Bessel A. van der Kolk, MD.
Harvard Medical School
HRI Trauma Center
227 Babcock Street
Boston, MA 02146
The author wishes to thank Rita Fisler, Ed.M. for
her editorial assistance.
BACKGROUND
For more than a century, ever since people's
responses to overwhelming experiences were first
systematically explored, it has been noted that the
psychological effects of trauma are expressed as
changes in the biological stress response. In 1889,
Pierre Janet (1), postulated that intense emotional
reactions make events traumatic by interfering with
the integration of the experience into existing
memory schemes. Intense emotions, Janet thought,
cause memories of particular events to be dissociated
from consciousness, and to be stored, instead, as
visceral sensations (anxiety and panic), or as visual
images (nightmares and flashbacks). Janet also
observed that traumatized patients seemed to react to
reminders of the trauma with emergency responses that
had been relevant to the original threat, but that
had no bearing on current experience. He noted that
victims had trouble learning from experience: unable
to put the trauma behind them, their energies were
absorbed by keeping their emotions under control at
the expense of paying attention to current exigencies.
They became fixated upon the past, in some cases by
being obsessed with the trauma, but more often by
behaving and feeling like they were traumatized over
and over again without being able to locate the
origins of these feelings (2,3).
Freud also considered the tendency to stay fixated
on the trauma to be biologically based: "After
severe shock.. the dream life continually takes the
patient back to the situation of his disaster from
which he awakens with renewed terror.. the patient
has undergone a physical fixation to the trauma"(4).
Pavlov's investigations continued the tradition of
explaining the effects of trauma as the result of
lasting physiological alterations. He, and others
employing his paradigm, coined the term "defensive
reaction" for a cluster of innate reflexive
responses to environmental threat (5). Many studies
have shown how the response to potent environmental
stimuli (unconditional stimuli-US) becomes a
conditioned reaction. After repeated aversive
stimulation, intrinsically non-threatening cues
associated with the trauma (conditional stimuli-CS)
become capable of eliciting the defensive reaction by
themselves (conditional response-CR). A rape victim
may respond to conditioned stimuli, such as the
approach by an unknown man, as if she were about to
be raped again, and experience panic. Pavlov also
pointed out that individual differences in
temperament accounted for the diversity of long term
adaptations to trauma.
Abraham Kardiner(6), who first systematically
defined posttraumatic stress for American audiences,
noted that sufferers from "traumatic neuroses"
develop an enduring vigilance for and sensitivity to
environmental threat, and stated that "the
nucleus of the neurosis is a physioneurosis. This is
present on the battlefield and during the entire
process of organization; it outlives every
intermediary accommodative device, and persists in
the chronic forms. The traumatic syndrome is ever
present and unchanged". In "Men under
Stress", Grinker and Spiegel (7) catalogue the
physical symptoms of soldiers in acute posttraumatic
states: flexor changes in posture, hyperkinesis,
"violently propulsive gait", tremor at rest,
masklike facies, cogwheel rigidity, gastric distress,
urinary incontinence, mutism, and a violent startle
reflex. They noted the similarity between many of
these symptoms and those of diseases of the
extrapyramidal motor system. Today we can understand
them as the result of stimulation of biological
systems, particularly of ascending amine projections.
Contemporary research on the biology of PTSD,
generally uninformed by this earlier research,
confirms that there are persistent and profound
alterations in stress hormones secretion and memory
processing in people with PTSD.
THE SYMPTOMATOLOGY OF PTSD.
Starting with Kardiner(6), and closely followed by
Lindemann (8), a vast literature on combat trauma,
crimes, rape, kidnapping, natural disasters,
accidents and imprisonment have shown that the trauma
response is bimodal: hypermnesia, hyper-reactivity to
stimuli and traumatic reexperiencing coexist with
psychic numbing, avoidance, amnesia and anhedonia (9,10,11,12).
These responses to extreme experiences are so
consistent across traumatic stimuli that this
biphasic reaction appears to be the normative
response to any overwhelming and uncontrollable
experience. In many people who have undergone severe
stress, the post-traumatic response fades over time,
while it persists in others. Much work remains to be
done to spell out issues of resilience and
vulnerability, but magnitude of exposure, prior
trauma, and social support appear to be the three
most significant predictors for developing chronic
PTSD (13,14).
In an apparent attempt to compensate for chronic
hyperarousal, traumatized people seem to shut down:
on a behavioral level, by avoiding stimuli
reminiscent of the trauma; on a psychobiological
level, by emotional numbing, which extends to both
trauma-related, and everyday experience (15). Thus,
people with chronic PTSD tend to suffer from numbing
of responsiveness to the environment, punctuated by
intermittent hyperarousal in response to conditional
traumatic stimuli. However, as Pitman has pointed out
(16), in PTSD, the stimuli that precipitate emergency
responses may not be conditional enough: many
triggers not directly related to the traumatic
experience may precipitate extreme reactions. Thus,
people with PTSD suffer both from generalized
hyperarousal and from physiological emergency
reactions to specific reminders(9,10) The loss of
affective modulation that is so central in PTSD
mayhelp explain the observation that traumatized
people lose the capacity to utilize affect states as
signals (18). Instead of using feelings as cues to
attend to incoming information, in people with PTSD
arousal is likely to precipitate flight or fight
reactions (19). Thus, they are prone to go
immediately from stimulus to response without making
the necessary psychological assessment of the meaning
of what is going on. This makes them prone to freeze,
or, alternatively, to overreact and intimidate others
in response to minor provocations (12,20).
PSYCHOPHYSIOLOGY
Abnormal psychophysiological responses in PTSD
have been demonstrated on two different levels: 1) in
response to specific reminders of the trauma and 2)
in response to intense, but neutral stimuli, such as
acoustic startle. The first paradigm implies
heightened physiological arousal to sounds, images,
and thoughts related to specific traumatic incidents.
A large number of studies have confirmed that
traumatized individuals respond to such stimuli with
significant conditioned autonomic reactions, such as
heart rate, skin conductance and blood pressure (20,21,22,23,
24,25). The highly elevated physiological responses
that accompany the recall of traumatic experiences
that happened years, and sometimes decades before,
illustrate the intensity and timelessness with which
traumatic memories continue to affect current
experience (3,16). This phenomenon has generally been
understood in the light of Peter Lang's work (26)
which shows that emotionally laden imagery correlates
with measurable autonomic responses. Lang has
proposed that emotional memories are stored as "associative
networks", that are activated when a person is
confronted with situations that stimulate a
sufficient number of elements that make up these
networks. One significant measure of treatment
outcome that has become widely accepted in recent
years is a decrease in physiological arousal in
response to imagery related to the trauma (27).
However, Shalev et al (28) have shown that
desensitization to specific trauma-related mental
images does not necessarily generalize to
recollections of other traumatic events, as well.
Kolb (29) was the first to propose that excessive
stimulation of the CNS at the time of the trauma may
result in permanent neuronal changes that have a
negative effect on learning, habituation, and
stimulus discrimination. These neuronal changes would
not depend on actual exposure to reminders of the
trauma for expression. The abnormal startle response
characteristic of PTSD (10) exemplifies such neuronal
changes.
Despite the fact that an abnormal acoustic startle
response (ASR) has been seen as a cardinal feature of
the trauma response for over half a century,
systematic explorations of the ASR in PTSD have just
begun. The ASR consists of a characteristic sequence
of muscular and autonomic responses elicited by
sudden and intense stimuli (30,31). The neuronal
pathways involved consist of only a small number of
mediating synapses between the receptor and effector
and a large projection to brain areas responsible for
CNS activation and stimulus evaluation (31). The ASR
is mediated by excitatory amino acids such as
glutamate and aspartate and is modulated by a variety
of neurotransmitters and second messengers at both
the spinal and supraspinal level (32). Habituation of
the ASR in normals occurs after 3 to 5 presentations
(30).
Several studies have demonstrated abnormalities in
habituation to the ASR in PTSD (33,34,35,36). Shalev
et al (33) found a failure to habituate both to CNS
and ANS-mediated responses to ASR in 93% of the PTSD
group, compared with 22% of the control subjects.
Interestingly, people who previously met criteria for
PTSD, but no longer do so now, continue to show
failure of habituation of the ASR (van der Kolk et al,
unpublished data; Pitman et al, unpublished data),
which raises the question whether abnormal
habituation to acoustic startle is a marker of, or a
vulnerability factor for developing PTSD.
The failure to habituate to acoustic startle
suggests that traumatized people have difficulty
evaluating sensory stimuli, and mobilizing
appropriate levels of physiological arousal(30). Thus,
the inability of people with PTSD to properly
integrate memories of the trauma and, instead, to get
mired in a continuous reliving of the past, is
mirrored physiologically in the misinterpretation of
innocuous stimuli, such as the ASR, as potential
threats.
THE HORMONAL STRESS RESPONSE AND THE
PSYCHOBIOLOGY OF PTSD.
Post Traumatic Stress Disorder develops following
exposure to events that are intensely distressing.
Intense stress is accompanied by the release of
endogenous, stress-responsive neurohormones, such as
cortisol, epinephrine and norepinephrine (NE),
vasopressin, oxytocin and endogenous opioids. These
stress hormones help the organism mobilize the
required energy to deal with the stress, ranging from
increased glucose release to enhanced immune function.
In a well-functioning organism, stress produces rapid
and pronounced hormonal responses. However, chronic
and persistent stress inhibits the effectiveness of
the stress response and induces desensitization (37).
Much still remains to be learned about the
specific roles of the different neurohormones in the
stress response. NE is secreted by the Locus
Coeruleus(LC) and distributed through much of the CNS,
particularly the neocortex and the limbic system,
where it plays a role in memory consolidation and
helps initiate fight/ flight behaviors.
Adrenocorticotropin (ACTH) is released from the
anterior pituitary, and activates a cascade of
reactions, eventuating in release of glucocorticoids
from the adrenals. The precise interrelation between
Hypothalamic-Pituitary-Adrenal (HPA) Axis hormones
and the catecholamines in the stress response is not
entirely clear, but it is known that stressors that
activate NE neurons also increase CRF concentrations
in the LC (38), while intracerebral ventricular
infusion of CRF increases NE in the forebrain (39).
Glucocorticoids and catecholamines may modulate each
other's effects: in acute stress, cortisol helps
regulate stress hormone release via a negative
feedback loop to the hippocampus, hypothalamus and
pituitary (40) and there is evidence that
corticosteroids normalize catecholamine-induced
arousal in limbic midbrain structures in response to
stress (41). Thus, the simultaneous activation of
corticosteroids and catecholamines could stimulate
active coping behaviors, while increased arousal in
the presence of low glucocorticoid levels may promote
undifferentiated fight or flight reactions (42).
While acute stress activates the HPA axis and
increases glucocorticoid levels, organisms adapt to
chronic stress by activating a negative feedback loop
that results in 1) decreased resting glucocorticoid
levels in chronically stressed organisms, (43), 2)
decreased glucocorticoid secretion in response to
subsequent stress (42), and 3) increased
concentration of glucocorticoid receptors in the
hippocampus (44). Yehuda has suggested that increased
concentration of glucocorticoid receptors could
facilitate a stronger glucocorticoid negative
feedback, resulting in a more sensitive HPA axis and
a faster recovery from acute stress (45).
Chronic exposure to stress affects both acute and
chronic adaptation: it permanently alters how an
organism deals with its environment on a day-to-day
basis, and it interferes with how it copes with
subsequent acute stress (45).
------------TABLE 1, PARTS 1 &
2 ABOUT HERE------------
NEUROENDOCRINE ABNORMALITIES IN PTSD.
Since there is an extensive animal literature on
the effects of inescapable stress on the biological
stress response of other species, such as monkeys and
rats, much of the biological research on people with
PTSD has focussed on testing the applicability of
those research findings to people with PTSD (46,47).
People with PTSD, like chronically and inescapbly
shocked animals, seem to suffer from a persistent
activation of the biological stress response upon
exposure to stimuli reminiscent of the trauma.
1) Catecholamines. Neuroendocrine studies
of Vietnam veterans with PTSD have found good
evidence for chronically increased sympathetic
nervous system activity in PTSD. One study (48) found
elevated 24h excretions of urinary NE and epinephrine
in PTSD combat veterans compared with patients with
other psychiatric diagnoses. While Pitman & Orr (49)
did not replicate these findings in 20 veterans and
15 combat controls, the mean urinary NE excretion
values in their combat controls (58.0 ug/day) were
substantially higher than those previously reported
in normal populations. The expected compensatory
downregulation of adrenergic receptors in response to
increased levels of norepinephrine was confirmed by a
study that found decreased platelet alpha-2
adrenergic receptors in combat veterans with PTSD,
compared with normal controls (50). Another study
also found an abnormally low alpha-2 adrenergic
receptor-mediated adenylate cyclase signal
transduction (51). In a recent study Southwick et al
(52) used yohimbine injections (0.4 mg/kg), which
activate noradrenergic neurons by blocking the alpha-2
auto- receptor, to study noradrenergic neuronal
dysregulation in Vietnam veterans with PTSD.
Yohimbine precipitated panic attacks in 70% of
subjects and flashbacks in 40%. Subjects responded
with larger increases in plasma MHPG than controls.
Yohimbine precipitated significant increases in all
PTSD symptoms.
2) Corticosteroids. Two studies have shown
that veterans with PTSD have low urinary cortisol
excretion, even when they have comorbid major
depressive disorder (42,53). One study failed to
replicate this finding (49). In a series of studies,
Yehuda et al (42,54) found increased numbers of
lymphocyte glucocorticoid receptors in Vietnam
veterans with PTSD. Interestingly, the number of
glucocorticoid receptors was proportional to the
severity of PTSD symptoms. Yehuda (54) also has
reported the results of an unpublished study by Heidi
Resnick, in which acute cortisol response to trauma
was studied from blood samples from 20 acute rape
victims. Three months later, a prior trauma history
was taken, and the subjects were evaluated for the
presence of PTSD. Victims with a prior history of
sexual abuse were significantly more likely to have
developed PTSD three months following the rape than
rape victims who did not develop PTSD. Cortisol
levels shortly after the rape were correlated with
histories of prior assaults: the mean initial
cortisol level of individuals with a prior assault
history was 15 ug/dl compared to 30 ug/dl in
individuals without. These findings can be
interpreted to mean either that prior exposure to
traumatic events result in a blunted cortisol
response to subsequent trauma, or in a quicker return
of cortisol to baseline following stress. The fact
that Yehuda et al (45) also found subjects with PTSD
to be hyperresponsive to low doses of dexamethasone
argues for an enhanced sensitivity of the HPA
feedback in traumatized patients.
3) Serotonin. While the role of serotonin
in PTSD has not been systematically investigated,
both the fact that inescapably shocked animals
develop decreased CNS serotonin levels (55), and that
serotonin re-uptake blockers are effective
pharmacological agents in the treatment of PTSD,
justify a brief consideration of the potential role
of this neurotransmitter in PTSD. Decreased serotonin
in humans has repeatedly been correlated with
impulsivity and aggression (56,57,58). The literature
tends to readily assume that these relationships are
based on genetic traits. However, studies of
impulsive, aggressive and suicidal patients seem to
find at least as robust an association between those
behaviors and histories of childhood trauma (e.g. 59,60,61).
It is likely that both temperament and experience
affect relative CNS serotonin levels (12).
Low serotonin in animals is also related to an
inability to modulate arousal, as exemplified by an
exaggerated startle (62,63), and increased arousal in
response to novel stimuli, handling, or pain (63).
The behavioral effects of serotonin depletion on
animals is characterized by hyperirritability,
hyperexitability, and hypersensitivity, and an
"...exaggerated emotional arousal and/or
aggressive display, to relatively mild stimuli"
(63). These behaviors bear a striking resemblance to
the phenomenology of PTSD in humans. Furthermore,
serotonin re-uptake inhibitors have been found to be
the most effective pharmacological treatment of both
obsessive thinking in people with OCD (64), and of
involuntary preoccupation with traumatic memories in
people with PTSD (65,66). It is likely that serotonin
plays a role in the capacity to monitor the
environment flexibly and to respond with behaviors
that are situation-appropriate, rather than reacting
to internal stimuli that are irrelevant to current
demands.
4). Endogenous opioids. Stress induced
analgesia (SIA) has been described in experimental
animals following a variety of inescapable stressors
such as electric shock, fighting, starvation and cold
water swim (67). In severely stressed animals, opiate
withdrawal symptoms can be produced both by
termination of the stressful stimulus or by naloxone
injections. Stimulated by the findings that fear
activates the secretion of endogenous opioid peptides,
and that SIA can become conditioned to subsequent
stressors and to previously neutral events associated
with the noxious stimulus, we tested the hypothesis
that in people with PTSD, re-exposure to a stimulus
resembling the original trauma will cause an
endogenous opioid response that can be indirectly
measured as naloxone reversible analgesia (68,69). We
found that two decades after the original trauma,
people with PTSD developed opioid-mediated analgesia
in response to a stimulus resembling the traumatic
stressor, which we correlated with a secretion of
endogenous opioids equivalent to 8 mg of morphine.
Self-reports of emotional responses suggested that
endogenous opioids were responsible for a relative
blunting of the emotional response to the traumatic
stimulus.
Endogenous opiates and Stress Induced Analgesia:
Possible implications for affective function.
When young animals are isolated, and older ones
attacked, they respond initially with aggression (hyperarousal-
fight- protest), and, if that does not produce the
required results, with withdrawal (numbing-flight-despair).
Fear-induced attack or protest patterns in the young
serve to attract protection, and in mature animals to
prevent or counteract the predator's activity. During
external attacks pain-inhibition is a useful
defensive capacity, because attention to pain would
interfere with effective defense: grooming or licking
wounds may attract opponents and stimulate further
attack (70). Thus defensive and pain-motivated
behaviors are mutually inhibitory. Stress-induced
analgesia protects organisms against feeling pain
while engaged in defensive activities. As early as
1946, Beecher (71), after observing that 75% of
severely wounded soldiers on the Italian front did
not request morphine, speculated that "strong
emotions can block pain". Today, we can
reasonably assume that this is due to the release of
endogenous opioids(68,69).
Endogenous opioids, which inhibit pain and reduce
panic, are secreted after prolonged exposure to
severe stress. Siegfried et al (70) have observed
that memory is impaired in animals when they can no
longer actively influence the outcome of a
threatening situation. They showed that both the
freeze response and panic interfere with effective
memory processing: excessive endogenous opioids and
NE both interfere with the storage of experience in
explicit memory. Freeze/numbing responses may serve
the function of allowing organisms to not "consciously
experience" or not to remember situations of
overwhelming stress (and which thus will also keep
them from learning from experience). We have proposed
that the dissociative reactions in people in response
to trauma may be analogous to this complex of
behaviors that occur in animals after prolonged
exposure to severe uncontrollable stress (68).
DEVELOPMENTAL LEVEL AFFECTS THE PSYCHOBIOLOGICAL
EFFECTS OF TRAUMA
While most studies on PTSD have been done on
adults, particularly on war veterans, in recent years
a small prospective literature is emerging that
documents the differential effects of trauma at
various age levels. Anxiety disorders, chronic
hyperarousal, and behavioral disturbances have been
regularly described in traumatized children (e.g.72,73,74).
In addition to the reactions to discrete, one time,
traumatic incidents documented in these studies,
intrafamilial abuse is increasingly recognized to
produce complex post-traumatic syndromes (75), which
involve chronic affect dysregulation, destructive
behavior against self and others, learning
disablities, dissociative problems, somatization, and
distortions in concepts about self and others (76,77).
The Field Trials for DSM IV showed that these this
conglomeration of symptoms tended to occur together
and that the severity of this syndrome was
proportional to the age of onset of the trauma and
its duration (78).
While current research on traumatized children is
outside the scope of this review, it is important to
recognize that a range of neurobiological
abnormalities are beginning to be identified in this
population. Frank Putnam's prospective, but as yet
unpublished, studies (personal communications, 1991,1992,1993)
are showing major neuroendocrine disturbances in
sexually abused girls compared with normals. Research
on the psychobiology of childhood trauma can be
profitably informed by the vast literature on the
psychobiological effects of trauma and deprivation in
non-human primates (12,79).
TRAUMA AND MEMORY: The flexibility of memory and
the engraving of trauma
One hundred years ago, Pierre Janet (1) suggested
that the most fundamental of mental activities is the
storage and categorization of incoming sensations
into memory, and the retrieval of those memories
under appropriate circumstances. He, like
contemporary memory researchers, understood that what
is now called semantic, or declarative, memory is an
active and constructive process and that remembering
depends on existing mental schemata (3,80): once an
event or a particular bit of information is
integrated into existing mental schemes, it will no
longer be accessible as a separate, immutable entity,
but be distorted both by prior experience, and by the
emotional state at the time of recall(3). PTSD, by
definition, is accompanied by memory disturbances,
consisting of both hypermnesias and amnesias (9,10).
Research into the nature of traumatic memories (3)
indicates that trauma interferes with delarative
memory, i.e. conscious recall of experience, but does
not inhibit implicit, or non-declarative memory, the
memory system that controls conditioned emotional
responses, skills and habits, and sensorimotor
sensations related to experience. There now is enough
information available about the biology of memory
storage and retrieval to start building coherent
hypotheses regarding the underlying psychobiological
processes involved in these memory disturbances (3,16,17,25).
------- FIGURE 1 (DIFFERENT FORMS
OF MEMORY) SOMEWHERE HERE -----
In the beginning of this century Janet already
noted that: "certain happenings ... leave
indelible and distressing memories-- memories to
which the sufferer continually returns, and by which
he is tormented by day and by night" (81).
Clinicians and researchers dealing with traumatized
patients have repeatedly made the observation that
the sensory experiences and visual images related to
the trauma seem not to fade over time, and appear to
be less subject to distortion than ordinary
experiences (1,49,82). When people are traumatized,
they are said to experience "speechless terror":
the emotional impact of the event may interfere with
the capacity to capture the experience in words or
symbols. Piaget (83) thought that under such
circumstances, failure of semantic memory leads to
the organization of memory on a somatosensory or
iconic level (such as somatic sensations, behavioral
enactments, nightmares and flashbacks). He pointed
out: "It is precisely because there is no
immediate accommodation that there is complete
dissociation of the inner activity from the external
world. As the external world is solely represented by
images, it is assimilated without resistance (i.e.
unattached to other memories) to the unconscious ego".
Traumatic memories are state dependent.
Research has shown that, under ordinary conditions,
many traumatized people, including rape victims (84),
battered women (85) and abused children (86) have a
fairly good psychosocial adjustment. However, they do
not respond to stress the way other people do. Under
pressure, they may feel, or act as if they were
traumatized all over again. Thus, high states of
arousal seem to selectively promote retrieval of
traumatic memories, sensory information, or behaviors
associated with prior traumatic experiences (9,10).
The tendency of traumatized organisms to revert to
irrelevant emergency behaviors in response to minor
stress has been well documented in animals, as well.
Studies at the Wisconsin primate laboratory have
shown that rhesus monkeys with histories of severe
early maternal deprivation display marked withdrawal
or aggression in response to emotional or physical
stimuli (such as exposure to loud noises, or the
administration of amphetamines), even after a long
period of good social adjustment (87). In experiments
with mice, Mitchell and his colleagues (88) found
that the relative degree of arousal interacts with
prior exposure to high stress to determine how an
animal will react to novel stimuli. In a state of low
arousal, animals tend to be curious and seek novelty.
During high arousal, they are frightened, avoid
novelty, and perseverate in familiar behavior,
regardless of the outcome. Under ordinary
circumstances, an animal will choose the most
pleasant of two alternatives. When hyperaroused, it
will seek whatever is familiar, regardless of the
intrinsic rewards. Thus, animals who have been locked
in a box in which they were exposed to electric
shocks and then released return to those boxes when
they are subsequently stressed. Mitchell concluded
that this perseveration is nonassociative, i.e.
uncoupled from the usual reward systems.
In people, analogous phenomena have been
documented: memories (somatic or symbolic) related to
the trauma are elicited by heightened arousal (89).
Information acquired in an aroused, or otherwise
altered state of mind is retrieved more readily when
people are brought back to that particular state of
mind (90,91). State dependent memory retrieval may
also be involved in dissociative phenomena in which
traumatized persons may be wholly or partially
amnestic for memories or behaviors enacted while in
altered states of mind (2,3,92).
Contemporary biological researchers have shown
that medications that stimulate autonomic arousal may
precipitate visual images and affect states
associated with prior traumatic experiences in people
with PTSD, but not in controls. In patients with PTSD
the injection of drugs such as lactate (93) and
yohimbine (52) tends to precipitate panic attacks,
flashbacks (exact reliving experiences) of earlier
trauma, or both. In our own laboratory, approximately
20% of PTSD subjects responded with a flashback of a
traumatic experience when they were presented with
acoustic startle stimuli.
Trauma, neurohormones and memory consolidation.
When people are under severe stress, they secrete
endogenous stress hormones that affect the strength
of memory consolidation. Based on animal models it
has been widely assumed (3,46,94) that massive
secretion of neurohormones at the time of the trauma
plays a role in the long term potentiation (LTP) (and
thus, the over- consolidation) of traumatic memories.
Mammals seem equipped with memory storage mechanisms
that ordinarily modulate the strength of memory
consolidation according to the strength of the
accompanying hormonal stimulation (95,96). This
capacity helps the organism evaluate the importance
of subsequent sensory input according to the relative
strength of associated memory traces. This phenomenon
appears to be largely mediated by NE input to the
amygdala (97,98, figure 2). In traumatized organisms,
the capacity to access relevant memories appears to
have gone awry: they become overconditioned to access
memory traces of the trauma and to "remember"
the trauma whenever aroused. While norepinephrine (NE)
seems to be the principal hormone involved in
producing LTP, other neurohormones secreted under
particular stressful circumstances, such as
endorphins and oxytocin, actually inhibit memory
consolidation (99).
The role of NE in memory consolidation has been
shown to have an inverted U-shaped function (95,96):
both very low and very high levels of CNS NE activity
interfere with memory storage. Excessive NE release
at the time of the trauma, as well as the release of
other neurohormones, such as endogenous opioids,
oxytocin and vasopressin, are likely to play a role
in creating the hypermnesias and the amnesias that
are a quintessential part of PTSD (9,10). It is of
interest that childbirth, which can be
extraordinarily stressful, almost never seems to
result in post traumatic problems (100). Oxytocin may
play a protective role that prevents the
overconsolidation of memories surrounding childbirth.
Physiological arousal in general can trigger
trauma-related memories, while, conversely, trauma-related
memories precipitate generalized physiological
arousal. It is likely that the frequent re-living of
a traumatic event in flashbacks or nightmares cause a
re-release of stress hormones which further kindle
the strength of the memory trace (46). Such a
positive feedback loop could cause subclinical PTSD
to escalate into clinical PTSD (16), in which the
strength of the memories appear so deeply engraved
that Pitman and Orr (17) have called it "the
Black Hole" in the mental life of the PTSD
patient, that attracts all associations to it, and
saps current life of its significance.
MEMORY, TRAUMA AND THE LIMBIC SYSTEM.
The limbic system is thought to be the part of the
CNS that maintains and guides the emotions and
behavior necessary for self-preservation and survival
of the species (101), and that is critically involved
in the storage and retrieval of memory. During both
waking and sleeping states signals from the sensory
organs continuously travel to the thalamus whence
they are distributed to the cortex (setting up a
"stream of thought"), to the basal ganglia
(setting up a "stream of movement") and to
the limbic system where they set up a "stream of
emotions"(102), that determine the emotional
significance of the sensory input. It appears that
most processing of sensory input occurs outside of
conscious awareness, and only novel, significant or
threatening information is selectively passed on to
the neocortex for further attention. Since people
with PTSD appear to over-interpret sensory input as a
recurrence of past trauma and since recent studies
have suggested limbic system abnormalities in brain
imaging studies of traumatized patients (103,104), a
review of the psychobiology of trauma would be
incomplete without considering the role of the limbic
system in PTSD (also see 105). Two particular areas
of the limbic system have been implicated in the
processing of emotionally charged memories: the
amygdala and the hippocampus (Table 2).
-------- TABLE 2 (FUNCTIONS OF
LIMBIC STRUCTURES) ABOUT HERE--------
The amygdala. Of all areas in the CNS, the
amygdala is most clearly implicated in the evaluation
of the emotional meaning of incoming stimuli (106).
Several investigators have proposed that the amygdala
assigns free-floating feelings of significance to
sensory input, which the neocortex then further
elaborates and imbues with personal meaning (101,106,107,108).
Moreover, it is thought to integrate internal
representations of the external world in the form of
memory images with emotional experiences associated
with those memories (80). After assigning meaning to
sensory information, the amygdala guides emotional
behavior by projections to the hypothalamus,
hippocampus and basal forebrain (106,107,109).
The septo-hippocampal system, which
anatomically is adjacent to the amygdala, is thought
to record in memory the spatial and temporal
dimensions of experience and to play an important
role in the categorization and storage of incoming
stimuli in memory. Proper functioning of the
hippocampus is necessary for explicit or declarative
memory (109). The hippocampus is thought to be
involved in the evaluation of spatially and
temporally unrelated events, comparing them with
previously stored information and determining whether
and how they are associated with each other, with
reward, punishment, novelty or non-reward (107,110).
The hippocampus is also implicated in playing a role
in the inhibition of exploratory behavior and in
obsessional thinking, while hippocampal damage is
associated with hyper-responsiveness to environmental
stimuli (111,112).
The slow maturation of the hippocampus, which is
not fully myelinated till after the third or fourth
year of life, is seen as the cause of infantile
amnesia (113,114). In contrast, it is thought that
the memory system that subserves the affective
quality of experience (roughly speaking procedural,
or "taxon" memory) matures earlier and is
less subject to disruption by stress (112).
As the CNS matures, memory storage shifts from
primarily sensorimotor (motoric action) and
perceptual representations (iconic), to symbolic and
linguistic modes of organization of mental experience
(83). With maturation, there is an increasing ability
to categorize experience, and link it with existing
mental schemes. However, even as the organism matures,
this capacity, and with it, the hippocampal
localization system, remains vulnerable to disruption
(45,107,110,115,116). A variety of external and
internal stimuli, such as stress induced
corticosterone production (117), decreases
hippocampal activity. However, even when stress
interferes with hippocampally mediated memory storage
and categorization, it is likely that some mental
representation of the experience is laid down by
means of a system that records affective experience,
but that has no capacity for symbolic processing and
placement in space and time (figure 2).
Decreased hippocampal functioning causes
behavioral disinhibition, possibly by stimulating
incoming stimuli to be interpreted in the direction
of "emergency" (fight/flight) responses.
The neurotransmitter serotonin plays a crucial role
in the capacity of the septo-hippocampal system to
activate inhibitory pathways that prevent the
initiation of emergency responses until it is clear
that they will be of use (110). This observation made
us very interested in a possible role for
serotonergic agents in the treatment of PTSD.
"Emotional memories are forever".
In animals, high level stimulation of the amygdala
interferes with hippocampal functioning (107, 109).
This implies that intense affect may inhibit proper
evaluation and categorization of experience. In
mature animals one-time intense stimulation of the
amygdala will produce lasting changes in neuronal
excitability and enduring behavioral changes in the
direction of either fight or flight (118). In
kindling experiments with animals, Adamec et al (119)
have shown that, following growth in amplitude of
amygdala and hippocampal seizure activity, permanent
changes in limbic physiology cause a lasting changes
in defensiveness and in predatory aggression. Pre-existing
"personality" played a significant role in
the behavioral effects of amygdala stimulation in
cats: animals that are temperamentally insensitive to
threat and prone to attack tend become more
aggressive, while in highly defensive animals
different pathways were activated, increasing
behavioral inhibition (119).
In a series of experiments, LeDoux has utilized
repeated electrical stimulation of the amygdala to
produce conditioned fear responses. He found that
cortical lesions prevent their extinction. This led
him to conclude that, once formed, the subcortical
traces of the conditioned fear response are indelible,
and that "emotional memory may be forever"
(118). In 1987, Lawrence Kolb (29) postulated that
patients with PTSD suffer from impaired cortical
control over subcortical areas responsible for
learning, habituation, and stimulus discrimination.
The concept of indelible subcortical emotional
responses, held in check to varying degrees by
cortical and septo-hippocampal activity, has led to
the speculation that delayed onset PTSD may be the
expression of subcortically mediated emotional
responses that escape cortical, and possibly
hippocampal, inhibitory control (3,16,94,120,121).
----- FIGURE 2 (effects of
emotional arousal) ABOUT HERE --------
Decreased inhibitory control may occur under a
variety of circumstances: under the influence of
drugs and alcohol, during sleep (as nightmares), with
aging, and after exposure to strong reminders of the
traumatic past. It is conceivable that traumatic
memories then could emerge, not in the distorted
fashion of ordinary recall, but as affect states,
somatic sensations or as visual images (nightmares [81]
or flashbacks [52]) that are timeless and unmodified
by further experience.
PSYCHOPHARMACOLOGICAL TREATMENT.
The goal of treatment of PTSD is to help people
live in the present, without feeling or behaving
according to irrelevant demands belonging to the past.
Psychologically, this means that traumatic
experiences need to be located in time and place and
distinguished from current reality. However,
hyperarousal, intrusive reliving, numbing and
dissociation get in the way of separating current
reality from past trauma. Hence, medications that
affect these PTSD symptoms are often essential for
patients to begin to achieve a sense of safety and
perspective from which to approach their tasks. While
numerous articles have been written about the drug
treatment of PTSD, to date, only 134 people with PTSD
have been enrolledin published double blind studies.
Most of these have been Vietnamcombat veterans.
Unfortunately, up until recently, only medications
which seem to be of limited therapeutic usefulness
have beenthesubject of adequate scientific scrutiny.
While the only published double blind studies of
medications in the treatment of PTSDhave been
tricyclic antidepressants and MAO Inhibitors (122,123,124),
it is sometimes assumed that they therefore also are
themosteffective. Three double-blind trials of
tricyclic antidepressants have been published (122,124,125),
two of which demonstrated modest improvement in PTSD
symptoms. While positive resultshave been claimed for
numerous other medications in case reportsand open
studies, at the present time there are no data
aboutwhich patient and which PTSD symptom will
predictably respond toanyof them. Success has been
claimed for just about every class ofpsychoactive
medication, including benzodiazepines (127),
tricyclic antidepressants (122,125), monamine oxidase
inhibitors (122,129) lithium carbonate (127), beta
adrenergic blockers and clonidine (130),
carbamezapine (131) and antipsychotic agents. The
accumulated clinical experience seems to indicate
that understanding thebasic neurobiology of arousal
and appraisal is the most useful guideinselecting
medications for people with PTSD (124,125). Autonomic
arousal can be reduced at different levels in the CNS:
throughinhibition of locus coeruleus noradrenergic
activity with clonidine and the beta adrenergic
blockers (130,132), or by increasing the inhibitory
effect of the gaba-ergic system with gaba-
ergicagonists (the benzodiazepines). During the past
two years a numberof case reports and open clinical
trials of fluoxetine were followedby our double blind
study of 64 PTSD subjects with fluoxetine (65).
Unlike the tricyclic antidepressants, which were
effective on either the intrusive (imipramine) or
numbing (amitryptiline) symptoms of PTSD, fluoxetine
proved to be effective forthewhole spectrum of PTSD
symptoms. It also acted more rapidly
thanthetricyclics. The fact that fluoxetine has
proven to be such aneffective treatment for PTSD
supports a larger role of the serotonergic system in
PTSD (66). Rorschach tests adminstered by
blindscorers revealed that subjects on fluoxetine
became able to takedistance from the emotional impact
of incoming stimuli and to becomeable to utilize
cognition to harness the emotional responses
tounstructured visual stimuli (van der Kolk et al,
unpublished).
While the subjects improved clinically, their
startle habituation got worse (van der Kolk et al,
unpublished). The 5-HT1a agonist buspirone shows some
promise in facilitating habituation (133) and thus
may play a useful adjunctive role in the pharmaco-
therapy of PTSD. Even newer research has suggested
abnormalities of the N-methyl-D-aspartate (NMDA)
receptor and of glutamate in PTSD (134), opening up
potential new avenues for the psychopharmacological
treatment of PTSD.
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