Bret S. Stetka, MD

Disclosures

June 10, 2014

In This Article

Early Experiences and Later Life Anxiety

So how do the various developing brain regions contribute to our emotional development? And how do our adolescent experiences steer brain maturation and contribute to later-life fear and anxiety? The answer resides partially in the amygdala, part of the subcortical limbic system and a key player in emotion regulation. Also involved is the prefrontal cortex (PFC), the anterior part of our cerebral cortex responsible for complex thought and emotion processing.

Numerous studies have shown that fearful cues lead to heightened amygdala activity. And as Casey pointed out, the PFC relays inhibitory signals to the amygdala as part of our fear regulation circuit. With repeated exposures to an initially fearful stimulus that turns out to be unthreatening, increased signaling from the PFC dampens amygdala activity. As a result, output to the autonomic nervous system is dampened, and we feel less fear.

Of course, the neurobiology of human anxiety is far more complex than a signal circuit: Sensory inputs project to the amygdala's lateral nucleus, where fear memories are maintained, and projections from the amygdala's central nucleus also influence our autonomic and endocrine responses to fear. But it's the relationship between the amygdala and the PFC that controls our ability to habituate to cues that might otherwise lead to anxiety and fear.

Work by Hare and colleagues (including Casey)[4] found that in children who rate themselves as having high anxiety, a fearful stimulus results in initial recruitment of amygdala activity as expected. However with repeated presentations of the same cue, the activity doesn't return to baseline, as it does in nonanxious control subjects. Their ability to habituate is impaired. Casey then explained the possible reasons why. Like so many mental and medical conditions, the culprit can be environmental, genetic, and oftentimes both.

To identify possible environmental influences on anxiety, Casey and her group turned to the often traumatic experience of an orphanage upbringing.[5] They wanted to assess how adversity early in life impacts emotion regulation, in a sense using an orphanage childhood as a proxy for disorganized parenting.

They looked at children raised in overseas orphanages who were adopted and relocated to the New York City area. Study subjects were between 5 and 15 years old and had been in the United States for at least 2 years, to ensure that they had had time to adjust to the new environment.

First, they were presented with a series of neutral visual cues on a screen. Next, a fear-inducing face was flashed, to which the subjects were asked not to pay attention. A higher percentage of those who grew up in orphanages exhibited increased amygdala activity in response to the fear cue; in controls, increased activity in the PFC was seen, presumably suppressing attention toward the fear cue.

An important part of emotional regulation is our ability to suppress inappropriate reactions -- in other words, to not waste our attention on emotional cues that have no significant relevance to a situation. Those who grew up in orphanages were unable to redirect their attention and ignore fearful cues.

The study also revealed how these findings might relate to real-world functioning. When the child participants came into the laboratory, they were asked to leave their adoptive parent to play a game with an experimenter for 10-15 minutes. When they came back, Casey's team would monitor their interactions with their adoptive parents; those with greater amygdala activity made significantly less eye contact following this separation and reunion with their parent.

Casey cautioned that a drawback of human naturalistic experiments is the lack of control over prenatal history and genetic background. So the findings of dysregulated fear could be due to factors other than the "disorganized parenting" of the orphanage experience.

To help disentangle causality, her group ran a parallel study[5] mimicking the orphanage experience in mice. Nesting material was removed from cages, and maternal behavior was monitored. The mothers spent more time foraging for nesting than with their pups. Mothers whose nesting wasn't removed spent more time grooming their litter.

This model was then used to assess fear habituation, using a similar approach as in the human experiment.[6] "How do you get mice to ignore a potential threat?" asked Casey. "As it turns out, they really like sweetened condensed milk," she followed. The mice were put in a "home" cage equipped with a milk nozzle. When moved to a new cage with a light, considered a threat by the rodents, they froze for a period of time before going after the milk.

This slower latency time in the presence of stress was correlated with heightened amygdala activity. This pattern of increased latency and amygdala activity remained even after the stressor was removed 20 days later and even after development of the PFC in adulthood, suggesting long-term dysregulation of emotion with early adversity.

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