fMRI Predictors of Treatment Response in Posttraumatic Stress Disorder (PTSD)

Posttraumatic stress disorder (PTSD) is highly prevalent and debilitating disorder. It is
defined by a fearful response to traumatic events, and its clinical picture includes
reexperiencing, arousal, and avoidance to reminders of the exposure. Despite efforts to
characterize the pathophysiology of PTSD, no biomarkers have been established that aid in
diagnosis, treatment development, or prediction of treatment response.

Several lines of evidence suggest that PTSD symptoms are mediated by dysfunctional processes
involving the brain's fear-circuitry network in general, and extinction learning and recall
deficits in particular. Based on our preliminary work in applying fear extinction task to
healthy humans and patients with PTSD the goal of this renewal RO1 application is to employ
an established extinction paradigm with functional magnetic resonance imaging (fMRI) and
Skin Conductance Response (SCR) assessments in a large and well characterized sample with
PTSD and trauma exposed healthy control (TE-HC) subjects. We plan to clarify circuits
underlying PTSD psychopathology and to probe, for the first time, neural circuitry of
symptomatic improvement in response to Prolonged Exposure (PE) treatment. This goal is
congruent with NIMH strategic plan strategy 1.3 ("identify and integrate biological markers
and behavioral indicators associated with mental disorders").

One hundred subjects including 60 individuals with a principal diagnosis of PTSD and 40
trauma exposed healthy controls will be assessed by fMRI and SCR to determine the neural
circuitry activation to the fear extinction task. fMRI data will be acquired simultaneously
with fear extinction and recall measurement quantified by SCR. All 60 PTSD subjects and 20
randomly assigned TE-HCs subjects will repeat these procedures 10 weeks later, after PTSD
subjects have completed 10 weeks of intensive PE treatment. Three months after treatment
completion clinical ratings of PTSD severity will be conducted to permit analysis of neural
predictors of long term treatment durability.

The aims above will be accomplished through four years of study, conducted by a
multi-disciplinary research team, comprised of research scientists from Columbia, Harvard
and New York Universities, who have conducted studies in PTSD and structural and functional
brain imaging. If successful, the study will produce highly needed information on the neural
circuitry which underlies deficient extinction and recall in PTSD, and will provide highly
important information about the neural effects of Prolonged Exposure treatment, a first line
treatment for PTSD. Together these lines of expected findings will not only advance
identification of biomarkers associated with PTSD, but also facilitate identification of
biomarkers for clinical reponse to an empirically supported treatment.

Inclusion Criteria:

1. Males or females between the ages of 18 and 60

2. Current DSM-IV PTSD

3. CAPS score equal or greater than 50.

4. Able to give consent, fluent in English or Spanish.

Exclusion Criteria:

1. History of Axis I psychiatric diagnosis (other than as specified), e.g., psychotic
disorder, bipolar disorder, obsessive compulsive disorder (OCD), tic disorder, or
eating disorder. Note that comorbid current major depressive disorder will be allowed
in up to one half of the PTSD group. This will enable inclusion of this common
comorbidity, but also enable an assessment of whether or not the presence of this
comorbid diagnosis is driving any observed significant between-group differences.

2. Depression which is antecedent to PTSD; score of > 25 on the Hamilton Rating Scale
for Depression (HAM-D-17-item); significant depression and /or depression related
impairment that is judged to warrant pharmacotherapy or combined medication and
psychotherapy.

3. Individuals at risk for suicide based on history and current mental state.

4. History of substance/alcohol dependence within the past six months, and abuse within
past two months

5. Patients who are receiving effective medication for their PTSD and/or depression

6. Antipsychotic, antidepressant, or mood stabilizer medications in the last 4 weeks
prior to the study (6 weeks for fluoxetine). Standing daily dosing of benzodiazepine
class of medication in the 2 weeks prior to the study (as needed use of
benzodiazepines is not an exclusion, but must be clinically judged to tolerate no
benzodiazepines for the 72-hour period before each of the fMRI days). Triptan
anti-migraine medications. Other medications that may interfere with fear circuitry
and fear memory such as blood-brain-barrier-penetrating β-blockers.

7. Pregnancy, or plans to become pregnant during the period of the study.

8. Paramagnetic metallic implants or devices contraindicating magnetic resonance imaging
or any other non-removable paramagnetic metal in the body.

9. Formal CBT psychotherapy initiated within 3 months of beginning this study.

10. Medical illness that could interfere with assessment of diagnosis, treatment response
or biological measures (SCR, fMRI), including organic brain impairment from stroke,
CNS tumor, or demyelinating disease; and renal, thyroid, hematologic or hepatic
impairment

11. Current unstable or untreated medical illness, and resting SBP≥140 and DBP≥90 and
HR<60 and HR>100

12. Any condition that would exclude clinical MR exam (e.g. pacemaker, paramagnetic
metallic prosthesis, surgical clips, shrapnel, necessity for constant medicinal
patch, some tattoos)

13. Significant claustrophobia that would preclude ability to remain calm within the MRI
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