Brain Changes in Fear

The purpose of this study is to use brain imaging technology to investigate brain changes in people exposed to predictable versus unpredictable unpleasant stimuli. Unpleasant events that can be predicted evoke a response of fear, whereas unpredictable, unpleasant stimuli cause chronic anxiety not associated with a specific event. Information gained from this study may help in the development of more effective treatments for anxiety disorders.

When confronted with fearful events, people eventually develop fear of specific cues that were associated with these events as well as to the environmental context in which the fearful event occurred. Evidence suggests that cued fear and contextual fear model different aspects of anxiety. However, studies that examine the way the brain affects expression of contextual fear have not been conducted. This study will use magnetic resonance imaging (MRI) or Magneto-encephalography (MEG) to compare the brain activity underlying fear brought on by predictable and unpredictable aversive stimuli.

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 and the visual and auditory systems. This will be investigated by means of event-related magneto-encephalography (MEG) and fMRI measurements.

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.

• Ameli R, Ip C, Grillon C. Contextual fear-potentiated startle conditioning in humans: replication and extension. Psychophysiology. 2001 May;38(3):383-90.
• Armony JL, Dolan RJ. Modulation of auditory neural responses by a visual context in human fear conditioning. Neuroreport. 2001 Oct 29;12(15):3407-11.
• Baas JM, Grillon C, Bocker KB, Brack AA, III Morgan CA, Kenemans JL, Verbaten MN. Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl). 2002 May;161(3):233-47.

• 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.
14. Reynauds syndrome for the cold pressor test experiment

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