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Every living thing, from the most complex mammals to single-celled organisms, instinctively responds to danger. Expose a bacterium to a toxic chemical and it will skirt away or rev up some other defense mechanism. When we humans are surprised by a loud noise or catch a glimpse of something slithery that might be a poisonous snake or venomous spider, our hearts start pounding and our palms sweat—signs of the physical and emotional state we call fear.
What is fear, exactly, and what’s going on in the brain when we’re frightened? A bevy of research has shed light on the brain circuitry involved, paving the way for new interventions and treatments for post traumatic stress disorder (PTSD), generalized anxiety disorder, and other fear-related maladies.
“Having an objective measure of brain activity when people respond to threatening situations can help us better understanding what’s going wrong in people with PTSD,” says John Hart, medical science director at the Center for BrainHealth and a distinguished professor at the University of Texas at Dallas.
Responding to threat involves many parts of the brain. But if any single brain structure can be seen as central to the process, it’s the amygdala—an almond-shaped bundle of neurons buried deep in each medial temporal lobe, located just above the brain stem.
“When you sense something potentially dangerous, the amygdala sends excitatory signals to other parts of the brain, effectively saying, ‘Hey everyone, pay attention!’” says Bambi DeLaRosa, a doctoral student at the Center for BrainHealth and lead author of a recent study on threat processing published online in the journal Brain and Cognition.
Scientists first began to identify the amygdala as the brain’s “fear center” in the late 1880s, when they noticed that monkeys with damaged amygdalae were relatively tame and did not show fear when confronted by snakes and other predators. Dozens of studies since have corroborated that damage to the amygdala coincides with abnormally low levels of fear.
Some of the most famous studies in humans have focused on a patient known as “SM,” a woman with a rare genetic disorder, Urbach-Wiethe disease, which causes the amygdalae to harden and shrivel. In a 1995 study published in The Journal of Neuroscience, wherein SM was made to identify emotions expressed in facial expressions, researchers found that “bilateral … damage to the human amygdala impairs the processing of fearful facial expressions.” (A follow-up study by the same researchers found that SM failed to recognize fearful expressions because she did not focus on the eyes; when directed to look specifically at the eyes, her ability to recognize fear in faces scored in the normal range.) A study published in Current Biology in 2010 described SM as utterly without fear, even when exposed to large snakes and spiders or during a tour of a haunted house set in the Waverly Hills Sanatorium—infamous as one of the most “haunted” buildings in the world. SM insisted on touching venomous snakes when taken to an exotic pet store and tried to chat with the “monsters” hidden throughout the haunted house. “The findings support the conclusion that the human amygdala plays a pivotal role in triggering a state of fear,” the researchers wrote, “and that the absence of such a state precludes the experience of fear itself.”
Beyond the amygdala
Other studies, though, have found that while the amygdala plays an important role in processing fear, it is not absolutely necessary. The same researchers who found SM to be fearless when exposed to threats were surprised to learn that she and two other patients with Urbach-Wiethe disease experienced intense fear and panic when made to inhale carbon dioxide, which induces choking. In a 2013 paper in Nature Neuroscience they concluded that “the amygdala is not required for fear and panic,” at least when triggered by internal bodily threats, such as CO2 inhalation.
“When we put people in a brain scanner and have them look at threatening images, we see activity not only in the amygdala but also in areas associated with language and memory,” says Andrew Lawrence, a professor of neuroscience at Cardiff University in Wales. For example, in DeLaRosa’s recent study, she and her colleagues found that threatening images induce activity not only in the amygdala but also in the frontal regions of the brain, which work as a sort of control. If the amygdala is like a hair trigger sounding the alarm, DeLaRosa says, frontal lobe areas associated with threat response evaluate the situation to help determine whether the threat is genuine or a false alarm.
Threat vs. fear
For neuroscientist Joseph LeDoux, advancing the science of neural threat processing requires not only looking beyond the amygdala but also differentiating between the brain’s chemical reaction to threat and our conscious experience of fear.
“When global organismic states [such as threat response] are witnessed by consciousness, we interpret them with the label fear,” says LeDoux, director of the Emotional Brain Institute at NYU and a member of the Dana Alliance for Brain Initiatives. “Fear is a concept, not a ‘thing’ in the brain. Yet we assume we can find human fear in a rat brain, which is ridiculous.”
Instead, LeDoux says, animal studies should focus on exploring brain mechanisms that detect and respond to threat and which might work similarly in humans. Otherwise, we risk applying flawed data to drug development. “We expect too much from animal research,” LeDoux says. “When we find a drug that releases rats from freezing behavior when exposed to a threat, for example, we interpret that as a drug able to curb anxiety in humans. But rats don’t experience ‘anxiety,’ at least not that we know of. That’s a social construct.”
A growing number of researchers are heeding LeDoux, focusing on the underlying neural mechanisms that give rise to fear and fear-related disorders. DeLaRosa’s study that found evidence for frontal lobe activity in the brain’s threat response, for example, broke new ground by controlling for arousal–the degree to which a person finds something to be threatening–which tends to vary widely. Doing so allowed her to focus more exclusively on the brain’s response to threat to establish a “baseline” model against which cases of abnormal threat response can be measured.
“A person with PTSD or an anxiety disorder is essentially over-responding to a frightening stimulus,” DeLaRosa says. “The more complete our model of how threat response works in ‘normal’ brains, the better able we’ll be to pinpoint what’s gone wrong in people who respond abnormally to threats.”