Joseph E. LeDoux

Center for Neural Science, New York University, New York, New York 10003; e-mail:

[email protected]

Key Words

fear, memory, learning, conditioning, amygdala, limbic system

Abstract

The field of neuroscience has, after a long period of looking the other

way, again embraced emotion as an important research area. Much of the progress

has come from studies of fear, and especially fear conditioning. This work has pin-

pointed the amygdala as an important component of the system involved in the acqui-

sition, storage, and expression of fear memory and has elucidated in detail how stimuli

enter, travel through, and exit the amygdala. Some progress has also been made in

understanding the cellular and molecular mechanisms that underlie fear conditioning,

and recent studies have also shown that the findings from experimental animals apply

to the human brain. It is important to remember why this work on emotion succeeded

where past efforts failed. It focused on a psychologically well-defined aspect of emo-

tion, avoided vague and poorly defined concepts such as “affect,” “hedonic tone,” or

“emotional feelings,” and used a simple and straightforward experimental approach.

With so much research being done in this area today, it is important that the mistakes

of the past not be made again. It is also time to expand from this foundation into

broader aspects of mind and behavior

INTRODUCTION

After decades of neglect, neuroscience has again embraced emotion as a research

topic. This new wave of interest raises the question of why emotion was over-

looked for so long. It is instructive to consider this question before examining

what has been learned about emotional circuits, as some of the factors that led

brain researchers to turn away from this topic may again hamper progress unless

they can be grappled with.

 

ESCAPING THE LIMBIC SYSTEM LEGACY:

FEAR CIRCUITS

One of the main exceptions to the bleak state of affairs regarding the brain mech-

anisms of emotion is the body of research concerned with neural system under-

lying fear, especially in the context of the behavioral paradigm called fear

conditioning. It has, in fact, been research on fear conditioning, and the progress

that has been made on this topic, that has been largely responsible for the renais-

sance of interest of emotion within neuroscience. In this work, the fear system

has been treated as a set of processing circuits that detect and respond to danger,

rather than as a mechanism through which subjective states of fear are experi-

enced. Through this approach, fear is operationalized, or made experimentally

tractable. Some limbic areas turn out to be involved in the fear system, but the

exact brain areas and the nature of their involvement would never have been

predicted by the limbic system theory.

 

Neuroanatomy of Fear Conditioning

Research from several laboratories combined in the 1980s to paint a relatively

simple and remarkably clear picture of the neuroanatomy of conditioned fear (see

Kapp et al 1992, LeDoux 1992, Davis 1992, Fanselow 1994). In short, condi-

tioned fear is mediated by the transmission of information about the CS and US

to the amygdala, and the control of fear reactions by way of output projections

from the amygdala to the behavioral, autonomic, and endocrine response control

systems located in the brainstem. Below, the input and output pathways, as well

as the connections within the amygdala that link inputs and outputs, are described.

The focus is on findings from rodents and other small mammals, as most of the

work on fear conditioning has involved these species (for the contribution of the

primate amygdala to fear and other emotions

 

THE HUMAN AMYGDALA

Over the past several years, there has been an explosion of interest in the role of

the human amygdala in fear. Deficits in the perception of the emotional meaning

of faces, especially fearful faces, have been found in patients with amygdala

damage (Adolphs et al 1995, Calder et al 1996). Similar results were reported for

detection of the emotional tone of voices (Scott et al 1997). Furthermore, damge

to the amygdala (Bechara et al 1995) or areas of temporal lobe including the

amygdala (LaBar et al 1995) produced deficits in fear conditioning in humans.

Functional imaging studies have shown that the amygdala is activated more

strongly in the presence of fearful and angry faces than of happy ones (Breiter et

al 1996) and that subliminal presentations of such stimuli lead to stronger acti-

vations than do freely seen ones (Whalen et al 1998). Fear conditioning also leads

to increases in amygdala activity, as measured by functional magnetic resonance

imaging (LaBar et al 1998, Buchel et al 1998), and these effects also occur to

subliminal stimuli (Morris et al 1998). Additionally, when the activity of the

amygdala during fear conditioning is cross correlated with the activity in other

regions of the brain, the strongest relations are seen with subcortical (thalamic

and collicular) rather than cortical areas, further emphasizing the importance of

the direct thalamao-amygdala pathway in the human brain (Morris et al 1999).

Other aspects of emotion and the human brain area are reviewed by Davidson &

Irwin (1999), Phelps & Anderson (1997), Cahill & McGaugh (1998).

CLINICAL IMPLICATIONS

Although it is clear that studies of acute fear responses elicited by conditioned

fear stimuli cannot account for all aspects of fear and fear disorders, there is

growing enthusiasm for the notion that fear learning processes similar to those

occurring in fear conditioning experiments might indeed be an important factor

in certain anxiety disorders. For example, fear conditioning models of posttrau-

matic stress disorder and panic disorder (Pitman & Orr 1999, Goddard et al 1998)

have been proposed recently by researchers in these fields.

Earlier in this century, the notion that conditioned fear contributes to phobias

and related fear disorders was fairly popular. However, this idea fell out of favor

because laboratory fear conditioning seemed to produce easily extinguishable

fear, whereas clinical fear is difficult to treat. The notion arose that fear disorders

involve a special kind of learning, called prepared learning, where the CS is

biologically significant rather than neutral (Seligman 1971, Marks 1987, Ohman

1992). Although preparedness may indeed contribute, there is another factor to

consider. In studies of rats, Morgan et al (1993; but see Gewirtz & Davis 1997)

found that easily extinguished fear could be converted into difficult-to-extinguish

fear in rats with damage to the medial prefrontal cortex. This suggested that

alterations in the organization of the medial prefrontal regions might predispose

certain people in some circumstances (such as stressful situations) to learn fear

in a way that is difficult to extinguish (treat) under normal circumstances. These

changes could come about because of genetic or experiential factors, or some

combination.

 CONCLUSION

Research on the emotional brain has progressed significantly in recent years,

largely as a result of a highly focused approach centered on the study of fear

mechanisms, and especially the mechanisms underlying fear conditioning. This

work has mapped out pathways involved in fear learning in both experimental

animals and humans, and it has begun to shed light on interactions between

emotional and cognitive processes in the brain. Although the focus on fear con-

ditioning has its limits, it has proven valuable as a research strategy and provides

a foundation upon which to build a broader understanding of mind and brain.

At the same time, there is a disturbing rush to embrace the amygdala as the

new center of the emotional brain. It seems unlikely that the amygdala is the

answer to how all emotions work, and it may not even explain how all aspects

of fear work. There is some evidence that the amygdala participates in postitive

emotional behaviors, but that role is still poorly understood. If an amygdala theory

of emotion is on the horizon, let it get there by data rather than by faith.

Neuroscience meetings these days have numerous papers on the role of the

brain in emotion, affect, hedonic tone, and the like. Unless these vague concepts

can be operationalized, as was done in the work on fear, they are likely to impede,

if not recede, the progress. The future of emotion research can be bright if we

keep in mind the way that emotion became respectable again: by focusing on a

psychologically well-defined aspect of emotion, by using an experimental

approach that simplified the problem in such a way as to make it tractable, by

circumventing vague and poorly defined aspects of emotion, and by removing

subjective experience as a roadblock to experimentation. This is not to suggest

that the hard problems should not be worked on but instead that they should be

worked on in a way that advances the field