EXCERPTS from “TAMING STRESS” by Robert Sapolsky (Scientific American, 2003):
“OVER THE CENTURIES, SOCIETY’S APPROACHES TO TREATing the mentally ill have shifted dramatically. At present, drugs that manipulate neurochemistry count as cutting-edge therapeutics. A few decades ago the heights of efficacy and compassion were lobotomies and insulin-induced comas. Before that, restraints and ice baths sufficed. Even earlier, and we’ve entered the realm of exorcisms.
Society has also shifted its view of the causes of mental illness. Once we got past invoking demonic possession, we put enormous energy into the debate over whether these diseases are more about nature or nurture. Such arguments are quite pointless given the vast intertwining of the two in psychiatric disease. Environment, in the form of trauma, can most certainly break the minds of its victims. Yet there is an undeniable biology that makes some individuals more vulnerable than others. Conversely, genes are most certainly important factors in understanding major disorders. Yet being the identical twin of someone who suffers one of those illnesses means a roughly 50 percent chance of not succumbing.
Obviously, biological vulnerabilities and envronmiental precipitants interact, and in this article I explore one arena of that interaction: the relation between external factors that cause stress and the biology of the mind’s response. Scientists have recently come to understand a great deal about the role that stress plays in the two most common classes of psychiatric disorders: anxiety and major depression, each of which affects close to 20 million Americans annually, according to the National Institute of Mental Health. And much investigation focuses on developing the next generation of relevant pharmaceuticals, on finding improved versions of Prozac, Wellbutrin, Valium and Librium that would work faster, longer or with fewer side effects.
At the same time, insights about stress are opening the way for novel drug development. These different tacks are needed for the simple fact that despite laudable progress in treating anxiety and depression, currently available medications do not work for vast numbers of people, or they en- tail side effects that are too severe.
Research in this area has applications well beyond treating and understanding these two illnesses. The diagnostic boundary that separates someone who is formally ill with an anxiety dis- order or major depression from everyone else is somewhat arbitrary. Investigations into stress are also teaching us about the everyday anxiety and depression that all of us experience at times.” (2003:87)
Out of Balance
WHEN A BODY is in homeostatic balance, various measures—such as temperature, glucose level and so on—are as close to “ideal” as possible. A stres- sor is anything in the environment that knocks the body out of homeostasis, and the stress response is the array of physiological adaptations that ultimately reestablishes balance. The response principally includes the secretion of two types of hormones from the adrenal glands: epinephrine, also known as adrenaline, and glucocorticoids. In hu- mans, the relevant glucocorticoid is called cortisol, also known as hydrocortisone.
This suite of hormonal changes is what stress is about for the typical mammal. It is often triggered by an acute physical challenge, such as fleeing from a predator. Epinephrine and glucocorticoids mobi- lize energy for muscles, increase cardiovascular tone so oxygen can travel more quickly, and turn off nonessential activities like growth. (The hormones work at different speeds. In a fight-or-flight scenario, epinephrine is the one handing out guns; glucocorticoids are the ones drawing up blueprints for new aircraft carriers needed for the war effort.)
Primates have it tough, however. More so than in other species, the primate stress response can be set in motion not only by a concrete event but by mere anticipation. When this assessment is accurate (“This is a dark, abandoned street, so I should pre- pare to run”), an anticipatory stress response can be highly adaptive. But when primates, human or otherwise, chronically and erroneously believe that a homeostatic challenge is about to come, they have entered the realm of neurosis, anxiety and paranoia.
In the 1950s and 1960s pioneers such as John Mason, Seymour Levine and Jay Weiss—then at the Walter Reed Army Medical Center, Stanford University and the Rockefeller University, respectively— began to identify key facets of psychological stress. They found that such stress is exacerbated if there is no outlet for frustration, no sense of control, no social support and no impression that something bet- ter will follow. Thus, a rat will be less likely to develop an ulcer in response to a series of electric shocks if it can gnaw on a bar of wood throughout, because it has an outlet for frustration. A baboon will secrete fewer stress hormones in response to frequent fighting if the aggression results in a rise, rather than a fall, in the dominance hierarchy; he has a perception that life is improving. A person will become less hypertensive when exposed to painfully loud noise if she believes she can press a button at any time to lower the volume; she has a sense of control.
But suppose such buffers are not available and the stress is chronic. Repeated challenges may demand repeated bursts of vigilance. At some point, this vigilance may become overgeneralized, leading an individual to conclude that he must always be on guard—even in the absence of the stress. And thus the realm of anxiety is entered. Alternatively, the chronic stress may be insurmountable, giving rise to feelings of helplessness. Again this response may be- come overgeneralized: a person may begin to feel she is always at a loss, even in circumstances that she can actually master. Depression is upon her.
Stress and Anxiety
FOR ITS PART , anxiety seems to wreak havoc in the limbic system, the brain region concerned with emotion. One structure is primarily affected: the amygdala, which is involved in the perception of and response to fear-evoking stimuli. (Interestingly, the amygdala is also central to aggression, underlining the fact that aggression can be rooted in fear—an observation that can explain much sociopolitical behavior.)
To carry out its role in sensing threat, the amygdala receives input from neurons in the outermost layer of the brain, the cortex, where much high-level processing takes place. Some of this input comes from parts of the cortex that process sensory information, including specialized areas that recognize individual faces, as well as from the frontal cortex, which is involved in abstract associations. In the realm of anxiety, an example of such an association might be grouping a gun, a hijacked plane and an anthrax-tainted envelope in the same category. The sight of a fire or a menacing face can activate the amygdala—as can a purely abstract thought.
The amygdala also takes in sensory information that bypasses the cortex. As a result, a subliminal preconscious menace can activate the amygdala, even before there is conscious awareness of the trigger.
Imagine a victim of a traumatic experience who, in a crowd of happy, talking people, suddenly finds her- self anxious, her heart racing. It takes her moments to realize that a man conversing behind her has a voice similar to that of the man who once assaulted her.
The amygdala, in turn, contacts an array of brain regions, making heavy use of a neurotransmitter called corticotropin-releasing hormone (CRH). One set of nerve cells projecting from the amygdala reaches evolutionarily ancient parts of the midbrain and brain stem. These structures control the autonomic nervous system, the network of nerve cells projecting to parts of the body over which you normally have no conscious control (your heart, for example). One half of the autonomic nervous system is the sympathetic nervous system, which mediates “fight or flight.” Activate your amygdala with a threat, and soon the sympathetic nervous system has directed your adrenal glands to secrete epineph- rine. Your heart is racing, your breathing is shallow, your senses are sharpened.
The amygdala also sends information back to the frontal cortex. In addition to processing abstract associations, as noted above, the frontal cortex helps to make judgments about incoming information and initiating behaviors based on those assessments. So it is no surprise that the decisions we make can be so readily influenced by our emotions. Moreover, the amygdala sends projections to the sensory cortices as well, which may explain, in part, why sensations seem so vivid when we are in certain emotional states—or perhaps why sensory memories (flash- backs) occur in victims of trauma.
Whether it orchestrates such powerful reimmersions or not, the amygdala is clearly implicated in certain kinds of memory. There are two general forms of memory. Declarative, or explicit, memory governs the recollection of facts, events or associations. Implicit memory has several roles as well. It includes procedural memory: recalling how to ride a bike or play a passage on the piano. And it is involved in fear. Remember the woman reacting to the similarity be- tween two voices without being aware of it. In that case, the activation of the amygdala and the sympathetic nervous system reflects a form of implicit memory that does not require conscious awareness.
Researchers have begun to understand how these fearful memories are formed and how they can be overgeneralized after repeated stress. The foundation for these insights came from work on declarative memory, which is most likely situated in a part of the brain called the hippocampus. Memory is established when certain sets of nerve cells communicate with one another repeatedly. Such communication entails the release of neurotransmitters—chemical messengers that travel across syn- apses, the spaces between neurons. Repeated stimulation of sets of neurons causes the communication across synapses to be strengthened, a condition called long-term potentiation (LTP).
Joseph LeDoux of New York University has shown that repeatedly placing rats in a fear-pro- voking situation can bring about LTP in the amyg- dala. Work by Sumantra Chattarji of the National Center for Biological Science in Bangalore extends this finding one remarkable step further: the amyg- dalic neurons of rats in stressful situations sprout new branches, allowing them to make more connections with other neurons. As a result, any part of the fear-inducing situation could end up triggering more firing between neurons in the amygdala. A victim— if he had been robbed several times at night, for in- stance—might experience anxiety and phobia just by stepping outside his home, even under a blazing sun.
LeDoux has proposed a fascinating model to re- late these changes to a feature of some forms of anxety. As discussed, the hippocampus plays a key role in declarative memory. As will become quite perti- nent when we turn to depression, glucocorticoid ex- posure can impair LTP in the hippocampus and can even cause atrophy of neurons there. This phenom- enon constitutes the opposite of the stress response in the amygdala. Severe stress can harm the hip- pocampus, preventing the consolidation of a con- scious, explicit memory of the event; at the same time, new neuronal branches and enhanced LTP facilitate
amygdala’s implicit memory machinery. In sub- sequent situations, the amygdala might respond to preconscious information—but conscious aware- ness or memory may never follow. According to LeDoux, such a mechanism could underlie forms of free-floating anxiety.
It is interesting that these structural changes come about, in part, because of hormones secreted by the adrenal glands, a source well outside the brain. As mentioned, the amygdala’s perception of stress ultimately leads to the secretion of epinephrine and glucocorticoids. The glucocorticoids then activate a brain region called the locus coeruleus. This struc- ture, in turn, sends a powerfully activating projection back to the amygdala, making use of a neurotransmitter called norepinephrine (a close relative of epinephrine). The amygdala then sends out more CRH, which leads to the secretion of more glucocorticoids. A vicious circle of mind-body feedback can result.
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