What is the biology of fear, the emotional response that drives so much behavior in humans and animals alike? Our guest on this edition of Focus In Sound, Dr. Kerry Ressler, is determined to answer that question, and in doing so to help the millions of people who suffer from fear-based disorders such as post-traumatic stress disorder and panic disorder. Kerry is an Associate Professor of Psychiatry and Behavioral Sciences at the Emory University School of Medicine in Atlanta. He is also on the faculty of the Center for Behavioral Neuroscience in Atlanta, and directs the Grady Trauma Project, which is a major study of the gene-environment interactions underlying post-traumatic stress disorder, which involves patients at Grady Memorial Hospital in Atlanta. In 2006, he received a five-year Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. In 2007, he was named a Howard Hughes Medical Institute Investigator. Kerry’s lab at the Yerkes National Primate Research Center at Emory is focused on the molecular and cellular mechanisms of fear learning and the process of extinction of fear in mouse models. He hopes that by understanding how fear works in the brain, it will improve our understanding of and advance treatments for fear-based
disorders.
Transcription of “Interview with Kerry Ressler”
00;00;04;12 – 00;00;28;13
Ernie Hood
Welcome to Focus In Sound, the podcast series from the Focus newsletter published by the Burroughs Wellcome Fund. I’m your host, science writer Ernie Hood. What is the biology of Fear? The emotional response that drives so much behavior in humans and animals alike. My guest on this edition of Focus In Sound, Dr. Kerry Ressler, is determined to answer that question.
00;00;28;21 – 00;01;02;20
Ernie Hood
And in doing so, to help the millions of people who suffer from fear based disorders such as post-traumatic stress disorder and panic disorder. Kerry is an associate professor of psychiatry and behavioral sciences at the Emory University School of Medicine in Atlanta. He is also on the faculty of the Center for Behavioral Neuroscience in Atlanta and directs the Grady Trauma Project, which is a major study of the gene environment interactions underlying post-traumatic stress disorder, which involves patients at Grady Memorial Hospital in Atlanta.
00;01;03;09 – 00;01;38;24
Ernie Hood
In 2006, he received a five year Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. In 2007, he was named a Howard Hughes Medical Institute investigator. KERRY His lab at the Yerkes National Primate Research Center at Emory is focused on the molecular and cellular mechanisms of fear learning and the process of extinction of fear in mouse models. He hopes that by understanding how fear works in the brain, it will improve our understanding of and advance treatments for fear based disorders.
00;01;39;08 – 00;01;41;05
Ernie Hood
Kerry, welcome to Focus In Sound.
00;01;41;08 – 00;01;42;21
Kerry Ressler
Thanks a lot. It’s a pleasure to be here.
00;01;43;04 – 00;01;49;16
Ernie Hood
To begin, Kerry, please tell us a little bit about your background and what led you to pursue this particular line of research.
00;01;50;10 – 00;02;22;03
Kerry Ressler
I was a molecular neurobiologist in graduate school focusing on the way we can understand health systems and circuits approach behavior. But my long term interests were emotional behavior and emotionally relevant learning. I did a residency in psychiatry, and I’ve always been interested in what motivates people and how people’s behavior is driven through neural circuits. When I started to put these ideas together at Emory, working with Dr. Michael Davis, these coalesce together in a focus on fear.
00;02;22;04 – 00;02;42;05
Kerry Ressler
Michael Davis is one of the world’s experts on the role of the amygdala in learning and behavior and fear. And it turns out that of all the psychiatric and psychologically relevant behaviors, probably the best is understood about the role of the amygdala and the neural circuits modulating the amygdala, a small brain region in the temporal lobes just inside the ears in a person.
00;02;42;18 – 00;03;08;28
Kerry Ressler
The best is understood about it in terms of how it controls behavior. And so it turns out that fear and fear related behaviors are among the best understood behaviors that we know. And in terms of psychiatric disorders. It’s quite relevant because the fear is really the underlying emotion underlying a number of disorders of anxiety, including panic disorder, phobias like social phobia and social anxiety disorder and post-traumatic stress disorder.
00;03;09;03 – 00;03;21;25
Kerry Ressler
Currently, then we work both at the animal level and trying to understand the neural circuitry and the molecular processes that underlie fear. And then at the human level, the psychology and genetics and biology of fear.
00;03;22;11 – 00;03;46;22
Ernie Hood
So in your work, you and your colleagues have been able to identify some of the neurobiological elements of both learning and a so-called extinction of fear, which is a learning process by which a pathological fear is eventually eliminated. Tell us about what you’ve discovered in terms of where these processes live in the brain and how they work in relation to fear related disorders such as you’ve described.
00;03;47;11 – 00;04;11;12
Kerry Ressler
A lot has been understood and was really defined most eloquently and initially by Ivan Pavlov in Russia over 100 years ago. Now in many of those same concepts in terms of basic what we now call Pavlovian conditioning or fear conditioning are at work. And so, as you allude to, we understand a lot now through decades of work by many researchers on the neural circuits of why we become afraid and how we learn to be afraid.
00;04;12;01 – 00;04;38;07
Kerry Ressler
But what’s become more recently understood is this idea of inhibiting fear. And in fact, we now understand that when we are originally afraid of something and learned to no longer be afraid of it, we don’t forget that memory. Rather, we make a new memory that inhibits that original memory. So for example, if someone is afraid of spiders, it goes through a therapy where they are exposed over and over again to spiders and then no longer are particularly afraid of spiders after this treatment.
00;04;38;13 – 00;04;57;12
Kerry Ressler
We think that that’s not because they actually forget or erase that original memory. Rather, they form new memories that in this place and in this time the spiders are safe. And we think that’s partly the frontal cortex controls the amygdala. These this brain region involved in fear and learns to inhibit it. And so that’s the process that we call extinction.
00;04;57;18 – 00;05;10;21
Kerry Ressler
And we study the molecular and circuit mechanisms of that process. And we think it’s clinically interesting and important because it seems to be the biological basis of many psychotherapies that are based on treating fear and anxiety related disorders.
00;05;11;11 – 00;05;20;06
Ernie Hood
Carry this new thinking about the role of the amygdala in memory formation. It’s really a radical departure from the neurobiology of the past, isn’t it?
00;05;20;16 – 00;05;39;21
Kerry Ressler
Well, I think the idea that there’s different parts of the brain involved in memory has been around for a while. But what’s relatively recent is understanding numerous memory systems and not just memory declarative memories, like, you know, where you were yesterday or where you parked your car or what facts are, or history, for example, but also emotional memories.
00;05;39;21 – 00;06;00;10
Kerry Ressler
And that when we think of emotion now, we not only think of emotion as being afraid or being excited or being surprised, but we also think of it as the learning events that hare and an experience or a history with that emotion. And so we can learn a lot about the learning and the parts of the brain involved in the learning of emotion.
00;06;00;25 – 00;06;06;10
Ernie Hood
So, Carrie, what kind of methods do you typically use to discover these neurobiological elements?
00;06;06;17 – 00;06;35;17
Kerry Ressler
Well, we do it at both a human level and at a basic science level, using transgenic modified mice as our primary model in the lab. So in humans, we study fear in a number of ways. We first ask questionnaires, for example, with standard psychological questionnaires, asking about people with their history, For example, with post-traumatic stress disorder. We’d ask about a history of trauma, a history of childhood trauma, history of adult trauma we find in our inner city populations that there’s large percentages of people who have been attacked or seen other people attacked or murdered.
00;06;35;23 – 00;07;00;03
Kerry Ressler
Similarly, with combat, it’s more obvious where people are traumatized. And then we ask a series of questions related to how they respond to those traumas and what their fear memories are related to those traumas. We also ask, and we can study in humans in a laboratory, a model of fear learning in which people are strapped up to a number of electrical devices that basically measure the motor output of various parts of their body.
00;07;00;03 – 00;07;17;11
Kerry Ressler
Specifically, we focus on the eye and what happens when one hears an unexpected noise that there’s a bit of an eye blink, startle reflex. But we know through people’s work, like Mike Davis and others, is that if one is afraid at the time of that unexpected noise, they will startle more than that. If they just startle and they’re not afraid, for example.
00;07;17;29 – 00;07;40;14
Kerry Ressler
And so there’s quantitative, scientific ways we can measure fear in the physiological readout of fear, including this startle behavior, as well as heart rate and those sorts of things. So we can, in the laboratory, train people to be afraid to mild stimuli and look at how they respond to fear and how they inhibit that fear. And similarly, in animals, we can do similar sorts of behaviors looking at their fear responses in a quantitative, measurable way.
00;07;40;18 – 00;07;47;11
Kerry Ressler
But we can do molecular manipulations and pharmacological manipulations of different parts of their brain to study that fear.
00;07;47;24 – 00;08;09;08
Ernie Hood
Terry, I’d like to get a little bit more detail at this point about Peter S.D. itself, and so much of your work involves that particular condition. I think we’ve all heard of PTSD, particularly in recent years, as it relates to so many veterans of the wars in Iraq and Afghanistan. But it’s not just about those veterans. I’m sure it can actually strike anyone, can’t it?
00;08;09;22 – 00;08;30;03
Kerry Ressler
That’s right. The diagnosis of PTSD entered the psychiatric lexicon in the seventies, really as a result of the Vietnam War. But if one looks back through history, it’s been known about for millennia and was even written about in ancient Greek and Roman times, peoples with soldiers, heart and people who were so shaky from the memories of the battlefield, they could not go back out and that sort of thing.
00;08;30;16 – 00;08;57;26
Kerry Ressler
What we’ve increasingly realized over the last decade or two is that trauma occurs in all sorts of people and not just in war veterans. And so you see PTSD with people who’ve had extreme forms of child abuse. Even in adulthood, they can have PTSD symptomatology and certainly traumas in adults. And so our larger study, the Grady Trauma Project study, is looking at a large population of inner city Atlanta, a large, impoverished, primarily African-American sample that has very high rates of trauma.
00;08;57;26 – 00;09;16;23
Kerry Ressler
And so the rates of trauma and the rates of post-traumatic stress disorder we see from this population are about as high as we see in Vietnam vets and the types of trauma we see in the kind of percentages we see or almost half of our population. Now, we’ve interviewed about 4000 people. About half of the population knows somebody personally who’s been murdered, a friend or family member.
00;09;17;14 – 00;09;42;24
Kerry Ressler
Almost two thirds of the men have been attacked with a weapon. And between a quarter and a third of the women have been sexually assaulted. So the rates of trauma are very high and the rates of post-traumatic stress disorder are very high. And the kind of symptoms we see with PTSD are a flashback acts where they feel like they’re re-experiencing the event, nightmares, being unable to fall asleep or having nightmares or minding the event, having sweats and palpitations and heart racing when they are reminded of the event and a lot of avoidance.
00;09;43;08 – 00;09;56;23
Kerry Ressler
All those clusters of symptoms can lead to a large amount of emotional reactivity, including co-morbid depression and just generally stress related impairment. That makes it very hard for people to function normally, to hold down a job, to have personal relationships and that sort of thing.
00;09;57;06 – 00;10;13;00
Ernie Hood
Kari One of the really fascinating aspects of your work is your ability to conduct basic research in rodent models and translate that quickly and apparently quite effectively into treatments in humans. Tell us about how that process has worked in terms of your work with PTSD.
00;10;13;15 – 00;10;35;23
Kerry Ressler
Learning about the process of how one becomes afraid is interesting and helps us understand the process and the biological basis of it, but it’s not so helpful immediately for treatments. What we focused on primarily for understanding how we might be able to improve treatments for fear related disorders like PTSD or like phobias or panic disorder is focusing more on this idea of inhibition of fear.
00;10;35;23 – 00;11;03;28
Kerry Ressler
What can we understand about how we inhibit fears, how psychotherapy works that involves exposure to fearful events? Well, it turns out that this idea of extinction of fear or repetitive exposure to a fearful stimulus does making that no longer fearful is very similar in humans as it is even in the most simple mammals and in mice. And so the same brain regions and we think to some extent the same molecular processes are similar in humans, in mice and rats.
00;11;04;06 – 00;11;28;14
Kerry Ressler
One example of this is a study we did several years ago now where we showed that a certain neurotransmitter in the brain called glutamate, acting on what’s called NMDA receptors is involved in the process of inhibiting fear. So we reasoned that if we had a a drug that would activate these receptors at the same time that the animal learned to inhibit the fear, they might do it better.
00;11;28;26 – 00;11;52;09
Kerry Ressler
This particular drug called B Cyclic Sirin, had, interestingly enough, already been approved for tuberculosis treatment through an entirely different mechanism. But we chose it as a drug because it was very well tolerated in humans at a much higher dose than was helpful for its effect on these glutamate receptors. So we showed in rats, first of all, that this drug enhanced the ability for the rats to extinguish or inhibit the fear.
00;11;52;17 – 00;12;17;18
Kerry Ressler
And then we tried it with a colleague, Barbara Ruff, in Patients with Fear related disorders. And we started with phobias and we found that it made the people learn to inhibit the fear or recover from the fear much faster. It made the psychotherapy work faster. And so now there’s been about seven or eight studies doing this across a number of phobia studies, specific phobia of heights, public speaking phobia, as well as panic disorder and obsessive compulsive disorder.
00;12;17;18 – 00;12;40;15
Kerry Ressler
And a number of ongoing studies are now looking at it with post-traumatic stress disorder. And in all of these cases, the idea and how you use a medication is quite different than historically. The idea is not that there is a disruption of chemicals in the brain at baseline. Rather, we need to specifically enhance the molecule or part of learning so people take the drug only at the time of the learning event or the therapy.
00;12;40;23 – 00;12;55;17
Kerry Ressler
And so in the study so far, it’s involved only 2 to 4 therapy sessions with 2 to 4 pills total over the entire course of the therapy. And they would take the pill right before the therapy. And it appears in many of the studies so far that the therapy is working more effective when that happens.
00;12;55;27 – 00;13;03;05
Ernie Hood
I know that the treatment has been in trials for a while now. Where does that stand in terms of becoming a mainline therapeutic modality?
00;13;03;10 – 00;13;38;07
Kerry Ressler
It’s still in the early phases. More studies need to be done. It’s currently a generic medication, and so the pharmaceutical companies have different opinions about whether it’s worth an investment or not. But whether it’s this medication or a different one that ends up making it to FDA approval and all of the hurdles that’s required for that. What’s exciting to us is sort of a new way of thinking about medications and psychiatry ones that specifically aid the learning process of psychotherapy and are only taken specifically with psychotherapy as opposed to medications that are taking long term without having such specific effects.
00;13;38;14 – 00;13;49;18
Ernie Hood
Do you see this as a whole new kind of burgeoning area for psycho pharmacological interventions? Do you think there may be many more drugs out there that could be beneficial in this particular way?
00;13;49;19 – 00;14;18;28
Kerry Ressler
Absolutely. I think one of the most exciting areas in the last decade or so in really the last couple of decades in neuroscience is idea of learning and memory and synaptic plasticity, how our brain can change with learning and the fields of therapy are getting more specific in their ability to target certain kinds of symptoms or others. And one way of looking at what psychotherapy does is very specifically use the brain, the cortical regions of the brain, to inhibit fear or control emotions.
00;14;19;07 – 00;14;42;26
Kerry Ressler
And what repetitive therapy does is essentially teach you new ways of controlling emotion. And as the neuroscience of understanding, learning and how the brain changes improves, then it seems quite possible that there will be a number of potentially available tools and molecular targets that would allow us to enhance the specific components of psychotherapy in this way.
00;14;43;15 – 00;15;05;18
Ernie Hood
You mentioned earlier the concept of the extinction of fear that it’s more than simply unlearning something that’s been learned. That is the initial fear response and the pathological pattern that emerges. But it’s actually a new learning process in and of itself. Tell us more about this extinction of fear and how what you’ve learned about it can potentially be exploited.
00;15;05;27 – 00;15;30;27
Kerry Ressler
So the basics of extinction, again, Pavlov originally defined it as if you have a person or an animal who has learned a pair. One cue we would call it a conditioned stimulus with other cue, like a shock or a painter and aversive and unconditioned stimulus. That over time the conditioned stimulus or you know, the memory of the trauma by itself is enough to elicit all the fear and all the same biological reflexes of fear as the original trauma or shock.
00;15;31;16 – 00;15;56;00
Kerry Ressler
The idea that then they showed as if you didn’t repeatedly present the conditioned stimulus. So the trauma or the reminder cue to the person or the animal over and over again, over time, the fear response will diminish or habituate. And he called it extinguish, suggesting that the animal or person wasn’t afraid of that cue anymore. What’s some of the psychological data that suggests that it’s not just an erasure of the memory is that there are several different lines of evidence.
00;15;56;00 – 00;16;12;10
Kerry Ressler
One suggests that if you extinguish your fears or it’s decreased and then wait a while, the fear will seem to come back. That’s called spontaneous recovery. Another one is if you extinguish the fear and it doesn’t seem to be there anymore, but the person or the animal gets stressed again, the fear will seem to come back. And you can see this certainly in clinical populations.
00;16;12;10 – 00;16;29;09
Kerry Ressler
People will be fine for a while and then another bad thing happens in their life that may have nothing to do with their original PTSD or their obsessive compulsive disorder or the panic disorder. They will reactivate those same set of symptoms. So that’s called reinstatement. And the third one is if you extinguish the fear in one place, but then bring them in a whole nother context, it might reactivate fear.
00;16;29;09 – 00;16;48;27
Kerry Ressler
So all of those are evidence that there’s the original memory. Trace of fear is still there. It’s just being actively inhibited by this process. And a number of labs have now shown that that inhibition process both requires the amygdala, but it also requires parts of the cortex and other parts of the brain that seem to actively inhibit the amygdala when this new learning occurs.
00;16;49;11 – 00;17;07;17
Kerry Ressler
And the whole field of by both understanding more of the circuitry of how we inhibit an emotion and the molecules of how we inhibit emotion, we think we’ll both increase our ability to target extinction and exposure therapy, but also might give us new insights into how to better design psychotherapies, to better teach people to control their emotions.
00;17;08;00 – 00;17;24;13
Ernie Hood
How big a problem are these conditions such as PTSD and phobias in terms of their cost to society? I would imagine that they must be quite common, quite burdensome, and remain quite long term and difficult to treat despite the advances you’ve been talking about.
00;17;24;29 – 00;17;45;18
Kerry Ressler
I don’t have the numbers in front of me as far as the morbidity analysis, but certainly in terms of the frequency and prevalence are very high. So among soldiers it’s about 15% of combat soldiers have gone to develop PTSD. In the inner city, we think it’s at least that high, if not 20%. And this percentage of people who often find it very difficult to hold a job, very difficult to have relationships.
00;17;45;18 – 00;18;03;22
Kerry Ressler
Many soldiers returning from Iraq and Afghanistan end up, you know, having difficulty with their relationships or getting getting divorced, not being able to hold a job afterwards. There’s already starting to be a number of soldiers from Iraq and Afghanistan that are already becoming homeless. And many of these people, it’s because of their inability to deal with their traumas and the PTSD.
00;18;04;02 – 00;18;19;03
Kerry Ressler
If we broaden the range of disorders that we’re talking about and things like obsessive compulsive disorder and panic disorder and other specific anxieties, it can be quite a large number. And that is very burdensome in terms of people being unable to function at their level that they could be able to.
00;18;19;16 – 00;18;22;22
Ernie Hood
So these really are hugely burdensome medical problems, aren’t they?
00;18;23;04 – 00;18;42;11
Kerry Ressler
I think so. And again, our focus on the inner city is really raising a whole nother question. When I think back about their very high rates of trauma that I quoted to you earlier and the very high rates of debilitating PTSD, like on the order of 15 or 20% in inner city populations, we also know that people with PTSD and other disorders have a higher rate of raising children with higher risks for disorders.
00;18;42;12 – 00;19;05;25
Kerry Ressler
A part of that’s genetic. A part of it, we think, is environmental. We’re finding data that people with post-traumatic stress disorder medically are at higher rates of cardiovascular disease, higher rates of metabolic syndrome and diabetes. And there’s some evidence that at least some of the explanation for health disparity differences in African-Americans and Caucasians, at least in inner city areas, may be, in fact, due to the higher trauma load and the higher untreated trauma burden.
00;19;05;27 – 00;19;14;20
Kerry Ressler
It also suggests that some of the higher rates of unemployment and things like that may in part be due to untreated and unrecognized trauma burden.
00;19;15;08 – 00;19;25;12
Ernie Hood
Well, the knowledge you’ve gained, perhaps eventually lead to preventive measures by identifying individuals who may be highly genetically susceptible to fear and anxiety disorders.
00;19;25;24 – 00;19;47;04
Kerry Ressler
Well, we certainly think it’s theoretically plausible that we would eventually have enough knowledge to be able to predict who is more at risk, given a trauma to having difficulty with that trauma, i.e. not recovering normally and going on to develop a disorder that was debilitating. There’s sort of the societal question of what do we do? You know, is it ethical to prevent people from being in combat if that’s what they want to do?
00;19;47;05 – 00;20;07;10
Kerry Ressler
Because we think it’s a risk. And then, on the other hand, is how can we help such people? And they’re certainly there known therapies that can help increase resilience. The flip side of everything we’ve talked about is the concept of resilience. On the one hand, you can say, well, why following a given particularly awful, horrible thing happening to someone, why do some people recover and other people go on to develop these psychopathology?
00;20;07;10 – 00;20;21;05
Kerry Ressler
Well, but the flip side of the question is why are some people resilient and recover just fine? And so we hope by understanding the biology of who recovers and who is more resilient in the face of particularly bad, stressful things, that will also help us understand better how to help people to be more resilient.
00;20;21;07 – 00;20;40;25
Ernie Hood
Absolutely. That definitely sounds like it’s well worthy of continued investigation. Kerry, we already talked a bit about your ability to conduct basic research in rodent models and translate that into working effectively with your patients in the clinical setting. That must be a really rewarding aspect of what you do.
00;20;41;00 – 00;21;00;05
Kerry Ressler
I think so. I mean, I think all of us who are involved in research and clinical work, we’re driven to help make a difference. And often things don’t turn around fast enough. And so it generally requires more patients than than we sometimes have. But a nice thing about having several parallel approaches like this going on is there’s generally progress being made somewhere at some given time.
00;21;00;05 – 00;21;06;18
Kerry Ressler
And as we get older, ten years seems to be relatively short and it actually feels like things are happening quite quickly. So. So yeah, it’s very rewarding.
00;21;06;27 – 00;21;08;29
Ernie Hood
So, Kerry, where is your research going from here?
00;21;09;12 – 00;21;29;14
Kerry Ressler
The overarching goal that we have is to use the animal models to both further our understanding of the neurobiology of these emotional processes and to thus by understanding those to develop new ideas about treatment and prevention as you suggest. And then from the top down, by understanding the psychology and the processes in humans to better model it in animals.
00;21;29;20 – 00;21;52;22
Kerry Ressler
But the other aspect of that is we have the ability in humans to identify the genes and the genetic pathways that we think underlie the biology risk versus resilience for things like post-traumatic stress disorder in the face of trauma, if we can identify those genes in humans, we can take those back to our genetic mouse models and manipulate genes and genetic pathways in the parts of the brain that we think are mediating these emotions.
00;21;52;28 – 00;22;10;03
Kerry Ressler
To really start to understand the mechanisms of how genes and biology interact with the world around them in environment, to change emotion and to regulate emotion. So we’re putting a lot of effort now into identifying the genes that are involved in post-traumatic stress disorder and the risk and resilience factors for post-traumatic stress disorder.
00;22;10;21 – 00;22;19;10
Ernie Hood
Kerry It’s been just fascinating to learn about your work, and we wish you the best of luck for continued success. Thanks so much for joining us today on Focus In Sound.
00;22;19;22 – 00;22;21;02
Kerry Ressler
Thank you very much. It was great to be here.
00;22;21;19 – 00;22;37;09
Ernie Hood
We hope you’ve enjoyed this edition of the Focus In Sound podcast. Until next time. This is Ernie Hood. Thanks for listening.
