Brain Changes in Fear

This protocol examines the neurobiology of fear and anxiety using various approaches. During
fear conditioning in which a phasic explicit cue (e.g., a light) is repeatedly associated
with an aversive unconditioned stimulus (e.g., a shock), the organism develops fear to the
explicit cue as well as to the environmental context in which the experiment took place.
Experimental evidence suggests that cued fear and contextual fear model different aspects of
anxiety. Studies in patients indicated that contextual fear may model an aspect that is
especially relevant to anxiety disorders. However, the neural basis for the expression of
contextual fear has not previously been elucidated in human imaging studies.

One important determinant of contextual fear is predictability: contextual fear increases
when a threat (e.g., electric shock) is unpredictable, as opposed to when the threat is
predictable. The aim of this study is to compare the neural substrates underlying fear evoked
by predictable versus unpredictable shocks. Animal studies have indicated that conditioned
responses to predictably cued threat and to less explicit threat are separate processes
mediated by distinct brain structures. Psychophysiological data suggest that the proposed
procedure can differentiate between these two responses. Hence, we anticipate that this
procedure will allow us to compare brain correlates of these responses in humans.

Another objective is to study effects of threat of shock on processing and learning of threat
cues in the amygdala, the visual and auditory systems, and motivation/reward systems. This
will be investigated by means of event-related magneto-encephalography (MEG) and fMRI
measurements using various paradigms.

Finally, a last project will examine how pharmacologic manipulation of gamma-aminobutyric
acid (GABA) levels with the benzodiazepine alprazolam affects the relationship between GABA
concentration (quantified with magnetic resonance spectroscopy, MRS), visual-and
auditory-induced gamma oscillations (measured with MEG), and fMRI BOLD response.

- INCLUSION CRITERIA:

All screening procedures described in this section are conducted under screening protocol
01-M-0254. Subjects must meet the following inclusion criteria in order to participate in
the study:

1. Male or female volunteers ages 18-50 years old.

2. Judged to be in good physical health on the basis of medical history, a clinical MRI
scan, and physical examination. Physical exams will be conducted by a NIMH
credentialed physician or nurse. Clinical laboratory tests will be ordered based on
his/her discretion.

3. Healthy subjects judged to be in good psychiatric health on the basis of the
Structured Clinical Interview for DSM-IV-TR. The SCID will be administered by a
credentialed NIMH clinician.

4. Able to understand procedures and agree to participate in the study by giving written
informed consent.

5. This protocol (02-M-0321) will include patients with a primary diagnosis (under the
clinical responsibility of Dr. Daniel Pine) of generalized anxiety disorder, panic
disorder, SAD, PTSD, specific phobia, and major depression according to DSM-IV.

6. Subjects will not be asked to completely stop smoking or drinking coffee during this
study because they may experience withdrawal symptoms, which could affect our study
results. However, they will be asked to abstain from drinking caffeinated beverage
including coffee, tea and caffeinated soft drinks and from smoking for at least 1 hour
prior to testing. They will also be instructed not to drink alcohol on the night prior
to testing and on the day of testing.

7. Speaks English or Spanish fluently (subjects with Major Depressive Disorder, healthy
volunteers)

8. Speaks English fluently (subjects with Anxiety Disorder)

EXCLUSION CRITERIA:

Subjects will be excluded from the study if they meet the following exclusion criteria:

1. Clinically significant organic disease, e.g., cardiovascular disease.

2. Clinically significant abnormalities in physical examination.

3. Any medical condition that increases risk for fMRI (e.g. pacemaker, metallic foreign
body in eye).

4. History of any disease, which in the investigators opinion may confound the results of
the study, including, but not limited to, history of organic mental disorders,
seizure, or mental retardation.

5. Have a current diagnosis of alcohol or substance abuse ACCORDING TO DSM IV CRITERIA

6. Have a lifetime diagnosis of alcohol or substance dependence ACCORDING TO DSM IV
CRITERIA.

7. Unless subject is enrolled as a patient, subjects should not have current Axis I
psychiatric disorders as identified with the Structured Clinical Interview for DSM-IV,
non-patient edition (SCID/NP).

8. If a healthy volunteer, past bipolar depression and any history of psychosis or
delusional disorders.

9. If a healthy volunteer, first degree relative with history of psychotic disorder such
as schizophrenia or bipolar disorder

10. If a healthy volunteer, psychotropic medication within 4 weeks of scanning

11. Medications that act on the central nervous system (e.g., Lorazepam, Codeine) and thus
may interfere with the interpretation of study results. Specific exclusionary drug
classes include but are not limited to: (opioid analgesics, DA receptor agonists,
anticholinergics, MAO inhibitors, COMT inhibitors, as well as any illicit substances).
In addition, healthy participants may not be on psychotropic medications.

12. Pregnancy, i.e., a positive Beta-HCG urine test conducted prior to each experiment
session.

13. Current or past history of cubital tunnel syndrome or carpal tunnel syndrome for shock
studies that use the wrist for placement of electrodes. Cubital tunnel and carpal
tunnel syndrome are exclusionary only for diagnosis on same arm as electrodes and are
not exclusionary for studies that place shocks on ankles or feet.

14. Reynauds syndrome for the cold pressor test experiment

15. Color blindness (for the active avoidance task only)

ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS:

Patients who would be unable to comply with study procedures or assessments

Specific phobia patients carrying a diagnosis of generalized anxiety disorder

Patients who are currently on psychotropic medications with the exception that PTSD
patients currently taking SSRI s, benzodiazepines, or tricyclic antidepressants will be
included. (Patients who are required to be free of all psychotropics must be off medication
for 2 weeks, 6 weeks for fluoxetine. Additionally, PTSD patients on psychotropics other
than SSRI s, benzodiazepines, or tricyclic antidepressants must be off medication for 2
weeks prior to testing. Patients will not be taken off medications for the purpose of the
study)

Patients will be excluded if they have a current or past history of any psychotic disorder,
bipolar disorder, delirium, dementia, amnestic disorder, cognitive disorder not otherwise
specified, any of the pervasive developmental disorders, or mental retardation

ADDITIONAL EXCLUSION CRITERIA FOR THE STUDY INVOLVING ALPRAZOLAM:

Adverse reactions to benzodiazepines

History of angioedema

High or low blood pressure

History of fainting

A first degree relative with a history of mania, schizophrenia, or other psychoses