link between mechanisms that control emotional learning, including fear generalization, and the brain mechanisms responsible for PTSD, where generalization of fear is abnormal,” Geffen notes. Future research will focus on defining and studying that link.
Do Antidepressants Impair the Ability to Extinguish Fear?
An interesting new report of animal research published in Biological Psychiatry suggests that common antidepressant medications may impair a form of learning that is important clinically.
(Photo: ALAMY)
Selective serotonin reuptake inhibitors, commonly called SSRIs, are a class of antidepressant widely used to treat depression, as well as a range of anxiety disorders, but the effects of these drugs on learning and memory are poorly understood.
In a previous study, Nesha Burghardt, then a graduate student at New York University, and her colleagues demonstrated that long-term SSRI treatment impairs fear conditioning in rats. As a follow-up, they have now tested the effects of antidepressant treatment on extinction learning in rats using auditory fear conditioning, a model of fear learning that involves the amygdala. The amygdala is a region of the brain vitally important for processing memory and emotion.
They found that long-term, but not short-term, SSRI treatment impairs extinction learning, which is the ability to learn that a conditioned stimulus no longer predicts an aversive event.
"This impairment may have important consequences clinically, since extinction-based exposure therapy is often used to treat anxiety disorders and antidepressants are often administered simultaneously," said Dr. Burghardt. "Based on our work, medication-induced impairments in extinction learning may actually disrupt the beneficial effects of exposure-therapy."
This finding is consistent with the results of several clinical studies showing that combined treatment can impede the benefits of exposure therapy or even natural resilience to the impact of traumatic stress at long-term follow-up.
The authors also suggest a mechanism for this effect on fear learning. They reported that the antidepressants decreased the levels of one of the subunits of the NMDA receptor (NR2B) in the amygdala. The NMDA receptor is critically involved in fear-related learning, so these reductions are believed to contribute to the observed effects.
Dr. John Krystal, Editor of Biological Psychiatry, commented, “We know that antidepressants play important roles in the treatment of depression and anxiety disorders. However, it is important to understand the limitations of these medications so that we can improve the effectiveness of the treatment for these disorders.”
(Source: elsevier.com)