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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

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”

• Extinction requires learning

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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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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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Selective Serotonin Reuptake Inhibitors (SSRIs)

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

• All 3 symptom clusters may respond

• Sexual dysfunction

• Arousal - “Jitteriness”

• Nausea, diarrhea, headache, insomnia

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Other Antidepressants

• Venlafaxine (Effexor)» dual mechanism of action

• Nefazodone (Serzone)» lower sexual dysfunction, liver toxicity?

• Mirtazapine (Remeron)» sedation, weight gain

• Buproprion (Wellbutrin)» activation, increased energy, smoking cessation

• Duloxetine (Cymbalta)» dual action, chronic pain?

• Tricyclic Antidepressants: Amitriptyline, Nortriptyline, Desipramine, Imipramine

» chronic pain, many side effects

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Antidepressant Mechanism of Action

• We really don’t know

• Delayed mechanism of action postulated to be via regulation of gene expression

» Genes for neurotransmitter receptors

» Genes for neurotrophic factors

• Often confusing for patient

» Assessment of family/friends may be important

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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.

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