Fear and anxiety are normal responses to a threat. However, anxiety is considered abnormal when the response to the threat is excessive or inappropriate. This study will examine changes in the body and brain that occur during unpleasant learning experiences in healthy volunteers with high, moderate, and low levels of anxiety.

A high degree of generalized anxiety is a component of many anxiety disorders and is regarded as a marker of vulnerability for these disorders. People with anxiety disorders and individuals with high degrees of anxiety have inappropriate expectations of unpleasant events. This study will investigate the development of expecting unpleasant events in healthy volunteers with varying degrees of anxiety using aversive conditioning models. A later phase of the study will enroll participants with anxiety disorders and compare their responses to those of healthy volunteers.

Healthy volunteers who have no history of psychiatric or major medical illness will be enrolled in this study. Volunteers will come to the NIH Clinical Center three times for outpatient testing.

High-generalized anxiety is a concomitant of many anxiety disorders and is often regarded as a vulnerability marker for these disorders. One characteristic of patients with anxiety disorders and high trait-anxious individuals is inappropriate expectancies of aversive events. The overall aim of the present protocol is to investigate mechanisms that may promote the development of these aversive expectancies using expectancy-based, associative-learning models.

During aversive 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. We have obtained preliminary evidence suggesting that contextual fear represents aspects of aversive states that are central to anxiety disorders. In this protocol, we seek further evidence for the relevance of contextual fear to mood anxiety disorders.

One important determinant of contextual fear in both humans and animals is predictability: contextual fear increases when aversive events (e.g., electric shock) are unpredictable, as opposed to when they are predictable. The present protocol will examine the role of predictability of aversive states and of conditioning on threat appraisal in anxious individuals.

A second aim is to examine processes that may promote the development of contextual fear. Classical aversive-conditioning is an ideal technique to explore cognitive, attentional, and emotional processes underlying the development of aversive expectations to explicit and contextual cues. We will attempt to relate conditioned performance to measures of 1) autonomic reactivity (orienting response and heart-rate variability) and 2) attentional bias. Substantial evidence suggests that autonomic reactivity has broad implication for cognitive and affective regulation and that attentional biases may imply a role in generating and/or maintaining maladaptive levels of anxiety.

Finally, the last aim is to use socially-relevant stimuli to examine fear and anxiety in social anxiety disorders. These include a speech stressor given in a virtual reality environment and using faces as conditioned stimuli and social words in a classical conditioning experiment.

• Grillon C, Ameli R, Goddard A, Woods SW, Davis M. Baseline and fear-potentiated startle in panic disorder patients. Biol Psychiatry. 1994 Apr 1;35(7):431-9.
• Grillon C, Morgan CA 3rd, Davis M, Southwick SM. Effects of experimental context and explicit threat cues on acoustic startle in Vietnam veterans with posttraumatic stress disorder. Biol Psychiatry. 1998 Nov 15;44(10):1027-36.
• Grillon C, Morgan CA 3rd. Fear-potentiated startle conditioning to explicit and contextual cues in Gulf War veterans with posttraumatic stress disorder. J Abnorm Psychol. 1999 Feb;108(1):134-42.

• INCLUSION CRITERIA FOR BOTH PATIENTS AND HEALTHY CONTROLS:
• Currently the study sample will consist of healthy subjects without a current or past history of psychiatric or major medical illness.
• Following implementation of an appropriate plan to care for psychiatric patients, this protocol will include patients with a primary diagnosis of generalized anxiety disorder, panic disorder, SAD, PTSD, or specific phobia according to DSM-IV.
• All subjects will be between 18 and 60 years old.
• Male and female subjects will be included.
• All subjects must be able to give written informed consent prior to participation in this study.
• All eligible subjects must be in good physical health as confirmed by a complete physical exam (including normal vital signs), electrocardiogram and neurological exam, and routine lab tests of blood and urine.

EXCLUSION CRITERIA FOR HEALTHY SUBJECTS:

• Female subjects who are currently pregnant.
• Subjects who meet DSM-IV criteria for alcohol and/or substance abuse or substance dependence within 6 months prior to screening.
• Current or past Axis I psychiatric disorders as identified with the Structured Clinical Interview for DSM-IV-TR axis disorders, non-patient edition (SCID-np).
• 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.
• Subjects who take psychoactive medications or medications that can interfere with the study.
• Medical or neurological illnesses likely to interfere with the study.

EXCLUSION CRITERIA FOR PATIENTS:

• Patients who would be unable to comply with study procedures or assessments.
• Female patients who are currently pregnant.
• Specific phobia patients carrying a diagnosis of generalized anxiety disorder.
• Patients who meet DSM-IV criteria for alcohol and/or substance abuse or substance dependence within 6 months prior to screening.
• 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 who are on a medication that may interfere with the study.
• Medical or neurological illnesses likely to interfere with 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.
• Patients with current major depressive disorder or a past history that occurred before the onset of their anxiety disorder will be excluded from the study. Excluding all patients with past major-depression was thought to be unrealistic given the high comorbidity-rates between anxiety disorders and major depression.
• Patients who either score above 38 on the Inventory of the Depressive Symptoms (IDS) or display significant suicidal ideation or behavior.