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PTSD: Neurobiology

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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”

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Adrenergic Alterations

• Exaggerated increases in cardiovascular responses to trauma-specific stimuli

• Increased catecholamines in urine, plasma, CSF

• Decreased platelet -2 receptors

• Yohimbine induced panic attacks

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HPA Axis Alterations

PTSD Major Depression

Cortisol levels Low High

Glucocorticoid receptors Increased Decreased

Dexamethasone Hypersuppression Nonsuppression

Negative feedback Stronger Weaker

CSF CRF levels Increased Increased

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HypothalamusCRF

PosteriorPituitary

AnteriorPituitary

ACTH

AdrenalKidney

Norepinephrine Cortisol

PTSD

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Stress Hormone Systems

•Norepinephrine – “revving up” hormone

•Cortisol – “quieting down” hormone

•Both hormones are released in response to stress. They are normally in balance.

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LeDoux, Scientific American, 1994

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Hiker and Snake

• Immediate response

- Fight or flight

- Quick and dirty

• Delayed response

- Recognition, planning

- Slow and accurate

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SENSORY CORTEX

SENSORY THALAMUS AMYGDALA

EMOTIONAL STIMULUS

EMOTIONAL RESPONSES

“High Road”

“Low Road”

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Why do I get so angry?What’s 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

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“Battlemind”

• In a dangerous situation you don’t 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.

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Neuroimaging in PTSD

• Amygdala – hyperactivity, responsivity isassociated with PTSD symptom severity

• Frontal cortex – volume loss, responsivity is inversely associated with PTSD

symptom severity

• Hippocampus – volume loss, decreased neuronal and functional integrity

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Anterior cingulate cortex

• Interprets emotional stimuli and processes responses

• Sympathetic ANS – “accelerator”

• Parasympathetic ANS – “brakes”

• Anterior cingulate – “clutch”

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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

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“Speechless Terror”

• Suppression of Broca’s area during traumatic reexperiencing (Rauch et al.)

• Construction of narrative promotes reencoding of traumatic memories

• Subcortical memories - somatosensory

• Cortical memories – verbal, symbolic

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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

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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”

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AMYGDALA

Medial Prefrontal CortexAnterior Cingulate Cortex

Hippocampus

Thalamus

SightsSounds

SmellsCoordinated

Response

+

+

+

_

_

Coordination of Threat Response

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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

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Individual Differences in a Husband and WifeWho Developed PTSD After a Motor Vehicle Accident: A Functional MRI Case Study

Lanius RA, Hopper JW, Menon RS.

Am J Psychiatry 160:4, April 2003 667-669

“Both subjects were trapped in their car forseveral minutes, during which they witnessed a child burn to death and feared that they toowould die.”

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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

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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

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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

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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

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Husband

Wife

Functional MRI Responses to Traumatic Imagery

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PTSD: Treatment

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Treatment Components

• Coping skills

• Medication

• Psychotherapy

• Alternative therapies

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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.”

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Treating people with PTSD is challenging and rewarding. Success requires creativity, flexibility, compassion, and clinical skill.

Be aware of secondary traumatization.

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Sri Lanka

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“Dream Bubbles of Smoke and Blood” Ray-Paul Nielsen

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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

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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

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Approach to Medication Treatment

Literature extremely limited, few controlled trials

No specific agent for PTSD

Treat prominent symptoms

Treat comorbidity

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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

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Explore the Meaning of Medication

Defective, weak, or damaged self

Drugging or numbing – don’t want to listen to complaints

Failure in psychotherapy

Unrealistic wish for med to erase traumatic event

 

> Assess fears and fantasies as you monitor benefits and side effects

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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

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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

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SSRIs

• Sertraline (Zoloft), Paroxetine (Paxil), Fluoxetine (Prozac), Citalopram (Celexa)

• All 3 symptom clusters may respond

• Sexual dysfunction

• Arousal - “Jitteriness”

• Nausea, diarrhea, headache, insomnia

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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

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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

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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)

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Newer Sleep Agents

• Zolpidem (Ambien)

• Zaleplon (Sonata)

• Eszopiclone (Lunesta)

• Different binding site on GABAA receptor

• Less addictive, expensive

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Anticonvulsants

- Valproic Acid, Divalproex (Depakote)

- Carbamazepine (Tegretol)

- Lamotrigine (Lamictal)

- Anger, moodswings, violent behavior

- Comorbid bipolar disorder

- Antidepressant augmentation

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Antipsychotics

• Risperidone (Risperdal), Olanzapine (Zyprexa), Ziprasidone (Geodon), Quetiapine (Seroquel), Aripiprazole (Abilify)

• “Psychotic” symptoms including prominent hallucinations, paranoia

• Affective instability (Borderline PD)

• Antidepressant augmentation

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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

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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

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Effective Therapies

• Exposure Therapy: Desensitization

• Cognitive Therapy: Dysfunctional beliefs and behaviors

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PFC -L PFC -M

thought extinction

AMYGDALADRUGS

side effects

AMYGDALA

Therapy for Fear/Anxiety Problems

(After LeDoux)

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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

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Alternative therapies

• Art therapy

• Somatic therapies/bodywork

• Acupuncture

• Yoga

• Tai Chi

• Religious/spiritual practices

• Virtual reality

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Traditional Sweat Lodge

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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

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