Brain Reacts Differently to Internal vs. External Threats

by Kayt Sukel

March 28, 2013

Some refer to the human amygdala as the body’s burglar alarm. This small almond-shaped region, nestled deep in the temporal lobes, close to the brain stem, has been implicated in the generation of fear in response to the outside world—the seat of the body’s so-called “fight or flight” response. But new research published online in the journal Nature Neuroscience suggests that the amgydala is not the only brain region involved in fear or panic responses, especially when they are generated internally. This surprising result may provide unique insights into our understanding of disorders involving anxiety, panic, and post-traumatic stress.

No Fear

SM, a 40-something woman with Urbach-Wiethe disease, shows normal intelligence scores and a friendly personality. At first meeting, you probably would not realize that she has not experienced fear since she developed this rare disorder during adolescence.

“Urbach-Wiethe is a rare genetic condition that results in the calcification of soft tissues in the body,” says Colin Buzza, a clinical research fellow at the University of Iowa Carver College of Medicine. “It results in thickened skin, thickened mucus membranes and also causes, and we’re not sure why, the calcification of certain brain structures like the amygdala.” 

Without a working amygdala, SM walks the world without fear. When confronted with snakes, horror movies or even a violent mugging, SM doesn’t freeze up, shake, or panic. Rather, she demonstrates a distinct absence of fear. People without amygdala function also show difficulty in interpreting ambiguous social situations and facial expressions, says Tony Buchanan, a neuroscientist at Saint Louis University.

“In general, we know that the amygdala plays a role in directing our attention towards and making us vigilant towards anything in the environment that is socially salient or potentially threatening,” he says. “It’s making sure we’re paying attention when we need to pay attention.”

External Versus Internal Threats

It had been thought that the amygdala acted in a similar manner regardless of whether the threat came from the outside world or from some type of internal reaction. Neuroimaging studies have shown amygdala activation during panic attacks—which Todd Farchione, a clinical psychologist at Boston University’s Center for Anxiety and Related Disorders, says is often an internal manifestation of “a fear of fear.” 

Another type of internal threat is exposure to carbon dioxide, which can make the body feel like it is suffocating for a few moments and induce a feeling of panic. When Buzza and colleagues at the University of Iowa demonstrated that the amygdala directly detected the carbon dioxide to produce a fear response in mice several years ago, they expected to see a similar effect in humans. Surprisingly, only three of twelve normal study participants panicked when they were exposed to the carbon dioxide. SM and two other Urbach-Wiethe patients, however, all showed a panicked response despite their lack of amygdala function—complete with gasps for air, accelerated heart rates, and physical distress. These three even tried to rip off their masks before the study condition was complete.

To take the study a step further, all participants were exposed to the carbon dioxide test several times. Healthy participants anticipated the carbon dioxide. They demonstrated sweating and heightened heart rate before the gas was administered. But even after experiencing a panic attack, none of the Urbach-Wiethe patients showed an anticipation response.

“This is what surprised me about this study—they knew that this fairly awful manipulation was coming but didn’t show any anticipation of it,” says Buchanan. “So information coming from the outside world, warning of a potential threat, didn’t trigger a fear response. Whereas, in normal, healthy people, there was what you might call a ‘dread’ response—sweating, the heart rate rising as they’re getting closer and closer to getting the carbon dioxide again.”

Buzza says that these results suggest that the amygdala is not essential to feelings of fear and panic. “We’ve shown that there are other brain structures that are sufficient to produce those feelings,” he says. “In fact, given that the patients with Urbach-Wiethe had panic attacks at a rate similar to people with panic disorder, it suggests that a healthy, functioning amygdala may actually inhibit panic.”

Buchanan agrees. “This suggests that the internal sense of feeling panic doesn’t necessarily rely on the amygdala. But the external sense of paying attention to what should be causing fear in the outside world does.”

Treating Panic Disorder in the Future

Farchione says that panic disorder is not just panic attacks. “These are rushes of intense discomfort accompanied by physical sensations like rapid heart rate, difficulty breathing, a smothering sensation, and dizziness,” he says. “But to be diagnosed with panic disorder, there also has to be at least once month of worry about the recurrence of panic attacks. To put it in perspective, about 30 percent of the general population may worry themselves into a panic at some point, but what separates it out as a disorder is the fact that people who suffer from panic attacks really worry about the panic attack itself.”

Currently, panic disorder is treated with anti-depressant or anti-anxiety medication or cognitive behavioral therapy. Cognitive behavioral therapy is quite successful, Farchione, but medications have had mixed results.

Buzza suggests that this study, though preliminary, may provide new treatment targets for medications, not only for panic disorders but also for anxiety and post-traumatic stress disorder (PTSD). “This work raises the question of whether some sort of amygdala dysfunction might contribute to those overwhelming feelings of panic you see in these disorders,” he says. “And by isolating specific pathways that can inhibit or promote panic, we may biologically and neuroanatomically put our foot in the door to help create new treatments—perhaps deep brain stimulation or some kind of pharmacologic modification.”