PTSD: Neurobiology

1
PTSD Neurobiology
2
Neurophysiologic Alterations in PTSD

• Stress hormone systems - adrenal gland
• Sympatho-adrenomedullary
• Hypothlamic-pituitary-adrenal
• Neurotransmitter systems
• Thyroid
• Immune system
• Amygdala hyperactivity fear and anger
• Hippocampal volume loss memory deficits
• Anterior cingulate emotional clutch

3
Adrenergic Alterations

• Exaggerated increases in cardiovascular responses
  to trauma-specific stimuli
• Increased catecholamines in urine, plasma, CSF
• Decreased platelet a-2 receptors
• Yohimbine induced panic attacks

4
HPA Axis Alterations
PTSD Major Depression

Cortisol levels
Low High Glucocorticoid receptors
Increased Decreased Dexamethasone
Hypersuppression Nonsuppression Negat
ive feedback Stronger
Weaker CSF CRF levels Increased
Increased
5

Hypothalamus
CRF
Posterior Pituitary
Anterior Pituitary
ACTH
PTSD
Adrenal
Norepinephrine ? Cortisol ?
Kidney
6
Stress Hormone Systems

• Norepinephrine revving up hormone
• Cortisol quieting down hormone
• Both hormones are released in response to stress.
  They are normally in balance.

7
LeDoux, Scientific American, 1994
8
Hiker and Snake

• Immediate response
• - Fight or flight
• - Quick and dirty
• Delayed response
• - Recognition, planning
• - Slow and accurate

9
SENSORY CORTEX
High Road
SENSORY THALAMUS
AMYGDALA
Low Road
EMOTIONAL STIMULUS
EMOTIONAL RESPONSES
10
Why do I get so angry?Whats wrong with my
memory?

• Amygdala
• Reptile brain, dinosaur brain
• Emotional response
• Fear, anger, fight or flight
• Frontal lobe
• Executive function
• Cognitive response
• Working memory, attention, carrying out tasks

11
(No Transcript)
12
(No Transcript)
13
Battlemind

• In a dangerous situation you dont want to sit
  around and think. You want to act immediately
  using your amygdala and bypassing your frontal
  lobe.
• In PTSD the brain acts like you are in a
  dangerous situation all the time. The amygdala is
  hyperactive and the frontal lobe functions
  poorly.
• Anger and poor concentration are related. They
  are both part of hyperarousal.

14
Neuroimaging in PTSD

• Amygdala hyperactivity, responsivity
  is associated with PTSD symptom severity
• Frontal cortex volume loss, responsivity is
  inversely associated with PTSD symptom severity
• Hippocampus volume loss, decreased neuronal
  and functional integrity

15
Anterior cingulate cortex

• Interprets emotional stimuli and processes
  responses
• Sympathetic ANS accelerator
• Parasympathetic ANS brakes
• Anterior cingulate clutch

16
Anterior cingulate in PTSD

• Emotional Counting Stroop paradigm (pressing
  buttons)
• Blood oxygenation measured by fMRI
• Recruitment of anterior cingulate increased when
  counting combat-related words only in controls
  and not in PTSD subjects
• - Shin et al, Biol Psychiatry 2001

17
Speechless Terror

• Suppression of Brocas area during traumatic
  reexperiencing (Rauch et al.)
• Construction of narrative promotes reencoding of
  traumatic memories
• Subcortical memories - somatosensory
• Cortical memories verbal, symbolic

18
Failure of Extinction in PTSD

• Extinction Decrease in conditioned response
  due to nonreinforcement
• PTSD
• Inability to extinguish conditioned fear
  responses
• Inability to distinguish between dangerous and
  safe situations

19
Extinction is an Active Cortical Process

• Cortical ablation studies LeDoux
• Acquisition of conditioned fear responses
  requires only subcortical structures
• Cortical ablation greatly prolongs or prevents
  extinction of fear responses
• Indelibility of subcortical emotional memories

20
Coordination of Threat Response
Sights Sounds
Medial Prefrontal Cortex Anterior Cingulate Cortex

_
AMYGDALA
Thalamus


Hippocampus
_
Smells
Coordinated Response
21
Salient Features of PTSD

• Hyperresponsiveness to stimuli that are reminders
  of the trauma
• ? Amygdalar hyperactivity
• Overgeneralization of stimuli
• ? Hippocampal dysfunction
• Anger dyscontrol, Failure of extinction
• ? Medial prefrontal cortex dysfunction

22
Individual Differences in a Husband and Wife Who
Developed PTSD After a Motor Vehicle Accident A
Functional MRI Case Study
Lanius RA, Hopper JW, Menon RS.
Am J Psychiatry 1604, April 2003 667-669
Both subjects were trapped in their car
for several minutes, during which they witnessed
a child burn to death and feared that they
too would die.
23
Trauma Response - Husband

• Extremely aroused, actively involved in rescue
  broke windshield
• Nightmares and flashbacks started next day, often
  felt as if accident were recurring
• Psychological and physiological arousal when
  thinking or talking about accident
• Severely impaired, unable to function at work

24
Trauma Response - Wife

• Felt in shock, frozen
• Nightmares and flashbacks started next day, often
  felt as if accident were recurring
• Reexperiencing involved feeling numb and frozen
• Severely impaired, unable to function at work
• H/O early parental loss, postpartum depression,
  mild panic disorder

25
Script-Driven Imagery - Husband

• Intense anxiety, arousal, escape-focused
  cognitions
• Increased heart rate
• Increased activation of multiple regions
  including anterior frontal, anterior cingulate,
  thalamus, amygdala
• Exposure therapy x 6 mos - No PTSD

26
Script-Driven Imagery - Wife

• Felt extremely numb and frozen
• No increase in heart rate
• Increased activation only in occipital region
• Exposure therapy x 6 mos - Still had PTSD

27
Functional MRI Responses to Traumatic Imagery
Husband
Wife
28
PTSD Treatment
29
(No Transcript)
30
Treatment Components

• Coping skills
• Medication
• Psychotherapy
• Alternative therapies

31
Institute of Medicine

• scientific evidence on treatment modalities
  for PTSD does not reach the level of certainty
  that would be desired for such a common and
  serious condition among veterans additional high
  quality research is essential for every treatment
  modality.

32

• Treating people with PTSD is challenging and
  rewarding. Success requires creativity,
  flexibility, compassion, and clinical skill.
• Be aware of secondary traumatization.

33
Sri Lanka
34
Dream Bubbles of Smoke and Blood Ray-Paul
Nielsen
35
(No Transcript)
36
When to Refer for Specialized Psychiatric Care

• Medication failures or side effects
• Suicidal or homicidal ideation
• Comorbid psychiatric problems including substance
  abuse
• Other life stressors, limited social support

37
Basic Skills

• Relaxation, meditation, mindfulness training,
  coping skills training, anger management,
  grounding, etc.
• Tolerate negative emotion
• Use social support
• Calm/soothe self
• Moderate self-loathing
• Control destructive impulses (self-harm,
  violence, substance abuse)
• Articulate feelings
• Maintain hope

38
Approach to Medication Treatment

• ? Literature extremely limited, few controlled
  trials
• ? No specific agent for PTSD
• ? Treat prominent symptoms
• ? Treat comorbidity

39
Therapeutic Relationship

• ? Common barriers to alliance
• problems with authority, feelings of
  powerlessness, fear of being exploited
• intense mistrust and/or isolation
• ? Support concurrent psychotherapy
• ? Initial pharmacotherapy may allow later
  psychotherapy and vice versa

40
Explore the Meaning of Medication

• ? Defective, weak, or damaged self
• ? Drugging or numbing dont want to listen to
  complaints
• ? Failure in psychotherapy
• ? Unrealistic wish for med to erase traumatic
  event
•  
• gt Assess fears and fantasies as you monitor
  benefits and side effects

41
Symptomatic Treatment

• Inventory all symptoms
• Identify target symptoms for a given medication
• Focus initial therapy on one or two most
  distressing symptoms
• Often significant resistance to improvement, e.g.
  hypervigilance

42
Psychoeducation and Control Issues

• Give patient (and family) information
• handouts, internet
• spark of recognition
• Give the patient control
• titration decisions
• meds like trazodone, hydroxyzine useful in this
  regard

43
SSRIs

• Sertraline (Zoloft), Paroxetine (Paxil),
  Fluoxetine (Prozac), Citalopram (Celexa)
• All 3 symptom clusters may respond
• Sexual dysfunction
• Arousal - Jitteriness
• Nausea, diarrhea, headache, insomnia

44
Other Antidepressants

• Nefazodone (Serzone)
• lower sexual dysfunction, liver toxicity?
• Venlafaxine (Effexor)
• dual mechanism of action
• Mirtazapine (Remeron)
• sedation, weight gain
• Buproprion (Wellbutrin)
• activation, increased energy, smoking cessation
• Tricyclic Antidepressants Amitriptyline,
  Nortriptyline, Desipramine, Imipramine
• chronic pain, many side effects

45
Benzodiazepines Anxiety and Sleep

• Alprazolam (Xanax) - short acting
• Clonazepam (Klonopin) - long acting
• Lorazepam (Ativan)
• Diazepam (Valium)
• Temazepam (Restoril) - sleep
• Chlordiazepoxide (Librium) alcohol withdrawal
• GABAA receptor binding and potentiation
• Caution - high addiction potential

46
Trazodone and Hydroxyzine

• Trazodone (Desyrel) - 50-200 mg for sleep, 25-100
  for anxiety
• Hydroxyzine (Vistaril, Atarax) - 25-100 mg for
  sleep and anxiety, also Diphenhydramine (Benadryl)

47
Newer Sleep Agents

• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)
• Different binding site on GABAA receptor
• Less addictive, expensive

48
Anticonvulsants

• Valproic Acid, Divalproex (Depakote)
• Carbamazepine (Tegretol)
• Lamotrigine (Lamictal)
• Anger, moodswings, violent behavior
• Comorbid bipolar disorder
• Antidepressant augmentation

49
Antipsychotics

• Risperidone (Risperdal), Olanzapine (Zyprexa),
  Ziprasidone (Geodon), Quetiapine (Seroquel),
  Aripiprazole (Abilify)
• Psychotic symptoms including prominent
  hallucinations, paranoia
• Affective instability (Borderline PD)
• Antidepressant augmentation

50
Prazosin for Nightmares

• Alpha-1 adrenergic antagonist commonly used to
  treat high blood pressure and enlarged prostate
• Lipid soluble crosses blood-brain barrier
• Slow titration
• Orthostatic dizziness, including first dose
  effect
• Headache, nausea, congestion, tachycardia

51
Approach to Psychotherapy

• Three stages safety, remembering, reconnection
• Education about trauma and PTSD
• Normalization and validation
• Relieve irrational guilt
• Determine ability to tolerate memories without
  decompensation or intolerable self-loathing
• Group therapy
• Evidence-based therapy

52
Effective Therapies

• Exposure Therapy Desensitization
• Cognitive Therapy Dysfunctional beliefs and
  behaviors

53
Therapy for Fear/Anxiety Problems
AMYGDALA
thought
extinction
AMYGDALA
DRUGS
side effects
(After LeDoux)
54
VA Therapeutic Menu

• Cognitive Behavioral Skills (CBT)
• Prolonged Exposure (PE)
• Cognitive Processing Therapy (CPT)
• Acceptance and Commitment Therapy (ACT)
• Eye Movement Desensitization and Reprocessing
  (EMDR)
• Addictions Treatment
• Behavioral Activation
• Interpersonal Skills
• Imagery Rehearsal Therapy
• Sleep Improvement
• Mindfulness
• Wellness (Diet, Exercise, Smoking Cessation)
• Work Readiness
• Life Transitions

55
Alternative therapies

• Art therapy
• Somatic therapies/bodywork
• Acupuncture
• Yoga
• Tai Chi
• Religious/spiritual practices
• Virtual reality

56
Traditional Sweat Lodge
57
(No Transcript)
58
D-Cycloserine

• Extinction is an active cortical process
  requires learning Joseph LeDoux
• NMDA receptor mediated calcium influx underlies
  learning and memory
• NMDA receptor agonist at the glycine site,
  potentiates neurotransmission, facilitates
  extinction of conditioned fear
• Increases effectiveness of treatment when paired
  with exposure therapy.
• Drug development company Mike Davis

59
(No Transcript)