A copse can beckon, with its dappled leaves and songbird trills. But linger past twilight, and tree, bush, and animal assume different dimensions. Trunks thicken and loom, bushes snatch at clothing, and the rustlings and skitters of feather and claw magnify. You become unsettled, unnerved. You run.
You do this because you’re afraid. Even without direct evidence of danger, you’re compelled to flee, to protect yourself. Why this compulsion? It’s the work of your amygdala, a tiny almond–shaped structure in your brain. Sensory signals alert it; in turn, it triggers a cascade of activity, deluging your body with messages that widen your eyes, prick your ears, accelerate your heart, quicken your breathing, wrench your stomach, moisten your palms, and launch a full–body, organ–clenching, corpuscle–filling chill. You run quite simply because fear grips you.
“You could call the amygdala a relevance detector,” says Nouchine Hadjikhani, an HMS associate professor of radiology who specializes in capturing the activity of the brain as it reacts to fear–provoking stimuli. “In less than 100 milliseconds, just one–tenth of a second, sensory information reaches the amygdala, which signals your brain to be aware. All your systems become more receptive. You’re now ready to fight, freeze, or flee.”
The good news is that, should the terror prove benign, you’ll not long be in fear’s thrall. For while your amygdala is providing survival insurance by spurring action, sensory clues are also traveling to your prefrontal cortex. The amygdala’s action buys you additional milliseconds, during which you might glimpse a light, stumble upon a traveled road, or receive other sensory stimuli that your prefrontal cortex will use to temper the initial response. You will calm, completing an arc of reaction that has been key to mammalian survival through eons.
Investigating what drives that arc of reaction spurs much of today’s research into the molecular mechanisms of the fear response. HMS scientists are providing tantalizing insights by explaining how we decipher danger in the gazes or body movements of others, by informing treatments for conditions such as post–traumatic stress disorder, and even by providing clues to the gender–based underpinnings of human response to fear.
A 2005 poll of U.S. teenagers revealed the power that emotion can have in searing fear–filled memories deeply; despite the teens’ limited direct experience, terrorist attacks, war, and nuclear war held top–ten berths in a list of fears. This finding hints at a phenomenon that Hadjikhani and her colleagues study: the contagion of fear. In her research, Hadjikhani has found that humans, like other animals, can experience fear indirectly, the result of another’s glance or muscle tensing, or, on a larger scale, that electric connection that turns a milling crowd into a stampeding throng.
“We’re born into this world with a system to read other people’s expressions,” says Hadjikhani. “Ten minutes after we’re born, we’re already oriented more to faces than to objects.” In 2008, Hadjikhani and colleagues reported on their investigation of one aspect of facial expression—the gaze—and its role in communicating danger. They found that while a direct gaze from a fear–filled face triggers activity in fear–response regions of the brain, the response is not as complex as that elicited by a fear–filled face in which the eyes are averted. A direct gaze signals an interaction between participants who know themselves to be non–threatening. But an averted gaze, “pointing with the eyes,” as the researchers call it, flags a possible environmental danger and sparks activity in brain regions skilled at reading faces, interpreting gazes, processing fear, and detecting motion.
In other research, Hadjikhani found that the brain can recognize happy and fearful expressions in body movements. A fearful posture—hands held open and in front of the body like shields, for example—activates brain regions that oversee emotion, vision, and action, while postures of happiness—arms loosely held from the body as if opened to embrace—spur activity only in vision–processing regions.
These physical communications of actual or perceived danger offer one avenue to developing a conditioned fear, a learned response founded upon emotion and impressed so firmly within memory that it remains active for a lifetime.
Raising the Dread
According to the National Institute of Mental Health, roughly 19 million people in the United States have mental illnesses that involve persistent, outsized fear responses to seemingly ordinary stimuli. A door slam becomes a gun’s report to a shattered combat veteran, for example, while smoke from burning leaves might trigger smell–based memories of pyres for a genocide survivor. Among the anxiety disorders linked to conditioned fear responses is one that’s much in the news: post–traumatic stress disorder.
For more than a decade, Vadim Bolshakov, an HMS associate professor of psychiatry and director of McLean Hospital’s Cellular Neurobiology Laboratory, has explored fear–driven disorders by investigating their molecular bases in the brains of rats. One early finding from his laboratory showed that learned fear changes the way the animals’ brains operate, offering a mechanism for conditioned fear’s persistence.
Bolshakov and colleagues taught rats to associate a harmless stimulus, a tone, with a painful event, a shock to their feet. The researchers found that neurons in the rodent amygdala exhibited remarkable sensitivity to the tone, so much so that the neurons continued to fire after the stimulus was removed. This sensitivity, known as long–term potentiation, is important to memory acquisition. It is normally modulated by glutamate, a chemical that is released into the synaptic spaces between neurons when a message is being passed, but then is deactivated to prevent message over–expression. Bolshakov’s team showed that the amygdala’s heightened sensitivity was the result of too much glutamate, either because the clean–up process failed or, as the researchers postulated, because production of the chemical went into overdrive.
Other studies by Bolshakov and colleagues identified two proteins essential to the innate and learned fear responses. When the researchers blocked production of one of the proteins, stathmin, fear–conditioned mice were less able to recall the learned fear—and lost the ability to recognize dangers that normally would have kicked their innate fear response into high gear. Blocking the gene that produced a protein known as transient receptor potential channel 5, normally found in high concentrations in the amygdala, decreased the rodents’ neurons’ sensitivity to cholecystokinin, a neuropeptide released when the innate fear response is triggered or a learned fear is recalled.
These insights are welcomed by Roger Pitman, an HMS professor of psychiatry, and Mohammed Milad, an HMS assistant professor of psychiatry. Based at Massachusetts General Hospital, these researchers seek to tease out treatments for people with anxiety disorders such as post–traumatic stress disorder.
Location, Location, Location
“You can never completely abolish a learned fear,” says Pitman. “Learned fears are deep and may strengthen by reconsolidating after recall. One way to help patients diminish the impact of an anxiety–producing memory is to guide them to form a new memory that inhibits, or extinguishes, expression of the fearful memory during any recall attempt.”
Or, as Pitman and colleagues discovered several years ago, people might be helped to stave off a fear–filled memory by preventing it from consolidating in the first place. In a controlled study of patients entering Mass General’s emergency department after traumatic experiences—assaults or car accidents, for example—Pitman provided some participants with a placebo and others with propranolol, a drug that blocks the effects of the hormone adrenaline. At follow–up interviews participants listened to audiotapes of their own accounts of their trauma the day it occurred. Propranolol recipients had weaker physical responses to the tapes than placebo users, who showed physical signs of the stirring of their fearful memory despite time’s passage.
Replicating these results has proven difficult, however, so Pitman and colleagues have shifted their focus to reactivating traumatic memories in people with post–traumatic stress disorder and then administering an anti–stress drug to try to weaken the memory’s reconsolidation.
Reliving a fear, even a trauma–induced one, is not necessarily pathologic, Milad points out. Recalling the source of high emotion or injury can serve as a safeguard, a warning that our brains can tap as needed. In addition, time often softens the intensity of response.
“Say you’re in a car accident,” Milad adds. “It occurs at a particular intersection at the same time a certain song is playing on the radio. For a period following that accident, whenever you go through that intersection or hear that song, you will re–experience at some level your initial fear. If over time nothing horrible happens to rekindle your memory, your conditioned response to either stimulus will lessen until the fear is extinguished. This extinction doesn’t erase the initial learned fear; instead, it leads to forming a new memory, a ‘safety memory.’ The learned fear—the neuronal connections that the experience formed within your amygdala and between your amygdala and certain cortical structures—remains.”
For some, the trauma never lessens. In people with post–traumatic stress disorder, Milad and Pitman have found that two brain regions involved in extinction, the hippocampus and a region of the prefrontal cortex, function at a lesser capacity, while activity in the amygdala and the dorsal anterior cingulate, a region involved in cognition and motor control, rachets up. These findings may explain the unending rawness that trauma–induced fears bring to people with the disorder.
Other research by these investigators suggests that hormones and biological cycles may play significant roles in fear learning and extinction.
“Although some data suggest that estrogen actually enhances fear learning,” says Milad, “other studies suggest the opposite, that it reduces fear and anxiety. Unfortunately, the area is underinvestigated. Anxiety disorders, for example, are twice as high in women—and we can’t say precisely why.”
The researchers’ work does provide intriguing clues, however. They have found that women with higher estrogen levels showed stronger activation of the ventromedial prefrontal cortex, a brain region key to fear control. These high–estrogen women were good at extinguishing fear. When the researchers repeated the study in rats and manipulated estrogen levels, they found that blocking estrogen impaired the animals’ ability to control fear. Reintroducing estrogen caused the rats to behave as if they felt safe.
Curiously, the researchers found that men’s ability to control fear was akin to that of high–estrogen women. How does it jibe, then, that women have twice the prevalence of anxiety disorders?
“We don’t know,” says Milad, “but the speculation is that estrogen alone doesn’t make you a super–extinguisher. It may be the lack of the hormone that puts a woman at higher risk. If a woman’s estrogen is high, she controls fear in a way comparable to men, but if her estrogen dips, as it would during a normal menstrual cycle, she may be at a higher risk for fear acquisition following a trauma or another emotion–laden incident.”
Such studies by Milad and others highlight a growing interest in finely parsing the mechanisms of fear acquisition and extinction in humans. Fundamentally, though, our response to fear remains basic, a primitive emotion essential to our survival and a core response that unifies our species.
“The amygdala is the amygdala,” says Milad. “Whether it’s in Taipei or in Cedar Rapids, it’s still a knee–jerk response to danger.”
Ann Marie Menting is Associate Editor of Harvard Medicine.
Images: Ocean/Corbis (top); Graham Gordon Ramsay (N.Hadjikhani); Rose Lincoln/Harvard News Office (V.Bolshakov); John Soares (R.Pittman, M.Milad)