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Biological Aspects of Fear and

Resilience

Rachel Yehuda, PhD


What is PTSD?

• Definition of PTSD:

– A condition that occurs following exposure to

extremely an traumatic event.

• Traumatic event:

– Life threat, threat to physical integrity

– Fear, helplessness, horror

– Watershed Event


DSM-IV Criteria For PTSD

A. Exposure to traumatic event

B. ≥1 persistent re-experiencing symptoms

- recollections; dreams; acting/feeling as if event were

recurring while awake; intense psychological distress or

reminders; physiological reactivity at reminders

C. Persistent avoidance and numbing, not present

before trauma avoidance of g thoughts, avoidance,

places, people; amnesia; diminished interest; detached or

estranged; restricted range of affect; foreshortened future

D. Persistently increased arousal, not present before

trauma difficulty sleeping; irritability or angry outbursts; poor

concentration; hypervigilance; exaggerated startle

E. Duration of B, C, D > 1 month

F. Clinically significant distress or impairment


Conceptual Origins of PTSD

• Intention: to explain prolonged responses to

trauma as resulting from a life event

• Response: skepticism

• Assumptions:

– traumatic events are unusual; the response is

normal

– almost all persons would develop PTSD; no

stigma

– condition is chronic; justifying compensation

– trauma is the major etiologic (if not sole) agent

– implicit: monogamous relationship between

trauma and PTSD


Prevalence of Trauma

More than half of U.S. population exposed to at least one trauma

(these events are not unusual!).

Percent of population

30

20

10

Prevalence of Trauma

0

Witness Accident Threat Attack Molestation Combat Abuse Rape

Kessler et al., 1995


Prevalence of trauma and PTSD

Percent of population

50

40

30

20

10

Prevalence of Trauma

Prevalence of PTSD

0

Witness Accident Threat Attack Molestation Combat Child Rape

Kessler et al., 1995


Most persons exposed to trauma do

not develop PTSD

Percent of population

90

80

70

60

50

40

30

20

10

0

Prevalence of Trauma

Prevalence of PTSD

Percent not developing PTSD

Witness Accident Threat Attack Molestation Combat Child Rape


Prevalence

Lifetime prevalence is 5-6% in men and 14-18% in women

Trauma PTSD No PTSD

Percent

(%)

100

80

60

40

20

60.7

8.1

91.9

51.2

20.4

79.6

0

Men

Women

Kessler et al. Arch Gen Psychiatry. 1995;52:1048.


Most people who develop PTSD

recover from it

94%

PTSD represents a failure to recover.

% w/PTSD

symptoms

47%

42%

?

25%-15%

W 3m 9m Years

Yehuda and Shalev, 1998


Describing PTSD Clinically

• A condition in which a person is haunted by

the memory of an extremely traumatic event.

• The event is traumatic because it results in a

memory that is uncontrollable and one

accompanied by physical and emotional

responses that were present at the time of the

event.

• This is NOT the normal path associated with

recovery from stress. Effect is very specific.


Factors that contribute to the

development of PTSD

• Things about the event

– Severity of the event

– Actual loss

• Things about the person

– Degree of perceived controllability and

predictability

– Feelings of shame, humiliation, guilt

– Feeling that one could have prevented

what happened

– Their subjective interpretation

– Pretraumatic factors


Immediate Responses can Influence

Long Term Emotional Memories

• Thoughts that might perpetuate arousal: “It is

my fault;” “I am being punished;” “the world is

not safe.”

• Thoughts that might attenuate arousal: “I did

the best I could” “These things happen – you

can’t control everything” and “the world is

usually safe, and fortunately I survived this

event.”


How important are early symptoms of

PTSD?

94%

% w/PTSD

symptoms

47%

42%

?

25%-15%

W 3m 9m Years

Yehuda and Shalev, 1998


Disorder is a function of time

Group A

Group B

94%

% w/PTSD

symptoms

47%

42%

?

25%-15%

W 3m 9m Years

The same symptoms and pathology associated with short term

responses simply continue.


Disorder is part of a known

trajectory: Risk Model

94%

% w/PTSD

symptoms

47%

42%

Group A

?

25%-15%

Group B

W 3m 9m Years

The pathologic response is fundamentally different

and can be distinguished from the normal response early on.


Implications

• Failure to recover:

– search for post-trauma factors that inhibit

recovery (clinically: provide prophylactic

treatment)

– biologic alterations are similar to those in stress

• Risk model:

– identify pretraumatic risk factors

– biologic alterations may be different in those

who do and do not develop PTSD before,

during, and in the long term aftermath of

trauma.


The role of biology

• Since we know a lot about the consequences

of stress we can compare PTSD effects to

those observed in stress.

• If similar – this argues for vertical line

• If different – this argues for horizontal line


Important points about the response

to fear

• Amygdala is activated, but before fight or

flight response, there is interpretation

(prefrontal).

• The activation of the amygdala does not

always produce fight or flight

• Interpretation and experience (sensitization)

• What is activated is subsequently inactivated

when the threat is removed (physiologic

homeostasis)


HPA Axis

Reticularis pontis caudalis

(startle response)

Amygdala

Hippocampus

Rostral ventral medulla

SNS

Solitary Tract

PNS


Reactivity of the amygdala in PTSD

3.5

3.0

2.5

% Change

2.0

1.5

1.0

0.5

0.0

Non-PTSD

PTSD

Rausch JL et al. Arch Gen Psychiatry. 1989;46:481-482.


Reduced anterior cingulate function in

PTSD (an fMRI study)

non-PTSD

PTSD

Shin et al., Biol Psych 50:932-942, 2001


Auditory startle response in PTSD

1.0

0.8

PTSD (n=14)

Trauma control (n=15)

Anxious (n=14)

No-trauma control (n=19)

Sq. root

(µS)

0.6

0.4

0.2

0

1 3 5 7 9 11 13 15

Trials

Orr, 1997.


Increased startle response is not

present until one month post-trauma

in PTSD

3

2.5

PTSD

Non-PTSD

2

1.5

1

0.5

One Week One Month Four Months

Shalev AY et al. Compr Psychiatry. 1997;38:269-273


PTSD is Associated with Increased

Catecholamines and SNS Activity

350

300

Plasma

Norepinephrine

pg/ml

250

200

150

100

50

0

Normal (n=18)

PTSD (n=23)

10 12 2 4 6 8 10 12 2 4 6 8 10

Time of Day

Yehuda et al, Biological Psychiatry 1998.


Cortisol levels are lower in PTSD

Plasma

Cortisol

(ug/dl)

20

15

10

PTSD

Normal

5

0

10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10

Time of Day

Yehuda et al. Biol Psychiatry. 1996.


(-) Cortisol is released in

relation to stressor

severity. An important role

of cortisol in stress is to

contain other biological

stress responses


Cortisol levels in PTSD and Depression

are in the Opposite Direction

20

15

PTSD

Normal

Depressed

Plasma

Cortisol

(ug/dl)

10

5

0

101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 10

Data re-drawn from Yehuda et al. Biol Psychiatry. 1996.

Time of Day


Urinary cortisol in PTSD

90

80

70

60

50

40

30

20

10

0

PTSD Depression Mania Schizophrenia Paranoia

Mason et al., JNMD, 1986


Numerous replications in our

laboratory

80

70

60

Mean

24-Hr Urinary

Cortisol

50

40

30

20

10

0

PTSD

N=55

Normal Controls

N=31

Depression

N=20

Yehuda et al. Encyclopedia Clin Psychiatry. 2000.


Why is it important to know that

cortisol is low in PTSD?

• Because, this means that what is happening

to persons who are not recovering from the

effects of a trauma are not simply undergoing

a ‘normal stress response.’

• In order to provide appropriate intervention, it

is critical to understand the nature of the

syndrome.

• Are low cortisol levels a consequence of

trauma, or did PTSD result in persons with

low cortisol?


When do neuroendocrine

alterations develop?

94%

% w/PTSD

symptoms

47%

42%

?

25%-15%

W 3m 9m Years

Shalev & Yehuda, 1999.


Cortisol levels in acute

aftermath of motor vehicle accidents

1600

Plasma

Cortisol

nmol/l

1400

1200

1000

800

600

400

200

…are actually

lower at trauma in

those who

develop PTSD.

0

No

Disorder

PTSD

Depression

Yehuda et al. Biological Psychiatry, 1998.


Cortisol in acute aftermath of rape

Cortisol

ug/100ml

45

40

35

30

25

20

15

10

5

0

Prior Assult

No Assault

Lower

cortisol

levels in

immediate

aftermath of

rape

associated

with the RISK

FACTOR of

prior assault

Resnick et al. 1995.


Studies of persons at risk for PTSD

• PTSD 3 times more likely in

children of Holocaust

survivors in response to

trauma vs demographicallymatched

controls

• Risk factor appears to be

parental PTSD, not parental

trauma

50

40

30

20

10

0

Comparison

Offspring

Prevalence of PTSD

Yehuda R et al. Am J Psychiatry. 1998;155:1163-1171.


Cortisol in offspring by risk factor of

parental and personal PTSD

80

70

60

High Risk

Group

Cortisol

ug/day

50

40

30

20

10

0

n=15 n=11

n=10

n=14

Comparison

No Parental

PTSD; No PTSD

Parental PTSD;

PTSD

Parental PTSD;

No PTSD

Yehuda et al, 2000.


Cortisol in offspring subdivided by

parental PTSD

Plasma Cortisol (µg/dl)*

16

14

12

10

8

6

4

Comparison Subjects

Offspring: No Parental PTSD

Offspring: with Parental PTSD

2

0

Group F (2, 42) =5.74, p=.006

Main Effect of Group F (1, 42) =5.79, p=.02

0630 0830 1030 1230 1430 1630 1830 2030 2230 0030 0230 0430 0600

Time of Day


Cortisol levels may have already

been present at the time of the

trauma and could have influenced

the response.

Low cortisol may be a risk factor for

PTSD that modifies the SNS at the

time of the trauma.


Consequences of “low cortisol” in

acute aftermath of trauma

↑ Catecholamines

“Overconsolidation” or pairing of memories and distress

Traumatic reminders would be distressing

Distress leads to further pairing with nonspecific stimuli

Failure of habituation and extinction

Survivor frequently anxious (HPA becomes activated)

Other behavioral consequences (eg, personality)


Do lower cortisol levels reflect

genetics or environment?

Do low cortisol levels inform clinical

treatment of PTSD?


Childhood trauma subdivided by parental

PTSD

25

20

15

Sexual abuse

Physical neglect

Physical abuse

Emotional neglect

Emotional abuse

CTQ

10

5

0

Comparison

Subjects (n=41)

Offspring no

Parental PTSD

(n=19)

Offspring one

parent PTSD

(n=15)

Offspring two

parents PTSD

(n=17)

(Yehuda et al., Stress and Development, 2001)


Relationship between cortisol in offspring

and PTSD symptoms in parents

Intrusive Sym ptom s (P arents)

30

25

20

15

10

5

0

partial r = -.48; df=35;p=.003

0 20 40 60 80 100 120 140 160

Urinary Cortisol Excretion (ug/day)


Cortisol levels in infants subdivided

on the basis of maternal PTSD

Log salivary cortisol (nm/µg)

8

7

6

5

4

3

Awakening

Bedtime

PTSD+ PTSD- PTSD+ PTSD-


Relationship between PTSD in

mothers and cortisol in babies

Salivary Cortisol Levels in Babies

9.00

8.00

7.00

6.00

5.00

R=-.416; n=34, p < .02

(controlling for trimester,

breastfeeding and babies

age)

10.00 20.00 30.00 40.00 50.00 60.00 70.00

Severity of PTSD in Mothers


Genetic, Epigenetic, and

Environmental Influences may all

affect Cortisol

• Regardless, the findings imply that PTSD

results from of a failure to recover from the

normal effects of stress.

• Low cortisol may be related to the kind of

prior experiences that lead to differences in

how individuals interpret trauma, which

may interfere with reduction of arousal.


Clinical implications

• Focusing on trauma exposure alone in

therapy will not sufficiently address all

relevant issues.

• It is important to also address and override

risk factors so as to prevent future

occurrences and promote the development of

resilience factors.

• Focusing on the biology of stress will likely

not yield the proper targets for drug

intervention.


Essential Requirements for Successful

Treatment of PTSD

• Individual must come to terms with the fact that

they are changed because of the traumatic

event that befell them.

• Individual must link current symptoms and

trauma-exposure.

• Individual must learn to identify, then modify

behaviors and cognitions that are altered, and

adapt new strategies for dealing with the

environment.


Interventions for PTSD

Psychodynamic: integration of trauma into the

meaning structure. Achieved by modifying

poor defenses and coping strategies.

Behavioral: emphasize the conditioned fear

response, attenuated through desensitization

and flooding to promote habituation and

ulmately extinction of learned responses.

Cognitive: Modifies misperceptions about

behaviors during the trauma.

Medication: Reduces arousal, may directly

target PTSD symptoms.


Early Treatments for War-Related PTSD

Humiliation, shaming threats, cigarette burns,

shocks. As these are applied, best results could

be achieved by saying:

“you must behave as the hero I expect you to

be...a man who has gone through so many

battles should have better control of himself.”

- Lewis Yealland, 1918, “Hysterical Disorders of Warfare.”


Engaging the treatment-naive

trauma survivor

• Link trauma exposure with current symptoms

• Reduce stigma

• Understand that most trauma survivors question

whether their symptoms are “real” or substantive.

• demonstrating biologic alterations in PTSD

helps convince them of the legitimacy of their

symptpms.

• Treatment-naïve trauma survivors are reluctant

to take medications and need a lot of education

about what the medications do, their safety, and

long-term effects.


Treating trauma survivors who

cannot overcome the psychological

effects of their experiences

• Reduce arousal and distress

• Confronting the memory of the event

• Identifying factors interfering with recovery

• Placing memory in context

• Learning to experience pleasure and broaden

the individual’s world so that there are other

things than the trauma.


What does it look like clinically, when

someone “gets over” a traumatic

experience?

• If I survived this, I can survive anything

• There was a purpose to my survival

• My survival compels further social action,

even if it is just to give testimony or provide

an example for others.

• My survival stimulates me to invest in building

community

• My survival gives me perspective.


Wrap-Up

• The immediate response to trauma is

universal, but also, nothing much to worry

about from a mental health perspective

• What can augment or delay natural recovery

are individual characteristics which have

biologic correlates, and antecedants.

• A variety of therapeutic approaches can be

used by a variety of persons to override

pathological processes or those that impede

normal recovery.

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