Neurobiology of Trauma J. Douglas Bremner, MD Emory

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Neurobiology of Trauma

• J. Douglas Bremner, MD
• Emory University,
• Atlanta, Georgia
• www.dougbremner.com

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Disclosures
Grant Support NIH R01 MH056120, T32 MH067547,
K24 MH076955, Veterans Administration Merit
Review, VET-HEAL Award National Alliance for
Research on Schizophrenia and Depression
(NARSAD), Independent Investigator Award American
Foundation for Suicide Prevention
(AFSP) GlaxoSmithKline Investigator Initiated
Medical Research Donations For Accutane
Research Mr. Liam Grant (80), lawyers involved
in Accutane litigation (20) Consulting
Novartis, Wyeth, GlaxoSmithKline,
Roundtable Expert Witness (current and past)
Accutane-psychiatric side effects
(Plaintiffs) Posttraumatic Stress Disorder
(Plaintiffs Defendants) Traumatic Brain Injury
(Defendants) Speakers Bureaus None Discussion
of Off Label Medication Use Phenytoin
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Functional Neuroanatomy of Trauma Spectrum
Disorders
Posterior Cingulate, Parietal and Motor Cortex
Sensory inputs
Visuospatial processing and assessment of threat
Thalamus
Medial PrefrontalCortex
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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Functional Neuroanatomy of Traumatic Stress
Stress
Parietal Cortex
Cerebral Cortex
Long-term storage of traumatic memories
Amygdala
Prefrontal Cortex
Conditioned fear
Hippocampus
Orbitofrontal Cortex
Glutamate
CRF
Extinction to fear through amygdala inhibition
Hypothalamus
NE
Attention and vigilance-fear behavior Dose
response effect on metabolism
Pituitary
ACTH
Locus Coeruleus
Output to cardiovascular system
Adrenal
Cortisol
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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 DecreasedHippocampal
Neurogenesis

Number of BrdU-Labeled Cells
Gould et al, 2002.
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Enriched Environment Promotes Hippocampal
Neurogenesis
70
neurons
astrocytes
60
neither
50
40
30
20
10
0
Control
Enr-WD
Enr-LT
New neurons
1000
900
New astrocytes
800
neither
700
600
500
400
300
200
100
0
Control
Enr-WD
Enr-LT
Kempermann et al, 1999.
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Antidepressant Treatments Promote Hippocampal
Neurogenesis




BrdU Labeled Cells/DG
Duman et al, 2002.
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Deficits in Verbal Memory inCombat-Related PTSD
plt.05


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Decreased Right Hippocampal Volumein
Combat-Related PTSD
plt.05
Hippocampal Volume (mm3)

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Hippocampal Volume Reduction in PTSD

• NORMAL PTSD
• MRI scan of the hippocampus in a normal control
  and patient with PTSD secondary to childhood
  abuse. The hippocampus, outlined in red, is
  visibly smaller in PTSD. Overall there was a 12
  reduction in volume in PTSD.

Bremner et al., Am. J. Psychiatry 1995
152973-981 Bremner et al., Biol. Psychiatry
1997 4123-32
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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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Smaller Hippocampal Volume in Women With
Childhood Abuse and Depression
plt.05


Vythilingam et al. Am J Psychiatry. 2002.
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Why a Twin Study?

• Questions about whether hippocampal volume
  reduction and memory deficits are related to
  stress or genetics
• The twin study design, with both monozygotic (MZ)
  (identical) and dizygotic (DZ) (fraternal) twins
  discordant for the risk factor of interest, and a
  matched control group of healthy twin pairs,
  can sort out genetic and environmental influences
• MZ twins any differences are due to environment
• DZ twins on average, 50 of the differences are
  due to environment

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Psychometric Assessments
plt0.001
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Smaller Right Hippocampal Volume in PTSD Twins
Compared to their Brothers

• 11 smaller volume
• in PTSD
• 8 in MZ, 12 in DZ
• p0.001

Black squares MZ (N13) Red triangles DZ
(N21) Lines connect brothers
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Verbal Memory Function in Twins with and without
PTSD
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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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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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HPA/Cortisol Axis in PTSD

• Decreased urinary cortisol from some groups, but
  not others
• Increased lymphocyte glucocorticoid receptors
• Super-suppression of cortisol with low-dose (0.5
  mg) dexamethasone
• Blunted ACTH response to CRF
• Increased CSF corticotropin releasing factor
  (CRF)
• Decreased hippocampal volume (regulates CRF
  release)
• Why low cortisol and hippocampal atrophy?

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Study Aims-Abuse-related PTSD

• 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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Early Trauma Inventory Psychometric Properties

• High level of inter-rater agreement ICC.99
  plt.0001
• High level of agreement on test-retest r.91
  plt.001
• High level of internal consistency Cronbach
  alpha.95 (items are measuring same construct)
• High item total correlations for most items
  (r.5-.78) in physical, emotional and sexual
  domains
• Construct validity shown by correlation with
  other trauma measure (CLTE) r.63 plt.05, and
  PTSD measure (Civilian Mississippi Scale) r.78
  plt.01
• Sensitive to discriminate PTSD vs other dx

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Memory Deficits in Women WithAbuse-Related PTSD

plt.05
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PTSD Symptom Severity Correlates With Impaired
Memory in Abused Women
R-0.44 plt.05
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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 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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Diurnal Cortisol Levels In Women With Childhood
Sexual Abuse-Related PTSD

Plasma Cortisol (microg/dL)
12-8 PM, PTSDlt controls
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Lower Baseline Cortisol Correlates With Increased
PTSD Symptoms in Women With Childhood Sexual Abuse
R-0.52
Afternoon Cortisol Levels (12-8 pm AUC)
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Increased Cortisol Response To Stressors In PTSD
Cognitive stress
Cortisol Level microg/dL
Response to acognitive stress challenge
PTSDgtControlTime -60 to 35F13.28 p.0003
J. Douglas Bremner, MD, Emory University.
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Increased Cortisol Response ToTrauma-Specific
Stress in PTSD
Cognitive stress
.12

.10
.08
Cortisol (?g/dl)
.06
.04
Control
PTSD
.02
-20
-10
-5
0
5
10
15
20
25
30
40
50
60
75
Time (Minutes)
Elzinga et al, Neuropsychopharmacology 2003 28
(9)1656-1665.
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Cortisol and Memory

• Stress increases cortisol
• Physiological levels of cortisol reversibly
  impair declarative memory in human subjects
• Stress induced cortisol release impairs
  declarative memory
• Cortisol associated with hippocampal damage,
  resultant long-term memory impairment

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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
110

100
90

80
plt.05
70
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Dehydroepiandrosterone (DHEA)and Stress

• DHEA released during stress
• DHEA has anti-glucocorticoid effects
• DHEA has protective effects on the hippocampus
• Increased diurnal DHEA in depression
• Decreased DHEA with aging
• Mixed findings for combat PTSD-single sample

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Elevated DHEA-S in Women With Childhood
Abuse-Related PTSD
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Trauma and the Medial Prefrontal Cortex

• Medial prefrontal cortex involved in inhibition
  of fear responses in the amygdala (Quirk)
• Early stress associated with decreased dendritic
  branching in medial prefrontal cortex (Radley)
• Neurological damage associated with deficits in
  emotional responding (includes orbitofrontal
  cortex and anterior cingulate)

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Decreased Anterior Cingulate Volume in Women with
Abuse Related PTSD
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Fear Conditining and Extinction in PTSD

• Pairing of light and shock leads to fear
  responses to light alone (fear conditioning)this
  is mediated by the amygdala
• 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
• Prefrontal Cortical inhibition of amygdala
  represents neural mechanism of extinction to fear
  responding
• Conditioning and extinction relevant to 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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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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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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Decreased Hippocampal Metabolism with Yohimbine
in PTSD

Glucose Metabolic Rate (mg/min/100 ml)
plt.05, yohimbine versus placebo in PTSD
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Replications of Findings fromFunctional Imaging
in PTSD
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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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Smaller Hippocampal Volume in Abused Women with
Dissociative Identity Disorder
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Neural Correlates of Memories of Abandonmentin
Borderline Personality Disorder
Fusiform/Inf. Temporal Gyrus
Medial Prefrontal Cortex
Areas of decreased Blood flow during reading of
script of an abandonment Situation vs control
Left Hippocampus
Schmahl et al. Biol Psychiatry. 2003 54142-151.
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Benzodiazepine Receptors and Stress

• Preclinical studies show reduction in
  benzodiazepine receptor binding in prefrontal
  cortex and hippocampus with both acute and
  chronic stress
• Benzodiazepine receptor function implicated in
  anxiety and stress
• Benzodiazepines efficacious in treatment of
  anxiety disorders and stress

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Nuclear Medicine Measurement of Benzodiazepine
Receptor Binding In Human Brain
Transaxial Slices of SPECT I-123iomazenil
Uptake
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Decreased Benzodiazepine Receptor Binding in PTSD
Decreased medial frontal cortex binding (area 9)
Statistical parametric map displayed on MR, z
scoregt3 plt.001
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Neural Circuits in PTSD

• Decreased anterior cingulate/medial prefrontal
  cortex function replicated finding in PTSD
• Other areas decreased function in hippocampus,
  visual association and parietal cortex, parts of
  dorsolateral prefrontal cortex
• Role for amygdala in 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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Sertraline (Zoloft) Treatment Results in
Reduction in PTSD Symptoms
Adjusted Mean Change
Visit Week
P ? .05 sertraline vs placebo. Brady K et al.
JAMA. 20002831837-1894.
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Paroxetine Fixed-Dose PTSD Study
Mean Change in CAPS-2 Total Score
0
Paroxetine 40 mg
-5
Paroxetine 20 mg
-10
Placebo
-15
-20
Adjusted Mean Change in CAPS-2 Total Score
-25

-30


-35


-40

-45
4
8
12
Week
LOCF dataset plt0.001 vs placebo Marshall et
al. Am J Psychiatry. (2001)
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Controlled Trials in PTSDMore Effective Than
Placebo

• Paroxetine for civilians and veterans (N551)1
• Sertraline for mostly civilians (N208)2
• Sertraline for mostly civilians (N187)3
• Fluoxetine for civilians (N53)4
• Fluoxetine for civilians and veterans (N64)5
• Amitriptyline for veterans (N46)6
• Phenelzine for veterans (N34)7 (N60)8
• Imipramine for veterans7,8
• Brofaromine for civilians and veterans with PTSD
  gt1 year (N45)9

1Marshall et al 2001 2Davidson et al, 2001
3Brady et al, 2000 4Connor et al, 1999 5van der
Kolk et al, 1994 6Davidson et al, 1990 7Frank
et al, 1988 8Kosten et al, 1991 9Katz et al,
1995
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Effects of Psychological Debriefing (PD) on MVA
Victimswith High and Low Initial Impact of Event
Scale (IES)
Randomized
Controlled Trial
IES
Mayou et al. Br J Psychiatry. 2001178182-183
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Prolonged Exposure, Stress Inoculation Training
and Supportive Counseling for Acute Stress
Disorder
Motor Vehicle Accident/Assault Victims with Acute
Stress Disorder
Impact of Event Scale
Bryant RA, et al. Am J Psychiatry.
19991561780-1786.
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Summary Recommendations for the Immediate
Management of Trauma Victims First Hours

• Move to safety
• Debriefing low arousal, facilitate cognitive
  processing
• Education and support
• Screening for risk factors and follow
• Propranolol for persistent anxiety
• Low dose trazadone for sleep
• Anxiety management therapy deep diaphragmatic
  breathing, progressive muscle relaxation

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Normal
Stress
Antidepressants

• Glucocorticoids

Serotonin and NE
BDNF
BDNF
Glucocorticoids
Normal Survival and Growth
Atrophy/Deathof Neurons
Increased Survival and Growth

• Other neuronal insults
• Hypoxia-ischemia
• Hypoglycemia
• Neurotoxins
• Viruses

Genetic Factors
Modifed from Duman, Heninger, and Nestler. AGP.
199754(7)597-606.
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Effects of Paroxetine on Hippocampal-Based Verbal
Declarative Memory in PTSD
Mean 35 improvement
Effects of 9-12 months of treatment with 10-40 mg
paroxetine. Vermetten et al. Biol Psychiatry.
2003.
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Increased Hippocampal Volume With Paxil in PTSD
plt.05


Effects of 9-12 months of treatment with 10-40 mg
paroxetine. Vermetten et al. Biol Psychiatry.
2003.
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Effect of Excitatory Amino Acid Antagonist on
Hippocampal Structure

Ccontrol, Vvehicle, Rrestraint, CGP 43487 is
an NMDA receptor antagonist.Magarinos AM and
McEwen BS. Neuroscience. 1995189-98.
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Some of the Dissociative State Symptoms Assessed
with the CADSS

• Do things seem to be moving in slow motion?
• Do things seem to be unreal to you, as if you are
  in a dream?
• Do you feel as if you are watching the situation
  as an observer or spectator?
• Do you feel disconnected from your own body?
• Do you see things as if you were in a tunnel, or
  looking through a wide angle photographic lense?
• Does this experience seem to take much longer
  than you would have expected?

Bremner et al. Journal of Traumatic Stress.
199811125-135.
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Increased Dissociative Symptom Levels at the Time
of Combat Trauma Predict Long-Term PTSD

• Retrospectively assessed dissociation at the time
  of combat trauma associated with long-term PTSD
  symptomatology beta.53, plt.0001
• Factors in the model combat exposure,
  atrocities, monthsin Vietnam
• Subjects matched forage, sex, education, time in
  service

plt.05

Bremner et al. Am J Psychiatry. 1992142218-332.
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The Natural History of Dissociationin the
Aftermath of Trauma
Dissociation
Preexisting stressors
Recurrent stress
Recurrent stress
Recurrent stress
Original trauma
Traumatic reminder
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Glutamate and Stress

• Glutamate excitatory amino acid acting atNMDA
  receptor
• Highly concentrated in the hippocampus
• Involved in memory at the molecular levels
• Excessive levels cause cytoxicity (eg, epilepsy)
• Stress inhibits glucose utilization, impairs
  reuptake of glutamate in glia
• Stress results in increased glutamate release

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Effects of NMDA Antagonist Ketamine on
Dissociative Symptoms in Normal Subjects
Minutes Postinjection

• Ketamine alsoimpaired memoryrecall

CADSSClinician Administered Dissociative States
Scale.Krystal et al. AGP. 199451199.
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Dissociative States Correlate With Smaller Left
Hippocampal Volume in Women Sexually Abused in
Childhood
Significant relationship between CADSS Score and
Left Hippocampal volume R Squared0.30, F3.90
df1 plt.05.
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Phenytoin and Stress

• Phenytoin (dilantin) efficacious in the treatment
  of epilepsy
• Modulates glutamatergic function
• Blocks the effects of stress onthe hippocampus
• Conducted pilot in 9 PTSD subjects

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Effect of Phenytoin onSymptoms of PTSD
plt.05

Nine patients with PTSD from mixed causes treated
for 3 months with Phenytoin 300 mg/day on an open
label basis.Bremner et al. Unpublished, Emory
University
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Effect of Phenytoin on Individual Symptoms of PTSD
Startle
Hypervigilance
Decreased Concentration
Irritability
Insomnia
Foreshortened Future
Numbing
Cut Off
Decreased Interest
Amnesia
Avoidance of Reminders
Avoidance of Thoughts
Physical Reminders
Upset With Reminders
Reexperiencing
Nightmares
Intrusive Memories
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Effects of Phenytoin onBrain Structure in PTSD

plt.05

• Phenytoin resulted in a significant increase in
  right brain volume similar increases in
  hippocampal volume were seen but not significant
  after controlling for changes in whole brain
  volume