Long Term Effects of Childhood Abuse on the Brain

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Long Term Effects of Childhood Abuse on the Brain

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

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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

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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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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.
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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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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 Other Problems
Number of Adverse Childhood Events
Anda et al
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Number of Adverse Childhood Events Increases
Risky Violent Behavior
Number of Adverse Childhood Events
Anda et al
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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 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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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

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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

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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
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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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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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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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Smaller Hippocampal Volume in Women with
Childhood Abuse and Depression


plt.05
Vythilingam et al.,Am J Psychiatry, 2002
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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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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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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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Diurnal Cortisol Levels In Women With Childhood
Sexual Abuse-Related PTSD

12-8 PM, PTSDlt controls
Bremner et al. JNMD 2006
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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 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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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, Neuropsychopharmacology,
2003
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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
Bremner et al. JNMD 2006
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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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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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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)
Bremner et al Am J Psychiatry 1999
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
Bremner et al Biol Psychiatry 2004
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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
Blue areas represent areas of relatively greater
decrease in blood flow, emotional v neutral
stroop, zgt3.09 plt0.001
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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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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 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