Decade of the Brain
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Discovering Our Selves: The Science of Emotion
Executive Summary

Panel: Encountering Daily Life:
How Our Emotions Affect Us

"The High Costs of Stress"

Philip W. Gold, M.D., is Chief of the Clinical Neuroendocrinology Branch at the National Institute of Mental Health, National Institutes of Health.

Empedocles noted in 500 B.C. that humans were beset by disturbing forces; to survive, he said, we need to maintain harmony (we now call it homeostasis) in the face of these disturbing forces. Empedocles also noted that there were corrective factors that would restore balance.

Today we call those corrective forces "the stress response." Though the word "stress" has many emotional, mostly negative, connotations to a physiologist, the stress response is utterly essential for survival. If the stress response is dysregulated, however--if it turns on but does not turn off--it can itself be the source of illness.

As we have seen, the stress response is an evolutionary response to danger: a system that prepares us to fight or flee. Our bodies produce stress hormones such as cortisol, epinephrine, and norepinephrine that affect us by breaking down certain tissues to mobilize fuel, increasing our heart rate, preparing our muscles to move us. All these responses are necessary when we are in danger, but they can have long-term medical consequences if stress becomes our chronic state.

Cortisol enhances fear-related behavior. If you are a rat being chased by a cat, you cannot afford to stop and smell the roses. Fear is essential to a rat's survival. So is what we call the "inhibition of vegetative functions." If you are a rat being chased by a cat, you should not stop to sleep or eat, even if you have missed a meal and it is past your bedtime. Internal programs for sexual behavior and metabolic programs for growth and reproduction are turned off. All mechanisms are focused on sustaining fight or flight--necessary in the context of an immediate danger--but counterproductive if sustained.

It is a testimony to the importance of these fear responses that a large proportion of the brain is dedicated both to generating fear reliably and rapidly and to evoking emotional memories of fear in contexts where they may be relevant; unfortunately, the brain also can generate and remember fear in contexts where it may not be relevant, or even counterproductive.

The amygdala, as we have seen, encodes the memories of fear. The prefrontal cortex is involved in shifting emotions from one state to another based on internally or externally changing conditions, assessing whether a stimulus is likely to be rewarding or punitive; it is also an important component in inhibiting conditioned fear and promoting the extinction of conditioned fear responses. The prefrontal cortex restrains the part of the brain that stimulates cortisol secretion; the amygdala activates it. The hypothalamus controls many of the vegetative functions and the secretion of stress hormones, and sexual behavior.

Now let us consider how stress relates to depression. Depression is a particularly cruel disorder. It darkens memory, diminishes hope, and precludes the taking of pleasure in everyday events or in the contemplation of what one has achieved or become, depriving those afflicted of the most gratifying aspects of their past and present. Depression also intrudes upon fundamental biological processes that regulate sleep, appetite, metabolic activity, autonomic function, neuroendocrine regulation, and growth and reproduction.

Not all depression reflects a suppression of thought and feeling. One of the most severe forms of depression actually is a state of pathological hyperarousal, but an exceedingly melancholic and anxious arousal. The anxiety is most often directed against the self and expressed as feelings of worthlessness and guilt. Such individuals, because they feel so deficient, then feel hopeless about the future.

Patients with melancholic depression show particular physiological alterations: loss of sleep, the inhibition of vegetative functions, early morning awakening, inhibition of programs for growth and reproduction, decreased libido and appetite.

When we study these patients with the tools of contemporary biology, we find high stress hormone levels and activation of their sympathetic nervous system. The stress response that we need to survive has been turned on and is either outrunning its counter-regulatory responses or is being overdriven by whatever ordinarily turns it on and sustains it. What is happening?

One functional imaging study of depression showed that the left prefrontal cortex (which, among other functions, inhibits the amygdala) is smaller in patients with major depression. Its metabolic activity is less.

We think that the mood and cognitive changes of depression are the tip of an iceberg of a syndrome that affects most of the body through hormonal and autonomic nervous system changes. The stress response alters a global system that modulates neuroendocrine secretion, influencing almost every cell in the body, and autonomic outflow. When such a system gets altered in a precise way for sustained periods of time, we pay a physiological price. Thus far, we see links at least to osteoporosis and coronary artery disease.

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