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.


Temperament: A Marker for Asthma?

Katie Chun

Have you noticed that certain people tend to get sick, while others do not? Think back to when you were a kid and schools gave out “perfect attendance” awards. Kids who were sick a lot could only dream of this award, while others received this award every single year. Questions about variation in health extend beyond just asking “who gets sick” to also ask “who gets sicker?”. Two people can be exposed to the same bug and one ramps up a significant immune response, knocking him out of work for a week with illness while the other just goes about her normal business as if nothing happened. There are countless examples of how our immune systems react in different ways.

There are lots of potential reasons that people’s immune function differs, but one possibility is that temperament or personality is associated with health. For example, personality traits related to negative affect (i.e. anxiety, hostility) have been consistently related to increased risk for illness. Another example is behavioral inhibition, which is a temperament style commonly studied in children that is similar to shyness. Behaviorally inhibited children tend to avoid social situations and react negatively to new situations. Kids who are behaviorally inhibited as infants and toddlers have a greater risk for developing anxiety later in life than those who are not behaviorally inhibited. In addition to anxiety, behavioral inhibition has also been associated with the development of asthma, a disease characterized by inappropriate responses in the immune system. Unfortunately, the exact way that asthma and behavioral inhibition are related is not yet known.

In a series of studies that I conducted as part of my doctoral work, we used a monkey model to try and understand the link Copyright Kathy West CNPRC 2015between behavioral inhibition and asthma. A common measure of asthma is how sensitive the lungs are to things that enter them (e.g., air pollutants, or aerosols). In asthmatics, the lungs are really reactive, causing constriction and decreasing airflow to produce an asthma attack. We first demonstrated that monkeys that were less likely to socialize with peers and who had more intense reactions to novel situations tended to have more reactive airways (an indicator of asthma) than control monkeys. That is—behavioral patterns associated with social behavior and emotion predicted who had a robust airway response. Interestingly, there was no relationship between behavioral inhibition and common asthma-related immune markers (e.g., immune cell numbers, inflammatory proteins). One possibility is that the relationship between behavioral inhibition and asthmatics is produced not by the immune system per se, but by the autonomic nervous system—the system that controls your heart, lungs, and guts and produces “fight or flight” and “rest and relax” responses to stimuli in the environment. Both behavioral inhibition and asthma have been related to alterations in the autonomic nervous system. It may be that alterations in the autonomic nervous system are a common link between behavioral inhibition and sensitive airways, which could be further investigated in future studies to sort out these mechanisms.

The take home message from our study, in concert with accumulating evidence from other research groups, is that variation in emotional life is related to health. Understanding the causal relationships between emotion and health (e.g., does emotional temperament like behavioral inhibition lead to reactive airways or do animals with reactive airways become behaviorally inhibited?) is the next critical step in this research program and will hopefully lead to interventions to promote well-being.

Photo credit: Kathy West CNPRC-UC Davis, copyright 2013