The neurobiology and psychology of fear

[David Baxter PhD]

The neurobiology of fear
Neurophilosophy Blog
October 31, 2007

Fear, that most primitive of emotions, is good, at least when it is kept under control. It is essential for survival, allowing an organism to detect a potential threat to its life. Too much fear, however, can lead to pathological conditions such as anxiety, phobia, paranoia, or post-traumatic stress disorder.

The neural circuitry which processes information about fear is well mapped, but otherwise, little else is known about the biological basis of this emotion. In recent years, however, neuroscientists elucidated some of the cellular and molecular mechnisms underlying fear. A greater understanding of these mechanisms could lead to new treatments for various neuropsychiatric conditions.

Although the word fear is hard to define, everyone knows how it feels to be afraid. The physiological response to fear is called the 'fight or flight' response, or the 'acute stress response', and was first described by the American physiologist Walter B. Cannon in the 1929. The response is caused by the actions of adrenaline, noradrenaline and the steroid cortisol, whose release is triggered by the sympathetic branch of the autonomic nervous system: heart rate increases and breathing speeds up; pupils dilate to let in more light, enabling one to see better; metabolism of fat and glucose in the liver increase to provide the energy that might be needed to escape; production and release of endorphins is stepped-up; and the brain's decision-making centres become primed for action.

Fear can broadly be characterized into two types. Conditioned fear is the process by which an insignificant and otherwise harmless stimulus becomes, by association, a sign of danger. The association between an innocuous stimulus and a fear response can easily be induced by classical conditioning, in which the stimulus is repeatedly associated with something scary, until the stimulus itself is feared. In contrast, unconditioned fear is not learnt, but, rather, is 'instinctive', and can be regarded as an evolutionary relic - we sometimes fear what our ancestors feared.

The amygdala, a small, almond-shaped part of the brain, is known to be involved in emotions, including fear. It is also involved in the recognition of facial expressions and, therefore, of other peoples' emotions. People with damage to the amygdala have difficulty recognizing facial expressions in others. Last year, researchers at the National Institute of Mental health reported that teenagers with bipolar disorder may misread the facial expressions of others; when asked to rate the hostility of a neutral facial expression, the amygdala was shown to be more active these teenagers than in others without the condition. Imaging studies show that, when people are presented with phobia-specific stimuli, the amygdala is activated more rapidly in those people with that particular phobia than in others without it.

The amygdala is part of the limbic system, a complex set of structures that includes the thalamus (or "deep chamber"), the hippocampus, hypothalamus, and olfactory bulb. It is attached to the anterior of hippocampus, and is involved, among other things, in encoding and consolidating memories of fearful experiences. The amygdala receives its main inputs from the visual, auditory and somatosensory cortices, and its main outputs are to the hypothalamus, which controls hormone production and homeostasis, and autonomic centres in the brainstem. The amygdala therefore couples these sensory stimuli (something scary) to the fight-or-flight response.




Most investigators now believe that the association between conditioned and unconditioned stimuli that occurs in fear conditioning involves synaptic plasticity in the amygdala. That is, learning the association between the stimuli requires the strengthening of connections in the lateral nucleus of the amgydala, which consolidates the memory of the association.


Neurons in one part of the lateral amygdala (the dorsal subnucleus) exhibit the sort of properties that would be required for fear conditioning. These cells receive inputs from sensory regions of the thalamus, and also from the cerebral cortex. The former inputs encode conditioned stimuli (e.g. a specific sound), and the latter encode unconditioned stimuli (e.g. an electric shock that becomes associated with that sound).

Because these different inputs converge on the same neurons, the response of the cells is enhanced when both the conditioned and unconditioned stimuli are presented together. This plasticity is short-lived, however. Once the association has been extinguished, and the animal no longer fears the conditioned stimulus, the responses of an adjacent group of cells become enhanced instead. This may explain why fears that have been treated successfully can sometimes come flooding back after a stressful event.


It was known for some time that the encoding and consolidation of fearful memories can be blocked by inhibiting protein synthesis in the amygdala, but it was not clear which proteins are involved. Recently, however, Gleb Shumyatsky and his colleagues at Rutgers University in New Jersey discovered several genes that are highly expressed in the amygdala, and which appear to be involved in this process. One of these encodes a protein called stathmin (also known as oncoprotein 18), which is now known to be involved in mediating the formation of memories of both conditioned and unconditioned fear. There is a high level of expression of the stathmin gene, and a corresponding high concentration of stathmin protein, in the amygdala, but not in the adjacent hippocampus.


Mutant mice lacking the stathmin gene were unable to learn new fears or to act instinctively in a fearful situation, i.e. they had weaker memories of fearful experiences. The stathmin knockout mice also showed less anxiety when presented with new mazes to explore or with potentially dangerous situations. Upon further examination, it was observed that mice lacking the stathmin gene had a less dynamic microtubule network than wild type (normal) mice. Memories are formed by the establishment of new synaptic connections, which require a re-arrangement of microtubules. In the absence of the stathmin protein, microtubules aren't re-arranged so easily, and, as a consequence, the synapses that would normally be modified during memory formation are not as plastic as they should be.

More recently, researchers have used functional magnetic resonance imaging (fMRI) to show that the rostral anterior cingulate cortex (rACC) modulates activity in the amygdala, effectively acting as an 'on-off' switch. Joy Hirsch and her colleagues at Columbia University used a variant of the Stroop test, which involves presenting words for colours, which are printed in a colour that differs from that of the meaning of the word (e.g. green). This discrepancy leads to a delay in the processing of the visual information, increasing the reaction time taken to perform the task.

Instead of using words, Hirsch's team presented participants in their experiments with photographs of happy or scared faces with the word 'HAPPY' or 'FEAR' written across them. It was found that the amygdala was activated before the rACC when the participants were presented with a happy face with the word 'FEAR' printed across it. Soon afterwards, though, the activity in the amygdala would be reduced. That is, initially, the amygdala processes the word 'FEAR', but, soon afterwards, the rACC processes the happy face, and inhibits activity in the amygdala to reduce the fear response. In contrast, when participants were presented with a photograph of a scared face which had the word 'FEAR' written across it, the rACC remained inactive, while activity in the hippocampus persisted for longer.

When we are faced with fearful stimuli but know that we are not in danger, the fight or flight response produced by fear can be enjoyable. Hence, people enjoy taking part in extreme sports such as bungee jumping or sky-diving. This is also why some people enjoy watching horror films. The ability to enjoy fear enables us to try new activities, to explore novel environments, and to be daredevils. Although we have gained some understanding of the neural mechanisms underlying fear and other emotions, this understanding is very basic, and much remains to be discovered. Further insights into how the brain processes fearful information will provide new methods, both cognitive and pharmacological, for treating conditions in which fear has become pathological, such as post-traumatic stress disorder.


References:

• Larson, C. L., et al. (2006). Fear is fast in phobic individuals: Amygdala activation in response to fear-relevant stimuli. Biol. Psychiatry 60: 410-417. [Full text]
• Nader, K. et al. (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406: 722-726. [Full text]

 

[David Baxter PhD]

The Primitive, Complicated, Essential Emotion Called Fear

The Primitive, Complicated, Essential Emotion Called Fear
by Carl Zimmer, Discover
February 16, 2010

Are you a man or a mouse? No matter how you answer, you experience fear the same way in your brain.


Any halfway decent thesaurus will provide a long list of synonyms for fear, and yet they are not very good substitutes. No one would confuse having the creeps with being terrified. It is strange that we have so many words for fear, when fear is such a unitary, primal feeling. Perhaps all those synonyms are just linguistic inventions. Perhaps, if we looked inside our brains, we would just find plain old fear.

That is certainly how things seemed in the early 1900s, when scientists began studying how we come to be scared of things. They built on Ivan Pavlov?s classic experiments on dogs, in which Pavlov would ring a bell before giving his dogs food. Eventually they learned to associate the bell with food and began to salivate in anticipation. Psychologists set up experiments to see if the same kind of learning could instill fear as well. The implicit assumption was that fear, like hunger, was a simple provoked response.

In one of the most famous (and infamous) of these experiments, American psychologist John Watson decided to see if he could teach an 11-month-old baby named Albert to become scared of arbitrary things. He presented Albert with a rat, and every time the baby reached out to touch it, Watson hit a steel bar with a hammer, producing a horrendous clang. After several rounds with the rat and the bar, Watson then brought out the rat on its own. ?The instant the rat was shown, the baby began to cry,? Watson wrote in a 1920 report. ?Almost instantly he turned sharply to the left, fell over on his 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.?

The ?little Albert? study, besides being cruel, was badly designed. Watson did not control it carefully to rule out a wide range of possible interpretations. In later decades, other scientists got much more rigorous in their study of fear, in many cases turning to rats rather than people as their test subjects. In a typical experiment, a rat was placed in a cage with a light. At first the light came on a few times so the animal could get accustomed to it. Later the scientists would turn on the light and then give the rats a little electric shock. After a few rounds, the rats would respond fearfully to the light, even if no shock came.
Further research revealed that the amygdala?an almond-shaped cluster of neurons deep within the brain?plays a pivotal role in the fear-association response in rats. Brain researchers discovered that the amygdala orchestrates human fear as well. The sight of a loaded gun, for example, triggers activity in this part of the brain. People with an injured amygdala have dampened emotional responses and so do not learn to fear new things through association. Science had identified a nexus of fear, it seemed.

Although this line of research yielded some major insights, it had an obvious shortcoming. In the real world, rats don?t spend their lives in cages waiting for lights to turn on; these experiments don?t capture the complex role that fear plays in a wild rat?s life.

In the 1980s Caroline and Robert Blanchard, working together at the University of Hawaii, carried out a pioneering study on the natural history of fear. They put wild rats in cages and then brought cats gradually closer to them. At each stage, they carefully observed how the rats reacted. The Blanchards found that the rats responded to each kind of threat with a distinct set of behaviors.

The first kind of behavior is a reaction to a potential threat, in which a predator isn?t visible but there is good reason to worry that it might be nearby. A rat might walk into a meadow that looks free of predators, for example, but that reeks of fresh cat urine. In such a case, a rat will generally explore the meadow cautiously, assessing the risk of staying there. A second, more concrete type of threat arises if a rat spots a cat at the other side of the meadow. The rat will freeze and then make a choice about what to do next. It may slink away, or it may remain immobile in hopes that the cat will eventually wander away without noticing it. Finally, the most active threat: The cat glances over, notices something, and walks toward the rat to investigate. At this point, the rat will flee if it has an escape route. If the cat gets close, the rat will choose either to fight or to run for its life.

Dean Mobbs, a neuroscientist at the Medical Research Council in Cambridge, England, wondered if humans have similarly layered fear responses. He and his colleagues were not about to send people into tiger-infested meadows, so they designed a clever alternative: They programmed a survival-themed video game that subjects could play while lying in an fMRI scanner. The game is similar to Pac-Man. You see yourself as a triangle in a maze and press keys to maneuver through it. At some point a circle appears. This is a virtual predator being guided by an artificial intelligence program to seek you out. If the predator captures you, you receive a small electric shock on the back of your hand.

This deceptively minimalist predator-prey game triggers some remarkably intense feelings. Mobbs measured the skin conductance of his players by rigging them up to a device similar to a lie detector. He found that when the predator was bearing down on players, they often experienced the same changes to their skin as those seen in people having panic attacks. Mobbs unleashed two kinds of predators on his players, a less adept one that was easy to escape, and a smarter one that was more likely to capture its victim. When people were chased by the better predator, they showed a stronger panic response in their skin, and they also crashed into the walls of the maze more often.

Meanwhile, striking changes were happening inside the brains of the players. The predators would first appear on the far side of the maze. While they remained at a distance, the same brain regions tended to become active in the players, a network that included parts of the amygdala as well as some other structures in the front of the brain. But when the predator was closing in, those brain regions shut down and a network of previously quiet regions farther back in the midbrain became active.

Mobbs?s results mesh nicely not only with the work of the Blanchards but also with some other, more recent studies of rat neurology. For example, one of the midbrain regions that Mobbs and his colleagues observed becoming active in humans when a ?predator? was close is an area called the periaqueductal gray region. This area showed higher activity in the people who crashed into the walls more often, providing further evidence that it plays an important role in panic. Researchers have explored the anatomy of fear more directly in rats; by manipulating different areas of the rat brain, they are able to alter parts of the standard fear-driven sequence of behavior. When neuroscientists put electrodes into the periaqueductal gray region of rat brains and stimulated the neurons there, the creatures immediately started to run and jump uncontrollably.

Fear, the new results suggest, is not a single thing after all. Rather, it is a complex, ever-changing strategy mammal brains deploy in order to cope with danger. When a predator is off in the distance, its prey?whether rat or human?powers up a forebrain network. The network primes the body, raising the heartbeat and preparing it for fast action. At the same time, the forebrain network sharpens the brain?s attention to the outside world, evaluating threats, monitoring subtle changes, and running through possible responses. Another important job it performs is keeping the midbrain network shut down so that, instead of fleeing at top speed, a prey animal keeps very still at first. As the predator gets closer, however, the forebrain?s grip on the midbrain loosens. Now the midbrain becomes active, orchestrating a powerful, quick response: fight or flight. At the same time it shuts down the slower, more deliberative forebrain. This is no time for thinking.

It may be unsettling to find that our brains work so much like a rat?s. But the amygdala and the periaqueductal gray are ancient parts of the brain, dating back hundreds of millions of years. Our small hominid ancestors probably faced the same kinds of threats that baboons do today from leopards, eagles, and other predators. Even after we evolved the ability to use weapons and became predators ourselves, this ancient brain circuit still offered a useful defense against members of our own species.

Unfortunately, our exquisitely sophisticated brains may make this predator-defense circuit vulnerable to misfiring. Instead of monitoring just the threats right in front of us, we can also imagine threats that do not exist. Feeding this imagination into the early-warning system may lead to crippling chronic anxiety. In other cases, people may not be able to keep their periaqueductal gray and other midbrain regions under control. As we perceive predators getting closer, our brains normally make the switch from the forebrain to the midbrain regions. People who suffer panic disorders may misjudge threats, seeing them as far more imminent than they really are.

To test these possibilities, Mobbs and his colleagues are beginning to study people who suffer from fear-related disorders as they play the predator game. Such work may not uncover a biological distinction between angst and the heebie-jeebies, but it may show how much better we can understand ourselves?and tame our inner demons?once we appreciate the many dimensions of fear.