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<DIV><FONT size=2>It's also worth remembering that people can be
traumatized</FONT></DIV>
<DIV><FONT size=2>before they learn to speak, which can make it
totally</FONT></DIV>
<DIV><FONT size=2>impossible to elicit the causes.</FONT></DIV>
<BLOCKQUOTE
style="PADDING-RIGHT: 0px; PADDING-LEFT: 5px; MARGIN-LEFT: 5px; BORDER-LEFT: #000000 2px solid; MARGIN-RIGHT: 0px">
<DIV style="FONT: 10pt arial">----- Original Message ----- </DIV>
<DIV
style="BACKGROUND: #e4e4e4; FONT: 10pt arial; font-color: black"><B>From:</B>
<A title=dsmith06@maine.rr.com href="mailto:dsmith06@maine.rr.com">David
Smith</A> </DIV>
<DIV style="FONT: 10pt arial"><B>To:</B> <A title=paleopsych@paleopsych.org
href="mailto:paleopsych@paleopsych.org">The new improved paleopsych list</A>
</DIV>
<DIV style="FONT: 10pt arial"><B>Sent:</B> Wednesday, June 30, 2004 9:32
PM</DIV>
<DIV style="FONT: 10pt arial"><B>Subject:</B> Re: [Paleopsych] why is the
amygdala so sneaky?</DIV>
<DIV><BR></DIV>
<DIV><FONT size=2>
<DIV><FONT face=Arial size=2>Howard</FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Actually, Freud thought that repression is an
<EM>unconscious</EM> act. </FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Freud thought that conscious states must have
sensory qualities in order to be conscious. Counscious is a fabric of
smells, tastes, sounds, sights etc. It follows that mental states
devoid of these 'qualia' (as they are nowadays called) must be
unconscious. Thought, then, has to be unconscious.</FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>How, then, do these nonsensory thoughts become
conscious? Freud thought that they have to become associated with
language. Language can serve as a go-between mediating the relationship
between thought and consciousness because it shares the same abstract
structure as thought but it is also a richly sensory symbol system.
</FONT></DIV>
<DIV><FONT face=Arial size=2></FONT><FONT face=Arial
size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Freud thought that repression is a motiviated
failure to translate unconscious thought into language, a failure to
articulate our own thoughts to ourselves. According to this thesis
repression can't be conscious because it <EM>undercuts</EM>
consciousness.</FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Cheers</FONT></DIV>
<DIV><FONT face=Arial size=2>David</FONT></DIV></FONT></DIV>
<BLOCKQUOTE
style="PADDING-RIGHT: 0px; PADDING-LEFT: 5px; MARGIN-LEFT: 5px; BORDER-LEFT: #000000 2px solid; MARGIN-RIGHT: 0px">
<DIV style="FONT: 10pt arial">----- Original Message ----- </DIV>
<DIV
style="BACKGROUND: #e4e4e4; FONT: 10pt arial; font-color: black"><B>From:</B>
<A title=HowlBloom@aol.com
href="mailto:HowlBloom@aol.com">HowlBloom@aol.com</A> </DIV>
<DIV style="FONT: 10pt arial"><B>To:</B> <A title=paleopsych@paleopsych.org
href="mailto:paleopsych@paleopsych.org">paleopsych@paleopsych.org</A> </DIV>
<DIV style="FONT: 10pt arial"><B>Sent:</B> Wednesday, June 30, 2004 11:30
PM</DIV>
<DIV style="FONT: 10pt arial"><B>Subject:</B> [Paleopsych] why is the
amygdala so sneaky?</DIV>
<DIV><BR></DIV>
<DIV>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman">The following tidbit from an article in The
Scientific American on stress and memory gives a<SPAN
style="mso-spacerun: yes"> </SPAN>neurobiological explanation for
something<SPAN style="mso-spacerun: yes"> </SPAN>Sigmund Freud
described way back in the early days of psycho-speculation…repression and
suppression.<SPAN style="mso-spacerun: yes"> </SPAN></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><SPAN
style="mso-spacerun: yes"></SPAN></FONT></FONT> </P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><SPAN style="mso-spacerun: yes"></SPAN>When something
ghastly happens to us, says this piece, which derives its wisdom from Joseph
LeDoux, a strange thing happens in our brain.<SPAN
style="mso-spacerun: yes"> </SPAN>The hippocampus, the traffic center
that sends material to the conscious mind, goes through shut down.<SPAN
style="mso-spacerun: yes"> </SPAN>It’s paralyzed by glucocorticooids,
stress hormones.<SPAN style="mso-spacerun: yes"> </SPAN>But something
very different happens to our fear and body-knowledge traffic center, the
amygdala.<SPAN style="mso-spacerun: yes"> </SPAN>The amygedala
thrives, grows new threads of connection to the sympathetic nervous system,
and implants memories of the frightful experience in us.<SPAN
style="mso-spacerun: yes"> </SPAN>Not only ss that memory of a
nightmare event woven into our permanent store of lessons about life, it
gets woven way down at a level that can kick our heart into a high-speed
trot, get our sweat glands oozing, and tie knots in our stomach. <SPAN
style="mso-spacerun: yes"> </SPAN>But it also gets woven in at a level
that’s impossible for us to “see” and think out.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Here’s the question.<SPAN style="mso-spacerun: yes">
</SPAN>What could the evolutionary value be of keeping key experiences
locked in a vault that the conscious mind can’t crack into?<SPAN
style="mso-spacerun: yes"> </SPAN>Is this one of the shortcuts the
mind uses to speed up our reactions by cutting the dither of thinking out of
the process?<SPAN style="mso-spacerun: yes"> </SPAN>Is it one of those
things that helps Val Geist sprint away from a murderous grizly bear before
he has a chance to think out a response, thus letting Val win the race with
the grizzly and live another 30 years or so?</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Many of<SPAN style="mso-spacerun: yes"> </SPAN>the responses
encoded into us by this trauma-reaction process are nowhere near as helpful
as Val’s instant dash to the nearest sturdy tree, his climb up its trunk,
and his victory swing<SPAN style="mso-spacerun: yes"> </SPAN>high in
the branches above the grizzly’s head.<SPAN style="mso-spacerun: yes">
</SPAN>Many, in fact, are paralyzing.<SPAN style="mso-spacerun: yes">
</SPAN>They’re the high-anxiety mind-and-body freezes of extreme
anxiety.<SPAN style="mso-spacerun: yes"> </SPAN>They’re the
torture-terrors of post-traumatic stress disorders.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>The Bloom Grand Unified Theory of Everything In the Universe
Including the Human Soul says that when they’re failing, individual
components of a learning system, components like cells in the body or like
bacteria in a colony, disable themselves or worse, kill themselves off.<SPAN
style="mso-spacerun: yes"> </SPAN>Why? So their influence will be
minimized.<SPAN style="mso-spacerun: yes"> </SPAN>Sp their mistaken
strategies won’t sway the decisions of the group. And so their mistakes will
stand as a warning to the others in the consultative assemblies of
collective intelligence.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Are humans disabled by their traumas and slowed to a painful crawl by
the mark of experiences they can’t remember as a lesson to the rest of
us?<SPAN style="mso-spacerun: yes"> </SPAN>If those who suffer
this sort of amygdalic sabotage can’t remember why they are breaking out in
a cold sweat and hiding in a corner, how in the world can their agonies add
to our understanding?</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Or is the bypass of consciousness an accidental result of a system
that was wired long before there was a thinking center in the brain, long
before there was a theater of awareness beneath the dome of the skull? <SPAN
style="mso-spacerun: yes"> </SPAN>Has that old system been retained so
it can take care of things too difficult for the conscious mind to
handle—tasks like digestion and orchestrating muscles to walk or ride a
bicycle?</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>One thing this amygdala-centered understanding hints at is this.<SPAN
style="mso-spacerun: yes"> </SPAN>Freud implied that repression was a
conscious act, a mistaken act of will or cowardice.<SPAN
style="mso-spacerun: yes"> </SPAN>We were conscious of the trauma when
it happened, couldn’t face its consequences, so tucked it out of sight.<SPAN
style="mso-spacerun: yes"> </SPAN>That’s not the way the LeDoux
scenario explains it.<SPAN style="mso-spacerun: yes"> </SPAN>LeDoux’s
work seems to imply that our experiences of horror trigger a system that
never bothers to show the conscious mind its perceptions and its decisions
about how to handle what it sees.<SPAN style="mso-spacerun: yes">
</SPAN>I suspect there’s a little bit of truth to both points of view.<SPAN
style="mso-spacerun: yes"> </SPAN>What do you think?<SPAN
style="mso-spacerun: yes"> </SPAN>Howard</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><SPAN
style="mso-spacerun: yes"><FONT face="Times New Roman"
size=2></FONT></SPAN> </P>
<P class=MsoNormal style="MARGIN: 0in 0.5in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>glucocorticoid exposure can impair LTP in the
hippocampus and can even cause atrophy of neurons there. This phenomenon
constitutes the opposite of the stress response in the amygdala. Severe
stress can harm the hippocampus, preventing the consolidation of a
conscious, explicit memory of the event; at the same time, new neuronal
branches and enhanced LTP facilitate the amygdala's implicit memory
machinery. In subsequent situations, the amygdala might respond to
preconscious information--but conscious awareness or memory may never
follow.</B> Retrieved June 30, 2004, from the World Wide Web<SPAN
style="mso-spacerun: yes"> </SPAN>EBSCOhost</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0.5in 0pt"><FONT
face="Times New Roman" size=2>Taming stress ,<SPAN
style="mso-spacerun: yes"> </SPAN>By: Salzano, Robert, Scientific
American, 00368733, Sep2003, Vol. 289, Issue 3</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Retrieved June 30, 2004, from the World Wide Web </FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>http://web9.epnet.com/citation.asp?tb=1&_ug=sid+BB4951D1%2DC74E%2D42C7%2DAB5A%2D27F66A8435DD%40sessionmgr6+dbs+aph+cp+1+D09B&_us=hs+True+cst+0%3B2+or+Date+ss+SO+sm+KS+sl+0+dstb+KS+ri+KAAACB4A00000109+37EF&_uso=tg%5B0+%2D+db%5B0+%2Daph+hd+False+clv%5B1+%2Dscientific++american+clv%5B0+%2D20030900%2D20030900+op%5B0+%2D+cli%5B1+%2DSO+cli%5B0+%2DDT1+st%5B0+%2Damygdala+1438&cf=1&fn=1&rn=1</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>EBSCOhost</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>: Taming stress ,<SPAN style="mso-spacerun: yes"> </SPAN>By:
Salzano, Robert, Scientific American, 00368733, Sep2003, Vol. 289, Issue
3</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>An emerging understanding of the brain's stress pathways points
toward treatments for anxiety and depression beyond Valium and
Prozac</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Obviously, biological vulnerabilities and environmental 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 entail
side effects that are too severe.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 disorder 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Out of Balance,</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 humans, the
relevant glucocorticoid is called cortisol, also known as
hydrocortisone.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>This suite of hormonal changes is what stress is about for the
typical mammal. Iris often triggered by an acute physical challenge, such as
fleeing from a predator. Epinephrine and glucocorticoids mobilize 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.)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 prepare 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 better 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 become 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress and Anxiety</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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, whi.ch 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.)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>To carry out its role in sensing threat, <B><SPAN
style="BACKGROUND: yellow; mso-highlight: yellow">the amygdala receives
input from </SPAN>neurons in the outermost layer of the brain, the
cortex</B>, where much high-level processing takes place.<B> Some of this
input comes from parts of the cortex that process sensory information,
including<SPAN style="BACKGROUND: yellow; mso-highlight: yellow">
specialized areas that recognize individual faces</SPAN>, as well as from
the frontal cortex, which is involved in abstract associations.</B> 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoBodyText style="MARGIN: 0in 0in 0pt"><STRONG><FONT
face="Times New Roman" size=2>The amygdala also takes in sensory information
that bypasses the cortex. As a result, a subliminal preconsci0us menace can
activate the amygdala, even before there is conscious awareness of the
trigger.</FONT></STRONG></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Imagine a victim of a traumatic experience who, in a crowd of happy,
talking people, suddenly finds herself 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>The amygdala, in turn, contacts an array of brain
regions, making heavy use of a neurotransmitter called
corticotropin-releasing hormone (CRH).</B> 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 symigathetic 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
epinephrine. Your heart is racing, your breathing is shallow, your senses
are sharpened.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>The amygdala also sends information back to the
frontal cortex.</B> 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. <B>Moreover, the amygdala sends projections to the sensory
cortices as well</B>, which may explain, in part, <B>[hb: could this explain
why everything goes into slow motion in an accident?]</B> why sensations
seem so vivid when we are in certain emotional states--or perhaps why
sensory memories (flashbacks) occur in victims of trauma.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman">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 between two voices without being aware
of it. In that case, <B>the activation of the amygdala and the sympathetic
nervous system reflects a form of implicit memory that does not require
conscious awareness.<o:p></o:p></B></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 synapses, 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).</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Joseph LeDoux of New York University has shown that repeatedly
placing rats in a fear-provoking situation can bring about LTP in the
amygdala. Work by Sumantra Chattarji of the National Center for Biological
Science in Bangalore extends this finding one remarkable step
further:<B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow"> the
amygdalic neurons of rats in stressful situations sprout new branches,
allowing them to make more connections with other neurons.</SPAN></B> 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 instance--might experience anxiety and phobia
just by stepping outside his home, even under a blazing sun.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>LeDoux has proposed a fascinating model to relate these changes to a
feature of some forms of anxiety. As discussed, the hippocampus plays a key
role in declarative memory. As will become quite pertinent when we turn to
depression, <B>glucocorticoid exposure can impair LTP in the hippocampus and
can even cause atrophy of neurons there. This phenomenon constitutes the
opposite of the stress response in the amygdala. Severe stress can harm the
hippocampus, preventing the consolidation of a conscious, explicit memory of
the event; at the same time, new neuronal branches and enhanced LTP
facilitate the amygdala's implicit memory machinery. In subsequent
situations, the amygdala might respond to preconscious information--but
conscious awareness or memory may never follow.</B> According to LeDoux,
such a mechanism could underlie forms of free-floating anxiety.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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 structure 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Assuaging Anxiety</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>AN UNDERSTANDING of the interactions between stress and anxiety has
opened the way for new therapies, some of which hold great promise. These
drugs are not presumed better or safer than those available today. Rather,
if successful, they will give clinicians more to work with.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>The medicines that already exist do target aspects of the stress
system. The minor tranquilizers, such as Valium and Librium, are in a class
of compounds called<B> benzodiazepines. They work in part by relaxing
muscles; they also inhibit the excitatory projection from the locus
coeruleus into the amygdala, thereby decreasing the likelihood that the
amygdala will mobilize the sympathetic nervous system.</B> The net result is
a calm body--and a less anxious body means a less anxious brain. While
effective, however, benzodiazepines are also sedating and addictive, and
considerable research now focuses on finding less troublesome
versions.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>In their Search for alternatives, researchers have sought to target
the stress response upstream of the locus coeruleus and amygdala.
Epinephrine activates a nerve called the vagus, which projects into a brain
region that subsequently stimulates the amygdala. A new therapy curtails
epinephrine's stimulation of the vagus nerve.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Chemical messengers such as epinephrine exert theft effects by
interacting with specialized receptors on the surface of target cells. A
receptor is shaped in such a way that it can receive only a certain
messenger-just as a mold will fit only the statue cast in it. But by
synthesizing imposter messengers, scientists have been able to block the
activity of some of the body's natural couriers.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Drugs called beta blockers fit into some kinds of epinephrine
receptors, preventing real epinephrine from transmitting any information.
Beta blockers have long been used to reduce high blood pressure driven by an
overactive sympathetic nervous system, as well as to reduce stage fright.
But Larry Cahill and James McGaugh of the University of California at Irvine
have shown that the drugs also blunt the formation of memories of
emotionally disturbing events or stories. Based on their findings and
others, clinicians such as Roger Pitman of Harvard University have started
studies in which beta blockers are given to people who have experienced
severe trauma in the hope of heading off the development of post-traumatic
stress disorder.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Other therapies are being designed to act in the amygdala itself. As
described, the amygdala's shift from merely responding to an arousing event
to becoming chronically overaroused probably involves memory formation as
well as the growth of new synapses. Work in my laboratory is exploring the
molecular biology underlying those changes. Because prolonged stress has
opposite effects on synapse formation in the hippocampus and the amygdala,
we would like to know how the profiles of genes turned on and off by stress
differ in those two structures. Our goal is to then try to block the changes
by introducing genes into the amygdala that might give rise to proteins that
could inhibit synapse formation during stress. In this work, viruses that
have been rendered safe are used to ferry genes to the amygdala [see Gene
Therapy in the Nervous System, by Dora Y. Ho and Robert M. Sapolsky;
SCIENTIFIC AMERICAN, July 1997].</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Another strategy--for both anxiety and depression--targets CRH, the
neurotransmitter used by the amygdala when it sends information elsewhere.
Based on insights into the structure of CRH and its receptors, scientists
have developed chemical imposters to bind with the receptors and block it.
In research by Michael Davis of Emory University, these compounds have
proved effective in rat models of anxiety. They have reduced the extent to
which a rat anxiously freezes when placed in a cage where it was previously
shocked.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress and Depression</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>IN CONTRAST TO ANXIETY, which can feel like desperate hyperactivity,
major depression is characterized by helplessness, despair,, an exhausted
sense of being too overwhelmed to do anything (psychomotor retardation) and
a loss of feelings of pleasure. Accordingly, depression has a different
biology and requires some different strategies for treatment. But it, too,
can be related to stress, and there is ample evidence of this association.
First of all, psychological stress entails feeling a loss of control and
predictability--an accurate description of depression. Second, major
stressful events seem to precede depressive episodes early in the course of
the disease. Finally, treating people with glucocorticoid hormones to
control conditions such as rheumatoid arthritis can lead to
depression.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman">One way in which stress brings about depression is by
acting on the brain's mood and pleasure pathways. To begin, <B>prolonged
exposure to glucocorticoid hormones depletes norepinephrine levels in the
locus coeruleus neurons. Most plausibly, this means that the animal--or
person--becomes less attentive, less vigilant, less active: psychomotor
retardation sets in.</B></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>Continued stress also decreases levels of
serotonin</B>--which may be important in the regulation of mood and sleep
cycles, among other things--as well as the number of serotonin receptors in
the frontal cortex. Serotonin normally arrives in the frontal cortex by way
of the raphe nucleus, a structure that also communicates with the locus
coeruleus. You can probably see where this is going. Normally, serotonin
stimulates the release of norepinephrine from the locus coeruleus. When
serotonin becomes scarce, less norepinephrine is released--exacerbating the
shortage caused by earlier unremitting glucocorticoid
bombardment.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress affects dopamine, the main currency of the pleasure pathway,
in a way that seems counterintuitive at first. Moderate and transient
amounts of stress--and the ensuing presence of glucocorticoids--increase
dopamine release in the pleasure pathway, which runs between a region called
the ventral tegmentum/nucleus accumbens and the frontal cortex. More
dopamine can lead to a feeling of well-being in situations of moderate or
transient stress during which a subject is challenged briefly and not too
severely. For a human, or a rat, this situation would entail a task that is
not trivial, but one in which there is, nonetheless, a reasonably high
likelihood of success--in other words, what we generally call "stimulation."
But with chronic glucocorticoid exposure, dopamine production is curbed and
the feelings of pleasure fade.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Not surprisingly, the amygdala also appears relevant to depression.
Wayne Drevets of the National Institute of Mental Health reports that the
images of the amygdala of a depressed person light up more in response to
sad faces than angry ones. Moreover, the enhanced autonomic arousal seen in
anxiety-- thought to be driven by the amygdala--is often observed in
depression as well. This fact might seem puzzling at first: anxiety is
characterized by a skittish: torrent of fight-or-flight signals, whereas
depression seems to be about torpor. Yet the helplessness of depression is
not a quiet, passive state. The dread is active, twitching,
energy-consuming, distracting, exhausting--but internalized. A classic
conceptualization of depression is that it represents aggression turned
inward--an enormous emotional battle fought entirely internally--and the
disease's physiology supports this analysis.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Memory and New Cells</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>STRESS ALSO ACTS ON the hippocampus, and this activity may bring
about some of the hallmarks of depression: difficulty learning and
remembering. As I explained before, stress and glucocorticoids can disrupt
memory formation in the hippocampus and can cause hippocampal neurons to
atrophy and lose some of their many branches. In the 1980s several
laboratories, including my own, showed that glucocorticoids can kill
hippocampal neurons or impair their ability to survive neurological insults
such as a seizure or cardiac arrest.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress can even prevent the growth of new nerve cells. Contrary to
long-held belief, adult brains do make some new nerve cells. This revolution
in our understanding has come in the past decade. And although some findings
remain controversial, it is clear that new neurons form in the olfactory
bulb and the hippocampus of many adult animals, including humans [see
"Brain, Repair Yourself," by Fred H. Gage]. Many things, including learning,
exercise and environmental enrichment, stimulate neurogenesis in the
hippocampus. But stress and glucocorticoids inhibit it.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>As would be expected, depression is associated with impaired
declarative memory. This impairment extends beyond remembering the details
of an acute trauma. Instead depression can interfere with declarative memory
formation in general--in people going about their everyday routine or
working or learning. Recent and startling medical literature shows that in
those who have been seriously depressed for years, the volume of the
hippocampus is 10 to 20 percent smaller than in well-matched control
subjects. There is little evidence that a small hippocampus predisposes
someone toward depression; rather the decreased volume appears to be a loss
in response to depression.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>At present, it is not clear whether this shrinkage is caused by the
atrophy or death of neurons or by the failure of neurogenesis. Disturbingly,
both the volume loss and at least some features of the cognitive impairments
persist even when the depression resolves. (It is highly controversial
whether new neurons are required for learning and memory; thus, it is not
clear whether an inhibition of neurogenesis would give rise to cognitive
deficits.)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Glucocorticoids may act on the hippocampus by inhibiting levels of a
compound called brain-derived neurotrophic factor (BDNF)--which may aid
neurogenesis. Several known antidepressants increase amounts of BDNF and
stimulate hippocampal neurogenesis in laboratory animals. These findings
have led some scientists to speculate that the stress-induced inhibition of
neurogenesis and of BDNF are central to the emotional symptoms of
depression. I find it to be somewhat of a stretch to connect altered
hippocampal function with the many facets of this disease. Nevertheless,
these hippocampal changes may play a large part in the substantial memory
dysfunction typical of major depression.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>New Drugs for Depression</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>THE CURRENT GENERATION of antidepressants boost levels of serotonin,
dopamine and norepinephrine, and there is tremendous ongoing research to
develop more effective versions of these drugs. But some novel therapies
target steps more intimately related to the interactions between stress and
depression.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Not surprisingly, some of that work focuses on the effects of
glucocorticoids. For example, a number of pharmaceuticals that are safe and
clinically approved for other reasons can transiently block the synthesis of
glucocorticoids in the adrenal glands or block access of glucocorticoids to
one of their important receptors in the brain. Fascinatingly, the key
compound that blocks glucocorticoid receptors is RU486, famous and
controversial for its capacity to also block progesterone receptors in the
uterus and for its use as the "abortion drug." Beverly Murphy of McGill
University, Owen Wolkowitz of the University of California at San Francisco
and Alan Schatzberg of Stanford have shown that such antiglucocorticoids can
act as antidepressants for a subset of severely depressed people with highly
elevated glucocorticoid levels. These findings are made even more promising
by the fact that this group of depressed individuals tend to be most
resistant to the effects of more traditional antidepressants.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Another strategy targets CRH. Because depression, like anxiety, often
involves an overly responsive amygdala and sympathetic nervous system, CRH
is a key neurotransmitter in the communication from the former to the
latter. Moreover, infusion of CRH into the brain of a monkey can cause some
depressionlike symptoms. These findings have prompted studies as to whether
CRH-receptor blockers can have an antidepressant action. It appears they
can, and such drugs are probably not far off.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Using the same receptor-blocking strategy, researchers have curbed
the action of a neurotransmitter called Substance P, which binds to the
neurokinin-1 (NK-1) receptor. In the early 1990s workers discovered that
drugs binding with NK-1 prevent some aspects of the stress response. In one
trial and several animal studies, Substance P has worked as an
antidepressant.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Other approaches center on the hippocampus. Investigators are
injecting BDNF into the brains of rats to counteract the inhibitory effects
of glucocorticoids on neurogenesis. My own laboratory is using gene therapy
to protect the hippocampus of rats from the effects of stress--much as we
are doing in the amygdala to prevent anxiety. These genes are triggered by
glucocorticoids; once activated, they express an enzyme that degrades
glucocorticoids. The net result blocks the deleterious effects of these
hormones. We are now exploring whether this treatment can work in
animals.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>As is now clear, I hope, anxiety and depression are connected. Yet a
state of constant vigilance and one of constant helplessness seem quite
different. When does stress give rise to one as opposed to the other? The
answer seems to lie in how chronic the stress is.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>The Stress Continuum</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>IMAGINE A RAT trained to press a lever to avoid a mild, occasional
shock--a task readily mastered. Thai rat is placed into a cage with the
lever, and the anticipatory sense of mastery might well activate the
pleasurable dopaminergic projections to the frontal cortex. When the
increase in glucocorticoid secretion is moderate and transient--as would
likely be the case here--the hormone enhances dopamine release.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Suppose that in this circumstance, however, the lever has been
disconnected; pressing it no longer prevents shocks. Initially this
alteration produces a wildly hypervigilant state in the rat as it seeks a
new coping response to stop the shocks. The animal presses the lever
repeatedly, frantically trying to regain control. This is the essence of
anxiety and of the multiple, disorganized attempts at coping.
Physiologically, this state is characterized by massive activation of the
sympathetic nervous system by epinephrine and of the norepinephrine
projection from the locus coeruleus, as well as moderately increased
glucocorticoid secretion.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>And as the shocks continue and the rat finds each attempt at coping
useless, a transition occurs. The stress response becomes more dominated by
high glucocorticoid levels than by epinephrine and the sympathetic nervous
system--which are largely in control of the immediate fight-or-flight
reaction. The brain chemistry begins to resemble that of depression as key
neurotransmitters become depleted and the animal ceases trying to cope. It
has learned to be helpless, passive and involuted. If anxiety is a
crackling, menacing brushfire, depression is a suffocating heavy blanket
thrown on top of it.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress and Genes</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>I DO NOT WANT to conclude this article having given the impression
that anxiety and depression are "all" or "only" about stress. Obviously,
they are not:. Both illnesses have substantial genetic components as well.
Genes code for the receptors for dopamine, serotonin and glucocorticoids.
They also code for the enzymes that synthesize and degrade those chemical
messengers, for the pumps that remove them from the synapses, for growth
factors like BDNF, and so on.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>But those genetic influences are not inevitable. Remember, if an
individual has one of the major psychiatric disorders, her identical twin
has only about a 50 percent chance of having it. Instead the genetic
influences seem to be most about vulnerability: how the brain and body react
to certain environments, including how readily the brain and body
reequilibrate after stress.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Experience, beginning remarkably early in life, also influences how
one responds to stressful environments. The amount of stress a female rat is
exposed to during pregnancy influences the amount of glucocorticoids that
cross the placenta and reach the fetus; that exposure can then alter the
structure and function of that fetus's hippocampus in adulthood. Separate a
newborn rat from its mother for a sustained period and it will have
increased levels of CRH as an adult. Seymour Levine, One of the giants of
psychobiology, illustrates this point with a quotation from William
Faulkner: "The past is not dead. It's not even the past."</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>An understanding of the role of stress in psychiatric disorders
offers much. It teaches us that a genetic legacy of anxiety or depression
does not confer a life sentence on sufferers of these tragic diseases. It is
paving the way for some new therapies that may help millions. Given that
there is a continuum between the biology of these disorders and that of the
"normal" aspects of emotion, these findings are not only pertinent to "them
and their diseases" but to all of us in our everyday lives. Perhaps most
important, such insight carries with it a social imperative: namely, that we
must find ways to heal a world in which so many people learn that they must
always feel watchful and on guard or that they must always feel
helpless.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>SOME NOVEL THERAPEUTIC STRATEGIES</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Substance P. This compound is released during painful sensations and
stress and are found throughout the central nervous system but in greater
amounts in the amygdala and locus coeruleus, among other stress related
areas. Current work-including one clinical trial--suggests that blocking the
action of Substance P may blunt anxiety and depression. But another clinical
trial did not support this finding.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Corticotropin-Releasing Hormone. This hormone is released by the
amygdala and initiates the stress cascade. Research efforts now include
trying to block receptors for CRH in the brain stem. Without information
from CRH, the brain stem will not set the sympathetic nervous system in
motion,, thus preventing the release of epinephrine by the adrenal glands.
This blockade could block anxiety and depression.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Brain-Derived Neurotrophic Factor. This substance is important to the
creation of new nerve cells. By injecting BDNF into brains, researchers hope
to counteract the deleterious effects of glucocorticoids on neurogenesis in
the hippocampus, thereby maintaining healthy memory function and preventing
the hippocampal atrophy often seen in depressed people.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Gene Therapy. This treatment can introduce novel genes to specific
regions of the brain; these genes can then produce proteins that can undo or
prevent the effects of stress. Current studies aim to figure out which genes
are active in the amygdala during stress. Introducing genes that inhibit
unwanted neural branching in the amygdala might then thwart the
anxiety-inducing effects of stress. For depression, the goal is different:
genes placed in the hippocampus could produce proteins that would break down
glucocorticoids, preventing damage to nerve cells-and, accordingly, the
memory impairment-that can accompany depression.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Anxiety becomes depression if stress is chronic and levels of
dopamine [D}, glucocorticoids [ G} and epinephrine [E} change accordingly.
If a rat knows how to press a lever to avoid a shock, it can feel pleasure
in that mastery. If the lever no longer works, however, anxiety sets in and
the animal desperately tries different strategies to avoid the shock (2}. As
coping proves elusive, hypervigilance is replaced by passivity and
depression (3).</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>MORE TO EXPLORE</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Why Zebras Don't Get Ulcers. Robert M. Sapolski. W. H. Freeman and
Company, 1998.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>The End of Stress as We Know It. Bruce McEwen, with Elizabeth Norton
Lasley. Joseph Henry Press, Washington D.C., 2002.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Better Than Prozac. Samuel H. Barondes. Oxford University Press,
2003.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>OVERVIEW / Battling Stress</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>• Scientists understand a lot about the role stress plays in the
development of anxiety disorders and major depression, which may affect as
many as 40 million people in the U.S. And they are coming to see the ways in
which unremitting stress can transform anxiety into depression.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>• Insights into the neurochemistry of stress are allowing researchers
to develop new ways of thinking about drug development. In addition to
refining drugs that are already on the market, these findings are leading to
entirely novel strategies for treatments.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>• Finding these alternatives is crucially important because many
people are not helped by currently available medications.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>VICIOUS CYCLE OF STRESS</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>STRESS PATHWAYS are diverse and involve many regions of the brain in
feedback loops that sometimes greatly amplify a response. The
process-simplified somewhat in this diagram-begins when an actual or
perceived threat activates the sensory and higher reasoning centers in the
cortex. The cortex then sends a message to the amygdala, the principal
mediator of the stress response. Separately, a preconscious signal my
precipitate activity in the amygdala. The amygdala releases
corticotropin-releasing hormone, which stimulates the brain stem to activate
the sympathetic nervous system via the spinal cord. In response, the adrenal
glands produce the stress hormone epinephrine; a different pathway
simultaneously triggers the adrenals to release glucocorticoids. The two
types of hormones act on the muscle, heart and lungs to prepare the body for
"fight or flight". If the stress becomes chronic, glucocorticoids induce the
locus coeruleus to release norepinephrine that communicates with the
amygdala, leading to the production of more CRH- and to ongoing reactivation
of stress pathways.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DEPRESSION'S EFFECTS</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DOPAMINE DEPLETION</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Prolonged exposure to stress hormones can increase the risk of
depression by depleting levels of dopamine. This neurotransmitter is
integral to the pleasure pathway, which involves many brain structures,
including the prefrontal cortex.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>NOREPINEPHRINE DEPLETION</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Because stimulation from the raphe nucleus falls off after chronic
stress, the locus coeruleus secretes less norepinephrine, and attentiveness
is accordingly diminished.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>SEROTONIN DEPLETION</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress brings about reduced secretion of the neurotransmitter
serotonin from the raphe nucleus, which communicates with the locus
coerlueus and the cortex.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>HIPPOCAMPAL SHRINKAGE</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress brings about cell death in the hippocampus- and studies have
found that this brain region is 10 to 20 percent smaller in depressed
individuals. Such impairment can lead to memory problems.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DIAGRAM</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DIAGRAM</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>GRAPH</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>GRAPH</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>GRAPH</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>PHOTO (COLOR)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>PHOTO (COLOR)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>PHOTO (COLOR)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>~~~~~~~~</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>By Robert Salzano</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>ROBERT SAPOLSKY is professor of biological science and neurology at
Stanford University and a research associate at the National Museums of
Kenya, where he has studied a population of wild baboons for more than two
decades. He earned a Ph.D. in neuroendocrinology from the Rockefeller
University in 1984. Sapolsky's research interests include neuronal death,
gene therapy and the physiology of primates.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Copyright of Scientific American is the property of Scientific
American Inc. and its content may not be copied or e-mailed to multiple
sites or posted to a listserv without the copyright holder`s express written
permission. However, users may print, download, or e-mail articles for
individual use.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Source: Scientific American, Sep2003, Vol. 289 Issue 3, p88,
10p</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Item: 10544899</FONT></P>
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<DIV> </DIV>
<DIV><FONT lang=0 face=Arial size=2 FAMILY="SANSSERIF"
PTSIZE="10">----------<BR>Howard Bloom<BR>Author of The Lucifer Principle: A
Scientific Expedition Into the Forces of History and Global Brain: The
Evolution of Mass Mind From The Big Bang to the 21st Century<BR>Visiting
Scholar-Graduate Psychology Department, New York University; Faculty Member,
The Graduate
Institute<BR>www.howardbloom.net<BR>www.bigbangtango.net<BR>Founder:
International Paleopsychology Project; founding board member: Epic of
Evolution Society; founding board member, The Darwin Project; founder: The
Big Bang Tango Media Lab; member: New York Academy of Sciences, American
Association for the Advancement of Science, American Psychological Society,
Academy of Political Science, Human Behavior and Evolution Society,
International Society for Human Ethology; advisory board member:
Youthactivism.org; executive editor -- New Paradigm book series.<BR>For
information on The International Paleopsychology Project, see:
www.paleopsych.org<BR>for two chapters from <BR>The Lucifer Principle: A
Scientific Expedition Into the Forces of History, see
www.howardbloom.net/lucifer<BR>For information on Global Brain: The
Evolution of Mass Mind from the Big Bang to the 21st Century, see
www.howardbloom.net<BR></FONT></DIV>
<P>
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