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Where Fear Is Stored In The Brain

ScienceDaily (July 8, 2009) — Fear is a powerful emotion, and neuroscientists have for the first time located the neurons responsible for fear conditioning in the mammalian brain. Fear conditioning is a form of Pavlovian, or associative, learning and is considered to be a model system for understanding human phobias, post-traumatic stress disorder and other anxiety disorders.

Using an imaging technique that enabled them to trace the process of neural activation in the brains of rats, University of Washington researchers have pinpointed the basolateral nucleus in the region of the brain called the of amygdala as the place where fear conditioning is encoded.

Neuroscientists previously suspected that both the amygdala and another brain region, the dorsal hippocampus, were where cues get associated when fear memories are formed. But the new work indicates that the role of the hippocampus is to process and transmit information about conditioned stimuli to the amygdala, said Ilene Bernstein, corresponding author of the new study and a UW professor of psychology.

The study is being published on July 6, in PLoS One, a journal of the Public Library of Science.

Associative conditioning is a basic form of learning across the animal kingdom and is regularly used in studying how brain circuits can change as a result of experience. In earlier research, UW neuroscientists looked at taste aversion, another associative learning behavior, and found that neurons critical to how people and animals learn from experience are located in the amygdala.

The new work was designed to look for where information about conditioned and unconditioned stimuli converges in the brain as fear memories are formed. The researchers used four groups of rats and placed individual rodents inside of a chamber for 30 minutes. Three of the groups had never seen the chamber before.

When control rats were placed in the chamber, they explored it, became less active and some fell asleep. A delayed shock group also explored the chamber, became less active and after 26 minutes received an electric shock through the floor of the chamber. The third group was acclimated to the chamber by a series of 10 prior visits and then went through the same procedure as the delayed shock rats. The final group was shocked immediately upon being introduced inside the chamber.

The following day the rats were individually returned to the chamber and the researchers observed them for freezing behavior. Freezing, or not moving, is the most common behavioral measure of fear in rodents. The only rats that exhibited robust freezing were those that received the delayed shock in a chamber which was unfamiliar to them.

“We didn’t know if we could delay the shock for 26 minutes and get a fear reaction after just one trial. I thought it would be impossible to do this with fear conditioning,” said Bernstein. “This allowed us to ask where information converged in the brain.”

To do this, the researchers repeated the procedure, but then killed the rats. They then took slices of the brains and used Arc catfish, an imaging technique, which allowed them to follow the pattern of neural activation in the animals.

Only the delayed shock group displayed evidence of converging activation from the conditioned stimulus (the chamber) and the unconditioned stimulus (the shock). The experiment showed that animals can acquire a long-term fear when a novel context is paired with a shock 26 minutes later, but not when a familiar context is matched with a shock.

“Fear learning and taste aversion learning are both examples of associative learning in which two experiences occur together. Often they are learned very rapidly because they are critical to survival, such as avoiding dangerous places or toxic foods,” said Bernstein.

“People have phobias that often are set off by cues from something bad that happened to them, such as being scared by a snake or being in a dark alley. So they develop an anxiety disorder,” she said.

“By understanding the process of fear conditioning we might learn how to treat anxiety by making the conditioning weaker or to go away. It is also a tool for learning about these brain cells and the underlying mechanism of fear conditioning.”

Co-authors of the study, all at the UW, are Sabiha Barot, who just completed her doctoral studies; Ain Chung, a doctoral student; and Jeansok Kim, an associate professor of psychology.

Journal reference:

1. Sabiha K. Barot, Ain Chung, Jeansok J. Kim, Ilene L. Bernstein. Functional Imaging of Stimulus Convergence in Amygdalar Neurons during Pavlovian Fear Conditioning. PLoS ONE, 2009; 4 (7): e6156 DOI: 10.1371/journal.pone.0006156

Adapted from materials provided by University of Washington.


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Tiny Brain Region Key To Fear Of Rivals And Predators

ScienceDaily (Mar. 15, 2009) — Mice lose their fear of territorial rivals when a tiny piece of their brain is neutralized, a new study reports.

The study adds to evidence that primal fear responses do not depend on the amygdala – long a favored region of fear researchers – but on an obscure corner of the primeval brain.

A group of neuroscientists led by Larry Swanson of the University of Southern California studied the brain activity of rats and mice exposed to cats, or to rival rodents defending their territory.

Both experiences activated neurons in the dorsal premammillary nucleus, part of an ancient brain region called the hypothalamus.

Swanson’s group then made tiny lesions in the same area. Those rodents behaved far differently.

“These animals are not afraid of a predator,” Swanson said. “It’s almost like they go up and shake hands with a predator.”

Lost fear of cats in rodents with such lesions has been observed before. More important for studies of social interaction, the study replicated the finding for male rats that wandered into another male’s territory.

Instead of adopting the usual passive pose, the intruder frequently stood upright and boxed with the resident male, avoided exposing his neck and back, and came back for more even when losing.

“It’s amazing that these lesions appear to abolish innate fear responses,” said Swanson, who added: “The same basic circuitry is found in primates and people that we find in rats and mice.”

The study was slated for online publication the week of March 9 in Proceedings of the National Academy of Sciences.

Swanson predicted that his group’s findings would shift some research away from the amygdala, a major target of fear studies for the past 30 years.

“This is a new perspective on what part of the brain controls fear,” he said.

He explained that most amygdala studies have focused on a different type of fear, which might more accurately be called caution or risk aversion.

In those studies, animals receive an electric shock to their feet. When placed in the same environment a few days later, they display caution and increased activity of the amygdala.

But the emotion experienced in that case may differ from the response to a physical attack.

“We’re not just dealing with one system that controls all fear,” Swanson said.

Swanson and collaborators have been studying the role of the hypothalamus in the fear response since 1992.

Because of its role in basic survival functions such as feeding, reproduction and the sleep-wake cycle, the hypothalamus seems a plausible candidate for fear studies.

Yet, said Swanson, “nobody’s paid any attention to it.”

The PNAS study is the most recent of several by Swanson on fear and the hypothalamus. The few other researchers in the area include Newton Canteras of the University of Sao Paulo in Brazil, who collaborated with Swanson on the PNAS study, as well as Robert and Caroline Blanchard of the University of Hawaii.

The other authors on the PNAS study were Simone Motta, Marina Goto, Flavia Gouveia and Marcus Baldo, all from the University of Sao Paulo.

The Brazilian government funded the study.

Journal reference:

1. Simone C. Motta, Marina Goto, Flavia V. Gouveia, Marcus V. C. Baldo, Newton S. Canteras, and Larry W. Swanson. Dissecting the brain’s fear system reveals the hypothalamus is critical for responding in subordinate conspecific intruders. Proceedings of the National Academy of Sciences, 2009; DOI: 10.1073/pnas.0900939106

Adapted from materials provided by University of Southern California.

Filed under: trauma, Violence, , , , ,

Does Biology Play a Role in Domestic Violence?

TUCSON—Between 20% and 30% of all men and women in the US will be victims of domestic violence in their lifetime. Domestic violence accounts for 20% of all emergency department visits, 50% of police calls, and about 30% of murdered women. While considerable research into understanding the perpetrator’s mindset has focused on learned behaviors and psychosocial issues, comparatively little effort has been devoted to exploring possible biological causes of the problem, according to David George, MD.

“Most people look at domestic violence from a psychodynamic/psychosocial perspective,” said Dr. George, Section Chief of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland. “These people believe that perpetrators feel inadequate and try to control other people by their behaviors or that they grew up in homes where they were exposed to violence, and, therefore, they’ve learned these patterns. I was particularly interested in the fact that there has been so little emphasis given to any biological understanding of what might be taking place.” Dr. George made his presentation at the 18th Annual Meeting of the American Neuropsychiatric Association.

The first step in determining whether biological abnormalities may lead to acts of domestic violence is to closely examine who the perpetrators are, according to Dr. George. The incidence of domestic violence is approximately equal in men and women, and about 70% of perpetrators abuse alcohol, he noted. Based on interviews with several hundred people who have committed acts of domestic violence, as well as their spouses and significant others, Dr. George has observed several recurring patterns. One of these patterns is that perpetrators are likely to have been in multiple fights during their childhood. “They are going to push their teachers,” noted Dr. George. “They fight with their siblings and with the kids down the street. As they grow older, most of them tend to limit their violence to the home and direct it toward their spouse or significant other.”

Perpetrators also have little insight into why they become violent, and most acts of domestic violence are impulsive, said Dr. George. “There are those with a predatory side, but I do not see it often. Alcohol plays an important role in domestic violence. Alcohol is a two-edged sword. Perpetrators are going to use alcohol to calm down, but often the alcohol contributes to the likelihood of violence.”

Typical behavioral symptoms in perpetrators include racing thoughts, supersensitivity to environmental stimuli, and mood swings that range from shutdown to flight, fight, and stalking. “I had one person tell me, ‘If you ever got in my mind, you would probably lock me up. You would think I was crazy.’ This is something that is going on inside of them,” said Dr. George. “Little things are going to set them off—spilled milk at the dinner table, dirty dishes that aren’t taken care of in the sink, the dinner that’s late. The most interesting thing was that they feel afraid at the time of the aggression. That was very difficult for me to comprehend, because so often we are working with large and aggressive perpetrators whose victims are smaller in stature. Fear just doesn’t look like it should be a significant factor.”


Dr. George has conducted a number of studies regarding domestic violence. One trial included perpetrators of domestic violence with alcohol dependence, nonviolent alcoholics, and healthy controls. The researchers found that violent alcoholics had a higher incidence of major depression, panic attacks, social phobia, obsessive-compulsive disorder, generalized anxiety, and certain personality disorders than did nonviolent alcoholics.

In a double-blind, placebo-controlled trial involving the administration of sodium lactate to participants, Dr. George and colleagues found that behavioral symptoms such as speech, breathing, facial grimacing, and motor activity in the arms and legs were much more accentuated in the perpetrators, as was their sense of fear, panic, and rage, compared with nonviolent controls. “These results were instrumental in changing my thinking about perpetrators of domestic violence,” commented Dr. George. “It moved me from seeing them as offensive individuals to seeing them as defensive individuals. This was extremely important to me, because it directed my attention to the neuropathways that have been shown in animals to mediate defensive aggression.”


Dr. George devised a basic model for understanding the psychopathology of perpetrators of domestic violence. “Perpetrators frequently misinterpret environmental stimuli, which gives rise to a perceived sense of threat,” he explained. “Sensory stimuli enter the thalamus, and from there are processed by both the cortex and the amygdala. The processing of the sensory stimuli in the amygdala is extremely fast and serves as an early warning system. The processing of the sensory stimuli in the cortex is going to be much slower and much more detailed than in the amygdala…. The cortex and the amygdala talk to each other. In certain situations, these sensory stimuli give rise to defensive behavior, autonomic arousal, and hypoalgesia…. If you talk to these people and ask them what it is like when they are hitting someone, they will tell you, ‘It feels like my hands and arms are like feathers. I have no feeling in my hands. I don’t feel as though I’m doing anything.’”

In formulating a theory for the etiology of domestic violence, Dr. George reasoned that threats trigger a conditioned fear response in perpetrators that is out of proportion to the stimulus, which may result in fear-induced aggression. “This misinterpretation arises from the abnormality in structures and pathways that mediate fear-induced aggression,” he said.

In a study using PET (18FDG) imaging to examine the neural structures and pathways involved in fear conditioning and fear-induced aggression, Dr. George’s group found that mean CMRglc in the right hypothalamus was significantly lower in perpetrators with alcohol dependence, compared with nonviolent alcoholics and healthy controls. “At rest, when you compare the activities in the left amygdala with various cortical and subcortical structures like the thalamus and cingulate, you see a strong correlation in the nonviolent alcoholics between these structures and the amygdala, whereas in the perpetrators, you had decreased correlations,” said Dr. George. “We are interpreting this to mean that the ability of the cortex to modulate the amygdala in these people is reduced. Similarly, we compared perpetrators with healthy controls. We found the same kind of finding here, decreased correlations [with the left and right amygdala]. And the nonviolent alcoholics had an increased correlation between the left thalamus and left posterior orbitofrontal cortex.”

Such findings may indicate different motivations to drink alcohol for nonviolent alcoholics and alcoholic perpetrators. “Basically, we arrived at two different possibilities,” Dr. George said. “The increased correlation found in nonviolent alcoholics maybe makes them more susceptible to environmental cues that trigger drinking. Whereas, I think alcoholic perpetrators are more prone, at least in the initial stages of the disease, to drink in order to decrease anxiety.”

In another study, Dr. George and colleagues performed lumbar puncture in the left lateral decubitus position in alcoholic perpetrators of domestic violence, nonalcoholic perpetrators, and healthy controls. The researchers found that the nonalcoholic violent group had lower 5-HIAA [5-hydroxyindoleacetic acid] concentrations than did the other two groups, which was “not particularly surprising, given the huge literature that’s out there saying that 5-HIAA is involved with impulsive types of aggression,” noted Dr. George. “It is unclear as to why the alcoholics didn’t have it. We then looked at testosterone, and there we found that [alcoholic perpetrators] did have higher levels of testosterone. So we have at least two neurotransmitter systems that theoretically could be involved, that could be modulating the way they process sensory information. We are looking at a number of other transmitter systems at this time.”


Dr. George’s current research is focusing on fMRI, genotyping, and potential treatments. To date, he emphasized, “Treatments for domestic violence are often ineffective.” In one ongoing trial, he has been comparing fluoxetine with placebo regarding their effect on measures of aggression, anxiety, and depression in those who commit acts of domestic violence. “What is really interesting is when you look at what serotonin does, it modulates sensory information,” noted Dr. George.

Dr. George believes that it is possible to piece together some of these findings to understand domestic violence on the basis of a biological pathway. “This is such a primitive pathway,” he commented. “Defensive aggression is present throughout the whole animal kingdom and promotes survival. With reduced cortical connection to the amygdala, perpetrators process sensory information very quickly. Based on fMRI studies, this processing of sensory information by the amygdala is out of the conscious awareness. I think that’s why therapy has been so ineffective in these individuals. They are responding so quickly to sensory information that they don’t even have time to think about it.”

Ultimately, Dr. George believes that further studies linking conditioned fear and fear avoidance with behaviors and psychiatric diagnoses will help change the way researchers and clinicians perceive and treat perpetrators of domestic violence.           

—Colby Stong

Suggested Reading
Fils-Aime ML, Eckardt MJ, George DT, et al. Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics. Arch Gen Psychiatry. 1996;53:211-216.
George DT, Phillips MJ, Doty L, et al. A model linking biology, behavior and psychiatric diagnoses in perpetrators of domestic violence. Med Hypotheses. 2006;67:345-353.
George DT, Umhau JC, Phillips MJ, et al. Serotonin, testosterone and alcohol in the etiology of domestic violence. Psychiatry Res. 2001;104:27-37.
Umhau JC, Petrulis SG, Diaz R, Rawlings R, George DT. Blood glucose is correlated with cerebrospinal fluid neurotransmitter metabolites. Neuroendocrinology. 2003;78:339-343.

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Emotion-Regulating Circuit Weakened in Borderline Personality Disorder (10/7/2008)

NIMH Press Release

 Differences in the working tissue of the brain, called grey matter, have been linked to impaired functioning of an emotion-regulating circuit in patients with borderline personality disorder (BPD). People with BPD had excess grey matter in a fear hub deep in the brain, which over-activated when they viewed scary faces. By contrast, the hub’s regulator near the front of the brain was deficient in grey matter and underactive, effectively taking the brakes off a runaway fear response, suggest researchers supported in part by NIMH.


The imaging studies are the first to link structural brain differences with functional impairment in the same sample of BPD patients. Similar changes in the same circuit have been implicated in mood and anxiety disorders, hinting that BPD might share common mechanisms with mental illnesses that have traditionally been viewed through the lens of biology.1


Michael Minzenberg, M.D., of the University of California, Davis, and NIMH grantees Antonia S. New, M.D., and Larry J. Siever, M.D., of Mount Sinai School of Medicine, and colleagues, reported on their magnetic resonance imaging (MRI) findings in the July, 2008 issue of the Journal of Psychiatric Research2 Their functional imaging findings were reported in the August 2007 issue of Psychiatric Research Neuroimaging.3

Accounting for up to 20 percent of psychiatric hospitalizations,4 BPD affects up to 1.4 percent of adults in a year.5 It is characterized by intense bouts of anger, depression, and anxiety that may last only hours, often in response to perceived rejection. People with this difficult to treat disorder typically experience tumultuous work and family life and may engage in risky, impulsive behaviors. Cutting, burning and other forms of self-harm are common. The completed suicide rate in BPD approaches 10%, and at least 75% of afflicted individuals attempt suicide at least once.6


Previous findings7 of lower-than-normal grey matter matter – neurons and their connections – in the regulator hub, called the anterior cingulate cortex (ACC), hinted that this might affect the way the brain works in BPD.


To find out, the researchers first used functional magnetic resonance imaging (fMRI), to compare responses of 12 adult BPD patients with those of 12 healthy controls to pictures of faces with fearful, angry and neutral expressions. In response to fearful faces, the amygdala, the fear hub, showed exaggerated activity in the BPD patients, while the ACC was relatively underactive. Since ACC activity would normally increase to dampen an overactive amygdala, this suggested weak regulation of emotion in the circuit.


Suspecting that this functional impairment mirrors structural differences – as has been found in depression – the researchers next used anatomical MRI to compare grey matter in the same patients and healthy controls. Consistent with the fMRI results and the earlier findings, grey matter density was increased in parts of the amygdala and decreased in parts of the ACC, in BPD patients relative to controls. This suggested an abnormality in the number or architecture of neurons in these key components of the emotion-regulating circuit, which other evidence links to impaired functioning of the serotonin chemical messenger system.

Note: This story has been adapted from a news release issued by The National Institute of Mental Health

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Brain Cells Related To Fear Identified, Paving The Way For More Effective Treatment Of Post-Traumatic Stress And Other Anxiety Disorders

ScienceDaily (July 11, 2008)— The National Institute of Mental Health estimates that in any given year, about 40 million adults (18 or older) will suffer from some form of anxiety disorder, including debilitating conditions such as phobias, panic disorders and post-traumatic stress disorder (PTSD).

It is estimated that nearly 15 percent of U.S. soldiers returning from Iraq and Afghanistan develop PTSD, underscoring the urgency to develop better treatment strategies for anxiety disorders.  These disorders can lead to myriad problems that hinder daily life – or ruin it altogether – such as drug abuse, alcoholism, marital problems, unemployment and suicide.

Functional imaging studies in combat veterans have revealed that the amygdala, a cerebral structure of the temporal lobe known to play a key role in fear and anxiety, is hyperactive in PTSD subjects. Potentially paving the way for more effective treatments of anxiety disorders, a recent Nature report by Denis Paré, professor at the Center for Molecular and Behavioral Neuroscience at Rutgers University in Newark, has identified a critical component of the amygdala’s neural network normally involved in the extinction, or elimination, of fear memories. Paré’s laboratory studies the amygdala and how its activity impacts behavior. His research was published online by Nature on July 9, 2008 and is scheduled to appear in the print edition later in July.

Earlier research has revealed that in animals and humans, the amygdala is involved in the expression of innate fear responses, such as the fear of snakes, along with the formation of new fear memories as a result of experience, such as learning to fear the sound of a siren that predicts an air raid.

In the laboratory, the circuits underlying learned fear are typically studied using an experimental paradigm called Pavlovian fear conditioning. In this research model on rats, a neutral  stimulus such as the sound of a tone elicited a fear response in the rats after they heard it paired with an noxious or unpleasant stimulus, such as a shock to the feet. However, this conditioned fear response was diminished with repetition of the neutral stimulus in the absence of the noxious stimulus. This phenomenon is known as extinction. This approach is similar to that used to treat human phobias, where the subject is presented with the feared object in the absence of danger.

Behavioral studies have demonstrated, however, that extinction training does not completely abolish the initial fear memory, but rather leads to the formation of a new memory that inhibits conditioned fear responses at the level of the amygdala. As such, fear responses can be expressed again when the conditioned stimulus is presented in a context other than the one where extinction training took place.

For example, suppose a rat is trained for extinction in a grey box smelling of roses, and later hears the tone again in a different box, with a different smell and appearance.  The rat will show no evidence of having been trained for extinction. The tone will evoke as much fear as if the rat had not been trained for extinction.

“Extinction memory will only be expressed if tested in the same environment where the extinction training occurred, implying that extinction does not erase the initial fear memory but only suppresses it in a context-specific manner,” notes Paré.

Importantly, it has been found that people with anxiety disorders exhibit an “extinction deficit,” or a failure to “forget.” However, until recently, the mechanisms of extinction have remained unknown.

As reported by Nature, Paré has found that clusters of amygdala cells, known as the intercalated (ITC) neurons, play a key role in extinction. His findings indicate that ITC cells inhibit amygdala outputs to the brain stem structures that generate fear responses. Indeed, Paré and his collaborators have shown that when ITC cells are destroyed with a targeted toxin in rats, extinction memory is impeded, mimicking the behavior seen in PTSD.

 The significance of this finding derives from earlier results suggesting that PTSD reflects an extinction deficit and that the amygdala is hyperactive in this disorder. As a result, it might be possible to compensate for this abnormality and facilitate extinction with pharmacological interventions that enhance the excitability of ITC cells to inhibit amygdala outputs.

Paré’s research is supported by a $1,487,897 grant from the National Institute of Mental Health. The research project was carried out in collaboration with Rutgers graduate students Ekaterina Likhtik and John Apergis-Scoute, post-doctoral student Daniela Popa, and research assistant G. Anthony Fidacaro.

Adapted from materials provided by Rutgers University.

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