SlideShare une entreprise Scribd logo
1  sur  22
Télécharger pour lire hors ligne
INDEX www.yassermetwally.com




                                        INTRODUCTION

                                        BRAIN REGIONS HYPOTHESIZED AS A PRIORI AS
                                         RELEVANT TO PTSD

                                        MRI OF THE HIPPOCAMPUS AND AMYGDAL

                                        FUNCTIONING NEUROIMAGING STUDIES




NEUROIMAGING OF POST-TRAUMATIC STRESS DISORDERS

We review some of the advances that have been made in understanding the structural,
biochemical, and functional neuroanatomy of post-traumatic stress disorder (PTSD). First, we
review the primary brain regions that had been hypothesized a priori, from the phenomenology
and neurobiology of PTSD, to be implicated in the pathophysiology. Next, we review findings from
neuroimaging studies of these brain regions in PTSD and explain the various experimental
methods and imaging technologies used in these studies. A broader perspective, including a
discussion of additional brain areas that may be involved in PTSD, is synthesized. We conclude
with a rationale and approach for studies testing sharply defined hypotheses and those using
multidisciplinary strategies that integrate neuroimaging data with other cognitive, biologic, and
genetic tools to study this complex disorder.

 BRAIN REGIONS HYPOTHESIZED A PRIORI AS RELEVANT TO PTSD

      The hippocampus

Post-traumatic stress disorder may occur following exposure to situations that induce strong
feelings of fear, helplessness, or horror (DSM-IV). One of the core symptoms in trauma survivors
with PTSD is a disturbance in memory function [1]. The hippocampus was one of the regions first
thought to be implicated in the pathophysiology of PTSD because of its role in both memory and
the neuroendocrine response to stress.

The first evidence that the hippocampus was involved in memory processing occurred in the late
1950s with the comprehensive neuropsychological evaluation of patient H.M., who underwent
bilateral surgical removal of the medial temporal lobes for treatment of intractable seizures and
became unable to acquire new memories [2]. H.M.'s intellectual ability (IQ), immediate memory,
knowledge from early life, and personality remained intact, suggesting that memory is a distinct
and separable cerebral function. Later, human cases with smaller lesions [3–5] and lesion studies
in primates [6–8] confirmed the hippocampus and adjacent cortical areas [9] (i.e., the medial
temporal lobe memory system) as essential for declarative memory formation. Declarative or
explicit memory entails information that can be recalled and described, such as memories of
events, faces, or special layouts [4,10]. Declarative memory is a distinct type of memory that
occurs in different brain regions from other types of memory; it includes memories for perceptual
and motor skills and other mnemonic processes such as priming, classical conditioning, operant
conditioning, habituation, and sensitization. Because the hippocampus is the physical region
critical for declarative memory function, one might hypothesize structural abnormalities in the
hippocampi of persons with PTSD.

In the hippocampi, there is a massive convergence of cortical neurons from various association
areas of the brain. Like an old-fashioned central telephone switchboard, the close physical
proximity created by this convergence allows for connections to be made. There is a biochemical
process by which declarative memories are formed through modification of neuronal connections
that is also relevant to the study of PTSD. Hebb was the first to describe memory as the formation
of an “assembly of association-area cells,” the synapses of which are more readily traversed by
some form of experience-induced synaptic strengthening [11]. Although significant questions
remain, it is believed that memories are formed through cellular-level changes in the synaptic
coupling between neurons related to an activity-dependent strengthening of that synaptic
connection, referred to as long-term potentiation (LTP) [12]. LTP is a form of synaptic plasticity
that strengthens the connection between neurons in the formation of networks that constitute an
experience, a memory, or learned information. The importance of this concept to PTSD is in
providing a putative cellular mechanism that might be disrupted or altered, thereby leading to
memory impairments in these individuals, even in the absence of any gross structural
hippocampal “damage.”

The physical integrity of the hippocampus and the biochemical process of LTP are relevant to
PTSD research from a neuroendocrine perspective. Alterations in systemic glucocorticoid (GC)
levels (either through direct manipulation or secondary to induced stress) have been shown
acutely to interfere with the biochemical processes of LTP and chronically to result in physical
damage to the hippocampus [13]. PTSD has been characterized by various alterations in the
hypothalamic-pituitary-adrenal (HPA) axis, such as decreased basal and circadian levels of
cortisol, decreased urinary excretion of cortisol, increased cortisol suppression following
dexamethasone, increased numbers of plasma lymphocyte GC receptors, and hypersecretion of
corticotrophin-releasing hormone [14].

Preclinical research has consistently demonstrated that sustained exposure to high GC levels via
exogenous GC administration leads to neuronal degeneration confined to the CA3 hippocampal
region in rats, tree shrews, and vervet monkeys [15–17]. Increased endogenous GC production as
a result of stressful conditions also results in a similar CA3 region hippocampal degeneration in
these animals [18–20] and in “dendritic pruning” [21–24]. Neuronal death and dendritic may lead
to a similar result in humans under similar high stress and high GC conditions.

How GCs mediate neuronal death and atrophy in the above studies is not completely known
[13,25]. Possible mechanisms include GC effects of decreasing hippocampal glucose uptake, which
may result in lowered ATP stores and heightened vulnerability or “endangerment” to insults [25];
augmenting excitatory amino acid accumulation in the hippocampus [26]; and increasing
expression of N-methyl-D-aspartate (NMDA) receptors [27,28]. Increased stimulation of both
NMDA and non-NMDA receptors may result in excitotoxicity, which results from excessive
mobilization of cytosolic calcium with overactivation of lipases, proteases, and nucleases and with
the generation of oxygen radicals [29]. It is not GCs acting alone but in combination with other
neurochemicals that produces dendritic pruning, neuronal atrophy, or neuronal death [13].

Despite our lack of understanding about the exact mechanism through which GCs exert their
effects on the hippocampus, there is little doubt that GCs affect not only the physical structure of
the hippocampus but also the hippocampus-based mechanism for declarative memory function.
Preclinical and human studies have explored the cognitive effects of stress-induced and exogenous
increases in GCs on declarative memory function. Healthy subjects given oral steroids display
increased errors of commission in verbal memory tasks (incorrectly identifying distractors as
target words), impaired verbal declarative memory, and impaired spacial memory (a form of
declarative memory) without changes in attention or level of arousal [29–31]. Intravenous infusion
of steroids produced impairment in both working memory and declarative memory in healthy
subjects [32]. Socially stressful situations, which increase endogenous GC levels, have similar
effects on declarative memory [33].

These acute effects of elevated GC levels (either through stress or exogenous administration) on
declarative memory are not via death or pruning of hippocampal neurons but rather through
directly impairing the biochemical process of LTP. Animal studies indicate that GC concentration
has an “inverse-U” relationship to hippocampal activity, with extremely low and high GC levels
disrupting hippocampal excitability and LTP [34]. Acute stress and GC receptor stimulation
impair LTP in a similar fashion [35–37].

In summary, increased GC levels may interfere with declarative memory through various
mechanisms of dendritic pruning, neuronal atrophy, neuronal death, and interfering with LTP.
However, most studies find decreased basal cortisol levels and increased negative feedback
sensitivity in subjects with PTSD. Several investigators have tried to resolve the apparent
paradox. The concept of “allostatic load,” for example, has been forwarded as a possible
mechanism for GC-mediated alterations in PTSD [38,39]. Allostasis refers to the ability to achieve
stability through change and is crucial for proper functioning of the HPA axis and other systems.
Accommodation is viewed as a stress that puts wear and tear on the system, eventually leading to
a harmful decrease in the system's ability to adapt to change [40]. Chronobiologic analyses of
circadian cortisol levels in PTSD have demonstrated a higher signal-to-noise ratio, which indicates
a more finely tuned and responsive system [41]. The greater responsiveness of the HPA axis in
PTSD may put larger accommodation stresses on the HPA axis, thereby leading to greater wear
and tear.

Another hypothesis centers on the role of steroid receptors, which are necessary to mediate the
effects of GCs. The concept of negative feedback inhibition has also been used to explain the
apparent paradox between low cortisol levels and hippocampal-related alterations in PTSD [14].
Under conditions of an increased negative feedback inhibition, GC-mediated effects on
hippocampal structure could occur despite lower ambient cortisol levels. It also is possible that
increased GC levels are present during and for an unspecified period following the trauma(s), and
after some passage of time, susceptible individuals' feedback sensitivity set-point is changed,
which then results in lower GC levels.

Hence, from a theoretical perspective, a disruption in hippocampal function as a result of
endocrine, metabolic, or other agents that interfere with the biochemical process of LTP or that
result in neuronal death or pruning could result in consequences that resemble core clinical
phenomena of PTSD, such as psychogenic amnesia and chronically impaired declarative memory
function [1]. The hippocampus may be a relevant region in the pathophysiology of PTSD, and for
this reason, the hippocampus has been widely studied, as reviewed below.
   The amygdala

The severe psychological trauma that is an antecedent to the development of PTSD must result in
the survivor experiencing fear, helplessness, or horror (DSM-IV). The individual with PTSD often
continues to experience marked fear during intrusive recollections, flashbacks, and nightmares.
Individuals with PTSD are often hypervigilant and may show an exaggerated startle response to a
variety of unexpected stimuli, particularly loud noises. The amygdala has been implicated in the
emotion of fear, fear learning, and control of the accompanying behavioral, autonomic, and
neuroendocrine correlates.

Some of the first evidence that the amygdala may be involved in fear came from the work of
Klüver and Bucy [42] in their primate lesion studies. Wild monkeys that were naturally aggressive
and fearful of humans underwent bilateral removal of their temporal lobes (which includes the
amygdala, hippocampus, and temporal cortex). This resulted in the monkeys becoming nonfearful
and docile. Later animal studies with more limited lesions localized the key structure responsible
for these behavioral changes as the amygdala [43]. A remarkable amount is known about fear
responding and the processing of auditory stimuli before and within the amygdala through
preclinical microlesion studies and through the use of the conditioned fear paradigm.

Classical fear conditioning is the process by which a neutral stimulus (the conditioned stimulus
[CS]) is paired with a fear-inducing stimulus (the unconditioned stimulus), such as a buzzer paired
with a shock, and eventually the original neutral stimulus alone will trigger a fearful response.
Fear conditioning seems to be an excellent animal model for what is clinically observed in
survivors with PTSD who often respond with fear to an increasing number of triggers, which are
conditioned stimuli that have been associated with an unconditioned stimulus (the trauma). One of
the best studied fear-conditioning pathways is the auditory pathway. The neuronal path of an
acoustic CS is through the auditory thalamus, the medial geniculate body, and then the
transmission is split. One part goes to the amygdala and the other to the auditory cortex [44]. The
auditory thalamus provides a rapid route to the amygdala, along with imprecise information
regarding the signal, whereas the signal to the amygdala from the auditory cortex is received later
but is more richly analyzed [45]. Fear conditioning to a single tone does not require the auditory
cortex, but this brain region appears necessary for fear conditioning to more complex auditory
stimuli [46]. Because the fear response is part of what helps to ensure the survival of the organism
in potentially lethal situations, it is of survival value to “act first and think later.” The more
rapidly transmitted crude signal may activate the amygdala, and the more later-received
cortically processed signal may inhibit amygdala activity. Disruption of either the lateral or
central amygdala nuclei interferes with animals' ability to acquire new fears (i.e., fear
conditioning is impaired) [47]. Although the particulars are beyond the scope of this review, it is
important to understand that different modalities of fear-inducing stimuli may be processed in
disparate brain regions, and alterations in these brain areas may differentially affect fear
responding or fear conditioning to different types of stimuli.

Studies in humans parallel animal findings. Functionally, the opposite of physically lesioning or
removing a structure is activating it. Epileptic activity is a pathologic activation that may occur in
virtually any brain region. In humans, temporal lobe epilepsy is frequently manifest by sudden
episodes of fear and poorly directed aggressive behavior. Humans with temporal lobe lesions show
deficits in fear conditioning [48], as do individuals with lesions primarily confined to the amygdala
[49]. Such individuals also show impairment in perceiving fear in facial expressions [50] and
voices [51]. Individuals with a rare disorder resulting in localized bilateral amygdala damage
show the above deficits, and although they are able to understand logically that some situations
are risky or will most likely have a negative outcome, they are largely unable to use this
information to act accordingly [52].
Functional neuroimaging studies in nonpsychiatric subjects show regional changes in brain
activity in response to various tasks. The amygdala is selectively activated in processing negative
emotional stimuli [53–55] and in fear conditioning [56,57].

The amygdala is also of interest to the study of PTSD not only because of its involvement in the
emotional/behavioral manifestation of fear but also because of the autonomic response. Perhaps
one of the most pathognomonic signs of PTSD is the increased startle response (related to fear
conditioning). The startle response is thought to give an indication of autonomic excitability and
can be measured through various means, such as heart rate, blood pressure, skin conductance,
and electromyography. The autonomic response also entails increased activity of the major
noradrenergic nuclei of the brain—the locus ceruleus. Survivors with PTSD, as compared with
normal control subjects and traumatized subjects without PTSD, have shown increased cardiac,
skin conductance, and electromyogram responses to loud tones [58,59].

Anatomically, the amygdala is located immediately anterior to the hippocampi, and numerous
reciprocal connections exist between these two structures [60]. In one study with nonpsychiatric
participants, subjects were shown neutral and emotionally unpleasant film clips while undergoing
imaging of brain function. A greater number of the unpleasant film clips were remembered by the
subjects 3 weeks later, and the number of unpleasant film clips remembered was highly correlated
with right amygdaloid complex activity [61]. Declarative memory has been investigated in humans
with a rare condition that results in selective bilateral amygdala damage. Both subjects showed
impairments in long-term declarative memory for emotionally arousing material [52]. In a
reciprocal fashion, the hippocampi play a role in fear conditioning and response by providing
contextual information to the memory (where, when, and other particulars of an traumatic
experience) [62,63].

Data indicate that gender and laterality are important considerations. A recent study found that
in females, memory for negative emotional film clips was related to left amygdala activation,
whereas the association in the male subjects was found with right amygdala activation [64]. These
and the aforementioned data support the hypothesis that the human amygdala normally provides
the emotional valence to a memory and also enhances acquisition of declarative knowledge
regarding emotionally arousing stimuli. It appears that the amygdala, like the hippocampus, uses
LTP. With regard to the amygdala, LTP seems to occur in the thalamo-amygdaloid pathways
during the process of fear learning [65–67]. It is of interest how various hormones and
neurotransmitters modulate efficacy of LTP in the amygdala as compared with the hippocampus.

In summary, numerous reasons exist to posit an overactive amygdala in individuals with PTSD.
Conversely, one would not anticipate some structural damage or other biologic effect resulting in
decreased amygdala activity in subjects with PTSD. The aforementioned studies highlight the
importance of stimulus modality, intensity and specific emotion(s) experienced, laterality, and
gender as significant experimental factors.

MRI OF THE HIPPOCAMPUS AND AMYGDALA

      Qualitative and quantitative magnetic resonance imaging

Magnetic resonance imaging (MRI) allows for high-resolution imaging of the brain with excellent
white and gray matter differentiation. A powerful magnet is used to align proton nuclei of water
in body tissues, which are then knocked out of alignment by a radio pulse. A signal is given off by
the proton nuclei as they are reverting back to their original disorder, which will be of differing
intensity according to the water content of that tissue (which does differ between white and gray
brain matter).
The clinical use of brain MRIs is usually of a qualitative nature; specific features (qualities) are
evaluated, such a cortical atrophy, infarctions, or neoplasms. In one study, clinical examination of
MRIs from PTSD patients revealed focal white matter lesions in a greater percentage of scans on
subjects with PTSD as compared with the healthy control subjects [68]. Another study reported
an increased incidence of the developmental abnormality cavum septum pellucidum in subjects
with PTSD [69]. Of greater applicability to research is the use of quantitative MRI for accurate
and precise measurement of the volume and shape of specific brain regions. Such measurements
of specific brain regions allow for testing of various pathophysiologic models of PTSD involving
structural or neurodevelopmental alterations.

The most commonly applied manual method by which the volume of a brain structure is
determined is by looking at successive MRI slices through the structure and tracing its perimeter,
often termed a “region of interest.” By multiplying the area of the structure on each slice by the
number of slices it appears on by the thickness of each slice, the total volume is easily obtained, or
the slices can be “stacked” to create a three-dimensional image.

To avoid experimental bias, the following conditions must be adhered to: (1) The person(s) tracing
the structure should not know the diagnostic group or subject conditions; (2) subject groups
should be mixed and not all of one group traced during one time period and the other group at a
later time (even if the tracers do not know which group they are tracing) because systematic
changes may occur over time in tracing technique; and (3) MRI scans should be obtained on the
same scanner type with identical sequence settings, and identical methods for “slicing” the scans
should be used (differences, if present, should at least be balanced between groups). Computer-
driven automatic tracing programs and automated methods that use alignment of pixel intensities
to assess size and shape change [70] are becoming available and decrease tracer bias.

      Quantitative MRI studies in PTSD

The first published study of hippocampal volume in PTSD compared Vietnam veterans with
PTSD to healthy comparison subjects with no history of combat or trauma exposure. Right
hippocampal volume in the PTSD subjects was a statistically significant 8% less than in
comparison subjects [71]. This study, however, did not control for combat exposure, which means
that it is impossible to say whether group differences were associated with exposure in itself or
specifically with PTSD. Furthermore, hippocampal volume was not adjusted for whole-brain
volume.

A later study controlled for combat exposure by studying Vietnam veterans with PTSD, combat-
exposed Vietnam veterans without PTSD, and eight healthy subjects without a history of trauma
[72]. This study found a significant bilateral decrease in hippocampal size (approximately 26%
between the PTSD subjects and the other two groups) after controlling for brain volume. The key
association with hippocampal volume in these subjects was the diagnosis of PTSD, not trauma
exposure in itself. Unfortunately, groups in this study showed significant differences in age,
education level, and alcohol use (which has been found to be associated with decreased
hippocampal size), and subjects were not intermingled in MRI analysis, which may have resulted
in subtle systematic differences in volumetric analysis (particularly during manual tracing).

Studies of other trauma survivors provide a more ambiguous picture regarding the associations
among hippocampal volume, trauma, and symptoms. Hippocampal volume has also been assessed
in adult survivors of severe childhood sexual abuse (CSA). The left hippocampal volume in
subjects with a history of CSA was 4.9% smaller than the left hippocampal volume in control
subjects without a history of CSA [73]. CSA subjects, however, did not all meet PTSD criteria;
71.4% met diagnostic criteria for PTSD, 71.4% met diagnostic criteria for a dissociative disorder,
and 28.6% met criteria for both diagnoses. Six of the subjects were experiencing a current major
depressive episode, and association between recurrent depression and smaller hippocampal
volume has been reported. Analyses differentiating the effects of CSA history from PTSD
diagnosis were not reported.

A second study assessed hippocampal volume in subjects with severe CSA histories (all of whom
had current PTSD) compared with healthy comparison subjects without a history of CSA.
Comparison regions of the amygdala, caudate, and temporal lobe were also used. Left
hippocampal volume was 12% smaller in the PTSD subjects, whereas the volumes of comparison
structures did not differ [74].

Preliminary results from recent studies have not found differences in hippocampal volume as
associated with trauma or PTSD in subjects with personality disorder [75] or in holocaust
survivors [76]. Furthermore, because an intact hippocampus is necessary for declarative memory
formation, the logical hypothesis is that GC-mediated hippocampal death and atrophy produces a
hippocampal lesion leading to effects similar to those observed in the surgical destruction of
hippocampal connects. These gross alterations in CA3 and dentate gyrus size are anticipated to
result in a smaller hippocampal volume. Therefore, cognitive deficits in PTSD, particularly
declarative memory, should be inversely correlated with hippocampal volume (i.e., greater
cognitive deficits with smaller hippocampal volume). The aforementioned studies of hippocampal
volume in PTSD assessed for this correlation, yet, despite findings of smaller hippocampal
volumes, only one study found a correlation between hippocampal volume and memory deficits
[71]. These authors reported a significant correlation between deficits in verbal memory
(measured by percent retention subscale of the logical component of the Wechsler Memory Scale)
and decreased hippocampal volume in PTSD subjects (r=0.64, df=20, P=0.05). This result was for
hippocampal volume uncorrected for brain size, which raises questions about the effect of body
size.

Smaller body size is associated with smaller brain size but could also be correlated with physical
vulnerability and social interaction patterns in combat, which deserve investigation in this context.
Furthermore, smaller hippocampal and temporal lobe size has been associated with poorer
memory performance in non-PTSD groups, so memory performance per mL of tissue may need to
be considered. The specificity of the finding needs to be considered. Patients with schizophrenia
and their relatives have been reported to have smaller amygdala and smaller hippocampal volume
[77], although this may be less marked in first-episode patients [78]. Patients with panic disorder
may also have reduced temporal lobe volumes, although Vythilingam et al. [79] found normal
hippocampal volume suggesting some distinction within anxiety disorders. None of the
aforementioned studies was longitudinal, and none involved prospective scanning before the
trauma. As such, any associations cannot be ascribed a causal relationship (e.g., PTSD or trauma
resulted in smaller hippocampi). It is equally plausible that smaller hippocampi may increase
vulnerability to developing PTSD following a stressor, lower stress resistance, or increase the risk
of encountering stress.

Studies of twins have suggested that there is a significant genetic contribution to the development
of both PTSD and generalized anxiety disorder (GAD) [80] (see review of genetic factors in PTSD
and their relationship to HPA axis abnormalities in [81]). In this unreported study using a novel
methodology, twins from the Vietnam registry who were concordant (both trauma exposed or
with PTSD) and discordant (one with and one without trauma exposure) were compared in
various ways. Of most interest was the comparison among the discordant twin of a soldier with
combat-related PTSD (i.e., the subject did not have trauma exposure or PTSD but did have a twin
who developed PTSD) as compared with the twin of an individual who had combat exposure but
who did not develop PTSD (i.e., the subject had neither exposure nor PTSD). The subject who did
not have PTSD but who had a twin with PTSD had significantly smaller hippocampal volumes
than the twin of the soldier who did not develop PTSD. Because neither of the subject groups had
PTSD or combat exposure, the difference in hippocampal volumes would be most parsimoniously
described as antedating the trauma and therefore more of a vulnerability factor. In this study, the
actual difference in hippocampal volumes between combat-exposed individuals with and without
PTSD was not statistically significant.

Recently, a longitudinal study was published in which individuals coming to an emergency room
after a psychologically traumatic event were given an MRI of the brain and diagnostic testing [82].
These individuals were tested 6 months later to ascertain who had developed PTSD or still had
PTSD, and again an MRI was obtained. The researchers did not find a change in hippocampal
volume from baseline in those subjects who had PTSD at 6 months, nor did they find a difference
in relative hippocampal volumes between those subjects with and those without PTSD at 6
months. This study had sufficient statistical power to find a difference if it were present to the
degree found in earlier hippocampal studies. One possibility mentioned by the authors is that the
trauma of these subjects occurred in adulthood. By a developmental hypothesis, trauma in
childhood and adolescence may interfere with growth and development of the hippocampus,
whereas by adulthood this structure is fully formed, and development of PTSD during the adult
years would not result in smaller hippocampal volume via impaired hippocampal development.
Another longitudinal study assessed hippocampal and other limbic region volumes in adolescent
PTSD subjects and control subjects at baseline and 2 years later. No significant volumetric
differences either at baseline or upon rescanning 2 years later were found between groups [83].

Many of the aforementioned studies analyzing hippocampal volume also explored amygdala
volume, and none found a significant difference in amygdala volume in subjects with PTSD as
compared with traumatized and nontraumatized control groups.

Assessing for gross volumetric changes in a structure may be a nonsensitive way to detect many if
not most physiologically relevant alterations. It is possible that significant biochemical changes
affecting the function of a structure might not be reflected in volumetric changes. Furthermore,
supportive and connective cells and other structural elements may maintain the general shape or
volume of a structure despite significant changes in neuron number, size, or viability. One way to
assess these possibilities is through the use of nuclear magnetic spectroscopy (NMS).

Nuclear magnetic spectroscopy uses an MRI-type setup, but instead of focusing on the signal
emitted by proton nuclei of H2O, the signal from a variety of molecules such as choline, n-acetyl
acetate (NAA), glutamate, and others is detected. NMS provides data about the relative
concentration of these molecules. The ability to detect various molecules differs according to how
strong and unique a signal they emit, the concentration of the compound, the strength of the
magnet, and the software being used. This technology is still in its infancy, and the physics of
detecting various compounds is still being worked out, as is the ability to create higher-power
magnets that allow detection of more compounds and also the ability to sample a smaller region of
the brain. NMS does allow for a “virtual” brain biopsy that provides information on behavioral
makeup that used to be obtainable only by taking a physical biopsy of the brain.

N-acetyl aspartate is an endogenous substance that is believed to be a marker for neuronal
density. In investigating whether the hippocampus is somehow smaller because of neuronal death
or atrophy, preliminary studies have assessed the NAA signal from the temporal lobe regions.
Present technology makes assessment of the hippocampus (which is a relatively small and
complex-shaped structure) extremely difficult, and NAA data are from the temporal lobe as a
whole and are not limited to the hippocampi. Schuff et al. [84] compared seven veteran PTSD
subjects with seven trauma-exposed veterans without PTSD. The right hippocampus in these
subjects was a nonsignificant 6% smaller, but there was a significant 18% decrease in NAA signal
from this region. Another NMS study also reported a lower NAA-creatine ratio in the right
temporal lobe in PTSD subjects compared with combat control veterans [85]. These findings may
indicate that NMS is a more sensitive technique for detecting hippocampal changes caused by
neuronal atrophy or degeneration, which, because of the presence of connective and supportive
tissues, may not be accompanied by an equal magnitude of change in hippocampal volume. Future
studies with higher resolution and using analysis for additional compounds can be anticipated.

FUNCTIONING NEUROIMAGING STUDIES

      Functional imaging technologies

From what was known of the amygdala in animal studies and models of fear and fear
conditioning, an overactivation of the amygdala in subjects with PTSD was a reasonable
hypothesis. This was a question of neuronal activity that required the use of “functional” imaging
technologies or those that allowed data to be gathered on the functioning of the brain through
such measures as regional rate of glucose metabolism, blood flow, and oxy/deoxyhemoglobin
concentrations. Furthermore, activity, unlike gross structure, is a rapidly changing measure, so it
is necessary to control for this factor through various experimental methods.

      Positron emission tomography

Positron emission tomography (PET) is a functional imaging technique in which a radioisotope is
used to measure glucose metabolism (by using 18flouro-deoxyglucose [18FDG]), blood flow ([15O]
H2O), or receptor density (using any of an increasing number of radiolabeled ligands). Decay of
the radioisotope produces positrons (antimatter electrons), which travel a short but variable
distance (one limiting factor in the ultimate resolution of PET data) before striking an electron.
The collision between matter and antimatter results in the release of energy in the form of two
gamma rays that have the property of being emitted in opposite directions (180° difference). An
array of detectors surrounding the subject's head registers the gamma rays, and, through
computer analyses, the origin can be calculated, which, when corrected for distance through the
brain it must travel, is used to calculate concentration and location of the ligand.

Functional imaging techniques provide a picture of the brain that may integrate a period from 1
minute (such as with [15O]H2O), 30 minutes (such as with 18FDG), or hours (such as with ligands
that bind to specific receptors or molecules). [15O]H2O is a tracer that allows a map of blood flow
to be made, which is useful because blood flow is highly correlated with regional brain activity
(metabolism). 18FDG is taken up by the brain like glucose in proportion to the neuron's energy
requirements and gets temporarily trapped inside the cell after being acted on by hexokinase. The
technique provides a more direct picture of regional brain metabolism but reflects a longer period
of activity (approximately 30 minutes).

      Functional MRI

Functional MRI (fMRI) uses the basic MRI setup with additional sensing hardware and software
modifications. fMRI works on the fact that hemoglobin and deoxyhemoglobin have different
magnetic properties. Because of this, the deoxygenated blood acts as a type of in situ tracer. This
allows for a measure of cerebral blood flow/metabolism that can detect small changes occurring
over very short periods (fractions of a second). Like quantitative MRI, the strength of the magnet
is a key variable in how high a spatial resolution can be obtained or over how short a period useful
data can be acquired. Because these techniques collect data of rapidly changing brain states, it is
important to construct experimental conditions that minimize the number of cognitive or
physiologic process that differ between the experimental and control conditions.

Functional imaging studies can give information regarding blood-flow and metabolism to a region,
but the ultimate explanation of the significance of this is unclear. Most significantly, one region
may serve primarily an inhibitory function; hence, if it is more “active,” it is more actively
inhibiting another region(s), and the relationship between these areas and their respective
functions is important. An analogy can be made with the human genome. One does not get all the
answers by simply knowing the sequence; the useful information resides in the products of the
genes, their role in the organism, and their interaction. This is a much more complicated and
challenging task.

      Symptom provocation

One of the first techniques used with functional neuroimaging in the study of PTSD was symptom
provocation, which had already been used in the study of other anxiety disorders with an elicitable
pathologic response (i.e., obsessive-compulsive disorder and panic disorder). As applied to PTSD,
stimuli such as listening to a traumatic script, seeing provocative pictures, or remembering the
previously experienced traumatic event often elicit fear, anxiety, flashbacks, and physiologic
activation (typically increased heart rate, blood pressure, and skin conductance).

      Functional imaging studies in PTSD

In a preliminary study, eight subjects with PTSD and high physiologic reactivity to reminders of
their trauma were studied using [15O]H2O, which is used to measure cerebral blood flow (CBF).
In the traumatic condition, subjects listened to audiotapes of their own accounts of the focal
traumas related to their PTSD, whereas subjects in the control condition listened to narratives of
neutral life events. Compared with the control subjects, the study subjects showed significantly
increased CBF in the anterior cingulate, orbitofrontal, right amygdala, and visual cortex, among
other regions. A decrease in CBF was noted in Broca's area [86]. Broca's area is a cortical region
found in the posterior superior gyrus of the temporal lobe (on the right side of the brain in the
vast majority of individuals) that is involved with language production. Lesions to this area most
commonly occur secondary to stroke and result in an inability to put one's thoughts into words
(Broca's aphasia). A hallmark of PTSD is the survivor's extreme difficulty in giving a coherent
verbal account of the focal trauma.

The authors commented that visual cortex and paralimbic activation was similar to the fear
response in provocation studies of other anxiety disorders. Activation of these areas optimizes
resources for response to a threatening situation; therefore, it was hypothesized that verbal
abilities during a crises were of secondary importance (hence, the deactivation of Broca's area).
Furthermore, a symptom of PTSD is usually the inability of the patient to give an integrated and
coherent verbal description of their trauma. This was also the first study of an anxiety disorder in
which amygdala activation was found. The lack of a control group made it impossible to
determine to what extent the findings were part of a pathologic response to trauma.

A later study by this group used the autobiographic script for traumatic activation (all subjects
experienced CSA), but this time approximately half the subjects did not have PTSD, and therefore
the effects of trauma versus PTSD per se could be controlled for [87]. As compared with control
subjects, those with PTSD showed a greater decrease in Broca's area CBF and significantly larger
increases in CBF in the orbitofrontal and anterior temporal regions.

The medial prefrontal cortex inhibits the excitatory output of the amygdala in animals, whereas in
humans, equivalent regions serving this role are thought to be the medial orbitofrontal cortex and
the anterior cingulate gyrus. Therefore, decreased activity in these brain regions could have a
disinhibiting effect on the amygdala and again result in an increased fear response through
inadequate response inhibition. A process counteracting the effects of fear conditioning is
extinction. If the neutral stimulus is no longer paired to the fear-inducing stimulus, the normal
animal will show a gradual fading away of the fearful response with successive repetitions of the
neutral stimulus alone. A clinical example of the failure of extinction is a PTSD patient's
continued fearful response to various triggers that are reminiscent of the traumatic stressor even
after extensive experiences after the traumatic event have presented the traumatic stimulus
without the fearful condition (i.e., the veteran feeling terror at the sound of a helicopter more than
30 years after combat and during these 30 years hearing helicopters without being in any physical
danger). Like the amygdala, these regions are not known to be structurally damaged by any
common neuroendocrine alteration.

In the aforementioned study, the anterior cingulate, the area that inhibits amygdala activation,
showed a greater CBF increase in response to the traumatic condition in the control subjects as
compared with the PTSD subjects. The authors hypothesized that the inability to adequately
recruit this structure for the inhibition of amygdala activity may be an important aspect of the
pathophysiology of PTSD. This later study did not find amygdala activation in the traumatic
condition, and the authors bring up an important consideration: In the second study, the
survivors of childhood sexual abuse reported experiencing primarily anger, disgust, and sadness,
whereas subjects in the first study reported primarily fear and anxiety. Furthermore, because of
the small size of the amygdala, the power for detection of significant differences in activation may
be significantly less than other larger brain regions. A SPECT study, using [99mTc]HMPAO in
combat veterans with PTSD, combat control subjects, and normal control subjects, found anterior
cingulated/middle prefrontal gyrus activation in all groups following hearing tape recordings of
combat sounds. Only in the PTSD group was activation of the left amygdala/nucleus accumbens
found [88].

Examination of correlations between flashback intensity and CBF during the experience
demonstrated positive correlations with the hippocampus, insula, putamen, somatosensory, and
cerebellar regions and negative correlations with the prefrontal cortex, fusiform, and medial
temporal cortices [89]. Decreased cortical and increased thalamic blood flow during an intense
flashback was also seen in a single patient study [90] and suggests a thalamocortical mechanism;
thalamic involvement in startle response was seen in a recent fMRI activation study [91].
Fernandez et al. [92] imaged a patient with torture-related PTSD before and after treatment with
fluoxetine. Before treatment, trauma reminders resulted in decreased rCBF in the insula,
prefrontal, and inferior frontal cortices consistent with the Osuch et al. [89] and Fernandez et al.
[92] studies. Increased activity was evident in the cerebellum, precuneus, and supplementary
motor cortex. This pattern was normalized after SSRI administration.

Another symptom provocation method in PTSD involves presenting startling auditory stimuli and
observing heightened eye-blink and skin conductance response [93,94] or even reduced reactivity
in chronic stress [95]. Because startle activates orbitofrontal cortex (a target area for PTSD
symptoms) in fMRI [91] and FDG-PET [96] studies, this provocation method may be useful in
PTSD imaging studies.

      Cognitive activation studies

Cognitive neuroscientists studying basic elements of various cognitive processes in normal brain
function pioneered activation paradigms. In this technique, an experimental and a control task
differ in one element, and subjects undergo functional imaging in each condition. The image in
one condition is subtracted from the other, presumably revealing the differences in regional brain
activity between the two conditions. Studying one group of essentially identical subjects can
provide information on the differences between conditions. Studying a control and experimental
group in the two conditions can provide information on differences in regional brain activity as a
function of condition, group, and group-by-condition interaction. In studying a disorder such as
PTSD, one would pick a cognitive task that activates a system believed to be abnormal (e.g.,
attention, processing of emotional stimuli, etc.). One group studied PTSD in six male veterans (five
with alcohol abuse) and acquired data during conditions of baseline, a continuous perfomance
task, and a verb generation task to evaluate brain activity as related to attention, reaction time,
response selection, and language/speech production. PET data on regional cerebral blood flow
(rCBF) were collected using 15O and published in two reports [97,98]. As compared with the
control group, the PTSD group showed a reduced left-to-right ratio of rCBF in the hippocampal
region and greater orbitofrontal cortex activation. On the continuous performance task, which
measures attention and reaction time, the PTSD group made more errors on the task and showed
less activation in parietal cortex. The abnormal functional asymmetry for the hippocampal
regions found in these studies may parallel some of the earlier reported findings of smaller
hippocampal volumes. Alcohol use in the subjects limits the generalizability of the findings.
Because the control group was not traumatized, it is also not possible to know if these differences
were associated with trauma alone or actual PTSD.

A later [15O]H2O study addressed these methodologic problems by using subjects without alcohol
dependence and controlling for combat exposure by studying 14 veterans, all of whom were
combat exposed but only seven of whom had PTSD [99]. Six conditions were studied: viewing
pictures and imagining neutral, negative, and combat related material. Group-by-condition
analyses showed that only the PTSD group showed a significant rCBF increase in the combat
versus neutral condition in the anterior cingulate and right amygdala and decreased activation in
Broca's area in the combat versus negative condition. A methodologic problem in all such
activation studies is the problem that the combat or fear-inducing material does not have an equal
psychologic impact in both groups. This is to be anticipated to some extent because reacting with
intense fear or having a flashback upon exposure to traumatic triggers is a criterion for PTSD. It
is unclear if the differences reported in such a study are related to the degree of fear (and would
therefore be observed in the control group if the stimulus was strong enough) or if they are unique
to PTSD pathophysiology.

To address the question of the amygdala's native reactivity, a novel method for selective activation
of the amygdala that does not activate the usual inhibitory anterior cingulate was used with fMRI
in combat-exposed veterans with and without PTSD. In this masked-faces method, neutral and
fearful faces are shown briefly to the subject and are followed by a neutral face (mask). The
subject is only consciously aware of seeing the mask, but the amygdala, which receives input
directly from the thalamus, is able to register the “danger/fear” without inhibitory influences
from the anterior cingulate gyrus. PTSD symptom severity correlated with amygdala activation,
and the PTSD group showed greater amygdala activation as compared with the combat control
subjects [100]. This argues for a state of amygdala hyper-responsivity in PTSD, even without
diminished anterior cingulate inhibitory activity. Consistent with this, Semple et al. [101] found
higher brain blood flow in the amygdala in PTSD patients than in normal subjects, although
cocaine addiction in these subjects limits generalizeability of the findings. Evidence for amygdala
hyper-responsivity in stress-related memory dysfunctions is also presented in a PET case study of
a psychogenic amnesic patient who showed amygdala activation during a facial memory test,
whereas control subjects showed only hippocampal activation [102].

      Pharmacologic challenges

This paradigm involves a pharmacologic agent that produces an effect on a brain system or region
that is believed to be implicated in the pathophysiology of a disorder. The effect in the control is
compared with the experimental group with regard to changes in blood flow or glucose
metabolism. As opposed to symptom provocation, which in the case of PTSD activates a myriad of
endocrine, biochemical and autonomic events, the pharmacologic challenge may be used as a way
to pharmacologically dissect the separate components of the response or systems. Pharmacologic
challenges can be paired to any neuroimaging technique that provides a functional picture of the
brain but is most frequently used with PET.
Yohimbine is an ?2 receptor antagonist that increases noradrenergic discharge. In one study,
yohimbine was used as a probe to assess whether individuals with PTSD have greater
autonomic/noradrenergic reactivity [103]. Ten combat veterans with PTSD and ten normal
control subjects were administered yohimbine and shortly thereafter underwent 18FDG PET
scanning. The PTSD subjects had a significantly higher incidence of flashbacks and panic attacks
in response to the yohimbine. The authors found that the PTSD group exhibited a widespread
decrease in cortical metabolism. Prior studies indicated that, at higher concentrations,
noradrenaline decreases rCBF, whereas CBF is increased at lower an intermediate noradrenaline
concentrations. One might ask why the locus ceruleus, the primary nucleus for noradrenergic
neurons in the brain, was not differentially activated. The findings from this study suggest that it
was, and one would anticipate that the greatest effects of norepinepherine release are to areas to
which locus ceruleus neurons project (not within the structure itself). The authors interpreted
their findings as an indication that noradrenergic activity is heightened in PTSD. Of course, such
a bimodal response makes interpretation of the results difficult. Nonetheless, this is consistent with
a model of inadequate activity in cortical regions paired with limbic overactivation.

Central sensitivity to GCs in PTSD is currently being assessed by studying changes in memory
function and regional glucose metabolism using 18FDG following a hydrocortisone challenge. GCs
cause a decrease in cell-surface glucose transporters, presumably paralleling the sensitivity of the
GC receptors to steroids. Because 18FDG looks like glucose to the neuron, one can measure to
what extent GCs inhibit the uptake of 18FDG. In preliminary analyses, we found that the PTSD
group, as compared with the non-PTSD control group, showed a greater decrease in glucose
uptake in the hippocampal regions following hydrocortisone [104]. Although preliminary, these
findings lend support to the hypothesis of increased central GC sensitivity in PTSD. We will also
be able to analyze this data in comparison to psychological testing results obtained after the
hydrocortisone-versus-placebo challenge.

      Radioligand studies

By using a cyclotron, radiochemists can create isotopes of various elements and then incorporate
them into a ligand. A variety of radiolabeled compounds can be designed to have specific affinities
for various neuronal receptors, binding sites, or other targets. In conjunction with a PET scanner,
the ligand acts as a tag and can provide such useful information as receptor numbers, location,
and affinity.

The GABA receptor is comprised of various combinations of subunits, on one of which a
benzodiazepine binding site is located. GABA is the main inhibitory neurotransmitter of the brain,
and, as such, it would be of interest if there were some alteration of this receptor in subjects with
PTSD. One PET study used a radioligand for the benzodiazepine binding site with PET scanning
and found decreased binding in the frontal cortex of PTSD subjects [105].

DISCUSSION

Quantitative MRI studies of hippocampal volume in subjects with PTSD have shown mixed
results. The majority of studies report a smaller hippocampal volume in PTSD subjects, but
negative findings are less frequently published. Recent preliminary reports from well controlled
studies with adequate power have not found significant differences in hippocampal volume.

Association does not imply cause and effect, and the possibility that smaller hippocampal volume
is a vulnerability factor for the development of PTSD following a trauma is just as plausible.
Three other possible relationships between smaller hippocampal volume and PTSD have been
enumerated [106]. Longitudinal studies can address this issue, and two published studies (one in
adults, the other in adolescents) did not find any significant changes in hippocampal volume either
at baseline or at 2-year follow-up in control and PTSD subjects. Factors such as longer follow-up
time, age at which the focal trauma was sustained, duration/severity of PTSD symptomatology,
and neurodevelopmental period of symptom evolution have not been adequately studied.

Hippocampal volumetric changes may be one of the measures least sensitive to the type of
alterations or dysfunction that may be present in subjects with PTSD. Preliminary studies of NAA
signal using NMS indicate a decreased number or integrity of temporal lobe neurons. Advances in
both magnet strength and computer software are anticipated to increase sensitivity, spatial
resolution, and the number of compounds that can be assayed through this noninvasive technique.
Studies of excitatory (primarily glutamate) and inhibitory (primarily GABA) neurotransmitter
concentration and location would be relevant.

Functional neuroimaging studies are beginning to show certain consistencies and have been
synthesized to form the constellation of a hyper-responsive amygdala and associated limbic
structures leading to heightened fear-conditioning, fearful response, and emotional learning, in
conjunction with a hypoactive anterior cingulate area that fails to properly inhibit amygdala
activity [107]. Decreased hippocampal function may impair the process of habituation or
extinction of the fearful response and may also lead to increased tendency for stimulus
generalization secondary to a decreased in contextual constraints that the hippocampus usually
may supply. Longitudinal studies and twin studies would be of great use in understanding the
progression, causal relationships, and genetic contribution of these findings. Radioligand studies
are in their infancy, but with the availability of a cyclotron and experienced radiochemists, a great
number of selective ligands should be possible to synthesize.

Because PTSD is perhaps the paradigmatic example of a disorder involving the complex
interaction of genes and environment, a deeper appreciation of this syndrome will require
longitudinal studies (which are best for sorting out cause-and-effect relationships) and
investigations that use a combination of modalities. The reason for the latter is that in the analysis
of a complex system, each additional modality of information provides a synergistic rather than
merely additive value to the data obtained. Such multidisciplinary or multimodal approaches may
combine, in various ways, structural, functional, and ligand neuroimaging, NMS, pharmacologic
challenges, neuropsychological testing, symptom provocation, cognitive activation, and
naturalistic and genetic data in the effort to understand interactions between these systems that
increase or decrease vulnerability or expression of particular signs or symptoms of PTSD. As
technology and methods improve, it is likely that additional brain regions will be found to be
relevant to the pathophysiology of this complex disorder.



References

[1]. Golier J, Yehuda R. Neuropsychological processes in post-traumatic stress disorder. Psychiatr
Clin N Am. 2002;25:in press

[2]. Scoville W, Milner B. Loss of recent memory after bilateral hippocampal lesions. J
Neuropsychiatry Clin Neurosci. 2000;12:103-113

[3]. Reed JM, Squire LR. Impaired recognition memory in patients with lesions limited to the
hippocampal formation. Behav Neurosci. 1997;111:667-675

[4]. Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and
humans. Psychol Rev. 1992;99:195-231
[5]. Zola-Morgan S, Squire LR. The neuropsychology of memory: parallel findings in humans and
nonhuman primates. Presented at the Conference of the National Institute of Mental Health
Philadelphia, 1989. Ann N Y Acad Sci. 1990;608:434

[6]. Zola-Morgan S, Squire LR, Rempel NL, Clower RP. Enduring memory impairment in
monkeys after ischemic damage to the hippocampus. J Neurosci. 1992;12:2582-2596

[7]. Zola-Morgan S, Squire LR. Memory impairment in monkeys following lesions limited to the
hippocampus. Behav Neurosci. 1986;100:155-160

[8]. Zola-Morgan S, Squire LR, Ramus SJ. Severity of memory impairment in monkeys as a
function of locus and extent of damage within the medial temporal lobe memory system.
Hippocampus. 1994;4:483-495

[9]. Alvarez P, Zola-Morgan S, Squire LR. Damage limited to the hippocampal region produces
long-lasting memory impairment in monkeys. J Neurosci. 1995;15:3796-3807

[10]. Squire LR, Zola-Morgan S. The medial temporal lobe memory system. Science.
1991;253:1380

[11]. Hebb D. The organization of behavior. New York: Wiley 1949

[12]. Bliss T, Gardner-Medwin A. Long-lasting potentiation of synaptic transmission in the
dentate area of the anaesthetised rabbit following stimulating of perforant path. J Physiol.
1973;232:357-374

[13]. McEwen BS. Possible mechanisms for atrophy of the human hippocampus. Mol Psychiatry.
1997;2:255-262

[14]. Yehuda R. Current status of cortisol findings in post-traumatic stress disorder. Psychiatr
Clin N Am. 2002;25:in press

[15]. Sapolsky RM, Uno H, Rebert C, Finch C. Hippocampal damage associated with prolonged
glucocorticoid exposure in primates. J Neurosci. 1990;10:2897-2902

[16]. Fuchs E, Uno H, Flugge G. Chronic psychosocial stress induces morphological alterations in
hippocampal pyramidal neurons of the tree shrew. Brain Res. 1995;673:275-282

[17]. McKittrick CR, Magarinos AM, Blanchard D, Blanchard R, McEwen BS. Chronic social
stress decreases binding to 5HT transporter sites and reduces dendritic arbors in CA3 of
hippocampus. [abstract] Soc Neurosci. 1996;22:2060

[18]. Arbel I, Kadad T, Silbermann M, Levy A. The effects of long-term corticosterone
administration on hippocampal morphology and cognitive performance of middle-aged rats.
Brain Res. 1994;657:227-235

[19]. Magarinos AM, McEwen BS, Flugge G, Fuchs E. Chronic psychosocial stress causes apical
dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci.
1996;16:3534-3540

[20]. Uno H, Tarara R, Else J, Suleman M, Sapolsky RM. Hippocampal damage associated with
prolonged and fatal stress in primates. J Neurosci. 1989;9:1705-1711
[21]. McEwen BS, Angulo J, Cameron H, Chao HM. Paradoxical effects of adrenal steroids on the
brain: protection versus degeneration. Biol Psychiatry. 1992;31:177-199

[22]. McEwen BS, Gould EA, Sakai RR. The vulnerability of the hippocampus to protective and
destructive effects of glucocorticoids in relation to stress. Br J Psychiatry. 1992;160:18-23

[23]. Woolley C, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic
morphology of adult hippocampal pyramidal neurons. Brain Res. 1990;531:225-231

[24]. Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of
hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341-345

[25]. Sapolsky RM. Stress, glucocorticoids, and damage to the nervous system: the current state of
confusion. Stress. 1996;1:1-19

[26]. Stein-Behrens B, Lin W, Sapolsky RM. Physiological elevations of glucocorticoids potentiate
glutamate accumulation in the hippocampus. J Neurochem. 1994;63:596-602

[27]. Bartanusz V, Aubry J, Pagliusi S, Jezove D, Baffi J, Kiss J. Stress-induced changes in
messenger RNA levels of N-methyl-D-Aspartate and ampa receptor subunits in selected regions of
the rat hippocampus and hypothalamus. Neuroscience. 1998;66:247-252

[28]. Wieland N, Orchnik M, McEwen BS. Corticosterone regulates mRNA levels of specific
subunits of the NMDA receptor in the hippocampus but not in cortex of rats. [abstract] Soc
Neurosci. 1998;21:502

[29]. Dugan L, Choi D. Excitotoxicity, free radicals, and cell membrane changes. Ann Neurol.
1998;35:S17-S21

[30]. Wolkowitz OM, Reus VI, Weingartner, Thompson K, Brier A, Doran A, et al. Cognitive
effects of corticosteroids. Am J Psychiatry. 1990;147:1297-1303

[31]. Newcomer JW, Craft S, Hershey T, Askins K. Glucocorticoid-induced impairment in
declarative memory performance in adult humans. J Neurosci. 1994;14:2047-2053

[32]. Lupien SJ, Gillin CJ, Hauger RL. Working memory is more sensitive than declarative
memory to the acute effects of corticosteroids: a dose-response study in humans. Behav Neurosci.
1999;113:420-430

[33]. Kirschbaum C, Wolf OT, May M, Wippich W. Stress- and treatment-induced elevations of
cortisol levels associated with impaired declarative memory in healthy adults. Life Sci.
1996;58:1475-1483

[34]. Foy M, Stanton M, Levine S, Thompson R. Behavioral stress impairs long-term potentiation
in rodent hippocampus. Behav Neural Biol. 1987;48:138-149

[35]. Coussen CM, Kerr DS, Abraham WC. Glucocorticoid receptor activation lowers the
threshold for NMDA-receptor-dependent homosynaptic long-term depression in the hippocampus
through activation of voltage-dependent calcium channels. J Neurophysiol. 1997;78:1-9

[36]. Pavlides C, Ogawa S, Kimura A, McEwen BS. Role of adrenal steroid mineralocorticoid and
glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices. Brain
Res. 1996;738:229-235

[37]. Diamond D, Bennet M, Fleshner M, Rose G. Inverted-U relationship between the level of
peripheral corticosterone and the magnitude of hippocampal primed burst potentiation.
Hippocampus. 1992;2:421-430

[38]. McEwen BS. Protective and damaging effects of stress mediators. New Engl J Med.
1998;338:171-179

[39]. McEwen BS. From molecules to mind: stress, individual differences, and the social
environment. Ann N Y Acad Sci. 2001;935:42-49

[40]. McEwen BS, Stellar E. Stress and the individual: mechanisms leading to disease. Arch Int
Med. 1993;153:2093-2101

[41]. Yehuda R, Teicher MH, Trestman RL, Levengood RA. Cortisol regulation in posttraumatic
stress disorder and major depression: a chronobiological analysis. Biol Psychiatry. 1996;40:79-88

[42]. Klüver H, Bucy PC. Psychic blindness and other symptoms following bilateral temporal
lobectomy in rhesus monkeys. Am J Physiol. 1937;119:352-353

[43]. Weiskrantz L. Behavioral changes associated with ablation of the amygdaloid complex in
monkeys. J Comp Physiol Psychol. 1956;49:381-391

[44]. LeDoux J. Fear and the brain: where have we been, and where are we going?. Biol
Psychiatry. 1998;44:1229-1238

[45]. LeDoux J. The emotional branch. London: Orian 1998

[46]. Jarrell TW, Gentile CG, Romanski LM, McCabe PM, Schneiderman N. Involvement of
cortical and thalamic auditory regions in retention of differential bradycardiac conditioning to
acoustic conditioned stimuli in rabbits. Brain Res. 1987;412:285-294

[47]. LeDoux JE, Cicchetti P, Xagoraris A, Romanski LM. The lateral amygdaloid nucleus:
sensory interface of the amygdala in fear conditioning. J Neurosci. 1990;10:1062-1069

[48]. LaBar KS, LeDoux JE, Spencer DD, Phelps EA. Impaired fear conditioning following
unilateral temporal lobectomy in humans. J Neurosci. 1995;15:6846-6855

[49]. Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR. Double dissociation
of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans.
Science. 1995;269:1115-1118

[50]. Adolphs R, Tranel D, Damasio H, Damasio A. Impaired recognition of emotion in facial
expressions following bilateral damage to the human amygdala. Nature. 1994;372:669-672

[51]. Scott SK, Young AW, Calder AJ, Hellawell DJ, Aggleton JP, Johnson M. Impaired auditory
recognition of fear and anger following bilateral amygdala lesions. Nature. 1997;385:254-257

[52]. Adolphs R, Cahill L, Schul R, Babinsky R. Impaired declarative memory for emotional
material following bilateral amygdala damage in humans. Learn Mem. 1997;4:291-300
[53]. Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, et al. Response
and habituation of the human amygdala during visual processing of facial expression. Neuron.
1996;17:875-887

[54]. Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ, et al. A differential
neural response in the human amygdala to fearful and happy facial expressions. Nature.
1996;383:812-815

[55]. Tabert MH, Borod JC, Lange G, Tang CY, Wei T-C, Johnson Jr. R, et al. Emotional decision
task with unpleasant words increases BOLD fMRI signal in the right amygdala.
Neuropsychologia. 2001;39:556-573

[56]. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation
during conditional fear acquisition and extinction: a mixed trial FMRI study. Neuron.
1998;20:937-945

[57]. Buchel C, Morris J, Dolan RJ, Friston KJ. Brain systems mediating aversive conditioning: an
event-related fMRI study. Neuron. 1998;20:947-957

[58]. Shalev AY, Orr SP, Peri T, Schreiber S, Pitman RK. Physiologic responses to loud tones in
Israeli patients with posttraumatic stress disorder. Arch Gen Psychiatry. 1992;49:870-875

[59]. Orr SP, Lasko NB, Shalev AY, Pitman RK. Physiologic responses to loud tones in Vietnam
veterans with posttraumatic stress disorder. J Abnorm Psychol. 1995;104:75-82

[60]. Duvernoy HM. The human hippocampus: Functional anatomy, vascularization, and serial
sections with MRI. (Second edition) Berlin-Heidelberg, Germany: Springer-Verlag 1998

[61]. Cahill L, Haier RJ, Fallon J, Alkire MT, Tang C, Keator D, et al. Amygdala activity at
encoding correlated with long-term, free recall of emotional information. Proc Natl Acad Sci USA.
1996;93:8016-8021

[62]. Selden NR, Everitt BJ, Jarrard LE, Robbins TW. Complementary roles for the amygdala
and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience.
1991;42:335-350

[63]. Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued
and contextual fear conditioning. Behav Neurosci. 1992;106:274-285

[64]. Cahill L, Haier RJ, White NS, Fallon J, Kilpatrick L, Lawrence C, et al. Sex-related
difference in amygdala activity during emotionally influenced memory storage. Neurobiol Learn
Mem. 2001;75:1-9

[65]. Rogan MT, Staubli UV, LeDoux JE. AMPA receptor facilitation accelerates fear learning
without altering the level of conditioned fear acquired. J Neurosci. 1997;17:5928-5935

[66]. McKernan MG, Shinnick-Gallagher P. Fear conditioning induces a lasting potentiation of
synaptic currents in vitro. Nature. 1997;390:607-611

[67]. Bauer EP, LeDoux JE, Nader K. Fear conditioning and LTP in the lateral amygdala are
sensitive to the same stimulus contingencies. Nat Neurosci. 2001;4:687-688
[68]. Canive JM, Lewine JD, Orrison Jr. WW, Edgar CJ, Provencal SL, Davis JT, et al. MRI
reveals gross structural abnormalities in PTSD. Ann N Y Acad Sci. 1997;821:512-515

[69]. Myslobodsky MS, Glicksohn J, Singer J, Stern M, Bar-Ziv J, Friedland N, et al. Changes of
brain anatomy in patients with posttraumatic stress disorder: a pilot magnetic resonance imaging
study. Psychiatry Res. 1995;58:259-264

[70]. Gaser C, Nenadic I, Buchsbaum BR, Hazlett EA, Buchsbaum MS. Deformation-based
morphometry and its relation to conventional volumetry of brain lateral ventricles in, MRI.
Neuroimage. 2001;13:1140-1145

[71]. Bremner JD, Randall P, Scott TM, Bronen RA. MRI-based measurement of hippocampal
volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry.
1995;152:973-981

[72]. Gurvits TV, Shenton ME, Hokama H, Ohta H. Magnetic resonance imaging study of
hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry.
1996;40:1091-1099

[73]. Stein MB, Koverola C, Hanna C, Torchia MG. Hippocampal volume in women victimized by
childhood sexual abuse. Psychol Med. 1997;27:951-959

[74]. Bremner JD, Randall P, Vermetten E, Staib L. Magnetic resonance imaging-based
measurement of hippocampal volume in posttraumatic stress disorder related to childhood
physical and sexual abuse: a preliminary report. Biol Psychiatry. 1997;41:23-32

[75]. Grossman R, Yehuda R, New A, Schmeidler J, Mitropoulou V, Silverman J, et al.
Hypothalamic-pituitary-adrenal axis activity and hippocampal volume in personality disordered
subjects: associations with psychological trauma, depression and comorbid posttraumatic stress
disorder. Biol Psychiatry. 2001;49:249

[76]. Golier J, Yehuda R, De Santi S, Convit A, de Leon M. Hippocampal volume and memory
performance in holocaust survivors with PTSD. Presented at the annual meeting of the Society for
Biological Psychiatry. 2001.

[77]. O'Driscoll GA, Florencio PS, Gagnon D, Wolff AV, Benkelfat C, Mikula L, et al. Amygdala-
hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients.
Psychiatry Res. 2001;107:75-85

[78]. Niemann K, Hammers A, Coenen VA, Thron A, Klosterkotter J. Evidence of a smaller left
hippocampus and left temporal horn in both patients with first episode schizophrenia and normal
control subjects. Psychiatry Res. 2000;99:93-110

[79]. Vythilingam M, Anderson ER, Goddard A, Woods SW, Staib LH, Charney DS, et al.
Temporal lobe volume in panic disorder: a quantitative magnetic resonance imaging study.
Psychiatry Res. 2000;99:75-82

[80]. Chantarujikapong SI, Scherrer JF, Xian H, Eisen SA, Lyons MJ, Goldberg J, et al. A twin
study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic
stress disorder in men. Psychiatry Res. 2001;103:133-145

[81]. Radant A, Tsuang D, Peskind ER, McFall M, Raskind W. Biological markers and diagnostic
accuracy in the genetics of posttraumatic stress disorder. Psychiatry Res. 2001;102:203-215

[82]. Bonne O, Brandes D, Gilboa A, Gomori JM, Shenton ME, Pitman RK, et al. Longitudinal
MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry.
2001;158:1248-1251

[83]. De Bellis MD, Hall J, Boring AM, Frustaci K, Moritz G. A pilot longitudinal study of
hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol
Psychiatry. 2001;50:305-309

[84]. Schuff N, Marmar CR, Weiss DS, Neylan TC, Schoenfeld F, Fein G, et al. Reduced
hippocampal volume and n-acetyl aspartate in posttraumatic stress disorder. Ann N Y Acad Sci.
1997;821:516-520

[85]. Freeman TW, Cardwell D, Karson CN, Komoroski RA. In vivo proton magnetic resonance
spectroscopy of the medial temporal lobes of subjects with combat-related posttraumatic stress
disorder. Magn Reson Med. 1998;40:66-71

[86]. Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR, et al. A symptom
provocation study of posttraumatic stress disorder using positron emission tomography and
script-driven imagery. Arch Gen Psychiatry. 1996;53:380-387

[87]. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, et al. Regional
cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET
investigation. Am J Psychiatry. 1999;156:575-584

[88]. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, et al. Brain
activation in PTSD in response to trauma-related stimuli. Biol Psychiatry. 1999;45:817-826

[89]. Osuch EA, Benson B, Geraci M, Podell D, Herscovitch P, McCann UD, et al. Regional
cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress
disorder. Biol Psychiatry. 2001;50:246-253

[90]. Liberzon I, Taylor SF, Fig LM, Koeppe RA. Alteration of corticothalamic perfusion ratios
during a PTSD flashback. Depress Anxiety. 1996–97;4:146-150

[91]. Hazlett EA, Buchsbaum MS, Tang CY, Fleischman MB, Wei TC, Byne W, et al. Thalamic
activation during an attention-to-prepulse startle modification paradigm: a functional MRI study.
Biol Psychiatry. 2001;50:281-291

[92]. Fernandez M, Pissiota A, Frans O, von Knorring L, Fischer H, Fredrikson M. Brain function
in a patient with torture related post-traumatic stress disorder before and after fluoxetine
treatment: a positron emission tomography provocation study. Neurosci Lett. 2001;297:101-104

[93]. Shalev AY, Peri T, Orr SP, Bonne O, Pitman RK. Auditory startle responses in help-seeking
trauma survivors. Psychiatry Res. 1997;69:1-7

[94]. Orr SP, Lasko NB, Metzger LJ, Pitman RK. Physiologic responses to non-startling tones in
Vietnam veterans with post-traumatic stress disorder. Psychiatry Res. 1997;73:103-107

[95]. Medina AM, Mejia VY, Schell AM, Dawson ME, Margolin G. Startle reactivity and PTSD
symptoms in a community sample of women. Psychiatry Res. 2001;101:157-169
[96]. Hazlett EA, Buchsbaum MS. Sensorimotor gating deficits and hypofrontality in
schizophrenia. Front Biosci. 2001;6:D1069-D1072

[97]. Semple WE, Goyer P, McCormick R, Morris E, Compton B, Muswick G, et al. Preliminary
report: brain blood flow using PET in patients with posttraumatic stress disorder and substance-
abuse histories. Biol Psychiatry. 1993;34:115-118

[98]. Semple WE, Goyer PF, McCormick R, Compton-Toth B, Morris E, Donovan B, et al.
Attention and regional cerebral blood flow in posttraumatic stress disorder patients with
substance abuse histories. Psychiatry Res. 1996;67:17-28

[99]. Shin LM, Kosslyn SM, McNally RJ, Alpert NM, Thompson WL, Rauch SL, et al. Visual
imagery and perception in posttraumatic stress disorder: a positron emission tomographic
investigation. Arch Gen Psychiatry. 1997;54:233-241

[100]. Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, et al.
Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a
functional MRI study. Biol Psychiatry. 2000;47:769-776

[101]. Semple WE, Goyer PF, McCormick R, Donovan B, Muzic Jr. RF, Rugle L, et al. Higher
brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid
cocaine and alcohol abuse compared with normals. Psychiatry. 2000;63:65-74

[102]. Yasuno F, Nishikawa T, Nakagawa Y, Ikejiri Y, Tokunaga H, Mizuta I, et al. Functional
anatomical study of psychogenic amnesia. Psychiatry Res. 2000;99:43-57

[103]. Bremner JD, Innis RB, Ng CK, Staib LH, Salomon RM, Bronen RA, et al. Positron
emission tomography measurement of cerebral metabolic correlates of yohimbine administration
in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54:246-254

[104]. Grossman R, Yehuda R, Sta. Maria N, Lee R, de Leon M, Buchsbaum M. Hydrocortisone
study of central glucocorticoid sensitivity. Presented at the 15th annual meeting of the
International Society For Traumatic Stress Studies. Miami, November, 1999

[105]. Bremner JD, Innis RB, Southwick SM, Staib L, Zoghbi S, Charney DS. Decreased
benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress
disorder. Am J Psychiatry. 2000;157:1120-1126

[106]. Pitman RK, Shin LM, Rauch SL. Investigating the pathogenesis of posttraumatic stress
disorder with neuroimaging. J Clin Psychiatry. 2001;62((Suppl 17)):47-54

[107]. Rauch SL, Shin LM, Pitman RK. Neuroimaging and the neuroanatomy of PTSD. CNS
Spectrums. 1998;3((Suppl 2)):30-41



Addendum

       A  new  version  of  topic  of  the  month  publication  is  uploaded  in  my  web  site  every  month  (it 
       remains for a month and is changed with the monthly update of the neurology bulletin
       at:.http://neurology.yassermetwally.com)
   To download the current version of topic of the month publication follow the link
       quot;http://neurology.yassermetwally.com/topic.zipquot;
      You can also download the current version of topic of the month publication from within the
       publication or go to my web site at: quot;http://yassermetwally.comquot; to download it.
      At the end of each year, all the publications are compiled on a single CD-ROM, please author to
       know more details.
      Screen resolution is better set at 1024*768 pixel screen area for optimum display
      For an archive of the previously published topics in downloadable PDF format go to
       http://yassermetwally.net, then under pages in the right panel, scroll down and click on the text
       entry quot;topic of the monthquot;
      In order to view a list of the previously published topics in downloadable PDF format, follow the
       link: http://wordpress.com/tag/neurological-topic-of-the-month/



The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo,
Egypt

 www.yassermetwally.com

Contenu connexe

En vedette

Short case...Herpes simplex type 1 encephalitis
Short case...Herpes simplex type 1 encephalitisShort case...Herpes simplex type 1 encephalitis
Short case...Herpes simplex type 1 encephalitisProfessor Yasser Metwally
 
Short case......Primary subependymal CNS lymphoma (MRI approach)
Short case......Primary subependymal CNS lymphoma (MRI approach)Short case......Primary subependymal CNS lymphoma (MRI approach)
Short case......Primary subependymal CNS lymphoma (MRI approach)Professor Yasser Metwally
 
Short case...Multiple pyogenic brain abscesses
Short case...Multiple pyogenic brain abscessesShort case...Multiple pyogenic brain abscesses
Short case...Multiple pyogenic brain abscessesProfessor Yasser Metwally
 
Topic of the month...The ischemic microvascular brain disease
Topic of the month...The ischemic microvascular brain diseaseTopic of the month...The ischemic microvascular brain disease
Topic of the month...The ischemic microvascular brain diseaseProfessor Yasser Metwally
 
Case record......Primary subependymal CNS lymphoma (MRI approach)
Case record......Primary subependymal CNS lymphoma (MRI approach)Case record......Primary subependymal CNS lymphoma (MRI approach)
Case record......Primary subependymal CNS lymphoma (MRI approach)Professor Yasser Metwally
 
Issues in brainmapping...hepatic encephalopathy
Issues in brainmapping...hepatic encephalopathyIssues in brainmapping...hepatic encephalopathy
Issues in brainmapping...hepatic encephalopathyProfessor Yasser Metwally
 
Case record...Arterial ectasia of the vertebro-basilar system
Case record...Arterial ectasia of the vertebro-basilar systemCase record...Arterial ectasia of the vertebro-basilar system
Case record...Arterial ectasia of the vertebro-basilar systemProfessor Yasser Metwally
 
Case record...Cerebral amyloid angiopathy (CAA),
Case record...Cerebral amyloid angiopathy (CAA),Case record...Cerebral amyloid angiopathy (CAA),
Case record...Cerebral amyloid angiopathy (CAA),Professor Yasser Metwally
 

En vedette (20)

Short case...Herpes simplex type 1 encephalitis
Short case...Herpes simplex type 1 encephalitisShort case...Herpes simplex type 1 encephalitis
Short case...Herpes simplex type 1 encephalitis
 
Short case...Tuberous sclerosis
Short case...Tuberous sclerosisShort case...Tuberous sclerosis
Short case...Tuberous sclerosis
 
Short case......Primary subependymal CNS lymphoma (MRI approach)
Short case......Primary subependymal CNS lymphoma (MRI approach)Short case......Primary subependymal CNS lymphoma (MRI approach)
Short case......Primary subependymal CNS lymphoma (MRI approach)
 
Short case...Multiple pyogenic brain abscesses
Short case...Multiple pyogenic brain abscessesShort case...Multiple pyogenic brain abscesses
Short case...Multiple pyogenic brain abscesses
 
Topic of the month...The ischemic microvascular brain disease
Topic of the month...The ischemic microvascular brain diseaseTopic of the month...The ischemic microvascular brain disease
Topic of the month...The ischemic microvascular brain disease
 
Case record......Primary subependymal CNS lymphoma (MRI approach)
Case record......Primary subependymal CNS lymphoma (MRI approach)Case record......Primary subependymal CNS lymphoma (MRI approach)
Case record......Primary subependymal CNS lymphoma (MRI approach)
 
Issues in brainmapping...hepatic encephalopathy
Issues in brainmapping...hepatic encephalopathyIssues in brainmapping...hepatic encephalopathy
Issues in brainmapping...hepatic encephalopathy
 
Neurological lectures...Vertigo
Neurological lectures...VertigoNeurological lectures...Vertigo
Neurological lectures...Vertigo
 
Case record...Postinfectious cerebellitis
Case record...Postinfectious cerebellitisCase record...Postinfectious cerebellitis
Case record...Postinfectious cerebellitis
 
Short case...Neuromyelitis optica
Short case...Neuromyelitis opticaShort case...Neuromyelitis optica
Short case...Neuromyelitis optica
 
Case record...Cerebral palsy
Case record...Cerebral palsyCase record...Cerebral palsy
Case record...Cerebral palsy
 
Case record...Arterial ectasia of the vertebro-basilar system
Case record...Arterial ectasia of the vertebro-basilar systemCase record...Arterial ectasia of the vertebro-basilar system
Case record...Arterial ectasia of the vertebro-basilar system
 
Case record... Behcet disease
Case record... Behcet diseaseCase record... Behcet disease
Case record... Behcet disease
 
Case record... Septo-optic dysplasia
Case record... Septo-optic dysplasiaCase record... Septo-optic dysplasia
Case record... Septo-optic dysplasia
 
Short case...Intramedullary cavernoma
Short case...Intramedullary cavernomaShort case...Intramedullary cavernoma
Short case...Intramedullary cavernoma
 
Shortcase...Hemimegalencephaly
Shortcase...HemimegalencephalyShortcase...Hemimegalencephaly
Shortcase...Hemimegalencephaly
 
Topic of the month.... Primary CNS lymphoma
Topic of the month.... Primary CNS lymphomaTopic of the month.... Primary CNS lymphoma
Topic of the month.... Primary CNS lymphoma
 
Case record...Cortical dysplasia
Case record...Cortical dysplasiaCase record...Cortical dysplasia
Case record...Cortical dysplasia
 
Case record...Cerebral amyloid angiopathy (CAA),
Case record...Cerebral amyloid angiopathy (CAA),Case record...Cerebral amyloid angiopathy (CAA),
Case record...Cerebral amyloid angiopathy (CAA),
 
Case record...Hemimegalencephaly
Case record...HemimegalencephalyCase record...Hemimegalencephaly
Case record...Hemimegalencephaly
 

Similaire à Topic of the month....Neuroimaging of posttraumatic stress disorders

Hanipsych, circuits in psych
Hanipsych, circuits in psychHanipsych, circuits in psych
Hanipsych, circuits in psychHani Hamed
 
Sculpting the hippocampus from within stress, spines, and crh
Sculpting the hippocampus from within  stress, spines, and crh Sculpting the hippocampus from within  stress, spines, and crh
Sculpting the hippocampus from within stress, spines, and crh Juan Rubio
 
Talking psychiatry...Functional neuroimaging of schizophrenia
Talking psychiatry...Functional neuroimaging of schizophreniaTalking psychiatry...Functional neuroimaging of schizophrenia
Talking psychiatry...Functional neuroimaging of schizophreniaProfessor Yasser Metwally
 
Early Life Stress Experiments
Early Life Stress ExperimentsEarly Life Stress Experiments
Early Life Stress ExperimentsNatalie Parnell
 
Pharmaco-therapy of Depression ~Prof. Dr.Tarek Asaad
Pharmaco-therapy of Depression ~Prof. Dr.Tarek AsaadPharmaco-therapy of Depression ~Prof. Dr.Tarek Asaad
Pharmaco-therapy of Depression ~Prof. Dr.Tarek AsaadDr Tarek Asaad
 
Regulation of depression by a new type of brain stimulation in addicted patie...
Regulation of depression by a new type of brain stimulation in addicted patie...Regulation of depression by a new type of brain stimulation in addicted patie...
Regulation of depression by a new type of brain stimulation in addicted patie...Mrsunny4
 
Chem Imbalance (For)
Chem Imbalance (For)Chem Imbalance (For)
Chem Imbalance (For)psych493
 
Psychotherapy the biological dimension
Psychotherapy the biological dimensionPsychotherapy the biological dimension
Psychotherapy the biological dimensionismail sadek
 
Regeneration of mind and brain
Regeneration of mind and brainRegeneration of mind and brain
Regeneration of mind and brainDevashish Konar
 
Targets of Antidepressant Therapy
Targets of Antidepressant TherapyTargets of Antidepressant Therapy
Targets of Antidepressant TherapyAngela Pascuzzi
 
Swoyam NEUROBIOLOGY OF MEMORY.pptx
Swoyam NEUROBIOLOGY OF MEMORY.pptxSwoyam NEUROBIOLOGY OF MEMORY.pptx
Swoyam NEUROBIOLOGY OF MEMORY.pptxRobinBaghla
 
Hanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depressionHanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depressionHani Hamed
 
Dr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBD
Dr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBDDr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBD
Dr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBDdrmanipavuluri
 
Stress And Neurodegenerative Diseases
Stress And Neurodegenerative DiseasesStress And Neurodegenerative Diseases
Stress And Neurodegenerative Diseasestraorefatima
 
The Function Of A Memory
The Function Of A MemoryThe Function Of A Memory
The Function Of A MemoryGina Alfaro
 
Running Head DEPRESSION .docx
Running Head DEPRESSION                                          .docxRunning Head DEPRESSION                                          .docx
Running Head DEPRESSION .docxtodd271
 

Similaire à Topic of the month....Neuroimaging of posttraumatic stress disorders (20)

Hanipsych, circuits in psych
Hanipsych, circuits in psychHanipsych, circuits in psych
Hanipsych, circuits in psych
 
Sculpting the hippocampus from within stress, spines, and crh
Sculpting the hippocampus from within  stress, spines, and crh Sculpting the hippocampus from within  stress, spines, and crh
Sculpting the hippocampus from within stress, spines, and crh
 
Talking psychiatry...Functional neuroimaging of schizophrenia
Talking psychiatry...Functional neuroimaging of schizophreniaTalking psychiatry...Functional neuroimaging of schizophrenia
Talking psychiatry...Functional neuroimaging of schizophrenia
 
1.pptx
1.pptx1.pptx
1.pptx
 
Early Life Stress Experiments
Early Life Stress ExperimentsEarly Life Stress Experiments
Early Life Stress Experiments
 
Pharmaco-therapy of Depression ~Prof. Dr.Tarek Asaad
Pharmaco-therapy of Depression ~Prof. Dr.Tarek AsaadPharmaco-therapy of Depression ~Prof. Dr.Tarek Asaad
Pharmaco-therapy of Depression ~Prof. Dr.Tarek Asaad
 
Regulation of depression by a new type of brain stimulation in addicted patie...
Regulation of depression by a new type of brain stimulation in addicted patie...Regulation of depression by a new type of brain stimulation in addicted patie...
Regulation of depression by a new type of brain stimulation in addicted patie...
 
Neuroplasticity
NeuroplasticityNeuroplasticity
Neuroplasticity
 
Chem Imbalance (For)
Chem Imbalance (For)Chem Imbalance (For)
Chem Imbalance (For)
 
Psychotherapy the biological dimension
Psychotherapy the biological dimensionPsychotherapy the biological dimension
Psychotherapy the biological dimension
 
Regeneration of mind and brain
Regeneration of mind and brainRegeneration of mind and brain
Regeneration of mind and brain
 
Targets of Antidepressant Therapy
Targets of Antidepressant TherapyTargets of Antidepressant Therapy
Targets of Antidepressant Therapy
 
Neuroplasticity and anesthesia
Neuroplasticity and anesthesia Neuroplasticity and anesthesia
Neuroplasticity and anesthesia
 
Swoyam NEUROBIOLOGY OF MEMORY.pptx
Swoyam NEUROBIOLOGY OF MEMORY.pptxSwoyam NEUROBIOLOGY OF MEMORY.pptx
Swoyam NEUROBIOLOGY OF MEMORY.pptx
 
Hanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depressionHanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depression
 
Dr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBD
Dr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBDDr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBD
Dr Mani Pavuluri - Integrating Pharmacotherapy and Psychotherapy for PBD
 
Stress And Neurodegenerative Diseases
Stress And Neurodegenerative DiseasesStress And Neurodegenerative Diseases
Stress And Neurodegenerative Diseases
 
Lect.1 Introduction to CNS and Drug Action
Lect.1 Introduction to CNS  and Drug ActionLect.1 Introduction to CNS  and Drug Action
Lect.1 Introduction to CNS and Drug Action
 
The Function Of A Memory
The Function Of A MemoryThe Function Of A Memory
The Function Of A Memory
 
Running Head DEPRESSION .docx
Running Head DEPRESSION                                          .docxRunning Head DEPRESSION                                          .docx
Running Head DEPRESSION .docx
 

Plus de Professor Yasser Metwally

The Snake, the Scorpion, the turtle in Egypt
The Snake, the Scorpion, the turtle in EgyptThe Snake, the Scorpion, the turtle in Egypt
The Snake, the Scorpion, the turtle in EgyptProfessor Yasser Metwally
 
Radiological pathology of epileptic disorders
Radiological pathology of epileptic disordersRadiological pathology of epileptic disorders
Radiological pathology of epileptic disordersProfessor Yasser Metwally
 
Radiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disordersRadiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disordersProfessor Yasser Metwally
 
Radiological pathology of spontaneous cerebral hemorrhage
Radiological pathology of spontaneous cerebral hemorrhageRadiological pathology of spontaneous cerebral hemorrhage
Radiological pathology of spontaneous cerebral hemorrhageProfessor Yasser Metwally
 
Radiological pathology of cerebral amyloid angiography
Radiological pathology of cerebral amyloid angiographyRadiological pathology of cerebral amyloid angiography
Radiological pathology of cerebral amyloid angiographyProfessor Yasser Metwally
 
Radiological pathology of cerebral microbleeds
Radiological pathology of cerebral microbleedsRadiological pathology of cerebral microbleeds
Radiological pathology of cerebral microbleedsProfessor Yasser Metwally
 
Issues in radiological pathology: Radiological pathology of watershed infarct...
Issues in radiological pathology: Radiological pathology of watershed infarct...Issues in radiological pathology: Radiological pathology of watershed infarct...
Issues in radiological pathology: Radiological pathology of watershed infarct...Professor Yasser Metwally
 
Radiological pathology of cortical laminar necrosis
Radiological pathology of cortical laminar necrosisRadiological pathology of cortical laminar necrosis
Radiological pathology of cortical laminar necrosisProfessor Yasser Metwally
 

Plus de Professor Yasser Metwally (20)

The Egyptian Zoo in Cairo 2015
The Egyptian Zoo in Cairo 2015The Egyptian Zoo in Cairo 2015
The Egyptian Zoo in Cairo 2015
 
End of the great nile river in Ras Elbar
End of the great nile river in Ras ElbarEnd of the great nile river in Ras Elbar
End of the great nile river in Ras Elbar
 
The Lion and The tiger in Egypt
The Lion and The tiger in EgyptThe Lion and The tiger in Egypt
The Lion and The tiger in Egypt
 
The monkeys in Egypt
The monkeys in EgyptThe monkeys in Egypt
The monkeys in Egypt
 
The Snake, the Scorpion, the turtle in Egypt
The Snake, the Scorpion, the turtle in EgyptThe Snake, the Scorpion, the turtle in Egypt
The Snake, the Scorpion, the turtle in Egypt
 
The Egyptian Parrot
The Egyptian ParrotThe Egyptian Parrot
The Egyptian Parrot
 
The Egyptian Deer
The Egyptian DeerThe Egyptian Deer
The Egyptian Deer
 
The Egyptian Pelican
The Egyptian PelicanThe Egyptian Pelican
The Egyptian Pelican
 
The Flamingo bird in Egypt
The Flamingo bird in EgyptThe Flamingo bird in Egypt
The Flamingo bird in Egypt
 
Egyptian Cats
Egyptian CatsEgyptian Cats
Egyptian Cats
 
Radiological pathology of epileptic disorders
Radiological pathology of epileptic disordersRadiological pathology of epileptic disorders
Radiological pathology of epileptic disorders
 
Radiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disordersRadiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disorders
 
Radiological pathology of spontaneous cerebral hemorrhage
Radiological pathology of spontaneous cerebral hemorrhageRadiological pathology of spontaneous cerebral hemorrhage
Radiological pathology of spontaneous cerebral hemorrhage
 
Radiological pathology of cerebral amyloid angiography
Radiological pathology of cerebral amyloid angiographyRadiological pathology of cerebral amyloid angiography
Radiological pathology of cerebral amyloid angiography
 
Radiological pathology of cerebral microbleeds
Radiological pathology of cerebral microbleedsRadiological pathology of cerebral microbleeds
Radiological pathology of cerebral microbleeds
 
The Egyptian Zoo in Cairo
The Egyptian Zoo in CairoThe Egyptian Zoo in Cairo
The Egyptian Zoo in Cairo
 
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
 
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
 
Issues in radiological pathology: Radiological pathology of watershed infarct...
Issues in radiological pathology: Radiological pathology of watershed infarct...Issues in radiological pathology: Radiological pathology of watershed infarct...
Issues in radiological pathology: Radiological pathology of watershed infarct...
 
Radiological pathology of cortical laminar necrosis
Radiological pathology of cortical laminar necrosisRadiological pathology of cortical laminar necrosis
Radiological pathology of cortical laminar necrosis
 

Dernier

How to Make a Field read-only in Odoo 17
How to Make a Field read-only in Odoo 17How to Make a Field read-only in Odoo 17
How to Make a Field read-only in Odoo 17Celine George
 
Drug Information Services- DIC and Sources.
Drug Information Services- DIC and Sources.Drug Information Services- DIC and Sources.
Drug Information Services- DIC and Sources.raviapr7
 
Riddhi Kevadiya. WILLIAM SHAKESPEARE....
Riddhi Kevadiya. WILLIAM SHAKESPEARE....Riddhi Kevadiya. WILLIAM SHAKESPEARE....
Riddhi Kevadiya. WILLIAM SHAKESPEARE....Riddhi Kevadiya
 
P4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdf
P4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdfP4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdf
P4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdfYu Kanazawa / Osaka University
 
EBUS5423 Data Analytics and Reporting Bl
EBUS5423 Data Analytics and Reporting BlEBUS5423 Data Analytics and Reporting Bl
EBUS5423 Data Analytics and Reporting BlDr. Bruce A. Johnson
 
Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...
Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...
Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...Dr. Asif Anas
 
Optical Fibre and It's Applications.pptx
Optical Fibre and It's Applications.pptxOptical Fibre and It's Applications.pptx
Optical Fibre and It's Applications.pptxPurva Nikam
 
DUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRA
DUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRADUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRA
DUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRATanmoy Mishra
 
Protein Structure - threading Protein modelling pptx
Protein Structure - threading Protein modelling pptxProtein Structure - threading Protein modelling pptx
Protein Structure - threading Protein modelling pptxvidhisharma994099
 
How to Send Emails From Odoo 17 Using Code
How to Send Emails From Odoo 17 Using CodeHow to Send Emails From Odoo 17 Using Code
How to Send Emails From Odoo 17 Using CodeCeline George
 
KARNAADA.pptx made by - saransh dwivedi ( SD ) - SHALAKYA TANTRA - ENT - 4...
KARNAADA.pptx  made by -  saransh dwivedi ( SD ) -  SHALAKYA TANTRA - ENT - 4...KARNAADA.pptx  made by -  saransh dwivedi ( SD ) -  SHALAKYA TANTRA - ENT - 4...
KARNAADA.pptx made by - saransh dwivedi ( SD ) - SHALAKYA TANTRA - ENT - 4...M56BOOKSTORE PRODUCT/SERVICE
 
How to Create a Toggle Button in Odoo 17
How to Create a Toggle Button in Odoo 17How to Create a Toggle Button in Odoo 17
How to Create a Toggle Button in Odoo 17Celine George
 
CapTechU Doctoral Presentation -March 2024 slides.pptx
CapTechU Doctoral Presentation -March 2024 slides.pptxCapTechU Doctoral Presentation -March 2024 slides.pptx
CapTechU Doctoral Presentation -March 2024 slides.pptxCapitolTechU
 
The basics of sentences session 10pptx.pptx
The basics of sentences session 10pptx.pptxThe basics of sentences session 10pptx.pptx
The basics of sentences session 10pptx.pptxheathfieldcps1
 
How to Show Error_Warning Messages in Odoo 17
How to Show Error_Warning Messages in Odoo 17How to Show Error_Warning Messages in Odoo 17
How to Show Error_Warning Messages in Odoo 17Celine George
 
In - Vivo and In - Vitro Correlation.pptx
In - Vivo and In - Vitro Correlation.pptxIn - Vivo and In - Vitro Correlation.pptx
In - Vivo and In - Vitro Correlation.pptxAditiChauhan701637
 
5 charts on South Africa as a source country for international student recrui...
5 charts on South Africa as a source country for international student recrui...5 charts on South Africa as a source country for international student recrui...
5 charts on South Africa as a source country for international student recrui...CaraSkikne1
 
Department of Health Compounder Question ‍Solution 2022.pdf
Department of Health Compounder Question ‍Solution 2022.pdfDepartment of Health Compounder Question ‍Solution 2022.pdf
Department of Health Compounder Question ‍Solution 2022.pdfMohonDas
 
10 Topics For MBA Project Report [HR].pdf
10 Topics For MBA Project Report [HR].pdf10 Topics For MBA Project Report [HR].pdf
10 Topics For MBA Project Report [HR].pdfJayanti Pande
 
Ultra structure and life cycle of Plasmodium.pptx
Ultra structure and life cycle of Plasmodium.pptxUltra structure and life cycle of Plasmodium.pptx
Ultra structure and life cycle of Plasmodium.pptxDr. Asif Anas
 

Dernier (20)

How to Make a Field read-only in Odoo 17
How to Make a Field read-only in Odoo 17How to Make a Field read-only in Odoo 17
How to Make a Field read-only in Odoo 17
 
Drug Information Services- DIC and Sources.
Drug Information Services- DIC and Sources.Drug Information Services- DIC and Sources.
Drug Information Services- DIC and Sources.
 
Riddhi Kevadiya. WILLIAM SHAKESPEARE....
Riddhi Kevadiya. WILLIAM SHAKESPEARE....Riddhi Kevadiya. WILLIAM SHAKESPEARE....
Riddhi Kevadiya. WILLIAM SHAKESPEARE....
 
P4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdf
P4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdfP4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdf
P4C x ELT = P4ELT: Its Theoretical Background (Kanazawa, 2024 March).pdf
 
EBUS5423 Data Analytics and Reporting Bl
EBUS5423 Data Analytics and Reporting BlEBUS5423 Data Analytics and Reporting Bl
EBUS5423 Data Analytics and Reporting Bl
 
Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...
Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...
Unveiling the Intricacies of Leishmania donovani: Structure, Life Cycle, Path...
 
Optical Fibre and It's Applications.pptx
Optical Fibre and It's Applications.pptxOptical Fibre and It's Applications.pptx
Optical Fibre and It's Applications.pptx
 
DUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRA
DUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRADUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRA
DUST OF SNOW_BY ROBERT FROST_EDITED BY_ TANMOY MISHRA
 
Protein Structure - threading Protein modelling pptx
Protein Structure - threading Protein modelling pptxProtein Structure - threading Protein modelling pptx
Protein Structure - threading Protein modelling pptx
 
How to Send Emails From Odoo 17 Using Code
How to Send Emails From Odoo 17 Using CodeHow to Send Emails From Odoo 17 Using Code
How to Send Emails From Odoo 17 Using Code
 
KARNAADA.pptx made by - saransh dwivedi ( SD ) - SHALAKYA TANTRA - ENT - 4...
KARNAADA.pptx  made by -  saransh dwivedi ( SD ) -  SHALAKYA TANTRA - ENT - 4...KARNAADA.pptx  made by -  saransh dwivedi ( SD ) -  SHALAKYA TANTRA - ENT - 4...
KARNAADA.pptx made by - saransh dwivedi ( SD ) - SHALAKYA TANTRA - ENT - 4...
 
How to Create a Toggle Button in Odoo 17
How to Create a Toggle Button in Odoo 17How to Create a Toggle Button in Odoo 17
How to Create a Toggle Button in Odoo 17
 
CapTechU Doctoral Presentation -March 2024 slides.pptx
CapTechU Doctoral Presentation -March 2024 slides.pptxCapTechU Doctoral Presentation -March 2024 slides.pptx
CapTechU Doctoral Presentation -March 2024 slides.pptx
 
The basics of sentences session 10pptx.pptx
The basics of sentences session 10pptx.pptxThe basics of sentences session 10pptx.pptx
The basics of sentences session 10pptx.pptx
 
How to Show Error_Warning Messages in Odoo 17
How to Show Error_Warning Messages in Odoo 17How to Show Error_Warning Messages in Odoo 17
How to Show Error_Warning Messages in Odoo 17
 
In - Vivo and In - Vitro Correlation.pptx
In - Vivo and In - Vitro Correlation.pptxIn - Vivo and In - Vitro Correlation.pptx
In - Vivo and In - Vitro Correlation.pptx
 
5 charts on South Africa as a source country for international student recrui...
5 charts on South Africa as a source country for international student recrui...5 charts on South Africa as a source country for international student recrui...
5 charts on South Africa as a source country for international student recrui...
 
Department of Health Compounder Question ‍Solution 2022.pdf
Department of Health Compounder Question ‍Solution 2022.pdfDepartment of Health Compounder Question ‍Solution 2022.pdf
Department of Health Compounder Question ‍Solution 2022.pdf
 
10 Topics For MBA Project Report [HR].pdf
10 Topics For MBA Project Report [HR].pdf10 Topics For MBA Project Report [HR].pdf
10 Topics For MBA Project Report [HR].pdf
 
Ultra structure and life cycle of Plasmodium.pptx
Ultra structure and life cycle of Plasmodium.pptxUltra structure and life cycle of Plasmodium.pptx
Ultra structure and life cycle of Plasmodium.pptx
 

Topic of the month....Neuroimaging of posttraumatic stress disorders

  • 1. INDEX www.yassermetwally.com  INTRODUCTION  BRAIN REGIONS HYPOTHESIZED AS A PRIORI AS RELEVANT TO PTSD  MRI OF THE HIPPOCAMPUS AND AMYGDAL  FUNCTIONING NEUROIMAGING STUDIES NEUROIMAGING OF POST-TRAUMATIC STRESS DISORDERS We review some of the advances that have been made in understanding the structural, biochemical, and functional neuroanatomy of post-traumatic stress disorder (PTSD). First, we review the primary brain regions that had been hypothesized a priori, from the phenomenology and neurobiology of PTSD, to be implicated in the pathophysiology. Next, we review findings from neuroimaging studies of these brain regions in PTSD and explain the various experimental methods and imaging technologies used in these studies. A broader perspective, including a discussion of additional brain areas that may be involved in PTSD, is synthesized. We conclude with a rationale and approach for studies testing sharply defined hypotheses and those using multidisciplinary strategies that integrate neuroimaging data with other cognitive, biologic, and genetic tools to study this complex disorder.  BRAIN REGIONS HYPOTHESIZED A PRIORI AS RELEVANT TO PTSD  The hippocampus Post-traumatic stress disorder may occur following exposure to situations that induce strong feelings of fear, helplessness, or horror (DSM-IV). One of the core symptoms in trauma survivors with PTSD is a disturbance in memory function [1]. The hippocampus was one of the regions first thought to be implicated in the pathophysiology of PTSD because of its role in both memory and the neuroendocrine response to stress. The first evidence that the hippocampus was involved in memory processing occurred in the late
  • 2. 1950s with the comprehensive neuropsychological evaluation of patient H.M., who underwent bilateral surgical removal of the medial temporal lobes for treatment of intractable seizures and became unable to acquire new memories [2]. H.M.'s intellectual ability (IQ), immediate memory, knowledge from early life, and personality remained intact, suggesting that memory is a distinct and separable cerebral function. Later, human cases with smaller lesions [3–5] and lesion studies in primates [6–8] confirmed the hippocampus and adjacent cortical areas [9] (i.e., the medial temporal lobe memory system) as essential for declarative memory formation. Declarative or explicit memory entails information that can be recalled and described, such as memories of events, faces, or special layouts [4,10]. Declarative memory is a distinct type of memory that occurs in different brain regions from other types of memory; it includes memories for perceptual and motor skills and other mnemonic processes such as priming, classical conditioning, operant conditioning, habituation, and sensitization. Because the hippocampus is the physical region critical for declarative memory function, one might hypothesize structural abnormalities in the hippocampi of persons with PTSD. In the hippocampi, there is a massive convergence of cortical neurons from various association areas of the brain. Like an old-fashioned central telephone switchboard, the close physical proximity created by this convergence allows for connections to be made. There is a biochemical process by which declarative memories are formed through modification of neuronal connections that is also relevant to the study of PTSD. Hebb was the first to describe memory as the formation of an “assembly of association-area cells,” the synapses of which are more readily traversed by some form of experience-induced synaptic strengthening [11]. Although significant questions remain, it is believed that memories are formed through cellular-level changes in the synaptic coupling between neurons related to an activity-dependent strengthening of that synaptic connection, referred to as long-term potentiation (LTP) [12]. LTP is a form of synaptic plasticity that strengthens the connection between neurons in the formation of networks that constitute an experience, a memory, or learned information. The importance of this concept to PTSD is in providing a putative cellular mechanism that might be disrupted or altered, thereby leading to memory impairments in these individuals, even in the absence of any gross structural hippocampal “damage.” The physical integrity of the hippocampus and the biochemical process of LTP are relevant to PTSD research from a neuroendocrine perspective. Alterations in systemic glucocorticoid (GC) levels (either through direct manipulation or secondary to induced stress) have been shown acutely to interfere with the biochemical processes of LTP and chronically to result in physical damage to the hippocampus [13]. PTSD has been characterized by various alterations in the hypothalamic-pituitary-adrenal (HPA) axis, such as decreased basal and circadian levels of cortisol, decreased urinary excretion of cortisol, increased cortisol suppression following dexamethasone, increased numbers of plasma lymphocyte GC receptors, and hypersecretion of corticotrophin-releasing hormone [14]. Preclinical research has consistently demonstrated that sustained exposure to high GC levels via exogenous GC administration leads to neuronal degeneration confined to the CA3 hippocampal region in rats, tree shrews, and vervet monkeys [15–17]. Increased endogenous GC production as a result of stressful conditions also results in a similar CA3 region hippocampal degeneration in these animals [18–20] and in “dendritic pruning” [21–24]. Neuronal death and dendritic may lead to a similar result in humans under similar high stress and high GC conditions. How GCs mediate neuronal death and atrophy in the above studies is not completely known [13,25]. Possible mechanisms include GC effects of decreasing hippocampal glucose uptake, which may result in lowered ATP stores and heightened vulnerability or “endangerment” to insults [25]; augmenting excitatory amino acid accumulation in the hippocampus [26]; and increasing expression of N-methyl-D-aspartate (NMDA) receptors [27,28]. Increased stimulation of both
  • 3. NMDA and non-NMDA receptors may result in excitotoxicity, which results from excessive mobilization of cytosolic calcium with overactivation of lipases, proteases, and nucleases and with the generation of oxygen radicals [29]. It is not GCs acting alone but in combination with other neurochemicals that produces dendritic pruning, neuronal atrophy, or neuronal death [13]. Despite our lack of understanding about the exact mechanism through which GCs exert their effects on the hippocampus, there is little doubt that GCs affect not only the physical structure of the hippocampus but also the hippocampus-based mechanism for declarative memory function. Preclinical and human studies have explored the cognitive effects of stress-induced and exogenous increases in GCs on declarative memory function. Healthy subjects given oral steroids display increased errors of commission in verbal memory tasks (incorrectly identifying distractors as target words), impaired verbal declarative memory, and impaired spacial memory (a form of declarative memory) without changes in attention or level of arousal [29–31]. Intravenous infusion of steroids produced impairment in both working memory and declarative memory in healthy subjects [32]. Socially stressful situations, which increase endogenous GC levels, have similar effects on declarative memory [33]. These acute effects of elevated GC levels (either through stress or exogenous administration) on declarative memory are not via death or pruning of hippocampal neurons but rather through directly impairing the biochemical process of LTP. Animal studies indicate that GC concentration has an “inverse-U” relationship to hippocampal activity, with extremely low and high GC levels disrupting hippocampal excitability and LTP [34]. Acute stress and GC receptor stimulation impair LTP in a similar fashion [35–37]. In summary, increased GC levels may interfere with declarative memory through various mechanisms of dendritic pruning, neuronal atrophy, neuronal death, and interfering with LTP. However, most studies find decreased basal cortisol levels and increased negative feedback sensitivity in subjects with PTSD. Several investigators have tried to resolve the apparent paradox. The concept of “allostatic load,” for example, has been forwarded as a possible mechanism for GC-mediated alterations in PTSD [38,39]. Allostasis refers to the ability to achieve stability through change and is crucial for proper functioning of the HPA axis and other systems. Accommodation is viewed as a stress that puts wear and tear on the system, eventually leading to a harmful decrease in the system's ability to adapt to change [40]. Chronobiologic analyses of circadian cortisol levels in PTSD have demonstrated a higher signal-to-noise ratio, which indicates a more finely tuned and responsive system [41]. The greater responsiveness of the HPA axis in PTSD may put larger accommodation stresses on the HPA axis, thereby leading to greater wear and tear. Another hypothesis centers on the role of steroid receptors, which are necessary to mediate the effects of GCs. The concept of negative feedback inhibition has also been used to explain the apparent paradox between low cortisol levels and hippocampal-related alterations in PTSD [14]. Under conditions of an increased negative feedback inhibition, GC-mediated effects on hippocampal structure could occur despite lower ambient cortisol levels. It also is possible that increased GC levels are present during and for an unspecified period following the trauma(s), and after some passage of time, susceptible individuals' feedback sensitivity set-point is changed, which then results in lower GC levels. Hence, from a theoretical perspective, a disruption in hippocampal function as a result of endocrine, metabolic, or other agents that interfere with the biochemical process of LTP or that result in neuronal death or pruning could result in consequences that resemble core clinical phenomena of PTSD, such as psychogenic amnesia and chronically impaired declarative memory function [1]. The hippocampus may be a relevant region in the pathophysiology of PTSD, and for this reason, the hippocampus has been widely studied, as reviewed below.
  • 4. The amygdala The severe psychological trauma that is an antecedent to the development of PTSD must result in the survivor experiencing fear, helplessness, or horror (DSM-IV). The individual with PTSD often continues to experience marked fear during intrusive recollections, flashbacks, and nightmares. Individuals with PTSD are often hypervigilant and may show an exaggerated startle response to a variety of unexpected stimuli, particularly loud noises. The amygdala has been implicated in the emotion of fear, fear learning, and control of the accompanying behavioral, autonomic, and neuroendocrine correlates. Some of the first evidence that the amygdala may be involved in fear came from the work of Klüver and Bucy [42] in their primate lesion studies. Wild monkeys that were naturally aggressive and fearful of humans underwent bilateral removal of their temporal lobes (which includes the amygdala, hippocampus, and temporal cortex). This resulted in the monkeys becoming nonfearful and docile. Later animal studies with more limited lesions localized the key structure responsible for these behavioral changes as the amygdala [43]. A remarkable amount is known about fear responding and the processing of auditory stimuli before and within the amygdala through preclinical microlesion studies and through the use of the conditioned fear paradigm. Classical fear conditioning is the process by which a neutral stimulus (the conditioned stimulus [CS]) is paired with a fear-inducing stimulus (the unconditioned stimulus), such as a buzzer paired with a shock, and eventually the original neutral stimulus alone will trigger a fearful response. Fear conditioning seems to be an excellent animal model for what is clinically observed in survivors with PTSD who often respond with fear to an increasing number of triggers, which are conditioned stimuli that have been associated with an unconditioned stimulus (the trauma). One of the best studied fear-conditioning pathways is the auditory pathway. The neuronal path of an acoustic CS is through the auditory thalamus, the medial geniculate body, and then the transmission is split. One part goes to the amygdala and the other to the auditory cortex [44]. The auditory thalamus provides a rapid route to the amygdala, along with imprecise information regarding the signal, whereas the signal to the amygdala from the auditory cortex is received later but is more richly analyzed [45]. Fear conditioning to a single tone does not require the auditory cortex, but this brain region appears necessary for fear conditioning to more complex auditory stimuli [46]. Because the fear response is part of what helps to ensure the survival of the organism in potentially lethal situations, it is of survival value to “act first and think later.” The more rapidly transmitted crude signal may activate the amygdala, and the more later-received cortically processed signal may inhibit amygdala activity. Disruption of either the lateral or central amygdala nuclei interferes with animals' ability to acquire new fears (i.e., fear conditioning is impaired) [47]. Although the particulars are beyond the scope of this review, it is important to understand that different modalities of fear-inducing stimuli may be processed in disparate brain regions, and alterations in these brain areas may differentially affect fear responding or fear conditioning to different types of stimuli. Studies in humans parallel animal findings. Functionally, the opposite of physically lesioning or removing a structure is activating it. Epileptic activity is a pathologic activation that may occur in virtually any brain region. In humans, temporal lobe epilepsy is frequently manifest by sudden episodes of fear and poorly directed aggressive behavior. Humans with temporal lobe lesions show deficits in fear conditioning [48], as do individuals with lesions primarily confined to the amygdala [49]. Such individuals also show impairment in perceiving fear in facial expressions [50] and voices [51]. Individuals with a rare disorder resulting in localized bilateral amygdala damage show the above deficits, and although they are able to understand logically that some situations are risky or will most likely have a negative outcome, they are largely unable to use this information to act accordingly [52].
  • 5. Functional neuroimaging studies in nonpsychiatric subjects show regional changes in brain activity in response to various tasks. The amygdala is selectively activated in processing negative emotional stimuli [53–55] and in fear conditioning [56,57]. The amygdala is also of interest to the study of PTSD not only because of its involvement in the emotional/behavioral manifestation of fear but also because of the autonomic response. Perhaps one of the most pathognomonic signs of PTSD is the increased startle response (related to fear conditioning). The startle response is thought to give an indication of autonomic excitability and can be measured through various means, such as heart rate, blood pressure, skin conductance, and electromyography. The autonomic response also entails increased activity of the major noradrenergic nuclei of the brain—the locus ceruleus. Survivors with PTSD, as compared with normal control subjects and traumatized subjects without PTSD, have shown increased cardiac, skin conductance, and electromyogram responses to loud tones [58,59]. Anatomically, the amygdala is located immediately anterior to the hippocampi, and numerous reciprocal connections exist between these two structures [60]. In one study with nonpsychiatric participants, subjects were shown neutral and emotionally unpleasant film clips while undergoing imaging of brain function. A greater number of the unpleasant film clips were remembered by the subjects 3 weeks later, and the number of unpleasant film clips remembered was highly correlated with right amygdaloid complex activity [61]. Declarative memory has been investigated in humans with a rare condition that results in selective bilateral amygdala damage. Both subjects showed impairments in long-term declarative memory for emotionally arousing material [52]. In a reciprocal fashion, the hippocampi play a role in fear conditioning and response by providing contextual information to the memory (where, when, and other particulars of an traumatic experience) [62,63]. Data indicate that gender and laterality are important considerations. A recent study found that in females, memory for negative emotional film clips was related to left amygdala activation, whereas the association in the male subjects was found with right amygdala activation [64]. These and the aforementioned data support the hypothesis that the human amygdala normally provides the emotional valence to a memory and also enhances acquisition of declarative knowledge regarding emotionally arousing stimuli. It appears that the amygdala, like the hippocampus, uses LTP. With regard to the amygdala, LTP seems to occur in the thalamo-amygdaloid pathways during the process of fear learning [65–67]. It is of interest how various hormones and neurotransmitters modulate efficacy of LTP in the amygdala as compared with the hippocampus. In summary, numerous reasons exist to posit an overactive amygdala in individuals with PTSD. Conversely, one would not anticipate some structural damage or other biologic effect resulting in decreased amygdala activity in subjects with PTSD. The aforementioned studies highlight the importance of stimulus modality, intensity and specific emotion(s) experienced, laterality, and gender as significant experimental factors. MRI OF THE HIPPOCAMPUS AND AMYGDALA  Qualitative and quantitative magnetic resonance imaging Magnetic resonance imaging (MRI) allows for high-resolution imaging of the brain with excellent white and gray matter differentiation. A powerful magnet is used to align proton nuclei of water in body tissues, which are then knocked out of alignment by a radio pulse. A signal is given off by the proton nuclei as they are reverting back to their original disorder, which will be of differing intensity according to the water content of that tissue (which does differ between white and gray brain matter).
  • 6. The clinical use of brain MRIs is usually of a qualitative nature; specific features (qualities) are evaluated, such a cortical atrophy, infarctions, or neoplasms. In one study, clinical examination of MRIs from PTSD patients revealed focal white matter lesions in a greater percentage of scans on subjects with PTSD as compared with the healthy control subjects [68]. Another study reported an increased incidence of the developmental abnormality cavum septum pellucidum in subjects with PTSD [69]. Of greater applicability to research is the use of quantitative MRI for accurate and precise measurement of the volume and shape of specific brain regions. Such measurements of specific brain regions allow for testing of various pathophysiologic models of PTSD involving structural or neurodevelopmental alterations. The most commonly applied manual method by which the volume of a brain structure is determined is by looking at successive MRI slices through the structure and tracing its perimeter, often termed a “region of interest.” By multiplying the area of the structure on each slice by the number of slices it appears on by the thickness of each slice, the total volume is easily obtained, or the slices can be “stacked” to create a three-dimensional image. To avoid experimental bias, the following conditions must be adhered to: (1) The person(s) tracing the structure should not know the diagnostic group or subject conditions; (2) subject groups should be mixed and not all of one group traced during one time period and the other group at a later time (even if the tracers do not know which group they are tracing) because systematic changes may occur over time in tracing technique; and (3) MRI scans should be obtained on the same scanner type with identical sequence settings, and identical methods for “slicing” the scans should be used (differences, if present, should at least be balanced between groups). Computer- driven automatic tracing programs and automated methods that use alignment of pixel intensities to assess size and shape change [70] are becoming available and decrease tracer bias.  Quantitative MRI studies in PTSD The first published study of hippocampal volume in PTSD compared Vietnam veterans with PTSD to healthy comparison subjects with no history of combat or trauma exposure. Right hippocampal volume in the PTSD subjects was a statistically significant 8% less than in comparison subjects [71]. This study, however, did not control for combat exposure, which means that it is impossible to say whether group differences were associated with exposure in itself or specifically with PTSD. Furthermore, hippocampal volume was not adjusted for whole-brain volume. A later study controlled for combat exposure by studying Vietnam veterans with PTSD, combat- exposed Vietnam veterans without PTSD, and eight healthy subjects without a history of trauma [72]. This study found a significant bilateral decrease in hippocampal size (approximately 26% between the PTSD subjects and the other two groups) after controlling for brain volume. The key association with hippocampal volume in these subjects was the diagnosis of PTSD, not trauma exposure in itself. Unfortunately, groups in this study showed significant differences in age, education level, and alcohol use (which has been found to be associated with decreased hippocampal size), and subjects were not intermingled in MRI analysis, which may have resulted in subtle systematic differences in volumetric analysis (particularly during manual tracing). Studies of other trauma survivors provide a more ambiguous picture regarding the associations among hippocampal volume, trauma, and symptoms. Hippocampal volume has also been assessed in adult survivors of severe childhood sexual abuse (CSA). The left hippocampal volume in subjects with a history of CSA was 4.9% smaller than the left hippocampal volume in control subjects without a history of CSA [73]. CSA subjects, however, did not all meet PTSD criteria; 71.4% met diagnostic criteria for PTSD, 71.4% met diagnostic criteria for a dissociative disorder, and 28.6% met criteria for both diagnoses. Six of the subjects were experiencing a current major
  • 7. depressive episode, and association between recurrent depression and smaller hippocampal volume has been reported. Analyses differentiating the effects of CSA history from PTSD diagnosis were not reported. A second study assessed hippocampal volume in subjects with severe CSA histories (all of whom had current PTSD) compared with healthy comparison subjects without a history of CSA. Comparison regions of the amygdala, caudate, and temporal lobe were also used. Left hippocampal volume was 12% smaller in the PTSD subjects, whereas the volumes of comparison structures did not differ [74]. Preliminary results from recent studies have not found differences in hippocampal volume as associated with trauma or PTSD in subjects with personality disorder [75] or in holocaust survivors [76]. Furthermore, because an intact hippocampus is necessary for declarative memory formation, the logical hypothesis is that GC-mediated hippocampal death and atrophy produces a hippocampal lesion leading to effects similar to those observed in the surgical destruction of hippocampal connects. These gross alterations in CA3 and dentate gyrus size are anticipated to result in a smaller hippocampal volume. Therefore, cognitive deficits in PTSD, particularly declarative memory, should be inversely correlated with hippocampal volume (i.e., greater cognitive deficits with smaller hippocampal volume). The aforementioned studies of hippocampal volume in PTSD assessed for this correlation, yet, despite findings of smaller hippocampal volumes, only one study found a correlation between hippocampal volume and memory deficits [71]. These authors reported a significant correlation between deficits in verbal memory (measured by percent retention subscale of the logical component of the Wechsler Memory Scale) and decreased hippocampal volume in PTSD subjects (r=0.64, df=20, P=0.05). This result was for hippocampal volume uncorrected for brain size, which raises questions about the effect of body size. Smaller body size is associated with smaller brain size but could also be correlated with physical vulnerability and social interaction patterns in combat, which deserve investigation in this context. Furthermore, smaller hippocampal and temporal lobe size has been associated with poorer memory performance in non-PTSD groups, so memory performance per mL of tissue may need to be considered. The specificity of the finding needs to be considered. Patients with schizophrenia and their relatives have been reported to have smaller amygdala and smaller hippocampal volume [77], although this may be less marked in first-episode patients [78]. Patients with panic disorder may also have reduced temporal lobe volumes, although Vythilingam et al. [79] found normal hippocampal volume suggesting some distinction within anxiety disorders. None of the aforementioned studies was longitudinal, and none involved prospective scanning before the trauma. As such, any associations cannot be ascribed a causal relationship (e.g., PTSD or trauma resulted in smaller hippocampi). It is equally plausible that smaller hippocampi may increase vulnerability to developing PTSD following a stressor, lower stress resistance, or increase the risk of encountering stress. Studies of twins have suggested that there is a significant genetic contribution to the development of both PTSD and generalized anxiety disorder (GAD) [80] (see review of genetic factors in PTSD and their relationship to HPA axis abnormalities in [81]). In this unreported study using a novel methodology, twins from the Vietnam registry who were concordant (both trauma exposed or with PTSD) and discordant (one with and one without trauma exposure) were compared in various ways. Of most interest was the comparison among the discordant twin of a soldier with combat-related PTSD (i.e., the subject did not have trauma exposure or PTSD but did have a twin who developed PTSD) as compared with the twin of an individual who had combat exposure but who did not develop PTSD (i.e., the subject had neither exposure nor PTSD). The subject who did not have PTSD but who had a twin with PTSD had significantly smaller hippocampal volumes than the twin of the soldier who did not develop PTSD. Because neither of the subject groups had
  • 8. PTSD or combat exposure, the difference in hippocampal volumes would be most parsimoniously described as antedating the trauma and therefore more of a vulnerability factor. In this study, the actual difference in hippocampal volumes between combat-exposed individuals with and without PTSD was not statistically significant. Recently, a longitudinal study was published in which individuals coming to an emergency room after a psychologically traumatic event were given an MRI of the brain and diagnostic testing [82]. These individuals were tested 6 months later to ascertain who had developed PTSD or still had PTSD, and again an MRI was obtained. The researchers did not find a change in hippocampal volume from baseline in those subjects who had PTSD at 6 months, nor did they find a difference in relative hippocampal volumes between those subjects with and those without PTSD at 6 months. This study had sufficient statistical power to find a difference if it were present to the degree found in earlier hippocampal studies. One possibility mentioned by the authors is that the trauma of these subjects occurred in adulthood. By a developmental hypothesis, trauma in childhood and adolescence may interfere with growth and development of the hippocampus, whereas by adulthood this structure is fully formed, and development of PTSD during the adult years would not result in smaller hippocampal volume via impaired hippocampal development. Another longitudinal study assessed hippocampal and other limbic region volumes in adolescent PTSD subjects and control subjects at baseline and 2 years later. No significant volumetric differences either at baseline or upon rescanning 2 years later were found between groups [83]. Many of the aforementioned studies analyzing hippocampal volume also explored amygdala volume, and none found a significant difference in amygdala volume in subjects with PTSD as compared with traumatized and nontraumatized control groups. Assessing for gross volumetric changes in a structure may be a nonsensitive way to detect many if not most physiologically relevant alterations. It is possible that significant biochemical changes affecting the function of a structure might not be reflected in volumetric changes. Furthermore, supportive and connective cells and other structural elements may maintain the general shape or volume of a structure despite significant changes in neuron number, size, or viability. One way to assess these possibilities is through the use of nuclear magnetic spectroscopy (NMS). Nuclear magnetic spectroscopy uses an MRI-type setup, but instead of focusing on the signal emitted by proton nuclei of H2O, the signal from a variety of molecules such as choline, n-acetyl acetate (NAA), glutamate, and others is detected. NMS provides data about the relative concentration of these molecules. The ability to detect various molecules differs according to how strong and unique a signal they emit, the concentration of the compound, the strength of the magnet, and the software being used. This technology is still in its infancy, and the physics of detecting various compounds is still being worked out, as is the ability to create higher-power magnets that allow detection of more compounds and also the ability to sample a smaller region of the brain. NMS does allow for a “virtual” brain biopsy that provides information on behavioral makeup that used to be obtainable only by taking a physical biopsy of the brain. N-acetyl aspartate is an endogenous substance that is believed to be a marker for neuronal density. In investigating whether the hippocampus is somehow smaller because of neuronal death or atrophy, preliminary studies have assessed the NAA signal from the temporal lobe regions. Present technology makes assessment of the hippocampus (which is a relatively small and complex-shaped structure) extremely difficult, and NAA data are from the temporal lobe as a whole and are not limited to the hippocampi. Schuff et al. [84] compared seven veteran PTSD subjects with seven trauma-exposed veterans without PTSD. The right hippocampus in these subjects was a nonsignificant 6% smaller, but there was a significant 18% decrease in NAA signal from this region. Another NMS study also reported a lower NAA-creatine ratio in the right temporal lobe in PTSD subjects compared with combat control veterans [85]. These findings may
  • 9. indicate that NMS is a more sensitive technique for detecting hippocampal changes caused by neuronal atrophy or degeneration, which, because of the presence of connective and supportive tissues, may not be accompanied by an equal magnitude of change in hippocampal volume. Future studies with higher resolution and using analysis for additional compounds can be anticipated. FUNCTIONING NEUROIMAGING STUDIES  Functional imaging technologies From what was known of the amygdala in animal studies and models of fear and fear conditioning, an overactivation of the amygdala in subjects with PTSD was a reasonable hypothesis. This was a question of neuronal activity that required the use of “functional” imaging technologies or those that allowed data to be gathered on the functioning of the brain through such measures as regional rate of glucose metabolism, blood flow, and oxy/deoxyhemoglobin concentrations. Furthermore, activity, unlike gross structure, is a rapidly changing measure, so it is necessary to control for this factor through various experimental methods.  Positron emission tomography Positron emission tomography (PET) is a functional imaging technique in which a radioisotope is used to measure glucose metabolism (by using 18flouro-deoxyglucose [18FDG]), blood flow ([15O] H2O), or receptor density (using any of an increasing number of radiolabeled ligands). Decay of the radioisotope produces positrons (antimatter electrons), which travel a short but variable distance (one limiting factor in the ultimate resolution of PET data) before striking an electron. The collision between matter and antimatter results in the release of energy in the form of two gamma rays that have the property of being emitted in opposite directions (180° difference). An array of detectors surrounding the subject's head registers the gamma rays, and, through computer analyses, the origin can be calculated, which, when corrected for distance through the brain it must travel, is used to calculate concentration and location of the ligand. Functional imaging techniques provide a picture of the brain that may integrate a period from 1 minute (such as with [15O]H2O), 30 minutes (such as with 18FDG), or hours (such as with ligands that bind to specific receptors or molecules). [15O]H2O is a tracer that allows a map of blood flow to be made, which is useful because blood flow is highly correlated with regional brain activity (metabolism). 18FDG is taken up by the brain like glucose in proportion to the neuron's energy requirements and gets temporarily trapped inside the cell after being acted on by hexokinase. The technique provides a more direct picture of regional brain metabolism but reflects a longer period of activity (approximately 30 minutes).  Functional MRI Functional MRI (fMRI) uses the basic MRI setup with additional sensing hardware and software modifications. fMRI works on the fact that hemoglobin and deoxyhemoglobin have different magnetic properties. Because of this, the deoxygenated blood acts as a type of in situ tracer. This allows for a measure of cerebral blood flow/metabolism that can detect small changes occurring over very short periods (fractions of a second). Like quantitative MRI, the strength of the magnet is a key variable in how high a spatial resolution can be obtained or over how short a period useful data can be acquired. Because these techniques collect data of rapidly changing brain states, it is important to construct experimental conditions that minimize the number of cognitive or physiologic process that differ between the experimental and control conditions. Functional imaging studies can give information regarding blood-flow and metabolism to a region, but the ultimate explanation of the significance of this is unclear. Most significantly, one region
  • 10. may serve primarily an inhibitory function; hence, if it is more “active,” it is more actively inhibiting another region(s), and the relationship between these areas and their respective functions is important. An analogy can be made with the human genome. One does not get all the answers by simply knowing the sequence; the useful information resides in the products of the genes, their role in the organism, and their interaction. This is a much more complicated and challenging task.  Symptom provocation One of the first techniques used with functional neuroimaging in the study of PTSD was symptom provocation, which had already been used in the study of other anxiety disorders with an elicitable pathologic response (i.e., obsessive-compulsive disorder and panic disorder). As applied to PTSD, stimuli such as listening to a traumatic script, seeing provocative pictures, or remembering the previously experienced traumatic event often elicit fear, anxiety, flashbacks, and physiologic activation (typically increased heart rate, blood pressure, and skin conductance).  Functional imaging studies in PTSD In a preliminary study, eight subjects with PTSD and high physiologic reactivity to reminders of their trauma were studied using [15O]H2O, which is used to measure cerebral blood flow (CBF). In the traumatic condition, subjects listened to audiotapes of their own accounts of the focal traumas related to their PTSD, whereas subjects in the control condition listened to narratives of neutral life events. Compared with the control subjects, the study subjects showed significantly increased CBF in the anterior cingulate, orbitofrontal, right amygdala, and visual cortex, among other regions. A decrease in CBF was noted in Broca's area [86]. Broca's area is a cortical region found in the posterior superior gyrus of the temporal lobe (on the right side of the brain in the vast majority of individuals) that is involved with language production. Lesions to this area most commonly occur secondary to stroke and result in an inability to put one's thoughts into words (Broca's aphasia). A hallmark of PTSD is the survivor's extreme difficulty in giving a coherent verbal account of the focal trauma. The authors commented that visual cortex and paralimbic activation was similar to the fear response in provocation studies of other anxiety disorders. Activation of these areas optimizes resources for response to a threatening situation; therefore, it was hypothesized that verbal abilities during a crises were of secondary importance (hence, the deactivation of Broca's area). Furthermore, a symptom of PTSD is usually the inability of the patient to give an integrated and coherent verbal description of their trauma. This was also the first study of an anxiety disorder in which amygdala activation was found. The lack of a control group made it impossible to determine to what extent the findings were part of a pathologic response to trauma. A later study by this group used the autobiographic script for traumatic activation (all subjects experienced CSA), but this time approximately half the subjects did not have PTSD, and therefore the effects of trauma versus PTSD per se could be controlled for [87]. As compared with control subjects, those with PTSD showed a greater decrease in Broca's area CBF and significantly larger increases in CBF in the orbitofrontal and anterior temporal regions. The medial prefrontal cortex inhibits the excitatory output of the amygdala in animals, whereas in humans, equivalent regions serving this role are thought to be the medial orbitofrontal cortex and the anterior cingulate gyrus. Therefore, decreased activity in these brain regions could have a disinhibiting effect on the amygdala and again result in an increased fear response through inadequate response inhibition. A process counteracting the effects of fear conditioning is extinction. If the neutral stimulus is no longer paired to the fear-inducing stimulus, the normal animal will show a gradual fading away of the fearful response with successive repetitions of the
  • 11. neutral stimulus alone. A clinical example of the failure of extinction is a PTSD patient's continued fearful response to various triggers that are reminiscent of the traumatic stressor even after extensive experiences after the traumatic event have presented the traumatic stimulus without the fearful condition (i.e., the veteran feeling terror at the sound of a helicopter more than 30 years after combat and during these 30 years hearing helicopters without being in any physical danger). Like the amygdala, these regions are not known to be structurally damaged by any common neuroendocrine alteration. In the aforementioned study, the anterior cingulate, the area that inhibits amygdala activation, showed a greater CBF increase in response to the traumatic condition in the control subjects as compared with the PTSD subjects. The authors hypothesized that the inability to adequately recruit this structure for the inhibition of amygdala activity may be an important aspect of the pathophysiology of PTSD. This later study did not find amygdala activation in the traumatic condition, and the authors bring up an important consideration: In the second study, the survivors of childhood sexual abuse reported experiencing primarily anger, disgust, and sadness, whereas subjects in the first study reported primarily fear and anxiety. Furthermore, because of the small size of the amygdala, the power for detection of significant differences in activation may be significantly less than other larger brain regions. A SPECT study, using [99mTc]HMPAO in combat veterans with PTSD, combat control subjects, and normal control subjects, found anterior cingulated/middle prefrontal gyrus activation in all groups following hearing tape recordings of combat sounds. Only in the PTSD group was activation of the left amygdala/nucleus accumbens found [88]. Examination of correlations between flashback intensity and CBF during the experience demonstrated positive correlations with the hippocampus, insula, putamen, somatosensory, and cerebellar regions and negative correlations with the prefrontal cortex, fusiform, and medial temporal cortices [89]. Decreased cortical and increased thalamic blood flow during an intense flashback was also seen in a single patient study [90] and suggests a thalamocortical mechanism; thalamic involvement in startle response was seen in a recent fMRI activation study [91]. Fernandez et al. [92] imaged a patient with torture-related PTSD before and after treatment with fluoxetine. Before treatment, trauma reminders resulted in decreased rCBF in the insula, prefrontal, and inferior frontal cortices consistent with the Osuch et al. [89] and Fernandez et al. [92] studies. Increased activity was evident in the cerebellum, precuneus, and supplementary motor cortex. This pattern was normalized after SSRI administration. Another symptom provocation method in PTSD involves presenting startling auditory stimuli and observing heightened eye-blink and skin conductance response [93,94] or even reduced reactivity in chronic stress [95]. Because startle activates orbitofrontal cortex (a target area for PTSD symptoms) in fMRI [91] and FDG-PET [96] studies, this provocation method may be useful in PTSD imaging studies.  Cognitive activation studies Cognitive neuroscientists studying basic elements of various cognitive processes in normal brain function pioneered activation paradigms. In this technique, an experimental and a control task differ in one element, and subjects undergo functional imaging in each condition. The image in one condition is subtracted from the other, presumably revealing the differences in regional brain activity between the two conditions. Studying one group of essentially identical subjects can provide information on the differences between conditions. Studying a control and experimental group in the two conditions can provide information on differences in regional brain activity as a function of condition, group, and group-by-condition interaction. In studying a disorder such as PTSD, one would pick a cognitive task that activates a system believed to be abnormal (e.g., attention, processing of emotional stimuli, etc.). One group studied PTSD in six male veterans (five
  • 12. with alcohol abuse) and acquired data during conditions of baseline, a continuous perfomance task, and a verb generation task to evaluate brain activity as related to attention, reaction time, response selection, and language/speech production. PET data on regional cerebral blood flow (rCBF) were collected using 15O and published in two reports [97,98]. As compared with the control group, the PTSD group showed a reduced left-to-right ratio of rCBF in the hippocampal region and greater orbitofrontal cortex activation. On the continuous performance task, which measures attention and reaction time, the PTSD group made more errors on the task and showed less activation in parietal cortex. The abnormal functional asymmetry for the hippocampal regions found in these studies may parallel some of the earlier reported findings of smaller hippocampal volumes. Alcohol use in the subjects limits the generalizability of the findings. Because the control group was not traumatized, it is also not possible to know if these differences were associated with trauma alone or actual PTSD. A later [15O]H2O study addressed these methodologic problems by using subjects without alcohol dependence and controlling for combat exposure by studying 14 veterans, all of whom were combat exposed but only seven of whom had PTSD [99]. Six conditions were studied: viewing pictures and imagining neutral, negative, and combat related material. Group-by-condition analyses showed that only the PTSD group showed a significant rCBF increase in the combat versus neutral condition in the anterior cingulate and right amygdala and decreased activation in Broca's area in the combat versus negative condition. A methodologic problem in all such activation studies is the problem that the combat or fear-inducing material does not have an equal psychologic impact in both groups. This is to be anticipated to some extent because reacting with intense fear or having a flashback upon exposure to traumatic triggers is a criterion for PTSD. It is unclear if the differences reported in such a study are related to the degree of fear (and would therefore be observed in the control group if the stimulus was strong enough) or if they are unique to PTSD pathophysiology. To address the question of the amygdala's native reactivity, a novel method for selective activation of the amygdala that does not activate the usual inhibitory anterior cingulate was used with fMRI in combat-exposed veterans with and without PTSD. In this masked-faces method, neutral and fearful faces are shown briefly to the subject and are followed by a neutral face (mask). The subject is only consciously aware of seeing the mask, but the amygdala, which receives input directly from the thalamus, is able to register the “danger/fear” without inhibitory influences from the anterior cingulate gyrus. PTSD symptom severity correlated with amygdala activation, and the PTSD group showed greater amygdala activation as compared with the combat control subjects [100]. This argues for a state of amygdala hyper-responsivity in PTSD, even without diminished anterior cingulate inhibitory activity. Consistent with this, Semple et al. [101] found higher brain blood flow in the amygdala in PTSD patients than in normal subjects, although cocaine addiction in these subjects limits generalizeability of the findings. Evidence for amygdala hyper-responsivity in stress-related memory dysfunctions is also presented in a PET case study of a psychogenic amnesic patient who showed amygdala activation during a facial memory test, whereas control subjects showed only hippocampal activation [102].  Pharmacologic challenges This paradigm involves a pharmacologic agent that produces an effect on a brain system or region that is believed to be implicated in the pathophysiology of a disorder. The effect in the control is compared with the experimental group with regard to changes in blood flow or glucose metabolism. As opposed to symptom provocation, which in the case of PTSD activates a myriad of endocrine, biochemical and autonomic events, the pharmacologic challenge may be used as a way to pharmacologically dissect the separate components of the response or systems. Pharmacologic challenges can be paired to any neuroimaging technique that provides a functional picture of the brain but is most frequently used with PET.
  • 13. Yohimbine is an ?2 receptor antagonist that increases noradrenergic discharge. In one study, yohimbine was used as a probe to assess whether individuals with PTSD have greater autonomic/noradrenergic reactivity [103]. Ten combat veterans with PTSD and ten normal control subjects were administered yohimbine and shortly thereafter underwent 18FDG PET scanning. The PTSD subjects had a significantly higher incidence of flashbacks and panic attacks in response to the yohimbine. The authors found that the PTSD group exhibited a widespread decrease in cortical metabolism. Prior studies indicated that, at higher concentrations, noradrenaline decreases rCBF, whereas CBF is increased at lower an intermediate noradrenaline concentrations. One might ask why the locus ceruleus, the primary nucleus for noradrenergic neurons in the brain, was not differentially activated. The findings from this study suggest that it was, and one would anticipate that the greatest effects of norepinepherine release are to areas to which locus ceruleus neurons project (not within the structure itself). The authors interpreted their findings as an indication that noradrenergic activity is heightened in PTSD. Of course, such a bimodal response makes interpretation of the results difficult. Nonetheless, this is consistent with a model of inadequate activity in cortical regions paired with limbic overactivation. Central sensitivity to GCs in PTSD is currently being assessed by studying changes in memory function and regional glucose metabolism using 18FDG following a hydrocortisone challenge. GCs cause a decrease in cell-surface glucose transporters, presumably paralleling the sensitivity of the GC receptors to steroids. Because 18FDG looks like glucose to the neuron, one can measure to what extent GCs inhibit the uptake of 18FDG. In preliminary analyses, we found that the PTSD group, as compared with the non-PTSD control group, showed a greater decrease in glucose uptake in the hippocampal regions following hydrocortisone [104]. Although preliminary, these findings lend support to the hypothesis of increased central GC sensitivity in PTSD. We will also be able to analyze this data in comparison to psychological testing results obtained after the hydrocortisone-versus-placebo challenge.  Radioligand studies By using a cyclotron, radiochemists can create isotopes of various elements and then incorporate them into a ligand. A variety of radiolabeled compounds can be designed to have specific affinities for various neuronal receptors, binding sites, or other targets. In conjunction with a PET scanner, the ligand acts as a tag and can provide such useful information as receptor numbers, location, and affinity. The GABA receptor is comprised of various combinations of subunits, on one of which a benzodiazepine binding site is located. GABA is the main inhibitory neurotransmitter of the brain, and, as such, it would be of interest if there were some alteration of this receptor in subjects with PTSD. One PET study used a radioligand for the benzodiazepine binding site with PET scanning and found decreased binding in the frontal cortex of PTSD subjects [105]. DISCUSSION Quantitative MRI studies of hippocampal volume in subjects with PTSD have shown mixed results. The majority of studies report a smaller hippocampal volume in PTSD subjects, but negative findings are less frequently published. Recent preliminary reports from well controlled studies with adequate power have not found significant differences in hippocampal volume. Association does not imply cause and effect, and the possibility that smaller hippocampal volume is a vulnerability factor for the development of PTSD following a trauma is just as plausible. Three other possible relationships between smaller hippocampal volume and PTSD have been enumerated [106]. Longitudinal studies can address this issue, and two published studies (one in adults, the other in adolescents) did not find any significant changes in hippocampal volume either
  • 14. at baseline or at 2-year follow-up in control and PTSD subjects. Factors such as longer follow-up time, age at which the focal trauma was sustained, duration/severity of PTSD symptomatology, and neurodevelopmental period of symptom evolution have not been adequately studied. Hippocampal volumetric changes may be one of the measures least sensitive to the type of alterations or dysfunction that may be present in subjects with PTSD. Preliminary studies of NAA signal using NMS indicate a decreased number or integrity of temporal lobe neurons. Advances in both magnet strength and computer software are anticipated to increase sensitivity, spatial resolution, and the number of compounds that can be assayed through this noninvasive technique. Studies of excitatory (primarily glutamate) and inhibitory (primarily GABA) neurotransmitter concentration and location would be relevant. Functional neuroimaging studies are beginning to show certain consistencies and have been synthesized to form the constellation of a hyper-responsive amygdala and associated limbic structures leading to heightened fear-conditioning, fearful response, and emotional learning, in conjunction with a hypoactive anterior cingulate area that fails to properly inhibit amygdala activity [107]. Decreased hippocampal function may impair the process of habituation or extinction of the fearful response and may also lead to increased tendency for stimulus generalization secondary to a decreased in contextual constraints that the hippocampus usually may supply. Longitudinal studies and twin studies would be of great use in understanding the progression, causal relationships, and genetic contribution of these findings. Radioligand studies are in their infancy, but with the availability of a cyclotron and experienced radiochemists, a great number of selective ligands should be possible to synthesize. Because PTSD is perhaps the paradigmatic example of a disorder involving the complex interaction of genes and environment, a deeper appreciation of this syndrome will require longitudinal studies (which are best for sorting out cause-and-effect relationships) and investigations that use a combination of modalities. The reason for the latter is that in the analysis of a complex system, each additional modality of information provides a synergistic rather than merely additive value to the data obtained. Such multidisciplinary or multimodal approaches may combine, in various ways, structural, functional, and ligand neuroimaging, NMS, pharmacologic challenges, neuropsychological testing, symptom provocation, cognitive activation, and naturalistic and genetic data in the effort to understand interactions between these systems that increase or decrease vulnerability or expression of particular signs or symptoms of PTSD. As technology and methods improve, it is likely that additional brain regions will be found to be relevant to the pathophysiology of this complex disorder. References [1]. Golier J, Yehuda R. Neuropsychological processes in post-traumatic stress disorder. Psychiatr Clin N Am. 2002;25:in press [2]. Scoville W, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neuropsychiatry Clin Neurosci. 2000;12:103-113 [3]. Reed JM, Squire LR. Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behav Neurosci. 1997;111:667-675 [4]. Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev. 1992;99:195-231
  • 15. [5]. Zola-Morgan S, Squire LR. The neuropsychology of memory: parallel findings in humans and nonhuman primates. Presented at the Conference of the National Institute of Mental Health Philadelphia, 1989. Ann N Y Acad Sci. 1990;608:434 [6]. Zola-Morgan S, Squire LR, Rempel NL, Clower RP. Enduring memory impairment in monkeys after ischemic damage to the hippocampus. J Neurosci. 1992;12:2582-2596 [7]. Zola-Morgan S, Squire LR. Memory impairment in monkeys following lesions limited to the hippocampus. Behav Neurosci. 1986;100:155-160 [8]. Zola-Morgan S, Squire LR, Ramus SJ. Severity of memory impairment in monkeys as a function of locus and extent of damage within the medial temporal lobe memory system. Hippocampus. 1994;4:483-495 [9]. Alvarez P, Zola-Morgan S, Squire LR. Damage limited to the hippocampal region produces long-lasting memory impairment in monkeys. J Neurosci. 1995;15:3796-3807 [10]. Squire LR, Zola-Morgan S. The medial temporal lobe memory system. Science. 1991;253:1380 [11]. Hebb D. The organization of behavior. New York: Wiley 1949 [12]. Bliss T, Gardner-Medwin A. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetised rabbit following stimulating of perforant path. J Physiol. 1973;232:357-374 [13]. McEwen BS. Possible mechanisms for atrophy of the human hippocampus. Mol Psychiatry. 1997;2:255-262 [14]. Yehuda R. Current status of cortisol findings in post-traumatic stress disorder. Psychiatr Clin N Am. 2002;25:in press [15]. Sapolsky RM, Uno H, Rebert C, Finch C. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci. 1990;10:2897-2902 [16]. Fuchs E, Uno H, Flugge G. Chronic psychosocial stress induces morphological alterations in hippocampal pyramidal neurons of the tree shrew. Brain Res. 1995;673:275-282 [17]. McKittrick CR, Magarinos AM, Blanchard D, Blanchard R, McEwen BS. Chronic social stress decreases binding to 5HT transporter sites and reduces dendritic arbors in CA3 of hippocampus. [abstract] Soc Neurosci. 1996;22:2060 [18]. Arbel I, Kadad T, Silbermann M, Levy A. The effects of long-term corticosterone administration on hippocampal morphology and cognitive performance of middle-aged rats. Brain Res. 1994;657:227-235 [19]. Magarinos AM, McEwen BS, Flugge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534-3540 [20]. Uno H, Tarara R, Else J, Suleman M, Sapolsky RM. Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci. 1989;9:1705-1711
  • 16. [21]. McEwen BS, Angulo J, Cameron H, Chao HM. Paradoxical effects of adrenal steroids on the brain: protection versus degeneration. Biol Psychiatry. 1992;31:177-199 [22]. McEwen BS, Gould EA, Sakai RR. The vulnerability of the hippocampus to protective and destructive effects of glucocorticoids in relation to stress. Br J Psychiatry. 1992;160:18-23 [23]. Woolley C, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990;531:225-231 [24]. Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341-345 [25]. Sapolsky RM. Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress. 1996;1:1-19 [26]. Stein-Behrens B, Lin W, Sapolsky RM. Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem. 1994;63:596-602 [27]. Bartanusz V, Aubry J, Pagliusi S, Jezove D, Baffi J, Kiss J. Stress-induced changes in messenger RNA levels of N-methyl-D-Aspartate and ampa receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscience. 1998;66:247-252 [28]. Wieland N, Orchnik M, McEwen BS. Corticosterone regulates mRNA levels of specific subunits of the NMDA receptor in the hippocampus but not in cortex of rats. [abstract] Soc Neurosci. 1998;21:502 [29]. Dugan L, Choi D. Excitotoxicity, free radicals, and cell membrane changes. Ann Neurol. 1998;35:S17-S21 [30]. Wolkowitz OM, Reus VI, Weingartner, Thompson K, Brier A, Doran A, et al. Cognitive effects of corticosteroids. Am J Psychiatry. 1990;147:1297-1303 [31]. Newcomer JW, Craft S, Hershey T, Askins K. Glucocorticoid-induced impairment in declarative memory performance in adult humans. J Neurosci. 1994;14:2047-2053 [32]. Lupien SJ, Gillin CJ, Hauger RL. Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans. Behav Neurosci. 1999;113:420-430 [33]. Kirschbaum C, Wolf OT, May M, Wippich W. Stress- and treatment-induced elevations of cortisol levels associated with impaired declarative memory in healthy adults. Life Sci. 1996;58:1475-1483 [34]. Foy M, Stanton M, Levine S, Thompson R. Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav Neural Biol. 1987;48:138-149 [35]. Coussen CM, Kerr DS, Abraham WC. Glucocorticoid receptor activation lowers the threshold for NMDA-receptor-dependent homosynaptic long-term depression in the hippocampus through activation of voltage-dependent calcium channels. J Neurophysiol. 1997;78:1-9 [36]. Pavlides C, Ogawa S, Kimura A, McEwen BS. Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices. Brain
  • 17. Res. 1996;738:229-235 [37]. Diamond D, Bennet M, Fleshner M, Rose G. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus. 1992;2:421-430 [38]. McEwen BS. Protective and damaging effects of stress mediators. New Engl J Med. 1998;338:171-179 [39]. McEwen BS. From molecules to mind: stress, individual differences, and the social environment. Ann N Y Acad Sci. 2001;935:42-49 [40]. McEwen BS, Stellar E. Stress and the individual: mechanisms leading to disease. Arch Int Med. 1993;153:2093-2101 [41]. Yehuda R, Teicher MH, Trestman RL, Levengood RA. Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry. 1996;40:79-88 [42]. Klüver H, Bucy PC. Psychic blindness and other symptoms following bilateral temporal lobectomy in rhesus monkeys. Am J Physiol. 1937;119:352-353 [43]. Weiskrantz L. Behavioral changes associated with ablation of the amygdaloid complex in monkeys. J Comp Physiol Psychol. 1956;49:381-391 [44]. LeDoux J. Fear and the brain: where have we been, and where are we going?. Biol Psychiatry. 1998;44:1229-1238 [45]. LeDoux J. The emotional branch. London: Orian 1998 [46]. Jarrell TW, Gentile CG, Romanski LM, McCabe PM, Schneiderman N. Involvement of cortical and thalamic auditory regions in retention of differential bradycardiac conditioning to acoustic conditioned stimuli in rabbits. Brain Res. 1987;412:285-294 [47]. LeDoux JE, Cicchetti P, Xagoraris A, Romanski LM. The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J Neurosci. 1990;10:1062-1069 [48]. LaBar KS, LeDoux JE, Spencer DD, Phelps EA. Impaired fear conditioning following unilateral temporal lobectomy in humans. J Neurosci. 1995;15:6846-6855 [49]. Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science. 1995;269:1115-1118 [50]. Adolphs R, Tranel D, Damasio H, Damasio A. Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature. 1994;372:669-672 [51]. Scott SK, Young AW, Calder AJ, Hellawell DJ, Aggleton JP, Johnson M. Impaired auditory recognition of fear and anger following bilateral amygdala lesions. Nature. 1997;385:254-257 [52]. Adolphs R, Cahill L, Schul R, Babinsky R. Impaired declarative memory for emotional material following bilateral amygdala damage in humans. Learn Mem. 1997;4:291-300
  • 18. [53]. Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, et al. Response and habituation of the human amygdala during visual processing of facial expression. Neuron. 1996;17:875-887 [54]. Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ, et al. A differential neural response in the human amygdala to fearful and happy facial expressions. Nature. 1996;383:812-815 [55]. Tabert MH, Borod JC, Lange G, Tang CY, Wei T-C, Johnson Jr. R, et al. Emotional decision task with unpleasant words increases BOLD fMRI signal in the right amygdala. Neuropsychologia. 2001;39:556-573 [56]. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during conditional fear acquisition and extinction: a mixed trial FMRI study. Neuron. 1998;20:937-945 [57]. Buchel C, Morris J, Dolan RJ, Friston KJ. Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron. 1998;20:947-957 [58]. Shalev AY, Orr SP, Peri T, Schreiber S, Pitman RK. Physiologic responses to loud tones in Israeli patients with posttraumatic stress disorder. Arch Gen Psychiatry. 1992;49:870-875 [59]. Orr SP, Lasko NB, Shalev AY, Pitman RK. Physiologic responses to loud tones in Vietnam veterans with posttraumatic stress disorder. J Abnorm Psychol. 1995;104:75-82 [60]. Duvernoy HM. The human hippocampus: Functional anatomy, vascularization, and serial sections with MRI. (Second edition) Berlin-Heidelberg, Germany: Springer-Verlag 1998 [61]. Cahill L, Haier RJ, Fallon J, Alkire MT, Tang C, Keator D, et al. Amygdala activity at encoding correlated with long-term, free recall of emotional information. Proc Natl Acad Sci USA. 1996;93:8016-8021 [62]. Selden NR, Everitt BJ, Jarrard LE, Robbins TW. Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience. 1991;42:335-350 [63]. Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci. 1992;106:274-285 [64]. Cahill L, Haier RJ, White NS, Fallon J, Kilpatrick L, Lawrence C, et al. Sex-related difference in amygdala activity during emotionally influenced memory storage. Neurobiol Learn Mem. 2001;75:1-9 [65]. Rogan MT, Staubli UV, LeDoux JE. AMPA receptor facilitation accelerates fear learning without altering the level of conditioned fear acquired. J Neurosci. 1997;17:5928-5935 [66]. McKernan MG, Shinnick-Gallagher P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature. 1997;390:607-611 [67]. Bauer EP, LeDoux JE, Nader K. Fear conditioning and LTP in the lateral amygdala are sensitive to the same stimulus contingencies. Nat Neurosci. 2001;4:687-688
  • 19. [68]. Canive JM, Lewine JD, Orrison Jr. WW, Edgar CJ, Provencal SL, Davis JT, et al. MRI reveals gross structural abnormalities in PTSD. Ann N Y Acad Sci. 1997;821:512-515 [69]. Myslobodsky MS, Glicksohn J, Singer J, Stern M, Bar-Ziv J, Friedland N, et al. Changes of brain anatomy in patients with posttraumatic stress disorder: a pilot magnetic resonance imaging study. Psychiatry Res. 1995;58:259-264 [70]. Gaser C, Nenadic I, Buchsbaum BR, Hazlett EA, Buchsbaum MS. Deformation-based morphometry and its relation to conventional volumetry of brain lateral ventricles in, MRI. Neuroimage. 2001;13:1140-1145 [71]. Bremner JD, Randall P, Scott TM, Bronen RA. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152:973-981 [72]. Gurvits TV, Shenton ME, Hokama H, Ohta H. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry. 1996;40:1091-1099 [73]. Stein MB, Koverola C, Hanna C, Torchia MG. Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med. 1997;27:951-959 [74]. Bremner JD, Randall P, Vermetten E, Staib L. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse: a preliminary report. Biol Psychiatry. 1997;41:23-32 [75]. Grossman R, Yehuda R, New A, Schmeidler J, Mitropoulou V, Silverman J, et al. Hypothalamic-pituitary-adrenal axis activity and hippocampal volume in personality disordered subjects: associations with psychological trauma, depression and comorbid posttraumatic stress disorder. Biol Psychiatry. 2001;49:249 [76]. Golier J, Yehuda R, De Santi S, Convit A, de Leon M. Hippocampal volume and memory performance in holocaust survivors with PTSD. Presented at the annual meeting of the Society for Biological Psychiatry. 2001. [77]. O'Driscoll GA, Florencio PS, Gagnon D, Wolff AV, Benkelfat C, Mikula L, et al. Amygdala- hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients. Psychiatry Res. 2001;107:75-85 [78]. Niemann K, Hammers A, Coenen VA, Thron A, Klosterkotter J. Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects. Psychiatry Res. 2000;99:93-110 [79]. Vythilingam M, Anderson ER, Goddard A, Woods SW, Staib LH, Charney DS, et al. Temporal lobe volume in panic disorder: a quantitative magnetic resonance imaging study. Psychiatry Res. 2000;99:75-82 [80]. Chantarujikapong SI, Scherrer JF, Xian H, Eisen SA, Lyons MJ, Goldberg J, et al. A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men. Psychiatry Res. 2001;103:133-145 [81]. Radant A, Tsuang D, Peskind ER, McFall M, Raskind W. Biological markers and diagnostic
  • 20. accuracy in the genetics of posttraumatic stress disorder. Psychiatry Res. 2001;102:203-215 [82]. Bonne O, Brandes D, Gilboa A, Gomori JM, Shenton ME, Pitman RK, et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry. 2001;158:1248-1251 [83]. De Bellis MD, Hall J, Boring AM, Frustaci K, Moritz G. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol Psychiatry. 2001;50:305-309 [84]. Schuff N, Marmar CR, Weiss DS, Neylan TC, Schoenfeld F, Fein G, et al. Reduced hippocampal volume and n-acetyl aspartate in posttraumatic stress disorder. Ann N Y Acad Sci. 1997;821:516-520 [85]. Freeman TW, Cardwell D, Karson CN, Komoroski RA. In vivo proton magnetic resonance spectroscopy of the medial temporal lobes of subjects with combat-related posttraumatic stress disorder. Magn Reson Med. 1998;40:66-71 [86]. Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR, et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry. 1996;53:380-387 [87]. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am J Psychiatry. 1999;156:575-584 [88]. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, et al. Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry. 1999;45:817-826 [89]. Osuch EA, Benson B, Geraci M, Podell D, Herscovitch P, McCann UD, et al. Regional cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress disorder. Biol Psychiatry. 2001;50:246-253 [90]. Liberzon I, Taylor SF, Fig LM, Koeppe RA. Alteration of corticothalamic perfusion ratios during a PTSD flashback. Depress Anxiety. 1996–97;4:146-150 [91]. Hazlett EA, Buchsbaum MS, Tang CY, Fleischman MB, Wei TC, Byne W, et al. Thalamic activation during an attention-to-prepulse startle modification paradigm: a functional MRI study. Biol Psychiatry. 2001;50:281-291 [92]. Fernandez M, Pissiota A, Frans O, von Knorring L, Fischer H, Fredrikson M. Brain function in a patient with torture related post-traumatic stress disorder before and after fluoxetine treatment: a positron emission tomography provocation study. Neurosci Lett. 2001;297:101-104 [93]. Shalev AY, Peri T, Orr SP, Bonne O, Pitman RK. Auditory startle responses in help-seeking trauma survivors. Psychiatry Res. 1997;69:1-7 [94]. Orr SP, Lasko NB, Metzger LJ, Pitman RK. Physiologic responses to non-startling tones in Vietnam veterans with post-traumatic stress disorder. Psychiatry Res. 1997;73:103-107 [95]. Medina AM, Mejia VY, Schell AM, Dawson ME, Margolin G. Startle reactivity and PTSD symptoms in a community sample of women. Psychiatry Res. 2001;101:157-169
  • 21. [96]. Hazlett EA, Buchsbaum MS. Sensorimotor gating deficits and hypofrontality in schizophrenia. Front Biosci. 2001;6:D1069-D1072 [97]. Semple WE, Goyer P, McCormick R, Morris E, Compton B, Muswick G, et al. Preliminary report: brain blood flow using PET in patients with posttraumatic stress disorder and substance- abuse histories. Biol Psychiatry. 1993;34:115-118 [98]. Semple WE, Goyer PF, McCormick R, Compton-Toth B, Morris E, Donovan B, et al. Attention and regional cerebral blood flow in posttraumatic stress disorder patients with substance abuse histories. Psychiatry Res. 1996;67:17-28 [99]. Shin LM, Kosslyn SM, McNally RJ, Alpert NM, Thompson WL, Rauch SL, et al. Visual imagery and perception in posttraumatic stress disorder: a positron emission tomographic investigation. Arch Gen Psychiatry. 1997;54:233-241 [100]. Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, et al. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry. 2000;47:769-776 [101]. Semple WE, Goyer PF, McCormick R, Donovan B, Muzic Jr. RF, Rugle L, et al. Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals. Psychiatry. 2000;63:65-74 [102]. Yasuno F, Nishikawa T, Nakagawa Y, Ikejiri Y, Tokunaga H, Mizuta I, et al. Functional anatomical study of psychogenic amnesia. Psychiatry Res. 2000;99:43-57 [103]. Bremner JD, Innis RB, Ng CK, Staib LH, Salomon RM, Bronen RA, et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54:246-254 [104]. Grossman R, Yehuda R, Sta. Maria N, Lee R, de Leon M, Buchsbaum M. Hydrocortisone study of central glucocorticoid sensitivity. Presented at the 15th annual meeting of the International Society For Traumatic Stress Studies. Miami, November, 1999 [105]. Bremner JD, Innis RB, Southwick SM, Staib L, Zoghbi S, Charney DS. Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry. 2000;157:1120-1126 [106]. Pitman RK, Shin LM, Rauch SL. Investigating the pathogenesis of posttraumatic stress disorder with neuroimaging. J Clin Psychiatry. 2001;62((Suppl 17)):47-54 [107]. Rauch SL, Shin LM, Pitman RK. Neuroimaging and the neuroanatomy of PTSD. CNS Spectrums. 1998;3((Suppl 2)):30-41 Addendum   A  new  version  of  topic  of  the  month  publication  is  uploaded  in  my  web  site  every  month  (it  remains for a month and is changed with the monthly update of the neurology bulletin at:.http://neurology.yassermetwally.com)
  • 22. To download the current version of topic of the month publication follow the link quot;http://neurology.yassermetwally.com/topic.zipquot;  You can also download the current version of topic of the month publication from within the publication or go to my web site at: quot;http://yassermetwally.comquot; to download it.  At the end of each year, all the publications are compiled on a single CD-ROM, please author to know more details.  Screen resolution is better set at 1024*768 pixel screen area for optimum display  For an archive of the previously published topics in downloadable PDF format go to http://yassermetwally.net, then under pages in the right panel, scroll down and click on the text entry quot;topic of the monthquot;  In order to view a list of the previously published topics in downloadable PDF format, follow the link: http://wordpress.com/tag/neurological-topic-of-the-month/ The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt  www.yassermetwally.com