Understanding the Early-Life Origins of Extreme Anxiety—Role of the Amgydala

Alex Shackman

The internalizing disorders—anxiety and depression—are a major human blight. According to the World Health Organization and National Institute of Mental Health, depression is responsible for more years lost to illness and disability than any other medical condition, including such familiar scourges as diabetes and chronic respiratory disorders. Anxiety disorders are the most common family of psychiatric disorder in the United States and rank sixth as a worldwide cause of disability. These disorders, which commonly co-occur, also impose a substantial and largely hidden burden on the global economy: hundreds of billions of dollars in healthcare costs and lost productivity each year. Unfortunately, existing therapeutic approaches are inconsistently effective or, in the case of many pharmaceutical approaches, are associated with significant side effects. Not surprisingly, the internalizing disorders have become an important priority for clinicians, economists, research funding agencies, and policy makers.

The internalizing disorders generally have their roots in the first three decades of life and there is clear evidence that children with a fearful, shy, or anxious temperament are more likely to suffer from anxiety disorders, major depression, or both as they grow older. As a postdoctoral fellow in Ned Kalin’s lab at the University of Wisconsin and, more recently, as the director of my own lab at the University of Maryland, I’ve used a range of tools and techniques to understand the brain systems that contribute to extreme anxiety early in life. Building on a tradition that dates back to pioneering studies at Wisconsin by Harry Harlow, Karl Pribram, and others, much of the work that I conducted as a postdoc used nonhuman primates to model and understand key features of childhood anxiety. Young rhesus monkeys are useful for deciphering the brain circuits that underlie childhood anxiety. Owing to the relatively recent evolutionary divergence of humans and Old World monkeys (~25 million years ago), the brains of monkeys and humans are biologically similar. Similar brains endow monkeys and children with a common repertoire of social and emotional behaviors, which makes it possible to measure anxiety in monkeys using procedures similar to those used with kids. Another virtue of working with monkeys is the opportunity to collect high-resolution measures of brain activity (using positron emission tomography or PET) while the animals freely respond—hiding in the corner, barking, and so on—to naturalistic threats, such as an unfamiliar human ‘intruder’s’ profile. This would be difficult or impossible to do in children and, somewhat surprisingly, has rarely been attempted in adults (most human imaging studies use fMRI, which requires that the subject remain dead still throughout the scan).

Large-scale brain imaging studies, each including hundreds of young monkeys—in humans terms, roughly equivalent to children and teens—show that anxious individuals respond to signs of potential threat with heightened activity in a number of brain regions. For present purposes, I’ll focus on the contribution of the amygdala, a small, almond-shaped region buried beneath the temporal lobe of the brain (the red regions in the accompanying animation).

Collectively, these studies teach us that amygdala activity systematically differs across individuals. Some individuals show chronically elevated activity; others consistently show much lower levels. Notably, elevated activity is associated with exaggerated reactions to potential danger: Monkeys with higher levels of metabolic activity in the amygdala tend to show higher levels of the stress hormone cortisol and to freeze longer (in an attempt to evade detection) in encounters with the human intruder. Like many other qualities that distinguish one individual from another, work by our group demonstrates that amygdala activity is:

1. Consistent over time and context: We can think of amygdala activity as a trait, like personality or IQ.

2. Heritable: Amygdala activity partially reflects the influence of genes. Parents marked by higher levels of amygdala activity are more likely to have offspring with this trait.

Of course, like any brain imaging study, it’s important to remember that these results do not let us to claim that the amygdala causes anxiety. From this perspective, it is reassuring that mechanistic work in monkeys and rodents demonstrates that it does: selective lesions and other biological manipulations of the amygdala sharply reduce (but do not entirely abolish) anxiety (see for example this very recent rodent study). This is consistent with observations of a handful of human patients with near-complete amygdala damage. For example, one relatively well-known patient (identified as ’SM,’ to protect her identity), has normal intellect, but reports a profound lack of fear and anxiety in response to scary movies, haunted houses, tarantulas, and snakes.

According to Justin Feinstein, Ralph Adolphs, and other researchers who have studied SM over the past two decades,

She has been held up at knife point and at gun point, she was once physically accosted by a woman twice her size, she was nearly killed in an act of domestic violence, and on more than one occasion she has been explicitly threatened with death…What stands out most is that, in many of these situations, SM’s life was in danger, yet her behavior lacked any sense of desperation or urgency. Police reports…corroborate SM’s recollection of these events and paint a picture of an individual who lives in a poverty-stricken area replete with crime, drugs, and danger…Moreover, it is evident that SM has great difficulty detecting looming threats in her environment and learning to avoid dangerous situations.

This and other evidence—spanning a range of species, populations, and measurement tools—indicates that anxious individuals’ exaggerated distress in the face of potential danger reflects hyper-reactivity in a brain circuit that includes the amygdala. Systematic differences in amygdala activity and connectivity first emerge early in life and can foretell the future development of anxious and depressive symptoms in humans. These and other observations suggest that enduring differences in amygdala function contribute to key features of childhood temperament, like shyness, and confer increased risk for the development of internalizing disorders, particularly among individuals exposed to stress or trauma. More importantly, this work lays a solid, brain-based foundation for developing better strategies for treating or even preventing these debilitating illnesses.

To learn more about the emotional disorders, please visit the Anxiety & Depression Association of America (ADAA) website, which features a number of useful videos, fact sheets, and other resources for patients, clinicians, and researchers.

Photo credit: The amygdala animation was generated by Life Science Databases, obtained from Wikimedia Commons, and is freely used under a Creative Commons license.


The emotional potency of peers during adolescence

Leah Somerville

If you had to choose one event that epitomizes your experience as a teenager, what would it be? For me, I immediately think of that moment at the school dance while I was dancing with my middle school crush to November Rain by Guns n Roses. Our slow dancing skills were passable during the first part of the song, but then the tempo picked up … and let’s just say, we were not very smooth at adapting our dancing styles. Although I hope (for your sake) that the same thing didn’t happen to you, I’d bet that whatever memory you do conjure when you think back to your own adolescence is socially and emotionally charged.

It turns out that my adolescent experiences were completely typical of most adolescents—social experiences take on heightened emotional and motivational importance during adolescence as compared to other stages of life. In a study we conducted, we wanted to see how sensitive adolescents were to even the simplest, most innocuous social provocation: being looked at by a peer. During our study, we measured brain activity with functional magnetic resonance imaging in tandem with physiological arousal (measured with the skin conductance response—how much sweat is secreted on the skin during emotional events). We observed that even the simple act of being looked at by a peer was enough to induce heightened emotion reports, physiological responses, and brain activity in adolescents (when compared to adults and younger children). For instance, we saw biased activity in regions of the brain important for representing the emotional value of stimuli and in brain regions involved in thinking about ourselves (to read more, see here). All of these findings add up to the general conclusion that adolescents are highly attuned and reactive to their social environments – even very subtle ones – and that this fact influences a variety of their daily choices and feelings.


The author of this post at age 13 showing off her spiral perm.

What’s interesting about these findings is that they seem not to be unique to human adolescents. The term ‘adolescence’ is a sociocultural construct that refers only to humans, defined by simultaneous physical and psychological change that ends when an individual takes on adult roles in society (adolescence is most often defined as the approximate ages ~13-17 years). However, some aspects of biological changes during this age range, including hormone changes that define puberty, occur in other mammals as well. Some surprising results have arisen from the study of pubertal-linked changes in social behavior in non-human mammals. Pubertal rats enjoy ‘social play’ (kind of like wrestling) more frequently than adult rodents, and also seek out more novel and potentially thrilling experiences. Perhaps most intriguingly, rodents undergoing puberty also approach potential rewards (in this case, consuming alcoholic beverages) more when in social groups. Whereas adult mice spent the same amount of time consuming alcoholic substances when alone and with peer animals, juvenile animals in the pubertal stage spent more time consuming alcohol when in a cage with familiar peer animals. And it wasn’t just a motivation to consume the tasty cocktail before others got to it – they each had their own sipper.

What lessons can we learn from our furry friends about adolescence and the social potency that characterizes this age range? It is often assumed that peers take on heightened importance in adolescence due to overt concern about social status. However, it seems unlikely that such complicated, strategic motivations would drive rodents to behave differently around peers. This raises a second possibility, that there are “undercover” or non-deliberate ways that adolescents are influenced by social contexts. We believe that adolescents’ brains are biased to assign importance to social information, which imbues social settings with an extra boost in power to shape their feelings, motivations, and decisions. Although more research needs to be done to address questions like “why” and “how”, I guess that’s why I’m still mildly embarrassed by my tragic bout of dancing (and simultaneously thankful I grew up before the days of smartphone cameras).

Humans aren’t the only lonely species. Monkeys may be lonely too.

Eliza Bliss-Moreau

More than two decades of research demonstrates that people who have more social connections do better—in terms of their general health, ability to recover from illness, and longevity (for a classic, oft cited study, see here; for a review, here; for popular press coverage and a lovely long read on human loneliness, here). Perhaps unsurprisingly, it’s not just the number of people you’re connected to that matters for your well-being. Whether people’s social relationships meet their social needs also has critical importance for health outcomes  regardless of how many social connections they have (for reviews of this literature see here, here, and here). That is, it’s possible to be well-connected socially and still feel totally alone in the world. It is also possible to have very few social relationships but not feel lonely at all.

Exciting new evidence illustrates that we humans might not be the only ones to experience loneliness—rhesus macaque monkeys may as well. As part of an interdisciplinary team, Dr. John Capitanio examined the social behavior of adult male macaques at the California National Primate Research Center and identified three different patterns. Some monkeys engaged in a lot of social interactions with other males, adult females, and younger monkeys. Other monkeys did not engage in a lot of social interactions at all. What’s critical some of these “lowly social” monkeys seemed fairly content with their lot in life—they went about their daily business without trying to build new relationships.

Housing&Enrichment©K.West-CNPRC,039The other lowly social monkeys did seem to care about their lot in life, however. They often physically approached adult females and younger animals, presumably in an effort to initiate an interaction. Similarly, the monkeys would walk by those animals to see what they were doing, even when trying not to engage with them. The fact that these behaviors were observed with adult females and younger monkeys suggests that these “lonely” adult male monkeys may have been looking for easy social relationships (because of how macaque societies are structured, relationships between adult males can be challenging). This heightened social interest persisted when evaluated 1.5 years later. In other words, there were monkeys who appeared to chronically desire social relationships but did not manage to make them happen—a potential monkey homologue of human loneliness. What’s more, as Capitanio points out, these lonely monkeys may be better models for human loneliness than previous animal models because the phenomenon emerged spontaneously in the context of large naturalistic social groups, rather than as a result of experimentally separating animals.

In and of itself, the finding that nonhuman animals might have the capacity to be lonely is an interesting one. It suggests that experiencing a mismatch between one’s social realities and one’s social desires is evolutionarily old, raising questions about what function loneliness might have served for our ancestors.

But perhaps more importantly, animal models of human psychological phenomena, such as a monkey model of loneliness, are critical to understanding the biological processes that contribute to them. Nonhuman primate (e.g., monkey) models are particularly important for understanding human function and dysfunction because we share so many biological and social features. Monkey models allow for precise experimental control (e.g., the ability to manipulate social environment, diet, sleep-cycles, etc.), intensive long-term longitudinal studies (i.e., the ability to track and evaluate many individual animals over the course of their entire lives), and the development of causal biological models. Understanding biological mechanisms is critical for developing effective early interventions and treatments for deleterious psychological experiences. Studying lonely monkeys may therefore unearth the biological and social processes that can be harnessed to help lonely humans in the future.

Photo: Adult male rhesus monkey at the CNPRC eating a zucchini. Photo Credit: Kathy West, CNPRC.

The Social Brain: Thinking about Others

Steve Chang

Our lives are greatly dependent on other people around us. As the holiday seasons approach, many of us are reminded that there are so many people whom we care about and who care about us. For some people, this time of the year may remind them of the loved ones who might no longer be around them. We are highly social animals, and we cannot escape this fact. Sociality creates, defines, and drives who we are.

Many scientists agree that the complexity of social environments was one of the key factors that actively steered primate brain evolution. This is of course supported by a seminal hypothesis known as the social brain hypothesis by Robin Dunbar. This hypothesis was primarily generated by the observations that there is a strong positive correlation between the brain size and the social group size across different primates (monkeys, apes, and humans). In a nutshell, larger the social group size became, the bigger the brain size became. It’s definitely not a stretch to state that social processing is one of the very most important functions carried out by our brains (especially in the parts of our brain called neocortex).kids playing

Animals that live in social groups are indeed very sensitive to information about other individuals in their societies. Processing social information can take many forms. Just to give some everyday examples, we constantly pay attention to what other people think of us, and vice versa. We are also very aware of things happening to others. We often feel happy, sad, angry, or jealous when we learn about others. Basically, it’s up to our brain to parse out the information about self and others in order to influence our future actions. Not surprisingly, this process is powerfully shaped by emotional feelings generated by different social information.

Neuroscientists are now hoping to unlock the mystery behind the “social brain”. This is a daunting task especially since social processing, by nature, is a product of numerous associations among sensory/motor, cognitive, and emotional processes. One of the big questions that many neuroscientists are asking is whether there are dedicated brain circuits for social processing. The alternative is that the neural circuits already being used for non-social processing also handle social functions. The answer still remains elusive, but the experiments asking questions about the social brain are becoming more sophisticated and more rigorous (which is exciting). We recently discussed how preexisting brain areas for carrying out non-social functions might have been repurposed and extended to serve social functions in primates. It remains to be seen whether some parts of the brain are newly expanded to accommodate exclusively social functions.

Let’s return to how the brain might process the information about others. In a recent study, we tested how the neurons in the brain that carry the information about one’s rewards (e.g., getting money, delicious food, etc.) respond when another individual is rewarded. In a task where monkeys got to choose whether they shared a reward with another monkey, we found that different parts of the prefrontal cortex (an area of the brain that is highly developed in humans and other primates) signal juice rewards received by an actor monkey and a recipient monkey in distinctive manners. Some neurons only care about one’s own reward outcome, but there are also other types of neurons that track the reward outcome of another individual either exclusively or in conjunction with one’s reward outcome. In another recent study, Matt Roesch and colleagues found that when a rat observes the rewarding event of another rat, dopamine is released in a brain region important for reinforcement learning. One important conclusion to be made from these and other recent studies (e.g., a, b, c) is that the brain structures that typically process one’s own information also signal the information of other individuals either by the same neurons or distinct “other” types of neurons.

The field investigating the mystery behind the social brain is rapidly growing. It would be fascinating to know more about how internal states, such as those regulated by emotion, control the way by which social information is computed. The success of our adventures into the social brain will critically depend on collective efforts by scientists who study human participants and non-human animals so that we can discover the complexities behind human social cognition as well as concurrently discover fundamental neuronal mechanisms in animal models. New exciting knowledge awaits us.

 photo credit: https://m.flickr.com/#/photos/kymberlyanne/2687290741/

Fido feels?

Eliza Bliss-Moreau

The emotional lives of dogs has become a hot topic as of late and made some big splashes in the media. In a recently published study, Christine Harris and Caroline Prouvost claim that dogs, like humans, experience jealousy.

The researchers tested pet dogs and their owners while their owners interacted with three different objects:  a toy dog that moved and made noise, a jack-o-lantern figure, and a children’s book that made noise.  Owners were instructed to interact with the objects and ignore their dogs.  When owners were interacting with the toy dog (compared to the other objects), their pets were more likely to touch them or the objects, move between the owner and object, and look more at the owner and object.  Dogs also “snapped” more at the animated toy dog than the other objects.  The authors state that these behaviors are “indicative of” jealously.

The report makes three fairly substantial, critical assumptions—two about the nature of emotion and one about how dogs behave with toys.

3210109272_df9c66d773_oThe first assumption is that behaviors map on to emotions in a specific way.  The idea here is that we can know the internal state of an individual based on his or her behavior.  In other words, if behavior X occurs, then emotion Y is present.  This is an intuitive idea that resonates with people.  But, the scientific evidence suggests this is not true. The problem is that there is a substantial amount of evidence that suggests this is not the case, even in humans who can tell us how they feel while they are behaving.  Overt behaviors don’t relate in specific ways to specific emotions.  Physiological patterns (e.g., what your heart is doing during an emotion) don’t relate in specific ways to specific emotions.  And so on.  Sometimes people (and rodents and dogs and monkeys) fight when they’re fearful and sometimes they run away.  Sometimes people smile when they’re happy, sometimes they make no facial behaviors at all, and sometimes people smile when they’re angry.   So particular behaviors aren’t “indicative of” particular emotions.

The second, related, assumption is that behaviors in animals are indicative of emotional states that are human-like.  This logical leap has been made for decades (particularly in studies of fear).  A freezing rat is said to be a fearful rat.  In actually, we have no way of knowing (yet) whether a freezing rat is experiencing human like fear at all.  Freezing is a fairly simple neurobiological reflex.  It’s hard to equate it with human experiences of emotion. Like for example, the experience you might have when you hear that a plane has crashed and your lover was on it, or the feeling you might have when you’re walking down a dark alley and hear heavy footsteps behind you.  Making the assumption that rat freezing is the same as one of those human experiences is a fairly large (and as I and others argue, problematic) logical leap.

The third assumption is that dogs’ behaviors differed with the toy dog because of emotion and not some other psychological state.  But there are a number of other possibilities.  For example, it’s possible that dogs were simply more interested in the toy dog because it was more complex or interesting or because it looked like a dog.  It’s possible that the dogs wished to play with it themselves, or were confused because it emulated a dog without being one.  Since the dogs were never tested with the objects and without the owner, or when the owner was not paying attention to the toy, none of these hypotheses can be excluded.

So, can Fido feel jealous? Possibly.  Humans have selectively breed dogs over thousands of years, creating modern day dog that is particularly responsive to human emotions, gestures, and eye-gaze.  Some of these capacities are unmatched even in our closest genetic relatives—the nonhuman primates.  Dogs also have fairly complex brains that may be capable of the computations needed for a complex socially oriented emotion like jealously.

But, based on this single study alone, the jealously jury is definitely still out.