Brain Changes in Fear

  • days left to enroll
  • participants needed
  • sponsor
    National Institute of Mental Health (NIMH)
Updated on 19 June 2022
depressive disorder
specific phobia
traumatic stress disorder
Accepts healthy volunteers


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, 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.

Condition Anxiety Disorders, Fear
Treatment Acoustic startle, Shock device
Clinical Study IdentifierNCT00047853
SponsorNational Institute of Mental Health (NIMH)
Last Modified on19 June 2022


Yes No Not Sure

Inclusion Criteria

All screening procedures described in this section are conducted under screening protocol
-M-0254. Subjects must meet the following inclusion criteria in order to participate in
the study
Male or female volunteers ages 18-50 years old
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
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
Speaks English fluently (subjects with Anxiety Disorder)
Able to understand procedures and agree to participate in the study by giving written
informed consent
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
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
Speaks English or Spanish fluently (subjects with Major Depressive Disorder, healthy

Exclusion Criteria

Clinically significant organic disease, e.g., cardiovascular disease
Clinically significant abnormalities in physical examination
Have a current diagnosis of alcohol or substance abuse ACCORDING TO DSM IV CRITERIA
If a healthy volunteer, psychotropic medication within 4 weeks of scanning
Subjects will be excluded from the study if they meet the following exclusion criteria
Reynauds syndrome for the cold pressor test experiment
Color blindness (for the active avoidance task only)
Any medical condition that increases risk for fMRI (e.g. pacemaker, metallic foreign
body in eye)
Patients who would be unable to comply with study procedures or assessments
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
Have a lifetime diagnosis of alcohol or substance dependence ACCORDING TO DSM IV
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)
If a healthy volunteer, past bipolar depression and any history of psychosis or
delusional disorders
If a healthy volunteer, first degree relative with history of psychotic disorder such
as schizophrenia or bipolar disorder
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
Pregnancy, i.e., a positive Beta-HCG urine test conducted prior to each experiment
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
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 (except PTSD) on psychotrophic medications within 2 wees of study visits, or
within 6 weeks of study visits for fluoxetine will be excluded
PTSD patients on psychotropics medication within 2 weeks of study visits will be excluded
with the exception of antidepressants, and benzodiazepines; the preceding two classes of
medications will not preclude enrollment for PTSD participants only
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