The body keeps the score:

The Body Keeps The Score:
Memory & the Evolving Psychobiology of Post Traumatic
Stress
by Bessel van der Kolk
Bessel A. van der Kolk, MD.
Harvard Medical School
HRI Trauma Center
227 Babcock Street
Boston, MA 02146
This is a version of an article first published in the Harvard Review of
Psychiatry, 1994, 1(5), 253-265. Note that this online version may
have minor differences from the published version.
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 & 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).
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 & 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
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 & Memory: The Flexibility of Memory & 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).
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 & 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).
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).
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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