Fear Potentiation and Fear Inhibition in Posttraumatic Stress Disorder
Condition: Posttraumatic Stress Disorder
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Interventional

Summary: 
      The current study will investigate the ability of people with and without fear symptoms after
      trauma to inhibit fear in an experimental situation.
    

Detailed description: 
      Title of addendum: fear potentiation, conditional discrimination, and fear inhibition in
      posttraumatic stress disorder.

      Principal Investigator: Erica Duncan, M.D.

      Co-Investigator: Seth Norrholm, M.D.

      Background:

      Fear potentiation of the acoustic startle response (ASR) can be demonstrated in both animals
      and humans (Davis et al., 1993; Grillon et al., 1991). The neural correlates of fear
      potentiated startle are well studied (Davis et al., 1993) and this paradigm has face validity
      with cardinal symptoms of posttraumatic stress disorder (PTSD). Central to the clinical
      problem of PTSD is the inability of these patients to inhibit their fear to stimuli
      reminiscent of their traumatic experience, even during safe conditions. The elucidation of
      mechanisms of fear inhibition that may be abnormal in these patients has the potential to
      advance the development of effective treatments for these patients.

      Two conditioning paradigms would permit the study of fear inhibition, but each has potential
      confounds complicating the interpretation of results. Extinction paradigms have the problem
      that the same stimulus causes both excitation of the response and later inhibition of
      response, so that it is difficult to tease apart whether a given experimental manipulation
      that enhances extinction does so by increasing inhibition or disrupting excitation.
      Conditioned inhibition (using an A+/AX- paradigm) has the advantage of having two separate
      stimuli for excitation and inhibition (A is excitatory; X is inhibitory), but has the
      disadvantage of potential second-order conditioning (i.e., it is possible that A will
      second-order condition X), which greatly complicates the separation of excitation and
      inhibition.

      The Davis lab has recently developed a discrimination procedure that avoids these problems
      and allows for the independent evaluation of excitation and inhibition of fear conditioning.
      The procedure, referred to as a conditional discrimination (abbreviated as AX+/BX-), is based
      on a paradigm used in earlier learning theory experiments (Rescorla and Wagner, 1972; Bouton
      and Swartzentruber, 1986). In this experiment, the response to X is conditional upon the
      presence of either A or B. A becomes excitatory with training as the subject learns that A
      and X presented together predicts the unconditioned stimulus (US). B becomes inhibitory in
      that B presented with X predicts safety from the US. The presentation of AB results in a
      reduced response compared to the response to A alone because B is inhibitory. Accordingly, a
      novel stimulus, C, paired with A results in a greater response compared to AB. X becomes
      excitatory to the degree that B is inhibitory. Testing of this paradigm with rats in the
      Davis lab has produced data in good accord with predicted values (see Figure 1 in Appendix),
      and does indeed allow for independent evaluation of excitatory and inhibitory processes
      within the conditioning test session. To date, this paradigm has not been well studied in
      human subjects. The translation of this paradigm to human subjects would present an important
      advance in methodology for studying the neurobiology of fear inhibition in clinical
      populations with anxiety disorders such as PTSD.

      Specific Aims:

        1. To establish methodology to assess baseline acoustic startle, fear potentiation of
           acoustic startle in a classical conditioning paradigm, and conditional discrimination
           (AX+/BX-) in 15 normal control subjects. Fear extinction will be assessed in one to
           three separate repeated experimental sessions.

        2. To compare 15 subjects with PTSD, 15 subjects with a history of combat exposure but no
           PTSD, and 15 normal controls using this acoustic startle methodology. We hypothesize
           that PTSD subjects will have normal baseline startle, intact fear potentiation, and
           impaired inhibition of fear potentiation as measured by the AX+/BX- paradigm. We predict
           that combat controls will have results intermediate between PTSD subjects and normals.

      Methods

      Subjects: 75 subjects with PTSD ages 18-80, 75 age and gender matched normal controls, and 75
      age and gender matched subjects with combat history but no PTSD will be recruited. Subjects
      will be screened and excluded for Axis I and II disorders (other than PTSD for the patient
      group), for significant medical illness, and for auditory or visual impairment.

      Assessment: PTSD subjects will be rated for current psychopathology with the Clinician
      Administered PTSD Scale and the Mississippi Scale for Combat-Related PTSD. In addition, PTSD
      subjects and combat controls will be rated for severity of combat exposure with the Combat
      Exposure Scale. In all subjects, childhood trauma will be assessed with the Early Trauma
      Inventory. Current depression and anxiety symptoms will be assessed using the Hamilton
      Depression and Hamilton Anxiety scales, respectively. Attention and distractibility will be
      assessed by means of the Continuous Performance Test, and motor function will be assessed
      with the Finger Tapping Test. Cognitive function will be assessed with the Benton Visual
      Retention Test, the California Verbal Learning Test, Wechsler Abbreviated Scale of
      Intelligence, Wechsler Memory Scale, Selective Reminding Test, and the Trails Test. Results
      of these tests will be used as covariates in the analysis of conditioning data in order to
      control for potential group differences in attention or memory. Total time of assessment
      should be about four to five hours.

      Procedure: Acoustic stimuli will be delivered binaurally through headphones (Maico,TDH39P).
      Acoustic startle stimuli will be 40 ms 116 dB white noise bursts with near instantaneous rise
      time delivered by a computerized electromyographic (EMG) startle response monitoring system
      (SR-LAB, San Diego Instruments). The eyeblink component of the acoustic startle response will
      be measured via EMG of the right orbicularis oculi muscle. EMG activity will be amplified and
      digitized using the SR-LAB (San Diego Instruments). According to methods established by Davis
      and Grillon (Grillon et al., 1991; Grillon and Ameli, 1998), aversive stimuli (US) will be
      40-250 ms airblasts with an intensity of 100 psi directed to the larynx, emitted by an
      compressed air tank attached to a polyethylene tubing and controlled by a solenoid switch. A,
      B, C, and X will be green, purple, orange, or blue lights (counterbalanced color assignment
      across subjects) or pictures. Subjects will be asked to press a button to indicate that they
      have learned the discrimination between the different colored lights or pictures. The test
      session will begin with startle probes to reduce initial startle reactivity and rule out
      nonstartlers. The training phase of the session will consist of trials in which stimuli A and
      X are paired with the US (AX+), and trials in which stimuli B and X are not paired with the
      US (BX-). The test phase will include startle probes alone or during presentation of the cues
      AB and AC (the order will be counterbalanced across subjects). Between the presentation of AB
      and AC, there will be reinforced trials of AX. Total time of test session will be
      approximately 20 minutes.

      Statistical Analysis: The basic approach will be a mixed model ANOVA, using Diagnostic Group
      as a between-subjects factor (for Specific Aim 2), and within-subjects factors of trial type
      (Cue + Startle vs. Startle Alone), and type of cue (AX, BX, AB, AC).

      Future Directions: This work will be coordinated with a series of preclinical studies planned
      in the Davis lab. The effects of pharmacologic probes on fear conditioning and fear
      inhibition will be explored in normal controls as a potential method for identifying new
      pharmacologic treatments for PTSD. Treatment effects on fear conditioning and inhibition will
      be studied in PTSD subjects. Data from the current project will serve as pilot data for
      future NIH R01 and VA Merit Review grant submissions.

      References:

      Bouton ME, Swartzentruber D (1986). Analysis of the associative and occasion-setting
      properties of contents participating in a Pavlovian discrimination. J Exp Psych Anim Behav
      Process 12:333-50.

      Davis M, Falls WA, Campeau S, Kim M (1993). Fear-potentiated startle: a neural and
      pharmacological analysis. Behav Brain Res 58:175-98.

      Grillon C, Ameli R (1998). Effects of threat and safety signals on startle during
      anticipation of aversive shocks, sounds, or airblasts. J Psychophysiol 12:329-337.

      Grillon C, Ameli R, Woods SW, Merikangas K, Davis M (1991). Fear-potentiated startle in
      humans: effects of anticipatory anxiety on the acoustic blink reflex. Psychophysiology
      28:588-595.

      Rescorla RA, Wagner AR (1972). A theory of Pavlovian conditioning: variations in the
      effectiveness of reinforcement and nonreinforcement. New York: Appleton-Century-Crofts.
    

Intervention name(s): Acoustic Startle Testing
Intervention type(s): Behavioral
Intervention description(s): See protocol description for methodological details
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: PTSD; Acoustic startle