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, 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.
Kerry, welcome to FOCUS In Sound…
Thanks a lot, it’s a pleasure to be here.
To begin, Kerry, please tell us a little bit about your background, and what led you to pursue this particular line of research.
I was a molecular neurobiologist in graduate school, focusing on the way we can understand how 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 coalesced together in a focus on fear. 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 of 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. 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 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. So currently then, we work both at the animal level in trying to understand the neural circuitry and the molecular processes that underlie fear, and at the human level, the psychology and genetics and biology of fear.
In your work, you and your colleagues have been able to identify some of the neurobiological elements of both learning and the 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…
A lot has been understood and was really defined most eloquently and initially by Ivan Pavlov in Russia over a hundred years ago now, and many of those 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. 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 learn 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 and 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, we think 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, this brain region involved in fear, and learns to inhibit it. And so that’s the process that we call extinction, 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.
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?
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 declarative memories like where you were yesterday, or where you parked your car, or what facts are history, for example, but also emotional memories, 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 pair 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.
What types of methods do you typically use to discover these neurobiological elements?
Well, we do it at both a human level and at a basic science level using transgenically modified mice as our primary model in the lab. So in humans, we study fear in a number of ways. We first ask questions, 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, a 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. 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 bodies. Specifically we focus on the eye, and what happens when one hears an unexpected noise is there’s a bit of an eye-blink, startle reflex. What 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 if they just startle and they’re not afraid, for example. And so there’s quantitative scientific ways we can measure fear and 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, but we can do molecular manipulations and pharmacological manipulations of different parts of their brains to study that fear.
Kerry, I’d like to get a little more detail at this point about PTSD itself, since 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?
That’s right. The diagnosis of PTSD entered the psychiatric lexicon in the 70s, 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; people with “soldier’s heart” and people who were so shaky from the memories of the battlefield they could not go back out, and that sort of thing. 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 in people who have had extreme forms of child abuse, even in adulthood they can have PTSD symptomatology, and certainly traumas in adults.
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. And so the rates of trauma and the rates of post-traumatic stress disorder we see from this population are about has high as we see in Vietnam vets. And the types of trauma we see and the percentages we see are about half of our population. Now we’ve interviewed about 4,000 people. About half of the population knows somebody personally who’s been murdered – a friend or a family member. 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 flashbacks where they feel like they’re re-experiencing the event, nightmares, being unable to fall asleep or having nightmares reminding them of the event, having sweats and palpitations and heart racing when they’re reminded of the event, and a lot of avoidance. All of those clusters of symptoms can lead to a large amount of emotional reactivity, including comorbid depression and just generally stress-related impairment that makes it very hard for people to function normally, to hold down a job, and to have personal relationships and that sort of thing.
Kerry, 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.
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’ve 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. 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, thus making that no longer fearful, is very similar in humans as it is in even 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 and mice. 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 drug that would activate these receptors at the same time that the animal learned to inhibit the fear, they might do it better.
This particular drug called cycloserine 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. And then we tried it, with a colleague, Barbara Rothbaum, 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, and a number of ongoing studies are now looking at it with post-traumatic stress disorder. And in all of these cases, the idea in how you use the 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 molecular learning. So people take the drug only at the time of the learning event, or the therapy. And so in the studies so far, it’s involved only two to four therapy sessions with two to four 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[ly] when that happens.
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?
It’s still in the early phases. More studies need to be done. It’s currently a generic medication, 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 taken long-term, without having such specific effects.
Do you see this as a whole new kind of burgeoning area for psychopharmacological interventions? Do you think there may be many more drugs out there that could be beneficial in this particular way?
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 the 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. 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.
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…
So, the basics of extinction, again, Pavlov originally defined it as if you have a person or an animal who has learned to pair one cue – we would call it a conditioned stimulus – with another cue like a shock or a pain or an aversive event, an unconditioned stimulus, that over time, the conditioned stimulus, or 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. They idea that they then showed is that if you 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 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. One suggests that if you extinguish a fear so 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 animal gets stressed again, the fear will seem to come back. And you can see this certainly in clinical populations. People will be fine for a while and then another bad thing happens in their life that may have nothing to do with the original PTSD, or their obsessive-compulsive disorder, or the panic disorder, but it 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 in a whole other context, it might reactivate the fear. So all of those are evidence that 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. And the whole field, by both understanding the circuitry of how we inhibit an emotion and the molecules of how we inhibit emotion, we think will both increase our ability to target extinction and exposure therapy, but also may give us new insights about how to better design psychotherapies to better teach people to control their emotions.
How big a problem are these conditions such as PTSD and phobias in terms of their cost to society? I would imagine they must be quite common, quite burdensome, and remain quite long-term and difficult to treat, despite the advances you’ve been talking about…
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 go on to develop PTSD. In the inner city we think it’s at least that high, if not 20%. And this percentage is of people who often find it very difficult to hold a job, very difficult to have relationships. Many soldiers returning from Iraq and Afghanistan end up having difficulty with their relationships, or getting divorced, or 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. If we broaden the range of disorders that we’re talking about to things like obsessive-compulsive disorder and panic disorder and other specific anxieties, it gets to 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.
These really are hugely burdensome medical problems, aren’t they?
I think so. And again our focus on the inner city is really raising another whole question. When I think back about the 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 high risks for disorders. Part of that’s genetic; 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. It also suggests that some of the higher rates of unemployment and things like that may be partly due to untreated and unrecognized trauma burden.
Will 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?
Well, we certainly think that 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? Is it ethical to prevent people from being in combat, if that’s what they want to do, because we think it’s a risk? And then on the other hand is, how can we help such people? Certainly there are 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, given a particularly awful or horrible thing happening to someone, why do some people recover and other people go on to develop these psychopathologies? Well 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 to understand better how to help people to be more resilient.
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…
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, so it generally requires more patience 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. As we get older, ten years seems to be relatively short, so it actually feels like things are happening quite quickly. So yeah, it’s very rewarding.
Where is your research going from here?
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. 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 [of] 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, to really start to understand the mechanisms of how genes and biology interact with the world around them and the 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.
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…
Thank you very much, it was great to be here.
We hope you’ve enjoyed this edition of the FOCUS In Sound podcast. Until next time, this is Ernie Hood. Thanks for listening!