Research Interview

Zachary Rosenthal co-runs the Misophonia program at Duke University.

Jennifer: What is the difference of an “emotion” and a “physiological state” such as the fight/flight response?

Zach: Emotions are widely considered to have three basic parts: (1) personal experience, (2) expressive behavior, and (3) physiology. This means that all emotions have underlying physiological components. One cannot experience or express emotion without underlying central and peripheral nervous systems. For example, our brains and bodies are wired with so-called “fight,” “flight,” and “freeze” systems to help us sense and respond to stimuli that may be threatening. These systems can be triggered by all sorts of cues, and when this happens, our physiology dynamically responds in complex ways, we approach, avoid, escape, or become immobile, and we may subjectively label our experience with particular emotional states. Another way to think about the difference between emotions and the physiological states of fight and flight is this: Our brains and bodies respond to threat cues, whether the cues truly are threatening or not, by activating a web of circuitry that functions to help us adapt and respond to these cues. Emotions are commonly a part of this process, but not all emotions are associated with an underlying fight or flight response.

Jennifer: So, Zach the lines between psychiatric disorders and disorders with underlying neurological causes are blurred? Is it fair to say that we are in a time during which we don’t quite have cohesive and accurate terminology and that this could be confusing to people?

Zach: I think it is fair to say that psychiatric problems have neurophysiological and environmental influences, and that many physical health problems, including those that some would call “neurological,” also are influences by both biology and the environment.  It would be so much easier to understand if there were simply such things as mental health problems and neurological problems, with completely different causes. But that is not the way it is. Scientists have a hard time understanding how all these things work, so it is no wonder when this is hard for the others to understand.

Jennifer: I’m not holding you to this or making this your responsibility. However, I saw on Wikipedia that Misophonia was described as a neuropsychiatric disorder? Some people call it a neurological disorder, and others call it a psychiatric disorder. If people asked me what it should be called what should I say? Again, I’m not asking you to classify this disorder but it’s very confusing to people.

Zach: I can see why it might be confusing to people. I have people in my own family who struggle with symptoms consistent with misophonia. They wonder what it happening. And they ask me! I would say that it is a syndrome which is not yet understood scientifically. This makes it hard to classify it in a category. The data and clinical anecdotes suggest it is a very real phenomenon, and it is hard to imagine how it could not involve neurological functions associated with sensory processing and the regulation of defensive motivational brain responses to particular sounds. The automatic response to certain sounds appears to resemble behavior consistent with what some have called the “survival circuitry,” which is to say emotional responses that function to move the person away from the sounds as efficiently as possible. The anger response that occurs around others is very interesting, as anger is a functional emotion we have when others are blocking us from our goals to approach desirable things or escape from unpleasant things. So I am not sure that misophonia is all about anger per se, or whether anger is the response to the cue when it is unpleasant, cannot be easily avoided, and the attribution made is that the person causing the sound “should” stop doing so. The other interesting thing is that misophonia symptoms seem to co-occur with various psychiatric problems. We need to do scientific research to determine whether and when misophonia symptoms should be expected in specific psychiatric disorders, non-specifically across mental health problems, or whether it commonly occurs without any co-occurring mental health problems.

Jennifer: Thank you for that great explanation. How would a person know the difference if they were experiencing and emotion or if they were experiencing a physiological reaction?

Zach: Emotions can be thought of as separate categories, such as when we say we feel anger, sadness, joy, and the like. In each of these subjective experiences or emotional expressions, there are complex underlying physiological reactions to environmental cues taking place. Alternatively, some researchers believe emotions are better described dimensionally with components of (1) emotional arousal from low (e.g., calm) to high (excited) and (2) emotional valence  from low (very unhappy) to high (e.g., very happy). From this way of thinking, emotions are complex, ongoing, interactive and changeable events with physiological underpinnings that occur in response to environmental cues (both outside and within the body). In both the categorical and dimensional ways of thinking about emotions, there are underlying physiological reactions that happen immediately before, during, and after emotions. So emotions have physiological foundations. Not all physiological reactions, on the other hand, occur during acute emotional states. When I have the physiological reaction of salivation in response to thoughts about key lime pie, I may not use emotion to describe my reaction. Instead, I might say I am hungry, ready for dessert, or the like. If I react with sleepiness when watching a TV show, I might describe feeling tired or sleepy. And so on.

Jennifer: Makes sense! What is the state of the field regarding conditioned versus inborn or genetic response or behavior?

Zach: When trying to make sense of complex health problems, we used to talk about nature versus nurture, conditioning versus genes, and environment versus biology. But what we now know–and in hindsight this is embarrassingly obvious– is that these are overly simplistic false divisions. These things that once were apparent distinctions as “either/or” now are becoming logically combined as “both/and.” The question is no longer whether a phenomenon is caused by conditioning or something physiological. The question is how and in what important ways do nature and nurture interact to predict human behavior? Nature and nurture reciprocally influence each other, likely in many ways and at many levels of analysis, their effects pinging and ponging off of each other. Genes and the environment interactively influence each other. The environment influences genetic expression, and genetic expression influences the environment. As an example, it would be overly simplistic, and flatly incorrect to assert that a disorder such as PTSD or OCD is caused by genes independent of any environmental influence. Genes impact conditioning, learning, and memory, and these processes influence the way in which we express ourselves in our environment, which influences how the world responds to us, which then impacts our underlying biology. It also would be overly simplistic to say that these problems are singularly caused by conditioning in the absence of any underlying biological influences. Conditioning processes are both biologically and environmentally influenced.

Jennifer: So Zach, what you are saying is that the question of nature versus nurture isn’t really the right question anymore, especially in psychiatry.  I know this is putting the matter very simply but I want to be very clear. The thinking about this has changed a lot, even since I was in graduate school. Many of us grew up thinking about nature versus nurture (or genetic versus environmental) as very separate ideas.

Zach: Yes. But this is also true outside of psychiatry. For example, environmental stressors can elicit neurobiological changes, and these changes can then influence how someone lives, which of course impacts how the world treats them, which then can influence their neurobiology. It is back and forth kind of thing throughout life.

Jennifer: Okay, in that case… We now know that even if identical twins both have the same “genes”, one twin might manifest symptoms of OCD, or any neurological or health related disorder, while the other may not. This is because genes and the environment interact with one another. Genes can be “turned on” and “turned off” according to factors in the environment, and within the individual human being. So, it’s a lot more complicated than we thought it was, and the take home message is that both nature and nurture contribute to human behavior in a complex and interactive way. Would you say that is a good synthesis of what you said?

Zach: Well said!

Jennifer: Thank you! Having said that, are there any specific disorders or diseases for which there is a clear distinction between a genetic cause versus an environmental cause?

Zach: The search for genetic causes in psychiatry is ongoing. Many researchers with and a whole lot of research funding are dedicated to the search for clear genetic markers of psychiatric disorders. Although there are data suggesting some psychiatric disorders are associated with certain polymorphisms, this is very different than concluding genes cause the disorder. On the other side, there are many examples of environmental correlates or predictors of psychiatric problems, but these environmental causes may also have genetic correlates. In addition, where there are data supportive of genetic correlates to psychiatric disorders, these genetic factors typically account for small amounts of the variance in the disorder and do not appear to be specific to individual disorders per se, but rather to groupings of disorders. The serotonin transporter gene polymorphism, for example, can be found in some people with mood disorders, but is not found in one specific mood disorder.

Jennifer: So, to restate what you said…There are  “neuropsychiatric” disorders that have been associated with particular gene polymorphisms. By polymorphism, you are talking about differences in genes that occur over a long time within portions of the population, for example people with Depression? For the sake of simplicity, can we just call them “gene differences” for now?

Zach: Sure.

Jennifer: These “gene differences”, however, that are found in depression, don’t only appear in depression. They might also appear in bipolar disorder, and other mood disorders. In other words, these “gene differences” appear in groups of disorders, such as mood disorders but they don’t really single out any particular disorder. So, the process for finding a cure for a disorder isn’t as simple as just finding “the gene”.

Zach: Absolutely correct. As much as we would all like to find a gene for each problem, or even a set of genes for each problem, the reality is that things are not that simple.

Jennifer: It is interesting; you mentioned serotonin, which is a neurotransmitter (a chemical messenger of neurologic information stated simply). You said, that genetic differences regarding serotonin have been found in people with mood disorders, but not specific to one particular mood disorder? I’m assuming this is true of the many different neurotransmitters we hear about all the time in terms of their associations with mental and other health disorders  (e.g. dopamine, etc.)  Is that correct?

Zach: Correct. It is important to remember that as advanced as we are in understanding physiology and human behavior compared to 100 years ago, there is a whole lot that we don’t know yet. In 100 years, I suspect people will look back at this time we are in and recognize that we oversimplified the role of neurotransmitters and the relationship between things like dopamine and human behavior. Just as brain regions do many different things rather than only one thing, so too do neurotransmitters like dopamine more than one thing.

Jennifer: So, again while the discovery, for example, of serotonin’s or dopamine’ relationship to numerous psychiatric or health disorders has been very helpful in some ways (e.g. medications) because of the complexity of the genetic/environment interaction, we can neither fully account for how neurotransmitters correspond with different disorders, nor have precision medications been mastered yet?

Zach: I think that is fair to say. There is a lot more precision needed. We are in an era of personalized medicine, where the goal is to understand for whom which interventions will work, and how. In order to understand what will work, for whom, to treat symptoms of misophonia, much much more research is needed.

Jennifer: I think you are also saying that gene polymorphisms or “gene differences” that have been identified in relationship to groups of disorders don’t account for what one can observe in terms of the different behavior of a person with depression or OCD (again just using those as examples). So, while, it is certainly helpful to identify gene/disorders associations, I’m not going to wake up next year and hear on the news that “they found the gene for OCD” or “depression” and thus the cure will be available in a year? Is that fair to say?

Zach: I will be surprised if that happens.

Jennifer: So will I. Ha ha. So, just to clarify my original question then, are there any specific disorders or diseases for which there is a clear distinction between a genetic cause versus an environmental cause? What are those disorders or diseases?

Zach: There are genetic disorders that may co-occur with certain psychiatric disorders (e.g., fragile X). And there are physical diseases with genetic components that are not singularly caused by genes and are influenced by environmental factors (e.g., Type II diabetes). But there are not psychiatric disorders caused only by genes in the absence of any environmental influences.

Jennifer: So, again for purposes of clarification, I’m going to rephrase and please let me know if this is correct. There are genetic conditions (such as Fragile X) for which we know the associated gene involved. Yet even in these genetic disorders environment can play an influence on how an individual is affected. In addition, even in regard to these genetic illnesses, because of this new way of thinking about genetic and environmental interaction we don’t really know how any of this will play out in medicine or psychiatry in the next decade.  We do know that in regard to psychiatry, and possibly health in general, we just cannot attribute a disorder only to genes. We are kind of in a new era of the way we think about genes and the environment. Is this fair to say?

Zach: Absolutely!

Jennifer:  Then we really can’t say anymore that there are any disorders in psychology for which maladaptive behaviors are definitely attributed to conditioning rather than inborn traits?

Zach: If you open up the DSM-5 and pick a disorder at random, the research investigating the etiology of the disorder will likely point to environmental influences associated with basic process underlying such things as learning, memory, emotion, social cognition, and attention, all of which are critical to conditioning. Even those traits we see early in life can be and are influenced by the environment.

Jennifer: Please continue…

Zach: Conditioning involves attention, learning, memory, and emotion. These processes are critical in the etiology (or multiple causes) and maintenance of all psychiatric disorders.

Jennifer: Are you saying that there are other factors having to do with an individual’s personality and neurological processing that affect conditioning? In other words, conditioning isn’t a simple cut and dry process, as we might believe based on how, for example, it is still represented in popular press?

Zach: Yes.

Jennifer: So again, we are talking about the interaction of nature and nurture (genetics and environment) in terms of any DSM-5 disorder?

Zach: Exactly.

Jennifer: Zach, do you think there are particular bodies of research we can pull from that already exist in order to begin the study of misophonia?

Zach: I do. I think we need to work together with those who study and treat neurological problems, such as neuropsychiatrists, neuropsychologists, audiologists and occupational therapists. I also think that we need to do research with child and adult psychologists, so that behavioral interventions can be developed, tested, and disseminated based on discoveries made by basic scientists.

Jennifer: Other than overlapping with other disorders, what might be a better way of characterizing Misophonia (just from what you know about it)?

Zach: I suspect misophonia symptoms may not be uniquely found in any one psychiatric disorder, but instead may be a transdiagnostic problem observed across those with different disorders. I also believe it is possible that misophonia symptoms may be observed on a spectrum of severity from low and irritating to high and debilitating among individuals with different psychiatric symptoms. Although some with misophonia symptoms likely meet criteria for various psychiatric disorders, I think it is quite possible that misophonia may not overlap with any psychiatric disorder, and may be something that emerges in some who do not meet criteria for any existing psychiatric disorder.

Jennifer: So, misophonia may be a stand-alone disorder, and symptoms of misophonia may manifest in psychiatric and/ or health disorders as well. Likely there will be a range in severity of symptoms, and we have seen some very  preliminary data in terms of this (as well as a lot of self-reporting that corresponds with ranges in severity). Classification is not easy, is it? In other interview I think I will address the reasons classification is important, and how difficult it is to do it!

All right, Zach, one final and somewhat more personal question…you are a renowned psychology practitioner as well as a researcher. Would you tell us a little bit about how you feel when you are faced with a patient who has a condition with which you cannot help based on traditional therapies?

Zach: What a great question! When this happens I often feel inspired and motivated to innovate. I try to make sense of where the gap may be between the patient’s problems and the evidence base for behavioral therapies and behavioral principles that may be applied. I make and test hypotheses about possible psychological processes (those that are both biologically and environmentally influenced) that are amenable to change. But if the patient is non-responsive or not interested in contemporary cognitive and/or behavioral approaches, I look to consult, work with a group of others across different disciplines, or refer the patient to treatment options that she or he may find more suitable. Or, in even better circumstances, I use my training as a behavioral scientist to try to scientifically investigate ways to develop new treatments for the problem.