Identifying Neural Mechanisms of PTSD Symptom Reduction Induced by Estrogen

Prolonged-exposure (PE) therapy is the treatment of choice for posttraumatic stress disorder
(PTSD). Despite its efficacy, a significant number of individuals will not benefit from it or
might drop out before the completion of all sessions. This underlies the importance of
finding ways to enhance the efficacy of PE in order to improve the life quality of
individuals suffering from PTSD. It is now widely accepted that extinction learning paradigms
used in fundamental studies are useful laboratory analogs to PE. Studies in healthy controls
have suggested that elevated estrogen levels benefit extinction learning by promoting its
consolidation and thus enhancing its recall when tested later for it. This is also being
reflected by changes in the activation of brain regions forming the fear extinction network,
including the amygdala, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal
cortex (vmPFC). It is still unknown whether estradiol (E2) administration can modulate the
activation of the fear extinction network in oral contraceptive (OC) users and which E2 dose
could yield the best results. The R61 phase of the current study will aim to establish which
of two E2 doses (placebo (Plc), 2mg or 4mg) can best engage the fear extinction network in
healthy women using OC by exposing participants to a validated fear conditioning and
extinction protocol. Functional fMRI (BOLD signal) and psychophysiological measures (skin
conductance responses - SCR) will be used to test the following hypotheses: 1) E2
administration will enhance extinction recall (indexed by lower SCR) in a dose-response
manner; 2) E2 administration will increase vmPFC and decrease dACC and amygdala activations
during recall in a dose-response manner. Once the optimal E2 dose has been identified, the
R33 phase will examine the impact of E2 administration (relative to Plc) in conjunction with
5 PE sessions in OC users women having significant symptoms of PTSD. Participants will be
exposed to the fear conditioning and extinction protocol before and after PE. BOLD signal,
SCR as well as symptom severity will be used before and after treatment to test these
hypotheses: 1) During extinction recall, both groups will show lower SCR at post- relative to
pre-PE, with E2+PE group showing the strongest effect. 2) Extinction-induced activations will
be higher in the vmPFC and lower in the dACC and amygdala in post relative to pre-PE, with
E2+PE group showing the strongest effect. 3) Information flow between the extinction nodes
will improve following therapy (indexed by dynamic-causal modeling), with stronger effects in
the E2+PE group. 4) PTSD symptom severity will be lower in the E2+PE group relative to the
Plc+PE group following treatment, as well as at the 3 and 6-month follow-up assessments. 5)
PTSD symptom reduction will correlate with BOLD and SCR changes observed during extinction
recall. These findings will elucidate the neural mechanisms underlying effective exposure
treatment for fear-based symptoms, and will reveal how E2 could be an adjunct to enhance the
efficacy of extinction-based therapies such as PE.

Inclusion Criteria:

1. 18 - 45 years of age

2. Right-handed (Edinburgh Inventory - Oldfield 1971)

3. SCID diagnosis consistent with no current or past history of Axis I psychiatric
disorders

4. To be matched for age, and years of education, as well as self-identified
race/ethnicity.

5. Use of oral contraceptives (20mcg ethinyl estradiol, 2nd or 3rd generation,
monophasic)

Exclusion Criteria:

1. Psychiatric, neurologic or medical condition that would interfere with study
procedures or confound results, ascertained by history.

2. History of seizure or significant head trauma (i.e., extended loss of consciousness,
neurological sequelae, or known structural brain lesion)

3. History of Axis I psychiatric diagnosis; e.g., history of substance use disorder,
psychotic disorder, bipolar disorder, tic disorder, or eating disorder.

4. Use of psychotropic medication within 4 weeks prior to study (within 6 weeks for
fluoxetine, or other long-lived compounds; within one year for neuroleptics).

5. Pregnancy (to be ruled out by urine ß-HCG).

6. Metallic implants or devices contraindicating magnetic resonance imaging.

7. History of a hormone-responsive cancer.