Brain Imaging of Trauma Spectrum Psychiatric Disorders

1
Brain Imaging of Trauma Spectrum Psychiatric
Disorders

• J. Douglas Bremner, MD,
• Departments of Psychiatry and Radiology,
• Director of Emory Center for Positron Emission
  Tomography (PET)
• And Faculty in Neurosciences Program, Emory
  University Atlanta VAMC

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Childhood Abuse-The Invisible Epidemic

• 16 of women have a history of childhood sexual
  abuse (rape or fondling) based on nationwide
  surveys (McCauley et al., 1997, JAMA)
• 10 of women (13 million) currently suffer from
  PTSD (Kessler et al., 1995, AGP), twice as common
  in women as in men
• Childhood sexual abuse most common cause of PTSD
  in women

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Number of Adverse Childhood Events Increases Risk
for Other Problems
Number of Adverse Childhood Events
Anda et al
4
Stress and Psychopathology
Stress may lead to a range of outcomes that do
not have validity as discrete constructs These
trauma-related disorders have been termed Trauma
Spectrum Disorders From Bremner JD Does Stress
Damage the Brain? Understanding Trauma-related
Disorders from a Mind-Body Perspective. New
York W. W. Norton, 2002.
Foreshortened future (suicidality)
Alcohol/substance abuse (self destructiveness)
avoidance
Panic Somatization Eating Disorders
Decreased Concentration
Sleep disturbance
Feeling cut off (flat affect)
flashbacks (depersonalization, derealization)
Hyperarousal, hypervigilance (agitation)
startle
Intrusive memories (ruminations)
amnesia
nightmares
Feeling worse with reminders (Depressed mood)
Identity disturbance (dissociative identity d.o.)
Decreased interest
Genetics, prior stressors
Numbing (anhedonia)
Dissociative Disorders
PTSD
BPD
depression
Stress
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Functional Neuroanatomy of Traumatic Stress
Stress
Parietal Cortex
Cerebral Cortex
long-term storage of traumatic memories
Amygdala
Prefrontal Cortex
conditioned fear
Hippocampus
Orbitofrontal Cortex
CRF
extinction to fear through amygdala inhibition
Hypothalamus
NE
Attention vigilance-fear behavior Dose response
effect on metabolism
Pituitary
ACTH
Locus Coeruleus
output to cardiovascular system
Adrenal
cortisol
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Functional Neuroanatomy of Trauma Spectrum
Disorders
Posterior Cingulate, Parietal Motor Cortex
Sensory inputs
Visuospatial processing assessment of threat
Thalamus
Medial Prefrontal Cortex
Sensory gateway
Cerebellum
Anterior Cingulate, orbitofrontal, subcallosal
gyrus Planning, execution, inhibition of
responses, extinction of fear response
Hippocampus
Amygdala
memory
Emotional valence
Motor responses, peripheral sympathetic and
cortisol response
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Effects of Stress on Physical Health

• Neurological and Cognitive Hippocampal atrophy
  with associated deficits in verbal declarative
  memory (new Leaning and memory)
• Endocrine Increased cortisol and HPA axis,
  increased catecholamines (norepinephrine and
  epinephrine)
• Metabolic insulin resistance, ?fat deposition
  around hips
• Cardiovascular ? heart disease, ? lipid levels,
  ?atherosclerosis
• Cancer
• Impaired immunity
• Psychiatric disorders

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PTSD Impairs Function and Quality of Life
PTSD Non-PTSD
50
Percent
25
0
Not Working
PhysicalLimitation
ReducedWell-Being
Fair orPoorHealth
Violent BehaviorPast Year
Zatzick DF et al. Am J Psychiatry.
1997(Dec)154(12)1690-1695
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Risk of Suicide Attempts Among Patients with
Anxiety Disorders
7
6
5
4
Odds Ratio
3
2
1
0
PTSD
GAD
Panic
Social
Any
Disorder
Anxiety
Anxiety
Disorder
Disorder
Kessler et al. Arch Gen Psychiatry. 199956617
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Non-Stressed
Stressed
Stress results in decreased dendritic branching
of neurons in the CA3 region of the hippocampus
(Woolley et al. 1990)
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Stress Results in Decreased Hippocampal
Neurogenesis
Gould et al 2002
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Enriched Environment Promotes Hippocampal
Neurogenesis
Kempermann et al 99
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Antidepressant Treatments Promote Hippocampal
Neurogenesis
Duman et al 2002
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Bremner et al 1997
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Hippocampal Volume Reduction in Childhood
Abuse-related PTSD

plt.05
12 reduction in left hippocampal volume in
abuse-related PTSD
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Hippocampal Volume Reduction in PTSD

• NORMAL PTSD

Bremner et al., Am. J. Psychiatry 1995
152973-981. Bremner et al.,
Biol. Psychiatry 1997 4123-32.
Gurvits et al., Biol Psychiatry 199640192-199.
Stein et al., Psychol Med
199727951-959. DeBellis 1999-no change in
children with PTSD
J Douglas Bremner, MD, Emory University
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Hippocampal Volume Reduction in Depression

248 SD
194 SD
269 SD
208 SD
p.009
Bremner et al, Am J Psychiatry 2000
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Smaller Hippocampal Volume in Women with
Childhood Abuse and Depression


plt.05
Vythilingam et al.,Am J Psychiatry, 2002
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Hippocampus in Trauma Spectrum Disorders
Stress
Genetics, resiliency, prior stressors,
chronicity, social support
Trauma spectrum disorders
Depression
PTSD
Hypercortisolemia Decreased BDNF Increased
EAA Other factors
Hypercortisolemia With stress?
Hypercortisolemia With depression?
Alterations in hippocampal morphology
Deficits in hippocampal-based declarative memory
Maintenance of chronicity of symptoms/recurrence
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Hippocampal Structure Studies in PTSD
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Effect Size Estimates for Hippocampal Volume in
Adults With Chronic PTSD vs Healthy Subjects
Pooled Meta-Analysis Demonstrates Smaller
Hippocampal Volume in PTSD
Gilbertson, 2002
Notestine, 2002
Gilbertson 02
Bremner, 1995
Bremner, 1997
Bremner, 2003
Notestine 02
Villareal, 2002
Gurvits, 1996
Bremner 95
Bremner 97
Bremner 03
Schuff, 2001
Villareal 02
Gurvits 96
Stein, 1997
Schuff 01
Stein 97
Overall
Overall
2
2
1
1
0
0
-1
-1
Effect Size
Effect Size
-2
-2
-3
-3
plt.05
-4
-4
plt.05
-5
-5
Left Hippocampus
Right Hippocampus
Effect size (black square) and 95 confidence
interval (red line) measured with Hedges GU.
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MRI Assessment of BPD with Early Abuse

• Women with early childhood sexual abuse and
  borderline personality disorder (BPD) compared to
  women without BPD
• 50 comorbidity with BPD and PTSD
• Studied on psychotropics (not benzodiazepines)

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Smaller Hippocampal and Amygdala Volume in Abused
Women with BPD
Volume (mm-3)
Schmahl et al., unpublished
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Hypothalamic-pituitary-adrenal Axis and Stress
Stress
CRF affects cognition and fear-behaviors
through direct brain effects
hippocampus
glucocorticoid receptors
-
-
hypothalamus (PVN)
corticotropin releasing factor (CRF)

-
pituitary

adrenocorticotropin hormone (ACTH)


adrenal
locus coeruleus
End Organs
energy usage, reproduction, metabolism,
inflammatory response
cortisol
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CRF and Stress

• CRF plays an important role in the stress
  response
• Stress exposure is associated with increases in
  CRF
• Central CRF administration is associated with
  fear related behaviors (decreased exploration,
  increased startle, decreased grooming)

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Effects of Stress on HPAA and Hippocampus-Preclini
cal Studies

• Stress-induced lesions of the hippocampus result
  in a removal of inhibition of CRF release from
  the hypothalamus
• Increased CRF
• Blunted ACTH response to CRF challenge
• Increased Cortisol in the periphery
• Resistance to negative feedback of dexamethasone

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Elevated CSF Concentrations Of Corticotropin
Releasing Factor In Combat-Related PTSD

Controls (N17)
PTSD (N11)
Plt.05.Bremner et al. Am J Psychiatry.
1997154624-629.
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Study Aims-Abuse-related PTSD

• Women with sexual abuse before 13
• Assess hippocampal structure with MRI
• Assess hippocampal function with PET in
  conjunction with paragraph encoding declarative
  memory task
• Assess hypothalamic-pituitary-adrenal axis
  function at baseline and with stressful challenge

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Women with Childhood Sexual Abuse-related PTSD

• Women with abuse and PTSD, women with abuse
  without PTSD, and women without abuse or PTSD
• Early childhood sexual abuse before the age of
  13 defined as rape or molestation
• Abuse assessed with the Early Trauma Inventory
• All subjects free of psychotropic medication for
  four weeks before study

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Hippocampal Function in PTSD-Methods

• PET Study-Women with abuse and PTSD (N10)
  compared to abused non-PTSD women (N12)
• scanned during encoding of paragraph and control
  with 0-15, Areas of activation compared between
  active-control tasks
• MR obtained for measurement of hippocampal
  volume, with additional group of non-abused
  normal women (total N33)

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Cortisol Assessment Methods

• Salivary cortisol measured before and after a 20
  minute cognitive challenge (arithmetic,
  color-word naming, problem solving under time
  pressure and negative feedback)

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Diurnal Cortisol Levels In Women With Childhood
Sexual Abuse-Related PTSD

12-8 PM, PTSDlt controls
Bremner et al. Unpublished data.
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Lower Baseline Cortisol Correlates with Increased
PTSD Symptoms in Women with Childhood Sexual
Abuse
R-0.52
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Smaller Hippocampal Volume in Women with Early
Childhood Sexual Abuse-related PTSD


Plt.05
Hippocampal Volume measured with Magnetic
Resonance Imaging (MRI) Bremner et al unpublished
data 2000
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Failure of Hippocampal Activation with
Memory Encoding in Women with Abuse-related PTSD

plt.05
Non-PTSD Non-PTSD
PTSD PTSD Control
Encoding Control Encoding
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Failure of Hippocampal Activation in Women with
PTSD Related to Childhood Sexual Abuse
L. Inferior Frontal Gyrus
Left Hippocampus Region
Abused Non-PTSD Women (N12)
Abused PTSD Women (N10)
Increased blood flow during encoding of paragraph
relative to control condition
Statistical parametric maps overlaid on MR (z
scoregt3.09 plt.001)
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Increased Cortisol Response To Stressors In PTSD
Cognitive stress
PTSDgtControlTime 60 to 35F13.28 P 0.0003
Response to aCognitive stress challenge
J. Douglas Bremner, MD, Emory University
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Increased Cortisol Response To Trauma-Specific
Stress in PTSD
Cognitive stress

Cortisol (?g/dl)
Time (minutes)
Elzinga, Bremner et al, unpublished data
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Cortisol and Memory in PTSD

• Stress induced cortisol release causes
  declarative memory impairment
• Probably acts at glucocorticoid receptors (GR) in
  the hippocampus
• Dexamethasone impairs memory in young subjects
  (not elderly)
• PTSD like accelerated aging, may have deficits
  in hippocampal GR?

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Failure of Memory Impairment with Dexamethasone
in PTSD

plt.05
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Failure of Extinction in PTSD

• Pairing of light and shock leads to fear
  responses to light alone
• With exposure to light alone there is a gradual
  decrease in fear responding (extinction to
  fear)
• Reexposure to light-shock at later time point
  results in rapid return of fear responding
• Medial prefrontal cortical inhibition of amygdala
  represents neural mechanism of extinction to fear
  responding
• This brain area mediates emotion (Phineas Gage)

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Role of the Medial Prefrontal Cortex in Emotion

• Phineas Gage-19th century-railroad spike entered
  through his eye socket and lesioned medial
  prefrontal cortex
• areas involved orbitofrontal, anterior cingulate
  (25/24/32), mesofrontal (9)
• Speech and cognition intact
• Marked deficits in ability to judge social
  contexts, behave appropriately in social
  contexts, assess emotional nonverbal signals from
  others

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Medial Prefrontal Cortex in Stress Emotion

• Orbitofrontal Cortex
• Gyrus rectus and medial orbitofrontal cortex
• Anterior Cingulate
• Subcallosal gyrus (area 25) mediates peripheral
  cortisol and sympathetic responses to stress
• Area 32 implicated in normal emotion, as well
  as attention/selection of action (Stroop)
• Anteromesal Prefrontal Cortex
• Superior Middle Frontal Gyrus (9)

Motor Cortex
Post. Cingulate (31)
24
Corpus callosum
Meso- frontal (9)
Ant. Cingulate (32)
hippocampus
AC Sub- callosal (25)
orbitofrontal
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Human Skull Size Makes More Room for the Brain
with Time
More skull space means more room for frontal
cortex
Frontal lobe
Frontal lobe
Homo erectus
Homo sapiens
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Smaller Volume of the Anterior Cingulate in Women
with Abuse PTSD
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Medial Prefrontal Cortical Dysfunction with
Traumatic Memories in PTSD
Medial PFC (BA 25)
AC (BA32)
Decreased function in medial prefrontal cortical
areas Anterior Cingulate BA 25, BA 32 in veterans
with PTSD compared to Veterans without PTSD
during viewing of combat-related slides
sounds Z score gt3.00 plt.001
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Neural Correlates of Traumatic Reminders in Women
with Childhood Sexual Abuse-related PTSD

• 22 med. free women with early childhood sexual
  abuse with and without PTSD
• Subjects/ staff prepared personalized script of
  traumatic childhood sexual abuse event
• 30 mCi O15 water injected during reading of
  traumatic scripts followed by positron emission
  tomography (PET) imaging
• Brain blood flow during 2 traumatic scripts
  compared to 2 neutral scripts

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Decreased Blood Flow during Memories of Abuse in
Women with Childhood Sexual Abuse-related PTSD
R. Hippocampus
Subcallosal Gyrus (Ant. Cing.)(25)
Fusiform/Inf Temp Gyrus (20)
R. Middle Frontal Gyrus (8/9)
Visual Ass. Ctx. (19)
R. Supramarginal Gyrus (40)
Areas displayed with z scoregt3.00 plt.001
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Neural Correlates of Emotionally Valenced
Declarative Memory in PTSD-Methods

• Women with abuse and PTSD (N10) compared to
  non-abused non-PTSD women (N11)
• All subjects medication free
• Subjects scanned during recall of paired
  associates (If before I said Gold-West and now
  I said Gold, you would say (West))
• Control task listen to the number of times you
  hear the letter D, Active listen and remember
  it for later
• Both neutral and emotional word pairs
  (rape-mutilate
• Areas of activation compared between
  active-control tasks

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Decreased Blood Flow During Recall of Emotionally
Valenced Words in Abuse-related PTSD
Retrieval of Word pairs like blood-stench
Left hippocampus
Medial prefrontal Orbitofrontal Cortex
Fusiform, inferior temporal gyrus
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Stroop Paradigm in PTSD

• Saying the color of a color word, e.g. green,
  leads to slowing of response time, due to
  inhibition of response
• Stroop paradigm associated with activation of
  anterior cingulate
• Decreased anterior cingulate (medial prefrontal
  cortex) function implicated in neural circuitry
  of PTSD
• Emotional stroop say the color of the word rape,
  slower response time in abuse-related (Foa et al)
  or combat-related PTSD body-bag (McNally et al)
  associated with increased PTSD symptoms

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Decreased Blood Flow with Emotional Stroop in
Abused Women with and without PTSD
R. Hippocampus
Anterior Cingulate (32,24)
PTSD
Abuse Controls
rape stench
Blue areas represent areas of relatively greater
decrease in blood flow, emotional v neutral
stroop, zgt3.09 plt0.001
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Neural Correlates of Memories of Abandonment in
Borderline Personality Disorder

• Patients with a history of childhood abuse with
  (N10) and without (N10) borderline personality
  disorder (BPD)
• Comorbid PTSD in 50 of BPD patients
• Script of personalized abandonment situation
  prepared with subjects
• Subjects assessed with psychophysiology and
  compared to abuse-related PTSD
• Subjects scanned with PET during reading of
  abandonment and control scripts

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Increased GSR Response in BPD with Abandonment
Scripts
Galvanic Skin Response Fluctuations
Schmahl et al, unpublished
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Neural Correlates of Memories of Abandonment in
Borderline Personality Disorder
Fusiform/Inf. Temporal Gyrus
Medial Prefrontal Cortex
Areas of decreased Blood flow during Reading of
script Of an abandonment Situation v control
Left Hippocampus
Schmahl et al., unpublished data
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Conditioned Fear in PTSD

• Pairing of light and shock leads to increased
  fear responding and increased startle to light
  alone (conditioned fear)
• Conditioned fear and startle response mediated by
  central nucleus of the amygdala
• Failure of extinction with lesions of medial
  prefrontal cortex (inhibits amygdala)
• Study design habituation (blue square), fear
  acquisition (blue square shock), extinction
  (blue square) control day random shocks

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Fear Conditioning in PTSD Study Design
Blue Squares 4 s duration, 6 s blank screen
Electric Shocks Paired with Blue Square (Paired
CS-US)
Conditioned Fear Acquisition (Paired CS-US)

• Scan ?

1 2 3 4 5 6
habituation habituation acquisition
acquisition extinction
extinction 1 2 1 2
1 2
Blue Squares 4 s duration, 6 s blank screen
Random Electric Shocks Plus Blue Square (Unpaired
CS-US)
1 2 3
4 5 6
Scan ?
Control (Unpaired CS-US)
habituation habituation sensitization
sensitization extinction
extinction 1 2 1 2 1 2
Conditioned Stimulus (CS)Blue Square Unconditione
d Stimulus (US)Electric Shock
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Increased Anxiety Symptoms with Fear Acquisition
and Extinction in Abuse-related PTSD
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Increased Blood Flow with Fear Acquisition versus
Control in Abuse-related PTSD
Orbitofrontal Cortex
Superior Temporal Gyrus
Left Amygdala
Yellow areas represent areas of relatively
greater increase in blood flow with paired vs.
unpaired US-CS in PTSD women alone, zgt3.09
plt0.001
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Decreased Blood Flow in Medial Prefrontal
Cortex/Anterior Cingulate with Extinction in PTSD
Anterior Cingulate (24,32)
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Decreased Blood Flow During Recall of Emotionally
Valenced Words in Abuse-related PTSD
Retrieval of Word pairs like blood-stench
Left hippocampus
Medial prefrontal Orbitofrontal Cortex
Fusiform, inferior temporal gyrus
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Decreased Blood Flow with Emotional Stroop in
Abused Women with and without PTSD
R. Hippocampus
Anterior Cingulate (32,24)
PTSD
Abuse Controls
rape mutilate
Blue areas represent areas of relatively greater
decrease in blood flow, emotional v neutral
stroop, zgt3.09 plt0.001
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Replications of Findings from Functional Imaging
in PTSD
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Brain Circuits in Trauma Spectrum Disorders
Brain Volumes
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Brain Circuits in Trauma Spectrum Disorders
Brain Function
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Conclusions

• Amygdala, hippocampus and prefrontal cortex
  mediate symptoms of trauma spectrum disorders
• Variations in interaction of stress with
  individual factors (genetics, etc) mediate
  differences in outcome
• Future research needed to assess similarities and
  differences in trauma spectrum disorders