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
• www.dougbremner.com

2
The Invisible Epidemic of Childhood Abuse

• 16 of women with childhood sexual abuse (rape or
  fondling) (McCauley et al., 1997, JAMA)
• 10 of women (13 million) with lifetime PTSD
  (Kessler et al., 1995, AGP), twice as common in
  women as in men
• Childhood sexual abuse most common cause of PTSD
  in women assault in men 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) (1/2 population,
  equal by gender)
• PTSD affects 15 of traumatized individuals risk
  factors early trauma, education, age, social
  support

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Number of Adverse Childhood Events Increases Risk
for Other Problems
Number of Adverse Childhood Events

• Anda Felitti et al 17,337 HMO members studied by
  CDC Kaiser Permanente ACE score based on
  scoring of Emotional, physical and sexual
  abuse, household dysfunction, substance abuse,
  mental Illness, mother treated violently,
  incarcerated household member, parental
  separation or divorce

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CAD and Abuse

• Patients with four or more childhood events had
  2.2 (1.3-3.7 CI) fold increased risk of ischemic
  heart disease (Felitti et al 1998)
• 7 or more (out of 10) adverse childhood events
  associated with a 3.6 (2.4-5.3 CI) fold increased
  risk of IHD after adjustment for CAD risk factors
• relationship between childhood trauma and IHD
  more strongly mediated by psychological factors
  associated with abuse (e.g. depressed affect
  (2.1, 1.9-2.4) and anger (2.5, 2.1-3.0) than by
  traditional cardiac risk factors (OR 1.2-1.7)
  (Dong et al 2004)

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Childhood Trauma and CHD in Twins
N180 pairs over-sampled for discordance of
depression Assessed with Early Trauma Inventory
With CHD
ETI Qrt 1-3
ETI Qrt 4
RR 2.05 95 CI 1.03-4.07 Adjusted for age and
current/past smoking
No effect for adult traumas Measured with
Lifetime Trauma Inventory
Vaccarino et al, presented APS Budapest 2007
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Longitudinal Course of Substance Abuse After
Trauma Exposure
Bremner et al AJP 1996
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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
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Early Trauma Inventory (ETI)

• 56 item interview for assessment of physical,
  emotional, sexual abuse and general traumas,
  assesses frequency, duration, onset/end of trauma
• takes 30-60 minutes to administer
• Inter-rater agreement ICC.99 plt.0001
• Test-retest r.91 plt.001
• Internal consistency Cronbach alpha.95
• Item total correlations for most items (r.5-.78)
  in physical, emotional and sexual domains
• Construct validity, correlates with other trauma
  measure (CLTE) r.63 plt.05, and PTSD measure
  (Civilian Mississippi Scale) r.78 plt.01
• Self report short from ETISR-SF validated from
  long form

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Risk for PTSD Following Traumatic Exposures
Measured with Odds Ratios ETI
Plt.0001 for all events--ORgt1 indicates increased
risk for PTSD
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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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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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(No Transcript)
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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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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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Smaller Hippocampal Volume in Women with
Childhood Abuse and Depression


plt.05
Vythilingam et al.,Am J Psychiatry, 2002
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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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Increased Dissociative States Correlate with
Smaller Hippocampal Volume in Women with Early
Abuse and DID
R-0.54 plt0.05
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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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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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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
• ACTH response to CRF-mixed
• Increased CSF corticotropin releasing factor
  (CRF)
• Increased cortisol response to stressors
• Decreased hippocampal volume (regulates CRF
  release)

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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-assess hippocampus with imaging cortisol
  at rest and with stress
• 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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Methods

• Subjects (N56) admitted to GCRC for 24 hour
  period, plasma cortisol measured at 15 minute
  intervals for 24 hours
• Cortisol measurement after reading of traumatic
  script and neutral scripts
• MRI of hippocampal volume PET declarative memory
  task (paragraph recall

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

12-8 PM, PTSDlt controls
Bremner et al. JNMD 2007
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Increased Cortisol Pulsatility in Abuse-related
PTSD
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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 Am J
Psychiatry 2003
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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 Trauma-Specific
Stress in PTSD
Cognitive stress

Cortisol (?g/dl)
Time (minutes)
Elzinga, Bremner et al, Neuropsychopharmacology
2003
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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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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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Decreased Anterior Cingulate Volume in Women with
Abuse Related 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
Bremner et al Biol Psychiatry 1999
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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
Bremner et al Am J Psychiatry 1999
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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
Bremner et al Biol Psychiatry 2003
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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
Emotional stroop say the color of the word rape
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
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Neural Correlates of Memories of Abandonment in
Borderline Personality Disorder with Early Trauma
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
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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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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
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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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Neurocardiac Model of Stress, Depression, and
Cardiovascular Function
Stress
Cerebral Cortex
Processing of stress
Amygdala
Anterior Cingulate/ Prefrontal Cortex
Fear response
Hippocampus
extinction to fear through amygdala inhibition
CRF
Hypothalamus
NE
Pituitary
ACTH
output to cardiovascular System, HR, BP Effects
on HRV, Endothelium, etc
Locus Coeruleus
Adrenal
cortisol
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Increased Stress Induced Myocardial Ischemia in
Trauma Depression
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Stress Induced Ischemia in a Representative
Subject with Depression and Trauma
Stress Rest
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CHD with Depression

• Decreased Anterior Cingulate Function
• with Stress in Depressed CHD Patients

Anterior Cingulate
CHD without Depression
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Decreased Anterior Cingulate Activation in
Patients with CHD and Depression during Stress
Induced Myocardial Ischemia
Anterior Cingulate

• Decreased blood flow in anterior cingulate
  (arrow) in patients with CHD and depression
  during stress-induced myocardial ischemia (N5)
  relative to patients with CHD and depression
  without stress-induced myocardial ischemia (N8).
  There were also decreases in hippocampus.

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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

Modifed from Duman. Heninger, Nestler, AGP
54(7)597-606, 1997
Genetic Factors
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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, Bremner 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, Bremner et al. Biol
Psychiatry 2003
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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