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.

Addiction Relapse Might Be Thwarted By Turning Off Brain Trigger

Researchers at the Ernest Gallo Clinic and Research Center at UC San Francisco have been able to identify and deactivate a brain pathway linked to memories that cause alcohol cravings in rats, a finding that may one day lead to a treatment option for people who suffer from alcohol abuse disorders and other addictions.

In the study, researchers were able to prevent the addicted animals from seeking alcohol and drinking it, the equivalent of relapse.

“One of the main causes of relapse is craving, triggered by the memory by certain cues – like going into a bar, or the smell or taste of alcohol,” said lead author Segev Barak, PhD, at the time a postdoctoral fellow in the lab of co-senior author Dorit Ron, PhD, a Gallo Center investigator and UCSF professor of neurology.

“We learned that when rats were exposed to the smell or taste of alcohol, there was a small window of opportunity to target the area of the brain that reconsolidates the memory of the craving for alcohol and to weaken or even erase the memory, and thus the craving” he said.

The study, also supervised by co-senior author Patricia H. Janak, PhD, a Gallo Center investigator and UCSF professor of neurology, was published online on June 23 in Nature Neuroscience.

Neural Mechanism That Triggers Alcohol Memory

In the first phase of the study, rats had the choice to freely drink water or alcohol over the course of seven weeks, and during this time developed a high preference for alcohol.

In the next phase, they had the opportunity to access alcohol for one hour a day, which they learned to do by pressing a lever. They were then put through a 10-day period of abstinence from alcohol.

Following this period, the animals were exposed for five minutes to just the smell and taste of alcohol, which cued them to remember how much they liked drinking it. The researchers then scanned the animals’ brains, and identified the neural mechanism responsible for the reactivation of the memory of the alcohol – a molecular pathway mediated by an enzyme known as mammalian target of rapamycin complex 1 (mTORC1).

They found that just a small drop of alcohol presented to the rats turned on the mTORC1 pathway specifically in a select region of the amygdala, a structure linked to emotional reactions and withdrawal from alcohol, and cortical regions involved in memory processing.

They further showed that once mTORC1 was activated, the alcohol-memory stabilized (reconsolidated) and the rats relapsed on the following days, meaning in this case, that they started again to push the lever to dispense more alcohol.

“The smell and taste of alcohol were such strong cues that we could target the memory specifically without impacting other memories, such as a craving for sugar,” said Barak, who added that the Ron research group has been doing brain studies for many years and has never seen such a robust and specific activation in the brain.

Drug that Erases the Memory of Alcohol

In the next part of the study, the researchers set out to see if they could prevent the reconsolidation of the memory of alcohol by inhibiting mTORC1, thus preventing relapse. When mTORC1 was inactivated using a drug called rapamycin, administered immediately after the exposure to the cue (smell, taste), there was no relapse to alcohol-seeking the next day.

Strikingly, drinking remained suppressed for up to 14 days, the end point of the study. These results suggest that rapamycin erased the memory of alcohol for a long period, said Ron.

The authors said the study is an important first step, but that more research is needed to determine how mTORC1 contributes to alcohol memory reconsolidation and whether turning off mTORC1 with rapamycin would prevent relapse for more than two weeks.

The authors also said it would be interesting to test if rapamycin, an FDA-approved drug currently used to prevent organ rejection after transplantation, or other mTORC1 inhibitors that are currently being developed in pharmaceutical companies, would prevent relapse in human alcoholics.

“One of the main problems in alcohol abuse disorders is relapse, and current treatment options are very limited.” Barak said. “Even after detoxification and a period of rehabilitation, 70 to 80 percent of patients will relapse in the first several years. It is really thrilling that we were able to completely erase the memory of alcohol and prevent relapse in these animals. This could be a revolution in treatment approaches for addiction, in terms of erasing unwanted memories and thereby manipulating the brain triggers that are so problematic for people with addictions.”

Team Points to Brain’s ‘Dark Side’ as Key to Cocaine Addiction

Scientists at The Scripps Research Institute (TSRI) have found evidence that an emotion-related brain region called the central amygdala—whose activity promotes feelings of malaise and unhappiness—plays a major role in sustaining cocaine addiction.

In experiments with rats, the TSRI researchers found signs that cocaine-induced changes in this brain system contribute to anxiety-like behavior and other unpleasant symptoms of drug withdrawal—symptoms that typically drive an addict to keep using. When the researchers blocked specific brain receptors called kappa opioid receptors in this key anxiety-mediating brain region, the rats’ signs of addiction abated.

“These receptors appear to be a good target for therapy,” said Marisa Roberto, associate professor in TSRI’s addiction research group, the Committee on the Neurobiology of Addictive Disorders. Roberto was the principal investigator for the study, which appears in the journal Biological Psychiatry.

Carrot or Stick?

In addition to its clinical implications, the finding represents an alternative to the pleasure-seeking, “positive” motivational circuitry that is traditionally emphasized in addiction.

While changes in these pleasure-seeking brain networks may dominate the early period of drug use, scientists have been finding evidence of changes in the “negative” motivational circuitry as well—changes that move a person to take a drug not for its euphoric effects but for its (temporary) alleviation of the anxiety-ridden dysphoria of drug withdrawal. George F. Koob, chair of TSRI’s Committee on the Neurobiology of Addictive Disorders, has argued that these “dark side” brain changes mark the transition to a more persistent drug dependency.

In a series of recent studies, TSRI researchers including Roberto and Koob have highlighted the role of one of these dark-side actors: the receptor for the stress hormone CRF. Found abundantly in the central amygdala, CRF receptors become persistently overactive there as drug use increases, and that overactivity helps account for the negative symptoms of drug withdrawal.

The central amygdala also contains a high concentration of a class of neurotransmitters called dynorphins, which bind to kappa opioid receptors. Much like the CRF system, the dynorphin/kappa opioid system mediates negative, dysphoric feelings—and there have been hints from previous studies that CRF doesn’t work alone in producing such feelings during addiction.

“Our hypothesis was that the dynorphin/kappa opioid receptor system in the central amygdala also becomes overactive with excessive cocaine use,” said Marsida Kallupi, first author of the paper, who was a postdoctoral research associate in Roberto’s laboratory at the time of the study.

Such overactivity would be expected to arise as the brain struggles to maintain “reward homeostasis”—a middle-of-the-road balance between pleasure and displeasure—despite frequent drug-induced swerves toward euphoria. “Dynorphin possibly acts to balance the euphoric effects produced by other opioid systems during recreational drug use,” said Scott Edwards, who is a research associate in the Koob laboratory and a co-author of the study.

Reducing Signs of Addiction

When the TSRI researchers gave rats extended access to cocaine, the rats escalated their daily intake as many human users would. Sensitive electrophysiological measurements revealed signs of a persistent functional overactivity of the GABAergic system in the rats’ central amygdalae—which corresponds to an anxiety-like state in the animals. Probing with compounds that activate or block kappa opioid receptors, the scientists found signs that these receptors, like CRF receptors, do indeed help drive the central amygdala into overactivity during excessive cocaine use.

When the researchers blocked the kappa opioid receptors, central amygdala overactivity was greatly reduced. The same kappa opioid receptor-blocking treatment (antagonist) also reduced two standard signs of addiction in cocaine-using rats—the escalating hyperactive behavior each time the drug is taken and the anxiety-like behavior during withdrawal.

These results give Roberto and her colleagues hope that a similar treatment might help human cocaine addicts feel less compelled to keep using. Kappa opioid receptor blockers are already being developed for the treatment of depression and anxiety.

Blocking negative-motivational factors such as the kappa opioid and CRF systems also has the potential advantage that it spares the positive motivational pathways—the targets of older addiction therapies such as naltrexone. “We need to keep our positive motivational pathways intact so that they can signal the many normal rewarding events in our lives,” said Roberto. By contrast, she suspects, our negative motivational pathways involving CRF and kappa opioid receptors become abnormally active only in disease states such as addiction, and thus may be blocked more safely.

Fear: A Justified Response or Faulty Wiring?

Fear is one of the most primal feelings known to man and beast. As we develop in society and learn, fear is hard coded into our neural circuitry through the amygdala, a small, almond-shaped nuclei of neurons within the medial temporal lobe of the brain. For psychologists and neurologists, the amygdala is a particularly interesting region of the brain because it plays a role in emotional learning and can have profound effects on human and animal behavior.

On June 3, 2013, a new article studying amygdala activity in human beings will be published as part of JoVE Behavior, a new section of the video journal that focuses on the behavioral sciences. The technique, developed by Dr. Fred Helmstetter and his research group at the University of Wisconsin-Milwaukee, studies how the brain responds to anticipated painful stimuli, in this case an electric shock, in volunteer test subjects.

“We’re interested in how the brain reacts to stimuli in the environment and how it changes when we form a memory of what we experience.” Dr. Helmstetter explains. “The amygdala is a part of the brain that’s important for the way we determine what is dangerous and what is safe around us and how we react to threat.  This experiment is novel in that we are able to look at activity in the amygdala on a very detailed time scale while it responds to human faces.“

The technique takes advantage of two neuroimaging techniques: magnetic resonance imaging and magnetoencephalography. Magnetic resonance imaging (MRI) is a method where a test subject’s brain can be imaged in high resolution while the test subject is immobilized, creating a map of the brain. Once this map has been obtained, magnetoencephalography (MEG) is used to record the magnetic fields created by the electrical activity within the brain. When the test subject is shocked, or anticipates a shock, amygdala activity is picked up by the MEG and mapped to the MRI computer model.

As an emotional control center in the brain, the amygdala serves as a key component in a line of neurological structures that identify and respond to perceived threat. Dr. Helmstetter tells us, “There is good evidence to suggest that anxiety disorders and other psychopathology might be directly related to altered functioning of the amygdala. Prior work with other non-invasive imaging modalities supports this idea but has only been able to average the results of neural activity over several seconds which results in a poor picture of how neurons react to a stimulus over time. This work represents a significant improvement and will allow new questions to be answered.”

The article is part of the launch of JoVE Behavior, the eighth section of JoVE. Founded in 2006, JoVE has rapidly expanded its scope from general biology to many disciplines by visualizing experimentation. Director of Content Aaron Kolski-Andreaco, PhD explains that, “By dedicating a section to behavior, JoVE has provided a platform for researchers to visualize experiments aimed at answering questions about how we think, feel, and communicate with one another.   Emphasizing this area of science is the next logical step for our journal, as the multidisciplinary study of behavior is enabled by technological advancements in physics, chemistry, and the life sciences - areas JoVE has already covered.”

Insomnia may cause dysfunction in emotional brain circuitry

A new study provides neurobiological evidence for dysfunction in the neural circuitry underlying emotion regulation in people with insomnia, which may have implications for the risk relationship between insomnia and depression.

“Insomnia has been consistently identified as a risk factor for depression,” said lead author Peter Franzen, PhD, an assistant professor of psychiatry at the University of Pittsburgh School of Medicine. “Alterations in the brain circuitry underlying emotion regulation may be involved in the pathway for depression, and these results suggest a mechanistic role for sleep disturbance in the development of psychiatric disorders.”

The study involved 14 individuals with chronic primary insomnia without other primary psychiatric disorders, as well as 30 good sleepers who served as a control group. Participants underwent an fMRI scan during an emotion regulation task in which they were shown negative or neutral pictures. They were asked to passively view the images or to decrease their emotional responses using cognitive reappraisal, a voluntary emotion regulation strategy in which you interpret the meaning depicted in the picture in order to feel less negative.

Results show that in the primary insomnia group, amygdala activity was significantly higher during reappraisal than during passive viewing.  Located in the temporal lobe of the brain, the amygdala plays an important role in emotional processing and regulation.

In analysis between groups, amygdala activity during reappraisal trials was significantly greater in the primary insomnia group compared with good sleepers. The two groups did not significantly differ when passively viewing negative pictures.

“Previous studies have demonstrated that successful emotion regulation using reappraisal decreases amygdala response in healthy individuals, yet we were surprised that activity was even higher during reappraisal of, versus passive viewing of, pictures with negative emotional content in this sample of individuals with primary insomnia,” said Franzen.

The research abstract was published recently in an online supplement of the journal SLEEP, and Franzen will present the findings Wednesday, June 5, in Baltimore, Md., at SLEEP 2013, the 27th annual meeting of the Associated Professional Sleep Societies LLC.

The American Academy of Sleep Medicine reports that about 10 to 15 percent of adults have an insomnia disorder with distress or daytime impairment. According to the National Institute of Mental Health, 6.7 percent of the U.S. adult population suffers from major depressive disorder. Both insomnia and depression are more common in women than in men.

For combat veterans suffering from post-traumatic stress disorder, ‘fear circuitry’ in the brain never rests

Chronic trauma can inflict lasting damage to brain regions associated with fear and anxiety. Previous imaging studies of people with post-traumatic stress disorder, or PTSD, have shown that these brain regions can over-or under-react in response to stressful tasks, such as recalling a traumatic event or reacting to a photo of a threatening face. Now, researchers at NYU School of Medicine have explored for the first time what happens in the brains of combat veterans with PTSD in the absence of external triggers.

Their results, published in Neuroscience Letters, and presented today at the annual meeting of the American Psychiatry Association in San Francisco, show that the effects of trauma persist in certain brain regions even when combat veterans are not engaged in cognitive or emotional tasks, and face no immediate external threats. The findings shed light on which areas of the brain provoke traumatic symptoms and represent a critical step toward better diagnostics and treatments for PTSD.

A chronic condition that develops after trauma, PTSD can plague victims with disturbing memories, flashbacks, nightmares and emotional instability. Among the 1.7 million men and women who have served in the wars in Iraq and Afghanistan, an estimated 20% have PTSD. Research shows that suicide risk is higher in veterans with PTSD. Tragically, more soldiers committed suicide in 2012 than the number of soldiers who were killed in combat in Afghanistan that year.

"It is critical to have an objective test to confirm PTSD diagnosis as self reports can be unreliable," says co-author Charles Marmar, MD, the Lucius N. Littauer Professor of Psychiatry and chair of NYU Langone’s Department of Psychiatry. Dr. Marmar, a nationally recognized expert on trauma and stress among veterans, heads The Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury at NYU Langone Medical Center.

The study, led by Xiaodan Yan, a research fellow at NYU School of Medicine, examined “spontaneous” or “resting” brain activity in 104 veterans of combat from the Iraq and Afghanistan wars using functional MRI, which measures blood-oxygen levels in the brain. The researchers found that spontaneous brain activity in the amygdala, a key structure in the brain’s “fear circuitry” that processes fearful and anxious emotions, was significantly higher in the 52 combat veterans with PTSD than in the 52 combat veterans without PTSD. The PTSD group also showed elevated brain activity in the anterior insula, a brain region that regulates sensitivity to pain and negative emotions.

Moreover, the PTSD group had lower activity in the precuneus, a structure tucked between the brain’s two hemispheres that helps integrate information from the past and future, especially when the mind is wandering or disengaged from active thought. Decreased activity in the precuneus correlates with more severe “re-experiencing” symptoms—that is, when victims re-experience trauma over and over again through flashbacks, nightmares and frightening thoughts.

Psychopaths are not neurally equipped to have concern for others

Prisoners who are psychopaths lack the basic neurophysiological “hardwiring” that enables them to care for others, according to a new study by neuroscientists at the University of Chicago and the University of New Mexico.

“A marked lack of empathy is a hallmark characteristic of individuals with psychopathy,” said the lead author of the study, Jean Decety, the Irving B. Harris Professor in Psychology and Psychiatry at UChicago. Psychopathy affects approximately 1 percent of the United States general population and 20 percent to 30 percent of the male and female U.S. prison population. Relative to non-psychopathic criminals, psychopaths are responsible for a disproportionate amount of repetitive crime and violence in society.

“This is the first time that neural processes associated with empathic processing have been directly examined in individuals with psychopathy, especially in response to the perception of other people in pain or distress,” he added. 

The results of the study, which could help clinical psychologists design better treatment programs for psychopaths, are published in the article, “Brain Responses to Empathy-Eliciting Scenarios Involving Pain in Incarcerated Individuals with Psychopathy,” which appears online April 24 in the journal JAMA Psychiatry.

Joining Decety in the study were Laurie Skelly, a graduate student at UChicago; and Kent Kiehl, professor of psychology at the University of New Mexico.

For the study, the research team tested 80 prisoners between ages 18 and 50 at a correctional facility. The men volunteered for the test and were tested for levels of psychopathy using standard measures.

They were then studied with functional MRI technology, to determine their responses to a series of scenarios depicting people being intentionally hurt. They were also tested on their responses to seeing short videos of facial expressions showing pain.

The participants in the high psychopathy group exhibited significantly less activation in the ventromedial prefrontal cortex, lateral orbitofrontal cortex, amygdala and periaqueductal gray parts of the brain, but more activity in the striatum and the insula when compared to control participants, the study found. 

The high response in the insula in psychopaths was an unexpected finding, as this region is critically involved in emotion and somatic resonance. Conversely, the diminished response in the ventromedial prefrontal cortex and amygdala is consistent with the affective neuroscience literature on psychopathy. This latter region is important for monitoring ongoing behavior, estimating consequences and incorporating emotional learning into moral decision-making, and plays a fundamental role in empathic concern and valuing the well-being of others.

“The neural response to distress of others such as pain is thought to reflect an aversive response in the observer that may act as a trigger to inhibit aggression or prompt motivation to help,” the authors write in the paper.

“Hence, examining the neural response of individuals with psychopathy as they view others being harmed or expressing pain is an effective probe into the neural processes underlying affective and empathy deficits in psychopathy,” the authors wrote.

Decety is one of the world’s leading experts on the biological underpinnings of empathy. His work also focuses on the development of empathy and morality in children.

Why Don’t Men Understand Women? Altered Neural Networks for Reading the Language of Male and Female Eyes

Men are traditionally thought to have more problems in understanding women compared to understanding other men, though evidence supporting this assumption remains sparse. Recently, it has been shown, however, that meńs problems in recognizing women’s emotions could be linked to difficulties in extracting the relevant information from the eye region, which remain one of the richest sources of social information for the attribution of mental states to others. To determine possible differences in the neural correlates underlying emotion recognition from female, as compared to male eyes, a modified version of the Reading the Mind in the Eyes Test in combination with functional magnetic resonance imaging (fMRI) was applied to a sample of 22 participants. We found that men actually had twice as many problems in recognizing emotions from female as compared to male eyes, and that these problems were particularly associated with a lack of activation in limbic regions of the brain (including the hippocampus and the rostral anterior cingulate cortex). Moreover, men revealed heightened activation of the right amygdala to male stimuli regardless of condition (sex vs. emotion recognition). Thus, our findings highlight the function of the amygdala in the affective component of theory of mind (ToM) and in empathy, and provide further evidence that men are substantially less able to infer mental states expressed by women, which may be accompanied by sex-specific differences in amygdala activity.

How two brain areas interact to trigger divergent emotional behaviors

New research from the University of North Carolina School of Medicine for the first time explains exactly how two brain regions interact to promote emotionally motivated behaviors associated with anxiety and reward.

The findings could lead to new mental health therapies for disorders such as addiction, anxiety, and depression. A report of the research was published online by the journal, Nature, on March 20, 2013.

Located deep in the brain’s temporal lobe are tightly packed clusters of brain cells in the almond shaped amygdala that are important for processing memory and emotion. When animals or people are in stressful situations, neurons in an extended portion of the amygdala called the bed nucleus of the stria terminalis, or BNST, become hyperactive.

But, almost paradoxically, neurons in the BNST, which modulate fear and anxiety, reach into a portion of the midbrain that’s involved in behavioral responses to reward, the ventral tegmental area, or VTA.

“For many years it’s been known that dopamine neurons in the VTA are involved in reward processing and motivation. For example, they’re activated during exposure to drugs of abuse and naturally rewarding experiences,” says study senior author Garret Stuber, PhD, assistant professor in the departments of Psychiatry and Cell Biology and Physiology, and the UNC Neuroscience Center.  “On the one hand, you have this area of the brain – the BNST – that’s associated with aversion and anxiety, but it’s in direct communication with a brain reward center. We wanted to figure out exactly how these two brain regions interact to promote different types of behavioral responses related to anxiety and reward.”

In the past, researchers have tried to get a glimpse into the inner workings of the brain using electrical stimulation or drugs, but those techniques couldn’t quickly and specifically change only one type of cell or one type of connection. But optogenetics, a technique that emerged about seven years ago, can.

In the technique, scientists transfer light-sensitive proteins called “opsins” – derived from algae or bacteria that need light to grow – into the mammalian brain cells they wish to study. Then they shine laser beams onto the genetically manipulated brain cells, either exciting or blocking their activity with millisecond precision.