CHAPTER SEVEN

REMEMBERING TO FORGET

The Biology of Fear and Emotional Memory

HELEN ANTHONY WAS IN HIGH SCHOOL WHEN IT HAPPENED. “I kept on saying, ‘Where are we going to go? What can we do? What difference does it make whether we get killed now or later?’ I was really hysterical,” she later recalled. “My two girlfriends and I were crying and holding each other and everything seemed so unimportant in the face of death. We felt it was terrible we should die so young” (p. 50).

Sylvia Holmes had a more practical thought: “I looked in the icebox and saw some chicken left from Sunday dinner that I was saving for Monday night dinner. I said to my nephew, ‘We may as well eat this chicken—we won’t be here in the morning’ ” (p. 54).¹

These women, like millions of other Americans, were glued to the news reports. Only miles away, terror had struck out of the blue in the form of a devastating attack on American soil. According to initial estimates, at least forty people lay dead near the site of the attack, “their bodies burned and distorted beyond all possible recognition.” A federal official urged calm and tried to reassure the nation that a military counterstrike was under way. But that was doubtless little comfort as word came that highways were clogged with vehicles fleeing the fiery explosions and poisonous black smoke.

Many Americans had gathered with their loved ones, preparing to meet death together, by the time the final announcement came:

Tonight the Columbia Broadcasting System, and its affiliated stations coast-to-coast, has brought you War of the Worlds by H. G. Wells . . . the seventeenth in its weekly series of dramatic broadcasts featuring Orson Welles and the Mercury Theatre on the Air.

The War of the Worlds broadcast, on Halloween night 1938, has become a legendary example of how fear and panic can be contagious on a large scale. As newspaperwoman Dorothy Thompson wrote in an editorial two days later, the most frightening thing about the show was the public’s irrational response. The broadcast was filled with patently implausible details: Martians had attacked New Jersey with death rays; millions of New Yorkers had reportedly fled the city minutes after the attack was announced; and other events that would have spanned hours were condensed into the brief timescale of a radio drama. Not to mention the fact that “the public was told at the beginning, at the end, and during the course of the drama that it was a drama.” But the really terrifying fact, she wrote, was that Welles and his colleagues had “uncovered the primeval fears lying under the thinnest surface of the so-called civilized man. . . . If people can be frightened out of their wits by mythical men from Mars, they can be frightened into fanaticism by the fear of Reds, or convinced that America is in the hands of sixty families, or aroused to revenge against any minority, or terrorized into subservience to leadership because of any imaginable menace.”

Sadly, Thompson’s analysis was amply confirmed in the years that followed with the frenzied anti-Semitism of Hitler’s Germany, the internment of Japanese Americans, McCarthyism, the Cold War, recurrent ethnic violence, and more recently, the anti-Muslim and anti-immigrant fearmongering of right-wing pundits. Fear has been a versatile tool for mobilizing opinion and action in the service of all sorts of agendas.

In a much more benign way, the attention-grabbing function of fear has not escaped marketers and media moguls. Just think of the “watch or die” promos that compel us to watch the nightly news:

“The popular toy that could kill your child!”

“Shocking new research: Is your shower giving you cancer?”

In the past few years, we’ve ridden waves of panic as apocalyptic warnings have ebbed and flowed: mad cow disease, bird and swine flu, global warming, economic collapse, and cyber-terror. As Robert Brockway lays out in his book Everything Is Going to Kill Everybody, there is no shortage of impending disasters you probably don’t even realize you should be worrying about. In a lighthearted entry on the end-of-days potential of genetically modified foods, he reassures us that “All joking aside, though: Plants are going to murder your family.”

All joking aside, though, we do seem to be living in an era of escalating fear. During his first inaugural address in 1933, Franklin Delano Roosevelt tried to calm a nation under economic duress by declaring that “the only thing we have to fear is fear itself.” But more than sixty years later, fear itself became a weapon of war. The “war on terror” marked the first time in history that the named enemy was not a nation state but an emotional state. In the years since 9/11, threat levels have risen and fallen, dragging our nervous systems along with them.

Why are we so susceptible to the power of fear? There is substantial evidence that fear occupies a privileged place in our minds. Natural selection has wired our brains to feel it. Our most basic fears are echoes of the threats our ancestors were likely to face. But the neural machinery that evolved to sense danger has left us vulnerable to fears and anxieties our ancestors never imagined.

With advances in neuroscience and molecular biology, we now have a much more nuanced picture of how fears arise, recede, and sometimes hijack our lives. In many ways, research on the biology of fear and anxiety has provided the best example of how a detailed understanding of the biology of normal can reveal both fundamental features of our everyday lives and how things can go awry to create disorder. And, as we’ll see in this chapter, scientists are beginning to exploit that same biology to tame terror.

THE ORIGINS OF FEAR

WHAT IS FEAR? A SIMPLE, BUT USEFUL, DEFINITION IS THAT FEAR is an emotional response to a perceived threat. Gordon Gekko, the fictional tycoon from Wall Street, famously said, “Greed is good.” The same could be said of fear. We need it to survive. In the face of danger, fear mobilizes us to fight or flee. When our ancestors faced the proverbial saber-toothed tiger, those who were afraid lived to tell the tale—and had children to pass it on to.

So it should come as no surprise that our minds are not blank slates when it comes to fear. Avoiding harm is so fundamental to survival that fear was the first emotional system to be wired into the animal nervous system. We all have fears, and some of them are almost universal. Polls typically find that Americans’ top five fears are heavily weighted toward things that would have been universal threats in our evolutionary history: (1) public speaking; (2) snakes; (3) confined spaces; (4) heights; and (5) spiders.² You might be wondering what public speaking has to do with our ancestral past. Obviously early hunter-gatherers weren’t giving PowerPoint lectures on the finer points of taking down a wildebeest or collecting berries. But the fear of public speaking is really about (real or imagined) social threat. What we fear when we speak in front of a group of people is that we’ll show signs of fear or embarrassment and be judged harshly. Evolutionary theories about social and performance anxiety have suggested that being stared at by strangers would have signaled a dangerous situation in our ancestral past and that blushing and other signs of social anxiety might have developed as appeasement displays that communicate submissiveness in an attempt to avoid attack by strangers.^3, 4 Public speaking fears are powerful and ubiquitous. As Jerry Seinfeld once joked, “According to most studies, people’s number-one fear is public speaking. ‘Death’ is number two! Now, this means to the average person, if you have to go to a funeral, you’re better off in the casket than doing the eulogy.”⁵

BE AFRAID, BE VERY AFRAID

THE WORLD IS A DANGEROUS PLACE. IN CHAPTER 2 WE LEARNED that our brains are tuned to sense threat and avoid harm from the very start of our lives. We are born with rudimentary neural circuitry dedicated to keeping us safe by allowing us to experience fear in the face of threat. But this early sensitivity to signs of danger can only get us so far. Natural selection has wired us to detect and avoid badness, but the infant brain can’t anticipate the endless variety of life’s possible dangers. We need a mechanism for reacting to the particulars of the environment we are born into—what specifically we should approach because it is safe or nurturing, and what we should avoid because it is dangerous or harmful. Fortunately, natural selection has given us that mechanism: we can learn to fear.

In the past two decades, research on the biology of fear has been extraordinarily productive. Electrophysiologic and neuroimaging studies have mapped the basic anatomy of fear circuitry. Neuroscientists have drilled down to the level of synapses and cells to identify the specific chemical events that create and modify emotional memories. And in just the past few years, researchers have used these discoveries to understand the biology of pathologic anxiety and develop promising methods that may relieve the suffering of the millions of people afflicted with disorders of fear and anxiety.

A DOG AND HIS BOY

IF A FRIEND ASKED YOU TO NAME THE MOST FAMOUS DOGS OF THE twentieth century, you might first wonder if your friend has too much time on his hands and then you might come up with names like Lassie, Rin Tin Tin, and Checkers, or maybe even Scooby Doo and Spuds Mackenzie. Chances are the names Beck, Milkah, Ikar, Ruslan, and Toi would not spring to mind. But in the canon of canines, they clearly deserve more credit.⁶ Along with a few dozen other dogs (whose names you also didn’t know), they helped lay the foundation for modern psychology and neuroscience. You probably know them by the more popular but sadly generic moniker they’ve been given: Pavlov’s dog. Their individual names may not ring a bell, but bell ringing was ironically the basis of their claim to fame.

In the late nineteenth century the Russian physiologist Ivan Pavlov was making major strides in unraveling the physiology of the digestive system. Pavlov discovered that much of how we digest food depends on neural reflexes that coordinate the secretion of “digestive juices” from the salivary glands, stomach, and pancreas. In 1904 he was awarded a Nobel Prize in Physiology or Medicine for his breakthrough experiments.

In the course of this work, Pavlov made another discovery that made his name a household word. He found that placing food in the mouth of a dog would reliably trigger the dog to secrete saliva and gastric acid. But he also found that if he rang a bell each time he fed the dog, the animal would begin to salivate at the sound of the bell—whether or not it was actually followed by food. Pavlov realized there were two kinds of reflexes at work here. The first, triggered by the real food, he called an “unconditioned reflex,” and the second, triggered by a stimulus that had merely been associated with the real thing, he called a “conditioned reflex.”

That simple observation, which seems almost self-evident today, was revolutionary. It illuminated something much more than the physiology of salivation. It revealed a fundamental mechanism behind learning and memory. It soon became clear that essentially any stimulus could be associated with a conditioned reflex. The implication was that animals can learn about how the world works and the complicated contingencies of their environment by this simple process of association. We can predict the future by registering how things occurred together in the past.

Today, Pavlov’s model of learning is known as classical conditioning. Several years after Pavlov reported his findings, an American psychologist named John B. Watson took Pavlov’s idea and ran much further with it. Watson founded an entire branch of psychology, which he called “behaviorism,” on the idea that both animal and human behavior can be explained by stimulus and response learning. He believed that psychology should be a science of observable behavior. In staking that claim, he challenged his colleagues to sweep aside the muddled and untestable jargon of studying the mind as a hidden entity, approachable only by introspection. As he put it in a 1920 article that later became a behaviorist manifesto:

I believe we can write a psychology . . . [and] . . . never use the terms consciousness, mental states, mind, content, introspectively verifiable, imagery, and the like. I believe that we can do it . . . in terms of stimulus and response, in terms of habit formation, habit integrations and the like. (pp. 166–67)⁷

When it came to the nature vs. nurture debate, Watson and his behaviorist disciples were squarely in the nurture camp. The birth and rise of behaviorism ushered in the ascendancy of the “blank slate” view of the human mind. Conditioning was the quill with which any life story could be written. Watson famously wrote:

Give me a dozen healthy infants, well-formed, and my own specified world to bring them up in and I’ll guarantee to take any one at random and train him to become any type of specialist I might select—doctor, lawyer, artist, merchant-chief and, yes, even beggar-man and thief, regardless of his talents, penchants, tendencies, abilities, vocations, and race of his ancestors. I am going beyond my facts and I admit it, but so have the advocates of the contrary and they have been doing it for many thousands of years. (p. 82)⁸

Watson never attempted the dozen healthy infants experiment, but in 1920 he reported another experiment on infant learning that was profoundly influential.⁹ He wanted to see whether he could use conditioning to create long-lasting emotional reactions in a human being. To test this, he performed an experiment on the infant son of a wet nurse in the Harriet Lane Home for Invalid Children. Albert B. (or, as he became known to generations of psychologists, “Little Albert”) was a healthy nine-month-old baby when Watson began a series of conditioning trials that seem remarkably cruel in retrospect. In the modern era of ethical review boards and research oversight, it’s clear that Watson’s study would never be allowed today.

The research began by documenting that Albert had never been seen to express fear. One day, Albert was placed near a four-foot steel bar that was suspended in the air. While one experimenter distracted him, another suddenly struck the bar with a hammer, creating a loud, frightening noise. Albert was startled and began flailing. The hammer blow was repeated a second and then a third time. “On the third stimulation,” Watson reported, “the child broke into a sudden crying fit. This was the first time an emotional situation in the laboratory has produced any fear or even crying in Albert.” Watson notes that he considered the possibility that maybe this wasn’t such a good thing to do to an infant, but he quickly dismissed the ethical issues, “comforting ourselves that such attachments would arise anyway as soon as the child left the sheltered environment of the nursery for the rough and tumble of the home.” (One has to wonder what kind of home Watson was raised in.)

About two months later, Watson began to try conditioning Little Albert. In this case, making a loud noise was analogous to holding out the meat that caused Pavlov’s dogs to salivate. Modern psychologists call this an “unconditioned stimulus” that triggers an innate “unconditioned response” (e.g., salivating or, in this case, a fear reflex). Now Watson’s task was to see whether pairing this unconditioned stimulus with something else, a “conditioned stimulus,” could make Albert learn to fear something new. When Albert was about eleven months old, Watson brought him back to the laboratory and pulled a white rat out of a basket. Albert was curious but “just as his hand touched the animal,” Watson reported, “the bar was struck immediately behind his head. The infant jumped violently and fell forward, burying his face in the mattress.” A moment later, as Albert again tried to touch the rat, the bar was struck again. Albert “jumped violently, fell forward and began to whimper.” Over the next two weeks, the scenario was repeated several times. And after the seventh trial, Watson presented the rat alone. The laboratory notes read that “The instant the rat was shown the baby began to cry. Almost instantly he turned sharply to the left, fell over on left side, raised himself on all fours and began to crawl away so rapidly that he was caught with difficulty before reaching the edge of the table” (Watson’s italics).

Watson wrote, exultantly, “This was as convincing a case of a completely conditioned fear response as could have been theoretically pictured.”

But it gets worse. Over the next two months Watson tested whether Little Albert’s fear would be transferable to objects that resembled the rat to varying degrees: a rabbit, a dog, a fur coat, cotton wool, a Santa Claus mask, a set of blocks. The results confirmed Watson’s suspicions. Albert had paroxysms of fear when presented with the similar stimuli—especially the bunny—but had no fear when given the blocks.

In summing up his findings, Watson noted, “These experiments would seem to show conclusively that directly conditioned emotional responses as well as those conditioned by transfer persist, although with certain loss in the intensity of the reaction, for a longer period than one month. Our view is that they persist and modify personality throughout life.” In other words, if all went according to plan, Little Albert would be screwed up for the rest of his life. At the conclusion of his case study, Watson suggested, prophetically, “It is probable that many of the phobias in psychopathology are true conditioned emotional reactions either of the direct or the transferred type.”

With the case of Little Albert, Watson established the experimental paradigm of “fear conditioning” that is still used in laboratories throughout the world and that has allowed neuroscientists to discover the neural and molecular basis of normal fear and anxiety disorders.

FEELING THE PAST

WHERE WERE YOU ON SEPTEMBER 7, 2001? HOW ABOUT NOVEMBER 15, 2001? Chances are, you can’t recall. But if I asked you where you were on the morning of September 11, 2001, you probably have a pretty good idea. By stamping the events of that morning with powerful feelings, your brain formed an emotional memory that’s lasted more than a decade.

Emotions are the brain’s way of attaching salience to our experience. By adding feeling to fact, they help us pick out the important signals from the infinite noise of the world around us. They focus our attention on potential rewards and looming threats. And they help us learn, remember, and then anticipate events that matter. In a sense, then, memory itself is more about the future than the past. We hold on to some experiences and associations because they help us predict what might happen again. We remember so that we can be prepared. And events and situations that elicit feelings get a privileged place in our minds. Fear learning and fear memories are a subset of emotional memory and we now know in great detail how they work, thanks to the legacy of Pavlov and Watson.

CIRCUIT TRAINING: THE ANATOMY OF FEAR

WE’RE ALL FAMILIAR WITH THE PHENOMENON OF CONDITIONED FEAR. Perhaps you were bitten by a dog when you were twelve and since then the sight of an approaching dog makes you sweat. Or maybe you fumbled a big presentation at work last week and now the thought of tomorrow’s presentation to the client has you panicking. But how do we learn to fear and how do emotional memories shape our lives?

We’ve already talked about the hub of the brain’s fear system—the amygdala—and we’ve seen that it has a role in everything from temperament and attachment to trust and empathy. In simple terms, you can think of the basic wiring diagram of our fear circuitry as an alarm system with three major nodes. The amygdala receives information about threats, stamps them with fear, and alerts the rest of the brain to focus attention and trigger stress hormones and fight-or-flight responses. The prefrontal cortex hears about the threat from the thalamus and the amygdala and has a calming, inhibiting effect on the amygdala. The cortex also generates the cognitive experience of fear and worry. And finally the hippocampus processes the context of the threat and also helps us remember the fear experience.

To give you a sense of how the circuit works, let’s consider a situation you might have experienced. You’re on an airplane en route from New York to Boston. All of a sudden, the seat belt light turns on, the pilot comes over the loudspeaker and says (in that nonchalant pilot way), “Ladies and gentlemen, we’re heading into a little bit of turbulence, and I’ve gone ahead and turned on the seat belt light. Please remain in your seats. Flight attendants, please be seated.” Next thing you know, the plane is shaking and you feel a sudden queasiness as the plane seems to drop and then bounce on a pocket of air. For fifteen long seconds, it’s nothing but shaking and shuddering, dropping and bumping. And then, after what feels like hours, the plane is once again humming along. You’re alive. As you peel your fingers off the armrest, you feel your heart pounding and beads of sweat on your brow. You grab a copy of SkyMall and try to get your mind off what just happened by studying the design features of an award-winning electronic mosquito trap.

What just happened? We can think of the frightening sensations of the turbulence as the unconditioned fear stimulus and the seat belt light and pilot’s voice as conditioned stimuli. As your senses took in these stimuli, they relayed the information to the thalamus, a structure deep in the brain that sends sensory information to the amygdala along two pathways. The first is a direct line from the thalamus to the amygdala and has been dubbed “the low road” by neuroscientist Joseph LeDoux, who helped define much of this circuitry.¹⁰ The low road is fast but crude, telegraphing a rough but instantaneous version of the fear stimulus (“danger! threat!”) into the amygdala and triggering an immediate fear response. The second route from the thalamus, which LeDoux calls “the high road,” runs up to the prefrontal cortex and then back down to the amygdala. The high road is longer and slower, but conveys more detailed information about the threat (“The plane may be going down! We’re shaking and falling!” “The pilot’s saying something!”).

As the plane was shaking up and down, the two paths converged on the front gate of the amygdala, a collection of neurons known as the basolateral amygdala. These neurons do the work of associating the unconditioned stimulus (the plunging plane) with the conditioned stimuli (seat belt light and pilot’s voice). Meanwhile, your hippocampus, which sits in the temporal lobe, fed your amygdala information about the context of the danger situation (the airplane in midflight). Neurons in the lateral amygdala then pass the information to the output side of the amygdala, known as the central nucleus. This part of the fear center alerts other brain regions that trigger stress responses (the hypothalamus), fearful thoughts and feelings (the prefrontal cortex), the fight-or-flight response (the brain stem), and memories of the fearful situation (the hippocampus).

Fear circuitry including detail of the amygdala and its connections to other fear-processing regions. BLA: basolateral amygdala; ITC: intercalated cells.

By the time you were in Boston, waiting at the luggage carousel, your plane ordeal had begun to fade from your mind. But in the deep recesses of your fear circuitry, a memory formed through a process known as consolidation, ready to reawaken if the conditions are right.

Now it’s a week later and you’re on a flight back to New York. As the plane approaches the airport, the fasten seat belt light comes on and the pilot begins to speak, “Ladies and gentleman . . .” All of a sudden, you freeze. Your heart is pounding and your grip tightens on the armrest. Your mind races back to the terrifying turbulence of your last flight and you’re too preoccupied to hear the pilot finish his sentence, “we’re approaching New York and we should be on the ground in about five minutes.” The conditioned fear memory has been retrieved.

In recent years, neuroscientists have been able to go beyond this basic map of our fear circuits and dissect the chemical and cellular events that generate our emotional memories.

To understand how our memories are formed, you should understand a little bit about the dynamic connections in our brains. Recall that a brain circuit is made up of a series of neurons that communicate with each other across synapses—tiny gaps of about 20 nanometers between neurons. When one neuron is stimulated, an electric charge flows down the neuron and causes the release of packets of neurotransmitters into the synapse. The neurotransmitters cross the synapse and bind to receptors on adjacent neurons, causing chemical or electrical changes that propagate an electrical signal along that neuron, and the chain continues from neuron to neuron.

Contrary to popular notions, memories are not sitting in some compartment of the brain waiting to be called up. Rather, they are stored in these dynamic synapses. In large part, laying down memories involves strengthening the biochemical connections within a circuit of neurons. When experience excites a circuit of neurons, it literally boosts the strength of the connection between the neurons in that circuit and enhances the transmission of signals. That process, known as “long-term potentiation” is a fundamental mechanism of learning and memory throughout the brain, and one of the best-understood examples of experience-dependent plasticity—that is, how experience remodels our brains (see Chapter 3).

A simplified picture of a glutamate synapse. Glutamate released from a presynaptic neuron binds to NMDA receptors on a postsynaptic neuron. Cofactors (glycine or d-serine) boost the effect of glutamate; the drug d-cycloserine (discussed later in this chapter) can also act as a cofactor that enhances the effect of glutamate.

That’s what appears to happen in the amygdala when fear conditioning occurs. Information about the unconditioned and conditioned fear stimuli is carried by neurons from the thalamus, which release a neurotransmitter called glutamate into synapses within the basolateral amygdala. The glutamate crosses the synapse to bind to a type of glutamate receptor called the NMDA receptor on the amygdala neurons. These synapses register the coincidence between the unconditioned fear stimuli (the plunging plane) and the conditioned stimuli (the seat belt light and pilot’s voice). Once the glutamate is bound, it opens a channel that allows calcium to rush into and stimulate the amygdala neurons.¹¹ The calcium also triggers a cascade of chemical events within the neuron that drive the formation of new proteins, including more NMDA receptors that make the neuron more sensitive to triggering a fear response the next time we encounter the conditioned stimuli. When two neurons communicate like this, the connection between them gets stronger by the process of long-term potentiation. The next time glutamate is released, the neural connection fires more easily. And it’s this strengthening of connections that encodes information as memories.

A whole set of other brain chemicals can dial up or down the intensity of this fear learning by changing our level of emotional arousal. In general, we pick up fears more easily when we’re more emotionally aroused. For example, emotional stress unleashes the hormones cortisol and norepinephrine, which enhance fear learning in the amygdala by stoking our arousal level.¹² The complex balance of these and other neurotransmitters, neuropeptides, and hormones determines how intensely we respond to threats and learn to fear them. New proteins and receptors are made that literally remodel neurons and synapses in the amygdala, leaving a physical trace of threat from the outside world.

LEARNING TO FORGET

IF OUR BRAINS WERE WIRED ONLY TO ACQUIRE FEAR, WE’D BE IN big trouble. We all experience lots of bad things in the course of a lifetime, or even just a day. If we held on to fear memories every time something bad happened, we’d be paralyzed by fears and unable to function. Fortunately, that doesn’t happen. Natural selection has also given us a mechanism for letting go of our fears. It’s called “fear extinction.” Thankfully, when our worst fears are not realized, they often lose their grip—that is, they can be extinguished. In the jargon of conditioning, when we repeatedly find that a conditioned stimulus is not followed by a real threat, the stimulus gradually loses its power. Extinction allows us to drop fears that are no longer relevant. Chances are, after a few more turbulence-free flights, the sight of the seat belt light and the sound of the pilot’s voice would go back to being just another part of the background of your life.

Surprisingly, overcoming learned fears doesn’t involve forgetting so much as learning—in other words, laying down new memories that separate the safe present from the dangerous past. Fear extinction involves writing a new story that’s more compelling and reassuring than the old one. That process requires a new round of learning—only this time we learn that the conditioned stimulus predicts safety rather than harm. Though the fear memory still exists, extinction works by giving priority to the “safe” memory. But if we’re exposed to the same frightening situation, the fear can easily come back. So rather than disappearing or fading away, our fears are submerged by a new extinction memory.

Fear extinction involves many of the same emotional brain regions that we use to learn fear in the first place: the basolateral amygdala, the medial prefrontal cortex, and the hippocampus.^13, 14 Like acquiring fears, extinguishing them involves synaptic plasticity in the basolateral amygdala, where glutamate binds to NMDA receptors, but this time the amygdala learns that the conditioned stimulus is associated with safety not harm. Meanwhile, the amygdala and the hippocampus tell the prefrontal cortex that there is an absence of danger signals. In turn, the prefrontal cortex sends inhibitory signals back to the basolateral amygdala, telling it there’s nothing to fear.¹⁵ The basolateral amygdala and prefrontal cortex convey these signals to inhibitory neurons (intercalated cells) within the amygdala, which then suppress firing of neurons in the amygdala’s central nucleus.¹⁶ As a consequence, the central nucleus no longer triggers fear responses and the circuit consolidates a memory of safety.

THE ANXIOUS BRAIN

PEOPLE OFTEN USE THE WORDS FEAR AND ANXIETY AS THOUGH they were synonyms. But psychologists and neuroscientists would tell you they are not quite the same. The distinction has to do with the nature of the threat. Fear refers to the emotional, behavioral, and physiological reaction to an immediate threat of harm—a clear and present danger. Imagine stepping off the curb and seeing a car barreling toward you. Suddenly, you experience a sense of terror, you startle, you may freeze or try to jump back onto the sidewalk, your body is flooded with stress hormones, your heart pounds, your breathing quickens, and you break into a sweat. Your fear system sensed the threat and mobilized your defenses (stress responses and fight-or-flight reactions). That’s fear.

Anxiety, on the other hand, is about the anticipation of threat, feelings that are often described as apprehension, vigilance, and hyperarousal. The threat may be distant, vague, or even undefined. And the feeling is often more chronic than sudden. The element of anticipation and apprehension adds a more cognitive quality to human anxiety. We don’t just panic—we worry and even dread. These are experiences that are uniquely human, that we alone bear. Perhaps they are the price we pay for being able to project ourselves beyond the present moment and imagine a future. In that sense, they are like another uniquely human experience, one that may be our compensation for the burden of anxiety: hope.

Although fear and anxiety are not quite the same, the brain systems that generate them are quite similar. Anxiety, like fear, involves coordinated activity of the amygdala, prefrontal cortex and hippocampus, and other regions of the emotional brain.¹⁷ In both fear and anxiety, stress hormones like cortisol, epinephrine, and norepinephrine are released; the sympathetic nervous system triggers fight-or-flight responses; and regions of the cortex generate fearful thoughts.

Anxiety, like fear, is an inescapable and universal part of the human condition. And, like fear, anxiety can be good for us. It drives us to do our best but prepare for the worst. The anxiety you felt before taking a test or giving a speech probably helped you focus your thoughts and motivated you to be prepared. But fear and anxiety can also take a toll. When they are intense and persistent, they can damage body and mind. In rare cases, they can even be deadly.

DEATH BY FEAR

IN 1915 THE GREAT HARVARD PHYSIOLOGIST WALTER B. CANNON developed the idea of the fight-or-flight response: the notion that, when we’re threatened, strong emotional reactions like fear and rage create physical symptoms by triggering the sympathetic nervous system and the release of adrenaline (epinephrine) from the adrenal glands. These emotional reactions, Cannon claimed, evolved to protect an animal from danger by preparing the body for “flight or conflict” (p. 277).¹⁸

In 1942 Cannon described a series of cases of “primitive people in widely scattered parts of the world” who had literally been scared to death: “When subjected to spells or sorcery or the use of ‘black magic,’ men may be brought to death,” he wrote. In the typical case, Cannon reported, some poor soul is condemned for breaking a tribal taboo or cursed by an enemy. In a gesture pregnant with drama, the enemy points a bone at the victim who now knows his fate has been sealed. Cannon cites a description of the terror that follows:

The man who discovers that he is being boned by an enemy is, indeed, a pitiable sight. He stands aghast, and with his hands lifted as though to ward off the lethal medium, which he imagines is pouring into his body. His cheeks blanch, and his eyes become glassy and the expression of his face become horribly distorted. . . . He attempts to shriek but usually the sound chokes in his throat, and all that one might see is froth at his mouth. His body begins to tremble, and the muscles twist involuntarily. He sways backwards and falls to the ground, and after a short time appears to be in a swoon; but soon after he writhes as if in mortal agony, and, covering his face with his hands, begins to moan. Unless help is forthcoming in the shape of a countercharm administered by the hands of the Nangarri, or medicine-man, his death is only a matter of a comparatively short time. (p. 184)¹⁹

Voodoo death, Cannon concluded, was the “fatal power of the imagination working through unmitigated terror” (p. 183), and he felt certain that “the rapidly fatal result is due to a persistent excessive activity of the sympathico-adrenal system” (p. 187). In other words, fear itself had driven the fight-or-flight system over a cliff.

At the time, Cannon based his conjecture on little evidence. In the years that followed, however, a number of detailed physiological studies supported many of his assumptions. Now cases of sudden death related to excessive fear or stress are recognized to be more than a curiosity of Cannon’s “primitive” cultures. As Cannon surmised, the cause of death seems to be a sympathetic storm, or rather, a paroxysm of neural activity that grips the heart. Neurons from the sympathetic nervous system tell the adrenal glands to release epinephrine into the bloodstream while simultaneously releasing norepinephrine into the cardiac muscle. Overstimulated muscle cells in the heart contract in a crushing squeeze, ultimately flooding them with calcium that poisons them and leaves them to die, locked in a state of contraction.²⁰ Less dramatic episodes of anxiety may also affect our physical health.^21, 22 For example, my colleagues and I asked a group of 3,369 older women if they had recently experienced a panic attack—a sudden attack of fear or anxiety accompanied by physical symptoms and fearful thoughts.²³ We found that, over the course of about the next five years, the women who had reported at least one panic attack had a threefold increased risk of heart attack or stroke and were nearly twice as likely to die from any cause.

But when fear and anxiety go awry, they’re more likely to take a toll on our mental health. For most people, fear and anxiety won’t kill you, but for some, they can create a living hell.

THE AGE OF ANXIETY

THE PROBLEM OF DRAWING LINES BETWEEN NORMAL AND PATHOLOGIC fear and anxiety is not at all straightforward. More than perhaps any other psychiatric symptoms, fear and anxiety are common to both mental health and mental illness.

The idea that there can be disorders of fear and anxiety has only been around since the mid-nineteenth century.²⁴ Between 1860 and 1900, European physicians began to group symptoms of anxiety into medical syndromes with names like neurasthenia, agoraphobia, and soldier’s heart. At the close of the nineteenth century, Sigmund Freud coined the term anxiety neurosis to describe a syndrome that included general irritability, anxious expectation and worry, sudden anxiety attacks, phobias, and a variety of physical symptoms.²⁵

The cause was—as you might guess with Freud—sexual, although he also claimed there was usually a hereditary predisposition at work. In particular, Freud believed anxiety neurosis was the result of excess sexual tension arising from sexual abstinence, coitus interruptus, or any other situation in which sexual gratification was frustrated.²⁶ He later came to see anxiety as a more general response to danger—but the danger, according to Freud, often originated within the mind itself.²⁷ Anxiety, he claimed, was a signal that the ego was in danger of being overwhelmed by unacceptable impulses and unconscious wishes. To contain this threat, Freud believed that the ego applies defense mechanisms like repression and displacement.

For the much of the twentieth century, the psychoanalytic theories of Freud and his intellectual descendants prevailed in psychiatry. As a result, psychiatrists and psychologists placed little emphasis on dissecting different syndromes of anxiety, in part because there was one treatment—psychoanalysis—that worked for everything.

But in the 1950s and 1960s, behavioral psychologists, influenced by John Watson and B. F. Skinner, were developing therapies designed to treat phobias, and psychiatrists began experimenting with drugs to treat agoraphobia and anxiety neurosis. Suddenly, it mattered what kind of anxiety you had. So when American psychiatrists unveiled the third edition of the DSM (DSM-III) in 1980, they introduced a whole portfolio of anxiety disorders. The most recent edition of the diagnostic manual, DSM-IV, includes seven major anxiety disorders: panic disorder, agoraphobia without a history of panic, generalized anxiety disorder, specific phobias, social phobia, posttraumatic stress disorder, and obsessive-compulsive disorder. Each of the syndromes has its own flavor of pathologic anxiety, but they all represent variations on normal fear and anxiety mechanisms that evolved to keep us safe in a dangerous world.

One of the most surprising facts about the anxiety disorders is just how common they are. The largest survey of U.S. adults found that about 29 percent—more than a quarter of the population!—will meet criteria for an anxiety disorder at some time in their lives.²⁸ As a group, anxiety disorders are the most common form of psychiatric disorder, edging out mood disorders such as depression and bipolar disorder, and substance use disorders such as alcohol and drug addiction. And anxiety disorders are not benign—in addition to incurring an enormous burden of personal suffering and economic costs (tens of billions of dollars per year in the United States alone), they are also among the most disabling chronic illnesses in all of medicine.

A recent study looked at a number of mental and physical illnesses in terms of how many days per month each illness knocked people out of work or their usual activities. The researchers found that anxiety disorders ranked second only to musculoskeletal disorders and far outpaced cancer, chronic obstructive pulmonary disease, digestive diseases, and even heart disease.²⁹

So can the biology of fear and emotional memory help us understand what’s going on in anxiety disorders? For the most common anxiety disorders, there is good reason to believe that a problem with the functioning of fear circuitry is at work. For example, compared to other people, those with anxiety disorders acquire conditioned fears more easily and have more difficulty extinguishing them.³⁰ People who suffer from panic disorder have a tendency to overgeneralize conditioned fear—that is, their fear responses are leaky and can attach to a broad range of stimuli.³¹ A large body of neuroimaging studies have shown that people with anxiety disorders have abnormalities in the structure and function of fear circuitry regions that include the amygdala, insula, prefrontal cortex, and hippocampus.^14, 32–35

As John Watson himself conjectured, phobias provide the most obvious example of fear conditioning gone awry. A phobia is an exaggerated fear and avoidance of some object, situation, or experience. Clinicians recognize three major flavors of phobic disorders, depending on what it is that you fear. For example, someone with a specific phobia has an extreme fear of a specific object or situation, like snakes, enclosed spaces, or thunderstorms. When the fear is of other people—that is, embarrassment and anxiety in social situations—it’s called social phobia; and when the fear is focused on the experience of paniclike sensations, we call it agoraphobia.

It’s important to remember that all of these fears can be normal, and some are universal. But normal fear becomes a phobia when it is excessive, persistent, and causes suffering or impairment. People with phobic disorders usually avoid whatever it is they fear—and that can lead to a very constricted life. If you have a specific phobia of enclosed spaces (claustrophobia), you may not be able to ride an elevator, travel by airplane, or have an MRI without panicking. If you fear social situations, you may avoid dating, eating in restaurants, going on job interviews, or participating in meetings. And if you’re afraid of having panicky feelings, you may avoid any situation where those feelings have occurred or where it might be hard to escape if they do—going to the mall, traveling over bridges, or even just leaving home.

The popular press has a fondness for coming up with names of esoteric phobias. Stick the word phobia onto any Greek or Latin root and presto—you’ve got a disorder: homichlophobia (fear of fog); chronophobia (fear of time); socerophobia (fear of in-laws); triskaidekaphobia (fear of the number thirteen); and so on. But as someone who’s been treating patients with anxiety disorders for nearly twenty years, I can tell you that these are not major public health problems. I’ve never seen a case of metrophobia (fear of poetry), let alone hippopotomonstrosesquippedaliophobia (fear of long words).

In reality, the most common fears and phobias have to do with dangers that we have been prepared to fear because they’ve been real threats throughout our evolutionary history: snakes, insects, and other dangerous animals, storms, heights, the sight of blood or injury, enclosed spaces, and social threats.

We can think of these kinds of threats as unconditioned fear stimuli—things we readily learn to fear because fearing them kept our ancestors safe.³⁶ Some of these—like the fear of heights and the fear of being separated from a caregiver—appear to be innate and ready to go the first time we ever encounter the threat. For others, we seem to be biologically prepared to learn them by fear conditioning.

CROCODILE FEARS

IN A SENSE, OUR TENDENCY TO PICK UP THESE FEARS IS ANOTHER example of experience-expectant learning: we’re innately tuned to respond to signs of danger, but we need some instruction about what’s really harmful and what isn’t.

In a series of experiments, psychologists Susan Mineka, Arne Öhman, and their colleagues have shown that primates are selectively biased to learn to fear certain things, and often do so by watching the reactions of others. Rhesus monkeys rapidly acquire fears of natural threats by watching their fellow monkeys—a process known as vicarious conditioning.³⁶ Monkeys in the wild have a fear of snakes, but lab-reared monkeys don’t, suggesting that some kind of learning is involved. If you show a lab monkey a video of another monkey reacting with fear to a toy snake or toy crocodile, the lab monkey quickly develops a fear of those animals.^37, 38 But when the video is doctored to make it look like the monkey was afraid of something that’s not naturally dangerous—flowers or a toy rabbit—the lab monkey doesn’t develop any fear. It’s as though the monkey’s fear-learning system is biased to pick up fears of natural threats but blind to phony ones.

The same kind of biased fear learning happens in human babies. If you present a snake to an infant, he or she is likely to be curious and unafraid—just like Little Albert was when he first encountered a rat. But infants as young as nine months will rapidly associate snakes with fear responses if they’re paired with the sound of a frightened voice.³⁹ And numerous studies have found that people can be conditioned to fear primal dangers (snakes, spiders, angry faces) much more easily and intensely than neutral stimuli (flowers, mushrooms, shapes) or even modern dangers (pointed guns, knives, damaged electrical outlets).³⁶

Phobias take hold when our normal fear-conditioning mechanisms—the same fear circuits that we all use to learn about danger—lock onto a perceived threat and don’t let go. For some people, a combination of genes and life experiences make that fear circuitry more sticky—they are particularly susceptible to picking up and holding on to fears that many of us would let pass. And they may not even recall an event that created their phobia of spiders or snakes.

PRISONERS OF WAR

THERE IS ONE ANXIETY DISORDER WHERE THE FEAR-CONDITIONING event is unforgettable. In fact, it’s one of the only disorders in all of psychiatry where a life experience is part of its very definition. I’m talking, of course, about posttraumatic stress disorder (PTSD).

The fact that trauma or extreme stress can cause debilitating anxiety and impairment became clear thanks to the oldest man-made disaster: war. After the American Civil War, physicians began recognizing long-lasting problems in soldiers who’d seen a lot of combat. In 1871 an army surgeon names Jacob Mendez Da Costa described a syndrome he called irritable heart (later known as Da Costa’s syndrome) among Civil War vets who seemed physically well but had bouts of chest pain, palpitations, shortness of breath, and exhaustion. One of Da Costa’s cases was an eighteen-year-old soldier who had “served with his regiment for one year, doing much marching and being much exposed. For a couple of months before he left it, he was frequently attacked at night with smothering or suffocating sensations, and with palpitations; and even prior to this had found it difficult to do his duty, and had signs of cardiac distress” (p. 21).⁴⁰

After World War I, tens of thousands of soldiers were crippled by what came to be known as shell shock—an incapacitating syndrome of panic, intrusive memories, nightmares, insomnia, and dissociation, which almost entirely captures the modern definition of PTSD. A typical case, reported in 1918 in the medical journal The Lancet hints at the torment these soldiers lived with. The victim was an officer who had been buried alive by the explosion of a shell, and later “collapsed altogether after a very trying experience, in which he had gone out to seek a fellow officer and had found his body blown into pieces, with head and limbs lying separated from the trunk”:

From that time he had been haunted at night by the vision of his dead and mutilated friend. When he slept he had nightmares in which his friend appeared, sometimes as he had seen him mangled on the field, sometimes in the still more terrifying aspect of one whose limbs and features had been eaten away by leprosy. The mutilated or leprous officer of the dream would come nearer and nearer until the patient suddenly awoke pouring with sweat and in a state of the utmost terror. He dreaded to go to sleep and spent each day looking forward in painful anticipation of the night. He had been advised to keep all thoughts of war from his mind, but the experience which recurred so often at night was so insistent that he could not keep it wholly from his thoughts, much as he tried to do so. (p. 174)⁴¹

Devastated by the brutal trench warfare of the Great War, as many as two hundred thousand soldiers were reportedly exempted from further duty as a result of shell shock.⁴² With each successive war, the story has been the same: thousands of young people carrying mental scars that would not heal.

As awareness of the syndrome grew, clinicians began recognizing it among victims of disasters, motor vehicle accidents, and violent crime. In the 1970s and 1980s two streams of cultural uproar brought the phenomenon of traumatic stress and its sequelae to center stage. The first was an apparent epidemic of psychological disability among Vietnam-era veterans (post-Vietnam syndrome), and the second was a growing conviction that childhood sexual and physical abuse were much more common and destructive than anyone had previously imagined. Advocates, families, and clinicians clamored for greater recognition of the scourge of psychic trauma. And so in 1980, when the DSM-III unveiled a new diagnostic system for psychiatry, the diagnosis of PTSD was formally born.

In addition to requiring that a person has suffered a terrifying traumatic event, the diagnosis involves three clusters of impairing symptoms that must persist for at least a month. The first of these clusters is known as reexperiencing symptoms. These are essentially trauma-related memories that come back and haunt the victim in the form of flashbacks, nightmares, unwanted recollections, or fear reactions triggered by cues that evoke the traumatic event. The second cluster of symptoms, known as avoidance and numbing symptoms, include efforts to avoid thoughts, activities, people, and feelings that remind the victim of the trauma. Victims may also feel emotionally numb or detached and have difficulty connecting with other people or imagining a normal future. And finally, there are hyperarousal symptoms, which resemble a state of persistent fear and alarm: insomnia, anger outbursts, trouble concentrating, hypervigilance, and exaggerated startle responses.

Despite widespread agreement that trauma can cause debilitating psychological symptoms, PTSD has become one of the most controversial and politically charged diagnoses in modern psychiatry. Even within the profession, some have criticized the diagnostic criteria for including symptoms that are common to many mood and anxiety disorder and not specific to traumatic causes,⁴³ or, on the other hand, may simply be normal reactions to major stress and not a disorder at all.⁴⁴

What’s more, the criteria for what constitutes a traumatic event have expanded over time. In the DSM’s current definition, a traumatic exposure requires that “the person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others,” and which evoked “intense fear, helplessness, or horror.”⁴⁵ The words confronted with had not appeared in prior editions of the diagnostic manual and opened the door to a much broader range of potentially traumatic experiences. For example, one can now qualify for a diagnosis of PTSD after having merely heard or read about a terrible event that happened to other people. The Harvard psychologist Richard J. McNally notes, “such secondhand exposure seems qualitatively distinct from being subjected to artillery bombardment for days on end while huddled in a muddy trench” (p. 231).⁴⁶ McNally believes that diluting the definition of trauma might make the PTSD diagnosis into such a heterogeneous mixture that it will be impossible to get a firm handle on what is going on at a psychobiological level: “it’s like nailing Jell-O to a wall,” he said.

But few question that major trauma can create conditioned fear reactions that are debilitating. There is increasing evidence that PTSD is not so much a disorder of fear learning, but one of fear extinction.⁴⁷ Virtually everyone can develop fears after a life-threatening trauma. What distinguishes PTSD is that the fears don’t go away.

UNFORGETTABLE IN EVERY WAY

AMY RAPPELL CAME TO MY OFFICE SEEKING HELP FOR ANXIETY. She was dressed in a business suit and spoke with a formality that I took as an indication of her discomfort at meeting with a psychiatrist. She had been having panic attacks that seemed to come on mostly at night. Her marriage of five years was falling apart, and she thought the first attack may have happened one night after her husband came home intoxicated and tried to pressure her to have sex.

Since then, the attacks occurred several nights a week. She and her husband were arguing frequently and had recently decided to separate. She denied having any symptoms of depression, except difficulty sleeping, and reported no prior history of anxiety problems or substance abuse. After an extensive review of her history and symptoms, she said that her only concern was getting relief from the panic attacks. Her busy schedule, she said, would make it hard for her to commit to psychotherapy, and she wondered if there was any medication that might help her. We tried an SSRI antidepressant, but after six weeks, she reported that the medicine only seemed to make her more jittery. We then began a trial of clonazepam, an antianxiety medication, and within two weeks, she reported that the panic had improved. Unfortunately, her recovery was short-lived: over the next month, she became increasingly depressed and again began experiencing daily anxiety attacks. But before we could address the problem, she stopped coming to her appointments.

Then one day a few months later, I received a call from a local hospital. “Dr. Smoller, this is Dr. Benham. We have your patient Amy Rappell here in our Emergency Room—she came in complaining of chest pain, but she’s ruled out for an MI [heart attack], and it looks like it was a panic attack. But she also tells us she’s been drinking daily for the past month, and she’s agreed to come in for detox.”

At our next meeting, Ms. Rappell told me the full story she had been too ashamed to confide before. The night her husband pressured her to have sex had reawakened terrifying memories of abuse she had suffered as a child at the hands of a family friend. She began having awful nightmares about the abuse, and almost every night she was flooded with unwanted memories that she couldn’t suppress.

The terror she felt was as intense as what she had experienced as a little girl, and she took to medicating her panic with alcohol. This would temporarily relieve her anxiety, but the horrifying memories would return and overwhelm her. She soon began drinking more and more, first to quell the anxiety, and eventually to achieve a nearly unconscious state that would finally blot out the fear memories.

She found that the fear and intrusive images could be triggered by anything that remotely reminded her of her childhood trauma—a crime drama on TV, an angry word from her husband, a dark room. She and her husband separated, and she found herself unable to sleep with the lights off. As her fear escalated, she installed a dead bolt lock on her bedroom and lay awake watching the door, her mind in the grip of memories so powerful that she now lived in a constant state of alarm, unable to distinguish the past from the present.

Thankfully, most of us will never experience the conspiracy of fear and memory that tormented Amy Rappell. And yet the suffering caused by PTSD and other anxiety disorders involves a subversion of the same emotional memory circuits our brains routinely use to remember which situations are safe and which we should fear.

In the case of PTSD, neuroimaging studies have found abnormalities in the activity of the ventromedial prefrontal cortex (vmPFC)—a key area in fear extinction learning. Research by my colleague Mohammed Milad at Massachusetts General Hospital has shown that people who are less able to overcome learned fears have thinner brain tissue and less activity in the vmPFC.^33, 48, 49 The vmPFC has a crucial role in teaching the amygdala that what we once learned to fear is actually safe. The hippocampus, in turn, helps retrieve these safety memories when we encounter reminders of the dangerous context. And so, just as we might expect, compared to healthy individuals, victims of PTSD have reduced activity in the vmPFC, smaller and less active hippocampi, and more highly reactive amygdalae (presumably because of less inhibition by the vmPFC and hippocampus).^{14, 32, 34} It’s as though the entire extinction circuit is dysfunctional: fear and startle reactions are more intense, and fears that were learned in one context now generalize to others that bear even vague connections to the trauma.

THE NATURE AND NURTURE OF ANXIETY

IF YOU THINK ABOUT IT, THOUGH, FEAR CONDITIONING CAN’T BE the whole story behind anxiety disorders like phobias and PTSD. We’re all exposed to heights, closed spaces, and spiders, but most of us don’t develop phobias. More than 60 percent of Americans are exposed to trauma at some point in their lives, including physical assault, life-threatening accidents, and the sudden loss of a loved one.⁵⁰ Trauma is even more common in areas of the world that have been ravaged by war, ethnic conflict, and natural disasters, such as the Middle East, Asia, and Africa. And yet most people who experience trauma don’t develop PTSD. For example, the lifetime rate of PTSD in the United States is about 7 percent, roughly one-tenth the proportion of people who experience traumatic events.²⁸

So being exposed to something frightening or even traumatic is not enough to cause an anxiety disorder. The obvious question then is what makes some people vulnerable to the transformation of normal fear and anxiety into disorder?

The answer is not entirely clear, but the evidence brings us back to the intersection of genes and experience. Studies have shown over and over that all the anxiety disorders run in families. For example, first-degree relatives (siblings and children) of people with phobias are about five times more likely to develop a phobia compared to relatives of people without the disorder. The same is true of panic disorder, agoraphobia, social phobia, generalized anxiety disorder, PTSD, and obsessive-compulsive disorder.⁵¹ Twin studies find that the heritability of all of these anxiety disorders is about 25 to 45 percent.⁵² At the same time, because the heritability is not 100 percent, environmental factors, including life experiences, must explain an even larger share of the vulnerability.

The leading theory of how these genetic and environmental influences make some people vulnerable and others resilient is often called the “stress-diathesis” model.⁵³ The word diathesis refers to an underlying predisposition. The idea is that there’s broad range of normal variation when it comes to fear and anxiety, but some of us, by virtue of our particular genetic endowment and life histories, are more sensitive to threat and prone to experiencing anxiety than others. When we encounter threatening experiences, those of us on the higher side of anxiety-proneness are susceptible to more intense and persistent anxiety symptoms. In other words, the combination of an anxiety-prone diathesis and stressful life events results in a tendency to go from normal anxiety to pathologic anxiety.

Anxiety-prone people often have a cognitive bias that makes them see danger where others might not.⁵⁴ Their attention is more easily drawn to any sign of threat, and they have a heightened sensitivity of brain regions involved in fear conditioning and emotion processing—especially the amygdala, insula, and prefrontal cortex.^55–62 And that seems to be part of the story of how variations in our genes cause variations in our emotional response to life—including how anxious and fearful we tend to be.

In Chapter 2, I told you the story of how my colleagues and I found that a gene called RGS2 is associated with anxiety proneness in children as well as hyperreactivity of the amygdala and insula when people look at fearful and angry faces.⁶³ A large number of studies have found similar effects for a variant of the serotonin transporter gene (SLC6A4) that seems to affect anxious temperament in animals from mice to monkeys to humans.^64–67 As I explained in Chapter 2, the protein made by this gene is the target of SSRI drugs that are widely used to treat anxiety disorders and depression.

There is a common genetic variant in the promoter of the gene that affects how actively the gene is expressed. The short allele version is missing forty-four base pairs of DNA compared to the long allele. These missing base pairs makes the serotonin transporter gene less active. Brain-imaging studies have shown that people who carry the short allele have a greater amygdala reaction when they look at emotional faces—especially fearful faces.⁶⁸ Moreover, the short allele has been associated with weaker connectivity between the amygdala and a region of the prefrontal cortex important in inhibiting the amygdala and extinguishing fear.⁶⁹ In other words, those of us who carry this specific genetic variant may have more difficulty controlling fear and anxiety reactions.

A similar story is emerging for a gene called BDNF, which makes brain-derived neurotrophic factor, a protein that promotes the growth and health of neurons. When animals are exposed to stress, BDNF levels increase in the hippocampus, where it has stress-buffering and antidepressant effects.^* BDNF also plays a critical role in fear learning, extinction, and memory in the amygdala, prefrontal cortex, and hippocampus by promoting synaptic plasticity,^71, 72, 73 and BDNF injections into the medial prefrontal cortex have been shown to extinguish conditioned fears in rats.⁷⁴ Several studies have now shown that people carrying a single variation in the DNA sequence of this gene have higher levels of anxiety proneness, amygdala reactivity, and impairments in memory, including fear extinction memory. The DNA variation causes one amino acid, methionine, to be substituted for valine in the BDNF protein and seems to be common among people of European-American ancestry.

In 2006 a team led by scientists at Cornell Medical College reported a remarkable experiment that directly linked the BDNF valine/methionine variation to anxiety proneness. Using genetic engineering, they inserted the human methionine allele (Met-allele) into a line of mice, creating animals that carry this single human DNA change.⁷⁵ Sure enough, the met-allele^* mice had increased stress-related anxiety behavior and impairments in memory—the same thing that had been reported in humans carrying this genetic variant.

Then, in 2010, the researchers performed fear-conditioning experiments with both the BDNF-met mice and with a group of human volunteers.⁷⁶ Both the mice and humans carrying the met allele had impaired fear extinction. The researchers then put the human subjects in an fMRI scanner during extinction learning, and discovered that the Met carriers had reduced activity in the ventromedial prefrontal cortex (vmPFC) and increased activity in the amygdala—exactly what we would expect because we know that fear extinction involves inhibition of the amygdala by the vmPFC. So here is a specific genetic variation that seems to increase anxiety proneness and interfere with letting go of fear by weakening the brakes on our fear circuitry.

The search for genes that affect anxiety proneness is an ongoing challenge. So far the few genes that have been found explain only a tiny fraction of the heritability estimated from twin studies. And that’s what we’d expect given that anxiety proneness and anxiety disorders are very complex and probably involve many (perhaps thousands) of genes that have small effects on their own. But these early results suggest that genes operate by subtly biasing the sensitivity of brain circuits involved in perceiving and processing fear and other emotions—adjusting the lens of salience through which we experience the world around us.

As we saw in Chapter 3, however, life experience can have the same effect. It’s now clear that experiences in childhood also shape how our brains process emotions and stressful life events. Child abuse, neglect, and other forms of adversity can have lasting effects on how anxious and fearful we become, especially if they occur during sensitive periods of brain development when thresholds for detecting threat and regulating our emotions are being set in the emotional circuits of our brains. Recall that early adversity can modify the chemistry of our chromosomes, causing epigenetic changes that may program anxiety and stress hormone responses in long-lasting ways that sensitize fear circuits. Epigenetic effects on BDNF gene expression, for example, can affect how tightly an animal holds on to fear memories.⁷⁷

For some of us, our genes may contribute to anxiety problems by actually increasing the chance that we’ll be exposed to dangerous situations. One twin study of Vietnam veterans found a heritability of 35 to 47 percent for exposure to combat-related trauma—that is, the likelihood that a soldier would find himself in harm’s way was itself influenced by genes.⁷⁸ Another study of civilians found that exposure to assaultive trauma, such as being the victim of a mugging, or sexual assault, had a heritability of 20 percent.⁷⁹

How could a person’s genes affect whether she would be in the wrong place at the wrong time? The most likely answer is again related to temperament and personality. Genes that contribute to risk-taking, seeking out new experiences, and even antisocial traits may increase the chance that you’ll find yourself in situations where trouble happens.⁸⁰

BOUNDARY VIOLATIONS

THERE’S AN INTERESTING IMPLICATION TO THE IDEA THAT VULNERABILITY to anxiety disorders begins with a general exaggeration of normal fear and anxiety systems. If that idea is true, we ought to see a lot of overlap in the biology of different anxiety disorders. The numerous anxiety disorders should share features with one another and with normal temperamental variation in anxiety proneness. And that’s exactly what the evidence shows.

It turns out that the genes that influence anxious personality and a broad range of anxiety disorders overlap substantially.^81–83 And there’s strong overlap at the level of brain function as well. Recall that neuroimaging studies find that healthy but anxiety-prone people have heightened reactivity of the amygdala when they’re presented with emotional stimuli—especially fearful faces.^56, 84 The same is true of people with a broad range of anxiety disorders: specific phobias, social anxiety disorder, agoraphobia, panic disorder, generalized anxiety disorder, and PTSD.¹⁴ Perhaps it’s not surprising then that the major treatments for anxiety disorders—antidepressants and cognitive behavioral therapy—tend to work for all anxiety disorders.

That’s not to say that all of these different anxiety disorders are really just different names for the same thing. They have different constellations of symptoms and a variety of different risk factors. But it does suggest that a clear boundary between normal and abnormal anxiety and even between the various anxiety disorders may be impossible to draw.

TAKE BACK THE FRIGHT

UNDERSTANDING THE BIOLOGY OF FEAR AND ANXIETY MAY HELP US understand how anxiety disorders develop. But for people afflicted with these disorders and those of us who try to help them, the real hope is that we can use this knowledge to improve treatment. In the last several years, psychologists, psychiatrists, and neuroscientists have come together to make good on that hope. Using insights from the molecular neuroscience of emotional memory, researchers and clinicians are developing methods to prevent, suppress, and perhaps even erase traumatic fears and painful memories. The results, though preliminary, are startling.

As we’ll see, each of these strategies exploits the biology of emotional memory to try to hack into the system and use it to our advantage. The first tries to use medications to block traumatic memories from taking hold to begin with. The second offers a drug that can boost the effects of psychotherapy to help extinguish fears that already exist. And the third hijacks the molecular basis of memory to rewrite a painful past.

FIRST RESPONDERS

WHAT IF WE COULD HAVE PREVENTED AMY RAPPELL’S TRAUMA from gelling into an indelible memory? Imagine the pain and suffering she would have been spared.

After a traumatic event, there’s a brief window of time before the fear becomes entrenched as a memory, and that creates an opportunity to intervene. One way to do that might be to quell the storm of stress hormones that prime the amygdala to generate fear memories.

The emotional arousal that accompanies stress and trauma involves a surge of epinephrine (adrenaline, from the adrenal glands) and its chemical cousin norepinephrine that act on the amygdala and help fuel the cascade of cellular events that consolidate emotional memories.⁸⁵ Drugs that trigger or mimic norepinephrine release in the brain enhance fear conditioning in rats and bias the amygdala toward threat in humans,^86, 87, 88 while drugs that block norepinephrine interfere with remembering emotionally charged events.⁸⁹

That kind of evidence suggested a bold idea to Harvard psychiatrist Roger Pitman and his colleagues—what if we could block the stress hormones that help etch traumatic memories into our synapses?

The drug propranolol has been used for decades to treat high blood pressure by blocking receptors for epinephrine and norepinephrine. These receptors are known as beta-adrenergic receptors, and so drugs like propanolol are referred to as beta-blockers. Propranolol is also well known to musicians and actors as a pill that can relieve stage fright—mainly by quieting the pounding heart, shaky voice, and tremulous hands that let people know you’re nervous.

Over the course of ten days, Pitman and his colleagues gave either propanolol or a placebo to patients who came to the emergency room at Massachusetts General Hospital after experiencing car accidents and other traumatic events.⁹⁰ Three months later, when the researchers reexamined the patients for symptoms of PTSD and physiological responses while recalling the traumatic event, those who had received propranolol had significantly lower stress responses. The implication was powerful: by interfering with the brain’s normal tendency to create powerful memories of stressful events, a commonly used blood pressure drug could spare trauma victims the pain of unforgettable fears. The jury is still out on just how effective propranolol really is, but the possibility of protecting the emotional brain from psychic trauma is an exciting one.

One reason that it may prove difficult to actually prevent the formation of traumatic memories has to do with timing. Our brains are very good at learning to fear things that are life-threatening. In the face of overwhelming stress—like a physical or sexual assault—the window for blocking memory consolidation may close quickly. Interfering with that process might require intervening within minutes of exposure to the danger. By the time a victim gets to an emergency room, it’s probably too late. Even if propranolol proves to be protective, it may just be unfeasible to get it into the brain before the window of conditioning closes for most people.

The importance of haste in blocking memory consolidation was clear in a study of nearly seven hundred Iraq War military personnel who had been severely injured on the battlefield by IEDs, gunshots, mortar, or rocket-propelled grenades.⁹¹ It’s common for injured soldiers to be given IV morphine to treat their pain early in the course of their emergency medical care. Pain is known to trigger an outpouring of stress hormones like epinephrine and norepinephrine, and there’s evidence that morphine, like propranolol, can interfere with memory consolidation by a beta-blocking effect.

The authors of the military personnel study wondered if the morphine might have a protective effect against developing PTSD. When they compared those who got morphine to those who didn’t, the effect was dramatic. Within two years of their injury, the incidence of PTSD was nearly cut in half among those who got morphine. And, importantly, more than 70 percent of those who were treated with IV morphine got it within an hour of their trauma. We don’t know for sure what would have happened if the morphine had been delayed, but it’s likely that immediate treatment made a difference.

THE PETER PRINCIPLE

OF COURSE, FOR PEOPLE WHO ALREADY HAVE PTSD, PREVENTION is not an option. Fortunately, our memories are not written in stone but in synapses, and synapses are plastic. Just as we can learn to fear, we can also learn not to fear—that’s what fear extinction is all about.

One of the oldest and most effective treatments for anxiety disorders is all about fear extinction. With the case of Little Albert, behaviorists established that fears and phobias can be learned. Four years after Watson’s “success” in terrorizing Little Albert, another American psychologist, Mary Cover Jones, reported the first successful use of conditioning to eliminate fear. Her first subject was a three-year-old boy named Peter who, like Albert, had developed a fear of a white rabbits. Jones and her team repeatedly exposed Peter to the rabbit while at the same time giving the boy food and candy. After a series of these sessions, Peter’s fear was gone.⁹²

Beginning in the 1950s, psychiatrists and psychologists began developing more formal therapies that moved behaviorism from the laboratory to the clinic. If fear reactions can be learned by so-called classical (Pavlovian) and operant (Skinnerian) conditioning, these new therapies showed that they can be conquered the same way. By gradually exposing a phobic patient to his worst fear in a safe context, the fear loses its power.

In the 1970s a psychiatrist named Aaron Beck at the University of Pennsylvania developed a variant of behavior therapy that he called cognitive therapy. The idea was to teach patients to recognize and challenge the automatic thoughts and faulty assumptions that were causing and perpetuating their problems. In the 1980s a merger of sorts occurred and cognitive-behavior therapy (CBT)—combining the active ingredients of both cognitive therapy and behavioral approaches—became increasingly popular.

From the perspective of modern neuroscience, we can think of behavior therapies and CBT as techniques that help extinguish painful emotional memories. By systematically desensitizing the patient to what he fears and reframing his catastrophic thoughts, CBT allows him to form safety memories where there were only fear memories. Gradually exposing someone to a feared (conditioned) stimulus in a safe setting extinguishes fear. When this treatment is successful, it’s also been shown to normalize amygdala reactivity when people are later shown the thing they most feared.⁹³

Over the past twenty-five years, a mountain of studies has established that behavior therapies, including CBT, are effective treatments for a broad range of anxiety disorders as well as depression, eating disorders, addiction, and even psychotic disorders. In fact, behavior therapies are the only treatment shown to provide lasting benefit for all the anxiety disorders, with success rates on the order of 50 to 80 percent.

In the months after Amy Rappell revealed the secret she had been keeping—the trauma that had hijacked her mind and revisited her in terrifying waves of panic—we struggled together to find a way to quiet her fears. When I recommended a course of CBT, she balked, saying she had tried therapy before and it had only made her feel worse. She was afraid that any kind of therapy would mean she would have to relive her trauma and that would be too frightening to bear. “I just need to forget,” she told me with a desperate look. We tried a series of medications—antidepressants, anticonvulsants, even antipsychotics—but any relief she found was short-lived. Finally, exhausted and nearly hopeless, she agreed to see the cognitive-behavioral therapist I’d referred her to.

We met again after she had completed her first month of CBT. Those first weeks had been difficult, and she confessed that she’d been on the verge of quitting before every session. I told her I admired her strength in persisting despite her impulses to quit and tried to reassure her that the feelings she had were not uncommon. We needed to help her stay with the treatment long enough for it to have a chance of working.

After a second month of treatment, she seemed to be making progress. She was sleeping through the night. Her bedroom door was unbolted. And then, when we met two months later, something had clearly changed. She looked different somehow. As I talked with her, I realized that I was seeing her face without the mask of tense vigilance that had covered it like a taut film for so long. She told me she was finally free of panic attacks and was able to focus on her work again. She’d even spent the weekend away, visiting friends for the first time since she and her husband had separated.

After five months, Amy completed the CBT, confident that she had been able to put the past in its place. In the years that have followed, that confidence has sometimes been shaken. Once, after she unexpectedly ran into the son of the “family friend” who’d been the source of her pain, the panic came back in full force, along with a relapse of drinking. She resumed CBT and was able to regain her balance. Today, she is doing well, thankful for the truce between her past and present but mindful that it may be provisional.

TURBO-CHARGED THERAPY

WHAT IF THERE WERE A WAY TO BOOST THE EFFECT OF BEHAVIOR therapy by exploiting the biology of emotional memory? Imagine a drug that could help extinguish pathologic fears.

Recall that fear extinction involves new learning and that, at a molecular level, this learning depends on synaptic changes that occur when the neurotransmitter glutamate activates NMDA receptors in the amygdala and prefrontal cortex. If you want a drug that could boost fear extinction, glutamate (or something like it) would be an obvious choice. The problem is chemicals that mimic glutamate itself can be toxic to the brain.

Fortunately, Emory University neuroscientist Michael Davis and his colleagues found another way. Davis, who had been one of the pioneers in defining the biology of fear extinction in rats, knew that glutamate needs a partner to do its job. Glycine, another neurotransmitter (or its cousin d-serine), has to bind to the NMDA receptor at the same time as the glutamate. In 2002 the Davis lab reported that directly infusing d-cycloserine (DCS), a drug that mimics glycine and d-serine, into the amygdala can enhance extinction learning in rats; that is, it helps them to let go of fear.⁹⁴ Obviously that strategy won’t work in humans because no one would agree to have amygdala injections (if it were even possible). But their results were exciting because DCS pills had been safely used in humans since the 1950s. Through an entirely different mechanism, DCS acts as an antibiotic and had long been used as a fallback drug for the treatment of tuberculosis.

Kerry Ressler, a psychiatry resident working in the lab at the time, had a hunch. If behavior therapy works for anxiety disorders by extinguishing fears, maybe DCS could make behavior therapy even more effective. Ressler, now a professor at Emory, and his colleague Barbara Rothbaum treated twenty-seven volunteers who had a phobia of heights (acrophobia) with virtual reality behavior therapy.⁹⁵ Before the treatment started, the subjects were randomized to receive either DCS or a placebo and told to take the pill about two to four hours before their therapy sessions. During the therapy sessions, subjects wore a virtual reality helmet that simulated the experience of being in a moving glass elevator. From inside the elevator, they could look down over a virtual railing. The therapy consisted of gradual exposure and desensitization to (virtual) heights. Each subject had two therapy sessions two weeks apart—a lot less than the usual two-month course needed to treat phobias.

At the end of the treatment, the results were clear. The DCS group had extinguished their fear of heights with only two sessions while the placebo group were still quaking in their virtual boots. Three months later, when the researchers had the subjects return and repeat the virtual elevator experience, the DCS group remained cured of their phobias. And the benefit wasn’t just in the virtual reality world—the DCS group had significantly decreased their avoidance of heights in the real world.

As word about the success of DCS-enhanced behavior therapy got around, other researchers put it to the test. Clinical trials have now shown that DCS can improve outcomes in a broad range of anxiety disorders that are traditionally treated with behavior therapy and CBT including obsessive-compulsive disorder, panic disorder, social anxiety disorder, public speaking phobia, spider phobia, and even dental phobia.^96–102

Consider for a moment what we’re talking about here: a drug that you could take before a therapy session to make the therapy work faster and better. There is one caveat about using DCS to turbo-charge psychotherapy—it has to be given intermittently. It turns out that the brain adapts quickly to DCS, so daily dosing won’t work. But that fits well with its use to augment psychotherapy, which is typically conducted on a weekly basis—a long enough interval to prevent the development of tolerance to the drug.

There’s still work to be done to better understand how and when DCS should be used, and so far, it’s not FDA-approved for the treatment of any psychiatric or emotional conditions. Still, if the early studies hold up, the DCS story will stand as a remarkable example of how understanding the biology of fear and memory can translate into therapeutic discoveries.

THE SPOTLESS MIND

RECENTLY, NEUROSCIENTISTS HAVE BEGUN TO PUSH THE ENVELOPE of conquering fear and anxiety even further by trying to delete memories that cause fear and anxiety. Behavior therapy can extinguish fears but it doesn’t erase them because fear extinction just creates a new memory of safety that inhibits the old memory of threat. But the original memory hasn’t gone away. Our deepest fears can still lurk in our synapses, even after we’ve subdued them. Under the right circumstances, when the original stimulus and context align or when you’re under stress, they can return.

But what if we could free ourselves of painful emotional memories—not just suppress them, but get rid of them? That was the premise of the 2004 film Eternal Sunshine of the Spotless Mind. The title was taken from Alexander Pope’s poignant poem Eloisa to Abelard about the epic, but illicit, romance between Heloise and the great scholar Pierre Abelard. After her vengeful uncle arranges for Abelard to be castrated, Heloise flees to a convent, where she is tormented by her separation from her lover and teacher. In Pope’s poem, Heloise is left only with her memories of their love and prays that she can find relief by forgetting.

Of all affliction taught a lover yet,

’Tis sure the hardest science to forget!

If only their illicit love had never been, she would have been spared her endless longing and could have had the peace of mind that innocent souls enjoy:

How happy is the blameless Vestal’s lot!

The world forgetting, by the world forgot:

Eternal sunshine of the spotless mind!

In the 2004 film, scientists at a commercial outfit called Lacuna, Inc. have perfected a technique for “the focused erasure of troubling memories.” The introverted and emotionally subdued Joel (Jim Carrey) signs up after he’s wounded by the news that his vibrant but impulsive ex-girlfriend Clementine (Kate Winslet) has already erased him from her mind. The procedure begins with a detailed interview at the Lacuna offices during which Joel is asked to bring in mementos of the relationship. He’s asked to recount the details of their love affair, which Lacuna uses to create a detailed brain map of his memories. Later, technicians will hunt down and zap away the memories using some kind of MRI technology. The film doesn’t bother much with scientific details—it’s a fantasy after all.

At least so far. In the few years since the movie’s release, scientists have begun to explore the possibility of rewriting our emotional past. The groundwork that made this possible was a surprising set of discoveries about how we remember. The common view of how memories are formed is analogous to how a computer stores files: like saving a document to a hard drive, our brains store a memory so that it can be retrieved when we need it. Calling up the memory is like opening and reading the saved file.

But that’s not what really happens. In fact, remembering is a dynamic process, in which a memory is re-created each time we retrieve it. As Harvard psychiatrist Roger Pitman put it, “when you remember something, you don’t remember what originally happened; what you remember is what you remembered the last time you remembered it. Each time you destabilize a memory by remembering it, you are updating it and changing the memory. So theoretically it’s impossible for us to ever remember something that originally happened to us. All we’re remembering is what we remembered the last time, which in turn is what we remembered the time before that, and so on. Memory is continually being sculpted.”

So when we retrieve a memory, it becomes unstable. To use the computer analogy, it’s as though we’ve called up the file and begun working on it again. The memory has briefly entered a vulnerable or labile state—like a computer file that’s in temporary (RAM) memory. If we don’t save (“reconsolidate”) it again, it can be lost.^*

The fragility of our memory seems like a problem. Why would natural selection have allowed for our minds to change or erase information that we presumably needed to remember? Perhaps because it also allows us to update our memories—to incorporate new information about changes in the world around us. Whatever the reason, this fragile window of memory formation may work to our advantage when the past is too much with us. For the victim of PTSD, there are some memories that may be better lost. The idea of erasing a traumatic memory would be like getting the memory into RAM and then corrupting the file before it can be saved again. But is such a thing really possible?

It turns out that the synaptic changes involved in reconsolidating memories require that neurons make new proteins. And it’s during this process that memories are in the vulnerable state. Once the protein synthesis is completed—within a few hours—the memory is reconsolidated (saved to the hard drive, if you will).

In a set of experiments published in 2000, NYU neuroscientists Karim Nader, Glenn Schafe, and Joseph LeDoux reported that they could disrupt memory reconsolidation of conditioned fears by injecting rats at just the right moment with a drug that interferes with protein synthesis. They had effectively erased the fear memory by hacking into the amygdala during the reconsolidation window. That was an exciting discovery, but it involved infusing a potentially dangerous drug directly into the amygdala. Not exactly an option for clinical use. In the years that followed, other researchers reported success in erasing fear memories in rats by equally dramatic measures, including poisoning amygdala neurons that had encoded the fear.¹⁰³

Then in 2009 LeDoux and his colleagues hit on a much safer alternative. Their idea was to evoke the fear memory, bringing it into the reconsolidation window, and then overwrite it by extinction learning.¹⁰⁴ Using a classic paradigm, they conditioned rats to fear the sound of a tone that had been paired with a shock. Then they divided the rats into three groups. For the first (early retrieval) group, they played the tone once, waited for up to an hour, and then performed the usual extinction procedure by presenting a series of the tones without the shock. The idea was that the isolated tone would evoke the memory, bringing it into the fragile state, and then they could overwrite it with extinction learning before the reconsolidation window had closed. The second (late retrieval) group got the same treatment as the first but instead of waiting an hour between the isolated tone and extinction, they waited at least six hours (by which time the reconsolidation window would have closed). And the third (control) group were simply put back in the conditioning cage without any tones or shock.

The results were fairly astounding. When they tested the rats a day later, the fear had been extinguished in all three groups. But when they retested the rats after a month, the fear had spontaneously returned for the late retrieval group and the control group. Not so for the early retrieval group—their fear was gone. In other words, by extinguishing the fear during the reconsolidation window, the researchers had rewritten the fear memory as a safe memory. They had, in effect, erased the fear.

The next question was whether something like this could work in humans. In 2010 LeDoux, Elizabeth Phelps, and their colleagues showed that it could.¹⁰⁵ Just as they’d done with rats, the scientists created a conditioned fear response in human volunteers and then eliminated the fear memory by performing extinction training within minutes of retrieving the memory. A comparison group who underwent extinction six hours after the memory was evoked (after the reconsolidation window had closed) had their fear return. And the difference was still there a year later.

Another team of researchers has now achieved the same effect—effectively erasing fear—by giving subjects propranolol during the reconsolidation window.^106, 107 It turns out that propranolol may act by indirectly inhibiting the protein synthesis required for memory reconsolidation.

In actuality, these techniques don’t erase the memory entirely. They preserve what’s called “declarative memory”—that is, the simple ability to recall that an event occurred. But they decouple the event from the emotion that was attached to it. Thinking back to the turbulent airplane ride example, you would presumably recall that you experienced a rough ride, but the fear you felt would be gone. It’s analogous to what happens when you remember a stomachache—you might recall that you had a pain in your belly, but the visceral experience of pain itself is hard to re-create in your mind.

Still, this is heady stuff. Rather than simply suppressing fears, these studies suggest that we can use behavioral treatments or drugs to actually delete them. Much work remains to be done before something like these techniques could be offered to people suffering from PTSD. For one thing, these studies used simple conditioning methods and mild fear stimuli in a laboratory setting. It’s not at all clear that the kind of intense, real-world trauma that leads to PTSD could be overwritten in the same way. But the stage has been set to find out.

Beyond the remarkable scientific achievement, these studies raise a more intriguing question about who we are and how far we want to go in altering our memories. If someone offered you the chance to erase an emotional memory of your past, would you take it? Victims of PTSD, for whom the past has become a prison, might welcome that chance. But in principle, the same techniques that might erase the pain of trauma could be used to scrub other life experiences of their emotional residue. How much of ourselves would we lose in the process? Many of our most meaningful experiences draw their beauty from indivisible shadings of shadow and light. Love entails loss, redemption can only follow a fall.

After they have been estranged by amnesia, Joel and Clementine find each other again and learn that they had both erased the hurt of their shared past. And yet, fully aware of the pain it may bring, they fall in love again. It’s worth it.

A REMEMBRANCE

IN THE CENTURY SINCE LITTLE ALBERT FIRST LEARNED TO FEAR rats and rabbits, the science of emotional memory has taken us from behavior to the molecular biology of the cell. By unraveling the mysteries of normal fear and anxiety, we are beginning to understand how anxiety can overwhelm the mind and how it can be quieted.

But as the science marched on, another mystery hung in the air: whatever happened to Little Albert, the infant who started it all? Watson’s case study of Little Albert was the last research paper he published, creating what has been called “one of the greatest mysteries in the history of psychology” (p. 605).¹⁰⁸ Did Watson ever try to decondition Albert’s fear or did he live out his days with a phobic fear of furry animals? Did he even know about the contribution he’d made to modern psychology?

In 2009 psychologist Hall Beck and his colleagues revealed that they had solved the mystery. After several years of painstaking detective work, they concluded that Albert’s real name was Douglas Merritte. He was the son of an unwed young woman who was the wet nurse at the Harriet Lane Home mentioned by Watson. Sadly, the record shows that little Douglas’s life was painful and brief. In 1922, at the age of three, he developed hydrocephalus and died three years later. As Beck wrote, “Our search of seven years was longer than the little boy’s life.”

But as we’ve seen, Albert’s legacy lives on. His fate is both poignant and fitting for a little boy whose story was so important to the study of emotion and memory: gone, but not forgotten.

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* On the other hand, BDNF has pro-depressant effects in reward centers of the brain.⁷⁰

* A word on notation: the methionine allele is abbreviated “Met” in humans and “met” in mice.

* It would be as though you started writing a book chapter and worked on it for hours and then your computer crashed and you realized you hadn’t saved it and you started pounding the table and yelling “What the hell is the matter with this !@#*ing thing!” and everyone in Starbucks turned and looked at you like you were out of your mind. It can happen.