Long Term Effects of Childhood Abuse on the Brain

1
Long Term Effects of Childhood Abuse on the Brain

• J. Douglas Bremner, MD
• Emory University,
• Atlanta, Georgia

2
Disclosures

• Grant Support
• NIH R01 MH56120, T32 MH067547, K24
  MH076955 (As co-investigator) R01 AG026255,
  R01 HL068630, R01 HL703824, R01 MH068791, P50
  MH58922
• 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)
• Georgia Research Alliance
• GlaxoSmithKline Investigator Initiated Medical
  Research
• Consulting
• Novartis
• GlaxoSmithKline
• Speakers Bureaus
• None
• Discussion of Off Label Medication Use
• Phenytoin

3
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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1830184018501860187018801890190019101920
19301940195019601970198019902000
Historical Timeline of the Development of
Concepts of Psychological Trauma

• Description of Railway Injuries-UK
• Lancet-Railway injury without physical trauma
• DaCostas Syndrome (US)- Soldiers Heart,
  nervousness and startle, cardiovascular etiology
• Erichsen (UK) On Railway and Other Injuries of
  the Spine and Nervous System confusion,
  amnesia, back pain, paralysis (related to unseen
  cord trauma)
• Charcot (Fr) Traumatic hysteria
• H. Oppenheim (Ger) Traumatic neurosis
• Freud Studies in Hysteria developed seduction
  theory, then quickly abandoned it.
• Struggles over pension neurosis (Ger)
• Great War shell shock (UK) mental symptoms
  from impact of shells (i.e. physical) war
  neurosis combat hysteria repressed wish to run
  from the battlefield (Freud) implied weakness of
  character defeat of traumatic neurosis in
  Europe compensation in US
• Rise of psychoanalysis in the US, emphasizes
  fantasy over reality (e.g. trauma)
• WWII- Gross Stress Reaction in soldiers (US)
  (similar to hysteria)
• Rise of biological psychiatry in US lays
  foundation for viewing a physical role in the
  development of symptoms whose etiology is
  emotional trauma
• DSMIII PTSD central role of trauma emphasized
  (US) VN veterans only
• Biological research in PTSD, popular
  acknowledgement of both VN combat child sexual
  trauma (US)
• Backlash of false memory movement

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Change In Rank Order Of Disease Burden Worldwide

• 1990
• 1. Lower respiratory infection
• 2. Diarrhea
• 3. Perinatal
• 4. Major depression
• 5. Ischemic heart disease
• 6. Cerebrovascular
• 9. Road traffic accidents
• 16. War
• 19. Violence

2020 1. Ischemic heart disease 2. Major
depression 3. Road traffic accidents
4. Cerebrovascular 5. COPD 8. War 12. Violence
Murray and Lopez. Lancet. 19973491498.
6
Epidemiology of Abuse

• 17,337 HMO members studied by CDC Kaiser
  Permanente (Anda, Giles et al)
• Adverse Childhood Experiences (ACE) based on 8
  categories derived from questionnaire Emotional,
  physical and sexual abuse, household
  dysfunction, substance abuse, mental Illness,
  mother treated violently, incarcerated household
  member, parental separation or divorce
• Number of adverse childhood experiences (ACE
  Score) 036, 126, 215, 39, 412

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Number of Adverse Childhood Events Increases Risk
for Psychiatric Symptoms
Number of Adverse Childhood Events
Anda et al
8
Number of Adverse Childhood Events Increases Risk
for Other Problems
Number of Adverse Childhood Events
Anda et al
9
Number of Adverse Childhood Events Increases
Risky Violent Behavior
Number of Adverse Childhood Events
Anda et al
10
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

11
Posttraumatic Stress Disorder

• Intrusive memories, nightmares, flashbacks,
  arousal, avoidance, startle, sleep disturbance,
  gaps in memory and concentration
• Associated with threat to life or other with
  fear/horror/helplessness (A)
• Affects 15 of traumatized individuals
• 16 of women with sexual abuse
• 8 lifetime PTSD prevalence (10 women)

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Lifetime Prevalence Of Trauma
Prevalence ()
Kessler. J Clin Psychiatry. 200061(Suppl 5)4.
13
PTSD Risk Factors

• Vietnam combat veterans with childhood abuse had
  4-fold increased relative risk of PTSD (Bremner
  et al 1992)
• Most significant factor after adjusting for level
  of combat exposure, months in Vietnam,
  participation in atrocities
• Other risk factors years of education, prior
  psychiatric illness, young age
• Twin studies 12 genetic

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Frequency of Dissociative Symptom (CADSS) Item
Endorsement in Patients with PTSD
subjects were 86 comorbid for
dissociative disorders Bremner, Krystal, Putnam,
Southwick, Marmar, Charney Mazure, 1998, JTS,
11125-135
15
What is Borderline Personality Disorder?

• 80 have early abuse
• More common in women
• Sense of emptiness, fears of abandonment
• Self destructive behavior cutting, risk taking
• Destructive relationships

16
Self Medication Hypothesis of Anxiety

• Kosten Krystal, 1989
• Substance abuse reflection of self medication for
  PTSD symptoms
• Opiates, benzodiazepines and alcohol decrease
  activity of the locus coeruleus
• Decreased NE activity leads to decreased symptoms
• Opposite Withdrawal leads to increased LC
  activity, increased symptoms

17
PTSD and Alcohol Co-Morbidity

• Women with abuse-related PTSD have a 28 history
  of past alcohol abuse/dependence versus 14 in
  non-PTSD women based on nationwide samples
  (Kessler et al 1995)
• 65 of patients with combat-related PTSD had
  lifetime history of alcohol abuse/dependence
  versus 35 in dizygotic twin brothers (Bremner et
  al unpublished).

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Longitudinal Course of Substance Abuse After
Trauma Exposure
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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
20
Early Trauma Inventory

• 56 item interview for assessment of physical,
  emotional, sexual abuse and general traumas
• assesses frequency, duration, onset/end of
  trauma, other factors
• takes 30-60 minutes to administer
• Good inter-rater reliability face validity

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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

22
Frequency of Reported Perpetrators of Abuse as
Assessed by the ETI

• Perpetrator Physical Emotional Sexual
• Male Primary Caretaker 43 48
  24
• Female Primary Caretaker 30 25 2
• Male Adult Family Member 2 2 6
• Female Adult Family Member 20 17 2
• Male Child Family Member 2 0 21
• Female Child Family Member 1 0 1
• Male Known Adult 0 2 26

23
Risk for PTSD Following Traumatic Exposures
Measured with Odds Ratios
Plt.0001 for all events--ORgt1 indicates increased
risk for PTSD
24
Risk for PTSD Following Traumatic Exposures
Measured with Odds Ratios
Plt.0001 for all events--ORgt1 indicates increased
risk for PTSD
25
Risk for PTSD Following Traumatic Exposures
Measured with Odds Ratios




Plt.001 for all events--ORgt1 indicates increased
risk for PTSD
26
Significant Correlation between Severity of
Emotional and Sexual Abuse
R.64, plt.05
27
Significant Correlation between Childhood Trauma
and PTSD Symptoms
R.78 plt.05
28
Early Trauma Conclusions

• ETI reliable and valid measure of childhood
  trauma
• Physical, emotional, and sexual abuse are highly
  correlated-victims in one domain likely to be
  victimized in another domain
• PTSD symptoms associated with a wide range of
  emotional, sexual and physical abuse events

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Trauma and Memory

• Trauma associated with a wide range of memory
  deficits
• Declarative (facts or lists) (hippocampus)
• Nondeclarative (riding a bike, conditioned
  responses)
• Perseverative errors (frontal)
• Gaps in memory (dissociative amnesia) ?relevant
  to delayed recall of abuse

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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
31
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
32
Non-Stressed
Stressed
Stress results in decreased dendritic branching
of neurons in the CA3 region of the hippocampus
(Woolley et al. 1990)
33
Stress Results in Decreased Hippocampal
Neurogenesis
Gould et al 2002
34
Enriched Environment Promotes Hippocampal
Neurogenesis
Kempermann et al 99
35
Antidepressant Treatments Promote Hippocampal
Neurogenesis
Duman et al 2002
36
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Bremner et al 1997
38
Hippocampal Volume Reduction in Childhood
Abuse-related PTSD

plt.05
12 reduction in left hippocampal volume in
abuse-related PTSD
39
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
40
Effect Size Estimates for Hippocampal Volume in
Adults with Chronic PTSD Versus Healthy Subjects
Pooled meta-analysis demonstrates smaller
hippocampal volume in PTSD
Plt0.05
Plt0.05
Left Hippocampus
Right Hippocampus
Effect size (black square) and 95 confidence
interval (red line) measured with Hedges GU
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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
42
Smaller Hippocampal Volume in Women with
Childhood Abuse and Depression


plt.05
Vythilingam et al.,Am J Psychiatry, 2002
43
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
44
Hippocampal Structure Studies in PTSD
45
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)

46
Smaller Hippocampal and Amygdala Volume in Abused
Women with BPD
Volume (mm-3)
Schmahl et al., unpublished
47
Smaller Hippocampal Volume in Abused Women with
Dissociative Identity Disorder
48
Binding of Memory Elements
Sound of leaves rustling
Feel of bark
Green
Memory of a Tree
Smell of pitch
Hippocampus is involved in integration of memory
elements into unified memory
49
Stress Splintered Memories
Smell of clothes
Dark place
Smothered feeling
Sound of a clock
Im afraid
Hippocampal dysfunction in PTSD may lead to
abnormalities in normal integration of diverse
memory elements into unified memory
50
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
51
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)

52
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.
54
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)
• Increased cortisol response to stressors
• Decreased hippocampal volume (regulates CRF
  release)

55
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

56
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

57
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)

58
Cortisol Assessment Methods

• Subjects (N56) admitted to GCRC for 24 hour
  period, plasma cortisol ACTH measured at 15
  minute intervals for 24 hours
• 40 units of ACTH administered intramuscularly at
  800 am on a separate day followed by measurement
  of plasma cortisol

59
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)

60
Diurnal Cortisol Levels In Women With Childhood
Sexual Abuse-Related PTSD

12-8 PM, PTSDlt controls
Bremner et al. JNMD 2007
61
Lower Baseline Cortisol Correlates with Increased
PTSD Symptoms in Women with Childhood Sexual
Abuse
R-0.52
62
Cortisol Response to ACTH Challenge in Women with
Childhood Sexual Abuse-related PTSD
F4.3 plt.05 PTSDltabused PTSD nonabused
nonPTSD
63
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 Am J
Psychiatry 2003
64
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
65
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)
66
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, Psychoneuroendocrinology
2003
67
Increased Cortisol Response To Trauma-Specific
Stress in PTSD
Cognitive stress

Cortisol (?g/dl)
Time (minutes)
Elzinga, Bremner et al, Neuropsychopharmacology
2003
68
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?

69
Failure of Memory Impairment with Dexamethasone
in PTSD
Plt.05
Bremner et al Psych Research 2005
70
Effects of Cognitive Challenge on Memory Recall
in Healthy Subjects
Elzinga, Bakker, Bremner, Psych Res, 2005
71
Increased Cortisol with Cognitive Challenge in
Healthy Subjects
72
Decreased Spatial Memory After Cognitive Challenge

Spatial memory task encoded before challenge
recalled better than task after challenge
Elzinga, Bakker, Bremner, Psych Res, 2005
73
Deficits in Recall Inversely Correlate with
Cortisol after Challenge
74
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

75
Elevated DHEA-S in Women with Childhood
Abuse-related PTSD
Bremner et al JNMD 2007
76
Estrogen and Stress

• Stress results in impairment in reproductive
  function
• Mechanism via gonadotropic pituitary adrenal
  (GPA) axis, exact mechanism unclear
• Mixed results on effects of stress on estradiol

77
Diurnal Estradiol in Women with Childhood Abuse
and PTSD
78
Increased Estradiol Pulsatility in Women with
Abuse PTSD
Normal PTSD
Increased Estradiol Pulsatility in PTSD
79
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)

80
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

81
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
82
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
83
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84
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
Bremner et al Biol Psychiatry 1999
85
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

86
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
Bremner et al Am J Psychiatry 1999
87
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

88
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
Bremner et al Biol Psychiatry 2003
89
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

90
Decreased Blood Flow with Emotional Stroop in
Abused Women with and without PTSD
R. Hippocampus
Anterior Cingulate (32,24)
PTSD
Abuse Controls
Blue areas represent areas of relatively greater
decrease in blood flow, emotional v neutral
stroop, zgt3.09 plt0.001 Bremner et al Biol
Psychiatry 2004
91
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

92
Increased GSR Response in BPD with Abandonment
Scripts
Galvanic Skin Response Fluctuations
Schmahl et al, Clin Psychol Psychot 2002
9271-276.
93
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., Biol Psychiatry 2003
94
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

95
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
96
Increased Anxiety Symptoms with Fear Acquisition
and Extinction in Abuse-related PTSD
97
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 Bremner et al Psychol Med 2005
98
Decreased Blood Flow in Medial Prefrontal
Cortex/Anterior Cingulate with Extinction in PTSD
Anterior Cingulate (24,32)
99
Paroxetine Treatment Of PTSD (ITT Population -
LOCF) Study 651 Fixed Dose
0
-5
-10
-15
Change In CAPS-2 Score
-20
-25

-30


-35


-40

-45
4
8
12
Week
P lt.001 Beebe et al. 2000.
100
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

Modifed from Duman. Heninger, Nestler, AGP
54(7)597-606, 1997
Genetic Factors
101
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, Bremner et al., Biol
Psychiatry 2003
102
Increased Hippocampal Volume with Paxil in PTSD


plt.05
Effects of 9-12 months of treatment with 10-40
mg paroxetine. Vermetten, Bremner et al. Biol
Psychiatry 2003
103
Decreased Cortisol Response to Stress Following
Paroxetine Treatment in PTSD
Pregtposttreatment for all times points except 15
90 min.
Vermetten, Bremner et al, Biol Psychiatry 2003
104
Decreased Heart Rate to Stress Following
Paroxetine in PTSD
Pregtposttreatment for all times points 0-20 min.
105
Effects of Cognitive Challenge on Subjective
Distress
SUDS Score
Time (min)
SUDSSubjective Distress