A&O READING – STRESS by Sapolsky (2003)

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 stressor 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.


Article continues at https://www.psychiatry.wisc.edu/courses/Nitschke/seminar/Sapolsky.2003.pdf